Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, ...we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
•European tree species exhibited increasing flowering intensities in last 66 years.•Flowering synchrony increased in time and decreases spatially between species.•GAMLSS model explained flowering ...well with weather cues and provenances.•Previous flowering significantly influenced flowering intensities in most species.•Flower masting regulated by sufficient resource and prevailing optimal climate.
Mast flowering and seeding is a well-known reproductive strategy of tree species with many ecological consequences regulating synchronous year-to-year flowering intensity variations at the population level. In contrast to flowering timing, the effects of climate change on flowering intensity across space, time, and species are largely unexplored. In this study, a long-term data set on flowering intensities for eight common tree species (Alnus glutinosa, Fagus sylvatica, Larix decidua, Picea abies, Pinus sylvestris, Pseudotsuga menziesii, Quercus petraea, and Quercus robur) in Germany was reassembled to analyse flowering mechanisms and strategies by applying GAMLSS (Generalised Additive Models for Location Scale and Shape) models together with climatic data (temperature, precipitation, and drought) and various time-lagged effects. All species showed increasing flowering intensities in the period 1954–2019. The flowering intensity of Larix and Pinus differed significantly across their respective ecological provenances. Time series revealed higher synchrony among broadleaf than conifer species, although correlation coefficients of both their flowering intensities generally increased over time. GAMLSS modelling mainly explained flowering intensities well, with R2 ranging between 0.58 (Pseudotsuga) and 0.25 (Alnus). Flowering intensity of almost all species was significantly influenced by flowering in previous years, indicating autocorrelative influences pointing to resource depletion and accumulation. Growing season temperature was modelled to be the main factor among weather cues, with the general pattern of flower masting being correlated negatively with temperature two years before masting and positively with temperature one year before masting. In addition, the short-term drought estimated by Standardised Precipitation-Evapotranspiration Index (12 months) increased flowering intensity in almost all cases. Therefore, it can be inferred that the heavy flowering of European common tree species has been regulated by sufficient resources and prevailing optimal climatic conditions.
Depression and substance use (SU) disorders are prevalent among people with HIV (PWH) and impact health outcomes despite successful antiretroviral therapy (ART). We explored quality of life, ...functional ability and associated factors among PWH screened positive for depression and/or SU.
This cross-sectional study recruited adult PWH during routine follow-up at five HIV clinical sites in the Asia-Pacific region. Participants were screened for depression using Patient Health Questionnaire-9 and SU using Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). Quality of life (QoL) was assessed with WHOQOL-HIV BREF and functional ability with World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Factors associated with mean QoL and disability scores were analysed using linear regression.
Of 864 PWH enrolled, 753 screened positive for depression or SU. The median (interquartile range, IQR) age was 38 (31-47) years and 97% were on ART. Overall mean WHOQOL-HIV BREF and WHODAS scores indicated greater impairment with increasing depressive symptom severity and SU risk. In multivariate analysis, PWH reporting previous trauma/stress (difference = 2.7, 95% confidence interval CI 1.5-3.9, P < 0.001) and past mental health diagnosis (difference = 5.0, 95% CI 2.9-7.1, P < 0.001) were associated with greater disability and poorer QoL scores across multiple domains ( P < 0.01 for all). Higher CD4 T-cell counts was also associated with better QoL scores and functional ability.
PWH with depression/SU experienced poorer QoL and function despite routine engagement in HIV care. Efforts to integrate mental health services and interventions addressing disability into HIV management should be prioritized in the region.
The trueness and precision of clinical laboratory results are ensured through total quality management systems (TQM), which primarily include internal quality control (IQC) practices. However, ...quality practices vary globally. To understand the current global state of IQC practice and IQC management in relation to TQM the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on Global Laboratory Quality (TF-GLQ) conducted a survey of IFCC member countries on IQC practices and management.
The survey included 16 questions regarding IQC and laboratory TQM practices and was distributed to IFCC full and affiliate member countries (n=110). A total of 46 (41.8 %) responses were received from all regions except North America.
Of the responding countries, 78.3 % (n=36) had legislative regulations or accreditation requirements governing medical laboratory quality standards. However, implementation was not mandatory in 46.7 % (n=21) of responding countries. IQC practices varied considerably with 57.1 % (n=28) of respondents indicating that they run 2 levels of IQC, 66.7 % (n=24) indicating they run IQC every 24 h and 66.7 % (n=28) using assay manufacturer IQC material sources. Only 29.3 % (n=12) of respondents indicated that every medical laboratory in their country has written IQC policies and procedures. By contrast, 97.6 % (n=40) of responding countries indicated they take corrective action and result remediation in the event of IQC failure.
The variability in TQM and IQC practices highlights the need for more formal programs and education to standardize and improve TQM in medical laboratories.
The recent global crisis has had a profound and widespread impact on humanity, eliciting a heightened appreciation for the importance of prosociality. In response, interdisciplinary scholars have ...called for further research to investigate strategies for cultivating kindness, generosity, and cooperation. To answer this call, we conducted a study examining the potential prosocial impact of online social interactions (OSIs) in two distinct cultures. Through a survey of 644 emerging adults from China and the United States, we found that OSIs positively led to prosocial tendencies in both samples, with social connectedness and trust serving as significant mediating factors. Nevertheless, among the American sample, trust can serve as the sole mediator linking OSIs and prosocial tendencies. Conversely, among the Chinese sample, the development of prosociality stemming from OSIs requires the intervening facilitation of social connectedness. This divergence may speak to cultural research regarding the essential role of interpersonal relationships in fostering trust and prosociality in collectivist societies. This study contributes to prosociality scholarship by highlighting the role of OSIs as a crucial enhancer across two distinct cultures, clarifying the underlying mechanisms, and identifying cultural differences in the process of prosocial development. The results have implications for both prosocial theory and practice.
Epidemiological studies of obesity, Type-2 diabetes (T2D), cardiovascular diseases and several common cancers have revealed an increased risk in Native Hawaiians compared to European- or ...Asian-Americans living in the Hawaiian islands. However, there remains a gap in our understanding of the genetic factors that affect the health of Native Hawaiians. To fill this gap, we studied the genetic risk factors at both the chromosomal and sub-chromosomal scales using genome-wide SNP array data on ~4,000 Native Hawaiians from the Multiethnic Cohort. We estimated the genomic proportion of Native Hawaiian ancestry ("global ancestry," which we presumed to be Polynesian in origin), as well as this ancestral component along each chromosome ("local ancestry") and tested their respective association with binary and quantitative cardiometabolic traits. After attempting to adjust for non-genetic covariates evaluated through questionnaires, we found that per 10% increase in global Polynesian genetic ancestry, there is a respective 8.6%, and 11.0% increase in the odds of being diabetic (P = 1.65×10-4) and having heart failure (P = 2.18×10-4), as well as a 0.059 s.d. increase in BMI (P = 1.04×10-10). When testing the association of local Polynesian ancestry with risk of disease or biomarkers, we identified a chr6 region associated with T2D. This association was driven by an uniquely prevalent variant in Polynesian ancestry individuals. However, we could not replicate this finding in an independent Polynesian cohort from Samoa due to the small sample size of the replication cohort. In conclusion, we showed that Polynesian ancestry, which likely capture both genetic and lifestyle risk factors, is associated with an increased risk of obesity, Type-2 diabetes, and heart failure, and that larger cohorts of Polynesian ancestry individuals will be needed to replicate the putative association on chr6 with T2D.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bsister genes have been identified as the closest relatives of class B floral homeotic genes. Previous studies have shown that Bsister genes from eudicots are involved in cell differentiation during ...ovule and seed development. However, the complete function of Bsister genes in eudicots is masked by redundancy with other genes and little is known about the function of Bsister genes in monocots, and about the evolution of Bsister gene functions. Here we characterize OsMADS29, one of three MADS-box Bsister genes in rice. Our analyses show that OsMADS29 is expressed in female reproductive organs including the ovule, ovule vasculature, and the whole seed except for the outer layer cells of the pericarp. Knock-down of OsMADS29 by double-stranded RNA-mediated interference (RNAi) results in shriveled and/or aborted seeds. Histological analyses of the abnormal seeds at 7 days after pollination (DAP) indicate that the symplastic continuity, including the ovular vascular trace and the nucellar projection, which is the nutrient source for the filial tissue at early development stages, is affected. Moreover, degeneration of all the maternal tissues in the transgenic seeds, including the pericarp, ovular vascular trace, integuments, nucellar epidermis and nucellar projection, is blocked as compared to control plants. Our results suggest that OsMADS29 has important functions in seed development of rice by regulating cell degeneration of maternal tissues. Our findings provide important insights into the ancestral function of Bsister genes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide ...association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We conducted a study to investigate the effect of different levels of dietary highly unsaturated fatty acids (HUFAs) on tissue fatty acid profiles and reproductive performance in female zebrafish. In ...addition, the mRNA expression of desaturase and elongase genes in liver, muscle and ovarian tissues were also analysed. Three
iso-nitrogenous experimental diets utilizing different ratios of squid oil and linseed oil which were SO (100% squid oil), SLO (1:1 squid oil:linseed oil) and LO (100% linseed oil) as lipid sources were formulated and fed to female zebrafish for 12 weeks. Spawning was carried out twice weekly during the experimental feeding period. Results showed that fatty acid profiles of liver, muscle, ovary and egg reflected profiles of the corresponding dietary treatment. In general, increasing levels of dietary linseed oil lowered deposition of docosahexaenoic acid (DHA, 22:6
n-3), eicosapentaenoic acid (EPA, 20:5
n-3) and arachidonic acid (ARA, 20:4
n-6) in all tissues. Liver fatty acid profile implied increasing biosynthesis activities during feeding of low dietary HUFA diets, which was supported by increased expression of hepatic desaturase and elongase mRNAs. However, the increased HUFA biosynthesis activities were unable to compensate for the inferior hepatic ARA, EPA and DHA levels of fish fed diet LO. In muscle and ovary tissues, relatively lower concentrations of ARA and EPA were also obtained with diet LO. There was no significant difference in EPA and ARA levels in eggs, which imply accumulation of EPA and ARA in eggs. We also showed an increasing trend of ovarian desaturase and elongase gene expression during low dietary HUFA levels. Highest egg production and hatching rate was obtained with diet SLO, which strongly suggests the need for both inclusion and balanced ratio of dietary
n-3 and
n-6 unsaturated fatty acids by spawning females. Collectively, this study shows that female zebrafish reproduction benefits from the supply of dietary HUFA during reproductive stages, despite possessing ability to increase transcription of desaturase and elongase in various tissues during low dietary HUFA intake.
Clinical laboratory results are required for critical medical decisions, underscoring the importance of quality results. As part of total quality management, external quality assessment (EQA) is a ...vital component to ensure laboratory accuracy. The goal of this survey was to evaluate the current status of global laboratory quality systems and assess the need for implementation, expansion, or harmonization of EQA programs (EQAP) for Clinical Chemistry and Laboratory Medicine.
The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on Global Laboratory Quality (TF-GLQ) conducted a survey of IFCC full and affiliate members (n=110) on laboratory quality practice. A total of 41 (37.3%) countries representing all IFCC regions except North America provided responses about EQA availability and practices.
All 41 countries perform EQA, 38 reported that their laboratories had EQA policies and procedures, and 39 further act/evaluate unacceptable EQA results. 39 countries indicated they have international and/or national EQAP and 30 use alternative performance assessments. EQA frequency varied among countries. Generally, an EQAP provided the EQA materials (40/41) with four countries indicating that they did not have an EQAP in their country.
Globally, most laboratories participate in an EQAP and have defined quality procedures for EQA. There remain gaps in EQA material availability and implementation of EQA as a part of a total laboratory quality system. This survey highlights the need for education, training, and harmonization and will guide efforts of the IFCC TF-GLQ in identifying areas for enhancing global laboratory quality practices.
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