bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular epidemiological and pharmaceutical studies of methicillin-resistant Staphylococcus aureus isolated at hospitals in Kure City, Japan
Authors: Maeda Ryuto , Kobayashi Hidetomo , Higashidani Mami , Matsuhisa Tetsuaki , Sawa Akihiro , Miyake Katsushi , Tayama Yoshitaka , Kimura Kouji , Itoh Hiroyuki , Okano Taichi , Seike Soshi , Yamanaka Hiroyasu
Published: February 2022

Introduction. Methicillin-resistant

Staphylococcus aureus

(MRSA) is one of the major pathogens of nosocomial infections throughout the world. In the medical field, it is extremely important to this pathogen’s trends when considering infection control.

Hypothesis/Gap Statement. We hypothesized that clarifying the characteristics of clinically isolated MRSA would contribute to infection control and proper use of antimicrobial agents against MRSA.

Aim. The purpose of this study is to elucidate the genetic and biological characteristics of the MRSA isolates found at our hospital and to reveal changes in the spread of this pathogen in the local area where we live.

Methodology. Pulse-field gel electrophoresis (PFGE) and polymerase chain reaction were used for the genetic analyses of MRSA isolates. Toxin production by each isolate was examined using toxin-specific detection systems.

Results. During the 3 years from 2017 through 2019, over 1000 MRSA strains were isolated at our hospital. Genomic analysis of 237 of these clinical isolates by PFGE revealed 12 PFGE types (types A to L), each consisting of five or more MRSA clinical strains with over 80% genetic similarity. Examination of the SCCmec genotypes found that 219 of 237 isolated MRSA strains (approximately 92%) were SCCmec genotype II or IV and that only four of the isolates carried the Panton−Valentine leukocidin (PVL) gene. Examination of the toxin production of the isolates using staphylococcal enterotoxin detection kits found that most isolates carrying the SCCmec genotype II produced enterotoxin B and/or C, and that most isolates carrying the SCCmec genotype IV produced enterotoxin A.

Conclusions. The present results revealed that MRSA isolates with common properties were isolated at certain rates throughout the 3 year study period, suggesting that relatively specific MRSA clones may have settled in the local area around our hospital. We also examine the relationship between antimicrobial usage over time and changes in MRSA isolation rates.
Evolution and systematics of the Aculeata and kin (Hymenoptera), with emphasis on the ants (Formicoidea: †@@@idae fam. nov., Formicidae)
Authors: Boudinot Brendon E. , Khouri Ziad , Richter Adrian , Griebenow Zachary H. , van de Kamp Thomas , Perrichot Vincent , Barden Phillip
Published: February 2022

Fossils provide unique opportunity to understand the tempo and mode of evolution and are essential for modeling the history of lineage diversification. Here, we interrogate the Mesozoic fossil record of the Aculeata, with emphasis on the ants (Formicidae), and conduct an extended series of ancestral state estimation exercises on distributions of tip-dated combined-evidence phylogenies. We developed and illustrated from ground-up a series of 576 morphological characters which we scored for 144 extant and 431 fossil taxa, including all families of Aculeata, Trigonaloidea, Evanioidea, and †Ephialtitoidea. We used average posterior probability support to guide composition of a target matrix of 303 taxa, for which we integrated strongly filtered ultraconserved element (UCE) data for 115 living species. We also implemented reversible jump MCMC (rjMCMC) and hidden state methods to model complex behavioral characters to test hypotheses about the pathway to obligate eusociality. In addition to revising the higher classification of all sampled groups to family or subfamily level using estimated character polarities to diagnose nodes across the phylogeny, we find that the mid-Cretaceous genera †Camelomeciaand †Camelospheciaform a clade which is robustly supported as sister to all living and fossil Formicidae. For this reason, we name this extinct clade as †@@@idaefam. nov.and provide a definition for the expanded Formicoidea. Based on our results, we recognize three major phases in the early evolution of the ants: (1) origin of Formicoidea as ground-adapted huntresses during the Late Jurassic in the “stinging aggressor” guild (Aculeata) among various lineages of “sneaking parasitoids” (non-aculeate Vespina); (2) the first formicoid radiation during the Early Cretaceous, by the end of which all major extant linages originated; and (3) turnover of the Formicoidea at the end-Cretaceous leading to the second formicoid radiation. We conclude with a concentrated series of considerations for future directions of study with this dataset and beyond.
Third dose of COVID-19 vaccine, CVnCoV, increased neutralizing activity against SARS-CoV-2 wild-type and Delta variant
Authors: Wolz Olaf-Oliver , Kays Sarah-Katharina , Junker Helga , Koch Sven D. , Mann Philipp , Quintini Gianluca , von Eisenhart-Rothe Philipp , Oostvogels Lidia
Published: February 2022

A third dose of CVnCoV, a former candidate mRNA vaccine against SARS-CoV-2, was previously shown to boost neutralizing antibody responses against SARS-CoV-2 wild-type in adults aged 18-60 and >60 years in a phase 2a clinical study. Here we report neutralizing antibody responses to wild-type and a variant of concern, Delta, after a third dose on day (D) 57 and D180. Neutralization activity was assessed using a microneutralization assay. Comparable levels of neutralizing antibodies against wild-type and Delta were induced. These were higher than those observed after the first two doses, irrespective of age or pre-SARS-CoV-2-exposure status, indicating that the first two doses induced immune memory. Four weeks after the third dose on D180, neutralizing titers for wild-type and Delta were two-fold higher in younger participants than in older participants; seroconversion rates were 100% for wild-type and Delta in the younger group and for Delta in the older group. A third CVnCoV dose induced similar levels of neutralizing responses against wild-type virus and the Delta variant in both naïve and pre-exposed participants, aligning with current knowledge from licensed COVID-19 vaccines that a third dose is beneficial against SARS-CoV-2 variants.
A high-throughput yeast display approach to profile pathogen proteomes for MHC-II binding
Authors: Huisman Brooke D. , Dai Zheng , Gifford David K. , Birnbaum Michael E.
Published: February 2022

T cells play a critical role in the adaptive immune response, recognizing peptide antigens presented on the cell surface by Major Histocompatibility Complex (MHC) proteins. While assessing peptides for MHC binding is an important component of probing these interactions, traditional assays for testing peptides of interest for MHC binding are limited in throughput. Here we present a yeast display-based platform for assessing the binding of tens of thousands of user-defined peptides in a high throughput manner. We apply this approach to assess a tiled library covering the SARS-CoV-2 proteome and four dengue virus serotypes for binding to human class II MHCs, including HLA-DR401, -DR402, and -DR404. This approach identifies binders missed by computational prediction, highlighting the potential for systemic computational errors given even state-of-the-art training data, and underlines design considerations for epitope identification experiments. This platform serves as a framework for examining relationships between viral conservation and MHC binding, and can be used to identify potentially high-interest peptide binders from viral proteins. These results demonstrate the utility of this approach for determining high-confidence peptide-MHC binding.
Mitoquinone mesylate targets SARS-CoV-2 infection in preclinical models
Authors: Petcherski Anton , Sharma Madhav , Satta Sandro , Daskou Maria , Vasilopoulos Hariclea , Hugo Cristelle , Ritou Eleni , Dillon Barbara Jane , Fung Eileen , Garcia Gustavo , Scafoglio Claudio , Purkayastha Arunima , Gomperts Brigitte N , Fishbein Gregory A , Arumugaswami Vaithilingaraja , Liesa Marc , Shirihai Orian S , Kelesidis Theodoros
Published: February 2022

To date, there is no effective oral antiviral against SARS-CoV-2 that is also anti-inflammatory. Herein, we show that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has potent antiviral activity against SARS-CoV-2 and its variants of concern in vitro and in vivo. Mito-MES had nanomolar in vitro antiviral potency against the Beta and Delta SARS-CoV-2 variants as well as the murine hepatitis virus (MHV-A59). Mito-MES given in SARS-CoV-2 infected K18-hACE2 mice through oral gavage reduced viral titer by nearly 4 log units relative to the vehicle group. We found in vitro that the antiviral effect of Mito-MES is attributable to its hydrophobic dTPP+ moiety and its combined effects scavenging reactive oxygen species (ROS), activating Nrf2 and increasing the host defense proteins TOM70 and MX1. Mito-MES was efficacious reducing increase in cleaved caspase-3 and inflammation induced by SARS-CoV2 infection both in lung epithelial cells and a transgenic mouse model of COVID-19. Mito-MES reduced production of IL-6 by SARS-CoV-2 infected epithelial cells through its antioxidant properties (Nrf2 agonist, coenzyme Q10 moiety) and the dTPP moiety. Given established safety of Mito-MES in humans, our results suggest that Mito-MES may represent a rapidly applicable therapeutic strategy that can be added in the therapeutic arsenal against COVID-19. Its potential long-term use by humans as diet supplement could help control the SARS-CoV-2 pandemic, especially in the setting of rapidly emerging SARS-CoV-2 variants that may compromise vaccine efficacy.

One-Sentence Summary

Mitoquinone/mitoquinol mesylate has potent antiviral and anti-inflammatory activity in preclinical models of SARS-CoV-2 infection.
Multiple bumps can enhance robustness to noise in continuous attractor networks
Authors: Wang Raymond , Kang Louis
Published: February 2022

A central function of continuous attractor networks is encoding coordinates and accurately updating their values through path integration. To do so, these networks produce localized bumps of activity that move coherently in response to velocity inputs. In the brain, continuous attractors are believed to underlie grid cells and head direction cells, which maintain periodic representations of position and orientation, respectively. These representations can be achieved with any number of activity bumps, and the consequences of having more or fewer bumps are unclear. We address this knowledge gap by constructing 1D ring attractor networks with different bump numbers and characterizing their responses to three types of noise: fluctuating inputs, spiking noise, and deviations in connectivity away from ideal attractor configurations. Across all three types, networks with more bumps experience less noise-driven deviations in bump motion. This translates to more robust encodings of linear coordinates, like position, assuming that each neuron represents a fixed length no matter the bump number. Alternatively, we consider encoding a circular coordinate, like orientation, such that the network distance between adjacent bumps always maps onto 360 degrees. Under this mapping, bump number does not significantly affect the amount of error in the coordinate readout. Our simulation results are intuitively explained and quantitatively matched by a unified theory for path integration and noise in multi-bump networks. Thus, to suppress the effects of biologically relevant noise, continuous attractor networks can employ more bumps when encoding linear coordinates; this advantage disappears when encoding circular coordinates. Our findings provide motivation for multiple bumps in the mammalian grid network.
Frailty in individuals with depression, bipolar disorder and anxiety disorders: longitudinal analyses of all-cause mortality
Authors: Mutz Julian , Choudhury Umamah , Zhao Jinlong , Dregan Alexandru
Published: February 2022

Background

Frailty is a medical syndrome that is strongly associated with mortality risk, and an emerging global health burden. Mental disorders are associated with reduced life expectancy and elevated levels of frailty. In this study, we examined the mortality risk associated with frailty in individuals with a lifetime history of mental disorders compared to non-psychiatric controls.

Methods

The UK Biobank study recruited >500,000 adults, aged 37–73, between 2006–2010. We derived the two most common albeit distinctive measures of frailty, the frailty phenotype and the frailty index. Individuals with lifetime depression, bipolar disorder or anxiety disorders were identified from multiple data sources. The primary outcome was all-cause mortality. We have also examined differences in frailty, separately by sex and age.

Outcomes

Analyses included up to 297,380 middle-aged and older adults with a median follow-up of 12.19 (IQR = 1.31) years, yielding 3,516,706 person-years of follow-up. We observed higher levels of frailty in individuals with mental disorders for both frailty measures. For key comparisons, individuals with a mental disorder had greater all-cause mortality hazards than their controls. The highest hazard ratio (3.65, 95% CI 2.40-5.54) was observed among individuals with bipolar disorder and frailty, relative to the non-frail controls.

Interpretation

Our findings highlight elevated levels of frailty across three common mental disorders. The increased mortality risk associated with frailty and mental disorders represents a potentially modifiable target for prevention and treatment to improve life expectancy.

Funding

Biotechnology and Biological Sciences Research Council.
Assessing the role of vascular risk factors in dementia: Mendelian randomization meta-analysis and comparison with observational estimates
Authors: Lee L , Walker R. M. , Whiteley W. N.
Published: February 2022

Importance

Although observational studies demonstrate that higher levels of vascular risk factors are associated with an increased risk of dementia, these associations might be explained by confounding or other biases. Mendelian randomization (MR) uses genetic instruments to test causal relationships in observational data.

Objective

To determine if genetically predicted modifiable risk factors (type 2 diabetes mellitus, low density lipoprotein cholesterol, high density lipoprotein cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, body mass index, and circulating glucose) are associated with dementia by meta-analysing published MR studies. Secondary objectives were to identify heterogeneity in effect estimates across primary MR studies and to compare meta-analysis results with observational studies.

Data sources

MR studies identified by systematic search of Web of Science, OVID and Scopus.

Study selection

Primary MR studies investigating the modifiable risk factors of interest. Only one study from each cohort per risk factor was included. A quality assessment tool was developed to primarily assess the three assumptions of MR for each MR study.

Data extraction and synthesis

Data were extracted on study characteristics, exposure and outcome, effect estimates per unit increase, and measures of variation. Effect estimates were pooled to generate an overall estimate, I2 and Cochrane Q values using fixed-effect model.

Main outcomes and measures

Odds ratio (OR) of developing dementia per standardized unit increase in the risk factor of interest.

Results

We screened 5211 studies and included 12 primary MR studies after applying inclusion and exclusion criteria. Higher genetically predicted body mass index was associated with a higher odds of dementia (OR 1.03 [1.01, 1.05] per 5 kg/m2 increase, one study, p = 0.00285). Overall estimates from MR studies showed a smaller number of associations than those from meta-analyses of observational studies.

Conclusion and relevance

Genetically predicted body mass index was associated with an increase in risk of dementia.

Key points

Question

Are genetically predicted modifiable risk factors associated with dementia?

Findings

Genetically predicted higher body mass index was associated with a higher odds of dementia. No evidence was found to support an association between genetically predicted type 2 diabetes mellitus, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, plasma glucose and dementia risk.

Meaning

Many modifiable risk factors associated with dementia in observational studies may not play a causative role.
The interleukin-6/interleukin-23/Thelper-17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: a precision nomothetic psychiatry analysis
Authors: Al-Hakeim Hussein Kadhem , Alhusseini Ali Fattah , Al-Dujaili Arafat Hussein , Debnath Monojit , Maes Michael
Published: February 2022

Schizophrenia and especially defcit schizophrenia (DSCZ)) are characterized by highly significantly increased activities of neuroimmunotoxic pathways and a generalized cognitive decline (G-CoDe). There are no data whether the interleukin(IL)-6/IL-23/Thelper-17 (IL6/IL23/Th17)-axis is more associated with DSCZ than with non-deficit schizophrenia (NDSCZ) and whether changes in this axis are associated with the G-CoDe and the phenome (a factor extracted from all symptom domains) of schizophrenia. This study included 45 DSCZ and 45 NDSCZ patients and 40 controls and delineated whether the IL6/IL23/Th17 axis, trace elements (copper, zinc) and ions (magnesium, calcium) are associated with DSCZ, the G-CoDe and phenome of schizophrenia. Increased plasma IL-23 and IL-6 levels were associated with Th17 upregulation, assessed as a latent vector (LV) extracted from IL-17, IL-21, IL-22, and TNF-α. The IL6/IL23/Th17-axis score, as assessed by a LV extracted from IL-23, IL-6, and the Th17 LV, was significantly higher in DSCZ than in NDSCZ and controls. We discovered that 70.7% of the variance in the phenome was explained by the IL6/IL23/Th17-axis (positively) and the G-CoDe and IL-10 (both inversely); and that 54.6% of the variance in the G-CoDe was explained by the IL6/IL23/Th17 scores (inversely) and magnesium, copper, calcium, and zinc (all positively). In conclusion, the pathogenic IL6/IL23/Th17-axis contributes to the generalized neurocognitive deficit and the phenome of schizophrenia and especially that of DSCZ due to its key role in peripheral inflammation and neuroinflammation and its consequent immunotoxic effects on neuronal circuits. These clinical impairments are more prominent in subjects with lowered IL-10, magnesium, calcium, and zinc.
Increase in SARS-CoV-2 RBD-specific IgA and IgG Antibodies in Human Milk from Lactating Women Following the COVID-19 Booster Vaccination
Authors: Henle Andrea M.
Published: February 2022

The CDC recommended a booster dose of the Pfizer-BioNTech Comirnaty (BNT162b2) COVID-19 mRNA vaccine in September 2021 for high-risk individuals. Pregnant and high-risk lactating women were encouraged to receive the booster to obtain potential prolonged protection for themselves and their infants. This study investigated the ability of the booster vaccine to increase IgA and IgG antibodies specific to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein in human milk compared to levels pre-booster. We found a significant increase in both anti-RBD-specific IgA and IgG antibodies in human milk 1-2 weeks after the Pfizer-BioNTech booster and at the study endpoint (60 days post-booster). These results suggest the booster vaccination enhances SARS-CoV-2 specific immunity in human breast milk, which may be protective for infants.

Key Points

Abs to SARS-COV-2 RBD are detected in blood ≥60 days post-Pfizer-BioNTech booster.

Human milk Abs to SARS-COV-2 RBD are higher ≥60 days post-booster vs pre-booster.
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

Epithelial 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

Wilms 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

Zika 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

Two 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

Background

House 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.

Methods

We 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.

Results

We 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.

Discussion

These 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

Tumor-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

RNA 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

Cell-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

Neuronal 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

Neuraminidase (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

Daphnia, 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

Epstein-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.

Highlights

Methionine metabolism is critical for Epstein-Barr virus B-cell latency

Extensive cross-talk enables methionine metabolism to control the EBV epigenome

Methionine restriction also impairs EBV-driven human B-cell immortalization

Dietary 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

In 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.
Kinetochore- and chromosome-driven transition of microtubules into bundles promotes spindle assembly
Authors: Matković Jurica , Ghosh Subhadip , Ćosić Mateja , Barišić Marin , Pavin Nenad , Tolić Iva M.
Published: February 2022

Mitotic spindle assembly is crucial for chromosome segregation and relies on bundles of microtubules that extend from the poles and overlap in the middle. However, how these structures form remains poorly understood. Here we show that overlap bundles arise through a network-to-bundles transition driven by kinetochores and chromosomes. STED super-resolution microscopy revealed that PRC1-crosslinked microtubules initially form loose arrays, which become rearranged into bundles. Kinetochores promote microtubule bundling by lateral binding via CENP-E/kinesin-7 in an Aurora B-regulated manner. Bundle separation is driven by steric interactions of the bundle-associated chromosomes at the spindle midplane since spindles with uncondensed or uncongressed chromosomes are narrower. In agreement with experiments, theoretical modeling suggests that bundles arise through competing attractive and repulsive mechanisms. Finally, perturbation of overlap bundles led to inefficient correction of erroneous kinetochore-microtubule attachments. Thus, kinetochores and chromosomes drive coarsening of a uniform microtubule array into overlap bundles, which promote not only spindle formation but also chromosome segregation fidelity.
Zebrafish Neuromesodermal Progenitors Undergo a Critical State Transition in vivo
Authors: Toh Kane , Saunders Dillan , Verd Berta , Steventon Benjamin
Published: February 2022

The transition state model of cell differentiation proposes that a transient window of gene expression stochasticity precedes entry into a differentiated state. As this has been assessed primarily in vitro, we sought to explore whether it can also be observed in vivo. Zebrafish neuromesodermal progenitors (NMps) differentiate into spinal cord and paraxial mesoderm at the late somitogenesis stages. We observed an increase in gene expression variability at the 24 somite stage (24ss) prior to their differentiation. From our analysis of a published 18ss scRNA-seq dataset, we showed that the NMp population possesses a signature consistent with a population undergoing a critical transition. By building in silico composite gene expression maps from our image data, we were able to assign an ‘NM index’ to each in silico NMp based on the cumulative expression of its neural and mesodermal markers. With the NM index distributions, we demonstrated that cell population heterogeneity of the NMps peaked at 24ss. We then incorporated stochasticity and non-autonomy into a genetic toggle switch model and uncovered the existence of rebellious cells, which we then confirmed by reexamining the composite maps. Taken together, our work supports the transition state model within an endogenous cell fate decision making event.
A case for newborn screening for pyridoxine-dependent epilepsy
Authors: Coughlin Curtis R , Tseng Laura A , van Karnebeek Clara DM
Published: February 2022

Pyridoxine dependent epilepsy due to mutations in ALDH7A1 (PDH-ALDH7A1) is a highly treatable developmental and epileptic encephalopathy. Pharmacologic doses of pyridoxine are associated with dramatic clinical seizure improvement and most patient achieve adequate seizure control with pyridoxine alone. Unfortunately, patients with PDE-ALDH7A1 have died prior to diagnosis and subsequent treatment with pyridoxine highlighting the importance of a timely diagnosis. Although critical for seizure control, pyridoxine treatment alone is not sufficient for normal outcomes as most patients suffer intellectual and developmental delay. Adjunct lysine reduction therapies are associated with significant developmental improvements although these treatments have limited efficacy if delayed after the first few months of life. Recently two biomarkers were identified that overcome previous technical hurdles for newborn screening. Herein we provide commentary that PDE-ALDH7A1 meets both current and historic criteria for newborn screening, and that a neonatal diagnosis and treatment can both reduce mortality from uncontrolled seizures and significantly improve the cognitive delay that is pervasive in this treatable disorder.
Crystal structures and Hirshfeld surface analysis of 5-amino-1-(4-methoxyphenyl)pyrazole-4-carboxylic acid and 5-amino-3-(4-methoxyphenyl)isoxazole
Authors: Pintro Chris J. , Long Analeece K. , Amonette Allison J. , Lobue James M. , Padgett Clifford W.
Published: February 2022

The title compounds, C11H11N3O3, (I), and C10H10N2O2, (II), are commercially available and were crystallized from ethyl acetate solution. The dihedral angle between the pyrazole and phenyl rings in (I) is 52.34 (7)° and the equivalent angle between the isoxazole and phenyl rings in (II) is 7.30 (13)°. In the crystal of (I), the molecules form carboxylic acid inversion dimers with an R(8) ring motif via pairwise O—H...O hydrogen bonds. In the crystal of (II), the molecules are linked via N—H...N hydrogen bonds forming chains propagating along [010] with a C(5) motif. A weak N—H...π interaction also features in the packing of (II). Hirshfeld surface analysis was used to explore the intermolecular contacts in the crystals of both title compounds: the most important contacts for (I) are H...H (41.5%) and O...H/H...O (22.4%). For (II), the most significant contact percentages are H...H (36.1%) followed by C...H/H...C (31.3%).