bluuebunny/crossref_metadata_2025_split huggingface dataset:
Higher-order thalamic nuclei facilitate the generalization and maintenance of spike-and-wave discharges of absence seizures
Authors: Atherton Zoe , Nagy Olivér , Barcsai Lívia , Sere Péter , Zsigri Nikolett , Földi Tamás , Berényi Antal , Crunelli Vincenzo , Lőrincz Magor L. 
Published: December 2022

ABSTRACTSpike-and-wave discharges (SWDs), generated by the cortico-thalamo-cortical (CTC) network, are pathological, large amplitude oscillations and the hallmark of absence seizures (ASs). SWDs begin in a cortical initiation network in both humans and animal models, including the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), where it is located in the primary somatosensory cortex (S1). The behavioral manifestation of an AS occurs when SWDs spread from the cortical initiation site to the whole brain, however, the mechanisms behind this rapid propagation remain unclear. Here we investigated these processes beyond the principal CTC network, in higher-order (HO) thalamic nuclei (lateral posterior (LP) and posterior (PO) nuclei) since their diffuse connectivity and known facilitation of intracortical communications make these nuclei key candidates to support SWD generation and maintenance. In freely moving GAERS, multi-site LFP in LP, PO and multiple cortical regions revealed a novel feature of SWDs: during SWDs there are short periods (named SWD-breaks) when cortical regions far from S1, such the primary visual cortex (V1), become transiently unsynchronized from the ongoing EEG rhythm. Inactivation of HO nuclei with local muscimol injections or optogenetic perturbation of HO nuclei activity increased the occurrence of SWD-breaks and the former intervention also increased the SWD propagation-time from S1. The neural underpinnings of these findings were explored further by silicon probe recordings from single units of PO which uncovered two previously unknown groups of excitatory neurons based on their burst firing dynamics at SWD onset. Moreover, a switch from tonic to burst firing at SWD onset was shown to be an important feature since it was much less prominent for non-generalized events, i.e. SWDs that remained local to S1. Additionally, one group of neurons showed a reverse of this switch during SWD-breaks, demonstrating the importance of this firing pattern throughout the SWD. In summary, these results support the view that multiple HO thalamic nuclei are utilized at SWD onset and contribute to cortical synchrony throughout the paroxysmal discharge.
Sfp1 integrates TORC1 and PKA activity towards yeast ribosome biogenesis
Authors: Vuillemenot Luc-Alban , Ho Franz Y. , Milias-Argeitis Andreas 
Published: December 2022

AbstractTarget of Rapamycin Complex 1 (TORC1) and Protein Kinase A (PKA) are two major regulators of cell growth inSaccharomyces cerevisiae, coupling nutrient availability with resource-intensive anabolic processes such as ribosome biogenesis. Even though TORC1 and PKA signaling converge on several shared targets, little is known on how these targets integrate signals from the two pathways. This is the case for Sfp1, a transcriptional activator of hundreds of ribosomal protein and ribosome biogenesis genes. To disentangle the roles of PKA and TORC1 in Sfp1 regulation, we constructed a large collection of Sfp1 (phospho)mutants and studied their intracellular localization and phosphorylation. Besides the already known TORC1 phosphorylation sites, we discovered that Sfp1 contains two PKA sites and a functional Nuclear Export Signal (NES) which is regulated by TORC1 and PKA. We further showed that TORC1 and PKA regulate Sfp1 phosphorylation independently of each other, with loss of activity of either pathway being sufficient to relocalize the protein from the nucleus to the cytoplasm, and the C-terminal zinc fingers being necessary for the responsiveness of Sfp1 to TORC1 and PKA inputs. This work contributes to our understanding of how cells regulate their growth by monitoring the outputs of multiple nutrient-sensing pathways.
Gut microbiota dysbiosis is associated with altered tryptophan metabolism and dysregulated inflammatory response in severe COVID-19
Authors: Essex Morgan , Pascual-Leone Belén Millet , Löber Ulrike , Kuhring Mathias , Zhang Bowen , Bruening Ulrike , Fritsche-Guenther Raphaela , Krzanowski Marta , Vernengo Facundo Fiocca , Brumhard Sophia , Röwekamp Ivo , Bielecka Agata Anna , Lesker Till Robin , Wyler Emanuel , Landthaler Markus , Mantei Andrej , Meisel Christian , Caesar Sandra , Thibeault Charlotte , Corman Victor , Marko Lajos , Suttorp Norbert , Strowig Till , Kurth Florian , Sander Leif E. , Li Yang , Kirwan Jennifer A. , Forslund Sofia K. , Opitz Bastian 
Published: December 2022

AbstractThe clinical course of the 2019 coronavirus disease (COVID-19) is variable and to a substantial degree still unpredictable, especially in persons who have neither been vaccinated nor recovered from previous infection. We hypothesized that disease progression and inflammatory responses were associated with alterations in the microbiome and metabolome. To test this, we integrated metagenome, metabolome, cytokine, and transcriptome profiles of longitudinally collected samples from hospitalized COVID-19 patients at the beginning of the pandemic (before vaccines or variants of concern) and non-infected controls, and leveraged detailed clinical information and post-hoc confounder analysis to identify robust within- and cross-omics associations. Severe COVID-19 was directly associated with a depletion of potentially beneficial intestinal microbes mainly belonging to Clostridiales, whereas oropharyngeal microbiota disturbance appeared to be mainly driven by antibiotic use. COVID-19 severity was also associated with enhanced plasma concentrations of kynurenine, and reduced levels of various other tryptophan metabolites, lysophosphatidylcholines, and secondary bile acids. Decreased abundance of Clostridiales potentially mediated the observed reduction in 5-hydroxytryptophan levels. Moreover, altered plasma levels of various tryptophan metabolites and lower abundances of Clostridiales explained significant increases in the production of IL-6, IFNγ and/or TNFα. Collectively, our study identifies correlated microbiome and metabolome alterations as a potential contributor to inflammatory dysregulation in severe COVID-19.Graphical Abstract
TheKlebsiella pneumoniae teroperon enhances stress tolerance
Authors: Mason Sophia , Vornhagen Jay , Smith Sara N. , Mike Laura A. , Mobley Harry L.T. , Bachman Michael A. 
Published: December 2022

AbstractHealthcare-acquired infections are a leading cause of disease in patients that are hospitalized or in long-term care facilities.Klebsiella pneumoniae(Kp) is a leading cause of bacteremia, pneumonia, and urinary tract infections in these settings. Previous studies have established that theteroperon, a genetic locus that confers tellurite oxide (K2TeO3) resistance, is associated with infection in colonized patients. Rather than enhancing fitness during infection, theteroperon increases Kp fitness during gut colonization; however, the biologically relevant function of this operon is unknown. First, using a murine model of urinary tract infection, we demonstrate a novel role for theteroperon protein TerC as a bladder fitness factor. To further characterize TerC, we explored a variety of functions, including resistance to metal-induced stress, resistance to ROS-induced stress, and growth on specific sugars, all of which were independent of TerC. Then, using well-defined experimental guidelines, we determined that TerC is necessary for tolerance to ofloxacin, polymyxin B, and cetylpyridinium chloride. We used an ordered transposon library constructed in a Kp strain lacking theteroperon to identify genes required to resist K2TeO3− and polymyxin B-induced stress, which suggested that K2TeO3-induced stress is experienced at the bacterial cell envelope. Finally, we confirmed that K2TeO3disrupts the Kp cell envelope, though these effects are independent ofter. Collectively, the results from these studies indicate a novel role for theteroperon as stress tolerance factor, therefore explaining its role in enhancing fitness in the gut and bladder.
Effect of Potassium Nitrate and Calcium Chloride priming on germination and seedling growth of Honesty (Lunaria annuaL.)
Authors: Bhat Reyaz Ahmad , Khan F U , Bhat Z. A. , Khan F. A. , Wani Javaid Ahmad , Manzar Abu , Nazki I. T , Neelofar  , Altaf Qazi , Masoodi Nasir Hamid 
Published: December 2022

AbstractSeed priming improves seed performance under environmental conditions. The study was designed to evaluate the effect of different priming treatments on the germination behaviour of Honesty (Lunaria annua L.). The experiment was conducted under a complete randomized design (CRD) with three replications. Seed priming was done with different concentrations of calcium chloride (CaCl2), potassium nitrate (KNO3) and hydro priming. All the treatments except T1(Control) had a significant effect on seedling establishment and seedling vigour, Results show that maximum invigoration was observed in seeds primed at 1% KNO3 while minimum invigoration was observed in T1(Control). It was concluded that the germination percentage could be increased by using lower concentrations of KNO3 and CaCl2.
Within-host viral growth and immune response rates predict FMDV transmission dynamics for African Buffalo
Authors: Macdonald Joshua C. , Gulbudak Hayriye , Beechler Brianna , Gorsich Erin E. , Gubbins Simon , Pérez-Martin Eva , Jolles Anna E. 
Published: December 2022

AbstractInfectious disease dynamics operate across biological scales: pathogens replicate within hosts but transmit among populations. Functional changes in the pathogen-host interaction thus generate cascading effects across organizational scales. We investigated within-host dynamics and among-host transmission of three strains (SAT-1, 2, 3) of foot-and-mouth disease viruses (FMDVs) in their wildlife host, African buffalo. We combined data on viral dynamics and host immune responses with mathematical models to ask (i) How do viral and immune dynamics vary among strains?; (ii) Which viral and immune parameters determine viral fitness within hosts?; and (iii) How do within-host dynamics relate to virus transmission? Our data reveal contrasting within-host dynamics among viral strains, with SAT-2 eliciting more rapid and effective immune responses than SAT-1 and SAT-3. Within-host viral fitness was overwhelmingly determined by variation among hosts in immune response activation rates but not by variation among individual hosts in viral growth rate. Our analyses investigating across-scale linkages indicate that viral replication rate in the host correlates with transmission rates among buffalo and that adaptive immune activation rate determines the infectious period. These parameters define the virus’s relative basic reproductive number (ℛ0), suggesting that viral invasion potential may be predictable from within-host dynamics.
Y chromosome sequence and epigenomic reconstruction across human populations
Authors: Esteller-Cucala Paula , Palmada-Flores Marc , Kuderna Lukas F. K. , Fontsere Claudia , Serres-Armero Aitor , Dabad Marc , Torralvo María , Faella Armida , Ferrández-Peral Luis , Llovera Laia , Fornas Oscar , Julià Eva , Ramírez Erika , González Irene , Hecht Jochen , Lizano Esther , Juan David , Marquès-Bonet Tomàs 
Published: December 2022

AbstractRecent advances in long-read sequencing technologies have allowed the generation and curation of more complete genome assemblies, enabling the analysis of traditionally neglected chromosomes, such as the human Y chromosome (chrY). Native DNA was sequenced on a MinION Oxford Nanopore Technologies sequencing device to generate genome assemblies for 7 major chrY human haplogroups. We analyzed and compared the chrY enrichment of sequencing data obtained using two different selective sequencing approaches: adaptive sampling and flow cytometry chromosome sorting. We show that adaptive sampling can produce data to create assemblies comparable to chromosome sorting while being a less expensive and time-consuming technique. We also assessed haplogroup-specific structural variants, which would be otherwise difficult to study using short-read sequencing data only. Finally, we took advantage of this technology to detect and profile epigenetic modifications amongst the considered haplogroups. Altogether, we provide a framework to study complex genomic regions with a simple, fast, and affordable methodology that could be applied to larger population genomics datasets.
Evolution Inspired Engineering of Megasynthetases
Authors: Bozhüyük Kenan A. J. , Präve Leonard , Kegler Carsten , Kaiser Sebastian , Shi Yan-Ni , Kuttenlochner Wolfgang , Schenk Leonie , Mohiuddin T. M. , Groll Michael , Hochberg Georg K. A. , Bode Helge B. 
Published: December 2022

AbstractMany clinically used drugs are derived from or inspired by bacterial natural products that often are biosynthesised via non-ribosomal peptide synthetases (NRPS), giant megasynthases that activate and join individual amino acids in an assembly line fashion. Since NRPS are not limited to the incorporation of the 20 proteinogenic amino acids, their efficient manipulation would allow the biotechnological generation of complex peptides including linear, cyclic and further modified natural product analogues, e.g. to optimise natural product leads. Here we describe a detailed phylogenetic analysis of several bacterial NRPS that led to the identification of a new recombination breakpoint within the thiolation (T) domain that is important for natural NRPS evolution. From this, an evolution-inspired eXchange Unit between T domains (XUT) approach was developed which allows the assembly of NRPS fragments over a broad range of GC contents, protein similarities, and extender unit specificities, as demonstrated for the specific production of a proteasome inhibitor designed and assembled from five different NRPS fragments.
Rhoenhancers play unexpectedly minor roles inRhodopsintranscription and rod cell integrity
Authors: Sun Chi , Ruzycki Philip A. , Chen Shiming 
Published: December 2022

ABSTRACTEnhancers function with a basal promoter to control the transcription of target genes. Enhancer regulatory activity is often studied using reporter-based transgene assays. However, unmatched results have been reported when selected enhancers are silencedin situ. In this study, using genomic deletion analysis in mice, we investigated the roles of two previously identified enhancers and the promoter of theRhogene that codes for the visual pigment rhodopsin. TheRhogene is robustly expressed by rod photoreceptors of the retina, and essential for the subcellular structure and visual function of rod photoreceptors. Mutations inRHOcause severe vision loss in humans. We found that eachRhoregulatory region can independently mediate local epigenomic changes, but only the promoter is absolutely required for establishing activeRhochromatin configuration and transcription and maintaining the cell integrity and function of rod photoreceptors. To our surprise, twoRhoenhancers that enable strong promoter activation in reporter assays are largely dispensable forRhoexpressionin vivo. Only small and age-dependent impact is detectable when both enhancers are deleted. Our results demonstrate context-dependent roles of enhancers and highlight the importance of studying functions ofcis-regulatory regionsin the native genomic context.
Mobile genetic element-encoded putative DNA primases composed of A-family polymerase - SSB pairs
Authors: Rice Phoebe A. 
Published: December 2022

1AbstractMobile genetic elements can encode a wide variety of genes that support their own stability and mobility as well as genes that provide accessory functions to their hosts. Such genes can be adopted from host chromosomes and can be exchanged with other mobile elements. Due to their accessory nature, the evolutionary trajectories of these genes can differ from those of essential host genes. The mobilome therefore provides a rich source of genetic innovation. We previously described a new type of primase encoded byS. aureusSCCmecelements that is composed of an A-family polymerase catalytic domain in complex with a small second protein that confers single-stranded DNA binding. Here we use new structure prediction methods in conjunction with sequence database searches to show that related primases are widespread among putative mobile genetic elements in the Firmicutes. Structure predictions show that the second protein adopts an OB fold (common among single-stranded DNA binding (SSB) proteins) and these predictions were far more powerful than simple sequence comparisons in identifying its homologs. The protein-protein interaction surface varies among these polymerase – SSB complexes and appears to have arisen repeatedly by exploiting partial truncations of the polymerase’s N-terminal accessory domains.
Immortalized bovine satellite cells for cultured meat applications
Authors: Stout Andrew J. , Arnett Miles J. , Chai Kristin M. , Guo Tina , Liao Lishu , Mirliani Addison B. , Rittenberg Miriam L. , Shub Michelle , White Eugene C. , Yuen John S. K. , Zhang Xiaoli , Kaplan David L. 
Published: December 2022

AbstractFor cultured meat to succeed at scale, muscle cells from food-relevant species must be expandedin vitroin a rapid and reliable manner to produce millions of metric tons of biomass annually. Toward this goal, genetically immortalized cells offer substantial benefits over primary cells, including rapid growth, escape from cellular senescence, and consistent starting cell populations for production. Here, we develop genetically immortalized bovine satellite cells (iBSCs) via constitutive expression of bovine Telomerase reverse transcriptase (TERT) and Cyclin-dependent kinase 4 (CDK4). These cells achieve over 120 doublings at the time of publication and maintain their capacity for myogenic differentiation. They therefore offer a valuable tool to the field, enabling further research and development to advance cultured meat.
Determinants of natriuretic, diuretic, and kaliuretic effects of diuretics: Sex and administration time
Authors: Dutta Pritha , Sadria Mehrshad , Layton Anita 
Published: December 2022

AbstractSex differences in renal function and blood pressure have been widely described across many species. Blood pressure dips during sleep and peaks in the early morning. Similarly, glomerular filtration rate, filtered electrolyte loads, urine volume, and urinary excretion all exhibit notable diurnal rhythms, which reflect, in part, the regulation of renal transporter proteins by circadian clock genes. That regulation is sexually dimorphic; as such, sex and time-of-day are not two independent regulators of kidney function and blood pressure. The objective of this study is to assess the effect of sex and administration time on the natriuretic and diuretic effects of loop, thiazide, and K+-sparing diuretics, which are common treatment for hypertension. Loop diuretics inhibit NKCC2 on the apical membrane of the thick ascending limb, thiazide diuretics inhibit NCC on the distal convoluted tubule, and K+-sparing diuretics inhibit ENaC on the connecting tubule and collecting duct. We simulate Na+transporter inhibition using our sex- and time-of-day-specific computational models of mouse kidney function. Simulations results highlight significant sex and time-of day differences in drug response. Loop diuretics induce larger natriuretic and diuretic effects during the active phase. The natriuretic and diuretic effects of thiazide diuretics exhibit sex and time-of-day differences, whereas these effects of K+-sparing diuretics exhibit significant time-of-day difference in females only. Kaliuretic effect depends on the type of diuretics and time of administration. The present computational models can be a useful tool in chronotherapy, to tailor drug administration time to match the body’s diurnal rhythms to optimize the drug effect.
A screen for modulation of nucleocapsid protein condensation identifies small molecules with anti-coronavirus activity
Authors: Quek Rui Tong , Hardy Kierra S. , Walker Stephen G. , Nguyen Dan T. , de Almeida Magalhães Taciani , Salic Adrian , Gopalakrishnan Sujatha M. , Silver Pamela A. , Mitchison Timothy J. 
Published: December 2022

AbstractBiomolecular condensates formed by liquid-liquid phase separation have been implicated in multiple diseases. Modulation of condensate dynamics by small molecules has therapeutic potential, but so far, few condensate modulators have been disclosed. The SARS-CoV-2 nucleocapsid (N) protein forms phase separated condensates that are hypothesized to play critical roles in viral replication, transcription and packaging, suggesting that N condensation modulators might have anti-coronavirus activity across multiple strains and species. Here, we show that N proteins from all seven human coronaviruses (HCoVs) vary in their tendency to undergo phase separation when expressed in human lung epithelial cells. We developed a cell-based high-content screening platform and identified small molecules that both promote and inhibit condensation of SARS-CoV-2 N. Interestingly, these host-targeted small molecules exhibited condensate-modulatory effects across all HCoV Ns. Some have also been reported to exhibit antiviral activity against SARS-CoV-2, HCoV-OC43 and HCoV-229E viral infections in cell culture. Our work reveals that the assembly dynamics of N condensates can be regulated by small molecules with therapeutic potential. Our approach allows for screening based on viral genome sequences alone and might enable rapid paths to drug discovery with value for confronting future pandemics.
Application of the IASP grading system for ‘nociplastic pain’ in chronic pain conditions: A field study
Authors: Schmidt Hannah , Drusko Armin , Renz Malika , Schlömp Lea , Tost Heike , Tesarz Jonas , Schuh-Hofer Sigrid , Meyer-Lindenberg Andreas , Treede Rolf-Detlef 
Published: December 2022

AbstractThe concept ‘nociplastic pain’ has been developed for patients in whom clinical and psychophysical findings suggest a predominant central sensitization type of pain that is not fully explained as nociceptive or neuropathic. Here we tested, how well the recently published grading system differentiates between chronic primary pain or chronic secondary pain conditions. We recruited patients with Fibromyalgia (FMS, 41), Complex Regional Pain Syndrome (CRPS, 11), Osteoarthritis (OA, 21) or Peripheral Nerve Injury (PNI, 8). We used clinical history, pain drawings, Quantitative Sensory Testing (QST) and questionnaires to classify patients’ pains as possibly or probably ‘nociplastic’ in nature.All FMS and CRPS patients exhibited widespread or regional pain that was not explainable by nociceptive nor neuropathic mechanisms. Widespread pain in 12 OA patients was fully explained as nociceptive and regional pain in 4 PNI patients as neuropathic in all but one in each group. QST provided evidence for hypersensitivity in 9/11 CRPS patients but only 27/41 FMS patients (possible ‘nociplastic pain’). 82% of the CRPS patients but only 54% of FMS patients reported a history of hypersensitivity and mental comorbidities (probable ‘nociplastic pain’). We suggest that clinical examination of hypersensitivity should be done in more than one region and that adding a high tender point count as evidence for hypersensitivity phenomena may be useful. Further we suggest to switch the sequence of steps so that self-reported hypersensitivity and comorbidities come before clinical examination of hypersensitivity; Since the ‘nociplastic pain’ concept calls for brainstem and cortical plasticity we discuss in detail potential measurement strategies.