The aberrant hypermethylation of BRCA1 promoter CpG islands induces the decreased expression of BRCA1 (Breast Cancer 1) protein. It can be detected in sporadic breast cancer without BRCA1 pathogenic variants, particularly in triple-negative breast cancers (TNBC). We investigated BRCA1 hypermethylation status (by methylation-specific polymerase chain reaction (MS-PCR) and MassARRAY® assays), and BRCA1 protein expression using immunohistochemistry (IHC), and their clinicopathological significance in 248 chemotherapy-naïve TNBC samples. Fifty-five tumors (22%) exhibited BRCA1 promoter hypermethylation, with a high concordance rate between MS-PCR and MassARRAY® results. Promoter hypermethylation was associated with reduced IHC BRCA1 protein expression (p = 0.005), and expression of Programmed death-ligand 1 protein (PD-L1) by tumor and immune cells (p = 0.03 and 0.011, respectively). A trend was found between promoter hypermethylation and basal marker staining (p = 0.058), and between BRCA1 expression and a basal-like phenotype. In multivariate analysis, relapse-free survival was significantly associated with N stage, adjuvant chemotherapy, and histological subtype. Overall survival was significantly associated with T and N stage, histology, and adjuvant chemotherapy. In addition, patients with tumors harboring BRCA1 promoter hypermethylation derived the most benefit from adjuvant chemotherapy. In conclusion, BRCA1 promoter hypermethylation is associated with TNBC sensitivity to adjuvant chemotherapy, basal-like features and PD-L1 expression. BRCA1 IHC expression is not a good surrogate marker for promoter hypermethylation and is not independently associated with prognosis. Association between promoter hypermethylation and sensitivity to Poly(ADP-ribose) polymerase PARP inhibitors needs to be evaluated in a specific series of patients.

Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the effects of H3R antagonist E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) were evaluated on the course of kindling development, kindling-induced memory deficit, oxidative stress levels (glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)), various brain neurotransmitters (histamine (HA), acetylcholine (ACh), γ-aminobutyric acid (GABA)), and glutamate (GLU), acetylcholine esterase (AChE) activity, and c-Fos protein expression in pentylenetetrazole (PTZ, 40 mg/kg) kindled rats. E177 (5 and 10 mg/kg, i.p.) significantly decreased seizure score, increased step-through latency (STL) time in inhibitory avoidance paradigm, and decreased transfer latency time (TLT) in elevated plus maze (all P < 0.05). Moreover, E177 mitigated oxidative stress by significantly increasing GSH, CAT, and SOD, and decreasing the abnormal level of MDA (all P < 0.05). Furthermore, E177 attenuated elevated levels of hippocampal AChE, GLU, and c-Fos protein expression, whereas the decreased hippocampal levels of HA and ACh were modulated in PTZ-kindled animals (all P < 0.05). The findings suggest the potential of H3R antagonist E177 as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment, highlighting the H3Rs as a potential target for the therapeutic management of epilepsy with accompanied memory deficits.

Satellite-based actual evapotranspiration (ETa) is becoming increasingly reliable and available for various water management and agricultural applications from water budget studies to crop performance monitoring. The Operational Simplified Surface Energy Balance (SSEBop) model is currently used by the US Geological Survey (USGS) Famine Early Warning System Network (FEWS NET) to routinely produce and post multitemporal ETa and ETa anomalies online for drought monitoring and early warning purposes. Implementation of the global SSEBop using the Aqua satellite's Moderate Resolution Imaging Spectroradiometer (MODIS) land surface temperature and global gridded weather datasets is presented. Evaluation of the SSEBop ETa data using 12 eddy covariance (EC) flux tower sites over six continents indicated reasonable performance in capturing seasonality with a correlation coefficient up to 0.87. However, the modeled ETa seemed to show regional biases whose natures and magnitudes require a comprehensive investigation using complete water budgets and more quality-controlled EC station datasets. While the absolute magnitude of SSEBop ETa would require a one-time bias correction for use in water budget studies to address local or regional conditions, the ETa anomalies can be used without further modifications for drought monitoring. All ETa products are freely available for download from the USGS FEWS NET website.

In this study, a head-mounted device was developed to track the gaze of the eyes and estimate the gaze point on the user's visual plane. To provide a cost-effective vision tracking solution, this head-mounted device is combined with a sized endoscope camera, infrared light, and mobile phone; the devices are also implemented via 3D printing to reduce costs. Based on the proposed image pre-processing techniques, the system can efficiently extract and estimate the pupil ellipse from the camera module. A 3D eye model was also developed to effectively locate eye gaze points from extracted eye images. In the experimental results, average accuracy, precision, and recall rates of the proposed system can achieve an average of over 97%, which can demonstrate the efficiency of the proposed system. This study can be widely used in the Internet of Things, virtual reality, assistive devices, and human-computer interaction applications.

Although mTOR inhibitors have been approved as first-line therapy for treating metastatic clear cell renal cell carcinoma (ccRCC), the lack of useful markers reduces their therapeutic effectiveness. The objective of this study was to estimate if inositol monophosphatase 2 (IMPA2) downregulation refers to a favorable outcome in metastatic ccRCC receiving mTOR inhibitor treatment. Gene set enrichment analysis predicted a significant activation of mTORC1 in the metastatic ccRCC with IMPA2 downregulation. Transcriptional profiling of IMPA2 and mTORC1-related gene set revealed significantly inverse correlation in ccRCC tissues. Whereas the enforced expression of exogenous IMPA2 inhibited the phosphorylation of Akt/mTORC1, artificially silencing IMPA2 led to increased phosphorylation of Akt/mTORC1 in ccRCC cells. The pharmaceutical inhibition of mTORC1 activity by rapamycin reinforced autophagy initiation but suppressed the cellular migration and lung metastatic abilities of IMPA2-silenced ccRCC cells. In contrast, blocking autophagosome formation with 3-methyladenine rescued the mitigated metastatic potential in vitro and in vivo in IMPA2-overexpressing ccRCC cells. Our findings indicated that IMPA2 downregulation negatively activates mTORC1 activity and could be a biomarker for guiding the use of mTOR inhibitors or autophagy inducers to combat metastatic ccRCC in the clinic.

Despite initial chemotherapy response, ovarian cancer is the deadliest gynecologic cancer, due to frequent relapse and onset of drug resistance. To date, there is no affordable diagnostic/prognostic biomarker for early detection of the disease. However, it has been recently shown that high grade serous ovarian cancers show peculiar oxidative metabolism, which is in turn responsible for inflammatory response and drug resistance. The molecular chaperone TRAP1 plays pivotal roles in such metabolic adaptations, due to the involvement in the regulation of mitochondrial respiration. Here, we show that platinum-resistant ovarian cancer cells also show reduced cholesterol biosynthesis, and mostly rely on the uptake of exogenous cholesterol for their needs. Expression of FDPS and OSC, enzymes involved in cholesterol synthesis, are decreased both in drug-resistant cells and upon TRAP1 silencing, whereas the expression of LDL receptor, the main mediator of extracellular cholesterol uptake, is increased. Strikingly, treatment with statins to inhibit cholesterol synthesis reduces cisplatin-induced apoptosis, whereas silencing of LIPG, an enzyme involved in lipid metabolism, or withdrawal of lipids from the culture medium, increases sensitivity to the drug. These results suggest caveats for the use of statins in ovarian cancer patients and highlights the importance of lipid metabolism in ovarian cancer treatment.

A previous study indicated that mutations in the transmembrane protease serine 3 (TMPRSS3) gene, which encodes a transmembrane serine protease, cause nonsyndromic hearing loss (NSHL). This was the first description of a serine protease involved in hearing loss (HL). In Taiwan, however, data on the TMPRSS3 gene's association with NSHL is still insufficient. In this study, we described 10 mutations of TMPRSS3 genes found in 14 patients after screening 230 children with NSHL. The prevalence of the TMPRSS3 mutation appeared to be 6.09% (14/230). Of the 10 mutations, three were missense mutations: c.239G>A (p.R80H), c.551T>C (p.L184S), and 1253C>T (p.A418V); three were silent mutations, and four were mutations in introns. To determine the functional importance of TMPRSS3 mutations, we constructed plasmids carrying TMPRSS3 mutations of p.R80H, p.L184S, and p.A418V. TMPRSS3 function can be examined by secretory genetic assay for site-specific proteolysis (sGASP) and Xenopus oocyte expression system. Our results showed that p.R80H, p.L184S, and p.A418V TMPRSS3 mutations gave ratios of 19.4%, 13.2%, and 27.6%, respectively, via the sGASP system. Moreover, these three TMPRSS3 mutations failed to activate the epithelial sodium channel (ENaC) in the Xenopus oocyte expression system. These results indicate that the p.R80H, p.L184S, and p.A418V missense mutations of TMPRSS3 resulted in greatly diminishing the proteolytic activity of TMPRSS3. Our study provides information for understanding the importance of TMPRSS3 in the NSHL of Taiwanese children and provides a novel molecular explanation for the role of TMPRSS3 in HL.

Urban infrastructure systems responsible for the provision of energy, transportation, shelter, and communication to populations are important determinants of health and health equity. The term "smart city" has been used synonymously with other terms, such as "digital city", "sustainable city", and "information city", even though definitional distinctions exist between terms. In this review, we use "smart cities" as a catch-all term to refer to an emerging concept in urban governance practice and scholarship that has been increasingly applied to achieve public health aims. The objective of this systematic review was to document and analyze the inclusion of equity considerations and dimensions (i.e., a measurement, analytical, or dialectical focus on systematic disparities in health between groups) in smart city interventions aimed to improve human health and well-being. Systematic searches were carried out in the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Psychological Information Database (PsycINFO), the PubMed database from the National Center for Biotechnology Information, Elsevier's database Scopus, and Web of Science, returning 3219 titles. Ultimately, 28 articles were retained, assessed, and coded for their inclusion of equity characteristics using the Cochrane PROGRESS-Plus tool (referring to (P) place of residence, (R) race, (O) occupation, (G) gender, (R) religion, (E) education, (S) socio-economic status (SES), and (S) social capital). The most frequently included equity considerations in smart city health interventions were place of residence, SES, social capital, and personal characteristics; conversely, occupation, gender or sex, religion, race, ethnicity, culture, language, and education characteristics were comparatively less featured in such interventions. Overall, it appears that most of intervention evaluations assessed in this review are still in the early testing phases, and thus did not include or feature robust evaluative designs or commercially available technologies.

casper has been a widely used transparent mutant of zebrafish. It possesses a combined loss of reflective iridophores and light-absorbing melanophores, which gives rise to its almost transparent trunk throughout larval and adult stages. Nevertheless, genomic causal mutations of this transparent phenotype are poorly defined. To identify the potential genetic basis of this fascinating morphological phenotype, we constructed genome maps by performing genome sequencing of 28 zebrafish individuals including wild-type AB strain, roy orbison (roy), and casper mutants. A total of 4.3 million high-quality and high-confidence homozygous single nucleotide polymorphisms (SNPs) were detected in the present study. We also identified a 6.0-Mb linkage disequilibrium block specifically in both roy and casper that was composed of 39 functional genes, of which the mpv17 gene was potentially involved in the regulation of iridophore formation and maintenance. This is the first report of high-confidence genomic mutations in the mpv17 gene of roy and casper that potentially leads to defective splicing as one major molecular clue for the iridophore loss. Additionally, comparative transcriptomic analyses of skin tissues from the AB, roy and casper groups revealed detailed transcriptional changes of several core genes that may be involved in melanophore and iridophore degeneration. In summary, our updated genome and transcriptome sequencing of the casper and roy mutants provides novel genetic clues for the iridophore loss. These new genomic variation maps will offer a solid genetic basis for expanding the zebrafish mutant database and in-depth investigation into pigmentation of animals.

Brassica vegetables and their components, the glucosinolates, have been suggested as good candidates as dietary coadjutants to improve health in non-communicable diseases (NCDs). Different preclinical and clinical studies have been performed in the last decade; however, some concerns have been posed on the lack of established and standardized protocols. The different concentration of bioactive compounds used, time of intervention or sample size, and the lack of blinding are some factors that may influence the studies' outcomes. This review aims to analyze the critical points of the studies performed with Brassica-related biomolecules and propose some bases for future trials in order to avoid biases.

The article is the product of the study "Development of innovative resources to improve logical-mathematical skills in primary school, through educational robotics", developed during the 2019 school year in three public schools in the province of Chiriquí, Republic of Panama. The teaching-learning process in students is influenced by aspects inside and outside the classroom, since not all schools have the necessary resources to deliver content or teaching material. The general objective of the project is to design, develop and implement educational robotics to improve logical-mathematical skills aimed at preschool and first grade students in public schools, using programmable educational robots. For this, a set of resources and activities were developed to improve the logical-mathematical skills of the initial stages, in public schools, obtaining significant results. Playful activities favor the teaching-learning process. Considering the analysis of the results made on the data obtained through the applied collection instruments, it can be argued that in general terms the values indicate that the students obtained a favorable level of performance in the different challenges proposed. The project has allowed the academic community to have an application of great value that allows teaching about the conservation of natural sites. The project only covers the area of mathematics in preschool and first grade.

To assess and compare dietpractices, body mass index (BMI), and oral health-related quality of life (OHRQoL) in adults with and without periodontitis.

The paper presented the methodology for the construction of a soft sensor used for activated sludge bulking identification. Devising such solutions fits within the current trends and development of a smart system and infrastructure within smart cities. In order to optimize the selection of the data-mining method depending on the data collected within a wastewater treatment plant (WWTP), a number of methods were considered, including: artificial neural networks, support vector machines, random forests, boosted trees, and logistic regression. The analysis conducted sought the combinations of independent variables for which the devised soft sensor is characterized with high accuracy and at a relatively low cost of determination. With the measurement results pertaining to the quantity and quality of wastewater as well as the temperature in the activated sludge chambers, a good fit can be achieved with the boosted trees method. In order to simplify the selection of an optimal method for the identification of activated sludge bulking depending on the model requirements and the data collected within the WWTP, an original system of weight estimation was proposed, enabling a reduction in the number of independent variables in a model-quantity and quality of wastewater, operational parameters, and the cost of conducting measurements.

The hepatitis B virus (HBV) regulatory HBx protein is required for infection, and its binding to cellular damaged DNA binding protein 1 (DDB1) is critical for this function. DDB1 is an adaptor protein for the cullin 4A Really Interesting New Gene (RING) E3 ubiquitin ligase (CRL4) complex and functions by binding cellular DDB1 cullin associated factor (DCAF) receptor proteins that recruit substrates for ubiquitination and degradation. We compared the proteins found in the CRL4 complex immunoprecipitated from uninfected versus HBV-infected hepatocytes from human liver chimeric mice for insight into mechanisms by which HBV and the cell interact within the CRL4 complex. Consistent with its role as a viral DCAF, HBx was found in the HBV CRL4 complexes. In tissue culture transfection experiments, we showed that HBx expression led to decreased levels of known restriction factor structural maintenance of chromosomes protein 6 (SMC6) and putative restriction factors stromal interaction molecule 1 (STIM1, zinc finger E-box binding homeobox 2 (ZEB2), and proteasome activator subunit 4 (PSME4). Moreover, silencing of these proteins led to increased HBV replication in the HepG2-sodium taurocholate cotransporting polypeptide (NTCP) infection model. We also identified cellular DCAF receptors in CRL4 complexes from humanized mice. Increasing amounts of HBx did not reveal competitive DCAF binding to cullin4 (CUL4)-DDB1 in plasmid-transfected cells. Our results suggest a model in which HBx benefits virus replication by directly or indirectly degrading multiple cellular restriction factors.

The present study aimed to determine the role of Salvia hispanica L., (chia seed) fatty acid content in adipocyte lipid accumulation and human macrophage immunoregulatory potential. Chia seed fatty acid was extracted using hexane by the cold percolation method. A gas chromatography-mass spectrometry (GC-MS) analysis showed a 3:1 ratio of omega 3 and omega 6 fatty acid composition and it was more beneficial for human health. We treated it with increasing concentrations (0-6.4 μg/mL) of chia seed fatty acid extract to determine the cytotoxicity on the preadipocytes and macrophage; no significant cytotoxicity was observed. Chia seed, in 0.2 and 0.4 μg/mL doses, significantly arrested adipocyte hypertrophy and macrophage foam cell development. The gene expression levels of adipocyte confirmed the increased expression of adipocyte mitochondrial thermogenesis related genes, such as uncoupling protein-1 (UCP-1), peroxisome proliferator activated receptor gamma coactivator 1 alpha (PPARγC1α) and PR domain containing 16 (PRDM16); and the down regulated expression of the lipid synthesis related gene sterol regulatory element binding of protein-1c (SREBP-1c). In addition, adipogenesis related genes, such as the proliferator activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBPα) expressions, have been down regulated by chia seed treatment. Macrophage treated with chia seed-treated adipocyte condition media significantly inhibited the obesity associated inflammatory genes and protein expression levels, such as monocyte chemo attractant protein-1 (MCP-1), prostaglandins E2, interleukin-6, plasminogen activator inhibitor-1 (PAI-1) and tumor necrosis factor-α (TNF-α). In conclusion, a 3:1 ratio of omega 3 and omega 6 fatty acid composition of chia seed fatty acid content potentially inhibits lipid accumulation, and enhanced fatty acid oxidation, via UCP-1 and PRDM16 expression. Macrophage recruitment to adipocyte and the development of obesity associated inflammation was suppressed by chia seeds.

Anaesthetic drugs are commonly used during the evaluation of laryngeal function in dogs. The aim of this review was to systematically analyse the literature describing the effects of anaesthetic drugs and doxapram on laryngeal motion in dogs and to determine which drug regime provides the best conditions for laryngeal examination. PubMed, Google Scholar, and EMBASE databases were used for the literature search up to November 2019. Relevant search terms included laryngeal motion, anaesthetic drugs and dogs. Studies were scored based on their level of evidence (LoE), according to the Oxford Centre for Evidence-based Medicine, and the quality was assessed using the risk-of-bias tool and SIGN-checklist. In healthy dogs, premedication before laryngeal examination provided better examination conditions and maintained overall adequate laryngeal motion in 83% of the studies. No difference in laryngeal motion between induction drugs was found in 73% of the studies but the effects in dogs with laryngeal paralysis remain largely unknown. Doxapram increased laryngeal motion in healthy dogs without serious side effects, but intubation was necessary for some dogs with laryngeal paralysis. Methodological characteristics varied considerably between studies, including the technique and timing of evaluation, number of assessors, study design, drug dose, combinations, route and speed of administration.

As part of a National Cancer Institute Moonshot P30 Supplement, the Stanford Cancer Center piloted and integrated tobacco treatment into cancer care. This quality improvement (QI) project reports on the process from initial pilot to adoption within 14 clinics. The Head and Neck Oncology Clinic was engaged first in January 2019 as a pilot site given staff receptivity, elevated smoking prevalence, and a high tobacco screening rate (95%) yet low levels of tobacco cessation treatment referrals (<10%) and patient engagement (<1% of smokers treated). To improve referrals and engagement, system changes included an automated "opt-out" referral process and provision of tobacco cessation treatment as a covered benefit with flexible delivery options that included phone and telemedicine. Screening rates increased to 99%, referrals to 100%, 74% of patients were reached by counselors, and 33% of those reached engaged in treatment. Patient-reported abstinence from all tobacco products at 6-month follow-up is 20%. In July 2019, two additional oncology clinics were added. In December 2019, less than one year from initiating the QI pilot, with demonstrated feasibility, acceptability, and efficacy, the tobacco treatment services were integrated into 14 clinics at Stanford Cancer Center.

Expanding agribusiness in Northern Mexico has increased demand for workers from Southern Mexico, with hundreds of thousands migrating for work annually. Extreme temperatures, physical labor, and low fluid consumption place workers at risk for heat strain and dehydration, commonly underreported hazards in the agricultural industry. The objectives of this pilot study were to assess heat exposure and hydration status of a population of migratory agricultural workers in Northern Mexico throughout the grape harvest season. In addition to demographic information, environmental conditions, hydration status, and core body temperatures were collected. The majority listed Chiapas as their home state, nearly half spoke an Indigenous language, and none had completed high school. The wet-bulb globe temperature was significantly higher during the harvest and post-harvest seasons compared to the pre-harvest season. Across the different seasons, the majority were dehydrated post-shift, and mean core body temperature of workers was not significantly different. This project highlights the need for targeted interventions to improve hydration and prevent heat stress in this region. As the number of warm days is expected to rise each year worldwide, it will be increasingly important to engage in practices to protect vulnerable populations, such as migratory agriculture workers.

Previous studies have shown that the use of dietary supplements is associated with the prevention of birth defects, negative pregnancy outcomes and cardiovascular diseases. However, there might be some ethnic disparities in supplement usage suggesting that women who could benefit from it are not frequent users. This study aimed to characterise the use of dietary supplement among Black African and Black Caribbean women living in the United Kingdom (UK). Furthermore, it evaluated possible associations between the use of dietary supplements and health and diet awareness. A total of 262 women self-ascribed as Black African and Black Caribbean living in the UK completed a comprehensive questionnaire on socio-demographic factors, diet, use of supplements and cultural factors. The main outcome variable was the regular use of any type of dietary supplement. Use of vitamin D and/or calcium was also explored. A stepwise logistic regression analysis was applied to identify predictors of regular use of dietary supplements. A total of 33.2% of women reported regular use of any dietary supplements and 16.8% reported use of vitamin D and/or calcium. There were no significant ethnic differences in the use of dietary supplements. Reporting use of the back of food packaging label (odds ratio (OR) 2.21; 95% CI 1.07-4.55); a self-rated healthy diet (OR 2.86; 95% CI 1.19-6.91) and having cardiovascular disease (CVD), hypertension and/or high cholesterol (OR 3.81; 95% CI 1.53-9.49) increased the likelihood of using any dietary supplement. However, having poorer awareness decreased the likelihood (OR 0.94; 95% CI 0.88-0.99) of using any dietary supplement. For the use of vitamin D and/or calcium supplements, the main predictor was having CVD, hypertension and/or high cholesterol (OR 4.43; 95% CI 1.90-10.35). The prevalence of dietary supplement use was low among African and Caribbean women. Thus, awareness of potential benefits of some dietary supplements (e.g., vitamin D) among the Black population should be promoted.

A type lamins are fundamental components of the nuclear lamina. Changes in lamin A expression correlate with malignant transformation in several cancers. However, the role of lamin A has not been explored in osteosarcoma (OS). Here, we wanted to investigate the role of lamin A in normal osteoblasts (OBs) and OS cells. Thus, we studied the expression of lamin A/C in OS cells compared to OBs and evaluated the effects of lamin A overexpression in OS cell lines. We show that, while lamin A expression increases during osteoblast differentiation, all examined OS cell lines express lower lamin A levels relative to differentiated OBs. The condition of low LMNA expression confers to OS cells a significant increase in migration potential, while overexpression of lamin A reduces migration ability of OS cells. Moreover, overexpression of unprocessable prelamin A also reduces cell migration. In agreement with the latter finding, OS cells which accumulate the highest prelamin A levels upon inhibition of lamin A maturation by statins, had significantly reduced migration ability. Importantly, OS cells subjected to statin treatment underwent apoptotic cell death in a RAS-independent, lamin A-dependent manner. Our results show that pro-apoptotic effects of statins and statin inhibitory effect on OS cell migration are comparable to those obtained by prelamin A accumulation and further suggest that modulation of lamin A expression and post-translational processing can be a tool to decrease migration potential in OS cells.