bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibiotic resistance detection and concomitant species identification of ESKAPE pathogens by proteomics
Authors: Blumenscheit Christian , Pfeifer Yvonne , Werner Guido , John Charlyn , Layer-Nicolaou Franziska , Schneider Andy , Lasch Peter , Doellinger Joerg 
Published: September 2024

AbstractAntimicrobial resistance (AMR) is an increasing challenge for therapy of bacterial infections. Currently, patient treatment is guided by antimicrobial susceptibility testing (AST) using phenotypic assays and species identification by MALDI-ToF biotyping. Bacterial phenotype prediction using omics technologies could offer several advantages over current diagnostic methods. It would allow species identification and AST to be combined in a single measurement, it would eliminate the need for secondary cultivation and could enable the prediction of phenotypes beyond AMR, such as virulence. In this study, the potential of proteomics for clinical microbiology was evaluated in an analysis of 126 clinical isolates covering 16 species including all ESKAPE genera and 29 of the most common AMR determinants. For this purpose, a flexible workflow was developed, which enables to report the AMR phenotype and the species of primary cultures within 2h. Proteomics provided high specificity (99.9%) and sensitivity (94.4 %) for AMR detection, while allowing species identification from very large sequence databases with high accuracy. The results show, that proteomics is well suited for phenotyping clinical bacterial isolates and has the potential to become a valuable diagnostic tool for clinical microbiology in the future.
Modeling Attention and Binding in the Brain through Bidirectional Recurrent Gating
Authors: Salehi Saeed , Lei Jordan , Benjamin Ari S. , Müller Klaus-Robert , Kording Konrad P. 
Published: September 2024

ABSTRACTAttention is a key component of the visual system, essential for perception, learning, and memory. Attention can also be seen as a solution to the binding problem: concurrent attention to all parts of an entity allows separating it from the rest. However, the rich models of attention in computational neuroscience are generally not scaled to real-world problems and there are thus many behavioral and neural phenomena that current models cannot explain. Here, we propose a bidirectional recurrent model of attention that is inspired by the emerging understanding of biological object-based attention and modern neural networks for image segmentation. It conceptualizes recurrent connections as a multi-stage internal gating process where bottom-up connections transmit features, while top-down and lateral connections transmit attentional gating signals. Our model can recognize and segment simple stimuli such as digits as well as objects in natural images and is able to be prompted with object labels, attributes or locations. It can learn to perform a range of behavioral findings, such as object binding, selective attention, inhibition of return, and visual search. It also replicates a variety of neural findings, including increased activity for attended objects, features, and locations, attention-invariant tuning, and relatively late onset attention. Most importantly, our proposed model unifies decades of cognitive and neurophysiological findings of visual attention into a single principled architecture. Our results highlight that the ability to selectively and dynamically focus on specific parts of stimulus streams can help artificial neural networks to better generalize and align with human brains.
Estrogen receptor alpha mediated repression of PRICKLE1 destabilizes REST and promotes uterine fibroid pathogenesis
Authors: McWilliams Michelle M. , Koohestani Faezeh , Jefferson Wendy N. , Gunewardena Sumedha , Shivashankar Kavya , Wertenberger Riley A. , Williams Carmen J. , Rajendra Kumar T. , Chennathukuzhi Vargheese M. 
Published: September 2024

ABSTRACTUterine fibroids (leiomyomas), benign tumors of the myometrial smooth muscle layer, are present in over 75% of women, often causing severe pain, menorrhagia and reproductive dysfunction. The molecular pathogenesis of fibroids is poorly understood. We previously showed that the loss of REST (RE-1SilencingTranscription factor), a tumor suppressor, in fibroids leads to activation of PI3K/AKT-mTOR pathway. We report here a critical link between estrogen receptor alpha (ERα) and the loss of REST,viaPRICKLE1. PRICKLE1 expression is markedly lower in leiomyomas, and the suppression of PRICKLE1 significantly down regulates REST protein levels. Conversely, overexpression of PRICKLE1 resulted in the restoration of REST in cultured primary leiomyoma smooth muscle cells (LSMCs). Crucially, mice exposed neonatally to environmental estrogens, proven risk factors for fibroids, expressed lower levels of PRICKLE1 and REST in the myometrium. Using mice that lack either endogenous estrogen (Lhb-/-mice) or ERα (Esr1-/-mice), we demonstrate thatPrickle1expression in the myometrium is suppressed by estrogen through ERα. Enhancer of zeste homolog 2 (EZH2) is known to participate in the repression of specific ERα target genes. Uterine leiomyomas express increased levels of EZH2 that inversely correlate with the expression of PRICKLE1. Using chromatin immunoprecipitation, we provide evidence for association of EZH2 with thePRICKLE1promoter and for hypermethylation of H3K27 within the regulatory region ofPRICKLE1in leiomyomas. Additionally, siRNA mediated knockdown of EZH2 leads to restoration of PRICKLE1 in LSMCs. Collectively, our results identify a novel link between estrogen exposure and PRICKLE1/REST-regulated tumorigenic pathways in leiomyomas.
Cost-effective solutions for high-throughput enzymatic DNA methylation sequencing
Authors: Longtin Amy , Watowich Marina M. , Sadoughi Baptiste , Petersen Rachel M. , Brosnan Sarah F. , Buetow Kenneth , Cai Qiuyin , Gurven Michael D. , Highland Heather M. , Huang Yi-Ting , Kaplan Hillard , Kraft Thomas S. , Lim Yvonne A. L. , Long Jirong , Melin Amanda D. , Roberson Jamie , Ng Kee-Seong , Stieglitz Jonathan , Trumble Benjamin C. , Venkataraman Vivek V. , Wallace Ian J. , Wu Jie , Snyder-Mackler Noah , Jones Angela , Bick Alexander G. , Lea Amanda J. 
Published: September 2024

ABSTRACTCharacterizing DNA methylation patterns is important for addressing key questions in evolutionary biology, geroscience, and medical genomics. While costs are decreasing, whole-genome DNA methylation profiling remains prohibitively expensive for most population-scale studies, creating a need for cost-effective, reduced representation approaches (i.e., assays that rely on microarrays, enzyme digests, or sequence capture to target a subset of the genome). Most common whole genome and reduced representation techniques rely on bisulfite conversion, which can damage DNA resulting in DNA loss and sequencing biases. Enzymatic methyl sequencing (EM-seq) was recently proposed to overcome these issues, but thorough benchmarking of EM-seq combined with cost-effective, reduced representation strategies has not yet been performed. To do so, we optimized Targeted Methylation Sequencing protocol (TMS)—which profiles ∼4 million CpG sites—for miniaturization, flexibility, and multispecies use at a cost of ∼$80. First, we tested modifications to increase throughput and reduce cost, including increasing multiplexing, decreasing DNA input, and using enzymatic rather than mechanical fragmentation to prepare DNA. Second, we compared our optimized TMS protocol to commonly used techniques, specifically the Infinium MethylationEPIC BeadChip (n=55 paired samples) and whole genome bisulfite sequencing (n=6 paired samples). In both cases, we found strong agreement between technologies (R² = 0.97 and 0.99, respectively). Third, we tested the optimized TMS protocol in three non-human primate species (rhesus macaques, geladas, and capuchins). We captured a high percentage (mean=77.1%) of targeted CpG sites and produced methylation level estimates that agreed with those generated from reduced representation bisulfite sequencing (R² = 0.98). Finally, we applied our protocol to profile age-associated DNA methylation variation in two subsistence-level populations—the Tsimane of lowland Bolivia and the Orang Asli of Peninsular Malaysia—and found age-methylation patterns that were strikingly similar to those reported in high income cohorts, despite known differences in age-health relationships between lifestyle contexts. Altogether, our optimized TMS protocol will enable cost-effective, population-scale studies of genome-wide DNA methylation levels across human and non-human primate species.
SIRT6 loss causes intervertebral disc degeneration in mice by promoting senescence and SASP status
Authors: Ramteke Pranay , Watson Bahiyah , Toci Mallory , Tran Victoria A , Johnston Shira , Tsingas Maria , Barve Ruteja A. , Mitra Ramkrishna , Loeser Richard F. , Collins John A. , Risbud Makarand V. 
Published: September 2024

AbstractIntervertebral disc degeneration is a major risk factor contributing to chronic low back and neck pain. While the etiological factors for disc degeneration vary, age is still one of the most important risk factors. Recent studies have shown the promising role of SIRT6 in mammalian aging and skeletal tissue health, however its role in the intervertebral disc health remains unexplored. We investigated the contribution of SIRT6 to disc health by studying the age-dependent spinal phenotype of mice with conditional deletion ofSirt6in the disc (AcanCreERT2;Sirt6fl/fl). Histological studies showed a degenerative phenotype in knockout mice compared toSirt6fl/flcontrol mice at 12 months which became pronounced at 24 months. RNA-Seq analysis of NP and AF tissues, quantitative histone analysis, andin vitromultiomics employing RNA-seq with ATAC-seq revealed that SIRT6-loss resulted in changes in acetylation and methylation status of specific Histone 3 lysine residues, thereby affecting DNA accessibility and transcriptomic landscape. A decrease in autophagy and an increase in DNA damage were also noted inSirt6-deficient cells. Further mechanistic insights revealed that loss of SIRT6 increased senescence and SASP burden in the disc characterized by increased p21, γH2AX, IL-6, and TGF-β abundance. Taken together our study highlights the contribution of SIRT6 in modulating DNA damage, autophagy and cell senescence, and its importance in maintaining disc health during aging thereby underscoring it as a potential therapeutic target to treat intervertebral disc degeneration.
Applications of some artificial intelligence tools in the drug design of some compounds targeting the main viral protease of the Feline Infectious Peritonitis Virus (FIPV) in cats
Authors: Khan Mohd Yasir , Shah Abid Ullah , Duraisamy Nithyadevi , Moawad Nadine , ElAlaoui Reda Nacif , Cherkaoui Mohammed , Hemida Maged Gomaa 
Published: September 2024

AbstractFeline infectious peritonitis virus (FIPV) is one of cats’ most serious viral infections. The FIPV infection induces a complicated syndrome in the affected cats, including immunosuppression and severe inflammatory conditions. Unfortunately, these vaccines cannot prevent cats from getting infected with these viral infections. There is ongoing research on preparing antiviral therapies against FIPV in cats. However, these are still in clinical trials and have not been fully approved by the drug authorities in many countries, including the USA. Targeting the main viral proteases is one of the promising trends in the drug design of many viral diseases, including coronaviruses. The main goal of the current study was to repurpose and test the efficacy of some known antiviral drugs to treat FIPV infection in cats by targeting the FIPV-main protease enzyme. To achieve these goals, we used the in-silico prediction and molecular docking tools to screen and identify some drugs targeting FIPV-MPro. We used the docking and binding energies as the main parameters for selecting target compounds (FIPV-MPro). Our results show that out of the 15 antiviral and immunomodulatory compounds, the top-ranked inhibitors for the FIPV-Mpro are (Michael acceptor inhibitors (N3), Sofosbuvir, and methotrexate).In conclusion, our results confirmed the potential applications of the predicted FIPV-Mpro inhibitors either independently or in combination with other immune-modulatory compounds. Further in vitro and in vivo studies are encouraged to test the efficacy of these identified compounds as potent inhibitors for the MPro of the FIPV in cats. This study will pave the way for the development of novel drugs that treat FIPV infection in cats.
Selective deuteration of an RNA:RNA complex for structural analysis using small-angle scattering
Authors: Munsayac Aldrex , Leite Wellington C. , Hopkins Jesse B. , Hall Ian , O’Neill Hugh M. , Keane Sarah C. 
Published: September 2024

ABSTRACTThe structures of RNA:RNA complexes regulate many biological processes. Despite their importance, protein-free RNA:RNA complexes represent a tiny fraction of experimentally-determined structures. Here, we describe a joint small-angle X-ray and neutron scattering (SAXS/SANS) approach to structurally interrogate conformational changes in a model RNA:RNA complex. Using SAXS, we measured the solution structures of the individual RNAs in their free state and of the overall RNA:RNA complex. With SANS, we demonstrate, as a proof-of-principle, that isotope labeling and contrast matching (CM) can be combined to probe the bound state structure of an RNA within a selectively deuterated RNA:RNA complex. Furthermore, we show that experimental scattering data can validate and improve predicted AlphaFold 3 RNA:RNA complex structures to reflect its solution structure. Our work demonstrates thatin silicomodeling, SAXS, and CM-SANS can be used in concert to directly analyze conformational changes within RNAs when in complex, enhancing our understanding of RNA structure in functional assemblies.
The landscape ofArabidopsistRNA aminoacylation
Authors: Ceriotti Luis F. , Warren Jessica M. , Virginia Sanchez-Puerta M. , Sloan Daniel B. 
Published: September 2024

ABSTRACTThe function of tRNAs depends on enzymes that cleave primary transcript ends, add a 3′ CCA tail, introduce post-transcriptional base modifications, and charge (aminoacylate) mature tRNAs with the correct amino acid. Maintaining an available pool of the resulting aminoacylated tRNAs is essential for protein synthesis. High-throughput sequencing techniques have recently been developed to provide a comprehensive view of aminoacylation state in a tRNA-specific fashion. However, these methods have never been applied to plants. Here, we treatedArabidopsis thalianaRNA samples with periodate and then performed tRNA-seq to distinguish between aminoacylated and uncharged tRNAs. This approach successfully captured every tRNA isodecoder family and detected expression of additional tRNA-like transcripts. We found that estimated aminoacylation rates and CCA tail integrity were significantly higher on average for organellar (mitochondrial and plastid) tRNAs than for nuclear/cytosolic tRNAs. Reanalysis of previously published human cell line data showed a similar pattern. Base modifications result in nucleotide misincorporations and truncations during reverse transcription, which we quantified and used to test for relationships with aminoacylation levels. We also determined that theArabidopsistRNA-like sequences (t-elements) that are cleaved from the ends of some mitochondrial mRNAs have post-transcriptionally modified bases and CCA-tail addition. However, these t-elements are not aminoacylated, indicating that they are only recognized by a subset of tRNA-interacting enzymes and do not play a role in translation. Overall, this work provides a characterization of the baseline landscape of plant tRNA aminoacylation rates and demonstrates an approach for investigating environmental and genetic perturbations to plant translation machinery.
Causal Associations Between Imaging-derived Phenotypes and Risk of Alzheimer’s Disease and Other Neurodegenerative Disorders: A Mendelian Randomization Study
Authors: Chen Zhichun , Liu Jun , You Yong 
Published: September 2024

ABSTRACTBackgroundAccumulating observational studies have suggested associations between imaging-derived phenotypes (IDPs) and common neurodegenerative disorders, especially Alzheimer’s disease (AD). The goal of this study is to evaluate the causal associations between structural and functional IDPs and 4 neurodegenerative disorders, including AD, Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS).MethodsBidirectional two-sample Mendelian randomization (MR) studies were conducted using summary statistics obtained from genome-wide association studies of 3909 IDPs from UK biobank and 4 neurodegenerative disorders.ResultsForward MR analysis showed that volume of cerebral white matter in the left hemisphere was associated with increased risk of ALS (odds ratio [OR] = 1.15, 95% confidence interval [CI] = 1.09-1.22,P= 3.52 x 10-6). In reverse MR analysis, we revealed genetically determined risk of AD and MS were associated with multiple IDPs (allP< 1.28 x 10-5[0.05/3909], 9 IDPs in AD and 4 IDPs in MS). For example, genetically determined risk of AD was causally associated with reduced volume of gray matter in right ventral striatum (OR = 0.95, 95% CI = 0.93-0.97,P= 4.68 x 10-7) and lower rfMRI amplitudes in several nodes (ICA25 node 9, ICA25 node 8, and ICA100 node 11). Additionally, genetically determined risk of MS was causally associated with reduced volume in left putamen (OR = 0.97, 95% CI = 0.97-0.98,P= 4.47 x 10-7) and increased orientation dispersion index in right hippocampus (OR = 1.03, 95% CI = 1.01-1.04,P= 2.02 x 10-6).ConclusionsOur study suggested plausible causal associations between risk of NDDs and brain IDPs. These findings might hold promise for identifying new disease mechanisms and developing novel preventative therapies for NDDs at the brain imaging levels.
Branched-chain amino acid metabolism is a crucial modulator of cellular senescence
Authors: Aramaki Yuma , Irie Kazuki , Obinata Hideru , Honda Shinya , Horii Takuro , Arakawa Satoko , Tsuchida Aiko , Hoshino Junki , Kobayashi Ryosuke , Izumi Takashi , Hatada Izuho , Shimizu Shigeomi , Minamishima Yoji A. , Konishi Akimitsu 
Published: September 2024

AbstractCellular senescence is a complex stress response that results in the permanent arrest of cell proliferation. The accumulation of senescent cells occurs during aging in living organisms, and contributes to tissue dysfunction. Although there are growing lines of evidence that various metabolic changes occur in senescent cells, the link between cellular metabolism and senescence is not yet fully understood. In this study, we demonstrate that alterations in the metabolism of branched-chain amino acids (BCAAs) play a crucial role in establishing cellular senescence. Furthermore, we identified mitochondrial BCAA transamination as a crucial step in this process. Our findings show that various types of cellular stress lead to a reduction in the expression of BCAA aminotransferase 2 (BCAT2), one of the BCAA catabolic enzymes, resulting in decreased catabolism of BCAAs and reduced synthesis of glutamate. The reduction of BCAA catabolites, together with the consequent limitation in glutathione production from glutamate, triggers cellular senescence. Furthermore, we demonstrate that a reduction in BCAT2 levels alone is sufficient to induce cellular senescence, both in cultured cells and in mice. Additionally, our results demonstrate that aging alters BCAA metabolism in both mice and humans. Our findings provide new insights into the metabolic mechanisms underlying cellular senescence, with a particular focus on the role of BCAAs.
Dark branes for dark matter
Authors: Koutroulis Fotis , Megías Eugenio , Pokorski Stefan , Quirós Mariano 
Published: September 2024

We propose a setup for the origin of dark matter based on spacetime with a warped extra dimension and three branes: the Planck brane, the TeV brane, at a (few) TeV scale ρT, and a dark brane, at a (sub-)GeV scale ρ1≲100  GeV≪ρT. The Standard Model (SM) is localized in the TeV brane, thus solving the Higgs hierarchy problem, while the dark matter χ, a Dirac fermion with mass mχ<ρ1, is localized in the dark brane. The radion, with mass mr<mχ, interacts strongly [∼mχ/ρ1∼O(1)] with dark matter and very weakly (∼mfρ1/ρT2≪1) with the Standard Model matter f. The generic conflict between the bounds on its detection signatures and its proper relic abundance is avoided as dark matter annihilation is p-wave suppressed. The former is determined by its very weak interactions with the SM and the latter by its much stronger annihilation into radions. Therefore, there is a vast range in the dark matter’s parameter space where the correct relic abundance is achieved consistently with the existing bounds. Moreover, for the dark brane with ρ1≲3  GeV, a confinement/deconfinement first order phase transition, where the radion condensates, produces a stochastic gravitational wave background at the nanohertz frequencies, which can be identified with the signal detected by the Pulsar Timing Array (PTA) experiments. In the PTA window, for 0.15≲mχ≲2  GeV the relic abundance is reproduced and all constraints are satisfied.

Published by the American Physical Society
2024
Role of electrostatic doping on the resistance of metal and two-dimensional materials edge contacts
Authors: Brahma Madhuchhanda , Van de Put Maarten L. , Chen Edward , Fischetti Massimo V. , Vandenberghe William G. 
Published: September 2024

In this theoretical study, we compare electrostatically doped metal-transition metal dichalcogenide (TMD) edge-contacts versus substitutionally doped edge-contacts in terms of their contact resistance. Our approach involves the utilization of electrostatic doping achieved by applying back-gate bias to the metal-TMD edge contacts, where carrier injection is primarily governed by the Schottky barrier at the interface. To analyze these contacts, we employ the Wentzel-Kramers-Brillouin (WKB) approximation to calculate the transmission coefficient and use density functional theory (DFT)-derived band structures. We numerically solve the Poisson equation to capture the electrostatic potential. We also account for the impact of the image force using Green's function for the Poisson equation with boundary conditions appropriate to our specific geometry. Our findings reveal that electrostatically doped TMD edge contacts exhibit higher contact resistance compared to impurity-doped edge contacts at equivalent carrier concentrations. At the same time, we find that, among the electrostatically doped edge contacts, a low-κ back-gate oxide in conjunction with low-κ top oxide is preferable in terms of improvement in contact resistance. For instance, in a metal-TMD edge contact scenario involving a monolayer MoS2 as the channel, SiO2 as the infinitely thick top oxide, and a SiO2 back-gate oxide with an equivalent oxide thickness (EOT) of 1nm, we demonstrate that it is possible to achieve an impressively low contact resistance of 50Ωµm when the back-gate bias exceeds or equals 2 V.

Published by the American Physical Society
2024