bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4 T cells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection
Authors: Foreman Taylor W. , Nelson Christine E. , Kauffman Keith D. , Lora Nickiana E. , Vinhaes Caian L. , Dorosky Danielle E. , Sakai Shunsuke , Gomez Felipe , Fleegle Joel D. , Parham Melanie , Perera Shehan R. , Lindestam Arlehamn Cecilia S. , Sette Alessandro ,   Tuberculosis Imaging Program, Brenchley Jason M. , Queiroz Artur T.L. , Andrade Bruno B. , Kabat Juraj , Via Laura E. , Barber Daniel L. 
Published: December 2021

ABSTRACTThe HIV-mediated decline in circulating CD4 T cells correlates with increased risk of active tuberculosis (TB)1–4. However, HIV/Mycobacterium tuberculosis (Mtb) co-infected individuals also have an increased incidence of TB prior to loss of CD4 T cells in blood3,5, raising the possibility that HIV co-infection leads to disruption of CD4 T cell responses at the site of lung infection before they are observed systemically. Here we used a rhesus macaque model of SIV/Mtb co-infection to study the early effects of acute SIV infection on CD4 T cells in pulmonary Mtb granulomas. Two weeks after SIV co-infection CD4 T cells were dramatically depleted from granulomas, before significant bacterial outgrowth, disease reactivation as measured by PET-CT imaging, or CD4 T cell loss in blood, airways, and lymph nodes. Mtb-specific CD4 T cells, CCR5-expressing, in granulomas were preferentially depleted by SIV infection. Moreover, CD4 T cells were preferentially depleted from the granuloma core and lymphocyte cuff relative to B cell-rich regions, and live imaging of granuloma explants showed that SIV co-infection reduced T cell motility. Thus, Mtb-specific CD4 T cells in pulmonary granulomas may be decimated before many patients even experience the first symptoms of acute HIV infection.
RNA viral communities are structured by host plant phylogeny in oak and conifer leaves
Authors: ter Horst Anneliek M. , Fudyma Jane D. , Bak Aurélie , Hwang Min Sook , Santos-Medellín Christian , Stevens Kristian A. , Rizzo David M. , Al Rwahnih Maher , Emerson Joanne B. 
Published: December 2021

AbstractWild plants can suffer devastating diseases, experience asymptomatic, persistent infections, and serve as reservoirs for viruses of agricultural crops, yet we have a limited understanding of the natural plant virosphere. To access representatives of locally and globally distinct wild plants and investigate their viral diversity, we extracted and sequenced dsRNA from leaves from 16 healthy oak and conifer trees in the UC Davis Arboretum (Davis, California). From de novo assemblies, we recovered 389 RNA-dependent RNA polymerase (RdRp) gene sequences from 384 putative viral species, and a further 580 putative viral contigs were identified with virus prediction software followed by manual confirmation of virus annotation. Based on similarity to known viruses, most recovered viruses were predicted to infect plants or fungi, with the highest diversity and abundance observed in the Totiviridae and Mitoviridae families. Phyllosphere viral community composition differed significantly by host plant phylogeny, suggesting the potential for host-specific viromes. The phyllosphere viral community of one oak tree differed substantially from other oak viral communities and contained a greater proportion of putative mycoviral sequences, potentially due to the tree’s more advanced senescence at the time of sampling. These results suggest that oaks and conifers harbor a vast diversity of viruses with as-yet unknown roles in plant health and phyllosphere microbial ecology.
A tale of two plasmids: contributions of plasmid associated phenotypes to epidemiological success among Shigella
Authors: De Silva P. Malaka , Stenhouse George E. , Blackwell Grace A. , Bengtsson Rebecca J. , Jenkins Claire , Hall James P.J. , Baker Kate S. 
Published: December 2021

AbstractDissemination of antimicrobial resistance (AMR) genes by horizontal gene transfer (HGT) mediated through plasmids is a major global concern. Genomic epidemiology studies have shown varying success of different AMR plasmids during outbreaks, but the underlying reasons for these differences are unclear. Here, we investigated two Shigella plasmids (pKSR100 and pAPR100) that circulated in the same transmission network but had starkly contrasting epidemiological outcomes to identify plasmid features that may have contributed to the differences. We used plasmid comparative genomics to reveal divergence between the two plasmids in genes encoding AMR, SOS response alleviation, and conjugation. Experimental analyses revealed that these genomic differences corresponded with reduced conjugation rates for the epidemiologically successful pKSR100, but more extensive AMR, reduced fitness costs, and a reduced SOS response in the presence of antimicrobials, compared with the less successful pAPR100. The discrepant phenotypes between the two plasmids are consistent with the hypothesis that plasmid associated phenotypes contribute to determining the epidemiological outcome of AMR HGT and suggest that phenotypes relevant in responding to antimicrobial pressure and fitness impact may be more important than those around conjugation in this setting. Plasmid phenotypes could thus be valuable tools in conjunction with genomic epidemiology for predicting AMR dissemination.
DrosophilaSPG12 ortholog, reticulon-like 1, governs presynaptic ER organization and Ca2+dynamics
Authors: Pérez-Moreno Juan José , Smith Rebecca C , Oliva Megan K , Gallo Filomena , Ojha Shainy , Müller Karin H. , O’Kane Cahir J 
Published: December 2021

ABSTRACTNeuronal endoplasmic reticulum (ER) appears continuous throughout the cell. Its shape and continuity are influenced by ER-shaping proteins, mutations in which can cause distal axon degeneration in Hereditary Spastic Paraplegia (HSP). We therefore asked how loss ofRtnl1, aDrosophilaortholog of the human HSP geneRTN2(SPG12), which encodes an ER-shaping protein, affects ER organization and the function of presynaptic terminals. Loss of Rtnl1 depleted ER membrane markers atDrosophilapresynaptic motor terminals, and appeared to deplete narrow tubular ER while leaving cisternae largely unaffected, thus suggesting little change in resting Ca2+storage capacity. Nevertheless, these changes were accompanied by major reductions in activity-evoked Ca2+fluxes in the cytosol, ER lumen, and mitochondria, as well as reduced evoked and spontaneous neurotransmission. We found that reduced STIM-mediated ER-plasma membrane contacts underlie presynaptic Ca2+defects inRtnl1mutants. Our results show the importance of ER architecture in presynaptic physiology and function which are therefore potential factors in the pathology of HSP.
Music-selective cortex is sensitive to structure in both pitch and time
Authors: Boebinger Dana L. , Norman-Haignere Sam V. , McDermott Josh H. , Kanwisher Nancy G. 
Published: December 2021

ABSTRACTConverging evidence suggests that neural populations within human non-primary auditory cortex respond selectively to music. These neural populations respond strongly to a wide range of music stimuli, and weakly to other natural sounds and to synthetic control stimuli matched to music in many acoustic properties, suggesting that they are driven by high-level musical features. What are these features? Here we used fMRI to test the extent to which musical structure in pitch and time contribute to music-selective neural responses. We used voxel decomposition to derive music-selective response components in each of 15 participants individually, and then measured the response of these components to synthetic music clips in which we selectively disrupted musical structure by scrambling either the note pitches and/or onset times. Both types of scrambling produced lower responses compared to when melodic or rhythmic structure was intact. This effect was much stronger in the music-selective component than in the other response components, even those with substantial spatial overlap with the music component. We further found no evidence for any cortical regions sensitive to pitch but not time structure, or vice versa. Our results suggest that the processing of melody and rhythm are intertwined within auditory cortex.
Cryo-EM structure of the human CST•Polα/Primase complex in a recruitment state
Authors: Cai Sarah W. , Zinder John C. , Svetlov Vladimir , Bush Martin W. , Nudler Evgeny , Walz Thomas , de Lange Titia 
Published: December 2021

AbstractThe CST•Polα/Primase complex is essential for telomere overhang maintenance and additionally functions to counteract resection at double-strand breaks. We report a 4.6-Å resolution cryo-EM structure of CST•Polα/Primase, captured prior to catalysis in a recruitment state, which provides insights into the architecture and stoichiometry of the fill-in machinery. Our model informs on human disease mutations that cause Coats plus syndrome.
Understanding the interaction of 14-3-3 proteins with hDMX and hDM2: a structural and biophysical study
Authors: Srdanovic Sonja , Wolter Madita , Trinh Chi H. , Ottmann Christian , Warriner Stuart L. , Wilson Andrew J. 
Published: December 2021

Abstractp53 plays a critical role in regulating diverse biological processes: DNA repair, cell cycle arrest, apoptosis, and senescence. The p53 pathway has therefore served as the focus for drug-discovery efforts. p53 is negatively regulated by hDMX and hDM2; prior studies have identified 14-3-3 proteins as hDMX and hDM2 client proteins. 14-3-3 proteins are adaptor proteins that modulate localisation, degradation and interactions of their targets in response to phosphorylation. Thus 14-3-3 proteins may indirectly modulate the interaction between hDMX or hDM2 and p53 and represent potential targets for modulation of the p53 pathway. In this manuscript we report on the biophysical and structural characterization of peptide/protein interactions that are representative of the interaction between 14-3-3 and hDMX or hDM2. The data establish that proximal phosphosites spaced ∼20-25 residues apart in both hDMX and hDM2 co-operate to facilitate high-affinity 14-3-3 binding and provide structural insight that can be utilized in future stabilizer/inhibitor discovery efforts.
Structural basis for the assembly and electron transport mechanisms of the dimeric photosynthetic RC–LH1 supercomplex
Authors: Cao Peng , Bracun Laura , Yamagata Atsushi , Christianson Bern M. , Negami Tatsuki , Zou Baohua , Terada Tohru , Canniffe Daniel P. , Shirouzu Mikako , Li Mei , Liu Lu-Ning 
Published: December 2021

AbstractThe reaction center (RC) and light-harvesting complex 1 (LH1) form a RC–LH1 core supercomplex that is vital for the primary reactions of photosynthesis in purple photosynthetic bacteria. Some species possess the dimeric RC–LH1 complex with an additional polypeptide PufX, representing the largest photosynthetic complex in anoxygenic phototrophs. However, the details of the architecture and assembly mechanism of the RC–LH1 dimer are unclear. Here we report seven cryo-electron microscopy (cryo-EM) structures of RC–LH1 supercomplexes from Rhodobacter sphaeroides. Our structures reveal that two PufX polypeptides are positioned in the center of the S-shaped RC–LH1 dimer, interlocking association between the components and mediating RC–LH1 dimerization. Moreover, we identify a new transmembrane peptide, designated PufY, which is located between the RC and LH1 subunits near the LH1 opening. PufY binds a quinone molecule and prevents LH1 subunits from completely encircling the RC, creating a channel for quinone/quinol exchange. Genetic mutagenesis, cryo-EM structures, and computational simulations enable a mechanistic understanding of the assembly and electron transport pathways of the RC–LH1 dimer and elucidate the roles of individual components in ensuring the structural and functional integrity of the photosynthetic supercomplex.
Mechanisms underlying sequence-dependent DNA hybridisation rates in the absence of secondary structure
Authors: Hertel Sophie , Spinney Richard E. , Xu Stephanie Y. , Ouldridge Thomas E. , Morris Richard G. , Lee Lawrence K. 
Published: December 2021

ABSTRACTThe kinetics of DNA hybridisation are fundamental to biological processes and DNA-based technologies. However, the precise physical mechanisms that determine why different DNA sequences hybridise at different rates are not well understood. Secondary structure is one predictable factor that influences hybridisation rates but is not sufficient on its own to fully explain the observed sequence-dependent variance. Consequently, to achieve a good correlation with experimental data, current prediction algorithms require many parameters that provide little mechanistic insight into DNA hybridisation. In this context, we measured hybridisation rates of 43 different DNA sequences that are not predicted to form secondary structure and present a parsimonious physically justified model to quantify their hybridisation rates. Accounting only for the combinatorics of complementary nucleating interactions and their sequence-dependent stability, the model achieves good correlation with experiment with only two free parameters, thus providing new insight into the physical factors underpinning DNA hybridisation rates.
KDM6B sensitizes PARthanatos via suppression of O6-methylguanine DNA methyltransferase repair and sustained checkpoint response
Authors: Yang Mingming , Wang Chenliang , Zhou Mi , Bao Lei , Wang Yanan , Kumar Ashwani , Xing Chao , Luo Weibo , Wang Yingfei 
Published: December 2021

AbstractPoly(ADP-ribose) polymerase-1 (PARP-1) is a DNA damage sensor and contributes to both DNA repair and cell death processes. However, how PARP-1 signaling is regulated to switch its function from DNA repair to cell death remains largely unknown. Here, we found that PARP-1 plays a central role in alkylating agent-induced PARthanatic cancer cell death. Lysine demethylase 6B (KDM6B) was identified as a key cell death effector in PARthanatos. Knockout of KDM6B or loss of KDM6B demethylase activity conferred cancer cells resistance to PARthanatic cell death in response to alkylating agents. Mechanistically, KDM6B knockout suppressed methylation at the promoter of O6-methylguanine-DNA methyltransferase (MGMT) to enhance MGMT expression and its direct DNA repair function, thereby inhibiting DNA damage-evoked PARP-1 hyperactivation and subsequent cell death. Moreover, KDM6B knockout triggered sustained Chk1 phosphorylation and activated a second repair machinery to fix DNA damage evading from MGMT repair. Inhibition of MGMT or checkpoint response re-sensitized KDM6B deficient cells to PARthanatos induced by alkylating agents. These findings provide new molecular insights into epigenetic regulation of PARP-1 signaling mediating DNA repair or cell death and identify KDM6B as a biomarker for prediction of cancer cell vulnerability to alkylating agent treatment.
Dynamic localisation of DamX regulates bacterial filamentation and division during UPEC dispersal from host cells
Authors: Söderström Bill , Daley Daniel O. , Duggin Iain G. 
Published: December 2021

AbstractUropathogenic Escherichia coli (UPEC) cells can grow into highly filamentous forms during infection of bladder epithelial cells, but this process is poorly understood. Herein we found that some UPEC filaments released from infected bladder cells in vitro grew very rapidly and by more than 100 µm before initiating division, whereas others did not survive, suggesting that filamentation is a stress response that promotes dispersal. The DamX bifunctional division protein, which is essential for UPEC filamentation, was initially non-localized but then assembled at multiple division sites in the filaments prior to division. DamX rings maintained consistent thickness during constriction and remained at the septum until after membrane fusion was completed, like in rod cell division. Our findings suggest a mechanism involving regulated dissipation of DamX, leading to division arrest and filamentation, followed by its reassembly into division rings to promote UPEC dispersal and survival during infection.
Escherichia coli BarA-UvrY regulates the pks island and kills Staphylococci via the genotoxin colibactin
Authors: Wong Jun Jie , Chong Kelvin K.L. , Ho Foo Kiong , Benjamin Ho Chee Meng , Neelakandan Ramesh , Choo Pei Yi , Keogh Damien , Chen John , Liu Chuan Fa , Kline Kimberly A. 
Published: December 2021

SummaryWound infections are often polymicrobial in nature and are associated with poor disease prognoses. Escherichia coli and Staphylococcus aureus are among the top five most cultured pathogens from wound infections. However, little is known about the polymicrobial interactions between E. coli and S. aureus during wound infections. In this study, we show that E. coli kills S. aureus both in vitro and in a mouse excisional wound model via the genotoxin, colibactin. We also show that the BarA-UvrY two component system (TCS) is a novel regulator of the pks island, which acts through the carbon storage global regulatory (Csr) system. Together, our data demonstrate the role of colibactin in inter-species competition and show that it is regulated by BarA-UvrY TCS, a previously uncharacterized regulator of the pks island.
COVID-19 endgame: from pandemic to endemic? Vaccination, reopening and evolution in a well-vaccinated population
Authors: Are Elisha B. , Song Yexuan , Stockdale Jessica E. , Tupper Paul , Colijn Caroline 
Published: December 2021

AbstractCOVID-19 remains a major public health concern, with large resurgences even where there has been widespread uptake of vaccines. Waning immunity and the emergence of new variants will shape the long-term burden and dynamics of COVID-19. We explore the transition to the endemic state, and the endemic incidence, using a combination of modelling approaches. We compare gradual and rapid reopening and reopening at different vaccination levels. We examine how the eventual endemic state depends on the duration of immunity, the rate of importations, the efficacy of vaccines and the transmissibility. These depend on the evolution of the virus, which continues to undergo selection. Slower reopening leads to a lower peak level of incidence and fewer overall infections: as much as a 60% lower peak and a 10% lower total in some illustrative simulations; under realistic parameters, reopening when 70% of the population is vaccinated leads to a large resurgence in cases. The long-term endemic behaviour may stabilize as late as January 2023, with further waves of high incidence occurring depending on the transmissibility of the prevalent variant, duration of immunity, and antigenic drift. We find that long term endemic levels are not necessarily lower than current pandemic levels: in a population of 100,000 with representative parameter settings (Reproduction number 5, 1-year duration of immunity, vaccine efficacy at 80% and importations at 3 cases per 100K per day) there are over 100 daily incident cases in the model. The consequent burden on health care systems depends on the severity of infection in immunized or previously infected individuals.
Evaluation of the Implementation of the 4C Mortality Score in United Kingdom hospitals during the second pandemic wave
Authors: Blunsum Andrew E. , Perkins Jonathan S. , Arshad Areeb , Bajpai Sukrit , Barclay-Elliott Karen , Brito-Mutunayagam Sanjita , Brooks Rebecca , Chan Terrence , Coates Dominic J. G. , Corobana Alina , Crocker-Buqué Tim , Evans Terry J. , Gordon-Brown Jasmine , Hack Berkin , Hiles Heather , Khanijau Aakash , Lalwani Salina , Leong Clare , MacKay Kirsty , Macrae Catriona , Martin Bryony , Martin Christopher A. , McKemey Emily , Nazareth Joshua , Pan Daniel , Scopazzini Marcello , Simons David , Swinhoe Sophie , Thomas Julia , Thorburn Fiona , Walpole Sarah , Warne Esmie , Wilson Rory , MacConnachie Alisdair , Ho Antonia 
Published: December 2021

ABSTRACTThe 4C Mortality Score (4C Score) was designed to risk stratify hospitalised patients with COVID-19. We assessed inclusion of 4C Score in COVID-19 management guidance and its documentation in patients’ case notes in January 2021 in UK hospitals. 4C Score was included within guidance by 50% of sites, though score documentation in case notes was highly variable. Higher documentation of 4C Score was associated with score integration within admissions proformas, inclusion of 4C Score variables or link to online calculator, and management decisions. Integration of 4C Score within clinical pathways may encourage more widespread use.
Measurement of the extent of Anxiety and Depression that has occurred in college students due to the COVID 19 pandemic: A Survey based cross-secConal study
Authors: Goswami Shubham , Chakraborty Soujanya , Chakraborty Aritra 
Published: December 2021

ABSTRACTOVERVIEWThe ongoing Pandemic because of the Coronavirus disease 2019 (COVID-19) has caused all the educational institutes including colleges to be closed for a very long time. As a result the students are compelled to remain in their homes for this time. Prolonged stay at home along with excess use of social media and other modes to “kill” the time are quite famous to cause certain health issues in a person, specially the teenagers and adolescents. Mental wellbegin, being a dimension of health as per WHO should not be ignored at all specially in these situations.METHOD OF STUDYAn Online Questionnaire is prepared based of the ZUNG Self Rating Anxiety and Self Rating Depression Scale (Pre-validated Scales). The Form is circulated digitally among the people and then we have collected the data in excel. Based on the result we have prepared our statistical chart.RESULTQuite a significant number of candidates were suffering due to the pandemic situation. 17.091% were suffering from mild to moderate anxiety, 1.785% had marked to severe anxiety levels(Constituting approximately 18.9% of the total). On the other hand, 8.673% of the students had mild depression, while 1 candidate (0.255%) had moderate depression and 1 (0.255%) had severe depression, (Constituting approximately 9.20% of the total). We found that candidates in the age group of 23-24 years had the maximum prevalence of depression, it was followed by candidates with age between 21-22 years. We found that the candidates with age between 23 to 24 years were having highest prevalence of significant anxiety levels which is closely followed by candidates having age which lies between 22 years to 23 years.
SARS-CoV-2 transmission potential and rural-urban disease burden disparities across Alabama, Louisiana, and Mississippi, March 2020 — May 2021
Authors: Ofori Sylvia K. , Ogwara Chigozie A. , Kwon Seoyon , Hua Xinyi , Martin Kamryn M. , Mallhi Arshpreet Kaur , Twum Felix , Chowell Gerardo , Fung Isaac C.-H. 
Published: December 2021

AbstractPurposeTo quantify and compare SARS-CoV-2 transmission potential across Alabama, Louisiana, and Mississippi and selected counties with populations in the 50th, 75th, and 100th percentile.MethodsTo determine the time-varying reproduction number Rt of SARS-CoV-2, we applied the R package EpiEstim to the time series of daily incidence of confirmed cases. Median Rt percentage change when policies changed was determined. Linear regression was performed between log10-transformed cumulative incidence and log10-transformed population size at four time points.ResultsStay-at-home orders, face mask mandates, and vaccinations were associated with the most significant reductions in SARS-CoV-2 transmission in the three southern states. Rt across the three states decreased significantly by 20% following stay-at-home orders. We observed varying degrees of reductions in Rt across states following other policies. Rural Alabama counties experienced higher per capita cumulative cases relative to urban ones as of June 17 and October 17, 2020. Meanwhile, Louisiana and Mississippi saw the disproportionate impact of SARS-CoV-2 in rural counties compared to urban ones throughout the study period.ConclusionState and county policies had an impact on local pandemic trajectories. The rural-urban disparities in case burden call for evidence-based approaches in tailoring health promotion interventions and vaccination campaigns to rural residents.