Miracle-dz/UniFAR-FTUs huggingface dataset:
Every protagonist has a sidekick: Structural aspects of human xeroderma pigmentosum‐binding proteins in nucleotide excision repair

The seven xeroderma pigmentosum proteins (XPps), XPA–XPG, coordinate the nucleotide excision repair (NER) pathway, promoting the excision of DNA lesions caused by exposition to ionizing radiation, majorly from ultraviolet light. Significant efforts are made to investigate NER since mutations in any of the seven XPps may cause the xeroderma pigmentosum and trichothiodystrophy diseases. However, these proteins collaborate with other pivotal players in all known NER steps to accurately exert their purposes. Therefore, in the old and ever‐evolving field of DNA repair, it is imperative to reexamine and describe their structures to understand NER properly. This work provides an up‐to‐date review of the protein structural aspects of the closest partners that directly interact and influence XPps: RAD23B, CETN2, DDB1, RPA (RPA70, 32, and 14), p8 (GTF2H5), and ERCC1. Structurally and functionally vital domains, regions, and critical residues are reexamined, providing structural lessons and perspectives about these indispensable proteins in the NER and other DNA repair pathways. By gathering all data related to the major human xeroderma pigmentosum‐interacting proteins, this review will aid newcomers on the subject and guide structural and functional future studies.
Mucin-type sialyl-Tn antigen is associated with PD-L1 expression and predicts poor clinical prognosis in breast cancer.

Background A recent study showed that mucin-type sialylated O-linked glycans could induce the increased expression of PD-L1 via binding to Siglec receptors. However, the relationship between the expression of the mucin-type sialyl-Tn antigen (sTn) and PD-L1 remains unclear in breast cancer (BC). Therefore, we investigate the clinicopathological and prognostic effects of sTn expression and its relationship with PD-L1 expression in BC tissues. Methods We retrospectively analyzed the clinical data of 380 invasive BC patients between January 2011 and January 2014. The last follow-up time was January 31, 2019 with a median follow-up of 62 months. The expression of the sTn antigen and PD-L1 in 380 tumor specimens was assessed by immunohistochemistry. Correlations between sTn/PD-L1 expression and clinicopathological features and prognoses were analyzed. Results In BC tissues, the positive expression rate of PD-L1 (20.5%) was much lower than that of sTn (41.8%). Pearson's contingency analysis showed that sTn and PD-L1 expression in tumor tissues demonstrated a high correlation (P<0.001). High sTn expression was associated with negative ER expression (P<0.001), positive HER-2 status (P<0.001), advanced tumor stage (P<0.001), high density of CD8+ tumor-infiltrating lymphocytes (TILs) (P=0.028), and positive lymph node metastasis (P=0.002). Moreover, patients with concomitant high expression of both markers had the highest risk of relapse (P<0.001) and mortality (P<0.001). The multivariate Cox regression model revealed that positive sTn expression (HRos: 1.941, 95% CI: 1.168, 3.223, Pos=0.028; HRpfs: 1.739, 95% CI: 1.063, 2.847, Ppfs=0.010) and positive PD-L1 expression (HRos: 1.912, 95% CI: 1.138, 3.212, Pos=0.017; HRpfs: 1.863, 95% CI: 1.116, 3.110, Ppfs=0.014) were independent indicators for poor overall survival (OS) and progression-free survival (PFS), respectively. Conclusions BC patients who expressed both sTn and PD-L1 had poorer survival. Therefore, combinational therapy with dual blockade might benefit BC patients with sTn(+)/PD-L1(+) expression, which requires further examination in future clinical trials.
Targeting the Myddosome in Systemic Autoimmunity: Ready for Prime Time?

Innate immune responses play key roles in the initiation and perpetuation of a variety of systemic autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). (1) While effective biologics and small molecules targeting innate and adaptive immune responses in these diseases are currently available, there are still significant gaps in the development of therapies that can hamper innate immune dysregulation in certain subgroups of patients where this pathway may play crucial pathogenic roles.
Acute Epstein‐Barr virus associated haemophagocytosis in an Asian female: What is the diagnosis?

Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK Department of Medicine, National University Health System, Singapore Department of Haematology Oncology, National University Cancer Institute Singapore, National University Health System, Singapore Department of Pathology, National University Health System, Singapore Cancer Science Institute of Singapore, National University of Singapore Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Mortality in dementia is predicted by older age of onset and cognitive presentation

Objectives: Survival information in dementia is important for future planning and service provision. There have been limited Australian data investigating survival duration and risk factors associated with mortality in younger-onset dementia. Methods: This was a cross-sectional retrospective study investigating survival in inpatients with a diagnosis of dementia admitted to a tertiary neuropsychiatry service from 1991 to 2014. The Australian Institute of Health and Welfare National Death Index was used to obtain mortality information. Results: A total of 468 inpatients were identified, of which 75% had symptom onset at ⩽65 years of age (defined as younger-onset dementia). Dementia was categorised into four subtypes, Alzheimer’s dementia, frontotemporal dementia, vascular dementia and other dementias; 72% of the patients had died. Overall median survival duration was 10.6 years with no significant differences in duration within the dementia subtypes (p = 0.174). Survival in older-onset dementia (symptom onset at >65 years of age) was about half of that in younger-onset dementia (median survival 6.3 years compared to 12.7 years, respectively). Independent predictors of mortality were having older-onset dementia (hazard ratio: 3.2) and having initial presenting symptoms being cognitive in nature (hazard ratio: 1.5). Females with an older-onset dementia had longer survival compared to males with an older-onset dementia, and this was reversed for younger-onset dementia. Older-onset dementia and younger-onset dementia conferred 3 and 6 times, respectively, increased risk of death compared to the general population. Conclusion: This is the largest Australian study to date investigating survival and risk factors to mortality in dementia. We report important clinical information to patients with dementia and their families about prognosis which will assist with future planning. Our findings suggest that for both older-onset dementia and younger-onset dementia, ‘new onset’ psychiatric symptoms precede the cognitive symptoms of a neurodegenerative process. This, and sex differences in survival depending on the age of onset of the dementia warrant further investigation.
Adjunctive benefit of ozonized water irrigation with mechanical debridement in the management of Stage III periodontitis- A randomised controlled clinical and biochemical study.

OBJECTIVE Periodontitis is a chronic inflammatory disease initiated by dysbiotic microbiota. Conventional mechanical debridement often needs adjunctive measures to control the disease process. The objective of the present study was to find out benefit of ozonized water irrigation along with nonsurgical periodontal therapy for the management of periodontitis. METHODS We have conducted a Randomized Controlled, triple blinded, parallel group clinical trial. Test Group (n=25) was treated with ozonized water irrigation whereas control group (n=25) received normal saline irrigation along with mechanical debridement. Full mouth plaque score, bleeding score, probing pocket depth and clinical attachment loss were evaluated at baseline and 4 weeks after treatment. Salivary Interleukin 1 beta was analyzed using enzyme linked immunosorbent assay. Analysis of covariance, t test and chi square test were used for intergroup comparison. Intragroup comparison was done using paired t test. RESULTS Adjunctive ozone water irrigation resulted in significant improvement in all clinical parameters except probing pocket depth after adjusting the extraneous effects due to initial confounding factors(p<0.001). But as per subgroup analysis ozone water irrigation resulted in significant reduction of pocket depth in deep pockets (p=0.01) and number of sites with pocket depth ≥4mm with bleeding on probing. Salivary Interleukin 1 Beta also reduced significantly in test group after therapy. CONCLUSION Ozone irrigation provide adjunctive benefit along with nonsurgical periodontal therapy in reducing clinical parameters as well as inflammatory mediator in saliva. But long- term benefits need to be assessed with future studies.
Children’s lung function in relation to changes in socioeconomic, nutritional, and household factors over 20 years in Lanzhou

Background Lanzhou has experienced rapid urbanization, leading to changes in socioeconomic, nutritional, and household factors. These changes may affect children’s lung function. Methods Two cross-sectional studies of school-age children (6–13 years of age) from the urban (Chengguan) (Period 1 in 1996 with n=390; Period 2 in 2017 with n=192) and the suburban (Xigu) (Period 1 n=344; Period 2 n=492) district were conducted. Demographic information, household factors, and nutrition status were obtained via a questionnaire survey. Forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) were measured in each period. Student’s t-test analysis of variance was used to assess the differences in FVC and FEV1 between Periods 1 and 2. Generalized linear models were used to analyze the associations between questionnaire derived factors and lung function. Analyses were done separately for girls and boys. Results Children had significantly lower mean FEV1 and FVC measures in Period 2 than in Period 1. This reduction was greater in children living in the urban area than those living in the suburban area. Obese children had significantly lower lung function but this was only statistically significant in Period 1. Conclusions Children’s lung function (FVC and FEV1) were lower in 2017 than in 1996. Rapid urbanization may have contributed to the decline of lung function. Obesity may be a risk factor for impaired lung function in children living in Lanzhou and possibly elsewhere.
Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates

The search for the pharmacophore of a bioactive compound, crucial for drug discovery studies, involves the adequate arrangement of different atoms in the molecule. As part of a continuous work aiming discovery of new drug candidates against the protozoan parasite Trypanosoma cruzi, the hexane extract of Hydrocotyle bonariensis was subjected to a bioactivity‐guided fractionation to afford two chemically related dibenzylbutyrolactone lignans – hinokinin (1) and hibalactone (2). Compounds 1 and 2 showed activity against trypomastigote with EC50 values of 17.0 and 69.4 μM, respectively. Compound 1 was also active against the clinically relevant form of the parasite, amastigotes, displaying an EC50 value of 34.4 μM. The structure‐activity relationship (SAR) indicated that the absence of the double bond at C‐7 is a crucial feature for the increment of the antiparasitic activity. The lethal action of the most potent compound 1 was investigated in the trypomastigotes. The fluorescent‐based assay with SYTOX Green demonstrated a significant alteration of the plasma membrane permeability of the parasite. Additionally, compound 1 demonstrated no significant hemolytic activity in mice erythrocytes at 200 μM. To search the pharmacophore, three different simplified compounds – 3,4‐methylenedioxydihydrocinnamic acid (3), 3,4‐methylenedioxydihydrocinnamic alcohol (4) and 3,4‐methylenedioxycinnamic acid (5) – were prepared and tested against T. cruzi. These derivatives displayed EC50 values of 37.2 (3), 25.8 (4) and 73.5 (5) μM against trypomastigotes, and 41.3 (3) and 48.2 (4) μM against amastigotes, whereas compound 5 was inactive. Except for compound 2, which resulted in a CC50 value of 114.5 μM, all compounds showed no mammalian cytotoxicity at 200 μM. An in silico ADMET study was performed and predicted values demonstrated an acceptable drug‐likeness profile for compounds 1–5. Despite the minor reduction in the potency, the simplified derivatives retained the antitrypanosomal activity against the intracellular amastigotes, even with 95 % reduction of their molecular weight. Additionally, in silico studies suggested them as more soluble compounds, making these simplified structures promising scaffolds for optimization studies in Chagas disease.
Association Between Testosterone Treatment and Risk of Incident Cardiovascular Events Among US Male Veterans With Low Testosterone Levels and Multiple Medical Comorbidities

Background Testosterone treatment is common in men, although risks for major cardiovascular events are unclear. Methods and Results A study was conducted in US male veterans, aged ≥40 years, with low serum testosterone and multiple medical comorbidities and without history of myocardial infarction, stroke, venous thromboembolism, prostate cancer, or testosterone treatment in the prior year. For the primary outcome, we examined if testosterone treatment was associated with a composite cardiovascular outcome (incident myocardial infarction, ischemic stroke, or venous thromboembolism). Testosterone use was modeled as intramuscular or transdermal and as current use, former use, and no use. Current testosterone users were compared with former users to reduce confounding by indication. The cohort consisted of 204 857 men with a mean (SD) age of 60.9 (9.9) years and 4.7 (3.5) chronic medical conditions. During follow‐up of 4.3 (2.8) years, 12 645 composite cardiovascular events occurred. In adjusted Cox regression analyses, current use of transdermal testosterone was not associated with risk for the composite cardiovascular outcome (hazard ratio [HR], 0.89; 95% CI, 0.76–1.05) in those without prevalent cardiovascular disease, and in those with prevalent cardiovascular disease was associated with lower risk (HR, 0.80; 95% CI, 0.70–0.91). In similar analyses, current use of intramuscular testosterone was not associated with risk for the composite cardiovascular outcome in men without or with prevalent cardiovascular disease (HR, 0.91; 95% CI, 0.80–1.04; HR, 0.98; 95% CI, 0.89–1.09, respectively). Conclusions In a large cohort of men without a history of myocardial infarction, stroke, or venous thromboembolism, testosterone treatment was not associated with increased risk for incident composite cardiovascular events.
The Masseteric-Facial Anastomosis With Intratemporal Translocation of the Facial Nerve: Step-by-Step Technique and Results

Abstract BACKGROUND In the absence of a viable proximal nerve stump, damaged after surgical procedures around the skull base, numerous techniques for facial reanimation have been developed over time, aiming to restore baseline symmetry and active mimicry. OBJECTIVE To report experience using the masseteric nerve as a direct transfer to the facial nerve rerouted after intratemporal translocation. This paper illustrates the main steps of the technique and the quality of results. METHODS Eleven patients were treated with a masseteric direct transfer to the facial nerve. Its extratemporal rerouting toward the zygoma allowed tension-free coaptation between donor and recipient nerves. RESULTS Of the 11 patients, 8 had a good to excellent recovery, showing different patterns of time and scores, according to age, surgical timing, and masseteric nerve function quality. The return of activity in the frontalis muscle, never obtained after reinnervation via the hypoglossal nerve, is of particular interest. The quality of the smile can be improved with re-education and practice but remains under volitional control. A true emotional response is still lacking. CONCLUSION The masseteric nerve is an excellent alternative to the hypoglossal nerve and can reinnervate the whole territory of the facial nerve rerouted after intratemporal translocation. The overall results are remarkable, but the low quality of the trigeminal nerve, eventually affected by the first surgery, may be an important limitation. Even if the patients appear more at ease in re-education than with other techniques, a fully natural facial expression remains impossible to obtain.
The association between meat consumption and the metabolic syndrome: a cross-sectional study and meta-analysis

Abstract The findings regarding the associations between red meat, fish and poultry consumption, and the metabolic syndrome (Mets) have been inconclusive, and evidence from Chinese populations is scarce. A cross-sectional study was performed to investigate the associations between red meat, fish and poultry consumption, and the prevalence of the Mets and its components among the residents of Suzhou Industrial Park, Suzhou, China. A total of 4424 participants were eligible for the analysis. A logistic regression model was used to estimate the OR and 95 % CI for the prevalence of the Mets and its components according to red meat, fish and poultry consumption. In addition, the data of our cross-sectional study were meta-analysed under a random effects model along with those of published observational studies to generate the summary relative risks (RR) of the associations between the highest v. lowest categories of red meat, fish and poultry consumption and the Mets and its components. In the cross-sectional study, the multivariable-adjusted OR for the highest v. lowest quartiles of consumption was 1·23 (95 % CI 1·02, 1·48) for red meat, 0·83 (95 % CI 0·72, 0·97) for fish and 0·93 (95 % CI 0·74, 1·18) for poultry. In the meta-analysis, the pooled RR for the highest v. lowest categories of consumption was 1·20 (95 % CI 1·06, 1·35) for red meat, 0·88 (95 % CI 0·81, 0·96) for fish and 0·97 (95 % CI 0·85, 1·10) for poultry. The findings of both cross-sectional studies and meta-analyses indicated that the association between fish consumption and the Mets may be partly driven by the inverse association of fish consumption with elevated TAG and reduced HDL-cholesterol and, to a lesser extent, fasting plasma glucose. No clear pattern of associations was observed between red meat or poultry consumption and the components of the Mets. The current findings add weight to the evidence that the Mets may be positively associated with red meat consumption, inversely associated with fish consumption and neutrally associated with poultry consumption.
Echocardiographic parameters and indices in 23 healthy Maltese dogs

Background Echocardiography is a primary tool used by veterinarians to evaluate heart diseases. In recent years, various studies have targeted standard echocardiographic values for different breeds. Reference data are currently lacking in Maltese dogs and it is important to fill this gap as this breed is predisposed to myxomatous mitral valve disease, which is a volume overload disease. Objectives To establish the normal echocardiographic parameters for Maltese dogs. Methods In total, 23 healthy Maltese dogs were involved in this study. Blood pressure measurements, thoracic radiography, and complete transthoracic echocardiography were performed. The effects of body weight, age and sex were evaluated, and the correlations between weight and linear and volumetric dimensions were calculated by regression analysis. Results The mean vertebral heart size was 9.1 ± 0.4. Aside from the ejection fraction, fractional shortening, and the left atrial to aorta root ratio, all the other echocardiographic parameters were significantly correlated with weight. Conclusion This study describes normal echocardiographic parameters that may be useful in the echocardiographic evaluation of Maltese dogs.
Immunosuppression-enhancing effect of the administration of allogeneic canine adipose-derived mesenchymal stem cells (cA-MSCs) compared with autologous cA-MSCs in vitro

Background Recently, mesenchymal stem cells therapy has been performed in dogs, although the outcome is not always favorable. Objectives To investigate the therapeutic efficacy of mesenchymal stem cells (MSCs) using dog leukocyte antigen (DLA) matching between the donor and recipient in vitro. Methods Canine adipose-derived MSCs (cA-MSCs) isolated from the subcutaneous tissue of Dog 1 underwent characterization. For major DLA genotyping (DQA1, DQB1, and DRB1), peripheral blood mononuclear cells (PBMCs) from two dogs (Dogs 1 and 2) were analyzed by direct sequencing of polymerase chain reaction (PCR) products. The cA-MSCs were co-cultured at a 1:10 ratio with activated PBMCs (DLA matching or mismatching) for 3 days and analyzed for immunosuppressive (IDO, PTGS2, and PTGES), inflammatory (IL6 and IL10), and apoptotic genes (CASP8, BAX, TP53, and BCL2) by quantitative real-time reverse transcriptase-PCR. Results cA-MSCs were expressed cell surface markers such as CD90+/44+/29+/45- and differentiated into osteocytes, chondrocytes, and adipocytes in vitro. According to the Immuno Polymorphism Database, DLA genotyping comparisons of Dogs 1 and 2 revealed complete differences in genes DQA1, DQB1, and DRB1. In the co-culturing of cA-MSCs and PBMCs, DLA mismatch between the two cell types induced a significant increase in the expression of immunosuppressive (IDO/PTGS2) and apoptotic (CASP8/BAX) genes. Conclusions The administration of cA-MSCs matching the recipient DLA type can alleviate the need to regulate excessive immunosuppressive responses associated with genes, such as IDO and PTGES. Furthermore, easy and reliable DLA genotyping technology is required because of the high degree of genetic polymorphisms of DQA1, DQB1, and DRB1 and the low readability of DLA 88.
Loss of Mir146b with aging contributes to inflammation and mitochondrial dysfunction in thioglycollate-elicited peritoneal macrophages

Macrophages undergo programmatic changes with age, leading to altered cytokine polarization and immune dysfunction, shifting these critical immune cells from protective sentinels to disease promoters. The molecular mechanisms underlying macrophage inflammaging are poorly understood. Using an unbiased RNA sequencing (RNA-seq) approach, we identified Mir146b as a microRNA whose expression progressively and unidirectionally declined with age in thioglycollate-elicited murine macrophages. Mir146b deficiency led to altered macrophage cytokine expression and reduced mitochondrial metabolic activity, two hallmarks of cellular aging. Single-cell RNA-seq identified patterns of altered inflammation and interferon gamma signaling in Mir146b-deficient macrophages. Identification of Mir146b as a potential regulator of macrophage aging provides novel insights into immune dysfunction associated with aging.
Strong Quantum Confinement Effects and Chiral Excitons in Bio-Inspired ZnO–Amino Acid Cocrystals

Elucidating the underlying principles behind band gap engineering is paramount for the successful implementation of semiconductors in photonic and optoelectronic devices. Recently it has been shown that the band gap of a wide and direct band gap semiconductor, such as ZnO, can be modified upon cocrystallization with amino acids, with the role of the biomolecules remaining unclear. Here, by probing and modeling the light-emitting properties of ZnO-amino acid cocrystals, we identify the amino acids' role on this band gap modulation and demonstrate their effective chirality transfer to the interband excitations in ZnO. Our 3D quantum model suggests that the strong band edge emission blue-shift in the cocrystals can be explained by a quasi-periodic distribution of amino acid potential barriers within the ZnO crystal lattice. Overall, our findings indicate that biomolecule cocrystallization can be used as a truly bio-inspired means to induce chiral quantum confinement effects in quasi-bulk semiconductors.