bluuebunny/crossref_metadata_2025_split huggingface dataset:
Projective oblique plane structured illumination microscopy
Authors: Chang Bo-Jui , Shepherd Douglas , Fiolka Reto 
Published: August 2023

AbstractStructured illumination microscopy (SIM) can double the spatial resolution of a fluorescence microscope and video rate live cell imaging in a two-dimensional format has been demonstrated. However, rapid implementations of 2D SIM typically only cover a narrow slice of the sample immediately at the coverslip, with most of the cellular volume out of reach. Here we implement oblique plane structured illumination microscopy (OPSIM) in a projection format to rapidly image an entire cell in a 2D SIM framework. As no mechanical scanning of the sample or objective is involved, this technique has the potential for rapid projection imaging with doubled resolution. We characterize the spatial resolution with fluorescent nanospheres, compare projection and 3D imaging using OPSIM and image mitochondria and ER dynamics across an entire cell at up to 2.7 Hz. To our knowledge, this represents the fastest whole cell SIM imaging to date.
Thiazolidinediones are partially effective bitter blockers
Authors: Nguyen Ha , Lin Cailu , Sasimovich Ivona , Bell Katherine , Huang Amy , Leszkowicz Emilia , Rawson Nancy E. , Reed Danielle R. 
Published: August 2023

AbstractPurposeThe bad bitter taste of some medicines is a barrier to overcoming non-compliance with medication use, especially life-saving drugs given to children and the elderly. Here we evaluated a new class of bitter blockers (thiazolidinediones; TZDs).MethodsIn this study, two TZDs were tested, rosiglitazone (ROSI) and a simpler form of TZD, using a high-potency sweetener as a positive control (neohesperidin dihydrochalcone, NHDC). We tested bitter-blocking effects using the bitter drugs tenofovir alafenamide fumarate (TAF), a treatment for HIV and hepatitis B infection, and praziquantel (PRAZ), a treatment for schistosomiasis, by conducting taste testing with two separate taste panels: a general panel (N=97, 20-23 yrs, 82.5% female, all Eastern European) and a genetically informative panel (N=158, including 68 twin pairs, 18-82 yrs, 76% female, 87% European ancestry). Participants rated the bitterness intensity of the solutions on a 100-point generalized visual analog scale.FindingsParticipants in both taste panels rated the bitter drugs TAF and PRAZ as less bitter on average when mixed with NHDC than when sampled alone. ROSI partially suppressed the bitterness of TAF and PRAZ, but effectiveness differed between the two panels: bitterness was significantly reduced for PRAZ but not TAF in the general panel and for TAF but not PRAZ in the genetically informative panel. ROSI was a more effective blocker than the other TZD.ImplicationsThese results suggest that TZDs are partially effective bitter blockers, suggesting other TZDs should be designed and tested with more drugs and on diverse populations to define which ones work best with which drugs and for whom. The discovery of bitter receptor blockers can improve compliance with medication use.
Xylem sap residue in cut-open conduits can affect gas discharge in pneumatic experiments
Authors: Miranda Marcela T. , Pereira Luciano , Pires Gabriel S. , Guan Xinyi , Silva Luciano M. , Kreinert Swetlana , Machado Eduardo C. , Jansen Steven , Ribeiro Rafael V. 
Published: August 2023

SummaryConsiderable progress has been made in understanding the mechanisms of embolism formation based on the pneumatic method, which relies on gas discharge measurements. Here, we test the assumption that cut-open conduits are gas-filled when samples are cut at high water potentials.We performed vulnerability curves (VC) with the Pneumatron and analysed sap extraction from cut-open vessels inCitrusbranches, while the optical method was applied as a reference method. VCs of 11 additional angiosperms were analysed to generalise our findings.We found an increase in gas discharge during early stages of dehydration, which affected the VC ofCitrus. Xylem sap was not absorbed immediately by surrounding tissue in cutCitrusbranches. The gas amount discharged increased until all sap residue was absorbed, which was near the turgor loss point. By analysing the slope of VCs, we could correct pneumatic VC, as evidenced by the strong agreement in embolism resistance between the pneumatic and the optical method.Since residual sap in cut-open conduits of some species could slightly reduce embolism resistance in some species, we propose to apply an easy correction for this novel artefact. Automated measurements with a Pneumatron are also required because of its high time resolution.
Gating mechanism of the human α1β GlyR by glycine
Authors: Liu Xiaofen , Wang Weiwei 
Published: August 2023

AbstractGlycine receptors (GlyRs) are members of the Cys-loop receptors that constitute a major portion of neurotransmitter receptors in the human nervous system. GlyRs are found in the spinal cord and brain mediating locomotive, sensory and cognitive functions, and are targets for pharmaceutical development. GlyRs share a general gating scheme with Cys-loop receptor family members, but the underlying mechanism is unclear. Recent resolution of heteromeric GlyRs structures in multiple functional states identified an invariable 4:1 α:β subunit stoichiometry and provided snapshots in the gating cycle, challenging previous beliefs and raising the fundamental questions of how α and β subunit functions in glycine binding and channel activation. In addition, how a single glycine-bound extracellular domain conformation leads to structurally and functionally different open and desensitized states remained enigmatic. In this study, we characterized in detail equilibrium properties as well as the transition kinetics between functional states. We show that while all allosteric sites bind cooperatively to glycine, occupation of 2 sites at the α-α interfaces is necessary and sufficient for GlyR activation. We also demonstrate differential glycine concentration dependence of desensitization rate, extent, and its recovery, which suggests separate but concerted roles of ligand-binding and ionophore reorganization. Based on these observations and available structural information, we developed a comprehensive quantitative gating model that accurately predicts both equilibrium and kinetical properties throughout glycine gating cycle. This model likely applies generally to the Cys-loop receptor family and informs on pharmaceutical endeavors in function modulation of this receptor family.
Systems-ecology designed bacterial consortium protects from severeClostridioides difficileinfection
Authors: Jenior Matthew L , Leslie Jhansi L , Kolling Glynis L , Archbald-Pannone Laurie , Powers Deborah A , Petri William A , Papin Jason A 
Published: August 2023

ABSTRACTFecal Microbiota Transplant (FMT) is an emerging therapy that has had remarkable success in treatment and prevention of recurrentClostridioides difficileinfection (rCDI). FMT has recently been associated with adverse outcomes such as inadvertent transfer of antimicrobial resistance, necessitating development of more targeted bacteriotherapies. To address this challenge, we developed a novel systems biology pipeline to identify candidate probiotic strains that would be predicted to interruptC. difficilepathogenesis. Utilizing metagenomic characterization of human FMT donor samples, we identified those metabolic pathways most associated with successful FMTs and reconstructed the metabolism of encoding species to simulate interactions withC. difficile. This analysis resulted in predictions of high levels of cross-feeding for amino acids in species most associated with FMT success. Guided by thesein silicomodels, we assembled consortia of bacteria with increased amino acid cross-feeding which were then validatedin vitro. We subsequently tested the consortia in a murine model of CDI, demonstrating total protection from severe CDI through decreased toxin levels, recovered gut microbiota, and increased intestinal eosinophils. These results support the novel framework that amino acid cross-feeding is likely a critical mechanism in the initial resolution of CDI by FMT. Importantly, we conclude that our predictive platform based on predicted and testable metabolic interactions between the microbiota andC. difficileled to a rationally designed biotherapeutic framework that may be extended to other enteric infections.
Mesenchymal stem cells of the bone marrow raise infectivity ofPlasmodium falciparumgametocytes
Authors: Suresh Ragavan Varadharajan , Deng Bingbing , Gebremicale Yonas , Roche Kyle , Miura Kazutoyo , Long Carole 
Published: August 2023

AbstractPlasmodium falciparumis a parasite that causes the deadly human disease, malaria, and exhibits a complex life cycle in the human and mosquito hosts. As the sexual stages of the parasite, gametocytes mature in the human body and propagate malaria when they are picked up by mosquitoes to infect new hosts. Previous research has shown that gametocytes home to the bone marrow of the host where they complete their maturation and alter the behavior of resident Mesenchymal Stem Cells (MSCs). In this study, we investigated the alternate side of this host-pathogen interaction, whether MSCs could alter the behavior of gametocytes. Gametocytes were co-cultured with MSCs until maturity and subsequently fed to mosquitoes to measure the oocysts produced. Here we report for the first time, that MSCs co-culture significantly elevated oocyst numbers in the infected mosquito compared to conventional culture medium. This enhancement appeared to be most effective during the early stages of gametocyte development and was not replicated by other cell types. MSC co-culture also increased infectivity of field isolatedP. falciparumparasites. This effect was partially mediated by soluble factor(s) as conditioned medium harvested from MSCs could also partially raise infectivity of gametocytes to nearly half compared to MSC co-culture. Together this study reveals novel host pathogen interactions, where the human MSCs are elevating the infectivity of malaria gametocytes.ImportanceWhile prior research has established thatPlasmodiumgametocytes sequester in the bone marrow and can influence resident stem cells, the question of why they would choose this compartment and these cells remained a mystery. This study for the first time, shows that being in the presence of MSCs alters the biology of theP. falciparumparasite and makes it more infectious to mosquitoes, hinting at novel mechanisms in its life cycle. This method also facilitates mosquito infections with field isolated parasites, affording research teams new infection models with parasite s which are challenging to infect into mosquitos using conventional culture methods. Finally, our findings that MSC conditioned medium can also raise infectivity opens avenues of investigation into mechanisms involved, but can also serve as a practical tool to researchers hoping to increase oocyst yields.
GenomeMUSter mouse genetic variation service enables multi-trait, multi-population data integration and analyses
Authors: Ball Robyn L. , Bogue Molly A. , Liang Hongping , Srivastava Anuj , Ashbrook David G. , Lamoureux Anna , Gerring Matthew W. , Hatoum Alexander S. , Kim Matthew , He Hao , Emerson Jake , Berger Alexander K. , Walton David O. , Sheppard Keith , Kassaby Baha El , Castellanos Francisco , Kunde-Ramamoorthy Govind , Lu Lu , Bluis John , Desai Sejal , Sundberg Beth A. , Peltz Gary , Fang Zhuoqing , Churchill Gary A. , Williams Robert W. , Agrawal Arpana , Bult Carol J. , Philip Vivek M. , Chesler Elissa J. 
Published: August 2023

ABSTRACTHundreds of inbred laboratory mouse strains and intercross populations have been used to functionalize genetic variants that contribute to disease. Thousands of disease relevant traits have been characterized in mice and made publicly available. New strains and populations including the Collaborative Cross, expanded BXD and inbred wild-derived strains add to set of complex disease mouse models, genetic mapping resources and sensitized backgrounds against which to evaluate engineered mutations. The genome sequences of many inbred strains, along with dense genotypes from others could allow integrated analysis of trait – variant associations across populations, but these analyses are not feasible due to the sparsity of genotypes available. Moreover, the data are not readily interoperable with other resources. To address these limitations, we created a uniformly dense data resource by harmonizing multiple variant datasets. Missing genotypes were imputed using the Viterbi algorithm with a data-driven technique that incorporates local phylogenetic information, an approach that is extensible to other model organism species. The result is a web– and programmatically-accessible data service called GenomeMUSter (https://muster.jax.org), comprising allelic data covering 657 strains at 106.8M segregating sites. Interoperation with phenotype databases, analytic tools and other resources enable a wealth of applications including multi-trait, multi-population meta-analysis. We demonstrate this in a cross-species comparison of the meta-analysis of Type 2 Diabetes and of substance use disorders, resulting in the more specific characterization of the role of human variant effects in light of mouse phenotype data. Other applications include refinement of mapped loci and prioritization of strain backgrounds for disease modeling to further unlock extant mouse diversity for genetic and genomic studies in health and disease.
Cellular hnRNPA0 limits HIV-1 production by interference with LTR-activity and programmed ribosomal frameshifting
Authors: Roesmann Fabian , Sertznig Helene , Klaassen Katleen , Wilhelm Alexander , Heininger Delia , Elsner Carina , Santiago Mario , Esser Stefan , Sutter Kathrin , Dittmer Ulf , Widera Marek 
Published: August 2023

AbstractThe interplay between host factors and viral components has a profound impact on the viral replication efficiency and fitness. Heterogeneous nuclear ribonucleoproteins (hnRNPs), in particular members of the subfamily A/B, have been broadly studied as HIV-1 host dependency factors, however, the least related member hnRNPA0 has so far not been functionally studied in its potential role affecting viral replication.In this study, we revealed that hnRNPA0 overexpression in HEK293T cells significantly reduced HIV-1 long terminal repeat (LTR) activity up to 3.5-fold, leading to a significant decrease in total viral mRNA (5.5-fold) and protein levels (3-fold). Conversely, knockdown of hnRNPA0 enhanced LTR activity, suggesting its negative regulatory role in viral gene expression. Moreover, the splicing pattern of HIV-1 remained largely unaffected by altered hnRNPA0 levels indicating changes in viral mRNA expression predominantly occurred at the transcriptional level. Moreover, hnRNPA0 overexpression was found to significantly reduce the programmed ribosomal frameshift efficiency of HIV-1, resulting in a shift in the HIV-1 p55/p15 ratio, compromising viral fitness. Synergistic inhibition of LTR activity and thus reduced viral mRNA transcription and impaired ribosomal frameshifting efficiency, which is important for viral infectivity, were detrimental to HIV-1 replication. Additionally, our study revealed that hnRNPA0 levels were lower in therapy naïve HIV-1-infected individuals compared to healthy controls and temporarily repressed after IFN-I treatment in HIV-1 target cells.Our findings highlight the significant role of hnRNPA0 in HIV-1 replication and suggests that its IFN-I regulated expression levels are decisive for viral fitness.ImportanceRNA binding proteins, in particular heterogeneous nuclear ribonucleoproteins (hnRNPs) have been extensively studied as host dependency factors for HIV-1 since they are involved in multiple cellular gene expression processes. However, the functional role of hnRNPA0, the least related member of the hnRNPA/B family, and its potential impact on viral replication remains unclear. For the first time, our findings demonstrate the significance of hnRNPA0 in restricting viral replication efficiency. We demonstrate that hnRNPA0 plays a pleiotropic role in limiting viral replication being a negative regulator of viral transcription and significantly impairing ribosomal frameshifting. Our study also revealed hnRNPA0 as an IFN-regulated host factor that is temporarily repressed after IFN-I treatment in HIV-1 target cells and lower expressed in therapy-naïve HIV-1-infected individuals compared to healthy controls. Understanding the mode of action between hnRNPA0 and HIV-1 might help to identify novel therapeutically strategies against HIV-1 and other viruses.
Interaction of PINK1 with nucleotides and kinetin
Authors: Gan Zhong Yan , Callegari Sylvie , Nguyen Thanh N. , Kirk Nicholas S , Leis Andrew , Lazarou Michael , Dewson Grant , Komander David 
Published: August 2023

AbstractPINK1 is a ubiquitin kinase that accumulates on damaged mitochondria to trigger mitophagy, and PINK1 loss-of-function mutations cause early onset Parkinson’s disease. Nucleotide analogues such as kinetin triphosphate (KTP) have been suggested to enhance PINK1 activity and may represent a therapeutic strategy for the treatment of Parkinson’s disease. Here, we investigate the interaction of PINK1 with nucleotides, including KTP. We establish a cryo-EM platform exploiting the previously observed dodecamer assembly ofPediculus humanus corporis(Ph) PINK1 to determine PINK1 structures bound to AMP-PNP and ADP, which reveal unexpected conformational changes in the kinase N-lobe to enable PINK1 to form a ubiquitin binding site. Strikingly, we find that KTP is unable to bindPhPINK1 or human (Hs) PINK1 due to a steric clash with the kinase ‘gatekeeper’ residue. Mutation of the gatekeeper to Ala or Gly is required to enable PINK1 to bind and utilise KTP as a phosphate donor in ubiquitin phosphorylation and mitophagy. Indeed,HsPINK1 M318G can be used to conditionally uncouple PINK1 stabilisation and activity on mitochondria.
Kin selection as a modulator of human handedness: sex-specific, parental and parent-of-origin effects
Authors: Dong Bing , Paracchini Silvia , Gardner Andy 
Published: August 2023

AbstractThe frequency of left-handedness in humans is ∼10% worldwide and slightly higher in males than females. Twin and family studies estimate the heritability of human handedness at around 25%. The low but substantial frequency of left-handedness has been suggested to imply negative frequency-dependent selection, e.g. owing to a “surprise” advantage of left-handers in combat against opponents more used to fighting right-handers. Because such game-theoretic hypotheses involve social interaction, here, we perform an analysis of the evolution of handedness based on kin-selection, which is understood to play a major role in the evolution of social behaviour generally. We show that: (1) relatedness modulates the balance of right-handedness versus left-handedness, according to whether left- handedness is marginally selfish versus marginally altruistic; (2) sex differences in relatedness to social partners may drive sex differences in handedness; (3) differential relatedness of parents and offspring may generate parent-offspring conflict and sexual conflict leading to the evolution of maternal and paternal genetic effects in relation to handedness; and (4) differential relatedness of maternal-origin versus paternal-origin genes may generate intragenomic conflict leading to the evolution of parent-of-origin-specific gene effects—such as “genomic imprinting”—and associated maladaptation.
Water, Sanitation and Hygiene Interventions in Schools for Effective Pandemic Response in Low and Middle-Income Countries: Scoping review protocol
Authors: Seroney Gladys Chepkorir , Mchunu Gugu Gladness , Kgarosi Kabelo , Magak Ng’wena Asha Gideon 
Published: August 2023

AbstractBackgroundThe impact of improved water, sanitation, and hygiene (WASH) access on mitigating illness is well documented. Despite continued national and international efforts, access to improved water and sanitation in schools remains limited in many developing countries. The proposed scoping review is aimed at mapping evidence on the status of WASH interventions in schools for effective pandemic response in low and middle-income countries. The scoping review will guide and improve schools’ WASH with an ultimate goal of preventing disease and protecting school-going children during infectious disease outbreaks, including the current COVID-19 pandemic.MethodsThe proposed scoping review will be guided by Arksey and O’Malley’s framework. A comprehensive keyword search for relevant articles presenting evidence on the status of WASH in school interventions will be conducted in the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Academic Search Complete, Google Scholar, and the Scopus electronic databases. Articles reporting on the status of WASH in schools published between January 2000 and September 2021 will be included. The review will employ the NVIVO version 12 software package to extract the relevant themes from the included articles using content thematic analysis.DiscussionWe anticipate to find relevant studies reporting on the status of WASH interventions in schools. The results of this review will provide information that is likely to inform the monitoring and evaluation of WASH interventions in schools and assist towards achievement of Sustainable Development Goal 6. It may also help in crafting relevant and up to date guidelines or policies in relation to WASH systems in schools.
Plasma Glycomic Markers of Accelerated Biological Aging During Chronic HIV Infection
Authors: Giron Leila B , Liu Qin , Adeniji Opeyemi S , Yin Xiangfan , Kannan Toshitha , Ding Jianyi , Lu David Y. , Langan Susan , Zhang Jinbing , Azevedo Joao L. L. C. , Li Shuk Hang , Shalygin Sergei , Azadi Parastoo , Hanna David B , Ofotokun Igho , Lazar Jason , Fischl Margaret A. , Haberlen Sabina , Macatangay Bernard , Adimora Adaora A. , Jamieson Beth D. , Rinaldo Charles , Merenstein Daniel , Roan Nadia R. , Kutsch Olaf , Gange Stephen , Wolinsky Steven , Witt Mallory , Post Wendy S. , Kossenkov Andrew , Landay Alan , Frank Ian , Tien Phyllis C. , Gross Robert , Brown Todd T. , Abdel-Mohsen Mohamed 
Published: August 2023

ABSTRACTPeople with HIV (PWH) experience an increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors that contribute to or are associated with this vulnerability remain uncertain. In the general population, alterations in the glycomes of circulating IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG glycomes of cross-sectional and longitudinal samples from 1,216 women and men, both living with virally suppressed HIV and those without HIV. Our glycan-based machine learning models indicate that living with chronic HIV significantly accelerates the accumulation of pro-aging-associated glycomic alterations. Consistently, PWH exhibit heightened expression of senescence-associated glycan-degrading enzymes compared to their controls. These glycomic alterations correlate with elevated markers of inflammatory aging and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit reduced anti-HIV IgG-mediated innate immune functions. These findings hold significant potential for the development of glycomic-based biomarkers and tools to identify and prevent premature aging and comorbidities in people living with chronic viral infections.