Miracle-dz/UniFAR-FTUs huggingface dataset:
Age-Dependent Dysregulation of Muscle Vasculature and Blood Flow Recovery after Hindlimb Ischemia in the mdx Model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD), caused by a lack of functional dystrophin, is characterized by progressive muscle degeneration. Interestingly, dystrophin is also expressed in endothelial cells (ECs), and insufficient angiogenesis has already been hypothesized to contribute to DMD pathology, however, its status in mdx mice, a model of DMD, is still not fully clear. Our study aimed to reveal angiogenesis-related alterations in skeletal muscles of mdx mice compared to wild-type (WT) counterparts. By investigating 6- and 12-week-old mice, we sought to verify if those changes are age-dependent. We utilized a broad spectrum of methods ranging from gene expression analysis, flow cytometry, and immunofluorescence imaging to determine the level of angiogenic markers and to assess muscle blood vessel abundance. Finally, we implemented the hindlimb ischemia (HLI) model, more biologically relevant in the context of functional studies evaluating angiogenesis/arteriogenesis processes. We demonstrated that both 6- and 12-week-old dystrophic mice exhibited dysregulation of several angiogenic factors, including decreased vascular endothelial growth factor A (VEGF) in different muscle types. Nonetheless, in younger, 6-week-old mdx animals, neither the abundance of CD31+α-SMA+ double-positive blood vessels nor basal blood flow and its restoration after HLI was affected. In 12-week-old mdx mice, although a higher number of CD31+α-SMA+ double-positive blood vessels and an increased percentage of skeletal muscle ECs were found, the abundance of pericytes was diminished, and blood flow was reduced. Moreover, impeded perfusion recovery after HLI associated with a blunted inflammatory and regenerative response was evident in 12-week-old dystrophic mice. Hence, our results reinforce the hypothesis of age-dependent angiogenic dysfunction in dystrophic mice. In conclusion, we suggest that older mdx mice constitute an appropriate model for preclinical studies evaluating the effectiveness of vascular-based therapies aimed at the restoration of functional angiogenesis to mitigate DMD severity.
A New Mouse Model for Complete Congenital Stationary Night Blindness Due to Gpr179 Deficiency

Mutations in GPR179 lead to autosomal recessive complete congenital stationary night blindness (cCSNB). This condition represents a signal transmission defect from the photoreceptors to the ON-bipolar cells. To confirm the phenotype, better understand the pathogenic mechanism in vivo, and provide a model for therapeutic approaches, a Gpr179 knock-out mouse model was genetically and functionally characterized. We confirmed that the insertion of a neo/lac Z cassette in intron 1 of Gpr179 disrupts the same gene. Spectral domain optical coherence tomography reveals no obvious retinal structure abnormalities. Gpr179 knock-out mice exhibit a so-called no-b-wave (nob) phenotype with severely reduced b-wave amplitudes in the electroretinogram. Optomotor tests reveal decreased optomotor responses under scotopic conditions. Consistent with the genetic disruption of Gpr179, GPR179 is absent at the dendritic tips of ON-bipolar cells. While proteins of the same signal transmission cascade (GRM6, LRIT3, and TRPM1) are correctly localized, other proteins (RGS7, RGS11, and GNB5) known to regulate GRM6 are absent at the dendritic tips of ON-bipolar cells. These results add a new model of cCSNB, which is important to better understand the role of GPR179, its implication in patients with cCSNB, and its use for the development of therapies.
Regression of Systolic Anterior Motion in Progressive Hypertrophic Cardiomyopathy

Patient: Female, 78-year-old Final Diagnosis: Hypertrophic cardiomyopathy Symptoms: Chest discomfort • dyspnea Medication: — Clinical Procedure: Mitral valve repair • transesophageal echocardiogram Specialty: Cardiology Objective: Unusual clinical course Background: Systolic anterior motion (SAM) is the dynamic anteriorly directed movement of the anterior mitral valve leaflet during systole toward the left ventricular outflow tract (LVOT). The history of SAM in progressive hypertrophic cardiomyopathy (HCM) is unclear. It is believed that SAM is an irreversible process that progresses as the gradient over the LVOT increases. We present a case where SAM regressed after extensive left atrial (LA) and left ventricle (LV) remodeling in a patient with progressive HCM. Case Report: A 78-year-old woman presented with effort dyspnea. Echocardiogram revealed HCM with an interventricular septal (IVS) thickness of 20 mm, significant pressure gradient over LVOT, and prominent SAM. The LV chamber dimensions were within normal range. The patient was prescribed medications against heart failure and discharged. Six years later, she was admitted with an acute respiratory infection. She underwent transthoracic and transesophageal echocardiograms, which showed no systolic function change. The IVS thickness was lower, LV and LA were significantly enlarged, and there was a significant mitral regurgitation with an anteriorly directed jet and no SAM. The transesophageal echocardiogram revealed a posterior leaflet’s prolapse with a flail P2 segment, which required percutaneous edge-to-edge mitral repair. Conclusions: Our case highlights the multiple theories behind the mechanism of SAM in HCM. The long-standing pressure gradient over the LVOT lead to extensive left side remodeling, which then altered the geometric, kinetic, and structural forces and, consequently, the Venturi effect. At the end stage of HCM, IVS lost its thickness, pressure gradient declined, and SAM regressed.
Vibration-Controlled Transient Elastography and Controlled Attenuation Parameter for the Diagnosis of Liver Steatosis and Fibrosis in Patients with Nonalcoholic Fatty Liver Disease

Vibration-Controlled Transient Elastography (VCTE) with Controlled Attenuation Parameter (CAP) is a widely used non-invasive technique for concomitant assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the level both of hepatic steatosis and fibrosis as well as the associated risk factors in patients referred to our unit with clinically suspected NAFLD or diagnosed by abdominal ultrasonography. Two hundred four patients were prospectively included in this study and assessed by VCTE with CAP. The final analysis included 181 patients with reliable liver stiffness measurements (LSMs) (53% female, mean age 57.62 ± 11.8 years and BMI 29.48 ± 4.85 kg/m2). According to the cut-off values for steatosis grading, there were 10 (5.5%) patients without steatosis (S0), 30 (16.6%) with mild (S1), 45 (24.9%) moderate (S2), and 96 (53%) severe (S3) steatosis. Based on LSM, there were 73 (40.3%) patients without fibrosis (F0), 42 (23.2%) with mild (F1), 32 (17.7%) significant (F2), 19 (10.5%) advanced (F3) fibrosis, and 15 (8.3%) with cirrhosis (F4). In addition, we found an association between several metabolic components and hepatic steatosis and fibrosis. Thus, in the multivariate analysis, higher BMI, fasting plasma glucose, triglycerides, low-density lipoprotein cholesterol, and serum uric were associated with increased CAP. Furthermore, higher serum uric acid and alpha-fetoprotein together with lower platelets count and albumin levels were associated with increased LSM. The assessment of steatosis and fibrosis using VCTE and CAP should be performed in all patients with suspected or previously diagnosed NAFLD in units with available facilities.
Heat Stress in Broiler Chickens and the Effect of Dietary Polyphenols, with Special Reference to Willow (Salix spp.) Bark Supplements—A Review

Over the last decade, there has been a growing interest in the use of a wide range of phytoadditives to counteract the harmful effects of heat stress in poultry. Willow (Salix spp.) is a tree with a long history. Among various forms, willow bark is an important natural source of salicin, β-O-glucoside of saligenin, but also of polyphenols (flavonoids and condensed tannins) with antioxidant, antimicrobial, and anti-inflammatory activity. In light of this, the current review presents some literature data aiming to: (1) describe the relationship between heat stress and oxidative stress in broilers, (2) present or summarize literature data on the chemical composition of Salix species, (3) summarize the mechanisms of action of willow bark in heat-stressed broilers, and (4) present different biological effects of the extract of Salix species in different experimental models.
Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.
Investigating well potential parameters on neural spike enhancement in a stochastic-resonance pre-emphasis algorithm

Objective. Background noise experienced during extracellular neural recording limits the number of spikes that can be reliably detected, which ultimately limits the performance of next-generation neuroscientific work. In this study, we aim to utilize stochastic resonance (SR), a technique that can help identify weak signals in noisy environments, to enhance spike detectability. Approach. Previously, an SR-based pre-emphasis algorithm was proposed, where a particle inside a 1D potential well is exerted by a force defined by the extracellular recording, and the output is obtained as the displacement of the particle. In this study, we investigate how the well shape and damping status impact the output signal-to-noise ratio (SNR). We compare the overdamped and underdamped solutions of shallow- and steep-wall monostable wells and bistable wells in terms of SNR improvement using two synthetic datasets. Then, we assess the spike detection performance when thresholding is applied on the output of the well shape-damping status configuration giving the best SNR enhancement. Main results. The SNR depends on the well-shape and damping-status type as well as the input noise level. The underdamped solution of the shallow-wall monostable well can yield to more than four orders of magnitude greater SNR improvement compared to other configurations for low noise intensities. Using this configuration also results in better spike detection sensitivity and positive predictivity than the state-of-the-art spike detection algorithms for a public synthetic dataset. For larger noise intensities, the overdamped solution of the steep-wall monostable well provides better spike enhancement than the others. Significance. The dependence of SNR improvement on the input signal noise level can be used to design a detector with multiple outputs, each more sensitive to a certain distance from the electrode. Such a detector can potentially enhance the performance of a successive spike sorting stage.
The frequency and effects of distractions in operating theatres

Operating theatres (OTs) are complex environments where team members complete difficult tasks under stress. Distractions in these environments can lead to errors that compromise patient safety. A range of potential distractions exist in OTs and previous research suggests they are common. This study assesses the nature, frequency and impact of distracting events in the OT at a tertiary New Zealand hospital.
Predicting colostrum and calf blood components based on refractometry

Abstract Provision of good quality colostrum is essential for the passive immunity and nutrition of newborn calves. In order to better predict the quality of colostrum and the transfer of passive immunity, the relationships between colostrum components and between calf serum components were examined in this study. Samples of bulk tank milk, colostrum pooled from several cows 0–4 d postpartum, and colostrum collected from individual cows twice daily for 3 d post-partum were compared. With the exception of fat percentage, there were strong correlations between the levels of the components in the pooled colostrum and in the individual cow colostrum collected 0–1 d postpartum. The correlations between total solids as measured by Brix refractometry and total protein, immunoglobulin G (IgG), lactose % and protein % in colostrum within 1 d postpartum and pooled colostrum were 0.92, 0.90, −0.88 and 0.98, respectively. These high correlations enabled these colostrum components to be accurately predicted from Brix % and therefore, the volume of colostrum required to feed neonate calves can be optimised based on Brix refractometry to avoid failure of passive immunity transfer. To assess whether the components obtained from colostrum were correlated in calf blood, newborn calves were separated from their dams before suckling and blood sampled before feeding (day 0), and on days 1 and 7, after receiving colostrum or milk twice a day. The correlations between glucose, total protein, IgG, and gamma-glutamyl transferase (GGT) levels in the calf blood were lower than the correlations observed between the colostrum components. The highest correlation was between serum protein measured by refractometer and serum IgG within one week postpartum. GGT activity was not a good indicator of serum IgG levels. However, serum protein refractometer measurements predicted serum IgG level with high accuracy, providing an on-farm test to determine that calves have received sufficient passive immunity and colostrum components.
Novel App-Based Portable Spirometer for the Early Detection of COPD

Chronic obstructive pulmonary disease (COPD) is preventable and treatable. However, many patients remain undiagnosed and untreated due to the underutilization or unavailability of spirometers. Accordingly, we used Spirobank Smart, an app-based spirometer, for facilitating the early detection of COPD in outpatient clinics. This prospective study recruited individuals who were at risk of COPD (i.e., with age of ≥40 years, ≥10 pack-years of smoking, and at least one respiratory symptoms) but had no previous COPD diagnosis. Eligible participants were examined with Spirobank Smart and then underwent confirmatory spirometry (performed using a diagnostic spirometer), regardless of their Spirobank Smart test results. COPD was defined and confirmed using the postbronchodilator forced expiratory volume in 1 s/forced vital capacity values of <0.70 as measured by confirmatory spirometry. A total of 767 participants were enrolled and examined using Spirobank Smart; 370 participants (94.3% men, mean age of 60.9 years and mean 42.6 pack-years of smoking) underwent confirmatory spirometry. Confirmatory spirometry identified COPD in 103 participants (27.8%). At the optimal cutoff point of 0.74 that was determined using Spirobank Smart for COPD diagnosis, the area under the receiver operating characteristic was 0.903 (95% confidence interval (CI) = 0.860–0.947). Multivariate logistic regression revealed that participants who have an FEV1/FVC ratio of <74% that was determined using Spirobank Smart (odds ratio (OR) = 58.58, 95% CI = 27.29–125.75) and old age (OR = 3.23, 95% CI = 1.04–10.07 for 60 ≤ age < 65; OR = 5.82, 95% CI = 2.22–15.27 for age ≥ 65) had a higher risk of COPD. The Spirobank Smart is a simple and adequate tool for early COPD detection in outpatient clinics. Early diagnosis and appropriate therapy based on GOLD guidelines can positively influence respiratory symptoms and quality of life.
Low P66shc with High SerpinB3 Levels Favors Necroptosis and Better Survival in Hepatocellular Carcinoma

Simple Summary Cell proliferation and escape from apoptosis are important pathological features of hepatocellular carcinoma, one of the tumors with the highest mortality rate worldwide. The aim of the study was to evaluate the expression of the pro-apoptotic p66shc and the anti-apoptotic SerpinB3 molecules in relation to clinical outcome in patients with hepatocellular carcinoma and to evaluate their effect on cell fate and tumor growth. In patients with hepatocellular carcinoma the best survival was observed in the subgroup with p66shc levels below median values and SerpinB3 levels above median values. Mice p66shc knockout showed high levels of SerpinB3, while in hepatoma cells overexpressing SerpinB3, p66shc expression was trivial. Hepatoma cells overexpressing SerpinB3 were more prone to die after oxidizing treatments. These cells injected in nude mice developed tumors five times smaller than those from controls. Tumors originating from hepatoma cells overexpressing SerpinB3 showed typical features of necroptosis. In conclusion, in patients affected by hepatocellular carcinoma, the pattern characterized by p66shc downregulation and elevated SerpinB3 levels was associated with markedly better survival. This pattern favored necroptosis in experimental high-stress conditions. Abstract Cell proliferation and escape from apoptosis are important pathological features of hepatocellular carcinoma (HCC), one of the tumors with the highest mortality rate worldwide. The aim of the study was to evaluate the expression of the pro-apoptotic p66shc and the anti-apoptotic SerpinB3 in HCCs in relation to clinical outcome, cell fate and tumor growth. p66shc and SerpinB3 were evaluated in 67 HCC specimens and the results were correlated with overall survival. Proliferation and cell death markers were analyzed in hepatoma cells overexpressing SerpinB3, under different stress conditions. p66shc−/− mice and xenograft models were also used to assess the effects of p66shc and SerpinB3 on tumor growth. In patients with HCC, the best survival was observed in the subgroup with p66shc levels below median values and SerpinB3 levels above median values. Mice p66shc−/− showed high levels of SerpinB3, while in HepG2 cells overexpressing SerpinB3, p66shc expression was trivial. HepG2 overexpressing SerpinB3 cells were more prone to die after oxidizing treatments, such as diamide or high concentration H2O2. These cells injected in nude mice developed tumors five times smaller than those from control HepG2 cells. Tumors originating from HepG2 overexpressing SerpinB3 cells showed decreased activated Caspase-8, with concomitant increase of RIP3K and decreased levels of cleaved RIP3K, typical features of necroptosis. In conclusion, in patients affected by HCC, the pattern characterized by p66shc downregulation and elevated SerpinB3 levels was associated with markedly better survival. This pattern favored necroptosis in experimental high-stress conditions.
Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study

PURPOSE The first interim analysis of the phase III, randomized, placebo-controlled TITAN study showed that apalutamide significantly improved overall survival (OS) and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving ongoing androgen deprivation therapy (ADT). Herein, we report final efficacy and safety results after unblinding and placebo-to-apalutamide crossover. METHODS Patients with mCSPC (N = 1,052) were randomly assigned 1:1 to receive apalutamide (240 mg QD) or placebo plus ADT. After unblinding in January 2019, placebo-treated patients were allowed to receive apalutamide. Efficacy end points were updated using the Kaplan-Meier method and Cox proportional-hazards model without formal statistical retesting and adjustment for multiplicity. Change from baseline in Functional Assessment of Cancer Therapy-Prostate total score was assessed. RESULTS With a median follow-up of 44.0 months, 405 OS events had occurred and 208 placebo-treated patients (39.5%) had crossed over to apalutamide. The median treatment duration was 39.3 (apalutamide), 20.2 (placebo), and 15.4 months (crossover). Compared with placebo, apalutamide plus ADT significantly reduced the risk of death by 35% (median OS not reached v 52.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P < .0001) and by 48% after adjustment for crossover (hazard ratio, 0.52; 95% CI, 0.42 to 0.64; P < .0001). Apalutamide plus ADT delayed second progression-free survival and castration resistance (P < .0001 for both). Health-related quality of life, per total Functional Assessment of Cancer Therapy-Prostate, in both groups was maintained through the study. Safety was consistent with previous reports. CONCLUSION The final analysis of TITAN confirmed that, despite crossover, apalutamide plus ADT improved OS, delayed castration resistance, maintained health-related quality of life, and had a consistent safety profile in a broad population of patients with mCSPC.
Effect of Bombyx mori on the Liver Protection of Non-Alcoholic Fatty Liver Disease Based on In Vitro and In Vivo Models

Edible insects, Bombyx mori (silkworm; SW), which feed on mulberry leaves, have been consumed by humans for a long time as supplements or traditional medication. Non-alcoholic fatty liver disease (NAFLD) is a liver metabolic disorder that affects many people worldwide. We examined the hepatoprotective effects of SW using in vitro and high-fat and high-fructose (HFHF) diet-induced obese in vivo model mice by real-time PCR, immunoblot analysis, and fecal microbiota analysis. SW significantly reduced lipid accumulation and expression of the lipogenic genes in HepG2 cells and the livers of HFHF-induced mice. SW caused significant reductions in triglycerides, and total cholesterol in serum and upregulation of fatty acid oxidation markers compared to the HFHF group. Besides, SW significantly induced phosphorylation of AMPK and ACC in both models, suggesting roles in AMPK activation and the ACC signaling pathway. Furthermore, the gut microbiota analysis demonstrated that SW treatment reduced Firmicutes to Bacteroidetes ratios and the relative abundance of the Lachnospiraceae family compared to HFHF-induced obese mice. These results provide a novel therapeutic agent of hepatoprotective effects of SW for non-alcoholic hepatic steatosis that targets hepatic AMPK and ACC-mediated lipid metabolism.