Miracle-dz/UniFAR-FTUs huggingface dataset:
SOX9 Induces Orbital Fibroblast Activation in Thyroid Eye Disease Via MAPK/ERK1/2 Pathway

Purpose To evaluate the expression of sry-box transcription factor 9 (SOX9) in orbital fibroblasts (OFs) of thyroid eye disease (TED) and to find its potential role and underlying mechanism in orbital fibrosis. Methods OFs were cultured from orbital connective tissues obtained from patients with TED (n = 10) and healthy controls (n = 6). SOX9 was depleted by small interfering RNA or overexpressed through lentivirus transduction in OFs. Fibroblast contractile activity was measured by collagen gel contraction assay and proliferation was examined by EdU assay. Transcriptomic changes were assessed by RNA sequencing. Results The mRNA and protein levels of SOX9 were significantly higher in OFs cultured from patients with TED than those from healthy controls. Extracellular matrix-related genes were down-regulated by SOX9 knockdown and up-regulated by SOX9 overexpression in TED-OFs. SOX9 knockdown significantly decrease the contraction and the antiapoptotic ability of OFs, whereas the overexpression of SOX9 increased the ability of transformation, migration, and proliferation of OFs. SOX9 knockdown suppressed the expression of phosphorylated ERK1/2, whereas its overexpression showed the opposite effect. Epidermal growth factor receptor (EGFR) is one of the notably down-regulated genes screened out by RNA sequencing. Chromatin immunoprecipitation-qPCR demonstrated SOX9 binding to the EGFR promoter. Conclusions A high expression of SOX9 was found in TED-OFs. SOX9 can activate OFs via MAPK/ERK1/2 signaling pathway, which in turn promotes proliferation and differentiation of OFs. EGFR was a downstream target gene of SOX9. SOX9/EGFR can be considered as therapeutic targets for the treatment of orbital fibrosis in TED.
The role of molecular imaging in detecting fibrosis in Crohn’s disease

Abstract Fibrosis is a pathological process that occurs due to chronic inflammation, leading to the proliferation of fibroblasts and the excessive deposition of extracellular matrix (ECM). The process of long-term fibrosis initiates with tissue hypofunction and progressively culminates in the ultimate manifestation of organ failure. Intestinal fibrosis is a significant complication of Crohn’s disease (CD) that can result in persistent luminal narrowing and strictures, which are difficult to reverse. In recent years, there have been significant advances in our understanding of the cellular and molecular mechanisms underlying intestinal fibrosis in inflammatory bowel disease (IBD). Significant progress has been achieved in the fields of pathogenesis, diagnosis, and management of intestinal fibrosis in the last few years. A significant amount of research has also been conducted in the field of biomarkers for the prediction or detection of intestinal fibrosis, including novel cross-sectional imaging modalities such as positron emission tomography (PET) and single photon emission computed tomography (SPECT). Molecular imaging represents a promising biomedical approach that enables the non-invasive visualization of cellular and subcellular processes. Molecular imaging has the potential to be employed for early detection, disease staging, and prognostication in addition to assessing disease activity and treatment response in IBD. Molecular imaging methods also have a potential role to enabling minimally invasive assessment of intestinal fibrosis. This review discusses the role of molecular imaging in combination of AI in detecting CD fibrosis.
Plasma SOMAmer proteomics of postoperative delirium

Abstract Background Postoperative delirium is prevalent in older adults and has been shown to increase the risk of long‐term cognitive decline. Plasma biomarkers to identify the risk for postoperative delirium and the risk of Alzheimer's disease and related dementias are needed. Methods This biomarker discovery case–control study aimed to identify plasma biomarkers associated with postoperative delirium. Patients aged ≥65 years undergoing major elective noncardiac surgery were recruited. The preoperative plasma proteome was interrogated with SOMAmer‐based technology targeting 1433 biomarkers. Results In 40 patients (20 with vs. 20 without postoperative delirium), a preoperative panel of 12 biomarkers discriminated patients with postoperative delirium with an accuracy of 97.5%. The final model of five biomarkers delivered a leave‐one‐out cross‐validation accuracy of 80%. Represented biological pathways included lysosomal and immune response functions. Conclusion In older patients who have undergone major surgery, plasma SOMAmer proteomics may provide a relatively non‐invasive benchmark to identify biomarkers associated with postoperative delirium.
Interim report of the reactogenicity and immunogenicity of SARS-CoV-2 XBB-containing vaccines.

BACKGROUND Monovalent Omicron XBB.1. 5-containing vaccines were approved for Coronavirus disease 2019 (COVID-19) 2023-2024 immunizations. METHODS This ongoing, open-label, phase 2/3 study evaluated mRNA-1273.815-monovalent (50-µg Omicron XBB.1.5-spike mRNA) and mRNA-1273.231-bivalent (25-µg each Omicron XBB.1.5- and BA.4/BA.5-spike mRNAs))vaccines, administered as 5th doses to adults who previously received a primary series, a 3rd dose of an original mRNA COVID-19 vaccine, and a 4th dose of an Omicron BA.4/BA.5 bivalent vaccine. Interim safety and immunogenicity results 29 days post-vaccination are reported. RESULTS Participants (randomized 1:1) received 50-µg mRNA-1273.815(n=50) or mRNA-1273.231(n=51); median (interquartile range) months from the prior BA.4/BA.5-bivalent dose were 8.2 (8.1-8.3) and 8.3 (8.1-8.4), respectively. Neutralizing antibody (nAb) increased from pre-booster levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants tested. Day 29 nAb fold-increases from pre-booster levels were numerically higher against XBB.1. 5, XBB.1. 16, EG.5.1, BA.2. 86, and JN.1 than BA.4/BA.5, BQ.1. 1 and D614G. The monovalent vaccine also cross-neutralized FL.1. 5.1, EG.5.1, BA.2. 86, HK.3. 1, HV.1 and JN.1 variants in a participant (n=20) subset, 15 days post-vaccination. Reactogenicity was similar to previously reported mRNA-1273 original and bivalent vaccines. CONCLUSIONS XBB.1. 5-containing mRNA-1273 vaccines elicit robust, diverse nAb responses against more recent SARS-CoV-2 variants including JN.1, supporting the XBB.1. 5-spike sequence selection for the 2023-2024 COVID-19 vaccine update.
Characterization of a new Pseudomonas aeruginosa Queuovirinae bacteriophage

ABSTRACT The ESKAPEE pathogen Pseudomonas aeruginosa is a common cause of chronic wound and cystic fibrosis lung infections, as well as acute burn and nosocomial infections. Many of these infections are recalcitrant to conventional antibiotic therapies due to both traditional antibiotic resistance mechanisms and antimicrobial tolerance. Recent successes with bacteriophage (phage) therapy to treat chronic human P. aeruginosa infections have led to a renewed interest in isolating and characterizing new P. aeruginosa phages. Here, we isolated and characterized a new lytic phage (termed PIP, pili-infecting phage) capable of infecting P. aeruginosa PA14. PIP is a tailed phage with an icosahedral head and flexible tail containing a genome that is 57,462 bp in length. Phylogenetic analysis reveals that PIP belongs to the subfamily Queuovirinae and genus Nipunavirus but is highly divergent in gene content from known Nipunaviruses. By isolating and characterizing a P. aeruginosa strain that spontaneously evolved resistance to PIP, we show that the receptor for PIP is Type IV pili. In summary, we isolated a new P. aeruginosa phage species with a unique genome, thus increasing the diversity of phages known to infect this important human pathogen. IMPORTANCE The opportunistic pathogen Pseudomonas aeruginosa causes both acute and chronic human infections. These infections are notoriously difficult to treat due to both antibiotic resistance and antibiotic tolerance. The increasing frequency of antibiotic failure in P. aeruginosa infections has led scientists to explore other treatment options, including bacteriophage (phage) therapy. To this end, there has been a significant effort to identify new Pseudomonas phages. Here, we isolated and characterized a bacteriophage (termed PIP, pili-infecting phage) that infects P. aeruginosa PA14. Examination of the PIP genome revealed that this phage represents a new species in the subclass Queuovirinae. The isolation and characterization of spontaneous PA14 mutants that are resistant to PIP infection revealed Type IV pili as the PIP receptor. Ultimately, this study characterizes a new species of Pseudomonas phage, thus enhancing the known diversity of phages that infect this important pathogen.
Stress experienced by dental students performing clinical training in different dental disciplines: a cross-sectional study

Abstract Objectives: To assess the stress level, the impact of stress factors, and discrepancies between fourth- and fifth-year undergraduate clinical students at the University of Jordan. Methods: A cross-sectional study was conducted in the academic year 2022/2023. The study group included fourth- and fifth-year dental students at the University of Jordan (n = 382) who were asked to voluntarily fill in an online dental environment stress (DES) questionnaire. Analysis was conducted using Mann-Whitney U test, independent t-test, χ2 test, and Spearman ρ rank correlations. Statistical significance was inferred when P < . 05. Results: Fourth-year students reported higher levels of nervousness before treating patients for the first time. Fifth-year students faced more difficulty, higher stress, and/or fear regarding the amount of assigned work, provided treatment, completed requirements, failing the course, time to finish assignments, patient comprehensive care, and financial expenses of the course. Comparison between groups revealed that the fifth-year students scored higher levels of stress on the total DES score and all partial DES scores. Furthermore, the total DES questionnaire scores were significantly correlated with grade point average (GPA) among the total study sample and the prosthodontics clinical course marks among the fourth-year students’ group. Conclusions: The stress level among students in clinical courses was influenced by their academic performance, gender, year level, and the type and time needed for the provided treatment. Completing course requirements was among the most commonly faced stressors. Future research endeavors might be considered to study each clinical factor, its impact on students’ stress level, and how to manage and positively improve these factors.
The molecular machinery of meiotic recombination

Meiotic recombination, a cornerstone of eukaryotic diversity and individual genetic identity, is essential for the creation of physical linkages between homologous chromosomes, facilitating their faithful segregation during meiosis I. This process requires that germ cells generate controlled DNA lesions within their own genome that are subsequently repaired in a specialised manner. Repair of these DNA breaks involves the modulation of existing homologous recombination repair pathways to generate crossovers between homologous chromosomes. Decades of genetic and cytological studies have identified a multitude of factors that are involved in meiotic recombination. Recent work has started to provide additional mechanistic insights into how these factors interact with one another, with DNA, and provide the molecular outcomes required for a successful meiosis. Here, we provide a review of the recent developments with a focus on protein structures and protein–protein interactions.
Preterm birth and subsequent intelligence and academic performance in youth: A cohort study.

INTRODUCTION Worldwide, more children than before survive preterm birth. Preterm birth can affect long-term cognitive outcomes. The aim of our study was to investigate the association between preterm birth and academic performance and intelligence in youth. MATERIAL AND METHODS This cohort study included all liveborn children in Denmark from 1978 to 2000. We used uni- and multivariable logistic and linear regressions to analyze associations between gestational age and school graduation, grade point average (GPA), attending conscription, and male intelligence scores at conscription. We adjusted for a priori defined potential confounders. RESULTS The study included 1 450 681 children and found an association between preterm birth and lower academic performance, with children born extremely preterm having the lowest odds of graduating from lower- and upper secondary education (LSE and USE) and appearing before the conscription board (odds ratios of 0.45 [0.38-0.54], 0.52 [0.46-0.59], and 0.47 [0.39-0.56] for LSE, USE, and conscription, respectively, compared to the term group). Statistically significant differences were observed in LSE for total GPA and core subject GPA with higher GPAs in the term group, which were considered clinically relevant for mathematics with a 0.71 higher grade point for the term compared to the extremely preterm. Conversely, USE differences were less evident, and in linear regression models we found that preterm birth was associated with higher GPAs in the adjusted analyses; however, this was not statistically significant. We demonstrated statistically significant differences in intelligence scores at conscription with lower scores in the three preterm groups (-5.13, -2.73, and - 0.76, respectively) compared to the term group. CONCLUSIONS Low gestational age at birth was associated with not graduating from LSE and USE, achieving lower GPAs in LSE, not attending conscription, and lower intelligence scores in young adulthood. The findings remained significant after adjusting for potential confounders.
Detection of resistance to macrolides and fluoroquinolones in Mycoplasma genitalium by targeted next-generation sequencing

ABSTRACT Mycoplasma genitalium is fastidious to culture, and its detection in human clinical specimens relies mainly on molecular methods. Phenotypic determination of antibiotic susceptibility for this bacterium is not a timely or feasible option for most clinical laboratories. This study sought to determine whether next-generation sequencing technologies can effectively be employed in determining genetic mutations associated with drug resistance in M. genitalium samples collected in Aptima Hologic tubes and possibly integrating them into viable workflows in public health laboratories. Following analysis by a custom-designed bioinformatics pipeline, at least one mutation/sample has been identified in 94/98 specimens in at least one of seven loci (macrolides: rrl, rplD, rplV; fluoroquinolones: parC, parE, gyrA, gyrB) described previously to be connected to antibiotic resistance. This method identified a total of 469 single nucleotide polymorphisms (SNPs) (452 mutations): 134 of 23S rRNA SNPs and 318 amino acid mutations: 114 substitutions and 204 synonymous; the turnaround time (sample to analyzed sequence) was typically 3 days. The assays and workflows described in this work demonstrated that the determination of a drug resistance profile for macrolides and fluoroquinolones of M. genitalium samples by using next-generation sequencing in clinical samples is a feasible approach that can be implemented in clinical laboratories, following thorough and extensive validation studies. IMPORTANCE The mechanisms of drug resistance in Mycoplasma genitalium are complex and involve several genetic loci. The molecular methods for accurately characterizing resistance to fluoroquinolones and macrolides in this organism are often not available or approved for patient use and do not cover all genetic determinants. To this end, we propose a next-generation sequencing-based method with a turnaround time of 3 days that includes the investigation of all drug resistance loci of M. genitalium. Following adaptation, validation, and verification for routine clinical use, assays based on this method may yield molecular results that can be used to guide proper treatment regimens and for surveillance of drug resistance in the general population.
Immunostimulation of Fibrous Nucleic Acid Nanoparticles Can be Modulated through Aptamer-Based Functional Moieties: Unveiling the Structure–Activity Relationship and Mechanistic Insights

Fibrous nanomaterials containing silica, titanium oxide, and carbon nanotubes are notoriously known for their undesirable inflammatory responses and associated toxicities that have been extensively studied in the environmental and occupational toxicology fields. Biopersistance and inflammation of “hard” nanofibers prevent their broader biomedical applications. To utilize the structural benefits of fibrous nanomaterials for functionalization with moieties of therapeutic significance while preventing undesirable immune responses, researchers employ natural biopolymers—RNA and DNA—to design “soft” and biodegradable nanomaterials with controlled immunorecognition. Nucleic acid nanofibers have been shown to be safe and efficacious in applications that do not require their delivery into the cells such as the regulation of blood coagulation. Previous studies demonstrated that unlike traditional therapeutic nucleic acids (e.g., CpG DNA oligonucleotides) nucleic acid nanoparticles (NANPs), when used without a carrier, are not internalized by the immune cells and, as such, do not induce undesirable cytokine responses. In contrast, intracellular delivery of NANPs results in cytokine responses that are dependent on the physicochemical properties of these nanomaterials. However, the structure–activity relationship of innate immune responses to intracellularly delivered fibrous NANPs is poorly understood. Herein, we employ the intracellular delivery of model RNA/DNA nanofibers functionalized with G-quadruplex-based DNA aptamers to investigate how their structural properties influence cytokine responses. We demonstrate that nanofibers’ scaffolds delivered to the immune cells using lipofectamine induce interferon response via the cGAS-STING signaling pathway activation and that DNA aptamers incorporation shields the fibers from recognition by cGAS and results in a lower interferon response. This structure–activity relationship study expands the current knowledge base to inform future practical applications of intracellularly delivered NANPs as vaccine adjuvants and immunotherapies.
Malaria in pregnancy: Meta-analyses of prevalence and associated complications

This review aims to assess the prevalence of malaria in pregnancy during antenatal visits and delivery, species-specific burden together with regional variation in the burden of disease. It also aims to estimate the proportions of adverse pregnancy outcomes in malaria-positive women. Based on the PRISMA guidelines, a thorough and systematic search was conducted in July 2023 across two electronic databases (including PubMed and CENTRAL). Forest plots were constructed for each outcome of interest highlighting the effect measure, confidence interval, sample size, and its associated weightage. All the statistical meta-analysis were conducted using R-Studio version 2022.07. Sensitivity analyses, publication bias assessment, and meta-regression analyses were also performed to ensure robustness of the review. According to the pooled estimates of 253 studies, the overall prevalence of malaria was 18.95% (95% CI: 16.95–21.11), during antenatal visits was 20.09% (95% CI: 17.43–23.06), and at delivery was 17.32% (95% CI: 14.47–20.61). The highest proportion of malarial infection was observed in Africa approximating 21.50% (95% CI: 18.52–24.81) during ANC and 20.41% (95% CI: 17.04–24.24) at the time of delivery. Our analysis also revealed that the odds of having anaemia were 2.40 times (95% CI: 1.87–3.06), having low birthweight were 1.99 times (95% CI: 1.60–2.48), having preterm birth were 1.65 times (95% CI: 1.29–2.10), and having stillbirths were 1.40 times (95% CI: 1.15–1.71) in pregnant women with malaria.
Tacrolimus trough level and oxidative stress in Tunisian kidney transplanted patients

Abstract Background The effect of tacrolimus (TAC) on oxidative stress after kidney transplantation (KT) is unclear. This study aimed to evaluate the influence of TAC trough levels of oxidative stress status in Tunisian KT patients during the post-transplantation period (PTP). Methods A prospective study including 90 KT patients was performed. TAC whole-blood concentrations were measured by the microparticle enzyme immunoassay method and adjusted according to the target range. Plasma levels of oxidants (malondialdehyde (MDA) and advanced oxidation protein products (AOPP)) and antioxidants (ascorbic acid, glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD)) were measured using spectrophotometry. The subjects were subdivided according to PTP into three groups: patients with early, intermediate, and late PT. According to the TAC level, they were subdivided into LL-TAC, NL-TAC, and HL-TAC groups. Results A decrease in MDA levels, SOD activity, and an increase in GSH levels and GPx activity were observed in patients with late PT compared to those with early and intermediate PT (p < 0.05). Patients with LL-TAC had lower MDA levels and higher GSH levels and GPx activity compared with the NL-TAC and HL-TAC groups (p < 0.05). Conclusion Our results have shown that in KT patients, despite the recovery of kidney function, the TAC reduced but did not normalize oxidative stress levels in long-term therapy, and the TAC effect significantly depends on the concentration used.
Cave Bears from the Paleolithic of the Greater Caucasus

I studied a series of skulls, mandibles, and molars of cave bears, Spelearctos (Carnivora, Ursidae), from multilayered Paleolithic faunal assemblages from the Kudaro 1 and Kudaro 3 caves in Transcaucasia (Georgia). Morphometric and morphotypical analyses of variation of molars have been made and a new technique for revealing morphotypes of teeth is proposed. A comparison of tooth morphotypes from different layers of the Kudaro caves demonstrates their usefulness for biostratigraphic subdivision of Quaternary cave deposits. The remains of bear from the Acheulean layer 5c in Kudaro 1 are placed in a new subspecies Spelearctos deningeri praekudarensis subsp. nov. The bear from the Mousterian fauna of Kudaro 3 (layers 3-4) belonged to the subspecies Spelearctos deningeri kudarensis. Cave bears of the Greater Caucasus had a slower rate of evolution than cave bears from Central and Eastern Europe. In the Late Pleistocene the cheek teeth retained an archaic structure. I traced evolutionary pathways of cave bear dentition in the course of their specialization for plant foods and these pathways are reported.
Soil Health Indicators of Rhizospheric Soils of apple (Malus Domestica Borkh.) Variety Delicious in Himalayan Kashmir.

Rhizospheric soils are rich sources of nutrients, enzymes, proteins, beneficial microbes responsible for sustainable growth of the plants. They supply principal elements to the plant and also promote microbial activity in the soil and improve its structure, aeration, and water holding capacity, which in turn improve the soil capabilities to respond to inputs. This discourse deals with the evaluation of thirty composite soil samples collected from different apple orchards of Baramulla district of Kashmir valley and analyzed for soil characteristics (organic carbon content, total available N, P, K, S; EC, pH, total viable bacterial, fungal and actinomycetes count) which in turn were used as chemical and microbial indicators of rhizospheric soil health of apple orchards in Himalayan Kashmir. It was observed that the soil characteristics were significantly correlated.