bluuebunny/crossref_metadata_2025 huggingface dataset:
Antibody Inhibition of Influenza A Virus Assembly and Release
Authors: He Yuanyuan , Guo Zijian , Subiaur Sofie , Benegal Ananya , Vahey Michael D.
Published: August 2023

Antibodies are frontline defenders against influenza virus infection, providing protection through multiple complementary mechanisms. Although a subset of monoclonal antibodies (mAbs) have been shown to restrict replication at the level of virus assembly and release, it remains unclear how potent and pervasive this mechanism of protection is, due in part to the challenge of separating this effect from other aspects of antibody function. To address this question, we developed imaging-based assays to determine how effectively a broad range of mAbs against the IAV surface proteins can specifically restrict viral egress. We find that classically neutralizing antibodies against hemagglutinin are broadly multifunctional, inhibiting virus assembly and release at concentrations one- to twenty-fold higher than the concentrations at which they inhibit viral entry. These antibodies are also capable of altering the morphological features of shed virions, reducing the proportion of filamentous particles. We find that antibodies against neuraminidase and M2 also restrict viral egress, and that inhibition by anti-neuraminidase mAbs is only partly attributable to a loss in enzymatic activity. In all cases, antigen crosslinking – either on the surface of the infected cell, between the viral and cell membrane, or both - plays a critical role in inhibition, and we are able to distinguish between these modes experimentally and through a structure-based computational model. Together, these results provide a framework for dissecting antibody multifunctionality that could help guide the development of improved therapeutic antibodies or vaccines, and that can be extended to other viral families and antibody isotypes.
Iterative Machine Learning for Classification and Discovery of Single-molecule Unfolding Trajectories from Force Spectroscopy Data
Authors: Doffini Vanni , Liu Haipei , Liu Zhaowei , Nash Michael A.
Published: August 2023

We report the application of machine learning techniques to accelerate classification and analysis of protein unfolding trajectories from force spectroscopy data. Using kernel methods, logistic regression and triplet loss, we developed a workflow called Forced Unfolding and Supervised Iterative Online (FUSION) where a user classifies a small number of repeatable unfolding patterns encoded as image data, and a machine is tasked with identifying similar images to classify the remaining data. We tested the workflow using two case studies on a multi-domain XMod-Dockerin/Cohesin complex, validating the approach first using synthetic data generated with a Monte Carlo algorithm, and then deploying the method on experimental atomic force spectroscopy data. FUSION efficiently separated traces that passed quality filters from unusable ones, classified curves with high accuracy, and identified unfolding pathways undetected by the user. This study demonstrates the potential of machine learning to accelerate data analysis, and generate new insights in protein biophysics.
In vivoMapping of Cellular Resolution Neuropathology in Brain Ischemia by Diffusion MRI
Authors: Wu Dan , Turnbill Victoria , Lee Hong-Hsi , Wang Xiaoli , Ba Ruicheng , Walczak Piotr , Martin Lee J. , Fieremans Els , Novikov Dmitry S. , Northington Frances J. , Zhang Jiangyang
Published: August 2023

Non-invasive mapping of cellular pathology can provide critical diagnostic and prognostic information. Recent developments in diffusion MRI have produced new tools for examining tissue microstructure at a level well below the imaging resolution. Here, we report the use of diffusion time (t)-dependent diffusion kurtosis imaging (tDKI) to simultaneously assess the morphology and transmembrane permeability of cells and their processes in the context of pathological changes in hypoxic-ischemic brain (HI) injury. Through Monte Carlo simulations and cell culture organoid imaging, we demonstrate feasibility in measuring effective size and permeability changes based on the peak and tail oftDKI curves. In a mouse model of HI,in vivoimaging at 11.7T detects a marked shift of thetDKI peak to longertin brain edema, suggesting swelling and beading associated with the astrocytic processes and neuronal neurites. Furthermore, we observed a faster decrease of thetDKI tail in injured brain regions, reflecting increased membrane permeability that was associated with upregulated water exchange upon astrocyte activation at acute stage as well as necrosis with disrupted membrane integrity at subacute stage. Such information, unavailable with conventional diffusion MRI at a singlet,can predict salvageable tissues. For a proof-of-concept,tDKI at 3T on an ischemic stroke patient suggested increased membrane permeability in the stroke region. This work therefore demonstrates the potential oftDKI forin vivodetection of the pathological changes in microstructural morphology and transmembrane permeability after ischemic injury using a clinically translatable protocol.
Predicting cell types with supervised contrastive learning on cells and their types
Authors: Heryanto Yusri Dwi , Zhang Yao-zhong , Imoto Seiya
Published: August 2023

Single-cell RNA-sequencing (scRNA-seq) is a powerful technique that provides high-resolution expression profiling of individual cells. It significantly advances our understanding of cellular diversity and function. Despite its potential, the analysis of scRNA-seq data poses considerable challenges relate to multicollinearity, data imbalance, and batch effect. One of the pivotal tasks in single-cell data analysis is cell type annotation, which classifies cells into discrete types based on their gene expression profiles. In this work, we propose a novel modeling formalism for cell type annotation with a supervised contrastive learning method, named SCLSC (SupervisedContrastiveLearning forSingleCell). Different from the previous usage of contrastive learning in single cell data analysis, we employed the contrastive learning for instance-type pairs instead of instance-instance pairs. More specifically, in the cell type annotation task, the contrastive learning is applied to learn cell and cell type representation that render cells of the same type to be clustered in the new embedding space. Through this approach, the knowledge derived from annotated cells is transferred to the feature representation for scRNA-seq data. The whole training process becomes more efficient when conducting contrastive learning for cell and their types. Our experiment results demonstrate that the proposed SCLSC method consistently achieves superior accuracy in predicting cell types compared to four state-of-the-art methods. SCLSC also performs well in identifying cell types in different batch groups. The simplicity of our method allows for scalability, making it suitable for analyzing datasets with a large number of cells. In a real-world application of SCLSC to monitor the dynamics of immune cell subpopulations over time, SCLSC demonstrates a capability to discriminate cell subtypes of CD19+ B cells that were not present in the training dataset.
Haplotype Function Score improves biological interpretation and cross-ancestry polygenic prediction of human complex traits
Authors: Song Weichen , Shi Yongyong , Lin Guan Ning
Published: August 2023

We propose a new framework for human genetic association studies: at each locus, a deep learning model (in this study, Sei) is used to calculate the functional genomic activity score for two haplotypes per individual. This score, defined as the Haplotype Function Score (HFS), replaces the original genotype in association studies. Applying the HFS framework to 14 complex traits in the UK Biobank, we identified 3,619 independent HFS-trait associations with a significance of p<5×10−8. Fine-mapping revealed 2,699 causal associations, corresponding to a median increase of 63 causal findings per trait compared with SNP-based analysis. HFS-based enrichment analysis uncovered 727 pathway-trait associations and 153 tissue-trait associations with strong biological interpretability, including “circadian pathway-chronotype” and “arachidonic acid-intelligence”. Lastly, we applied LASSO regression to integrate HFS prediction score with SNP-based polygenic risk scores, which showed an improvement of 16.1% to 39.8% in cross-ancestry polygenic prediction. We concluded that HFS is a promising strategy for understanding the genetic basis of human complex traits.
Crystal Structure of Histone Deacetylase 6 Complexed with (R)-Lipoic Acid, an Essential Cofactor in Central Carbon Metabolism
Authors: Watson Paris R. , Stollmaier Juana Goulart , Christianson David W.
Published: August 2023

The enzyme cofactor (R)-lipoic acid plays a critical role in central carbon metabolism due to its catalytic function in the generation of acetyl-CoA, which links glycolysis with the tricarboxylic acid cycle. This cofactor is also essential for the generation of succinyl CoA within the tricarboxylic acid cycle. However, the biological functions of (R)-lipoic acid extend beyond metabolism owing to its facile redox chemistry. Most recently, the reduced form of (R)-lipoic acid, (R)-dihydrolipoic acid, has been shown to inhibit histone deacetylases (HDACs) with selectivity for the inhibition of HDAC6. Here, we report the 2.4 Å-resolution X-ray crystal structure of the HDAC6–(R)-dihydrolipoic acid complex, and we report a dissociation constant (KD) of 350 nM for this complex as determined by isothermal titration calorimetry. The crystal structure illuminates key affinity determinants in the enzyme active site, including thiolate-Zn2+coordination and S-π interactions in the F583-F643 aromatic crevice. This study provides the first visualization of the connection between HDAC function and the biological response to oxidative stress: the dithiol moiety of (R)-dihydrolipoic acid can serve as a redox-regulated pharmacophore capable of simultaneously targeting the catalytic Zn2+ion and the aromatic crevice in the active site of HDAC6.
Within-Individual Organization of the Human Cerebral Cortex: Networks, Global Topography, and Function
Authors: Du Jingnan , DiNicola Lauren M. , Angeli Peter A. , Saadon-Grosman Noam , Sun Wendy , Kaiser Stephanie , Ladopoulou Joanna , Xue Aihuiping , Yeo B.T. Thomas , Eldaief Mark C. , Buckner Randy L.
Published: August 2023

The human cerebral cortex is populated by specialized regions that are organized into networks. Here we estimated networks using a Multi-Session Hierarchical Bayesian sModel (MS-HBM) applied to intensively sampled within-individual functional MRI (fMRI) data. The network estimation procedure was initially developed and tested in two participants (each scanned 31 times) and then prospectively applied to 15 new participants (each scanned 8 to 11 times). Detailed analysis of the networks revealed a global organization. Locally organized first-order sensory and motor networks were surrounded by spatially adjacent second-order networks that also linked to distant regions. Third-order networks each possessed regions distributed widely throughout association cortex. Moreover, regions of distinct third-order networks displayed side-by-side juxtapositions with a pattern that repeated similarly across multiple cortical zones. We refer to these as Supra-Areal Association Megaclusters (SAAMs). Within each SAAM, two candidate control regions were typically adjacent to three separate domain-specialized regions. Independent task data were analyzed to explore functional response properties. The somatomotor and visual first-order networks responded to body movements and visual stimulation, respectively. A subset of the second-order networks responded to transients in an oddball detection task, consistent with a role in orienting to salient or novel events. The third-order networks, including distinct regions within each SAAM, showed two levels of functional specialization. Regions linked to candidate control networks responded to working memory load across multiple stimulus domains. The remaining regions within each SAAM did not track working memory load but rather dissociated across language, social, and spatial / episodic processing domains. These results support a model of the cerebral cortex in which progressively higher-order networks nest outwards from primary sensory and motor cortices. Within the apex zones of association cortex there is specialization of large-scale networks that divides domain-flexible from domain-specialized regions repeatedly across parietal, temporal, and prefrontal cortices. We discuss implications of these findings including how repeating organizational motifs may emerge during development.
Projective oblique plane structured illumination microscopy
Authors: Chang Bo-Jui , Shepherd Douglas , Fiolka Reto
Published: August 2023

Structured 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

Purpose

The 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).

Methods

In 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.

Findings

Participants 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.

Implications

These 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

Considerable 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

Glycine 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

Fecal 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

Plasmodium 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.

Importance

While 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

Hundreds 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

The 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.

Importance

RNA 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

PINK1 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

The 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

Background

The 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.

Methods

The 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.

Discussion

We 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

People 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.
The landscape of antibiotic resistance genes in the nasopharynx of preterm infants: Prolonged signature of hospitalization and effects by antibiotics
Authors: Dhariwal Achal , Rajar Polona , Salvadori Gabriela , Åmdal Heidi Aarø , Berild Dag , Saugstad Ola Didrik , Fugelseth Drude , Greisen Gorm , Dahle Ulf , Haaland Kirsti , Petersen Fernanda Cristina
Published: August 2023

Respiratory pathogens, commonly colonizing nasopharynx, are among the leading causes of death due to antimicrobial resistance. Yet, antibiotic resistance determinants within nasopharyngeal microbial communities remain poorly understood. Utilizing shotgun metagenomics, we investigated the nasopharynx resistome development in preterm infants, assessed early antibiotic impact on its trajectory, and explored its association with clinical covariates. Our findings revealed widespread nasopharyngeal carriage of antibiotic resistance genes (ARGs) with resistomes undergoing transient changes, including increased ARG diversity, abundance, and composition alterations due to early antibiotic exposure. ARGs associated with the critical nosocomial pathogenSerratia marcescenspersisted up to 8-10 months of age, representing a long-lasting hospitalization signature. The nasopharyngeal resistome strongly correlated with microbiome composition, with inter-individual differences and postnatal age explaining most of the variation. Our report on the collateral effects of antibiotics and prolonged hospitalization underscores the urgency of further studies focused on this relatively unexplored reservoir of pathogens and ARGs.
Akr1b7functions as a master regulator in ovarian aging
Authors: Isayama Keishiro , Watanabe Kenji , Ohtsuka Masato , Kimura Seisuke , Murata Tomoaki , Honda Takeshi , Asagiri Masataka , Sato Shun , Tamura Hiroshi , Sugino Norihiro , Mizukami Yoichi
Published: August 2023

At the beginning of ovarian aging, the ovulation of immature oocytes is accelerated, leading to the arrest of ovulation despite the remaining oocytes. Here, RNA expression in the ovarian aging of mice is comprehensively analyzed during the estrous cycle after ovulation stimulation. The aldo-keto reductaseAkr1b7pathway transiently activated in the ovaries of young mice disappears in those of old mice.Akr1b7—/—mice attenuate oocyte Akt activation essential for the follicular development in primordial follicles, and enhanced ovulation in immature oocytes. The estrous cycle is extended because of the prolonged diestrous stage by a sustained progesterone level inAkr1b7—/—mice ovaries, which is caused by the decline ofCyp17a1, a major metabolic enzyme of progesterone inAkr1b7-expressed theca cell layers. In summary, the decreasedAkr1b7pathway causes ovulation of immature oocytes and a prolonged estrous cycle, typical symptoms of ovarian aging.
Comparative Analysis, Diversification and Functional Validation of Plant Nucleotide-Binding Site Domain Genes
Authors: Hussain Athar , Khan Aqsa Anwer , Aslam Muhammad Qasim , Nazar Aquib , Zaman Nadir , Amin Ayesha , Mahmood Muhammad Arslan , Mukhtar M. Shahid , Rahman Hafiz Ubaid Ur , Farooq Muhammed , Saeed Muhammed , Amin Imran , Mansoor Shahid
Published: August 2023

Nucleotide-binding site (NBS) domain genes are one of a superfamily of resistance genes involved in plant responses to pathogens. The current study identified presumably identified 12,820 NBS-containing genes across 34 species covering from mosses to monocots and dicots. These identified genes classified into 168 classes with several novel domain architectures patterns encompassing significant diversity among plant species. Several classical (NBS, NBS-LRR, TIR-NBS, TIR-NBS-LRR etc.) and species-specific structural patterns (TIR-NBS-TIR-Cupin_1-Cupin_1, TIR-NBS-Prenyltransf, Sugar_tr-NBS etc.) were discovered. We observed 603 orthogroups (OGs) with some core (most common orthogroups; OG0, OG1, OG2etc.) and unique (highly specific to species; OG80, OG82etc) OGs with tandem duplications. The expression profiling presented the putative upregulation of OG2, OG6,and OG15in different tissues under various biotic and abiotic stresses in susceptible and tolerant plants to CLCuD. The genetic variation between susceptible (Coker 312) and tolerant (Mac7)G. hirsutumaccessions identified several unique variants in NBS genes of Mac7 (6,583 varaints) and Coker312 (5,173 variants). The protein-ligand and proteins-protein interaction showed a strong interaction of some putative NBS proteins with ADP/ATP and different core proteins of cotton leaf curl disease virus. The silencing ofGaNBS(OG2) in resistant cotton through virus-induced gene silencing (VIGS) demonstrated its putative role in virus tittering. The presented study will be further helpful to understand the plant adaptation mechanism.
Characterization of a selective, iron-chelating antifungal compound that disrupts fungal metabolism and synergizes with fluconazole
Authors: Corrales Jeanne , Ramos-Alonso Lucía , González-Sabín Javier , Ríos-Lombardía Nicolás , Trevijano-Contador Nuria , Berg Henriette Engen , Skottvoll Frøydis Sved , Moris Francisco , Zaragoza Óscar , Chymkowitch Pierre , Garcia Ignacio , Enserink Jorrit M.
Published: August 2023

Fungal infections are a growing global health concern due to the limited number of available antifungal therapies as well as the emergence of fungi that are resistant to first-line antimicrobials, particularly azoles and echinocandins. Development of novel, selective antifungal therapies is challenging due to similarities between fungal and mammalian cells. An attractive source of potential antifungal treatments is provided by ecological niches co-inhabited by bacteria, fungi and multicellular organisms, where complex relationships between multiple organisms has resulted in evolvement of a wide variety of selective antimicrobials. Here, we characterized several analogs of the one such natural compound, Collismycin A. We show that NR-6226C has antifungal activity against several pathogenicCandidaspecies, includingC. albicansandC. glabrata, whereas it only has little toxicity against mammalian cells. Mechanistically, NR-6226C selectively chelates iron, which is a limiting factor for pathogenic fungi during infection. As a result, NR-6226C treatment causes severe mitochondrial dysfunction, leading to formation of reactive oxygen species, metabolic reprogramming and a severe reduction in ATP levels. Using anin vivomodel for fungal infections, we show that NR-6226C significantly increases survival ofCandida-infectedGalleria mellonellalarvae. Finally, our data indicate that NR-6226C synergizes strongly with fluconazole in inhibition ofC. albicans. Taken together, NR-6226C is a promising antifungal compound that acts by chelating iron and disrupting mitochondrial functions.

Importance statement

Drug-resistant fungal infections are an emerging global threat, and pan-resistance to current antifungal therapies is an increasing problem. Clearly, there is a need for new antifungal drugs. In this study, we characterized a novel antifungal agent, the Collismycin analog NR-6226C. NR-6226C has a favorable toxicity profile for human cells, which is essential for further clinical development. We unraveled the mechanism of action of NR-6226C and found that it disrupts iron homeostasis and thereby depletes fungal cells of energy. Importantly, NR-6226C strongly potentiates the antifungal activity of fluconazole, thereby providing inroads for combination therapy that may reduce or prevent azole resistance. Thus, NR-6226C is a promising compound for further development into antifungal treatment.
Tetrapod vocal evolution: higher frequencies and faster rates of evolution in mammalian vocalizations
Authors: Muñoz Matías I. , Marsot Myriam , Ellers Jacintha , Halfwerk Wouter
Published: August 2023

Using the voice to produce sound is a widespread form of communication and plays an important role in contexts as diverse as parent-offspring interactions and courtship. Variation in the tempo and mode of vocal signal evolution has been studied in a phylogenetic context within orders or classes, but understanding vocal signal evolution ultimately requires comparison across all major lineages involved. Here we used comparative analyses to investigate the evolution of dominant frequency (i.e., the frequency with the highest energy content) and its association with body weight across 873 species of mammals, birds and frogs. In agreement with previous studies, we found that the negative allometric relationship between body weight and vocal frequency is a general feature of vocal systems. In addition, we found mammals to consistently vocalize at higher frequencies, and evolved their vocalizations at around 6-fold faster rates than those of birds and frogs. Although all three groups strongly rely on vocal communication, our findings show that only mammals have extensively explored the spectral acoustic space. We argue that such high vocal diversity of mammals is made possible by their unique hearing system, which evolved in the context of a small, parental-caring, nocturnal and insectivore ancestor, and has allowed them to detect, and therefore to evolve, a richer array of frequencies than other tetrapods.
Temperature variation drives coordinated scaling of temporal and dynamic features of transcription in embryonic development
Authors: Martini Gabriella , Garcia Hernan
Published: August 2023

Temperature affects the timing of development in most poikilothermic organisms that cannot regulate their internal body temperature. In the fruit fly,Drosophila melanogaster, similar quantitative trends characterize changes in the timing of morphological events in embryogenesis from cellularization to hatching across a 10°C temperature range, such that the relative duration of each of these stages is temperature-independent. However, the extent to which the timing of the individual molecular and cellular processes underlying these morphological events recapitulates this relationship with temperature is largely unknown. Here, we characterized how the spatiotemporal dynamics of the process of transcription, which are so fundamental to cell fate commitment, scale with temperature in single cells of living fly embryos. Using thehunchbackgene as a case study, we discovered that the duration of the cell cycle and the temporal and dynamic features ofhunchbacktranscription scaled in a coordinated fashion such that the relative rates of all observed processes were temperature independent and, perhaps most surprisingly, such that the total amount of mRNA produced by the gene is unaltered by temperature changes. Our approach provides a crucial tool for understanding both developmental robustness in the face of environmental variation and for applying biochemical approaches in livingDrosophilaembryos.