Miracle-dz/UniFAR-FTUs huggingface dataset:
Overexpression of the PTPN22 Autoimmune Risk Variant LYP-620W Fails to Restrain Human CD4+ T Cell Activation

A missense mutation (R620W) of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), which encodes lymphoid-tyrosine phosphatase (LYP), confers genetic risk for multiple autoimmune diseases including type 1 diabetes. LYP has been putatively demonstrated to attenuate proximal T and BCR signaling. However, limited data exist regarding PTPN22 expression within primary T cell subsets and the impact of the type 1 diabetes risk variant on human T cell activity. In this study, we demonstrate endogenous PTPN22 is differentially expressed and dynamically controlled following activation. From control subjects homozygous for the nonrisk allele, we observed 2.1- (p < 0.05) and 3.6-fold (p < 0.001) more PTPN22 transcripts in resting CD4+ memory and regulatory T cells (Tregs), respectively, over naive CD4+ T cells, with expression peaking 24 h postactivation. When LYP was overexpressed in conventional CD4+ T cells, TCR signaling and activation were blunted by LYP-620R (p < 0.001) but only modestly affected by the LYP-620W risk variant versus mock-transfected control, with similar results observed in Tregs. LYP overexpression only impacted proliferation following activation by APCs but not anti-CD3– and anti-CD28–coated microbeads, suggesting LYP modulation of pathways other than TCR. Notably, proliferation was significantly lower with LYP-620R than with LYP-620W overexpression in conventional CD4+ T cells but was similar in Treg. These data indicate that the LYP-620W variant is hypomorphic in the context of human CD4+ T cell activation and may have important implications for therapies seeking to restore immunological tolerance in autoimmune disorders. Key Points The PTPN22 autoimmune risk allele confers loss of function in human T cells. Natural APC activation is required for LYP to inhibit CD4+ T cell proliferation. Inhibition of proliferation by the LYP risk variant is not defective in Treg.
Effect of Dimer Structure and Inhomogeneous Broadening of Energy Levels on the Action of Flavomononucleotide in Rigid Polyvinyl Alcohol Films

The results of time-resolved fluorescence measurements of flavin mononucleotide (FMN) in rigid polyvinyl alcohol films (PVA) demonstrate that fluorescence intensity decays are strongly accelerated in the presence of fluorescent dimers and nonradiative energy transfer processes. The fluorescence decay originating both from H and J dimer states of FMN was experimentally observed for the first time. The mean fluorescence lifetimes for FMN dimers were obtained: τfl = 2.66 ns (at λexc = 445 nm) and τfl = 2.02 (at λexc = 487 nm) at λobs = 600 nm and T = 253 K from H and J state of dimers, respectively. We show that inhomogeneous orientational broadening of energy levels (IOBEL) affects the shape of the fluorescence decay and leads to the dependence of the average monomer fluorescence lifetime on excitation wavelength. IOBEL affected the nonradiative energy transfer and indicated that different flavin positioning in the protein pocket could (1) change the spectroscopic properties of flavins due to the existence of “blue” and “red” fluorescence centers, and (2) diminish the effectiveness of energy transfer between FMN molecules.
Knock-Out of ACBD3 Leads to Dispersed Golgi Structure, but Unaffected Mitochondrial Functions in HEK293 and HeLa Cells

The Acyl-CoA-binding domain-containing protein (ACBD3) plays multiple roles across the cell. Although generally associated with the Golgi apparatus, it operates also in mitochondria. In steroidogenic cells, ACBD3 is an important part of a multiprotein complex transporting cholesterol into mitochondria. Balance in mitochondrial cholesterol is essential for proper mitochondrial protein biosynthesis, among others. We generated ACBD3 knock-out (ACBD3-KO) HEK293 and HeLa cells and characterized the impact of protein absence on mitochondria, Golgi, and lipid profile. In ACBD3-KO cells, cholesterol level and mitochondrial structure and functions are not altered, demonstrating that an alternative pathway of cholesterol transport into mitochondria exists. However, ACBD3-KO cells exhibit enlarged Golgi area with absence of stacks and ribbon-like formation, confirming the importance of ACBD3 in Golgi stacking. The glycosylation of the LAMP2 glycoprotein was not affected by the altered Golgi structure. Moreover, decreased sphingomyelins together with normal ceramides and sphingomyelin synthase activity reveal the importance of ACBD3 in ceramide transport from ER to Golgi.
Oxidative Stress—A Key Player in the Course of Alcohol-Related Liver Disease

Oxidative stress is known to be an inseparable factor involved in the presentation of liver disorders. Free radicals interfere with DNA, proteins, and lipids, which are crucial in liver metabolism, changing their expression and biological functions. Additionally, oxidative stress modifies the function of micro-RNAs, impairing the metabolism of hepatocytes. Free radicals have also been proven to influence the function of certain transcriptional factors and to alter the cell cycle. The pathological appearance of alcohol-related liver disease (ALD) constitutes an ideal example of harmful effects due to the redox state. Finally, ethanol-induced toxicity and overproduction of free radicals provoke irreversible changes within liver parenchyma. Understanding the underlying mechanisms associated with the redox state in the course of ALD creates new possibilities of treatment for patients. The future of hepatology may become directly dependent on the effective action against reactive oxygen species. This review summarizes current data on the redox state in the natural history of ALD, highlighting the newest reports on this topic.
Time Spent in Nature Is Associated with Increased Pro-Environmental Attitudes and Behaviors

Urbanization, screen dependency, and the changing nature of childhood and parenting have led to increased time indoors, creating physical and emotional distancing from nature and time spent in natural environments. Substantial evidence from observational and intervention studies indicates that overall time spent in nature leads to increased perceived value for connectedness to nature and, subsequently, greater pro-environmental attitudes and behaviors (PEAB). This narrative review of the recent literature evaluates associations between time spent in nature with values ascribed to nature and nature connectedness, as well as PEAB. We discuss the influence of nature exposure and education in childhood on subsequent development of PEAB in adulthood. We analyze theoretical frameworks applied to this research as well as metrics employed, populations studied, and individual and societal values before presenting limitations of this research. We conclude with suggestions for future research directions based on current knowledge, underscoring the importance of promoting time spent in nature and PEAB in the face of growing challenges to planetary health. Research indicates that overall time spent in nature, regardless of the quality of environmental conditions, leads to increased perceived values ascribed to nature, which is associated with PEAB; however, this literature is predominantly cross-sectional. Furthermore, personal and social factors may influence PEAB. Thus, more longitudinal studies that consider these factors are needed to assess the duration and frequency of time spent in nature in childhood and its impact on PEAB throughout the life course. Identifying contexts which cultivate PEAB and reverse alienation from nature beginning in childhood may better sensitize adults to the urgency of environmental issues such as climate change, which adversely impact individual and environmental health.
Small Rab GTPases in Intracellular Vesicle Trafficking: The Case of Rab3A/Raphillin-3A Complex in the Kidney

Small Rab GTPases, the largest group of small monomeric GTPases, regulate vesicle trafficking in cells, which are integral to many cellular processes. Their role in neurological diseases, such as cancer and inflammation have been extensively studied, but their implication in kidney disease has not been researched in depth. Rab3a and its effector Rabphillin-3A (Rph3A) expression have been demonstrated to be present in the podocytes of normal kidneys of mice rats and humans, around vesicles contained in the foot processes, and they are overexpressed in diseases with proteinuria. In addition, the Rab3A knockout mice model induced profound cytoskeletal changes in podocytes of high glucose fed animals. Likewise, RphA interference in the Drosophila model produced structural and functional damage in nephrocytes with reduction in filtration capacities and nephrocyte number. Changes in the structure of cardiac fiber in the same RphA-interference model, open the question if Rab3A dysfunction would produce simultaneous damage in the heart and kidney cells, an attractive field that will require attention in the future.
Out-of-Network Billing in Privately Insured Patients Undergoing Elective Orthopaedic Surgery

Background: Out-of-network charges during hospital care can result in unexpected or surprise bills for the patient. The aim of this study was to ascertain the frequency of out-of-network (OON) billing by the primary orthopaedic surgeon for commonly performed elective, inpatient procedures: total hip arthroplasty (THA), total knee arthroplasty (TKA), anterior cervical diskectomy and fusion (ACDF), and posterior lumbar fusion (PLF). Methods: Patients undergoing TKA, THA, one-level ACDF, and one-level PLF from 2010 to 2018 were queried using a commercially insured claims database with Current Procedural Terminology codes. The in-network (IN) versus OON status of the primary surgeon's submitted charges and the payor's reimbursement was recorded for each case. All costs were adjusted for inflation and reported in terms of 2018 real dollars. Bivariate analyses were performed. Results: Among the 549,868 elective orthopaedic cases, 6.7% were billed as OON by the primary orthopaedic surgeon: 6.1% TKA cases, 6.5% THA, 9.9% ACDF, and 8.5% PLF. From 2010 to 2018, a declining trend was seen in proportion of cases billed as OON by orthopaedic surgeons (P < 0.001 for each case). Mean reimbursement for claims paid as OON was 2.6 times higher than claims paid at the IN rate (range: 1.5 to 3.1 times higher; P < 0.001). The mean OON payments were higher by $1,284 for TKA, $2,516 for THA, $10,097 for ACDF, and $15,104 for PLF compared with mean IN payments (P < 0.001 for each). Compared with health maintenance organization–type plans, preferred provider organization–type plans reimbursed a greater percentage of the submitted claims at the OON rate (14.3% versus 44.5%, P < 0.001). Conclusion: OON billing by the orthopaedic surgeon for TKA, THA, ACDF, and PLF is an uncommon and declining phenomenon. Level of Evidence: IV
Compatibility of Distinct Label-Free Proteomic Workflows in Absolute Quantification of Proteins Linked to the Oocyte Quality in Human Follicular Fluid

We present two separate label-free quantitative workflows based on different high-resolution mass spectrometers and LC setups, which are termed after the utilized instrument: Quad-Orbitrap (nano-LC) and Triple Quad-TOF (micro-LC) and their directed adaptation toward the analysis of human follicular fluid proteome. We identified about 1000 proteins in each distinct workflow using various sample preparation methods. With assistance of the Total Protein Approach, we were able to obtain absolute protein concentrations for each workflow. In a pilot study of twenty samples linked to diverse oocyte quality status from four donors, 455 and 215 proteins were quantified by the Quad-Orbitrap and Triple Quad-TOF workflows, respectively. The concentration values obtained from both workflows correlated to a significant degree. We found reasonable agreement of both workflows in protein fold changes between tested groups, resulting in unified lists of 20 and 22 proteins linked to oocyte maturity and blastocyst development, respectively. The Quad-Orbitrap workflow was best suited for an in-depth analysis without the need of extensive fractionation, especially of low abundant proteome, whereas the Triple Quad-TOF workflow allowed a more robust approach with a greater potential to increase in effectiveness with the growing number of analyzed samples after the initial effort of building a comprehensive spectral library.
Interval State Estimation in Active Distribution Systems Considering Multiple Uncertainties

Distribution system state estimation (DSSE) plays a significant role for the system operation management and control. Due to the multiple uncertainties caused by the non-Gaussian measurement noise, inaccurate line parameters, stochastic power outputs of distributed generations (DG), and plug-in electric vehicles (EV) in distribution systems, the existing interval state estimation (ISE) approaches for DSSE provide fairly conservative estimation results. In this paper, a new ISE model is proposed for distribution systems where the multiple uncertainties mentioned above are well considered and accurately established. Moreover, a modified Krawczyk-operator (MKO) in conjunction with interval constraint-propagation (ICP) algorithm is proposed to solve the ISE problem and efficiently provides better estimation results with less conservativeness. Simulation results carried out on the IEEE 33-bus, 69-bus, and 123-bus distribution systems show that the our proposed algorithm can provide tighter upper and lower bounds of state estimation results than the existing approaches such as the ICP, Krawczyk-Moore ICP(KM-ICP), Hansen, and MKO.
Combination of Au-Ag Plasmonic Nanoparticles of Varied Compositions with Carbon Nitride for Enhanced Photocatalytic Degradation of Ibuprofen under Visible Light

Au-Ag/g-C3N4 nanohybrids 2–3 were synthesized by the one-pot self-reduction of the organometallic precursor [Au2Ag2(C6F5)4(OEt2)2]n in the presence of graphitic carbon nitride (g-C3N4), leading to two populations of alloyed Au-Ag nanoparticles (NPs) of different size and composition on the surface of g-C3N4, i.e., Ag-enriched Au-Ag NPs of smaller size and Au-enriched Au-Ag NPs of larger size. The combination of these two types of plasmonic NPs with g-C3N4 semiconductor displays enhanced photocatalytic properties towards the degradation of ibuprofen under visible light by the increased charge carrier separation provided by the inclusion of the plasmonic NPs on g-C3N4.
Therapeutic Cancer Vaccination with Immunopeptidomics-Discovered Antigens Confers Protective Antitumor Efficacy

Simple Summary Immunotherapy has revolutionized cancer treatment, yet many tumors remain resistant to current immuno-oncology therapies. Here we explore a novel, customized oncolytic adenovirus vaccine platform as immunotherapy in a resistant tumor model. We present a workflow for customizing the oncolytic vaccine for improved tumor targeting. This targeting is based on experimentally discovered tumor antigens, which are incorporated as active components of the vaccine formulation. The pipeline may be further applied for designing personalized therapeutic cancer vaccines. Abstract Knowledge of clinically targetable tumor antigens is becoming vital for broader design and utility of therapeutic cancer vaccines. This information is obtained reliably by directly interrogating the MHC-I presented peptide ligands, the immunopeptidome, with state-of-the-art mass spectrometry. Our manuscript describes direct identification of novel tumor antigens for an aggressive triple-negative breast cancer model. Immunopeptidome profiling revealed 2481 unique antigens, among them a novel ERV antigen originating from an endogenous retrovirus element. The clinical benefit and tumor control potential of the identified tumor antigens and ERV antigen were studied in a preclinical model using two vaccine platforms and therapeutic settings. Prominent control of established tumors was achieved using an oncolytic adenovirus platform designed for flexible and specific tumor targeting, namely PeptiCRAd. Our study presents a pipeline integrating immunopeptidome analysis-driven antigen discovery with a therapeutic cancer vaccine platform for improved personalized oncolytic immunotherapy.
Intensity Modulated Proton Beam Therapy versus Volumetric Modulated Arc Therapy for Patients with Nasopharyngeal Cancer: A Propensity Score-Matched Study

Simple Summary Based on literature evidence, it is difficult to conclude the advantages and safety of IMPT in patients with NPC. We performed propensity score matching analysis of patients treated with IMPT and VMAT by the same group of physicians within the same institute. Finally, we observed that IMPT reduced the requirement of nasogastric tube insertion and body weight loss during treatment, and the oncologic outcomes were potentially better than that of VMAT. However, IMPT increased the rate of grade III radiation dermatitis. Our current data indicate that IMPT is safe and beneficial as a frontline therapy for patients with NPC. Abstract (1) Background: We compared the outcomes of patients with nasopharyngeal carcinoma treated with IMPT and VMAT. (2) Methods: We performed a retrospective propensity score matching analysis (1:1) of patients treated with IMPT (years: 2016–2018) and VMAT (2014–2018). Survival was estimated using the Kaplan–Meier method. Multivariate Cox proportional hazards regression analysis was used to identify the independent predictors of survival. Binary toxicity endpoint analyses were performed using a Cox model and logistic regression. (3) Results: Eighty patients who received IMPT and VMAT were included. The median follow-up time was 24.1 months in the IMPT group. Progression-free survival (PFS) and overall survival (OS) were not statistically different between the two groups but potentially better in IMPT group. In multivariate analysis, advanced N-stage and body weight loss (BWL; >7%) during radiotherapy were associated with decreased PFS. The IMPT group had significantly less requirement for nasogastric (NG) tube placement and BWL during treatment. The mean oral cavity dose was the only predictive factor in stepwise regression analysis, and IMPT required a significantly lower mean dose. However, IMPT increased the grade 3 radiation dermatitis. (4) Conclusions: IMPT is associated with reduced rates of NG tube insertion and BWL through reducing oral mean dose, potentially producing better oncologic outcomes.
ILs and MMPs Levels in Inflamed Human Dental Pulp: A Systematic Review

A wide range of mediators are released from the pulp tissue because of bacterial invasion which causes inflammation. Interleukins (ILs) and matrix metalloproteinases (MMPs) have a leading role in initiating and spreading of inflammation because of their synergic action. Biomarkers such as ILs and MMPs can be identified via several methods, establishing the inflammatory response of the dental pulp. The aim of this systematic review is to evaluate the levels of ILs and/or MMPs in human dental pulp. PubMed, OVID, Cochrane, Scopus, Web of Science and Wiley online library databases were searched for original clinical studies. After applying inclusion and exclusion criteria, a quality assessment of studies was performed based on a modified Newcastle-Ottawa scale. In the review were included articles that evaluated the presence of ILs and/or MMPs in pulp tissue using enzyme-linked immunosorbent assay (ELISA) or western blot or multiplex assay. Six articles were included in the present synthesis. Although various diagnostic methods were used, statistically significant higher levels of ILs and/or MMPs were mostly found in the experimental groups compared to healthy pulp samples. The biomarkers studied can be a promising tool to evaluate pulp tissue health or even in pulpitis treatment.
Diffusion kurtosis imaging as an imaging biomarker for predicting prognosis in chronic kidney disease patients.

BACKGROUND Renal fibrosis is the strongest prognosis predictor of end-stage renal disease (ESRD) in chronic kidney disease (CKD). Diffusion kurtosis imaging (DKI) is a promising method of magnetic resonance imaging (MRI) successfully used to assess renal fibrosis in IgA nephropathy. This study first evaluated the long-term prognostic value of DKI in CKD patients. METHODS Forty-two patients with CKD were prospectively enrolled, and underwent DKI on a clinical 3 T MR scanner. We excluded patients with comorbidities that could affect the volume or the components of the kidney. DKI parameters, including mean kurtosis (K), mean diffusivity (D) and apparent diffusion coefficient (ADC) of kidney cortex were obtained by region-of-interest measurement. We followed up these patients for a median of 43 months and investigated the correlations between each DKI parameter and overall renal prognosis. RESULTS Both K and ADC values were correlated well with the eGFR on recruitment and the eGFR of the last visit in follow-up (p＜0.001). K and ADC values were also well associated with the eGFR slopes in CKD patients, both with the first-last time point slope (p = 0.011 and p＜0.001, respectively) and with the regression slope (p = 0.010 and p＜0.001, respectively). Cox proportional hazard regression indicated that lower eGFR and ADC values independently predicted eGFR loss of more than 30% and ESRD. The receiver operating characteristic analysis showed that K and ADC values were predictable for renal prognosis, and ADC displayed better capabilities for both ESRD (AUC 0.936, sensitivity 92.31%, specificity 82.76%) and the composite endpoint (eGFR loss>30% or ESRD) (AUC 0.881, sensitivity 66.67%, specificity 96.3%). CONCLUSIONS Renal ADC values obtained from DKI showed significant predictive value for the prognosis of CKD patients, which could be a promising noninvasive technique in follow-up.
Arthroscopic Tenotomy of the Long Head of the Biceps Tendon and Section of the Anterior Joint Capsule Produce Moderate Osteoarthritic Changes in an Experimental Sheep Model

Osteoarthritis (OA) of the glenohumeral (GH) joint is a common cause of shoulder pain, resulting in considerable invalidity. Unfortunately, the study of its pathogenesis is challenging. Models of OA are necessary to identify specific targets for therapy and to be able to interfere with the development and evolution of OA. This study aims to assess the effect of an arthroscopic tenotomy of the long head of the biceps tendon (LHBT) and section of the anterior glenohumeral joint capsule on the ovine glenohumeral joint. In addition, the authors aim to validate and evaluate the reliability of a modified semi-quantitative MRI score to assess joint degeneration in a sheep’s shoulder. Eight skeletally mature sheep received an arthroscopic tenotomy of the LHBT and section of the anterior joint capsule and were euthanized four months after surgery. All animals tolerated the surgery well, and no complication was recorded for six weeks. Moderate degenerative changes to the ovine shoulder joint were found on MRI and histological evaluation. The arthroscopic tenotomy of the LHBT and the anterior glenohumeral joint capsule section caused moderate degenerative changes to the ovine shoulder joint.