bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Mimicry as a Mechanism of Viral Immune Evasion and Autoimmunity
Authors: Maguire Cole , Wang Chumeng , Ramasamy Akshara , Fonken Cara , Morse Brinkley , Lopez Nathan , Wylie Dennis , Melamed Esther 
Published: March 2024

AbstractMimicry of host protein structures (“molecular mimicry”) is a common mechanism employed by viruses to evade the host’s immune system. To date, studies have primarily evaluated molecular mimicry in the context of full protein structural mimics. However, recent work has demonstrated that short linear amino acid (AA) molecular mimics can elicit cross-reactive antibodies and T-cells from the host, which may contribute to development and progression of autoimmunity. Despite this, the prevalence of molecular mimics throughout the human virome has not been fully explored. In this study, we evaluate 134 human infecting viruses and find significant usage of linear mimicry across the virome, particularly those in the herpesviridae and poxviridae families. Furthermore, we identify that proteins involved in cellular replication and inflammation, those expressed from autosomes, the X chromosome, and in thymic cells are over-enriched in viral mimicry. Finally, we demonstrate that short linear mimicry from Epstein-Barr virus (EBV) is significantly higher in auto-antibodies found in multiple sclerosis patients to a greater degree than previously appreciated. Our results demonstrate that human-infecting viruses frequently leverage mimicry in the course of their infection, point to substantial evolutionary pressure for mimicry, and highlight mimicry’s important role in human autoimmunity. Clinically, our findings could translate to development of novel therapeutic strategies that target viral infections linked to autoimmunity, with the goal of eliminating disease-associated latent viruses and preventing their reactivation.
Highly Dynamic and Sensitive NEMOer Calcium Indicators for Imaging ER Calcium Signals in Excitable Cells
Authors: Gu Wenjia , Chen Jia-Hui , Zhang Yiyin , Wang Zhirong , Li Jia , Wang Sijia , Zhang Hanhan , Jiang Amin , Zhong Ziyi , Zhang Jiaxuan , Xi Chao , Hou Tingting , Gill Donald L. , Li Dong , Mu Yu , Wang Shi-Qiang , Tang Ai-Hui , Wang Youjun 
Published: March 2024

AbstractEndoplasmic/sarcoplasmic reticulum (ER/SR) sits at the heart of the calcium (Ca2+) signaling machinery, yet current genetically encoded Ca2+indicators (GECIs) lack the ability to detect elementary Ca2+release events from ER/SR, particularly in muscle cells. Here we report a set of organellar GECIs, termed NEMOer, to efficiently capture ER Ca2+dynamics with increased sensitivity and responsiveness. Compared to G-CEPIA1er, NEMOer indicators exhibit dynamic ranges that are an order of magnitude larger, which enables up to 5-fold more sensitive detection of Ca2+oscillation in both non-excitable and excitable cells. The ratiometric version further allows super-resolution monitoring of local ER Ca2+homeostasis and dynamics. Notably, the NEMOer-f variant enabled the inaugural detection of Ca2+blinks, elementary Ca2+releasing signals from the SR of cardiomyocytes, as well asin vivospontaneous SR Ca2+releases in zebrafish. In summary, the highly dynamic NEMOer sensors expand the repertoire of organellar Ca2+sensors that allow real-time monitoring of intricate Ca2+dynamics and homeostasis in live cells with high spatiotemporal resolution.
Combining Cell-Intrinsic and -Extrinsic Resistance to HIV-1 By Engineering Hematopoietic Stem Cells for CCR5 Knockout and B Cell Secretion of Therapeutic Antibodies
Authors: Feist William N. , Luna Sofia E. , Ben-Efraim Kaya , Filsinger Interrante Maria V. , Amorin Nelson A. , Johnston Nicole M. , Bruun Theodora U. J. , Ghanim Hana Y. , Lesch Benjamin J. , Dudek Amanda M. , Porteus Matthew H. 
Published: March 2024

AbstractAutologous transplantation ofCCR5null hematopoietic stem and progenitor cells (HSPCs) is the only known cure for HIV-1 infection. However, this treatment is limited because of the rarity ofCCR5-null matched donors, the morbidities associated with allogeneic transplantation, and the prevalence of HIV-1 strains resistant to CCR5 knockout (KO) alone. Here, we propose a one-time therapy through autologous transplantation of HSPCs genetically engineeredex vivoto produce both CCR5 KO cells and long-term secretion of potent HIV-1 inhibiting antibodies from B cell progeny. CRISPR-Cas9-engineered HSPCs maintain engraftment capacity and multi-lineage potentialin vivoand can be engineered to express multiple antibodies simultaneously. Human B cells engineered to express each antibody secrete neutralizing concentrations capable of inhibiting HIV-1 pseudovirus infectionin vitro. This work lays the groundwork for a potential one-time functional cure for HIV-1 through combining the long-term delivery of therapeutic antibodies against HIV-1 and the known efficacy ofCCR5KO HSPC transplantation.
In vitroandin vivovalidation of cwlM and pbpB essentiality for viability and resistance to imipenem inMycobacterium abscessus
Authors: Lee Jin , Li Si-Yang , Rifat Dalin , Kurepina Natalia , Chen Liang , Kreiswirth Barry N. , Nuermberger Eric L. 
Published: March 2024

AbstractMycobacterium abscessuslung infection is notoriously difficult to treat due, in part, to the intrinsic resistance of this pathogen to most marketed antibiotics. β-Lactams, namely imipenem and cefoxitin, are first-line drugs in combination regimens used to treat this infection; and there is growing interest in dual-β-lactam-based regimens. Better understanding of the molecular basis of β-lactam activity through study of the genetic determinants of β-lactam susceptibility and tolerance would enable more rational drug combinations and guide discovery of novel drug targets to complement β-lactams. We recently used an inducible CRISPR interference (CRISPRi) system to silencecwlMandpbpBand confirm their essentiality forin vitrogrowth and resistance to sub-MIC concentrations of imipenem. Here, we extend those findings to show that silencing either gene alone is bactericidal and augments the bactericidal activity of imipenemin vitro. Furthermore, using CRISPRi in a mouse model ofM. abscessuslung infection for the first time, we confirm the essentiality of each gene forin vivosurvival. These results validatecwlMandpbpBas essential genes and promising drug targets in this pathogen, including for potentiation of carbapenem activity. The results further establish CRISPRi as a powerful method for validating drug targets and studying gene-gene and gene-drug interactionsin vitroandin vivo.
Antimicrobial Resistance in Diverse Urban Microbiomes: Uncovering Patterns and Predictive Markers
Authors: Toscan Rodolfo Brizola , Lesiński Wojciech , Stomma Piotr , Subramanian Balakrishnan , Łabaj Paweł P. , Rudnicki Witold R. 
Published: March 2024

ABSTRACTAntimicrobial resistance (AMR) poses a significant global health threat, exacerbated by urbanization and anthropogenic activities. This study investigates the distribution and dynamics of AMR within urban microbiomes from six major U.S. cities using metagenomic data provided by the CAMDA 2023 challenge. We employed a range of analytical tools to investigate sample resistome, virome, and mobile genetic elements (MGEs) across these urban environments. Our results demonstrate that AMR++ and Bowtie outperform other tools in detecting diverse and abundant AMR genes, with binarization of data enhancing classification performance. The analysis revealed that a portion of resistome markers is closely associated with MGEs, and their removal drastically impacts the resistome profile and the accuracy of resistome modeling. These findings highlight the importance of preserving key MGEs in resistome studies to maintain the integrity and predictive power of AMR profiling models. This study underscores the heterogeneous nature of AMR in urban settings and the critical role of MGEs, providing valuable insights for future research and public health strategies.
Interplay between ß-propeller subunits WDR26 and muskelin regulates the CTLH E3 ligase supramolecular complex
Authors: Maitland Matthew E.R. , Onea Gabriel , Owens Dominic D. G. , Gonga-Cavé Brianna C. , Wang Xu , Arrowsmith Cheryl H. , Barsyte-Lovejoy Dalia , Lajoie Gilles A. , Schild-Poulter Caroline 
Published: March 2024

AbstractThe Pro/N-degron recognizing C-terminal to LisH (CTLH) complex is an E3 ligase of emerging interest in the developmental field and for targeted protein degradation (TPD) modalities. The human CTLH complex forms distinct supramolecular ring-shaped structures dependent on the multimerization of WDR26 or muskelin ß-propeller proteins. Here, we find that, in human cells, CTLH complex E3 ligase activity is dictated by a dynamic exchange between WDR26 and muskelin in tandem with muskelin autoregulation. Proteomic experiments revealed that complex-associated muskelin protein turnover is a major ubiquitin-mediated degradation event dependent on the CTLH complex in unstimulated HeLa cells. We observed that muskelin and WDR26 binding to the scaffold of the complex is interchangeable, indicative of the formation of separate WDR26 and muskelin complexes, which correlated with distinct proteomes in WDR26 and muskelin knockout cells. We found that mTOR inhibition-induced degradation of Pro/N-degron containing protein HMGCS1 is distinctly regulated by a muskelin-specific CTLH complex. Finally, we found that mTOR inhibition also activated muskelin degradation, likely as an autoregulatory feedback mechanism to regulate CTLH complex activity. Thus, rather than swapping substrate receptors, the CTLH E3 ligase complex controls substrate selectivity and its autoregulation through exchanging its β-propeller oligomeric subunits WDR26 and muskelin.
A low-footprint, fluorescence-based bacterial time-kill assay for estimating dose-dependent cell death dynamics
Authors: King Eshan S. , Stacy Anna E. , Scott Jacob G. 
Published: March 2024

ABSTRACTDose-response curves that describe the relationship between antibiotic dose and growth rate in bacteria are commonly measured with optical density (OD) based assays. While being simple and high-throughput, any dose-dependent cell death dynamics are obscured, as OD assays in batch culture can only quantify a positive net change in cells. Time-kill experiments can be used to quantify cell death rates, but current techniques are extremely resource-intensive and may be biased by residual drug carried over into the quantification assay. Here, we report a novel, fluorescence-based time-kill assay leveraging resazurin as a viable cell count indicator. Our method improves upon previous techniques by greatly reducing the material cost and being robust to residual drug carry-over. We demonstrate our technique by quantifying a dose-response curve inEscherichia colisubject to cefotaxime, revealing dose-dependent death rates. We also show that our method is robust to extracellular debris and cell aggregation. Dose-response curves quantified with our method may provide a more accurate description of pathogen response to therapy, paving the way for more accurate integrated pharmacodynamic-pharmacokinetic studies.
Effect of pH on the thermostability and redox properties of cytochromec552fromWolinella succinogenes
Authors: Mordido Vitor H. , Carepo Marta S. P. , Cordas Cristina M. , Paul Navendu , Simon Jörg , Moura Isabel , Pauleta Sofia R. 
Published: March 2024

AbstractCytochromec552fromWolinella succinogenesis one of the few examples of a low reduction potential class Ic-type cytochrome with a mixture of high/low spin state populations observed in its visible spectrum. Analysis of its structural model suggests that the heme is Met/His coordinated and highly solvent-exposed. This supports the hypothesis that it is the solvent accessibility of the propionate groups that controls the reduction potential of smallc-type cytochromes. The visible spectra obtained at different pH values reveal the presence of a protonable group with a pKaof 7.3, which also influences the reduction potential of this small cytochromec552(Em0’of 97 ± 5 mV, pH 7.0) and can be either an H2O/OH-group distantly coordinating the heme iron, or one of the propionate groups. The thermostability of cytochromec552has been studied by circular dichroism and differential scanning calorimetry, indicating a highly stable protein at pH 5-7 (90 °C to 77 °C).
A matter of salt: global assessment of the effect of salt ionic composition as a driver of aquatic bacterial diversity
Authors: Szabó Attila , Székely Anna J. , Boros Emil , Márton Zsuzsanna , Csitári Bianka , Barteneva Natalie , Anda Dóra , Dobosy Péter , Eiler Alexander , Bertilsson Stefan , Felföldi Tamás 
Published: March 2024

AbstractWhile the strong general effects of salinity on microbial diversity are well-known and described for marine and freshwater habitats, the impact of the specific composition of major inorganic ions remains largely unexplored. In this study, we assess how microbial community structure in inland saline aquatic habitats is influenced by ionic composition as compared to salinity, spatial factors, and other environmental parameters. We collected and analysed 16S rRNA gene V4 and V3-V4 amplicon datasets from freshwater to hypersaline aquatic environments worldwide (in total 375 samples from 130 lakes). With an emphasis on saline inland waters characterised by highly variable ionic composition, we demonstrated that the ionic composition of the major ions explained more variability in community composition than bulk salinity and that the geographic location of the sampling sites had only an ambiguous effect. We also identified the taxa contributing the most to the observed dissimilarity between communities from sites with different ionic composition and found mostly lineages known to be characteristic for a given habitat type, such as Actinobacteria acI in freshwater, Halomonadaceae in saline, or Nitriliruptorales in soda and soda-saline habitats. Many of these habitat type-specific indicator lineages were monophyletic, underpinning ionic composition as a crucial eco-evolutionary driver of aquatic microbial diversity.
Digitalization and Resource Mobilization
Authors: Inceoglu Ilke , Vanacker Tom , Vismara Silvio 
Published: March 2024

AbstractDigitalization can profoundly change resource mobilization, including the search, access and governance of resources. In this introductory paper to the Special Issue on Digitalization and Resource Mobilization, we review existing research to identify different approaches towards digitalization, different conceptualizations of what resources are in this context and different aspects of resource mobilization across studies and theories. Drawing on these insights, we illustrate contemporary research examples and outline the way forward for two research streams focusing on resource mobilization in a digital context – specifically, the crowdfunding and human resources literature. We conclude by proposing four new areas to further advance the field.
Investigating the economic impact of climate change on agriculture in Iran: Spatial spillovers matter
Authors: Malaekeh Sayed Morteza , Shiva Layla , Safaie Ammar 
Published: March 2024

AbstractIn this study, we enhance our understanding of the economic impacts of climate change on agriculture in Iran to provide further information for moving Iran's climate policy forward by linking farmland net revenue to novel climatic and non‐climatic variables. We take advantage of spatial panel econometrics to better circumvent omitted factors extraneous to the agricultural sector and to develop a more reliable and consistent model when data are inherently spatial. In contrast to conventional panel studies which relied on year‐to‐year weather observations, we exploit a hybrid approach to compromise between the disadvantages and advantages of longer‐term cross‐sectional analysis and shorter‐term panel models. We estimate the potential impacts of climate change on agriculture under several global warming scenarios based on the Sixth Phase of the Coupled Model Intercomparison Project (CMIP6). We find that (I) farmlands’ net revenues are projected to decline by 8%–19% and 14%–51% by 2050 and 2080; (II) the distributional impacts of climate change would highly depend on climate zones and geographical locations; (III) a few counties might benefit from climate changes; (IV) finally, failing to account for spatial spillovers when they are present leads to a misspecified model.
Great expectations: The effect of unmet labor market expectations after higher education on ideology
Authors: Cox Loreto 
Published: March 2024

AbstractHigher education has massively expanded around the world, yet we know little about the political consequences of this expansion. Students generally have overly optimistic expectations about the returns to educational investment, and the effects of unmet expectations on graduates’ political behavior have been overlooked. I study this phenomenon in Chile with observational and experimental methods, using unique panel survey data collected from new graduates covering 72% of higher education enrollment. The survey tracks students before and after they enter the labor market and includes an experiment that induces variation in their expectations. The panel data reveals that 65% of students have unmet expectations, and both methods indicate that this induces a shift toward progovernment/proequality ideology. Overall, this study shows that the gap between aspirations and reality upon graduation can be an important driver of political attitudes.
Young people's alcohol use in and around water: A scoping review of the literature
Authors: Carey Renee N. , Crawford Gemma , Jancey Jonine , Lam Tina , Nimmo Lauren , Trapp Gina , Pollard Christina , Hooper Paula , Leavy Justine E. 
Published: March 2024

AbstractIssuesThe surrounding social and commercial context, including alcohol advertising, heavily influences alcohol consumption. Alcohol use is a major risk factor for both fatal and non‐fatal drowning, particularly for young people.ApproachWe conducted a scoping review to explore the peer‐reviewed literature on the use of alcohol by young people (aged 15–34 years) in the context of aquatic environments. Five electronic academic databases were searched for English‐language studies conducted in high‐income countries and published in the last 15 years (since 2008). The MetaQAT framework was used to assess methodological quality of included studies.Key FindingsThe review included a total of 24 studies, including those addressing the prevalence of and/or risk factors for alcohol use in aquatic environments among young people (n = 13); the epidemiology of alcohol‐related unintentional drowning in young people (n = 9); and interventions to reduce alcohol‐related harm around water (n = 3). Findings suggest that young people commonly consume alcohol around water, particularly young men. We found multiple influences on this behaviour, including the perception of risk, location of aquatic activity and presence of others, particularly peers.ImplicationsUnderstanding the literature addressing alcohol use around water among young people will assist in identifying and setting priorities for drowning prevention, including the need to mitigate the effects of alcohol advertising which promotes drinking in and around water.ConclusionThere is a clear imperative to address the use of alcohol by young people in aquatic environments. These findings have key implications for public health policy, advocacy and practice.
A flavonoid metabolon: cytochrome b5 enhances B‐ring trihydroxylated flavan‐3‐ols synthesis in tea plants
Authors: Ruan Haixiang , Gao Liping , Fang Zhou , Lei Ting , Xing Dawei , Ding Yan , Rashid Arif , Zhuang Juhua , Zhang Qiang , Gu Chunyang , Qian Wei , Zhang Niuniu , Qian Tao , Li Kongqing , Xia Tao , Wang Yunsheng 
Published: March 2024

SUMMARYFlavan‐3‐ols are prominent phenolic compounds found abundantly in the young leaves of tea plants. The enzymes involved in flavan‐3‐ol biosynthesis in tea plants have been extensively investigated. However, the localization and associations of these numerous functional enzymes within cells have been largely neglected. In this study, we aimed to investigate the synthesis of flavan‐3‐ols in tea plants, particularly focusing on epigallocatechin gallate. Our analysis involving the DESI‐MSI method to reveal a distinct distribution pattern of B‐ring trihydroxylated flavonoids, primarily concentrated in the outer layer of buds. Subcellular localization showed that CsC4H, CsF3′H, and CsF3′5′H localizes endoplasmic reticulum. Protein–protein interaction studies demonstrated direct associations between CsC4H, CsF3′H, and cytoplasmic enzymes (CHS, CHI, F3H, DFR, FLS, and ANR), highlighting their interactions within the biosynthetic pathway. Notably, CsF3′5′H, the enzyme for B‐ring trihydroxylation, did not directly interact with other enzymes. We identified cytochrome b5 isoform C serving as an essential redox partner, ensuring the proper functioning of CsF3′5′H. Our findings suggest the existence of distinct modules governing the synthesis of different B‐ring hydroxylation compounds. This study provides valuable insights into the mechanisms underlying flavonoid diversity and efficient synthesis and enhances our understanding of the substantial accumulation of B‐ring trihydroxylated flavan‐3‐ols in tea plants.
How diverse a monocentric chromosome can be? Repeatome and centromeric organization of Juncus effusus (Juncaceae)
Authors: Dias Yhanndra , Mata‐Sucre Yennifer , Thangavel Gokilavani , Costa Lucas , Báez Mariana , Houben Andreas , Marques André , Pedrosa‐Harand Andrea 
Published: March 2024

SUMMARYJuncus is the largest genus of Juncaceae and was considered holocentric for a long time. Recent findings, however, indicated that 11 species from different clades of the genus have monocentric chromosomes. Thus, the Juncus centromere organization and evolution need to be reassessed. We aimed to investigate the major repetitive DNA sequences of two accessions of Juncus effusus and its centromeric structure by employing whole‐genome analyses, fluorescent in situ hybridization, CENH3 immunodetection, and chromatin immunoprecipitation sequencing. We showed that the repetitive fraction of the small J. effusus genome (~270 Mbp/1C) is mainly composed of Class I and Class II transposable elements (TEs) and satellite DNAs. Three identified satellite DNA families were mainly (peri)centromeric, with two being associated with the centromeric protein CENH3, but not strictly centromeric. Two types of centromere organization were discerned in J. effusus: type 1 was characterized by a single CENH3 domain enriched with JefSAT1‐155 or JefSAT2‐180, whereas type 2 showed multiple CENH3 domains interrupted by other satellites, TEs or genes. Furthermore, while type 1 centromeres showed a higher degree of satellite identity along the array, type 2 centromeres had less homogenized arrays along the multiple CENH3 domains per chromosome. Although the analyses confirmed the monocentric organization of J. effusus chromosomes, our data indicate a more dynamic arrangement of J. effusus centromeres than observed for other plant species, suggesting it may constitute a transient state between mono‐ and holocentricity.
Tranexamic acid in trauma: After 3 hours from injury, when is it safe and effective to use again?
Authors: Barrett Christopher D. , Neal Matthew D. , Schoenecker Jonathan G. , Medcalf Robert L. , Myles Paul S. 
Published: March 2024

AbstractTranexamic acid (TXA) has proven mortality benefit if used early after traumatic injury, likely related to a combination of bleeding reduction and other non‐bleeding effects. If TXA is given more than 3 h after traumatic injury, there is a significant and paradoxical increased risk of death due to bleeding. TXA has level 1 evidence for use as a bleeding reduction agent in isolated orthopedic operations, but in polytrauma patients undergoing orthopedic operations, it is not clear if and when TXA is safe or effective once outside the 3‐h window of proven trauma efficacy.