bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineering, structure, and immunogenicity of a Crimean–Congo hemorrhagic fever virus pre-fusion heterotrimeric glycoprotein complex
Authors: McFadden Elizabeth , Monticelli Stephanie R. , Wang Albert , Ramamohan Ajit R. , Batchelor Thomas G. , Kuehne Ana I. , Bakken Russell R. , Tse Alexandra L. , Chandran Kartik , Herbert Andrew S. , McLellan Jason S. 
Published: April 2024

ABSTRACTCrimean–Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus that can cause severe disease in humans with case fatality rates of 10–40%. Although structures of CCHFV glycoproteins GP38 and Gc have provided insights into viral entry and defined epitopes of neutralizing and protective antibodies, the structure of glycoprotein Gn and its interactions with GP38 and Gc have remained elusive. Here, we used structure-guided protein engineering to produce a stabilized GP38-Gn-Gc heterotrimeric glycoprotein complex (GP38-GnH-DS-Gc). A cryo-EM structure of this complex provides the molecular basis for GP38’s association on the viral surface, reveals the structure of Gn, and demonstrates that GP38-Gn restrains the Gc fusion loops in the prefusion conformation, facilitated by an N-linked glycan attached to Gn. Immunization with GP38-GnH-DS-Gc conferred 40% protection against lethal IbAr10200 challenge in mice. These data define the architecture of a GP38-Gn-Gc protomer and provide a template for structure-guided vaccine antigen development.
How Mycobacterium tuberculosis builds a home: Single-cell analysis reveals M. tuberculosis ESX-1-mediated accumulation of anti-inflammatory macrophages in infected mouse lungs
Authors: Zheng Weihao , Borja Michael , Dorman Leah , Liu Jonathan , Zhou Andy , Seng Amanda , Arjyal Ritwicq , Sunshine Sara , Nalyvayko Alina , Pisco Angela , Rosenberg Oren , Neff Norma , Zha Beth Shoshana 
Published: April 2024

AbstractMycobacterium tuberculosis (MTB) infects and replicates in lung mononuclear phagocytes (MNPs) with astounding ability to evade elimination. ESX-1, a type VII secretion system, acts as a virulence determinant that contributes to MTB’s ability to survive within MNPs, but its effect on MNP recruitment and/or differentiation remains unknown. Here, using single-cell RNA sequencing, we studied the role of ESX-1 in MNP heterogeneity and response in mice and murine bone marrow-derived macrophages (BMDM). We found that ESX-1 is required for MTB to recruit diverse MNP subsets with high MTB burden. Further, MTB induces an anti-inflammatory signature in MNPs and BMDM in an ESX-1 dependent manner. Similarly, spatial transcriptomics revealed an upregulation of anti-inflammatory signals in MTB lesions, where monocyte-derived macrophages concentrate near MTB-infected cells. Together, our findings suggest that MTB ESX-1 mediates the recruitment and differentiation of anti-inflammatory MNPs, which MTB can infect and manipulate for survival.
Nanocluster-antibody-drug conjugates (NADC) as an intravesical precision theranostic agent for interstitial cystitis
Authors: Lin Zhijun , Wang Wanyan , Liu Dingxin , Xu Zhifeng , Wu Zhiming , Zhou Xiangfu , Zhang Xiaodong , Huang Yong , Zhao Qi , Yang Jiang 
Published: April 2024

AbstractInterstitial cystitis (IC) is a chronic inflammatory disorder characterized by recurring severe pain in the bladder and surrounding pelvic areas, lacking timely diagnostic and therapeutic options. Here, we propose a unitary theranostic nanocluster-antibody-drug conjugate (NADC) by covalently placing dihydroorotate dehydrogenase inhibitors (DHODHi) and ultrasmall gold quantum clusters (AuQCs) on a nerve growth factor (NGF) antagonistic antibody with simultaneous X-ray computed tomographic and near-infrared fluorescence imaging contrasts. Combining anti-inflammatory effects from all individual components, intravesical NADC specifically homed to bladder mucosal lesions and capably alleviated inflammation in chronic, acute, and prophylactic IC models of rats, as revealed by behavioral and pathological evaluations. Transcriptomics unveiled cytokine modulation and concomitant inhibition of perturbed IL-17, NF-κB, TNF, and JAK-STAT signaling pathways. Interestingly, the NADC reconstructed the host bladder microbiota by differentially varying anti-inflammatory and pro-inflammatory bacteria diversities. Distinct from conventional nanoparticles conjugated with antibodies and drugs, NADC relies on the antibody framework and represents a state-of-the-art category of precision theranostic agents with translational potential for diagnosing and treating IC patients.
Energetically costly functional network dynamics in cognitively impaired multiple sclerosis patients
Authors: Broeders T.A.A. , van Dam M. , Pontillo G. , Rauh V. , Douw L. , van der Werf Y.D. , Killestein J. , Barkhof F. , Vinkers C.H. , Schoonheim M.M. 
Published: April 2024

AbstractBackground and objectivesPatients with multiple sclerosis (MS) often experience cognitive impairment, and this is related to structural disconnection and subsequent functional reorganization. It is not clear how specific patterns of functional reorganization might make it harder for cognitively impaired (CI) MS patients to dynamically adapt how brain regions communicate, which is crucial for normal cognition. To identify patterns relevant to cognitive impairment in MS, we performed a temporally detailed analysis of connectivity state transitions and quantified the effort associated with such dynamic alterations.MethodsResting-state functional and diffusion MRI was acquired from 95 controls and 330 MS patients (mean disease duration: 15 years) in a cross-sectional design, of whom 86 were classified as CI (≥2/7 domains Z < −2) and 65 as mildly CI (≥2/7 domains Z < −1.5) based on the performance on an expanded Brief Repeatable Battery of Neuropsychological Tests. Four functional connectivity states were determined usingK-means clustering of moment-to- moment co-fluctuations (i.e., edge time series), and the resulting state sequence was used to characterize the frequency of transitions between network configurations. The control energy associated with the transitions between states was then calculated using the structural network of each subject with network control theory.ResultsCI patients transition less frequently between connectivity states. Relative to the time spent in a particular state, CI patients specifically transition less from a weakly connected and highly modular state (i.e., theweakly connected state) to a more integrated state that featured strong involvement of the visual network (i.e., thevisual network state), but more in the opposite direction. CI patients also required more control energy to transition between states.DiscussionThis study showed that it became more effortful for MS patients with cognitive impairment to dynamically change the organization of the functional network, providing an intuitive understanding of why these transitions occur less frequently in some patients. In particular, transitions between theweakly connected stateand the more integratedvisual network statewere relevant for cognition in these patients. The findings highlight a possible underpinning of disturbed cognition in MS patients and also provide novel avenues for studying and possibly improving network dynamics.
Age and gender profiles of HIV infection burden and viraemia: novel metrics for HIV epidemic control in African populations with high antiretroviral therapy coverage
Authors: Brizzi Andrea , Kagaayi Joseph , Ssekubugu Robert , Abeler-Dörner Lucie , Blenkinsop Alexandra , Bonsall David , Chang Larry W. , Fraser Christophe , Galiwango Ronald M. , Kigozi Godfrey , Kyle Imogen , Monod Mélodie , Nakigozi Gertrude , Nalugoda Fred , Rosen Joseph G. , Laeyendecker Oliver , Quinn Thomas C. , Grabowski M. Kate , Reynolds Steven J. , Ratmann Oliver 
Published: April 2024

AbstractIntroductionTo prioritize and tailor interventions for ending AIDS by 2030 in Africa, it is important to characterize the population groups in which HIV viraemia is concentrating.MethodsWe analysed HIV testing and viral load data collected between 2013-2019 from the open, population-based Rakai Community Cohort Study (RCCS) in Uganda, to estimate HIV seroprevalence and population viral suppression over time by gender, one-year age bands and residence in inland and fishing communities. All estimates were standardized to the underlying source population using census data. We then assessed 95-95-95 targets in their ability to identify the populations in which viraemia concentrates.ResultsFollowing the implementation of Universal Test and Treat, the proportion of individuals with viraemia decreased from 4.9% (4.6%-5.3%) in 2013 to 1.9% (1.7%-2.2%) in 2019 in inland communities and from 19.1% (18.0%-20.4%) in 2013 to 4.7% (4.0%-5.5%) in 2019 in fishing communities. Viraemia did not concentrate in the age and gender groups furthest from achieving 95-95-95 targets. Instead, in both inland and fishing communities, women aged 25-29 and men aged 30-34 were the 5-year age groups that contributed most to population-level viraemia in 2019, despite these groups being close to or had already achieved 95-95-95 targets.ConclusionsThe 95-95-95 targets provide a useful benchmark for monitoring progress towards HIV epidemic control, but do not contextualize underlying population structures and so may direct interventions towards groups that represent a marginal fraction of the population with viraemia.
Commensal bacteria inhibit viral infections via a tryptophan metabolite
Authors: Jiang Danting , Soo Nicole , Tan Chin Yee , Dankwa Sedem , Wang Hsuan-Yuan , Theriot Barbara S. , Ardeshir Amir , Siddiqui Nazema Y. , Rompay Koen K. A. Van , Paris Kristina De , Permar Sallie R. , Goswami Ria , Surana Neeraj K. 
Published: April 2024

ABSTRACTThere is growing appreciation that commensal bacteria impact the outcome of viral infections, though the specific bacteria and their underlying mechanisms remain poorly understood. Studying a simian–human immunodeficiency virus (SHIV)-challenged cohort of pediatric nonhuman primates, we bioinformatically associatedLactobacillus gasseriand the bacterial family Lachnospiraceae with enhanced resistance to infection. We experimentally validated these findings by demonstrating two different Lachnospiraceae isolates,Clostridium immunisandRuminococcus gnavus, inhibited HIV replication in vitro and ex vivo. Given the link between tryptophan catabolism and HIV disease severity, we found that an isogenic mutant ofC. immunisthat lacks the aromatic amino acid aminotransferase (ArAT) gene, which is key to metabolizing tryptophan into 3-indolelactic acid (ILA), no longer inhibits HIV infection. Intriguingly, we confirmed that a second commensal bacterium also inhibited HIV in an ArAT-dependent manner, thus establishing the generalizability of this finding. In addition, we found that purified ILA inhibited HIV infection by agonizing the aryl hydrocarbon receptor (AhR). Given that the AhR has been implicated in the control of multiple viral infections, we demonstrated thatC. immunisalso inhibited human cytomegalovirus (HCMV) infection in an ArAT-dependent manner. Importantly, metagenomic analysis of individuals at-risk for HIV revealed that those who ultimately acquired HIV had a lower fecal abundance of the bacterial ArAT gene compared to individuals who did not, which indicates our findings translate to humans. Taken together, our results provide mechanistic insights into how commensal bacteria decrease susceptibility to viral infections. Moreover, we have defined a microbiota-driven antiviral pathway that offers the potential for novel therapeutic strategies targeting a broad spectrum of viral pathogens.
Liming enhances the abundance and stability of nitrogen-cycling microbes: The buffering effect of long-term lime application
Authors: Mitsuta Akari , Lourenco Kesia Silva , Chang Jingjing , Ros Mart , Schils René , Uchida Yoshitaka , Kuramae Eiko Eurya 
Published: April 2024

AbstractLime application (liming) has historically been used to ameliorate soil acidity in grasslands. Liming effectively improves soil pH, plant productivity, and soil physicochemical properties, but the long-term impact of acidity control by liming on key microbial nitrogen (N)-cycling genes in semi-natural grasslands is unknown. We investigated the effect of 65 years of liming on N-cycling processes in the limed and control plots of the Ossekampen long-term grassland experiment in the Netherlands. These plots have not received any other fertilizers for 65 years. Soil sampling and nitrous oxide (N2O) emission measurements were conducted three times in spring and four times in summer, and quantitative real-time PCR was performed to determine the abundances of N-cycling genes, including ammonia-oxidation (amoA), denitrification (nirS,nirK,nosZ), and N-fixation (nifH) genes. Long-term liming increased the abundances of nitrifiers and denitrifiers but did not increase N2O emissions. Additionally, liming had a buffering effect that stabilized the population of N-cycling microbes against seasonal variations in abundance. Our results indicate that improving soil acidity through liming facilitates microbial N-cycling processes without increasing N2O emissions.Highlights:65 years of liming increased bacterial but not archaeal and fungal community abundance.Liming increased the abundance of microbial N-cycling genes.The buffering effect of liming reduced seasonal variations in the abundance of N microbes.
The role of chloroplast SRP54 domains and its C-terminal tail region in post- and cotranslational protein transportin vivo
Authors: Bischoff Annika , Ortelt Jennifer , Dünschede Beatrix , Zegarra Victor , Bedrunka Patricia , Bange Gert , Schünemann Danja 
Published: April 2024

AbstractIn the chloroplast, the 54 kDa subunit of the signal recognition particle (cpSRP54) is involved in the posttranslational transport of the light-harvesting chlorophyll a/b-binding proteins (LHCPs) and the cotranslational transport of plastid-encoded subunits of the photosynthetic complexes to the thylakoid membrane. It forms a high-affinity complex with plastid-specific cpSRP43 for posttranslational transport, while a ribosome-associated pool coordinates its cotranslational function. CpSRP54 constitutes a conserved multidomain protein, comprising a GTPase (NG) and a methionine-rich (M) domain linked by a flexible region. It is further characterized by a plastid-specific C-terminal tail region containing the cpSRP43-binding motif. To characterize the physiological role of the various regions of cpSRP54 in thylakoid membrane protein transport, we generatedArabidopsis thalianacpSRP54 knockout (ffc1-2) lines producing truncated cpSRP54 variants or a GTPase point mutation variant. Phenotypic characterization of the complementation lines demonstrated that the C-terminal tail region of cpSRP54 plays an important role specifically in posttranslational LHCP transport. Furthermore, we show that the GTPase activity of cpSRP54 plays an essential role in the transport pathways for both nuclear-as well as plastid-encoded proteins. In addition, our data revealed that plants expressing cpSRP54 without the C-terminal region exhibit a strongly increased accumulation of a photosystem I assembly intermediate.HighlightThis study elucidates the important role of the chloroplast SRP subunit, cpSRP54, in the biogenesis of both the LHC antenna and the cores of photosystem I and IIin vivo.
From Bulk to Binding: Decoding the Entry of PET into Hydrolase Binding Pockets
Authors: Jäckering Anna , Göttsch Frederike , Schäffler Moritz , Doerr Mark , Bornscheuer Uwe T. , Wei Ren , Strodel Birgit 
Published: April 2024

AbstractPlastic-degrading enzymes hold promise for biocatalytic recycling of poly(ethylene terephthalate) (PET), a key synthetic polymer. Despite their potential, the current activity of PET hydrolases is not sufficient for industrial use. To unlock their full potential, a deep mechanistic understanding followed by protein engineering is required. Using cuttingedge molecular dynamics simulations and free energy analysis methods, we uncover the entire pathway from the initial binding of two PET hydrolases – the thermophilic leaf-branch compost cutinase (LCC) and polyester hydrolase 1 (PES-H1) – to an amorphous PET material to a PET chain entering the active site and adopting a hydrolyzable geometry. Our results reveal the initial PET binding and elucidate its non-specific nature driven by electrostatic and hydrophobic forces. Upon PET entry into the active site, we uncover that this process can occur via one of three key pathways and detect barriers to it arising from both PET–PET and PET–enzyme interactions, with specific residues identified byin silicoandin vitromutagenesis. These insights not only advance our understanding of PET degradation mechanisms and pave the way for targeted enzyme enhancement strategies, but also offer an innovative approach applicable to enzyme studies across disciplines.
A guide to plant morphometrics using Gaussian Mixture Models
Authors: Tiburtini Manuel , Scrucca Luca , Peruzzi Lorenzo 
Published: April 2024

SummaryPlant morphology is crucial in defining and circumscribing the plant diversity around us. Statistically speaking, the study of morphology is done using morphometry, that in the context of plant systematics is used to verify hypotheses of morphological independence between taxa. Nevertheless, methods currently used to analyse morphological data do not match with the conceptual model behind species circumscription on morphological grounds. Here we 1) provide a step-by-step guide to perform linear morphometric analyses in the context of plant systematics and 2) we develop a new conceptual, statistical, and probabilistic framework for analyzing morphometric data using Gaussian Mixture Models (GMMs) in plant taxonomy to compare alternative taxonomic hypotheses.
Association between functional ability, chronic diseases and lifestyle risk factors in older community dwelling adults: protocol for a prospective observational Chinese cohort study
Authors: Wei Xin , Dan Xu , Zulin Dou , Angela Jacques , Josephine Umbella , Yuling Fan , Longsheng Zhang , Haiwen Yang , Hong Cai , Anne-Marie Hill 
Published: April 2024

AbstractBackgroundThe increasing proportion of the ageing population has become a significant focus for healthcare and social services in many countries worldwide, including China. Impaired physical fitness or the presence of chronic diseases may decrease functional ability and health related quality of life for older adults. The aim of the study is to investigate the association between functional abilities, including motor and cognitive function, with lifestyle risk factors, including activities of daily living (ADL), physical activity falls, frailty, and chronic diseases in older adults living in Guangzhou, China.MethodsA prospective observational cohort study will be conducted. Older adults aged 60 years and over living in urban Guangzhou, China will be eligible for inclusion. This study will be conducted in a community health service centre in Guangzhou. Inclusion criteria are that older adults can independently ambulate short distances indoors with or without a walking aid and can provide written informed consent. The outcomes are functional ability measured using, i Timed Up and Go test (TUGT), gait speed, handgrip strength and Functional Reach Test (FRT), cognition measured using the Mini-Cog, ADL measured with the Lawton Instrumental Activities of Daily Living Scale (Lawton IADL), HR-QoL measured using the European Quality of Life 5 Dimensions 3 Level Version (EQ5D3L), physical activity, falls history, lifestyle risk factors, anthropometric data, presence of chronic diseases measured by standardized blood tests, and blood pressure. Data collection will be performed by two senior physiotherapists and nurses working in the community centre.Trial registrationEthical approval (II2023-155-02) for this study was obtained from the Health Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.Chinese Clinical Trial Registry CentreChiCTR2300076095.
Evaluation of easy-to-implement anti-stress interventions in a series of N-of-1 trials: Study protocol of the Anti-Stress Intervention Among Physicians Study (ASIP)
Authors: Vetter Valentin Max , Kurth Tobias , Konigorski Stefan 
Published: April 2024

AbstractBackgroundAdverse effects of chronically high levels of stress on physical and mental health are well established. In physicians, the effects of elevated stress levels exceed the individual level and include treatment errors and reduced quality of patient-doctor relationships. Breathing and mindfulness-based exercises have been shown to reduce stress and could serve as an immediate and easy-to-implement anti-stress intervention among physicians. Due to the heterogeneity of their effect on stress, we aim to evaluate the intervention effect of performing a short daily breathwork-based or mindfulness-based intervention on the everyday level of perceived stress in physicians in residence in Germany in a series of N-of-1 trials.MethodsStudy participants will choose between two short interventions, box breathing, and one guided more complex mindfulness-based breathing exercise. Each participant subsequently will be randomly allocated to a sequence of 1-week intervention (A) and control (B, everyday life) phases. Each N-of-1 trial consists of two two-week cycles (AB or BA), resulting in a total trial duration of 4 weeks (ABAB or BABA). Perceived levels of stress will be assessed daily via the StudyU App on the participant’s smartphone. Additionally, participants will be asked to complete a questionnaire at baseline and three months after completion of the study that contains questions about basic participant characteristics, lifestyle factors, individual living situations, and validated psychological questionnaires. Intervention effects will be estimated by Bayesian multi-level random effects models on the individual and population level.DiscussionThis study contributes to the development of short-term solutions to reduce work-related stress for physicians in residence. This is expected to benefit the individual and increase the quality of overall healthcare due to a reduction in treatment errors and an increase in the quality of doctor-patient relationships.Trial RegistraionClinicalTrials.gov:NCT06368791, first registered April 16, 2024.