Miracle-dz/UniFAR-FTUs huggingface dataset:
Biased Effect of Cardiotonic Steroids on Na/K-ATPase–Mediated Signal Transduction

Recent studies have revealed that Na/K-ATPase (NKA) can transmit signals through ion-pumping–independent activation of pathways relayed by distinct intracellular protein/lipid kinases, and endocytosis challenges the traditional definition that cardiotonic steroids (CTS) are NKA inhibitors. Although additional effects of CTS have long been suspected, revealing its agonist impact through the NKA receptor could be a novel mechanism in understanding the basic biology of NKA. In this study, we tested whether different structural CTS could trigger different sets of NKA/effector interactions, resulting in biased signaling responses without compromising ion-pumping capacity. Using purified NKA, we found that ouabain, digitoxigenin, and somalin cause comparable levels of NKA inhibition. However, although endogenous ouabain stimulates both protein kinases and NKA endocytosis, digitoxigenin and somalin bias to protein kinases and endocytosis, respectively, in LLC-PK1 cells. The positive inotropic effects of CTS are traditionally regarded as NKA inhibitors. However, CTS-induced signaling occurs at concentrations at least one order of magnitude lower than that of inotropy, which eliminates their well known toxic actions on the heart. The current study adds a novel mechanism that CTS could exert its biased signaling properties through the NKA signal transducer. SIGNIFICANCE STATEMENT Although it is now well accepted that NKA has an ion-pumping–independent signaling function, it is still debated whether direct and conformation-dependent NKA/effector interaction is a key to this function. Therefore, this investigation is significant in advancing our understanding of the basic biology of NKA-mediated signal transduction and gaining molecular insight into the structural elements that are important for cardiotonic steroid’s biased action.
Emergence of Lyme Disease on Treeless Islands, Scotland, United Kingdom

Lyme disease is usually associated with forested habitats but has recently emerged on treeless islands in the Western Isles of Scotland. The environmental and human components of Lyme disease risk in open habitats remain unknown. We quantified the environmental hazard and risk factors for human tick bite exposure among treeless islands with low and high Lyme disease incidence in the Western Isles. We found a higher prevalence of Borrelia burgdorferi sensu lato–infected ticks on high-incidence than on low-incidence islands (6.4% vs. 0.7%); we also found that residents of high-incidence islands reported increased tick bite exposure. Most tick bites (72.7%) occurred <1 km from the home, including many in home gardens. Residents of high Lyme disease incidence islands reported increasing problems with ticks; many suggested changing deer distribution as a potential driver. We highlight the benefits of an integrated approach in understanding the factors that contribute to Lyme disease emergence.
Morphea in a Crohn’s disease patient undergoing ustekinumab treatment

EJD, vol. 31, n◦ 1, January-February 2021 without relapse; p=0.25). Finally, only Stage T3 was found to be associated with skin recurrence (55.0% for Stage T3 versus 14.3% for T1 and 35.3% T2; p=0.02). Our series is clinically representative of the common features of PCLZM [2]. Our results highlight the very low prevalence of an identical skin and blood B-cell clone in PCMLZ (6.9%). Moreover, when present, this had no prognostic value for the skin-relapse rate. We confirm that the initial spread of skin lesions (Stage T3) is the only predictive factor for skin relapse, as previously described [4]. In our patients, paraproteinaemia was rare (15.5%), as previously described in PCLZM [6], and was not correlated with relapse rate. In a recent study of 23 PCLZM cases, 8/9 (89%) patients with paraproteinaemia experienced a relapse [5], suggesting an association with the clinical course of PCLZM, especially since the levels of paraproteinaemia were correlated with relapse and treatment response. The data from our larger cohort do not confirm the above findings, which concerned a limited set of patients who displayed an unusual rate of restricted blood heavy and light chain expression (67%; compared to 16% in our series and 21% in another series of PCMZL [6]). Although clonality analysis has some utility for the differential diagnosis of PCMZL relative to reactive lymphoid hyperplasia [7], our study indicates that assessing blood B-cell clonality has no clinical relevance for therapeutic choice and prognosis, which depend on clinical staging.
COVID-19 evolution during the pandemic – Implications of new SARS-CoV-2 variants on disease control and public health policies

School of Environmental Sciences, Norwich Research Park, University of East Anglia, United Kingdom; Earlham Institute, Norwich Research Park, Norwich, United Kingdom; Center of Excellence for Bionanoscience Research, King Abdul Aziz University, Jeddah, Saudi Arabia; Department of Veterinary & Biomedical Sciences, University of Minnesota Twin Cities, St. Paul, MN, United States; Norwich Medical School, University of East Anglia, Norwich, United Kingdom
Imaging Tumor-Infiltrating Lymphocytes in Brain Tumors with [64Cu]Cu-NOTA-anti-CD8 PET

Purpose: Glioblastoma (GBM) is the most common malignant brain tumor in adults. Various immunotherapeutic approaches to improve patient survival are being developed, but the molecular mechanisms of immunotherapy resistance are currently unknown. Here, we explored the ability of a humanized radiolabeled CD8-targeted minibody to noninvasively quantify tumor-infiltrating CD8-positive (CD8+) T cells using PET. Experimental Design: We generated a peripheral blood mononuclear cell (PBMC) humanized immune system (HIS) mouse model and quantified the absolute number of CD8+ T cells by flow cytometry relative to the [64Cu]Cu-NOTA-anti-CD8 PET signal. To evaluate a patient-derived orthotopic GBM HIS model, we intracranially injected cells into NOG mice, humanized cohorts with multiple HLA-matched PBMC donors, and quantified CD8+ tumor-infiltrating lymphocytes by IHC. To determine whether [64Cu]Cu-NOTA-anti-CD8 images brain parenchymal T-cell infiltrate in GBM tumors, we performed PET and autoradiography and subsequently stained serial sections of brain tumor tissue by IHC for CD8+ T cells. Results: Nontumor-bearing NOG mice injected with human PBMCs showed prominent [64Cu]Cu-NOTA-anti-CD8 uptake in the spleen and minimal radiotracer localization to the normal brain. NOG mice harboring intracranial human GBMs yielded high-resolution PET images of tumor-infiltrating CD8+ T cells. Radiotracer retention correlated with CD8+ T-cell numbers in spleen and tumor tissue. Our study demonstrates the ability of [64Cu]Cu-NOTA-anti-CD8 PET to quantify peripheral and tumor-infiltrating CD8+ T cells in brain tumors. Conclusions: Human CD8+ T cells infiltrate an orthotopic GBM in a donor-dependent manner. Furthermore, [64Cu]Cu-NOTA-anti-CD8 quantitatively images both peripheral and brain parenchymal human CD8+ T cells.
Pseudopeptide Amyloid Aggregation Inhibitors: In Silico, Single Molecule and Cell Viability Studies

Neurodegeneration in Alzheimer’s disease (AD) is defined by pathology featuring amyloid-β (Aβ) deposition in the brain. Aβ monomers themselves are generally considered to be nontoxic, but misfold into β-sheets and aggregate to form neurotoxic oligomers. One suggested strategy to treat AD is to prevent the formation of toxic oligomers. The SG inhibitors are a class of pseudopeptides designed and optimized using molecular dynamics (MD) simulations for affinity to Aβ and experimentally validated for their ability to inhibit amyloid-amyloid binding using single molecule force spectroscopy (SMFS). In this work, we provide a review of our previous MD and SMFS studies of these inhibitors and present new cell viability studies that demonstrate their neuroprotective effects against Aβ(1–42) oligomers using mouse hippocampal-derived HT22 cells. Two of the tested SG inhibitors, predicted to bind Aβ in anti-parallel orientation, demonstrated neuroprotection against Aβ(1–42). A third inhibitor, predicted to bind parallel to Aβ, was not neuroprotective. Myristoylation of SG inhibitors, intended to enhance delivery across the blood-brain barrier (BBB), resulted in cytotoxicity. This is the first use of HT22 cells for the study of peptide aggregation inhibitors. Overall, this work will inform the future development of peptide aggregation inhibitors against Aβ toxicity.
Association of prior lymphopenia with mortality in pneumonia: a cohort study in UK primary care

Background Lymphopenia (reduced lymphocyte count) during infections, such as pneumonia, is common and is associated with increased mortality. Little is known about the relationship between lymphocyte count before developing infections and mortality risk. Aim To identify whether patients with lymphopenia who develop pneumonia have increased risk of death. Design and setting A cohort study set in the Clinical Practice Research Datalink (CPRD) linked to national death records, in primary care. This database is representative of the UK population and is extracted from routine records. Method Patients aged >50 years with a pneumonia diagnosis were included from January 1998 until January 2019. The relationship between lymphocyte count and mortality was measured, using a time-to-event (multivariable Cox regression) approach, adjusted for age, sex, social factors, and potential causes of lymphopenia. The primary analysis used the most recent test before pneumonia. The primary outcome was 28-day, all-cause mortality. Results A total of 40 909 participants with pneumonia were included, with 28 556 having had a lymphocyte count test before pneumonia (median time between test and diagnosis was 677 days). When lymphocyte count was categorised (0–1 × 109 cells/L, 1–2 × 109 cells/L, 2–3 × 109 cells/L, >3 × 109 cells/L, never tested), both 28-day and 1-year mortality varied significantly: 14%, 9.2%, 6.5%, 6.1%, and 25%, respectively, for 28-day mortality, and 41%, 29%, 22%, 20%, and 52% for 1-year mortality. In multivariable Cox regression, lower lymphocyte count was consistently associated with increased hazard of death. Conclusion Lymphopenia is an independent predictor of mortality in primary care pneumonia. Even low–normal lymphopenia (1–2 × 109 cells/L) is associated with an increase in short- and long-term mortality compared with higher counts.
Limited Utility of Procalcitonin in Identifying Community-Associated Bacterial Infections in Patients Presenting with Coronavirus Disease 2019

The role of procalcitonin in identifying community-associated bacterial infections among patients with coronavirus disease 2019 is not yet established. In 2,443 patients with 148 bacterial coinfections, mean procalcitonin levels were significantly higher with any bacterial infection (13.16 ± 51.19 ng/ml; P = 0.0091) and with bacteremia (34.25 ± 85.01 ng/ml; P = 0.0125) than without infection (2.00 ± 15.26 ng/ml). ABSTRACT The role of procalcitonin in identifying community-associated bacterial infections among patients with coronavirus disease 2019 is not yet established. In 2,443 patients of whom 148 had bacterial coinfections, mean procalcitonin levels were significantly higher with any bacterial infection (13.16 ± 51.19 ng/ml; P = 0.0091) and with bacteremia (34.25 ± 85.01 ng/ml; P = 0.0125) than without infection (2.00 ± 15.26 ng/ml). Procalcitonin (cutoff, 0.25 or 0.50 ng/ml) did not reliably identify bacterial coinfections but may be useful in excluding bacterial infection.
Knowledge on tuberculosis and utilization of DOTS service by tuberculosis patients in Lalitpur District, Nepal

Background Tuberculosis is one of the major infectious diseases and is both complex and serious. It is spread from person to person through the air, causing a public health burden, especially in low- and middle-income countries. This study aims to assess the knowledge on tuberculosis and the utilization of Directly-Observed Therapy, Short Course (DOTS) service from the public DOTS centers in Lalitpur district of Nepal. Method A structured questionnaire was used to collect data from 23 DOTS centers in Lalitpur district. Univariate and multivariate logistic regression was applied to assess the knowledge on tuberculosis and utilization of DOTS among people living with tuberculosis. Results Among 390 respondents, 80% of patients had knowledge of tuberculosis and 76.92% utilized the DOTS service from the DOTS center. People of higher age (50–60 years) [aOR; 13.96, 95% CI 4.79,40.68], [aOR; 10.84,95% CI 4.09,28.76] had significantly more knowledge on TB and utilization of the DOTS service compared to the younger group. Additionally, those who completed twelfth class [aOR; 2.25, 95% CI 0.46,11.07] and [aOR;2.47, 95% CI 0.51,11.28] had greater knowledge of Tuberculosis and utilization of DOTS compared to those who had not completed twelfth class. Likewise, compared to urban residents, respondents in rural areas (aOR; 0.51, 95% CI 0.27,0.97) had less knowledge of tuberculosis, (aOR; 0.57, 95% CI 0.32,1) and less chance of utilization of the DOTS service from the DOTS center. Conclusion Approximately one quarter of patients did not have adequate knowledge of tuberculosis and were not utilizing the DOTS service, particularly in younger age groups, people living in a combined family, with no education, poor economic position, and from rural areas. Findings of this study revealed that some specific programs are needed for enhancing the knowledge and utilization of DOTS, particularly for those patients whose economic situations extended from low to mid range.
Mitochondrial Genome Evolution, Genetic Diversity, and Population Structure in British Water Voles (Arvicola amphibius)

The European water vole (Arvicola amphibius) is a rodent within the subfamily Arvicolinae. In Britain, water voles have declined rapidly during the last century, making them a conservation priority. The relationship of Arvicola to other genera within Arvicolinae remains debated. Additionally, the impact that captive breeding programs in Britain are having on the genetic diversity of water voles is unknown. We use available mitochondrial genomes to construct the phylogeny of species within Arvicolinae, followed by sequencing the mitochondrial DNA control region of 17 individuals from a captive population of water voles in Britain to assess their genetic diversity and population structure. Our study first provides an updated phylogenetic tree of Arvicolinae using the mitochondrial genome of 31 species. Second, our results show considerable genetic diversity in the captive population of water voles, when compared with natural populations in Britain. We confirm the grouping of British water voles into two clades, with all captive individuals found in the English/Welsh clade. Moreover, captive water voles clustered closely with populations in the South East and East of England. The mitochondrial genome provides a useful marker to study the phylogenetics of this rodent clade and in addition, our study provides support for the breeding program at Wildwood Trust and provides a framework for future conservation genetics studies in this species.
Targeted Next-Generation Sequencing of Liquid Biopsy Samples from Patients with NSCLC

Liquid biopsy tests have become an integral part of the molecular diagnosis of patients with non-small cell lung cancer (NSCLC). We describe a new test panel that uses very low input (20 ng) of cell-free nucleic acids extracted from human plasma, which is designed to yield results in less than 72 h. In this study, we performed novel amplicon-based targeted next-generation sequencing with a semiconductor-based system, the Ion GeneStudio S5 Prime. The analytic performance of the assay was evaluated using contrived and retrospectively collected clinical specimens. The cumulative percent coefficient of variation for the new test process was very precise at 8.4% for inter-day, 4.0% for inter-operator and 3.4% for inter-instrument. We also observed significant agreement (95.7–100%) with an orthogonal, high-sensitivity droplet digital™ Polymerase Chain Reaction (ddPCR) test. This method offers a valuable supplement to assessing targeted mutations from blood while conserving specimens and maintaining sensitivity, with rapid turn-around times to actionable results.
Synthesis of Tetravalent Thio- and Selenogalactoside-Presenting Galactoclusters and Their Interactions with Bacterial Lectin PA-IL from Pseudomonas aeruginosa

Synthesis of tetravalent thio- and selenogalactopyranoside-containing glycoclusters using azide-alkyne click strategy is presented. Prepared compounds are potential ligands of Pseudomonas aeruginosa lectin PA-IL. P. aeruginosa is an opportunistic human pathogen associated with cystic fibrosis, and PA-IL is one of its virulence factors. The interactions of PA-IL and tetravalent glycoconjugates were investigated using hemagglutination inhibition assay and compared with mono- and divalent galactosides (propargyl 1-thio- and 1-seleno-β-d-galactopyranoside, digalactosyl diselenide and digalactosyl disulfide). The lectin-carbohydrate interactions were also studied by saturation transfer difference NMR technique. Both thio- and seleno-tetravalent glycoconjugates were able to inhibit PA-IL significantly better than simple d-galactose or their intermediate compounds from the synthesis.
Proteomics Analysis of Gastric Cancer Patients with Diabetes Mellitus

Proteomics is a powerful approach to study the molecular mechanisms of cancer. In this study, we aim to characterize the proteomic profile of gastric cancer (GC) in patients with diabetes mellitus (DM) type 2. Forty GC tissue samples including 19 cases from diabetic patients and 21 cases from individuals without diabetes (control group) were selected for the proteomics analysis. Gastric tissues were processed following the single-pot, solid-phase-enhanced sample preparation approach—SP3 and enzymatic digestion with trypsin. The resulting peptides were analyzed by LC-MS Liquid Chromatography—Mass Spectrometry (LC-MS). The comparison of protein expression levels between GC samples from diabetic and non-diabetic patients was performed by label-free quantification (LFQ). A total of 6599 protein groups were identified in the 40 samples. Thirty-seven proteins were differentially expressed among the two groups, with 16 upregulated and 21 downregulated in the diabetic cohort. Statistical overrepresentation tests were considered for different annotation sets including the Gene Ontology(GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Disease functional databases. Upregulated proteins in the GC samples from diabetic patients were particularly enriched in respiratory electron transport and alcohol metabolic biological processes, while downregulated proteins were associated with epithelial cancers, intestinal diseases, and cell–cell junction cellular components. Taken together, these results support the data already obtained by previous studies that associate diabetes with metabolic disorders and diabetes-associated diseases, such as Alzheimer’s and Parkinson’s, and also provide valuable insights into seven GC-associated protein targets, claudin-3, polymeric immunoglobulin receptor protein, cadherin-17, villin-1, transglutaminase-2, desmoglein-2, and mucin-13, which warrant further investigation.
Long-term durability of bicuspid aortic valve repair: a comparison of 2 annuloplasty techniques.

OBJECTIVES To compare long-term outcomes after bicuspid aortic valve (BAV) repair utilizing the Cabrol annuloplasty versus valve sparing Reimplantation technique. METHODS From 1996 to 2018, 340 consecutive patients underwent BAV repair. Eighty underwent Cabrol annuloplasty and 189 underwent Reimplantation. Exclusion criteria were re-repairs (n = 6), active endocarditis (n = 4), no annuloplasty (n = 41) and ring or suture annuloplasty (n = 20). We compared both groups for survival, reoperations, valve related events and recurrent severe aortic regurgitation (AR > 2+). Inverse probability weighting (IPW) was used to balance the 2 groups. Cox regression analysis was used to identify outcome predictors. RESULTS After weighting, pre- and intraoperative characteristics were similar between groups, except for aorta replacement techniques and operative time, which was longer in the Reimplantation group (P < 0.001). At 12 years, overall survival was similar between groups (IPW: Cabrol 97 ± 2% vs Reimplantation 94 ± 3%, P = 0.52). Freedom from reoperation and freedom from AR > 2+ were significantly lower in the Cabrol group (reoperation IPW: 69 ± 9% vs 91 ± 4%, P = 0.004 and AR > 2+ IPW: 71 ± 8% vs 97 ± 2%, P < 0.001). The Reimplantation technique was the only independent predictor of reoperation (hazard ratio 0.31; confidence interval 0.19-0.7; P = 0.005). CONCLUSIONS In this study, comparing 2 annuloplasty strategies for BAV repair, we found statistically significant differences in long-term durability favouring the Reimplantation technique, and no differences in overall survival. The results support our current strategy of Reimplantation technique and repair of AR in patients with BAV. Cabrol annuloplasty is obsolete and should be generally abandoned in patients undergoing BAV repair for AR.
Olfactory Perception and Different Decongestive Response of the Nasal Mucosa During Menstrual Cycle

Background Sex hormones are known to have some influence on nasal functions, but their effect on the decongestive response of the nasal mucosa during menstrual cycle is still undetermined. Objectives The aim of this study was to examine the nasal physiology, the interconnectedness of olfactory and respiratory nasal function and the decongestive response of the nasal mucosa during menstrual cycle. Methods This study included 101 healthy women aged 23.26 ± 4.81 years with a regular menstrual cycle. The nasal respiratory function and the decongestive response of the nasal mucosa were examined by rhinomanometry. Subjective sense of nasal obstruction and the subjective odor intensity were assessed by standardized questionnaires. The odor identification ability was assessed by Sniffin’ Sticks test. Results Statistically significant higher values of nasal resistance (0.311 ± 0.107 Pa/cm3/s) and NOSE score (11.893 ± 13.83) were observed in the ovulatory phase compared to the luteal (0.281 ± 0.084 Pa/cm3/s and 9.029 ± 11.12). An odor identification test score was significantly higher in luteal phase (12.476 ± 1.48) compared to the ovulatory phase (11.971 ± 1.51), opposite of odor intensity. The difference of nasal resistance before and after decongestion was significantly higher in ovulatory phase (0.105 ± 0.097 Pa/cm3/s) compared to the luteal (0.084 ± 0.079 Pa/cm3/s). Correlation between subjective and objective parameters of the examinated nasal functions was not statistically significant in any menstrual phase. Conclusion In the population of women studied, total nasal resistance and NOSE score were significantly lower in the luteal phase of the menstrual cycle. Odor identification was significantly higher in the luteal phase but odor intensity significantly higher in the ovulatory phase. The decongestive response of nasal mucosa was better in the ovulatory phase of the menstrual cycle.