Occlusion of lip movements impairs reconstruction of acoustic speech features and higher-level segmentational features in the presence of a distractor speaker Multisensory integration enables stimulus representation even when the sensory input in a single modality is weak. In the context of speech, when confronted with a degraded acoustic signal, congruent visual inputs promote comprehension. When this input is occluded speech comprehension consequently becomes more difficult. But it still remains inconclusive which levels of speech processing are affected under which circumstances by occlusion of the mouth area. To answer this question, we conducted an audiovisual (AV) multi-speaker experiment using naturalistic speech. In half of the trials, the target speaker wore a (surgical) face mask, while we measured the brain activity of normal hearing participants via magnetoencephalography (MEG). We additionally added a distractor speaker in half of the trials in order to create an ecologic difficult listening situation. A decoding model on the clear AV speech was trained and used to reconstruct crucial speech features in each condition. We found significant main effects of face masks on the reconstruction of acoustic features, such as the speech envelope and spectral speech features (i.e. pitch and formant frequencies), while reconstruction of higher level features of speech segmentation (phoneme and word onsets) were especially impaired through masks in difficult listening situations. As we used surgical face masks in our study, which only show mild effects on speech acoustics, we interpret our findings as the result of the occluded lip movements. This idea is in line with recent research showing that visual cortical regions track spectral modulations. Our findings extend previous behavioural results, by demonstrating the complex contextual effects of occluding relevant visual information on speech processing.

HighlightsO_LISurgical face masks impair neural tracking of speech features
C_LIO_LITracking of acoustic features is generally impaired, while higher level segmentational features show their effects especially in challenging listening situations
C_LIO_LIAn explanation is the prevention of a visuo-phonological transformation contributing to audiovisual multisensory integration
C_LI
State-dependent network interactions differentially gate sensory input at the motor and command neuron level in Caenorhabditis elegans Neural responses are influenced by both external stimuli and internal network states. While network states have been linked to behavioral and stimulus states, little is known about how sensory inputs are filtered by whole-brain activity to affect motor and command neurons. Here, we recorded whole-brain activity of Caenorhabditis elegans experiencing bacterial food stimuli, and modeled how sensory inputs affect motor and command neurons in a network state-dependent manner. First, we classified active neurons into six functional clusters: two sensory neuron clusters (ON, OFF), and four motor/command neuron clusters (AVA, RME, SMDD, SMDV). Using encoding models, we found that ON and OFF sensory neurons that respond to onset and removal of bacteria, respectively, employ different adaptation strategies. Next, we used decoding models to show that bacterial onset and removal differentially drive AVA and RME cluster activity. To explore state-dependent effects on AVA and RME clusters, we developed a model that identified network states and fitted submodels for each state to predict how each of the six functional clusters drive AVA and RME cluster activity. We also identified network states in which AVA and RME clusters were either largely unperturbed by or receptive to bacterial sensory input. Furthermore, this model allowed us to disentangle the state-dependent contributions of stimulus timescales and bacterial content to neural activity. Collectively, we present an interpretable approach for modeling network dynamics that goes beyond implication of neurons in particular states, and moves toward explicitly dissecting how neural populations work together to produce state dependence.

Significance StatementA major function of the brain is to transform sensory information into behavior. As the first receiver of sensory input, sensory neuron activity is often most correlated with stimulus features. However, this high-fidelity representation of sensory input becomes diluted as it travels to downstream neurons, where sensory information is integrated with network activity. By the time sensory information reaches motor neurons, it is often difficult to dissociate the influence of sensory input from the influence of network activity. Here, we describe a method that is fully interpretable such that we can show how neural populations on a whole-brain scale interact to produce network states. From there, we can attribute motor neuron activity to network history and sensory input.
A framework for assessing the skill and value of operational recruitment forecasts Forecasting variation in the recruitment to fish stocks is one of the most challenging and long-running problems in fisheries science and essentially remains unsolved today. Traditionally recruitment forecasts are developed and evaluated based on explanatory and goodness-of-fit approaches that do not reflect their ability to predict beyond the data on which they were developed. Here we propose a new generic framework that allows the skill and value of recruitment forecasts to be assessed in a manner that is relevant to their potential use in an operational setting. We assess forecast skill based on predictive power using a retrospective forecasting approach inspired by meterology, and emphasise the importance of assessing these forecasts relative to a baseline. We quantify the value of these forecasts using an economic cost-loss decision model that is directly relevant to many forecast users. We demonstrate this framework using four stocks of lesser sandeel (Ammodytes marinus) in the North Sea, showing for the first time in an operationally realistic setting that skilful and valuable forecasts are feasible in two of these areas. This result shows the ability to produce valuable short-term recruitment forecasts, and highlights the need to revisit our approach to and understanding of recruitment forecasting. Medium-throughput zebrafish optogenetic platform identifies deficits in subsequent neural activity following brief early exposure to cannabidiol and Δ-9-tetrahydrocannabinol In the light of legislative changes and the widespread use of cannabis as a recreational and medicinal drug, delayed effects of cannabis upon brief exposure during embryonic development are of high interest as early pregnancies often go undetected. Here, zebrafish embryos were exposed to cannabidiol (CBD) and {Delta}-9-tetrahydrocannabinol l (THC) until the end of gastrulation (1-10 hours post-fertilization) and analyzed later in development (4-5 days post-fertilization). In order to measure neural activity, we implemented CaMPARI (Calcium-Modulated Photoactivatable Ratiometric Integrator) and optimized the protocol for a 96-well format complemented by locomotor analysis. Our results revealed that neural activity was decreased by CBD more than THC. At higher doses, both cannabinoids could dramatically reduce neural activity and locomotor activity. Interestingly, the decrease was more pronounced when CBD and THC were combined. At the receptor level, CBD-mediated reduction of locomotor activity was partially prevented using cannabinoid type 1 and 2 receptor inhibitors. Overall, we report that CBD toxicity occurs via two cannabinoid receptors and is synergistically enhanced by THC exposure to negatively impact neural activity late in larval development. Future studies are warranted to reveal other cannabinoids and receptors involved in this pathway to understand the subsequent health implications of cannabis consumption on fetal development. Determinants of Murine Skin Microbiota Composition in Homeostasis and Wound Healing Animal microbiota have complex interactions with hosts and environment that determines its composition. Yet the ability of hosts to determine their microbiota composition is less well studied. In this study, to investigate the role host genetics in determining skin microbiota, we used 30 different mouse strains from the recombinant inbred panel, the Collaborative Cross. Murine skin microbiota composition was strongly dependent on murine strain with > 50% of the variation explained by murine strain. In particular, a quantitative trait locus on chromosome 4 associates both with Staphylococcus abundance and principal-component multi-trait analyses. Additionally, excisional wound associated changes in microbiota composition were not uniform across mouse strains and were host-specific, the genetic background accounting for about 40% of the variation in microbiota. Genetic background also had the highest effect on the healing speed of wounds accounting for over 50% of the variation while mouse age and microbiota composition change accounted only for 20% and 5% of the healing speed despite reaching statistical significance. In conclusion, host genetics has a significant impact on the skin microbiota composition during both homeostasis and wound healing. These findings have long reaching implications in our understanding of associations between microbiota dysbiosis and disease. The adenoviral E1B-55k protein present in HEK293 cells mediates abnormal accumulation of key WNT signaling proteins in large cytoplasmic aggregates. HEK293 cells are one of the most widely used cell lines in research and HEK293 cells are frequently used as an in vitro model for studying the WNT signaling pathway. The HEK293 cell line was originally established by transfection of human embryonic kidney cells with sheared adenovirus 5 DNA and it is known that that HEK293 cells stably express the adenoviral E1A and E1B-55k proteins. Here we show that HEK293 cells display an unexpected distribution of key components of the WNT/{beta}-catenin signaling pathway where AXIN1, APC, DVL2 and tankyrase are all co-localized in large spherical cytoplasmic aggregates. The cytoplasmic aggregates are enclosed by a narrow layer of the adenoviral E1B-55k protein. Reduction of E1B-55k protein levels leads to disappearance of the cytoplasmic aggregates thus corroborating an essential role of the E1B-55k protein in mediating the formation of the aggregates. Furthermore, HEK293 cells with reduced E1B-55k protein levels display reduced levels of transcriptional activation of WNT/{beta}-catenin signaling upon stimulation by the Wnt3A agonist. The demonstrated influence of the E1B-55k protein on the cellular localization of WNT/{beta}-catenin signaling components and on transcriptional regulation of WNT/{beta}-catenin signaling asks for caution in the interpretation of data derived from the HEK293 cell line. High-plex Multiomic Analysis in FFPE at Subcellular Level by Spatial Molecular Imaging The Spatial Molecular Imaging platform (CosMxTM SMI, NanoString, Seattle, WA) utilizes a high-plex in-situ imaging chemistry for both RNA and protein detection. This automated instrument provides 1000s of plex, at high sensitivity (1 to 2 copies/cell), very low error rate (0.0093 false calls/cell), and background ([~]0.04 counts/cell). The imaging system generates three-dimensional super-resolution localization of analytes (< 50 nm in the X-Y plane), at [~] 1 million cells per sample, four samples per run. Cell segmentation is antibody-based, compatible with FFPE samples. Multiomic data (980 RNAs, 108 proteins) were measured at subcellular resolution using FFPE tissues (non-small cell lung (NSCLC) and breast cancer) and allowed identification of over 18 distinct cell types, 10 unique tumor microenvironments, and 100 pairwise ligand-receptor interactions. Over 800,000 single cells and [~]260 million transcripts data are released into the public domain allowing extended data analysis by the entire spatial biology research community. The "LINC" in between Delta40p53-miRNA axis in the regulation of cellular processes Recently, we showed that {Delta}40p53, the translational isoform of p53, can inhibit cell growth independently of p53 by regulating microRNAs. Here, we explored the role of {Delta}40p53 in regulating the lncRNA-miRNA axis. Based on early research from our laboratory, we selected LINC00176 for further exploration. LINC00176 levels were affected by the overexpression and knockdown of {Delta}40p53. Further, under DNA damage, ER stress, and glucose deprivation, LINC00176 was upregulated in HCT116 p53-/- cells (harboring only {Delta}40p53) compared to HCT116 p53+/+ cells. Additionally, ChIP and RNA stability assays revealed that {Delta}40p53 transactivates LINC00176 transcriptionally and stabilizes it post-transcriptionally. We ectopically overexpressed and knocked down LINC00176 in HCT116 p53-/- cells, which affected proliferation, cell viability, and the expression of epithelial markers. Finally, RNA pulldown revealed that LINC00176 sequesters several putative miRNA targets. These results provide important insights into the pivotal role of {Delta}40p53 in regulating the lncRNA-miRNA axis.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=171 HEIGHT=200 SRC="FIGDIR/small/489891v2_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@1035f85org.highwire.dtl.DTLVardef@74185borg.highwire.dtl.DTLVardef@1eb3704org.highwire.dtl.DTLVardef@168ebab_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Model depicting the regulation of {Delta}40p53-LINC00176-miRNA axis

(A) In absence of {Delta}40p53, LINC00176 levels do not increase which leads to increased pool of free miRNAs which probably binds to several mRNA targets preventing their function, ultimately resulting in increased cell proliferation. (B) However, when {Delta}40p53 is present it upregulates LINC00176 levels both at the level of transcription and post-transcription, which sequesters oncogenic miRNAs preventing it to bind to their respective mRNA targets, which ultimately results in decreased cell proliferation.

C_FIG Characterising ontogeny of numerosity discrimination in zebrafish reveals the use of multiple, numerical and non- numerical mechanisms. A sense of non-symbolic numerical magnitudes is widespread in the animal kingdom and has been documented in adult zebrafish. Here we investigated the ontogeny of this ability using a group size preference task in juvenile zebrafish. Fish showed group size preference from 21 days post fertilization (dpf) and reliably chose the larger group when presented with discriminations of between 1 vs. 3, 2 vs. 5 and 2 vs. 3 conspecifics but not 2 vs. 4 conspecifics. When the ratio between the number of conspecifics in each group was maintained at 1:2, fish could discriminate between 1 vs. 2 individuals and 3 vs. 6, but again, not when given a choice between 2 vs. 4 individuals. These findings are in agreement with studies in other species suggesting the systems involved in quantity representation do not operate separately from other cognitive mechanisms. Rather they suggest quantity processing in fish may be the result of an interplay between attentional, cognitive and memory-related mechanisms as in humans and other animals. Our results emphasise the potential of the use of zebrafish to explore the genetic and neural processes underlying the ontogeny and function of number cognition. Strength of interactions in the Notch gene regulatory network determines patterning and fate in the notochord Development of multicellular organisms requires the generation of gene expression patterns that determines cell fate and organ shape. Groups of genetic interactions known as Gene Regulatory Networks (GRNs) play a key role in the generation of such patterns. However, how the topology and parameters of GRNs determine patterning in vivo remains unclear due to the complexity of most experimental systems. To address this, we use the zebrafish notochord, an organ where coin-shaped precursor cells are initially arranged in a simple unidimensional geometry. These cells then differentiate into vacuolated and sheath cells. Using newly developed transgenic tools together with in vivo imaging, we identify jag1a and her6/her9 as the main components of a Notch GRN that generates a lateral inhibition pattern and determines cell fate. Making use of this experimental system and mathematical modeling we show that lateral inhibition patterning requires that ligand-receptor interactions are stronger within the same cell than in neighboring cells. Altogether, we establish the zebrafish notochord as an experimental system to study pattern generation, and identify and characterize how the properties of GRNs determine self-organization of gene patterning and cell fate. A humanized nanobody phage display library yields potent binders of SARS CoV-2 spike Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two distinct binding modes. The most potent nanobody, RBD-1-2G(NCATS-BL8125), tolerates the N501Y RBD mutation and remains capable of neutralizing the B.1.1.7 (Alpha) variant. Molecular dynamics simulations provide a structural basis for understanding the neutralization process of nanobodies exclusively focused on the spike-ACE2 interface with and without the N501Y mutation on RBD. A primary human airway air-lung interface (ALI) ex vivo model showed that RBD-1-2G-Fc antibody treatment was effective at reducing viral burden following WA1 and B.1.1.7 SARS-CoV-2 infections. Therefore, this presented strategy will serve as a tool to mitigate the threat of emerging SARS-CoV-2 variants. Diverse wMel variants of Wolbachia pipientis differentially rescue fertility and cytological defects of the bag of marbles partial loss of function mutation in Drosophila melanogaster In Drosophila melanogaster, the maternally inherited endosymbiont Wolbachia pipientis interacts with germline stem cell genes during oogenesis. One such gene, bag of marbles (bam) is the key switch for differentiation and also shows signals of adaptive evolution for protein diversification. These observations have led us to hypothesize that W. pipientis could be driving the adaptive evolution of bam for control of oogenesis. To test this hypothesis, we must understand the specificity of the genetic interaction between bam and W. pipientis. Previously, we documented that the W. pipientis variant, wMel, rescued the fertility of the bamBW hypomorphic mutant as a transheterozygote over a bam null. However, bamBW was generated more than 20 years ago in an uncontrolled genetic background and maintained over a balancer chromosome. Consequently, the chromosome carrying bamBW accumulated mutations that have prevented controlled experiments to further assess the interaction. Here, we used CRISPR/Cas9 to engineer the same single amino acid bam hypomorphic mutation (bamL255F) and a new bam null disruption mutation into the w1118 isogenic background. We assess the fertility of wildtype bam, bamL255F/bamnull hypomorphic, and bamL255F/ bamL255F mutant females, each infected individually with ten W. pipientis wMel variants representing three phylogenetic clades. Overall, we find that all of the W. pipientis variants tested here rescue bam hypomorphic fertility defects with wMelCS-like variants exhibiting the strongest rescue effects. Additionally, these variants did not increase wildtype bam female fertility. Therefore, both bam and W. pipientis interact in genotype-specific ways to modulate female fertility, a critical fitness phenotype. Frequency modulated timer regulates mammalian hibernation Mammalian hibernators decrease basal metabolism and body temperature (Tb) to minimize energy expenditure in harsh seasons. During hibernation, Tb drops to low temperature (<10 {degrees}C) and remains constant for days, known as deep torpor in small mammalian hibernators. Spontaneous interbout arousals interrupt torpor bouts, when Tb recovers to euthermic state ~37 {degrees}C. Torpor-interbout arousal event repeats during several months of hibernation. However, little is known about mechanisms governing Tb fluctuation across torpor-interbout arousal cycles during hibernation. Recent improvement in data-logging techniques enables us to monitor Tb for more than hundred days with high precision, opening up new avenues for quantitative analysis to address the principle governing Tb fluctuation. Here, we analyzed Tb fluctuation across torpor-interbout arousal cycle of Syrian hamster, which can hibernate in response to chronic cold and short photoperiod under a laboratory condition, using generalized harmonic analysis and discovered a model with frequency modulation quantitatively reproducing Tb fluctuation. This analysis also identified an unexpectedly longer period of 120-430 days as the period that modulates another period of several days, generating Tb fluctuation for Syrian hamster. We propose that concerted action of two endogenous periods governs torpor-interbout arousal cycles during hibernation. CryoEM of endogenous mammalian V-ATPase interacting with the TLDc protein mEAK-7 V-ATPases are rotary proton pumps that serve as signaling hubs with numerous proposed binding partners in cells. We used cryoEM combined with exhaustive focused classification to detect endogenous proteins that associate with V-ATPase from porcine kidney. A super-stoichiometric copy of subunit C was found in ~3% of complexes, while an additional ~1.6% of complexes bound mEAK-7, a protein with proposed roles in dauer formation in nematodes and mTOR signaling in mammals. High-resolution cryoEM of porcine kidney V-ATPase with recombinant mEAK-7 shows that mEAK-7s TLDc domain interacts with V-ATPases stator while its C-terminal  helix binds V-ATPases rotor. This crosslink would be expected to inhibit rotary catalysis. However, unlike inhibition of yeast V-ATPase by the TLDc protein Oxr1p, exogenous mEAK-7 does not inhibit V-ATPase and mEAK-7 overexpression in cells does not alter lysosomal or phagosomal pH. Instead, cryoEM suggests that interaction of mEAK-7 with V-ATPase is disrupted by ATP-induced rotation of the rotor. Comparison of Oxr1p and mEAK-7 binding explains this difference. Together, these results show that differences in V-ATPase binding by TLDc domain-containing proteins can lead to effects ranging from strong inhibition to formation of labile interactions that are sensitive to the enzymes activity. The adapted Activity-By-Contact model for enhancer-gene assignment and its application to single-cell data Identifying regulatory regions in the genome is of great interest for understanding the epigenomic landscape in cells. One fundamental challenge in this context is to find the target genes whose expression the regulatory regions affect. A recent successful method is the Activity-By-Contact (ABC) model [10] which scores enhancer-gene interactions based on enhancer activity and the contact frequency of an enhancer to its target gene. It requires two types of assays to measure enhancer activity, which limits the applicability. The ABC score describes regulatory interactions entirely from a genes perspective, and does not account for all the candidate target genes of an enhancer. Moreover, there is no implementation available which would allow for an integration with transcription factor (TF) binding information or an efficient analysis of single-cell data. We show that the ABC-model is comparably accurate with only one assay to measure enhancer activity. Further, we demonstrate that it can yield a higher accuracy by adapting the enhancer activity according to the number of contacts the enhancer has to its candidate target genes. We combined our adapted ABC-model with TF binding information and illustrate an analysis of a single-cell ATAC-seq data set of the human heart. We were able to characterise cell type-specific regulatory interactions as well as to prioritise candidate TFs that drive cell type-specific expression. All executed processing steps are incorporated into our new computational pipeline STARE. The software is available at https://github.com/schulzlab/STARE. One billion synthetic 3D-antibody-antigen complexes enable unconstrained machine-learning formalized investigation of antibody specificity prediction Machine learning (ML) is a key technology to enable accurate prediction of antibody-antigen binding, a prerequisite for in silico vaccine and antibody design. Two orthogonal problems hinder the current application of ML to antibody-specificity prediction and the benchmarking thereof: (i) The lack of a unified formalized mapping of immunological antibody specificity prediction problems into ML notation and (ii) the unavailability of large-scale training datasets. Here, we developed the Absolut! software suite that allows the parameter-based unconstrained generation of synthetic lattice-based 3D-antibody-antigen binding structures with ground-truth access to conformational paratope, epitope, and affinity. We show that Absolut!-generated datasets recapitulate critical biological sequence and structural features that render antibody-antigen binding prediction challenging. To demonstrate the immediate, high-throughput, and large-scale applicability of Absolut!, we have created an online database of 1 billion antibody-antigen structures, the extension of which is only constrained by moderate computational resources. We translated immunological antibody specificity prediction problems into ML tasks and used our database to investigate paratope-epitope binding prediction accuracy as a function of structural information encoding, dataset size, and ML method, which is unfeasible with existing experimental data. Furthermore, we found that in silico investigated conditions, predicted to increase antibody specificity prediction accuracy, align with and extend conclusions drawn from experimental antibody-antigen structural data. In summary, the Absolut! framework enables the development and benchmarking of ML strategies for biotherapeutics discovery and design.



O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/451258v2_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@14295d2org.highwire.dtl.DTLVardef@7a12bdorg.highwire.dtl.DTLVardef@647102org.highwire.dtl.DTLVardef@375112_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOGraphical abstractC_FLOATNO The software framework Absolut! enables (A,B) the generation of virtually arbitrarily large numbers of in silico 3D-antibody-antigen structures, (C,D) the formalization of antibody specificity as machine learning (ML) tasks as well as the exploration of ML strategies for paratope-epitope prediction.

C_FIG Highlights- Software framework Absolut! to generate an arbitrarily large number of in silico 3D-antibody-antigen structures
- Generation of one billion in silico antigen-antibody structures reflecting biological layers of complexity that make ML predictions challenging
- Immunological antibody specificity prediction problems formalized as machine learning tasks for which the in silico complexes are immediately usable as benchmark.
- Exploration of machine learning architectures for paratope-epitope interaction prediction accuracy as a function of neural network depth, dataset size, and sequence-structure encoding Conformational decoupling in acid-sensing ion channels uncovers mechanism and stoichiometry of PcTx1-mediated inhibition Acid-sensing ion channels (ASICs) are trimeric proton-gated cation channels involved in fast synaptic transmission. Pharmacological inhibition of ASIC1a reduces neurotoxicity and stroke infarct volumes, with the cysteine knot toxin Psalmotoxin-1 (PcTx1) being one of the most potent and selective inhibitors. PcTx1 binds at the subunit interface in the extracellular domain (ECD), but the mechanism and conformational consequences of the interaction, as well as the number of toxin molecules required for inhibition remain unknown. Here we use voltage-clamp fluorometry and subunit concatenation to decipher the mechanism and stoichiometry of PcTx1 inhibition of ASIC1a. Besides the known inhibitory binding mode, we propose PcTx1 to have at least two additional binding modes that are decoupled from the pore. One of these modes induces a long-lived ECD conformation that reduces the activity of an endogenous neuropeptide. This long-lived conformational state is proton-dependent and can be destabilized by a mutation that decreases PcTx1 sensitivity. Lastly, the use of concatemeric channel constructs reveal that disruption of a single PcTx1 binding site is sufficient to destabilize the toxin-induced conformation, while functional inhibition is not impaired until two or more binding sites are mutated. Together, our work provides insight into the mechanism of PcTx1 inhibition of ASICs and uncovers a prolonged conformational change with possible pharmacological implications. 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. Agrobacterium mediated transformation and deciphering SNPs in TaLr67 gene homeologs for gene editing in wheat. Diseases adversely affect grain yield of crop plants. Leaf rust is a major disease of wheat. As race-specific resistance breaks down, introduction of newer sources of resistance often from older accessions is necessary. Linkage drag from the donor accessions adversely impacts grain yield. As a result, CIMMYT breeding effort has shifted to using durable resistance, also referred to as race non-specific host resistance, which allows slow rusting but maintains grain yield. One of the key genes for durable resistance is Lr67 and the resistant form of this gene is absent in CIMMYT elite lines. Hence, we have initiated efforts to convert the susceptible copy of Lr67 into its resistant form directly in these elite lines using gene editing. This would eliminate backcrossing and thus save time as well as eliminate linkage drag that would accompany the resistant copy of the gene if it were to be introgressed from an older accession. As first steps, we have isolated and sequenced the genomic copies from each of the A, B, and D genome of the Lr67 gene from three elite lines and an experimental line. Identification of more than 50 single nucleotide polymorphisms (SNPs) in the open reading frames (ORF) among these lines would be useful in designing the guide RNA molecules with precision. Further, we have streamlined genetic transformation of these elite lines, a prerequisite step for gene editing. Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy As of October 2021, coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global emergency, and novel therapeutics are urgently needed. Here we describe human single chain variable fragment (scFv) antibodies (76clAbs) that block an epitope of the SARS-CoV-2 spike protein essential for ACE2-mediated entry into cells. 76clAbs neutralize the delta variant and other variants being monitored (VBMs) and inhibit spike-mediated pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. In two independent animal models, intranasal administration counteracted the infection. Due to high efficiency, remarkable stability, resilience to nebulization and low production cost, 76clAbs may become a relevant tool for rapid, self-administrable early intervention in SARS-CoV-2-infected subjects independently of their immune status. Fatal neuroinvasion and SARS-CoV-2 tropism in K18-hACE2 mice is partially independent on hACE2 expression Animal models recapitulating distinctive features of severe COVID-19 are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. The precise mechanisms of lethality in this mouse model remain unclear. Here, we evaluated the spatiotemporal dynamics of SARS-CoV-2 infection for up to 14 days post-infection. Despite infection and moderate pneumonia, rapid clinical decline or death of mice was invariably associated with viral neuroinvasion and direct neuronal injury (including brain and spinal neurons). Neuroinvasion was observed as early as 4 dpi, with virus initially restricted to the olfactory bulb supporting axonal transport via the olfactory neuroepithelium as the earliest portal of entry. No evidence of viremia was detected suggesting neuroinvasion occurs independently of entry across the blood brain barrier. SARS-CoV-2 tropism was not restricted to ACE2-expressing cells (e.g., AT1 pneumocytes), and some ACE2-positive lineages were not associated with the presence of viral antigen (e.g., bronchiolar epithelium and brain capillaries). Detectable ACE2 expression was not observed in neurons, supporting overexpression of ACE2 in the nasal passages and neuroepithelium as more likely determinants of neuroinvasion in the K18-hACE2 model. Although our work incites caution in the utility of the K18-hACE2 model to study global aspects of SARS-CoV-2 pathogenesis, it underscores this model as a unique platform for exploring the mechanisms of SARS-CoV-2 neuropathogenesis that may have clinical relevance acknowledging the growing body of evidence that suggests COVID-19 may result in long-standing neurologic consequences.

IMPORTANCECOVID-19 is predominantly a respiratory disease caused by SARS-CoV-2 that has infected more than 191 million people with over 4 million fatalities (2021-07-20). The development of animal models recapitulating distinctive features of severe COVID-19 is critical to enhancing our understanding of SARS-CoV-2 pathogenesis and in the evaluation of vaccine and therapeutic efficacy. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. Here, we show lethality of this model is invariably associated with viral neuroinvasion linked with viral replication and assembly. Importantly, pneumonia albeit invariably present was generally moderate with the absence of culturable infectious virus at peak neuroinvasion. The dynamics of viral neuroinvasion and pneumonia were only partially dependent on hACE2. Overall, this study provides an in-depth sequential characterization of the K18-hACE2 model following SARS-CoV-2 infection, highlighting its significance to further study the mechanisms of SARS-CoV-2 neuropathogenesis. Trypanosomal variant surface glycoprotein expression in human African trypanosomiasis patients Trypanosoma brucei gambiense, an extracellular protozoan parasite, is the primary causative agent of human African trypanosomiasis. T. b. gambiense is endemic to West and Central Africa, where it is transmitted by the bite of infected tsetse flies. In the bloodstream of an infected host, the parasite evades antibody recognition by altering the Variant Surface Glycoprotein (VSG) that forms a dense coat on its cell surface through a process known as antigenic variation. Each VSG has a variable N-terminal domain exposed to the host and a less variable C-terminal domain that is partially hidden from host antibodies. Our lab developed VSG-seq, a targeted RNA-seq method, to study VSG gene expression in T. brucei. Studies using VSG-seq to characterize antigenic variation in a mouse model have revealed marked diversity in VSG expression within parasite populations, but this finding has not yet been validated in a natural human infection. Here, we used VSG-seq to analyze VSGs expressed in the blood of 12 patients infected with T. b. gambiense. The number of VSGs identified per patient ranged from one to 14; notably, two VSGs were shared by more than one patient. Analysis of expressed VSG N-terminal domain types revealed that 82% of expressed VSGs encoded a type B N-terminus, a bias not seen in datasets from other T. brucei subspecies. C-terminal types in T. b. gambiense infection were also restricted. These results demonstrate a bias either in the underlying VSG repertoire of T. b. gambiense or in this subspecies expression of VSGs during infection. This work demonstrates the feasibility of using VSG-seq to study antigenic variation in human infections and highlights the importance of understanding VSG repertoires in the field.

Author SummaryHuman African Trypanosomiasis is a neglected tropical disease primarily caused by the extracellular parasite Trypanosoma brucei gambiense. To avoid elimination by the host, these parasites repeatedly replace their dense surface coat of Variant Surface Glycoprotein (VSG). Despite the important role of VSGs in prolonging infection, VSG expression during natural human infections is poorly understood. A better understanding of natural VSG gene expression dynamics can clarify the mechanisms that T. brucei uses to alter its VSG coat and improve how trypanosomiasis is diagnosed in humans. We analyzed the expressed VSGs detected in the blood of patients with trypanosomiasis. Our findings indicate that parasites in both natural and experimental infections express diverse sets of VSGs. Ecological specialization, rather than the island effect, explains morphological diversification in an ancient radiation of geckos Island colonists are often assumed to experience higher levels of phenotypic diversification than continental taxa. However, empirical evidence has uncovered exceptions to this "island effect". Here, we tested this pattern using the geckos of the genus Pristurus from continental Arabia and Africa and the Socotra Archipelago. Using a recently published phylogeny and an extensive morphological dataset, we explore the differences in phenotypic evolution between Socotran and continental taxa. Moreover, we reconstructed ancestral habitat occupancy to examine if ecological specialisation is correlated with morphological change, comparing phenotypic disparity and trait evolution between habitats. We found a heterogeneous outcome of island colonisation. Namely, only one of the three colonisation events resulted in a body size increase. However, in general, Socotran species do not present higher levels or rates of morphological diversification than continental groups. Instead, habitat specialisation explains better the body size and shape evolution in Pristurus. Particularly, the colonisation of ground habitats appears as the main driver of morphological change, producing the highest disparity and evolutionary rates. Additionally, arboreal species show very similar body size and head proportions. These results reveal a determinant role of ecological mechanisms in morphological evolution and corroborate the complexity of ecomorphological dynamics in continent-island systems. 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. Naming of human diseases on the wrong side of history BackgroundIn the medical sphere, understanding naming conventions strengthen the integrity of naming human diseases remains nominal rather than substantial yet. Since the current nosology-based standard for human diseases could not offer a one-size-fits-all corrective mechanism, many idiomatic but flawed names frequently appear in scientific literature and news outlets at the cost of sociocultural impacts.

ObjectiveWe attempt to examine the ethical oversights of current naming practices and propose heuristic rationales and approaches to determine a pithy name instead of an inopportune nosology.

MethodsFirst, we examined the compiled global online news volumes and emotional tones on some inopportune nosology like German measles, Middle Eastern Respiratory Syndrome, Spanish flu, Hong Kong flu, and Huntingtons disease in the wake of COVID-19. Second, we prototypically scrutinize the lexical dynamics and pathological differentials of German measles and common synonyms by leveraging the capacity of the Google Books Ngram Corpus. Third, we demonstrated the empirical approaches to curate an exclusive substitute for an anachronistic nosology German measles based on deep learning models and post-hoc explanations.

ResultsThe infodemiological study shows that the public informed the offensive names with extremely negative tones in textual and visual narratives. The findings of the historiographical study indicate that many synonyms of German measles did not survive, while German measles became an anachronistic usage, and rubella has taken the dominant place since 1994. The PubMedBERT model could identify rubella as a potential substitution for German measles with the highest semantic similarity. The results of the semantic drift experiments further indicate that rubella tends to survive during the ebb and flow of semantic drift.

ConclusionsOur findings indicate that the nosological evolution of anachronistic names could result in sociocultural impacts without a corrective mechanism. To mitigate such impacts, we introduce some ethical principles for formulating an improved naming scheme. Based on deep learning models and post-hoc explanations, our illustrated experiments could provide hallmark references to the remedial mechanism of naming practices and pertinent credit allocations. 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.