A behavioral paradigm for cortical control of a robotic arm by freely moving rats in a one-dimensional two-target reaching task Controlling the trajectory of a neuroprosthetic device to reach multiple targets is a commonly used brain-machine interface (BMI) task in primates and has not been available for rodents yet. Here, we describe a novel experimental paradigm which enables this task for rats in one-dimensional space for reaching two distant targets depending on their limited cognitive and visual capabilities compared to primates. An online transform was used to convert the activity of a pair of primary motor cortex (M1) units into two robotic actions. The rats were shaped to adapt to the transform and direct the robotic actuator toward the selected target by modulating the activity of the M1 neurons. All three rats involved in the study were capable of achieving randomly selected targets with at least 78% accuracy. A total of 9 out of 16 pairs of units examined were eligible for exceeding this success criterion. Two out of three rats were capable of reversal learning, where the mapping between the activity of the unit pairs and the robotic actions were reversed. The present work is the first demonstration of trajectory-based control of a neuroprosthetic device by rodents to reach two distant targets using visual feedback. The paradigm introduced here may be used as a cost-effective platform for elucidating the information processing principles in the neural circuits related to neuroprosthetic control and for studying the performance of novel BMI technologies using freely moving rats.
Temporal responses of bumblebee gustatoryneurons to sugars The sense of taste permits the recognition of valuable nutrients and the avoidance of potential toxins. Models of gustatory coding propose that within modalities (e.g. sweet, bitter, etc.), taste ligands are not distinct stimuli. However, these models are based on data from mice or flies that have omnivorous, non-specialist diets. A specialist feeder might, however, be expected to have acuity within modality if stimulus resolution was critical to survival. Previously, we found that bumblebees have a specialized mechanism for sensing sugars whereby two gustatory receptor neurons (GRNs) within the galeal sensilla of the bees mouthparts exhibit burst of spikes. Here, we show that the temporal firing patterns of these GRNs separate sugars into four distinct groups that correlate with sugar nutritional value and palatability. We also identified a third GRN that responded to stimulation with relatively high concentrations of fructose, sucrose, and maltose. Sugars that were non-metabolizable or toxic suppressed the responses of bursting GRNs to sucrose. These abilities to encode information about sugar value are a refinement to the bumblebees sense of sweet taste that could be an adaptation that enables precise calculations of the nature and nutritional value of floral nectar.
HYBRID REACTION-DIFFUSION AND CLOCK-AND-WAVEFRONT MODEL FOR THE ARREST OF OSCILLATIONS IN THE SOMITOGENESIS SEGMENTATION CLOCK AO_SCPLOWBSTRACTC_SCPLOWThe clock and wavefront paradigm is arguably the most widely accepted model for explaining the embryonic process of somitogenesis. According to this model, somitogenesis is based upon the interaction between a genetic oscillator, known as segmentation clock, and a differentiation wavefront, which provides the positional information indicating where each pair of somites is formed. Shortly after the clock and wavefront paradigm was introduced, Meinhardt presented a conceptually different mathematical model for morphogenesis in general, and somitogenesis in particular. Recently, Cotterell et al. rediscovered an equivalent model by systematically enumerating and studying small networks performing segmentation. Cotterell et al. called it a progressive oscillatory reaction-diffusion (PORD) model. In the Meinhardt-PORD model, somitogenesis is driven by short-range interactions and the posterior movement of the front is a local, emergent phenomenon, which is not controlled by global positional information. With this model, it is possible to explain some experimental observations that are incompatible with the clock and wavefront model. However the Meinhardt-PORD model has some important disadvantages of its own. Namely, it is quite sensitive to fluctuations and depends on very specific initial conditions (which are not biologically realistic). In this work, we propose an equivalent Meinhardt-PORD model, and then amend it to couple it with a wavefront consisting of a receding morphogen gradient. By doing so, we get a hybrid model between the Meinhardt-PORD and the clock-and-wavefront ones, which overcomes most of the deficiencies of the two originating models.

Somitogenesis, the process by which somites are formed, is an essential developmental stage in many vertebrates. This process occurs with a strikingly regular periodicity, that is preserved among embryos of a single species. The clock and wavefront paradigm is arguably the most widely accepted model for explaining somitogenesis. However, it is incapable of explaining some experimental facts, like the appearance of somites in the absence of an external wavefront (i.e. a receding morphogen gradient). Shortly after the clock and wavefront paradigm was introduced, Meinhardt presented a conceptually different mathematical model for morphogenesis in general, and somitogenesis in particular. Recently, Cotterell et al. rediscovered an equivalent model by systematically enumerating and studying small networks performing segmentation, and called it a progressive oscillatory reaction-diffusion (PORD) model. The Meinhardt-PORD model tackles some of the deficiencies of the clock and wave-front models, but it has some serious issues of its own. In the present work, we introduce an equivalent Meinhardt-PORD model, and then amend it to couple it with a receding morphogen gradient. By doing so, we get a hybrid model that incorporates characteristics of the Meinhardt-PORD and clock-and-wavefront models. We show that this hybrid model under-goes a bifurcation, from a stable to an unstable limit cycle, as the value of the parameter accounting for a background regulatory input (associated to the receding morphogen gradient) decreases. This bifurcation allows the model to explain why somites can form in the absence of an external wavefront, reassesses the role of the receding morphogen gradient as a conductor for somitogenesis, and makes the model behavior robust to random fluctuations, as well as independent from specific initial conditions (the latter, are two of the weak points of the Meinhardt-PORD model). We argue that this findings provide convincing evidence that reaction-diffusion and positional information (receding morphogen gradient) mechanisms could work together in somitogenesis. A rationalized definition of tumor suppressor microRNAsexcludes miR-34a While several microRNAs (miRNAs) have been proposed to act as tumor suppressors, a consensual definition of tumor suppressing miRNAs is still missing. Similarly to coding genes, we propose that tumor suppressor miRNAs must show evidence of genetic or epigenetic inactivation in cancers, and exhibit an anti-tumorigenic (e.g., anti-proliferative) activity under endogenous expression levels. Here we observe that this definition excludes the most extensively studied tumor suppressor candidate miRNA, miR-34a. In analyzable cancer types, miR-34a does not appear to be down-regulated in primary tumors relatively to normal adjacent tissues. Deletion of miR-34a is occasionally found in human cancers, but it does not seem to be driven by an anti-tumorigenic activity of the miRNA, since it is not observed upon smaller, miR-34a-specific alterations. Its anti-proliferative action was observed upon large, supra-physiological transfection of synthetic miR-34a in cultured cells, and our data indicates that endogenous miR-34a levels do not have such an effect. Our results therefore argue against a general tumor suppressive function for miR-34a, providing an explanation to the lack of efficiency of synthetic miR-34a administration against solid tumors. Inhibitors of ERp44, PDIA1, and AGR2 induce disulfide-mediated oligomerization of Death Receptors 4 and 5 and cancer cell death Breast cancer mortality remains unacceptably high, indicating a need for safer and more effective therapeutic agents. Disulfide bond Disrupting Agents (DDAs) were previously identified as a novel class of anticancer compounds that selectively kill cancers that overexpress the Epidermal Growth Factor Receptor (EGFR) or its family member HER2. DDAs kill EGFR+ and HER2+ cancer cells via the parallel downregulation of EGFR, HER2, and HER3 and activation/oligomerization of Death Receptors 4 and 5 (DR4/5). However, the mechanisms by which DDAs mediate these effects are unknown. Affinity purification analyses employing biotinylated-DDAs reveal that the Protein Disulfide Isomerase (PDI) family members AGR2, PDIA1, and ERp44 are DDA target proteins. Further analyses demonstrate that shRNA-mediated knockdown of AGR2 and ERp44, or expression of ERp44 mutants, enhance basal and DDA-induced DR5 oligomerization. DDA treatment of breast cancer cells disrupts PDIA1 and ERp44 mixed disulfide bonds with their client proteins. Together, the results herein reveal DDAs as the first small molecule, active site inhibitors of AGR2 and ERp44, and demonstrate roles for AGR2 and ERp44 in regulating the activity, stability, and localization of DR4 and DR5, and activation of Caspase 8. A Hierarchy of Biomolecular Proportional-Integral-Derivative Feedback Controllers for Robust Perfect Adaptation and Dynamic Performance Proportional-Integral-Derivative (PID) feedback controllers have been the most widely used controllers in industry for almost a century due to their good performance, simplicity, and ease of tuning. Motivated by their success in various engineering disciplines, PID controllers recently found their way into synthetic biology, where the design of feedback molecular control systems has been identified as an important goal. In this paper, we consider the mathematical realization of PID controllers via biomolecular interactions. We propose an array of topologies that offer a compromise between simplicity and high performance. We first demonstrate that different Proportional-Integral (PI) controllers exhibit different capabilities for enhancing the dynamics and reducing variance (cell-to-cell variability). Next, we introduce several derivative controllers that are realized based on incoherent feedforward loops acting in a feedback configuration. Alternatively, we show that differentiators can be realized by placing molecular integrators in a negative feedback loop--an arrangement that can then be augmented by PI components to yield PID feedback controllers. We demonstrate that the derivative component can be exploited for enhancing system stability, dramatically increasing the molecular control systems dynamic performance, and for reducing the noise effect on the output of interest. The PID controller features are established through various deterministic and stochastic analyses as well as numerical simulations. Finally, we provide an experimental demonstration using a recently developed hybrid setup, the cyberloop, where the controller is implemented in silico to control a biological genetic circuit in vivo. The large array of novel biomolecular PID controllers introduced here forms a basis for the design and construction of advanced high-performance biomolecular control systems that robustly regulate the dynamics of living systems. TRF2 rescues telomere attrition and prolongs cell survival in Duchenne muscular dystrophy cardiomyocytes derived from human iPSCs Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Heart failure, driven by cardiomyocyte death, fibrosis, and the development of dilated cardiomyopathy, is the leading cause of death in DMD patients. Current treatments decrease the mechanical load on the heart, but do not address the root cause of dilated cardiomyopathy: cardiomyocyte death. Previously, we showed that telomere shortening is a hallmark of cardiomyocytes in DMD patient cardiac tissues and in a mouse model of DMD we generated that manifests dilated cardiomyopathy. We also found that this telomere shortening is recapitulated in DMD cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs). Here we further characterize that DMD cardiomyocytes exhibit reduced cell size, nuclear size, and sarcomere density compared to healthy isogenic controls. The telomere-binding protein, TRF2, is a core component of the shelterin complex, which protects chromosome ends and is expressed at lower levels in DMD cardiomyocytes compared to controls. We investigated whether preservation of telomere length could be achieved with upregulation of TRF2. We found that TRF2 upregulation in DMD cardiomyocytes increased telomere lengths, cell size, nuclear size, sarcomere density, and cell survival. These data suggest TRF2 gene therapy has the potential to delay the onset of dilated cardiomyopathy. A variable-gain stochastic pooling motif mediates information transfer from receptor assemblies into NF-κB A myriad of inflammatory cytokines regulate signaling pathways to maintain cellular homeostasis. The IKK complex is an integration hub for cytokines that govern NF-{kappa}B signaling. In response to inflammation, IKK is activated through recruitment to receptor-associated protein assemblies. How and what information IKK complexes transmit about the milieu are open questions. Here we track dynamics of IKK complexes and nuclear NF-{kappa}B to identify upstream signaling features that determine same-cell responses. Experiments and modeling of single complexes reveals their size, number, and timing relays cytokine-specific information with feedback control that is independent of transcription. Our results provide evidence for variable-gain stochastic pooling, a noise-reducing motif that enables parsimonious and cytokine-specific information transfer. We propose that emergent properties of stochastic pooling are general principles of receptor signaling.

One Sentence SummaryA variable-gain stochastic pooling motif mediates robust and tunable information transmission from the extracellular milieu into the cell. A bacterial effector counteracts host autophagy by promoting degradation of an autophagy component Beyond its role in cellular homeostasis, autophagy plays anti- and pro-microbial roles in host-microbe interactions, both in animals and plants. One prominent role of anti-microbial autophagy is to degrade intracellular pathogens or microbial molecules, in a process termed xenophagy. Consequently, microbes evolved mechanisms to hijack or modulate autophagy to escape elimination. Although well-described in animals, the extent to which xenophagy contributes to plant-bacteria interactions remains unknown. Here, we provide evidence that Xanthomonas campestris pv. vesicatoria (Xcv) suppresses host autophagy by utilizing type-III effector XopL. XopL interacts with and degrades the autophagy component SH3P2 via its E3 ligase activity to promote infection. Intriguingly, XopL is targeted for degradation by defense-related selective autophagy mediated by NBR1/Joka2, revealing a complex antagonistic interplay between XopL and the host autophagy machinery. Our results implicate plant antimicrobial autophagy in depletion of a bacterial virulence factor and unravels an unprecedented pathogen strategy to counteract defense-related autophagy. The initial response of females towards congeneric males matches the propensity to hybridise in Ophthalmotilapia. AO_SCPLOWBSTRACTC_SCPLOWCichlid radiations often harbour closely related species with overlapping niches and distribution ranges. Such species sometimes hybridise in nature, which raises the question how can they coexist. This also holds for the Tanganyika mouthbrooders Ophthalmotilapia ventralis and O. nasuta. Earlier studies found indications of asymmetrical hybridisation with females of O. ventralis accepting males of O. nasuta, but not the other way around. We hypothesised that this was due to differences in the capacity for species recognition. Given the higher propensity of O. ventralis females towards hybridisation, we expect a reduced ability for species recognition in O. ventralis females, compared to O. nasuta females. We staged two experiments, one focusing on 22 female O. nasuta and one on 21 female O. ventralis. These fish were placed in one half of a tank and briefly exposed to a conspecific or a heterospecific male, a conspecific female, or nothing (control). Female response was evaluated by scoring six tracking parameters and by noting the occurrence of ten discrete behaviours before and during the encounter. Females always responded to the presence of another fish by approaching it. Remarkably, for both O. nasuta and O. ventralis, we did not find a different response between encounters with conspecific males and females. However, in agreement with our hypothesis, O. nasuta females behaved differently towards conspecific or heterospecific males, whereas O. ventralis females did not. When presented with a heterospecific male, O. nasuta females performed a lower number of  ram behaviours. Additionally, they never displayed the  flee behaviour, a component of the species mating repertoire that was seen in all but one of the presentations with a conspecific male. Our findings show that differences in species recognition at first encounter predict to a large degree the outcome of the mating process, even in the absence of mating behaviour. Diverse stem-chondrichthyan oral structures and evidence for an independently acquired acanthodid dentition The teeth of sharks famously form a series of transversely-organised files with conveyor-belt replacement that are borne directly on the jaw cartilages, in contrast to the dermal plate-borne dentition of bony fishes that undergoes site-specific replacement. A major obstacle in understanding how this system evolved is the poorly understood relationships of the earliest chondrichthyans and the profusion of morphologically and terminologically diverse bones, cartilages, splints and whorls that they possess. Here we use tomographic methods to investigate mandibular structures in several early branching  acanthodian-grade stem-chondrichthyans. We show that the dentigerous jaw bones of disparate genera of ischnacanthids are united by a common construction, being growing bones with non-shedding dentition. Mandibular splints, which support the ventro-lateral edge of the Meckels cartilage in some taxa, are formed from dermal bone and may be an acanthodid synapomorphy. We demonstrate that the teeth of Acanthodopsis are borne directly on the mandibular cartilage and that this taxon is deeply nested within an edentulous radiation, representing an unexpected independent origin of teeth. Many or even all of the range of unusual oral structures may be apomorphic, but they should nonetheless be considered when building hypotheses of tooth and jaw evolution, both in chondrichthyans and more broadly. Polycystins are upregulated in fibrotic kidneys and promote renal fibrosis Autosomal polycystic kidney disease (ADPKD) is caused by mutations in PKD1or PKD2 gene, which encodes polycystin-1 or polycystin-2 respectively. Paradoxically, polycystins are up-regulated in human ADPKD kidneys and overexpression of polycystin-1 even induced renal cyst formation in mice, suggesting that up-regulation of polycystin is pathogenic. In this study, we determined the role of polycystin in renal fibrosis and explored its underlying mechanisms. We found that the expression of polycystin-1 or polycystin-2 was positively correlated with the expression of collagen-I in the kidney of three different fibrotic mouse models. Pharmaceutical inhibition or genetic knockout of polycystin-2 reduced the expression of pro-fibrotic markers in fibrotic kidneys of two animal models. Moreover, conditional knockout of Pkd1 gene attenuated renal fibrosis in two mouse models. Enhancer of Zeste homolog 2 (EZH2) is a methyltransferase which plays important role in renal fibrosis. We found that EZH2 was positively correlated with the expression of polycystins in fibrotic kidneys. Conditional knockout of the Ezh2 attenuated the anti-fibrotic responses induced by Pkd1 deletion in fibrotic kidneys.

In conclusion, polycystins are up-regulated in injured kidneys and polycystins promote renal fibrosis through up-regulation of EZH2 in fibrotic kidneys, suggesting that renal fibrosis in polycystic kidneys is not the direct effect of PKD gene mutations.

SignificanceMutations of polycystins cause autosomal polycystic kidney disease (ADPKD) which is associated with increased renal fibrosis in cystic kidneys. However, the role of polycystin in renal fibrosis remains unclear. Here, we showed that the expression of polycystins is positively correlated with the development of renal fibrosis in injured kidneys. Pharmaceutical inhibition or genetic deletion of polycystin-2 attenuated renal fibrosis in fibrotic kidneys. Moreover, genetic deletion of polycystin-1 inhibited renal fibrosis in two different animal models. Finally, we showed that ablation of the methyltransferase EZH2 mitigated the anti-fibrotic effect of polycystin-1 deletion in fibrotic kidneys. We conclude that polycystin promotes through EZH2 and renal fibrosis in cystic kidney is not the direct effect of PKD gene mutations. Host cell membrane capture by the SARS CoV-2 spike protein fusion intermediate Cell entry by SARS-CoV-2 is accomplished by the S2 subunit of the spike S protein on the virion surface by capture of the host cell membrane and fusion with the viral envelope. Capture and fusion require the prefusion S2 to transit to its potent, fusogenic form, the fusion intermediate (FI). However, the FI structure is unknown, detailed computational models of the FI are unavailable, and the mechanisms and timing of membrane capture and fusion are not established. Here, we constructed a full-length model of the CoV-2 FI by extrapolating from known CoV-2 pre- and postfusion structures. In atomistic and coarse-grained molecular dynamics simulations the FI was remarkably flexible and executed large bending and extensional fluctuations due to three hinges in the C-terminal base. Simulations suggested a host cell membrane capture time of [~] 2 ms. Isolated fusion peptide simulations identified an N-terminal helix that directed and maintained binding to the membrane but grossly underestimated the binding time, showing that the fusion peptide environment is radically altered when attached to its host fusion protein. The large configurational fluctuations of the FI generated a substantial exploration volume that aided capture of the target membrane, and may set the waiting time for fluctuation-triggered refolding of the FI that draws the viral envelope and host cell membrane together for fusion. These results describe the FI as a machinery designed for efficient membrane capture and suggest novel potential drug targets.



O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/439051v3_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@1374b59org.highwire.dtl.DTLVardef@133d21forg.highwire.dtl.DTLVardef@127f2ddorg.highwire.dtl.DTLVardef@1b9ab8f_HPS_FORMAT_FIGEXP  M_FIG C_FIG Priority conservation areas and a global population estimate for the Critically Endangered Philippine Eagle derived from modelled range metrics using remote sensing habitat characteristics Many range-restricted taxa are currently experiencing population declines yet lack fundamental information regarding distribution and population size. Establishing baseline estimates for both these key biological parameters is however critical for directing conservation planning for at-risk range-restricted species. The International Union for the Conservation of Nature (IUCN) Red List uses three range metrics that define species distributions and inform extinction risk assessments: extent of occurrence (EOO), area of occupancy (AOO) and area of habitat (AOH). However, calculating all three metrics using standard IUCN approaches relies on a geographically representative sample of locations, which for rare species is often spatially biased. Here, we apply model-based interpolation using Species Distribution Models (SDMs), correlating occurrences with remote-sensing covariates, to calculate IUCN range metrics, protected area coverage and a global population estimate for the Critically Endangered Philippine Eagle (Pithecophaga jefferyi). Our final range wide continuous SDM had high predictive accuracy (Continuous Boyce Index = 0.927) and when converted to a binary model estimated an AOH = 23,185 km2, a maximum EOO = 605,759 km2, a minimum EOO = 272,272 km2, with an AOO = 53,867 km2. Based on inferred habitat from the AOH metric, we estimate a global population of 318 breeding pairs (range: 258-362 pairs), or 636 mature individuals, across the Philippine Eagle global range. Protected areas covered 34 % of AOH, 15 % less than the target representation, with the continuous model identifying key habitat as priority conservation areas. We demonstrate that even when occurrences are geographically biased, robust habitat models can be built that enable quantification of baseline IUCN range metrics, protected area coverage, and a population size estimate. In the absence of adequate location data for many rare and threatened taxa, our method is a promising spatial modelling tool with widespread applications, in particular for island endemics facing high extinction risk. HLA-SPREAD: A Natural Language Processing based resource for curating HLA association from PubMed abstracts Extreme complexity in the Human Leukocyte Antigens (HLA) system and its nomenclature makes it difficult to interpret and integrate relevant information for HLA associations with diseases, Adverse Drug Reactions (ADR) and Transplantation. PubMed search displays [~]144,000 studies on HLA reported from multiple diseases in diverse locations. Currently, IPD-IMGT/HLA database houses data on 28,320 HLA alleles. We developed an automated pipeline with a unified graphical user interface HLA-SPREAD that provides a structured information on SNPs, Populations, REsources, ADRs and Diseases information. Information on HLA was extracted from [~]24 million PubMed abstracts extracted using Natural Language Processing (NLP). Python scripts were used to mine and curate information on diseases, filter false positives and categorize to 24 tree hierarchical groups and named Entity Recognition (NER) algorithms followed by semantic analysis to infer HLA association(s). This resource from 112 countries and 32 ethnic groups provides interesting insights on: markers associated with allelic/haplotypic association in autoimmune, cancer, viral and skin diseases, transplantation outcome and ADRs for hypersensitivity. Summary information on clinically relevant biomarkers related to HLA disease associations with mapped susceptible/risk alleles are readily retrievable from HLASPREAD. The resource is available at URL http://hla-spread.igib.res.in/. This resource is first of its kind that can help uncover novel patterns in HLA gene-disease associations. Clonal Dynamics of Cancer-Initiating Cells in a Mouse Genetic Mosaic Model of Serous Ovarian Cancer High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy. Early detection remains the most promising strategy to decrease mortality and requires a deep understanding of the cancer initiation process. Recent breakthroughs identified the fallopian tube (FT) Pax8+ cells as a cell-of-origin for HGSOC. However, the progressive trajectory from an initiated Pax8+ cell toward malignancy remains elusive. Here, we use a mouse genetic mosaic system called MADM (Mosaic Analysis with Double Markers), which generates sporadic mutant cells labeled with GFP, to trace the clonal dynamics of HGSOC development. Surprisingly, we observed dichotomous clonal expansion kinetics of individual cancer-initiating Pax8+ cells; while the vast majority stalled immediately, a few significantly expanded. Clonal analysis of wildtype cells showed concordant dichotomy, suggesting that a small fraction of Pax8+ cells intrinsically carry higher expansion potential. Furthermore, although all wildtype clones stalled shortly after development, some mutant clones continued to progress, indicating that oncogenic mutations prolong clonal expansion beyond the cell-intrinsic potential. Finally, intra-clonal fate mapping revealed that progressing mutant clones have a higher propensity to produce Pax8+ cells, linking imbalanced cell differentiation to disease progression. In summary, our studies reveal that the earliest clonal expansion during HGSOC initiation emerges when oncogenic mutations exaggerate the intrinsic expansion potential of a rare Pax8+ subset and bias its differentiation potential, warranting future investigation as a readout for early detection and cancer prevention.

SIGNIFICANCE STATEMENTEffective early detection is the most promising approach to manage cancer, but it requires a thorough understanding of cancer initiation and early progression. Serous ovarian cancer has been found to originate from Pax8+ cells in the fallopian tube. To assess the clonal dynamics of cancer-initiating cells, we established a mouse genetic mosaic model that enables clonal analysis of mutant Pax8+ cells in the fallopian tube. We uncovered that the earliest clonal event in ovarian cancer development emerges from a rare subset of stem/progenitor-like cells with intrinsic expansion potential, and that oncogenic mutations exaggerate and prolong this potential to promote cancer initiation. Our findings pinpoint a precise target for future early-detection and cancer prevention studies.

HIGHLIGHTSO_LIOvarian cancer initiation revealed by a mouse genetic mosaic model.
C_LIO_LIDichotomous expansion capacity of initiated cells at the clonal level.
C_LIO_LISynergies between cell-intrinsic properties and onco-mutations fuels clonal expansion.
C_LIO_LIImbalanced differentiation within highly expansive clones leads to Pax8 clusters.
C_LI Severe COVID-19 associated variants linked to chemokine receptor gene control in monocytes and macrophages Genome-wide association studies have identified 3p21.31 as the main risk locus for severe disease in COVID-19 patients, although underlying biological mechanisms remain elusive. We performed a comprehensive epigenomic dissection of the 3p21.31 locus, identifying a CTCF-dependent tissue-specific 3D regulatory chromatin hub that controls the activity of several tissue-homing chemokine receptor (CCR) genes in monocytes and macrophages. Risk SNPs colocalized with regulatory elements and were linked to increased expression of CCR1, CCR2 and CCR5 in monocytes and macrophages. As excessive organ infiltration of inflammatory monocytes and macrophages is a hallmark of severe COVID-19, our findings provide a rationale for the genetic association of 3p21.31 variants with elevated risk of hospitalization upon SARS-CoV-2 infection. Identification of druggable host targets needed for SARS-CoV-2 infection by combined pharmacological evaluation and cellular network directed prioritization both in vitro and in vivo. Identification of host factors contributing to replication of viruses and resulting disease progression remains a promising approach for development of new therapeutics. Here, we evaluated 6710 clinical and preclinical compounds targeting 2183 host proteins by immunocytofluorescence-based screening to identify SARS-CoV-2 infection inhibitors. Computationally integrating relationships between small molecule structure, dose-response antiviral activity, host target and cell interactome networking produced cellular networks important for infection. This analysis revealed 389 small molecules, >12 scaffold classes and 813 host targets with micromolar to low nanomolar activities. From these classes, representatives were extensively evaluated for mechanism of action in stable and primary human cell models, and additionally against Beta and Delta SARS-CoV-2 variants and MERS-CoV. One promising candidate, obatoclax, significantly reduced SARS-CoV-2 viral lung load in mice. Ultimately, this work establishes a rigorous approach for future pharmacological and computational identification of novel host factor dependencies and treatments for viral diseases. Analysis of science journalism reveals gender and regional disparities in coverage Science journalism is a critical way in which the public can remain informed and benefit from new scientific findings. Such journalism also shapes the publics view of the current state of scientific findings and legitimizes experts. Those covering science can only cite and quote a limited number of sources. Sources may be identified by the journalists research or by recommendations by other scientists. In both cases, biases may influence who is identified and ultimately included as an expert. To analyze possible biases in science journalism, we analyzed 22,001 non-research articles published by Nature. We chose to analyze Nature non-research articles since its research articles provide a natural comparator. Our analysis considered two possible sources of disparity: gender and name origin. To explore these sources of disparity, we extracted cited authors names as well as extracted names of quoted speakers. While citations and quotations within a piece do not reflect the entire information-gathering process, they can provide insight into the demographics of visible sources. We then used the extracted names to predict gender and name origin of the cited authors and speakers.

In order to appropriately quantify the level of difference, we must identify a suitable reference set for comparison. We chose first and last authors within primary research articles in Nature and a subset of Springer Nature articles in the same time period as our comparator. In our analysis, we found a skew towards male quotation in Nature science journalism-related articles. However, quotation is trending toward equal representation at a faster rate than first and last authorship in academic publishing. Interestingly, we found that the gender disparity in Nature quotes was column-dependent, with the "Career Features" column reaching gender parity. Our name origin analysis found a significant over-representation of names with predicted Celtic/English origin and under-representation of names with a predicted East Asian origin. This finding was observed both in extracted quotes and journal citations, but dampened in citations. Rapid genotyping of tilapia lake virus (TiLV) using Nanopore sequencing Infectious diseases represent one of the major challenges to sustainable aquaculture production. Rapid, accurate diagnosis and genotyping of emerging pathogens during early-suspected disease cases is critical to facilitate timely response to deploy adequate control measures and prevent or reduce spread. Currently, most laboratories use PCR to amplify partial pathogen genomic regions, occasionally combined with sequencing of PCR amplicon(s) using conventional Sanger sequencing services for confirmatory diagnosis. The main limitation of this approach is the lengthy turnaround time. Here, we report an innovative approach using a previously developed specific PCR assay for pathogen diagnosis combined with a new Oxford Nanopore Technologies (ONT)-based amplicon sequencing method for pathogen genotyping. Using fish clinical samples, we applied this approach for the rapid confirmation of PCR amplicon sequences identity and genotyping of tilapia lake virus (TiLV), a disease-causing virus affecting tilapia aquaculture globally. The consensus sequences obtained after polishing exhibit strikingly high identity to references derived by Illumina and Sanger methods (99.83-100%). This study suggests that ONT-based amplicon sequencing is a promising platform to deploy in regional aquatic animal health diagnostic laboratories in low and medium income countries, for fast identification and genotyping of emerging infectious pathogens from field samples within a single day. Optimal strategies for learning multi-ancestry polygenic scores vary across traits Polygenic scores (PGSs) are individual-level measures that aggregate the genome-wide genetic predisposition to a given trait. As PGS have predominantly been developed using European-ancestry samples, trait prediction using such European ancestry-derived PGS is less accurate in non-European ancestry individuals. Although there has been recent progress in combining multiple PGS trained on distinct populations, the problem of how to maximize performance given a multiple-ancestry cohort is largely unexplored. Here, we investigate the effect of sample size and ancestry composition on PGS performance for fifteen traits in UK Biobank. For some traits, PGS estimated using a relatively small African-ancestry training set outperformed, on an African-ancestry test set, PGS estimated using a much larger European-ancestry only training set. We observe similar, but not identical, results when considering other minority-ancestry groups within UK Biobank. Our results emphasise the importance of targeted data collection from underrepresented groups in order to address existing disparities in PGS performance. Lower limb in sprinters with larger relative mass but not larger normalized moment of inertia Inhomogeneous muscle hypertrophy in response to daily motor executions is a morphological adaptation in humans. Inhomogeneous morphological adaptation would change the mass distribution, which in turn may affect the mechanical difficulty in moving from an inertia perspective; however, the morphological adaptation from the inertia perspective has not been examined. Here we show no corresponding differences in the normalized mass and normalized moment of inertia between the sprinters and the untrained non-sprinters. We analyzed the fat- and water-separated magnetic resonance images from the lower limbs of 11 male sprinters (100 m best time of 10.44-10.83 s) and 12 untrained non-sprinters. The lower-limb relative mass was significantly larger in sprinters (18.7{+/-}0.7% body mass) than in non-sprinters (17.6{+/-}0.6% body mass), while the normalized moment of inertia of the lower limb around the hip in the anatomical position was similar between them (0.044{+/-}0.002 vs. 0.042{+/-}0.002 [a. u.]). The thigh relative mass in sprinters (12.9{+/-}0.4% body mass) was significantly larger than that in non-sprinters (11.9{+/-}0.4% body mass), whereas the shank and foot relative masses were similar. We revealed that the adaptation to sprinting in humans does not relatively increase the mechanical difficulty to swing the lower limb in terms of inertia, even though the lower-limb mass increases, reflecting muscular hypertrophy. This is suggested to be one of the significant advantages of human morphology for adaptability to explosive motor tasks.

NEW & NOTEWORTHYWe compared the lower-limb inertia properties between male sprinters and untrained non-sprinters by using the fat- and water-separated magnetic resonance images. Sprinters had lower limbs with a larger relative mass but not a larger normalized moment of inertia than non-sprinters. We suggest one of the practical advantages of human morphological characteristics for their adaptation to explosive motor tasks, which provides a novel perspective to the literature for understanding human morphological adaptability. A nontoxic tetrodotoxin analog, 5,6,11-trideoxytetrodotoxin, as an olfactory chemoattractant for the grass puffer Toxic puffers contain the potent neurotoxin, tetrodotoxin (TTX). Although TTX is considered to serve as a defense substance, previous behavioral studies have demonstrated that TTX acts as an attractive pheromone for some toxic puffers. To elucidate the physiological mechanism of putative pheromonal action of TTX, we examined whether grass puffers Takifugu alboplumbeus can detect TTX. Electroolfactogram (EOG) results suggest that the olfactory epithelium (OE) of grass puffers responded to a type of TTX analog (5,6,11-trideoxyTTX), although it did not respond to TTX. We also examined the attractive action of 5,6,11-trideoxyTTX on grass puffers by recording their swimming behavior under dark conditions. Grass puffers preferred to stay on the side of the aquarium where 5,6,11-trideoxyTTX was administered, and their swimming speed decreased. Additionally, odorant-induced labeling of olfactory sensory neurons by immunohistochemistry against neural activity marker (phosphorylated extracellular signal regulated kinase; pERK) revealed that labeled olfactory sensory neurons were localized in the region surrounding "islets" where there was considered as nonsensory epithelium. 5,6,11-trideoxyTTX has been known to accumulate in grass puffers, but its toxicity is much lower (almost nontoxic) than TTX. Our results suggest that toxic puffers may positively use this unknown function TTX analog as an olfactory chemoattractant. We get by with a little help from our friends: shared adaptive variation provides a bridge to novel ecological specialists during adaptive radiation 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. Soluble ECM promotes organotypic formation in lung alveolar model Micropatterned suspension culture creates consistently sized and shaped cell aggregates but has not produced organotypic structures from stable cells, thus restricting its use in accurate disease modeling. Here, we show that organotypic structure is achieved in hybrid suspension culture via supplementation of soluble extracellular matrix (ECM). We created a viable lung organoid from epithelial, endothelial, and fibroblast human stable cell lines in suspension culture. We demonstrate the importance of soluble ECM in organotypic patterning with the emergence of lumen-like structures with airspace showing feasible gas exchange units, formation of branching, perfusable vasculature, and long-term 70-day maintenance of lumen structure. Our results show a dependent relationship between enhanced fibronectin fibril assembly and the incorporation of ECM in the organoid. We successfully applied this technology in modeling lung fibrosis via bleomycin induction and test a potential antifibrotic drug in vitro while maintaining fundamental cell-cell interactions in lung tissue. Our human fluorescent lung organoid (hFLO) model represents features of pulmonary fibrosis which were ameliorated by fasudil treatment. We also demonstrate a 3D culture method with potential of creating organoids from mature cells, thus opening avenues for disease modeling and regenerative medicine, enhancing understanding of lung cell biology in health and lung disease. Inhibitory proteins block substrate access by occupying the active site cleft of Bacillus subtilis intramembrane metalloprotease SpoIVFB Intramembrane proteases function in numerous signaling pathways that impact health, but knowledge about regulation of intramembrane proteolysis is limited. We examined inhibition of intramembrane metalloprotease SpoIVFB by proteins BofA and SpoIVFA. We found that BofA residues in and near a predicted transmembrane segment are required for SpoIVFB inhibition, and cross-linking experiments indicated that this transmembrane segment occupies the SpoIVFB active site cleft. SpoIVFA is also required for SpoIVFB inhibition. The inhibitory proteins block access of the substrate N-terminal Proregion to the membrane-embedded SpoIVFB active site, based on additional cross-linking experiments; however, the inhibitory proteins did not prevent interaction between the substrate C-terminal region and the SpoIVFB soluble domain. A structural model was built of SpoIVFB in complex with BofA and parts of SpoIVFA and substrate, using partial homology and constraints from cross-linking and co-evolutionary analyses. The model predicts that conserved BofA residues interact to stabilize a transmembrane segment and a membrane-embedded C-terminal region. SpoIVFA is predicted to bridge the BofA C-terminal region and SpoIVFB, forming a membrane-embedded inhibition complex. Our results reveal a novel mechanism of intramembrane protease inhibition with clear implications for relief from inhibition in vivo and design of inhibitors as potential therapeutics.