bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel conceptual model of heart rate autonomic modulation based on a small-world modular structure and heterogeneous innervation of the sinoatrial node
Authors: Maltsev Alexander V , Stern Michael D , Lakatta Edward G , Maltsev Victor A 
Published: August 2023

AbstractThe current theory of cardiac pacemaker rate modulation by the autonomic nervous system is based on the concept that a primary pacemaker cell or a group of cells in the center of the sinoatrial node (SAN) can change its AP firing rate within a broad range, driving respective myocardium contractions to commensurate body demands. Experimental data show, however, that pacemaker cells are extremely heterogeneous, with different areas of the SAN or cell clusters specializing to drive APs at specific rates. Thus, higher heart rates under stress are mainly driven by cell clusters in superior SAN, whereas low rates by cell clusters in inferior SAN, with basal state rates generated somewhere in the middle of the node. Cells within different clusters feature different intrinsic electrophysiological and Ca cycling properties, sympathetic and parasympathetic innervation, and vasculature, thereby supporting effective shift of the system to an optimal rate (under given conditions) accompanied by respective shifts in the leading pacemaker site. Thus, the popular single-cell-based pacemaker theory does not capture this complex emerging paradigm of pacemaker function of SAN tissue revealed by recent experimental studies. Here we propose a more realistic, conceptual model of heart rate autonomic modulation based on these studies. Our new model (the ‘gear model’) simulates the SAN as a brain-like structure featuring a small world of loosely connected clusters (functional modules) of tightly coupled cells, modeled as Maltsev-Lakatta coupled-clock system. One module (the higher chronotropic gear) generates higher AP rates in basal state and under β-adrenergic stimulation, but its activity is strongly suppressed by parasympathetic stimulation. The other module (the lower gear) generates lower rates and has low sensitivity to parasympathetic stimulation. Such modular, gear-like system reproduces the respective shifts of the leading pacemaker site observed experimentally and features a wide range of rate modulation and robust function whilst conserving energy. In perspective, future refinement and application of this new pacemaker tissue mechanism will provide better understanding of cardiac pacemaker function, its deterioration in aging and disease, and ultimately the creation of new therapies to treat sick sinus syndrome and other SAN function-related cardiac arrythmias.
Assessment of emissions and potential occupational exposure to carbon monoxide during biowaste composting
Authors: Sobieraj Karolina , Giez Karolina , Koziel Jacek A. , Białowiec Andrzej 
Published: August 2023

AbstractTo date, only a few studies focused on the carbon monoxide (CO) production during waste composting; all targeted on CO inside piles. Here, the CO net emissions from compost piles and the assessment of worker’s occupational risk of exposure to CO at large-scale composting plants are shown for the first time. CO net emissions were measured at two plants processing green waste, sewage sludge, or undersize fraction of municipal solid waste. Effects of the location of piles (hermetised hall vs. open yard) and turning (before vs. after) were studied. Higher CO net emission rates were observed from piles located in a closed hall. The average CO flux before turning was 23.25 and 0.60 mg‧m−2‧h−1for hermetised and open piles, respectively, while after – 69.38 and 5.11 mg‧m−2‧h−1. The maximum CO net emissions occurred after the compost was turned (1.7x to 13.7x higher than before turning). The top sections of hermetised piles had greater CO emissions compared to sides. Additionally, 5% of measurement points of hermetised piles switched to ‘CO sinks’. The 1-h concentration in hermetised composting hall can reach max. ∼50 mg CO·m−3before turning, and >115 mg CO·m−3after, exceeding the WHO thresholds for a 1-h and 15-min exposures, respectively.
CURCUMIN HAS LOWER IC50 VALUES AGAINST A549 LUNG CANCER CELLS
Authors: Kaçar Sedat , Tomsuk Özlem , Şahintürk Varol 
Published: August 2023

AbstractIn this study, we aimed to determine the toxic effect of curcumin on A549 lung cancer cells and to show how this effect is reflected in morphology. Firstly, the toxic doses of curcumin against A549 lung cancer cells were determined via MTT and neutral red cytotoxicity tests by using the doses of 6.25, 12.5, 25, 50, 100, 200 and 400 µM. The morphological examination was performed using inverted microscope and light microscope with hematoxylin-eosin eosin.As a result, the IC50 dose of curcumin against A549 cells was 33 µM according to MTT cytotoxicity test and 52 µM according to the neutral red cytotoxicity test. When these doses were administered, the rounded and shrunken cells were visible in the inverted microscope, while apoptotic hallmarks such as nucleus condensation, renal nucleus structure and cellular shrinkage were detected in hematoxylin-eosin staining. In conclusion, the low IC50 values of curcumin for 24 hours indicate that curcumin is effective against A549 cells. It has the potential to be used either alone or in combination with other agents in cancer studies in case its low toxic effect on normal was assured.
Environmental effects on reproductive performance in preindustrial women
Authors: Colejo-Durán Lidia , Pelletier Fanie , Dillon Lisa , Gagnon Alain , Bergeron Patrick 
Published: August 2023

AbstractEarly life environments can have long-lasting effects on adult reproductive performance, but disentangling the influence of early and adult life environments on fitness is challenging, especially for long-lived species. Using a detailed dataset spanning over two centuries, we studied how early and adult life environments impact reproductive performance in preindustrial women. We assessed the effect of environmental conditions associated with the parish of birth and the parish where the women had their offspring. We considered resource availability differences between rural, urban, northern, and southern parishes by comparing women who switched environments during their lifetime with those who did not. We found that urban-born women had an earlier age at first reproduction and lower offspring survival to adulthood than rural-born women, while South Québec women had more offspring born than North Québec women. Moreover, switching from urban to rural led to higher offspring survival, while the reverse had the opposite effect. In addition, moving from South to North resulted in fewer offspring born and surviving, whereas moving from North to South had the inverse effect. Finally, women who changed from rural to urban and from South to North had their first child at an older age compared to those who stayed in the same urbanity type. Our study underscores the complex and interactive effects of early and adult life environments on reproductive traits, highlighting the need to consider both when studying environmental effects on reproductive outcomes.
RACER-m Leverages Structural Features for Sparse T Cell Specificity Prediction
Authors: Wang Ailun , Lin Xingcheng , Chau Kevin Ng , Onuchic José N. , Levine Herbert , George Jason T. 
Published: August 2023

AbstractReliable prediction of T cell specificity against antigenic signatures is a formidable task, complicated primarily by the immense diversity of T cell receptor and antigen sequence space and the resulting limited availability of training sets for inferential models. Recent modeling efforts have demonstrated the advantage of incorporating structural information to overcome the need for extensive training sequence data, yet disentangling the heterogeneous TCR-antigen structural interface to accurately predict the MHC-allele-restricted TCR-peptide binding interactions remained challenging. Here, we present RACER-m, a coarse-grained structural template model leveraging key biophysical information from the diversity of publicly available TCR-antigen crystal structures. We find explicit inclusion of structural content substantially reduces the required number of training examples for reliable prediction of TCR-recognition specificity and sensitivity across diverse biological contexts. We demonstrate that our structural model capably identifies biophysically meaningful point-mutants that affect overall binding affinity, distinguishing its ability in predicting TCR specificity of point mutants peptides from alternative sequence-based methods. Collectively, our approach combines biophysical and inferential learning-based methods to predict TCR-peptide binding events using sparse training data. Its application is broadly applicable to studies involving both closely-related and structurally diverse TCR-peptide pairs.
A parametrized two-domain thermodynamic model explains diverse mutational effects on protein allostery
Authors: Liu Zhuang , Gillis Thomas , Raman Srivatsan , Cui Qiang 
Published: August 2023

AbstractNew experimental findings continue to challenge our understanding of protein allostery. Recent deep mutational scanning study showed that allosteric hotspots in the tetracycline repressor (TetR) and its homologous transcriptional factors are broadly distributed rather than spanning well-defined structural pathways as often assumed. Moreover, hotspot mutation-induced allostery loss was rescued by distributed additional mutations in a degenerate fashion. Here, we develop a two-domain thermodynamic model for TetR, which readily rationalizes these intriguing observations. The model accurately captures the in vivo activities of various mutants with changes in physically transparent parameters, allowing the data-based quantification of mutational effects using statistical inference. Our analysis reveals the intrinsic connection of intra- and inter-domain properties for allosteric regulation and illustrate epistatic interactions that are consistent with structural features of the protein. The insights gained from this study into the nature of two-domain allostery are expected to have broader implications for other multidomain allosteric proteins.
Analyses of cell wall synthesis inClostridioides difficilereveal a diversification in cell division mechanisms in endospore-forming bacteria
Authors: Shrestha Shailab , Taib Najwa , Gribaldo Simonetta , Shen Aimee 
Published: August 2023

AbstractCurrent models of bacterial cell division assume that the core synthases of the multiprotein divisome complex, FtsW-FtsI, are the primary drivers of septal peptidoglycan (PG) synthesis. These enzymes are typically encoded in the highly conserved division and cell wall (dcw) cluster and are considered to be universally essential for cell division. Here, we combine bioinformatics analyses with functional characterization in the pathogenClostridioides difficileto show thatdcw-encoded PG synthases have undergone a surprising specialization in the sole endospore-forming phylum, Firmicutes, to fulfill sporulation-specific roles. We describe a novel role for these enzymes in synthesizing septal PG during the sporulation-specific mode of cell division inC. difficile. Although these enzymes are directly regulated by canonical divisome components during this process,dcw-encoded PG synthases and their divisome regulators are unexpectedly dispensable for cell division during normal growth. Instead,C. difficileuses its sole bifunctional class A penicillin-binding protein (aPBP) to drive cell division, revealing a previously unreported role for this class of PG synthases as the core divisome enzyme. Collectively, our findings reveal how the emergence of endosporulation in the Firmicutes phylum was a key driver for the functional repurposing of an otherwise universally conserved cellular process such as cell division. Moreover, they indicate thatC. difficile,and likely other clostridia, assemble a divisome that differs markedly from previously studied bacteria, thus representing an attractive, unique target for therapeutic purposes.
WITHDRAWN: A Survey of CRISPR Across Pectobacterium atrosepticum
Authors: Alahmadi Ramzi Atiah 
Published: August 2023

Withdrawal StatementThe authors have withdrawn their manuscript because permission to publish the genome data has not yet been obtained from the owners. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Distinct modulation of calcium-activated chloride channel TMEM16A by a novel drug-binding site
Authors: Roh Jae Won , Gee Heon Yung , Wainger Brian , Kim Woo Kyung , Lee Wook , Nam Joo Hyun 
Published: August 2023

ABSTRACTTMEM16A is a calcium-activated chloride channel with significant role in multiple cellular processes. Several TMEM16A inhibitors have been identified; however, their binding sites and inhibitory mechanisms remain unclear. Using magnolol and honokiol, the two regioisomeric inhibitors, as chemical probes, we have identified a novel drug-binding site distinct from the pore region, in TMEM16A, which is described here. With electrophysiology, unbiased molecular docking and clustering, molecular dynamics simulations, and experimental validation with mutant cycle analysis, we show that magnolol and honokiol utilize different drug-binding sites, pore and non-pore pockets. The pore blocker utilizes amino acids crucial for chloride passage, whereas the non-pore blocker allosterically modulates the pore residues to hinder ion permeation. Among 17 inhibitors tested, 11 were pore blockers and six were non-pore blockers, indicating the importance of this newly identified non-pore pocket. Our study provides insights into drug-binding mechanism in TMEM16A together with a rationale for future drug development.
Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements
Authors: Umeki Nobuhisa , Kabashima Yoshiyuki , Sako Yasushi 
Published: August 2023

The RAS-MAPK system plays an important role in regulating various cellular processes, including growth, differentiation, apoptosis, and transformation. Dysregulation of this system has been implicated in genetic diseases and cancers affecting diverse tissues. To better understand the regulation of this system, we employed information flow analysis based on transfer entropy (TE) between the activation dynamics of two key elements in cells stimulated with EGF: SOS, a guanine nucleotide exchanger for the small GTPase RAS, and RAF, a RAS effector serine/threonine kinase. TE analysis allows for model-free assessment of the timing, direction, and strength of the information flow regulating the system response. We detected significant amounts of TE in both directions between SOS and RAF, indicating feedback regulation. Importantly, the amount of TE did not simply follow the input dose or the intensity of the causal reaction, demonstrating the uniqueness of TE. TE analysis proposed regulatory networks containing multiple tracks and feedback loops and revealed temporal switching in the reaction pathway primarily responsible for reaction control. This proposal was confirmed by the effects of a MEK inhibitor on TE. Furthermore, TE analysis identified the functional disorder of a SOS mutation associated with Noonan syndrome, a human genetic disease, of which the pathogenic mechanism has not been precisely known yet. TE assessment holds significant promise as a model-free analysis method of reaction networks in molecular pharmacology and pathology.SignificanceIntracellular signal processing relies on intricate regulatory networks composed of various molecular reactions. Ordinary differential equation (ODE) modeling, which proposes the reaction formula and parameter values, is a conventional approach to analyzing the mechanism of reaction networks. In contrast, statistical analyses focus on the correlations among the reactions and complement ODE modeling. Among them, TE analysis is advantageous in dealing with the regulation of the reaction by capturing the dynamics of causality between the reactions. In this study, we analyzed the TE in the cell signaling pathway. The results demonstrate the usefulness of TE assessment as a model-free network analysis method.
Baseline and treatment-emergent bedaquiline resistance in drug-resistant tuberculosis: A systematic review and meta-analysis
Authors: Perumal Rubeshan , Bionghi Neda , Nimmo Camus , Letsoalo Marothi , Cummings Matthew J. , Hopson Madeleine , Wolf Allison , Jubaer Shamim Al , Padayatchi Nesri , Naidoo Kogieleum , Larsen Michelle H. , O’Donnell Max 
Published: August 2023

AbstractRationaleBedaquiline is a novel antimycobacterial agent for drug-resistant tuberculosis (DR-TB) and is classified as a World Health Organization (WHO) Group A drug due to its excellent clinical efficacy, high bactericidal activity, and potent sterilizing effect. Baseline and treatment-emergent bedaquiline resistance have been described but prevalence and incidence have not been reported, leading to gaps in the knowledge required to design strategies to optimize MDR-TB clinical outcomes and prevent the amplification of bedaquiline resistance.MethodsWe performed a systematic review and meta-analysis to estimate the frequency of, and mutations associated with, baseline and acquired (treatment-emergent) bedaquiline resistance in clinicalMtbisolates. Pooled estimates of bedaquiline resistance were generated by proportional meta-analysis in R version 4.2.2 using dmetar, metafor and meta packages. Resistance associated variants associated with prevalent and incident bedaquiline resistance were identified.ResultsData from 14 studies were included; 14 and 9 studies reported on pre-treatment and acquired bedaquiline resistance, respectively. The pooled prevalence of pre-treatment bedaquiline resistance was 2.4% (95% CI 1.7 – 3.5), with significant heterogeneity across all studies (I266%, p<0.01). The pooled prevalence of treatment-emergent bedaquiline resistance was 2.1% (95% CI 1.4 - 3.0), with no significant heterogeneity across the included studies (I20%, p=0.97).DiscussionWe found a concerning frequency of bedaquiline resistance present at baseline and acquired during treatment. Urgent strategies are required to mitigate further resistance to this crucial drug.
Loss of HSC stemness identity is associated with exhaustion and hyporesponsiveness in GATA2 deficiency syndrome
Authors: Largeaud Laetitia , Fregona Vincent , Jamrog Laura , Hamelle Camille , Dufrechou Stéphanie , Prade Naïs , Sellam Esmaa , Enfedaque Pauline , Bayet Manon , Hébrard Sylvie , Bouttier Mathieu , Didier Christine , Delabesse Eric , Gerby Bastien , Pasquet Marlène , Broccardo Cyril 
Published: August 2023

AbstractGermlineGATA2mutations lead to a syndrome involving both immunodeficiency and myeloid malignancies. Since GATA2 is a key player in hematopoietic initiation and development, we specify the impact of these germline mutations on hematopoietic homeostasis by generated a knock-in mouse model expressing the recurrentGata2R396Q missense mutation. These mice exhibit a hematopoietic stem and progenitor cell (HSPC) compartment profoundly impacted with increased HSC number, decreased self-renewal potential and inability to respond to acute inflammatory stimuli. Moreover, mutated HSPCs are predisposed to be hyporesponsive, as evidenced by lower interferon signaling and enrichment of inflammatory stress signatures. Furthermore, a Gata2 allelic specific expression results in a molecular and functional heterogeneity of the mutated Long Term-HSC population. Altogether, we highlight that Gata2 plays a crucial role in the ability of HSCs to perceive and respond to their environment, and that germline mutation contributes to the decline in HSC functionality.
The shape of Cannabis sativa L. seeds for the differentiation of commercial medicinal cultivars from Argentina
Authors: Torne Francisco Fernandez , Bosco Tomas , Idaszkin Yanina L. , Bigatti Gregorio , Garcés Natahiel , Lozada Mariana , González-José Rolando , Márquez Federico 
Published: August 2023

SummaryThe Cannabis sativa L. plant has been used since ancient times as food, a source of fiber, and medicine, resulting in crosses that led to hybridization that currently does not allow for morphological differentiation among the three varieties of the genus (sativa, indica, and ruderalis). Currently, three chemotypes are differentiated based on their cannabinoid content (THC/CBD). Starting in the year 2023, seeds of two contrasting chemotype medicinal cultivars developed by CONICET (National Council for Scientific and Technical Research) and registered with INASE (National Institute of Seeds) can be commercialized in Argentina. In a previous study, we reported a relationship between the shape of Cannabis seeds and the chemical fingerprint associated with the chemotype. The objective of this study is to morphometrically characterize the seeds of two cultivars of Cannabis sativa L. with contrasting chemotypes: type I (high THC) and type III (high CBD). For this purpose, 2D geometric morphometrics based on landmarks and semilandmarks were used, allowing for the independent study of shape and size variation. Seed size between cultivars was compared using univariate statistics of an unbiased size estimator. To understand the magnitude and direction of shape change and determine shape characters that maximize separation between cultivars, a multivariate statistical approach was employed. Seeds belonging to the Malvina cultivar (type I cultivar, THC only) had, on average, smaller size and a rounded shape, whereas seeds from the Pachamama cultivar (type III, high CBD content) had larger size and a tendency towards an elongated oval shape. The use of a discriminant function based on seed shape allowed for over 97% correct assignments between cultivars. Our results could be used for implementing seed shape as a quality and authenticity seal for registered cultivars in the Argentine Cannabis market.
A kinome-wide synthetic lethal CRISPR/Cas9 screen reveals that mTOR inhibition prevents adaptive resistance to CDK4/CDK6 blockade in HNSCC
Authors: Goto Yusuke , Koshizuka Keiichi , Ando Toshinori , Izumi Hiroki , Wu Xingyu , Ford Kyle , Feng Xiaodong , Wang Zhiyong , Arang Nadia , Allevato Michael M. , Kishore Ayush , Mali Prashant , Gutkind J. Silvio 
Published: August 2023

AbstractThe comprehensive genomic analysis of the head and neck cancer (HNSCC) oncogenome revealed frequent loss of p16INK4A(CDKN2A) in most HPV negative HNSCC lesions, often concomitant with amplification of the cyclin D1 (CCND1) gene locus. However, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors as single agents have shown modest effect in the clinic, even when combined with cetuximab. The aberrant activation of PI3K/mTOR pathway is highly prevalent in HNSCC, and recent clinical trials targeting mTOR showed promising results in terms of objective responses and progression free survival. However, the clinical efficacy of mTOR inhibitors (mTORi) for advanced HNSCC patients may be limited due to intrinsic or acquired resistance. By a kinome-wide CRISPR/Cas9 screen, we identified cell cycle inhibition as a synthetic lethal target for mTORi. Combination of mTORi and palbociclib, a CDK4/6 specific inhibitor, showed strong synergism in HNSCC-derived cells in vitro and in vivo. Remarkably, we found that adaptive increase in cyclin E1 (CCNE1) expression upon palbociclib treatment underlies the rapid acquired resistance to this CDK4/6 inhibitor in HNSCC. Mechanistically, mTORi inhibits the formation of eIF4G-CCNE1mRNA complexes, with the consequent reduction in mRNA translation and CCNE1 protein expression. Our findings suggest that concomitant mTOR blockade reverts the adaptive resistance to palbociclib, thereby providing a novel multimodal therapeutic option for HNSCC patients by co-targeting mTOR and CDK4/6. Our findings may have broad implications to halt the emergence of palbociclib resistance.