Miracle-dz/UniFAR-FTUs huggingface dataset:
Metformin regulates TRPM6, a potential explanation for magnesium imbalance in type 2 diabetes patients.

Metformin therapy is associated with lower serum magnesium (Mg2+) levels in type 2 diabetes (T2D) patients. The TRPM6 channel determines the fine-tuning of Mg2+ (re)absorption in intestine and kidney. Therefore, we aimed to investigate the short- and long-term effects of metformin on TRPM6. Patch clamp recordings and biotinylation assays were performed upon 1h of incubation with metformin in TRPM6-transfected HEK293 cells. Additionally, 24h treatment of mDCT15 kidney and hCaco-2 colon cells with metformin was applied to measure the effects on endogenous TRPM6 expression by RT-qPCR. To assess Mg2+ absorption, 25Mg2+ uptake measurements were performed using ICP-MS. Short-term effects of metformin significantly increased TRPM6 activity and its cell surface trafficking. In contrast, long-term effects significantly decreased TRPM6 mRNA expression and 25Mg2+ uptake. Metformin lowered TRPM6 mRNA levels independently of insulin- and AMPK-mediated pathways. Moreover, in T2D patients, metformin therapy was associated with lower plasma Mg2+ concentrations and fractional excretion of Mg2+. Thereby, short-term metformin treatment increases TRPM6 activity explained by enhanced cell surface expression. Conversely, long-term metformin treatment results in downregulation of TRPM6 gene expression in intestine and kidney cells. This long-term effect translated in an inverse correlation between metformin and plasma Mg2+ concentration in T2D patients.
ADAM-17: a novel therapeutic target for triple negative breast cancer.

BACKGROUND Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 [i.e., those with triple-negative (TN) disease]. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR/HER family of receptors. PATIENTS AND METHODS Expression of ADAM-17 was measured in 86 triple-negative and 96 non-triple-negative breast cancers. The ADAM-17 specific inhibitor, PF-5480090 (TMI-002, Pfizer) was tested in a panel of breast cancer cell lines for effects on functional outputs. RESULTS In this study we show using both Western blotting and immunohistochemistry that ADAM-17 is expressed at significantly higher levels in TN than non-TN breast cancers. Using a panel of breast cancer cell lines in culture, PF-5480090 was found to decrease release of the EGFR ligand, TGF-alpha, decrease levels of phosphorylated EGFR and block cell proliferation in a cell-type-dependent manner. Potentially important was the finding of a significant and moderately strong correlation between ADAM-17 activity and extent of proliferation inhibition by PF-5480090 (r = 0.809; p = 0.003; n = 11). Pretreatment of cell lines with PF-5480090 enhanced response to several different cytotoxic and anti-EGFR/HER agents. CONCLUSION It is concluded that inhibition of ADAM-17, especially in combination with chemotherapy or anti-EGFR/HER inhibitors, may be a new approach for treating breast cancer, including patients with TN disease.
Comparative QSAR model generation using pyrazole derivatives for screening Janus kinase‐1 inhibitors

Asthma is a multitargeted disease. IL‐4‐JAK‐STAT signaling pathway is a promising route for the effective control of the disease. JAK inhibition by small molecules could effectively block the IL‐4 signaling pathway. It was established that JAK1 is responsive toward IL‐4‐mediated signaling process. In the present study, three‐dimensional QSAR analyses on a set of pyrazole derivatives against JAK1 and JAK2 enzyme inhibition had been executed. Molecular docking studies were conducted with the target JAK1 using the pyrazole derivative compounds and found out potential intermolecular interactions operating among them. The binding energy of all the derivative compounds with the target JAK1 has calculated and found out their affinity toward the target system. These models have predicted the JAK1 inhibitory activity of some five JAK1 active drugs and 50 structurally similar compounds. These models can, thus, suggestively be recommended for virtual screening of JAK1‐selective candidates as a lead for immunomodulatory diseases like asthma.
Improved detection of coarctation of the aorta using speckle‐tracking analysis of fetal heart on last examination prior to delivery

The false‐positive rate for prenatal diagnosis of coarctation of the aorta (FP‐CoA) commonly exceeds 50%, with an accurate detection rate of < 50%. This study was conducted to determine if the sensitivity for prenatal detection of true CoA and the FP‐CoA rate could be improved by evaluating the fetal epicardial size and shape in the four‐chamber view (4CV) and the endocardial right (RV) and left (LV) ventricular size, shape and contractility.
Ecophysiology of coral reef primary producers across an upwelling gradient in the tropical central Pacific

Upwelling is an important source of inorganic nutrients in marine systems, yet little is known about how gradients in upwelling affect primary producers on coral reefs. The Southern Line Islands span a natural gradient of inorganic nutrient concentrations across the equatorial upwelling region in the central Pacific. We used this gradient to test the hypothesis that benthic autotroph ecophysiology is enhanced on nutrient-enriched reefs. We measured metabolism and photophysiology of common benthic taxa, including the algae Porolithon, Avrainvillea, and Halimeda, and the corals Pocillopora and Montipora. We found that temperature (27.2–28.7°C) was inversely related to dissolved inorganic nitrogen (0.46–4.63 μM) and surface chlorophyll a concentrations (0.108–0.147 mg m-3), which increased near the equator. Contrary to our prediction, ecophysiology did not consistently track these patterns in all taxa. Though metabolic rates were generally variable, Porolithon and Avrainvillea photosynthesis was highest at the most productive and equatorial island (northernmost). Porolithon photosynthetic rates also generally increased with proximity to the equator. Photophysiology (maximum quantum yield) increased near the equator and was highest at northern islands in all taxa. Photosynthetic pigments also were variable, but chlorophyll a and carotenoids in Avrainvillea and Montipora were highest at the northern islands. Phycobilin pigments of Porolithon responded most consistently across the upwelling gradient, with higher phycoerythrin concentrations closer to the equator. Our findings demonstrate that the effects of in situ nutrient enrichment on benthic autotrophs may be more complex than laboratory experiments indicate. While upwelling is an important feature in some reef ecosystems, ancillary factors may regulate the associated consequences of nutrient enrichment on benthic reef organisms.
Biogenesis pathways of α-helical mitochondrial outer membrane proteins

Abstract Mitochondria harbor in their outer membrane (OM) proteins of different topologies. These proteins are encoded by the nuclear DNA, translated on cytosolic ribosomes and inserted into their target organelle by sophisticated protein import machineries. Recently, considerable insights have been accumulated on the insertion pathways of proteins into the mitochondrial OM. In contrast, little is known regarding the early cytosolic stages of their biogenesis. It is generally presumed that chaperones associate with these proteins following their synthesis in the cytosol, thereby keeping them in an import-competent conformation and preventing their aggregation and/or mis-folding and degradation. In this review, we outline the current knowledge about the biogenesis of different mitochondrial OM proteins with various topologies, and highlight the recent findings regarding their import pathways starting from early cytosolic events until their recognition on the mitochondrial surface that lead to their final insertion into the mitochondrial OM.
Guanidinoacetic acid supplementation is favourable to broiler diets even containing poultry by-product meal

ABSTRACT 1. Two consecutive trials were conducted to evaluate the effects of guanidinoacetic acid (GAA) supplementation (a creatine precursor) and energy levels in broiler diets based on maize-soybean meal (Trial 1) or that additionally included poultry by-product meal (PBPM; Trial 2) on growth performance, carcass yield and breast meat quality to 41 days of age. 2. A total of 792, one-day-old male Ross 308 broiler chickens were randomly distributed into six treatments – three energy levels (sufficient AMEn or 0.2 and 0.4 MJ/kg reduced AMEn) and two GAA levels (0.00% or 0.06%) with eight replicates for each trial. 3. Reducing dietary energy resulted in poorer body weight gain (BWG) and feed conversion ratios (FCR) for each trial (P < 0.05). However, GAA supplementation improved FCR, BWG and European Production Efficiency Factor (EPEF) (P < 0.05). 4. Dietary energy level and GAA addition had no significant effect on carcass parameters, drip loss, pH and chemical composition of breast meat (P > 0.05), but decreased relative liver weight (P < 0.05). 5. It was concluded that, regardless of dietary energy levels, supplementation of GAA to plant-based diets or those including PBPM has the potential to improve growth performance in broilers.
1st workshop on human factors and activity recognition in healthcare, wellness and assisted living: recognise2interact

Context-aware systems have the potential to revolutionize the way humans interact with information technology. The first workshop on Human Factors and Activity Recognition in Healthcare, Wellness and Assisted Living (Recognise2Interact) aims to enable researchers and practitioners from both, Activity Recognition and Human Computer Interaction to interact and bridge the gap between these two fields. The workshop will provide a comprehensive overview on current technological solutions that benefit from the synergy of activity recognition and human computer interaction with particular focus to Healthcare, Wellness and Assisted living applications. The workshop is supported by the iCareNet network.
A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude

Proper function of many physiological processes requires a robust circadian clock. Disruptions of the circadian clock can result in metabolic diseases, mood disorders, and accelerated aging. Therefore, identifying small molecules that specifically modulate regulatory core clock proteins may potentially enable better management of these disorders. In this study, we applied a structure-based molecular-docking approach to find small molecules that specifically bind to the core circadian regulator, the transcription factor circadian locomotor output cycles kaput (CLOCK). We identified 100 candidate molecules by virtual screening of ∼2 million small molecules for those predicted to bind closely to the interface in CLOCK that interacts with its transcriptional co-regulator, Brain and muscle Arnt-like protein-1 (BMAL1). Using a mammalian two-hybrid system, real-time monitoring of circadian rhythm in U2OS cells, and various biochemical assays, we tested these compounds experimentally and found one, named CLK8, that specifically bound to and interfered with CLOCK activity. We show that CLK8 disrupts the interaction between CLOCK and BMAL1 and interferes with nuclear translocation of CLOCK both in vivo and in vitro. Results from further experiments indicated that CLK8 enhances the amplitude of the cellular circadian rhythm by stabilizing the negative arm of the transcription/translation feedback loop without affecting period length. Our results reveal CLK8 as a tool for further studies of CLOCK's role in circadian rhythm amplitude regulation and as a potential candidate for therapeutic development to manage disorders associated with dampened circadian rhythms.
High Diagnostic Accuracy of RT-QuIC Assay in a Prospective Study of Patients with Suspected sCJD

The early and accurate in vivo diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) is essential in order to differentiate CJD from treatable rapidly progressive dementias. Diagnostic investigations supportive of clinical CJD diagnosis include magnetic resonance imaging (MRI), electroencephalogram (EEG), 14-3-3 protein detection, and/or real-time quaking-induced conversion (RT-QuIC) assay positivity in the cerebrospinal fluid (CSF) or in other tissues. The total CSF tau protein concentration has also been used in a clinical setting for improving the CJD diagnostic sensitivity and specificity. We analyzed 182 CSF samples and 42 olfactory mucosa (OM) brushings from patients suspected of having sCJD with rapidly progressive dementia (RPD), in order to determine the diagnostic accuracy of 14-3-3, the total tau protein, and the RT-QuIC assay. A probable and definite sCJD diagnosis was assessed in 102 patients. The RT-QuIC assay on the CSF samples showed a 100% specificity and a 96% sensitivity, significantly higher compared with 14-3-3 (84% sensitivity and 46% specificity) and tau (85% sensitivity and 70% specificity); however, the combination of RT-QuIC testing of the CSF and OM samples resulted in 100% sensitivity and specificity, proving a significantly higher accuracy of RT-QuIC compared with the surrogate biomarkers in the diagnostic setting of patients with RPD. Moreover, we showed that CSF blood contamination or high protein levels might interfere with RT-QuIC seeding. In conclusion, we provided further evidence that the inclusion of an RT-QuIC assay of the CSF and OM in the diagnostic criteria for sCJD has radically changed the clinical approach towards the diagnosis.
Symptom Clusters Change Over Time in Patients With Lung Cancer During Perichemotherapy

Background Lung cancer has become the leading cause of cancer-related deaths in China, and patients often experience multiple symptoms and substantial discomfort. Understanding and managing concurrent symptoms of patients with lung cancer are crucial during perichemotherapy. Objective To determine the types and components of symptom clusters according to the severity dimension and to understand how they change over time during perichemotherapy in a homogeneous population of patients with lung cancer. Methods Patients were recruited using convenience sampling. The Chinese version of the MD Anderson Symptom Inventory and the revised lung cancer module were used to measure multiple symptoms at the following 3 separate points: 2 weeks before chemotherapy (T1), chemotherapy cycle 1 (T2), and chemotherapy cycle 4 (T3). Symptom clusters were identified by exploratory factor analysis. Results A total of 144 patients with non–small cell lung cancer participated in the study. Six symptom clusters were identified at the 3 time points. Among the 6 symptom clusters, 3 symptom clusters remained stable at all time points, and differences were found in symptom clusters before and after chemotherapy. Conclusions Symptom clusters can change during perichemotherapy, showing some stability and differences over time. Implications for Practice An improved understanding of symptom cluster trajectories in patients with lung cancer may facilitate effective assessment, prevention, and management of multiple concurrent symptoms. These findings will help clinicians to develop predictive interventions and reduce the symptom burden of patients undergoing chemotherapy.
The clinical significance of the retromolar canal and foramen in dentistry

The mandibular canal is nowadays acknowledged as a major trunk with multiple smaller branches running roughly parallel to it. Most of these accessory canals contain branches of the inferior alveolar neurovascular bundle that supplies the dentition, jawbone, and soft tissue around the gingiva and lower lip. This article reviews the prevalence, classification and morphometric measurements of the retromolar canal and its aperture. A retromolar canal is a bifid variation of the mandibular canal that divides from above this main canal, and travels anterosuperiorly within the bone to exit via a single foramen or multiple foramina into the retromolar fossa. This foramen, termed the retromolar foramen, allows accessory branches of the inferior alveolar neurovascular bundles to supply tissues at the retromolar trigone. Clinically, it is of the utmost importance to determine the exact location of the mandibular canal and to identify its retromolar accessory branches when surgery in the posterior mandible is to be performed.
The Genome of Setaria digitata: A Cattle Nematode Closely Related to Human Filarial Parasites

Abstract Here we present the draft genome sequence of Setaria digitata, a parasitic nematode affecting cattle. Due to its similarity to Wuchereria bancrofti, the parasitic nematode that causes lymphatic filariasis in humans, S. digitata has been used as a model organism at the genomic level to find drug targets which can be used for the development of novel drugs and/or vaccines for human filariasis. Setaria digitata causes cerebrospinal nematodiasis in goats, sheep, and horses posing a serious threat to livestock in developing countries. The genome sequence of S. digitata will assist in finding candidate genes to use as drug targets in both S. digitata and W. bancrofti. The assembled draft genome is ∼90 Mb long and contains 8,974 genomic scaffolds with a G+C content of 31.73%.
Contemporary Speech and Oral Language Care for Deaf and Hard-of-Hearing Children Using Hearing Devices

Contemporary speech and language interventions are not limited to disabilities but embrace the pragmatics of communication behaviors from the perspective of functional social participation. Accordingly, current speech and language therapies for deaf and hard-of-hearing children include a broad spectrum of approaches and techniques. This paper explores contemporary approaches and techniques for speech and oral language interventions for deaf and hard-of-hearing children using hearing devices, evidence of efficacy and how they are implemented in diverse clinical practices.
Gestational risk factors and childhood cancers: A cohort study in Taiwan

Gestational risk factors such as birth weight, gestational age and parity have been repeatedly found to be related to pediatric cancers, but few reports have emerged from Asian countries. Here we report on demographic and gestational factors in a Taiwanese cohort. Our study included all children born in Taiwan 2004–2014 for whom there was a birth record (n = 2,079,037), of which 1900 children had been diagnosed with cancer prior to age 12. We conducted multivariable hazard regression to examine associations between demographic and gestational factors with cancer. Greater parity (family with 2+ older children) was related to acute myeloid leukemia [Hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.31, 3.55), central nervous system tumors (HR = 1.67, CI: 1.13, 2.48) and neuroblastoma (HR = 1.67, CI: 1.07, 2.63). Hepatoblastoma cases had a higher risk of low birth weight (<2,500 g; HR = 3.01, CI: 1.85, 4.91), very preterm birth (<33 weeks gestation; HR = 13.71, CI: 7.45, 25.23), plural pregnancies (HR = 2.37, CI: 1.10, 5.14) and both small (HR = 2.13, CI: 1.23, 3.67) and large (HR = 1.83, CI: 1.01, 3.32) for gestational age. Germ cell tumors were more common among children born in rural areas (HR = 1.63, CI: 1.02, 2.60). Despite that Taiwan has lower rates of both high and low birthweight compared to other developed nations, we observed several similar associations to those reported in Western Countries. Further research should examine unique exposures in Taiwan that may be contributing to higher incidence of certain cancer types.
Activation of group 2 innate lymphoid cells alleviates aging-associated cognitive decline

Fung et al. show that group 2 innate lymphoid cells (ILC2) accumulate in the choroid plexus (CP) of the aged brain. These aging-associated CP-resident ILC2 exhibit unique functional and molecular properties, and their activation revitalizes the aged brain and alleviates aging-associated cognitive decline.
The role of platelet function analyzer-200 in predicting perioperative bleeding risk

Background/Aims Various preoperative screening tests, such as platelet count, prothrombin time, activated partial thromboplastin time, and bleeding time, have been widely used to evaluate the risk of bleeding during surgery. Use of platelet function analyzer (PFA)-100/200 for assessing platelet function instead of bleeding time is increasing. However, its role in predicting the perioperative risk of bleeding remains controversial. Methods Data of 703 patients who underwent surgery under general anesthesia were retrospectively analyzed. Preoperative platelet function was measured using PFA-200 system and the association with intraoperative bleeding was assessed. Additionally, other variables that could affect PFA-200 results were assessed by logistic regression analysis. Results Collagen/epinephrine (COL/EPI) test was prolonged in 199/703 (28.3%) patients (EPI group), while 99/212 (46.7%) patients showed COL/adenosine diphosphate test abnormalities. Bleeding over 300 mL during surgery occurred in 14.3% and 20.1% of patients in the normal and EPI groups, respectively (p = 0.058). In addition, red blood cell transfusion within 72 hours after surgery rate was significantly higher in the EPI group than in the normal group (31.7% vs. 23.4%, p = 0.024). In multivariate logistic analysis, prolongation closure time with COL/EPI (p = 0.068) was marginally associated with risk of bleeding during surgery. Furthermore, PFA-200 results were influenced by various factors, such as nonsteroidal anti-inflammatory drug use, blood group, hematocrit, and time of blood collection. Conclusions Preoperative PFA-200 test may be helpful in predicting the risk of perioperative bleeding. However, its results should be carefully interpreted because they are affected by several factors.
Clinical impact of frailty among patients with severe vital sign derangement: An observational study

Frailty is associated with increased morbidity and mortality and frail patients may have reduced ability to tolerate severe vital sign derangement such as estimated by a high National Early Warning Score (NEWS). The clinical impact of frailty among patients that develop high NEWS during hospital admissions is sparsely studied. The aim of this study was to investigate the association between clinical frailty and admission to intensive care unit (ICU) among these patients.
Sporadic desmoid-type fibromatosis: a stepwise approach to a non-metastasising neoplasm-a position paper from the Italian and the French Sarcoma Group.

Desmoid-type fibromatosis (DF) is a rare locally aggressive monoclonal proliferation of myofibroblasts lacking metastatic capacity. It may be observed in nearly every part of the body. Considering the variable clinical presentations, anatomic locations, and biologic behaviors, an individualized treatment approach is required. The pathogenesis of DF is not completely understood even if a high prevalence (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the Wnt/&bgr;-catenin pathway. No established and evidence-based approach for the treatment of this neoplasm is available as of today. Considering the unpredictable behavior and the heterogeneity of this disease, we propose a treatment algorithm approved by the French and the Italian Sarcoma Group, based on a front-line wait and see approach and subsequent therapy in the case of progression. A careful counseling at a referral center is mandatory and should be offered to all patients affected by sporadic DF from the time of their diagnosis.