bluuebunny/crossref_metadata_2025_split huggingface dataset:
CryoEM structures of the human CLC-2 voltage gated chloride channel reveal a ball and chain gating mechanism
Authors: Xu Mengyuan , Neelands Torben , Powers Alexander S. , Liu Yan , Miller Steven D. , Pintilie Grigore , Bois J. Du , Dror Ron O. , Chiu Wah , Maduke Merritt 
Published: August 2023

ABSTRACTCLC-2 is a voltage-gated chloride channel that contributes to electrical excitability and ion homeostasis in many different mammalian tissues and cell types. Among the nine mammalian CLC homologs, CLC-2 is uniquely activated by hyperpolarization, rather than depolarization, of the plasma membrane. The molecular basis for the divergence in polarity of voltage gating mechanisms among closely related CLC homologs has been a long-standing mystery, in part because few CLC channel structures are available, and those that exist exhibit high conformational similarity. Here, we report cryoEM structures of human CLC-2 at 2.46 – 2.76 Å, in the presence and absence of the potent and selective inhibitor AK-42. AK-42 binds within the extracellular entryway of the Cl--permeation pathway, occupying a pocket previously proposed through computational docking studies. In the apo structure, we observed two distinct apo conformations of CLC-2 involving rotation of one of the cytoplasmic C-terminal domains (CTDs). In the absence of CTD rotation, an intracellular N-terminal 15-residue hairpin peptide nestles against the TM domain to physically occlude the Cl--permeation pathway from the intracellular side. This peptide is highly conserved among species variants of CLC-2 but is not present in any other CLC homologs. Previous studies suggested that the N-terminal domain of CLC-2 influences channel properties via a “ball-and-chain” gating mechanism, but conflicting data cast doubt on such a mechanism, and thus the structure of the N-terminal domain and its interaction with the channel has been uncertain. Through electrophysiological studies of an N-terminal deletion mutant lacking the 15-residue hairpin peptide, we show that loss of this short sequence increases the magnitude and decreases the rectification of CLC-2 currents expressed in mammalian cells. Furthermore, we show that with repetitive hyperpolarization WT CLC-2 currents increase in resemblance to the hairpin-deleted CLC-2 currents. These functional results combined with our structural data support a model in which the N-terminal hairpin of CLC-2 stabilizes a closed state of the channel by blocking the cytoplasmic Cl--permeation pathway.
Efferent projections ofNps-expressing neurons in the parabrachial region
Authors: Zhang Richie , Huang Dake , Gasparini Silvia , Geerling Joel C. 
Published: August 2023

AbstractIn the brain, connectivity determines function. Neurons in the parabrachial nucleus (PB) relay diverse information to widespread brain regions, but the connections and functions of PB neurons that expressNps(neuropeptide S) remain mysterious. Here, we use Cre-dependent anterograde tracing and whole-brain analysis to map their output connections. While many other PB neurons project ascending axons through the central tegmental tract, NPS axons reach the forebrain via distinct periventricular and ventral pathways. Along the periventricular pathway, NPS axons target the tectal longitudinal column and periaqueductal gray then continue rostrally to target the paraventricular nucleus of the thalamus. Along the ventral pathway, NPS axons blanket much of the hypothalamus but avoid the ventromedial and mammillary nuclei. They also project prominently to the ventral bed nucleus of the stria terminalis, A13 cell group, and magnocellular subparafasciular nucleus. In the hindbrain, NPS axons have fewer descending projections, targeting primarily the superior salivatory nucleus, nucleus of the lateral lemniscus, and periolivary region. Combined with what is known about NPS and its receptor, the output pattern ofNps-expressing neurons in the PB region predicts a role in threat response and circadian behavior.
Uncovering the lung cancer mechanisms through the chromosome structural ensemble characteristics
Authors: Chu Wen-Ting , Wang Jin 
Published: August 2023

AbstractLung cancer is one of the most common cancers in human. However, it is still lack of understanding the mechanisms of a normal cell developing to the cancer cell. Here we develop the chromosome dynamic structural model and quantify the important characteristics of the chromosome structural ensemble of the normal lung cell and the lung cancer A549 cell. Our results demonstrate the essential relationship among the chromosome ensemble, the epigenetic marks, and the gene expressions, which suggests the linkage between chromosome structure and function. The analysis reveals that the lung cancer cell may have higher level of relative ensemble fluctuation as well as higher degree of the phase separation between the two compartments than the normal lung cells. In addition, the significant conformational“switching off”events (from compartment A to B) are more than the significant conformational“switching on”events during the lung cancerization. The kinetic lung cancerization pathway is not the same as the reversion pathway by characterizing the hot spots and interaction networks of the lung cancer transitions. These investigations have revealed the cell fate determination mechanism of the lung cancer process, which will be helpful for the further prevention and control of cancers.
Early spiral arteriole remodeling in the uterine-placental interface: a rat model
Authors: Bacon Sarah J. , Zhu Yuxi , Ghosh Priyanjali 
Published: August 2023

AbstractThe mammalian placenta’s interface with the parent is a richly vascularized tissue whose development relies upon communication between many different cell types within the uterine microenvironment. The uterine blood vessels of the interface are reshaped during pregnancy into wide-bore, flaccid vessels that convey parental blood to the exchange region of the placenta. Fetally-derived invasive trophoblast as well as parental uterine macrophages and Natural Killer cells are involved in the stepwise remodeling of these vessels and their respective contributions to this crucial process are still being delineated. However, the earliest steps in arteriole remodeling are understudied as they are difficult to study in humans, and other species lack the deep trophoblast invasion that is so prominent a feature of placentation in humans. Here, we establish the rat, with deep hemochorial placentation akin to humans, as a model system in which to tease apart the earliest, relatively understudied events in spiral arteriole remodeling. We show that the rat uterine placental interface increases in size and vascularity rapidly, before trophoblast invasion. The remodeling stages in the arterioles of the rat uterine-placental interface follow a sequence of anatomical changes similar to those in humans, and there are changes to the arterioles’ muscular tunica media prior to the marked influx of immune cells. The rat is a tractable model in which to better understand the cell/cell interactions occurring in vivo in an intact tissue microenvironment over time.
SARS-CoV-2 Neutralizing Antibodies Following a Second BA.5 Bivalent Booster
Authors: Wang Qian , Bowen Anthony , Ho Jerren , Zhang Richard , Valdez Riccardo , Stoneman Emily , Gordon Aubree , Liu Lihong , Ho David D. 
Published: August 2023

AbstractBivalent COVID-19 mRNA vaccines expressing both the ancestral D614G and Omicron BA.5 spike proteins were introduced in August 2022 with the goal of broadening immunity to emerging SARS-CoV-2 Omicron subvariants. Subsequent studies on bivalent boosters found neutralizing antibody responses similar to boosters with the original monovalent vaccine, likely the result of immunological imprinting. Guidelines allow for administration of a second bivalent booster in high-risk groups, but it remains unknown whether this would broaden antibody responses. To address this question, we assessed longitudinal serum SARS-CoV-2-neutralizing titers in 18 elderly immunocompetent individuals (mean age 69) following a fourth monovalent booster and two BA.5 bivalent booster vaccines using pseudovirus neutralization assays against D614G, Omicron BA.5, and Omicron XBB.1.5. There was a small but significant increase in peak neutralizing antibody responses against Omicron BA.5 and XBB.1.5 following the first bivalent booster, but no significant increase in peak titers following the second bivalent booster. Omicron-specific neutralizing titers remained low after both doses of the BA.5 bivalent booster. Our results suggest that a second dose of the BA.5 bivalent booster is not sufficient to broaden antibody responses and to overcome immunological imprinting. A monovalent vaccine targeting only the spike of the recently dominant SARS-CoV-2 may mitigate the “back boosting” associated with the “original antigenic sin.”
The Spatial Patterns and Determinants of Cerebrospinal Fluid Circulation in the Human Brain
Authors: Nazeri Arash , Dehkharghanian Taher , Lindsay Kevin E. , LaMontagne Pamela , Shimony Joshua S. , Benzinger Tammie L.S. , Sotiras Aristeidis 
Published: August 2023

AbstractThe circulation of cerebrospinal fluid (CSF) is essential for maintaining brain homeostasis and clearance, and impairments in its flow can lead to various brain disorders. Recent studies have shown that CSF circulation can be interrogated using low b-value diffusion magnetic resonance imaging (low-bdMRI). Nevertheless, the spatial organization of intracranial CSF flow dynamics remains largely elusive. Here, we developed a whole-brain voxel-based analysis framework, termed CSF pseudo-diffusion spatial statistics (CΨSS), to examine CSF mean pseudo-diffusivity (MΨ), a measure of CSF flow magnitude derived fromlow-bdMRI. We showed that intracranial CSF MΨ demonstrates characteristic covariance patterns by employing seed-based correlation analysis. Importantly, we applied non-negative matrix factorization analysis to further elucidate the covariance patterns of CSF MΨ in a hypothesis-free, data-driven way. We identified distinct CSF spaces that consistently displayed unique pseudo-diffusion characteristics across multiple imaging datasets. Our study revealed that age, sex, brain atrophy, ventricular anatomy, and cerebral perfusion differentially influence MΨ across these CSF spaces. Notably, individuals with anomalous CSF flow patterns displayed incidental findings on multimodal neuroradiological examinations. Our work sets forth a new paradigm to study CSF flow, with potential applications in clinical settings.
Evolutionary conservation of secondary structures in the lncRNAs of plants
Authors: Corona-Gomez Jose Antonio , Stadler Peter F. , Fernandez-Valverde Selene L. 
Published: August 2023

AbstractLncRNAs are essential regulators of eukaryotic gene expression. They exert their gene regulatory functions by interacting with DNA, RNA, and protein. These functions are considered at least in part associated with their capacity to fold into complex three-dimensional structures. The conservation of lncRNA structure in mammalian genomes has been assessed in several studies, however, very little is known about the conservation of lncRNA structures in plants. Here, we analyze the structural conservation of lncRNAs inBrassicaceae, using a whole genome alignment of 16Brassicaceaespecies. We found that 44.2% (1925 of 4354) of the intergenic lncRNAs (lincRNAs) and 75.1% (1549 of 2060) of the natural antisense transcripts (NATs) ofArabidopsis thalianahave conserved structural motifs in at least 2 of the 16 species. Also, 3612 lncRNAs have conserved structural motifs in multiple species; 2264 of which are tissue-specific, and 841 can be associated with a function by a co-expression network inA. thaliana. Indeed, we find evidence for the conservation of structural motifs in several lncRNAs with known functions, including,lncCOBRA1, FLORE, IPS1, ELENA1andCOOLAIR.The latter was shown previously to have a conserved structure. Overall, we have identified numerous lncRNAs with conserved structures inBrassicaceaethat warrant further experimental explorationin vivoto understand whether these lncRNAs and their conserved structures are of biological significance.
Inbreeding or outbreeding depression? How to manage an endangered and locally adapted population of red grouseLagopus scotica
Authors: Walsh Grace , McMahon Barry J. , Thörn Filip , Rödin-Mörch Patrik , Irestedt Martin , Höglund Jacob 
Published: August 2023

AbstractThe balance between the inbreeding and outbreeding continuum is a fundamental debate within conservation genomics. To inform this debate we use genome wide data to show that inbreeding is higher in Irish red grouse (Lagopus scotica) and that this smaller and isolated population exhibits divergence from the British. Outlier analysis identified divergence in several genomic regions linked to genes coding for ecologically important traits such as phenotypic differences in plumage colour and sequence divergence among coding regions in the melanin pathway. We also find differences among immune genes and loci involved in food intake and energy control. The two populations thus appear locally adapted. Divergence between the source and the target population when used for conservation aided restocking may have negative consequences if locally adapted alleles are swamped and/or maladapted genotypes are introduced, leading to outbreeding depression. While avoiding inbreeding by maintaining large populations is important, our study illustrates that conservationists and managers should also consider population divergence and local adaptation. We argue against translocations among Ireland and Britain as a conservation strategy. The results of our study demonstrate the value of focusing on local populations and habitat management when aiming to enhance the conservation status of specific species.
An ancestral dual function of OmpM as outer membrane tether and nutrient uptake channel in diderm Firmicutes
Authors: Silale Augustinas , Zhu Yiling , Witwinowski Jerzy , Smith Robert E. , Newman Kahlan E. , Bhamidimarri Satya P. , Baslé Arnaud , Khalid Syma , Beloin Christophe , Gribaldo Simonetta , Berg Bert van den 
Published: August 2023

AbstractThe outer membrane (OM) in diderm, or Gram-negative, bacteria must be tethered to peptidoglycan (PG) for mechanical stability and to maintain cell morphology. Most diderm phyla from the Terrabacteria group lack well-characterised OM attachment systems such as Braun’s lipoprotein, Pal and OmpA, but instead have the OmpM protein. OmpM has a periplasmic region containing an S-layer homology domain and a β-barrel region that is embedded in the OM. Here, we have determined the structure of the most abundant OmpM protein from the diderm firmicuteVeillonella parvulaby single particle cryogenic electron microscopy (cryo-EM). We reveal an OM portion similar to well-characterised trimeric general porins and a mobile periplasmic PG-binding region. Combining the cryo-EM data with crystal structures, structure predictions and molecular dynamics simulations, we show that the periplasmic region of OmpM likely adopts multiple conformations. Single-channel electrophysiology demonstrates ion conductance properties similar toE. coliOmpF. Finally, we demonstrate via functional assays that the four OmpM paralogues are likely to be the only general porins inV. parvula. Together, our results show that OM tethering and nutrient acquisition are genetically linked inV. parvula(and other diderm Firmicutes), suggesting that concurrent loss of two key OM-related functions, tethering and nutrient uptake, promoted the multiple OM loss events that have been inferred in the Terrabacteria.
Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow
Authors: Huang Tongling , Lu Zhaocheng , Wang Zihui , Cheng Lixin , Gao Lu , Gao Jun , Zhang Ning , Geng Chang-An , Zhao Xiaoli , Wang Huaiyu , Wong Chi-Wai , Yeung Kelvin W K , Pan Haobo , Lu William Weijia , Guan Min 
Published: August 2023

AbstractEctopic bone marrow adipocytes (BMAds) accumulation occurring under diverse pathophysiological conditions leads to bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency rescues osteogenesis and vascular formation in adipocyte-rich bone marrow due to estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); and positively modulatesLeptinexpression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased LEPTIN secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu.Graphic abstract
Detecting inbreeding depression in structured populations
Authors: Lavanchy Eléonore , Weir Bruce S. , Goudet Jérôme 
Published: August 2023

AbstractMeasuring inbreeding as well as its consequences on fitness is central for many areas in biology including human genetics and the conservation of endangered species. However, there is no consensus on the most appropriate method, neither for quantification of inbreeding itself nor for the model to estimate its effect on specific traits. In this project, we simulated traits based on simulated genomes from a large pedigree and empirical whole-genome sequences of human data from populations with various sizes and structure (from the 1,000 Genomes project). We compare the ability of various inbreeding coefficients (F) to quantify the strength of inbreeding depression: allele sharing, two versions of the correlation of uniting gametes which differ in the weight they attribute to each locus and two identical-by-descent segments-based estimators. We also compare two models: the standard linear model and a linear mixed model including a genetic relatedness matrix (GRM) as random effect to account for the non-independence of observations. We find linear mixed models give better results in scenarios with population or family structure. Within the mixed models, we compare three different GRM matrices and show that in homogeneous populations, there is little difference among the differentFand GRM for inbreeding depression quantification. However, as soon as strong population or family structure is present, the strength of inbreeding depression can be most efficiently estimated only if (i) the phenotypes are regressed on inbreeding coefficient based on a weighted version of the correlation of uniting gametes, which gives more weight to common alleles and (ii) with the GRM obtained from an allele sharing relatedness estimator.
Effects of combined exposure to ethanol and delta-9-tetrahydrocannabinol during adolescence on synaptic plasticity in the prefrontal cortex of Long Evans rats
Authors: Shi Linyuan , Kang Shuo , Choi Chan Young , Noonan Brynn L. , Carrica Lauren K. , Liang Nu-Chu , Gulley Joshua M. 
Published: August 2023

ABSTRACTSignificant exposure to alcohol or cannabis during adolescence can induce lasting disruptions of neuronal signaling in brain regions that are later to mature, such as the medial prefrontal cortex (mPFC). Considerably less is known about the effects of alcohol and cannabis co-use, despite its common occurrence. Here, we used male and female Long-Evans rats to investigate the effects of early-life exposure to ethanol, delta-9-tetrahydrocannabinol (THC), or their combination on high frequency stimulation (HFS)-induced plasticity in the prelimbic region of the mPFC. Animals were injected daily from postnatal days 30 to 45 with vehicle or THC (escalating doses, 3-20 mg/kg) and allowed to drink vehicle (0.1% saccharin) or 10% ethanol immediately after each injection.In vitrobrain slice electrophysiology was then used to record population responses of layer V neurons following HFS in layer II/III after 3-4 weeks of abstinence. We found that THC exposure reduced body weight gains observed inad libitumfed rats, and reduced intake of saccharin and ethanol. Compared to controls, there was a significant reduction in HFS-induced long-term depression (LTD) in rats exposed to either drug alone, and an absence of LTD in rats exposed to the drug combination. Bath application of indiplon or AR-A014418, which enhance GABAAreceptor function or inhibit glycogen synthase kinase 3β (GSK3β), respectively, suggested the effects of ethanol, THC or their combination were due in part to lasting adaptations in GABA and GSK3β signaling. These results suggest the potential for long-lasting adaptations in mPFC output following co-exposure to alcohol and THC.
Soft rot pathogenDickeya dadantii3937 produces tailocins resembling the tails ofEnterobacteriabacteriophage P2
Authors: Borowicz Marcin , Krzyżanowska Dorota M. , Narajczyk Magdalena , Sobolewska Marta , Rajewska Magdalena , Czaplewska Paulina , Węgrzyn Katarzyna , Czajkowski Robert 
Published: August 2023

AbstractTailocins are nanomolecular machines with bactericidal activity. They are produced by bacteria to contribute to fitness in mixed communities, and hence, they play a critical role in their ecology in a variety of habitats. Here, we characterized the new tailocin produced byDickeya dadantiistrain 3937, a well-characterized member of plant pathogenic Soft RotPectobacteriaceae(SRP). Tailocins induced inD. dadantiiwere ca. 166 nm long tubes surrounded by contractive sheaths with baseplates having tail fibers at one end. A 22-kb genomic cluster involved in their synthesis and having high homology to the cluster coding for the tail of the Enterobacteriophage P2 was identified. TheD. dadantiitailocins, termed dickeyocin P2D1 (phage P2-like dickeyocin 1), were resistant to inactivation by pH (3.5 – 12), temperature (4 – 50 °C), and elevated osmolarity (NaCl concentration: 0.01 – 1 M). P2D1 could kill a variety of differentDickeyaspp. but not any strain ofPectobacteriumspp. tested and were not toxic toCaenorhabditis elegans.TeaserTailocins are nanomolecular entities similar to syringes that are produced by various bacteria to fight other microorganisms present in the same environment.
An actor-model framework for visual sensory encoding
Authors: Leong Franklin , Rahmani Babak , Psaltis Demetri , Moser Christophe , Ghezzi Diego 
Published: August 2023

AbstractA fundamental challenge in neuroengineering is determining a proper input to a sensory system that yields the desired functional output. In neuroprosthetics, this process is known as sensory encoding, and it holds a crucial role in prosthetic devices restoring sensory perception in individuals with disabilities. For example, in visual prostheses, one key aspect of image encoding is to down-sample the images captured by a camera to a size matching the number of inputs and resolution of the prosthesis. Here, we show that down-sampling an image using the inherent computation of the retinal network yields better performance compared to a learning-free down-sampling encoding. We validated a learning-based approach (actor-model framework) that exploits the signal transformation from photoreceptors to retinal ganglion cells measured in explanted retinas. The actor-model framework generates down-sampled images eliciting a neuronal response in-silico and ex-vivo with higher neuronal reliability to the one produced by original images compared to a learning-free approach (i.e. pixel averaging). In addition, the actor-model learned that contrast is a crucial feature for effective down-sampling. This methodological approach could serve as a template for future image encoding strategies. Ultimately, it can be exploited to improve encoding strategies in visual prostheses or other sensory prostheses such as cochlear or limb.