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 bioactive phlebovirus-like envelope protein in a hookworm endogenous retrovirus Endogenous retroviruses (ERVs), accounting for 14% of our genome, serve as a genetic reservoir from which new genes can emerge. Nematode ERVs are particularly diverse and informative of retrovirus evolution. We identify Atlas virus - a novel, intact ERV in the human hookworm Ancylostoma ceylanicum with an envelope protein genetically related to GN-GC glycoproteins from phleboviruses. A cryo-EM structure of Atlas GC reveals a class II viral membrane fusion protein fold not previously seen in retroviruses. Atlas GC has the structural hallmarks of an active fusogen. Atlas GC trimers insert into membranes with endosomal lipid compositions and low pH. When expressed on the plasma membrane, Atlas GC has cell-cell fusion activity. Atlas virus is transcriptionally active at specific stages of hookworm development. The preserved activities and expression pattern of Atlas GC suggest it has acquired a cellular function. Our work reveals an unexpected degree of structural and genetic plasticity in retroviruses.
Low dose rate γ-irradiation protects Drosophila melanogaster chromosomes from double strand breaks and telomere fusions by modulating the expression of the esi-RNA biogenesis factor Loquacious. It is still continuously debated whether the low-dose/dose-rate (LDR) of ionizing radiation represents a hazard for humans. Model organisms, such as fruit flies, are considered valuable systems to reveal insights into this issue. We found that, in wild-type Drosophila melanogaster larval neuroblasts, the frequency of Chromosome Breaks (CBs), induced by acute {gamma}-irradiation, is significantly reduced when flies are previously exposed to a protracted dose of 0.4Gy delivered at a dose rate of 2.5mGy/h. This indicates that this exposure, which is associated with an increased expression of DNA damage response proteins, induces a radioadaptive response (RAR) that protects Drosophila from extensive DNA damage. Interestingly, the same exposure reduces the frequency of telomere fusions (TFs) from Drosophila telomere capping mutants suggesting that the LDR can generally promote a protective response on chromatin sites that are recognized as DNA breaks. Deep RNA sequencing revealed that RAR is associated with a reduced expression of Loquacious D (Loqs-RD) gene that encodes a well-conserved dsRNA binding protein required for esiRNAs biogenesis. Remarkably, loss of Loqs mimics the LDR-mediated chromosome protection as it decreases the IR-induced CBs and TF frequency. Thus, our molecular characterization of RAR identifies Loqs as a key factor in the cellular response to LDR and unveils unprecedented epigenetic routes involved in radioresistance. DeGlyPHER: an ultrasensitive method for analysis of viral spike N-glycoforms Viruses can evade the host immune system by displaying numerous glycans on their surface "spike-proteins" that cover immune epitopes. We have developed an ultrasensitive "single pot" method to assess glycan occupancy and the extent of glycan processing from high-mannose to complex forms at each N-glycosylation site. Though aimed at characterizing glycosylation of viral spike-proteins as potential vaccines, this method is applicable for analysis of site-specific glycosylation of any glycoprotein. Robust and Remote Measurement of Heart Rate Based on A Surveillance Camera Arrhythmia is a marked symptom of many cardiovascular diseases (CVDs). The accurate and timely detection of heart rate can greatly reduce the harm of arrhythmia to people. However, it is still a challenge to robustly and remotely measure heart rate in daily life due to the changing environmental conditions during measurement, such as the varying light intensity, the movement of people, and the uncertain distance between the sensor to people. In this study, we propose a method to accurately measure human heart rate within a distance of 4.5 meters under different light intensities by simply using a surveillance camera. After a 20-second color video of a persons hand is captured by the camera, a method based on the Fast Fourier Transform (FFT) algorithm is designed to extract the blood volume pulse wave to calculate the heart rate. According to the comparison between the real heart rate and results measured by electrocardiography (ECG), the proposed method achieves an accuracy of 95.8% when the measurement is performed within a distance of 4.5 meters and 90% when within 5.0 meters. Our experiments show that when the illuminance varies between 100-1000 lux (lighting level indoor), we still get the correct results. Our experiments also demonstrate that the proposed method accurately obtain heart rate even when the light intensity is below 32 lux (300-500 lux in a workplace environment). The methods strong adaptability to changing environmental conditions makes it applicable to many scenarios, such as homes of the elderly, classrooms, and other public spaces. Engineered bacteria detect tumor DNA Advances in bacterial engineering have catalysed the development of living cell diagnostics and therapeutics1-3, including microbes that respond to diseases such as gut inflammation4, intestinal bleeding5, pathogens6 and hypoxic tumors7. Bacteria can easily access the entire gastrointestinal tract via oral administration8, and they can produce outputs that can be noninvasively measured in stool4 or urine7. Cellular memory, such as bistable switches4,9,10 or genomic rearrangement11, has been used to allow bacteria to store information over time. However, living biosensors have not yet been engineered to detect specific DNA sequences or mutations from outside the cell. Here, we engineer naturally competent Acinetobacter baylyi to detect donor DNA from the genomes of colorectal cancer (CRC) cells and organoids. We characterize the functionality of the biosensors in vitro with co-culture assays and then validate in vivo with sensor bacteria delivered orally or rectally into mice injected with orthotopic donor CRC organoids. We observe horizontal gene transfer from the tumor to the sensor bacteria in vivo, allowing their detection in stool. The sensor bacteria achieved 100% discrimination between mice with and without CRC using both delivery methods. Our findings establish a framework for biosensing applications that require the detection of mutations or organisms within environments that are difficult to sample. In addition, the platform can be readily expanded to include in situ production and delivery of therapeutic payloads at the detection site. Bacterial and fungal communities experience rapid secondary succession during the first year following a wildfire in a California chaparral. The rise in wildfire frequency and severity across the globe has increased interest in secondary succession. However, despite the role of soil microbial communities in the regeneration of post-fire vegetation and biogeochemical cycling, the lack of measurements immediately post-fire and at high temporal resolution has resulted in a limited understanding of microbial secondary succession. To fill this knowledge gap, we sampled soils at 17, 25, 34, 67, 95, 131, 187, 286, and 376 days after a Southern California wildfire in fire-adapted chaparral shrublands. We assessed bacterial and fungal biomass with qPCR of 16S and 18S and richness and composition with Illumina MiSeq sequencing of 16S and ITS2 amplicons. Fire severely reduced bacterial biomass by 47% and richness by 46%, but the impacts were stronger for fungi, with biomass decreasing by 86% and richness by 68%. While bacterial biomass and richness oscillated in response to precipitation, the declines in biomass and richness for both groups persisted for the entire year. In contrast to the unburned plots, burned fungal and bacterial communities experienced rapid succession, with 5-6 compositional turnover periods. Analogous to plants, "fire-loving" pyrophilous microbes increased post-fire and drove successional dynamics. Interestingly, many of the same pyrophilous taxa found in forests worldwide also dominated post-fire chaparral and traded off markedly in abundance over time. For fungi, an initial peak in the Basidiomycete yeast Geminibasidium traded off with the filamentous Ascomycetes Pyronema, Aspergillus, and Penicillium. For bacteria, the Proteobacteria genus Massilia dominated burned plots throughout the year, but the following most dominant bacteria, the Firmicute Bacillus and Proteobacteria Noviherbaspirillum, traded off in abundance over time. Our unprecedented high-resolution temporal sampling allowed us to capture post-fire microbial secondary successional dynamics and show that putative tradeoffs in thermotolerance, colonization, and competition among dominant pyrophilous microbes control microbial succession with possible implications for ecosystem function. Partial exogastrulation due to apical-basal polarity of F-actin distribution disruption in sea urchin embryo by omeprazole Gastrulation is a universal process in the morphogenesis of many animal embryos. Although morphological and molecular events in gastrulation have been well studied, the mechanical driving forces and underlying regulatory mechanisms are not fully understood. Here, we investigated the gastrulation of embryos of a sea urchin, Hemicentrotus pulcherrimus, which involves the invagination of a single-layered vegetal plate into the blastocoel. We observed that omeprazole, a proton pump inhibitor capable of perturbing the left-right asymmetry of sea urchin embryo, induced "partial exogastrulation" where the secondary invagination proceeds outward. During early gastrulation, intracellular apical-basal polarity of F-actin distribution in vegetal half were higher than those in animal half, while omeprazole treatment disturbed the apical-basal polarity of F-actin distribution in vegetal half. Furthermore, gastrulation stopped and even partial exogastrulation did not occur when F-actin polymerization or degradation in whole embryo was partially inhibited via RhoA or YAP1 knockout. A mathematical model of the early gastrulation reproduced the shapes of both normal and exogastrulating embryos using cell-dependent cytoskeletal features based on F-actin. Additionally, such cell position-dependent intracellular F-actin distributions might be regulated by intracellular pH distributions. Therefore, apical-basal polarity of F-actin distribution disrupted by omeprazole may induce the partial exogastrulation via anomalous secondary invagination. Repeated introduction of micropollutants enhances microbial succession despite stable degradation patterns The increasing-volume release of micropollutants into natural surface waters has raised great concern due to their environmental accumulation. Persisting micropollutants can impact multiple generations of organisms, but their microbially-mediated degradation and their influence on community assembly remain understudied. Here, freshwater microbes were treated with several common micropollutants, alone or in combination, and then transferred every 5 days to fresh medium containing the same micropollutants to mimic the repeated exposure of microbes. Metabarcoding of 16S rRNA gene makers was chosen to study the succession of bacterial assemblages following micropollutant exposure. The removal rates of micropollutants were then measured to assess degradation capacity of the associated communities. The degradation of micropollutants did not accelerate over time but altered the microbial community composition. Community assembly was dominated by stochastic processes during early exposure, via random community changes and emergence of seedbanks, and deterministic processes later in the exposure, via advanced community succession. Early exposure stages were characterized by the presence of sensitive microorganisms such as Actinobacteria and Planctomycetes, which were then replaced by more tolerant bacteria such as Bacteroidetes and Gammaproteobacteria. Our findings have important implication for ecological feedback between microbe-micropollutants under anthropogenic climate change scenarios. Outsourced hearing in an orb-weaving spider that uses its web as an auditory sensor Hearing is a fundamental sense of many animals, including all mammals, birds, some reptiles, amphibians, fish, and arthropods. The auditory organs of these animals are extremely diverse in anatomy after hundreds of millions of years of evolution, yet all are made up of cellular tissues and are morphologically part of bodies of animals. Here we show hearing in the orb-weaving spider, Larinioides sclopetarius is not constrained by the organisms body but is extended through outsourcing hearing to its extended phenotype, the proteinaceous, self-manufactured orb-web. We find the wispy, wheel-shaped orb-web acts as a hyperacute acoustic "antenna" to capture the sound-induced air particle movements that approach the maximum physical efficiency, better than the acoustic responsivity of all previously known eardrums. By sensing the motion of web threads, the spider remotely detects and localizes the source of an incoming airborne acoustic wave such as those emitted by approaching prey or predators. By outsourcing its acoustic sensors to its web, the spider is released from body size constraints and permits the araneid spider to increase its sound-sensitive surface area enormously, up to 10,000 times greater than the spider itself. The spider also enables the flexibility to functionally adjust and regularly regenerate its "external eardrum" according to its needs. The "outsourcing" and "supersizing" of auditory function in spiders provides unique features for studying extended and regenerative sensing, and designing novel acoustic flow detectors for precise fluid dynamic measurement and manipulation. A Eukaryotic Circuit for Secrete-and-Sense Autonomy Cancers represent complex autonomous robust systems, displaying interconnectivity with feedback control. Autonomous growth is fueled by a cancer cells ability to  secrete-and-sense growth factors: a poorly understood phenomenon. Using an integrated systems and experimental approach, here we dissect the impact of a feedback-coupled GTPase circuit within the secretory pathway that imparts secretion-coupled autonomy. The circuit is assembled when the Ras-superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase Giabg and their corresponding GAPs and GEFs are coupled by GIV/Girdin, a protein that is known to fuel aggressive traits in diverse cancers. One forward and two key negative feedback loops within the circuit create closed-loop control (CLC), allow the two GTPases to coregulate each other, and convert the expected switch-like behavior of Arf1-dependent secretion into an unexpected dose response alignment behavior of sensing and secretion. Such behavior translates into cell survival that is self-sustained by stimuli-proportionate secretion. Findings highlight how enhanced coupling of two biological switches in cancer cells is critical for multiscale feedback control to achieve secretion-coupled autonomy.

GRAPHIC ABSTRACT

O_FIG O_LINKSMALLFIG WIDTH=163 HEIGHT=200 SRC="FIGDIR/small/436048v3_ufig1.gif" ALT="Figure 1">
View larger version (51K):
org.highwire.dtl.DTLVardef@183ff5corg.highwire.dtl.DTLVardef@f21de7org.highwire.dtl.DTLVardef@1893683org.highwire.dtl.DTLVardef@159d966_HPS_FORMAT_FIGEXP  M_FIG C_FIG In BriefThis work delivers an experimentally validated dynamical systems model of the cooperativity between two distinct classes of biological switches in eukaryotic cells and reveals the basis of secretion-coupled cellular autonomy in cancer.

HIGHLIGHTSO_LIModeling and experimental approaches were used to dissect a coupled GTPase circuit
C_LIO_LICoupling enables closed loop feedback and mutual control of GTPases
C_LIO_LICoupling generates dose response alignment behavior of sensing and secretion.
C_LIO_LICoupling is critical for multiscale feedback control to achieve secretion-coupled autonomy.
C_LI An ex vivo human bone marrow milieu identifies CDH2 as a driver of niche-mediated treatment resistance in leukaemia Being able to clinically target the interaction of leukaemic cells with their microenvironment has remained a key therapeutic obstacle. Leukaemia cells re-program their microenvironment to provide support and protection from standard chemotherapy, molecularly targeted therapies as well as immunotherapy. To address this challenge, we have developed experimentally accessible human induced pluripotent stem cell engineered (iPSC) niches ex vivo to reveal insights into druggable cancer-niche interactions. We show that mesenchymal (iMSC) and vascular niche-like (iANG) cells support ex vivo proliferation of patient-derived leukaemia cells, impact dormancy and mediate therapy resistance. Mesenchymal stem cells protected both cycling and non- cycling blasts against dexamethasone treatment while vascular niche-like cells only protected dormant cells. Growth support and protection from dexamethasone induced- apoptosis was dependent on direct cell-cell contact and was mediated by N-cadherin (CDH2). To explore the therapeutic potential of disrupting this cell-cell interaction, we tested the CDH2 antagonist ADH-1 (previously in phase I / II for solid tumours) in a very aggressive patient-derived xenograft acute lymphoblastic leukaemia mouse model. ADH-1 showed high in vivo efficacy and combination therapy with ADH-1 and dexamethasone was superior compared with dexamethasone alone. These findings provide a proof-of-concept starting point to develop novel and potentially safer anti- cancer therapeutics that target niche-mediated cancer cell dependencies in haematological malignancies.

One Sentence SummaryCDH2 drives niche-dependent treatment resistance targetable via ADH-1, a low toxic potential candidate for future leukaemia clinical trials. Genome-wide mechanisms of rediploidization in paleopolyploid teleosts revealed by a high-resolution comparative atlas across 74 fishes Teleost fishes are ancient tetraploids stemming from an ancestral whole-genome duplication that may have contributed to the impressive diversification of this clade. Whole-genome duplications can occur via self-doubling (autopolyploidy) or via hybridization between different species (allopolyploidy). The mode of tetraploidization conditions subsequent evolutionary processes by which descendant genomes return to a diploid state through gene losses and functional divergence. How teleosts became tetraploid remains however unresolved, leaving a fundamental gap to interpret their functional evolution. As legacy of the whole genome duplication, identifying orthologous and paralogous genomic regions across teleosts is challenging, hindering genome-wide investigations into their polyploid history. Here, we combine tailored gene phylogeny methodology together with the state-of-the-art ancestral karyotype reconstruction to establish the first high-resolution comparative atlas of paleopolyploid regions across 74 teleost genomes. We then leverage this atlas to investigate the genome-wide mechanisms of rediploidization after tetraploidization in teleosts. We uncover that meiotic recombination persisted between duplicated chromosomes for over 60 million years, with entire chromosomes only functionally diverging after the separation of major teleost families. This evidence suggests that the teleost ancestor was an autopolyploid. Further, ancient duplicated chromosomes have evolved asymmetrically in teleosts, disputing unbalanced evolution as a hallmark of polyploidization through hybridization. Design of a radial multi-offset detection pattern for in vivo phase contrast imaging of the retinal ganglion cells in humans Previous work has shown that multi-offset detection in adaptive optics scanning laser ophthalmoscopy (AOSLO) can be used to image retinal ganglion cells (RGCs) in monkeys and humans. However, though images of RGCs in anesthetized monkeys with high light levels produced high contrast images of RGCs, images from humans failed to reach the same contrast due to several drawbacks in the previous dual-wavelength multi-offset approach. Our aim here was to design and build a multi-offset detection pattern for humans at safe light levels that could reveal the retinal ganglion cell layer neurons with a contrast, robustness and acquisition time approaching results only previously obtained in monkeys. Here, we present a new imaging system using only one light source, compared to the previous dual-wavelength used on monkeys. Our single-wavelength solution allows for increased light power and eliminates problematic chromatic aberrations. Then, we demonstrate that a radial multi-offset detection pattern with an offset distance of 8-10 Airy Disk Diameter (ADD) is optimal to detect photons multiply scattered in all directions from RGCs thereby enhancing their contrast. This new setup and image processing pipeline led to improved imaging of retinal ganglion cells using multi-offset imaging in AOSLO. Ineffectual AEC1 differentiation from KRT8hi transitional state without fibrosis is associated with fatal COVID-19 ARDS ARDS due to COVID-19 and other etiologies results from injury to the alveolar epithelial cell (AEC) barrier resulting in noncardiogenic pulmonary edema, which causes acute respiratory failure; clinical recovery requires epithelial regeneration. During physiologic regeneration in mice, AEC2s proliferate, exit the cell cycle, and transiently assume a transitional state before differentiating into AEC1s; persistence of the transitional state is associated with pulmonary fibrosis in humans. It is unknown whether transitional cells emerge and differentiate into AEC1s without fibrosis in human ARDS and why transitional cells differentiate into AEC1s during physiologic regeneration but persist in fibrosis. We hypothesized that incomplete but ongoing AEC1 differentiation from transitional cells without fibrosis may underlie persistent barrier permeability and fatal acute respiratory failure in ARDS. Immunostaining of postmortem ARDS lungs revealed abundant transitional cells in organized monolayers on alveolar septa without fibrosis. They were typically cuboidal or partially spread, sometimes flat, and occasionally expressed AEC1 markers. Immunostaining and/or interrogation of scRNAseq datasets revealed that transitional cells in mouse models of physiologic regeneration, ARDS, and fibrosis express markers of cell cycle exit but only in fibrosis express a specific senescence marker. Thus, in severe, fatal early ARDS, AEC1 differentiation from transitional cells is incomplete, underlying persistent barrier permeability and respiratory failure, but ongoing without fibrosis; senescence of transitional cells may be associated with pulmonary fibrosis. Prenatal environmental conditions underlie alternative reproductive tactics that drive the formation of a mixed-kin cooperative society Although animal societies often evolve due to limited natal dispersal that results in kin clustering and facilitates cooperation among relatives, many species form cooperative groups with low and variable kin structure. Groups in such mixed-kin societies often comprise residents and immigrants of the same sex that compete for breeding opportunities. To understand how such mixed-kin societies form despite their potential for social conflict, we investigated the environmental causes and subsequent fitness consequences of dispersal decisions in male cooperatively breeding superb starlings (Lamprotornis superbus) that live in a climatically unpredictable environment. We show that the two alternative reproductive tactics--natal dispersal or philopatry--exhibit reproductive tradeoffs resulting in equal lifetime inclusive fitness. The tactic an individual adopts is governed by the environment its parents experience prior to laying rather than the environment it experiences during its juvenile stage. When individuals adopt the tactic not predicted by early life environmental conditions, their fitness is reduced. Ultimately, climate-driven oscillating selection may help stabilize mixed-kin animal societies, despite their reduced kin structure and potential for social conflict. 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. Venomics and antivenomics of Indian spectacled cobra (Naja naja) from the Western Ghats Venom proteome profiling of Naja naja from the Western Ghats region in Kerala was achieved through SDS-PAGE and RP-HPLC followed by Q-TOF LC-MS/MS analysis, incorporating PEAKS and Novor assisted de novo sequencing methodologies. A total of 115 proteins distributed across 17 different enzymatic and non-enzymatic venom protein families were identified through conventional and 39 peptides through homology-driven proteomics approaches. Fourteen peptides derived through de novo complements the Mascot data indicating the importance of homology-driven approaches in improving protein sequence information. Among the protein families identified, glutathione peroxidase and endonuclease were reported for the first time in the Indian cobra venom. Immunological cross-reactivity assessed using Indian polyvalent antivenoms suggested that VINS showed better EC50 (2.48 g/mL) value than that of PSAV (6.04 g/mL) and Virchow (6.03 g/mL) antivenoms. Western blotting experiments indicated that all the antivenoms elicited poor binding specificities, especially towards low molecular mass proteins. Second-generation antivenomics studies revealed that VINS antivenom was less efficient to detect many low molecular mass proteins such as three-finger toxins and Kunitz-type serine protease Inhibitors. Taken together, the present study enabled a large-scale characterization of the venom proteome of Naja naja from the Western Ghats and emphasized the need for developing more efficient antivenoms.

HighlightsO_LIProteomics of cobra venom resulted in the identification of 115 proteins representing 17 snake venom protein families.
C_LIO_LIDe novo approaches exclusively yielded 39 peptides harbouring multiple amino acid mutations.
C_LIO_LIGlutathione peroxidase and endonuclease were identified for the first time in Indian cobra venom.
C_LIO_LIIndian polyvalent antivenoms showed varying cross-reactivity towards cobra venom.
C_LIO_LIVINS antivenom was less efficient to detect many low molecular mass proteins (< 20 kDa).
C_LI Infant brain regional cerebral blood flow dynamics supporting emergence of vital functional networks Human infancy is characterized by most rapid cerebral blood flow (rCBF) increases across lifespan and emergence of a fundamental brain system default-mode network (DMN). However, how infant rCBF change spatiotemporally across the brain and how the rCBF dynamics support emergence of vital functional networks such as DMN remains unknown. Here, by acquiring cutting-edge multi-modal MRI including pseudo-continuous arterial-spin-labeled perfusion MRI and resting-state functional MRI of infants aged 0 to 24 months, we elucidated unprecedented 4D spatiotemporal infant rCBF framework and region-specific physiology-function coupling across infancy. We found faster rCBF increases in the DMN than other regions. We also found strongly coupled increases of rCBF and network strength specifically in the DMN, suggesting faster local blood flow increase to meet extra neuronal metabolic demands in the DMN maturation. These results offer insights into physiological mechanism of brain functional network emergence and have important implications in altered network maturation in brain disorders. Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate A main clinical parameter of COVID-19 pathophysiology is hypoxia. Here we show that hypoxia decreases the attachment of the receptor binding domain (RBD) and the S1 subunit (S1) of the spike protein of SARS-CoV-2 to epithelial cells. In Vero E6 cells, hypoxia reduces the protein levels of ACE2 and neuropilin-1 (NRP1), which might in part explain the observed reduction of the infection rate. In addition, hypoxia inhibits the binding of the spike to NCI-H460 human lung epithelial cells by decreasing the cell surface levels of heparan sulfate (HS), a known attachment receptor of SARS-CoV-2. This interaction is also reduced by lactoferrin, a glycoprotein that blocks HS moieties on the cell surface. The expression of syndecan-1, an HS-containing proteoglycan expressed in lung, is inhibited by hypoxia on a HIF-1-dependent manner. Hypoxia or deletion of syndecan-1 results in reduced binding of the RBD to host cells. Our study indicates that hypoxia acts to prevent SARS-CoV-2 infection, suggesting that the hypoxia signaling pathway might offer therapeutic opportunities for the treatment of COVID-19. Naming Human Diseases: Ethical Principles of Curating Exclusive Substitute for Inopportune Nosology 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. A human antibody reveals a conserved site on beta-coronavirus spike proteins and confers protection against SARS-CoV-2 infection Broadly neutralizing antibodies (bnAbs) to coronaviruses (CoVs) are valuable in their own right as prophylactic and therapeutic reagents to treat diverse CoVs and, importantly, as templates for rational pan-CoV vaccine design. We recently described a bnAb, CC40.8, from a coronavirus disease 2019 (COVID-19)-convalescent donor that exhibits broad reactivity with human beta-coronaviruses ({beta}-CoVs). Here, we showed that CC40.8 targets the conserved S2 stem-helix region of the coronavirus spike fusion machinery. We determined a crystal structure of CC40.8 Fab with a SARS-CoV-2 S2 stem-peptide at 1.6 [A] resolution and found that the peptide adopted a mainly helical structure. Conserved residues in {beta}-CoVs interacted with CC40.8 antibody, thereby providing a molecular basis for its broad reactivity. CC40.8 exhibited in vivo protective efficacy against SARS-CoV-2 challenge in two animal models. In both models, CC40.8-treated animals exhibited less weight loss and reduced lung viral titers compared to controls. Furthermore, we noted CC40.8-like bnAbs are relatively rare in human COVID-19 infection and therefore their elicitation may require rational structure-based vaccine design strategies. Overall, our study describes a target on {beta}-CoV spike proteins for protective antibodies that may facilitate the development of pan-{beta}-CoV vaccines.

SUMMARYA human mAb isolated from a COVID-19 donor defines a protective cross-neutralizing epitope for pan-{beta}-CoV vaccine design strategies First detection of herpesvirus and prevalence of mycoplasma infection in free-ranging Hermann s tortoises (Testudo hermanni), and in potential pet vectors AO_SCPLOWBSTRACTC_SCPLOWTwo types of pathogens cause highly contagious upper respiratory tract diseases (URTD) in Chelonians: testudinid herpesviruses (TeHV) and a mycoplasma (Mycoplasma agassizii). In captivity, these infections are frequent and can provoke outbreaks. Pet trade generates international flow of tortoises, often without sanitary checking; individuals intentionally or accidentally released in the wild may spread pathogens. A better understanding of the transmission of infectious agents from captivity to wild tortoises is needed. Many exotic individuals have been introduced in populations of the endangered western Hermanns tortoise (Testudo hermanni hermanni), notably spur-thighed tortoises (Testudo graeca). We assessed the presence of TeHV and mycoplasma in native western Hermanns tortoises and in potential pet vectors in south-eastern France. Using a large sample (N=572 tortoises), this study revealed, by PCR, the worrying presence of herpesvirus in 7 free-ranging individuals (3 sub-populations). Additionally, Mycoplasma agassizii was detected, by PCR, in 15 of the 18 populations sampled with a frequency ranging from 3.4% (1 of 29 tortoises) to 25% (3 of 12 tortoises). Exotic spur-thighed tortoises showed high frequency of mycoplasma infection in captivity (18.2%) and in individuals (50%) found in native Hermanns tortoise sub-populations, suggesting that this species could be a significant vector. The paucity of information of TeHV on European tortoise URTD in natural settings, especially in combination with mycoplasma, prompts for further studies. Indeed, sick tortoises remain concealed and may not be easily detected in the field. Our results indicate a good health for most infected tortoise but it should be screened in the field as well as in captivity. Network Propagation-based Prioritization of Long Tail Genes in 17 Cancer Types IntroductionThe diversity of genomic alterations in cancer pose challenges to fully understanding the etiologies of the disease. Recent interest in infrequent mutations, in genes that reside in the "long tail" of the mutational distribution, uncovered new genes with significant implication in cancer development. The study of these genes often requires integrative approaches with multiple types of biological data. Network propagation methods have demonstrated high efficacy in uncovering genomic patterns underlying cancer using biological interaction networks. Yet, the majority of these analyses have focused their assessment on detecting known cancer genes or identifying altered subnetworks. In this paper, we introduce a network propagation approach that entirely focuses on long tail genes with potential functional impact on cancer development.

ResultsWe identify sets of often overlooked, rarely to moderately mutated genes whose biological interactions significantly propel their mutation-frequency-based rank upwards during propagation in 17 cancer types. We call these sets "upward mobility genes" (UMGs, 28-83 genes per cancer type) and hypothesize that their significant rank improvement indicates functional importance. We report new cancer-pathway associations based on UMGs that were not previously identified using driver genes alone, validate UMGs role in cancer cell survival in vitro--alone and compared to other network methods--using extensive genome-wide RNAi and CRISPR data repositories, and further conduct in vitro functional screenings resulting the validation of 8 previously unreported genes.

ConclusionOur analysis extends the spectrum of cancer relevant genes and identifies novel potential therapeutic targets. A small molecule antagonizes jasmonic acid perception and auxin responses in vascular and nonvascular plants The phytohormone JA-Ile regulates many stress responses and developmental processes in plants. A co-receptor complex formed by the F-box protein COI1 (Coronatine Insensitive 1) and a JAZ (Jasmonate ZIM-domain) repressor perceives the hormone. JA-Ile antagonists are invaluable tools for exploring the role of JA-Ile in specific tissues and developmental stages, and for identifying regulatory processes of the signalling pathway. Using two complementary chemical screens, we identified three compounds that exhibit a robust inhibitory effect on both the hormone-mediated COI-JAZ interaction and degradation of JAZ1 and JAZ9 in vivo. One molecule, J4, also restrains specific JA-induced physiological responses in different angiosperm plants, including JA-mediated gene expression, growth inhibition, chlorophyll degradation and anthocyanin accumulation. Interaction experiments with purified proteins indicate that J4 directly interferes with the formation of the Arabidopsis (Arabidopsis thaliana) COI1-JAZ complex otherwise induced by JA. The antagonistic effect of J4 on COI1- JAZ also occurs in the liverwort Marchantia polymorpha, suggesting the mode of action is conserved in land plants. Besides JA signalling, J4 works as an antagonist of the closely-related auxin signalling pathway, preventing TIR1/Aux-IAA interaction and auxin responses in planta, including hormone-mediated degradation of an auxin repressor, gene expression and gravitropic response. However, J4 does not affect other hormonal pathways. Altogether, our results show that this dual antagonist competes with JA-Ile and auxin, preventing the formation of phylogenetically related receptor complexes. J4 may be a useful tool to dissect both the JA-Ile and auxin pathways in particular tissues and developmental stages since it reversibly inhibits these pathways.

One sentence summaryA chemical screen identified a molecule that antagonizes jasmonate perception by directly interfering with receptor complex formation in phylogenetically distant vascular and non-vascular plants. Collective polymerase dynamics emerge from DNA supercoiling during transcription All biological processes ultimately come from physical interactions. The mechanical properties of DNA play a critical role in transcription. RNA polymerase can over or under twist DNA (referred to as DNA supercoiling) when it moves along a gene resulting in mechanical stresses in DNA that impact its own motion and that of other polymerases. For example, when enough supercoiling accumulates, an isolated polymerase halts and transcription stops. DNA supercoiling can also mediate non-local interactions between polymerases that shape gene expression fluctuations. Here, we construct a comprehensive model of transcription that captures how RNA polymerase motion changes the degree of DNA supercoiling which in turn feeds back into the rate at which polymerases are recruited and move along the DNA. Surprisingly, our model predicts that a group of three or more polymerases move together at a constant velocity and sustain their motion (forming what we call a polymeton) whereas one or two polymerases would have halted. We further show that accounting for the impact of DNA supercoiling on both RNA polymerase recruitment and velocity recapitulates empirical observations of gene expression fluctuations. Finally, we propose a mechanical toggle switch whereby interactions between genes are mediated by DNA twisting as opposed to proteins. Understanding the mechanical regulation of gene expression provides new insights into how endogenous genes can interact and informs the design of new forms of engineered interactions.

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