Miracle-dz/UniFAR-FTUs huggingface dataset:
Functional Phenotypic Diversity of Regulatory T Cells Remaining in Inflamed Skin

Regulatory T cells (Tregs) migrate between lymphoid and peripheral tissues for maintaining immune homeostasis. Tissue-specific function and functional heterogeneity of Tregs have been suggested, however, correlation between them and inter-tissue movement remain unknown. We used a contact hypersensitivity model of mice expressing a photoconvertible protein for tracking migratory cells. After marking cells in skin, we purified Tregs exhibiting a different migration pattern [Tregs recruiting to or remaining in the skin and emigrating from the skin to draining lymph nodes (dLNs) within half a day] and examined single-cell gene and protein expression profiles. Correlation and unsupervised clustering analyses revealed that Tregs in both skin and dLNs comprised two subpopulations, one highly expressing Nrp1 with variable CD25, Granzyme B, and/or CTLA-4 expression and another with 3 subsets strongly expressing CD25, Granzyme B, or CTLA-4 together with CD39. Characteristic subsets of Tregs remaining in the skin displayed higher CD25 and CD39 expression and lower Granzyme B and CTLA-4 expression compared with Tregs migrating to the skin. In addition, CCR5 expression in Tregs in skin was positively and negatively correlated with CD39 and Nrp-1 expression, respectively. To assess the predictive value of these data for immunotherapy, we blocked CCR5 signaling and found modest downregulation of CD39 and modest upregulation of Nrp1 expression in skin Tregs. Our data reveal a high functional diversity of Tregs in skin that is strongly related to trafficking behavior, particularly skin retention. Modulation of tissue-specific trafficking and function is a promising clinical strategy against autoimmune, infectious, and neoplastic diseases. Significance Statement Regulatory T cells (Tregs) are essential for maintaining immune homeostasis. To reveal tissue-specific immunoinhibitory functions and inter-tissue movement correlation based on Treg functional heterogeneity, we examined single-cell gene and protein expression profiles of Tregs recruited to, remaining in, or emigrating from the contact hypersensitivity-induced inflamed skin. Tregs in skin were composed of several subpopulations; one with high Nrp1 expression and another with 3 subsets strongly expressing CD25, Granzyme B, or CTLA-4 together with CD39. Tregs remaining in skin displayed highCD25, CD39, and CCR5 expression, and CCR5 signaling blockade downregulated CD39. A high Treg functional diversity in skin is strongly related to trafficking behavior. Tissue-specific trafficking and functional modulation are a promising clinical strategy against autoimmune, infectious, and neoplastic diseases.
A Novel Collateral Imaging Method Derived from Time-Resolved Dynamic Contrast-Enhanced MR Angiography in Acute Ischemic Stroke: A Pilot Study

The purpose of this study was to introduce a multiphase MRA collateral map derived from time-resolved dynamic contrast-enhanced MRA and to verify the value of the multiphase MRA collateral map in acute ischemic stroke by comparing it with the multiphase collateral imaging method (MRP collateral map) derived from dynamic susceptibility contrast-enhanced MR perfusion. The authors generated collateral maps using dynamic signals from dynamic contrast-enhanced MRA and DSC-MRP in 67 patients using a Matlab-based in-house program and graded the collateral scores of the multiphase MRA collateral map and the MRP collateral map independently. Interobserver reliabilities and intermethod agreement between both collateral maps for collateral grading were tested. The interobserver reliabilities forcollateral grading using multiphase MRA or MRP collateral maps were excellent. They conclude that the dynamic signals of dynamic contrast-enhanced MRA can generate multiphasecollateral images and show the possibility of the multiphase MRA collateral map as a useful collateral imaging method in acute ischemic stroke. BACKGROUND AND PURPOSE: Assessment of the collateral status has been emphasized for appropriate treatment decisions in patients with acute ischemic stroke. The purpose of this study was to introduce a multiphase MRA collateral imaging method (collateral map) derived from time-resolved dynamic contrast-enhanced MRA and to verify the value of the multiphase MRA collateral map in acute ischemic stroke by comparing it with the multiphase collateral imaging method (MRP collateral map) derived from dynamic susceptibility contrast-enhanced MR perfusion. MATERIALS AND METHODS: From a prospectively maintained registry of acute ischemic stroke, MR imaging data of patients with acute ischemic stroke caused by steno-occlusive lesions of the unilateral ICA and/or the M1 segment of the MCA were analyzed. We generated collateral maps using dynamic signals from dynamic contrast-enhanced MRA and DSC-MRP using a Matlab-based in-house program and graded the collateral scores of the multiphase MRA collateral map and the MRP collateral map independently. Interobserver reliabilities and intermethod agreement between both collateral maps for collateral grading were tested. RESULTS: Seventy-one paired multiphase MRA and MRP collateral maps from 67 patients were analyzed. The interobserver reliabilities for collateral grading using multiphase MRA or MRP collateral maps were excellent (weighted κ = 0.964 and 0.956, respectively). The agreement between both collateral maps was also excellent (weighted κ = 0.884; 95% confidence interval, 0.819–0.949). CONCLUSIONS: We demonstrated that the dynamic signals of dynamic contrast-enhanced MRA could be used to generate multiphase collateral images and showed the possibility of the multiphase MRA collateral map as a useful collateral imaging method in acute ischemic stroke.
Molecular mechanisms relating to amino acid regulation of protein synthesis

Abstract Some amino acids (AA) act through several signalling pathways and mechanisms to mediate the control of gene expression at the translation level, and the regulation occurs, specifically, on the initiation and the signalling pathways for translation. The translation of mRNA to protein synthesis proceeds through the steps of initiation and elongation, and AA act as important feed-forward activators that are involved in many pathways, such as the sensing and the transportation of AA by cells, in these steps in many tissues of mammals. For the translation, phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is a critical molecule that controls the translation initiation and its functions can be regulated by some AA. Another control point in the mRNA binding step in the translation initiation is at the regulation by mammalian target of rapamycin, which requires a change of phosphorylation status of ribosomal protein S6. In fact, the change of phosphorylation status of ribosomal protein S6 might be involved in global protein synthesis. The present review summarises recent work on the molecular mechanisms of the regulation of protein synthesis by AA and highlights new findings.
Engineered herpes simplex virus DNA polymerase point mutants: the most highly conserved region shared among alpha-like DNA polymerases is involved in substrate recognition

Eucaryotic, viral, and bacteriophage DNA polymerases of the alpha-like family share blocks of sequence similarity, the most conserved of which has been designated region I. Region I includes a YGDTDS motif that is almost invariant within the alpha-like family and that is similar to a motif conserved among RNA-directed polymerases and also includes adjacent amino acids that are more moderately conserved. To study the function of these conserved amino acids in vivo, site-specific mutagenesis was used to generate herpes simplex virus region I mutants. A recombinant virus constructed to contain a mutation within the nearly invariant YGDTDS motif was severely impaired for growth on Vero cells which do not contain a viral polymerase gene. However, three recombinants constructed to contain mutations altering more moderately conserved residues grew on Vero cells and exhibited altered sensitivities to nucleoside and PPi analogs and to aphidicolin. Marker rescue and DNA sequencing of one such recombinant demonstrated that the region I alteration confers the altered drug sensitivity phenotype. These results indicate that this region has an essential role in polymerase function in vivo and is involved directly or indirectly in drug and substrate recognition.
Effectiveness of Autologous Platelet-Rich Plasma for the Healing of Ulcers after Endoscopic Submucosal Dissection

Background/Aims Platelet-rich plasma (PRP) has been used for wound healing in various medical fields. The aim of this study was to evaluate the clinical efficacy and safety of local PRP injections after endoscopic submucosal dissection (ESD). Methods Patients were non-randomly divided into the following two groups: (1) control group in which patients were administered only an intravenous proton pump inhibitor (PPI), and (2) a study group in which patients were administered an intravenous PPI and a topical PRP injection. We assessed the reduction in the ulcer area and stage of the ulcer after the procedure (24 hours, 48 hours, and 28 days after endoscopic surgery). Results We enrolled 7 study and 7 control patients. In the study group, the rate of ulcer reduction was 59% compared to 52% in the control group (p=0.372), 28 days after ESD. There were 5 patients in the S stage and 2 patients in the H stage in the study group compared to no patient in the S stage and 7 patients in the H stage in the control group (p=0.05), 28 days after ESD. There were no serious complications in either group. Conclusions The local injection of PRP is a safe and effective procedure for ulcer healing after ESD.
From Microscale to Macroscale: Nine Orders of Magnitude for a Comprehensive Modeling of Hydrogels for Controlled Drug Delivery

Because of their inherent biocompatibility and tailorable network design, hydrogels meet an increasing interest as biomaterials for the fabrication of controlled drug delivery devices. In this regard, mathematical modeling can highlight release mechanisms and governing phenomena, thus gaining a key role as complementary tool for experimental activity. Starting from the seminal contribution given by Flory–Rehner equation back in 1943 for the determination of matrix structural properties, over more than 70 years, hydrogel modeling has not only taken advantage of new theories and the increasing computational power, but also of the methods offered by computational chemistry, which provide details at the fundamental molecular level. Simulation techniques such as molecular dynamics act as a “computational microscope” and allow for obtaining a new and deeper understanding of the specific interactions between the solute and the polymer, opening new exciting possibilities for an in silico network design at the molecular scale. Moreover, system modeling constitutes an essential step within the “safety by design” paradigm that is becoming one of the new regulatory standard requirements also in the field-controlled release devices. This review aims at providing a summary of the most frequently used modeling approaches (molecular dynamics, coarse-grained models, Brownian dynamics, dissipative particle dynamics, Monte Carlo simulations, and mass conservation equations), which are here classified according to the characteristic length scale. The outcomes and the opportunities of each approach are compared and discussed with selected examples from literature.
Variation of 3D outer and inner crown morphology in modern human mandibular premolars

Abstract Objectives This study explores the outer and inner crown of lower third and fourth premolars (P3, P4) by analyzing the morphological variation among diverse modern human groups. Materials and Methods We studied three‐dimensional models of the outer enamel surface and the enamel–dentine junction (EDJ) from μCT datasets of 77 recent humans using both an assessment of seven nonmetric traits and a standard geometric morphometric (GM) analysis. For the latter, the dental crown was represented by four landmarks (dentine horns and fossae), 20 semilandmarks along the EDJ marginal ridge, and pseudolandmarks along the crown and cervical outlines. Results Certain discrete traits showed significantly different regional frequencies and sexual dimorphism. The GM analyses of both P3s and P4s showed extensive overlap in shape variation of the various populations (classification accuracy 15–69%). The first principal components explained about 40% of shape variance with a correlation between 0.59 and 0.87 of the features of P3s and P4s. Shape covariation between P3s and P4s expressed concordance of high and narrow or low and broad crowns. Conclusions Due to marked intragroup and intergroup variation in GM analyses of lower premolars, discrete traits such as the number of lingual cusps and mesiolingual groove expression provide better geographic separation of modern human populations. The greater variability of the lingual region suggests a dominance of functional constraints over geographic provenience or sex. Additional information about functionally relevant aspects of the crown surface and odontogenetic data are needed to unravel the factors underlying dental morphology in modern humans.
Amyloidosis causes downregulation of SorLA, SorCS1 and SorCS3 expression in mice

Abstract Accumulation of β-amyloid peptide (Aβ) is regarded as a primary cause of Alzheimer’s disease (AD). Aβ is derived by sequential cleavage of the amyloid precursor protein (APP). Alterations in the subcellular targeting of APP are thought to affect the degree of Aβ production. Sorting receptors, such as SorLA, convey subcellular targeting of APP. Dysfunction of SorLA, and likely of the related receptors SorCS1 and SorCS3, cause AD. Nevertheless, disease progression could also provoke altered expression of the receptors. Here, we assessed if Aβ plaque formation promotes altered expression of SorLA, SorCS1 and SorCS3. We analyzed transcript levels during aging and after amyloidosis in brain areas characterized by early amyloid plaque formation in an AD mouse model (APPPS1) and wild types. We observed stable expression levels during aging (1–12 months). After plaque formation, SorCS1 and SorLA expression were markedly reduced in the frontal cerebral cortex and to a minor extent in the hippocampus, whereas SorCS3 expression was solely reduced in the frontal cerebral cortex. Our results indicate that disease progression, associated with Aβ accumulation, can negatively regulate expression of the receptors.
State Estimation of Hemodynamic Model for fMRI Under Confounds: SSM Method

Through hemodynamic models, the change of neuronal state can be estimated from functional magnetic resonance imaging (fMRI) signals. Usually, there are confounds in the fMRI signal, which will degrade the performance of the estimation for the neuronal state change. For the reason, this paper introduces a state-space model with confounds, from a conventional hemodynamic model. In this model, a successive state estimation method requires a state value vector, an error covariance, an innovation covariance, and a cross covariance to be re-derived. Thus, a confounds square-root cubature Kalman smoothing (CSCKS) algorithm is proposed in this paper. We use a Balloon–Windkessel model to generate simulation data and add confounds signals to evaluate the performance of the proposed algorithm. The experiment results show that when the signal-to-interference ratio is less than 21 dB, the CSCKS proposed in this paper reduced estimation error to 16%, whereas the traditional algorithm reduced it to only 73%.
Effect of short-term intravenous ascorbic acid on reducing ferritin in hemodialysis patients

Resistance to recombinant erythropoietin (rEPO) in hemodialysis patients may be due to inadequate iron recruitment and defect in iron use. In this cross over randomized clinical trial, 30 hemodialysis patients with serum ferritin levels of ≥500 ng/ml, hemoglobin ≤11.0 g/dl, and transferrin saturation (TSAT) of 20% or less were administrated intravenous iron (50-100 mg/wk) and rEPO (120-360 U/kg/wk) for 6 months. Patients were excluded if there was a clear explanation for rEPO hyporesponsiveness. Patients were divided into two groups. Group1 received standard care and 500 mg of intravenous ascorbic acid (IVAA) with each dialysis session in the first week of each month for a total of 3 months. Group 2 received standard care only. After 2 month washout period, groups were crossed over. Each month hemoglobin (Hb) was assessed. Iron, TIBC (transferrin iron binding capacity), TSAT, iPTH (intact parathyroid hormone), liver enzymes, albumin and cholesterol levels were measured every 3 months. After 3 months of intervention, Hb significantly increased from 10.11 to 12.19 g/dl (P <0 0.001; 95% confidence interval [CI] 2.7-1.4) and TSAT increased from 18.9 to 28.1% (P = 0.008; 95% CI 0.09-3), while ferritin and serum iron declined significantly from 1391 to 938 ng/ml (P = 0.001; 95% CI 216-689), 97.2 to 64.6 (P = 0.001; 95% CI 14.8-50.4) in the study group. Change of Hb over time in IVAA group was significant (P < 0.0005). There were significant differences between two groups in change of Hb level over time (P < 0.0005) and treatment effect (P = 0.002). Baseline laboratory tests were similar in the two groups and there was no carry over effect at phase 2. We showed that low amount of IVAA could reduce ferritin level and enhance Hb and TSAT, suggesting improved iron utilization.
Non-Contact Physiological Parameters Extraction Using Facial Video Considering Illumination, Motion, Movement and Vibration

Objective: In this paper, four physiological parameters, i.e., heart rate (HR), inter-beat-interval (IBI), heart rate variability (HRV), and oxygen saturation (SpO2), are extracted from facial video recordings. Methods: Facial videos were recorded for 10 min each in 30 test subjects while driving a simulator. Four regions of interest (ROIs) are automatically selected in each facial image frame based on 66 facial landmarks. Red-green-blue color signals are extracted from the ROIs and four physiological parameters are extracted from the color signals. For the evaluation, physiological parameters are also recorded simultaneously using a traditional sensor “cStress,” which is attached to hands and fingers of test subjects. Results: The Bland Altman plots show 95% agreement between the camera system and “cStress” with the highest correlation coefficient R = 0.96 for both HR and SpO2. The quality index is estimated for IBI considering 100 ms R-peak error; the accumulated percentage achieved is 97.5%. HRV features in both time and frequency domains are compared and the highest correlation coefficient achieved is 0.93. One-way analysis of variance test shows that there are no statistically significant differences between the measurements by camera and reference sensors. Conclusion: These results present high degrees of accuracy of HR, IBI, HRV, and SpO2 extraction from facial image sequences. Significance: The proposed non-contact approach could broaden the dimensionality of physiological parameters extraction using cameras. This proposed method could be applied for driver monitoring application under realistic conditions, i.e., illumination, motion, movement, and vibration.
Genomic Observations of a Rare/Pathogenic SMAD3 Variant in Loeys–Dietz Syndrome 3 Confirmed by Protein Informatics and Structural Investigations

Background and objectives: Loeys–Dietz syndrome 3, also known as aneurysms-–osteoarthritis syndrome, is an autosomal dominant genetic connective tissue disease caused by pathogenic variants in SMAD3, a transcription factor involved in TGF-β signaling. This disorder is characterized by early-onset osteoarthritis and arterial aneurysms. Common features include scoliosis, uvula abnormalities, striae, and velvety skin. Materials and Methods: The pathogenicity of a variant of uncertain significance in the SMAD3 gene was evaluated (variant c.220C > T) through personalized protein informatics and molecular studies. Results: The case of a 44-year-old male, who was originally presumed to have Marfan syndrome, is presented. An expanded gene panel determined the probable cause to be a variant in SMAD3, c.220C > T (p.R74W). His case was complicated by a history of stroke, but his phenotype was otherwise characteristic for Loeys–Dietz syndrome 3. Conclusion: This case emphasizes the importance of comprehensive genetic testing to evaluate patients for connective tissue disorders, as well as the potential benefit of utilizing a protein informatics platform for the assessment of variant pathogenicity.
Do cycle disturbances explain the age-related decline of female fertility? Cycle characteristics of women aged over 40 years compared with a reference population of young women.

BACKGROUND The cause of declining fertility with age, in women who still have regular menstrual cycles, is not clear. METHODS Follicle development, endometrial growth and hormonal patterns were evaluated in cycles of older women (aged 41-46 years; n = 26) who previously were normally fertile, and these cycles were compared with a reference group of relatively young fertile women (aged 22-34 years; n = 35). RESULTS Clearly abnormal cycles were found in only two women in the older age group, and in one woman in the younger group. The main differences between the age groups were a shorter follicular phase and cycle length in the older group, in combination with higher FSH levels in the late luteal and early follicular phase. In contrast to published data which suggest an "accelerated" follicle development in older women, sonographical and hormonal evidence was found of an "advanced" follicle growth, with an earlier start already during the luteal phase of the preceding cycle, and an advanced selection and ovulation of the dominant follicle. CONCLUSIONS Such an earlier start of follicle growth in a possibly less favourable hormonal environment, as well as a limited oocyte pool, may contribute to a decreased follicle and oocyte quality, resulting in diminished fertility in ageing women.
Molecularly Imprinted Polymer Materials as Selective Recognition Sorbents for Explosives: A Review

Explosives are of significant interest to homeland security departments and forensic investigations. Fast, sensitive and selective detection of these chemicals is of great concern for security purposes as well as for triage and decontamination in contaminated areas. To this end, selective sorbents with fast binding kinetics and high binding capacity, either in combination with a sensor transducer or a sampling/sample-preparation method, are required. Molecularly imprinted polymers (MIPs) show promise as cost-effective and rugged artificial selective sorbents, which have a wide variety of applications. This manuscript reviews the innovative strategies developed in 57 manuscripts (published from 2006 to 2019) to use MIP materials for explosives. To the best of our knowledge, there are currently no commercially available MIP-modified sensors or sample preparation methods for explosives in the market. We believe that this review provides information to give insight into the future prospects and potential commercialization of such materials. We warn the readers of the hazards of working with explosives.