Cytokinin oxidase/dehydrogenase family genes exhibit functional divergence and overlap in rice growth and development, especially in control of tillering Cytokinins play key roles in plant growth and development; hence, cytokinin biosynthesis and degradation have been extensively studied. Cytokinin oxidase/dehydrogenases (CKXs) are a group of enzymes that regulate oxidative cleavage to maintain cytokinin homeostasis. In rice, 11 OsCKX genes have been identified to date; however, most of their functions remain unknown. Here, we comprehensively analyzed the expression patterns and functions of OsCKX genes. Using CRISPR/Cas9 technology, we constructed mutants of all OsCKX genes to determine the functions of OsCKXs in rice development. The results revealed that the single osckx and higher-order osckx4 osckx9 mutant lines showed functional overlap and subfunctionalization. Notably, the osckx1 osckx2 and osckx4 osckx9 double mutants displayed contrasting phenotypic changes in tiller number and panicle size compared to the wild type. Moreover, we identified several genes with significantly altered expression in osckx4 and osckx9 single and double mutant plants. Many differentially expressed genes were found to be associated with auxin and cytokinin pathways. Additionally, the cytokinins in osckx4 osckx9 mutants were increased compared to the wild type. Overall, our findings provide new insights into the functions of OsCKX genes in rice growth and may be used as a foundation for future studies aimed at improving rice yield. Key words: Cytokinin, expression pattern, OsCKX, panicle, phenotype, rice, tiller

HighlightThe osckx4 osckx9 double mutant had a significantly greater number of tillers, whereas the osckx1 osckx2 double mutant showed the opposite phenotypic change, compared to the wild type
High expression of VRT2 increases the number of rudimentary basal spikelets in wheat Spikelets are the fundamental building blocks of Poaceae inflorescences and their development and branching patterns determine the various inflorescence architectures and grain yield of grasses. In wheat, the central spikelets produce the most and largest grains, while spikelet size gradually decreases acro- and basipetally, giving rise to the characteristic lanceolate shape of wheat spikes. The acropetal gradient correlates with the developmental age of spikelets, however the basal spikelets are developed first and the cause of their small size and rudimentary development is unclear. Here, we adapted G&T-seq, a low-input transcriptomics approach, to characterise gene expression profiles within spatial sections of individual spikes before and after the establishment of the lanceolate shape. We observed larger differences in gene expression profiles between the apical, central and basal sections of a single spike than between any section belonging to consecutive developmental timepoints. We found that SVP MADS-box transcription factors, including VRT-A2, are expressed highest in the basal section of the wheat spike and display the opposite expression gradient to flowering E-class SEP1 genes. Based on multi-year field trials and transgenic lines, we show that higher expression of VRT-A2 in the basal sections of the spike is associated with increased numbers of rudimentary basal spikelets. Our results, supported by computational modelling, suggest that the delayed transition of basal spikelets from vegetative to floral developmental programmes results in the lanceolate shape of wheat spikes. This study highlights the value of spatially resolved transcriptomics to gain new insights into developmental genetics pathways of grass inflorescences.

One sentence summaryLarge transcriptional gradients exist within a wheat spike and are associated with rudimentary basal spikelet development, resulting in the characteristic lanceolate shape of wheat spikes.
Evolution of class-structured populations in fluctuating environments What is the influence of periodic environmental fluctuations on life-history evolution? We present a general theoretical framework to understand and predict the long-term evolution of lifehistory traits under a broad range of ecological scenarios. Specifically, we investigate how periodic fluctuations affect selection when the population is also structured in distinct classes. This analysis yields time-varying selection gradients that clarify the influence of the fluctuations of the environment on the competitive ability of a specific life-history mutation. We use this framework to analyse the evolution of key life-history traits of pathogens. We examine three different epidemiological scenarios and we show how periodic fluctuations of the environment can affect the evolution of virulence and transmission as well as the preference for different hosts. These examples yield new and testable predictions on pathogen evolution, and illustrate how our approach can provide a better understanding of the evolutionary consequences of time-varying environmental fluctuations in a broad range of scenarios. SARS-CoV-2 spike-glycoprotein processing at S1/S2 and S2' and shedding of the ACE2 viral receptor: roles of Furin and TMPRSS2 and implications for viral infectivity and cell-to-cell fusion The spike (S)-protein of SARS-CoV-2 binds ACE2 and requires proteolytic "priming" at PRRAR685{downarrow} into S1 and S2 (cleavage at S1/S2), and "fusion-activation" at a S2 site for viral entry. In vitro, Furin cleaved peptides mimicking the S1/S2 cleavage site more efficiently than at the putative S2, whereas TMPRSS2 inefficiently cleaved both sites. In HeLa cells Furin-like enzymes mainly cleaved at S1/S2 during intracellular protein trafficking, and S2 processing by Furin at KPSKR815{downarrow} was strongly enhanced by ACE2, but not for the optimized S2 KRRKR815{downarrow} mutant (S2), whereas individual/double KR815AA mutants were retained in the endoplasmic reticulum. Pharmacological Furin-inhibitors (Boston Pharmaceuticals, BOS-inhibitors) effectively blocked endogenous S-protein processing in HeLa cells. Furthermore, we show using pseudotyped viruses that while entry by a "pH-dependent" endocytosis pathway in HEK293 cells did not require Furin processing at S1/S2, a "pH-independent" viral entry in lung-derived Calu-3 cells was sensitive to inhibitors of Furin (BOS) and TMPRSS2 (Camostat). Consistently, these inhibitors potently reduce infectious viral titer and cytopathic effects, an outcome enhanced when both compounds were combined. Quantitative analyses of cell-to-cell fusion and spike processing revealed the key importance of the Furin sites for syncytia formation. Our assays showed that TMPRSS2 enhances fusion and proteolysis at S2 in the absence of cleavage at S1/S2, an effect that is linked to ACE2 shedding by TMPRSS2. Overall, our results indicate that Furin and TMPRSS2 play synergistic roles in generating fusion-competent S-protein, and in promoting viral entry, supporting the combination of Furin and TMPRSS2 inhibitors as potent antivirals against SARS-CoV-2.

IMPORTANCESARS-CoV-2 is the etiological agent of COVID-19 that resulted in >5 million deaths. The spike protein (S) of the virus directs infection of the lungs and other tissues by binding the angiotensin-converting enzyme 2 (ACE2) receptor. For effective infection, the S-protein is cleaved at two sites: S1/S2 and S2. Cleavage at S1/S2, induces a conformational change favoring the recognition of ACE2. The S2 cleavage is critical for cell-to-cell fusion and virus entry into host cells. Our study contributes to a better understanding of the dynamics of interaction between Furin and TMPRSS2 during SARS-CoV-2 entry and suggests that the combination of a non-toxic Furin inhibitor with a TMPRSS2 inhibitor could significantly reduce viral entry in lung cells, as evidenced by an average synergistic [~]95% reduction of viral infection. This represents a powerful novel antiviral approach to reduce viral spread in individuals infected by SARS-CoV-2 or future related coronaviruses. Limitations of composability of cis-regulatory elements in messenger RNA Genes are commonly abstracted into a coding sequence and cis-regulatory elements (CREs), such as promoters and terminators, and short sequence motifs within these regions. Modern cloning techniques allow easy assembly of synthetic genetic constructs from discrete cis-regulatory modules. However, it is unclear how much the contributions of CREs to gene expression depend on other CREs in the host gene. Using budding yeast, we probe the extent of composability, or independent effects, of distinct CREs. We confirm that the quantitative effect of a terminator on gene expression depends on both promoter and coding sequence. We then explore whether individual cisregulatory motifs within terminator regions display similar context dependence, using transcriptomewide datasets of mRNA decay. To test the extent of composability, we construct reporter genes consisting of combinations of motifs within various terminator contexts, paired with different promoters. Our results show that the effect of a motif on RNA abundance depends both on its host terminator, and also on the associated promoter sequence. This emphasises the need for improved motif inference that includes both local and global context effects, which in turn could aid in the accurate use of CREs for the engineering of synthetic genetic constructs. Robust retrieval of data stored in DNA by de Bruijn graph-based de novo strand assembly DNA data storage is a rapidly developing technology with great potential due to its high density, long-term durability, and low maintenance cost. The major technical challenges include various errors, such as the strand breaks, rearrangements, and indels that frequently arise during DNA synthesis, amplification, sequencing, and preservation. Through a de novo assembly strategy, we developed an algorithm based on the de Bruijn graph and greedy path search (DBGPS) to address these issues. DBGPS shows distinct advantages in handling DNA breaks, rearrangements, and indels. The robustness of DBGPS is demonstrated by accelerated aging, multiple independent data retrievals, deep error-prone PCR, and large data scale simulations. Remarkably, 6.8 MB of data can be retrieved accurately from a seriously corrupted sample that has been treated at 70 {degrees}C for 70 days. With DBGPS, we were able to achieve a logical density of 1.30 bits/cycle and a physical density of 295 PB/g.

One-Sentence SummaryA de Bruijn graph-based de novo assembly algorithm for DNA data storage enables fast and robust data readouts even with DNA samples that have been severely corrupted. Genome-wide association study suggests an independent genetic basis of zinc and cadmium concentrations in fresh sweet corn kernels Despite being one of the most consumed vegetables in the United States, the elemental profile of sweet corn (Zea mays L.) is limited in its dietary contributions. To address this through genetic improvement, a genome-wide association study was conducted for the concentrations of 15 elements in fresh kernels of a sweet corn association panel. In concordance with mapping results from mature maize kernels, we detected a probable pleiotropic association of zinc and iron concentrations with nicotianamine synthase5 (nas5), which purportedly encodes an enzyme involved in synthesis of the metal chelator nicotianamine. Additionally, a pervasive association signal was identified for cadmium concentration within a recombination suppressed region on chromosome 2. The likely causal gene underlying this signal was heavy metal ATPase3 (hma3), whose counterpart in rice, OsHMA3, mediates vacuolar sequestration of cadmium and zinc in roots, whereby regulating zinc homeostasis and cadmium accumulation in grains. In our association panel, hma3 associated with cadmium but not zinc accumulation in fresh kernels. This finding implies that selection for low cadmium will not affect zinc levels in fresh kernels. Although less resolved association signals were detected for boron, nickel, and calcium, all 15 elements were shown to have moderate predictive abilities via whole-genome prediction. Collectively, these results help enhance our genomics-assisted breeding efforts centered on improving the elemental profile of fresh sweet corn kernels. FGFR2 fusion protein-driven mouse models of intrahepatic cholangiocarcinoma unveil a necessary role for Erk signaling Background and aimsAbout 15% of intrahepatic cholangiocarcinoma (iCCA) express fibroblast growth factor receptor 2 (FGFR2) fusion proteins (FFs), most often in concert with mutationally inactivated TP53, CDKN2A or BAP1. FFs span residues 1-768 of FGFR2 fused to sequences encoded by any of a long list (>60) of partner genes, a configuration sufficient to ignite oncogenic FF activation. In line, FGFR-specific tyrosine kinase inhibitors (F-TKI) were shown to provide clinical benefit in FF+ iCCA, although responses were partial and/or limited by resistance mechanisms, including the FF V565F gatekeeper mutation. Herein we present an FF-driven murine iCCA model and exploit its potential for pre-clinical studies on FF therapeutic targeting.

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

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

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

Abbreviations used in this paper: ANOVA, analysis of variance; Bap1, BRCA1-Associated-Protein 1; Cdkn2a, cyclin-dependent kinase inhibitor 2A; Cftr, cystic fibrosis transmembrane conductance regulator; Ck19, cytokeratin 19; Cyp3A, cytochrome P450, family 3, subfamily A; EGF, Epidermal growth factor; EGFR, Epidermal growth factor receptor; EpCAM, epithelial cell adhesion molecule; Erk, extracellular signal-regulated kinase; FGFR2, fibroblast growth factor receptor 2; FRS2, fibroblast growth factor receptor substrate 2; GRB2, growth factor receptor-bound 2; GSEA, gene set enrichment analysis; GSVA, gene set variation analysis; H&E, hematoxylin and eosin; HepPar1, hepatocyte Paraffin 1; Hnf4-7, hepatocyte nuclear factor 4 alpha; Hprt, hypoxanthine-guanine phosphoribosyl transferase; LGR5, leucine-rich repeat-containing G-protein coupled receptor 5; NTRK, neurotrophic Tyrosine Kinase; Parp, Poly (ADP-ribose) polymerase; RECIST, response evaluation criteria in solid tumors; SHP2, Src homology phosphatase 2; Ttr, transthyretin. Point Mutations in SARS-CoV-2 Variants Induce Long-Range Dynamical Perturbations in Neutralizing Antibodies Monoclonal antibodies are emerging as a viable treatment for the coronavirus disease 19 (COVID-19). However, newly evolved variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can reduce the efficacy of currently available antibodies and can diminish vaccine-induced immunity. Here, we demonstrate that the microscopic dynamics of neutralizing monoclonal antibodies can be profoundly modified by the mutations present in the spike proteins of the SARS-COV-2 variants currently circulating in the world population. The dynamical perturbations within the antibody structure, which alter the thermodynamics of antigen recognition, are diverse and can depend both on the nature of the antibody and on the spatial location of the spike mutation. The correlation between the motion of the antibody and that of the spike receptor binding domain (RBD) can also be changed, modulating binding affinity. Using protein-graph-connectivity networks, we delineated the mutant-induced modifications in the information-flow along allosteric pathway throughout the antibody. Changes in the collective dynamics were spatially distributed both locally and across long-range distances within the antibody. On the receptor side, we identified an anchor-like structural element that prevents the detachment of the antibodies; individual mutations there can significantly affect the antibody binding propensity. Our study provides insight into how virus neutralization by monoclonal antibodies can be impacted by local mutations in the epitope via a change in dynamics. This realization adds a new layer of sophistication to the efforts for rational design of monoclonal antibodies against new variants of SARS-CoV2, taking the allostery in the antibody into consideration. Comparative Analysis of non-coding small-RNAs in Pseudomonas aeruginosa Keratitis Strains with Different Antibiotic Susceptibility Pseudomonas aeruginosa, is a gram-negative bacterium causes opportunistic or nosocomial infections in immunocompromised individuals. In recent years, a steady increase in human corneal infections of P. aeruginosa has been reported with increased multi-drug resistance (MDR) or extensively drug resistance (XDR). Several non-coding sRNAs, has been identified to regulate various physiological processes in P. aeruginosa, including biofilm formation, quorum sensing. However, the regulatory mechanism of sRNAs in MDR/XDR pathways of P. aeruginosa keratitis strains is not yet studied. In this study, we identified bacterial sRNAs in publicly available P. aeruginosa keratitis genomes and investigated their regulatory role in MDR/XDR pathways using bioinformatic analysis. Totally, 46 P. aeruginosa keratitis strains from different geographical regions were included. Of 46, Eight (30%) out of Twenty-seven and Nine (52) out of Nineteen P. aeruginosa strains from India and Australia were identified as not-MDR. Whereas, 10 (38%) Indian and 9 (47%) Australian strains were identified as MDR. Eight Indian strains were identified as XDR. Out of 46 strains, 23 (50%) carried ExoU, 21(45%) carried ExoS and two (5%) strains carried both ExoU and ExoS, exotoxins for their virulence. The sRNA, SPA0021 was identified in 18 MDR/XDR and 6 not-MDR strains along with UCBPP-PA14. Interestingly, majority of the imipenem resistant P. aeruginosa keratitis strains from the present study was found to be carried SPA0023 sRNA (18 out of 30 strains). The outer membrane porin protein OprD, identified as binding target of SPA0023. Negative regulation or inactivation of OprD, reported in increased imipenem resistance in P. aeruginosa. Mutation analysis revealed that SPA0023 carrying P. aeruginosa keratitis strains contains a lesser number of amino acid changes in OprD protein than other strains. These findings indicate, imipenem resistance in SPA0023 carried strains might arose from the negative regulation or inhibition of OprD by SPA0023. However, functional studies are warranted with large number of P. aeruginosa keratitis strains to confirm the negative regulation of OprD by SPA0023 and imipenem resistance. Pak1 kinase controls cell shape through ribonucleoprotein granules Fission yeast cells maintain a rod shape due to conserved signaling pathways that organize the cytoskeleton for polarized growth. We discovered a mechanism linking the conserved protein kinase Pak1 with cell shape through the RNA-binding protein Sts5. Pak1 (also called Shk1 and Orb2) prevents Sts5 association with P bodies by directly phosphorylating its intrinsically disordered region (IDR). Pak1 and the cell polarity kinase Orb6 both phosphorylate the Sts5 IDR but at distinct residues. Mutations preventing phosphorylation in the Sts5 IDR cause increased P body formation and defects in cell shape and polarity. Unexpectedly, when cells encounter glucose starvation, PKA signaling triggers Pak1 recruitment to stress granules with Sts5. Through retargeting experiments, we reveal that Pak1 localizes to stress granules to promote rapid dissolution of Sts5 upon glucose addition. Our work reveals a new role for Pak1 in regulating cell shape through ribonucleoprotein granules during normal and stressed growth conditions. 3D viscoelastic drag forces contribute to cell shape changes during organogenesis in the zebrafish embryo The left-right organizer in zebrafish embryos, Kupffers Vesicle (KV), is a simple organ that undergoes programmed asymmetric cell shape changes that are necessary to establish the left-right axis of the embryo. We use simulations and experiments to investigate whether 3D mechanical drag forces generated by the posteriorly-directed motion of the KV through the tailbud tissue are sufficient to drive such shape changes. We develop a fully 3D vertex-like (Voronoi) model for the tissue architecture, and demonstrate that the tissue can generate drag forces and drive cell shape changes. Furthermore, we find that tailbud tissue presents a shear-thinning, viscoelastic behavior consistent with those observed in published experiments. We then perform live imaging experiments and particle image velocimetry analysis to quantify the precise tissue velocity gradients around KV as a function of developmental time. We observe robust velocity gradients around the KV, indicating that mechanical drag forces must be exerted on the KV by the tailbud tissue. We demonstrate that experimentally observed velocity fields are consistent with the viscoelastic response seen in simulations. This work also suggests that 3D viscoelastic drag forces could be a generic mechanism for cell shape change in other biological processes.

HighlightsO_LInew physics-based simulation method allows study of dynamic tissue structures in 3D
C_LIO_LImovement of an organ through tissue generates viscoelastic drag forces on the organ
C_LIO_LIthese drag forces can generate precisely the cell shape changes seen in experiment
C_LIO_LIPIV analysis of experimental data matches simulations and probes tissue mechanics
C_LI

Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY Propionate ameliorates diabetes-induced neurological dysfunction through regulating the PI3K/Akt/eNOS signaling pathway A large body of research has established diabetes-related cognitive deterioration, sometimes known as "diabetic encephalopathy." Current evidence supports that oxidative stress, neuronal apoptosis, and cerebral microcirculation weakness are associated with cognition deficits induced by diabetes. The present study explores the effect of propionate on neurological deficits, cerebral blood flow, and oxidative stress in diabetic mice. Propionate can markedly improve neurological function, which is correlated with its capabilities of stimulating nitric oxide (NO) production, increasing cerebral microcirculation, suppressing oxidative stress and reducing neuron loss in the hippocampus. In addition, the results of Western Blotting indicated that the brain-protective function of propionate in streptozocin (STZ)-induced insulin-dependent diabetes mellitus (IDDM) mice is related to phosphoinositide 3-kinase (PI3K)/serine-threonine protein kinase (Akt)/endothelial nitric oxide synthase(eNOS) signaling pathway. In a diabetic mouse model, propionate reduces cerebral microcirculation, hippocampus apoptosis, and neurological impairment. Thus, propionate, now employed as a food preservative, may also help slow diabetes-induced cognitive loss.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/464493v2_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@81fa09org.highwire.dtl.DTLVardef@1469451org.highwire.dtl.DTLVardef@b37fa1org.highwire.dtl.DTLVardef@8037e7_HPS_FORMAT_FIGEXP  M_FIG C_FIG HighlightsO_LIPropionate ameliorates diabetic-induced depression-like behavior, spatial learning and memory deficits.
C_LIO_LIPropionate increases cerebral microcirculation by enhancing NO production in diabetic mice.
C_LIO_LIPropionate suppresses oxidative stress and reduces neuron loss in the hippocampus.
C_LIO_LIThe brain-protective function of propionate is related to PI3K/Akt/eNOS signaling pathway.
C_LI Existence of log-phase Escherichia coli persisters and lasting memory of a starvation pulse The vast majority of a bacterial population is quickly killed when treated with a lethal concentration of antibiotics. The time scale of this killing is often comparable with the bacterial generation time before addition of antibiotics. Yet, a small subpopulation typically survives for an extended period. However, the long-term killing dynamics of bacterial cells has not been fully quantified even in well-controlled laboratory conditions. We constructed a week-long killing assay and followed the survival fraction of Escherichia coli K12 exposed to a high concentration of ciprofloxacin. We found that long-term survivors were formed during exponential growth, with some cells surviving at least 7 days. The long-term dynamics contained at least three timescales, which greatly enhances predictions of the population survival time compared to the biphasic extrapolation from the short term behavior. Furthermore, we observed a surprisingly long memory effect of a brief carbon starvation pulse, which was dependent on the (p)ppGpp synthase relA. Specifically, one hour of carbon starvation prior to antibiotics exposure increased the surviving fraction by nearly 100-fold even after 4 days of ciprofloxacin treatment. Host species identity shapes the diversity and structure of insect microbiota As for most of the life that inhabits our planet, microorganisms play an essential role in the fitness of insects, including nutrition, reproduction, defence, and many other functions. More recently, we assisted in an exponential growth of studies describing the taxonomical composition of bacterial communities across insects phylogeny. However, there is still an outstanding question that needs to be answered: which factors contribute most to shape insects microbiomes? This study tries to find an answer to this question by taking advantage of publicly available sequencing data and reanalysing over 4,000 samples of insect-associated bacterial communities under a common framework. Results suggest that insect taxonomy has a wider impact on the structure and diversity of their associated microbial communities than the other factors considered (diet, sex, life stage, sample origin, and treatment). However, when specifically testing for signatures of co-diversification of insect species and their microbiota, analyses found weak support for this, suggesting that while insect species strongly drive the structure and diversity of insect microbiota, the diversification of those microbial communities did not follow their hosts phylogeny. Furthermore, a parallel survey of the literature highlights several methodological limitations that need to be considered in future research endeavours. First Report of Lactoria cornuta from Karnataka, West coast of India, Role of tropical cyclones in Range Extension India is known for its rich biodiversity and is fortunate to have several endemic species from different classes of vertebrates. India is home to 7.5% of the global fish diversity, with 91 endemic species of ray finned fishes, the actinopterygians. Some fish species have never been reported until recently, one such example is the long-horned Cowfish (Ostracidae), best known for inhabiting only certain areas of the Indo-Pacific oceans. However, this fish has been reported from Bay of Bengal, Costs of Goa and Lakshadweep. This is the first time this fish has been found on the Coasts of Karnataka, west coast of India. Given its morphology, the migration seems highly improbable since it can only endure lethargic swimming. In this article, we have explored the role of other external forces that could have contributed to its range extension in the east and west coast of India. In this paper we are exploring the role of Super Cyclones as a vital force in determining the expansion of its range. The fact of collection longhorn cowfish for the first time from the coast of Karwar coincides with the passage of Cyclone Ockhi on the west coast of India this suggests the possible role of super cyclone in its range extension. A year later, another specimen was recovered from a location very close to the first, which indicates the successful establishment of Lacturia cornuta in its new environment. Related morphometric and meristic studies of our specimens are consistent with previous studies reported in the Bay of Bengal. A multivariate view of cognitive performance reveals positive correlation in the Trinidadian Guppy (Poecilia reticulata) Cognitive variation is common among-individuals and can be consistent across time and context. From an evolutionary perspective, among-individual variation is important as a pre-requisite for natural selection and adaptive evolution. Selection is widely hypothesized to favor high cognitive performance but directional selection should erode variation over time, how then is cognitive variation maintained? As selection does not act on traits in isolation, covariance among specific cognitive traits and/or other aspects of phenotype (e.g. personality) could result in fitness trade-offs that are important in shaping evolutionary dynamics. Here we test this using Trinidadian guppies (Poecilia reticulata), using a multivariate approach by characterising the correlation structure among task-specific cognitive performance measures and a personality trait. We estimate the among-individual correlation matrix (ID) in performance across three cognitive tasks; colour association learning task; motor learning task; reversal learning task, and the personality trait  boldness measured as emergence time from a shelter. We found no support for trade-offs among performance in these tasks. Nor do we find evidence of hypothesised speed-accuracy trade-offs within the association learning task. Rather we find strong positive correlation structure in ID, with 57% of variation explained by the leading eigen vector. While noting that non-cognitive factors and assay composition may affect the structure of ID, we suggest our findings are consistent with the g-model of cognitive performance variation, in which a dominant axis of variation loads positively on all performance measures. Thus, we add to a growing body of support for general variation among individuals in animal cognitive ability. An Essential Role of UBXN3B in B Lymphopoiesis Hematopoiesis is finely regulated to enable timely production of the right numbers and types of mature immune cells to maintain tissue homeostasis. Dysregulated hematopoiesis may compromise antiviral immunity and/or exacerbate immunopathogenesis. Herein, we report an essential role of UBXN3B in maintenance of hematopoietic homeostasis and restriction of immunopathogenesis during respiratory viral infection. Ubxn3b deficient (Ubxn3b-/-) mice are highly vulnerable to SARS-CoV-2 and influenza A infection, characterized by more severe lung immunopathology, lower virus-specific IgG, significantly fewer B cells, but more myeloid cells than Ubxn3b+/+ littermates. This aberrant immune compartmentalization is recapitulated in uninfected Ubxn3b-/- mice. Mechanistically, UBXN3B controls precursor B-I (pre-BI) transition to pre-BII and subsequent proliferation in a cell-intrinsic manner, by maintaining BLNK protein stability and pre-BCR signaling. These results reveal an essential role of UBXN3B for the early stage of B cell development. The integrity and assay performance of tissue mitochondrial DNA is considerably affected by choice of isolation method The integrity of mitochondrial DNA (mtDNA) isolated from solid tissues is critical for analyses such as long-range PCR, but is typically assessed under conditions that fail to provide information on the individual mtDNA strands. Using denaturing gel electrophoresis, we show that commonly-used isolation procedures generate mtDNA containing several single-strand breaks per strand. Through systematic comparison of DNA isolation methods, we identify a procedure yielding the highest integrity of mtDNA that we demonstrate displays improved performance in downstream assays. Our results highlight the importance of isolation method choice, and serve as a resource to researchers requiring high-quality mtDNA from solid tissues. A tool for assessing alignment of biomedical data repositories with open, FAIR, citation and trustworthy principles Increasing attention is being paid to the operation of biomedical data repositories in light of efforts to improve how scientific data is handled and made available for the long term. Multiple groups have produced recommendations for functions that biomedical repositories should support, with many using requirements of the FAIR data principles as guidelines. However, FAIR is but one set of principles that has arisen out of the open science community. They are joined by principles governing open science, data citation and trustworthiness, all of which are important aspects for biomedical data repositories to support. Together, these define a framework for data repositories that we call OFCT: Open, FAIR, Citable and Trustworthy. Here we developed an instrument using the open source PolicyModels toolkit that attempts to operationalize key aspects of OFCT principles and piloted the instrument by evaluating eight biomedical community repositories listed by the NIDDK Information Network (dkNET.org). Repositories included both specialist repositories that focused on a particular data type or domain, in this case diabetes and metabolomics, and generalist repositories that accept all data types and domains. The goal of this work was both to obtain a sense of how much the design of current biomedical data repositories align with these principles and to augment the dkNET listing with additional information that may be important to investigators trying to choose a repository, e.g., does the repository fully support data citation? The evaluation was performed from March to November 2020 through inspection of documentation and interaction with the sites by the authors. Overall, although there was little explicit acknowledgement of any of the OFCT principles in our sample, the majority of repositories provided at least some support for their tenets. Glucose inhibits haemostasis and accelerates diet-induced hyperlipidaemia in zebrafish larvae Hyperglycaemia damages the microvasculature in part through the reduced recruitment of immune cells and interference with platelet signalling, leading to poor wound healing and accelerated lipid deposition in mammals. We investigated the utility of zebrafish larvae to model the effect of glucose on neutrophil and macrophage recruitment to a tail wound, wound-induced haemostasis, and chicken egg yolk feed challenge-induced hyperlipidaemia by supplementing larvae with exogenous glucose by immersion or injection. Neither method of glucose supplementation affected the recruitment of neutrophils and macrophages following tail transection. Glucose injection reduced thrombocyte retention and fibrin plug formation while only thrombocyte retention was reduced by glucose immersion following tail transection. We observed accelerated lipid accumulation in glucose-injected larvae challenged with high fat chicken egg yolk feeding. Our study identifies conserved and divergent effects of high glucose on inflammation, haemostasis, and hyperlipidaemia in zebrafish larvae compared to mammals. Towards a cumulative science of vocal markers of autism: a cross-linguistic meta-analysis-based investigation of acoustic markers in American and Danish autistic children Acoustic atypicalities in speech production are argued to be potential markers of clinical features in Autism Spectrum Disorder (ASD). A recent meta-analysis highlighted shortcomings in the field, in particular small sample sizes and study heterogeneity (Fusaroli et al., 2017). We showcase a cumulative (i.e., explicitly building on previous studies both conceptually and statistically) yet self-correcting (i.e., critically assessing the impact of cumulative statistical techniques) approach to prosody in ASD to overcome these issues.

We relied on the recommendations contained in the meta-analysis to build and analyze a cross-linguistic corpus of multiple speech productions in 77 autistic and 72 neurotypical children and adolescents (>1000 recordings in Danish and US English). We used meta-analytically informed and skeptical priors, with informed priors leading to more generalizable inference. We replicated findings of a minimal cross-linguistically reliable distinctive acoustic profile for ASD (higher pitch and longer pauses) with moderate effect sizes. We identified novel reliable differences between the two groups for normalized amplitude quotient, maxima dispersion quotient, and creakiness. However, the differences were small, and there is likely no one acoustic profile characterizing all autistic individuals. We identified reliable relations of acoustic features with individual differences (age, gender), and clinical features (speech rate and ADOS sub-scores).

Besides cumulatively building our understanding of acoustic atypicalities in ASD, the study shows how to use systematic reviews and meta-analyses to guide the design and analysis of follow-up studies. We indicate future directions: larger and more diverse cross-linguistic datasets, focus on heterogeneity, self-critical cumulative approaches and open science.

Lay SummaryAutistic individuals are reported to speak in distinctive ways. Distinctive vocal production can affect social interactions and social development and could represent a noninvasive way to support the assessment of ASD. We systematically checked whether acoustic atypicalities highlighted in previous articles could be actually found across multiple recordings and two languages. We find a minimal acoustic profile of ASD: higher pitch, longer pauses, increased hoarseness and creakiness of the voice. However, there is much individual variability (by age, sex, language, and clinical characteristics). This suggests that the search for one common "autistic voice" might be naive and more fine-grained approaches are needed. State transitions in the statistically stable place cell population are determined by rate of perceptual change The hippocampus plays a central role in mammalian navigation and memory, yet an implementational understanding of the rules that govern the granularity of location encoding and the spatial-statistics of the population as a whole are lacking. We analysed large numbers of CA1 place fields recorded while rats foraged in environments up to 8.75 m2. We found that place cell propensities to form fields were proportional to open-field area, gamma-distributed, and conserved across environments. The properties of place fields varied positionally with a denser distribution of smaller fields near boundaries. Remarkably, field size and density were in a dynamic equilibrium, such that population-level activity statistics remained constant. We showed that the rate of transition through the statistically stable place cell population matched the rate of change in the animals visual scenes - demonstrating that the resolution of the spatial-memory system is bounded by perceptual information afforded by the environment. Suppression of sost/sclerostin and dickkopf-1 promote intervertebral disc structure in mice Intervertebral disc (IVD) degeneration is a leading cause of low back pain and characterized by accelerated extracellular matrix breakdown and IVD height loss but there is no approved pharmacological therapeutic. Deletion of Wnt signaling receptor Lrp5 induces IVD degeneration and suggests that Wnt signaling in the IVD may be responsive to inhibition of Wnt signaling inhibitors sost(gene)/sclerostin(protein) or dickkopf-1 (dkk1). Anti-sclerostin antibody (Scl-Ab) is an FDA-approved bone therapeutic that activates Wnt signaling. We (1) determined if pharmacological neutralization of sclerostin, dkk1 or their combination stimulate Wnt signaling and promote IVD structure and (2) determined the extent of the response of the IVD to global, persistent deletion of sost. Nine-week-old C57Bl/6J female mice (n=6-7/grp) were subcutaneously injected 2x/wk for 5.5 wk with scl-Ab (25 mg/kg), dkk1-Ab (25 mg/kg), 3:1 scl-Ab/dkk1-Ab (18.75:6.25 mg/kg) or vehicle (Veh). Separately, IVD of sost KO and WT (wildtype) mice (n=8, grp) were harvested at 16 weeks of age. First, compared to vehicle, scl-Ab, dkk1-Ab and 3:1 scl-Ab/dkk1-Ab similarly increased lumbar IVD height and {beta}-catenin gene expression. Despite these similarities, scl-Ab decreased cellular stress-related heat shock protein gene expressions while neither dkk1-Ab nor scl-Ab/dkk1-Ab altered the same. Genetically and compared to WT, sost KO increased MRI-determined hydration and proteoglycan staining in the IVD. Notably, persistent deletion of sost was compensated by upregulation of dkk1, which consequently reduced the cell nuclear fraction for Wnt signaling transcription factor {beta}-catenin in whole IVD. Lastly, RNA-sequencing pathway analysis confirmed the compensatory suppression of Wnt signaling and determined a reduction of cellular stress pathways. Together, suppression of sost/sclerostin or dkk1 each promote IVD structure by stimulating Wnt signaling, but sclerostin and dkk1 may differentially regulate cellular stress pathways. Ultimately, postmenopausal women prescribed scl-Ab injections to prevent vertebral fracture may also benefit from a restoration of IVD height and health.

Graphical abstract

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org.highwire.dtl.DTLVardef@db2e17org.highwire.dtl.DTLVardef@1af1bbborg.highwire.dtl.DTLVardef@145cc4corg.highwire.dtl.DTLVardef@167a19e_HPS_FORMAT_FIGEXP  M_FIG C_FIG Suppression of Wnt signaling inhibitors by genetic or pharmacological approaches promotes intervertebral disc structure and hydration by Wnt signaling. However, persistent activation of Wnt signaling induces a compensatory reduction of Wnt signaling that shifts IVD cells toward a chondrocyte-like (CLC) phenotype. AF: annulus fibrosus, NC: notochordal cell, NP: nucleus pulposus, PG: proteoglycan The longevity response to warm temperature is neurally controlled via the regulation of collagen genes Studies in diverse species have associated higher temperatures with shorter lifespan and lower temperatures with longer lifespan. However, the mechanisms behind these inverse effects of temperature on longevity are not well understood. Here, we demonstrate that in Caenorhabditis elegans, functional loss of NPR-8, a G protein-coupled receptor related to mammalian neuropeptide Y receptors, increases worm lifespan at 25{degrees}C but not at 20{degrees}C or 15{degrees}C, and that the lifespan increase at 25{degrees}C is regulated by the NPR-8-expressing AWB and AWC chemosensory neurons as well as AFD thermosensory neurons. RNA sequencing revealed that both warm temperature and old age profoundly alter gene expression. Further investigation uncovered that the NPR-8-dependent longevity response to warm temperature is achieved by regulating the expression of a subset of collagen genes. As elevated collagen expression is a common feature of many lifespan-extending interventions and enhanced stress resistance, collagen expression could be critical for healthy aging. 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.