Miracle-dz/UniFAR-FTUs huggingface dataset:
NUV-Sensitive Silicon Photomultiplier Technologies Developed at Fondazione Bruno Kessler

Different applications require different customizations of silicon photomultiplier (SiPM) technology. We present a review on the latest SiPM technologies developed at Fondazione Bruno Kessler (FBK, Trento), characterized by a peak detection efficiency in the near-UV and customized according to the needs of different applications. Original near-UV sensitive, high-density SiPMs (NUV-HD), optimized for Positron Emission Tomography (PET) application, feature peak photon detection efficiency (PDE) of 63% at 420 nm with a 35 um cell size and a dark count rate (DCR) of 100 kHz/mm2. Correlated noise probability is around 25% at a PDE of 50% at 420 nm. It provides a coincidence resolving time (CRT) of 100 ps FWHM (full width at half maximum) in the detection of 511 keV photons, when used for the readout of LYSO(Ce) scintillator (Cerium-doped lutetium-yttrium oxyorthosilicate) and down to 75 ps FWHM with LSO(Ce:Ca) scintillator (Cerium and Calcium-doped lutetium oxyorthosilicate). Starting from this technology, we developed three variants, optimized according to different sets of specifications. NUV-HD–LowCT features a 60% reduction of direct crosstalk probability, for applications such as Cherenkov telescope array (CTA). NUV-HD–Cryo was optimized for cryogenic operation and for large photosensitive areas. The reference application, in this case, is the readout of liquid, noble-gases scintillators, such as liquid Argon. Measurements at 77 K showed a remarkably low value of the DCR of a few mHz/mm2. Finally, vacuum-UV (VUV)-HD features an increased sensitivity to VUV light, aiming at direct detection of photons below 200 nm. PDE in excess of 20% at 175 nm was measured in liquid Xenon. In the paper, we discuss the specifications on the SiPM related to different types of applications, the SiPM design challenges and process optimizations, and the results from the experimental characterization of the different, NUV-sensitive technologies developed at FBK.
Long non‐coding RNA metastasis‐associated lung adenocarcinoma transcript 1/microRNA‐202‐3p/periostin axis modulates invasion and epithelial–mesenchymal transition in human cervical cancer

The human cervical cancer (CC) has been identified as one of the most common tumors in women, and the molecular regulation in CC still remains unclear. The dysregulation of periostin has been found in a variety of cancers, but whether it is involved in the regulation of CC is unknown. The present study aimed to investigate the biological roles of periostin in CC and to explore the potential molecular regulation mechanisms. Here we found that the expression of periostin was overexpressed in CC tissues and CC cell lines (HeLa and SiHa). Knockdown of periostin in HeLa or SiHa cells significantly decreased cell viability, cell migration and invasion, and reduced epithelial–mesenchymal transition (EMT). Moreover, periostin knockdown suppressed the activation of Akt/the mammalian target of rapamycin (mTOR) signaling pathway, which is crucial for periostin to regulate the above biological activities in CC cells. Furthermore, we found that the periostin expression was positively correlated with the expression of metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1), and negatively correlated with the expression of microRNA (miR)‐202‐3p in CC tissues. We confirmed that MALAT1 positively regulated the expression of periostin by negatively modulating miR‐202‐3p. In addition, the MALAT1/miR‐202‐3p/periostin axis was deeply associated with the regulation of the cell viability, cell migration and invasion, and EMT in CC cells. Taken together, these findings suggest that periostin, which can be regulated by the MALAT1‐miR‐202‐3p axis, plays an important role in regulating cell viability, cell migration and invasion, and EMT of CC cells via activating Akt/mTOR signaling.
The adaptor protein Ste50 directly modulates yeast MAPK signaling specificity through differential connections of its RA domain

Discriminating among diverse environmental stimuli is critical for organisms to ensure their proper development, homeostasis, and survival. Saccharomyces cerevisiae regulates mating, osmoregulation, and filamentous growth using three different MAPK signaling pathways that share common components and therefore must ensure specificity. The adaptor protein Ste50 activates Ste11p, the MAP3K of all three modules. Its Ras association (RA) domain acts in both hyperosmolar and filamentous growth pathways, but its connection to the mating pathway is unknown. Genetically probing the domain, we found mutants that specifically disrupted mating or HOG-signaling pathways or both. Structurally these residues clustered on the RA domain, forming distinct surfaces with a propensity for protein–protein interactions. GFP fusions of wild-type (WT) and mutant Ste50p show that WT is localized to the shmoo structure and accumulates at the growing shmoo tip. The specifically pheromone response–defective mutants are severely impaired in shmoo formation and fail to localize ste50p, suggesting a failure of association and function of Ste50 mutants in the pheromone-signaling complex. Our results suggest that yeast cells can use differential protein interactions with the Ste50p RA domain to provide specificity of signaling during MAPK pathway activation.
A new sesquiterpene, a new monoterpene and other constituents with anti-inflammatory activities from the roots of Aristolochia debilis

Abstract A new sesquiterpene (1) and a new monoterpene (2), together with thirteen known compounds (3–15) were isolated from an ethanol extract of the roots of Aristolochia debilis Sieb. et Zucc. The structures of compounds 1 and 2 were elucidated using HR-ESI-MS, 1D and 2D NMR spectroscopy. Anti-inflammatory effects of the isolated compounds were evaluated in terms of inhibition of nitric oxide, tumour-necrosis factor-α and interleukin-6 production in lipopolysaccharide-stimulated RAW264.7 cells. Compounds 1–9 and 12–15 significantly inhibited the levels of NO, TNF-α and IL-6 in LPS-induced RAW264.7 cells from concentrations of 3 μM to 30 μM.
Sympathetic Activation in Heart Failure and Its Treatment With β-Blockade

Multiple models explaining the pathogenesis of heart failure have been put forth during the past 5 decades. These models were modified as clinical evidence supported or refuted their assumptions. During the past 2 decades, heart failure models emphasized the importance of neurohormonal systems in heart failure progression. The positive impact that angiotensin-converting enzyme inhibitors have had on mortality from heart failure has bolstered the neurohormonal theory. Attention recently has turned to the sympathetic nervous system and its potential deleterious effects on the cardiovascular system in heart failure. The sympathetic nervous system can negatively impact the cardiovascular system in heart failure in several ways, including down-regulating β 1 -receptors, exerting direct toxic effects on the myocardium, and contributing to myocardial remodeling and life-threatening arrhythmias. β-Adrenergic blockers have shown promise for reducing morbidity and mortality in heart failure, but definitive reductions in mortality remain to be shown by future investigations.
Toll-like receptor 10 (TLR10) exhibits suppressive effects on inflammation of prostate epithelial cells

Prostate inflammation (PI) is closely related to the development and progression of chronic prostatic diseases: benign prostatic hyperplasia and prostate cancer. Toll-like receptor (TLR) 2 has been reported to be associated with inflammatory diseases, such as infections, autoimmune diseases, and cancers. Meanwhile, TLR10, which can form heterodimers with TLR2, has been considered an orphan receptor without an exact function. The present study therefore aims to examine the effects of TLR2 and TLR10 on PI. Prostate samples and clinical data were obtained from the patients diagnosed with benign prostatic hyperplasia. The inflammatory cell model was established by adding lipopolysaccharide to RWPE-1 cells. Prostate tissues/cells were examined by histological, molecular, and biochemical approaches. Both TLR2 and TLR10 were found to be expressed in prostate tissues and RWPE-1 cells. mRNA/protein expression levels of TLR2 and TLR10 were both positively correlated with prostate tissue inflammatory grades. Lipopolysaccharide-stimulated RWPE-1 cells expressed higher levels of TLR2, TLR10, high mobility group box 1 (HMGB1), phospho-nuclear factor kappa-light-chain-enhancer of activated B-cells P65 (phospho-NF-κB P65), interleukin (IL)-6, and IL-8 than control cells. Moreover, HMGB1, phospho-NF-κB P65, IL-6, and IL-8 were downregulated after TLR2 knockdown and upregulated after TLR10 knockdown in RWPE-1 cells. TLR2 stimulation can activate the inflammatory signaling cascade in prostate epithelial cells. Conversely, TLR10 exhibited suppressive effects on inflammation. With antagonistic functions, both TLR2 and TLR10 were involved in PI. TLR10 could be a novel target in modulating inflammatory signal transduction of prostate epithelial cells.
Efficacy of heavy eccentric calf training for treating mid-portion Achilles tendinopathy: a systematic review and meta-analysis

Objective To assess the effectiveness of heavy eccentric calf training (HECT) in comparison with natural history, traditional physiotherapy, sham interventions or other exercise interventions for improvements in pain and function in mid-portion Achilles tendinopathy. Design A systematic review and meta-analysis were conducted as per the PRISMA guidelines. Data sources PUBMED, CINAHL (Ovid) and CINAHL (EBSCO) were searched from inception until 24 September 2018. Eligibility criteria Randomised controlled trials comparing HECT to natural history, sham exercise, traditional physiotherapy and other exercise interventions were included. Primary outcome assessing pain and function was the Victorian Institute of Sports Assessment-Achilles. Results Seven studies met the inclusion criteria. This review suggests HECT may be superior to both natural history, mean difference (MD) (95% CI) of 20.6 (11.7 to 29.5, one study) and traditional physiotherapy, MD (95% CI) of 17.70 (3.75 to 31.66, two studies). Following removal of one study, at high risk of bias, due to pre-planned sensitivity analysis, this review suggests HECT may be inferior to other exercise interventions, MD (95% CI) of −5.65 (-10.51 to −0.79, three studies). However, this difference is unlikely to be clinically significant. Conclusion Current evidence suggests that HECT may be superior to natural history and traditional physiotherapy while HECT may be inferior to other exercise interventions. However, due to methodological limitations, small sample size and a lack of data we are unable to be confident in the results of the estimate of the effect, as the true effect is likely to be substantially different. Systematic review registry PROSPERO registration number: CRD4201804493 Protocol reference This protocol has been published open access: Murphy M, Travers MJ, Gibson, W. Is heavy eccentric calf training superior to natural history, sham rehabilitation, traditional physiotherapy and other exercise interventions for pain and function in mid-portion Achilles tendinopathy? Systematic Reviews 2018; 7: 58
Hepatic Insulin Extraction in NAFLD Is Related to Insulin Resistance Rather Than Liver Fat Content.

CONTEXT Total insulin clearance is decreased in nonalcoholic fatty liver disease (NAFLD), but the relationship between liver fat and hepatic insulin extraction (HIE) is unknown. OBJECTIVE This cross-sectional study addresses the hypothesis that HIE is reduced in NAFLD and investigates metabolic and/or anthropometric characteristics most closely associated with insulin clearance. PARTICIPANTS Nondiabetic subjects with NAFLD (n = 13) and age- and body mass index (BMI)-matched controls with normal liver enzymes (n = 15) underwent abdominal CT, dual-energy X-ray absorptiometry, oral glucose tolerance test (OGTT), and labeled two-step hyperinsulinemic-euglycemic clamps. OUTCOME MEASUREMENTS Liver fat was estimated by the CT liver/spleen ratio. Hepatic and extrahepatic insulin clearances were modeled using clamp and OGTT data. RESULTS Extrahepatic insulin clearance and HIE were not different between NAFLD and controls and did not correlate with liver fat. HIE was positively correlated with insulin sensitivity [rate of glucose disposal (Rd; low r = +0.7, P < 0.001; high r = +0.6, P = 0.001), adiponectin (r = +0.55, P = 0.004), and insulin-mediated suppression of clamp nonesterified free fatty acid (NEFA; r = +0.67, P < 0.001)] but was not associated with fasting NEFA, insulin-mediated suppression of glucose production, or measures of adiposity. Extrahepatic insulin clearance was positively associated with percent body fat (r = +0.44, P = 0.02) and subcutaneous fat (r = +0.42, P = 0.03) but not BMI, intra-abdominal fat, liver fat, Rd, adiponectin, or NEFA. CONCLUSIONS HIE is not directly associated with hepatic steatosis but is associated with muscle and adipose tissue insulin resistance. The data suggest differential regulation of insulin clearance with extrahepatic insulin clearance being associated with body fat and not insulin sensitivity.
A Pyk2 inhibitor incorporated into a PEGDA-gelatin hydrogel promotes osteoblast activity and mineral deposition

Pyk2 is a non-receptor tyrosine kinase that belongs to the family of focal adhesion kinases. Studies from our laboratory and others demonstrated that mice lacking the Pyk2 gene (Ptk2B) have high bone mass, which was due to increased osteoblast activity, as well as decreased osteoclast activity. It was previously reported that a chemical inhibitor that targets both Pyk2 and its homolog FAK, led to increased bone formation in ovariectomized rats. In the current study, we developed a hydrogel containing poly(ethylene glycol) diacrylate (PEGDA) and gelatin which was curable by visible-light and was suitable for the delivery of small molecules, including a Pyk2-targeted chemical inhibitor. We characterized several critical properties of the hydrogel, including viscosity, gelation time, swelling, degradation, and drug release behavior. We found that a hydrogel composed of PEGDA1000 plus 10% gelatin (P1000:G10) exhibited Bingham fluid behavior that can resist free flowing before in situ polymerization, making it suitable for use as an injectable carrier in open wound applications. The P1000:G10 hydrogel was cytocompatible and displayed a more delayed drug release behavior than other hydrogels we tested. Importantly, the Pyk2-inhibitor-hydrogel retained its inhibitory activity against the Pyk2 tyrosine kinase, and promoted osteoblast activity and mineral deposition in vitro. Overall, our findings suggest that a Pyk2-inhibitor based hydrogel may be suitable for the treatment of craniofacial and appendicular skeletal defects and targeted bone regeneration.
Temperature and Precipitation Associate With Ischemic Stroke Outcomes in the United States

Background There is disagreement in the literature about the relationship between strokes and seasonal conditions. We sought to (1) describe seasonal patterns of stroke in the United States, and (2) determine the relationship between weather variables and stroke outcomes. Methods and Results We performed a cross‐sectional study using Get With The Guidelines‐Stroke data from 896 hospitals across the continental United States. We examined effects of season, climate region, and climate variables on stroke outcomes. We identified 457 638 patients admitted from 2011 to 2015 with ischemic stroke. There was a higher frequency of admissions in winter (116 862 in winter versus 113 689 in spring, 113 569 in summer, and 113 518 in fall; P<0.0001). Winter was associated with higher odds of in‐hospital mortality (odds ratio [OR] 1.08 relative to spring, confidence interval [CI] 1.04–1.13, P=0.0004) and lower odds of discharge home (OR 0.92, CI 0.91–0.94, P<0.0001) or independent ambulation at discharge (OR 0.96, CI 0.94–0.98, P=0.0006). These differences were attenuated after adjusting for climate region and case mix and became inconsistent after controlling for weather variables. Temperature and precipitation were independently associated with outcome after multivariable analysis, with increases in temperature and precipitation associated with lower odds of mortality (OR 0.95, CI 0.93–0.97, P<0.0001 and OR 0.95, CI 0.90–1.00, P=0.035, respectively). Conclusions Admissions for ischemic stroke were more frequent in the winter. Warmer and wetter weather conditions were independently associated with better outcomes. Further studies should aim to identify sensitive populations and inform public health measures aimed at resource allocation, readiness, and adaptive strategies.
The Association of Biochemical Hypoglycemia with the Subsequent Risk of a Severe Hypoglycemic Event: Analysis of the DCCT Data Set.

OBJECTIVE To evaluate the association of biochemical hypoglycemia with subsequent severe hypoglycemia (SH) events using the Diabetes Control and Complications Trial (DCCT) data set. RESEARCH DESIGN AND METHODS The frequency of biochemical hypoglycemia (percentage of values <70 and <54 mg/dL [3.9 and 3.0 mmol/L) was assessed using DCCT blood glucose concentrations measured at a central laboratory from seven finger-stick samples (7-point testing: pre- and 90-min postmeals and at bedtime) collected during 1 day every 3 months. SH events required a change in mental status necessitating the involvement of another individual to provide treatment. A Poisson model accounting for repeated measures from each participant was used to assess the association of biochemical hypoglycemia frequency, computed from the 7-point finger-stick data, with the development of SH events. RESULTS The risk of SH during a 3-month period was substantially higher (P < 0.001) when there was at least one hypoglycemic blood glucose value in the preceding 7-point profile, with similar results seen for both the 70 mg/dL (rate ratio = 3.0 [95% confidence interval: 2.6-3.3]) and 54 mg/dL (rate ratio = 2.7 [95% confidence interval: 2.4-3.1]) thresholds. CONCLUSIONS The occurrence of biochemical hypoglycemia <70 or <54 mg/dL is associated with an increased risk of SH. For this reason as well as the deleterious effects of hypoglycemia on glucose counter-regulation and hypoglycemia awareness, cognition, quality of life, and arrhythmias, it is important in diabetes management to avoid hypoglycemic glucose levels as much as possible.
Knights in Shining Armor.

With recent advances in sequencing technology, our understanding of the role of the gut microbiota in human health and disease has expanded significantly. In cardiovascular disease, the total number of studies is still small, with the majority reporting associations between the composition of the gut microbiota and markers of cardiovascular disease. Different bacteria synthesize and secrete a variety of metabolites that, through transport in the circulation, could act on distant host tissues. For example, higher concentrations of circulating lipopolysaccharides, which are components of the outer cell wall membrane of gram-negative bacteria, have been linked to atherosclerosis likely through increasing local inflammation.
A Phase I dose-escalation study of the BRAF inhibitor vemurafenib in combination with the MTOR inhibitor everolimus in subjects with advanced cancer

Vemurafenib has been approved in the United States for the treatment of relapsed or refractory BRAF mutation positive malignant melanoma and is being investigated in various other malignancies. The RAS/RAF/MEK/ERK (MAPK) pathway is critical to cell proliferation in many human cancers. The mTOR inhibitors are well known to exert profound anticancer effects across malignancies through inhibition of the PTEN/PI3K/AKT/mTOR (mTOR) pathway. We hypothesize that the toxicity profile of the combination of vemurafenib and everolimus will be well tolerated. The primary objective is to find the maximum tolerated dose (MTD) and the toxicity of the combination of vemurafenib and everolimus following a standard 3 + 3 design. The most common diagnosis was melanoma in 5 out of 10 patients
Evolutionary Modeling of Spatial Information

From the Publisher: Evolutionary models (e.g. genetic algorithms, artificial life), explored in other fields for the past two decades, are emerging as an important new tool for geographic information systems for a number of reasons. First, they are highly appropriate for modeling geographic phenomena; secondly, geographical problems are often spatially separate (broken down into local or regional problems), and evolutionary algorithms can exploit this structure; and finally, the ability to store, manipulate, and visualize spatial data has increased to the point that space-time-attribute databases can be easily handled. This book is meant to sere as a guide to the evolutionary modleing of spatial phenomena.
Changes in psychological and biological signals after completing an adaptive training program requiring working memory related cognitive processes

En este trabajo se estudian los efectos del entrenamiento adaptativo en la n-back dual sobre una serie de constructos (estimados a partir de tres medidas cada uno): inteligencia fluida, inteligencia cristalizada, memoria de trabajo y control atencional. A nivel biologico se estudia el efecto sobre la estructura cerebral, aplicando tecnicas de morfometria basada en superficie (SBM) porque permite estudiar cambios en el grosor cortical (cortical thickness, CT) y el area de superficie cortical (cortical surface area, CSA). Ademas, se estudia el efecto del programa sobre las conexiones (materia blanca) que unen regiones (predefinidas) de la corteza. Para evitar los problemas metodologicos denunciados por Thomas y Baker (2013a) aqui se estudia la interaccion. Por tanto, los cambios psicologicos y biologicos del pretest al posttest (TIEMPO) del grupo de entrenamiento se han comparado con los cambios ocurridos en un grupo control (GRUPO). Por ultimo, se ha comprobado (a) si las mejoras conductuales observadas durante el entrenamiento se mantienen en el tiempo y (b) la posible transferencia al rendimiento academico.
Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials

Background Randomised controlled trials (RCTs) of vitamin D to prevent COPD exacerbations have yielded conflicting results. Individual participant data meta-analysis could identify factors that explain this variation. Methods PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched from inception up to and including 5 October 2017 to identify RCTs of vitamin D supplementation in patients with COPD that reported incidence of acute exacerbations. Individual participant data meta-analysis was performed using fixed effects models adjusting for age, sex, Global Initiative for Chronic Obstructive Lung Disease spirometric grade and trial. Results Four eligible RCTs (total 560 participants) were identified; individual participant data were obtained for 469/472 (99.4%) participants in three RCTs. Supplementation did not influence overall rate of moderate/severe COPD exacerbations (adjusted incidence rate ratio (aIRR) 0.94, 95% CI 0.78 to 1.13). Prespecified subgroup analysis revealed that protective effects were seen in participants with baseline 25-hydroxyvitamin D levels <25 nmol/L (aIRR 0.55, 95% CI 0.36 to 0.84) but not in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (aIRR 1.04, 95% CI 0.85 to 1.27; p for interaction=0.015). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted OR 1.16, 95% CI 0.76 to 1.75). Conclusions Vitamin D supplementation safely and substantially reduced the rate of moderate/severe COPD exacerbations in patients with baseline 25-hydroxyvitamin D levels <25 nmol/L but not in those with higher levels. Trial registration number CRD42014013953.