Multiscale model of primary motor cortex circuits predicts in vivo cell type-specific, behavioral state-dependent dynamics Understanding cortical function requires studying multiple scales: molecular, cellular, circuit and behavior. We developed a biophysically detailed multiscale model of mouse primary motor cortex (M1) with over 10,000 neurons and 30 million synapses. Neuron types, densities, spatial distributions, morphologies, biophysics, connectivity and dendritic synapse locations were tightly constrained by experimental data. The model includes long-range inputs from 7 thalamic and cortical regions, as well as noradrenergic inputs from locus coeruleus. Connectivity depended on cell class and cortical depth at sublaminar resolution. The model accurately predicted in vivo layer- and cell type-specific responses (firing rates and LFP) associated with behavioral states (quiet wakefulness and movement) and experimental manipulations (noradrenaline receptor blocking and thalamus inactivation). It also enabled evaluation of multiple mechanistic hypotheses underlying the observed activity. This quantitative theoretical framework can be used to integrate and interpret M1 experimental data and sheds light on the cell type-specific multiscale dynamics associated with a range of experimental conditions and behaviors.
Intracranial human recordings reveal intensity coding for the pain of others in the insula Based on neuroimaging data, the insula is considered important for people to empathize with the pain of others, whether that pain is perceived through facial expressions or the sight of limbs in painful situations. Here we present the first report of intracranial electroencephalographic (iEEG) recordings from the insulae collected while 7 presurgical epilepsy patients rated the intensity of a womans painful experiences viewed in movies. In two separate conditions, pain was deduced from seeing facial expressions or a hand being slapped by a belt. We found that broadband activity in the 20-190 Hz range correlated with the trial-by-trial perceived intensity in the insula for both types of stimuli. Using microwires at the tip of a selection of the electrodes, we additionally isolated 8 insular neurons with spiking that correlated with perceived intensity. Within the insula, we found a patchwork of locations with differing selectivities within our stimulus set, some representing intensity only for facial expressions, others only for the hand being hit, and others for both. That we found some locations with intensity coding only for faces, and others only for hand across simultaneously recorded locations suggests that insular activity while witnessing the pain of others cannot be entirely reduced to a univariate salience representation. Psychophysics and the temporal properties of our signals indicate that the timing of responses encoding intensity for the sight of the hand being hit are best explained by kinematic information; the timing of those encoding intensity for facial expressions are best explained by shape information in the face. In particular, the furrowing of the eyebrows and the narrowing of the eyes of the protagonist in the movies suffice to predict both the rating of and the timing of the neuronal response to the facial expressions. Comparing the broadband activity in the iEEG signal with spiking activity and an fMRI experiment with similar stimuli revealed a consistent spatial organization for the representation of intensity from our hand stimuli, with stronger intensity representation more anteriorly and around neurons with intensity coding. In contrast, for the facial expressions, we found that the activity at the three levels of measurement do not coincide, suggesting a more disorganized representation. Together, our intracranial recordings indicate that the insula encodes, in a partially intermixed layout, both static and dynamic cues from different body parts that reflect the intensity of pain experienced by others.
An estimate of the deepest branches of the tree of life from ancient vertically-evolving genes Core gene phylogenies provide a window into early evolution, but different gene sets and analytical methods have yielded substantially different views of the tree of life. Trees inferred from a small set of universal core genes have typically supported a long branch separating the archaeal and bacterial domains. By contrast, recent analyses of a broader set of non-ribosomal genes have suggested that Archaea may be less divergent from Bacteria, and that estimates of inter-domain distance are inflated due to accelerated evolution of ribosomal proteins along the inter-domain branch. Resolving this debate is key to determining the diversity of the archaeal and bacterial domains, the shape of the tree of life, and our understanding of the early course of cellular evolution. Here, we investigate the evolutionary history of the marker genes key to the debate. We show that estimates of a reduced Archaea-Bacteria (AB) branch length result from inter-domain gene transfers and hidden paralogy in the expanded marker gene set. By contrast, analysis of a broad range of manually curated marker gene datasets from an evenly sampled set of 700 Archaea and Bacteria reveal that current methods likely underestimate the AB branch length due to substitutional saturation and poor model fit; that the best-performing phylogenetic markers tend to support longer inter-domain branch lengths; and that the AB branch lengths of ribosomal and non-ribosomal marker genes are statistically indistinguishable. Furthermore, our phylogeny inferred from the 27 highest-ranked marker genes recovers a clade of DPANN at the base of the Archaea, and places CPR within Bacteria as the sister group to the Chloroflexota. Adaptive anti-tumor immunity is orchestrated by a population of CCL5-producing tissue-resident NK cells T cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the IFN{gamma}-IL-12 pathway relies on the ability of a population of tissue-resident NK (trNK) cells to orchestrate an anti-tumor microenvironment. Particularly, utilizing an engineered adenoviral platform, we show that paracrine IL-12 enhances functional DC-CD8 T cell interactions to generate adaptive anti-tumor immunity. This effect depends on the abundance of trNK cells and specifically their capacity to produce the cDC1-chemoattractant CCL5. Failure to respond to IL-12 and other IFN{gamma}-inducing therapies such as immune checkpoint blockade in tumors with low trNK cell infiltration could be overcome by intra-tumoral delivery of CCL5. Our findings reveal a novel barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC crosstalk can be enhanced to promote anti-tumor immunity and overcome resistance.

SignificanceWe identified the lack of CCL5-producing, tissue-resident NK (trNK) cells as a barrier to T cell-focused therapies. While IL-12 induces anti-tumoral DC-T cell crosstalk in trNK cellrich tumors, resistance to IL-12 or anti-PD-1 in trNK cellpoor tumors can be overcome by the additional delivery of CCL5. Effect of sublethal prenatal endotoxaemia on murine placental transport systems and lipid homeostasis Infection alters the expression of transporters that mediate the placental exchange of xenobiotics, lipids and cytokines. We hypothesized that lipopolysaccharide (LPS) modifies the expression of placental transport systems and lipid homeostasis. LPS (150 g/kg; i.p.) treatments were administered for 4 h or 24 h, animals were euthanized at gestational days (GD) 15.5 or 18.5, and maternal blood, foetuses and placentae were collected. Increased rates of foetal demise were observed at GD15.5 following LPS treatment, whereas at GD18.5, high rates of early labour occurred and were associated with distinct proinflammatory responses. LPS did not alter ABC transporter mRNA expression but decreased Fabppm at GD15.5 (LPS-4 h) and increased Fat/Cd36 lipid transporter mRNA at GD18.5 (LPS-4 h). At the protein level, breast cancer-related protein (BCRP) and Abcg1 levels were decreased in the placental labyrinth zone (Lz) at GD15.5, whereas P-glycoprotein (P-gp) and Bcrp Lz-immunostaining was decreased at GD18.5. In the placental junctional zone (Jz), P-gp, Bcrp and Abcg1 levels were higher at GD18.5. Specific maternal plasma and placental changes in triacylglycerol, free fatty acid, cholesterol, cholesterol ester and monoacylglycerol levels were detected in a gestational age-dependent manner. In conclusion, LPS-induced foetal death and early labour were associated with altered placental ABC and lipid transporter expression and deranged maternal plasma and placental lipid homeostasis. These changes likely modify foetal xenobiotic exposure and placental lipid exchange in cases of bacterial infection. Identifying and correcting multiple sources of misspecification in GWAS summary statistics for polygenic scores Publicly available genome-wide association studies (GWAS) summary statistics exhibit uneven quality, which can impact the validity of follow-up analyses. First, we present an overview of possible misspecifications that come with GWAS summary statistics. Then, in both simulations and real data analyses, we show that additional information such as imputation INFO scores, allele frequencies, and per-variant sample sizes in GWAS summary statistics can be used to detect possible issues and correct for misspecifications in the GWAS summary statistics. One important motivation for us is to improve the predictive performance of polygenic scores built from these summary statistics. Unfortunately, due to the lack of reporting standards for GWAS summary statistics, this additional information is not systematically reported. We also show that using well-matched LD references can improve model fit and translate into more accurate prediction. Finally, we discuss how to make polygenic score methods such as lassosum and LDpred2 more robust to these misspecifications to improve their predictive power. Viral manipulation of mechanoresponsive signaling disassembles processing bodies Processing bodies (PBs) are ribonucleoprotein granules that suppress cytokine mRNA translation that are targeted for disassembly by many viruses. Kaposis sarcoma-associated herpesvirus is the etiological agent of the inflammatory endothelial cancer, Kaposis sarcoma, and a PB-regulating virus. The virus encodes Kaposin B (KapB), which induces actin stress fibres (SFs) and cell spindling as well as PB disassembly. We now show that KapB-mediated PB disassembly requires actin rearrangements, RhoA effectors and the mechanoresponsive transcription activator, YAP. Moreover, ectopic expression of active YAP or exposure of ECs to mechanical forces caused PB disassembly in the absence of KapB and mechanoresponsive PB disassembly also required YAP. Using the viral protein KapB, we identified a new consequence of the exposure of cells to mechanical forces that alter actin dynamics and activate YAP, namely the disassembly of PBs.

ImportanceFor the first time, we demonstrate that processing bodies (PBs), cytoplasmic sites of RNA decay, are regulated by mechanical signaling events that alter actin dynamics and that this requires the mechanoresponsive transcription factor, YAP. Using the overexpression of a viral protein called KapB, known previously to mediate PB disassembly, we show that actin stress fibers (SFs) and the mechanoresponsive transcription factor, YAP, are required for PB loss. We also show that other established mechanical signals (shear stress or stiff extracellular matrix) that lead to the formation of SFs and activate YAP also cause PB disassembly. This is important because it means that KapB activates, from the inside out, a pathway that links cell shape to post-transcriptional gene regulation via cytoplasmic PBs. Optimized detection of allelic imbalances specific for homologous recombination deficiency improves the prediction of clinical outcomes in cancer Homologous recombination DNA-repair deficiency (HRD) is a common driver of genomic instability and confers a therapeutic vulnerability in human cancer. Using a systematic pan- cancer characterization, we revealed distinct patterns of somatic allelic imbalances (AIs) in high-grade serous ovarian cancer (HGSC). Using machine learning on a multi-omics dataset, we generated an optimized algorithm to detect HRD in HGSC (ovaHRDscar). ovaHRDscar improved the prediction of clinical outcomes in three independent validation cohorts. Characterization of 98 spatiotemporally distinct tumor samples indicated ovary/adnex as the preferred site to assess HRD. Cancer-specific optimization improved the prediction of clinical outcomes also in triple-negative breast cancer (tnbcHRDscar). In conclusion, our systematic approach based on multi-omics data improves the detection of HRD with the premise to improve patient selection for HR-targeted therapies. Reconstitution of minimal motility system based on Spiroplasma swimming by expressing two bacterial actins in synthetic minimal bacterium Motility is one of the most important features of life, but its evolutionary origin remains unknown. In this study, we focused on Spiroplasma, commensal, or parasitic bacteria. They swim by switching the helicity of a ribbon-like cytoskeleton that comprises six proteins, each of which evolved from a nucleosidase and bacterial actin called MreB. We expressed these proteins in a synthetic, non-motile minimal bacterium, JCVI-syn3.0B, whose reduced genome was computer-designed and chemically synthesized. The synthetic bacterium exhibited swimming motility with features characteristic of Spiroplasma swimming. Moreover, some combinations of the two proteins produced a helical cell shape and swimming, suggesting that the swimming originated from the differentiation and coupling of bacterial actins, and we also obtained a minimal system for motility of the synthetic bacterium.

One-Sentence SummaryThe minimal system comprised two bacterial actins that provided cell helicity and swimming to the synthetic minimal bacterium. Protein cost minimization promotes the emergence of coenzyme redundancy Coenzymes distribute a variety of chemical moieties throughout cellular metabolism, participating in group (e.g., phosphate, acyl) and electron transfer. For a variety of reactions requiring acceptors or donors of specific resources, there often exist degenerate sets of molecules (e.g., NAD(H) and NADP(H)) that carry out similar functions. Although the physiological roles of various coenzyme systems are well established, it is unclear what selective pressures may have driven the emergence of coenzyme redundancy. Here we use genome-wide metabolic modeling approaches to decompose the selective pressures driving enzymatic specificity for either NAD(H) or NADP(H) in the metabolic network of Escherichia coli. We found that few enzymes are thermodynamically constrained to using a single coenzyme, and in principle, a metabolic network relying on only NAD(H) is feasible. However, structural and sequence analyses revealed widespread conservation of residues that retain selectivity for either NAD(H) or NADP(H), suggesting that additional forces may shape specificity. Using a model accounting for the cost of oxidoreductase enzyme expression, we found that coenzyme redundancy universally reduces the minimal amount of protein required to catalyze coenzyme-coupled reactions, inducing individual reactions to strongly prefer one coenzyme over another when reactions are near thermodynamic equilibrium. We propose that protein minimization generically promotes coenzyme redundancy, and that coenzymes typically thought to exist in a single pool (e.g., CoA) may exist in more than one form (e.g., dephospho-CoA).

Significance statementMetabolism relies on a small class of molecules (coenzymes) that serve as universal donors and acceptors of key chemical groups and electrons. Although metabolic networks crucially depend on structurally redundant coenzymes (e.g., NAD(H) and NADP(H)) associated with different enzymes, the criteria that led to the emergence of this redundancy remain poorly understood. Our combination of modeling, and structural and sequence analysis indicates that coenzyme redundancy is not essential for metabolism, but rather an evolved strategy promoting efficient usage of enzymes when biochemical reactions are near equilibrium. Our work suggests that early metabolism may have operated with fewer coenzymes, and that adaptation for metabolic efficiency may have driven the rise of coenzyme diversity in living systems. Outbreak.info Research Library: A standardized, searchable platform to discover and explore COVID-19 resources and data To combat the ongoing COVID-19 pandemic, scientists have been conducting research at breakneck speeds, producing over 52,000 peer reviewed articles within the first 12 months. In contrast, a little over 1,000 peer reviewed articles were published within the first 12 months of the SARS-CoV-1 pandemic starting in 2002. In addition to publications, there has also been an upsurge in clinical trials to develop vaccines and treatments, scientific protocols to study SARS-CoV-2, methodology for epidemiological modeling, and datasets spanning molecular studies to social science research. One of the largest challenges has been keeping track of the vast amounts of newly generated disparate data and research that exist in independent repositories. To address this issue, we developed outbreak.info, which provides a standardized, searchable interface of heterogeneous resources on COVID-19 and SARS-CoV-2. Unifying metadata from twelve repositories, we have assembled a collection of over 260,000 publications, clinical trials, datasets, protocols, and other resources as of March 2022. We used a rigorous schema to enforce a consistent format across different data sources and resource types, and linked related resources where possible. This enables users to quickly retrieve information across data repositories, regardless of resource type or repository location. Outbreak.info also combines the combined research library with spatiotemporal genomics data on SARS-CoV-2 variants. The web interface provides interactive visualizations and reports to explore the unified data and generate hypotheses. In addition to providing a web interface, we also publish the data we have assembled and standardized in a high performance public API and an R package. Finally, we discuss the challenges inherent in combining metadata from scattered and heterogeneous resources and provide recommendations to streamline this process to aid scientific research. 3D Echo Planar Time-resolved Imaging (3D-EPTI) for ultrafast multi-parametric quantitative MRI Multi-parametric quantitative MRI has shown great potential to improve the sensitivity and specificity of clinical diagnosis and to enhance our understanding of complex brain processes, but suffers from long scan time especially at high spatial resolution. To address this long-standing challenge, we introduce a novel approach, termed 3D Echo Planar Time-resolved Imaging (3D-EPTI), which significantly increases the acceleration capacity of MRI sampling, and provides high acquisition efficiency for multi-parametric MRI. This is achieved by exploiting the spatiotemporal correlation of MRI data at multiple timescales through new encoding strategies within and between efficient continuous readouts. Specifically, an optimized spatiotemporal CAIPI encoding within the readouts combined with a radial-block sampling strategy across the readouts enables an acceleration rate of 800 folds in the k-t space. A subspace reconstruction was employed to resolve thousands of artifact-free high-quality multi-contrast images spaced at a time interval of ~1 ms. We have demonstrated the ability of 3D-EPTI to provide robust and repeatable whole-brain simultaneous T1, T2, T2*, PD and B1+ mapping at high isotropic resolution within minutes (e.g., 1-mm isotropic resolution in 3 minutes), and to enable submillimeter multi-parametric imaging to study detailed brain structures.

HighlightsO_LIUltra-fast acquisition for 3D multi-parametric quantitative MRI.
C_LIO_LISimultaneous T1 T2 T2* PD and B1+ mapping.
C_LIO_LI3-minute scan at 1-mm isotropic resolution with whole-brain coverage.
C_LIO_LIMulti-parametric mapping at 700-m isotropic resolution in 10 minutes.
C_LIO_LIRepeatable quantification and cortical-depth analysis.
C_LI Conformist social learning inoculates against adverse risk aversion Given the ubiquity of potentially adverse behavioural bias owing to myopic trial-and-error learning, it seems paradoxical that improvements in decision-making performance through conformist social learning, a process widely considered to be bias amplification, still prevail in animal collective behaviour. Here we show, through model analyses and large-scale interactive behavioural experiments with 585 human subjects, that conformist influence can indeed promote favourable risk taking in repeated experience-based decision making, even though many individuals are systematically biased towards adverse risk aversion. Although strong positive feedback conferred by copying the majoritys behaviour could result in unfavourable informational cascades, our differential equation model of collective behavioural dynamics identified a key role for increasing exploration by negative feedback arising when a weak minority influence undermines the inherent behavioural bias. This  collective behavioural rescue, emerging through coordination of positive and negative feedback, highlights a benefit of collective learning in a broader range of environmental conditions than previously assumed and resolves the ostensible paradox of adaptive collective behavioural flexibility under conformist influences. Identification and characterization of the WYL BrxR protein and its gene asseparable regulatory elements of a BREX phage restriction system Bacteriophage exclusion ( BREX) phage restriction systems are found in a wide range of bacteria. Various BREX systems encode unique combinations of proteins that usually include a site-specific methyltransferase; none appear to contain a nuclease. Here we describe the identification and characterization of a Type I BREX system from Acinetobacter and the effect of deleting each BREX ORF on growth, methylation, and restriction. We identified a previously uncharacterized gene in the BREX operon that is dispensable for methylation but involved in restriction. Biochemical and crystallographic analyses of this factor, which we term BrxR ( BREX Regulator), demonstrate that it forms a homodimer and specifically binds a DNA target site upstream of its transcription start site. Deletion of the BrxR gene causes cell toxicity, reduces restriction, and significantly increases the expression of BrxC. In contrast, the introduction of a premature stop codon into the BrxR gene, or a point mutation blocking its DNA binding ability, has little effect on restriction, implying that the BrxR coding sequence and BrxR protein play independent functional roles. We speculate that the BrxR coding sequence is involved in cis regulation of anti-phage activity, while the BrxR protein plays an additional regulatory role, perhaps during horizontal transfer. Tetrazoles as PPARγ ligands: A Structural and Computational Investigation. Diabetes is an important chronic disease affecting about 10% of the adult population in the US and over 420 million people worldwide, resulting in 1.6 million deaths every year, according to the World Health Organization. The most common type of the disease, type 2 diabetes, can be pharmacologically managed using oral hypoglycemic agents or thiazolidinediones (TZDs), such as pioglitazone, which act by activating the Peroxisome Proliferated-Activated Receptor {gamma}. Despite their beneficial effects in diabetes treatment, TZDs like rosiglitazone and troglitazone were withdrawn due to safety reasons, creating a void in the pharmacological options for the treatment of this important disease. Here, we explored a structure-based approach in the screening for new chemical probes for a deeper investigation of the effects of PPAR{gamma} activation. A class of tetrazole compounds was identified and the compounds named T1, T2 and T3 were purchased and evaluated for their ability to interact with the PPAR{gamma} ligand binding domain (LBD). The compounds were binders with micromolar range affinity, as determined by their IC50 values. A Monte Carlo simulation of the compound T2 revealed that the tetrazole ring makes favorable interaction with the polar arm of the receptor binding pocket. Finally, the crystal structure of the PPAR{gamma}-LBD-T2 complex was solved at 2.3 [A], confirming the binding mode for this compound. The structure also revealed that, when the helix H12 is mispositioned, an alternative binding conformation is observed for the ligand suggesting an H12-dependent binding conformation for the tetrazole compound. High Spatial Resolution MALDI Imaging Mass Spectrometry ofFresh-Frozen Bone Bone and bone marrow are vital to mammalian structure, movement, and immunity. These tissues are also commonly subjected to molecular alterations giving rise to debilitating diseases like rheumatoid arthritis, osteoporosis, osteomyelitis, and cancer. Technologies such as matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) enable the discovery of spatially resolved chemical information in biological tissue samples to help elucidate the complex molecular processes underlying pathology. Traditionally, preparation of native osseous tissue for MALDI IMS has been difficult due to the mineralized composition and heterogenous morphology of the tissue, and compensation for these challenges with decalcification and fixation protocols can remove or delocalize molecular species. Here, sample preparation methods were advanced to enable multimodal MALDI IMS of undecalcified, fresh-frozen murine femurs allowing the distribution of endogenous lipids to be linked to specific tissue structures and cell types. Adhesive-bound bone sections were mounted onto conductive glass slides with a microscopy-compatible glue and freeze-dried to minimize artificial bone marrow damage. Subliming matrix does not induce further bone marrow cracking, and recrystallizing the deposited matrix improves lipid signal. High spatial resolution (10 m) MALDI IMS was employed to characterize lipid distributions in fresh-frozen bone, and use of complementary microscopy modalities aided tissue and cell assignments. For example, various phosphatidylcholines localize to bone marrow, adipose tissue, marrow adipose tissue, and muscle. Further, sphingomyelin(42:1) was abundant in megakaryocytes, whereas sphingomyelin(42:2) was diminished in this cell type. These data reflect the vast molecular and cellular heterogeneity indicative of the bone marrow and the soft tissue surrounding the femur. Multimodal MALDI IMS has the potential to advance bone-related biomedical research by offering deep molecular coverage with spatial relevance in a preserved native bone microenvironment. Royal knifefish generate powerful suction feeding through large neurocranial elevation and high epaxial muscle power Suction feeding in ray-finned fishes involves powerful buccal cavity expansion to accelerate water and food into the mouth. Previous XROMM studies in largemouth bass (Micropterus salmoides), bluegill sunfish (Lepomis macrochirus), and channel catfish (Ictalurus punctatus) have shown that more than 90% of suction power in high performance strikes comes from the axial musculature. Thus, the shape of the axial muscles and skeleton may impact suction feeding mechanics. Royal knifefish (Chitala blanci) have an unusual postcranial morphology, with a ventrally flexed vertebral column and relatively large mass of epaxial muscle. Based on their body shape, we hypothesized that royal knifefish would generate high power strikes by utilizing large neurocranial elevation, vertebral column extension, and epaxial shortening. As predicted, C. blanci generated high suction expansion power compared to the other three species studied to date (up to 160 W), which was achieved by increasing both the rate of volume change and the intraoral subambient pressure. The large epaxial muscle (25% of body mass) shortened at high velocities to produce large neurocranial elevation and vertebral extension (up to 41 deg, combined), as well as high muscle mass-specific power (up to 800 W kg-1). For the highest power strikes, axial muscles generated 95% of the power, and 64% of the axial muscle mass consisted of the epaxial muscles. The epaxial-dominated suction expansion of royal knifefish supports our hypothesis that postcranial morphology may be a strong predictor of suction feeding biomechanics.

SUMMARY STATEMENTRoyal knifefish rely on their distinct postcranial morphology--with a curved vertebral column and large dorsal body muscles--to produce large neurocranial elevation and powerful suction feeding. Prevalence, complete genome and metabolic potentials of a phylogenetically novel cyanobacterial symbiont in the coral-killing sponge, Terpios hoshinota Terpios hoshinota is a ferocious, space-competing sponge that kills a variety of stony corals by overgrowth. Outbreaks of this species have led to intense coral reef damage and declines in living corals on the square kilometer scale in many geographical locations. Our large-scale 16S rRNA gene survey across three oceans revealed that the core microbiome of T. hoshinota included operational taxonomic units (OTUs) related to Prochloron, Endozoicomonas, Pseudospirillum, SAR116, Magnetospira, and Ruegeria. A Prochloron- related OTU was the most dominant cyanobacterium in T. hoshinota in the western Pacific Ocean, South China Sea, and Indian Ocean. The complete metagenome-assembled genome of the Prochloron-related cyanobacterium and our pigment analysis revealed that this bacterium had phycobiliproteins and phycobilins and lacked chlorophyll b, inconsistent with the iconic definition of Prochloron. Furthermore, the phylogenetic analyses based on 16S rRNA genes and 120 single-copy genes demonstrated that the bacterium was phylogenetically distinct to Prochloron, strongly suggesting that it should be a sister taxon to Prochloron; we therefore proposed this symbiotic cyanobacterium as a novel species under a new genus: Candidatus Paraprochloron terpiosii. With the recovery of the complete genome, we characterized the metabolic potentials of the novel cyanobacterium in carbon and nitrogen cycling and proposed a model for the interaction between Ca. Pp. terpiosi LD05 and T. hoshinota. In addition, comparative genomics analysis revealed that Ca. Paraprochloron and Prochloron showed distinct features in transporter systems and DNA replication.

ImportanceThe finding that one species predominates cyanobacteria in T. hoshinota from different geographic locations indicates that this sponge and Ca. Pp. terpiosi LD05 share a tight relationship. This study builds the foundation for T. hoshinotas microbiome and paves a way for understanding the ecosystem, invasion mechanism, and causes of outbreak of this coral-killing sponge. Also, the first Prochloron-related complete genome enables us to study this bacterium with molecular approaches in the future and broadens our knowledge of the evolution of symbiotic cyanobacteria. Thirteen independent genetic loci associated with preserved processing speed in a study of cognitive resilience in 330,097 individuals in the UK Biobank Cognitive resilience is the ability to withstand the negative effects of stress on cognitive functioning and is important for maintaining quality of life while aging. UK Biobank (UKB) does not have direct measurements of the same cognitive phenotype at distal timepoints. Therefore, we used number of education years (EY) as a proxy phenotype for past cognitive performance. Current cognitive performance was determined based on processing speed. This approach captured an average time span of 40 years between past and current cognitive performance in 330,097 individuals. A confounding factor was that EY is highly polygenic and masked the genetics of resilience. To overcome this, we employed Genomics Structural Equation Modelling (GenomicSEM) to perform a GWAS-by-subtraction using two GWAS, one GWAS of EY and resilience and a second GWAS of EY but not resilience. Subtracting one from the other generated a GWAS of Resilience. Replication of this approach was shown using independent discovery and replication samples within UKB and the full UKB GWAS results show significant genetic correlation with a GWAS of cognitive change in the independent Health and Retirement Study (N=9,526; P=1.5x10-3). We found 13 independent genetic loci for Resilience. Functional analyses showed enrichment in several brain regions and involvement of specific cell types, including GABAergic neurons (P=6.59x10-8) and glutamatergic neurons (P=6.98x10-6) in the cortex. Gene-set analyses implicated the biological process "neuron differentiation" (P=9.7x10-7) and the cellular component "synaptic part" (P=2.14x10-6). Mendelian randomization analysis showed a causative effect of white matter volume on cognitive resilience. These results enhance neurobiological understanding of resilience. High school science fair: Experiences of two groups of undergraduate bioscience students Science fairs offer potential opportunities for students to learn first-hand about the practices of science. Over the past six years we have been carrying out voluntary and anonymous surveys with regional and national groups of high school and post high school students to learn about their high school science fair experiences regarding help received, obstacles encountered, and opinions about the value and impact of science fair. Understanding what students think about science fairs will help educators make science fairs more effective learning opportunities. In this paper, we focus on the findings with two national groups of post high school students - undergraduate research fellows (SURF students) who did research at UT Southwestern Medical Center during 2014-2019 and undergraduates biology students attending the 2019 Howard Hughes Medical Institute Science Education Alliance (SEA) summer symposium. About 25% of the students who completed surveys indicated that they had participated in high school science fair, but more than half attended high schools where science fairs were unavailable. Effectively, 6 out of every 10 students participated in science fair if available. Students who could have participated in high school science fair but chose not to do so identified not enough time and coming up with their project idea as major reasons why not. About half the SURF students favored requiring non-competitive science fair regardless whether they themselves had participated in science fair. On the other hand, less than 1 in 5 thought that competitive science fair should be required. Introduction to the scientific process and general learning were mentioned most frequently as the reasons to require non-competitive science fair; these reasons were mentioned rarely in connection with competitive science fair. Unlike the national cohort of high school students we surveyed previously, who mostly did science fair in 9th and 10th grades, SURF students participated in science fair throughout high school and were twice as likely as high school students to have carried out science fair more than once. In conclusion, our findings suggest that participation of the undergraduate bioscience majors in high school science fairs occurs far more frequently than recognized previously. The findings emphasize further the importance of incentivizing rather than requiring science fair participation, especially in 9th and 10th grades, and the potential value of developing non-competitive science fairs. Feline tooth resorption findings from a questionnaire survey on 8115 Finnish cats and a case-control study for a more defined population drawn from the survey Tooth resorption (TR) is one of the most common dental diseases in cats. It is a painful disease characterised by progressive dental destruction, which eventually results in loss of teeth. The aetiology of the disease remains unclear, but associations with old age, breed, other oral and dental diseases, and certain environmental factors have been suspected. We collected health and environmental information of 8115 Finnish cats from 41 breeds through an online survey for cat owners to study TR in Finland with an observational study. The frequency of TR that the owner reported as veterinarian-diagnosed was 3.9% in the entire data (316/8115) and 15% in cats that the owner reported as having veterinarian-diagnosed oral or dental disease (316/2070). We determined the risk factors and breed variation of feline TR by logistic regression with the entire data and a case-control study in a more defined population drawn from the entire data. In the entire data, we defined those cats that the owners had reported as being diagnosed with TR by a veterinarian as TR-cats and compared them to all other cats. In the case-control study, we included only cats with owner-reported veterinarian-diagnosed oral and dental diseases. We defined cats with TR-diagnosis made under sedation as TR-cases. Other veterinarian-diagnosed TR-cats were excluded. Cats with other oral and dental diseases were used as controls. The model with the entire population included 308 TR-cats compared with 7508 cats, and the case-control study included 198 TR-cats and 1683 controls. Although the diagnoses were reportedly made by a veterinarian, the owner answered the survey and might have understood, remembered, or interpreted the diagnoses in a way that could affect the results. The results indicated an increasing risk of TR with age. Dental calculus, gingivitis, and periodontitis were potential risk factors for TR. These findings and the interaction between dental calculus and gingivitis suggest that inflammatory changes caused by dental calculus increase the risk of TR. Keeping food available constantly was a potential protective factor. We found that Cornish Rex, European, and Ragdoll breeds were at higher risk for TR. The observed differences between breeds highlight a genetic contribution. Structure-Functional-Selectivity Relationship Studies on A-86929 Analogs and Small biaryl Fragments toward Discovery of biased D1 agonists Dopamine regulates normal functions such as movement, reinforcement learning, and cognition, and its dysfunction has been implicated in multiple psychiatric and neurological disorders. Dopamine acts through the D1- (D1R and D5R) and D2-class (D2R, D3R and D4R) of seven transmembrane receptors, and activates both G-protein- and {beta}-arrestin-dependent signaling pathways, to mediate its physiological effects. Current dopamine receptor-based therapies are used to ameliorate motor deficits in Parkinsons disease, or as antipsychotic medications for schizophrenia. These drugs show efficacy for ameliorating only some symptoms caused by dopamine dysfunction and are plagued by debilitating side-effects. Studies in primates and rodents have shown that shifting the balance of dopamine receptor signaling towards the arrestin pathway can be beneficial for inducing normal movement, while reducing motor side-effects such as dyskinesias, and can be efficacious at enhancing cognitive function compared to balanced agonists. Several structure-activity-relationship (SAR) studies have embarked on discovering {beta}-arrestin-biased dopamine agonists, focused on D2 partial agonists, non-catechol D1 agonists, and mixed D1/D2R dopamine receptor agonists. Here, we describe an SAR study to identify novel D1R {beta}-arrestin biased ligands using A-86929, a high-affinity D1R catechol agonist, as a core scaffold. Previously described and novel analogs of A-86929 were synthesized and screened in vitro for structure-functional-selectivity relationships (SFSR) studies to identify chemical motifs responsible for {beta}-arrestin biased activity at both D1 and D2Rs. Most of the A-86929 analogs screened were G protein biased but none of them were exclusively arrestin-biased. Additionally, various catechol aryl fragments were designed and synthesized. Other compounds surveyed included hydroxyl and chloro analogs of dopamine to test for hydrogen bonding and ionic interactions. Some of these small molecular probes displayed weak bias towards the {beta}-arrestin pathway. Continued in-depth SFSR studies informed by structure determination, molecular modeling, and mutagenesis studies will facilitate discovery of potent and efficacious arrestin-biased dopamine receptor ligands. Precartilage condensation during limb skeletogenesis occurs by tissue phase separation controlled by a bistable cell-state switch with suppressed oscillatory dynamics The tetrapod limb skeleton is initiated in unpatterned limb bud mesenchyme by the formation of precartilage condensations. Here, based on time-lapse videographic analysis of a forming condensation in a high-density culture of chicken limb bud mesenchyme, we observe a phase transition to a more fluidized state for cells within spatial compacted foci (protocondensations that will progress to condensations), as reflected in their spatial confinement, cell-substratum interaction and speed of motion. Previous work showed that galectin-8 and galectin-1A, two proteins of the galactoside-binding galectin family, are the earliest determinants of this process in the chicken limb bud, and that their interactions in forming skeletogenic patterns of condensations can be interpreted mathematically through a reaction-diffusion-adhesion framework. Based on this framework, we use an ordinary differential equation-based approach to analyze the core switching modality of the galectin reaction network and characterize the states of the network independent of the diffusive and adhesive arms of the patterning mechanism. We identify two steady states where the concentrations of both galectins are respectively, negligible, and very high. An explicit Lyapunov function shows that there are no periodic solutions. For sigmoidal galectin production terms, the model exhibits a bistable switch that arises from a monostable state via saddle-node bifurcation. Our model therefore predicts that the galectin network exists in low and high expression states separated in space or time without any intermediate states. This provides a causal basis for the observed outside vs. inside transition observed in the in vitro video data. We performed a quantitative analysis of the distribution of galectin-1A in cultures of condensing chick limb mesenchymal cells and found that the interior of the protocondensations had concentrations of this protein (compared to the immediate exterior) over and above that expected from its higher cell density, consistent with the models predictions. The galectin-based patterning network is thus suggested, on theoretical grounds, to incorporate a core switch independent of any spatial or temporal dynamics, that drives the chondrogenic cell state transition in limb skeletogenesis. Exploitation of the genetic variability in the genotype of Egyptian Wheat by studding Molecular Markers, Molecular Docking and Nano Composites. Regulation of leaf and stem rust This manuscript has been withdrawn by the authors as it was submitted and made public without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. The combined treatment of Molnupiravir and Favipiravir results in a marked potentiation of efficacy in a SARS-CoV2 hamster infection model through an increased frequency of mutations in the viral genome. Favipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV2. In recent days preliminary efficacy data have been reported in COVID-19 patients. We here studied the combined antiviral effect of the drugs in the SARS-CoV2 hamster infection model. We first demonstrate that Molnupiravir can reduce infectious virus titers in lungs of infected animals in a dose-dependent manner by up to 3.5 log10 which is associated with a marked improvement of virus-induced lung pathology. When animals are treated with a combination of suboptimal doses of Molnupiravir and Favipiravir (that each alone result in respectively a 1.3 log10 and 1.1 log10 reduction of infectious virus titers in the lungs), a marked combined potency is observed. Infectious virus titers in the lungs of animals treated with the combo are on average reduced by 4.5 log10 and infectious virus are no longer detected in the lungs of 60% of treated infected animals. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs. In the combo-treated hamsters an increased frequency of C-to-T and G-to-A mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination. Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir and Favipiravir in the treatment of COVID-19. 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.