Background Height is an important anthropometric measurement and is associated with many health-related outcomes. Genome-wide association studies (GWASs) have identified hundreds of genetic loci ...associated with height, mainly in individuals of European ancestry. Methods We performed genome-wide association analyses and replicated previously reported GWAS-determined single nucleotide polymorphisms (SNPs) in the Taiwanese Han population (Taiwan Biobank; n = 67,452). A genetic instrument composed of 251 SNPs was selected from our GWAS, based on height and replication results as the best-fit polygenic risk score (PRS), in accordance with the clumping and p-value threshold method. We also examined the association between genetically determined height (PRS.sub.251) and measured height (phenotype). We performed observational (phenotype) and genetic PRS.sub.251 association analyses of height and health-related outcomes. Results GWAS identified 6843 SNPs in 89 genomic regions with genome-wide significance, including 18 novel loci. These were the most strongly associated genetic loci (EFEMP1, DIS3L2, ZBTB38, LCORL, HMGA1, CS, and GDF5) previously reported to play a role in height. There was a positive association between PRS.sub.251 and measured height (p < 0.001). Of the 14 traits and 49 diseases analyzed, we observed significant associations of measured and genetically determined height with only eight traits (p < 0.05/14 + 49). Height was positively associated with body weight, waist circumference, and hip circumference but negatively associated with body mass index, waist-hip ratio, body fat, total cholesterol, and low-density lipoprotein cholesterol (p < 0.05/14 + 49). Conclusions This study contributes to the understanding of the genetic features of height and health-related outcomes in individuals of Han Chinese ancestry in Taiwan. Keywords: Height, Genome-wide association studies, Genetic single nucleotide polymorphisms, Polygenic risk score, Health-related outcomes
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Light switches on the photomorphogenic development of young plant seedlings, allowing young seedlings to acquire photosynthetic capacities and gain survival fitness. Light regulates gene expression ...at all levels of the central dogma, including alternative splicing (AS) during the photomorphogenic development. However, accurate determination of full-length (FL) splicing variants has been greatly hampered by short-read RNA sequencing technologies.
In this study, we adopt PacBio isoform sequencing (Iso-seq) to overcome the limitation of the short-read RNA-seq technologies. Normalized cDNA libraries used for Iso-seq allows for comprehensive and effective identification of FL AS variants. Our analyses reveal more than 30,000 splicing variant models from approximately 16,500 gene loci and additionally identify approximately 700 previously unannotated genes. Among the variants, approximately 12,000 represent new gene models. Intron retention (IR) is the most frequently observed form of variants, and many IR-containing AS variants show evidence of engagement in translation. Our study reveals the formation of heterodimers of transcription factors composed of annotated and IR-containing AS variants. Moreover, transgenic plants overexpressing the IR forms of two B-BOX DOMAIN PROTEINs exhibits light-hypersensitive phenotypes, suggesting their regulatory roles in modulating optimal light responses.
This study provides an accurate and comprehensive portrait of full-length transcript isoforms and experimentally confirms the presence of de novo synthesized AS variants that impose regulatory functions in photomorphogenic development in Arabidopsis.
The ongoing COVID-19 pandemic has caused more than 193,825 deaths during the past few months. A quick-to-be-identified cure for the disease will be a therapeutic medicine that has prior use ...experiences in patients in order to resolve the current pandemic situation before it could become worsening. Artificial intelligence (AI) technology is hereby applied to identify the marketed drugs with potential for treating COVID-19.
An AI platform was established to identify potential old drugs with anti-coronavirus activities by using two different learning databases; one consisted of the compounds reported or proven active against SARS-CoV, SARS-CoV-2, human immunodeficiency virus, influenza virus, and the other one containing the known 3C-like protease inhibitors. All AI predicted drugs were then tested for activities against a feline coronavirus in in vitro cell-based assay. These assay results were feedbacks to the AI system for relearning and thus to generate a modified AI model to search for old drugs again.
After a few runs of AI learning and prediction processes, the AI system identified 80 marketed drugs with potential. Among them, 8 drugs (bedaquiline, brequinar, celecoxib, clofazimine, conivaptan, gemcitabine, tolcapone, and vismodegib) showed in vitro activities against the proliferation of a feline infectious peritonitis (FIP) virus in Fcwf-4 cells. In addition, 5 other drugs (boceprevir, chloroquine, homoharringtonine, tilorone, and salinomycin) were also found active during the exercises of AI approaches.
Having taken advantages of AI, we identified old drugs with activities against FIP coronavirus. Further studies are underway to demonstrate their activities against SARS-CoV-2 in vitro and in vivo at clinically achievable concentrations and doses. With prior use experiences in patients, these old drugs if proven active against SARS-CoV-2 can readily be applied for fighting COVID-19 pandemic.
With the progression of molecular techniques, the detection of circulating plasma DNA (cpDNA) is clinically feasible. However, the role of the cpDNA levels in gastric cancer is not well understood. ...This study assessed the mutational profile in primary tumors and clarified the clinical utility of quantitative and qualitative cpDNA alterations in 277 patients with advanced gastric cancer. The concentrations of cpDNA were measured by TaqMan qPCR, and 68 mutations in 8 genes were studied for cpDNA mutations. The median cpDNA concentrations in patients with stages I, II, and III gastric cancer were 3979, 3390 and 4278 copies/mL, respectively, and increased to 11,380 copies/mL in patients with Stage IV gastric cancer (p < 0.001). Among the 35 patients harboring cpDNA mutations, Stage IV patients (100%) were more likely to display high cpDNA levels than were Stage I (33.3%), II (75%) and III patients (66.7%) (p = 0.037). Patients displaying high cpDNA levels were more likely to experience peritoneal recurrence and exhibited significantly lower 5‐year overall survival rates (39.2% vs. 45.8%, p = 0.039) than did patients displaying low cpDNA levels. Only for late stage (Stages III or IV) gastric cancer, patients harboring cpDNA mutations were more likely to experience vascular invasion (20% vs. 2.4%, p = 0.036) and exhibited a lower 5‐year overall survival rate than did those lacking cpDNA mutations (5.6% vs. 31.5%, p = 0.028). High cpDNA levels are associated with peritoneal recurrence and poor prognosis in patients with advanced gastric cancer; harboring cpDNA mutations is associated with poor prognosis among patients with late stage gastric cancer.
What's new?
Patients whose gastric cancer returns despite curative surgery tend to suffer poor prognosis. According to the authors of this study; however, it may be possible to catch recurrent disease before it reaches advanced stages using circulating plasma (cp) DNA, a blood‐based biomarker. In advanced gastric cancer patients, cpDNA levels were associated with tumor recurrence and initial recurrence pattern, with high cpDNA levels signaling an increased likelihood of peritoneal recurrence versus locoregional or distant recurrence. Primary tumor mutations in cpDNA were linked to reductions in 5‐year survival, suggesting that cpDNA mutational status can predict poor prognosis in late‐stage disease.
Background
Despite recent advances in understanding the pathophysiology of cancer cachexia, prevention/treatment of this debilitating disease remains an unmet medical need.
Methods
We developed an ...integrated, multi‐tiered strategy involving both in vitro and in vivo muscle atrophy platforms to identify traditional Chinese medicine (TCM)‐based anti‐cachectic agents. In the initial screening, we used inflammatory cytokine‐induced atrophy of C2C12 myotubes as a phenotypic screening platform to assess the protective effects of TCMs. The selected TCMs were then evaluated for their abilities to protect Caenorhabditis elegans from age‐related reduction of mobility and contractility, followed by the C‐26 colon adenocarcinoma mouse model of cachexia to confirm the anti‐muscle atrophy effects (body/skeletal muscle weights, fibre size distribution, grip strengths, and serum IL‐6). Transcriptome analysis, quantitative real‐time polymerase chain reaction, and immunoblotting were performed to gain understanding of the potential mechanism(s) by which effective TCM protected against C26 tumour‐induced muscle atrophy.
Results
Of 29 widely used TCMs, Dioscorea radix (DR) and Mu Dan Pi (MDP) showed a complete protection (all P values, 0.0002) vis‐à‐vis C26 conditioned medium control in the myotube atrophy platform. MDP exhibited a unique ability to ameliorate age‐associated decreases in worm mobility, accompanied by improved total body contractions, relative to control (P < 0.0001 and <0.01, respectively), which, however, was not noted with DR. This differential in vivo protective effect between MDP and DR was also confirmed in the C‐26 mouse model. MDP at 1000 mg/kg (MDP‐H) was effective in protecting body weight loss (P < 0.05) in C‐26 tumour‐bearing mice without changing food or water intake, accompanied by the restoration of the fibre size distribution of hindleg skeletal muscles (P < 0.0001) and the forelimb grip strength (P < 0.05). MDP‐treated C‐26‐tumour‐bearing mice were alert, showed normal posture and better body conditions, and exhibited lower serum IL‐6 levels (P = 0.06) relative to vehicle control. This decreased serum IL‐6 was associated with the in vitro suppressive effect of MDP (25 and 50 μg/mL) on IL‐6 secretion into culture medium by C26 cells. RNA‐seq analysis, followed by quantitative real‐time polymerase chain reaction and/or immunoblotting, shows that MDP's anti‐cachectic effect was attributable to its ability to reverse the C‐26 tumour‐induced re‐programming of muscle homoeostasis‐associated gene expression, including that of two cachexia drivers (MuRF1 and Atrogin‐1), in skeletal muscles.
Conclusions
All these findings suggest the translational potential of MDP to foster new strategies for the prevention and/or treatment of cachexia. The protective effect of MDP on other types of muscle atrophy such as sarcopenia might warrant investigations.
This study aimed to explore trends, in 3 periods, in the intake of energy and macronutrients among Taiwanese older adults.
Study subjects were those aged ≥65 years in the Nutrition and Health Survey ...in Taiwan 1999-2000 as well as the surveys in 2005-2008 and 2013-2016. Twenty-four-hour dietary recall data were obtained. This study used the 3 nutrition survey datasets for 1999-2000, 2005-2008, and 2013-2016, including data on the questionnaire, physical examination, and dietary intakes. Each nutrition survey involved the face-to-face household interview, and individual's dietary intake of carbohydrate, fat, and protein (% of energy) was estimated. Subsequently, intake statuses of the three macronutrients were classified into below, meeting, and above intake categories.
In the 2013-2016 survey, approximately 40% of the older adults had a low intake of energy. The prevalence of older adults with a meeting intake of carbohydrate, fat, and protein have increased from the 1999-2000 to 2013-2016 periods. The prevalence of people having a low intake of carbohydrate declined from the 1999-2000 period to the 2013-2016 period. The prevalence of high fat intake in 2013-2016 was approximately 5% higher than that in 1999-2000. In the 2013-2016 period, the prevalence of low intake of carbohydrate, fat, and protein were 25.9, 24.5, and 4.9%, respectively; moreover, the prevalence of high intake of the aforementioned macronutrients were 38.7, 36.2, and 17.6%, respectively.
Our study provides important evidence on the dietary patterns, as well as their changes over time among Taiwanese older adults. Such information would be useful for health policy makers about the burden of unbalanced diet and for nutrition educators on planning nutrition promotion interventions about well-balanced dietary for the older persons.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this study, different probiotics commonly used to produce fermented dairy products were inoculated independently for Chenopodium formosanum Koidz. fermentation. The strain with the highest level ...of antioxidant activity was selected and the fermentation process was further optimized via response surface methodology (RSM). Lactobacillus plantarum BCRC 11697 was chosen because, compared to other lactic acid bacteria, it exhibits increased free radical scavenging ability and can produce more phenolic compounds, DPPH (from 72.6% to 93.2%), and ABTS (from 64.2% to 76.9%). Using RSM, we further optimize the fermentation protocol of BCRC 11697 by adjusting the initial fermentation pH, agitation speed, and temperature to reach the highest level of antioxidant activity (73.5% of DPPH and 93.8% of ABTS). The optimal protocol (pH 5.55, 104 rpm, and 24.4°C) resulted in a significant increase in the amount of phenolic compounds as well as the DPPH and ABTS free radical scavenging ability of BCRC 11697 products. The IC50 of the DPPH and ABTS free radical scavenging ability were 0.33 and 2.35 mg/mL, respectively, and both protease and tannase activity increased after RSM. An increase in lower molecular weight (<24 kDa) protein hydrolysates was also observed. Results indicated that djulis fermented by L. plantarum can be a powerful source of natural antioxidants for preventing free radical-initiated diseases.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Detection of Diatomic Carbon in 2I/Borisov Lin, Hsing Wen; Lee, Chien-Hsiu; Gerdes, D. W. ...
Astrophysical journal. Letters,
02/2020, Letnik:
889, Številka:
2
Journal Article
Recenzirano
Odprti dostop
2I/Borisov is the first-ever observed interstellar comet (and the second detected interstellar object (ISO)). It was discovered on 2019 August 30 and has a heliocentric orbital eccentricity of ∼3.35, ...corresponding to a hyperbolic orbit that is unbound to the Sun. Given that it is an ISO, it is of interest to compare its properties-such as composition and activity-with the comets in our solar system. This study reports low-resolution optical spectra of 2I/Borisov. The spectra were obtained by the MDM Observatory Hiltner 2.4 m telescope/Ohio State Multi-Object Spectrograph (on 2019 October 31.5 and November 4.5, UT). The wavelength coverage spanned from 3700 to 9200 . The dust continuum reflectance spectra of 2I/Borisov show that the spectral slope is steeper in the blue end of the spectrum (compared to the red). The spectra of 2I/Borisov clearly show CN emission at 3880 , as well as C2 emission at both 4750 and 5150 . Using a Haser model to covert the observed fluxes into estimates for the molecular production rates, we find Q(CN) = 2.4 0.2 × 1024 s−1, and Q(C2) = (5.5 0.4) × 1023 s−1 at the heliocentric distance of 2.145 au. Our Q(CN) estimate is consistent with contemporaneous observations, and the Q(C2) estimate is generally below the upper limits of previous studies. We derived the ratio Q(C2)/Q(CN) = 0.2 0.1, which indicates that 2I/Borisov is depleted in carbon-chain species, but is not empty. This feature is not rare for the comets in our solar system, especially in the class of Jupiter-family comets.
It is essential to subculture the cells once cultured cells reach confluence. For this, trypsin is frequently applied to dissociate adhesive cells from the substratum. However, due to the proteolytic ...activity of trypsin, cell surface proteins are often cleaved, which leads to dysregulation of the cell functions.
In this study, a triplicate 2D-DIGE strategy has been performed to monitor trypsin-induced proteome alterations. The differentially expressed spots were identified by MALDI-TOF MS and validated by immunoblotting.
36 proteins are found to be differentially expressed in cells treated with trypsin, and proteins that are known to regulate cell metabolism, growth regulation, mitochondrial electron transportation and cell adhesion are down-regulated and proteins that regulate cell apoptosis are up-regulated after trypsin treatment. Further study shows that bcl-2 is down-regulated, p53 and p21 are both up-regulated after trypsinization.
In summary, this is the first report that uses the proteomic approach to thoroughly study trypsin-induced cell physiological changes and provides researchers in carrying out their experimental design.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The membrane-bound serine proteases prostasin and matriptase and the Kunitz-type protease inhibitors HAI-1 and HAI-2 are all expressed in human skin and may form a tightly regulated proteolysis ...network, contributing to skin pathophysiology. Evidence from other systems, however, suggests that the relationship between matriptase and prostasin and between the proteases and the inhibitors can be context-dependent. In this study the in vivo zymogen activation and protease inhibition status of matriptase and prostasin were investigated in the human skin. Immunohistochemistry detected high levels of activated prostasin in the granular layer, but only low levels of activated matriptase restricted to the basal layer. Immunoblot analysis of foreskin lysates confirmed this in vivo zymogen activation status and further revealed that HAI-1 but not HAI-2 is the prominent inhibitor for prostasin and matriptase in skin. The zymogen activation status and location of the proteases does not support a close functional relation between matriptase and prostasin in the human skin. The limited role for HAI-2 in the inhibition of matriptase and prostasin is the result of its primarily intracellular localization in basal and spinous layer keratinocytes, which probably prevents the Kunitz inhibitor from interacting with active prostasin or matriptase. In contrast, the cell surface expression of HAI-1 in all viable epidermal layers renders it an effective regulator for matriptase and prostasin. Collectively, our study suggests the importance of tissue distribution and subcellular localization in the functional relationship between proteases and protease inhibitors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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