title: MESMERISED: Super-accelerating T1 relaxometry and diffusion MRI with STEAM at 7 T for quantitative multi-contrast and diffusion imaging

abstract: There is an increasing interest in quantitative imaging of T1, T2 and diffusion contrast in the brain due to greater robustness against bias fields and artifacts, as well as better biophysical interpretability in terms of microstructure. However, acquisition time constraints are a challenge, particularly when multiple quantitative contrasts are desired and when extensive sampling of diffusion directions, high b-values or long diffusion times are needed for multi-compartment microstructure modeling. Although ultra-high fields of 7 T and above have desirable properties for many MR modalities, the shortening T2 and the high specific absorption rate (SAR) of inversion and refocusing pulses bring great challenges to quantitative T1, T2 and diffusion imaging. Here, we present the MESMERISED sequence (Multiplexed Echo Shifted Multiband Excited and Recalled Imaging of STEAM Encoded Diffusion). MESMERISED removes the dead time in Stimulated Echo Acquisition Mode (STEAM) imaging by an echo-shifting mechanism. The echo-shift (ES) factor is independent of multiband (MB) acceleration and allows for very high multiplicative (ESxMB) acceleration factors, particularly under moderate and long mixing times. This results in super-acceleration and high time efficiency at 7 T for quantitative T1 and diffusion imaging, while also retaining the capacity to perform quantitative T2 and B1 mapping. We demonstrate the super-acceleration of MESMERISED for whole-brain T1 relaxometry with total acceleration factors up to 36 at 1.8 mm isotropic resolution, and up to 54 at 1.25 mm resolution qT1 imaging, corresponding to a 6x and 9x speedup, respectively, compared to MB-only accelerated acquisitions. We then demonstrate highly efficient diffusion MRI with high b-values and long diffusion times in two separate cases. First, we show that super-accelerated multi-shell diffusion acquisitions with 370 whole-brain diffusion volumes over 8 b-value shells up to b = 7000 s/mm2 can be generated at 2 mm isotropic in under 8 minutes, a data rate of almost a volume per second, or at 1.8 mm isotropic in under 11 minutes, achieving up to 3.4x speedup compared to MB-only. A comparison of b = 7000 s/mm2 MESMERISED against standard MB pulsed gradient spin echo (PGSE) diffusion imaging shows 70% higher SNR efficiency and greater effectiveness in supporting complex diffusion signal modeling. Second, we demonstrate time-efficient sampling of different diffusion times with 1.8 mm isotropic diffusion data acquired at four diffusion times up to 290 ms, which supports both Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI) at each diffusion time. Finally, we demonstrate how adding quantitative T2 and B1+ mapping to super-accelerated qT1 and diffusion imaging enables efficient quantitative multi-contrast mapping with the same MESMERISED sequence and the same readout train. MESMERISED extends possibilities to efficiently probe T1, T2 and diffusion contrast for multi-component modeling of tissue microstructure.


title: Simvastatin Therapy Attenuates Memory Deficits that Associate with Brain Monocyte Infiltration in Chronic Hypercholesterolemia

abstract: Evidence associates cardiovascular risk factors with unfavorable systemic and neuro-inflammation and cognitive decline in the elderly. Cardiovascular therapeutics (e.g., statins and anti-hypertensives) possess immune-modulatory functions in parallel to their cholesterol- or blood pressure (BP)-lowering properties. How their ability to modify immune responses affects cognitive function is unknown. Here, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice. Chronic hypercholesterolemia that was accompanied by moderate blood pressure elevations associated with apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE-/- mice. The persistent low-grade immune activation that is associated with chronic hypercholesterolemia facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE-/- but not wild-type mice, and links to memory dysfunction. Therapeutic cholesterol-lowering through simvastatin reduced systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE-/- mice with chronic hypercholesterolemia. BP-lowering therapy alone (i.e., hydralazine) attenuated some neuro-inflammatory signatures but not the occurrence of memory deficits. Our study suggests a link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment and encourages cholesterol-lowering therapy as safe strategy to control hypercholesterolemia-associated memory decline during ageing.

category: physiology


title: Genomic diversity of 39 samples of Pyropia species grown in Japan

abstract: Some Pyropia species, such as nori (P. yezoensis), are important marine crops. We conducted a phylogenetic analysis of 39 samples of Pyropia species grown in Japan using organellar genome sequences. A comparison of the chloroplast DNA sequences with those from China showed a clear genetic separation between Japanese and Chinese P. yezoensis. Conversely, comparing the mitochondrial DNA sequences did not separate Japanese and Chinese P. yezoensis. Analysis of organellar genomes showed that the genetic diversity of Japanese P. yezoensis used in this study is lower than that of Chinese wild P. yezoensis. To analyze the genetic relationships between samples of Japanese Pyropia, we used whole-genome resequencing to analyze their nuclear genomes. In the offspring resulting from cross-breeding between P. yezoensis and P. tenera, nearly 90% of the genotypes analyzed by mapping were explained by the presence of different chromosomes originating from two different parental species. Although the genetic diversity of Japanese P. yezoensis is low, analysis of nuclear genomes genetically separated each sample. Samples isolated from the sea were often genetically similar to those being farmed. Study of genetic heterogeneity of samples within a single aquaculture strain of P. yezoensis showed that samples were divided into two groups and the samples with frequent abnormal budding formed a single, genetically similar group. The results of this study will be useful for breeding and the conservation of Pyropia species.

category: genomics


title: CRYPTOCHROME suppresses the circadian proteome and promotes protein homeostasis

abstract: The daily organisation of most mammalian cellular functions is attributed to circadian regulation of clock-controlled protein expression, driven by daily cycles of CRYPTOCHROME-dependent transcriptional feedback repression. To test this, we compared the circadian proteome and phosphoproteome of wild type and CRY-deficient fibroblast cells. Strikingly, CRY-deficient cells showed a two-fold increase in circadian-regulated proteins, phosphopeptides, and K+ transport. This was accompanied by extensive remodelling of the cellular proteome overall, including reduced phosphatase and proteasome subunit expression. These adaptations rendered CRY-deficient cells more sensitive to stress, which may account for their reduced circadian robustness and contribute to the wide-ranging phenotypes of CRY-deficient mice. We suggest that CRY ultimately functions to suppress, rather than generate, daily rhythms in cellular protein abundance, thereby maintaining protein and osmotic homeostasis.

category: cell biology


title: Multifocal imaging for precise, label-free tracking of fast biological processes in 3D

abstract: Many biological processes happen on a nano-to millimeter scale and within milliseconds. Established methods such as confocal microscopy are suitable for precise 3D recordings but lack the temporal or spatial resolution to resolve fast 3D processes and require labeled samples. Multifocal imaging (MFI) allows high-speed 3D imaging but is limited by the compromise between high spatial resolution and large field-of-view (FOV), and the requirement for bright fluorescent labels. Here, we provide a new open-source 3D reconstruction algorithm for multifocal images that allows using MFI for fast, precise, label-free tracking spherical and filamentous structures in a large FOV and across a high depth. We characterize fluid flow and flagellar beating of human and sea urchin sperm with a high z-precision of 0.15 m, in a large volume of 240 x 260 x 21 m, and at high speed (500 Hz). The large sampling volume allowed to follow sperm trajectories while simultaneously recording their flagellar beat. Our MFI concept is cost-effective, can be easily implemented, and does not rely on object labeling, which renders it broadly applicable.


title: Human.miRFFL.DB- A curated resource for human miRNA coregulatory networks and associated regulatory-circuits

abstract:
Gene regulation is viewed as a complex process where regulatory elements and their targets form highly complex network interactions thus affecting normal biological physiology and also disease-initiation and progress. Transcription factors (TF) and microRNA (miRNA) are fundamental transcriptional and post-transcriptional regulators of the gene expression controlling important biological processes. In recent years, many high throughput studies revealed that the complex regulatory interactions are mediated by the complex interplay between miRNA and TF regulating a Target Gene (TG) in conjunction. miRNAs and TFs are also known to regulate each other. This complex coregulatory mechanism may be represented in the form of miRNA:TF:TG coregulatory network. This network can be used to identify several small recurring subgraphs known as regulatory-circuits. One of these regulatory-circuits also called the Feed-Forward Loops (FFLs) is a three-node pattern which is composed of a miRNA and a TF, one of which regulates the other and both jointly regulate a TG. These regulatory-circuits have proven useful in elucidating the complex interplay of gene regulation during many physiological and pathological conditions.

Human.miRFFL.DB is a comprehensive integrated resource for human miRNA:TF:TG coregulatory directed networks and their associated regulatory-circuits. In-house scripts based on the graph theory principle have been used to identify both types of FFL motifs i.e. miRNA-FFL and TF-FFL. The database additionally provides an interactive visualization of the coregulatory networks and associated FFLs. Human.miRFFL.DB can be used as a comprehensive ready reference for human miRNA:TF:TG coregulatory networks and associated FFLs for decrypting complex cellular interactions of these regulatory biomolecules. Human.miRFFL.DB is available online at http://mirffldb.in/human/

category: bioinformatics


title: BrainGNN: Interpretable Brain Graph Neural Network for fMRI Analysis

abstract: Understanding which brain regions are related to a specific neurological disorder or cognitive stimuli has been an important area of neuroimaging research. We propose BrainGNN, a graph neural network (GNN) framework to analyze functional magnetic resonance images (fMRI) and discover neurological biomarkers. Considering the special property of brain graphs, we design novel ROI-aware graph convolutional (Ra-GConv) layers that leverage the topological and functional information of fMRI. Motivated by the need for transparency in medical image analysis, our BrainGNN contains ROI-selection pooling layers (R-pool) that highlight salient ROIs (nodes in the graph), so that we can infer which ROIs are important for prediction. Furthermore, we propose regularization terms--unit loss, topK pooling (TPK) loss and group-level consistency (GLC) loss--on pooling results to encourage reasonable ROI-selection and provide flexibility to encourage either fully individual- or patterns that agree with group-level data. We apply the BrainGNN framework on two independent fMRI datasets: an Autism Spectrum Disorder (ASD) fMRI dataset and data from the Human Connectome Project (HCP) 900 Subject Release. We investigate different choices of the hyper-parameters and show that BrainGNN outperforms the alternative fMRI image analysis methods in terms of four different evaluation metrics. The obtained community clustering and salient ROI detection results show a high correspondence with the previous neuroimaging-derived evidence of biomarkers for ASD and specific task states decoded for HCP. We will make BrainGNN codes public available after acceptance.

category: neuroscience


title: Identification of deleterious single nucleotide polymorphism (SNP)s on the human TBX5 gene & prediction of their structural & functional consequences: An in silico approach

abstract:
T-box transcription factor 5 (TBX5) gene encodes the transcription factor TBX5, which plays a crucial role in developing the heart and upper limbs. Damaging single nucleotide variants in this gene alters the protein structure, disturbs the functions of TBX5, and ultimately causes Holt-Oram Syndrome (HOS). By analyzing available single nucleotide polymorphism information in the dbSNP database, this study was designed to identify the most deleterious TBX5 SNPs through silico approaches and predict their structural and functional consequences.

Fifty-eight missense substitutions were found damaging by sequences homology-based tools like SIFT and PROVEAN and structure homology-based tools like PolyPhen-2. These SNPs were further scrutinized by various disease association meta-predictor tools. Additionally, the conservation profile of amino acid residues, their surface accessibility, stability, and structural integrity of the native protein upon mutations was assessed. From these analyses, finally 5 SNPs were detected as the most damaging ones [rs1565941579 (P85S), rs1269970792 (W121R), rs772248871 (V153D), rs769113870 (E208D), and rs1318021626 (I222N)]. Analyses of stop-loss, nonsense, UTR, and splice site SNPs were also conducted.

Through integrative bioinformatics analyses, this study has identified SNPs that are deleterious to the TBX5 protein structure and have the potential to cause HOS. Further wet-lab experiments can validate these findings.

category: genetics


title: Single caudate neurons encode temporally discounted value for formulating motivation for action

abstract: The term  temporal discounting describes both choice preferences and motivation for delayed rewards. Here we show that neuronal activity in the dorsal part of the primate caudate head (dCDh) signals the temporally discounted value needed to compute the motivation for delayed rewards. Macaque monkeys performed an instrumental task, in which visual cues indicated the forthcoming size and delay duration before reward. Single dCDh neurons represented the temporally discounted value without reflecting changes in the animals physiological state. Bilateral pharmacological or chemogenetic inactivation of dCDh markedly distorted the normal task performance based on the integration of reward size and delay, but did not affect the task performance for different reward sizes without delay. These results suggest that dCDh is involved in encoding the integrated multidimensional information critical for motivation.


title: Individual differences in spatial learning are correlated across cognitive tasks but not associated with stress response behaviour in the Trinidadian guppy

abstract: Cognition is vital for carrying out behaviours required for survival and reproduction. In animals, we now know that cognitive performance varies not just among species, but also among individuals within populations. While this variation is a prerequisite for contemporary natural selection, it is also true that selection does not act on traits in isolation. The extent to which cognitive traits covary with other aspects of phenotype (e.g. personality traits) is therefore expected to be an important factor in shaping evolutionary dynamics. Here we adopt a multivariate approach to test for spatial learning ability in a captive population of male Trinidadian guppies (Poecilia reticulata), and ask whether differences in cognitive performance are associated with (repeatable) differences in stress response behaviour. We focus on stress response for two reasons. First, functional links between cognitive traits and  stress coping style have been hypothesised. Second, individual-level studies of cognitive performance typically rely on multiple testing paradigms that may themselves be a stressor. Thus, there is a risk that variation in stress responsiveness is itself a cause of apparent, but artefactual variance in cognitive ability. Using a set of fish exposed repeatedly to two distinct spatial learning tasks (maze layouts), and an acute stress response test (open field trial), we find differences among-individuals in task performance that are repeatable within- and across maze layouts. On average performance improves with experience in the first maze, consistent with spatial learning, but not in the second. In both mazes, there is among-individual variation in the trajectory of mean performance with trial number suggesting individuals differ in  learning rate. Acute stress response behaviour is repeatable but predicts neither average time to solve the maze nor learning rate. We thus find no support for among-individual correlation between acute stress response and cognitive performance. However, we highlight the possibility that cumulative, chronic stress effects may nonetheless cause observed declines in performance across repeats for some individuals (leading to lack of improvement in mean time to solve the second maze). If so, this may represent a pervasive but difficult challenge for our ability to robustly estimate learning rates in studies of animal cognition.

category: animal behavior and cognition


title: Unique habitat and macroinvertebrate assemblage structures in spring-fed stream: a comparison among clastic lowland tributaries and mainstreams in northern Japan

abstract: The stable flow and temperature regimes of spring-fed streams are distinct from the dynamic regimes of other streams. We investigated differences in habitat and macroinvertebrate assemblages among three stream types (spring-fed tributary, non-spring-fed tributary and mainstream) in a clastic lowland of northern Japan. Current velocity was the slowest in the spring-fed reach, where the percent of fine sediment deposition was also 3.8-11.4 times higher than in the other stream types. The standing stock of detritus was also greater in the spring-fed reach. These results suggest that the stable flow regime in the spring-fed stream leads to the accumulation of fine sediment and detritus on the streambed. Oligochaeta and chironomids, which are burrower-gatherers, were remarkably abundant in the spring-fed reach. Total macroinvertebrate abundance was 3.8-12.2 times greater in the spring-fed reach than in the other stream types. Sprawler-grazer ephemeropterans were the most abundant in the mainstream reaches, likely due to higher primary productivity. Allomyia sp, which depend on cool spring-fed habitats, were found only in the spring-fed reach. The indicator species analysis also indicated multiple taxa of detritivores and Allomyia sp. for the spring-fed tributary. The macroinvertebrate assemblage in the spring-fed reach was characterized by numerous burrowers, collector-gatherers, and crenobiont taxa, highlighting the uniqueness and its contribution to enhance beta diversity in river networks.

category: ecology


title: Resolving complex structures at oncovirus integration loci with conjugate graph

abstract:
Oncovirus integrations cause copy number variations (CNVs) and complex structural variations (SVs) on host genomes. However, the understanding of how inserted viral DNA impacts the local genome remains limited. The linear structure of the oncovirus integrated local genomic map (LGM) will lay the foundations to understand how oncovirus integrations emerge and compromise the host genome s functioning. We propose a conjugate graph model to reconstruct the rearranged local genomic map at integrated loci. Simulation tests prove the reliability and credibility of the algorithm. Applications of the algorithm to whole-genome sequencing data of Human papillomavirus (HPV) and hepatitis B virus (HBV)-infected cancer samples gained biological insights on oncovirus integrations. We observed five affection patterns of oncovirus integrations from the HPV and HBV-integrated cancer samples, including the exon loss, promoter gain, hyper-amplification of tumor gene, the viral cis-regulation inserted at the single intron and at the intergenic region. We found that the focal duplicates and host SVs are frequent in the HPV-integrated LGMs, while the focal deletions and complex virus SVs are prevalent in HBV-integrated LGMs. Furthermore, with the results yields from our method, we found the enhanced microhomology-mediated end joining (MMEJ) might lead to both HPV and HBV integrations, and conjectured that the HPV integrations might mainly occur during the DNA replication process. The conjugate graph algorithm code and LGM construction pipeline, available at https://github.com/deepomicslab/FuseSV.

Key pointsO_LIConjugate graph model resolves complex local genomic strcuture at oncovirus integration loci.
C_LIO_LILocal genome maps reveal five affection patterns of oncovirus integrations.
C_LIO_LIMicrohomology bases and small insertions are enriched at the junctions of structural variations and virus integrations.
C_LIO_LIHPV and HBV integrations may be induced by the enhanced microhomology-meditated mechanism.
C_LI


title: The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

abstract:
BackgroundAutism Spectrum Disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis resulting in changes in microbiota composition as well as fecal, serum and urine levels of microbial metabolites. Yet, a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice.

ResultsMice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol levels compared to mice transplanted with the microbiota of control mice and identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability and fecal p-Cresol levels when transplanted to p-Cresol-treated mice.

ConclusionsThe microbial metabolite p-Cresol induces ASD core behavioral symptoms in mice via a gut microbiota-dependent mechanism. Our study paves the way for therapeutic interventions targeting the microbiota to treat patients with ASD.


title: Senile plaques in Alzheimer's disease arise from Cathepsin D and Aβ-enriched proteinaceous mixtures out of hemolysis and vascular degeneration

abstract: The senile plaque is a prominent pathological hallmark of Alzheimers disease (AD), yet the mechanism governing senile plaque generation remains intensively debated. Many researchers believed that senile plaques are derived from neuronal cells; however, there is also strong evidence that senile plaques are linked to cerebral microhemorrhage. We analyzed major neural markers, blood vessel and blood markers on AD brain sections with immunohistochemistry, TUNEL assay, fluorescence imaging and histochemical staining. We found little co-expression between neural markers and plaque A{beta} while abundant co-expression between blood markers such as HBA, HbA1C or ApoE and plaque A{beta}. Senile plaques additionally colocalized with a characteristic blue autofluorescence, which also prominently existed in red blood cells. Moreover, platelets were found along blood vessel walls and in plaques, suggesting that platelets also contribute to senile plaque formation. Senile plaque formation was intrinsically linked to vascular degeneration as showed by ColIV, ACTA2 and LRP1 immunostaining. We found that A{beta} distributes unevenly among red cells or in the blood vessels, enriching in domains of red cell damage or vascular damage, and with the presence of luminal Cathepsin D expression. In addition, the senile plaques have a constitutive Cathepsin D expression overlapping with A{beta}, HBA and HbA1C, reiterating a senile plaque connection with hemolysis. With Rhodanine staining, we further proved that there is widespread hemolysis in AD brain tissues, which concurs with A{beta} aggregation, Cathepsin D and ApoE expression. Moreover, we provided the biochemical evidence that A{beta} directly interacts with hemoglobin (Hb) and form protease-sensitive complexes in an in vitro polymerization assay. In summary, our data suggested that senile plaques arise from Cathepsin D and A{beta}-enriched proteinaceous mixtures out of hemolysis and vascular degeneration. In addition, hemoglobin could be a primary physiological target of A{beta} in hemolysis and in senile plaques.


title: Quantitative Mapping of Human Hair Graying and Reversal in Relation to Life Stress

abstract: Hair graying is a universal hallmark of aging believed to be linked to psychological stress. Here we develop a novel approach to quantitatively profile natural graying events along individual human hair shafts, resulting in a quantifiable physical timescale of hair pigmentation patterns (HPPs). Using this approach, we quantify rare events of white/gray hairs that naturally regain pigmentation within days to weeks, thereby quantitatively defining the reversibility of graying in healthy, unmedicated individuals. Proteomic analysis shows that graying is marked by the upregulation of proteins related to energy metabolism, mitochondria, and antioxidant defenses. Combining hair pigmentation profiling and proteomics at the single hair level, we also report hair graying and its reversal occurring in parallel with behavioral and psychological stressors. A computational simulation suggests a threshold-based mechanism for the temporary reversibility of graying. Quantitatively mapping HPPs in humans provides an opportunity to longitudinally examine the influence of life exposures on biological aging.


title: Integrated information structure collapses with anesthetic loss of conscious arousal in Drosophila melanogaster

abstract:
The physical basis of consciousness remains one of the most elusive concepts in current science. One influential conjecture is that consciousness is to do with some form of causality, measurable through information. The integrated information theory of consciousness (IIT) proposes that conscious experience, filled with rich and specific content, corresponds directly to a hierarchically organised, irreducible pattern of causal interactions; i.e. an integrated informational structure among elements of a system. Here, we tested this conjecture in a simple biological system (fruit flies), estimating the information structure of the system during wakefulness and general anesthesia. Consistent with this conjecture, we found that integrated interactions among populations of neurons during wakefulness collapsed to isolated clusters of interactions during anesthesia. We used classification analysis to quantify the accuracy of discrimination between wakeful and anesthetised states, and found that informational structures inferred conscious states with greater accuracy than a scalar summary of the structure, a measure which is generally championed as the main measure of IIT. In stark contrast to a view which assumes feedforward architecture for insect brains, especially fly visual systems, we found rich information structures, which cannot arise from purely feedforward systems, occurred across the fly brain. Further, these information structures collapsed uniformly across the brain during anesthesia. Our results speak to the potential utility of the novel concept of an "informational structure" as a measure for level of consciousness, above and beyond simple scalar values.

Author summaryThe physical basis of consciousness remains elusive. Efforts to measure consciousness have generally been restricted to simple, scalar quantities which summarise the complexity of a system, inspired by integrated information theory, which links a multi-dimensional, informational structure to the contents of experience in a system. Due to the complexity of the definition of the structure, assessment of its utility as a measure of conscious arousal in a system has largely been ignored. In this manuscript we evaluate the utility of such an information structure in measuring the level of arousal in the fruit fly. Our results indicate that this structure can be more informative about the level of arousal in a system than even the single-value summary proposed by the theory itself. These results may push consciousness research towards the notion of multi-dimensional informational structures, instead of traditional scalar summaries.


title: Short- and long-read metagenomics of South African gut microbiomes reveal a transitional composition and novel taxa

abstract: Human gut microbiome research focuses on populations living in high-income countries or on the other end of the spectrum, namely non-urban agriculturalist and hunter-gatherer societies. The scarcity of research between these extremes limits our understanding of how the gut microbiota relates to health and disease in the majority of the worlds population. We present the first study evaluating gut microbiome composition in transitioning South African populations using short- and long-read sequencing. We analyzed stool samples from adult females (age 40 - 72) living in rural Bushbuckridge municipality (n=118) or urban Soweto (n=51) and find that these microbiomes are taxonomically intermediate between those of individuals living in high-income countries and traditional communities. We demonstrate that reference collections are incomplete for characterization of microbiomes of individuals living outside high-income countries, resulting in artificially low species-level beta diversity measurements. To improve reference databases, we generated complete genomes of undescribed taxa, including Treponema, Lentisphaerae, and Succinatimonas species. Our results suggest that the gut microbiome in South African populations do not exist along a simple "western-nonwestern" axis and that these populations contain microbial diversity that remains to be described.


title: Use and abuse of potential rates in soil microbiology

abstract: Potential rate assays are used in soil microbial ecology to determine the rates of a functional process in environmental samples under a defined set of conditions. While they can be used appropriately to provide mechanistic insights, potential rates are also often used to estimate the abundance of specific taxonomic groups and their in situ activity. These estimates incorrectly assume that all contributing organisms in a community are active at a maximum rate under one set of  optimal incubation conditions and that potential rates reflect activity in the soil. While investigators now recognise that populations within communities are physiologically diverse, they often ignore the consequent suboptimal activity, or even inactivity, of the majority of community members performing that function. In this short perspective article, we discuss when potential assays can be informative and highlight the underlying conceptual problems under circumstances where potential assays are misused, using potential nitrification rate (PNR) as an example. PNR was originally developed to estimate the size of active ammonia oxidising communities in environmental samples. It is routinely determined in short-term shaken slurry incubations by measuring assumed maximum rates of nitrate or nitrite production under optimal, non-substrate-limiting conditions. As with other functional processes, it is now recognised that a broad diversity of organisms contribute to aerobic ammonia oxidation in terrestrial and other habitats, and this diversity represents a substantial range of physiologies, including variation in substrate affinity, ammonia tolerance, cell specific activity and substrate preference. Despite this, PNR, and other potential rate assays, are often inappropriately used in an attempt to determine an ecologically relevant measurement of activity in soil. As with any potential assay, PNR has inherent biases towards particular functional groups and its use in investigating the ecology of ammonia oxidisers in natural systems should be carefully considered.

category: microbiology


title: Fungi are more dispersal-limited than bacteria among flowers

abstract: Variation in dispersal ability among taxa affects community assembly and biodiversity maintenance within metacommunities. Although fungi and bacteria frequently coexist, their relative dispersal abilities are poorly understood. Nectar-inhabiting microbial communities affect plant reproduction and pollinator behavior, and are excellent models for studying dispersal of bacteria and fungi in a metacommunity framework. Here, we assay dispersal ability of common nectar bacteria and fungi in an insect-based dispersal experiment. We then compare these results to the incidence and abundance of culturable flower-inhabiting bacteria and fungi within naturally occurring flowers across two coflowering communities in California across two flowering seasons. Our microbial dispersal experiment demonstrates that bacteria disperse among habitat patches more readily than fungi via thrips. Across all flowers, bacterial and fungal incidence and abundance were positively correlated but bacteria were much more widespread, suggesting shared dispersal routes or habitat requirements but differences in dispersal and colonization frequency. The finding that bacteria are more common among flowers sampled here, in part due to superior insect-mediated dispersal, may have broad relevance for microbial life-history, community assembly of microbes and plant-pollinator interactions.


title: Whole-Brain High-Resolution Metabolite Mapping with 3D Compressed-Sensing-SENSE-LowRank 1H FID-MRSI

abstract: There is a growing interest in the neuroscience community to map the distribution of brain metabolites in vivo. Magnetic resonance spectroscopic imaging (MRSI) is often limited by either a poor spatial resolution and/or a long acquisition time which severely limits its applications for clinical or research purposes. Building on a recently developed technique of acquisition-reconstruction for 2D MRSI, we combined fast Cartesian 1H-FID-MRSI acquisition sequence, compressed-sensing acceleration, and low-rank total-generalized-variation constrained reconstruction to produce 3D high-resolution whole-brain MRSI with a significant acquisition time reduction. We first evaluated the acceleration performance using retrospective undersampling of a fully-sampled dataset. Second, a 20 min accelerated MRSI acquisition was performed on the brain of three healthy volunteers resulting in metabolite maps with 5 mm isotropic resolution. The metabolite maps exhibited the detailed neurochemical composition of all brain regions and revealed parts of the underlying brain anatomy. The latter assessment used previous reported knowledge and a brain atlas-based analysis to show consistency of the concentration contrasts and ratio across all brain regions. These results acquired on a clinical 3 Tesla MRI successful combinae of the 3D 1H-FID-MRSI with a constrained reconstruction to produce detailed mapping of metabolite concentrations at high-resolution over the whole brain, with an acquisition time suitable for clinical or research settings.


title: Vimentin Intermediate Filaments Stabilize Dynamic Microtubules by Direct Interactions

abstract: The cytoskeleton determines cell mechanics and lies at the heart of important cellular functions. Growing evidence suggests that the manifold tasks of the cytoskeleton rely on the interactions between its filamentous components - actin filaments, intermediate filaments and microtubules. However, the nature of these interactions and their impact on cytoskeletal dynamics are largely unknown. Here, we show in a reconstituted in vitro system that vimentin intermediate filaments stabilize microtubules against depolymerization and support microtubule rescue. To understand these stabilizing effects, we directly measured the interaction forces between individual microtubules and vimentin filaments. Combined with numerical simulations, our observations provide detailed insight into the physical nature of the interactions and how they affect microtubule dynamics. Thus, we describe an additional, direct mechanism for cells to establish the fundamental cross-talk of cytoskeletal components alongside linker proteins. Moreover, we suggest a novel strategy to estimate the binding energy of tubulin dimers within the microtubule lattice.

category: biophysics


title: Evolutionary transition to XY sex chromosomes associated with Y-linked duplication of a male hormone gene in a terrestrial isopod

abstract: Sex chromosomes are highly variable in some taxonomic groups, but the evolutionary mechanisms underlying this diversity are not well understood. In terrestrial isopod crustaceans, evolutionary turnovers in sex chromosomes are frequent, possibly caused by Wolbachia, a vertically-transmitted endosymbiont causing male-to-female sex reversal. Here, we use surgical manipulations and genetic crosses, plus genome sequencing, to examine sex chromosomes in the terrestrial isopod Trachelipus rathkei. Although an earlier cytogenetics study suggested a ZZ/ZW sex chromosome system in this species, we surprisingly find multiple lines of evidence that in our study population, sex is determined by an XX/XY system. Consistent with a recent evolutionary origin for this XX/XY system, the putative male-specific region of the genome is small. The genome shows evidence of Y-linked duplications of the gene encoding the androgenic gland hormone, a major component of male sexual differentiation in isopods. Our analyses also uncover sequences horizontally acquired from past Wolbachia infections, consistent with the hypothesis that Wolbachia may have interfered with the evolution of sex determination in T. rathkei. Overall, these results provide evidence for the co-occurrence of multiple sex chromosome systems within T. rathkei, further highlighting the relevance of terrestrial isopods as models for the study of sex chromosome evolution.

category: evolutionary biology


title: Evolution of genes involved in the unusual genitals of the bear macaque, Macaca arctoides

abstract: Genital divergence is thought to contribute to reproductive barriers by establishing a "lock- and-key" mechanism for reproductive compatibility. One such example, Macaca arctoides, the bear macaque, has compensatory changes in both male and female genital morphology as compared to close relatives. Macaca arctoides also has a complex evolutionary history, having extensive introgression between the fascicularis and sinica macaque species groups. Here, phylogenetic relationships were analyzed via whole genome sequences from five species, including M. arctoides, and two species each from the putative parental species groups. This analysis revealed [~]3x more genomic regions supported placement in the sinica species group as compared to the fascicularis species group. Additionally, introgression analysis of the M. arctoides genome revealed it is a mosaic of recent polymorphisms shared with both species groups. To examine the evolution of their unique genital morphology further, the prevalence of candidate genes involved in genital morphology were compared against genome-wide outliers in various population genetic metrics, while accounting for background variation in recombination rate. This analysis identified 66 outlier genes, including several genes that influence baculum morphology in mice, which were of interest since the bear macaque has the longest primate baculum. The mean of several metrics was statistically different in the candidate genes as compared to the rest of the genome, suggesting that genes involved in genital morphology have increased divergence and decreased diversity beyond expectations. These results highlight how extensive introgression may have contributed to reproductive isolation and shaped the unique genital morphology in the bear macaque.


title: GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

abstract: To investigate mechanisms of hepatocellular damage, we performed genome-wide association studies (GWAS) on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities across 411,048 subjects from four ancestry groups in the UK Biobank, and found 100 loci associating with both enzymes. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with a larger elevation in ALT and AST than any other variant tested and this association also replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These associations suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.


title: Glyphosate Inhibits Melanization and Increases Susceptibility to Infection in Insects

abstract: Melanin, a black-brown pigment found throughout all kingdoms of life, has diverse biological functions including: UV protection, thermoregulation, oxidant scavenging, arthropod immunity, and microbial virulence. Given melanins broad roles in the biosphere, particularly in insect immune defenses, it is important to understand how exposure to ubiquitous environmental contaminants affects melanization. Glyphosate - the most widely used herbicide globally - inhibits melanin production, which could have wide-ranging implications in the health of many organisms, including insects. Here, we demonstrate that glyphosate has deleterious effects on insect health in two evolutionary distant species, Galleria mellonella (Lepidoptera: Pyralidae) and Anopheles gambiae (Diptera: Culicidae), suggesting a broad effect in insects. Glyphosate reduced survival of G. mellonella caterpillars following infection with the fungus Cryptococcus neoformans and decreased the size of melanized nodules formed in hemolymph, which normally help eliminate infection. Glyphosate also increased the burden of the malaria- causing parasite Plasmodium falciparum in A. gambiae mosquitoes, altered uninfected mosquito survival, and perturbed the microbial composition of adult mosquito midguts. Our results show that glyphosates mechanism of melanin inhibition involves antioxidant synergy and disruption of the reaction oxidation-reduction balance Overall, these findings suggest that glyphosates environmental accumulation could render insects more susceptible to microbial pathogens due to melanin inhibition, immune impairment, and perturbations in microbiota composition, potentially contributing to declines in insect populations.


title: Chemical probe-based Nanopore Sequencing to Selectively Assess the RNA modifications

abstract:
Current methods to identify RNA modifications with short-read sequencing are laborious and direct RNA sequencing gets proclaimed as the viable alternative. Herein, we harness the selective reactivity of the acrylonitrile towards the Inosine (I) and pseudouridine ({Psi}) modifications and developed a chemical probe-based direct RNA sequencing method. We first demonstrated that the chemical probe-induced differential signature profile using nanopore sequencing could facilitate the selective assessment of I and{Psi} in the in vitro synthesized RNA. Furthermore, we verified the I and{Psi} modification with single-nucleotide resolution using RNA derived from mouse brain without the need for a null dataset using knockouts. Our chemical probe-based nanopore sequencing strategy can be extended to profile multiple RNA modifications on a single RNA and may facilitate the diagnosis of disease-associated epitranscriptome markers by generating a comparative dataset in clinical scenarios.

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category: synthetic biology


title: The calcium binding protein S100β marks hedgehog-responsive resident vascular stem cells within vascular lesions

abstract: A hallmark of subclinical atherosclerosis is the accumulation of vascular smooth muscle cell (SMC)-like cells leading to intimal thickening. While medial SMCs contribute, the participation of hedgehog responsive resident vascular stem cells (vSCs) to lesion formation remains unclear. Using transgenic eGFP mice and genetic lineage tracing of S100{beta} vSCs in vivo, we identified S100{beta}/Sca1 cells derived from a S100{beta} non-SMC parent population within lesions that co-localise with smooth muscle -actin (SMA) cells following iatrogenic flow restriction, an effect attenuated following hedgehog inhibition with the smoothened inhibitor, cyclopamine. In vitro, S100{beta}/Sca1 cells isolated from atheroprone regions of the mouse aorta expressed hedgehog signalling components, acquired the di-methylation of histone 3 lysine 4 (H3K4me2) stable SMC epigenetic mark at the Myh11 locus and underwent myogenic differentiation in response to recombinant sonic hedgehog (SHh). Both S100{beta} and PTCH1 cells were present in human vessels while S100{beta} cells were enriched in arteriosclerotic lesions. Recombinant SHh promoted myogenic differentiation of human induced pluripotent stem cell-derived S100{beta} neuroectoderm progenitors In vitro. We conclude that hedgehog responsive S100{beta} vSCs contribute to lesion formation and support targeting hedgehog signalling to treat subclinical arteriosclerosis.


title: SPATIAL ORGANIZATION OF TRANSCRIBED EUKARYOTIC GENES

abstract: Despite the well-established role of nuclear organization in gene expression regulation, little is known about the reverse: how transcription shapes the spatial organization of the genome. Owing to small sizes of most previously studied genes and the limited resolution of microscopy, the structure and spatial arrangement of a single transcribed gene are still poorly understood. Here, we make use of several long highly expressed genes and demonstrate that they form transcription loops with polymerases moving along the loops and carrying nascent RNAs. Transcription loops can span across microns resembling lampbrush loops and polytene puffs. Extension and shape of transcription loops suggest their intrinsic stiffness, which we attribute to decoration with multiple voluminous nascent RNPs. Our data contradict the model of transcription factories and indicate that although microscopically resolvable transcription loops are specific for long highly expressed genes, the mechanisms underlying their formation can represent a general aspect of eukaryotic transcription.


title: Montane species track rising temperatures better in the tropics than in the temperate zone

abstract: Many species are responding to global warming by shifting their distributions upslope to higher elevations, but the observed rates of shifts vary considerably among studies. Here we test the hypothesis that this variation is in part explained by latitude, with tropical species being generally more responsive to warming temperatures than are temperate species. We find support for this hypothesis in each of two independent empirical datasets--shifts in species elevational ranges, and changes in composition of forest inventory tree plots. Tropical species are tracking rising temperatures 2.1-2.4 times (range shift dataset) and 10 times (tree plot dataset) better than their temperate counterparts. Models predict that for a 100 m upslope shift in temperature isotherm, species at the equator have shifted their elevational ranges 93-96 m upslope, while species at 45{degrees} latitude have shifted only 37-42 m upslope. For tree plots, models predict that a 1{degrees}C increase in temperature leads to an increase in community temperature index (CTI), a metric of the average temperature optima of tree species within a plot, of 0.56 {degrees}C at the equator but no change in CTI at 45{degrees} latitude (-0.033). This latitudinal gradient in temperature tracking suggests that tropical montane biotas may be on an "escalator to extinction" as global temperatures continue to rise.


title: No evidence for dominance-discovery tradeoffs in Pheidole (Hymenoptera: Formicidae) assemblages

abstract: Understanding the mechanisms that allow species coexistence across spatial scales is of great interest to ecologists. Many such proposed mechanisms involve tradeoffs between species in different life-history traits, with distinct tradeoffs being expected to be prevalent at varying temporal and spatial scales. The dominance-discovery tradeoff posits that species differ in their ability to find and use resources quickly, in contraposition to their ability to monopolize those resources, a mechanism analogous to the competition-colonization tradeoff. We investigated the occurrence of this structuring mechanism in Pheidole (Hymenoptera: Formicidae) assemblages in Atlantic Forest remnants. According to the dominance-discovery tradeoff, we should observe a consistent interspecific variation along the axis of discovery and dominance. We established 55 sampling units across two sites, with each unit consisting of a sardine bait monitored for three hours. There was no distinction among Pheidole species in their ability to find or dominate food sources, suggesting that the dominance-discovery tradeoff does not explain their coexistence. The low levels of aggression between Pheidole species could prevent the establishment of dominance hierarchies, whereas the species order of arrival at food sources could allow for resource partitioning through priority effects.


title: AHLF: ad hoc learning of peptide fragmentation from mass spectra enables an interpretable detection of phosphorylated and cross-linked peptides

abstract:
Mass spectrometry-based proteomics provides a holistic snapshot of the entire protein set of a living cell on a molecular level. Currently, only a few deep learning approaches that involve peptide fragmentation spectra, which represent partial sequence information of proteins, exist. Commonly, these approaches lack the ability to characterize less studied or even unknown patterns in spectra because of their use of explicit domain knowledge. To elevate unrestricted learning from spectra, we introduce AHLF, a deep learning model that is end-to-end trained on 19.2 million spectra from multiple phosphoproteomic data sets. AHLF is interpretable and we show that peak-level feature importances and pairwise interactions between peaks are in line with corresponding peptide fragments. We demonstrate our approach by detecting post-translational modifications, specifically protein phosphorylation based on only the fragmentation spectrum without a database search. AHLF increases the area under the receiver operating characteristic curve (AUC) by an average of 9.4% on recent phosphoproteomic data compared to the current-state-of-the-art on this task. To show the broad applicability of AHLF we use transfer learning to also detect cross-linked peptides, as used in protein structure analysis, with an AUC of up to 94%. We expect our approach to directly apply to cell signaling and structural biology which use phosphoproteomic and cross-linking data, but in principal any mass spectrometry based study can benefit from an interpretable, end-to-end trained model like AHLF.

Availabilityhttps://gitlab.com/dacs-hpi/ahlf

Contactbernhard.renard@hpi.de


title: The choices we make and the impacts they have: Machine learning and species delimitation in North American box turtles (Terrapene spp.)

abstract: Model-based approaches that attempt to delimit species are hampered by computational limitations as well as the unfortunate tendency by users to disregard algorithmic assumptions. Alternatives are clearly needed, and machine-learning (M-L) is attractive in this regard as it functions without the need to explicitly define a species concept. Unfortunately, its performance will vary according to which (of several) bioinformatic parameters are invoked. Herein, we gauge the effectiveness of M-L-based species-delimitation algorithms by parsing 64 variably-filtered versions of a ddRAD-derived SNP dataset collected from North American box turtles (Terrapene spp.). Our filtering strategies included: (A) minor allele frequencies (MAF) of 5%, 3%, 1%, and 0% (=none), and (B) maximum missing data per-individual/per-population at 25%, 50%, 75%, and 100% (=no filtering). We found that species-delimitation via unsupervised M-L impacted the signal-to-noise ratio in our data, as well as the discordance among resolved clades. The latter may also reflect biogeographic history, gene flow, incomplete lineage sorting, or combinations thereof (as corroborated from previously observed patterns of differential introgression). Our results substantiate M-L as a viable species-delimitation method, but also demonstrate how commonly observed patterns of phylogenetic discordance can seriously impact M-L-classification.


title: Corticothalamic feedback sculpts visual spatial integration in mouse thalamus

abstract: En route from retina to cortex, visual information passes through the dorsolateral geniculate nucleus of the thalamus (dLGN), where extensive corticothalamic (CT) feedback has been suggested to modulate spatial processing. How this modulation arises from direct excitatory and indirect inhibitory CT feedback pathways remains enigmatic. Here we show that in awake mice, retinotopically organized cortical feedback sharpens receptive fields (RFs) and increases surround suppression in the dLGN. Guided by a network model indicating that widespread inhibitory CT feedback is necessary to reproduce these effects, we targeted the visual sector of the thalamic reticular nucleus (visTRN) for recordings. We found that visTRN neurons have large receptive fields, show little surround suppression, and exhibit strong feedback-dependent responses to large stimuli. These features make them an ideal candidate for mediating feedback-enhanced surround suppression in the dLGN. We conclude that cortical feedback sculpts spatial integration in dLGN, likely via recruitment of neurons in visTRN.


title: Controlling for background genetic effects using polygenic scores improves the power of genome-wide association studies

abstract: Ongoing increases in the size of human genotype and phenotype collections offer the promise of improved understanding of the genetics of complex diseases. In addition to the biological insights that can be gained from the nature of the variants that contribute to the genetic component of complex trait variability, these data bring forward the prospect of predicting complex traits and the risk of complex genetic diseases from genotype data. Here we show that advances in phenotype prediction can be applied to improve the power of genome-wide association studies. We demonstrate a simple and efficient method to model genetic background effects using polygenic scores derived from SNPs that are not on the same chromosome as the target SNP. Using simulated and real data we found that this can result in a substantial increase in the number of variants passing genome-wide significance thresholds. This increase in power to detect trait-associated variants also translates into an increase in the accuracy with which the resulting polygenic score predicts the phenotype from genotype data. Our results suggest that advances in methods for phenotype prediction can be exploited to improve the control of background genetic effects, leading to more accurate GWAS results and further improvements in phenotype prediction.


title: From Hi-C Contact Map to Three-dimensional Organization of Interphase Human Chromosomes

abstract: The probability of two loci, separated by a certain genome length, being in contact can be inferred using the Chromosome Conformation Capture (3C) method and related Hi-C experiments. How to go from the contact map, a matrix listing the mean contact probabilities between a large number of pairs of loci, to an ensemble of three-dimensional structures is an open problem. A solution to this problem, without assuming an assumed energy function, would be the first step in understanding the way nature has solved the packaging of chromosomes in tight cellular spaces. We created a theory, based on polymer physics characteristics of chromosomes and the maximum entropy principles, referred to as HIPPS (Hi-C-Polymer-Physics-Structures) method, that allows us to calculate the 3D structures solely from Hi-C contact maps. The first step in the HIPPS method is to relate the mean contact probability [Formula] between loci i and j and the average spatial distance, [Formula]. This is a difficult problem to solve because the cell population is heterogeneous, which means that a given contact exists only in a small unknown fraction of cells. Despite the population heterogeneity, we first prove that there is a theoretical lower bound connecting [<]pij[>] and [Formula] via a power-law relation. We show, using simulations of a precisely solvable model, that the overall organization is accurately captured by constructing the distance map from the contact map even when if the cell population is highly heterogeneous, thus justifying the use of the lower bound. In the second step, the mean distance matrix, with elements [Formula], is used as a constraint in the maximum entropy principle to obtain the joint distribution of spatial positions of the loci. Using the two steps, we created an ensemble of 3D structures for the 23 chromosomes from lymphoblastoid cells using the measured contact maps as inputs. The HIPPS method shows that conformations of chromosomes are heterogeneous even in a single cell type. The differences in the conformational heterogeneity of the same chromosome in different cell types (normal as well as cancerous cells) can also be quantitatively discerned using our theory. We validate the method by showing that the calculated volumes of the 23 chromosomes from the predicted 3D structures are in good agreement with experimental estimates. Because the method is general, the 3D structures for any species may be calculated directly from the contact map without the need to assume a specific polymer model, as is customarily done.


title: Application of a novel haplotype-based scan for local adaptation to study high-altitude adaptation in rhesus macaques

abstract:
When natural populations split and migrate to different environments, they may experience different selection pressures that can lead to local adaptation. To capture the genomic patterns of a local selective sweep, we develop XP-nSL, a genomic scan for local adaptation that compares haplotype patterns between two populations. We show that XP-nSL has power to detect ongoing and recently completed hard and soft sweeps, and we then apply this statistic to search for evidence of adaptation to high altitude in rhesus macaques. We analyze the whole genomes of 23 wild rhesus macaques captured at high altitude (mean altitude > 4000m above sea level) to 22 wild rhesus macaques captured at low altitude (mean altitude < 500m above sea level) and find evidence of local adaptation in the high-altitude population at or near 303 known genes and several unannotated regions. We find the strongest signal for adaptation at EGLN1, a classic target for convergent evolution in several species living in low oxygen environments. Furthermore, many of the 303 genes are involved in processes related to hypoxia, regulation of ROS, DNA damage repair, synaptic signaling, and metabolism. These results suggest that, beyond adapting via a beneficial mutation in one single gene, adaptation to high altitude in rhesus macaques is polygenic and spread across numerous important biological systems.

Impact SummaryWhen positive selection is ongoing or a beneficial mutation has recently fixed in a population, genetic diversity is reduced in the vicinity of the adaptive allele, and we expect to observe long homozygous haplotypes at high frequency. Here we develop a statistic that summarizes these expected patterns and compares between two populations in order to search for evidence of adaptation that may have occurred in one but not the other. We implement this statistic in a popular and easy-to-use software package, and then apply it to study adaptation to high altitude in rhesus macaques.

Extreme environments pose a challenge to life on multiple fronts. Very high-altitude environments are one such example, with low atmospheric oxygen, increased ultraviolet light exposure, harsh temperatures, and reduced nutrition availability. In spite of these challenges, many plants and animals, including humans, have genetically adapted to cope with these hardships. Here we study two populations of rhesus macaques, one living at high altitude and one living close to sea level. We apply our novel statistic to compare their haplotype patterns between them to search for evidence of genetic changes that are indicative of adaptation to their environment.

We find evidence for adaptation at a critical gene that helps control physiological response to low-oxygen, one that has been the target of repeated convergent evolution across many species. We also find evidence for positive selection across a range of traits, including metabolic and neurological. This work helps to explain the evolutionary history of the rhesus macaque and furthers our understanding about the ways organisms genetically adapt to high-altitude environments.


title: Examining Blunted Initial Response to Reward and Recent Suicidal Ideation in Children and Adolescents Using Event-Related Potentials: Failure to Conceptually Replicate Across Two Independent Samples

abstract: A recent study by Tsypes and colleagues (2019) found that children with recent suicidal ideation had blunted neural reward processing, as measured by the reward positivity (RewP), compared to matched controls, and that this difference was driven by reduced neural responses to monetary loss, rather than by blunted neural response to monetary reward. Here, we aimed to conceptually replicate and extend these findings in two samples (n = 275, 27 with suicidal ideation; and n = 235, 48 with suicidal ideation at T1) of children and adolescents (11 to 15 years and 8 to 15 years, respectively). Results from both samples showed no evidence that children and adolescents with suicidal ideation have abnormal reward or loss processing, nor that reward processing predicts suicidal ideation two years later. The results highlight the need for greater statistical power, as well as continued research examining the neural underpinnings of suicidal thoughts and behaviors.


title: Time course of alterations in adult spinal motoneuron properties in the SOD1(G93A) mouse model of ALS

abstract:
Although ALS is an adult-onset neurodegenerative disease, motoneuron electrical properties are already altered during embryonic development. Motoneurons must therefore exhibit a remarkable capacity for homeostatic regulation to maintain a normal motor output for most of the life of the patient. In the present paper, we demonstrate how maintaining homeostasis could come at a very high cost. We studied the excitability of spinal motoneurons from young adult SOD1(G93A) mice to end-stage. Initially homeostasis is highly successful in maintaining their overall excitability. This initial success, however, is achieved by pushing some cells far above the normal range of passive and active conductances. As the disease progresses, both passive and active conductances shrink below normal values in the surviving cells. This shrinkage may thus promote survival, implying the previously large values contribute to degeneration. These results support the hypothesis that motoneuronal homeostasis may be "hyper-vigilant" in ALS and a source of accumulating stress.

Significance StatementDuring ALS, motoneurons exhibit a remarkable ability to maintain a normal motor output despite continuous alterations of their electrophysiological properties, up to the point when overt symptoms become apparent. We show that this homeostatic process can sometimes push motoneurons beyond the normal range, which may be causing long-lasting harm.


title: Hypothetical control of postural sway

abstract: Quiet standing exhibits strongly intermittent variability that has inspired at least two interpretations. First, variability can be intermittent through the alternating engagement and disengagement of complementary control processes at distinct scales. A second and perhaps deeper way to interpret this intermittency is through the possibility that postural control depends on cascade-like interactions across many timescales at once, suggesting specific non-Gaussian distributional properties at different timescales. Multiscale probability density function (PDF) analysis shows that quiet standing on a stable surface exhibits a crossover from low, increasing non-Gaussianity (consistent with exponential distributions) at shorter timescales, reflecting inertial control, towards higher non-Gaussianity. Feedback-based control at medium to longer timescales yields a linear decrease characteristic of cascade dynamics. Destabilizing quiet standing with unstable surface or closed eyes serves to attenuate inertial control and to elicit more of the feedback-based control over progressively shorter timescales. The result was to strengthen the appearance of the linear decay indicating cascade dynamics. Finally, both linear and nonlinear indices of postural sway also govern the relative strength of crossover or of linear decay, suggesting that tempering of non-Gaussianity across log-timescale is a function of both extrinsic constraints and endogenous postural control. These results provide new evidence that cascading interactions across longer-timescales supporting postural corrections can even recruit shorter-timescale processes with novel task constraints that can destabilize posture.


title: Development of thalamus mediates paternal age effect on offspring reading: A preliminary investigation

abstract:
The importance of (inherited) genetic impact in reading development is well-established. De novo mutation is another important contributor that is recently gathering interest as a major liability of neurodevelopmental disorders, but has been neglected in reading research to date. Paternal age at childbirth (PatAGE) is known as the most prominent risk factor for de novo mutation, which has been repeatedly shown by molecular genetic studies. As one of the first efforts, we performed a preliminary investigation of the relationship between PatAGE, offsprings reading, and brain structure in a longitudinal neuroimaging study following 51 children from kindergarten through third grade. The results showed that greater PatAGE was associated significantly with worse reading, explaining an additional 9.5% of the variations after controlling for a number of confounds--including familial factors and cognitive-linguistic reading precursors. Moreover, this effect was mediated by volumetric maturation of the left posterior thalamus from ages 5 to 8. Complementary analyses indicated the PatAGE-related thalamic region was most likely located in the pulvinar nuclei and related to the dorsal attention network by using brain atlases, public datasets, and offsprings diffusion imaging data. Altogether, these findings provide novel insights into neurocognitive mechanisms underlying the PatAGE effect on reading acquisition during its earliest phase and suggest promising areas of future research.

HighlightsO_LIPaternal age at childbirth (PatAGE) is negatively correlated with offsprings reading abilities.
C_LIO_LIPatAGE is related to volumetric maturation of the left posterior thalamus.
C_LIO_LIThalamic development mediates the PatAGE effect on reading.
C_LIO_LIThe PatAGE-related thalamic area is more likely to connect with the dorsal attention network.
C_LI


title: Transcriptional Profiling Reveals the Transcription Factor Networks Regulating the Survival of Striatal Neurons

abstract: The striatum is structurally highly diverse, and its organ functionality critically depends on normal embryonic development. Although several studies have been conducted on the gene functional changes that occur during striatal development, a system-wide analysis of the underlying molecular changes is lacking. Here, we present a comprehensive transcriptome profile that allowed us to explore the trajectory of striatal development and identify the correlation between the striatal development and Huntingtons disease (HD). Furthermore, we applied an integrative transcriptomic profiling approach based on machine learning to systematically map a global landscape of 277 transcription factor (TF) networks. Most of these TF networks are linked to biological processes, and some unannotated genes provide information about the corresponding mechanisms. For example, we found that the Meis2 and Six3 were crucial for the survival of striatal neurons, which was verified using conditional knockout (CKO) mice. Finally, we used RNA-Seq to speculate their downstream targets.


title: Derivation of ringed seal (Phoca hispida) induced multipotent stem cells

abstract: Induced pluripotent stem (iPS) cells have been produced just for a few species among order Carnivora: snow leopard, Bengal tiger, serval, jaguar, cat, dog, ferret, and American mink. We applied the iPS cell derivation protocol to the ringed seal (Phoca hispida) fibroblasts. The resulting cell line had the expression of pluripotency marker gene Rex1. Differentiation in embryoid body-like structures allowed us to register expression of AFP, endoderm marker, and Cdx2, trophectoderm marker, but not neuronal (ectoderm) markers. The cells readily differentiated into adipocytes and osteocytes, mesoderm cell types of origin. Transcriptome analysis allowed us to conclude that the cell line does not resemble human pluripotent cells, and, therefore, most probably are not pluripotent. Thus, we produced ringed seal multipotent stem cell line capable of differentiation into adipo- and osteocytes.

category: developmental biology


title: FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma

abstract:
Background and aimsAbout 15% of intrahepatic cholangiocarcinoma (iCCA) express fibroblast growth factor receptor 2 (FGFR2) fusion proteins (FFs), most often in concert with mutationally inactivated TP53, CDKN2A or BAP1. FFs span residues 1-768 of FGFR2 fused to sequences encoded by any of a long list (>60) of partner genes, a configuration sufficient to ignite oncogenic FF activation. In line, FGFR-specific tyrosine kinase inhibitors (F-TKI) were shown to provide clinical benefit in FF+ iCCA, although responses were partial and/or limited by resistance mechanisms, including the FF V565F gatekeeper mutation. Herein we present an FF-driven murine iCCA model and exploit its potential for pre-clinical studies on FF therapeutic targeting.

MethodsFour iCCA FFs carrying different fusion sequences were expressed in Tp53-/- mouse liver organoids. Tumorigenic properties of genetically modified liver organoids were assessed by intrahepatic/subcutaneous transplantation in immuno-deficient mice. Cellular models derived from neoplastic lesions were exploited for pre-clinical studies.

ResultsTumors diagnosed as CCA were obtained upon transplantation of FF-expressing liver organoids. The penetrance of this tumorigenic phenotype was influenced by FF identity. Tumor organoids and 2D cell lines derived from CCA lesions were addicted to FF signaling via Ras-Erk, regardless of FF identity or presence of V565F mutation. Double blockade of FF-Ras-Erk pathway by concomitant pharmacological inhibition of FFs and Mek1/2 provided greater therapeutic efficacy than single agent F-TKI in vitro and in vivo.

ConclusionsFF-driven iCCA pathogenesis was successfully modelled in murine Tp53-/- background. This model revealed biological heterogeneity among structurally different FFs. Double blockade of FF-Erk signaling deserves consideration for improving precision-based approaches against human FF+ iCCA.

Abbreviations used in this paper: ANOVA, analysis of variance; Bap1, BRCA1-Associated-Protein 1; Cdkn2a, cyclin-dependent kinase inhibitor 2A; Cftr, cystic fibrosis transmembrane conductance regulator; Ck19, cytokeratin 19; Cyp3A, cytochrome P450, family 3, subfamily A; EGF, Epidermal growth factor; EGFR, Epidermal growth factor receptor; EpCAM, epithelial cell adhesion molecule; Erk, extracellular signal-regulated kinase; FGFR2, fibroblast growth factor receptor 2; FRS2, fibroblast growth factor receptor substrate 2; GRB2, growth factor receptor-bound 2; GSEA, gene set enrichment analysis; GSVA, gene set variation analysis; H&E, hematoxylin and eosin; HepPar1, hepatocyte Paraffin 1; Hnf4-7, hepatocyte nuclear factor 4 alpha; Hprt, hypoxanthine-guanine phosphoribosyl transferase; LGR5, leucine-rich repeat-containing G-protein coupled receptor 5; NTRK, neurotrophic Tyrosine Kinase; Parp, Poly (ADP-ribose) polymerase; RECIST, response evaluation criteria in solid tumors; SHP2, Src homology phosphatase 2; Ttr, transthyretin.

category: cancer biology


title: FGFR2 fusion protein-driven mouse models of intrahepatic cholangiocarcinoma unveil a necessary role for Erk signaling


title: Body size and tree species composition determine variation in prey consumption in a forest-inhabiting generalist predator

abstract:
Trophic interactions may strongly depend on body size and environmental variation, but this prediction has been seldom tested in nature. Many spiders are generalist predators that use webs to intercept flying prey. The size and mesh of orb webs increases with spider size, allowing a more efficient predation on larger prey. We studied to this extent the orb-weaving spider Araneus diadematus inhabiting forest fragments differing in edge distance, tree diversity and tree species. These environmental variables are known to correlate to insect composition, richness and abundance. We anticipated these forest characteristics to be a principle driver of prey consumption. We additionally hypothesised them to impact spider size at maturity and expect shifts towards larger prey-size distributions in larger individuals independently from the environmental context.

We quantified spider diet by means of metabarcoding of nearly 1000 A. diadematus from a total of 53 forest plots. This approach allowed a massive screening of consumption dynamics in nature, though at the cost of identifying the exact prey identity, as well as their abundance and putative intraspecific variation. Our study confirmed A. diadematus as a generalist predator, with more than 300 prey ZOTUs detected in total. At the individual level, we found large spiders to consume fewer different species, but adding larger species to their diet. Tree species composition affected both prey species richness and size in the spiders diet, although tree diversity per se had no influence on the consumed prey. Edges had an indirect effect on the spider diet as spiders closer to the forest edge were larger and therefore consumed larger prey. We conclude that both intraspecific size variation and tree species composition shape the consumed prey of this generalist predator.


title: The human SKI complex prevents DNA-RNA hybrid-associated telomere instability

abstract: Super killer (SKI) complex is a well-known cytoplasmic 3' to 5' mRNA decay complex that functions with the exosome to degrade excessive and aberrant mRNAs. Recently, SKIV2L, the 3' to 5' RNA helicase of the human SKI (hSKI) complex has been implicated in the degradation of nuclear non-coding RNAs escaping to the cytoplasm. Here, we show that hSKI is present in the nucleus, on chromatin and in particular at telomeres during the G2 cell cycle phase. In cells, SKIV2L prevents telomeric loss, and DNA damage response activation, and its absence leads to DNA-RNA hybrid-mediated telomere fragility. Moreover, we demonstrate that purified hSKI complex preferentially unwinds telomeric DNA-RNA hybrids in vitro. Taken together, our results provide a nuclear function of the hSKI complex in overcoming replication stress caused by aberrant processing of telomeric DNA-RNA hybrids and thus maintaining telomere stability.

category: molecular biology


title: TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation

abstract: Existing knowledge of the role of epigenetic modifiers in pancreas development has exponentially increased. However, the function of TET dioxygenases in pancreatic endocrine specification remains obscure. We set out to tackle this issue using a human embryonic stem cell (hESC) differentiation system, in which TET1/TET2/TET3 triple knock-out cells display severe defects in pancreatic {beta}-cell specification. Integrative whole-genome analysis identifies unique cell-type-specific hypermethylated regions (hyper-DMRs) displaying reduced chromatin activity and remarkable enrichment of FOXA2, a pioneer transcription factor essential for pancreatic endoderm specification. Intriguingly, TET depletion leads to significant changes in FOXA2 binding at pancreatic progenitor stage, in which gene loci with decreased FOXA2 binding features low levels of active chromatin modifications and enriches for bHLH motifs. Transduction of full-length TET1 but not the TET1-catalytic-domain in TET-deficient cells effectively rescues {beta}-cell differentiation accompanied by restoring PAX4 hypomethylation. Taking these findings together with the defective generation of functional {beta}-cells upon TET1-inactivation, our study unveils an essential role of TET1-dependent demethylation in establishing {beta}-cell identity. Moreover, we discover a physical interaction between TET1 and FOXA2 in endodermal lineage intermediates, which provides a new mechanistic clue regarding the complex crosstalk between TET dioxygenases and pioneer transcription factors in epigenetic regulation during pancreas specification.


title: The impact of neural attentional filters on listening behaviour in a large cohort of ageing individuals

abstract: Successful listening crucially depends on intact attentional filters that separate relevant from irrelevant information. Research into their neurobiological implementation has focused on two potential auditory filter strategies: the lateralization of alpha power and selective neural speech tracking. However, the functional interplay of the two neural filter strategies and their potency to index listening success in an ageing population remains unclear. Using electroencephalography and a dual-talker task in a representative sample of listeners (N=155; age=39-80 years), we here demonstrate an often-missed link from single-trial behavioural outcomes back to trial-by-trial changes in neural attentional filtering. First, we observe preserved attentional-cue-driven modulation of both neural filters across chronological age and hearing levels. Second, neural filter states vary independently of one another, demonstrating complementary neurobiological solutions of spatial selective attention. Stronger neural speech tracking but not alpha lateralization boosts trial-to-trial behavioural performance. Our results highlight the translational potential of neural speech tracking as an individualized neural marker of adaptive listening behaviour.


title: Neural attentional-filter mechanisms of listening success in a representative sample of ageing individuals


title: Neural attentional-filter mechanisms of listening success in middle-aged and older individuals


title: Convolutional Neural Networks for Classifying Melanoma Images

abstract: In this work, we address the problem of skin cancer classification using convolutional neural networks. A lot of cancer cases early on are misdiagnosed leading to severe consequences including the death of patient. Also there are cases in which patients have other problems and doctors interpret it as skin cancer. This leads to unnecessary time and money spent for further diagnosis. In this work, we address both of the above problems using deep neural networks and transfer learning architecture. We have used publicly available ISIC databases for both training and testing our network. Our model achieves an accuracy of 0.935, precision 0.94, recall 0.77, F1 score 0.85 and ROC-AUC 0.861 which is better than the previous state of the art approaches.


title: Integrated cross-study datasets of genetic dependencies in cancer

abstract: CRISPR-Cas9 viability screens are increasingly performed at a genome-wide scale across large panels of cell lines to identify new therapeutic targets for precision cancer therapy. Integrating the datasets resulting from these studies is necessary to adequately represent the heterogeneity of human cancers and to assemble a comprehensive map of cancer genetic vulnerabilities. Here, we integrated the two largest public independent CRISPR-Cas9 screens performed to date (at the Broad and Sanger institutes) by assessing, comparing, and selecting methods for correcting biases due to heterogeneous single guide RNA efficiency, gene-independent responses to CRISPR-Cas9 targeting originated from copy number alterations, and experimental batch effects. Our integrated datasets recapitulate findings from the individual datasets, provide greater statistical power to cancer- and subtype-specific analyses, unveil additional biomarkers of gene dependency, and improve the detection of common essential genes. We provide the largest integrated resources of CRISPR-Cas9 screens to date and the basis for harmonizing existing and future functional genetics datasets.


title: The hippocampus as the switchboard between perception and memory

abstract:
Adaptive memory recall requires a rapid and flexible switch from external perceptual reminders to internal mnemonic representations. However, owing to the limited temporal or spatial resolution of brain imaging modalities used in isolation, the hippocampal-cortical dynamics supporting this process remain unknown. We thus employed an object-scene cued recall paradigm across two studies, including intracranial Electroencephalography (iEEG) and high-density scalp EEG. First, a sustained increase in hippocampal high gamma power (60-110 Hz) emerged 500 ms after cue onset and distinguished successful vs. unsuccessful recall. This increase in gamma power for successful recall was followed by a decrease in hippocampal alpha power (8-12 Hz). Intriguingly, the hippocampal gamma power increase marked the moment at which extrahippocampal activation patterns shifted from perceptual cue towards mnemonic target representations. In parallel, source-localised EEG alpha power revealed that the recall signal progresses from hippocampus to posterior parietal cortex and then to medial prefrontal cortex. Together, these results identify the hippocampus as the switchboard between perception and memory and elucidate the ensuing hippocampal-cortical dynamics supporting the recall process.

SignificanceHow do we adaptively switch from perceiving the external world to retrieving goal-relevant internal memories? To tackle this question, we used - in a cued-recall paradigm - direct intracranial recordings from the human hippocampus complemented by high-density scalp Electroencephalography (EEG). We found that a hippocampal signal ~500 ms after a perceptual cue marks the conversion from external (perceptual) to internal (mnemonic) representations. This sets in motion a recall cascade involving posterior parietal and medial prefrontal cortex, revealed via source-localised and time-resolved EEG alpha power. Together, these results unveil the hippocampal-cortical dynamics supporting rapid and flexible memory recall.


title: Allelic expression analysis of Imprinted and X-linked genes from bulk and single-cell transcriptomes

abstract: Genomic imprinting and X chromosome inactivation (XCI) are two prototypical epigenetic mechanisms whereby a set of genes is expressed mono-allelically in order to fine-tune their expression levels. Defects in genomic imprinting have been observed in several neurodevelopmental disorders, in a wide range of tumours and in induced pluripotent stem cells (iPSCs). Single Nucleotide Variants (SNVs) are readily detectable by RNA-sequencing allowing determination of whether imprinted or X-linked genes are aberrantly expressed from both alleles, although standardised analysis methods are still missing. We have developed a tool, named BrewerIX, that provides comprehensive information about the allelic expression of a large, manually-curated set of imprinted and X-linked genes. BrewerIX does not require programming skills, runs on a standard personal computer, and can analyze both bulk and single-cell transcriptomes of human and mouse cells directly from raw sequencing data. BrewerIX confirmed previous observations regarding the bi-allelic expression of some imprinted genes in naive pluripotent cells and extended them to preimplantation embryos. BrewerIX identified also misregulated imprinted genes in breast cancer cells and in human organoids and identified new genes escaping XCI in human somatic cells. We believe BrewerIX will be useful for the study of genomic imprinting and XCI during development and reprogramming, and for detecting aberrations in cancer, iPSCs and organoids. Due to its ease of use to non-computational biologists, its implementation could become standard practice during sample assessment, thus raising robustness and reproducibility of future studies.


title: On Using Transfer Learning For Plant Disease Detection

abstract: Deep neural networks has been highly successful in image classification problems. In this paper, we show how neural networks can be used for plant disease recognition in the context of image classification. We have used publicly available Plant Village dataset which has 38 classes of diseases. Hence, the problem that we have addressed is a multi class classification problem. We compared five different architectures including VGG16, ResNet50, InceptionV3, InceptionResNet and DenseNet169 as the backbones for our work. We found that ResNet50 achieves the best result on the test set. For evaluation, we used metrics: accuracy, precision, recall, F1 score and class wise confusion metric. Our model achieves the best of results using ResNet50 with accuracy of 0.982, precision of 0.94, recall of 0.94 and F1 score of 0.94.

category: plant biology


title: Mathematical framework for place coding in the auditory system

abstract:
In the auditory system, tonotopy is postulated to be the substrate for a place code, where sound frequency is encoded by the location of the neurons that fire during the stimulus. Though conceptually simple, the computations that allow for the representation of intensity and complex sounds are poorly understood. Here, a mathematical framework is developed in order to define clearly the conditions that support a place code. To accommodate both frequency and intensity information, the neural network is described as a topological space with elements that represent individual neurons and clusters of neurons. A bijective mapping is then constructed from acoustic space to neural space so that frequency and intensity are encoded, respectively, by the location and size of the clusters. Algebraic operations -addition and multiplication- are derived to elucidate the rules for representing, assembling, and modulating multi-frequency sound in networks. The predicted outcomes of these operations are consistent with network simulations as well as with electrophysiological and psychophysical data. The analyses show how both frequency and intensity can be encoded with a purely place code, without the need for rate or temporal coding schemes. The algebraic operations are used to describe loudness summation and suggest a mechanism for the critical band. The mathematical approach complements experimental and computational approaches and provides a foundation for interpreting data and constructing models.

Author SummaryOne way of encoding sensory information in the brain is with a so-called place code. In the auditory system, tones of increasing frequencies activate sets of neurons at progressively different locations along an axis. The goal of this study is to elucidate the mathematical principles for representing tone frequency and intensity in neural networks. The rigorous, formal process ensures that the conditions for a place code and the associated computations are defined precisely. This mathematical approach offers new insights into experimental data and a framework for constructing network models.


title: Optimizing predictive models to prioritize viral discovery in zoonotic reservoirs

abstract: Despite global investment in One Health disease surveillance, it remains difficult--and often very costly--to identify and monitor the wildlife reservoirs of novel zoonotic viruses. Statistical models can be used to guide sampling prioritization, but predictions from any given model may be highly uncertain; moreover, systematic model validation is rare, and the drivers of model performance are consequently under-documented. Here, we use bat hosts of betacoronaviruses as a case study for the data-driven process of comparing and validating predictive models of likely reservoir hosts. In the first quarter of 2020, we generated an ensemble of eight statistical models that predict host-virus associations and developed priority sampling recommendations for potential bat reservoirs and potential bridge hosts for SARS-CoV-2. Over more than a year, we tracked the discovery of 40 new bat hosts of betacoronaviruses, validated initial predictions, and dynamically updated our analytic pipeline. We find that ecological trait-based models perform extremely well at predicting these novel hosts, whereas network methods consistently perform roughly as well or worse than expected at random. These findings illustrate the importance of ensembling as a buffer against variation in model quality and highlight the value of including host ecology in predictive models. Our revised models show improved performance and predict over 400 bat species globally that could be undetected hosts of betacoronaviruses. Although 20 species of horseshoe bats (Rhinolophus spp.) are known to be the primary reservoir of SARS-like viruses, we find at least three-fourths of plausible betacoronavirus reservoirs in this bat genus might still be undetected. Our study is the first to demonstrate through systematic validation that machine learning models can help optimize wildlife sampling for undiscovered viruses and illustrates how such approaches are best implemented through a dynamic process of prediction, data collection, validation, and updating.


title: Preprinting the COVID-19 pandemic

abstract: The world continues to face a life-threatening viral pandemic. The virus underlying the COVID-19 disease, SARS-CoV-2, has caused over 98 million confirmed cases and 2.2 million deaths since January 2020. Although the most recent respiratory viral pandemic swept the globe only a decade ago, the way science operates and responds to current events has experienced a paradigm shift in the interim. The scientific community has responded rapidly to the COVID-19 pandemic, releasing over 125,000 COVID-19 related scientific articles within 10 months of the first confirmed case, of which more than 30,000 were hosted by preprint servers. We focused our analysis on bioRxiv and medRxiv, two growing preprint servers for biomedical research, investigating the attributes of COVID-19 preprints, their access and usage rates, as well as characteristics of their propagation on online platforms. Our data provides evidence for increased scientific and public engagement with preprints related to COVID-19 (COVID-19 preprints are accessed more, cited more, and shared more on various online platforms than non-COVID-19 preprints), as well as changes in the use of preprints by journalists and policymakers. We also find evidence for changes in preprinting and publishing behaviour: COVID-19 preprints are shorter and reviewed faster. Our results highlight the unprecedented role of preprints and preprint servers in the dissemination of COVID-19 science, and the impact of the pandemic on the scientific communication landscape.

category: scientific communication and education


title: Cell-state transitions and collective cell movement generate an endoderm-like region in gastruloids

abstract: Shaping the animal body plan is a complex process that involves the spatial organization and patterning of the different germ layers. Recent advances in live imaging have started to unravel the cellular choreography underlying this process in mammals, however, the sequence of events transforming an unpatterned cell ensemble into structured territories is largely unknown. Here, using gastruloids -3D aggregates of mouse embryonic stem cells-we study the formation of one of the three germ layers, the endoderm. We show that the endoderm is generated from an epiblast-like homogeneous state by a three-step mechanism: (i) a loss of E-cadherin mediated contacts in parts of the aggregate leading to the appearance of islands of E-cadherin expressing cells surrounded by cells devoid of E-cadherin, (ii) a separation of these two populations with islands of E-cadherin expressing cells flowing toward the aggregate tip, and (iii) their differentiation into an endoderm population. During the flow, the islands of E-cadherin expressing cells are surrounded by cells expressing T-Brachyury, reminiscent of the process occurring at the primitive streak. Consistent with recent in vivo observations, the endoderm formation in the gastruloids does not require an epithelial-to-mesenchymal transition, but rather a maintenance of an epithelial state for a subset of cells coupled with fragmentation of E-cadherin contacts in the vicinity, and a sorting process. Our data emphasize the role of signaling and tissue flows in the establishment of the body plan.


title: ZDHHC5 directs Protocadherin 7 to the mitotic cell surface and cleavage furrow by a palmitoylation-dependent mechanism for a successful cell division

abstract: Cell division requires dramatic reorganization of the cell cortex that is primarily driven by the actomyosin network. We previously reported that Protocadherin 7 (PCDH7) enriches at the cell surface during mitosis which is required for building up the full mitotic rounding pressure. Here we showed that PCDH7 gets palmitoylated and interacts with the palmitoyltransferase, ZDHHC5. Both PCDH7 and ZDHHC5 co-localize at the mitotic cell surface and get enriched at the cleavage furrow during cytokinesis. PCDH7s localization is ZDHHC5 dependent. Loss of expression of ZDHHC5 or PCDH7 leads to defects in cleavage furrow ingression and cytokinesis. At the mitotic cell surface and cleavage furrow, PCDH7 interacts with Myosin Phosphatase Target Subunit1 (MYPT1). We propose that this interaction tunes phospho-myosin levels at the cleavage furrow for regulating the myosin activity during cytokinesis. This work uncovers a palmitoylation-dependent translocation for PCDH7 which regulates myosin activity at the cortex and cleavage furrow for a successful division in human cells.


title: BRAFV600E induces reversible mitotic arrest in human melanocytes via microRNA-mediated suppression of AURKB.

abstract: Benign melanocytic nevi frequently emerge when an acquired BRAFV600E mutation triggers unchecked proliferation and subsequent arrest in melanocytes. Recent observations have challenged the role of oncogene-induced senescence in melanocytic nevus formation, necessitating investigations into alternative mechanisms for the establishment and maintenance of proliferation arrest in nevi. We compared the transcriptomes of melanocytes from healthy human skin, nevi, and melanomas arisen from nevi and identified a set of microRNAs as highly expressed nevus-enriched transcripts. Two of these microRNAs - MIR211-5p and MIR328-3p - induced mitotic failure, genome duplication and proliferation arrest in human melanocytes through convergent targeting of AURKB. We demonstrate that BRAFV600E induces a similar proliferation arrest in primary human melanocytes that is both reversible and conditional. Specifically, BRAFV600E expression stimulates either arrest or proliferation depending on the differentiation state of the melanocyte. We report genome duplication in human melanocytic nevi, reciprocal expression of AURKB and microRNAs in nevi and melanomas, and rescue of arrested human nevus cells with AURKB expression. Together, our data describe an alternative molecular mechanism for melanocytic nevus formation that is congruent with both experimental and clinical observations.