Brain-heart dynamics in emotional regulation under uncertainty indexes depressive risk Recent studies highlight interoception as essential to processing healthy emotion and to pathology of major depressive disorder (MDD). It has been reported that interoceptive responses are impaired in MDD and in healthy individuals with a high depressive risk (HDR). However, it is unclear how individual differences in HDR relate to neurophysiological underpinnings for interoceptive and emotional reactions under different degrees of certainty. We examined whether HDR mediates the relationship between a neurophysiological marker for interoception, heartbeat-evoked potential (HEP), and an index for cardiac reactivity, heart rate (HR) or heart rate variability (HRV). In a concurrent EEG-ECG experiment, 26 healthy participants underwent an emotion-evoking picture-evaluation task. Each of differential auditory cues was associated with certainty of the upcoming pleasant or unpleasant picture. The results showed attenuated HRV activity for certain cues in HDR individuals. Neural and physiological reactions to uncertain, unpleasant pictures were enhanced by depressive risk. These results suggest reduced responses in prediction processing and enlarged precision-weighted prediction error for unpleasant pictures. Finally, HDR significantly mediated the HEP and HR relationship for unexpected unpleasant stimuli. This study provides evidence that interoceptive predictive coding in the cardiac domain is altered by HDR and suggests that investigating brain-heart interactions related to predictive coding will offer insights into how to estimate depressive risk.
Changing the social brain: plasticity along macro-scale axes of functional connectivity following social mental training. AO_SCPLOWBSTRACTC_SCPLOWDespite the importance of our ability to understand the thoughts and feelings of others, the social brain remains incompletely understood. Here, we studied the plasticity of social brain function in healthy adults following the targeted training of attention-mindfulness, socio-affective, and socio-cognitive skills for 9 months. All participants were followed with repeated multimodal neuroimaging and behavioral testing. Longitudinal analyses of functional networks indicated marked and specific reorganization following mental training. Socio-cognitive training resulting in an increased integration of multiple demand and default mode regions whereas attention-mindfulness resulted in their segregation. Socio-affective training resulted in an increased functional integration of ventral attention network with these regions. Changes in functional network organization were robust after varying analysis parameters, and predictive of change in behavioral markers of compassion and perspective-taking. Our results advance the understanding of the social brain, describing its intrinsic functional organization and reorganization following mental training.
Systematic monitoring of 2-Cys peroxiredoxin-derived redox signals unveiled its role in attenuating carbon assimilation rate Transmission of reductive cues from the photosynthetic electron transport chain to redox-regulated proteins plays a crucial role in activating chloroplast metabolism. However, deciphering the role of their counterbalanced oxidative signals is challenging due to monitoring difficulties. Here, we demonstrate the light-depended redox modification of chloroplast-targeted 2-Cys peroxiredoxins and introduce peroxiredoxin-based biosensors to monitor photosynthetically-derived oxidative signals. By employing a set of genetically encoded biosensors, we show the induction of oxidative signals under habitual light intensities and their inverse relationship with NADPH levels, unraveling the combined activity of reducing and oxidizing signals in fine-tuning chloroplast metabolism. A faster increase in carbon assimilation rates during photosynthesis induction phase was measured in plants deficient in 2-Cys peroxiredoxins compared to wild-type, suggesting the involvement of oxidative signals in attenuating photosynthesis under variable light environments. We suggest that oxidative signals measured by peroxiredoxin-based biosensors reflect the limitation to photosynthesis imposed by the redox regulatory system.

One-Sentence SummaryA genetically encoded biosensor unmasked the dominant role of photosynthetically-derived oxidative signals under habitual conditions. Mechanisms of A-type lamin targeting to nuclear ruptures are disrupted in LMNA- and BANF1-associated progerias Mutations in the genes LMNA and BANF1 can lead to accelerated aging syndromes called progeria. The protein products of these genes, A-type lamins and BAF, respectively, are nuclear envelope (NE) proteins that interact and participate in various cellular processes, including nuclear envelope rupture and repair. BAF localizes to sites of nuclear rupture and recruits NE-repair machinery, including the LEM-domain proteins, ESCRT-III complex, A-type lamins, and membranes. Here, we show that it is a mobile, nucleoplasmic population of A-type lamins that is rapidly recruited to ruptures in a BAF-dependent manner via BAFs association with the Ig-like {beta} fold domain of A-type lamins. These initially mobile lamins become progressively stabilized at the site of rupture. Farnesylated prelamin A and lamin B1 fail to localize to nuclear ruptures, unless that farnesylation is inhibited. Progeria-associated LMNA mutations inhibit the recruitment affected A-type lamin to nuclear ruptures, due to either permanent farnesylation or inhibition of BAF binding. A progeria-associated BAF mutant targets to nuclear ruptures but is unable to recruit A-type lamins. Together, these data reveal the mechanisms that determine how lamins respond to nuclear ruptures and how progeric mutations of LMNA and BANF1 impair recruitment of A-type lamins to nuclear ruptures. Data-Driven Network Models for Genetic Circuits From Time-Series Data with Incomplete Measurements Synthetic gene networks are frequently conceptualized and visualized as static graphs. This view of biological programming stands in stark contrast to the transient nature of biomolecular interaction, which is frequently enacted by labile molecules that are often unmeasured. Thus, the network topology and dynamics of synthetic gene networks can be difficult to verify in vivo or in vitro, due to the presence of unmeasured biological states. Here we introduce the dynamical structure function as a new mesoscopic, data-driven class of models to describe gene networks with incomplete measurements. We introduce a network reconstruction algorithm and a code base for reconstructing the dynamical structure function from data, to enable discovery and visualization of graphical relationships in a genetic circuit diagram as time-dependent functions rather than static, unknown weights. We prove a theorem, showing that dynamical structure functions can provide a data-driven estimate of the size of crosstalk fluctuations from an idealized model. We illustrate this idea with numerical examples. Finally, we show how data-driven estimation of dynamical structure functions can explain failure modes in two experimentally implemented genetic circuits, a historical genetic circuit and a new E. coli based transcriptional event detector. 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. H2A.B is a cancer/testis factor involved in activation of ribosome biogenesis in Hodgkin Lymphoma Testis-specific regulators of chromatin function are commonly ectopically expressed in human cancers, but their roles are poorly understood. Examination of 81 primary Hodgkin Lymphoma (HL) samples showed that the ectopic expression of the eutherian testis-specific histone variant H2A.B is an inherent feature of HL. In experiments using two HL-derived cell lines derived from different subtypes of HL, H2A.B knockdown inhibited cell proliferation. H2A.B was enriched in both the nucleoli of these HL cell lines and primary HL samples. We found that H2A.B enhanced ribosomal DNA (rDNA) transcription, was enriched at the rDNA promoter and transcribed regions, and interacted with RNA Pol I. Depletion of H2A.B caused the loss of RNA Pol I from rDNA chromatin. Remarkably, H2A.B was also required for high levels of ribosomal protein gene expression being located at the transcriptional start site and within the gene body. H2A.B knockdown reduced gene body chromatin accessibility of active RNA Pol II genes concurrent with a decrease in transcription. Taken together, our data show that in HL H2A.B has acquired a new function, the ability to increase ribosome biogenesis. Remarked Suppression of Aβ42 Protomer-protomer Dissociation Reaction via Pentamer Dimerization Elucidated by Molecular Dynamics Simulation Multimeric protein complexes are molecular apparatuses to regulate biological systems and often determine their fate. Among proteins forming such molecular assemblies, amyloid proteins have drawn attention over a half-century since amyloid fibril formation of these proteins is supposed to be a common pathogenic cause for neurodegenerative diseases. This process is triggered by the accumulation of fibril-like aggregates, while the microscopic mechanisms are mostly elusive due to technical limitation of experimental methodologies in individually observing each of diverse aggregate species in the aqueous solution. We then addressed this problem by employing atomistic molecular dynamics simulations for the paradigmatic amyloid protein, amyloid-{beta} (1-42) (A{beta}42). Seven different dimeric forms of oligomeric A{beta}42 fibril-like aggregate in aqueous solution, ranging from tetramer to decamer, were considered. We found additive effects of the size of these fibril-like aggregates on their thermodynamic stability and have clarified kinetic suppression of protomer-protomer dissociation reactions at and beyond the point of pentamer dimer formation. This observation was obtained from the specific combination of the A{beta}42 protomer structure and the physicochemical condition that we here examined, while it is worthwhile to recall that several amyloid fibrils take dimeric forms of their protomers. We could thus conclude that the stable formation of fibril-like protomer dimer should be involved in a turning point where rapid growth of amyloid fibrils is triggered. A CTP-dependent gating mechanism enables ParB spreading on DNA Proper chromosome segregation is essential in all living organisms. The ParA-ParB-parS system is widely employed for chromosome segregation in bacteria. Previously, we showed that Caulobacter crescentus ParB requires cytidine triphosphate to escape the nucleation site parS and spread by sliding to the neighboring DNA 1. Here, we provide the structural basis for this transition from nucleation to spreading by solving co-crystal structures of a C-terminal domain truncated C. crescentus ParB with parS and with a CTP analog. Nucleating ParB is an open clamp, in which parS is captured at the DNA-binding domain (the DNA-gate). Upon binding CTP, the N-terminal domain (NTD) self-dimerizes to close the NTD-gate of the clamp. The DNA-gate also closes, thus driving parS into a compartment between the DNA-gate and the C-terminal domain. CTP hydrolysis and/or the release of hydrolytic products are likely associated with re-opening of the gates to release DNA and to recycle ParB. Overall, we suggest a CTP-operated gating mechanism that regulates ParB nucleation, spreading, and recycling. Citation needed? Wikipedia and the COVID-19 pandemic BackgroundWith the COVID-19 pandemics outbreak, millions flocked to Wikipedia for updated information. Amid growing concerns regarding an "infodemic", ensuring the quality of information is a crucial vector of public health. Investigating if and how Wikipedia remained up to date and in line with science is key to formulating strategies to counter misinformation. Using citation analyses, we asked: which sources informed Wikipedias COVID-19-related articles before and during the pandemics first wave (January-May 2020).

ResultsWe found that coronavirus-related articles referenced trusted media sources and high-quality academic research. Moreover, despite a surge in COVID-19 preprints, Wikipedia had a clear preference for open-access studies published in respected journals and made little use of preprints. Building a timeline of English COVID-19 articles from 2001-2020 revealed a nuanced trade-off between quality and timeliness. It further showed how preexisting articles on key topics related to the virus created a framework for integrating new knowledge. Supported by a rigid sourcing policy, this "scientific infrastructure" facilitated contextualization and regulated the influx of new information. Lastly, we constructed a network of DOI-Wikipedia articles, which showed the shifting landscape of pandemic-related knowledge on Wikipedia and how academic citations create a web of shared knowledge supporting topics like COVID-19 vaccine development.

ConclusionsUnderstanding how scientific research interacts with the digital knowledge-sphere during the pandemic provides insight into how Wikipedia can facilitate access to science. It also reveals how, aided by what we term its "citizen encyclopedists", it successfully fended off COVID-19 disinformation and how this unique model may be deployed in other contexts. Anaerobic oxidation of methane in sediments of a nitrate-rich, oligo-mesotrophic boreal lake The identity of electron acceptors in promoting anaerobic oxidation of methane (AOM) in the sediments of boreal lakes is currently unknown. Here, we studied the AOM rate of sediment slurries collected from three profundal stations of a nitrate-rich, oligo-mesotrophic, boreal lake (Lake Paajarvi, Finland), under varying nitrate concentrations using 13C-labelling. Furthermore, vertical profiles of the sediment and porewater geochemistry, and the microbial communities (16S rRNA gene and shotgun metagenomic sequencing) were analyzed. Despite geochemical data indicating that simultaneous consumption of nitrate and methane took place at the sediment layers chosen for incubations, AOM rate was not enhanced by nitrate amendments at either of the stations. AOM rate was much higher at the shallow Station 1 (0.9-6.8 nmol C cm-3 d-1) with high contents of labile phytoplankton-derived organic matter, than at the deeper stations, Station 2 (0-0.3 nmol C cm-3 d-1) and 3 (0-0.2 nmol C cm-3 d-1). Accordingly, a higher relative abundance of methanotrophic archaea (Candidatus Methanoperedens) and bacteria (Methylococcales) were observed in the layers chosen for incubations at Station 1 than at the other stations. Besides nitrate, the geochemical profiles indicated that AOM was potentially coupled with iron or sulfate reduction at all stations. Furthermore, putative nitrite-reducing methanotrophs (Ca. Methylomirabilis) were the most abundant methanotrophs above the incubation layer at Station 2 and 3, which suggests that nitrite reduction also plays a role in driving AOM in the study lake. We conclude that AOM is not uniquely coupled to nitrate reduction in sediments of nitrate-rich, oligo-mesotrophic, boreal lakes. ZIKV disrupts placental ultrastructure and drug transporter expression in mice Congenital Zika virus (ZIKV) infection can induce fetal brain abnormalities. Here, we investigated whether maternal ZIKV infection affects placental physiology and metabolic transport potential and impacts the fetal outcome, regardless of viral presence in the fetus at term. Low (103 PFU-ZIKVPE243; low ZIKV) and high (5x107 PFU-ZIKVPE243; high ZIKV) virus titers were injected into immunocompetent (ICompetent C57BL/6) and immunocompromised (ICompromised A129) mice at gestational day (GD) 12.5 for tissue collection at GD18.5 (term). High ZIKV elicited fetal death rates of 66% and 100%, whereas low ZIKV induced fetal death rates of 0% and 60% in C57BL/6 and A129 dams, respectively. All surviving fetuses exhibited intrauterine growth restriction (IUGR) and decreased placental efficiency. High-ZIKV infection in C57BL/6 and A129 mice resulted in virus detection in maternal spleens and placenta, but only A129 fetuses presented virus RNA in the brain. Nevertheless, pregnancies in both strains produced fetuses with decreased head sizes (p<0.05). Low-ZIKV-A129 dams had higher IL-6 and CXCL1 levels (p<0.05), and their placentas showed increased CCL-2 and CXCL-1 contents (p<0.05). In contrast, low-ZIKV-C57BL/6 dams had an elevated CCL2 serum level and increased type I and II IFN expression in the placenta. Notably, less abundant microvilli and mitochondrial degeneration were evidenced in the placental labyrinth zone (Lz) of ICompromised and high-ZIKV-ICompetent mice but not in low-ZIKV-C57BL/6 mice. In addition, decreased placental expression of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) and the lipid transporter Abca1 was detected in all ZIKV-infected groups, but Bcrp and Abca1 were only reduced in ICompromised and high-ZIKV ICompetent mice. Our data indicate that gestational ZIKV infection triggers specific proinflammatory responses and affects placental turnover and transporter expression in a manner dependent on virus concentration and maternal immune status. Placental damage may impair proper fetal-maternal exchange function and fetal growth/survival, likely contributing to congenital Zika syndrome. The Social Role of Inhibition in Primates and Other Animals The capacity to inhibit prepotent actions (inhibitory self-control) plays an important role in many aspects of the behaviour of birds and mammals. Although a number of studies have used it as an index of foraging skills, inhibition is, in fact, also crucial for maintaining the temporal and spatial coherence of bonded social groups. Using two sets of comparative data, we show that, in primates, the capacity to inhibit behaviour correlates better with the demands of social contexts than the demands of foraging contexts, whereas a more generalised capacity for causal reasoning correlates with both social and foraging contexts. In addition, we confirm the Passingham-Wise Conjecture that the capacity to inhibit prepotent action is unique to anthropoid primates, and suggest that it may be crucial for the spatio-temporal integrity of their unique bonded social groups. Diet effects on mouse meiotic recombination: a warning for recombination studies Meiotic recombination is a critical process for sexually reproducing organisms. This exchange of genetic information between homologous chromosomes during meiosis is important not only because it generates genetic diversity, but also because it is often required for proper chromosome segregation. Consequently, the frequency and distribution of crossovers are tightly controlled to ensure fertility and offspring viability. However, in many systems it has been shown that environmental factors can alter the frequency of crossover events. Two studies in flies and yeast point to nutritional status affecting the frequency of crossing over. However, this question remains unexplored in mammals. Here we test how crossover frequency varies in response to diet in Mus musculus males. We use immunohistochemistry to estimate crossover frequency in multiple genotypes under two diet treatments. Our results indicate that while crossover frequency was unaffected by diet in some strains, other strains were sensitive even to small composition changes between two common laboratory chows. Therefore, recombination is both resistant and sensitive to certain dietary changes in a strain-dependent manner and, hence, this response is genetically determined. Our study is the first to report a nutrition effect on genome-wide levels of recombination. Moreover, our work highlights the importance of controlling diet in recombination studies and may point to diet as a potential source of variability among studies, which is relevant for reproducibility. Nothing in evolution makes sense except in the light of parasitism: evolution of complex replication strategies Parasitism emerges readily in models and laboratory experiments of RNA world and would lead to extinction unless prevented by compartmentalisation or spatial patterning. Modelling replication as an active computational process opens up many degrees of freedom that are exploited to meet environmental challenges, and to modify the evolutionary process itself. Here we use automata chemistry models and spatial RNA world models to study the emergence of parasitism and the complexity that evolves in response. The system is initialised with a hand-designed replicator that copies other replicators with a small chance of point mutation. Almost immediately, short parasites arise; these are copied more quickly, and so have an evolutionary advantage. The replicators also become shorter, and so are replicated faster; they evolve a mechanism to slow down replication, which reduces the difference of replication rate of replicators and parasites. They also evolve explicit mechanisms to discriminate copies of self from parasites; these mechanisms become increasingly complex. New parasite species continually arise from mutated replicators, rather than from evolving parasite lineages. Evolution itself evolves, eg by effectively increasing point mutation rates, and by generating novel emergent mutational operators. Thus, parasitism drives the evolution of complex replicators and complex ecosystems. Feline tooth resorption findings from a questionnaire survey on 8115 Finnish cats and a case-control study for a more defined population drawn from the survey Tooth resorption (TR) is one of the most common dental diseases in cats. It is a painful disease characterised by progressive dental destruction, which eventually results in loss of teeth. The aetiology of the disease remains unclear, but associations with old age, breed, other oral and dental diseases, and certain environmental factors have been suspected. We collected health and environmental information of 8115 Finnish cats from 41 breeds through an online survey for cat owners to study TR in Finland with an observational study. The frequency of TR that the owner reported as veterinarian-diagnosed was 3.9% in the entire data (316/8115) and 15% in cats that the owner reported as having veterinarian-diagnosed oral or dental disease (316/2070). We determined the risk factors and breed variation of feline TR by logistic regression with the entire data and a case-control study in a more defined population drawn from the entire data. In the entire data, we defined those cats that the owners had reported as being diagnosed with TR by a veterinarian as TR-cats and compared them to all other cats. In the case-control study, we included only cats with owner-reported veterinarian-diagnosed oral and dental diseases. We defined cats with TR-diagnosis made under sedation as TR-cases. Other veterinarian-diagnosed TR-cats were excluded. Cats with other oral and dental diseases were used as controls. The model with the entire population included 308 TR-cats compared with 7508 cats, and the case-control study included 198 TR-cats and 1683 controls. Although the diagnoses were reportedly made by a veterinarian, the owner answered the survey and might have understood, remembered, or interpreted the diagnoses in a way that could affect the results. The results indicated an increasing risk of TR with age. Dental calculus, gingivitis, and periodontitis were potential risk factors for TR. These findings and the interaction between dental calculus and gingivitis suggest that inflammatory changes caused by dental calculus increase the risk of TR. Keeping food available constantly was a potential protective factor. We found that Cornish Rex, European, and Ragdoll breeds were at higher risk for TR. The observed differences between breeds highlight a genetic contribution. Naturally occurring combinations of receptors from single cell transcriptomics in endothelial cells VEGF inhibitor drugs have been successful, especially in ophthalmology, but not all patients respond to them. Combinations of drugs are likely to be needed for more effective therapies of angiogenesis-related diseases. In this paper we describe naturally occurring combinations of receptors in endothelial cells that might help to understand how cells communicate and to identify targets for drug combinations. We also develop and share a new software tool called DECNEO to identify them.

Single-cell gene expression data are used to identify a set of co-expressed endothelial cell receptors, conserved among species (mice and humans) and enriched, within a network, of connections to up-regulated genes. This set includes several receptors previously shown to play a role in angiogenesis. Multiple statistical tests from large datasets, including an independent validation set, support the reproducibility, evolutionary conservation and role in angiogenesis of these naturally occurring combinations of receptors. We also show tissue-specific combinations and, in the case of choroid endothelial cells, consistency with both well-established and recent experimental findings, presented in a separate paper.

The results and methods presented here advance the understanding of signaling to endothelial cells. The methods are generally applicable to the decoding of intercellular combinations of signals. Experimental evolution in TP53 deficient human gastric organoids recapitulates tumorigenesis The earliest events during human tumor initiation are poorly characterized but may hold clues as to how to detect and prevent malignancy. Here we model occult pre-neoplasia by engineering TP53 deficiency, a common and early event in gastric cancer, into human gastric organoids. By performing experimental evolution in multiple clonally derived cultures over two years we define causal relationships between this common initiating genetic lesion and resulting phenotypes. TP53 loss elicited progressive aneuploidy, including copy number alterations and complex structural variants that are common in gastric cancers and which follow preferred temporal orders. Longitudinal single cell sequencing of TP53 deficient gastric organoids similarly indicates progression towards malignant transcriptional programs. Moreover, lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programs repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a striking degree of phenotypic convergence in pre-malignant epithelial organoids, implying that the earliest stages of tumorigenesis may be predictable while illuminating evolutionary constraints and barriers to malignant transformation.

Graphical abstract

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org.highwire.dtl.DTLVardef@122debborg.highwire.dtl.DTLVardef@4cd2daorg.highwire.dtl.DTLVardef@1a720d6org.highwire.dtl.DTLVardef@15ccaa7_HPS_FORMAT_FIGEXP  M_FIG C_FIG Naive human B cells engage the receptor binding domain of SARS-CoV-2, variants of concern, and related sarbecoviruses Exposure to a pathogen elicits an adaptive immune response aimed to control and eradicate. Interrogating the abundance and specificity of the naive B cell repertoire contributes to understanding how to potentially elicit protective responses. Here, we isolated naive B cells from 8 seronegative human donors targeting the SARS-CoV-2 receptor-binding domain (RBD). Single B cell analysis showed diverse gene usage with no restricted complementarity determining region lengths. We show that recombinant antibodies engage SARS-CoV-2 RBD, circulating variants, and pre-emergent coronaviruses. Representative antibodies signal in a B cell activation assay and can be affinity matured through directed evolution. Structural analysis of a naive antibody in complex with spike shows a conserved mode of recognition shared with infection-induced antibodies. Lastly, both naive and affinity-matured antibodies can neutralize SARS-CoV-2. Understanding the naive repertoire may inform potential responses recognizing variants or emerging coronaviruses enabling the development of pan-coronavirus vaccines aimed at engaging germline responses.

One Sentence SummaryIsolation of antibody germline precursors targeting the receptor binding domain of coronaviruses. T606-phosphorylation deprives the function of Kaiso as a transcription factor and cancer repressor It is well known that Kaiso protein encoded by ZBTB33 gene is a transcription repressor and that Kaiso-P120ctn interaction increases the shift of Kaiso from the nucleus into the cytoplasm. However, the regulatory mechanisms of Kaiso compartmentalization are far from clear. Here, we reported that AKT1 could phosphorylate 606-threonine residue (T606) within the RSSTIP motif of Kaiso in the cytoplasm. The T606-phosphorylated Kaiso (pT606-Kaiso) could directly bind to 14-3-3 family proteins and the depletion of T606 phosphorylation by T606A mutation abolished most of the Kaiso-14-3-3 binding. In addition, the Kaiso-P120ctn interaction was essential for the pT606-Kaiso accumulation in the cytoplasm. Notably, enforced 14-3-3{sigma} (SFN) overexpression could increase the pT606-Kaiso accumulation in the cytoplasm and de-repress the transcription of Kaiso target gene CDH1. Decreased amounts of both pT606-Kaiso and CDH1 proteins were frequently observed in human gastric cancer tissues relative to paired normal controls. The mRNA levels of 14-3-3{sigma} and Kaiso target gene CDH1 were positively and significantly correlated with each other in bioinformatics analyses using publicly available RNA-seq datasets for human normal tissues (n=11688, r=0.60, p<0.001) in the GTEx project and for cancer cell lines (n=1156, r=0.41, p<0.001) in the CCLE project. Furthermore, Kaiso T606A mutant (unable to be phosphorylated) significantly increased the migration and invasion of cancer cells in vitro as well as boosted the growth of these cells in vivo. In conclusion, Kaiso could be phosphorylated by AKT1 at the T606 and the pT606-Kaiso accumulates in the cytoplasm through binding to 14-3-3/P120ctn that de-represses the expression of Kaiso target gene CDH1 in normal tissues. Decreased Kaiso phosphorylation may contribute to the development of gastrointestinal cancer. The status of Kaiso phosphorylation is a determinant factor for the role of Kaiso in the development of cancer. The coiled-coil domain of E. coli FtsLB is a structurally detuned element critical for modulating its activation in bacterial cell division The FtsLB complex is a key regulator of bacterial cell division, existing in either an off or on state which supports the activation of septal peptidoglycan synthesis. In Escherichia coli, residues known to be critical for this activation are located in a region near the C-terminal end of the periplasmic coiled-coil domain of FtsLB, raising questions about the precise role of this conserved domain in the activation mechanism. Here, we investigate an unusual cluster of polar amino acids found within the core of the FtsLB coiled coil. We hypothesized that these amino acids likely reduce the structural stability of the domain and thus may be important for governing conformational changes. We found that mutating these positions to hydrophobic residues increased the thermal stability of FtsLB but caused cell division defects, suggesting that the coiled-coil domain is a "detuned" structural element. In addition, we identified suppressor mutations within the polar cluster, indicating that the precise identity of the polar amino acids is important for fine-tuning the structural balance between the off and on states. We propose a revised structural model of the tetrameric FtsLB (named the "Y-model") in which the periplasmic domain splits into a pair of coiled-coil branches. In this configuration, the hydrophilic terminal moieties of the polar amino acids remain more favorably exposed to water than in the original four-helix bundle model ("I-model"). We propose that a shift in this architecture, dependent on its marginal stability, is involved in activating the FtsLB complex and triggering septal cell wall reconstruction. Fungal Ice2p is in the same superfamily as SERINCs, restriction factors for HIV and other viruses Ice2p is an integral endoplasmic reticulum (ER) membrane protein in budding yeast S. cerevisiae named ICE because it is required for Inheritance of Cortical ER. Ice2p has also been reported to be involved in an ER metabolic branch-point that regulates the flux of lipid either to be stored in lipid droplets or to be used as membrane components. Alternately, Ice2p has been proposed to act as a tether that physically bridges the ER at contact sites with both lipid droplets and the plasma membrane via a long loop on the proteins cytoplasmic face that contains multiple predicted amphipathic helices. Here we carried out a bioinformatic analysis to increase understanding of Ice2p. Firstly, regarding topology, we found that diverse members of the fungal Ice2 family have ten transmembrane helices, which places the long loop on the exofacial face of Ice2p, where it cannot form inter-organelle bridges. Secondly, we identified Ice2 as a full-length homologue of SERINC (serine incorporator), a family of proteins with ten transmembrane helices found universally in eukaryotes. Since SERINCs are potent restriction factors for HIV and other viruses, study of Ice2p may reveal functions or mechanisms that shed light on viral restriction by SERINCs. 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. The Temporal Statistics of Musical Rhythm across Western Genres: An Amplitude Modulation Phase Hierarchy Model Statistical learning by the human brain plays a core role in the development of cognitive systems like language and music. Both music and speech have structured inherent rhythms, however the acoustic sources of these rhythms are debated. Theoretically, rhythm structures in both systems may be related to a novel set of acoustic statistics embedded in the amplitude envelope, statistics originally revealed by modelling childrens nursery rhymes. Here we apply similar modelling to explore whether the amplitude modulation (AM) timescales underlying rhythm in music match those in child-directed speech (CDS). Utilising AM-driven phase hierarchy modelling previously applied to infant-directed speech (IDS), adult-directed speech (ADS) and CDS, we test whether the physical stimulus characteristics that yield speech rhythm in IDS and CDS describe rhythm in music. Two models were applied. One utilized a low-dimensional representation of the auditory signal adjusted for known mechanisms of the human cochlear, and the second utilized probabilistic amplitude demodulation, estimating the modulator (envelope) and carriers using Bayesian inference. Both models revealed a similar hierarchically-nested temporal modulation structure across Western musical genres and instruments. Core bands of AM and spectral patterning matched prior analyses of IDS and CDS, and music showed strong phase dependence between slower bands of AMs, again matching IDS and CDS. This phase dependence is critical to the perception of rhythm. Control analyses modelling other natural sounds (wind, rain, storms, rivers) did not show similar temporal modulation structures and phase dependencies. We conclude that acoustic rhythm in language and music has a shared statistical basis. F1F0 ATP Hydrolysis is a Determinant of Metabolic Rate, a Correlate of Lifespan, and a Weakness of Cancer Dramatic rectal temperature decrease, in mice administered with a drug that specifically inhibits F1F0 ATP hydrolysis, suggests that F1F0 ATP hydrolysis is a major determinant of metabolic rate in vivo. Across twelve investigated species, less F1F0 ATP hydrolysis correlates with greater maximal lifespan. Specific drug inhibition of F1F0 ATP hydrolysis exerts potent anti-cancer activity in vitro. High-throughput submicron-resolution microscopyof entire C. elegans populations under strongimmobilization by cooling cultivation plates Despite its profound impact on biology, most high-resolution in vivo microscopy approaches remain low throughput because current immobilization techniques require significant manual effort. We greatly accelerate imaging of the nematode Caenorhabditis elegans by implementing a simple cooling approach to easily immobilize entire populations directly on their cultivation plates. We optimize and characterize cooling immobilization. Counterintuitively, relatively warmer temperatures immobilize animals significantly more effectively than colder temperatures utilized in prior studies. This enhanced immobilization enables clear submicron-resolution fluorescence imaging, which is challenging to achieve with most current immobilization techniques. We demonstrate 64x magnification 3D imaging and timelapse recording of neurons in adults and embryos without motion blur. Compared to standard azide immobilization, cooling immobilization reduces the animal preparation and recovery time by >98%, significantly increasing experimental speed. By obviating individual animal manipulation, our approach could also empower automated imaging of large C. elegans populations within standard experimental setups and workflows.