bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influenza A Viral Burst Size from Thousands of Infected Single Cells Using Droplet Quantitative PCR (dqPCR)
Authors: Zath Geoffrey K. , Thomas Mallory M. , Loveday Emma Kate , Bikos Dimitri A. , Sanche Steven , Ke Ruian , Brooke Christopher B. , Chang Connie B. 
Published: February 2024

AbstractAn important aspect of how viruses spread and infect is the viral burst size, or the number of new viruses produced by each infected cell. Surprisingly, this value remains poorly characterized for influenza A virus (IAV), commonly known as the flu. In this study, we screened tens of thousands of cells using a microfluidic method called droplet quantitative PCR (dqPCR). The high-throughput capability of dqPCR enabled the measurement of a large population of infected cells producing progeny virus. By measuring the fully assembled and successfully released viruses from these infected cells, we discover that the viral burst sizes for both the seasonal H3N2 and the 2009 pandemic H1N1 strains vary significantly, with H3N2 ranging from 101to 104viruses per cell, and H1N1 ranging from 101to 103viruses per cell. Some infected cells produce average numbers of new viruses, while others generate extensive number of viruses. In fact, we find that only 10% of the single-cell infections are responsible for creating a significant portion of all the viruses. This small fraction produced approximately 60% of new viruses for H3N2 and 40% for H1N1. On average, each infected cell of the H3N2 flu strain produced 709 new viruses, whereas for H1N1, each infected cell produced 358 viruses. This novel method reveals insights into the flu virus and can lead to improved strategies for managing and preventing the spread of viruses.Author summaryViruses infect and exploit host cells to reproduce and spread. The viral burst size, or the number of viral particles released from an infected cell, plays a critical role in understanding infection dynamics and overall viral fitness. However, accurately determining burst size for many single cells using conventional laboratory methods can be challenging. Here, we introduce dqPCR, a droplet microfluidic method for the rapid measurement of influenza virus numbers produced by thousands of individual cells. Our findings revealed that only a small proportion of infected cells are responsible for producing a significant portion of the total viral population. By utilizing this method in future studies, we can gain a deeper understanding of the role of diversity in rapidly evolving viruses.
Chlorpromazine inhibits EAG1 channels by altering the coupling between the PAS, CNBH and pore domains
Authors: Ghorbani Mahdi , Wang Ze-Jun , Chen Xi , Tiwari Purushottam B. , Klauda Jeffery B. , Brelidze Tinatin I. 
Published: February 2024

ABSTRACTEAG1 depolarization-activated potassium selective channels are important targets for treatment of cancer and neurological disorders. EAG1 channels are formed by a tetrameric subunit assembly with each subunit containing an N-terminal Per-Arnt-Sim (PAS) domain and C-terminal cyclic nucleotide-binding homology (CNBH) domain. The PAS and CNBH domains from adjacent subunits interact and form an intracellular tetrameric ring that regulates the EAG1 channel gating, including the movement of the voltage sensor domain (VSD) from closed to open states. Small molecule ligands can inhibit EAG1 channels by binding to their PAS domains. However, the allosteric pathways of this inhibition are not known. Here we show that chlorpromazine, a PAS domain small molecule binder, alters interactions between the PAS and CNBH domains and decreases the coupling between the intracellular tetrameric ring and the pore of the channel, while having little effect on the coupling between the PAS and VSD domains. In addition, chlorpromazine binding to the PAS domain did not alter Cole-Moore shift characteristic of EAG1 channels, further indicating that chlorpromazine has no effect on VSD movement from the deep closed to opened states. Our study provides a framework for understanding global pathways of EAG1 channel regulation by small molecule PAS domain binders.
Anti-viral defense by an ADP-ribosyltransferase that targets mRNA to block translation
Authors: Vassallo Christopher N. , Doering Christopher R. , Laub Michael T. 
Published: February 2024

AbstractHost-pathogen conflicts are crucibles of molecular innovation. Selection for immunity to pathogens has driven the evolution of sophisticated immunity mechanisms throughout biology, including in bacteria that must evade their viral predators known as bacteriophages. Here, we characterize a widely distributed anti-phage defense system, CmdTAC, that provides robust defense against infection by the T-even family of phages. Our results support a model in which CmdC detects infection by sensing viral capsid proteins, ultimately leading to the activation of a toxic ADP-ribosyltransferase effector protein, CmdT. We show that newly synthesized capsid protein triggers dissociation of the chaperone CmdC from the CmdTAC complex, leading to destabilization and degradation of the antitoxin CmdA, with consequent liberation of the CmdT ADP-ribosyltransferase. Strikingly, CmdT does not target a protein, DNA, or structured RNA, the known targets of other ADP-ribosyltransferases. Instead, CmdT modifies the N6 position of adenine in GA dinucleotides within single-stranded RNAs leading to arrest of mRNA translation and the inhibition of viral replication. Our work reveals a new mechanism of anti-viral defense and a previously unknown but broadly distributed class of ADP-ribosyltransferases that target mRNA.
Not only ClpC1 but also ClpX are drug targets of Ilamycins
Authors: Gao Yamin , Fang Cuiting , Zhou Biao , Hameed H.M. Adnan , Sun Changli , Tian Xirong , He Jing , Han Xingli , Zhang Han , Li Jun , Ju Jianhua , Chen Xinwen , Zhong Nanshan , Ma Junying , Xiong Xiaoli , Zhang Tianyu 
Published: February 2024

AbstractThe mycobacterial caseinolytic protease (Clp) system has been recognized as a promising therapeutic target. A group of natural cyclic peptides including ilamycins, are traditionally thought to target the ClpC1 component of the ClpC1P1P2 proteasome. However, our study reveals that not only ClpC1 but also ClpX can be targeted by ilamycins. Specifically, ilamycin E (ILE) and ilamycin F (ILF) demonstrated superior delayed mycobactericidal activities compared to other ilamycin components. We identified a unique mutation inclpXand a novel insertion inclpC1, both of which confer resistance to ILE and ILF in mycobacteria, as confirmed through gene editing. Crucially, we found that ILE significantly disrupts the proteolytic functions of both the ClpXP1P2 and ClpC1P1P2 complexes. This is the first report highlighting ClpX as a critical target for mycobacterial killing, alongside ClpC1. Our findings emphasize the potential of ilamycins to target multiple components of the Clp protease system, offering a novel dual-target strategy for combating mycobacterial infections.
Preference for and resistance to a toxic sulfur volatile opens up a unique niche inDrosophila busckii
Authors: Mahadevan Venkatesh Pal , Galagovsky Diego , Knaden Markus , Hansson Bill S. 
Published: February 2024

AbstractThe ability to tolerate otherwise toxic compounds can open up unique niches in nature. Among drosophilid flies few examples of such adaptations are known and then typically from highly host specific species. Here we show that the human commensalDrosophila busckiiuses dimethyldisulfide (DMDS) as a key mediator in its host selection. Despite DMDS’s neurotoxic properties1,D. busckiihas evolved tolerance towards high concentrations and uses the compound as an olfactory cue to pinpoint food and oviposition sites. This adaptability is likely linked to an insensitive cytochrome c oxidase (COX), a DMDS target in other insects. Our findings positionD. busckiias a potential model for studying resistance to toxic gases affecting COX and offer valuable insights into evolutionary adaptations within specific ecological contexts.
Decoding the role of DNA sequence on protein-DNA co-condensation
Authors: Singh Rohit Kumar , Swain Pinaki , Ganji Mahipal , Choubey Sandeep 
Published: February 2024

AbstractThe eukaryotic genome is organized within the cell nucleus through three-dimensional compaction. The physical principles that govern genome organizationin vivoremain less understood. Phase separation of protein and DNA has emerged as an attractive mechanism for reshaping chromatin and compacting the genome.In vitrostudies have shed light on the biophysical principles of protein-DNA condensates driven by protein-protein and protein-DNA interactions. However, the role of DNA sequence and its impact on protein-DNA condensation remains elusive. Guided by experiments, this paper presents a simple polymer-based model of protein-mediated DNA condensation that explicitly incorporates the influence of DNA sequence on protein binding. Using coarse-grained Brownian dynamics simulations, we demonstrate that, in the case of a homogeneous DNA, only one condensate forms in equilibrium. In sharp contrast, DNA sequence heterogeneity can result in the coexistence of multiple condensates, giving rise to the formation of structures resembling pearl-necklaces. Interestingly, we observe that protein binding affinity of interfacial DNA governs the capillary forces arising from the protein-DNA condensates. To demonstrate the usefulness of our modeling framework, we compare the simulation results against published data for co-condensation of Dps, Sox2, and HP1. We find that while Dps exhibits sequence-independent binding, DNA sequence heterogeneity dictates the co-condensation of Sox2 and HP1 with DNA. Overall, the framework developed here can be harnessed to gain mechanistic insights into the role of DNA sequence on protein-DNA co-condensation and pave the way for developing a deeper understanding of genome organisation.
Characterization of the microbiome ofAedes albopictuspopulations in different habitats from Spain and São Tomé: implications for vector control
Authors: Melo Tiago , Sousa Carla Alexandra , Delacour-Estrella Sarah , Bravo-Barriga Daniel , Seixas Gonçalo 
Published: February 2024

AbstractThe mosquito microbiome significantly influences vector competence, including inAedes albopictus, a globally invasive ectoparasite. Describing the microbiome andWolbachiastrains ofAe. albopictusfrom different regions can guide area-specific control strategies. Mosquito samples from Spain and São Tomé were analyzed using 16S rRNA gene sequencing and metagenomic sequencing.Wolbachiainfection was genotyped, and statistical analysis compared infection patterns by sex and population. Results revealed a dominance of dualWolbachiainfections in the microbiome of both populations ofAe. albopictus, especially among females. The two populations presented a shared microbiome, although 5 and 9 other genera were only present in Spain and São Tomé populations, respectively. Genera likePelomonasandNevskiawere identified for the first time inAedesmosquitoes. This study is the first to describe theAe. albopictusbacteriome in Spain and São Tomé, offering insights for the development of targeted mosquito control strategies.
Code for Collagen Folding Deciphered
Authors: Malcor Jean-Daniel , Ferruz Noelia , Romero-Romero Sergio , Dhingra Surbhi , Sagar Vamika , Jalan Abhishek A. 
Published: February 2024

AbstractCollagen triple helix folds in two steps: nucleation of three polypeptides at the C-termini followed by zip-chain like propagation. The triple helices found in all domains of life as well as viruses contain upto 6000 amino acids in each polypeptide that are also frequently interrupted with non-helical sequences that disrupt folding and reduce stability. Given the length of polypeptide and the disruptive interruptions, compensating mechanisms that stabilize against local unfolding during propagation and offset the entropic cost of folding the long polypeptides are not fully understood. Here, we show that the information for correct folding of collagen triple helices is encoded in their sequence as interchain electrostatic interactions. In case of humans, disrupting these interactions causes severe to lethal diseases.Key ResultCollagen triple helices found in all the three domains of life as well as viruses have converged on similar mechanism to fold correctly.
A Prediction Model of PTSD in the Israeli Population in the Aftermath of October 7th, 2023, Terrorist Attack and the Israel-Hamas War
Authors: Katsoty Dana , Greidinger Michal , Neria Yuval , Segev Aviv , Lurie Ido 
Published: February 2024

ABSTRACTBackgroundOn October 7th, 2023, a mass terror attack was launched by Hamas militants, which was followed by the Israel-Hamas war. These events constitute a nationwide trauma with major ramifications for public mental health. This article presents an evidence-based model for the prediction of the prevalence of posttraumatic stress disorder (PTSD) related to the terrorist attack and the war.Main bodyThe creation of the model consisted of several steps. Firstly, the Israeli population was divided into six groups based on the intensity, context, and type of traumatic exposure (direct exposure to terror, close proximity to terror, soldiers in combat and support units, intense exposure to rocket attacks, moderate exposure to rocket attacks, and indirectly affected communities), and the population size of each group was assessed using official national databases. Secondly, an estimation of the expected prevalence of PTSD in each of the exposure groups was based on a review of the relevant literature. A random-effects meta-analysis of the prevalence rates was conducted separately per each exposure group. Finally, the predicted number of PTSD causalities in the population was calculated by multiplying the group size and the PTSD prevalence estimation. Based on population size and estimated PTSD prevalence within each exposure category, the model predicts that approximately 5.3% (N=519,923) of the Israeli population (95% prediction interval, 160,346-879,502), may develop PTSD as a result of the terrorist attack and the war.ConclusionsThe predicted number of individuals with PTSD following mass trauma is expected to be considerable. The presented model can assist policymakers, clinicians, and researchers in preparing and devising adequate interventions for the mental health needs of large populations. Moreover, this model can be applied in other instances of mass-trauma exposure.
Telemedicine’s Impact on Diabetes Care during the COVID-19 Pandemic: A Cohort Study in a Large Integrated Healthcare System
Authors: Patel Reysha , Huang Jie , Hsueh Loretta , Gopalan Anjali , Millman Andrea , Franklin Isabelle , Reed Mary 
Published: February 2024

ABSTRACTIntroductionTo examine if patients exposed to primary care telemedicine (telephone or video) early in the COVID-19 pandemic had higher rates of downstream HbA1cmeasurement and improved HbA1clevels in the second year of the pandemic.Research Design and MethodsIn a cohort of 242, 848 Kaiser Permanente Northern California patients with diabetes, we examined associations between early-pandemic patient-initiated telemedicine visit and downstream HbA1cmonitoring and results during the second year of the pandemic.ResultsAdjusted HbA1cmeasurement rates were significantly higher among patients with telemedicine exposure in the early-pandemic prior year than those with no visits in the prior year (91.0% testing for patients with video visits, 90.5% for telephone visits, visits, 86.7% for no visits,p< 0.05). Among those with HbA1cmeasured, the rates of having an HbA1c< 8% in the second year of the COVID-19 pandemic were also statistically significantly higher among patients with telemedicine exposure in the early-pandemic prior year than those with no visits in the prior year (68.5% with HbA1c< 8% for video visits, 67.3% for telephone visits, 66.6% for no visits,p< 0.05).ConclusionsAccess to telephone and video telemedicine throughout the early COVID-19 pandemic was associated with patients’ continued engagement in recommended diabetes care. Although our study analyzed telemedicine use during a pandemic, telemedicine visits may continue to support ongoing health care access and positive clinical outcomes.KEY MESSAGESThe pandemic significantly increased telemedicine adoption, providing an opportunity to maintain health care access for patients with diabetes. Our study investigates the impact of telemedicine, including both telephone and video visits, on diabetes care during the early COVID-19 period. The results demonstrate that patients utilizing telemedicine exhibit higher rates of HbA1cmeasurement and at-goal HbA1c. These findings suggest that telemedicine can be a valuable tool in supporting clinical outcomes in the management of chronic health conditions.
The association of ethnicity and oncologic outcomes for oral cavity squamous cell carcinoma (OSCC)
Authors: Mahboubi Kiana , Nakoneshny Steven C. , Sauro Khara , Roberts Samuel , Hart Rob , Matthews T Wayne , Dort Joseph , Chandarana Shamir P 
Published: February 2024

AbstractObjectiveTo compare oncologic outcomes of South Asian (SA) patients treated at a regional cancer centre in Canada, for oral squamous cell carcinoma (OSCC), to the general population.MethodsAdult patients who underwent primary surgical resection of OSCC +/- adjuvant treatment between 2009 and 2022 (N=697) were included. SA patients were identified using a validated method and compared to non-SA patients. Baseline characteristics, including betel nut consumption, were compared, and disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using Kaplan-Meier methods, with median follow-up time of 36.4 months [SD 31.02]. Cox proportional hazard regression models adjusted for potential confounders. A p-value < 0.05 was considered statistically significant.ResultsSA patients (9% of cohort, n = 64) were significantly younger and had lower rates of smoking and alcohol consumption compared to non-SA patients. There were no differences in tumor characteristics or the use of adjuvant radiation. SA patients had a two-fold higher risk of recurrence and significantly worse disease-specific survival, even after adjusting for stage and high-risk features [RFS: HR 2.01(1.28 - 3.14), DSS: HR 1.79(1.12 - 2.88)]. The consumption of betel nut was not associated with outcomes.ConclusionTo our knowledge, this study is the first to compare the oncological outcomes of SA patients with OSCC to non-SA patients. SA patients had significantly worse outcomes, even after controlling for known predictors of recurrence and disease-specific survival. These findings can inform personalized treatment decisions and influence public health policies when managing patients with different ethnic backgrounds.
Continuous-Time and Dynamic Suicide Attempt Risk Prediction with Neural Ordinary Differential Equations
Authors: Sheu Yi-han , Simm Jaak , Wang Bo , Lee Hyunjoon , Smoller Jordan W. 
Published: February 2024

ABSTRACTSuicide is one of the leading causes of death in the US, and the number of attributable deaths continues to increase. Risk of suicide-related behaviors (SRBs) is dynamic, and SRBs can occur across a continuum of time and locations. However, current SRB risk assessment methods, whether conducted by clinicians or through machine learning models, treat SRB risk as static and are confined to specific times and locations, such as following a hospital visit. Such a paradigm is unrealistic as SRB risk fluctuates and creates time gaps in the availability of risk scores. Here, we develop two closely related model classes, Event-GRU-ODE and Event-GRU-Discretized, that can predict the dynamic risk of events as a continuous trajectory based on Neural ODEs, an advanced AI model class for time series prediction. As such, these models can estimate changes in risk across the continuum of future time points, even without new observations, and can update these estimations as new data becomes available. We train and validate these models for SRB prediction using a large electronic health records database. Both models demonstrated high discrimination performance for SRB prediction (e.g., AUROC > 0.92 in the full, general cohort), serving as an initial step toward developing novel and comprehensive suicide prevention strategies based on dynamic changes in risk.
Taxonomic distribution of SbmA/BacA and BacA-like antimicrobial peptide transporters suggests independent recruitment and convergent evolution in host-microbe interactions
Authors: Smith Nicholas T. , Boukherissa Amira , Antaya Kiera , Howe Graeme W. , Rodríguez de la Vega Ricardo C , Shykoff Jacqui A. , Alunni Benoît , diCenzo George C. 
Published: February 2024

ABSTRACTSmall, antimicrobial peptides are often produced by eukaryotes to control bacterial populations in both pathogenic and mutualistic symbioses. These include proline-rich mammalian immune peptides and cysteine-rich peptides produced by legume plants in symbiosis with rhizobia. The fitness of the bacterial partner is dependent upon their ability to persist in the presence of these antimicrobial peptides. In the case ofEscherichia coliandMycobacterium tuberculosispathogens and nitrogen-fixing legume symbionts (rhizobia), the ability to survive exposure to these peptides depends on peptide transporters called SbmA (also known as BacA) or BclA (for BacA-like). However, how broadly these transporters are distributed amongst bacteria, and their evolutionary history, is poorly understood. Here, we used hidden Markov models, phylogenetic analysis, and sequence similarity networks to examine the distribution of SbmA/BacA and BclA proteins across a representative set of 1,255 species from across the domainBacteria. We identified a total of 71 and 177 SbmA/BacA and BclA proteins, respectively. Phylogenetic and sequence similarity analyses suggest that these protein families likely did not evolve from a common ancestor and that their functional similarity is instead a result of convergent evolution.In vitrosensitivity assays using the legume peptide NCR247 and several of the newly-identified BclA proteins confirmed that transport of antimicrobial peptides is a common feature of this protein family. Analysis of the taxonomic distribution of these proteins showed that SbmA/BacA orthologs were encoded only by species in the phylumPseudomonadotaand that they were primarily identified in just two orders:Hyphomicrobiales(classAlphaproteobacteria) andEnterobacterales(classGammaproteobacteria). BclA orthologs were somewhat more broadly distributed and were found in clusters across four phyla. These included several orders of the phylaPseudomonadotaandCyanobacteriota, as well as the orderMycobacteriales(phylumActinomycetota) and the classNegativicutes(phylumBacillota). Notably, many of the clades enriched for species encoding BacA or BclA orthologs also include many species known to interact with eukaryotic hosts in mutualistic or pathogenic interactions. Collectively, these observations suggest that SbmA/BacA and BclA proteins have been repeatedly co-opted to facilitate both mutualistic and pathogenic associations with eukaryotic hosts by allowing bacteria to cope with host-encoded antimicrobial peptides.