title: High confidence identification of intra-host single nucleotide variants for person-to-person influenza transmission tracking in congregate settings

abstract: Influenza within-host viral populations are the source of all global influenza diversity and play an important role in driving the evolution and escape of the influenza virus from human immune responses, antiviral treatment, and vaccines, and have been used in precision tracking of influenza transmission chains. Next Generation Sequencing (NGS) has greatly improved our ability to study these populations, however, major challenges remain, such as accurate identification of intra-host single nucleotide variants (iSNVs) that represent within-host viral diversity of influenza virus. In order to investigate the sources and the frequency of called iSNVs in influenza samples, we used a set of longitudinal influenza patient samples collected within a University of Maryland (UMD) cohort of college students in a living learning community. Our results indicate that technical replicates aid in removal of random RT-PCR, PCR, and platform sequencing errors, while the use of clonal plasmids for removal of systematic errors is more important in samples of low RNA abundance. We show that the choice of reference for read mapping affects the frequency of called iSNVs, with the sample self-reference resulting in the lowest amount of iSNV noise. The importance of variant caller choice is also highlighted in our study, as we observe differential sensitivity of variant callers to the mapping reference choice, as well as the poor overlap of their called iSNVs. Based on this, we develop an approach for identification of highly probable iSNVs by removal of sequencing and bioinformatics algorithm-associated errors, which we implement in phylogenetic analyses of the UMD samples for a greater resolution of transmission links. In addition to identifying closely related transmission connections supported by the presence of highly confident shared iSNVs between patients, our results also indicate that the rate of minor variant turnover within a host may be a limiting factor for utilization of iSNVs to determine patient epidemiological links.


title: Large-scale topological disruption of chromosome territories 9 and 22 is associated with nonresponse to treatment in CML

abstract: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm defined by the presence of t(9;22) translocation whose origin has been associated with the tridimensional genome organization. This rearrangement leads to the fusion of BCR and ABL1 genes giving rise to a chimeric protein with constitutive kinase activity. Imatinib, a tyrosine kinase inhibitor (TKI), is used as a first-line treatment for CML, though approximately 40% of CML patients do not respond. Here, using structured illumination microscopy (SIM) and 3D reconstruction, we studied the 3D organization patterns of the ABL1 and BCR genes, and their chromosome territories (CTs) CT9 and CT22, in CD34+ cells from CML patients that responded or not to Imatinib. We found that TKI resistance in CML is associated with high levels of structural disruption of CT9 and CT22 in CD34+ cells, increased CT volumes (especially for CT22), intermingling between CT9 and CT22, and open-chromatin epigenetic mark, in CT22. Altogether our results suggest that large-scale disruption of CT9 and CT22 correlates with the clinical response of CML patients, which could be translated in a potential prognostic marker of response to treatment in this disease and provide novel insights into the mechanisms underlying resistance to TKI in CML.

category: cancer biology


title: Living with high potassium: an asset or a hindrance

abstract:
O_LIHigh potassium (K) in the growth medium is more toxic to plants than Na at similar concentrations. However, the molecular mechanisms underlying plant responses to K-induced salt stress are virtually unknown.
C_LIO_LIWe examined Arabidopsis thaliana and its extremophyte relative Schrenkiella parvula, using a comparative multi-omics approach to identify cellular processes affected by excess K and understand which deterministic regulatory pathways are active to avoid tissue damage while sustaining growth.
C_LIO_LIA. thaliana showed limited capacity to curb excess K accumulation and prevent nutrient depletion contrasting to S. parvula which could limit excess K accumulation without restricting nutrient uptake. Facilitated by a targeted transcriptomic response, promoting nitrogen uptake along with other key nutrients and uninterrupted N assimilation into primary metabolites during excess K-stress allowed S. parvula to boost its antioxidant and osmolyte pools concurrently leading to sustained growth. Antithetically, A. thaliana showed transcriptional responses indicative of a poor balance between stress signaling, increased ROS levels, and reduced photosynthesis, subsequently leading to inhibited growth.
C_LIO_LIThe ability to regulate independent nutrient uptake and a coordinated transcriptomic response to avoid non-specific stress signaling are two main deterministic steps towards building stress resilience to excess K+-induced salt stress.
C_LI

category: plant biology


title: Living with high potassium: how plants balance nutrient acquisition during K-induced salt stress


title: Living with high potassium: a balance between nutrient acquisition and stress signaling during K-induced salt stress


title: Atypical gaze patterns in autism are heterogeneous across subjects but reliable within individuals

abstract: People with autism spectrum disorder (ASD) have atypical gaze onto both static visual images 1,2 and dynamic videos 3,4 that could be leveraged for diagnostic purposes 5,6. Eye tracking is important for characterizing ASD across the lifespan 7 and nowadays feasible at home (e.g., from smartphones 8). Yet gaze-based classification has been difficult to achieve, due to sources of variance both across and within subjects. Here we test three competing hypotheses: (a) that ASD could be successfully classified from the fact that gaze patterns are less reliable or noisier than in controls, (b) that gaze patterns are atypical and heterogeneous across ASD subjects but reliable over time within a subject, or (c) that gaze patterns are individually reliable and also homogenous among individuals with ASD. Leveraging dense eye tracking data from two different full-length television sitcom episodes in a total of over 150 subjects (N = 53 ASD, 107 controls) collected at two different sites, we demonstrate support for the second of these hypotheses. The findings pave the way for the investigation of autism subtypes, and for elucidating the specific visual features that best discriminate gaze patterns -- directions that will also inform neuroimaging and genetic studies of this complex disorder.

category: neuroscience


title: Maturation of distinct neural components of the cognitive control network support early development of inhibitory control

abstract: Crucial for goal-directed behavior is the capacity to suppress impulses and predominant behavioral responses, called inhibitory control (IC). This ability emerges in early childhood, and a distinction according to neutral ( cold) and emotional ( hot) contexts has been suggested. Here, we ask which maturational changes in the childs brain underlie the emergence of this critical ability. We relate behavioral changes in 3-and 4-year-olds  hot and  cold IC to brain maturation, using a multimodal approach that combines cortical and subcortical grey matter structure with white matter connectivity. Our results show that the maturation of distinct parts of the cognitive control brain network support early development of the different IC domains: Whereas  cold IC is related to frontoparietal regions and the left thalamus,  hot IC is associated with the left supramarginal gyrus and right thalamus. This dissociation of brain networks involved in  cold and  hot IC is confirmed by independent patterns of thalamocortical connectivity, supporting that IC in neutral and emotional settings relies on independent processes.


title: Behavioral origin of sound-evoked activity in visual cortex

abstract: Sensory cortices are increasingly thought to encode multisensory information. For instance, primary visual cortex (V1) appears to be influenced by sounds. Here we show that sound-evoked responses in mouse V1 are low-dimensional, similar across neurons and across brains, and can be explained by highly stereotyped uninstructed movements of eyes and body. Thus, neural activity previously interpreted as being sensory or multisensory may have a behavioral origin.


title: Knockout of Anopheles stephensi immune gene LRIM1 by CRISPR-Cas9 reveals its unexpected role in reproduction and vector competence

abstract: PfSPZ Vaccine against malaria is composed of Plasmodium falciparum (Pf) sporozoites (SPZ) manufactured using aseptically reared Anopheles stephensi mosquitoes. Immune response genes of Anopheles mosquitoes such as Leucin-Rich protein (LRIM1), inhibit Plasmodium SPZ development (sporogony) in mosquitoes by supporting melanization and phagocytosis of ookinetes. With the aim of increasing PfSPZ infection intensities, we generated an A. stephensi LRIM1 knockout line , {Delta}aslrim1 , by embryonic genome editing using CRISPR-Cas9. {Delta}aslrim1 mosquitoes had a significantly increased midgut bacterial load and an altered microbiome composition, including elimination of commensal acetic acid bacteria.  The alterations in the microbiome caused increased mosquito mortality and unexpectedly, significantly reduced sporogony. The survival rate of {Delta}aslrim1 and their ability to support PfSPZ development, were partially restored by antibiotic treatment of the mosquitoes, and fully restored to baseline when {Delta}aslrim1 mosquitoes were produced aseptically. Deletion of LRIM1 also affected reproductive capacity: oviposition, fecundity and male fertility were significantly compromised. Attenuation in fecundity was not associated with the altered microbiome. This work demonstrates that LRIM1s regulation of the microbiome has a major impact on vector competence and longevity of A. stephensi. Additionally, LRIM1 deletion identified an unexpected role for this gene in fecundity and reduction of sperm transfer by males.

category: microbiology


title: Diversity begets diversity through shared adaptive genetic variation: discovery of a cryptic wide-mouthed scale-eater

abstract: Adaptive radiations involve astounding bursts of phenotypic, ecological, and species diversity. However, the microevolutionary processes that underlie the origins of these bursts are still poorly understood. We report the discovery of an intermediate  wide-mouth scale-eating ecomorph in a sympatric radiation of Cyprinodon pupfishes, illuminating the transition from a widespread algae-eating generalist to a novel microendemic scale-eating specialist. We first show that this ecomorph occurs in sympatry with generalist C. variegatus and scale-eating specialist C. desquamator on San Salvador Island, Bahamas, but is genetically differentiated, morphologically distinct, and often consumes scales. We then compared the timing of selective sweeps on shared and unique adaptive variants in trophic specialists to characterize their adaptive walk. Shared adaptive regions swept first in both the specialist desquamator and the intermediate  wide-mouth ecomorph, followed by unique sweeps of introgressed variation in  wide-mouth and de novo variation in desquamator. The two scale-eating populations additionally shared 9% of their hard selective sweeps with molluscivores C. brontotheroides, despite no single common ancestor among specialists. Our work provides a new microevolutionary framework for investigating how major ecological transitions occur and illustrates how both shared and unique genetic variation can provide a bridge for multiple species to access novel ecological niches.

category: evolutionary biology


title: We get by with a little help from our friends: diversity begets diversity through shared adaptive genetic variation


title: We get by with a little help from our friends: shared adaptive variation provides a bridge to novel ecological specialists during adaptive radiation


title: Functional constraints on insect immune system components govern their evolutionary trajectories

abstract: The role of constraints in shaping evolutionary outcomes is often investigated in the contexts of developmental biology and population genetics, in terms of the capacity to generate new variants as well as how selection either limits or promotes consequent phenotypic change. Comparative genomics also recognises the role of constraints, in terms of shaping the evolution of gene and genome architectures, sequence evolutionary rates, and gene gains and losses, as well as on molecular phenotypes. Characterising patterns of genomic change where putative functions and interactions of system components are relatively well-described offers opportunities to explore whether genes with similar or analogous roles exhibit similar evolutionary trajectories, possibly governed by common constraints. Using insect innate immunity as our study system, we hypothesise that quantitative characterisation of gene evolutionary histories can define distinct dynamics associated with different functional roles. We develop metrics that quantify gene evolutionary histories, employ these to characterise evolutionary features of immune gene repertoires, and explore relationships between gene family evolutionary profiles and their roles in immunity to understand how different constraints may relate to distinct dynamics. We identified three main axes of evolutionary trajectories characterised by gene duplication and synteny, maintenance/stability and sequence conservation, and loss and sequence divergence, highlighting similar and contrasting patterns across these axes amongst subsets of immune genes. Our results indicate that where and how genes participate in immune responses limit the range of possible evolutionary scenarios they exhibit. Comparative genomics approaches therefore offer opportunities to characterise how functional constraints on different components of biological systems govern their evolutionary trajectories.


title: DETECTING PHYLODIVERSITY-DEPENDENT DIVERSIFICATION WITH A GENERAL PHYLOGENETIC INFERENCE FRAMEWORK

abstract:
AO_SCPLOWBSTRACTC_SCPLOWDiversity-dependent diversification models have been extensively used to study the effect of ecological limits and feedback of community structure on species diversification processes, such as speciation and extinction. Current diversity-dependent diversification models characterise ecological limits by carrying capacities for species richness. Such ecological limits have been justified by niche filling arguments: as species diversity increases, the number of available niches for diversification decreases.

However, as species diversify they may diverge from one another phenotypically, which may open new niches for new species. Alternatively, this phenotypic divergence may not affect the species diversification process or even inhibit further diversification. Hence, it seems natural to explore the consequences of phylogenetic diversity-dependent (or phylodiversity-dependent) diversification. Current likelihood methods for estimating diversity-dependent diversification parameters cannot be used for this, as phylodiversity is continuously changing as time progresses and species form and become extinct.

Here, we present a new method based on Monte Carlo Expectation-Maximization (MCEM), designed to perform statistical inference on a general class of species diversification models and implemented in the R package emphasis. We use the method to fit phylodiversity-dependent diversification models to 14 phylogenies, and compare the results to the fit of a richness-dependent diversification model. We find that in a number of phylogenies, phylogenetic divergence indeed spurs speciation even though species richness reduces it. Not only do we thus shine a new light on diversity-dependent diversification, we also argue that our inference framework can handle a large class of diversification models for which currently no inference method exists.


title: Detecting phylodiversity-dependent diviersification with a general phylogenetic inference framework


title: Evolution and diversity of bat and rodent Paramyxoviruses from North America

abstract:
Paramyxoviruses are a diverse group of negative-sense, single-stranded RNA viruses of which several species cause significant mortality and morbidity. In recent years the collection of paramyxoviruses sequences detected in wild mammals has substantially grown, however little is known about paramyxovirus diversity in North American mammals. To better understand natural paramyxovirus diversity, host range, and host specificity, we sought to comprehensively characterize paramyxoviruses across a range of diverse co-occurring wild small mammals in Southern Arizona. We used highly degenerate primers to screen fecal and urine samples and obtained a total of 55 paramyxovirus sequences from 12 rodent species and 6 bat species. We also performed illumina RNA-seq and de novo assembly on 14 of the positive samples to recover a total of 5 near full-length viral genomes. We show there are at least 2 clades of rodent-borne paramyxoviruses in Arizona, while bat-associated paramyxoviruses formed a putative single clade. Using structural homology modeling of the viral attachment protein, we infer that three of the five novel viruses likely bind sialic acid in a manner similar to other Respiroviruses, while the other two viruses from Heteromyid rodents likely bind a novel host receptor. We find no evidence for cross-species transmission, even among closely related sympatric host species. Taken together, these data suggest paramyxoviruses are a common viral infection in some bat and rodent species present in North America, and illuminate the evolution of these viruses.

ImportanceThere are a number of viral lineages that are potential zoonotic threats to humans. One of these, paramyxoviruses, have jumped into humans multiple times from wild and domestic animals. We conducted one of the largest viral surveys of wild mammals in the United States to better understand paramyxovirus diversity and evolution.


title: Inducible Yeast Two-Hybrid with Quantitative Measures

abstract: The yeast two-hybrid (Y2H) assay has long been used to identify new protein-protein interaction pairs and to compare relative interaction strengths. Traditional Y2H formats may be limited, however, by use of constitutive strong promoters if expressed proteins have toxic effects or post-transcriptional expression differences in yeast among a comparison group. As a step toward more quantitative Y2H assays, we modified a common vector to use an inducible CUP1 promoter, which showed quantitative induction of several "bait" proteins with increasing copper concentration. Using mouse Nxf1 (homologous to yeast Mex67p) as a model bait, copper titration achieved levels that bracket levels obtained with the constitutive ADH1 promoter. Using a liquid growth assay for an auxotrophic reporter in multiwell plates allowed log-phase growth rate to be used as a measure of interaction strength. These data demonstrate the potential for quantitative comparisons of protein-protein interactions using the Y2H system.

category: genetics


title: An Automated SNP-Based Approach for Contaminant Identification in Biparental Polyploid Populations of Tropical Forage Grasses

abstract: Artificial hybridization plays a fundamental role in plant breeding programs since it generates new genotypic combinations that can result in desirable phenotypes. Depending on the species and mode of reproduction, controlled crosses may be challenging, and contaminating individuals can be introduced accidentally. In this context, the identification of such contaminants is important to avoid compromising further selection cycles, as well as genetic and genomic studies. The main objective of this work was to propose an automated multivariate methodology for the detection and classification of putative contaminants, including apomictic clones, self-fertilized individuals, half-siblings and full contaminants, in biparental polyploid progenies of tropical forage grasses. We established a pipeline to identify contaminants in genotyping-by-sequencing (GBS) data encoded as allele dosages of single nucleotide polymorphism (SNP) markers by integrating principal component analysis (PCA), genotypic analysis (GA) measures based on Mendelian segregation and clustering analysis (CA). The combination of these methods allowed the correct identification of all contaminants in all simulated progenies and the detection of putative contaminants in three real progenies of tropical forage grasses, providing an easy and promising methodology for the identification of contaminants in biparental progenies of tetraploid and hexaploid species. The proposed pipeline was made available through the polyCID Shiny app and can be easily coupled with traditional genetic approaches, such as linkage map construction, thereby increasing the efficiency of breeding programs.

category: genomics


title: Temporal Gene Expression in Apical Culms Shows Early Changes in Cell Wall Biosynthesis Genes in Sugarcane

abstract: Multiple genes in sugarcane control sucrose accumulation and the biosynthesis of cell wall components; however, it is unclear how these genes are expressed in its apical culms. To better understand this process, we sequenced mRNA from +1 stem internodes collected from four genotypes with different concentrations of soluble solids. Culms were collected at four different time points, ranging from six to 12-month-old plants. Here we show differentially expressed genes related to sucrose metabolism and cell wall biosynthesis, including genes encoding invertases, sucrose synthase and cellulose synthase. Our results showed increased expression of invertases in IN84-58, the genotype with lower sugar and higher fiber content, as well as delayed expression of secondary cell wall-related cellulose synthase for the other genotypes. Interestingly, genes involved with hormone metabolism were differentially expressed across time points in the three genotypes with higher soluble solids content. A similar result was observed for genes controlling maturation and transition to reproductive stages, possibly a result of selection against flowering in sugarcane breeding programs. These results indicate that carbon partitioning in apical culms of contrasting genotypes is mainly associated with differential cell wall biosynthesis, and may include early modifications for subsequent sucrose accumulation. Co-expression network analysis identified transcription factors related to growth and development, showing a probable time shift for carbon partitioning occurred in 10-month-old plants.


title: ionbot: a novel, innovative and sensitive machine learning approach to LC-MS/MS peptide identification

abstract:
Mass spectrometry-based proteomics generates vast amounts of signal data that require computational interpretation to obtain peptide identifications. Dozens of algorithms for this task exist, but all exploit only part of the acquired data to judge a peptide-to-spectrum match (PSM), ignoring important information such as the observed retention time and fragment ion peak intensity pattern. Moreover, only few identification algorithms allow open modification searches that can substantially increase peptide identifications.

We here therefore introduce ionbot, a novel open modification search engine that is the first to fully merge machine learning with peptide identification. This core innovation brings the ability to include a much larger range of experimental data into PSM scoring, and even to adapt this scoring to the specifics of the data itself. As a result, ionbot substantially increases PSM confidence for open searches, and even enables a further increase in peptide identification rate of up to 12% by also considering lower-ranked, co-eluting matches for a fragmentation spectrum. Moreover, the exclusive use of machine learning for scoring also means that any future improvements to predictive models for peptide behavior will also result in more sensitive and accurate peptide identification.

category: bioinformatics


title: Mining all publicly available expression data to compute dynamic microbial transcriptional regulatory networks

abstract: We are firmly in the era of biological big data. Millions of omics datasets are publicly accessible and can be employed to support scientific research or build a holistic view of an organism. Here, we introduce a workflow that converts all public gene expression data for a microbe into a dynamic representation of the organisms transcriptional regulatory network. This five-step process walks researchers through the mining, processing, curation, analysis, and characterization of all available expression data, using Bacillus subtilis as an example. The resulting reconstruction of the B. subtilis regulatory network can be leveraged to predict new regulons and analyze datasets in the context of all published data. The results are hosted at https://imodulondb.org/, and additional analyses can be performed using the PyModulon Python package. As the number of publicly available datasets increases, this pipeline will be applicable to a wide range of microbial pathogens and cell factories.


title: FishExp: a comprehensive database and analysis platform for gene expression and alternative splicing of fish species

abstract: The publicly archived RNA-seq data has grown exponentially, but its valuable information has not yet been fully discovered and utilized, especially for alternative splicing. This is true for fish species, which play important roles in ecology, research, and the food industry. To mitigate this, we present FishExp, a web-based data platform covering gene expression and alternative splicing in 26,081 RNA-seq experiments from 44 fishes. In addition to searching by gene identifiers and symbols, FishExp allows users to query the data using various functional terms and BLAST alignment. Notably, the user can customize experiments and tools to perform differential/specific expression and alternative splicing analysis, provided with functional enrichments. The results of retrieval and analysis can be visualized on the gene-, transcript- and splicing event-level webpage in a highly interactive and intuitive manner. The manually curated sample information, uniform data processing and visualization tools make it efficient for users to gain new insights from these large datasets. All data in FishExp can be downloaded for more in-depth analysis. FishExp is freely accessible at https://bioinfo.njau.edu.cn/fishExp.


title: SPOROS: A pipeline to analyze DISE/6mer seed toxicity

abstract: micro(mi)RNAs are (18-22nt long) noncoding short (s)RNAs that suppress gene expression by targeting the 3 untranslated region of target mRNAs. This occurs through the seed sequence located in position 2-7/8 of the miRNA guide strand, once it is loaded into the RNA induced silencing complex (RISC). G-rich 6mer seed sequences can kill cells by targeting C-rich 6mer seed matches located in genes that are critical for cell survival. This results in induction of Death Induced by Survival gene Elimination (DISE), also referred to as 6mer seed toxicity. miRNAs are often quantified in cells by aligning the reads from small (sm)RNA sequencing to the genome. However, the analysis of any smRNA Seq data set for 6mer seed toxicity requires an advanced workflow, solely based on the exact position 2-7 of any sRNA that can enter the RISC. Therefore, we developed SPOROS, an automated pipeline that produces multiple useful outputs to compare 6mer seed toxicity of all cellular sRNAs, regardless of their nature, between different samples. We provide two examples to illustrate the capabilities of SPOROS: Example one involves the analysis of RISC-bound sRNAs in a cancer cell line (either wild-type or two mutant lines unable to produce most miRNAs). Example two is based on a publicly available smRNA Seq data set from postmortem brains (either from normal or Alzheimers patients). Our methods are designed to be used to analyze a variety of smRNA Seq data in various normal and disease settings.


title: The role of pro- and antiangiogenic factors in angiogenesis process by Raman spectroscopy

abstract:
Raman spectroscopy and Raman imaging are powerful techniques to monitor biochemical composition around blood vessel. The aim of this study was to understand the role of pro- and antiangiogenic factors in angiogenesis process. Raman imaging and Raman single spectrum measurements allow the diagnosis of cancer biochemical changes in blood vessel based on several biomarkers simultaneously. We have demonstrated that Raman imaging combined with statistical methods are useful to monitoring pro- and antiangiogenic factors responsible for angiogenesis process. In this paper Raman markers of proangiogenic and antiangiogenic factors were identified based on their vibrational signatures. Obtained results can help understand how growing tumor create its vascular system.

Graphical Abstract

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title: Sulfated polysaccharides from red seaweed Gracilaria cornea induce macrophages polarization to an antitumor M1 phenotype

abstract: Marine seaweeds are a rich source of sulfated polysaccharides with several biological activities, including antitumor effect. Some polysaccharides are also described to activate macrophages (M{phi}s) to an antitumor M1-like phenotype. Here, we evaluated the capacity of sulfated galactans (SGs) extracts obtained from three seaweed species, Gracilaria cornea (Gc-E), Gracilaria birdiae (Gb-E), and Solieria filiformis (Sf-E), to activate the M{phi}s antitumor M1 phenotype. The nitric oxide production, MHCII, and CD86 (M1 markers) were evaluated to screening the bioactive SGs profile on murine M{phi}s (RAW 264.7 cells). The direct SGs antiproliferative effect was tested on melanoma B16-F10 cells. In another experimental setting, B16-F10 cells were incubated with a conditioned medium obtained from M{phi}s exposed to SGs. The three SGs tested induced NO release. Sf-E directly inhibited B16-F10 cells proliferation compared with the saline group, but Gc-E and Gb-E failed to inhibit cell proliferation. Notably, a conditioned medium (CM) of M{phi}s incubated with Gc-E and Sf-E, but not of Gb-E, inhibited the proliferation of B16-F10 cells. Gc-E also induced TNF- release and increase of M1 markers such as iNOS, MHCII, and CD86. Therefore, Gc-E activates M{phi}s to M1 phenotype, which in turn releases a factor that inhibits B16-F10 proliferation.

category: pharmacology and toxicology


title: The Effect of a Fennel Extract on the STAT Signaling and Intestinal Barrier Function

abstract:
BackgroundFoeniculum vulgare, F. vulgare, commonly known as fennel, is believed to be one of the worlds oldest medicinal herbs and has been exploited by people for centuries as a nutritional aid for digestive disorders. In many southeast Asian countries it is ingested as an after-meal snack, mukhvas, due to its breath-freshening and digestive aid properties. F. vulgare is used in some countries, such as Iran, as a complementary and alternative treatment for inflammatory bowel disease (IBD).

MethodsThis study investigated the effects of F. vulgare on the barrier function of the intestinal epithelium Signal Transducer and Activator of Transcription (STAT) pathway, which is active in inflammatory bowel disease.

To study the protective effects of F. vulgare extract in vitro, monolayers derived from the T84 colonic cell line were challenged with interferon-gamma (IFN-{gamma}) and monitored with and without F. vulgare extract. To complement our in vitro studies, the dextran sodium sulfate induced murine colitis model was employed to ascertain whether the protective effect of F. vulgare extract can be recapitulated in vivo.

ResultsF. vulgare extract was shown to exert a protective effect on TEER in both T84 and murine models and showed increases in tight junction-associated mRNA in T84 cell monolayers. Both models demonstrated significant decreases in phosphorylated STAT1 (pSTAT1), indicating reduced activation of the STAT pathway. Additionally, mice treated with F. vulgare showed significantly lower ulcer indices than control mice.

ConclusionsWe conclude barrier function of the gastrointestinal tract is improved by F. vulgare, suggesting the potential utility of this agent as an alternative or adjunctive therapy in IBD.


title: Time to recover from daily caffeine intake.

abstract: Caffeine elicits widespread effects in the central nervous system and is the most frequently consumed psychostimulant worldwide. First evidence indicates that, during daily intake, the elimination of caffeine may slow down and the primary metabolite, paraxanthine, may accumulate. The neural impact of such adaptions is virtually unexplored. In this report, we leveraged the data of a laboratory study with N= 20 participants and three within-subject conditions: caffeine (150 mg caffeine x 3/day x 10 days), placebo (150 mg mannitol x 3/day x 10 days), and withdrawal (caffeine x 9 days, afterwards placebo x 1 day). Using liquid chromatography-mass spectrometry coupled with tandem mass spectrometry, we determined the course of salivary caffeine and paraxanthine, measured regularly at day 10. We assessed grey matter (GM) intensity and cerebral blood flow (CBF) in the withdrawal condition as compared to their changes in caffeine in our previous report. The results indicate high remaining levels of paraxanthine and of caffeine carried overnight during daily intake, and the levels of paraxanthine remained higher than in placebo during withdrawal. After 36 h of withdrawal, the previously reported caffeine-induced GM reduction was partially mitigated, while CBF was elevated compared to placebo. Our findings unveil that conventional daily caffeine intake does not provide sufficient time to clear up psychoactive compounds and restore cerebral responses, even after 36 hours of abstinence. They also suggest investigating consequences of a paraxanthine accumulation during daily caffeine intake.


title: The impact of heat on human physical work capacity; Part III: the impact of solar radiation varies with air temperature, humidity, and clothing coverage.

abstract: It is well-known that heat impacts human labour/physical work capacity (PWC), but systematic evaluations of solar radiation (SOLAR) effects and the interaction with air temperature and humidity levels and clothing are lacking, as most lab-studies are conducted in semi-nude subjects without radiation or only in a single climatic condition. Due to the high relevance of SOLAR in various occupations, this study quantified how SOLAR interacts with clothing and other primary environmental factors (air temperature/humidity) of importance to determine PWC in the heat. The data allowed the development of a SOLAR correction factor for predicting PWC in major outdoor industries. Fourteen young adult males (7 wearing a standardised work coverall (0.9 Clo), 7 with shorts and trainers (0.3 Clo) walked for 1-hour at a fixed heart rate of 130 b{middle dot}min-1, in seven combinations of air temperature (25 to 45{degrees}C) and relative humidity (20 or 80%), with and without SOLAR (800 W/m2 from solar lamps). Cumulative energy expenditure in the heat, relative to the work achieved in a cool reference condition, was used to determine PWC%. Skin temperature was the primary determinant of PWC in the heat. In dry climates with exposed skin (0.3 Clo), SOLAR caused PWC to decrease exponentially with rising air temperature, whereas work coveralls (0.9 Clo) negated this effect. In humid conditions, the SOLAR-induced reduction in PWC was consistent and linear across all levels of air temperature, and clothing conditions. WBGT and UTCI based prediction equations of PWC represented SOLAR correctly. For heat indices not intrinsically accounting for SOLAR, correction factors are provided enabling forecasting of heat effects on work productivity.

category: physiology


title: Understanding hydropower impacts on Amazonian wildlife is limited by a lack of robust evidence: results from a systematic review

abstract:
Background and Research AimsAlthough hydropower provides energy to fuel economic development across Amazonia, strategies to minimize or mitigate impacts in highly biodiverse Amazonian environments remain unclear. The growing number of operational and planned hydroelectrics requires robust scientific evidence to evaluate impacts of these projects on Amazonian vertebrates. Here we investigated the existing scientific knowledge base documenting impacts of hydropower developments on vertebrates across Brazilian Amazonia.

MethodsWe reviewed the scientific literature from 1945 to 2020 published in English, Spanish and Portuguese to assess the temporal and spatial patterns in publications and the types of study design adopted as well as scientific evidence presented.

ResultsA total of 24 published articles documented impacts on fish (n = 20), mammals (n = 3) and freshwater turtles (n = 1). Most study designs (87.5%) lacked appropriate controls and only three studies adopted more robust Before-After-Control-Impact designs. The published evidence did not generally support causal inference with only two studies (8.3%) including appropriate controls and/or confounding variables.

ConclusionDecades of published assessments (54.2% of which were funded by hydropower developers or their subsidiaries) do not appear to have established robust evidence of impacts of hydropower developments on Amazonian vertebrates. This lack of robust evidence could limit the development of effective minimization and mitigation actions for the diverse vertebrate groups impacted by hydroelectrics across Brazilian Amazonia.

Implications for ConservationTo avoid misleading inferences there is a need to integrate more robust study designs into impact assessments of hydropower developments in the Brazilian Amazon.

category: scientific communication and education


title: Identifying Site-specific Superoxide and Hydrogen Peroxide Production Rates from the Mitochondrial Electron Transport System Using a Computational Strategy

abstract: Mitochondrial reactive oxygen species (ROS) play important roles in cellular signaling; however, certain pathological conditions such as ischemia/reperfusion (I/R) injury disrupt ROS homeostasis and contribute to cell death. A major impediment to developing therapeutic measures against oxidative stress induced cellular damage is the lack of a quantitative framework to identify the specific sources and regulatory mechanisms of mitochondrial ROS production. We developed a thermodynamically consistent, mass-and-charge balanced, kinetic model of mitochondrial ROS homeostasis focused on redox sites of electron transport chain complexes I, II, and III. The model was calibrated and validated using comprehensive data sets relevant to ROS homeostasis. The model predicts that complex I ROS production dominates other sources under conditions favoring a high membrane potential with elevated NADH and QH2 levels. In general, complex I contributes to significant levels of ROS production under pathological conditions, while complexes II and III are responsible for basal levels of ROS production, especially when QH2 levels are elevated. The model also reveals that hydrogen peroxide production by complex I underlies the non-linear relationship between ROS emission and O2 at low O2 concentrations. Lastly, the model highlights the need to quantify scavenging system activity under different conditions to establish a complete picture of mitochondrial ROS homeostasis. In summary, we describe the individual contributions of the ETS complex redox sites to total ROS emission in mitochondria respiring under various combinations of NADH- and Q-linked respiratory fuels under varying work rates.

category: systems biology


title: PEPSDI: Scalable and flexible inference framework for stochastic dynamic single-cell models

abstract: Mathematical modelling is an invaluable tool to describe dynamic cellular processes and to rationalise cell-to-cell variability within the population. This requires statistical methods to infer unknown model parameters from dynamic, multi-individual data accounting for heterogeneity caused by both intrinsic and extrinsic noise. Here we present PEPSDI, a scalable and flexible framework for Bayesian inference in state-space mixed-effects stochastic dynamic single-cell models. Unlike previous frameworks, PEPSDI imposes a few modelling assumptions when inferring unknown model parameters from time-lapse data. Specifically, it can infer model parameters when intrinsic noise is modelled by either exact or approximate stochastic simulators, and when extrinsic noise is modelled by either time-varying, or time-constant parameters that vary between cells. This allowed us to identify hexokinase activity as a source of extrinsic noise, and to deduce that sugar availability dictates cell-to-cell variability in the budding yeast Saccharomyces cerevisiae SNF1 nutrient sensing pathway.


title: Signaling receptor localization maximizes cellular information acquisition in spatially-structured, natural environments

abstract: Cells in natural environments like tissue or soil sense and respond to extracellular ligands with intricately structured and non-monotonic spatial distributions, sculpted by processes such as fluid flow and substrate adhesion. In this work, we show that spatial sensing and navigation can be optimized by adapting the spatial organization of signaling pathways to the spatial structure of the environment. We develop an information-theoretic framework for computing the optimal spatial organization of a sensing system for a given signaling environment. We find that receptor localization maximizes information acquisition in simulated natural contexts, including tissue and soil. Receptor localization extends naturally to produce a dynamic protocol for continuously redistributing signaling receptors, which when implemented using simple feedback, boosts cell navigation efficiency by 30-fold. Broadly, our work shows how cells can maximize the fidelity of information transfer by adapting the spatial organization of signaling molecules to the spatial structure of the environment.


title: Receptor localization maximizes information acquisition in natural cell environments


title: Localization of signaling receptors maximizes cellular informationacquisition in spatially-structured natural environments


title: A validation standard for Area of Habitat maps for terrestrial birds and mammals

abstract: Area of Habitat (AOH) is a deductive model which maps the distribution of suitable habitat at suitable altitudes for a species inside its broad geographical range. AOH maps have been validated using presence-only data for small subsets of species for different taxonomic groups, but no standard validation method exists when absence data are not available. We develop a novel two-step validation protocol for AOH which includes first a model-based evaluation of model prevalence (i.e, the proportion of suitable habitat within a species range), and second a validation using species point localities (presence-only) data. We applied the protocol to AOH maps of terrestrial birds and mammals. In the first step we built logistic regression models to predict expected model prevalence (the proportion of the range retained as AOH) as a function of each species elevation range, mid-point of elevation range, number of habitats, realm and, for birds, seasonality. AOH maps with large difference between observed and predicted model prevalence were identified as outliers and used to identify a number of sources of systematic error which were then corrected when possible. For the corrected AOH, only 1.7% of AOH maps for birds and 2.3% of AOH maps for mammals were flagged as outliers in terms of the difference between their observed and predicted model prevalence. In the second step we calculated point prevalence, the proportion of point localities of a species falling in pixels coded as suitable in the AOH map. We used 48,336,141 point localities for 4889 bird species and 107,061 point localities for 420 mammals. Where point prevalence exceeded model prevalence, the AOH was a better reflection of species distribution than random. We also found that 4689 out of 4889 (95.9%) AOH maps for birds, and 399 out of 420 (95.0%) AOH maps for mammals were better than random. Possible reasons for the poor performance of a small proportion of AOH maps are discussed.

category: zoology


title: Hippocampal theta oscillations are modulated by behaviour in the ferret but persist during both locomotion and immobility

abstract: Theta oscillations are a hallmark of hippocampal activity across mammals and play a critical role in many hippocampal models of memory and spatial navigation. To reconcile the cross-species differences observed in the presence and properties of theta, we recorded hippocampal local field potentials in rats and ferrets during auditory and visual localisation tasks designed to vary locomotion and sensory attention. Here, we show that theta oscillations occur during locomotion in both ferrets and rats, however during periods of immobility, theta oscillations persisted in the ferret, contrasting starkly with the switch to large irregular activity (LIA) in the rat. Theta during immobility in the ferret was identified as Type 2 theta due to its sensitivity to atropine, and was modulated by behavioural state, with the strongest theta observed during reward epochs. These results demonstrate that even under similar behavioural conditions, differences exist between species in the relationship between theta and behavioural state.


title: Postsynaptic plasticity of cholinergic synapses underlies the induction and expression of appetitive memories in Drosophila

abstract: In vertebrates, memory-relevant synaptic plasticity involves postsynaptic rearrangements of glutamate receptors. In contrast, previous work indicates that Drosophila and other invertebrates store memories using presynaptic plasticity of cholinergic synapses. Here, we provide evidence for postsynaptic plasticity at cholinergic output synapses from the Drosophila mushroom bodies (MBs). We find that the nicotinic acetylcholine receptor (nAChR) subunit 5 is required within specific MB output neurons (MBONs) for appetitive memory induction, but is dispensable for aversive memories. In addition, nAChR 2 subunits mediate memory expression downstream of 5 and the postsynaptic scaffold protein Dlg. We show that postsynaptic plasticity traces can be induced independently of the presynapse, and that in vivo dynamics of 2 nAChR subunits are changed both in the context of associative and non-associative memory formation, underlying different plasticity rules. Therefore, regardless of neurotransmitter identity, key principles of postsynaptic plasticity support memory storage across phyla.


title: Network diffusion model predicts neurodegeneration in limb-onset amyotrophic lateral sclerosis

abstract: The trans-neural propagation of phosphorylated 43-kDa transactive response DNA-binding protein (pTDP-43) contributes to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). We investigated whether Network Diffusion Model (NDM), a biophysical model of spread of pathology via the brain connectome, could capture the severity and progression of neurodegeneration (atrophy) in ALS. We measured degeneration in limb-onset ALS patients (n=14 at baseline, 12 at 6-months, and 9 at 12 months) and controls (n=12 at baseline) using FreeSurfer analysis on the structural T1-weighted Magnetic Resonance Imaging (MRI) data. The NDM was simulated on the canonical structural connectome from the IIT Human Brain Atlas. To determine whether NDM could predict the atrophy pattern in ALS, the accumulation of pathology modelled by NDM was correlated against atrophy measured using MRI. The cross-sectional analyses revealed that the network diffusion seeded from the inferior frontal gyrus (pars triangularis and pars orbitalis) significantly predicts the atrophy pattern in ALS compared to controls. Whereas, atrophy over time with-in the ALS group was best predicted by seeding the network diffusion process from the inferior temporal gyrus at 6-month and caudal middle frontal gyrus at 12-month. Our findings suggest the involvement of extra-motor regions in seeding the spread of pathology in ALS. Importantly, NDM was able to recapitulate the dynamics of pathological progression in ALS. Understanding the spatial shifts in the seeds of degeneration over time can potentially inform further research in the design of disease modifying therapeutic interventions in ALS.


title: Wild lab: A naturalistic free viewing experiment reveals previously unknown EEG signatures of face processing.

abstract: Neural mechanisms of face perception are predominantly studied in well-controlled experimental settings that involve random stimulus sequences and fixed eye positions. While powerful, the employed paradigms are far from what constitutes natural vision. Here, we demonstrate the feasibility of ecologically more valid experimental paradigms using natural viewing behavior, by combining a free viewing paradigm on natural scenes, free of photographer bias, with advanced data processing techniques that correct for overlap effects and co-varying nonlinear dependencies of multiple eye movement parameters. We validate this approach by replicating classic N170 effects in neural responses, triggered by fixation onsets (fERPs). Importantly, our more natural stimulus paradigm yielded smaller variability between subjects than the classic setup. Moving beyond classic temporal and spatial effect locations, our experiment furthermore revealed previously unknown signatures of face processing. This includes modulation of early fERP components, as well as category-specific adaptation effects across subsequent fixations that emerge even before fixation onset.


title: Identifying components that vary in space and time from resting-state functional MRI

abstract: A widespread assumption of fMRI-derived large-scale intrinsic connectivity networks (ICNs) is that they are spatially static over time. However, the assumption of spatial stationarity of ICNs has been challenged by a range of techniques that allow for time-varying connectivity between brain regions and demonstration that canonical networks like the default model network (DMN) can be fractionated according to time-varying connectivity relationships of their subcomponents. Previously, we developed a simple spatiotemporal ICA (stICA) technique to allow the discovery of patterns of spatiotemporal evolution in task fMRI data in a way that avoided the traditional constraint of spatial stationarity on brain networks, and we validated the approach in fMRI of task-to-rest transitions. Here, we apply our stICA technique to resting-state fMRI datasets to explore whether spatiotemporally evolving components of brain activity can be identified in the absence of an overt behavioural task. We found that stICA components could generally be described in terms of graded onsets and offsets of ICNs that had been calculated based on techniques that assumed spatial stationarity. Our results suggest that, to a reasonable approximation, stable ICNs can be taken to be building blocks of the spatiotemporal patterns measured with resting-state fMRI.


title: Edge-centric analysis of time-varying functional brain networks with applications in autism spectrum disorder

abstract: The interaction between brain regions changes over time, which can be characterized using time-varying functional connectivity (tvFC). The common approach to estimate tvFC uses sliding windows and offers limited temporal resolution. An alternative method is to use the recently proposed edge-centric approach, which enables the tracking of moment-to-moment changes in co-fluctuation patterns between pairs of brain regions. Here, we first examined the dynamic features of edge time series and compared them to those in the sliding window tvFC (sw-tvFC). Then, we used edge time series to compare subjects with autism spectrum disorder (ASD) and healthy controls (CN). Our results indicate that relative to sw-tvFC, edge time series captured rapid and bursty network-level fluctuations that synchronize across subjects during movie-watching. The results from the second part of the study suggested that the magnitude of peak amplitude in the collective co-fluctuations of brain regions (estimated as root sum square (RSS) of edge time series) is similar in CN and ASD. However, the trough-to-trough duration in RSS signal is greater in ASD, compared to CN. Furthermore, an edge-wise comparison of high-amplitude co-fluctuations showed that the within-network edges exhibited greater magnitude fluctuations in CN. Our findings suggest that high-amplitude co-fluctuations captured by edge time series provide details about the disruption of functional brain dynamics that could potentially be used in developing new biomarkers of mental disorders.


title: Differential impact of TNFRSF co-stimulation on CD8+ T cell cytokine production by feedback control of surface receptor expression

abstract: T cell responses towards infections and cancers are regulated by a host of co-signalling receptors that are largely grouped into the binary categories of co-stimulation and co-inhibition. The TNF receptor superfamily (TNFRSF) members 4-1BB, CD27, GITR, and OX40 are well-established co-stimulation receptors with largely shared molecular pathways raising the question of whether they also have a similar impact on quantitative T cell responses, such as the efficacy, sensitivity, and duration of T cell responses. Here, we systematically stimulated primary human CD8+ T cell blasts with dose ranges of antigen and ligands for TNFRSF members to screen for their quantitative effects on cytokine production. Although both 4-1BB and CD27 increased efficacy, only 4-1BB was able to prolong the duration of cytokine production, and both had only a modest impact on antigen sensitivity. An operational model could explain these divergent quantitative phenotypes using a shared signalling mechanism based on the surface expression of 4-1BB, but not CD27, being regulated through a signalling feedback. The model predicted that CD27 co-stimulation would increase 4-1BB expression and subsequent 4-1BB co-stimulation, which we confirmed experimentally. Although GITR and OX40 produced only minor changes in cytokine production on their own, we found that like 4-1BB, CD27 could enhance GITR expression and subsequent GITR co-stimulation. Thus, feedback control of induced TNFRSF surface expression explains both synergy and differential impact on cytokine production. The work highlights that different co-stimulation receptors can have different quantitative phenotypes on the same output allowing for highly regulated control of T cell responses.

category: immunology


title: Mapping Protein Numbers in Living Cells

abstract: We introduce a new, robust method to map the numbers of proteins in living cells. The method can be applied to laser scanning, spinning disk, and lattice light-sheet microscopes in a robust, reproducible, and scalable fashion. The method uses calibrated EGFP solutions that are imaged with the appropriate microscope modality to create a calibration curve that is then applied to convert the fluorescence intensities from 3D microscope images into molecule numbers. We applied this method to human induced pluripotent stem cells in which proteins representing key cellular structures were endogenously tagged with mEGFP. We used the ratio of mEGFP-tagged proteins to total proteins to create 3D maps of live cells showing the density of total proteins measured in molecules per {micro}m3. The method opens the door to new quantitative single cell analyses of cellular protein numbers in the context of single cell gene expression, associations with cellular complexes, and changes in cellular behaviors. The method is capable of quantifying protein numbers, over three orders of magnitude, in the cytoplasm or within various cellular structures while offering the unique advantages of each microscopy modality.

category: cell biology


title: Clonal dynamics of normal hepatocyte expansions in homeostatic human livers and their association with the biliary epithelium

abstract: The majority of human liver research is disease-focused such that far less is known of cellular dynamics within normal human liver. We have leveraged cytochrome c oxidase deficiency as a marker of clonal hepatocyte populations in such tissues. We demonstrate these populations commonly associate with portal tracts and lineage-trace hepatocytes with cholangiocytes, indicating the presence of a bipotential common ancestor at this niche. We also observe rare periportal SOX9+ hepatocytes progenitor candidates in our human tissues. To understand clonal expansion dynamics, we measured methylation diversity and identified mtDNA variants by next-generation sequencing within spatially-defined clonal hepatocyte patches. We coupled our sequencing with mathematical modelling and Bayesian inference to compare spatial patterns of mtDNA variants under assumptions with or without faster expansion from a portal-associated niche. These datasets support the existence of a periportal progenitor niche and indicate that clonal patches slowly expand, perhaps due to acute environmental stimuli, then quiesce. These findings crucially contribute to our understanding of hepatocyte dynamics in normal human liver and provide a baseline for understanding how such dynamics may be modulated in diseased liver.


title: Neutrophil and natural killer cell imbalances prevent muscle stem cell mediated regeneration following murine volumetric muscle loss

abstract:
Volumetric muscle loss (VML) overwhelms the innate regenerative capacity of mammalian skeletal muscle (SkM), leading to numerous disabilities and reduced quality of life. Immune cells are critical responders to muscle injury and guide tissue resident stem cell and progenitor mediated myogenic repair. However, how immune cell infiltration and inter-cellular communication networks with muscle stem cells are altered following VML and drive pathological outcomes remains underexplored. Herein, we contrast the cellular and molecular mechanisms of VML injuries that result in fibrotic degeneration or regeneration of SkM. Following degenerative VML injuries, we observe heightened infiltration of natural killer (NK) cells as well as persistence of neutrophils beyond two weeks post injury. Functional validation of NK cells revealed an antagonistic role on neutrophil accumulation in part via inducing apoptosis and CCR1 mediated chemotaxis. The persistent infiltration of neutrophils in degenerative VML injuries was found to contribute to impairments in muscle stem cell regenerative function, which was also attenuated by transforming growth factor beta 1 (TGF{beta}1). Blocking TGF{beta} signaling reduced neutrophil accumulation and fibrosis, as well as improved muscle specific force. Collectively, these results enhance our understanding of immune cell-stem cell crosstalk that drives regenerative dysfunction and provide further insight into possible avenues for fibrotic therapy exploration.

SINGLE SENTENCE SUMMARYComparison of muscle injuries resulting in regeneration or fibrosis reveals inter-cellular communication between neutrophils and natural killer cells impacts muscle stem cell mediated repair.


title: Amino acid and nucleotide metabolism shape the selection of trophic levels in animals

abstract: What an animal eats determines its trophic level (TL) in the food web. The diet of high-TL animals is thought to contain more energy because it contains higher levels of lipids. This however has not been systematically examined in the context of comprehensive metabolic networks of different animals. Here, we reconstruct species-specific genome-scale metabolic models (GEMs) of 32 animals, and calculate the maximum ATP production per unit of food for each animal. Surprisingly, we find that ATP production is closely associated with metabolic flux through central carbon metabolism and amino acid metabolism, while correlation with lipid metabolism is low. Further, metabolism of specific amino acids and nucleotides underlie maximum ATP production from food. Our analyses indicate that amino acid and nucleotide metabolism, rather than lipid metabolism, are major contributors to the selection of animal trophic levels, demonstrating that species-level metabolic flux plays key roles in trophic interactions and evolution.

category: ecology


title: Effects of warming winter embryo incubation temperatures on larval cisco (Coregonus artedi) survival, growth, and critical thermal maximum

abstract: Freshwater whitefishes, Salmonidae Coregoninae, are cold stenothermic fishes of ecological and socio-economic importance in northern hemisphere lakes that are warming in response to climate change. To address the effect of warming waters on coregonine reproduction we experimentally evaluated different embryo incubation temperatures on post-hatching survival, growth, and critical thermal maximum of larval cisco (Coregonus artedi) sampled from lakes Superior and Ontario. Embryos were incubated at water temperatures of 2.0, 4.4, 6.9, and 8.9{degrees}C to simulate present and increased winter temperatures, and hatched larvae were reared in a common environment. For both populations, larval survival and critical thermal maximum were negatively related to incubation temperature, and larval growth was positively related to incubation temperature. The magnitude of change across incubation temperatures was greater in the population sampled from Lake Superior than Lake Ontario for all traits examined. The more rapid decrease in survival and critical thermal maximum across incubation temperatures for larval cisco in Lake Superior, compared to those from Lake Ontario, suggests that Lake Superior larvae may possess a more limited ability to acclimate to and cope with increasing winter water temperatures. However, the rapid increase in growth rates across incubation temperatures in Lake Superior larvae suggests they could recover better from hatching at a small length induced by warm winters, as compared to Lake Ontario larvae. Our results suggest propagation and restoration programs may want to consider integrating natural habitat preferences and maximizing phenotypic variability to ensure offspring are set up for success upon stocking.


title: Aboveground biomass increments over 26 years (1993-2019) in an old-growth cool-temperate forest in northern Japan

abstract: Assessing long-term changes in biomass of old-growth forests is critical in evaluating forest ecosystem functions under a changing climate. Long-term biomass changes are the result of accumulated short-term changes, which can be affected by endogenous processes such as gap filling in small-scale canopy openings. Here, we used 26 years (1993-2019) of repeated tree census data in an old-growth, cool-temperate, deciduous mixed forest that contains three topographic units (riparian, denuded slope, and terrace) in northern Japan to document decadal changes in aboveground biomass (AGB) and their processes in relation to endogenous processes and climatic factors. AGB increased steadily over the 26 years in all topographic units, but different tree species contributed to the increase among the topographic units. AGB gain within each topographic unit exceeded AGB loss via tree mortality in most of the measurement periods despite substantial temporal variation in AGB loss. At the local scale, variations in AGB gain were partially explained by compensating growth of trees around canopy gaps. Climate affected the local-scale AGB gain: the gain was larger in the measurement periods with higher mean temperature during the current summer but smaller in those with higher mean temperature during the previous autumn, synchronously in all topographic units. The decadal climate trends of warming are likely to have contributed to the steady increase in AGB in this old-growth forest.


title: Combining taxonomic, phylogenetic and functional diversity reveals new global priority areas for tetrapod conservation

abstract: We are in the midst of a sixth mass extinction but little is known about the global patterns of biodiversity when accounting for taxonomic, phylogenetic and functional information. Here, we present the first integrated analysis of global variation in taxonomic, functional diversity and phylogenetic diversity of more than 17,000 tetrapod species (terrestrial mammals, amphibians, reptiles and birds). We used a new metric (z-Diversity) able to synthetize taxonomic, functional and phylogenetic information across different sets of species to provide a comprehensive estimation of biodiversity. Our analyses reveal that hotspots of tetrapod diversity are clustered in specific regions of the world such as central Africa and the Indian peninsula, and that climate stability and energy availability have an overarching importance in explaining tetrapod spatial patterns. Future research might take advantage of these methods to perform an informed prioritization of protected areas.


title: Using stationary vital rates in impact assessments may underestimate potential threat

abstract: Population viability analysis (PVA) is commonly used to assess future potential risks to threatened species. These models are typically based on mean vital rates, such as survival and fecundity, with some level of environmental stochasticity. However, the vital rates of wild populations, especially those already exhibiting declining trajectories, may be nonstationary, such that the mean or variance changes over time. In this study, we examined whether including observed temporal trends in vital rates affects the predictive accuracy of PVA, as well as the projected impact associated with a hypothetical threat. To achieve this, we ran a series of simulations using Leslie matrix PVA models that included different combinations of environmental stochasticity, temporal trends in vital rates, and threat. We apply our analysis to a long-lived colonial species of seabird, the black-legged kittiwake Rissa tridactyla, that is classified as globally Vulnerable and is potentially highly sensitive to offshore renewable energy development. We found that including observed temporal trends in vital rates was (i) crucial for the accurate reconstruction of observed population dynamics and (ii) had a dramatic effect on the projected impact from the hypothetical threat. In an era when many animal and plant populations are declining due to long-term trends in their vital rates, we identify that including this demographic structure is essential for robustly evaluating potential threats using PVA models. Omitting observed temporal trends in vital rates from impact assessments is highly likely to yield unreliable results that could misinform conservation and management decision making. This result has immediate application for conducting impact assessments on protected species and populations.


title: More-curated data outperforms more data: treatment of cryptic and known paralogs improves phylogenomic analysis and resolves a northern Andean origin of Freziera (Pentaphylacaceae)

abstract: The Andes mountains in South America are a biodiversity hotspot within a hotspot, the New World Tropics, for seed plants. Much of this diversity is concentrated at middle-elevations in cloud forests, yet the evolutionary patterns underlying this extraordinary diversity remain poorly understood. This is partially due to a paucity of resolved phylogenies for cloud forest plant lineages: the young age of the Andes and generally high diversification rates among Andean systems precludes robust phylogenetic inference, and remote populations, few genomic resources, and generally understudied organisms make acquiring high-quality data difficult. We present the first phylogeny of Freziera (Pentaphylacaceae), an Andean-centered, cloud forest radiation with potential to provide insight into some of the abiotic and extrinsic factors that promote the highest diversity observed on the globe. Our dataset, representing data for 50 of the ca. 75 spp. obtained almost entirely from herbarium specimens via hybrid-enriched target sequence capture with the universal bait set Angiosperms353, included a proportion of poorly assembled loci likely representing multi-copy genes, but with insufficient data to be flagged by paralog filters: cryptic paralogs. These cryptic paralogs likely result from limitations in data collection that are common in herbariomics combined with a history of genome duplication and are likely common in other plant phylogenomic datasets. Standard empirical metrics for identifying poor-quality genes, which typically focus on filtering for genes with high phylogenetic informativeness, failed to identify problematic loci in our dataset where strong but inaccurate signal was a greater problem. Filtering by bipartition support was the most successful method for selecting genes and resulted in a species tree with lower discordance, higher support, and a more accurate topology relative to a consensus tree. Using known paralogs, we investigate the utility of multi-copy genes in phylogenetic inference and find a role for paralogs in resolving deep nodes and major clades, though at the expense of gene tree concordance and support. With the first phylogeny, we infer the biogeographic history of Freziera and identify the northern Andes as a source region. We also identify distinct modes of diversification in the northern and central Andes, highlighting the importance of fine-scale biogeographic study in Andean cloud forest systems.


title: Broad-scale variation in human genetic diversity levels is predicted by purifying selection on coding and non-coding elements

abstract: Analyses of genetic variation in many taxa have established that neutral genetic diversity is shaped by natural selection at linked sites. Whether the mode of selection is primarily the fixation of strongly beneficial alleles (selective sweeps) or purifying selection on deleterious mutations (background selection) remains unknown, however. We address this question in humans by fitting a model of the joint effects of selective sweeps and background selection to autosomal polymorphism data from the 1000 Genomes Project. After controlling for variation in mutation rates along the genome, a model of background selection alone explains [~]60% of the variance in diversity levels at the megabase scale. Adding the effects of selective sweeps driven by adaptive substitutions to the model does not improve the fit, and when both modes of selection are considered jointly, selective sweeps are estimated to have had little or no effect on linked neutral diversity. The regions under purifying selection are best predicted by phylogenetic conservation, with [~]80% of the deleterious mutations affecting neutral diversity occurring in non-exonic regions. Thus, background selection is the dominant mode of linked selection in humans, with marked effects on diversity levels throughout autosomes.


title: Interplay between BALL and CBP maintains H3K27 acetylation on active genes in Drosophila

abstract: CREB binding protein (CBP) is a multifunctional transcriptional co-activator that interacts with a variety of transcription factors and acts as a histone acetyltransferase. In Drosophila, CBP mediated acetylation of histone H3 lysine 27 (H3K27ac) is a known hallmark of gene activation regulated by trithorax group proteins (trxG). Recently, we have shown that a histone kinase Ballchen (BALL) substantially co-localizes with H3K27ac at trxG target loci and is required to maintain gene activation in Drosophila. Here, we report direct interaction between BALL and CBP, which positively regulates H3K27ac. Analysis of genome-wide binding profile of BALL and CBP reveals major overlap and their co-localization at actively transcribed genes. We show that BALL biochemically interacts with CBP and depletion of BALL results in drastic reduction in H3K27ac. Together, these results demonstrate a previously unknown synergy between BALL and CBP and reveals a potentially new pathway required to maintain gene activation during development.


title: On the contingent nature of satellite DNA evolution

abstract:
BackgroundThe full catalogue of satellite DNA (satDNA) within a same genome constitutes the satellitome. The Library Hypothesis predicts that satDNA in relative species reflects that in their common ancestor, but the evolutionary mechanisms and pathways of satDNA evolution have never been analyzed for full satellitomes. We compare here the satellitomes of two Oedipodine grasshoppers (Locusta migratoria and Oedaleus decorus) which shared their most recent common ancestor about 22.8 Ma ago.

ResultsWe found that about one-third of their satDNA families (near 60 in every species) showed sequence homology and were grouped into 12 orthologous superfamilies. The turnover rate of consensus sequences was extremely variable among the 20 orthologous family pairs analyzed in both species. The satDNAs shared by both species showed poor association with sequence signatures and motives frequently argued as functional, except for short inverted repeats allowing short dyad symmetries and non-B DNA conformations. Orthologous satDNAs frequently showed different FISH patterns at both intra- and interspecific levels. We defined indices of homogenization and degeneration and quantified the level of incomplete library sorting between species.

ConclusionsOur analyses revealed that satDNA degenerates through point mutation and homogenizes through partial turnovers caused by massive tandem duplications (the so-called satDNA amplification). Remarkably, satDNA amplification increases homogenization, at intragenomic level, and diversification between species, thus constituting the basis for concerted evolution. We suggest a model of satDNA evolution by means of recursive cycles of amplification and degeneration, leading to mostly contingent evolutionary pathways where concerted evolution emerges promptly after lineages split.


title: Satellitome comparison of two oedipodine grasshoppers highlights the contingent nature of satellite DNA evolution


title: OpenSense: An open-source toolbox for Inertial-Measurement-Unit-based measurement of lower extremity kinematics over long durations

abstract:
BackgroundThe ability to measure joint kinematics in natural environments over long durations using inertial measurement units (IMUs) could enable at-home monitoring and personalized treatment of neurological and musculoskeletal disorders. However, drift, or the accumulation of error over time, inhibits the accurate measurement of movement over long durations. We sought to develop an open-source workflow to estimate lower extremity joint kinematics from IMU data that was accurate, and capable of assessing and mitigating drift.

MethodsWe computed IMU-based estimates of kinematics using sensor fusion and an inverse kinematics approach with a constrained biomechanical model. We measured kinematics for 11 subjects as they performed two 10-minute trials: walking and a repeated sequence of varied lower-extremity movements. To validate the approach, we compared the joint angles computed with IMU orientations to the joint angles computed from optical motion capture using root mean square (RMS) difference and Pearson correlations, and estimated drift using a linear regression on each subjects RMS differences over time.

ResultsIMU-based kinematic estimates agreed with optical motion capture; median RMS differences over all subjects and all minutes were between 3-6 degrees for all joint angles except hip rotation and correlation coefficients were moderate to strong (r = 0.60 to 0.87). We observed minimal drift in the RMS differences over ten minutes; the average slopes of the linear fits to these data were near zero (-0.14 to 0.17 deg/min).

ConclusionsOur workflow produced joint kinematics consistent with those estimated by optical motion capture, and could mitigate kinematic drift even in the trials of continuous walking without rest, obviating the need for explicit sensor recalibration (e.g. sitting or standing still for a few seconds or zero-velocity updates) used in current drift-mitigation approaches. This could enable long-duration measurements, bringing the field one step closer to estimating kinematics in natural environments.

category: bioengineering


title: A comparative life cycle analysis of electromicrobial production systems

abstract: Electromicrobial production (EMP) processes represent an attractive strategy for the capture and conversion of CO2 into carbon-based products. We describe the development and application of comprehensive reactor, process, and life cycle impact models to analyze three major EMP systems relying on formate, H2, and acetate as intermediate molecules. Our results demonstrate that EMP systems can achieve a smaller carbon footprint than traditional bioprocessing strategies provided the electric grid is composed of >~90% renewable energy sources. For each of the three products we consider (biomass, enzymes, and lactic acid), the H2-mediated Knallgas bacteria system achieves the lowest overall global warming potential, indicating that this EMP strategy may be best-suited for industrial efforts based on current technology. We also identify environmental hotspots and process limitations that are key sites for future engineering and research efforts for each EMP system. Our analysis demonstrates the utility of an integrated bioelectrochemical model/life cycle assessment framework in both analyzing and aiding the ecodesign of electromicrobial processes and should help guide the design of working, scalable, and sustainable systems.


title: Characterizing collaborative transcription regulation with a graph-based deep learning approach

abstract: Human epigenome and transcription activities have been characterized by a number of sequence-based deep learning approaches which only utilize the DNA sequences. However, transcription factors interact with each other, and their collaborative regulatory activities go beyond the linear DNA sequence. Therefore leveraging the informative 3D chromatin organization to investigate the collaborations among transcription factors is critical. We developed ECHO, a graph-based neural network, to predict chromatin features and characterize the collaboration among them by incorporating 3D chromatin organization from 200-bp high-resolution Micro-C contact maps. ECHO predicts 2, 583 chromatin features with significantly higher average AUROC and AUPR than the best sequence-based model. We observed that chromatin contacts of different distances affected different types of chromatin features prediction in diverse ways, suggesting complex and divergent collaborative regulatory mechanisms. Moreover, ECHO was interpretable via gradient-based attribution methods. The attributions on chromatin contacts identify important contacts relevant to chromatin features. The attributions on DNA sequences identify TF binding motifs and TF collaborative binding. Furthermore, combining the attributions on contacts and sequences reveals important sequence patterns in the neighborhood which are relevant to target sequences chromatin feature prediction. The attribution results that reveal TF collaboration activities are provided on a website https://echo.dcmb.med.umich.edu/echo/.


title: In-silico pharmacophore and Molecular Docking based drug discovery against Marburg Virus Viral Protein VP35; A potent of MAVD.

abstract: Marburg virus is a member of filoviridae and spreads severe Marburg hemorrhagic illness in humans and animals. Nowadays, there is no vaccine available that can completely stop the replication of Marburg replication. Therefore, this study is designed to repurpose the effective therapeutic antiviral drug by using a computational approach against exploring the mechanism of Marburg virus Viral protein 35. We have retrieved about 40570 drug-like small compounds from the ZINC database using the "ZINC Pharmer" online tool. Molecular docking of the ligands from the ready-to-dock database has been carried out using MOE. The five drugs have been identified to bind with VP35 possibly. A study was also performed to evaluate the drug-like characteristics of the substances for absorption, distribution, metabolism, and excretion (ADME). The findings clearly showed that ligands are interacting with the MARV VP35 protein. Interestingly, Lipinskis rule of five was observed by all ligands. These findings provide the foundation for reconstituting and utilizing molecules as a possible therapy for Marburg Virus Disease (MVD).


title: Locality-sensitive hashing enables signal classification in high-throughput mass spectrometry raw data at scale

abstract: Mass spectrometry is an important experimental technique in the field of proteomics. However, analysis of certain mass spectrometry data faces a combination of two challenges: First, even a single experiment produces a large amount of multi-dimensional raw data and, second, signals of interest are not single peaks but patterns of peaks that span along the different dimensions. The rapidly growing amount of mass spectrometry data increases the demand for scalable solutions. Existing approaches for signal detection are usually not well suited for processing large amounts of data in parallel or rely on strong assumptions concerning the signals properties. In this study, it is shown that locality-sensitive hashing enables signal classification in mass spectrometry raw data at scale. Through appropriate choice of algorithm parameters it is possible to balance false-positive and false-negative rates. On synthetic data, a superior performance compared to an intensity thresholding approach was achieved. The implementation scaled out up to 88 threads on real data. Locality-sensitive hashing is a desirable approach for signal classification in mass spectrometry raw data. Generated data and code are available at https://github.com/hildebrandtlab/mzBucket. Raw data is available at https://zenodo.org/record/5036526.


title: Knowledge-based antibody repertoire simulation, a novel allele detection tool evaluation and application

abstract: Detailed knowledge of the diverse immunoglobulin germline genes is critical for the study of humoral immunity. Hundreds of alleles have been discovered by analyzing antibody repertoire sequencing (Rep-seq or Ig-seq) data via multiple novel allele detection tools (NADTs). However, the performance of these NADTs through antibody sequences with intrinsic somatic hypermutations (SHMs) is unclear. Here, we developed a tool to simulate repertoires by integrating the full spectrum features of an antibody repertoire such as germline gene usage, junctional modification, position-specific SHM and clonal expansion based on 2152 high-quality datasets. We then systematically evaluated these NADTs using both simulated and genuine Ig-seq datasets. Finally, we applied these NADTs to 687 Ig-seq datasets and identified 43 novel alleles using defined criteria. Twenty-five alleles were validated through findings of other sources. In addition to the novel alleles detected, our simulation tool, the results of our comparison, and the streamline of this process may benefit further humoral immunity studies via Ig-seq.


title: Gradient-mixing LEGO robots for purifying DNA origami nanostructures of multiple components rate-zonal centrifugation

abstract: DNA origami purification is critical in emerging applications of functionalized DNA nanostructures from basic fundamental biophysics, nanorobots to therapeutics. Advances in DNA origami purification have led to the establishment of rate-zonal centrifugation (RZC) as a scalable, high-yield, and contamination-free approach to purifying DNA origami nanostructures. In RZC purification, a linear density gradient is created using viscous agents, such as glycerol and sucrose, to separate molecules based on their mass and shape during high-rpm centrifugation. However, current methods for creating density gradients are typically time-consuming because of their reliance on slow passive diffusion. Here, we built a LEGO gradient mixer to rapidly create a quasi-continuous density gradient with minimal layering of concentrations using simple rotational motion. We found that rotating two layers of different concentrations at an angle can reduce the diffusion time from a few hours to mere minutes. The instrument needed to perform the movement can be constructed from low-cost components, such as Arduino and LEGO Mindstorms pieces, and has comparable efficacy to commercial gradient mixers currently available. Our results demonstrate that the creation of a linear density gradient can be achieved with minimal labor, time, and cost with this machine. With the recent advances in DNA origami production, we anticipate our findings to further improve the viability of scaling up DNA origami purification in grams quantities. Our simple process enables automated large-scale purification of functionalized DNA origami more feasible in resource-constrained settings.

category: biophysics


title: Gradient-mixing LEGO robots for purifying DNA origami nanostructures of multiple components by rate-zonal centrifugation


title: Associations between Acoustic Features of Maternal Speech and Infants' Emotion Regulation following a Social Stressor

abstract: Caregiver voices may provide cues to mobilize or calm infants. This study examined whether maternal prosody predicted changes in infants biobehavioral state during the Still Face, a stressor in which the mother withdraws and reinstates social engagement. Ninety-four dyads participated in the study (infant age 4-8 months). Infants heart rate and respiratory sinus arrhythmia (measuring cardiac vagal tone) were derived from an electrocardiogram (ECG). Infants behavioral distress was measured by negative vocalizations, facial expressions, and gaze aversion. Mothers vocalizations were measured with spectral analysis and spectro-temporal modulation using a two-dimensional fast Fourier transformation of the audio spectrogram. High values on the maternal prosody composite were associated with decreases in infants heart rate ({beta}=-.26, 95% CI: [-.46, -.05]) and behavioral distress ({beta}=-.20, 95% CI: [-.38, -.02]), and increases in cardiac vagal tone in infants whose vagal tone was low during the stressor (1 SD below mean {beta}=.39, 95% CI: [.06, .73]). High infant heart rate predicted increases in the maternal prosody composite ({beta}=.18, 95% CI: [.03, .33]). These results suggest specific vocal acoustic features of speech that are relevant for regulating infants biobehavioral state and demonstrate mother-infant bi-directional dynamics.


title: The spatial transcriptomic landscape of the healing intestine following damage

abstract: The intestinal barrier is composed of a complex cell network defining highly compartmentalized and specialized structures. Here, we use spatial transcriptomics (ST) to define how the transcriptomic landscape is spatially organized in the steady state and healing murine colon. At steady state conditions, we demonstrate a previously unappreciated molecular regionalization of the colon, which dramatically changes during mucosal healing. Here, we identified spatially-organized transcriptional programs defining compartmentalized mucosal healing, and regions with dominant wired pathways. Furthermore, we showed that decreased p53 activation defined areas with increased presence of proliferating epithelial stem cells. Finally, we used our resource to map transcriptomics modules associated with human diseases demonstrating that ST can be used to inform clinical practice. Overall, we provide a publicly available resource defining principles of transcriptomic regionalization of the colon during mucosal healing and a framework to develop and progress further hypotheses.


title: A topographical and physiological exploration of C-tactile afferents and their response to menthol and histamine.

abstract: Numerous microneurography studies in the human peroneal nerve have suggested that CT afferents are lacking in the more distal parts of the limbs. Here we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves, with the most distal receptive fields located on the proximal phalanx of the third finger for the superficial branch of the radial nerve, and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial, radial and peroneal nerves. Moreover, we found that while CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared to C nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, including a lack of responsiveness to heat, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch.


title: Behavioral and fMRI evidence that arousal enhances bottom-up attention and memory selectivity in young but not older adults

abstract: During a challenge or emotional experience, increases in arousal help us focus on the most salient or relevant details and ignore distracting stimuli. The noradrenergic system integrates signals about arousal states throughout the brain and helps coordinate this adaptive attentional selectivity. However, age-related changes in the noradrenergic system and attention networks in the brain may reduce the efficiency of arousal to modulate selective processing in older adults. In the current neuroimaging study, we examined age differences in how arousal affects bottom-up attention to category-selective stimuli differing in perceptual salience. We found a dissociation in how arousal modulates selective processing in the young and older brain. In young adults, emotionally arousing sounds enhanced selective incidental memory and brain activity in the extrastriate body area for salient versus non-salient images of bodies. Older adults showed no such advantage in selective processing under arousal. These age differences could not be attributed to changes in the arousal response or less neural distinctiveness in old age. Rather, our results suggest that, relative to young adults, older adults become less effective at focusing on salient over non-salient details during increases in emotional arousal.


title: The Role of the Human Brain Neuron-Glia-Synaptic Composition in Forming Resting State Functional Connectivity Networks

abstract: While significant progress has been achieved in studying resting state functional networks in a healthy human brain and in a wide range of clinical conditions, many questions related to their relationship to the brains cellular constituents remain open. Herein we use quantitative Gradient-Recalled-Echo (qGRE) MRI for mapping human brain cellular composition, and BOLD (blood oxygen level dependent) MRI to explore how the brain cellular constituents relate to resting state functional networks. Results show that the BOLD-signal-defined synchrony of connections between cellular circuits in network-defined individual functional units is mainly associated with the regional neuronal density, while the between-functional-units connectivity strength is also influenced by the glia and synaptic components of brain tissue cellular constituents. These mechanisms lead to a rather broad distribution of resting state functional networks properties. Visual networks with the highest neuronal density (but lowest density of glial cells and synapses) exhibit the strongest coherence of BOLD signal, as well as the strongest intra-network connectivity. The Default Mode Network (DMN) is positioned near the opposite part of the spectrum with relatively low coherence of the BOLD signal but a remarkably balanced cellular content enabling DMN prominent role in the overall organization of the brain and the hierarchy of functional networks.


title: Environmental transmission of Pseudogymnoascus destructans to hibernating little brown bats

abstract: Pathogens with persistent environmental stages can have devastating effects on wildlife communities. White-nose syndrome (WNS), caused by the fungus Pseudogymnoascus destructans, has caused widespread declines in bat populations of North America. In 2009, during the early stages of the WNS investigation and before molecular techniques had been developed to readily detect P. destructans in environmental samples, we initiated this study to assess whether P. destructans can persist in the hibernaculum environment in the absence of its conclusive bat host and cause infections in naive bats. We transferred little brown bats (Myotis lucifugus) from an unaffected winter colony in northwest Wisconsin to two P. destructans contaminated hibernacula in Vermont where native bats had been excluded. Infection with P. destructans was apparent on some bats within 8 weeks following the introduction of unexposed bats to these environments, and mortality from WNS was confirmed by histopathology at both sites 14 weeks following introduction. These results indicate that environmental exposure to P. destructans is sufficient to cause the infection and mortality associated with WNS in naive bats, which increases the probability of winter colony extirpation and complicates conservation efforts.


title: Blockade of pro-fibrotic response mediated by the miR-143/-145 cluster prevents targeted therapy-induced phenotypic plasticity and resistance in melanoma

abstract: Lineage dedifferentiation towards a mesenchymal-like state is a common mechanism of adaptive response and resistance to targeted therapy in melanoma. Yet, the transcriptional network driving this phenotypic plasticity remains elusive. Remarkably, this cellular state displays myofibroblast and fibrotic features and escapes MAPK inhibitors (MAPKi) through extracellular matrix (ECM) remodeling activities. Here we show that the anti-fibrotic drug Nintedanib/BIBF1120 is active to normalize the fibrous ECM network, enhance the efficacy of MAPK-targeted therapy and delay tumor relapse in a pre-clinical model of melanoma. We also uncovered the molecular networks that regulate the acquisition of this resistant phenotype and its reversion by Nintedanib, pointing the miR-143/-145 pro-fibrotic cluster as a driver of the therapy-resistant mesenchymal-like phenotype. Upregulation of the miR-143/-145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile of resistant cells. The 2 mature miRNAs generated from this cluster, miR-143-3p and miR-145-5p collaborated to mediate phenotypic transition towards a drug resistant undifferentiated mesenchymal-like state by targeting Fascin actin-bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics as well as contributing to a fine-tuning of mechanotransduction pathways. Our study brings insights into a novel miRNA-mediated regulatory network that contributes to non-genetic adaptive drug resistance and provides proof-of-principle that preventing MAPKi-induced pro-fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.

category: cancer biology


title: Co-deletion of ATAD1 with PTEN primes cells for BIM-mediated apoptosis

abstract: PTEN is a potent tumor suppressor gene that is frequently mutated or deleted in human cancers. Such deletions often include portions of the 10q23 locus beyond the bounds of PTEN itself, in many cases resulting in the disruption of additional genes. Coincidental loss of PTEN-adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically. Here we describe how the loss of ATAD1, which is adjacent to and frequently co-deleted with PTEN, predisposes cancer cells to apoptosis and correlates with improved survival in cancer patients. ATAD1 directly and specifically extracts the pro-apoptotic BIM protein from mitochondria to inactivate it. Cells lacking ATAD1 are hypersensitive to clinically used proteasome inhibitors, which increase BIM and trigger apoptosis. Thus, we demonstrate that mitochondrial protein quality control interfaces with cell death in a clinically actionable manner.