Miracle-dz/UniFAR-FTUs huggingface dataset:
Androgen receptor: A promising therapeutic target in breast cancer

Abstract Breast cancer (BCa) is the second most common cancer worldwide and the most prevalent cancer in women. The majority of BCa cases are positive (+) for the estrogen receptor (ER+, 80%) and progesterone receptor (PR+, 65%). Estrogen and progesterone hormones are known to be involved in cancer progression, and thus hormonal deprivation is used as an effective treatment for ER+PR+ BCa subtypes. However, some ER+PR+ BCa patients develop resistance to such therapies. Meanwhile, chemotherapy is the only available treatment for ER-PR- BCa tumors. Another hormone receptor known as the androgen receptor (AR) has also been found to be widely expressed in human breast carcinomas. However, the mechanisms of AR and its endogenous androgen ligands is not well-understood in BCa and its biological role in this hormone-related disease remains unclear. In this review, we aim to address the importance of the AR in BCa diagnosis and prognosis, current AR-targeting approaches in BCa, and the potential for AR-downstream molecules to serve as therapeutic targets.
Factors Explaining Interpersonal Variation in Plasma Enterolactone Concentrations in Humans

Abstract Lignans are diphenolic plant compounds with potential health modulating properties that are absorbed to the circulation and metabolized to the enterolignans enterodiol (END) and enterolactone (ENL) by gut microbiota. Epidemiological studies have inconsistently shown that a high lignan intake and circulating ENL are associated with reduced risk of breast‐, prostate‐, and colorectal cancer as well as cardiovascular disease and total and cause‐specific mortality. Inconsistencies can be due to interpersonal variation of ENL formation or responses. The aim of this review is to identify and evaluate the impact of factors influencing variability in plasma concentrations of the main enterolignan, ENL. The main determinants of plasma ENL concentrations are intake of lignan and lignan‐rich foods, composition and activity of intestinal microflora, antimicrobial use, nutrient intake, BMI, smoking, sex, and age. Composition and activity of the intestinal microbiota appear to be the most critical factor governing interpersonal variability in plasma ENL concentration followed by the use of antibiotics. Future studies with combined data from gut microbiota and metabolomics with food intake and life style data can be used to estimate the relative contribution of the different factors to ENL concentration in quantitative terms.
Plasmatic free light chains in polycystic ovary syndrome

Abstract Polycystic ovary syndrome (PCOS), as systemic disease, is accompanied by different indexes of inflammation. Free light chains of immunoglobulins (FLCs), produced by plasmacells, are released in slight excess for the immune requests, with still poorly defined physiological role but surely they represent a marker of inflammation. In order to evaluate their levels and correlate them with hyperandrogenism, we have studied a group of PCOS patients, age range 18–37 yrs, mean ± SEM body mass index (BMI) 24.1 ± 0.9 kg/m2), compared with age- and BMI-matched controls, with assay of k and λ FLCs, by turbidimetric method, and their ratio in blood plasma. PCOs exhibited higher levels vs. controls: (mean ± SEM λ: 10.0 ± 0.85 mg/L vs. 8.41 ± 0.45 mg/L; k: 12.45 ± 0.72 mg/L vs. 6.41 ± 0.34 mg/L; k/λ: 1.31 ± 0.07 vs. 0.78 ± 0.04). A significant direct correlation was observed between λ-FLCs and testosterone levels, no correlation was indeed found with HOMA-IR index. These data confirm high levels of FLCs in PCOS, suggesting systemic inflammatory state and a possible role in the pathophysiology of such complex syndrome.
2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

This document was approved by the American College of Cardiology Cli American Heart Association Science Advisory and Coordinating Committee i in February 2017. The American College of Cardiology requests that this document be cited a Fleisher LA, Jneid H, Mack MJ, McLeod CJ, O’Gara PT, Rigolin VH, Sundt TM guideline for the management of patients with valvular heart disease: a repo Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;70:252–89. This article has been copublished in Circulation. Copies: This document is available on the World Wide Web sites of the Association (professional.heart.org). For copies of this document, please c (reprints@elsevier.com). Permissions: Multiple copies, modification, alteration, enhancement, and permission of the American College of Cardiology. Requests may be compl author-agreement/obtaining-permission). Vera H. Rigolin, MD, FACC{ Thoralf M. Sundt III, MD, FACC*# Annemarie Thompson, MD**
Could the monocyte/HDL cholesterol ratio be an early marker of erectile dysfunction?

Abstract Objective Research evaluating the relationship between the Monocyte/HDL-C ratio (MHR) and ED is limited in number. We aimed for determining whether MHR could be an early marker of ED in our study. Material and methods Eighty-nine patients diagnosed with ED during the period of April 2018–November 2018 and 100 patients that did not have any systemic diseases and erectile dysfunction were included in our study. The presence of ED was evaluated with International Erectile Function Index (IIEF-5). Peripheral blood samples were collected from the patients for complete blood count and biochemical analyses. The relationship between ED and MHR was evaluated for both groups. Results Body mass indices (BMI) of the ED group and the control group were significantly different in statistical terms. While a significant difference was observed for fasting blood glucose, total testosterone, luteinizing hormone values between the ED group and the control group, and follicle stimulant hormone values were found to be similar with each other. MHR values of two groups were found to be significantly different. Discussion MHR can be used as a marker for the determination of ED's severity and for its monitoring. We also believe that a large series of clinical and research studies are required for it to be applicable in clinical practice. Being the first prospective study in literature, we believe that our study would provide important contributions to the literature.
The implications of time on the ground on running economy: less is not always better

ABSTRACT A lower duty factor (DF) reflects a greater relative contribution of leg swing versus ground contact time during the running step. Increasing time on the ground has been reported in the scientific literature to both increase and decrease the energy cost (EC) of running, with DF reported to be highly variable in runners. As increasing running speed aligns running kinematics more closely with spring–mass model behaviours and re-use of elastic energy, we compared the centre of mass (COM) displacement and EC between runners with a low (DFlow) and high (DFhigh) duty factor at typical endurance running speeds. Forty well-trained runners were divided in two groups based on their mean DF measured across a range of speeds. EC was measured from 4 min treadmill runs at 10, 12 and 14 km h−1 using indirect calorimetry. Temporal characteristics and COM displacement data of the running step were recorded from 30 s treadmill runs at 10, 12, 14, 16 and 18 km h−1. Across speeds, DFlow exhibited more symmetrical patterns between braking and propulsion phases in terms of time and vertical COM displacement than DFhigh. DFhigh limited global vertical COM displacements in favour of horizontal progression during ground contact. Despite these running kinematics differences, no significant difference in EC was observed between groups. Therefore, both DF strategies seem energetically efficient at endurance running speeds. Summary: Larger forward and smaller vertical COM displacements were observed in runners with a high versus a low duty factor, with the two duty factor groups demonstrating comparable running economy values.
Epigenetic changes during aging and their reprogramming potential

Abstract The aging process results in significant epigenetic changes at all levels of chromatin and DNA organization. These include reduced global heterochromatin, nucleosome remodeling and loss, changes in histone marks, global DNA hypomethylation with CpG island hypermethylation, and the relocalization of chromatin modifying factors. Exactly how and why these changes occur is not fully understood, but evidence that these epigenetic changes affect longevity and may cause aging, is growing. Excitingly, new studies show that age-related epigenetic changes can be reversed with interventions such as cyclic expression of the Yamanaka reprogramming factors. This review presents a summary of epigenetic changes that occur in aging, highlights studies indicating that epigenetic changes may contribute to the aging process and outlines the current state of research into interventions to reprogram age-related epigenetic changes.
Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior

Neurodevelopmental disorders offer insight into synaptic mechanisms. To unbiasedly uncover these mechanisms, we studied the 22q11.2 syndrome, a recurrent copy number variant, which is the highest schizophrenia genetic risk factor. We quantified the proteomes of 22q11.2 mutant human fibroblasts from both sexes and mouse brains carrying a 22q11.2-like defect, Df(16)A+/−. Molecular ontologies defined mitochondrial compartments and pathways as some of top ranked categories. In particular, we identified perturbations in the SLC25A1-SLC25A4 mitochondrial transporter interactome as associated with the 22q11.2 genetic defect. Expression of SLC25A1-SLC25A4 interactome components was affected in neuronal cells from schizophrenia patients. Furthermore, hemideficiency of the Drosophila SLC25A1 or SLC25A4 orthologues, dSLC25A1-sea and dSLC25A4-sesB, affected synapse morphology, neurotransmission, plasticity, and sleep patterns. Our findings indicate that synapses are sensitive to partial loss of function of mitochondrial solute transporters. We propose that mitoproteomes regulate synapse development and function in normal and pathological conditions in a cell-specific manner. SIGNIFICANCE STATEMENT We address the central question of how to comprehensively define molecular mechanisms of the most prevalent and penetrant microdeletion associated with neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. This complex mutation reduces gene dosage of ∼63 genes in humans. We describe a disruption of the mitoproteome in 22q11.2 patients and brains of a 22q11.2 mouse model. In particular, we identify a network of inner mitochondrial membrane transporters as a hub required for synapse function. Our findings suggest that mitochondrial composition and function modulate the risk of neurodevelopmental disorders, such as schizophrenia.
Effects of Maternal Sildenafil Treatment on Vascular Function in Growth-Restricted Fetal Sheep

Objective— The objective of this study was to investigate the effect of intravenous maternal sildenafil citrate (SC) administration on vascular function in growth-restricted fetal sheep. Approach and Results— Fetal growth restriction (FGR) results in cardiovascular adaptations that redistribute cardiac output to optimize suboptimal intrauterine conditions. These adaptations result in structural and functional cardiovascular changes, which may underlie postnatal neurological and cardiovascular sequelae. Evidence suggests SC, a potent vasodilator, may improve FGR. In contrast, recent clinical evidence suggests potential for adverse fetal consequence. Currently, there is limited data on SC effects in the developing fetus. We hypothesized that SC in utero would improve vascular development and function in an ovine model of FGR. Preterm lambs (0.6 gestation) underwent sterile surgery for single umbilical artery ligation or sham (control, appropriately grown) surgery to replicate FGR. Ewes received continuous intravenous SC (36 mg/24 h) or saline from surgery until 0.83 gestation. Fetuses were delivered and immediately euthanized for collection of femoral and middle cerebral artery vessels. Vessel function was assessed via in vitro wire myography. SC exacerbated growth restriction in growth-restricted fetuses and resulted in endothelial dysfunction in the cerebral and femoral vasculature, irrespective of growth status. Dysfunction in the cerebral circulation is endothelial, whereas smooth muscle in the periphery is the origin of the deficit. Conclusions— SC crosses the placenta and alters key fetal vascular development. Extensive studies are required to investigate the effects of SC on fetal development to address safety before additional use of SC as a treatment.
Stopping RAS Inhibitors to Minimize AKI: More Harm than Good?

Drugs that inhibit the renin-angiotensin system, in particular angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are cornerstones of nephrology care. In particular, they slow progression of proteinuric CKD and markedly improve prognosis for patients with
First Report of Downy Mildew on Basil (Ocimum basilicum) in Italy.

Sweet basil (Ocimum basilicum) is an economically important herb in several Mediterranean countries. Approximately 80 ha are grown annually in Italy for fresh and processed consumption. In 2003, a damaging foliar disease was observed in several greenhouses located in the Liguria Region of northern Italy. More that 50% of the plants were affected. Leaves of infected plants were initially slightly chlorotic, especially near the central vein. Within 2 to 3 days, a characteristic gray, furry growth was evident on the lower surface of infected leaves. These symptoms sometimes occurred on the top sides of leaves. Although the distribution of the disease was generally uniform, symptoms appeared first in a patchy pattern in the central part of the greenhouses where air temperature and relative humidity were highest. Where air circulation was apparently poor, bottom leaves were severely affected by the disease. Microscopic observations revealed conidiophores branching two to seven times. Conidiophores with a length of 250 to 500 μm (average 350 μm) ended with sterigmata bearing single conidia. Conidia measured 15 to 25 × 20 to 35 μm (average 22 × 28 μm) and were elliptical and grayish in mass. The pathogen was identified as a Peronospora sp. based on its morphological characteristics (3). Pathogenicity was confirmed by inoculating leaves of 40-day-old healthy plants with a conidial suspension (1 × 105 conidia per ml). Three containers containing 150 plants each of O. basilicum cv. Genovese gigante were used as replicates. Noninoculated plants served as controls. Inoculated and noninoculated plants were maintained in a growth chamber at 20°C (12 h of light per day) and 90 to 95% relative humidity. The pathogenicity test was carried out twice. After 6 days, typical symptoms of downy mildew developed on the inoculated plants and a Peronospora sp. was observed on the leaves. Noninoculated plants did not show symptoms. To our knowledge, this is the first report of a Peronospora sp. on basil in Italy. Peronospora sp. and P. lamii were previously reported on sweet basil in Uganda (1,2). References: (1) C. G. Hansford. Rev. Appl. Mycol. 12:421, 1933. (2) C. G. Hansford. Rev. Appl. Mycol. 17:345, 1938. (3) D. M. Spencer. The Downy Mildews. Academic Press, N.Y. , 1978.
Structural roles of PCV2 capsid protein N-terminus in PCV2 particle assembly and identification of PCV2 type-specific neutralizing epitope

Postweaning multisystemic wasting disease (PMWS) in piglets caused by porcine circovirus type 2 (PCV2) is one of the major threats to most pig farms worldwide. Among all the PCV types, PCV2 is the dominant genotype causing PMWS and associated diseases. Considerable efforts were made to study the virus-like-particle (VLP) assembly and the specific PCV2-associated epitope(s) in order to establish the solid foundation for engineered PCV2 vaccine development. Although the N-terminal fragment including Nuclear Localization Signal (NLS) sequence seems important for recombinant PCV2 capsid protein expression and VLP assembly, the detailed structural and functional information regarding this important fragment are largely unknown. In this study, we report crystal structure of PCV2 VLP assembled from N-terminal NLS truncated PCV2 capsid protein at 2.8 Å resolution and cryo-EM structure of PCV2 VLP assembled from full-length PCV2 capsid protein at 4. 1Å resolution. Our in vitro PCV2 VLP assembly results show that NLS-truncated PCV2 capsid protein only forms instable VLPs which were easily disassembled in solution, whereas full-length PCV2 capsid protein forms stable VLPs due to interaction between 15PRSHLGQILRRRP27 (α-helix) and 33RHRYRWRRKN42 (NLS-B) in a repeated manner. In addition, our results also showed that N-terminal truncation of PCV2 capsid protein up to 27 residues still forms PCV2 particles in solution with similar size and immunogenicity, while N-terminal truncation of PCV2 capsid protein with more than 30 residues is not able to form stable PCV2 particles in solution, demonstrating the importance of interaction between the α-helix at N-terminal and NLS-B in PCV2 VLP formation. Moreover, we also report the cryo-EM structure of PCV2 VLP in complex with 3H11-Fab, a PCV2 type-specific neutralizing antibody, at 15 Å resolution. MAb-3H11 specifically recognizes one exposed epitope located on the VLP surface EF-loop (residues 128–143), which is further confirmed by PCV1-PCV2 epitope swapping assay. Hence, our results have revealed the structural roles of N-terminal fragment of PCV2 capsid protein in PCV2 particle assembly and pinpointed one PCV2 type-specific neutralizing epitope for the first time, which could provide clear clue for next generation PCV2 vaccine and diagnostic kits development.
Down-regulated TMED10 in Alzheimer disease induces autophagy via ATG4B activation

ABSTRACT Several studies have shown that dysfunction of macroautophagy/autophagy is associated with many human diseases, including neurodegenerative disease and cancer. To explore the molecular mechanisms of autophagy, we performed a cell-based functional screening with SH-SY5Y cells stably expressing GFP-LC3, using an siRNA library and identified TMED10 (transmembrane p24 trafficking protein 10), previously known as the γ-secretase-modulating protein, as a novel regulator of autophagy. Further investigations revealed that depletion of TMED10 induced the activation of autophagy. Interestingly, protein-protein interaction assays showed that TMED10 directly binds to ATG4B (autophagy related gene 4B cysteine peptidase), and the interaction is diminished under autophagy activation conditions such as rapamycin treatment and serum deprivation. In addition, inhibition of TMED10 significantly enhanced the proteolytic activity of ATG4B for LC3 cleavage. Importantly, the expression of TMED10 in AD (Alzheimer disease) patients was considerably decreased, and downregulation of TMED10 increased amyloid-β (Aβ) production. Treatment with Aβ increased ATG4B proteolytic activity as well as dissociation of TMED10 and ATG4B. Taken together, our results suggest that the AD-associated protein TMED10 negatively regulates autophagy by inhibiting ATG4B activity.Abbreviations: Aβ: amyloid-β; AD: Alzheimer disease; ATG: autophagy related; BECN1: beclin 1; BiFC: bimolecular fluorescence complementation; CD: cytosolic domain; GFP: green fluorescent protein; GLUC: Gaussia luciferase; IP: immunoprecipitation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LD: luminal domain; PD: Parkinson disease; ROS: reactive oxygen species; siRNA: small interfering RNA; SNP: single-nucleotide polymorphisms; TD: transmembrane domain; TMED10: transmembrane p24 trafficking protein 10; VC: C terminus of Venus fluorescent protein; VN: N terminus of Venus fluorescent protein.
The Prevalence of Metabolically Healthy and Unhealthy Obesity according to Different Criteria

Objective: Obesity-related disease risks may vary depending on whether the subject has metabolically healthy obesity (MHO) or metabolically unhealthy obesity (MUO). At least 5 definitions/criteria of obesity and metabolic disorders have been documented in the literature, yielding uncertainties in a reliable international comparison of obesity phenotype prevalence. This report aims to compare differences in MHO and MUO prevalence according to the 5 most frequently used definitions. Methods: A random sample of 4,757 adults aged 35 years and older (male 51.1%) was enrolled. Obesity was defined either according to body mass index or waist circumference, and the definitions of metabolic abnormalities were derived from 5 different criteria. Results: In MHO, the highest prevalence was obtained when using the homeostasis model assessment (HOMA) criteria (13.6%), followed by the Chinese Diabetes Society (11.4%), Adult Treatment Panel III (10.3%), Wildman (5.2%), and Karelis (4.2%) criteria; however, the MUO prevalence had an opposite trend to MHO prevalence. The magnitude of differences in the age-specific prevalence of MHO and MUO varied greatly and ranked in different orders. The proportion of insulin resistance for MHO and MUO individuals differed significantly regardless of which metabolic criterion was used. Conclusion: The prevalence of MHO and MUO in the Chinese population varies according to different definitions of obesity and metabolic disorders.
Bone marrow stromal cells from β-thalassemia patients have impaired hematopoietic supportive capacity

BACKGROUND. The human bone marrow (BM) niche contains a population of mesenchymal stromal cells (MSCs) that provide physical support and regulate hematopoietic stem cell (HSC) homeostasis. &bgr;-Thalassemia (BT) is a hereditary disorder characterized by altered hemoglobin beta-chain synthesis amenable to allogeneic HSC transplantation and HSC gene therapy. Iron overload (IO) is a common complication in BT patients affecting several organs. However, data on the BM stromal compartment are scarce. METHODS. MSCs were isolated and characterized from BM aspirates of healthy donors (HDs) and BT patients. The state of IO was assessed and correlated with the presence of primitive MSCs in vitro and in vivo. Hematopoietic supportive capacity of MSCs was evaluated by transwell migration assay and 2D coculture of MSCs with human CD34+ HSCs. In vivo, the ability of MSCs to facilitate HSC engraftment was tested in a xenogenic transplant model, whereas the capacity to sustain human hematopoiesis was evaluated in humanized ossicle models. RESULTS. We report that, despite iron chelation, BT BM contains high levels of iron and ferritin, indicative of iron accumulation in the BM niche. We found a pauperization of the most primitive MSC pool caused by increased ROS production in vitro which impaired MSC stemness properties. We confirmed a reduced frequency of primitive MSCs in vivo in BT patients. We also discovered a weakened antioxidative response and diminished expression of BM niche–associated genes in BT-MSCs. This caused a functional impairment in MSC hematopoietic supportive capacity in vitro and in cotransplantation models. In addition, BT-MSCs failed to form a proper BM niche in humanized ossicle models. CONCLUSION. Our results suggest an impairment in the mesenchymal compartment of BT BM niche and highlight the need for novel strategies to target the niche to reduce IO and oxidative stress before transplantation. FUNDING. This work was supported by the SR-TIGET Core grant from Fondazione Telethon and by Ricerca Corrente.