Search Results (13)

Diabetic foot infections (DFIs) are a severe complication of diabetes and are increasing in prevalence globally. The microbiology of DFIs exhibits significant regional variation, with Acinetobacter baumannii frequently emerging as the predominant pathogen. This study aimed to investigate the microbiological profile of A. baumannii in DFIs of different Wagner grades. Pus and tissue specimens from 480 diabetic patients treated for DFIs between September 2016 and August 2019 were collected, and antimicrobial susceptibility testing was performed. Multiplex PCR was conducted to amplify extended spectrum β-lactamase (ESBL) and metallo-β-lactamase (MBL) genes. A. baumannii had a prevalence of 14.58% in DFIs, with 100% resistance to cephalosporins. Among the 70 A. baumannii isolates, 19 (27.14%) were ESBL producers and 43 (61.43%) were MBL producers. blaTEM was the most prevalent gene (52.94%) in ESBL producers; blaNDM-1 was the most prevalent gene (52.94%) in MBL producers. Our findings highlight the need for regular antimicrobial susceptibility testing, molecular surveillance, and robust antimicrobial stewardship programmes to effectively manage A. baumannii DFIs and mitigate their resistance. Full article

Refusals and delay in receiving COVID-19 vaccines due to vaccine hesitancy present major barriers to optimal vaccine uptake and thus epidemic control, with crisis-affected populations facing additional challenges. International Medical Corps conducted a cross-sectional survey to evaluate knowledge, attitudes, and perceptions regarding COVID-19 and identify determinants of COVID-19 vaccine hesitancy among 413 healthcare workers (HCW) working at 90 national primary healthcare centers in Lebanon, just prior to widespread vaccine rollout. Logistic regression was used to assess predictors of vaccine acceptance using the health belief Model. More than half (56.9%) of HCWs were categorized as being vaccine-hesitant, while 43.1% reported they would receive a vaccine when available. Perceived benefits, cues to action, and social norms were positively associated with vaccine acceptance. More than half (56.4%) believed the national health system was not capable of ensuring safe administration of the COVID-19 vaccine. Targeted interventions that emphasize the benefits of COVID-19 vaccination, highlight cues to vaccinate, and promote vaccination as a social norm are critical in motivating HCWs to get vaccinated. Increasing HCW trust in Lebanon’s national health system is critical to building confidence toward COVID-19 vaccines and has implications for the success of future responses to infectious disease outbreaks. Full article

The Module-0 Demonstrator is a single-phase 600 kg liquid argon time projection chamber operated as a prototype for the DUNE liquid argon near detector. Based on the ArgonCube design concept, Module-0 features a novel 80k-channel pixelated charge readout and advanced high-coverage photon detection system. In this paper, we present an analysis of an eight-day data set consisting of 25 million cosmic ray events collected in the spring of 2021. We use this sample to demonstrate the imaging performance of the charge and light readout systems as well as the signal correlations between the two. We also report argon purity and detector uniformity measurements and provide comparisons to detector simulations. Full article

Protein farnesylation is a post-translational modification where a 15-carbon farnesyl isoprenoid is appended to the C-terminal end of a protein by farnesyltransferase (FTase). This process often causes proteins to associate with the membrane and participate in signal transduction pathways. The most common substrates of FTase are proteins that have C-terminal tetrapeptide CaaX box sequences where the cysteine is the site of modification. However, recent work has shown that five amino acid sequences can also be recognized, including the pentapeptides CMIIM and CSLMQ. In this work, peptide libraries were initially used to systematically vary the residues in those two parental sequences using an assay based on Matrix Assisted Laser Desorption Ionization–Mass Spectrometry (MALDI-MS). In addition, 192 pentapeptide sequences from the human proteome were screened using that assay to discover additional extended CaaaX-box motifs. Selected hits from that screening effort were rescreened using an in vivo yeast reporter protein assay. The X-ray crystal structure of CMIIM bound to FTase was also solved, showing that the C-terminal tripeptide of that sequence interacted with the enzyme in a similar manner as the C-terminal tripeptide of CVVM, suggesting that the tripeptide comprises a common structural element for substrate recognition in both tetrapeptide and pentapeptide sequences. Molecular dynamics simulation of CMIIM bound to FTase further shed light on the molecular interactions involved, showing that a putative catalytically competent Zn(II)-thiolate species was able to form. Bioinformatic predictions of tetrapeptide (CaaX-box) reactivity correlated well with the reactivity of pentapeptides obtained from in vivo analysis, reinforcing the importance of the C-terminal tripeptide motif. This analysis provides a structural framework for understanding the reactivity of extended CaaaX-box motifs and a method that may be useful for predicting the reactivity of additional FTase substrates bearing CaaaX-box sequences. Full article

Animal studies are typically utilized to understand the complex mechanisms associated with toxicant-induced hepatotoxicity. Among the alternative approaches to animal studies, in vitro pooled human hepatocytes have the potential to capture population variability. Here, we examined the effect of the hepatotoxicant thioacetamide on pooled human hepatocytes, divided into five lots, obtained from forty diverse donors. For 24 h, pooled human hepatocytes were exposed to vehicle, 1.33 mM (low dose), and 12 mM (high dose) thioacetamide, followed by RNA-seq analysis. We assessed gene expression variability using heat maps, correlation plots, and statistical variance. We used KEGG pathways and co-expression modules to identify underlying physiological processes/pathways. The co-expression module analysis showed that the majority of the lots exhibited activation for the bile duct proliferation module. Despite lot-to-lot variability, we identified a set of common differentially expressed genes across the lots with similarities in their response to amino acid, lipid, and carbohydrate metabolism. We also examined efflux transporters and found larger lot-to-lot variability in their expression patterns, indicating a potential for alteration in toxicant bioavailability within the cells, which could in turn affect the gene expression patterns between the lots. Overall, our analysis highlights the challenges in using pooled hepatocytes to understand mechanisms of toxicity. Full article

Acute kidney injury, which is associated with high levels of morbidity and mortality, affects a significant number of individuals, and can be triggered by multiple factors, such as medications, exposure to toxic chemicals or other substances, disease, and trauma. Because the kidney is a critical organ, understanding and identifying early cellular or gene-level changes can provide a foundation for designing medical interventions. In our earlier work, we identified gene modules anchored to histopathology phenotypes associated with toxicant-induced liver and kidney injuries. Here, using in vivo and in vitro experiments, we assessed and validated these kidney injury-associated modules by analyzing gene expression data from the kidneys of male Hartley guinea pigs exposed to mercuric chloride. Using plasma creatinine levels and cell-viability assays as measures of the extent of renal dysfunction under in vivo and in vitro conditions, we performed an initial range-finding study to identify the appropriate doses and exposure times associated with mild and severe kidney injuries. We then monitored changes in kidney gene expression at the selected doses and time points post-toxicant exposure to characterize the mechanisms of kidney injury. Our injury module-based analysis revealed a dose-dependent activation of several phenotypic cellular processes associated with dilatation, necrosis, and fibrogenesis that were common across the experimental platforms and indicative of processes that initiate kidney damage. Furthermore, a comparison of activated injury modules between guinea pigs and rats indicated a strong correlation between the modules, highlighting their potential for cross-species translational studies. Full article

Vaccine hesitancy among displaced populations is associated with inequitable access to services and mistrust of authorities, among other factors. This study evaluated variations in attitudes toward COVID-19 vaccines and factors associated with vaccine acceptance among refugees and Lebanese nationals accessing 60 International Medical Corps-supported health facilities through two cross-sectional surveys pre- (n = 3927; Survey 1) and post- (n = 4174; Survey 2) vaccine rollout. Logistic regression was used to assess predictors of vaccine acceptance using the health beliefs model. Refugees comprised 52.9% (Survey 1) and 54.2% (Survey 2) of respondents. Vaccine acceptance was low among both groups in Survey 1 (25.9% refugees vs. 23.1% Lebanese nationals), but higher in Survey 2 in Lebanese (57.6%) versus refugees (32.9%). Participants reported greater perceived benefits of vaccination, higher perceived COVID-19 susceptibility, and lower perceived vaccination barriers in Survey 2 versus Survey 1. Post-vaccine rollout, refugees had lower odds of vaccine acceptance compared to Lebanese (OR 0.50, 95%CI 0.41–0.60), while older age (OR 1.37, 95%CI 1.06–1.78, ≥51 years vs. 18–30 years) was associated with greater vaccine acceptance. Health beliefs model variables were associated with vaccine acceptance in both surveys. Tailored strategies to respond dynamically to changes in vaccine attitudes among vulnerable groups in Lebanon are essential for equitable vaccine uptake. Full article

The blood-spinal cord barrier (BSCB) has been long thought of as a functional equivalent to the blood-brain barrier (BBB), restricting blood flow into the spinal cord. The spinal cord is supported by various disc tissues that provide agility and has different local immune responses compared to the brain. Though physiologically, structural components of the BSCB and BBB share many similarities, the clinical landscape significantly differs. Thus, it is crucial to understand the composition of BSCB and also to establish the cause–effect relationship with aberrations and spinal cord dysfunctions. Here, we provide a descriptive analysis of the anatomy, current techniques to assess the impairment of BSCB, associated risk factors and impact of spinal disorders such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), peripheral nerve injury (PNI), ischemia reperfusion injury (IRI), degenerative cervical myelopathy (DCM), multiple sclerosis (MS), spinal cavernous malformations (SCM) and cancer on BSCB dysfunction. Along with diagnostic and mechanistic analyses, we also provide an up-to-date account of available therapeutic options for BSCB repair. We emphasize the need to address BSCB as an individual entity and direct future research towards it. Full article

The Deep Underground Neutrino Experiment (DUNE) is an international, world-class experiment aimed at exploring fundamental questions about the universe that are at the forefront of astrophysics and particle physics research. DUNE will study questions pertaining to the preponderance of matter over antimatter in the early universe, the dynamics of supernovae, the subtleties of neutrino interaction physics, and a number of beyond the Standard Model topics accessible in a powerful neutrino beam. A critical component of the DUNE physics program involves the study of changes in a powerful beam of neutrinos, i.e., neutrino oscillations, as the neutrinos propagate a long distance. The experiment consists of a near detector, sited close to the source of the beam, and a far detector, sited along the beam at a large distance. This document, the DUNE Near Detector Conceptual Design Report (CDR), describes the design of the DUNE near detector and the science program that drives the design and technology choices. The goals and requirements underlying the design, along with projected performance are given. It serves as a starting point for a more detailed design that will be described in future documents. Full article

Cigarette smoke (CS) has been consistently demonstrated to be an environmental risk factor for amyotrophic lateral sclerosis (ALS), although the molecular pathogenic mechanisms involved are yet to be elucidated. Here, we propose different mechanisms by which CS exposure can cause sporadic ALS pathogenesis. Oxidative stress and neuroinflammation are widely implicated in ALS pathogenesis, with blood–spinal cord barrier disruption also recognised to be involved in the disease process. In addition, immunometabolic, epigenetic and microbiome alterations have been implicated in ALS recently. Identification of the underlying pathophysiological mechanisms that underpin CS-associated ALS will drive future research to be conducted into new targets for treatment. Full article

In most of the Indian cities, around half of the urban water requirement is fulfilled by groundwater. Recently, seasonal urban droughts have been frequently witnessed globally, which adds more stress to groundwater systems. Excessive pumping and increasing demands in several Indian cities impose a high risk of running out of groundwater storage, which could potentially affect millions of lives in the future. In this paper, groundwater level changes have been comprehensively assessed for seven densely populated and rapidly growing secondary cities across India. Several statistical analyses were performed to detect the trends and non-stationarity in the groundwater level (GWL). Also, the influence of rainfall and land use/land cover changes (LULC) on the GWL was explored. The results suggest that overall, the groundwater level was found to vary between ±10 cm/year in the majority of the wells. Further, the non-stationarity analysis revealed a high impact of rainfall and LULC due to climate variability and anthropogenic activities respectively on the GWL change dynamics. Statistical correlation analysis showed evidence supporting that climate variability could potentially be a major component affecting the rainfall and groundwater recharge relationship. Additionally, from the LULC analysis, a decrease in the green cover area (R = 0.93) was found to have a higher correlation with decreasing groundwater level than that of urban area growth across seven rapidly developing cities. Full article

Growth differentiation factor (GDF) family members have been implicated in the development and maintenance of healthy nucleus pulposus (NP) tissue, making them promising therapeutic candidates for treatment of intervertebral disc (IVD) degeneration and associated back pain. GDF6 has been shown to promote discogenic differentiation of mesenchymal stem cells, but its effect on NP cells remains largely unknown. Our aim was to investigate GDF6 signalling in adult human NP cells derived from degenerate tissue and determine the signal transduction pathways critical for GDF6-mediated phenotypic changes and tissue homeostatic mechanisms. This study demonstrates maintained expression of GDF6 receptors in human NP and annulus fibrosus (AF) cells across a range of degeneration grades at gene and protein level. We observed an anabolic response in NP cells treated with recombinant GDF6 (increased expression of matrix and NP-phenotypic markers; increased glycosaminoglycan production; no change in catabolic enzyme expression), and identified the signalling pathways involved in these responses (SMAD1/5/8 and ERK1/2 phosphorylation, validated by blocking studies). These findings suggest that GDF6 promotes a healthy disc tissue phenotype in degenerate NP cells through SMAD-dependent and -independent (ERK1/2) mechanisms, which is important for development of GDF6 therapeutic strategies for treatment of degenerate discs. Full article

Urine extracellular vesicles are a valuable low-invasive source of information, especially for the cells of the genitourinary tract. In the search for biomarkers, different techniques have been developed to isolate and characterize the cargo of these vesicles. In the present work, we compare five of these different isolation methods (three commercial isolation kits, ultracentrifugation, and lectin-based purification) and perform miRNA profiling using a multiplex miRNA assay. The results showed high correlation through all isolation techniques, and 48 out of 68 miRNAs were detected above the detection limit at least 10 times. The results obtained by multiplex assay were validated through Taqman qPCR. In addition, using this technique combined with a clinically friendly extracellular vesicle (uEV)-enrichment method, we performed the analysis of selected miRNAs in urine from patients affected with bladder cancer, benign prostate hyperplasia, or prostate cancer. Importantly, we found that those miRNAs could be detected in almost 100% of the samples, and no significant differences were observed between groups. Our results support the feasibility of analyzing exosomes-associated miRNAs using a methodology that requires a small volume of urine and is compatible with a clinical environment and high-throughput analysis. Full article