bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resident microbes shape the vaginal epithelial glycan landscape
Authors: Agarwal Kavita , Choudhury Biswa , Robinson Lloyd S. , Allsworth Jenifer E. , Lewis Amanda L. , Lewis Warren G. 
Published: February 2022

AbstractEpithelial cells are covered in carbohydrates. This glycan coat or “glycocalyx” interfaces directly with microbes, providing a protective barrier against potential pathogens. Bacterial vaginosis is a condition associated with adverse health outcomes in which bacteria reside in direct proximity to the vaginal epithelium. Some of these bacteria, including Gardnerella, produce glycosyl hydrolase enzymes. However, glycans of the vaginal epithelial surface have not been studied in detail. Here we elucidate key characteristics of the vaginal epithelial glycan landscape and determine the impact of resident microbes on the surface glycocalyx. In BV, the glycocalyx was visibly diminished. We show that the “normal” vaginal epithelium displays sialylated N- and O-glycans by biochemical and mass spectrometric analysis. In contrast, BV-epithelial cell glycans were strikingly depleted of sialic acids, with underlying galactose residues exposed on the surface. Treatment of cells from BV-negative women with recombinant Gardnerella sialidases generated BV-like glycan characteristics. Together these data provide the first evidence that the vaginal epithelial glycocalyx is attacked by hydrolytic enzymes in BV. Given the widespread structural and functional roles of sialoglycans in biology and disease, these findings may point to a shared epithelial pathophysiology underlying the many adverse outcomes associated with BV.
Targeting TRIP13 in Wilms Tumor with Nuclear Export Inhibitors
Authors: Mittal Karuna , Lee Benjamin P. , Cooper Garrett W. , Shim Jenny , Jonus Hunter C. , Kim Won Jun , Doshi Mihir , Almanza Diego , Kynnap Bryan D. , Christie Amanda L. , Yang Xiaoping , Cowley Glenn S. , Leeper Brittaney A. , Morton Christopher L. , Dwivedi Bhakti , Lawrence Taylor , Rupji Manali , Keskula Paula , Meyer Stephanie , Clinton Catherine M. , Bhasin Manoj , Crompton Brian D. , Tseng Yuen-Yi , Boehm Jesse S. , Ligon Keith L. , Root David E. , Murphy Andrew J. , Weinstock David M. , Gokhale Prafulla C. , Spangle Jennifer M. , Rivera Miguel N. , Mullen Elizabeth A. , Stegmaier Kimberly , Goldsmith Kelly C. , Hahn William C. , Hong Andrew L. 
Published: February 2022

ABSTRACTWilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies in a systematic manner remains challenging in part due to the lack of faithful preclinicalin vitromodels. We established ten short-term patient-derived WT cell lines and characterized these models using low-coverage whole genome sequencing, whole exome sequencing and RNA-sequencing, which demonstrated that these ex-vivo models faithfully recapitulate WT biology. We then performed targeted RNAi and CRISPR-Cas9 loss-of-function screens and identified the nuclear export genes (XPO1andKPNB1) as strong vulnerabilities. We observed that these models are sensitive to nuclear export inhibition using the FDA approved therapeutic agent, selinexor (KPT-330). Selinexor treatment of FHWT suppressedTRIP13 expression, which was required for survival. We further identifiedin vitroandin vivosynergy between selinexor and doxorubicin, a chemotherapy used in high risk FHWT. Taken together, we identified XPO1 inhibition with selinexor as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissionsin vivo.
EARLY AND MID-GESTATION ZIKA VIRUS (ZIKV) INFECTION IN THE OLIVE BABOON (PAPIO ANUBIS) LEADS TO FETAL CNS PATHOLOGY BY TERM GESTATION
Authors: Gurung Sunam , Reuter Darlene , Norris Abby , Dubois Molly , Maxted Marta , Singleton Krista , Castillo-Castrejon Marisol , Papin James F. , Myers Dean A. 
Published: February 2022

ABSTRACTZika virus (ZIKV) infection in pregnancy can produce catastrophic teratogenic damage to the developing fetus including microcephaly and congenital Zika syndrome (CZS). We previously described fetal CNS pathology occurring by three weeks post-ZIKV infection in Olive baboons at mid-gestation, including neuroinflammation, loss of radial glia (RG), RG fibers, neuroprogenitor cells (NPCs) resulting in disrupted NPC migration. In the present study, we explored fetal brain pathologies at term gestation resulting from ZIKV infection during either first or second trimester in the Olive baboon. In all dams, viremia resolved after 7 days post infection (dpi). One first trimester infected dam aborted at 5 dpi. All dams developed IgM and IgG response to ZIKV with ZIKV IgG detected in fetal serum. Substantial placental pathology and inflammation was observed including disruption of syncytiotrophoblast layers, delayed villous maturation, partially or fully thrombosed vessels, calcium mineralization and fibrin deposits. In the uterus, ZIKV was detected in ¾ first trimester but not in second trimester infected dams. While ZIKV was not detected in any fetal tissue at term, all fetuses exhibited varying degrees of neuropathology. Fetal brains from ZIKV infected dams exhibited a range of gross brain pathologies including irregularities of the major gyri and sulci of the cerebral cortex and cerebellar pathology. Frontal cortices of ZIKV fetuses showed a general disorganization of the six-layered cortex with degree of disorganization varying among the fetuses from the two groups. Frontal cortices from first but not second trimester infections exhibited increased microglia and astrocyte numbers (white matter) in both trimester infections. In the cerebellum, increased microglia were observed in both first and second trimester infected fetuses and decreased oligodendrocyte precursor cell populations in the cerebellar white matter in first trimester infections. In general, our observations are in accordance with those described in human ZIKV infected fetuses.
Pre-clinical testing of two serologically distinct chimpanzee-origin adenovirus vectors expressing spike of SARS-CoV-2
Authors: Novikov Mikhail , Hasanpourghadi Mohadeseh , Ambrose Robert , Chekaoui Arezki , Newman Dakota , Giles-Davis Wynetta , Xiang Zhiquan , Zhou Xiang Yang , Ertl Hildegund CJ 
Published: February 2022

ABSTRACTTwo serologically distinct chimpanzee-origin, replication-defective adenovirus (AdC) vectors expressing the spike (S) protein of an early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolate were generated and tested for induction of antibodies in young and aged mice. Both vectors induced S protein-specific antibodies including neutralizing antibodies. Levels of antibodies increased after a boost. The effectiveness of the boost depended on vector dose and timing between the two immunizations. Using two heterologous AdC vectors was more effective than vaccinating with the same vector repeatedly. Antibodies partially crossreacted between different S protein variants. Cross-reactivity increased after booster immunization with vectors carrying the same S gene, expression of two different S proteins by the AdC vectors used for the prime and the boost did not selectively increase responses against the variants.
Population Dynamics and Resource Availability Drive Seasonal Shifts in the Consumptive and Competitive Impacts of Introduced House Mice (Mus musculus) on an Island Ecosystem
Authors: Polito Michael J. , Robinson Bret , Warzybok Pete , Bradley Russell W. 
Published: February 2022

AbstractBackgroundHouse mice (Mus musculus) are widespread and invasive on many islands where they can have both direct and indirect ecological impacts on native ecological communities. Given their opportunistic, omnivorous nature the consumptive and competitive impacts of house mice on islands have the potential to vary over time in concert with resource availability and mouse population dynamics.MethodsWe examined the ecological niche of invasive house mice on Southeast Farallon Island, California, USA using a combination of mouse trapping, food resource surveys, and stable isotope analysis to better understand their trophic interactions with native flora and fauna.ResultsWe found that plants were the important resource for house mice during the spring months when vegetation is abundant and mouse populations are low. However, plants decline in dietary importance throughout the summer and fall as mouse populations increase, and seabird and insect resources become relatively more available and consumed by house mice. Mouse abundance peaks and other resource availability are low in the fall months when the isotopic niches of house mice and salamanders overlap significantly indicating the potential for competition, most likely for insect prey.DiscussionThese results indicate how seasonal shifts in both the mouse abundance and resource availability are key factors that mediate the consumptive and competitive impacts of introduced house mice on this island ecosystem.
CD81 partners with CD44 in promoting exosome biogenesis, tumor cluster formation, and lung metastasis in triple negative breast cancer
Authors: Ramos Erika K. , Tsai Chia-Feng , Dashzeveg Nurmaa K. , Jia Yuzhi , Cao Yue , Manu Megan , Taftaf Rokana , Hoffmann Andrew D. , El-Shennawy Lamiaa , Gritsenko Marina A. , Adorno-Cruz Valery , Schuster Emma J. , Scholten David , Patel Dhwani , Liu Xia , Patel Priyam , Wray Brian , Zhang Youbin , Zhang Shanshan , Moore Ronald J. , Mathews Jeremy V. , Schipma Matthew J. , Liu Tao , Tokars Valerie L. , Cristofanilli Massimo , Shi Tujin , Shen Yang , Liu Huiping 
Published: February 2022

AbstractTumor-initiating cells with reprogramming plasticity are thought to be essential for cancer development and metastatic regeneration in many cancers; however, the molecular mechanisms are not fully understood. This study reports that CD81, a tetraspanin protein marker of small extracellular vesicles (exosomes), functions as a binding partner of CD44 and facilitates self-renewal of tumor initiating cells. Using machine learning-assisted protein structure modeling, co-immunoprecipitation, and mutagenesis approaches, we further demonstrate that CD81 interacts with CD44 on the cellular membrane through their extracellular regions. In-depth global and phosphoproteomic analyses of clustering tumor cells unveils endocytosis-related signature pathways of proteins and phosphorylation patterns regulated by CD81 and CD44 specifically or shared between two. Notably, CRISPR Cas9-mediated depletion of either CD44 or CD81 results in loss of both proteins in cancer cell-secreted exosomes, a state which abolishes exosome-induced self-renewal of recipient cells for mammosphere formation. CD81 is expressed in >80% of human circulating tumor cells (CTCs) and specifically enriched in clustered CTCs along with CD44 isolated from breast cancer patients. Mimicking the phenotypes of CD44 deficiency, loss of CD81 also inhibits tumor cluster aggregation, tumorigenesis, and lung metastasis of triple negative breast cancer (TNBC), supporting the clinical significance of CD81 in association with patient outcomes. Our study highlights the novel role of CD81 and its partnership with CD44 in cancer exosomes, self-renewal, CTC clustering, and metastasis initiation of TNBC.
Identification of cytoplasmic chaperone networks relevant for respiratory syncytial virus replication
Authors: Latorre Victor , Geller Ron 
Published: February 2022

ABSTRACTRNA viruses have limited coding capacity and must therefore successfully subvert cellular processes to facilitate their replication. A fundamental challenge faced by both viruses and their hosts is the ability to achieve the correct folding and assembly of their proteome while avoiding misfolding and aggregation. In cells, this process is facilitated by numerous chaperone systems together with a large number of co-chaperones. In this work, we set out to define the chaperones and co-chaperones involved in the replication of respiratory syncytial virus (RSV). Using an RNAi screen, we identify multiple members of cellular protein folding networks whose knockdown alters RSV replication. The reduced number of chaperones and co-chaperones identified in this work can facilitate the unmasking of specific chaperone subnetworks required for distinct steps of the RSV life cycle and identifies new potential targets for antiviral therapy. Indeed, we show that the pharmacological inhibition of one of the genes identified in the RNAi screen, valosin-containing protein (VCP/p97), can impede the replication of RSV by interfering with the infection cycle at multiple steps.
Plasma membrane protrusions mediate host cell-cell fusion induced by Burkholderia thailandensis
Authors: Kostow Nora , Welch Matthew D. 
Published: February 2022

AbstractCell-cell fusion is important for biological processes including fertilization, development, immunity, and microbial pathogenesis. Bacteria in the pseudomallei group of Burkholderia species, including B. thailandensis, spread between host cells by inducing cell-cell fusion. Previous work showed that B. thailandensis-induced cell-cell fusion requires intracellular bacterial motility and a bacterial protein secretion apparatus called the type VI secretion system-5 (T6SS-5), including the T6SS-5 protein VgrG5. However, the cellular level mechanism and T6SS-5 proteins important for bacteria-induced cell-cell fusion remained incompletely described. Using live cell imaging, we found bacteria used actin-based motility to push on the host cell plasma membrane to form plasma membrane protrusions that extended into neighboring cells. Then, membrane fusion occurred within these membrane protrusions, either proximal to the bacterium at the tip or elsewhere within a protrusion. Expression of VgrG5 by bacteria within membrane protrusions was required to promote cell-cell fusion. Furthermore, a second predicted T6SS-5 protein, TagD5, was also required for cell-cell fusion. In the absence of VgrG5 or TagD5, bacteria in plasma membrane protrusions were engulfed into neighboring cells. Our results suggest that the T6SS-5 effectors VgrG5 and TagD5 are secreted within membrane protrusions and act locally to promote membrane fusion.
Myelin lipids as nervous system energy reserves
Authors: Asadollahi Ebrahim , Trevisiol Andrea , Saab Aiman S. , Looser Zoe J. , Dibaj Payam , Kusch Kathrin , Ruhwedel Torben , Möbius Wiebke , Jahn Olaf , Baes Myriam , Weber Bruno , Abel E. Dale , Balabio Andrea , Popko Brian , Kassmann Celia M. , Ehrenreich Hannelore , Hirrlinger Johannes , Nave Klaus-Armin 
Published: February 2022

AbstractNeuronal functions and impulse propagation depend on the continuous supply of glucose1,2. Surprisingly, the mammalian brain has no obvious energy stores, except for astroglial glycogen granules3. Oligodendrocytes make myelin for rapid axonal impulse conduction4 and also support axons metabolically with lactate5–7. Here, we show that myelin itself, a lipid-rich membrane compartment, becomes a local energy reserve when glucose is lacking. In the mouse optic nerve, a model white matter tract, oligodendrocytes survive glucose deprivation far better than astrocytes, by utilizing myelin lipids which requires oxygen and fatty acid beta-oxidation. Importantly, fatty acid oxidation also contributes to axonal ATP and basic conductivity. This metabolic support by fatty acids is an oligodendrocyte function, involving mitochondria and myelin-associated peroxisomes, as shown with mice lacking Mfp2. To study reduced glucose availability in vivo without physically starving mice, we deleted the Slc2a1 gene from mature oligodendrocytes. This caused a significant decline of the glucose transporter GLUT1 from the myelin compartment leading to myelin sheath thinning. We suggest a model in which myelin turnover under low glucose conditions can transiently buffer axonal energy metabolism. This model may explain the gradual loss of myelin in a range of neurodegenerative diseases8 with underlying hypometabolism9.
Prevalence and mechanisms of evolutionary contingency in human influenza H3N2 neuraminidase
Authors: Lei Ruipeng , Tan Timothy J.C. , Garcia Andrea Hernandez , Wang Yiquan , Teo Chuyun , Gopan Gopika , Dargani Zahra Tavakoli , Teo Qi Wen , Graham Claire S. , Nair Satish K. , Wu Nicholas C. 
Published: February 2022

ABSTRACTNeuraminidase (NA) of human influenza H3N2 virus has evolved rapidly and been accumulating mutations for more than half-century. However, biophysical constraints that govern the evolutionary trajectories of NA remain largely elusive. Here, we show that among 70 natural mutations that are present in the NA of a recent human H3N2 strain, >10% are deleterious for an ancestral strain. By mapping the permissive mutations using combinatorial mutagenesis and next-generation sequencing, an extensive epistatic network is revealed. Biophysical and structural analyses further demonstrate that certain epistatic interactions can be explained by non-additive stability effect, which in turn modulates membrane trafficking and enzymatic activity of NA. Additionally, our results suggest that other biophysical mechanisms also contribute to epistasis in NA evolution. Overall, these findings not only provide mechanistic insights into the evolution of human influenza NA and elucidate its sequence-structure-function relationship, but also have important implications for the development of next-generation influenza vaccines.
Phenotypic and transcriptional response of Daphnia pulicaria to the combined effects of temperature and predation
Authors: Oliver Aaron , Cavalheri Hamanda B. , Lima Thiago G. , Jones Natalie T. , Podell Sheila , Zarate Daniela , Allen Eric , Burton Ronald S. , Shurin Jonathan B. 
Published: February 2022

AbstractDaphnia, an ecologically important zooplankton species in lakes, shows both genetic adaptation and phenotypic plasticity in response to temperature and fish predation, but little is known about the molecular basis of these responses and their potential interactions. We performed a factorial experiment exposing laboratory-propagated Daphnia pulicaria clones from two lakes in the Sierra Nevada mountains of California to normal or high temperature (15°C or 25°C) in the presence or absence of fish kairomones, then measured changes in life history and gene expression. Exposure to kairomones increased upper thermal tolerance limits for physiological activity in both clones. Cloned individuals matured at a younger age in response to higher temperature and kairomones, while size at maturity, fecundity and population intrinsic growth were only affected by temperature. At the molecular level, both clones expressed more genes differently in response to temperature than predation, but specific genes involved in metabolic, cellular, and genetic processes responded differently between the two clones. Although gene expression differed more between clones from different lakes than experimental treatments, similar phenotypic responses to predation risk and warming arose from these clone-specific patterns. Our results suggest that phenotypic plasticity responses to temperature and kairomones interact synergistically, with exposure to fish predators increasing the tolerance of Daphnia pulicaria to stressful temperatures, and that similar phenotypic responses to temperature and predator cues can be produced by divergent patterns of gene regulation.
Methionine Metabolism Controls the B-cell EBV Epigenome and Viral Latency
Authors: Guo Rui , Liang Jin Hua , Zhang Yuchen , Lutchenkov Michael , Li Zhixuan , Wang Yin , Trujillo-Alonso Vicenta , Puri Rishi , Giulino-Roth Lisa , Gewurz Benjamin E. 
Published: February 2022

SummaryEpstein-Barr virus (EBV) subverts host epigenetic pathways to switch between viral latency programs, colonize the B-cell compartment and reactivate. Within memory B-cells, the reservoir for lifelong infection, EBV genomic DNA and histone methylation marks restrict gene expression. But, this epigenetic strategy also enables EBV-infected tumors, including Burkitt lymphomas to evade immune detection. Little is known about host cell metabolic pathways that support EBV epigenome landscapes. We therefore used amino acid restriction, metabolomic and CRISPR approaches to identify that an abundant methionine supply, and interconnecting methionine and folate cycles, maintain Burkitt EBV gene silencing. Methionine restriction, or methionine cycle perturbation, hypomethylated EBV genomes, de-repressed latent membrane protein and lytic gene expression. Methionine metabolism also shaped EBV latency gene regulation required for B-cell immortalization. Dietary methionine restriction altered murine Burkitt xenograft metabolomes and de-repressed EBV immunogensin vivo. These results highlight epigenetic/immunometabolism crosstalk supporting the EBV B-cell lifecycle and suggest therapeutic approaches.HighlightsMethionine metabolism is critical for Epstein-Barr virus B-cell latencyExtensive cross-talk enables methionine metabolism to control the EBV epigenomeMethionine restriction also impairs EBV-driven human B-cell immortalizationDietary methionine restriction unmasks EBV antigens in Burkitt xenografts in vivo
Three-dimensional cilia structures from animals’ closest unicellular relatives, the Choanoflagellates
Authors: Pinskey Justine M. , Lagisetty Adhya , Gui Long , Phan Nhan , Reetz Evan , Fu Gang , Nicastro Daniela 
Published: February 2022

AbstractIn most eukaryotic organisms, cilia perform a variety of life-sustaining roles related to environmental sensing and motility. Cryo-electron microscopy has provided considerable insight into the morphology and function of ciliary structures, but studies have been limited to less than a dozen of the millions of known eukaryotic species. Ultrastructural information is particularly lacking for unicellular organisms in the opisthokont clade, leaving a sizeable gap in our understanding of cilia evolution between unicellular species and multicellular metazoans (animals). Choanoflagellates are important aquatic heterotrophs, uniquely positioned within the opisthokonts as the metazoans’ closest living unicellular relatives. We performed cryo-focused ion beam milling and cryo-electron tomography on cilia from the choanoflagellate species Salpingoeca rosetta. We show that the axonemal dyneins, radial spokes, and central pair complex in S. rosetta more closely resemble metazoan structures than those of unicellular organisms from other suprakingdoms. In addition, we describe unique features of S. rosetta cilia, including microtubule holes, microtubule inner proteins, and the ciliary vane: a fine, net-like extension that has been notoriously difficult to visualize using other methods. Furthermore, we report barb-like structures of unknown function on the extracellular surface of the ciliary membrane. Together, our findings provide new insights into choanoflagellate biology and cilia evolution between unicellular and multicellular opisthokonts.