title: Improving replicability using interaction with laboratories: a multi-lab experimental assessment

abstract:
Experimentation with mouse and rat models has become a central strategy for discovering mammalian gene function, and for preclinical testing of pharmacological treatments, yet the utility of any findings critically depends on their replicability in other laboratories. In previous publications we proposed a statistical approach for estimating the inter-laboratory replicability of novel discoveries made in a single laboratory. We demonstrated that previous phenotyping results from multi-lab databases can be used to derive a Genotype-by-Lab (GxL) adjustment factor to greatly enhance the replicability of the single-lab findings, for similarly measured phenotypes, even before making the effort of replicating these finding in additional laboratories.

This demonstration, however, still raised several important questions that could only be answered by an additional large-scale prospective experiment: 1) Does GxL-adjustment work in single-lab experiments that were not intended to be standardized across laboratories, and with genotypes that were not included in the previous experiments? And 2) Can it be used to adjust the results of pharmacological experiments? We investigated these questions by attempting to replicate, across three laboratories, results from five single-lab studies in the Mouse Phenome Database (MPD), offering 212 comparisons, including 60 involving a pharmacological treatment: 18 mg/kg/day fluoxetine. In addition, we define and use a dimensionless GxL factor, by dividing the GxL variance by the standard deviation between animals within groups, as a more robust vehicle to transfer the adjustment from the multi-lab analysis to very different labs and genotypes.

For genotype comparisons, GxL-adjustment reduced the rate of non-replicable discoveries from 60% to 12%, for the price of reducing the power to make replicable discoveries from 87% to 66%. In absolute numbers, the adjustment prevented 23 non-replicable discoveries for the price of missing only three replicated ones. Tools and data needed for deployment of this method across other mouse experiments are publicly available in MPD. Our results further point at some phenotypes as more prone to produce non-replicable results, while others, known to be more difficult to measure, are as likely to produce replicable results (once adjusted) such as the physiological measure, body weight.


title: Inference of Brain States under Anesthesia with Meta Learning Based Deep Learning Models

abstract: Monitoring the depth of unconsciousness during anesthesia is useful in both clinical settings and neuroscience investigations to understand brain mechanisms. Electroencephalogram (EEG) has been used as an objective means of characterizing brain altered arousal and/or cognition states induced by anesthetics in real-time. Different general anesthetics affect cerebral electrical activities in different ways. However, the performance of conventional machine learning models on EEG data is unsatisfactory due to the low Signal to Noise Ratio (SNR) in the EEG signals, especially in the office-based anesthesia EEG setting. Deep learning models have been used widely in the field of Brain Computer Interface (BCI) to perform classification and pattern recognition tasks due to their capability of good generalization and handling noises. Compared to other BCI applications, where deep learning has demonstrated encouraging results, the deep learning approach for classifying different brain consciousness states under anesthesia has been much less investigated. In this paper, we propose a new framework based on meta-learning using deep neural networks, named Anes-MetaNet, to classify brain states under anesthetics. The Anes-MetaNet is composed of Convolutional Neural Networks (CNN) to extract power spectrum features, and a time consequence model based on Long Short-Term Memory (LSTM) Networks to capture the temporal dependencies, and a meta-learning framework to handle large cross-subject variability. We used a multi-stage training paradigm to improve the performance, which is justified by visualizing the high-level feature mapping. Experiments on the office-based anesthesia EEG dataset demonstrate the effectiveness of our proposed Anes-MetaNet by comparison of existing methods.

category: bioengineering


title: A novel paradigm for optimal mass feature peak picking in large scale LC-MS datasets using the isopair: isoLock, autoCredential and anovAlign

abstract: Untargeted metabolomics enables direct quantification of metabolites without apriori knowledge of their identity. Liquid chromatography mass spectrometry (LC-MS), a popular method to implement untargeted metabolomics, identifies metabolites via combined mass/charge (m/z) and retention time as mass features. Improvements in the sensitivity of mass spectrometers has increased the complexity of data produced, leading to computational obstacles. One outstanding challenge is calling metabolite mass feature peaks rapidly and accurately in large LC-MS datasets (dozens to thousands of samples) in the presence of measurement and other noise. While existing algorithms are useful, they have limitations that become pronounced at scale and lead to false positive metabolite predictions as well as signal dropouts. To overcome some of these shortcomings, biochemists have developed hybrid computational and carbon labeling techniques, such as credentialing. Credentialing can validate metabolite signals, but is laborious and its applicability is limited. We have developed a suite of three computational tools to overcome the challenges of unreliable algorithms and inefficient validation protocols: isolock, autoCredential and anovAlign. Isolock uses isopairs, or metabolite-istopologue pairs, to calculate and correct for mass drift noise across LC-MS runs. autoCredential leverages statistical features of LC-MS data to amplify naturally present 13C isotopologues and validate metabolites through isopairs. This obviates the need to artificially introduce carbon labeling. anovAlign, an anova-derived algorithm, is used to align retention time windows across samples to accurately delineate retention time windows for mass features. Using a large published clinical dataset as well as a plant dataset with biological replicates across time, genotype and treatment, we demonstrate that this suite of tools is more sensitive and reproducible than both an open source metabolomics pipelines, XCMS, and the commercial software progenesis QI. This software suite opens a new era for enhanced accuracy and increased throughput for untargeted metabolomics.

category: bioinformatics


title: PIPP: Improving peptide identity propagation using neural networks

abstract: Peptide identity propagation (PIP) can substantially reduce missing values in label-free mass spectrometry quantification by transferring peptides identified by tandem mass (MS/MS) spectra in one run to experimentally related runs where the peptides are not identified by MS/MS. The existing frameworks for matching identifications between runs perform peak tracing and propagation based on similarity of precursor features using only a limited number of dimensions available in MS1 data. These approaches do not produce accompanying confidence estimates and hence cannot filter probable false positive identity transfers. We introduce an embedding based PIP that uses a higher dimensional representation of MS1 measurements that is optimized to capture peptide identities using deep neural networks. We developed a propagation framework that works entirely on MaxQuant results. Current PIP workflows typically perform propagation mainly using two feature dimensions, and rely on deterministic tolerances for identification transfer. Our framework overcomes both these limitations while additionally assigning probabilities to each transferred identity. The proposed embedding approach enables quantification of the empirical false discovery rate (FDR) for peptide identification, while also increasing depth of coverage through coembedding the runs from the experiment with experimental libraries. In published datasets with technical and biological variability, we demonstrate that our method reduces missing values in MaxQuant results, maintains high quantification precision and accuracy, and low false transfer rate.


title: scBERT: a Large-scale Pretrained Deep Langurage Model for Cell Type Annotation of Single-cell RNA-seq Data

abstract: Reliable cell type annotation is a prerequisite for downstream analysis of single-cell RNA sequencing data. Existing annotation algorithms typically suffer from improper handling of batch effect, lack of curated marker gene lists, or difficulty in leveraging the latent gene-gene interaction information. Inspired by large scale pretrained langurage models, we present a pretrained deep neural network-based model scBERT (single-cell Bidirectional Encoder Representations from Transformers) to overcome the above challenges. scBERT follows the state-of-the-art paradigm of pre-train and fine-tune in the deep learning field. In the first phase of scBERT, it obtains a general understanding of gene-gene interaction by being pre-trained on huge amounts of unlabeled scRNA-seq data. The pre-trained scBERT can then be used for the cell annotation task of unseen and user-specific scRNA-seq data through supervised fine-tuning. Extensive and rigorous benchmark studies validate the superior performance of scBERT on various tasks, including cell type annotation, novel cell type discovery, as well as investigation of gene-gene interactions. Thus, scBERT enjoys the advantages of improved generalization and interpretability than existing annotation tools.


title: Control of nuclear size by osmotic forces in Schizosaccharomyces pombe

abstract: The size of the nucleus scales robustly with cell size so that the nuclear-to-cell volume ratio (N/C ratio) is maintained during cell growth in many cell types. The mechanism responsible for this scaling remains mysterious. Previous studies have established that the N/C ratio is not determined by DNA amount but is instead influenced by factors such as nuclear envelope mechanics and nuclear transport. Here, we developed a quantitative model for nuclear size control based upon colloid osmotic pressure and tested key predictions in the fission yeast Schizosaccharomyces pombe. This model posits that the N/C ratio is determined by the numbers of macromolecules in the nucleoplasm and cytoplasm. Osmotic shift experiments showed that the fission yeast nucleus behaves as an ideal osmometer whose volume is primarily dictated by osmotic forces. Inhibition of nuclear export caused accumulation of macromolecules and an increase in crowding in the nucleoplasm, leading to nuclear swelling. We further demonstrated that the N/C ratio is maintained by a homeostasis mechanism based upon synthesis of macromolecules during growth. These studies demonstrate the functions of colloid osmotic pressure in intracellular organization and size control.

category: biophysics


title: Characterization of epigenetic alterations in esophageal cancer by whole-genome bisulfite sequencing

abstract: Esophageal carcinoma is a common and aggressive malignancy, and its patients have dismal clinical outcomes. The epigenetic dysregulation in both major subtypes, esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), awaits further characterization. Here, we perform whole-genome bisulfite sequencing (WGBS) on a total of 43 esophageal cancer and normal samples, generating one of the largest WGBS datasets in this cancer to date. Focusing on hypomethylated regions in cancer, we show that they are associated with increased chromatin activity and enhancer RNA expression. Using this large collection of WGBS dataset, we reveal and validate novel clusters in both ESCC and EAC. We further identify specific molecular features in each cluster, with potential clinical implications. These data together advance our understanding of the epigenetic alterations in esophageal cancer and provide a rich resource for the research community of this disease.

category: cancer biology


title: Type-I interferon signaling is essential for robust metronomic chemo-immunogenic tumor regression in murine triple-negative breast cancer

abstract:
Triple-negative breast cancer (TNBC) is characterized by poor prognosis and aggressive growth, with limited therapeutic options for many patients. Here, we use two syngeneic mouse TNBC models, 4T1 and E0771, to investigate the chemo-immunogenic potential of cyclophosphamide and the mechanistic contributions of cyclophosphamide-activated type-I interferon (IFN) signaling to therapeutic activity.

Chemically-activated cyclophosphamide induced robust IFN/{beta} receptor-1-dependent signaling linked to hundreds of IFN-stimulated gene responses in both TNBC lines. Further, in 4T1 tumors, cyclophosphamide given on a medium-dose, 6-day intermittent metronomic schedule induced strong IFN signaling but comparatively weak immune cell infiltration associated with long-term tumor growth stasis. Induction of IFN signaling was somewhat weaker in E0771 tumors but was followed by extensive downstream gene responses, robust immune cell infiltration and prolonged tumor regression. The immune dependence of these effective anti-tumor responses was established by CD8 T-cell immunodepletion, which blocked cyclophosphamide-induced E0771 tumor regression and led to tumor stasis followed by regrowth. Strikingly, IFN/{beta} receptor-1 antibody blockade was even more effective in preventing E0771 immune cell infiltration and blocked the major tumor regression induced by cyclophosphamide treatment. Type-I IFN signaling is thus essential for the robust chemo-immunogenic response of these TNBC tumors to cyclophosphamide administered on a metronomic schedule.

SignificanceTNBC has poor prognosis and few therapeutic options. We show that cyclophosphamide treatment can induces extensive tumor regression in syngeneic mouse models of TNBC via a chemo-immunogenic mechanism linked to type-I IFN production. Our findings establish that IFN signaling is essential for the robust anti-tumor actions of cyclophosphamide and suggest that treatment resistance may stem from silencing the IFN pathway. This suggests a new avenue for improving TNBC treatment efficacy.


title: NAD metabolism modulates mitochondrial function and inflammation and prevents progression of diabetic kidney disease

abstract:
BackgroundDiabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. In spite of all of the beneficial interventions implemented in patients with diabetes, there remains a need for additional therapeutic targets in diabetic kidney disease (DKD). Mitochondrial dysfunction and inflammation are increasingly recognized as important causes of the development and progression of DKD. However, the molecular connection between mitochondrial function, inflammation, and fibrosis remains to be elucidated.

MethodsIn the present studies we tested the hypothesis that enhancing NAD metabolism could increase mitochondrial sirtuin 3 (SIRT3) activity, improve mitochondrial function, decrease mitochondrial DNA damage, and prevent inflammation and progression of DKD.

ResultsWe found that treatment of db-db mice with type 2 diabetes with nicotinamide riboside (NR) prevented albuminuria, increased urinary KIM1 excretion, and several parameters of DKD. These effects were associated with increased SIRT3 activity, improved mitochondrial function, and decreased inflammation at least in part via inhibiting the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway.

ConclusionsNR supplementation boosted the NAD metabolism to modulate mitochondrial function and inflammation and prevent progression of diabetic kidney disease.

category: pathology


title: Quantitative genetic analysis of interactions in the pepper-Phytophthora capsici pathosystem

abstract: The development of pepper cultivars with durable resistance to the oomycete Phytophthora capsici has been challenging due to differential interactions between the species that allow certain pathogen isolates to cause disease on otherwise resistant host genotypes. Currently, little is known about the pathogen genes that are involved in these interactions. To investigate the genetic basis of P. capsici virulence on individual pepper genotypes, we inoculated sixteen pepper accessions - representing commercial varieties, sources of resistance, and host differentials - with 117 isolates of P. capsici, for a total of 1,864 host-pathogen combinations. Analysis of disease outcomes revealed a significant effect of inter-species genotype-by-genotype interactions, although these interactions were quantitative rather than qualitative in scale. Isolates were classified into five pathogen subpopulations, as determined by their genotypes at over 60,000 single-nucleotide polymorphisms (SNPs). While absolute virulence levels on certain pepper accessions significantly differed between subpopulations, a multivariate phenotype reflecting relative virulence levels on certain pepper genotypes compared to others showed the strongest association with pathogen subpopulation. A genome-wide association study (GWAS) identified four pathogen loci significantly associated with virulence, two of which colocalized with putative RXLR effector genes and another with a polygalacturonase gene cluster. All four loci appeared to represent broad-spectrum virulence genes, as significant SNPs demonstrated consistent effects regardless of the host genotype tested. Host genotype-specific virulence variants in P. capsici may be difficult to map via GWAS, perhaps controlled by many genes of small effect or by multiple alleles that have arisen independently at the same loci.

category: plant biology


title: Characteristics and data reporting of rare disease clinical trials: Getting better but still room for improvement

abstract:
BackgroundIt is estimated that there are more than 7,000 rare diseases (RDs) worldwide, impacting the lives of approximately 400 million people and only 5% have an approved therapy. Facing special challenges, including patient scarceness, incomplete knowledge of the natural history and only few specialized clinical sites, clinical trials (CT) are limited, making the data from trials critical for research and clinical care. Despite the introduction of the U.S. Food and Drug Administration Amendment Act (FDAAA) in 2007 requiring certain CTs to post results on the registry ClinicalTrials.gov within 12 months following completion, compliance has been reportedly poor. Here, we describe general characteristics of RD CTs, identify trends, and evaluate result reporting practices under the FDAAA aiming to draw awareness to the problem of non-compliance.

MethodsCTs conducted between 2008 and 2015 were extracted from the public U.S. trial registry ClinicalTrials.gov using the text mining software I2E (Linguamatics). Disease names were matched with rare disease names from the Orphanet Rare Disease Ontology (ORDO, v2.5, Orphanet). Statistical analyses and data visualization were performed using GraphPad Prism 7 and R (v3.5). The Students t-test was employed to calculate significance using p-value cut-offs of <0.05 or <0.001.

ResultsWe analyzed 1,056 RD CTs of which 55.7% were phase 2, 7.7% phase 2/3 and 36.7% phase 3 trials. The studies were mostly one- and two-armed experimental CTs with the majority (60.2%) being funded by industry. Cystic fibrosis and sickle cell disease represented the most frequently investigated diseases (25.0% and 16.5%). Industry-led phase 2 RD CTs were significantly (p<0.0001) shorter than their equivalent led by academia/non-profit (22 vs. 33 months). Screening CTs completed before the end of 2015, we found that of the 725 analyzed studies, 55.2% predominantly phase 2 CTs, did not report results. Taking their potential applicability to the FDAAA into account, 25.2% industry-funded and 28.0% academia/non-profit-funded trials failed to disclose results on ClinicalTrial.gov.

ConclusionRD CTs tend to be comparatively small, industry-funded studies focusing on genetic and neurologic conditions. Sponsor-related differences in study design, duration, and enrollment were observed. There are still substantial shortcomings when it comes to result publication.

category: scientific communication and education


title: Met/HGFR triggers detrimental reactive microglia in TBI

abstract:
The complexity of the signaling events, cellular responses unfolding in neuronal, glial and immune cells upon Traumatic brain injury (TBI) constitutes an obstacle in elucidating pathophysiological links and targets for intervention. We used array phosphoproteomics in a murine mild blunt TBI to reconstruct the temporal dynamics of tyrosine-kinase signaling in TBI and then to scrutinize the large-scale effects of the perturbation of cMet/HGFR, VEGFR1 and Btk signaling by small molecules. cMet/HGFR emerged as a selective modifier of the early microglial response, and cMet/HGFR blockade prevented the induction of microglial inflammatory mediators, of reactive microglia morphology and of TBI-associated responses in neurons, vessels and brain extracellular matrix. Acute or prolonged cMet/HGFR inhibition ameliorated neuronal survival and motor recovery. Early elevation of HGF itself in the CSF of TBI patients suggest that this mechanism has translational value in human subjects. Our findings identify cMet/HGFR as a modulator of early neuroinflammation in TBI with translational potential and indicate several RTK families as possible additional targets for TBI treatment.

SummaryControlling neuroinflammation in neurotrauma is an important but unachieved goal. This study exploits a moderate TBI model and array-based proteomics to identify cMet as a new inducer of reactive microglia. A small-molecule inhibitor of cMet contains microglial reactivity, reduces neuronal and vascular alterations, limits behavioural disturbances and accelerates recovery.

HighlightsO_LIMet is activated in microglia upon TBI and drives microglial reactivity.
C_LIO_LIA Met inhibitor reduces motor dysfunction upon TBI and promotes recovery.
C_LIO_LIBlockade of MET prevents the appearance of a reactive microglia.
C_LIO_LIThe cMET inhibitor reduces the sub-acute neuronal loss after TBI.
C_LI

category: neuroscience


title: Interoceptive sensitivity modulates heart rate and insula activity when listening to music

abstract: Interoception plays an important role in emotion processing, but the relationship between the physiological responses associated with emotional experience and interoception is unclear. In this study, we measured interoceptive sensitivity using the heartbeat discrimination task and investigated the effects of individual differences in interoceptive sensitivity on changes in heart rate and insula activity in response to music-induced emotions. We found that the heart rate increased when listening to the music pieces rated as emotionally high-touching in the high interoceptive sensitivity group only. Compared to the emotionally low-touching music, listening to the emotionally high-touching music was associated with higher insula activity. Furthermore, relative to individuals with low interoceptive sensitivity, the region of interest analysis of the insula subregions for individuals with high interoceptive sensitivity revealed significant activity in the bilateral dorsal granular insula, the right ventral dysgranular insula, and the right granular and dorsal dysgranular insula while listening to the high-touching music pieces. Our results suggest that individuals with high interoceptive sensitivity use their physical condition to assess their emotional level when listening to music. Furthermore, the insula activity may reflect the use of interoception to estimate emotions.


title: Visualizing cell death in live retina: Using calpain activity detection as a biomarker for retinal degeneration

abstract: Calpains are a family of calcium-activated proteases involved in numerous disorders. Notably, previous studies have shown that calpain activity was substantially increased in various models for inherited retinal degeneration (RD). In the present study, we tested the capacity of the t-BOC-Leu-Met-CMAC calpain-specific substrate to detect calpain activity in living retina, in organotypic retinal explant cultures derived from wild-type mice, as well as from rd1 and RhoP23H/+ RD-mutant mice. Test conditions were refined until the calpain substrate readily detected large numbers of cells in the photoreceptor layer of RD retina but not in wild-type retina. At the same time, the calpain substrate was not obviously toxic to photoreceptor cells. Comparison of calpain activity with an immunostaining for activated calpain-2 furthermore suggested that individual calpain isoforms may be active in distinct temporal stages of photoreceptor cell death. Notably, calpain-2 activity may be a relatively short-lived event, occurring only towards the end of the cell death process. Finally, our results support the development of calpain activity detection as a novel in vivo biomarker for RD, suitable for combination with non-invasive imaging techniques.


title: Computational simulations and Ca2+ imaging reveal that slow synaptic depolarizations (slow EPSPs) inhibit fast EPSP evoked action potentials for most of their time course in enteric neurons

abstract:
Transmission between neurons in the extensive enteric neural networks of the gut involves synaptic potentials with vastly different time courses and underlying conductances. Most enteric neurons exhibit fast excitatory post-synaptic potentials (EPSPs) lasting 20-50 ms, but many also exhibit slow EPSPs that last up to 100 s. When large enough, slow EPSPs excite action potentials at the start of the slow depolarization, but how they affect action potentials evoked by fast EPSPs is unknown. Furthermore, two other sources of synaptic depolarization probably occur in enteric circuits, activated via GABAA or GABAC receptors; how these interact with other synaptic depolarizations is also unclear. We built a compartmental model of enteric neurons incorporating realistic voltage-dependent ion channels, then simulated fast EPSPs, slow EPSPs and GABAA or GABAC ligand-gated Cl- channels to explore these interactions. Model predictions were tested by imaging Ca2+ transients in myenteric neurons ex vivo as an indicator of their activity during synaptic interactions. The model could mimic firing of myenteric neurons in mouse colon evoked by depolarizing current during intracellular recording and the fast and slow EPSPs in these neurons. Subthreshold fast EPSPs evoked spikes during the rising phase of a slow EPSP, but suprathreshold fast EPSPs could not evoke spikes later in a slow EPSP. This predicted inhibition was confirmed by Ca2+ imaging in which stimuli that evoke slow EPSPs suppressed activity evoked by fast EPSPs in many myenteric neurons. The model also predicted that synchronous activation of GABAA receptors and fast EPSPs potentiated firing evoked by the latter, while synchronous activation of GABAC receptors with fast EPSPs, potentiated firing and then suppressed it. The results reveal that so-called slow EPSPs have a biphasic effect being likely to suppress fast EPSP evoked firing over very long periods, perhaps accounting for prolonged quiescent periods seen in enteric motor patterns.

Author SummaryThe gastrointestinal tract is the only organ with an extensive semi-autonomous nervous system that generates complex contraction patterns independently. Communication between neurons in this "enteric" nervous system is via depolarizing synaptic events with dramatically different time courses including fast synaptic potentials lasting around 20-50 ms and slow depolarizing synaptic potentials lasting for 10 - 120 s. Most neurons have both. We explored how slow synaptic depolarizations affect generation of action potentials by fast synaptic potentials using computational simulation of small networks of neurons implemented as compartmental models with realistic membrane ion channels. We found that slow synaptic depolarizations have biphasic effects; they initially make fast synaptic potentials more likely to trigger action potentials, but then actually prevent action potential generation by fast synaptic potentials with the inhibition lasting several 10s of seconds. We confirmed the inhibitory effects of the slow synaptic depolarizations using live Ca imaging of enteric neurons from mouse colon in isolated tissue. Our results identify a novel form of synaptic inhibition in the enteric nervous system of the gut, which may account for the vastly differing time courses between signalling in individual gut neurons and rhythmic contractile patterns that often repeat at more than 60 s intervals.


title: A tool for the in vivo gating of gene expression in neurons using the co-occurrence of neural activity and light

abstract: Advancements in genetically based technologies have begun to allow us to better understand the relationships between underlying neural activity and the patterns of measurable behavior that can be reproducibly studied in the laboratory. As this field develops, there are key limitations to the currently available technologies hindering their full potential to deliver meaningful datasets. The limitations which are most critical to advancement of these technologies in behavioral neuroscience are: the temporal resolution at which physiological events can be windowed, the divergent molecular pathways in signal transduction that introduce ambiguity into the output of activity sensors, and the impractical size of the genetic material that requires 3-4 separate AAV vectors to deliver a fully functional system into a cell. To address these limitations and help bring the potential of these types of technologies into better realization, we have engineered a nucleus localized light-sensitive Ca2+-dependent gene expression system based on AsLOV2 and the downstream responsive element antagonist modulator (DREAM). The design and engineering of each component was performed in such a way to: 1) preserve behaviorally relevant temporal dynamics, 2) preserve signal fidelity appropriate for studying experience-driven neural activity patterns and their relationship to specific animal responses, and 3) have full delivery of the genetic material via a single AAV vector. The system was tested in vitro and subsequently in vivo with neural activity induced by Channelrhodopsin and could be used in the future with behaviorally-driven neural activity. To our knowledge this is the first optogenetic tool for the practical use of linking activity-dependent gene activation in response to direct nuclear calcium transduction.


title: Endurance exercise ameliorates phenotypes in Drosophila models of Spinocerebellar Ataxias

abstract: Endurance exercise is a potent intervention with widespread benefits proven to reduce disease incidence and impact across species. While endurance exercise supports neural plasticity, enhanced memory, and reduced neurodegeneration, less is known about the effect of chronic exercise on the progression of movement disorders such as ataxias. Here, we focused on three different types of ataxias, Spinocerebellar Ataxias Type (SCAs) 2, 3, and 6, belonging to the polyglutamine (polyQ) family of neurodegenerative disorders. In Drosophila models of these SCAs, flies progressively lose motor function. Here, we observe marked protection of speed and endurance in exercised SCA2 flies and modest protection in exercised SCA6 models, while no benefit is observed in SCA3 flies. Causative protein levels are reduced in SCA2 flies after chronic exercise, but not in SCA3 models, linking protein levels to exercise-based benefits. Additional investigations indicate that the exercise-inducible protein, Sestrin (Sesn) suppresses mobility decline and improves early death in SCA2 flies, even without exercise, coincident with disease protein level reduction and increased autophagic flux. These improvements depend on previously established functions of Sesn that reduce oxidative damage and modulate mTOR activity. Our study suggests differential responses of polyQ SCAs to exercise, highlighting the potential for more extensive application of exercise-based therapies in the prevention of polyQ neurodegeneration. Defining the mechanisms by which endurance exercise suppresses polyQ SCAs will open the door for more effective treatment for these diseases.


title: Sleep Dependent Changes of Lactate Concentration in Human Brain

abstract:
Lactate is an important cellular metabolite that is present at high concentrations in the brain, both within cells and in the extracellular space between cells. Small animal studies demonstrated high extracellular concentrations of lactate during wakefulness with reductions during sleep and/or anesthesia with a recent study suggesting the glymphatic activity as the mechanism for the reduction of lactate concentrations. We have recently developed a rigorous non-invasive imaging approach combining simultaneous magnetic resonance spectroscopy (MRS) and polysomnography (PSG) measurements, and here, we present the first in-vivo evaluation of brain lactate levels during sleep-wake cycles in young healthy humans. First, we collected single voxel proton MRS (1H-MRS) data at the posterior cingulate with high temporal resolution (every 7.5 sec), and simultaneously recorded PSG data while temporally registering with 1H-MRS time-series. Second, we evaluated PSG data in 30 s epochs, and classified into four stages Wake (W), Non-REM sleep stage 1 (N1), Non-REM sleep stage 2 (N2), and Non-REM sleep stage 3 (N3). Third, we determined lactate signal intensity from each 7.5-s spectrum, normalized to corresponding water signal, and averaged over 30-s for each PSG epoch. In examinations of nine healthy participants (four females, five males; mean age 24.2 ({+/-}2; SD) years; age range: 21-27 years) undergoing up to 3-hour simultaneous MRS/PSG recordings, we observed a group mean reduction of [4.9 {+/-} 4.9] % in N1, [10.4 {+/-} 5.2] % in N2, and [24.0 {+/-} 5.8] % in N3 when compared to W. Our finding is consistent with more than 70 years of invasive lactate measurements from small animal studies. In addition, reduced brain lactate was accompanied by a significant reduction the apparent diffusion coefficient of brain lactate. Taken together, these findings are consistent with the loss of lactate from the extracellular space during sleep while suggesting lactate metabolism is altered and/or lactate clearance via glymphatic exchange is increased during sleep.

Significance StatementThis study describes a non-invasive magnetic resonance spectroscopy/polysomnography technique that allows rigorous measurement of brain metabolite levels together with simultaneous characterization of brain arousal state as either wakeful or one of the several sleep states. The results provide the first in-vivo demonstration of reductions in brain lactate concentration and diffusivity during sleep versus wakefulness in young healthy human brain. These findings are consistent with invasive small-animal studies showing the loss of extracellular lactate during sleep, and support the notion of altered lactate metabolism and/or increased glymphatic activity in sleeping human brain.


title: Utilizing occupancy-detection models with museum specimen data: promise and pitfalls

abstract: Historical museum records provide potentially useful data for identifying drivers of change in species occupancy. However, because museum records are typically obtained via many collection methods, methodological developments are needed in order to enable robust inferences. Occupancy-detection models, a relatively new and powerful suite of methods, are a potentially promising avenue because they can account for changes in collection effort through space and time. Here we present a methodological road-map for using occupancy models to analyze historical museum records. We use simulated data-sets to identify how and when patterns in data and/or modelling decisions can bias inference. We focus primarily on the consequences of contrasting methodological approaches for dealing with species ranges and inferring species non-detections in both space and time. We find that not all data-sets are suitable for occupancy-detection analysis but, under the right conditions (namely, data-sets that span long durations and contain a high fraction of community-wide collections, or collection events that focus on communities of organisms), models can accurately estimate trends. Finally, we present a case-study on eastern North American odonates where we calculate long-term trends of occupancy by using our most robust workflow.

category: ecology


title: Growth rate as a modulator of tooth patterning during adaptive radiations

abstract: The discovery of mechanistic rules that underlie phenotypic variation has been a longstanding goal of evolutionary biology. Developmental processes offer a potential source for such rules because they translate genomic variation into the population-scale phenotypic variation. However, our understanding of developmental rules is based on a handful of well-established model species which hindered identifying rules and investigating their evolution. Recent methodological advances, such as {micro}CT scanning on soft tissues, two-photon imaging and modelling have facilitated the study of how developmental processes shape phenotypic variation in diverse, non-traditional model species. Here, we use the outstanding dental diversity of bats to investigate how the interplay between developmental processes can explain the morphological diversity in teeth. We find that the inhibitory cascade model, which has been used to predict the proportions of teeth and other serial organs, poorly predicts the variation in tooth number and size in bats. Instead, by tinkering with reaction/diffusion processes, we identify jaw growth as a key driver of the phenotypic evolution of tooth number and size critical to the different diets. By studying developmental processes in the context of adaptive evolution, we are able to discover a new developmental rule that explain and predict interspecific variation in serial organ number and proportion.

category: evolutionary biology


title: Meta Analysis of the Ralstonia solanacearum species complex (RSSC) based on comparative evolutionary genomics and reverse ecology

abstract:
Ralstonia solanacearum species complex (RSSC) strains are bacteria that colonize plant xylem and cause vascular wilt diseases. However, individual strains vary in host range, optimal disease temperatures, and physiological traits. To increase our understanding of the evolution, diversity, and biology of the RSSC, we performed a meta-analysis of 100 representative RSSC genomes. These 100 RSSC genomes contain 4,940 genes on average, and a pangenome analysis found that there are 3,262 genes in the core genome ([~]60% of the mean RSSC genome) with 13,128 genes in the extensive flexible genome. Although a core genome phylogenetic tree and a genome similarity matrix aligned with the previously named species (R. solanacearum, R. pseudosolanacearum, R. syzygii) and phylotypes (I-IV), these analyses also highlighted an unrecognized sub-clade of phylotype II. Additionally, we identified differences between phylotypes with respect to gene content and recombination rate, and we delineated population clusters based on the extent of horizontal gene transfer. Multiple analyses indicate that phylotype II is the most diverse phylotype, and it may thus represent the ancestral group of the RSSC. Additionally, we also used our genome-based framework to test whether the RSSC sequence variant (sequevar) taxonomy is a robust method to define within-species relationships of strains. The sequevar taxonomy is based on alignments of a single conserved gene (egl). Although sequevars in phylotype II describe monophyletic groups, the sequevar system breaks down in the highly recombinogenic phylotype I, which highlights the need for an improved cost-effective method for genotyping strains in phylotype I. Finally, we enabled quick and precise genome-based identification of newly sequenced Ralstonia strains by assigning Life Identification Numbers (LINs) to the 100 strains and by circumscribing the RSSC and its sub-groups in the LINbase Web service.

IMPACT STATEMENTThe Ralstonia solanacearum species complex (RSSC) includes dozens of economically important pathogens of many cultivated and wild plants. The extensive genetic and phenotypic diversity that exists within the RSSC has made it challenging to subdivide this group into meaningful subgroups with relevance to plant disease control and plant biosecurity. This study provides a solid genome-based framework for improved classification and identification of the RSSC by analyzing one hundred representative RSSC genome sequences with a suite of comparative evolutionary genomic tools. The results also lay the foundation for additional in-depth studies to gain further insights into evolution and biology of this heterogeneous complex of destructive plant pathogens.

DATA SUMMARYThe authors confirm that all raw data and code and protocols have been provided within the manuscript. All publicly available sequencing data used for analysis have been supplemented with accession numbers to access the data. The assembled genome of strain 19-3PR_UW348 was submitted to NCBI under Bioproject PRJNA775652 Biosample SAMN22612291. This Whole Genome Shotgun project has been deposited at GenBank under the accession JAJMMU000000000. The version described in this paper is version JAJMMU010000000.

category: genomics


title: Low-affinity CAR T cells exhibit reduced trogocytosis, preventing fratricide and antigen-negative tumor escape while preserving anti-tumor activity

abstract:
Chimeric antigen receptor (CAR) T cells using the high-affinity CD19 binding domain FMC63 are an effective treatment for patients with relapsed and aggressive B cell lymphoma. However, antigen loss and poor CAR T cell persistence remain common causes for relapse in these patients. Using primary patient samples, we now show that FMC63-based CAR T cells confer rapid antigen loss in all major tumor types currently approved for treatment with CD19 CAR T cells via trogocytosis, the stripping of antigen from tumor cells by CAR T cells. We show that CAR T cell-mediated trogocytosis can be dramatically reduced across a wide range of B cell malignancies by replacing FMC63 with a low affinity CD19 antibody. This reduction in trogocytosis does not alter the direct anti-tumor activity of CD19 CAR T cells but prevents the emergence of antigen-negative tumor cells and significantly increases CAR T cell viability by reducing fratricide of CD19 CAR T cells following trogocytosis.

TEASERA reduction in CAR affinity does not affect tumor killing but prolongs T cell persistence and prevents antigen-negative tumor escape.


title: panModule: detecting conserved modules in the variable regions of a pangenome graph

abstract: The recent years have seen the rise of pangenomes as comparative genomic tools to better understand the evolution of gene content among microbial genomes in close phylogenetic groups such as species. While the core or persistent genome is often well-known as it includes essential or ubiquitous genes, the variable genome is usually less characterized and includes many genes with unknown functions even among the most studied organisms. It gathers important genes for strain adaptation that are acquired by horizontal gene transfer. Here, we introduce panModule, an original method to identify conserved modules in pangenome graphs built from thousands of microbial genomes. These modules correspond to synteny blocks composed of consecutive genes that are conserved in a subset of the compared strains. Identifying conserved modules can provide insights on genes involved in the same functional processes, and as such is a very helpful tool to facilitate the understanding of genomic regions with complex evolutionary histories. The panModule method was benchmarked on a curated dataset of conserved modules in Escherichia coli genomes. Its use was illustrated through a study of a high pathogenicity island in Klebsiella pneumoniae that allowed a better understanding of this region. panModule is freely available and accessible through the PPanGGOLiN software suite (https://github.com/labgem/PPanGGOLiN).


title: Mitochondrial mutational spectrum is associated with mammalian longevity: a novel signature of oxidative damage.

abstract: The mutational spectrum of the mitochondrial DNA (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different organisms is still incomprehensible. Since mitochondria is tightly involved in aerobic energy production, it is expected that mtDNA mutational spectra is affected by the oxidative damage. Assuming that oxidative damage increases with age, we analyze mtDNA mutagenesis of different species. Analysing (i) dozens thousands of somatic mtDNA mutations in samples of different age (ii) 70053 polymorphic synonymous mtDNA substitutions, reconstructed in 424 mammalian species with different generation length and (iii) synonymous nucleotide content of 650 complete mitochondrial genomes of mammalian species we observed that the frequency of AH>GH substitutions (H - heavy chain notation) is twice higher in species with high versus low generation length making their mtDNA more AH poor and GH rich. Considering that AH>GH substitutions are also sensitive to the time spent single stranded (TSSS) during asynchroniuos mtDNA replication we demonstrated that AH>GH substitution rate is a function of both species-specific generation length and position specific TSSS. We propose that AH>GH is a mitochondria-specific signature of oxidative damage associated with both aging and TSSS.


title: A mitochondria-specific mutational signature of aging: increased rate of A>G substitutions on a heavy chain.


title: Oscillatory movement of a dynein-microtubule complex crosslinked with DNA origami

abstract: During repetitive bending of cilia and flagella, axonemal dynein molecules move in an oscillatory manner along a microtubule (MT), but how the minus-end-directed motor dynein can oscillate back and forth is unknown. There are various factors that may regulate the dynein activities, e.g., the nexin-dynein regulatory complex, radial spokes, and central apparatus. In order to understand the basic mechanism of the oscillatory movement, we constructed a simple model system composed of MTs, outer-arm dyneins, and DNA origami that crosslinks the MTs. Electron microscopy (EM) showed patches of dynein molecules crossbridging two MTs in two opposite orientations; the oppositely oriented dyneins are expected to produce opposing forces. The optical trapping experiments showed that the dynein-MT-DNA-origami complex actually oscillate back and forth after photolysis of caged ATP. Intriguingly, the complex, when held at one end, showed repetitive bending motions. The results show that a simple system composed of ensembles of oppositely oriented dyneins, MTs, and inter-MT crosslinkers, without the additional regulatory structures, has an intrinsic ability to cause oscillation and repetitive bending motions.


title: Tissue remodeling and cell signaling underpin changes in tumor microenvironment heterogeneity in glioma oncogenesis

abstract: Brain tumor cells thrive by adapting to the signals in their microenvironment. Understanding how the tumor microenvironment evolves during disease progression is crucial to deciphering the mechanisms underlying the functional behavior of cancer cells. To adapt, cancer cells activate signaling and transcriptional programs and migrate to establish micro-niches, in response to signals from neighboring cells and non-cellular stromal factors. Using multiple tissue analysis approaches to identify and measure immune cell infiltration and extracellular matrix deposition in brain tumors, we show that low-grade glioma is largely devoid of infiltrating immune cells and extracellular matrix proteins, while high-grade glioma exhibits abundant immune cell infiltration and activation, as well as extensive collagen deposition. Spatial analysis shows that most T-cells are sequestered in perivascular nests, but macrophages penetrate deep into tumor cell rich regions. High-grade gliomas exhibit heterogeneous PI3K and MAPK signaling, which correlates with distinct pathological hallmarks, including tumor angiogenesis, tumor cell density and extracellular matrix deposition. Our results also provide compelling evidence that tissue remodeling is an important element in glioma progression, and that targeting the extracellular matrix will be critical to improving GBM therapy.


title: Cathelicidin-3 associated with serum extracellular vesicles enables early diagnosis of a transmissible cancer

abstract: The identification of practical early diagnosis biomarkers is a cornerstone of improved prevention and treatment of cancers. Such a case is devil facial tumour disease (DFTD), a highly lethal transmissible cancer afflicting virtually an entire species, the Tasmanian devil (Sarcophilus harrisii). Despite a latent period that can exceed one year, to date DFTD diagnosis requires visual identification of tumour lesions. To enable earlier diagnosis, which is essential for the implementation of effective conservation strategies, we analysed the extracellular vesicle (EV) proteome of 87 Tasmanian devil serum samples. The antimicrobial peptide cathelicidin-3 (CATH3) was enriched in serum EVs of both devils with clinical DFTD (87.9% sensitivity and 94.1% specificity) and devils with latent infection (i.e., collected while overtly healthy, but 3-6 months before subsequent DFTD diagnosis; 93.8% sensitivity and 94.1% specificity). As antimicrobial peptides can play a variety of roles in the cancer process, our results suggest that the specific elevation of serum EV-associated CATH3 may be mechanistically involved in DFTD pathogenesis. This EV-based approach to biomarker discovery is directly applicable to improving understanding and diagnosis of a broad range of diseases in other species, and these findings directly enhance the capacity of conservation strategies to ensure the viability of the imperilled Tasmanian devil population.


title: Leveraging a physiologically based quantitative translational modeling platform for designing bispecific T cell engagers for treatment of multiple myeloma

abstract:
Bispecific T cell engager (TCE) is an emerging anti-cancer modality which redirects cytotoxic T cells to tumor cells expressing tumor-associated antigen (TAA) thereby forming immune synapses to exerts anti-tumor effects. Considering the protein engineering challenges in designing and optimizing size and pharmacokinetically acceptable TCEs in the context of the complexity of intercellular bridging between T cells and tumor cells, a physiologically relevant and clinically verified computational modeling framework is of crucial importance to guide the process to understand the protein engineering trade offs. In this study, we developed a quantitative, physiologically based computational framework to predict immune synapse formation for a variety of molecular format of TCEs in tumor tissue. Our model incorporated the molecular size dependent biodistribution using the two pore theory, extra-vascularization of T cells and hematologic cancer cells, mechanistic bispecific intercellular binding of TCEs and competitive inhibitory interaction by shed targets. The biodistribution of TCE was verified by positron emission tomography imaging of [89Zr]AMG211 (a carcinoembryonic antigen-targeting TCE) in patients. Parameter sensitivity analyses indicated that immune synapse formation was highly sensitive to TAA expression, degree of target shedding and binding selectivity to tumor cell surface TAA over shed target. Interestingly, the model suggested a "sweet spot" for TCEs CD3 binding affinity which balanced the trapping of TCE in T cell rich organs. The final model simulations indicated that the number of immune synapses is similar ([~]50/tumor cell) between two distinct clinical stage B cell maturation antigen (BCMA)-targeting TCEs, PF-06863135 in IgG format and AMG420 in BiTE format, at their respective efficacious dose in multiple myeloma patients, demonstrating the applicability of the developed computational modeling framework to molecular design optimization and clinical benchmarking for TCEs. This framework can be employed to other targets to provide a quantitative means to facilitate the model-informed best in class TCE discovery and development.

Author summaryCytotoxic T cells play a crucial role in eliminating tumor cells. However, tumor cells develop mechanisms to evade from T cell recognition. Bispecific T cell engager (TCE) is designed to overcome this issue with bringing T cells to close proximity of tumor cells through simultaneous bivalent binding to both tumor-associated antigen and T cells. After successful regulatory approval of blinatumomab (anti-CD19 TCE), more than 40 TCEs are currently in clinical development with a variety of molecular size and protein formats. In this study, we developed a quantitative computational modeling framework for molecular design optimization and clinical benchmarking of TCEs. The model accounts for molecular size dependent biodistribution of TCEs to tumor tissue and other organs as well as following bispecific intercellular bridging of T cells and tumor cells. The model simulation highlighted the importance of binding selectivity of TCEs to tumor cell surface target over shed target. The model also demonstrated a good agreement in predicted immune synapse number for two distinct molecular formats of TCEs at their respective clinically efficacious dose levels, highlighting the usefulness of developed computational modeling framework for best in class TCE discovery and development.

category: pharmacology and toxicology


title: High School Science Fair: Ethnicity Trends in Student Participation and Experience

abstract: In this paper, we report ethnicity trends in student participation and experience in high school science and engineering fair (SEFs). SEF participation showed significant ethnic diversity. For survey students, the approximate distribution was Asian-32%; Black-11%; Hispanic-20%; White-33%; Other-3%. Comparing the SEF level at which students competed from school to district to region to state levels, we observed that black students made up only 4.5% of the students who participated in SEF beyond the school level, whereas students from other ethnic groups were more equally represented at all levels. The lower percentage of Black students resulted from a combination of lower overall participation in SEF and lower percentage of those students who did participate to advance to SEFs beyond the school level. Students who advanced to SEFs beyond the school level frequently received help from scientists, coaching for the interview, and were not required to participate in SEF. Black students received the least help from scientists, were least likely to receive coaching for the interview, and were most likely to be required to participate in SEF. They also were most likely to receive no help from parents, teachers, or scientists. Asian and Hispanic students (63.8% and 56.8%) indicated a greater interest in careers in science and engineering (S&E) compared to Black and White students (43.7% & 50.7%). In addition to career interest, the most important experiences that correlated with students who indicated that SEF increased their interests in S&E were getting help from the internet, books and magazines; getting help fine tuning the report; and overcoming obstacles by doing more background research, making a timeline, and perseverance. Black students did not report a positive effect of any of these strategies but experienced time pressure as more of an obstacle than did other students. Our findings identify a wide range of student experiences associated with positive SEF outcomes that could be enhanced for all students but especially Black students. More involvement of scientists in helping students who participate in SEFs would be particularly valuable.


title: Molecular Mechanisms of Neurotransmitter Release Control Distinct Features of Sensory Coding Reliability

abstract: A key requirement for the repeated identification of a stimulus is a reliable neural representation each time it is encountered. Neural coding is often considered to rely on two major coding schemes: the firing rate of action potentials, known as rate coding, and the precise timing of action potentials, known as temporal coding. Synaptic transmission is the major mechanism of information transfer between neurons. While theoretical studies have examined the effects of neurotransmitter release probability on neural code reliability, it has not yet been addressed how different components of the release machinery affect coding of physiological stimuli in vivo. Here, we use the first synapse of the Drosophila olfactory system to show that the reliability of the neural code is sensitive to perturbations of specific presynaptic proteins controlling distinct stages of neurotransmitter release. Notably, the presynaptic manipulations decreased coding reliability of postsynaptic neurons only at high odor intensity. We further show that while the reduced temporal code reliability arises from monosynaptic effects, the reduced rate code reliability arises from circuit effects, which include the recruitment of inhibitory local neurons. Finally, we find that reducing neural coding reliability decreases behavioral reliability of olfactory stimulus classification.


title: Selective representations of texture and motion in mouse higher visual areas

abstract: Mice have a constellation of higher visual areas, but their functional specializations are unclear. Here, we used a data-driven approach to examine neuronal representations of complex visual stimuli across mouse higher visual areas, measured using large field-of-view two-photon calcium imaging. Using specialized stimuli, we found higher fidelity representations of texture in area LM, compared to area AL. Complementarily, we found higher fidelity representations of motion in area AL, compared to area LM. We also observed this segregation of information in response to naturalistic videos. Finally, we explored how popular models of visual cortical neurons could produce the segregated representations of texture and motion we observed. These selective representations could aid in behaviors such as visually guided navigation.


title: Microevidence for microdosing with psilocybin mushrooms: a double-blind placebo-controlled study of subjective effects, behavior, creativity, perception, cognition, and brain activity

abstract: The use of low sub-hallucinogenic doses of psychedelics ("microdosing") has gained popularity in recent years. Although anecdotal reports claim multiple benefits associated with this practice, the lack of placebo-controlled studies limits our knowledge of microdosing and its effects. Moreover, research conducted in laboratory settings might fail to capture the motivation of individuals engaged in microdosing protocols. We recruited 34 individuals planning to microdose with psilocybin mushrooms (Psilocybe cubensis), one of the materials most frequently used for this purpose. Following a double-blind placebo-controlled design, we investigated the effects of 0.5 g dried mushrooms on subjective experience, behavior, creativity, perception, cognition, and brain activity. The reported acute effects were significantly more intense for the active dose compared to the placebo, which could be explained by unblinding. For the other measurements, we observed either null effects or a trend towards cognitive impairment and, in the case of EEG, towards reduced theta band spectral power. Our findings support the possibility that expectation effects underlie at least some of the anecdotal benefits attributed to microdosing with psilocybin mushrooms.


title: Short latency stretch reflexes depend on the balance of activity in agonist and antagonist muscles during ballistic elbow movements

abstract:
The spinal stretch reflex is a fundamental building block of motor function, with a sensitivity that varies continuously during movement and when changing between movement and posture. Many have investigated task-dependent reflex sensitivity, but few have provided simple, quantitative analyses of the relationship between the volitional control and stretch reflex sensitivity throughout tasks that require coordinated activity of several muscles. Here we develop such an analysis and use it to test the hypothesis that modulation of reflex sensitivity during movement can be explained by the balance of activity within agonist and antagonist muscles better than by activity only in the muscle homonymous with the reflex. Subjects completed hundreds of flexion and extension movements as small, pseudo-random perturbations of elbow angle were applied to obtain estimates of stretch reflex amplitude throughout the movement. A subset of subjects performed a postural control task at muscle activities matched to those during movement. We found that reflex modulation during movement can be described by background activity in antagonist muscles about the elbow much better than by activity only in the muscle homonymous to the reflex (p<0.001). Agonist muscle activity enhanced reflex sensitivity whereas antagonist activity suppressed it. Surprisingly, the magnitude of these effects was similar, suggesting a balance of control between agonists and antagonists very different from the dominance of sensitivity to homonymous activity during posture. This balance is due to a large decrease in sensitivity to homonymous muscle activity during movement rather than substantial changes in the influence of antagonistic muscle activity.

New and NoteworthyThis study examined the sensitivity of the stretch reflexes elicited in elbow muscles to the background activity in these same muscles during movement and postural tasks. We found a heightened reciprocal control of reflex sensitivity during movement that was not present during maintenance of posture. These results help explain previous discrepancies in reflex sensitivity measured during movement and posture and provide a simple model for assessing their contributions to muscle activity in both tasks.


title: Disentangling hand and tool processing: distal effects of neuromodulation

abstract: The neural processing within a brain region that responds to more than one object category can be separated by looking at the horizontal modulations established by that region, which suggests that local representations can be affected by connections to distal areas, in a category-specific way. Here we first wanted to test whether by applying transcranial direct current stimulation (tDCS) to a region thatre sponds both to hands and tools (posterior middle temporal gyrus; pMTG), while participants performed either a hand- or tool-related training task, we would be able to specifically target the trained category, and thereby dissociate the overlapping neural processing. Second, we wanted to see if these effects were limited to the target area or extended to distal but functionally connected brain areas. After each combined tDCS and training session, participants therefore viewed images of tools, hands, and animals, in an fMRI scanner. Using multivoxel pattern analysis, we found that tDCS stimulation to pMTG indeed improved the classification accuracy between tools vs. animals, but only when combined with a tool training task (not a hand training task). However, surprisingly, tDCS stimulation to pMTG also improved the classification accuracy between hands vs. animals when combined with a tool training task (not a hand training task). Our findings suggest that overlapping but functionally-specific networks can be separated by using a category-specific training task together with tDCS - a strategy that can be applied more broadly to other cognitive domains using tDCS - and demonstrates the importance of horizontal modulations in objectcategory representations.


title: Task-dependent switching of feedback controllers

abstract: The separation of distinct motor memories by contextual cues is a well known and well studied phenomenon of feedforward human motor control. However, there is no clear evidence of such context-induced separation in feedback control. Here we test both experimentally and computationally if context-dependent switching of feedback controllers is possible in the human motor system. Specifically, we probe visuomotor feedback responses of our human participants in two different tasks - stop and hit - and under two different schedules. The first, blocked schedule, is used to measure the behaviour of stop and hit controllers in isolation, showing that it can only be described by two independent controllers with two different sets of control gains. The second, mixed schedule, is then used to compare how such behaviour evolves when participants regularly switch from one task to the other. Our results support our hypothesis that there is contextual switching of feedback controllers, further extending the accumulating evidence of shared features between feedforward and feedback control.


title: Neural dynamics of causal inference in the macaque frontoparietal circuit

abstract: Natural perception relies inherently on inferring causal structure in the environment. However, the neural mechanisms and functional circuits that are essential for representing and updating the hidden causal structure and corresponding sensory representations during multisensory processing are unknown. To address this, monkeys were trained to infer the probability of a potential common source from visual and proprioceptive signals on the basis of their spatial disparity in a virtual reality system. The proprioceptive drift reported by monkeys demonstrated that they combined historical information and current multisensory signals to estimate the hidden common source and subsequently updated both the causal structure and sensory representation. Single-unit recordings in premotor and parietal cortices revealed that neural activity in premotor cortex represents the core computation of causal inference, characterizing the estimation and update of the likelihood of integrating multiple sensory inputs at a trial-by-trial level. In response to signals from premotor cortex, neural activity in parietal cortex also represents the causal structure and further dynamically updates the sensory representation to maintain consistency with the causal inference structure. Thus, our results indicate how premotor cortex integrates historical information and sensory inputs to infer hidden variables and selectively updates sensory representations in parietal cortex to support behavior. This dynamic loop of frontal-parietal interactions in the causal inference framework may provide the neural mechanism to answer long-standing questions regarding how neural circuits represent hidden structures for body-awareness and agency.


title: Response plasticity of Drosophila olfactory sensory neurons

abstract:
In insect olfaction, sensitization refers to the amplification of a weak olfactory signal when the stimulus is repeated within a specific time window. In the vinegar fly, Drosophila melanogaster, his occurs already at the periphery, at the level of olfactory sensory neurons (OSNs) located in the antenna. In our study, we investigate whether sensitization is a widespread property in a set of seven types of OSNs, as well as the mechanisms involved. First, we characterize and compare differences in spontaneous activity, response velocity and response dynamics among the selected OSN types. These express different receptors with distinct tuning properties and behavioral relevance. Second, we show that sensitization is not a general property. Among our selected OSNs types, it occurs in those responding to more general food odors, while OSNs involved in very specific detection of highly specific ecological cues like pheromones and warning signals show no sensitization. Moreover, we show that mitochondria play an active role in sensitization by contributing to the increase in intracellular Ca2+ upon weak receptor activation. Thus, by using a combination of single sensillum recordings (SSR), calcium imaging and pharmacology, we widen the understanding of how the olfactory signal is processed at the periphery.

O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY


title: PACAP-PAC1 Receptor Inhibition is Effective in Models of Opioid-Induced Medication Overuse Headache

abstract:
Opioids are regularly prescribed for migraine and can result in medication overuse headache and dependence. We recently showed that pituitary adenylate cyclase activating polypeptide (PACAP) is upregulated following opioid administration or in a model of chronic migraine. The goal of this study was to determine if PACAP was a link between opioid use and headache chronification. We tested the effect of PACAP-PAC1 receptor inhibition in novel models of opioid-exacerbated migraine pain and aura; and examined the co-expression between mu opioid receptor (MOR), PAC1, and PACAP in headache-associated brain and peripheral regions.

To model opioid exacerbated migraine pain, mice were injected daily with morphine (10 mg/kg) or vehicle for 11 days. On days 3,5,7,9, and 11 they also received the known human migraine trigger nitroglycerin (0.1 mg/kg) or vehicle. To model opioid exacerbated aura, mice were treated with vehicle or morphine twice daily for 4 days (20 mg/kg on days 1-3, 40 mg/kg on day 4), a well-established paradigm for causing opioid-induced hyperalgesia. On day 5 they underwent cortical spreading depression, a physiological correlate of migraine aura. The effect of the PAC1 inhibitor, M65 (0.1 mg/kg), was tested in these models. Fluorescent in situ hybridization was used to investigate the expression of MOR, PAC1, and PACAP.

Only mice treated with combined morphine and nitroglycerin developed chronic cephalic allodynia (n=18/group). M65 reversed this hypersensitivity (n=9/group). Morphine significantly increased the number of CSD events (n=8-9/group); and M65 decreased this exacerbation by morphine (n=8-12/group). PAC1 and/or PACAP were highly co-expressed with MOR, and varied by region (n=6/group). MOR and PACAP were co-expressed in the trigeminal ganglia, while MOR and PAC1 receptor showed near complete overlap in the trigeminal nucleus caudalis and periaqueductal gray. The cortex showed similar cellular co-expression between MOR-PACAP and MOR-PAC1.

These results show that opioids facilitate the transition to chronic headache through induction of PACAPergic mechanisms. Antibodies or pharmacological agents targeting PACAP or PAC1 receptor may be particularly beneficial for the treatment of opioid-induced medication overuse headache.


title: MitoVisualize: A resource for analysis of variants in human mitochondrial RNAs and DNA

abstract: We present MitoVisualize, a new tool for analysis of the human mitochondrial DNA (mtDNA). MitoVisualize enables visualization of: (1) the position and effect of variants in mitochondrial transfer RNA (tRNA) and ribosomal RNA (rRNA) secondary structures alongside curated variant annotations, (2) data across RNA structures, such as to show all positions with disease-associated variants or with post-transcriptional modifications, and (3) the position of a base, gene or region in the circular mtDNA map, such as to show the location of a large deletion. All visualizations can be easily downloaded as figures for reuse. MitoVisualize can be useful for anyone interested in exploring mtDNA variation, though is designed to facilitate mtDNA variant interpretation in particular. MitoVisualize can be accessed via https://www.mitovisualize.org/. The source code is available at https://github.com/leklab/mito_visualize/.

category: genetics


title: The accuracy of absolute differential abundance analysis from relative count data

abstract: Concerns have been raised about the use of relative abundance data derived from next generation sequencing as a proxy for absolute abundances. For example, in the differential abundance setting, compositional effects in relative abundance data may give rise to spurious differences (false positives) when considered from the absolute perspective. In practice however, relative abundances are often transformed by renormalization strategies intended to compensate for these effects and the scope of the practical problem remains unclear. We used simulated data to explore the consistency of differential abundance calling on renormalized relative abundances versus absolute abundances and find that, while overall consistency is high, with median sensitivities (true positive rates) and specificities (1 - false positive rates) each of around 0.90, consistency can be much lower where there is widespread change in the abundance of features across conditions. We confirm these findings on a large number of real data sets drawn from 16S metabarcoding, expression array, bulk RNA-seq, and single-cell RNA-seq experiments, where data sets with the greatest change between experimental conditions are also those with the highest false positive rates. Finally, we evaluate the predictive utility of summary features of relative abundance data themselves. Estimates of sparsity and the prevalence of feature-level change in relative abundance data give accurate predictions of discrepancy in differential abundance calling in simulated data and provide useful bounds for worst-case outcomes in real data.


title: Interplay between stress and reproduction: Novel epigenetic markers in response to shearing patterns in Australian Merino sheep (Ovis aries)

abstract:
In this study, we determined the effect(s) of shearing on Australian Merino ewes (Ovis aries). To test this research question, we used a suite of field and laboratory methods including GPS collars, wool cortisol and novel epigenetic markers identified using Illumina NovaSeq RRBS. Single shorn ewes (n =24) kept on their full fleece throughout the entire gestation period while twice shorn ewes (n =24) had their wool shorn early in gestation. We have discovered one locus (Chr20:50404014) which was significantly associated with different shearing treatments (twice or single shorn ewes), (FDR = 0.005). This locus is upstream of a protein coding gene (ENSOARG00000002778.1), which shows similarities to the forkhead box C1 (FOXC1) mRNA using BLAST searches. We discovered that 36 gene loci were significantly modulated either between different shearing treatments or late vs early pregnancy ewes. Similarly, in lambs we identified 16 annotated gene loci that were significant between late vs early pregnancy. Early shorn ewes grazed 10% higher and maintained stronger body condition. Wool cortisol levels were significantly lower in the early shorn ewes during mid- and late gestation. Lambs bred from twice shorn ewes had on average better visual wool quality parameters in terms of micron, spin finesses and curvature. Collectively, this research provides a new dataset combining physiological, molecular epigenetics and digital tracking indices that advances our understanding of how Merino ewes respond to shearing frequency and this information could guide further research on sheep breeding and welfare.

Significance StatementThis study provides novel data on the molecular epigenetic signatures in Merino sheep under exposure to natural environmental and management factors. We have discovered DNA methylation profiles from ewes and lambs that are directly associated with whole- animal physiology, development and growth. The baseline data can provide a useful resource for future research in many key areas such as animal welfare, diseases and climatic resilience that will benefit sheep and wool production.


title: Among-individual variation of risk-taking behaviour in group and solitary context is uncorrelated but independently repeatable in a juvenile Arctic charr (Salvelinus alpinus) aquaculture strain.

abstract: Behavioural traits have been shown to have implications in fish welfare and growth performances in aquaculture. If several studies have demonstrated the existence of repeatable and heritable behavioural traits (i.e., animal personality), the methodology to assess personality in fishes is often carried out in solitary context, which appears to somewhat limit their use from a selective breeding perspective because these tests are too time consuming. To address this drawback, group-based tests have been developed. In Nordic country, Arctic charr (Salvelinus alpinus) is widely used in aquaculture, but no selection effort on behavioural traits has yet been carried out. Specifically, in this study we examined if risk-taking behaviour was repeatable and correlated in group and solitary context and if the early influences of physical environment affect the among-individual variation of behavioural trait across time in order to verify whether a group risk-taking test could be used as a selective breeding tool. Here, we found that in both contexts and treatments, the risk-taking behaviour was repeatable across a short period of 6 days. However, no cross-context consistency was found between group and solitary, which indicates that Arctic charr express different behavioural trait in group and solitary.

category: animal behavior and cognition


title: PEDOT:PSS-Modified Cotton Conductive Thread for Mass Manufacturing of Textile-Based Electrical Wearable Sensors by Computerized Embroidery

abstract: The textile industry has advanced processes that allow computerized manufacturing of garments at large volumes with precise visual patterns. The industry, however, is not able to mass fabricate clothes with seamlessly integrated wearable sensors, using its precise methods of fabrication (such as computerized embroidery). This is due to the lack of conductive threads compatible with standard manufacturing methods used in industry. In this work, we report a low-cost poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS)-modified cotton conductive thread (PECOTEX) that is compatible with computerized embroidery. The PECOTEX was produced using a crosslinking reaction between PEDOT:PSS and cotton thread using divinyl sulfone as the crosslinker. We extensively characterized and optimized our formulations to create a mechanically robust conductive thread that can be produced in large quantities in a roll-to-roll fashion. Using PECOTEX and a domestic computerized embroidery machine, we produced a series of wearable electrical sensors including a facemask for monitoring breathing, a t-shirt for monitoring heart activity and textile-based gas sensors for monitoring ammonia as technology demonstrators. PECOTEX has the potential to enable mass manufacturing of new classes of low-cost wearable sensors integrated into everyday clothes.


title: MIRA: Joint regulatory modeling of multimodal expression and chromatin accessibility in single cells

abstract: Rigorously comparing gene expression and chromatin accessibility in the same single cells could illuminate the logic of how coupling or decoupling of these mechanisms regulates fate commitment. Here, we present MIRA: Probabilistic Multimodal Models for Integrated Regulatory Analysis, a comprehensive methodology that systematically contrasts transcription and accessibility to infer the regulatory circuitry driving cells along developmental trajectories. MIRA leverages topic modeling of cell states and regulatory potential modeling of individual gene loci. MIRA thereby represents cell states in an efficient and interpretable latent space, infers high fidelity lineage trees, determines key regulators of fate decisions at branch points, and exposes the variable influence of local accessibility on transcription at distinct loci. Applied to epidermal maintenance differentiation and embryonic brain development from two different multimodal platforms, MIRA revealed that early developmental genes were tightly regulated by local chromatin landscape whereas terminal fate genes were titrated without requiring extensive chromatin remodeling.


title: Degradation of lactoferrin caused by droplet atomization process via two fluid nozzle: The detrimental effect of air water interfaces

abstract: Biological macromolecules, especially therapeutic proteins, are delicate and highly sensitive to degradation from stresses encountered during the manufacture of dosage forms. Thin-film freeze-drying (TFFD) and spray freeze-drying (SFD) are two processes used to convert liquid forms of protein into dry powders. In the production of inhalable dry powders that contain proteins, these potential stressors fall into three categories based on their occurrence during the primary steps of the process: (1) droplet formation (e.g., the mechanism of droplet formation, including spray atomization), (2) freezing, and (3) frozen water removal (e.g., sublimation). This study compares the droplet formation mechanism used in TFFD and SFD by investigating the effects of spraying on the stability of proteins, using lactoferrin as a model. This study considers various perspectives on the degradation (e.g., conformation) of lactoferrin after subjecting the protein solution to the atomization process using a pneumatic two-fluid nozzle (employed in SFD) or a low-shear drop application through the nozzle. The surface activity of lactoferrin was examined to explore the interfacial adsorption tendency, diffusion, and denaturation process. Subsequently, this study also investigates the secondary and tertiary structure of lactoferrin, the quantification of monomers, oligomers, and ultimately, aggregates. The spraying process affected the tertiary structure more negatively than the tightly woven secondary structure, resulting in a 1.5 nm red shift in peak position corresponding to the Tryptophan (Trp) residues. This conformational change can either (a) be reversed at low concentrations via relaxation or (b) proceed to form irreversible aggregates at higher concentrations. Interestingly, when the sample was allowed to progress into micron-sized aggregates, such a dramatic change was not detected using methods such as size-exclusion chromatography, polyacrylamide gel electrophoresis, and dynamic light scattering at 173{degrees}. A more complete understanding of the heterogeneous protein sample was achieved only through a combination of 173{degrees} and 13{degrees} backward and forward scattering, a combination of derived count rate measurements, and micro-flow imaging (MFI). Finally, compared to the low-shear dripping used in the TFFD process, lactoferrin underwent a relatively fast conformational change upon exposure to the high air-water interface of the two-fluid atomization nozzle used in the SFD process as compared to the low shear dripping used in the TFFD process. The interfacial induced denaturation that occurred during spraying was governed primarily by the size of the atomized droplets, regardless of the duration of exposure to air.


title: EpyNN: Educational python for Neural Networks

abstract:
SummaryArtificial Neural Networks (ANNs) have achieved unequaled performance for numerous problems in many areas of Science, Business, Public Policy, and more. While experts are familiar with performance-oriented software and underlying theory, ANNs are difficult to comprehend for non-experts because it requires skills in programming, background in mathematics and knowledge of terminology and concepts. In this work, we release EpyNN, an educational python resource meant for a public willing to understand key concepts and practical implementation of scalable ANN architectures from concise, homogeneous and idiomatic source code. EpyNN contains an educational Application Programming Interface (API), educational workflows from data preparation to ANN training and a documentation website setting side-by-side code, mathematics, graphical representation and text to facilitate learning and provide teaching material. Overall, EpyNN provides basics for python-fluent individuals who wish to learn, teach or develop from scratch.

AvailabilityEpyNN documentation is available at https://epynn.net and repository can be retrieved from https://github.com/synthaze/epynn.

ContactStephanie Olivier-Van-Stichelen, solivier@mcw.edu.

Supplementary InformationSupplementary files and listings.


title: A luciferase prosubstrate and a red bioluminescent calcium indicator to image neuronal activity

abstract: Genetically encoded fluorescent indicators have been broadly used to monitor neuronal activity in live animals, but invasive surgical procedures are required. This study presents a functional bioluminescence imaging (fBLI) method for recording the activity of neuronal ensembles in the brain in awake mice. We developed a luciferase prosubstrate activatable in vivo by nonspecific esterase to enhance the brain delivery of the luciferin. We further engineered a bright, bioluminescent indicator with robust responsiveness to calcium ions (Ca2+) and appreciable emission above 600 nm. Integration of these advantageous components enabled the imaging of Ca2+ dynamics in awake mice minimally invasively with excellent signal- to-background and subsecond temporal resolution. This study thus establishes a new paradigm for studying brain functions in health and disease.


title: A deep learning-based multisite neuroimage harmonization framework established with traveling-subject dataset

abstract: The accumulation of multisite large-sample MRI datasets collected by large brain research projects in the last decade has provided a critical resource for understanding the neurobiological mechanisms underlying cognitive functions and brain disorders. However, the significant site effects, observed in the imaging data and their derived structural and functional features, has prevented the derivation of consistent findings across different studies. The development of harmonization methods that can effectively eliminate complex site effects while maintaining biological characteristics in neuroimaging data has become a vital and urgent requirement for multisite imaging studies. Here, we proposed a deep learning-based framework to harmonize imaging data from pairs of sites, in which site factors and brain features can be disentangled and encoded. We trained the proposed framework with a publicly available traveling-subject dataset from SRPBS and harmonized the gray matter volume maps from eight source sites to a target site. The proposed framework significantly eliminated inter-site differences in gray matter volume. The embedded encoders successfully captured both the abstract texture of site factors and the concrete brain features. Moreover, the proposed framework exhibited outstanding performance relative to conventional statistical harmonization methods in site effect removal, data distribution homogenization, and intra-subject similarity improvement. Together, the proposed method offers a powerful and interpretable deep learning-based harmonization framework for multisite neuroimaging data that could enhance reliability and reproducibility in multisite studies for brain development and brain disorders.


title: Graded variation in cortical T1w/T2w myelination during adolescence

abstract:
Myelination influences brain connectivity during sensitive periods of development by enhancing neural signaling speed and regulating synapse formation to reduce plasticity. However, in vivo studies characterizing the maturational timing of cortical myelination during human development remain scant. Here, we take advantage of recent advances in high-resolution cortical T1w/T2w myelin mapping methods, including principled correction of B1+ transmit field effects, using data from the Human Connectome Project in Development (N=628, ages 8-21) to characterize the maturational timing of myelination from childhood through early adulthood throughout the cerebral neocortex. We apply Bayesian spline models and functional latent clustering analysis to demonstrate graded variation in the rate of cortical T1w/T2w myelin growth in neocortical areas that is strongly correlated with the sensorimotor-association (S-A) axis of cortical organization reported by others. In sensorimotor areas T1w/T2w myelin starts at high levels at early ages, increases at a fast pace, and decelerates at later ages (18-21). In intermediate multimodal areas along the S-A axis, T1w/T2w myelin tends to start at intermediate levels and increase linearly at an intermediate pace. In transmodal/paralimbic association areas high along the S-A axis, T1w/T2w myelin tends to start at low levels and increase linearly at the slowest pace. These data provide evidence for graded variation along the S-A axis in the rate of cortical myelination during adolescence, which could reflect ongoing plasticity underlying the development of complex information processing and psychological functioning.

Significance StatementMyelin is a lipid membrane that is essential to healthy brain function. Myelin wraps axons to increase neural signaling speed, enabling complex neuronal functioning underlying learning and cognition. Here we characterize the developmental timing of myelination across the cerebral cortex during adolescence using recent advances in non-invasive myelin mapping. Our results provide new evidence demonstrating graded variation across the cortex in the timing of myelination during adolescence, with rapid myelination in lower-order sensory areas and gradual myelination in higher-order association areas. This spatial pattern of microstructural brain development closely parallels the sensorimotor-to-association axis of cortical organization and plasticity during ontogeny.


title: Learning Active Multimodal Subspaces in the Brain

abstract: Here we introduce a multimodal framework to identify subspaces in the human brain that are defined by collective changes in structural and functional measures and are actively linked to demographic, biological and cognitive indicators in a population. We determine the multimodal subspaces using principles of active subspace learning (ASL) and demonstrate its application on a sample learning task (biological ageing) on a Schizophrenia dataset. The proposed multimodal ASL method successfully identifies latent brain representations as subsets of brain regions and connections forming co-varying subspaces in association with biological age. We show that Schizophrenia is characterized by different subspace patterns compared to those in a cognitively normal brain. The multimodal features generated by projecting structural and functional MRI components onto these active subspaces perform better than several PCA-based transformations and equally well when compared to non-transformed features on the studied learning task. In essence, the proposed method successfully learns active brain subspaces associated with a specific brain condition but inferred from the brain imaging data along with the biological/cognitive traits of interest.


title: Sociodemographic effects on immune cell composition in a free-ranging non-human primate.

abstract: Aging results in declines in immune function and increases in inflammation, which underlie many age-related diseases. These immunosenescent signatures are similar to those seen in individuals exposed to social adversity, who may age more rapidly than those unexposed. Yet, it is unclear how social adversity alters immunity across demographic factors - data that are essential to identify how it might increase aging-related diseases. Here, we investigated how age, sex, and social adversity predicted immune cell proportions in 250 rhesus macaques living in a semi-naturalistic colony. As macaques aged, they exhibited signatures of immunosenescence. Older individuals had signatures of diminished antibody production and adaptive immunity, with declines in CD20+ B cells, CD20+/CD3+ cell ratio, and the CD4+/CD8+ T cell ratio. At all ages, females had higher CD20+/CD3+ and CD4+/CD8+ ratios, indicative of a stronger antibody and adaptive immune response that may facilitate pathogen clearance even with increasing age. Older individuals had signatures of inflammation, with higher proportions of CD3+/CD8+ Cytotoxic T cells, CD16+/CD3- Natural Killer cells, CD3+/CD4+/CD25+ and CD3+/CD8+/CD25+ T regulatory cells, and CD14+/CD16+/HLA-DR+ intermediate monocytes, combined with lower levels of CD14+/CD16-/HLA-DR+ classical monocytes. Notably, we found an interaction between age and social adversity, where low-status individuals had higher proportions of CD3+/CD4+/CD25+ T regulatory cells for their age, compared to higher-status individuals. Together, our study identifies immune cell types that are affected by age and sex in the premier nonhuman primate model of human biology and behavior, and demonstrate a novel link between inflammatory CD4+ T regulatory cells and social adversity.

category: immunology


title: The SUMO protease Ulp2 regulates genome stability and drug resistance in the human fungal pathogen Candida albicans

abstract: Stress-induced genome instability in microbial organisms is emerging as a critical regulatory mechanism for driving rapid and reversible adaption to drastic environmental changes. In Candida albicans, a human fungal pathogen that causes life-threatening infections, genome plasticity confers increased virulence and antifungal drug resistance. Discovering the mechanisms regulating C. albicans genome plasticity is a priority to understand how this and other microbial pathogens establish life-threatening infections and develop resistance to antifungal drugs. We identified the SUMO protease Ulp2 as a critical regulator of C. albicans genome integrity through genetic screening. Deletion of ULP2 leads to hypersensitivity to genotoxic agents and increased genome instability. This increased genome diversity causes reduced fitness under standard laboratory growth conditions but enhances adaptation to stress, making ulp2{Delta}/{Delta} cells more likely to thrive in the presence of antifungal drugs. Whole-genome sequencing indicates that ulp2{Delta}/{Delta} cells counteract antifungal drug-induced stress by developing segmental aneuploidies of chromosome R and chromosome I. We demonstrate that intrachromosomal repetitive elements drive the formation of complex novel genotypes with adaptive power.

category: microbiology


title: Power laws from the bird species abundance distribution

abstract: A recent study found that bird species with fewer individuals are abundant, but large species are rare. We show that this new data strongly suggests a power-law distribution rather than the most accepted log-normal. Moreover, we discuss extinction risk across the bird phylogeny and future conservation efforts by profiting from the hierarchical structure revealed by the new data.


title: Dispersal syndrome and landscape fragmentation in the salt-marsh specialist spider Erigone longipalpis

abstract: Dispersal and its evolution play a key role for population persistence in fragmented landscapes where habitat loss and fragmentation increase the cost of between-habitat movements. In such contexts, it is important to know how variation in dispersal and other traits is structured, and whether responses to landscape fragmentation are aligned with underlying dispersal-trait correlations, or dispersal syndromes. We therefore studied trait variation in Erigone longipalpis, a European spider species specialist of (often patchy) salt marshes. We collected spiders in two salt-marsh landscapes differing in habitat availability. We then reared lab-born spiders for two generations in controlled conditions, and measured dispersal and its association with various key traits. E. longipalpis population densities were lower in the more fragmented landscape. Despite this, we found no evidence of differences in dispersal, or any other trait we studied, between the two landscapes. While a dispersal syndrome was present at the among-individual level (dispersers were more fecund and faster growing, among others), there was no indication it was genetically driven: among-family differences in dispersal were not correlated with differences in other traits. Instead, we showed that the observed phenotypic covariations were mostly due to within-family correlations. We hypothesize that the dispersal syndrome is the result of asymmetric food access among siblings, leading to variation in development rates and carrying over to adult traits. Our results show we need to better understand the sources of dispersal variation and syndromes, especially when dispersal may evolve rapidly in response to environmental change.


title: Floral evolution and pollinator diversification in Hedychium J.Koenig (Zingiberaceae): one of Mr. Darwin's tropical fantasies

abstract:
PREMISEHedychium J.Koenig (ginger lilies: Zingiberaceae) is endemic to the Indo-Malayan Realm (IMR) and is known for its fragrant flowers. Two different pollination syndromes characterize the genus: diurnal or bird pollination and nocturnal or moth pollination systems. To date, no attempt has been undertaken to understand the evolution of floral traits in this genus.

METHODSWe estimated ancestral character-states, phylogenetic signals, and character correlations for thirteen discrete and eight continuous floral traits representing 75% species diversity of Hedychium. Diversification rate estimation analyses were also employed to understand trait-dependent diversification in the genus.

RESULTSInflorescence structure, cincinnus capacity, and curvature of floral tubes revealed strong phylogenetic dependence, whereas number of open flowers per inflorescence per day, color of the labellum, and exertion of the stigma characterized higher ecological effects. Diversification rate estimations suggested that the labellum width, floral tube length, and labellum color played a major role in the evolutionary diversification of Hedychium.

CONCLUSIONSWe identified bract type and cincinnus capacity as synapomorphies for Hedychium, while the island-specific clade III was characterized by slender cylindrical inflorescence, coiling of floral tubes, and longer bract to calyx ratio. The circum-Himalayan clade IV is the most speciose, derived, and with most variable floral traits. Although floral color and size lacked any association with pollinator-specific traits (moth and bird pollination), pale colored flowers were most common in the early diverging clades (clade I, II-el., and II-de.), indicating their ancestral nature, when compared to brightly colored flowers.