bluuebunny/crossref_metadata_2025_split huggingface dataset:
isGWAS: ultra-high-throughput, scalable and equitable inference of genetic associations with disease
Authors: Foley Christopher N , Kuncheva Zhana , Marioni Riccardo E. , Runz Heiko , Sun Benjamin B 
Published: July 2023

AbstractGenome-wide association studies (GWAS) have proven a powerful tool for human geneticists to generate biological insights or hypotheses for drug discovery. Nevertheless, a dependency on sensitive individual-level data together with ever-increasing cohort sample sizes, numbers of variants and phenotypes studied put a strain on existing algorithms, limiting the GWAS approach from maximising potential. Here we present in-silico GWAS (isGWAS), a uniquely scalable algorithm to infer regression parameters in case-control GWAS from cohort-level summary data. For any sample size, isGWAS computes a variant-disease association parameter in ∼1 millisecond, or ∼11m variants in UK-Biobank within ∼4 minutes (∼1500-fold faster than state-of-the-art). Extensive simulations and empirical tests demonstrate that isGWAS results are highly comparable to traditional regression-based approaches. We further introduce a heuristic re-sampling algorithm, leapfrog re-sampler (LRS), to extrapolate association results to semi-virtually enlarged cohorts. Owing to significant computational gains we anticipate a broad use of isGWAS and LRS which are customizable on a web interface.
Exuberantde novodendritic spine growth in mature neurons
Authors: Krüssel Sarah , Deb Ishana , Son Seungkyu , Ewall Gabrielle , Chang Minhyeok , Lee Hey-Kyoung , Heo Won do , Kwon Hyung-Bae 
Published: July 2023

SUMMARYDendritic spines are structural correlates of excitatory synapses maintaining stable synaptic communications. However, this strong spine-synapse relationship was mainly characterized in excitatory pyramidal neurons (PyNs), raising a possibility that inferring synaptic density from dendritic spine number may not be universally applied to all neuronal types. Here we found that the ectopic expression of H-Ras increased dendritic spine numbers regardless of cortical cell types such as layer 2/3 pyramidal neurons (PyNs), parvalbumin (PV)- and vasoactive intestinal peptide (VIP)-positive interneurons (INs) in the primary motor cortex (M1). The probability of detecting dendritic spines was positively correlated with the magnitude of H-Ras activity, suggesting elevated local H-Ras activity is involved in the process of dendritic spine formation. H-Ras overexpression caused high spine turnover rate via adding more spines rather than eliminating them. Two-photon photolysis of glutamate triggeredde novodendritic spine formation in mature neurons, suggesting H-Ras induced spine formation is not restricted to the early development. In PyNs and PV-INs, but not VIP-INs, we observed a shift in average spine neck length towards longer filopodia-like phenotypes. The portion of dendritic spines lacking key excitatory synaptic proteins were significantly increased in H-Ras transfected neurons, suggesting that these increased spines have other distinct functions. High spine density caused by H-Ras did not result in change in the frequency or the amplitude of miniature excitatory postsynaptic currents (mEPSCs). Thus, our results propose that dendritic spines possess more multifaceted functions beyond the morphological proxy of excitatory synapse.
Hummingbirds use wing inertial effects to improve maneuverability
Authors: Haque Mohammad Nasirul , Cheng Bo , Tobalske Bret W. , Luo Haoxiang 
Published: July 2023

AbstractHummingbirds outperform other birds in terms of aerial agility at low flight speeds. To reveal the key mechanisms that enable such unparalleled agility, we reconstructed body and wing motion of hummingbird escape maneuvers from high-speed videos; then, we performed computational fluid dynamics modeling and flight mechanics analysis, in which each wingbeat was resolved. We found that the birds utilized the inertia of their wings to achieve peak body rotational acceleration within half a wingbeat before the aerodynamic forces became dominant. The aerodynamic forces instead counteracted the reversed inertial forces in the other half wingbeat, thereby to sustain body rotation, albeit at a lower acceleration. Thus, individual wingbeat cycles that generated body rotations can be split into an agility phase with rapid inertial acceleration, and a stability phase with counteracting aerodynamic and inertial acceleration. This mechanism involving inertial steering enables hummingbirds to generate instantaneous body acceleration at any phase of a wingbeat, and it is likely the key to understanding the unique dexterity distinguishing them from aircraft that solely rely on aerodynamics for maneuvering.
Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling
Authors: Hayes Anna M. R. , Lauer Logan Tierno , Kao Alicia E. , Sun Shan , Klug Molly E. , Tsan Linda , Rea Jessica J. , Subramanian Keshav S. , Gu Cindy , Tanios Natalie , Ahuja Arun , Donohue Kristen N. , Décarie-Spain Léa , Fodor Anthony A. , Kanoski Scott E. 
Published: July 2023

AbstractWestern diet (WD) consumption during development yields long-lasting memory impairments, yet the underlying neurobiological mechanisms remain elusive. Here we developed an early life WD rodent model to evaluate whether dysregulated hippocampus (HPC) acetylcholine (ACh) signaling, a pathology associated with memory impairment in human dementia, is causally-related to WD-induced cognitive impairment. Rats received a cafeteria-style WD (access to various high-fat/high-sugar foods; CAF) or healthy chow (CTL) during the juvenile and adolescent periods (postnatal days 26-56). Behavioral, metabolic, and microbiome assessments were performed both before and after a 30-day healthy diet intervention beginning at early adulthood. Results revealed CAF-induced HPC-dependent contextual episodic memory impairments that persisted despite healthy diet intervention, whereas CAF was not associated with long-term changes in body weight, body composition, glucose tolerance, anxiety-like behavior, or gut microbiome. HPC immunoblot analyses after the healthy diet intervention identified reduced levels of vesicular ACh transporter in CAF vs. CTL rats, indicative of chronically reduced HPC ACh tone. To determine whether these changes were functionally related to memory impairments, we evaluated temporal HPC ACh binding via ACh-sensing fluorescent reporterin vivofiber photometry during memory testing, as well as whether the memory impairments could be rescued pharmacologically. Results revealed dynamic HPC ACh binding during object-contextual novelty recognition was highly predictive of memory performance and was disrupted in CAF vs. CTL rats. Further, HPC alpha-7 nicotinic receptor agonist infusion during consolidation rescued memory deficits in CAF rats. Overall, these findings identify dysregulated HPC ACh signaling as a mechanism underlying early life WD-associated memory impairments.
Injectable microcapillary network hydrogels engineered by liquid-liquid phase separation for stem cell transplantation
Authors: Nishiguchi Akihiro , Ito Shima , Nagasaka Kazuhiro , Komatsu Hiyori , Uto Koichiro , Taguchi Tetsushi 
Published: July 2023

AbstractInjectable hydrogels are promising carriers for cell delivery in regenerative medicine. However, injectable hydrogels composed of crosslinked polymer networks are often non porous and prevent biological communication with host tissues through signals, nutrients, oxygen, and cells, thereby limiting graft survival and tissue integration. Here we report injectable hydrogels with liquid-liquid phase separation-induced microcapillary networks (µCN) as stem cell-delivering scaffolds. The molecular modification of gelatin with hydrogen bonding moieties induced liquid-liquid phase separation when mixed with unmodified gelatin to form µCN structures in the hydrogels. Through spatiotemporally controlled covalent crosslinking and dissolution processes, porous µCN structures were formed in the hydrogels, which can enhance mass transport and cellular activity. The encapsulation of cells with injectable µCN hydrogels improved cellular adhesion, spreading, migration, and proliferation. Transplantation of mesenchymal stem cells with injectable µCN hydrogels enhanced graft survival and recovered hindlimb ischemia by enhancing material-tissue communication with biological signals and cells through µCN. This facile approach may serve as an advanced scaffold for improving stem cell transplantation therapies in regenerative medicine.
CysQuant: simultaneous quantification of cysteine oxidation and protein abundance using data dependent or independent acquisition mass spectrometry
Authors: Huang Jingjing , Staes An , Impens Francis , Demichev Vadim , Van Breusegem Frank , Gevaert Kris , Willems Patrick 
Published: July 2023

AbstractProtein cysteinyl thiols are susceptible to reduction-oxidation reactions that can influence protein function. Accurate quantification of cysteine oxidation is therefore crucial for decoding protein redox regulation. Here, we present CysQuant, a novel approach for simultaneous quantification of cysteine oxidation degrees and protein abundancies. CysQuant involves light/heavy iodoacetamide isotopologues for differential labeling of reduced and reversibly oxidized cysteines analyzed by data-dependent acquisition (DDA) or data-independent acquisition mass spectrometry (DIA-MS). Using plexDIA within silicopredicted spectral libraries, we quantified an average of 18% cysteine oxidation inArabidopsis thalianaby DIA-MS, including a subset of highly oxidized cysteines forming disulfide bridges in AlphaFold2 predicted structures. Applying CysQuant to Arabidopsis seedlings exposed to excessive light, we successfully quantified the well-established increased reduction of Calvin-Benson cycle enzymes and discovered yet uncharacterized redox-sensitive disulfides in chloroplastic enzymes. Overall, CysQuant is a highly versatile tool for assessing the cysteine modification status that can be widely applied across various mass spectrometry platforms and organisms.
Ion selectivity and activation mechanism for kalium channelrhodopsins
Authors: Zhang Mingfeng , Shan Yuanyue , Zhao Liping , Li Xiao , Pei Duanqing 
Published: July 2023

SummaryChannelrhodopsins harvest the light and convert photons to the cellular ion flow. The ion selectivity and activation mechanism at the atomic level remains unknown. Here we describe cryo-EM structures forH. catenoideskalium channelrhodopsin (HcKCR1), its paralog, sodium selective channelrhodopsin (HcCCR), an open state ofHcKCR1 (C110T), the voltage-dependent inwardly rectifier (D116N) and higher potassium selective channelrhodopsin (B1ChR2) fromBilabrum sp, illuminating the ion selectivity and activation mechanism. Briefly, the hourglass shaped lumen is occupied by the stepwise dehydrated potassium in both intracellular and extracellular side. The aromatic amino acids likely function as partial dehydrated potassium filter in the extracellular lumen, and intracellular dehydrated ion occupying layer chooses the right size of dehydrated ion, thus specifying ion selectivity and the higher dehydration capacity, the higher potassium selectivity. Furthermore, structural comparison ofHcKCR1 and C110T suggested that the conformational changes of retinal triggers the extracellular side of TM6 extension as well as the retinal interaction residues motion, which then leads to ion flow. Our results not only uncovered the ion selectivity mechanism of potassium or sodium selective channelrhodopsins, but also elucidated their activation mechanism. It may provide a framework for designing next generation optogenetic tools.
The dynamics and geometry of choice in premotor cortex
Authors: Genkin Mikhail , Shenoy Krishna V. , Chandrasekaran Chandramouli , Engel Tatiana A. 
Published: July 2023

ABSTRACTThe brain represents sensory variables in the coordinated activity of neural populations, in which tuning curves of single neurons define the geometry of the population code. Whether the same coding principle holds for dynamic cognitive variables remains unknown because internal cognitive processes unfold with a unique time course on single trials observed only in the irregular spiking of heterogeneous neural populations. Here we show the existence of such a population code for the dynamics of choice formation in the primate premotor cortex. We developed an approach to simultaneously infer population dynamics and tuning functions of single neurons to the population state. Applied to spike data recorded during decision-making, our model revealed that populations of neurons encoded the same dynamic variable predicting choices, and heterogeneous firing rates resulted from the diverse tuning of single neurons to this decision variable. The inferred dynamics indicated an attractor mechanism for decision computation. Our results reveal a common geometric principle for neural encoding of sensory and dynamic cognitive variables.
PIEZO1 force sensing controls global lipid homeostasis
Authors: Lichtenstein Laeticia , Cheng Chew W , Evans Elizabeth L , Gaunt Hannah J , Bartoli Fiona , Chuntharpursat-Bon Eulashini , Patel Shaili , Konstantinou Charalampos , Futers T Simon , Reay Melanie , Parsonage Gregory , Bertrand-Michel Justine , Sukumar Piruthivi , Roberts Lee D , Beech David J 
Published: July 2023

ABSTRACTHow cardiovascular activity beneficially regulates lipid homeostasis is unclear. Here we hypothesise a mechanism in which mechanical force sensed by PIEZO1 ion channels in endothelium links blood flow to lipid regulation. We engineered mice for conditional deletion of PIEZO1 in endothelium and determined consequences for lipid regulation. Prominent are upregulated expression of hepaticCyp7a1and intestinalLdlrgenes, which are pivotal in cholesterol catabolism and excretion. Consistent with such regulation is endothelial PIEZO1-dependence of hepatic, intestinal and whole body cholesterol and bile homeostasis. There is organ perfusion-dependent gene regulation via endothelial PIEZO1 and downstream nitric oxide synthase. Endothelial PIEZO1-deleted mice are protected against hyperlipidaemia and ectopic fat deposition. HumanPIEZO1gene variants and a recapitulated humanPIEZO1gain-of-function variant in mice associate with dyslipidaemia. The data suggest lipid-promoting effects of endothelial force sensing and new opportunity for understanding and addressing problems of hyperlipidaemia.
Repeated Caffeine Intake Suppresses Cerebral Grey Matter Responses to Chronic Sleep Restriction in an A1Adenosine Receptor-Dependent Manner
Authors: Lin Yu-Shiuan , Lange Denise , Baur Diego , Foerges Anna , Chu Congying , Li Changhong , Elmenhorst Eva-Maria , Neumaier Bernd , Bauer Andreas , Aeschbach Daniel , Landolt Hans-Peter , Elmenhorst David 
Published: July 2023

AbstractEvidence has shown that both sleep loss and daily caffeine intake can induce changes in grey matter (GM). Caffeine is frequently used to combat sleepiness and impaired performance caused by insufficient sleep. It is unclear 1) whetherdailyuse of caffeine could prevent or exacerbate the GM alterations induced bychronicsleep restriction, and 2) whether the potential impact on GM plasticity depends on individual differences in the availability of adenosine receptors, which are involved in mediating effects of caffeine on sleep and waking function. In this double-blind, randomized, controlled study, 36 healthy adults (aged 28.9 ± 5.2 y/o; 15 females; habitual daily caffeine intake < 450 mg; 29 homozygous C/C allele carriers of the A2A adenosine receptor (A2AR) gene variant rs5751876 ofADORA2A) underwent a 9-day laboratory visit consisting of one adaption day, 2 baseline days (BL), 5-day sleep restriction (CSR, 5 h time-in-bed), and a recovery day (REC) after an 8-h sleep opportunity. Nineteen participants received 300 mg caffeine in coffee through the 5 days of CSR (CAFF group), while 17 matched participants received decaffeinated coffee (DECAF group). We measured the GM morphology on the 2ndBL Day, 5thCSR Day, and REC Day. Moreover, we used [18F]-CPFPX PET to quantify the baseline availability of A1adenosine receptors (A1R) and their relation to GM plasticity. The voxel-wise multimodal whole-brain analysis on T1-weighted images controlled for variances of cerebral blood flow indicated a significant interaction between caffeine and CSR in four brain regions: 1) right temporal-occipital region, 2) right thalamus, 3) left dorsolateral, and 4) dorsomedial prefrontal region. The post-hoc analyses indicated increased GM intensity in the DECAF group in all four regions but decreased GM in the thalamus as well as dorsolateral and dorsomedial prefrontal regions in the CAFF group after sleep restriction. Furthermore, lower baseline subcortical A1R availability predicted larger reduction in the CAFF group after CSR of all brain regions except for the caffeine-associated thalamic reduction. In conclusion, our data suggest an adaptive upregulation in GM after 5-day CSR, while concomitant use of caffeine instead leads to a GM reduction. The lack of consistent association with individual A1R availability may suggest that CSR and caffeine affect GM plasticity predominantly by a different mechanism. Future studies on the role of adenosine A2Areceptors (ADORA2A) in CSR-induced GM plasticity are warranted.
Prostate Cancer Reshapes the Secreted and Extracellular Vesicle Urinary Proteomes
Authors: Khoo Amanda , Govindarajan Meinusha , Qiu Zhuyu , Liu Lydia Y. , Ignatchenko Vladimir , Waas Matthew , Macklin Andrew , Keszei Alexander , Main Brian P. , Yang Lifang , Lance Raymond S. , Downes Michelle R. , Semmes O. John , Vesprini Danny , Liu Stanley K. , Nyalwidhe Julius O. , Boutros Paul C. , Kislinger Thomas 
Published: July 2023

ABSTRACTUrine is a complex biofluid that reflects both overall physiologic state and the state of the genitourinary tissues through which it passes. It contains both secreted proteins and proteins encapsulated in tissue-derived extracellular vesicles (EVs). To understand the population variability and clinical utility of urine, we quantified the secreted and EV proteomes from 190 men, including a subset with prostate cancer. We demonstrate that a simple protocol enriches prostatic proteins in urine. Secreted and EV proteins arise from different subcellular compartments. Urinary EVs are faithful surrogates of tissue proteomes, but secreted proteins in urine or cell line EVs are not. The urinary proteome is longitudinally stable over several years. It can accurately and non-invasively distinguish malignant from benign prostatic lesions, and can risk-stratify prostate tumors. This resource quantifies the complexity of the urinary proteome, and reveals the synergistic value of secreted and EV proteomes for translational and biomarker studies.
O-GlcNAcylation of Keratin 18 coordinates TCA cycle to promote cholangiocarcinoma progression
Authors: Meng Xiangfeng , Zhou Yue , Xu Lei , Wang Changjiang , Tian Xiao , Zhang Xiang , Hao Yi , Cheng Bo , Wang Lei , Liu Jialin , Xie Ran 
Published: July 2023

SummaryGlycosylation in human cholangiocarcinoma (CCA) actively contributes to pathophysiological steps of tumor progression. Of note is the dynamic modification of proteins byO-linked β-N-acetyl-glucosamine (O-GlcNAcylation) that modulates various tumor-associated biological activities. By using a cutting-edge chemical proteomic methodology for intact glycopeptide analysis, we show herein thatO-GlcNAcylation of Keratin 18 (K18) coordinates the tricarboxylic acid (TCA) cycle enzymes, namely isocitrate dehydrogenases (IDHs), to promote CCA progression. Mechanistically, site-specificO-GlcNAcylation of K18 on Ser 30 stabilizes K18, which benefits the expression of cell cycle checkpoints to enhance cell cycle progression and cell growth. Interaction with IDHs down-regulates the level of citrate and isocitrate, while up-regulates the level of α-ketoglutarate (α-KG). Our study thus expands the current understanding of proteinO-GlcNAcylation, and adds another dimension of complexity to post-translational control over metabolism and tumorigenesis.
Genetic characterization and dissemination ofStaphylococcus aureusand Staphylococci genus: food and health perspective
Authors: Alkuraythi Dalal M. , Alkhulaifi Manal M. , Binjomah Abdulwahab Z. , Alarawi Mohammed , Aldakhil Hind M , Mujallad Mohammed I. , Alharbi Saleh Ali , Alshomrani Mohammed , Alshahrani Saeed Mastour , Gojobori Takashi , Alajel Sluiman M 
Published: July 2023

AbstractHospitals and communities are significant hubs for antibiotic-resistant staphylococcal infections, but recently there have been spread of the Staphylococci to other settings including farms and food chains. This study aimed to compare the methicillin-resistantStaphylococcus aureus(MRSA) isolates from humans and food to understand the genetic characteristics and similarities between the circulating clones across both groups. A total of 250 samples of meat (camel, beef, chicken, fish, and lamb) were collected from different retailers in Riyadh, Saudi Arabia. Culture, and Genomics analysis of the isolates yielded 53S.aureusout of which (42/53; 79%) were methicillin-sensitiveS.aureus(MSSA) and (11/53; 21%) were MRSA in addition to to other Staphylococci. 80 clinically confirmed MRSA isolates were obtained from patients in the same city. The most commonS. aureusclone in patients and retail meat belonged to clonal complex (CC5). In meat, ST6 and ST97 were the most common clones found in (6/11; 54.5%) of MRSA isolates, and ST1153 (9/42; 21.42%), ST672 (7/42; 16.66%) of MSSA isolates. The majority of MRSA isolates in meat carried SCCmectype V, which was observed in (6/11; 54.54%) of isolates. While in patients, ST5 and ST6 were the predominant clones found in (37/80; 46%) of MRSA isolates. The most prevalent SCCmectypes in MRSA isolates from patients were SCCmectype IVa, which was observed in (39/80; 48.7%) of isolates. While there was no MRSA found in beef, camel meat had the highest prevalence of MRSA ST6-t2450 contamination. The other two clones, CC97 and CC361, were the second-most prevalent clones in meat and were relatively common among patients. NovelS. aureuslineages were sequenced and characterized for the first time ST8109 from meat and ST8110 and ST8111 from patients. A structured One Health approach onS. aureusconsidering its dissemination, genetic characterization, antibiotic resistance, and overall impact on food intended for human consumption and its effect on human health is advised.