bluuebunny/crossref_metadata_2025 huggingface dataset:
Mycobacterium canettii Tuberculosis Lymphadenopathy in a 3-Year-old Child
Authors: Faury Hélène , Stanzelova Anna , Ferroni Agnès , Belhous Kahina , Morand Philippe , Toubiana Julie , Bille Emmanuelle , Isnard Pierre , Simon François , Lécuyer Hervé
Published: May 2023

A 3-year-old male originating from Djibouti presented with a cervical mass evolving for 2 months. Tuberculous lymphadenopathy was suspected based on biopsy results, and he improved quickly on standard antituberculous quadritherapy. Subsequently some features of the mycobacterium that grew in culture were unusual. The isolate was eventually identified as Mycobacterium canettii, a peculiar species of the Mycobacterium tuberculosis complex.
Topical analgesics for acute corneal pain: current options and emerging therapeutics
Authors: Lafreniere J. Daniel , Szczesniak Anna-Maria , Courtney Emma , Kelly Melanie E.M. , Faktorovich Ella G.
Published: May 2023

Acute corneal pain is a common complaint that causes significant distress to patients and continues to challenge therapeutic avenues for pain management. Current topical treatment options have marked limitations in terms of both efficacy and safety, thus often prompting the adjunctive use of systemic analgesics, including opioids. In general, there have not been extensive advancements in pharmacologic options for the management of corneal pain over the past several decades. Despite this, multiple promising therapeutic avenues exist which hold the potential to transform the ocular pain landscape, including druggable targets within the endocannabinoid system. This review will summarize the current evidence base for topical nonsteroidal anti-inflammatory drugs, anticholinergic agents, and anesthetics before focusing on several potential avenues in the setting of acute corneal pain management, including autologous tear serum, topical opioids and endocannabinoid system modulators.
Trends in the mortality, incidence and disability-adjusted life-years of appendicitis in EU15+ countries: an observational study of the global burden of disease database, 1990-2019
Authors: Proctor Dominic W. , Goodall Richard , Borsky Kim , Salciccioli Justin D. , Marshall Dominic C. , Shanmugarajah Kumaran , Mohamed Abdulla , Shalhoub Joseph
Published: May 2023

Background:

Appendicitis places a substantial burden on healthcare systems, with acute appendicitis alone being the most common abdominal surgical emergency worldwide. Further characterisation of the disease burden in EU15+ countries may help optimise the distribution of healthcare resources. The aim of this observational study was to assess the trends in mortality, incidence and DALYs of appendicitis across European Union (EU) 15+ countries between the years 1990 and 2019, Supplemental Digital Content 3, http://links.lww.com/JS9/A589.

Materials and methods:

Age standardised mortality rates (ASMRs), age standardised incidence rates (ASIRs) and disability adjusted life years (DALYs) data for appendicitis in males and females were extracted from the 2019 Global Burden of Disease (GBD) study. Temporal trends within the study period were analysed using Joinpoint regression analysis.

Results:

The median ASMRs across EU15+ countries in 2019 were 0.08/100,000 and 0.13/100,000 for females and males, respectively. Between 1990 and 2019 the median percentage change in ASMR was −52.12% for females and −53.18% in males. The median ASIRs in 2019 for females and males were 251/100,000 and 278/100,000, respectively, with a median percentage change of +7.22% for females and +3.78% for males during the observation period. Decreasing trends in DALYs were observed over the 30-year study period, with median percentage changes of −23.57% and −33.81% for females and males, respectively, Supplemental Digital Content 3, http://links.lww.com/JS9/A589.

Conclusion:

Overall, a general trend of decreasing appendicitis ASMRs and DALYs was observed across EU15+ countries, despite small overall increases in appendicitis ASIRs, Supplemental Digital Content 3, http://links.lww.com/JS9/A589. Variations in both diagnostic and management strategies over the study period are likely contributory to the changing trends.
Management of External Auditory Canal Anterior Wall Defect: A Case Series and Literature Review
Authors: Jin Siyeon , Park Min-Hyun
Published: May 2023

Objectives

Although rare in etiology, anterior bony wall defects of the external auditory canal (EAC) accompanied by temporomandibular joint herniation may cause various otologic symptoms. Surgical treatment can be considered based on symptom severity because many previous case reports have highlighted its efficacy. This study aimed to review the long-term results of surgical treatment of EAC anterior wall defect and to suggest a stepwise approach when creating a treatment plan.

Methods

We performed a retrospective review of 10 patients who underwent surgical management to address the EAC anterior wall defect and its associated symptoms. Medical records, temporal bone computed tomography scans, audiometry, and endoscopic examination findings were analyzed.

Results

The primary repair of the EAC defect was the first to be surgically addressed in most cases, excluding one case with a severe combined infection. Of the 10 cases, 3 patients exhibited either postoperative complications or symptom recurrence. Six patients had resolved symptoms consequent to primary surgical repair, and four patients underwent revision surgery undergoing a more invasive procedure, such as canalplasty or mastoidectomy.

Conclusion

Primary repair of the anterior wall defect of the EAC seems to be overpromoted for lasting results but is not as promising as previously noted. We therefore propose to create a novel treatment flowchart regarding the surgical treatment of anterior wall defects of the EAC based on clinical experience.

Level of Evidence

IV.
Sex Estimation From the Paranasal Sinus Volumes Using Semiautomatic Segmentation, Discriminant Analyses, and Machine Learning Algorithms
Authors: Hekimoglu Yavuz , Sasani Hadi , Etli Yasin , Keskin Siddik , Tastekin Burak , Asirdizer Mahmut
Published: May 2023

The aims of this study were to determine whether paranasal sinus volumetric measurements differ according to sex, age group, and right-left side and to determine the rate of sexual dimorphism using discriminant function analysis and machine learning algorithms. The study included paranasal computed tomography images of 100 live individuals of known sex and age. The paranasal sinuses were marked using semiautomatic segmentation and their volumes and densities were measured. Sex determination using discriminant analyses and machine learning algorithms was performed. Males had higher mean volumes of all paranasal sinuses than females (P < 0.05); however, there were no statistically significant differences between age groups or sides (P > 0.05). The paranasal sinus volumes of females were more dysmorphic during sex determination. The frontal sinus volume had the highest accuracy, whereas the sphenoid sinus volume was the least dysmorphic. In this study, although there was moderate sexual dimorphism in paranasal sinus volumes, the use of machine learning methods increased the accuracy of sex estimation. We believe that sex estimation rates will be significantly higher in future studies that combine linear measurements, volumetric measurements, and machine-learning algorithms.
Approach to Imaging Ischemia in Women
Authors: Parwani Purvi , Mohammad Adeba , Liberman Yuval , Litmanovich Diana E.
Published: May 2023

Approach to imaging ischemia in women Coronary artery disease in women tends to have a worse short- and long-term prognosis relative to men and remains the leading cause of mortality worldwide. Both clinical symptoms and diagnostic approach remain challenging in women due to lesser likelihood of women presenting with classic anginal symptoms on one hand and underperformance of conventional exercise treadmill testing in women on the other. Moreover, a higher proportion of women with signs and symptoms suggestive of ischemia are more likely to have nonobstructive coronary artery disease (CAD) that requires additional imaging and therapeutic considerations. New imaging techniques such as coronary computed tomography (CT) angiography, CT myocardial perfusion imaging, CT functional flow reserve assessment, and cardiac magnetic resonance imaging carry substantially better sensitivity and specificity for the detection of ischemia and coronary artery disease in women. Familiarity with various clinical subtypes of ischemic heart disease in women and with the major advantages and disadvantages of advanced imaging tests to ensure the decision to select one modality over another is one of the keys to successful diagnosis of CAD in women. This review compares the 2 major types of ischemic heart disease in women – obstructive and nonobstructive, while focusing on sex-specific elements of its pathophysiology.
It’s not all about the MIC: Daptomycin synergy with β-lactams varies between enterococcal species where cardiolipin synthase mutations confer daptomycin resistance
Authors: McKew Genevieve
Published: May 2023

Introduction: Administering daptomycin with b-lactams may prevent resistance or achieve synergy in enterococcal infections. Daptomycin-non-susceptibility (DAP-NS) phenotype is commonly associated with mutations in the liaFSR and YycFGHIJ systems. Cardiolipin synthase (cls) mutations have been found in conjunction with liaFSR mutations, associated with higher MICs, suggesting they are stepwise mutations. In vitro, ampicillin restores daptomycin bactericidal activity in Enterococcus faecium isolates with liaFSR mutations, but not when they occur in the cls gene; cls-only Enterococcus faecalis mutants have not yet been reported.
Aim: The aim was to explore daptomycin synergy with b-lactams for high-MIC DAP-NS E. faecalis and E. faeciumcls mutants.
Methodology: Experimentally-induced DAP-NS E. faecalis (A7) and DAP-NS E. faecium (C_002) from a persistent infection on daptomycin-ampicillin therapy had whole-genome sequencing (AB SOLiD 5500, CLC Genomics Workbench 9). Time-kill studies were performed with DAP, ampicillin, and DAP-AMP for both isolates; and ceftriaxone and DAP-ceftriaxone for E. faecalis.
Results: Both isolates’ only DAP-NS-associated mutation was in cls. DAP-ceftriaxone demonstrated bactericidal activity and synergy for E. faecalis A7, whereas E. faecium C_002 grew in the presence of DAP and DAP-AMP.

Conclusion: High-level DAP-NS arose in association with a cls mutation alone in E. faecalis A7, and in the absence of other documented DAP-NS-associated genetic mutations in E. faecium C_002. DAP-ceftriaxone combination therapy may be a useful salvage option in DAP-NS E. faecalis infections carrying the cls mutation identified in this study. There was no in vitro DAP-ampicillin synergy for cls-associated DAP-NS E. faecium C_002.
Viral infectivity in paediatric SARS-CoV-2 clinical samples does not vary by age
Authors: Schmidt Madaline M. , Despres Hannah W. , Shirley David J. , Bose Michael E. , McCaul Kate C. , Crothers Jessica W. , Henrickson Kelly J. , Lee Benjamin , Bruce Emily A.
Published: May 2023

At the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there was much uncertainty about the role of children in infection and transmission dynamics. Through the course of the pandemic, it became clear that children were susceptible to SARS-CoV-2 infection, although they were experiencing a notable lack of severe disease outcomes as compared to the adult population. This trend held true with the emergence of new SARS-CoV-2 variants, even in paediatric populations that were ineligible to be vaccinated. The difference in disease outcomes has prompted questions about the virological features of SARS-CoV-2 infection in this population. In order to determine if there was any difference in the infectivity of the virus produced by children with coronavirus disease 2019 (COVID-19), we compared viral RNA levels (clinical RT-qPCR C
T) and infectious virus titres from 144 SARS-CoV-2-positive clinical samples collected from children aged 0 to 18 years old. We found that age had no impact on the infectiousness of SARS-CoV-2 within our cohort, with children of all ages able to produce high levels of infectious virus.
Flavobacterium lacisediminis sp. nov., a bacterium isolated from lake sediment
Authors: Zhang Bo-Yuan , Yuan Ye , Zhou Jia , Wang Xi-Feng , Li Hai-Feng , Qu Jian-Hang
Published: May 2023

A taxonomic identification using polyphasic approach was performed on strain TH16-21T, which was isolated from the interfacial sediment of Taihu Lake, PR China. Strain TH16-21T was Gram-stain-negative, aerobic, rod-shaped and catalase-positive. Phylogenetic analysis based on the 16S rRNA gene and genomic sequences indicated that strain TH16-21T was classified within the genus of

Flavobacterium

. The 16S rRNA gene sequence of strain TH16-21T showed the highest similarity to

Flavobacterium cheniae

NJ-26T (98.9 %). The average nucleotide identity and digital DNA–DNA hybridization values between strain TH16-21T and

F. cheniae

NJ-26T were 91.2 and 45.9 %, respectively. The respiratory quinone was menaquinone 6. The major cellular fatty acids (>10 %) comprised iso-C15 : 0, iso-C16 : 0, iso-C15 : 1 G and iso-C16 : 0 3-OH. The genomic DNA G+C content was 32.2 mol%. Phosphatidylethanolamine, six amino lipids and three phospholipids were the main polar lipids. Based on the phenotypic features and phylogenetic position, a novel species with the name Flavobacterium lacisediminis sp. nov. is proposed. The type strain is TH16-21T (=MCCC 1K04592T=KACC 22896T).
Chromatic fusion: generative multimodal neuroimaging data fusion provides multi-informed insights into schizophrenia
Authors: Geenjaar Eloy P.T. , Lewis Noah L. , Fedorov Alex , Wu Lei , Ford Judith M. , Preda Adrian , Plis Sergey M. , Calhoun Vince D.
Published: May 2023

Full abstract

This work proposes a novel generative multimodal approach to jointly analyze multimodal data while linking the multimodal information to colors. By linking colors to private and shared information from modalities, we introduce chromatic fusion, a framework that allows for intuitively interpreting multimodal data. We test our framework on structural, functional, and diffusion modality pairs. In this framework, we use a multimodal variational autoencoder to learn separate latent subspaces; a private space for each modality, and a shared space between both modalities. These subspaces are then used to cluster subjects, and colored based on their distance from the variational prior, to obtain meta-chromatic patterns (MCPs). Each subspace corresponds to a different color, red is the private space of the first modality, green is the shared space, and blue is the private space of the second modality. We further analyze the most schizophrenia-enriched MCPs for each modality pair and find that distinct schizophrenia subgroups are captured by schizophrenia-enriched MCPs for different modality pairs, emphasizing schizophrenia’s heterogeneity. For the FA-sFNC, sMRI-ICA, and sMRI-ICA MCPs, we generally find decreased fractional corpus callosum anisotropy and decreased spatial ICA map and voxel-based morphometry strength in the superior frontal lobe for schizophrenia patients. To additionally highlight the importance of the shared space between modalities, we perform a robustness analysis of the latent dimensions in the shared space across folds. These robust latent dimensions are subsequently correlated with schizophrenia to reveal that for each modality pair, multiple shared latent dimensions strongly correlate with schizophrenia. In particular, for FA-sFNC and sMRI-sFNC shared latent dimensions, we respectively observe a reduction in the modularity of the functional connectivity and a decrease in visual-sensorimotor connectivity for schizophrenia patients. The reduction in modularity couples with increased fractional anisotropy in the left part of the cerebellum dorsally. The reduction in the visual-sensorimotor connectivity couples with a reduction in the voxel-based morphometry generally but increased dorsal cerebellum voxel-based morphometry. Since the modalities are trained jointly, we can also use the shared space to try and reconstruct one modality from the other. We show that cross-reconstruction is possible with our network and is generally much better than depending on the variational prior. In sum, we introduce a powerful new multimodal neuroimaging framework designed to provide a rich and intuitive understanding of the data that we hope challenges the reader to think differently about how modalities interact.
Multimodal Risk Prediction with Physiological Signals, Medical Images and Clinical Notes
Authors: Wang Yuanlong , Yin Changchang , Zhang Ping
Published: May 2023

The broad adoption of electronic health records (EHRs) provides great opportunities to conduct healthcare research and solve various clinical problems in medicine. With recent advances and success, methods based on machine learning and deep learning have become increasingly popular in medical informatics. Combining data from multiple modalities may help in predictive tasks. To assess the expectations of multimodal data, we introduce a comprehensive fusion framework designed to integrate temporal variables, medical images, and clinical notes in Electronic Health Record (EHR) for enhanced performance in down-stream predictive tasks. Early, joint, and late fusion strategies were employed to effectively combine data from various modalities. Model performance and contribution scores show that multimodal models outperform uni-modal models in various tasks. Additionally, temporal signs contain more information than CXR images and clinical notes in three explored predictive tasks. Therefore, models integrating different data modalities can work better in predictive tasks.
The impact of poverty on mental illness: Emerging evidence of a causal relationship
Authors: Marchi Mattia , Alkema Anne , Xia Charley , Thio Chris H. L. , Chen Li-Yu , Schalkwijk Winni , Galeazzi Gian M. , Ferrari Silvia , Pingani Luca , Kweon Hyeokmoon , Evans-Lacko Sara , Hill W. David , Boks Marco P.
Published: May 2023

The link between poverty and mental illness has sparked discussions concerning the poverty role as a risk factor for poor mental health. If poverty has as a causal role in mental illness, it would have profound implications for our comprehension of mental well-being and guide efforts to address the increasing incidence of mental health disorders.

Building on the recent breakthrough discovery of heritability of poverty traits and utilizing large-scale genome-wide association studies of mental illness, we used Genomic Structural Equation Modeling (GSEM) and Mendelian randomization (MR) to examine the evidence of a causal relationship between poverty and mental illness. A common factor of poverty was derived from household income (HI), occupational income (OI), and social deprivation (SD). The causal effect of poverty was examined on 9 mental illnesses: attention deficit and hyperactivity disorder (ADHD), anorexia nervosa (AN), anxiety disorders (ANX), autism spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and schizophrenia (SZ), while accounting for the influence of cognitive ability (CA).

Our analysis highlights HI as the measure of poverty with the strongest correlation with the common factor, when compared to OI and SD. Using the common factor of poverty, bidirectional MR provided evidence that mental illness leads to poverty, consistent with the existing paradigm. What is new is evidence that higher levels of poverty likely pose a causal factor in developing ADHD (Inverse Variance Weighted Odds Ratio per Standard Deviation change [IVW OR]=3.43[95%CI:2.95-3.99]), MDD (IVW OR=1.49[95%CI:1.29-1.72]), and SZ (IVW OR=1.53[95%CI:1.35-1.73]), but exerts a protective effect against AN (IVW OR=0.50[95%CI:0.40-0.62]). The direct effect of poverty on mental illness remained following adjustment for CA, albeit with reduced effect sizes.

Our research indicates that higher poverty levels are likely causal risk factors for MDD and SZ, but protective against AN. Notably, CA explains a significant portion of the impact of poverty, aligning with prior reports that highlight the contribution of impaired cognitive function to severe mental illnesses. Although individuals’ skills and abilities tied to earning capacity may be the variables with the actual causal effect of poverty on mental illness, our findings warrant further investigations into interventions targeting poverty and cognitive abilities to advance mental health.
Uniform Manifold Approximation and Projection-based Assessment of Chronic Kidney Disease Aetiologies based on Urinary Peptidomics
Authors: Mavrogeorgis Emmanouil , He Tianlin , Mischak Harald , Latosinska Agnieszka , Vlahou Antonia , Schanstra Joost P. , Catanese Lorenzo , Amann Kerstin , Huber Tobias B. , Beige Joachim , Rupprecht Harald , Siwy Justyna
Published: May 2023

Background

The impact of artificial intelligence combined with advanced techniques is ever-increasing in the biomedical field appearing promising, among others, in chronic kidney disease (CKD) diagnosis. However, existing models are often single-aetiology specific. Proposed here is a pipeline for the development of single models able to distinguish and spatially visualize multiple CKD aetiologies.

Methods

Acquired were from the Human Urinary Proteome Database the urinary peptide data of 1850 healthy control (HC) and CKD (diabetic kidney disease-DKD, IgA nephropathy-IgAN, vasculitis) participants. The uniform manifold approximation and projection (UMAP) method was coupled to a support vector machine (SVM) algorithm. Binary (DKD, HC) and multiclass (DKD, HC, IgAN, vasculitis) classifications were performed, including or skipping the UMAP step. Last, the pipeline was compared to the current state-of-the-art single-aetiology CKD urinary models.

Findings

In an independent test set, the developed models (including the UMAP step) achieved 90.35% and 70.13% overall predictive accuracies, respectively, for the binary and the multiclass classifications (96.14% and 85.06%, skipping the UMAP step). Overall, the HC class was distinguished with the highest accuracy. The different classes displayed a tendency to form distinct clusters in the 3D-space based on their disease state.

Interpretation

Urinary peptide data appear to potentially be an effective basis for CKD aetiology differentiation. The UMAP step may provide a unique visualization advantage capturing the relevant molecular (patho)physiology. Further studies are warranted to validate the pipeline’s clinical potential in the presented as well as other CKD aetiologies or even other diseases.
Population context drives cell-to-cell variability in interferon response in epithelial cells
Authors: Metz-Zumaran Camila , Doldan Patricio , Muraca Francesco , Keser Yagmur , Lukas Pascal , Kuropka Benno , Küchenhoff Leonie , Talemi Soheil Rastgou , Höfer Thomas , Freund Christian , Cavalcanti-Adam Elisabetta Ada , Graw Frederik , Stanifer Megan , Boulant Steeve
Published: May 2023

Isogenic cells respond in a heterogeneous manner to interferon. Using a micropatterning approach combined with high-content imaging and spatial analyses, we characterized how the population context (position of a cell with respect to the neighboring cells) of human intestinal epithelial cells affects single cell response to interferons. We identified that cells at the edge of a cellular colony are significantly more responsive than cells embedded within this colony. We determined that this spatial heterogeneity in IFN response was the result of the polarized basolateral distribution of the IFN receptors making cells located in the center of a cellular colony not responsive to ectopic IFN stimulation. We could demonstrate that this population context driven cell-to-cell variability influences the outcome of viral infection as cells embedded in a cellular colony are not protected by interferons and therefore more susceptible to infection. Our data highlights that the behavior of individual isolated cells does not directly translate to their behavior in a population, placing the population context as a key driver of cell-to-cell heterogeneity in IFN response.
ClearX9-Stem™: an efficient, affordable & sustainable stem cell culture medium for biotech and cell-cultivated meat industries
Authors: Gautam Sumit , Verma Neeraj , Manvati Siddharth , Dhar Pawan K.
Published: May 2023

Stem cells are extraordinary cells with a unique ability of self-renewal and differentiation into various cell types such as muscle, nerve, bone, and blood cells. Historically, they have found significant applications in the biotech and pharma sectors. To grow and maintain stem cells artificially, researchers use basal media formulations supplemented with nutrients and growth factors, with Fetal bovine serum (FBS) as the key component of the culture medium. However, to maintain this supply every year, millions of pregnant cows are slaughtered for preparing FBS. The process of harvesting FBS also raises concerns about contamination with pathogens, animal proteins that may interfere with cellular behavior and ethical considerations regarding animal welfare. To overcome these limitations, here we report ClearX9-Stem™ - an affordable, sustainable, effective, and ethical replacement for an FBS-enriched stem cell culture medium. A specialized ClearX9-Stem™ cell culture medium formulation was designed to grow chicken embryonic fibroblast (SL-29) in the absence of FBS. Based on the results obtained, ClearX9-Stem™ is undergoing further refinement to meet the growing academic and industrial demand for serum-free culture media formulations. In the future, there is a need to customize and optimize ClearX9-Stem™ for the scalable growth of cells in bioreactors.

HIGHLIGHTS

ClearX9-Stem™ provides good nutritional support for the growth of chicken embryonic fibroblast cells.

ClearX9-Stem™ cell growth performance is comparable to the serum-enriched culture medium

ClearX9-Stem™ maintains a healthy morphological profile of cells during division

ClearX9-Stem™ generates a stress-free environment within cells

ClearX9-Stem™ does not require animal slaughter and reduces the environmental footprint

ClearX9-Stem™ has applications in the biotechnology, pharma, and cell-cultivated meat industries
The sequestration of miR-642a-3p by a complex formed by HIV-1 Gag and human Dicer increases AFF4 expression and viral production
Authors: Alpuche-Lazcano Sergio P. , Dunkley Owen R. S. , Scarborough Robert J. , Daniels Sylvanne M. , Daher Aïcha , Truchi Marin , Estable Mario C. , Mari Bernard , Mouland Andrew J. , Gatignol Anne
Published: May 2023

Micro (mi)RNAs are critical regulators of gene expression in human cells, the functions of which can be affected during viral replication. Here, we show that the human immunodeficiency virus type 1 (HIV-1) structural precursor Gag protein interacts with the miRNA processing enzyme Dicer. RNA immunoprecipitation and sequencing experiments show that Gag modifies the retention of a specific miRNA subset without affecting Dicer’s pre- miRNA processing activity. Among the retained miRNAs, miR-642a-3p shows an enhanced occupancy on Dicer in the presence of Gag and is predicted to target AFF4 mRNA, which encodes an essential scaffold protein for HIV-1 transcriptional elongation. miR-642a-3p gain- or loss-of-function negatively or positively regulates AFF4 protein expression at mRNA and protein levels with concomitant modulations of HIV-1 production, consistent with an antiviral activity. By sequestering miR-642a-3p with Dicer, Gag enhances AFF4 expression and HIV- 1 production without affecting miR-642a-3p levels. These results identify miR-642a-3p as a strong suppressor of HIV-1 replication and uncover a novel mechanism by which a viral structural protein directly disrupts an miRNA function for the benefit of its own replication.

IMPORTANCE:

Virus-host relationships occur at different levels and the human immunodeficiency virus type 1 (HIV-1) can modify the expression of microRNAs in different cells. Here, we identify a virus- host interaction between the HIV-1 structural protein Gag and the miRNA-processing enzyme Dicer. Gag does not affect the microRNA processing function of Dicer but affects the functionality of a subset of microRNAs that are enriched on the Dicer-Gag complex compared to on Dicer alone. We show that miR-642a-3p, the most enriched microRNA on the Dicer- Gag complex targets and degrades AFF4 mRNA coding for a protein from the super transcription elongation complex, essential for HIV-1 and cellular transcription. Interestingly, the silencing capacity by miR-642a-3p is hindered by Gag and heightened in its absence, consequently affecting HIV-1 transcription. These findings unveil a new paradigm that a microRNA function rather than its abundance can be affected by a viral protein through its enhanced retention on Dicer.
Vascular Endothelial-derived SPARCL1 Exacerbates Viral Pneumonia Through Pro-Inflammatory Macrophage Activation
Authors: Zhao Gan , Gentile Maria E. , Xue Lulu , Cosgriff Christopher V. , Weiner Aaron I. , Adams-Tzivelekidis Stephanie , Wong Joanna , Li Xinyuan , Kass-Gergi Sara , Holcomb Nicolas P. , Basal Maria C. , Stewart Kathleen M. , Planer Joseph D. , Cantu Edward , Christie Jason D. , Crespo Maria M. , Mitchell Michael J. , Meyer Nuala J. , Vaughan Andrew E.
Published: May 2023

Inflammation upon infectious lung injury is a double-edged sword: while tissue-infiltrating immune cells and cytokines are necessary to control infection, these same factors often aggravate injury. Full appreciation of both the sources and targets of inflammatory mediators is required to facilitate strategies to maintain antimicrobial effects while minimizing off-target epithelial and endothelial damage. Recognizing that the vasculature is centrally involved in tissue responses to injury and infection, we observed that pulmonary capillary endothelial cells (ECs) exhibit dramatic transcriptomic changes upon influenza injury punctuated by profound upregulation ofSparcl1. Endothelial deletion and overexpression of SPARCL1 implicated this secreted matricellular protein in driving key pathophysiologic symptoms of pneumonia, which we demonstrate result from its effects on macrophage polarization. SPARCL1 induces a shift to a pro-inflammatory “M1-like” phenotype (CD86+CD206-), thereby increasing associated cytokine levels. Mechanistically, SPARCL1 acts directly on macrophagesin vitroto induce the pro-inflammatory phenotype via activation of TLR4, and TLR4 inhibitionin vivoameliorates inflammatory exacerbations caused by endothelialSparcl1overexpression. Finally, we confirmed significant elevation of SPARCL1 in COVID-19 lung ECs in comparison with those from healthy donors. Survival analysis demonstrated that patients with fatal COVID-19 had higher levels of circulating SPARCL1 protein compared to those who recovered, indicating the potential of SPARCL1 as a biomarker for prognosis of pneumonia and suggesting that personalized medicine approaches might be harnessed to block SPARCL1 and improve outcomes in high-expressing patients.
dsSurvival 2.0: Privacy enhancing survival curves for survival models in the federated DataSHIELD analysis system
Authors: Banerjee Soumya , Bishop Tom R.P.
Published: May 2023

Objective

Survival models are used extensively in biomedical sciences, where they allow the investigation of the effect of exposures on health outcomes. It is desirable to use diverse data sets in survival analyses, because this offers increased statistical power and generalisability of results. However, there are often challenges with bringing data together in one location or following an analysis plan and sharing results.

DataSHIELD is an analysis platform that helps users to overcome these ethical, governance and process difficulties. It allows users to analyse data remotely, using functions that are built to restrict access to the detailed data items (federated analysis).

Previous works have provided survival modelling functionality in DataSHIELD (dsSurvival package), but there is a requirement to provide functions that offer privacy enhancing survival curves that retain useful information.

Results

We introduce an enhanced version of the dsSurvival package which offers privacy enhancing survival curves for DataSHIELD. Different methods for enhancing privacy were evaluated for their effec-tiveness in enhancing privacy while maintaining utility. We demonstrated how our selected method could enhance privacy in different scenarios using real survival data. The details of how DataSHIELD can be used to generate survival curves can be found in the associated tutorial.
Colonization and Dissemination ofKlebsiella pneumoniaeis Dependent on Dietary Carbohydrates
Authors: Hecht Aaron L. , Harling Lisa C. , Friedman Elliot S. , Tanes Ceylan , Lee Junhee , Firrman Jenni , Tu Vincent , Liu LinShu , Bittinger Kyle , Goulian Mark , Wu Gary D.
Published: May 2023

Dysbiosis of the gut microbiota is increasingly appreciated as both a consequence and precipitant of human disease. The outgrowth of the bacterial familyEnterobacteriaceaeis a common feature of dysbiosis, including the human pathogenKlebsiella pneumoniae. Dietary interventions have proven efficacious in the resolution of dysbiosis, though the specific dietary components involved remain poorly defined. Based on a previous human diet study, we hypothesized that dietary nutrients serve as a key resource for the growth of bacteria found in dysbiosis. Through human sample testing, andex-vivo, andin vivomodeling, we find that nitrogen is not a limiting resource for the growth ofEnterobacteriaceaein the gut, contrary to previous studies. Instead, we identify dietary simple carbohydrates as critical in colonization ofK. pneumoniae. We additionally find that dietary fiber is necessary for colonization resistance againstK. pneumoniae, mediated by recovery of the commensal microbiota, and protecting the host against dissemination from the gut microbiota during colitis. Targeted dietary therapies based on these findings may offer a therapeutic strategy in susceptible patients with dysbiosis.
From interaction networks to interfaces: Scanning intrinsically disordered regions using AlphaFold2
Authors: Bret Hélène , Andreani Jessica , Guerois Raphaël
Published: May 2023

The revolution brought about by AlphaFold2 and the performance of AlphaFold2-Multimer open promising perspectives to unravel the complexity of protein-protein interaction networks. Nevertheless, the analysis of interaction networks obtained from proteomics experiments does not systematically provide the delimitations of the interaction regions. This is of particular concern in the case of interactions mediated by intrinsically disordered regions, in which the interaction site is generally small. Using a dataset of protein-peptide complexes involving intrinsically disordered protein regions that are non-redundant with the structures used in AlphaFold2 training, we show that when using the full sequences of the proteins involved in the interaction networks, AlphaFold2-Multimer only achieves 40% success rate in identifying the correct site and structure of the interface. By delineating the interaction region into fragments of decreasing size and combining different strategies for integrating evolutionary information, we managed to raise this success rate up to 90%. Beyond the correct identification of the interaction site, our study also explores specificity issues. We show the advantages and limitations of using the AlphaFold2 confidence score to discriminate between alternative binding partners, a task that can be particularly challenging in the case of small interaction motifs.
Three genes controlling streptomycin susceptibility inAgrobacterium fabrum
Authors: Howarth Robyn E. , Pattillo Curtis M. , Griffitts Joel S. , Calvopina-Chavez Diana G.
Published: May 2023

Streptomycin is a commonly used antibiotic for its efficacy against diverse bacteria. The plant pathogenAgrobacterium fabrumis a model for studying pathogenesis and interkingdom gene transfer. Streptomycin-resistant variants ofA. fabrumare commonly employed in genetic analyses, yet mechanisms of resistance and susceptibility to streptomycin in this organism have not previously been investigated. We observe that resistance to a high concentration of streptomycin arises at high frequency inA. fabrumand we link this trait to the presence of a chromosomal gene (strB) encoding a putative aminoglycoside phosphotransferase. We show howstrB, along withrpsL(encoding ribosomal protein S12) andrsmG(encoding a 16S rRNA methyltransferase) modulate streptomycin sensitivity inA. fabrum.
Heterogeneous subpopulations of GABAAR-responding neurons coexist in physiological and pathological mature neuronal networks at increasing scales of complexity
Authors: Colombi I. , Rastogi M. , Parrini M. , Alberti M. , Chiappalone M. , Nanni M. , Contestabile A. , Cancedda L.
Published: May 2023

GABA is the main inhibitory neurotransmitter in adults. Depolarizing/excitatory GABA responses have been well characterized at the level of neuronal-populationaverageduring typicalneurodevelopmentand partially in pathology. However, no investigation has specifically assessed whether amosaicismof cells with either depolarizing/excitatory or hyperpolarizing/inhibitory GABAergic responses exists inadultanimals in health/disease. Here, we showed that such mosaicism is present both in adult WT and Down syndrome (DS) mice, as assessed at increasing scales of neuronal-network complexity (cultures, brain- slices, behaving mice). Nevertheless, WT mice presented a lower percentage of cells with depolarizing GABA than DS mice. Restoring the mosaicism of hyperpolarizing and depolarizing GABA-responding neurons to WT levels rescued anxiety behaviour in DS mice. We also found heterogeneous GABAergic responses in mature control and trisomic human iPSC-derived neurons. Thus, a heterogeneous population of GABA-responding cells exists in physiological/pathological conditions in mature mouse and human neurons, possibly contributing to disease-associated behaviours.
Cation permeability and pore dynamics in TRPV1 ion channels
Authors: García-Ávila Miriam , Tello-Marmolejo Javier , Rosenbaum Tamara , Islas León D.
Published: May 2023

The Transient Receptor Vanilloid 1 (TRPV1) is a non-selective ion channel, which is activated by several chemical ligands and heat. We have previously shown that activation of TRPV1 by different ligands result in single-channel openings with different conductance, suggesting that the selectivity filter is highly dynamic. TRPV1 is weakly voltage-dependent, here we sought to explore whether the permeation of different monovalent ions could influence the voltage-dependence of this ion channel. By using single-channel recordings, we show that TRPV1 channels undergo rapid transitions to closed states that are directly connected to the open state, which may result from structural fluctuations of their selectivity filters. Moreover, we demonstrate that the rates of these transitions are strongly influenced by the permeant ion, suggesting that ion permeation regulates the voltage dependence of these channels.
Modeling kidney development, disease, and plasticity with clonal expandable nephron progenitor cells and nephron organoids
Authors: Huang Biao , Zeng Zipeng , Li Hui , Li Zexu , Chen Xi , Guo Jinjin , Zhang Chennan C. , Schreiber Megan E. , Vonk Ariel C. , Xiang Tianyuan , Patel Tadrushi , Li Yidan , Parvez Riana K. , Der Balint , Chen Jyun Hao , Liu Zhenqing , Thornton Matthew E. , Grubbs Brendan H. , Diao Yarui , Dou Yali , Gnedeva Ksenia , Lindström Nils O. , Ying Qilong , Pastor-Soler Nuria M. , Fei Teng , Hallows Kenneth R. , McMahon Andrew P. , Li Zhongwei
Published: May 2023

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here we report manipulation of p38 and YAP activity creates a synthetic niche that allows the long-term clonal expansion of primary mouse and human NPCs, and induced NPCs (iNPCs) from human pluripotent stem cells. Cultured iNPCs resemble closely primary human NPCs, generating nephron organoids with abundant distal convoluted tubule cells, which are not observed in published kidney organoids. The synthetic niche reprograms differentiated nephron cells into NPC state, recapitulating the plasticity of developing nephronin vivo. Scalability and ease of genome-editing in the cultured NPCs allow for genome-wide CRISPR screening, identi-fying novel genes associated with kidney development and disease. A rapid, efficient, and scala-ble organoid model for polycystic kidney disease was derived directly from genome-edited NPCs, and validated in drug screen. These technological platforms have broad applications to kidney development, disease, plasticity, and regeneration.
Optimal Filters for ERP Research I: A General Approach for Selecting Filter Settings
Authors: Zhang Guanghui , Garrett David R. , Luck Steven J.
Published: May 2023

Filtering plays an essential role in event-related potential (ERP) research, but filter settings are usually chosen on the basis of historical precedent, lab lore, or informal analyses. This reflects, in part, the lack of a well-reasoned, easily implemented method for identifying the optimal filter settings for a given type of ERP data. To fill this gap, we developed an approach that involves finding the filter settings that maximize the signal-to-noise ratio for a specific amplitude score (or minimizes the noise for a latency score) while minimizing waveform distortion. The signal is estimated by obtaining the amplitude score from the grand average ERP waveform (usually a difference waveform). The noise is estimated using the standardized measurement error of the single-subject scores. Waveform distortion is estimated by passing noise-free simulated data through the filters. This approach allows researchers to determine the most appropriate filter settings for their specific scoring methods, experimental designs, subject populations, recording setups, and scientific questions. We have provided a set of tools in ERPLAB Toolbox to make it easy for researchers to implement this approach with their own data.
A role for DNA methylation in bumblebee morphogenesis hints at female-specific developmental erasure
Authors: Hunt B. J. , Pegoraro M. , Marshall H. , Mallon E. B.
Published: May 2023

Epigenetic mechanisms, such as DNA methylation, are crucial factors in animal development. In some mammals almost all DNA methylation is erased during embryo development and re-established in a sex- and cell-specific manner. This erasure and re-establishment is thought to primarily be a vertebrate-specific trait. Insects are particularly interesting in terms of development as many species often undergo remarkable morphological changes en route to maturity, i.e. morphogenesis. However, little is known about the role of epigenetic mechanisms in this process across species. We have used whole genome bisulfite sequencing to track genome-wide DNA methylation changes through the development of an economically and environmentally important pollinator species, the bumblebee Bombus terrestris. We find overall levels of DNA methylation vary throughout development and we find developmentally relevant differentially methylated genes throughout. Intriguingly, we have identified a depletion of DNA methylation in ovaries and an enrichment in sperm. We suggest this could represent a sex-specific DNA methylation erasure event. To our knowledge this is the first suggestion of possible developmental DNA methylation erasure in an insect species. This study lays the required groundwork for functional experimental work to determine if there is a causal-nature to the DNA methylation differences identified. Additionally, the application of single-cell methylation sequencing to this system will enable more accurate identification of when/if DNA methylation is erased during development.
Assessing the role of institutional effectiveness on carbon sequestration: the case of China's nature reserve policy
Authors: Chen Yuquan , Fiankor Dela-Dem Doe , Kang Kuan , Zhang Qian
Published: May 2023

Purpose

Carbon storage in protected land is a practical climate stabilization strategy. It is increasingly being recognized as an essential means of safeguarding biomass carbon and improving local ecological conditions. Yet, increasing soil carbon sequestration by setting aside nature reserves does not depend only on the scale of the reserve but more so on the implementation and enforcement of the reserve protection policy. This paper aims to discuss the aforementioned issues.

Design/methodology/approach

The authors show how nature reserves established and managed by different administrative levels affect carbon sequestration. Empirically, the authors estimate a time-varying difference-in-difference model that exploits China's distinct four-layered hierarchical nature reserve management system at the county level.

Findings

The findings show that higher administrative level (i.e. national and provincial) nature reserves have no effects on the carbon dynamic. However, reserves managed by lower administrative levels (i.e. prefecture- and county-level) are associated with reduced carbon sequestration. The results imply local governments fail to fulfil their responsibilities for nature reserves protection, leading to increased extractive activities and declined ecological biomass.

Research limitations/implications

Responsibility and accountability mechanisms for the violation of the nature reserves requirements need to be stipulated accordingly. Greater emphasis should be placed on nature reserves at the base level. The central government should continue efforts toward the establishment of ad hoc and independent management agencies at the ground-management level that are free of influence from base-level governments.

Originality/value

The heterogeneity in the performance of nature reserves across administrative levels confirms that ecosystem service quality is highly dependent on establishment, management and supervision. This provides a better understanding of the socio-ecological interdependence of protected areas.
The tail that wags the dog: lessons from the UK's independent unions for class struggle trade unionism
Authors: Weghmann Vera
Published: May 2023

Purpose

This article examines in what way strategies of new independent trade unions in London – that achieved pioneering, victories to end outsourcing – offer learning opportunities for more established trade unions. It proposes to (re-)encourage a culture of class struggle trade unionism. The article builds on existing research that outlined the organising practices of these independent trade unions but breaks down the binary analysis of independent versus established trade unions. The author uses the acronym CARE (Collectivising individual grievances, Action, Relations of trust and care, Escalating confrontations) as an analytical framework for exploring class struggle trade unionism, and examines in what ways these strategies have been (re)-learnt by established trade unions through the example of independent trade unions. In doing so, this article contributes to a much wider debate on trade union renewal.

Design/methodology/approach

This article offers an insider perspective of an “academic activist” (Chatterton et al., 2007). The article draws on author’s experiences and reflection as the co-founder of the trade union United Voices of the World (UVW) created in 2014, and previously involvement in the establishment of the Independent Workers of Great Britain (IWGB) in 2012. Findings are based on author’s ethnographic engagement as well as a selection of 29 interviews from a much larger data set on independent trade unions comprising focus groups and interviews.

Findings

This article demonstrates that class struggle trade unionism has in some ways been remembered and hence pioneered by the new independent trade unions, yet they are possible in established trade unions alike.

Originality/value

This is the first time an article systematically explores the strategies that established trade unions can learn – and indeed are learning – from independent trade unions.