Erlandsenpallesen4012

Post-translational modifications (PTMs) of Cyclin-dependent kinase 5 (CDK5) have emerged as important regulatory mechanisms that modulate cancer development in patients. Though CDK5 is an atypical member of the cyclin-dependent kinase family, its aberrant expression links to cell proliferation, DNA damage response, apoptosis, migration and angiogenesis in cancer. Current studies suggested that, new PTMs on CDK5, including S-nitrosylation, sumoylation, and acetylation, serve as molecular switches to control the kinase activity of CDK5 in the cell. However, a majority of these modifications and their biological significance in cancer remain uncharacterized. In this review, we discussed the role of PTMs on CDK5-mediated signaling cascade, and their possible mechanisms of action in malignant tumors, as well as the challenges and future perspectives in this field. On the basis of the newly identified regulatory signaling pathways of CDK5 related to PTMs, researchers have investigated the cancer therapeutic potential of chemical compounds, small-molecule inhibitors, and competitive peptides by targeting CDK5 and its PTMs. Results of these preclinical studies demonstrated that targeting PTMs of CDK5 yields promising antitumor effects and that clinical translation of these therapeutic strategies is warranted.The congenital disorders of glycosylation (CDG) are a family of metabolic diseases in which glycosylation of proteins or lipids is deficient. GDP-mannose pyrophosphorylase B (GMPPB) mutations lead to CDG, characterized by neurological and muscular defects. Floxuridine concentration However, the genotype-phenotype correlation remains elusive, limiting our understanding of the underlying mechanism and development of therapeutic strategy. Here, we report a case of an individual presenting congenital muscular dystrophy with cerebellar involvement, who presents two heterozygous GMPPB mutations (V111G and G214S). The V111G mutation significantly decreases GMPPB's enzymatic activity. By measuring enzymatic activities of 17 reported GMPPB mutants identified in patients diagnosed with GMPPB-CDG, we discover that all tested GMPPB variants exhibit significantly decreased enzymatic activity. Using a zebrafish model, we find that Gmppb is required for neuronal and muscle development, and further demonstrate that enzymatic activity of GMPPB mutants correlates with muscular and neuronal phenotypes in zebrafish. Taken together, our findings discover the importance of GMPPB enzymatic activity for the pathogenesis of GMPPB-CDG, and shed light for the development of additional indicators and therapeutic strategy.

Artistic gymnastics is a popular Olympic discipline where female athletes compete in four and male athletes in six events with floor exercise having the longest competition duration in Women's and Men's artistic gymnastics (WAG, MAG). To date no valid information on the energetics of floor gymnastics is available although this may be important for specific conditioning programming. This study evaluated the metabolic profile of a simulated floor competition in sub-elite gymnasts.

17 (9 male, 8 female) sub-elite gymnasts aged 22.5 ± 2.6y took part in a floor-training-competition where oxygen uptake was measured during and until 15min post-exercise. Additionally, resting and peak blood lactate concentration after exercise were obtained. The PCr-LA-O

method was used to calculate the metabolic energy and the relative aerobic (W

), anaerobic alactic (W

) and anaerobic lactic (W

) energy contribution. Further, the athletes completed a 30s Bosco-jumping test, a countermovement jump and a drop jump.

The comymnastic specific aerobic training should not be neglected, while a different aerobic share in WAG and MAG strengthens sex-specific conditioning. All in all, the specific metabolic share must secure adequate energy provision, while relative proportions of the two anaerobic pathways seem to depend on training and competition history.

The results show a predominant aerobic energy contribution and a considerable anaerobic contribution with no significant difference between anaerobic shares. Consequently, gymnastic specific aerobic training should not be neglected, while a different aerobic share in WAG and MAG strengthens sex-specific conditioning. All in all, the specific metabolic share must secure adequate energy provision, while relative proportions of the two anaerobic pathways seem to depend on training and competition history.

Ensuring access to health services for all is the main goal of universal health coverage (UHC) plan. Out-of-pocket (OOP) payment still remains the main source of funding for healthcare in Bangladesh. The association between barriers to accessing healthcare and over-reliance on OOP payments has not been explored in Bangladesh using nationally representative household survey data. This study is a novel attempt to examine the burden of OOP payment and forgone healthcare in Bangladesh, and further explores the inequalities in catastrophic health expenditures (CHE) and forgone healthcare at the national and sub-national levels.

This study used data from the most recent nationally representative cross-sectional survey, Bangladesh Household Income and Expenditure Survey, conducted in 2016-17 (N= 39,124). In order to identify potential determinants of CHE and forgone healthcare, multilevel Poisson regression was used. Inequalities in CHE and forgone healthcare were measured using the slope index of inequality.

Around 25% of individuals incurred CHE and 14% of the population had forgone healthcare for any reasons. The most common reasons for forgone healthcare were treatment cost (17%), followed by none to accompany or need for permission (5%), and distance to health facility (3%). Multilevel analysis indicated that financial burden and forgone care was higher among households with older populations or chronic illness, and those who utilize either public or private health facilities. Household consumption quintile had a linear negative association with forgone care and positive association with CHE.

This study calls for incorporation of social safety net in health financing system, increase health facility, and gives priority to the disadvantaged population to ensure access to health services for all.

This study calls for incorporation of social safety net in health financing system, increase health facility, and gives priority to the disadvantaged population to ensure access to health services for all.

Point of care ultrasound (PoCUS) is a useful tool for the early diagnosis of thrombosis related to the central venous catheter for dialysis (TR-CVCd). However, the application of PoCUS is still not common as a bedside imaging examination and TR-CVCd remains often underdiagnosed in the routine practice. The aim of this study was to investigate if a compression technique for the diagnosis of TR-CVCd blindly performed by PoCUS experts and medical students is accurate when compared to a Doppler study.

Two medical students without prior knowledge in PoCUS received a short theoretical-practical training to evaluate TR-CVCd of the internal jugular vein by means of the ultrasound compression technique. After the training phase, patients with central venous catheter for dialysis (CVCd) were evaluated by the students in a private hemodialysis clinic. The results were compared to those obtained on the same population by doctors with solid experience in PoCUS, using both the compression technique and the color Doppler.

Eighty-one patients were eligible for the study and the prevalence of TR-CVCd diagnosed by Doppler was 28.4%. The compression technique performed by the students and by experts presented, respectively, a sensitivity of 59.2% (CI 51.6-66.8) vs 100% and a specificity of 89.6% (CI 84.9-94.3) vs 94.8% (CI 91.4-98.2).

The compression technique in the hands of PoCUS experts demonstrated high accuracy in the diagnosis of TR-CVCd and should represent a standard in the routine examination of dialytic patients. The training of PoCUS inexperienced students for the diagnosis of TR-CVCd is feasible but did not lead to a sufficient level of sensitivity.

The compression technique in the hands of PoCUS experts demonstrated high accuracy in the diagnosis of TR-CVCd and should represent a standard in the routine examination of dialytic patients. The training of PoCUS inexperienced students for the diagnosis of TR-CVCd is feasible but did not lead to a sufficient level of sensitivity.Interleukins (IL)-17A and F are critical cytokines in anti-microbial immunity but also contribute to auto-immune pathologies. Recent evidence suggests that they may be differentially produced by T-helper (Th) cells, but the underlying mechanisms remain unknown. To address this question, we built a regulatory graph integrating all reported upstream regulators of IL-17A and F, completed by ChIP-seq data analyses. The resulting regulatory graph encompasses 82 components and 136 regulatory links. The graph was then supplemented by logical rules calibrated with original flow cytometry data using naive CD4+ T cells, in conditions inducing IL-17A or IL-17F. The model displays specific stable states corresponding to virtual phenotypes explaining IL-17A and IL-17F differential regulation across eight cytokine stimulatory conditions. Our model analysis points to the transcription factors NFAT2A, STAT5A and SMAD2 as key regulators of the differential expression of IL-17A and IL-17F, with STAT5A controlling IL-17F expression, and an interplay of NFAT2A, STAT5A and SMAD2 controlling IL-17A expression. We experimentally observed that the production of IL-17A was correlated with an increase of SMAD2 transcription, and the expression of IL-17F correlated with an increase of BLIMP-1 transcription, together with an increase of STAT5A expression (mRNA), as predicted by our model. Interestingly, RORγt presumably plays a more determinant role in IL-17A expression as compared to IL-17F expression. In conclusion, we propose the first mechanistic model accounting for the differential expression of IL-17A and F in Th cells, providing a basis to design novel therapeutic interventions in auto-immune and inflammatory diseases.

[

F]PR04.MZ is a new PET imaging agent for dopamine transporters, providing excellent image quality and allowing for the evaluation of patients with movement disorders such as Parkinson's disease. The objective of this study was to evaluate the biodistribution and radiation dosimetry of [

F]PR04.MZ by serial PET imaging.

Six healthy subjects (n = 3 males, n = 3 females) were enrolled in this study. A series of 14 whole-body PET/CT scans were acquired until 5.5h post-injection of 200 ± 11MBq of [

F]PR04.MZ. After rigid co-registration, volumes of interest were outlined either on CT or PET images. Time-integrated activity coefficients were calculated for selected source organs. Organ absorbed doses, and the effective dose were calculated using IDAC-Dose 2.1.

Physiological uptake of [

F]PR04.MZ was mainly observed in the striatum, brain, liver, gall bladder, intestine, red marrow and cortical bone. [

F]PR04.MZ was primarily excreted via hepatobiliary clearance and, to a lower extent, via renal clearance.