bluuebunny/crossref_metadata_2025_split huggingface dataset:
The enrichment of self-domestication and neural crest function loci in the heritability of neurodevelopmental disorders is not independent of genomic regulatory functions
Authors: Koller Dora , Benítez-Burraco Antonio , Polimanti Renato 
Published: September 2022

AbstractSelf-domestication could play an important role in contributing to shape the biology of human brain and the predisposition to neurodevelopmental disorders. Leveraging genome-wide data from the Psychiatric Genomics Consortium, we tested the enrichment of self-domestication and neural crest function loci with respect to the heritability of autism spectrum disorder, schizophrenia (SCZ in East Asian and European ancestries, EAS and EUR, respectively), attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, and Tourette’s syndrome (TS). Considering only self-domestication and neural-crest-function annotations in the linkage disequilibrium score regression (LDSC) model, our partitioned heritability analysis revealed statistically significant enrichments across all disorders investigated. The estimates of the heritability enrichments for self-domestication loci were similar across neurodevelopmental disorders, ranging from 0.902 (EAS SCZ, p=4.55×10−20) to 1.577 (TS, p=5.85×10−5). Conversely, a wider spectrum of heritability enrichment estimates was present for neural crest function with the highest enrichment observed for TS (enrichment=3.453, p=2.88×10−3) and the lowest for EAS SCZ (enrichment=1.971, p=3.8l×10−3). Although these estimates appear to be strong, the enrichments for self-domestication and neural crest function were null once we included additional annotations related to different genomic features. This indicates that the effect of self-domestication on the polygenic architecture of neurodevelopmental disorders is not independent of other functions of human genome.
Clonally related, Notch-differentiated spinal neurons integrate into distinct circuits
Authors: Bello-Rojas Saul , Bagnall Martha W. 
Published: September 2022

AbstractShared lineage has diverse effects on patterns of neuronal connectivity. In mammalian cortex, excitatory sister neurons assemble into shared microcircuits, whereas throughout the Drosophila nervous system, Notch-differentiated sister neurons diverge into distinct circuits. Notch-differentiated sister neurons have been observed in vertebrate spinal cord and cerebellum, but whether they integrate into shared or distinct circuits remains unknown. Here we evaluate the connectivity between sister V2a/b neurons in the zebrafish spinal cord. Using an in vivo labeling approach, we identified pairs of sister V2a/b neurons born from individual Vsx1+ progenitors and observed that they have similar axonal trajectories and proximal somata. However, paired whole-cell electrophysiology and optogenetics revealed that sister V2a/b neurons receive input from distinct presynaptic sources, do not communicate with each other, and connect to largely distinct targets. These results resemble the divergent connectivity in Drosophila and represent the first evidence of Notch-differentiated circuit integration in a vertebrate system.
Covariance-based decoding reveals content-specific feature integration and top-down processing during visual imagery
Authors: Mantegna Francesco , Olivetti Emanuele , Schwedhelm Philipp , Baldauf Daniel 
Published: September 2022

AbstractWhen we internally generate mental images, we need to combine multiple features into a whole. Direct evidence for such feature integration during visual imagery is still lacking. Moreover, cognitive control mechanisms, including memory and attention, exert top-down influences on the perceptual system during mental images generation. However, it is unclear whether such top-down processing is content-specific or not. Feature integration and top-down processing involve short-range connectivity within visual areas, and long-range connectivity between control and visual areas, respectively. Here, we used a minimally constrained experimental paradigm wherein imagery categories were prompted using visual word cues only, and we decoded face versus place imagery based on their underlying connectivity patterns. Our results show that face and place imagery can be decoded from both short-range and long-range connections. These findings suggest that feature integration does not require an external stimulus but occurs also for purely internally generated images. Furthermore, control and visual areas exchange information specifically tailored to imagery content.TeaserDecoding visual imagery from brain connectivity reveals a content-specific interconnected neural code for internal image generation.
Identification of potential human pancreatic α-amylase inhibitors from natural products by molecular docking, MM/GBSA calculations, MD simulations, and ADMET analysis
Authors: Basnet Santosh , Ghimire Madhav Prasad , Lamichhane Tika Ram , Adhikari Rajendra , Adhikari Achyut 
Published: September 2022

AbstractHuman pancreatic α-amylase (HPA), which works as a catalyst for carbohydrate hydrolysis, is one of the viable targets to control type 2 diabetes. The inhibition of α-amylase lowers blood glucose levels and helps to alleviate hyperglycemia complications. Herein, we systematically screened the potential HPA inhibitors from an in-house library of natural products by molecular modeling. The modeling encompasses molecular docking, MM/GBSA binding energy calculations, MD simulations, and ADMET analysis. This research identified newboulaside B, newboulaside A, quercetin-3-O-β-glucoside, and sasastilboside A as the top four potential HPA inhibitors from the library of natural products, whose Glide docking scores and MM/GBSA binding energies range from −9.191 to −11.366 kcal/mol and −19.38 to −50.29 kcal/mol, respectively. Based on the simulation, among them, newboulaside B was found as the best HPA inhibitor. Throughout the simulation, with the deviation of 3Å (acarbose = 3Å), it interacted with ASP356, ASP300, ASP197, THR163, ARG161, ASP147, ALA106, and GLN63 via hydrogen bonding. Additionally, the comprehensive ADMET analysis revealed that it has good pharmacokinetic properties having not acutely toxic, moderately bioavailable, and non-inhibitor nature toward cytochrome P450. All the results suggest that newboulaside B might be a promising candidate for drug discovery against type 2 diabetes.Graphical Abstract
Conserved YKL-40 changes in mice and humans after postoperative delirium
Authors: David-Bercholz Jennifer , Acker Leah , Caceres Ana I , Wu Pau Yen , Goenka Saanvi , Franklin Nathan O , Rodriguiz Ramona M , Wetsel William C , Devinney Michael , Wright Mary Cooter , Zetterberg Henrik , Yang Ting , Berger Miles , Terrando Niccolò 
Published: September 2022

AbstractDelirium is a common postoperative neurologic complication among older adults. Despite its prevalence of 14-50% and likely association with inflammation, the exact mechanisms underlying postoperative delirium are unclear. This project aimed at characterizing systemic and central nervous system (CNS) inflammatory changes following surgery in both mice and humans. Matched plasma and cerebrospinal fluid (CSF) samples from the “Investigating Neuroinflammation Underlying Postoperative Brain Connectivity Changes, Postoperative Cognitive Dysfunction, Delirium in Older Adults” (INTUIT;NCT03273335) were used to parallel murine endpoints. Delirium-like behavior was evaluated in aged mice using the 5-Choice Serial Reaction Time Test (5-CSRTT). Using a well-established orthopedic surgical model in the FosTRAP reporter mouse, we detected neuronal changes in the prefrontal cortex, an area implicated in attention, but notably not in the hippocampus. In aged mice, plasma interleukin-6 (IL-6), chitinase-3-like protein 1 (YKL-40), and neurofilament light chain (NfL) levels increased after orthopedic surgery, but hippocampal YKL-40 expression was decreased. Given the growing role of YKL-40 in delirium and other neurodegenerative conditions, we assayed human plasma and CSF samples. Plasma YKL-40 levels were also similarly increased after surgery, with a trend toward greater post-operative plasma YKL-40 increase in patients with delirium. In contrast to plasma, YKL-40 levels in CSF decreased following surgery, which paralleled the findings in the mouse brain. Finally, we confirmed changes in blood-brain barrier (BBB) after surgery as early as 9 hours in mice, which warrants for more detailed and acute evaluations of BBB integrity following surgery in humans. All together, these results provide a nuanced understanding of the neuroimmune interactions underlying post-operative delirium in mice and humans, and highlight translational biomarkers to test potential cellular targets and mechanisms.
Efficient CRISPR/Cas9 mediated large insertions using long single-stranded oligonucleotide donors in C. elegans
Authors: Eroglu Matthew , Yu Bin , Derry Brent 
Published: September 2022

AbstractHighly efficient generation of deletions, substitutions, and small insertions (up to ∼150 bp) into the C. elegans genome by CRISPR/Cas9 has been facilitated by use of single-stranded oligonucleotide donors as repair templates. However, efficient insertion of larger sequences such as fluorescent markers and other functional proteins remains inefficient due to lack of standardized methods for generating repair templates and labor intensive or cost prohibitive synthesis. We have optimized the simple and efficient generation of long single-stranded DNA for use as donors in CRISPR/Cas9 using a standard PCR followed by an enzymatic digest by lambda exonuclease. Comparison of long single-stranded DNA donors to previously described methods using double-stranded DNA yields orders of magnitude increased efficiency for single-stranded DNA donors. This efficiency can be leveraged to simultaneously generate multiple large insertions as well as successful edits without use of selection or co-conversion (coCRISPR) markers when necessary. Our approach complements the CRISPR/Cas9 toolkit for C. elegans to enable highly efficient insertion of longer sequences with a simple, standardized and labor-minimal protocol.
The promiscuous development of an unconventional Qa1b-restricted T cell population
Authors: Valerio Michael Manoharan , Arana Kathya , Guan Jian , Chan Shiao Wei , Yang Xiaokun , Kurd Nadia , Lee Angus , Shastri Nilabh , Coscoy Laurent , Robey Ellen A. 
Published: September 2022

AbstractMHC-E restricted CD8 T cells show promise in vaccine settings, but their development and specificity remain poorly understood. Here we focus on a CD8 T cell population reactive to a self-peptide (FL9) bound to mouse MHC-E (Qa-1b) that is presented in response to loss of the MHC I processing enzyme ERAAP, termed QFL T cells. We find that mature QFL thymocytes are predominantly CD8αβ+CD4-, show signs of agonist selection, and give rise to both CD8αα and CD8αβ intraepithelial lymphocytes (IEL), as well as memory phenotype CD8αβ T cells. QFL T cells require the MHC I subunit β-2 microglobulin (β2m), but do not require Qa1bor classical MHC I for positive selection. However, QFL thymocytes do require Qa1bfor agonist selection and full functionality. Our data highlight the relaxed requirements for positive selection of an MHC-E restricted T cell population and suggest a CD8αβ+CD4-pathway for development of CD8αα IELs.
Studies on theEscherichia coliExbD Transmembrane Domain, Residue L132, and an Inhibitory Cyclic Peptide
Authors: Jana Bimal , Kopp Dale , Xie Mingchao , Vakharia-Rao Hema , Postle Kathleen 
Published: September 2022

ABSTRACTThe TonB system ofEscherichia coliuses the cytoplasmic membrane protonmotive force (PMF) to energize active transport of nutrients across the otherwise unenergized outer membrane. Because it overcomes limitations for nutrient diffusion through outer membrane size-limiting porins, it provides a growth advantage and is widespread among Gram-negative bacteria. It consists of three known cytoplasmic membrane proteins, TonB, ExbB and ExbD that energize a variety of customized TonB-dependent transporters in the outer membrane. The sole ExbD transmembrane domain is proposed to consist of residues 23-43 (Kampfenkel and Braun, 1992, J. Bacteriol. 174:5485-7). Here we showed that the charge and location of residue Asp25 were essential for activity of the TonB system, thus identifying it as the only PMF-responsive element in the TonB system. The proposed boundaries of the transmembrane domain α-helix were revised to consist of residues 23-39, with residues 40-43 initiating the subsequent disordered region required for signal transduction (Kopp and Postle, 2020, J. Bacteriol. 202, e00687-19). Trapping of disulfide-linked ExbD homodimers through T42C or V43C prevented TonB system activity that was restored by addition of the reducing agent dithiothreitol, indicating a requirement for motion. Invivophoto-cross-linking experiments suggested that motion was rotation of ExbD transmembrane domains. Inactivity of ExbD L132Q, the first ExbD mutant identified, was likely due to steric hindrance. A conserved and defined site ofin vivoExbD interaction with TonB was identified. Exogenous addition of a cyclic peptide based on that site inhibited ExbD-TonB interaction while concomitantly decreasing iron transport efficiency. This suggested that a novel antimicrobial strategy against ESKAPE and other Gram-negative pathogens could be developed by targeting ExbD protein-protein interactions.
Widespread sympatry in a species-rich clade of marine fishes (Carangoidei)
Authors: Glass Jessica R. , Harrington Richard C. , Cowman Peter F. , Faircloth Brant C. , Near Thomas J. 
Published: September 2022

AbstractThe patterns of speciation in marine fishes are largely unknown, in part due to the deficiency of species-level phylogenies and information on species’ distributions, and partly due to conflicting relationships between species’ dispersal, range size, and patterns of co- occurrence. Most research on global patterns of marine fish speciation has focused on coral reef or pelagic species. Carangoidei is a clade of marine fishes including the trevallies, remoras, and dolphinfishes that utilize both coral reef and pelagic environments, spanning the ecologies of coral reef obligate and open-ocean species. We used sequence capture of 1314 ultraconserved elements (UCEs) from 154 taxa to generate a phylogeny of Carangoidei and its parent clade, Carangiformes. Age-range correlation analyses of the geographic distributions and divergence times of sister species pairs reveal widespread sympatry, with 73% of sister species pairs exhibiting a sympatric geographic distribution, regardless of node age, and most species pairs co-existing across large portions of their ranges. We also observe greater disparity in body size and water column depth utilization between sympatric than allopatric sister species. These and other ecological or behavioral attributes likely facilitate sympatry among the most closely related carangoid species, which exhibit sympatry at a larger taxonomic scale than has previously been described in marine fishes.
Traditional phylogenetic models fail to account for variations in the effective population size
Authors: Borges Rui , Kotari Ioanna , Bergman Juraj , Chase Madeline A. , Mugal Carina F. , Kosiol Carolin 
Published: September 2022

AbstractA substitution represents the emergence and fixation of an allele in a population or species and is the fundamental event from which phylogenetic models of sequence evolution are devised. Because of the increasing availability of genomic sequences, we are now able to take advantage of intraspecific variability when reconstructing the tree of life. As a result, substitutions can be more realistically modeled as the product of mutation, selection, and genetic drift. However, it is still unclear whether this increased complexity affects our measures of evolutionary times and rates. This study seeks to answer this question by contrasting the traditional substitution model with a population genetic equivalent using data from 4385 individuals distributed across 179 populations and representing 17 species of animals, plants, and fungi. We found that when the population genetics dynamic is modeled via the substitution rates, the evolutionary times and rates of the two models are well correlated, suggesting that the phylogenetic model is able to capture the time and pace of its population counterpart. However, a closer inspection of this result showed that the traditional models largely ignore the effect of the effective population size, even when it is explicitly accounted for in the substitution rates. Our findings suggest that superimposing population-genetics results on the substitution rates is an effective strategy to study mutation and selection biases, while other data sources (e.g., life history traits or polymorphisms) may need to be additionally integrated to make the traditional substitution models sensitive to the impact of genetic drift. When combined with the known effect of ancestral population size on generating phylogenomic incongruence due to incomplete lineage sorting, our findings provide further evidence that unaccounted-for variations in the effective population size may be one of the primary causes of errors in phylogenetic analyses at shorter time scales.
A small molecule that inhibits the evolution of antibiotic resistance
Authors: Johnson Anna E. , Bracey Harrison , Hernandez Viera Angel Joel , Carvajal-Garcia Juan , Simsek Esra N. , Kim Kwangho , Merrikh Houra 
Published: September 2022

SummaryAntimicrobial resistance (AMR) rapidly develops against almost all available therapeutics. New antibiotics target essential processes in bacteria but fail to address the root of the problem: mutagenesis and evolution. We recently proposed that inhibiting the molecular mechanisms underlying bacterial evolution is the ultimate solution to preventing AMR development. Here, we describe the first compound that inhibits the occurrence and progression of AMR by directly targeting a highly conserved bacterial evolvability factor, Mfd. We previously found that this RNA polymerase-associated translocase is required for rapid AMR development across highly divergent pathogens. Through an in vivo screen, we identified 43 potential Mfd-inhibiting compounds. Here we present on target validation, biochemical characterization, and in vivo efficacy studies of a lead compound, referred to as ARM-1. ARM-1 binds Mfd and modulates its RNA polymerase interaction. Inhibition of Mfd activity by ARM-1 delays the development of mutations and resistance acquisition, both in pure culture and during infection. Importantly, our data show that this compound prevents the evolution of AMR across highly divergent pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus, Listeria monocytogenes, and Salmonella enterica serovar Typhimurium. The novel compound we present here has the potential to develop into a clinically useful “anti-evolution” drug. This work demonstrates that the molecular mechanisms of evolution are pharmaceutically targetable, and that this strategy could help prevent AMR development.
SCFFBXW7 regulates G2-M progression through control of CCNL1 ubiquitination
Authors: O’Brien Siobhan , Kelso Susan , Steinhart Zachary , Orlicky Stephen , Mis Monika , Kim Yunhye , Lin Sichun , Sicheri Frank , Angers Stephane 
Published: September 2022

AbstractFBXW7, which encodes a substrate specific receptor of an SCF E3 ligase complex, is a frequently mutated human tumor suppressor gene known to regulate the post-translational stability of various proteins involved in cellular proliferation. Here, using genome-wide CRISPR screens we report a novel synthetic lethal genetic interaction between FBXW7 and CCNL1 and describe CCNL1 as a new substrate of the SCF-FBXW7 E3 ligase. Further analysis showed that the CCNL1-CDK11 complex is critical at the G2-M phase of the cell cycle since defective CCNL1 accumulation, resulting from FBXW7 mutation, leads to shorter mitotic time. Cells harboring FBXW7 loss-of-function mutations are hypersensitive to treatment with a CDK11 inhibitor, highlighting a genetic vulnerability that could be leveraged for cancer treatment.
Amyloid and Tau Pathology are Associated with Cerebral Blood Flow in a Mixed Sample of Nondemented Older Adults with and without Vascular Risk Factors for Alzheimer’s Disease
Authors: Swinford Cecily G. , Risacher Shannon L. , Vosmeier Aaron , Deardorff Rachael , Chumin Evgeny J. , Dzemidzic Mario , Wu Yu-Chien , Gao Sujuan , McDonald Brenna C. , Yoder Karmen K. , Unverzagt Frederick W. , Wang Sophia , Farlow Martin R. , Brosch Jared R. , Clark David G. , Apostolova Liana G. , Sims Justin , Wang Danny J. , Saykin Andrew J. 
Published: September 2022

AbstractAlzheimer’s disease (AD) is the leading cause of dementia in individuals over 65 in the U.S. Prevalence is projected to double by 2050, but current treatments cannot stop the progression of AD. Treatments administered before severe cognitive decline may be effective; identification of biomarkers for preclinical and prodromal stages of AD is therefore imperative. Cerebral blood flow (CBF) is a potential early biomarker for AD; generally, older adults with AD have decreased CBF compared to normally aging peers. Characterization should include the relationships between CBF and AD risk factors and pathologies. We assessed the relationships between CBF quantified by arterial spin labeled MRI, hypertension,APOEε4, and tau and amyloid PET in 77 older adults: cognitively normal, subjective cognitive decline, and mild cognitive impairment. Tau and amyloid aggregation were related to altered CBF, and some of these relationships were dependent on hypertension orAPOEε4 status. Our findings suggest a complex relationship between risk factors, AD pathologies, and CBF that warrants future studies of CBF as a potential early biomarker for AD.
Aero-thermal investigation of thermal interactions between turboprop engine exhaust and selected parts of the airplane skin for tractor configured aircraft
Authors: C.A. Vinay , G.N. Kumar 
Published: September 2022

Purpose
Development or upgradation of airplanes requires many different analyses, e.g. thermal, aerodynamic, structural and safety. Similar studies were performed during configuration change design of commuter category aircraft equipped with pusher turboprop engines. In this paper, thermo-fluid analyses of interactions of the new propulsion system in tractor configuration with selected elements of airplane skin are carried out. This study aims to check the airplane skin material, and its geometry, including the Plexiglas passenger window material degradation, due to hot exhaust gas plume impingement. The impact of change in exhaust stub angle and asymmetric inboard-outboard stubs on the jet thrust at various flight operating conditions like minimum off-route altitude and cruise performance is assessed.

Design/methodology/approach
Commercial software-based numerical models were developed. In the first stage, heat and fluid flow analysis was performed over a twin-engine airplane’s nacelle, wing and center fuselage with its powerplant mounted in the high wing configuration. Subsequently, numerical simulations of thermal interactions between the hot exhaust gases, which leave the exhaust system close to the nacelle, flaps and the center fuselage, were estimated for various combinations of exhaust stub angles with asymmetry between inboard-outboard stubs at different airplane configurations and operating conditions.

Findings
The results of the simulations are used to recommend modifications to the design of the considered airplane in terms of material selection and/or special coatings. The importance and impact of exhaust jet thrust on the overall aircraft performance are investigated.

Originality/value
The advanced numerical model for the exhaust jet-airplane skin thermal interaction was developed to estimate the temperature effects on the propeller blades and aircraft fuselage surfaces during different flight operating conditions with multiple combinations of stub orientations.