The Arabidopsis active demethylase ROS1 < i > cis < /i > -regulates defense genes by erasing DNA methylation at promoter-regulatory regions
Active DNA demethylation has emerged as an important regulatory process of plant and mammalian immunity. However, very little is known about the mechanisms by which active demethylation controls transcriptional immune reprogramming and disease resistance. Here, we first show that the Arabidopsis active demethylase ROS1 promotes basal resistance towardsPseudomonas syringae by antagonizing RNA-directed DNA methylation (RdDM). Furthermore, we find that ROS1 facilitates the flagellin-triggered induction of the disease resistance geneRMG1by limiting RdDM at the 3' boundary of a remnant RC/Helitron transposable element (TE) embe...
Source: eLife - January 20, 2021 Category: Biomedical Science Tags: Genetics and Genomics Plant Biology Source Type: research

Comparison of induced neurons reveals slower structural and functional maturation in humans than in apes
We generated induced excitatory neurons (iNeurons, iNs) from chimpanzee, bonobo and human stem cells by expressing the transcription factor neurogenin ‑2 (NGN2). Single cell RNA sequencing (scRNAseq) showed that genes involved in dendrite and synapse development are expressed earlier during iNs maturation in the chimpanzee and bonobo than the human cells. In accordance, during the first two weeks of differentiation, chimpanzee and bonobo iNs sho wed repetitive action potentials and more spontaneous excitatory activity than human iNs, and extended neurites of higher total length. However, the axons of human iNs were sligh...
Source: eLife - January 20, 2021 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

Collateral sensitivity associated with antibiotic resistance plasmids
Collateral sensitivity (CS) is a promising alternative approach to counteract the rising problem of antibiotic resistance (ABR). CS occurs when the acquisition of resistance to one antibiotic produces increased susceptibility to a second antibiotic. Recent studies have focused on CS strategies designed against ABR mediated by chromosomal mutations. However, one of the main drivers of ABR in clinically relevant bacteria is the horizontal transfer of ABR genes mediated by plasmids. Here, we report the first analysis of CS associated with the acquisition of complete ABR plasmids, including the clinically important carbapenem-...
Source: eLife - January 20, 2021 Category: Biomedical Science Tags: Evolutionary Biology Microbiology and Infectious Disease Source Type: research

Metabolomic profiling of rare cell populations isolated by flow cytometry from tissues
Little is known about the metabolic regulation of rare cell populations because most metabolites are hard to detect in small numbers of cells. We previously described a method for metabolomic profiling of flow cytometrically-isolated hematopoietic stem cells (HSCs) that detects 60 metabolites in 10,000 cells (Agathocleous et al., 2017). Here we describe a new method involving hydrophilic liquid interaction chromatography and high-sensitivity orbitrap mass spectrometry that detected 160 metabolites in 10,000 HSCs, including many more glycolytic and lipid intermediates. We improved chromatographic separation, increased mass ...
Source: eLife - January 20, 2021 Category: Biomedical Science Tags: Stem Cells and Regenerative Medicine Source Type: research

Highly redundant neuropeptide volume co-transmission underlying episodic activation of the GnRH neuron dendron
The necessity and functional significance of neurotransmitter co-transmission remains unclear. The glutamatergic 'KNDy' neurons co-express kisspeptin, neurokinin B (NKB) and dynorphin and exhibit a highly stereotyped synchronized behavior that reads out to the gonadotropin-releasing hormone (GnRH) neuron dendrons to drive episodic hormone secretion. Using expansion microscopy, we show that KNDy neurons make abundant close, non-synaptic appositions with the GnRH neuron dendron. Electrophysiology and confocal GCaMP6 imaging demonstrated that, despite all three neuropeptides being released from KNDy terminals, only kisspeptin...
Source: eLife - January 19, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Phenotypic and molecular evolution across 10,000 generations in laboratory budding yeast populations
Laboratory experimental evolution provides a window into the details of the evolutionary process. To investigate the consequences of long-term adaptation, we evolved 205Saccharomyces cerevisiae populations (124 haploid and 81 diploid) for ~10,000,000 generations in three environments. We measured the dynamics of fitness changes over time, finding repeatable patterns of declining adaptability. Sequencing revealed that this phenotypic adaptation is coupled with a steady accumulation of mutations, widespread genetic parallelism, and historical contingency. In contrast to long-term evolution inE. coli, we do not observe long-t...
Source: eLife - January 19, 2021 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Serotonin 2A receptor signaling coordinates central metabolic processes to modulate aging in response to nutrient choice
It has been recognized for nearly a century that diet modulates aging. Despite early experiments suggesting that reduced caloric intake augmented lifespan, accumulating evidence indicates that other characteristics of the diet may be equally or more influential in modulating aging. We demonstrate that behavior, metabolism, and lifespan inDrosophila are affected by whether flies are provided a choice of different nutrients or a single, complete medium, largely independent of the amount of nutrients that are consumed. Meal choice elicits a rapid metabolic reprogramming that indicates a potentiation of TCA cycle and amino aci...
Source: eLife - January 19, 2021 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research

Climate-driven deoxygenation elevates fishing vulnerability for the ocean's widest ranging shark
Climate-driven expansions of ocean hypoxic zones are predicted to concentrate pelagic fish in oxygenated surface layers, but how expanding hypoxia and fisheries will interact to affect threatened pelagic sharks remains unknown. Here, analysis of satellite-tracked blue sharks and environmental modelling in the eastern tropical Atlantic oxygen minimum zone (OMZ) shows shark maximum dive depths decreased due to combined effects of decreasing dissolved oxygen (DO) at depth, high sea surface temperatures, and increased surface-layer net primary production. Multiple factors associated with climate-driven deoxygenation contribute...
Source: eLife - January 19, 2021 Category: Biomedical Science Tags: Ecology Source Type: research

Freshwater monitoring by nanopore sequencing
While traditional microbiological freshwater tests focus on the detection of specific bacterial indicator species, including pathogens, direct tracing of all aquatic DNA through metagenomics poses a profound alternative. Yet, in situ metagenomic water surveys face substantial challenges in cost and logistics. Here, we present a simple, fast, cost-effective and remotely accessible freshwater diagnostics workflow centred around the portable nanopore sequencing technology. Using defined compositions and spatiotemporal microbiota from surface water of an example river in Cambridge (UK), we provide optimised experimental and bi...
Source: eLife - January 19, 2021 Category: Biomedical Science Tags: Ecology Microbiology and Infectious Disease Source Type: research

Behavioral role of PACAP reflects its selective distribution in glutamatergic and GABAergic neuronal subpopulations
This report signals a new perspective on the role of neuropeptide signaling in supporting excitatory and inhibitory neurotransmission in the nervous system within functionally coherent polysynaptic circuits. (Source: eLife)
Source: eLife - January 19, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Atomic structures of respiratory complex III < sub > 2 < /sub > , complex IV, and supercomplex III < sub > 2 < /sub > -IV from vascular plants
We present atomic models of CIII2, CIV, and SC III2+IV fromVigna radiata determined by single-particle cryoEM. The structures reveal plant-specific differences in the MPP domain of CIII2 and define the subunit composition of CIV. Conformational heterogeneity analysis of CIII2 revealed long-range, coordinated movements across the complex, as well as the motion of CIII2’s iron-sulfur head domain. The CIV structure suggests that, in plants, proton translocation does not occur via the H channel. The supercomplex interface differs significantly from that in yeast and bacteria in its interacting subunits, angle of approach...
Source: eLife - January 19, 2021 Category: Biomedical Science Tags: Plant Biology Structural Biology and Molecular Biophysics Source Type: research

The two roles of complex III in plants
Atomic structures of mitochondrial enzyme complexes in plants are shedding light on their multiple functions. (Source: eLife)
Source: eLife - January 19, 2021 Category: Biomedical Science Tags: Plant Biology Structural Biology and Molecular Biophysics Source Type: research

Evidence for adaptive evolution in the receptor-binding domain of seasonal coronaviruses OC43 and 229E
Seasonal coronaviruses (OC43, 229E, NL63 and HKU1) are endemic to the human population, regularly infecting and reinfecting humans while typically causing asymptomatic to mild respiratory infections. It is not known to what extent reinfection by these viruses is due to waning immune memory or antigenic drift of the viruses. Here, we address the influence of antigenic drift on immune evasion of seasonal coronaviruses. We provide evidence that at least two of these viruses, OC43 and 229E, are undergoing adaptive evolution in regions of the viral spike protein that are exposed to human humoral immunity. This suggests that rei...
Source: eLife - January 19, 2021 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

< i > fruitless < /i > tunes functional flexibility of courtship circuitry during development
Drosophila male courtship is controlled by the male-specific products of thefruitless (fruM) gene and its expressing neuronal circuitry.fruM is considered a master gene that controls all aspects of male courtship. By temporally and spatially manipulatingfruM expression, we found thatfruM is required during a critical developmental period for innate courtship towards females, while its function during adulthood is involved in inhibiting male-male courtship. By altering or eliminatingfruM expression, we generated males that are innately heterosexual, homosexual, bisexual, or without innate courtship but could acquire such be...
Source: eLife - January 19, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci
To uncover novel significant association signals (p
Source: eLife - January 18, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Genetics and Genomics Source Type: research

Cytomegalovirus restricts ICOSL expression on antigen presenting cells disabling T cell co-stimulation and contributing to immune evasion
Viral infections are controlled, and very often cleared, by activated T lymphocytes. The inducible co-stimulator (ICOS) mediates its functions by binding to its ligand ICOSL, enhancing T-cell activation and optimal germinal center (GC) formation. Here, we show that ICOSL is heavily downmodulated during infection of antigen presenting cells by different herpesviruses. We found that, in murine cytomegalovirus (MCMV), the immunoevasin m138/fcr-1 physically interacts with ICOSL, impeding its maturation and promoting its lysosomal degradation. This viral protein counteracts T-cell responses, in an ICOS-dependent manner, and lim...
Source: eLife - January 18, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

Equity, Diversity and Inclusion: Racial inequity in grant funding from the US National Institutes of Health
Biomedical science and federal funding for scientific research are not immune to the systemic racism that pervades American society. A groundbreaking analysis of NIH grant success revealed in 2011 that grant applications submitted to the National Institutes of Health in the US by African-American or Black Principal Investigators (PIs) are less likely to be funded than applications submitted by white PIs, and efforts to narrow this funding gap have not been successful. A follow-up study in 2019 showed that this has not changed. Here, we review those original reports, as well as the response of the NIH to these issues, which...
Source: eLife - January 18, 2021 Category: Biomedical Science Source Type: research

Ablation of STAT3 in Purkinje cells reorganizes cerebellar synaptic plasticity in long-term fear memory network
Emotional memory processing engages a large neuronal network of brain regions including the cerebellum. However, the molecular and cellular mechanisms of the cerebellar cortex modulating the fear memory network are unclear. Here, we illustrate that synaptic signaling in cerebellar Purkinje cells (PCs)via STAT3 regulates long-term fear memory. Transcriptome analyses revealed that PC-specific STAT3 knockout (STAT3PKO) results in transcriptional changes that lead to an increase in the expression of glutamate receptors. The amplitude of AMPA receptor-mediated excitatory postsynaptic currents at parallel fiber (PF) to PC synaps...
Source: eLife - January 18, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Antagonism between Germ cell-less and Torso regulates transcriptional quiescence underlying germline/soma distinction
Transcriptional quiescence, an evolutionarily conserved trait, distinguishes the embryonic primordial germ cells 
(PGCs) from their somatic neighbors. InDrosophilamelanogaster, PGCs from embryos maternally compromised forgerm cell-less (gcl) misexpress somatic genes, possibly resulting in PGC loss. Recent studies documented a requirement for Gcl during proteolytic degradation of the terminal patterning determinant, Torso receptor. Here we demonstrate that the somatic determinant of female fate,Sex-lethal (Sxl), is a biologically relevant transcriptional target of Gcl. Underscoring the significance of transcriptional sile...
Source: eLife - January 18, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Repeated outbreaks drive the evolution of bacteriophage communication
We present a mathematical model of the ecological and evolutionary dynamics of such viral communication, and show that a communication strategy in which phages use the lytic cycle early in an outbreak (when susceptible host cells are abundant) but switch to the lysogenic cycle later (when susceptible cells become scarce) is favoured over a bet-hedging strategy in which cells are lysogenised with constant probability. However, such phage communication can evolve only if phage-bacteria populations are regularly perturbed away from their equilibrium state, so that acute outbreaks of phage infections in pools of susceptible ce...
Source: eLife - January 18, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Evolutionary Biology Source Type: research

Regulatory roles of < i > Escherichia coli < /i > 5' UTR and ORF-internal RNAs detected by 3' end mapping
Many bacterial genes are regulated by RNA elements in their 5 ´ untranslated regions (UTRs). However, the full complement of these elements is not known even in the model bacteriumEscherichia coli. Using complementary RNA-sequencing approaches, we detected large numbers of 3 ´ ends in 5´ UTRs and open reading frames (ORFs), suggesting extensive regulation by premature transcription termination. We documented regulation for multiple transcripts, including spermidine induction involving Rho and translation of an upstream ORF for an mRNA encoding a spermidine efflux pump . In addition to discovering novel si...
Source: eLife - January 18, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Bi-channel Image Registration and Deep-learning Segmentation (BIRDS) for efficient, versatile 3D mapping of mouse brain
We have developed an open-source software called BIRDS (bi-channel image registration and deep-learning segmentation) for the mapping and analysis of 3D microscopy data and applied this to the mouse brain. The BIRDS pipeline includes image pre-processing, bi-channel registration, automatic annotation, creation of a 3D digital frame, high-resolution visualization, and expandable quantitative analysis. This new bi-channel registration algorithm is adaptive to various types of whole-brain data from different microscopy platforms and shows dramatically improved registration accuracy. Additionally, as this platform combines reg...
Source: eLife - January 18, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Neuroscience Source Type: research

Global and local tension measurements in biomimetic skeletal muscle tissues reveals early mechanical homeostasis
Tension and mechanical properties of muscle tissue are tightly related to proper skeletal muscle function, which makes experimental access to the biomechanics of muscle tissue formation a key requirement to advance our understanding of muscle function and development. Recently developed elastic in vitro culture chambers allow for raising 3D muscle tissue under controlled conditions and to measure global tissue force generation. However, these chambers are inherently incompatible with high resolution microscopy limiting their usability to global force measurements, and preventing the exploitation of modern fluorescence base...
Source: eLife - January 18, 2021 Category: Biomedical Science Tags: Physics of Living Systems Stem Cells and Regenerative Medicine Source Type: research

Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells
Germline inactivating mutations in Folliculin (FLCN) cause Birt –Hogg–Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing to kidney tumors. FLCN is a conserved, essential gene linked to diverse cellular processes but the mechanisms by which FLCN prevents kidney cancer remain unknown. Here we show that deleting FLCN activates TFE3, upregulat ing its downstream E-box genes in human renal tubular epithelial cells (RPTEC/TERT1), including RRAGD and GPNMB, without modifying mTORC1 activity. Surprisingly, deletion of FLCN or its binding partners FNIP1/FNIP2 also induces interferon response gen...
Source: eLife - January 18, 2021 Category: Biomedical Science Tags: Cancer Biology Genetics and Genomics Source Type: research

Endothelial cell type-specific molecular requirements for angiogenesis drive fenestrated vessel development in the brain
Vascular endothelial cells (vECs) in the brain exhibit structural and functional heterogeneity. Fenestrated, permeable brain vasculature mediates neuroendocrine function, body-fluid regulation, and neural immune responses, however its vascular formation remains poorly understood. Here we show that specific combinations of vascular endothelial growth factors (Vegfs) are required to selectively drive fenestrated vessel formation in the zebrafish myelencephalic choroid plexus (mCP). We found that the combined, but not individual, loss of Vegfab, Vegfc, and Vegfd causes severely impaired mCP vascularization with little effect ...
Source: eLife - January 18, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Modeling transfer of vaginal microbiota from mother to infant in early life
Early-life microbiota has been linked to the development of chronic inflammatory diseases. It has been hypothesized that maternal vaginal microbiota is an important initial seeding source and therefore might have lifelong effects on disease risk. To understand maternal vaginal microbiota ’s role in seeding the child’s microbiota and the extent of delivery mode-dependent transmission, we studied 665 mother–child dyads from the COPSAC2010 cohort. The maternal vaginal microbiota was evaluated twice in the third trimester and compared with the children ’s fecal (at 1 week, 1 month, and 1 year of age) an...
Source: eLife - January 15, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Microbiology and Infectious Disease Source Type: research

Female-biased upregulation of insulin pathway activity mediates the sex difference in < i > Drosophila < /i > body size plasticity
Nutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work inDrosophila showed that body size plasticity was higher in females, yet the mechanisms underlying increased female body size plasticity remain unclear. Here, we discover that a protein-rich diet augments body size in females and not males because of a female-biased increase in activity of the conserved insulin/insulin-like growth factor signaling pathway (IIS). This sex-biased upregulation of IIS activity was triggered by a diet-induced increase instunted mRNA in females, and requiredDrosophilainsulin-like p...
Source: eLife - January 15, 2021 Category: Biomedical Science Tags: Developmental Biology Genetics and Genomics Source Type: research

A flagellate-to-amoeboid switch in the closest living relatives of animals
Amoeboid cells are fundamental to animal biology and broadly distributed across animal diversity, but their evolutionary origin is unclear. The closest living relatives of animals, the choanoflagellates, display a polarized cell architecture (with an apical flagellum encircled by microvilli) that closely resembles that of epithelial cells and suggests homology, but this architecture differs strikingly from the deformable phenotype of animal amoeboid cells. Here, we show that choanoflagellates subjected to confinement differentiate into an amoeboid form by retracting their flagella and activating myosin-based motility. This...
Source: eLife - January 15, 2021 Category: Biomedical Science Tags: Cell Biology Evolutionary Biology Source Type: research

Bi-fated tendon-to-bone attachment cells are regulated by shared enhancers and KLF transcription factors
The mechanical challenge of attaching elastic tendons to stiff bones is solved by the formation of a unique transitional tissue. Here, we show that murine tendon-to-bone attachment cells are bi-fated, activating a mixture of chondrocyte and tenocyte transcriptomes, under regulation of shared regulatory elements and Kr üppel-like factors (KLFs) transcription factors. High-throughput bulk and single-cell RNA sequencing of humeral attachment cells revealed expression of hundreds of chondrogenic and tenogenic genes, which was validated by in situ hybridization and single-molecule ISH. ATAC sequencing showed that att achme...
Source: eLife - January 15, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research

The orchestrated cellular and molecular responses of the kidney to endotoxin define a precise sepsis timeline
Sepsis is a dynamic state that progresses at variable rates and has life-threatening consequences. Staging patients along the sepsis timeline requires a thorough knowledge of the evolution of cellular and molecular events at the tissue level. Here, we investigated the kidney, an organ central to the pathophysiology of sepsis. Single-cell RNA-sequencing in a murine endotoxemia model revealed the involvement of various cell populations to be temporally organized and highly orchestrated. Endothelial and stromal cells were the first responders. At later time points, epithelial cells upregulated immune-related pathways while co...
Source: eLife - January 15, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Medicine Source Type: research

Evolutionary conflicts and adverse effects of antiviral factors
Human cells are equipped with a plethora of antiviral proteins protecting them against invading viral pathogens. In contrast to apoptotic or pyroptotic cell death, which serves as ultima ratio to combat viral infections, these cell-intrinsic restriction factors may prevent or at least slow down viral spread while allowing the host cell to survive. Nevertheless, their antiviral activity may also have detrimental effects on the host. While the molecular mechanisms underlying the antiviral activity of restriction factors are frequently well investigated, potential undesired effects of their antiviral functions on the host cel...
Source: eLife - January 15, 2021 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Identification of distinct pH-and zeaxanthin-dependent quenching in LHCSR3 from < i > Chlamydomonas reinhardtii < /i >
Under high light, oxygenic photosynthetic organisms avoid photodamage by thermally dissipating absorbed energy, which is called non-photochemical quenching. In green algae, a chlorophyll and carotenoid-binding protein, light-harvesting complex stress-related (LHCSR3), detects excess energy via a pH drop and serves as a quenching site. Using a combined in vivo and in vitro approach, we investigated quenching within LHCSR3 fromChlamydomonas reinhardtii. In vitro two distinct quenching processes, individually controlled by pH and zeaxanthin, were identified within LHCSR3. The pH-dependent quenching was removed within a mutant...
Source: eLife - January 15, 2021 Category: Biomedical Science Tags: Plant Biology Structural Biology and Molecular Biophysics Source Type: research

An interbacterial DNA deaminase toxin directly mutagenizes surviving target populations
When bacterial cells come in contact, antagonism mediated by the delivery of toxins frequently ensues. The potential for such encounters to have long-term beneficial consequences in recipient cells has not been investigated. Here we examined the effects of intoxication by DddA, a cytosine deaminase delivered via the type VI secretion system (T6SS) ofBurkholderia cenocepacia. Despite its killing potential, we observed that several bacterial species resist DddA and instead accumulate mutations. These mutations can lead to the acquisition of antibiotic resistance, indicating that even in the absence of killing, interbacterial...
Source: eLife - January 15, 2021 Category: Biomedical Science Tags: Genetics and Genomics Microbiology and Infectious Disease Source Type: research

Reproducible analysis of disease space via principal components using the novel R package syndRomics
We present a new software package,syndRomics, an open-source R package with utility for component visualization, interpretation, and stability for syndromic analysis. We document the implementation ofsyndRomics and illustrate the use of the package in case studies of neurological trauma data. (Source: eLife)
Source: eLife - January 14, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Medicine Source Type: research

Temperature-dependent fasciation mutants provide a link between mitochondrial RNA processing and lateral root morphogenesis
Although mechanisms that activate organogenesis in plants are well established, much less is known about the subsequent fine-tuning of cell proliferation, which is crucial for creating properly structured and sized organs. Here we show, through analysis of temperature-dependent fasciation (TDF) mutants of Arabidopsis,root redifferentiation defective 1 (rrd1),rrd2, androot initiation defective 4(rid4), that mitochondrial RNA processing is required for limiting cell division during early lateral root (LR) organogenesis. These mutants formed abnormally broadened (i.e., fasciated) LRs under high-temperature conditions due to e...
Source: eLife - January 14, 2021 Category: Biomedical Science Tags: Plant Biology Source Type: research

A mechanistic model for long-term immunological outcomes in South African HIV-infected children and adults receiving ART
This study proposes a novel 'ratio' model that relates CD4+ T-cell counts of HIV-infected individuals to the CD4+ count reference values from healthy populations. We use mixed-effects regression to fit the model to data from 1,616 children (median age 4.3 years at ART initiation) and 14,542 adults (median age 36 years at ART initiation). We found that the scaled carrying capacity, maximum CD4+ count relative to an HIV-negative individual of similar age, and baseline scaled CD4+ counts were closer to healthy values in children than in adults. Post-ART initiation, CD4+ growth rate was inversely correlated with baseline CD4+ ...
Source: eLife - January 14, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Brain functional networks associated with social bonding in monogamous voles
In this study, we used resting state magnetic resonance imaging to explore bonding behaviors and functional connectivity of brain regions previously associated with pair bonding. Thirty-two male and female prairie voles were scanned at baseline, 24h and 2 weeks after the onset of cohabitation By using network based statistics, we identified that the functional connectivity of a cortico-striatal network predicted the onset of affiliative behavior, while another predicted the amount of social interaction during a partner preference test. Furthermore, a network with significant changes in time was revealed, also showing assoc...
Source: eLife - January 14, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Cytokine ranking via mutual information algorithm correlates cytokine profiles with presenting disease severity in patients infected with SARS-CoV-2
Although the range of immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is variable, cytokine storm is observed in a subset of symptomatic individuals. To further understand the disease pathogenesis and, consequently, to develop an additional tool for clinicians to evaluate patients for presumptive intervention we sought to compare plasma cytokine levels between a range of donor and patient samples grouped by a COVID-19 Severity Score (CSS) based on need for hospitalization and oxygen requirement. Here we utilize a mutual information algorithm that classifies the information gain for CSS pred...
Source: eLife - January 14, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Medicine Source Type: research

Oxytocin modulates human chemosensory decoding of sex in a dose-dependent manner
There has been accumulating evidence of human social chemo-signaling, but the underlying mechanisms remain poorly understood. Considering the evolutionarily conserved roles of oxytocin and vasopressin in reproductive and social behaviors, we examined whether the two neuropeptides are involved in the subconscious processing of androsta-4,16,-dien-3-one and estra-1,3,5 (10),16-tetraen-3-ol, two human chemosignals that convey masculinity and femininity to the targeted recipients, respectively. Psychophysical data collected from 216 heterosexual and homosexual men across five experiments totaling 1056 testing sessions consiste...
Source: eLife - January 13, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

High-resolution mapping of the neutralizing and binding specificities of polyclonal sera post HIV Env trimer vaccination
Mapping polyclonal serum responses is critical to rational vaccine design. However, most high-resolution mapping approaches involve isolating and characterizing individual antibodies, which incompletely defines the polyclonal response. Here we use two complementary approaches to directly map the specificities of the neutralizing and binding antibodies of polyclonal anti-HIV-1 sera from rabbits immunized with BG505 Env SOSIP trimers. We used mutational antigenic profiling to determine how all mutations in Env affected viral neutralization and electron microscopy polyclonal epitope mapping (EMPEM) to directly visualize serum...
Source: eLife - January 13, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research

ARL3 activation requires the co-GEF BART and effector-mediated turnover
The ADP-ribosylation factor-like 3 (ARL3) is a ciliopathy G-protein which regulates the ciliary trafficking of several lipid-modified proteins. ARL3 is activated by its guanine exchange factor (GEF) ARL13B via an unresolved mechanism. BART is described as an ARL3 effector which has also been implicated in ciliopathies, although the role of its ARL3 interaction is unknown. Here we show that, at physiological GTP:GDP levels, human ARL3GDP is weakly activated by ARL13B. However, BART interacts with nucleotide-free ARL3 and, in concert with ARL13B, efficiently activates ARL3. In addition, BART binds ARL3GTP and inhibits GTP di...
Source: eLife - January 13, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Stable transplantation of human mitochondrial DNA by high-throughput, pressurized isolated mitochondrial delivery
Generating mammalian cells with specific mtDNA-nDNA combinations is desirable but difficult to achieve and would be enabling for studies of mitochondrial-nuclear communication and coordination in controlling cell fates and functions. We developed 'MitoPunch', a pressure-driven mitochondrial transfer device, to deliver isolated mitochondria into numerous target mammalian cells simultaneously. MitoPunch and MitoCeption, a previously described force-based mitochondrial transfer approach, both yield stable isolated mitochondrial recipient (SIMR) cells that permanently retain exogenous mtDNA, whereas coincubation of mitochondri...
Source: eLife - January 13, 2021 Category: Biomedical Science Tags: Cell Biology Source Type: research

Release probability increases towards distal dendrites boosting high-frequency signal transfer in the rodent hippocampus
Dendritic integration of synaptic inputs involves their increased electrotonic attenuation at distal dendrites, which can be counterbalanced by the increased synaptic receptor density. However, during network activity the influence of individual synapses depends on their release fidelity, the dendritic distribution of which remains poorly understood. Here, we employed classical optical quantal analyses and a genetically encoded optical glutamate sensor in acute hippocampal slices of rats and mice to monitor release at CA3-CA1 synapses. We find that their release probability increases with greater distances from the soma. S...
Source: eLife - January 13, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

A retrospective analysis of the peer review of more than 75,000 Marie Curie proposals between 2007 and 2018
Most funding agencies rely on peer review to evaluate grant applications and proposals, but research into the use of this process by funding agencies has been limited. Here we explore if two changes to the organization of peer review for proposals submitted to various funding actions by the European Union has an influence on the outcome of the peer review process. Based on an analysis of more than 75,000 applications to three actions of the Marie Curie programme over a period of 12 years, we find that the changes – a reduction in the number of evaluation criteria used by reviewers and a move from in-person to virtual...
Source: eLife - January 13, 2021 Category: Biomedical Science Source Type: research

Thymic stromal lymphopoietin limits primary and recall CD8 < sup > + < /sup > T-cell anti-viral responses
Thymic stromal lymphopoietin (TSLP) is a cytokine that acts directly on CD4+ T cells and dendritic cells to promote progression of asthma, atopic dermatitis, and allergic inflammation. However, a direct role for TSLP in CD8+ T-cell primary responses remains controversial and its role in memory CD8+ T cell responses to secondary viral infection is unknown. Here, we investigate the role of TSLP in both primary and recall responses in mice using two different viral systems. Interestingly, TSLP limited the primary CD8+ T-cell response to influenza but did not affect T cell function nor significantly alter the number of memory ...
Source: eLife - January 13, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

MITF reprograms the extracellular matrix and focal adhesion in melanoma
The microphthalmia associated transcription factor (MITF) is a critical regulator of melanocyte development and differentiation. It also plays an important role in melanoma where it has been described as a molecular rheostat that, depending on activity levels, allows reversible switching between different cellular states. Here we show that MITF directly represses the expression of genes associated with the extracellular matrix (ECM) and focal adhesion pathways in human melanoma cells as well as of regulators of epithelial to mesenchymal transition (EMT) such as CDH2, thus affecting cell morphology and cell-matrix interacti...
Source: eLife - January 13, 2021 Category: Biomedical Science Tags: Cancer Biology Genetics and Genomics Source Type: research

A transcriptomic taxonomy of < i > Drosophila < /i > circadian neurons around the clock
Many different functions are regulated by circadian rhythms, including those orchestrated by discrete clock neurons within animal brains. To comprehensively characterize and assign cell identity to the 75 pairs ofDrosophila circadian neurons, we optimized a single cell RNA sequencing method and assayed clock neuron gene expression at different times of day. The data identify at least 17 clock neuron categories with striking spatial regulation of gene expression. Transcription factor regulation is prominent and likely contributes to the robust circadian oscillation of many transcripts, including those that encode cell-surfa...
Source: eLife - January 13, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Neuroscience Source Type: research

Improving preclinical studies through replications
The purpose of preclinical research is to inform the development of novel diagnostics or therapeutics, and the results of experiments on animal models of disease often inform the decision to conduct studies in humans. However, a substantial number of clinical trials fail, even when preclinical studies have apparently demonstrated the efficacy of a given intervention. A number of large-scale replication studies are currently trying to identify the factors that influence the robustness of preclinical research. Here, we discuss replications in the context of preclinical research trajectories, and argue that increasing validit...
Source: eLife - January 12, 2021 Category: Biomedical Science Tags: Medicine Source Type: research

Spatial correlations constrain cellular lifespan and pattern formation in corneal epithelium homeostasis
Homeostasis in adult tissues relies on the replication dynamics of stem cells, their progenitors and the spatial balance between them. This spatial and kinetic coordination is crucial to the successful maintenance of tissue size and its replenishment with new cells. However, our understanding of the role of cellular replicative lifespan and spatial correlation between cells in shaping tissue integrity is still lacking. We developed a mathematical model for the stochastic spatial dynamics that underlie the rejuvenation of corneal epithelium. Our model takes into account different spatial correlations between cell replicatio...
Source: eLife - January 12, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Physics of Living Systems Source Type: research

Proteomics reveals synergy between biomass degrading enzymes and inorganic Fenton chemistry in leaf-cutting ant colonies
The symbiotic partnership between leaf-cutting ants and fungal cultivars processes plant biomass via ant fecal fluid mixed with chewed plant substrate before fungal degradation. Here we present a full proteome of the fecal fluid ofAcromyrmex leaf-cutting ants, showing that most proteins function as biomass degrading enzymes and that ca. 85% are produced by the fungus and ingested, but not digested, by the ants. Hydrogen peroxide producing oxidoreductases were remarkably common in the proteome, inspiring us to test a scenario in which hydrogen peroxide reacts with iron to form reactive oxygen radicals after which oxidized i...
Source: eLife - January 12, 2021 Category: Biomedical Science Tags: Ecology Evolutionary Biology Source Type: research