bluuebunny/crossref_metadata_2025_split huggingface dataset:
AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor
Authors: Trepte Philipp , Secker Christopher , Kostova Simona , Maseko Sibusiso B. , Choi Soon Gang , Blavier Jeremy , Minia Igor , Ramos Eduardo Silva , Cassonnet Patricia , Golusik Sabrina , Zenkner Martina , Beetz Stephanie , Liebich Mara J. , Scharek Nadine , Schütz Anja , Sperling Marcel , Lisurek Michael , Wang Yang , Spirohn Kerstin , Hao Tong , Calderwood Michael A. , Hill David E. , Landthaler Markus , Olivet Julien , Twizere Jean-Claude , Vidal Marc , Wanker Erich E. 
Published: June 2023

ABSTRACTProtein-protein interactions (PPIs) offer great opportunities to expand the druggable proteome and therapeutically tackle various diseases, but remain challenging targets for drug discovery. Here, we provide a comprehensive pipeline that combines experimental and computational tools to identify and validate PPI targets and perform early-stage drug discovery. We have developed a machine learning approach that prioritizes interactions by analyzing quantitative data from binary PPI assays and AlphaFold-Multimer predictions. Using the quantitative assay LuTHy together with our machine learning algorithm, we identified high-confidence interactions among SARS-CoV-2 proteins for which we predicted three-dimensional structures using AlphaFold Multimer. We employed VirtualFlow to target the contact interface of the NSP10-NSP16 SARS-CoV-2 methyltransferase complex by ultra-large virtual drug screening. Thereby, we identified a compound that binds to NSP10 and inhibits its interaction with NSP16, while also disrupting the methyltransferase activity of the complex, and SARS-CoV-2 replication. Overall, this pipeline will help to prioritize PPI targets to accelerate the discovery of early-stage drug candidates targeting protein complexes and pathways.
High-resolution mapping of cell cycle dynamics during T-cell development and regenerationin vivo
Authors: Kunze-Schumacher Heike , Verheyden Nikita A. , Grewers Zoe , Meyer-Hermann Michael , Greiff Victor , Robert Philippe A. , Krueger Andreas 
Published: June 2023

AbstractControl of cell proliferation is critical for the lymphocyte life cycle. However, little is known on how stage-specific alterations in cell cycle behavior drive proliferation dynamics during T-cell development. Here, we employedin vivodual-nucleoside pulse labeling combined with determination of DNA replication over time as well as fluorescent ubiquitination-based cell cycle indicator mice to establish a quantitative high-resolution map of cell cycle kinetics of thymocytes. We developed an agent-based mathematical model of T-cell developmental dynamics. To generate the capacity for proliferative bursts, cell cycle acceleration followed a ‘stretch model’, characterized by simultaneous and proportional contraction of both G1 and S phase. Analysis of cell cycle phase dynamics during regeneration showed tailored adjustments of cell cycle phase dynamics. Taken together, our results highlight intrathymic cell cycle regulation as an adjustable system to maintain physiologic tissue homeostasis and foster our understanding of dysregulation of the T-cell developmental program.
Phage predation, disease severity and pathogen genetic diversity in cholera patients
Authors: Madi Naïma , Cato Emilee T. , Sayeed Md. Abu , Creasy-Marrazzo Ashton , Cuénod Aline , Islam Kamrul , Khabir Md. Imam UL. , Bhuiyan Md. Taufiqur R. , Begum Yasmin A. , Freeman Emma , Vustepalli Anirudh , Brinkley Lindsey , Kamat Manasi , Bailey Laura S. , Basso Kari B. , Qadri Firdausi , Khan Ashraful I. , Shapiro B. Jesse , Nelson Eric J. 
Published: June 2023

AbstractDespite an increasingly detailed picture of the molecular mechanisms of phage-bacterial interactions, we lack an understanding of how these interactions evolve and impact disease within patients. Here we report a year-long, nation-wide study of diarrheal disease patients in Bangladesh. Among cholera patients, we quantifiedVibrio cholerae(prey) and its virulent phages (predators) using metagenomics and quantitative PCR, while accounting for antibiotic exposure using quantitative mass spectrometry. Virulent phage (ICP1) and antibiotics suppressedV. choleraeto varying degrees and were inversely associated with severe dehydration depending on resistance mechanisms. In the absence of anti-phage defenses, predation was ‘effective,’ with a high predator:prey ratio that correlated with increased genetic diversity among the prey. In the presence of anti-phage defenses, predation was ‘ineffective,’ with a lower predator:prey ratio that correlated with increased genetic diversity among the predators. Phage-bacteria coevolution within patients should therefore be considered in the deployment of phage-based therapies and diagnostics.One Sentence SummaryA survey of cholera patients in Bangladesh identifies phage predation as a biomarker of disease severity and driver of coevolution within patients.
Analysis of structure-activity and structure-mechanism relationships among thyroid stimulating hormone receptor binding chemicals by leveraging ToxCast library
Authors: Sahoo Ajaya Kumar , Baskaran Shanmuga Priya , Chivukula Nikhil , Kumar Kishan , Samal Areejit 
Published: June 2023

AbstractThyroid stimulating hormone receptor (TSHR) is an integral part of the hypothalamic-pituitary-thyroid axis. Notably, dysregulation in TSHR activation in humans can lead to adverse effects such as Grave’s disease, hypothyroidism and Hashimoto’s disease. Moreover, animal studies have shown that binding of endocrine disrupting chemicals (EDCs) with TSHR can lead to developmental toxicity. Several such chemicals have also been screened for their adverse physiological effects in human cell lines through various high-throughput assays under the ToxCast project. The vast resource of data generated through ToxCast has enabled the development of different toxicity predictors, but they can be limited in their predictive ability due to the heterogeneity in structure-activity relationships among chemicals. In an attempt to explore this heterogeneity, we systematically investigated structure-activity and structure-mechanism relationships among the TSHR binding chemicals from ToxCast. By employing structure-activity similarity (SAS) map, we identified 79 activity cliffs among 509 chemicals in the TSHR agonist dataset and 69 activity cliffs among 650 chemicals in the TSHR antagonist dataset. Further, by using the matched molecular pair (MMP) approach, we find that the resultant activity cliffs (MMP-cliffs) are a subset of activity cliffs identified via the SAS map approach. Moreover, by leveraging ToxCast mechanism of action (MOA) annotations for chemicals common to both TSHR agonist and antagonist datasets, we identified 3 chemical pairs as Strong MOA-cliffs and 19 chemical pairs as Weak MOA-cliffs. In conclusion, the insights from this systematic analysis of the structure-activity as well as the structure-mechanism relationships of TSHR binding chemicals are likely to inform ongoing efforts towards development of better predictive toxicity models for characterizing the chemical exposome.
Characterizing the power spectrum dynamics of the NREM to REM sleep transition
Authors: Serantes Diego , Cavelli Matías , González Joaquín , Mondino Alejandra , Benedetto Luciana , Torterolo Pablo 
Published: June 2023

AbstractThe transition from NREM to REM sleep is considered a transitional or intermediate stage (IS), characterized by high amplitude spindles in the frontal cortex and theta activity in the occipital cortex. Early reports in rats showed an IS lasting from 1 to 5 s, but recent studies suggested a longer duration of this stage. To further characterize the IS, we analyzed its spectral characteristics on electrocorticogram (ECoG) recordings of the olfactory bulb (OB), motor (M1), somato-sensory (S1) and secondary visual cortex (V2) in twelve Wistar male adult rats. By comparing the IS to consolidated NREM/REM epochs, our results reveal that the IS has specific power spectral patterns that statistically differ from both NREM and REM sleep states. Specifically, the main findings were that sigma (11-16 Hz) and beta (17-30 Hz) power in OB, M1, and S1 increased during the IS compared to NREM and REM sleep and began 55 s before REM sleep onset. Additionally, low gamma (31-48 Hz) in the OB started transitioning from NREM levels to REM ones 65 s before its onset. Finally, the high-frequency oscillations (102-198 Hz) in OB, M1, and S1 showed a power increase that began 40 s before REM sleep and reached REM sleep values 10 s after its onset. Thus, we argue that the NREM to REM transition contains its own spectral profile and is more extended than previously described.
An inducible germ cell ablation chicken model for high-grade germline chimeras
Authors: Chen Yi-Chen , Saito Daisuke , Suzuki Takayuki , Takemoto Tatsuya 
Published: June 2023

AbstractChicken embryos are a powerful and widely used animal model in developmental biology studies. After the development of CRISPR technology, gene-edited chickens have been generated by transferring primordial germ cells (PGCs) after genetic modifications. However, the low inheritance caused by the competition between host germ cells and the transferred ones is the most common complication and largely reduces the production efficiency in this way. Here, we generated a gene-edited chicken, in which germ cells can be ablated in a drug-dependent manner, as recipients for gene-edited PGC transfer. We used the nitroreductase/metronidazole (NTR/Mtz) system for cell ablation, in which NTR produces cytotoxic alkylating agents from administered Mtz, causing cell apoptosis. The chicken Vasa homolog (CVH) gene locus is used to drive the expression of the NTR gene in a germ cell-specific manner. In addition, a fluorescent protein gene, mCherry, was also placed in the CVH locus to visualize the PGCs. We named this systemgerm cell-SpecificAutonoMoUsRemovAlInduction (gSAMURAI). gSAMURAI chickens will be an ideal recipient to produce offspring derived from transplanted exogenous germ cells.
Evolutionary engineering a larger porin using a loop-to-hairpin mechanism
Authors: Dhar Rik , Bowman Alexander M. , Hatungimana Brunojoel , Slusky Joanna SG 
Published: June 2023

AbstractIn protein evolution, diversification is generally driven by genetic duplication. The hallmarks of this mechanism are visible in the repeating topology of various proteins. In outer membrane β-barrels, duplication is visible with β-hairpins as the repeating unit of the barrel. In contrast to the overall use of duplication in diversification, a computational study hypothesized evolutionary mechanisms other than hairpin duplications leading to increases in the number of strands in outer membrane β-barrels. Specifically, the topology of some 16- and 18-stranded β-barrels appear to have evolved through a loop to β-hairpin transition. Here we test this novel evolutionary mechanism by creating a chimeric protein from an 18-stranded β-barrel and an evolutionarily related 16-stranded β-barrel. The chimeric combination of the two was created by replacing loop L3 of the 16-stranded barrel with the sequentially matched transmembrane β-hairpin region of the 18-stranded barrel. We find the resulting chimeric protein is stable and has characteristics of increased strand number. This study provides the first experimental evidence supporting the evolution through a loop to β-hairpin transition.HighlightsWe find evidence supporting a novel diversification mechanism in membrane β-barrelsThe mechanism is the conversion of an extracellular loop to transmembrane β-hairpinA chimeric protein modeling this mechanism folds stably in the membraneThe chimera has more β-structure and a larger pore, consistent with a loop-to-hairpin transition
A KDELR-mediated ER retrieval system guides the signaling pathways of UPR and AMPK to maintain cellular homeostasis
Authors: Zhu Mengdan , Fang Zheng , Wu Yifan , Dong Fenfen , Wang Yuzhou , Zheng Fan , Ma Xiaopeng , Ma Shisong , He Jiajia , Hill Donald L. , Liu Xing , Yao Xuebiao , Fu Chuanhai 
Published: June 2023

AbstractKDELR (Erd2 in yeasts) mediates the retrieval of ER-resident proteins from the Golgi apparatus, yet how the KDELR-mediated ER retrieval system is involved in regulating cellular homeostasis has been unclear. Here we report that the loss of the Erd2-mediated ER retrieval system induces the unfolded protein response (UPR) and increases mitochondrial respiration and reactive oxygen species (ROS) in an UPR-dependent manner. Moreover, transcriptomic analysis revealed that expression of the genes involved in mitochondrial respiration and the tricarboxylic acid cycle is enhanced in an UPR-dependent manner in cells lacking Erd2. In cells lacking Erd2, the enhancement of mitochondrial respiration and ROS is required for maintaining cell viability. The loss of the Erd2-mediated ER retrieval system also activates AMPK, and consequently derepresses carbon catabolite repression. Hence, our work establishes a role of the KDELR/Erd2-mediated ER retrieval system in guiding the signalling pathways of AMPK and UPR and underscores the crucial role of the KDELR/Erd2-mediated ER retrieval system in the maintenance of cellular homeostasis.
LRRK2 regulates the activation of the unfolded protein response and antigen presentation in macrophages during inflammation
Authors: Fahmy Ahmed M. , Cannon Tyler , Paredes Camberly Herdandez , Ahmadi Ali , Xu Yong Zhong , Barette Benoit , Ibrahim Maha , Lanoix Joël , Arango-Duque Guillermo , Schurr Erwin , Chevet Eric , Thibault Pierre , Gruenheid Samantha , McBride Heidi , Desjardins Michel 
Published: June 2023

AbstractWhile the contribution of inflammation in the pathological process leading to Parkinson’s disease (PD) is well established, a growing body of evidence supports a role for the long-lasting adaptive immune system in the disease. We showed that, in inflammatory conditions, the PD-proteins PINK1 and Parkin negatively regulate the presentation of mitochondrial antigens on MHC I molecules, a process referred to as MitAP (MitochondrialAntigenPresentation). In the absence of PINK1, over-activation of this pathway in antigen-presenting cells (APCs) engages autoimmune mechanisms leading to the establishment of cytotoxic CD8+T cells. Co-culture of dopaminergic neurons (DNs) with these T cells led to neuronal cell death, suggesting that the MitAP in DNs made them susceptible to T cell-mediated destruction. In the present study, we used a pharmacological and genetic approach to characterize the MitAP pathway at the molecular level. We showed that this antigen presentation pathway is induced in APCs in response to inflammatory signals through the sequential activation of TLR4, cGAS-STING and the Unfolded Protein Response (UPR). A “UPR motif” present on a STING cytoplasmic domain was shown to specifically activate the UPR sensor IRE1. Remarkably, the PD-related protein LRRK2, acted with STING upstream of the UPR to regulate the transition from innate to adaptive immunity, thereby identifying this PD-related protein as a key player in the immune response during inflammation.
Structural alterations in the amygdala and impaired social incentive learning in a mouse model of a genetic variant associated with neurodevelopmental disorders
Authors: Hiramoto Takeshi , Sumiyoshi Akira , Kato Risa , Yamauchi Takahira , Kang Gina , Matsumura Bailey , Stevens Lucas J. , Ryoke Rie , Nonaka Hiroi , Machida Akihiro , Nomoto Kensaku , Mogi Kazutaka , Hiroi Yukiko J. , Kikusui Takefumi , Kawashima Ryuta , Hiroi Noboru 
Published: June 2023

AbstractCopy number variants (CNVs) are robustly associated with psychiatric disorders and their dimensions and changes in brain structures and behavior. However, as CNVs contain many genes, the precise gene-phenotype relationship remains unclear. Although various volumetric alterations in the brains of 22q11.2 CNV carriers have been identified in humans and mouse models, it is unknown how the genes in the 22q11.2 region individually contribute to structural alterations and associated mental illnesses and their dimensions. Our previous studies have identifiedTbx1, a T-box family transcription factor encoded in 22q11.2 CNV, as a driver gene for social interaction and communication, spatial and working memory, and cognitive flexibility. However, it remains unclear howTBX1impacts the volumes of various brain regions and their functionally linked behavioral dimensions. In this study, we used volumetric magnetic resonance imaging analysis to comprehensively evaluate brain region volumes in congenicTbx1heterozygous mice. Our data show that the volumes of anterior and posterior portions of the amygdaloid complex and its surrounding cortical regions were reduced inTbx1heterozygous mice. Moreover, we examined the behavioral consequences of an altered volume of the amygdala.Tbx1heterozygous mice were impaired for their ability to detect the incentive value of a social partner in a task that depends on the amygdala. Our findings identify the structural basis for a specific social dimension associated with loss-of-function variants ofTBX1and 22q11.2 CNV.
Interstage flow matrices: population statistic derived from matrix population models
Authors: Yokomizo Hiroyuki , Fukaya Keiichi , Lambrinos John G. , Kawai Yuka , Takada Takenori 
Published: June 2023

AbstractMany population statistics describe the characteristics of populations within and among species. These are useful for describing population dynamics, understanding how environmental factors alter demographic patterns, testing hypotheses related to the evolution of life history characteristics, and informing the effective management of populations.In this study, we propose a population statistic: the interstage flow. The interstage flow is defined as the product of the element in theith row, thejth column of the population projection matrix, and thejth element of the normalized stable stage distribution.The sum of the interstage flow matrix elements is equal to the population growth rate, which is the dominant eigenvalue of the population projection matrix. The interstage flow matrix elements allow decomposition of population growth rate into component contributions made by transitions between developmental stages.We demonstrate the utility of interstage flow matrices using matrix population models from the COMPADRE plant matrix database. We compared interstage flows among four life history/functional groups (semelparous herbs, iteroparous herbs, shrubs, and trees) and described how population growth rate reflected individual transitions related to stasis, fecundity, and growth. We found that the individual flows are different among functional groups.Synthesis:The proposed population statistic, the interstage flow matrix, describes the contribution of individual developmental stage transitions to the population growth rate. The flow of individuals between developmental stages differs in distinctive ways among different life histories and functional groups. The interstage flow matrix is a valuable statistic for describing these differences.
Spatially clustered neurons encode vocalization categories in the bat midbrain
Authors: Lawlor Jennifer , Wohlgemuth Melville J. , Moss Cynthia F. , Kuchibhotla Kishore V. 
Published: June 2023

AbstractRapid categorization of vocalizations enables adaptive behavior across species. While categorical perception is thought to arise in the neocortex, humans and other animals could benefit from functional organization of ethologically-relevant sounds at earlier stages in the auditory hierarchy. Here, we developed two-photon calcium imaging in the awake echolocating bat (Eptesicus fuscus)to study encoding of sound meaning in the Inferior Colliculus, which is as few as two synapses from the inner ear. Echolocating bats produce and interpret frequency sweep-based vocalizations for social communication and navigation. Auditory playback experiments demonstrated that individual neurons responded selectively to social or navigation calls, enabling robust population-level decoding across categories. Strikingly, category-selective neurons formed spatial clusters, independent of tonotopy within the IC. These findings support a revised view of categorical processing in which specified channels for ethologically-relevant sounds are spatially segregated early in the auditory hierarchy, enabling rapid subcortical organization of call meaning.
Effectiveness of filtering or decontaminating air to reduce or prevent respiratory infections: A systematic review
Authors: Brainard Julii , Jones Natalia R. , Swindells Isabel Catalina , Archer Elizabeth J. , Kolyva Anastasia , Letley Charlotte , Pond Katharine , Lake Iain R. , Hunter Paul R. 
Published: June 2023

AbstractBACKGROUNDInstallation of technologies to remove or deactivate respiratory pathogens from indoor air is a plausible non-pharmaceutical disease control strategy.METHODSWe undertook a systematic review of observational and experimental studies, published 1970-2022, to synthesise evidence about the effectiveness of suitable indoor air treatment technologies to prevent respiratory or gastrointestinal infections. We searched for data about infection and symptom outcomes for persons who spent minimum 20 hours/week in shared indoor spaces subjected to air treatment strategies hypothesised to change risk of respiratory or gastrointestinal infections or symptoms.RESULTSPooled data suggested no net benefits for symptom severity or symptom presence, in absence of confirmed infection. There was weak evidence that air treatment technologies tended to reduce confirmed infections, but these data evinced strong publication bias.CONCLUSIONAlthough environmental and surface samples are reduced after air treatment by several air treatment strategies, especially germicidal lights and high efficiency particulate air filtration, robust evidence has yet to emerge to confirm that these technologies are effective in real world settings. Data from several relevant randomised trials have yet to report and will be welcome to the evidence base.
Guanine-containing ssDNA and RNA induce dimeric and tetrameric SAMHD1 in cryo-EM and binding studies
Authors: Orris Benjamin , Sung Min Woo , Bhat Shridhar , Xu Yingrong , Huynh Kevin W. , Han Seungil , Johnson Darren C. , Bosbach Benedikt , Shields David J. , Stivers James T. 
Published: June 2023

ABSTRACTThe dNTPase activity of tetrameric SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) plays a critical role in cellular dNTP regulation. SAMHD1 also associates with stalled DNA replication forks, DNA repair foci, ssRNA, and telomeres. The above functions require nucleic acid binding by SAMHD1, which may be modulated by its oligomeric state. Here we establish that the guanine-specific A1 activator site of each SAMHD1 monomer is used to target the enzyme to guanine nucleotides within single-stranded (ss) DNA and RNA. Remarkably, nucleic acid strands containing a single guanine base induce dimeric SAMHD1, while two or more guanines with ∼20 nucleotide spacing induce a tetrameric form. A cryo-EM structure of ssRNA-bound tetrameric SAMHD1 shows how ssRNA strands bridge two SAMHD1 dimers and stabilize the structure. This ssRNA-bound tetramer is inactive with respect to dNTPase and RNase activity.