Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS ...are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10−11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10−15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.
G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome. Their signaling is regulated by scaffold proteins containing PDZ domains, but although ...these interactions are important for GPCR function, they are still poorly understood. We here present a quantitative characterization of the kinetics and affinity of interactions between GPCRs and one of the best characterized PDZ scaffold proteins, postsynaptic density protein 95 (PSD-95), using fluorescence polarization (FP) and surface plasmon resonance (SPR). By comparing these in vitro findings with colocalization of the full-length proteins in cells and with previous studies, we suggest that the range of relevant interactions might extend to interactions with K i = 450 µM in the in vitro assays. Within this range, we identify novel PSD-95 interactions with the chemokine receptor CXCR2, the neuropeptide Y receptor Y2, and four of the somatostatin receptors (SSTRs). The interaction with SSTR1 was further investigated in mouse hippocampal neurons, where we found a clear colocalization between the endogenously expressed proteins, indicating a potential for further investigation of the role of this interaction. The approach can easily be transferred to other receptors and scaffold proteins and this could help accelerate the discovery and quantitative characterization of GPCR-PDZ interactions.
Identifying reliable predictors of long-term weight loss (LTWL) could lead to improved weight management.
To identify some predictors of LTWL.
The DPP (Diabetes Prevention Program) was a randomized ...controlled trial that compared weight loss with metformin, intensive lifestyle intervention (ILS), or placebo. Its Outcomes Study (DPPOS) observed patients after the masked treatment phase ended. (ClinicalTrials.gov: NCT00004992 and NCT00038727).
27 DPP and DPPOS clinics.
Of the 3234 randomly assigned participants, 1066 lost at least 5% of baseline weight in the first year and were followed for 15 years.
Treatment assignment, personal characteristics, and weight.
After 1 year, 289 (28.5%) participants in the metformin group, 640 (62.6%) in the ILS group, and 137 (13.4%) in the placebo group had lost at least 5% of their weight. After the masked treatment phase ended, the mean weight loss relative to baseline that was maintained between years 6 and 15 was 6.2% (95% CI, 5.2% to 7.2%) in the metformin group, 3.7% (CI, 3.1% to 4.4%) in the ILS group, and 2.8% (CI, 1.3% to 4.4%) in the placebo group. Independent predictors of LTWL included greater weight loss in the first year in all groups, older age and continued metformin use in the metformin group, older age and absence of either diabetes or a family history of diabetes in the ILS group, and higher fasting plasma glucose levels at baseline in the placebo group.
Post hoc analysis; examination of nonrandomized subsets of randomized groups after year 1.
Among persons with weight loss of at least 5% after 1 year, those originally randomly assigned to metformin had the greatest loss during years 6 to 15. Older age and the amount of weight initially lost were the most consistent predictors of LTWL maintenance.
National Institutes of Health.
From November 12th to 13th in 1872, an extreme coastal flood event occurred in the south Baltic Sea. An unusual combination of winds created a storm surge reaching up to 3.5 m above mean sea level, ...which is more than a meter higher than all other observations over the past 200 years. On the Danish, German, and Swedish coasts, about 300 people lost their lives. The consequences of the storm in Denmark and Germany were more severe than in Sweden, with significantly larger destruction and higher numbers of casualties. In Denmark and Germany, the 1872 storm has been more extensively documented and remembered and still influences local and regional risk awareness. A comparative study indicates that the collective memory of the 1872 storm is related to the background knowledge about floods, the damage extent, and the response to the storm. Flood marks and dikes help to remember the events. In general, coastal flood defence is to the largest degree implemented in the affected areas in Germany, followed by Denmark, and is almost absent in Sweden, corresponding to the extent of the collective memory of the 1872 storm. Within the affected countries, there is local variability of flood risk awareness associated with the collective memory of the storm. Also, the economic dependency on flood-prone areas and conflicting interests with the tourism industry have influence on flood protection decisions. The processes of climate change adaptation and implementation of the EU Floods Directive are slowly removing these differences in flood risk management approaches.
Genome‐wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and ...limited access to disease‐relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single‐molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree‐ and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology.
CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. ...Recently, we found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations. Using mass cytometry and microarray experiments, we demonstrate that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression. Thus, CD161 expression identifies NK cells that may contribute to inflammatory disease pathogenesis and correlates with an innate responsiveness to cytokines in both T and NK cells.
Abstract Oligotrophic ocean gyre ecosystems may be expanding due to rising global temperatures 1–5. Models predicting carbon flow through these changing ecosystems require accurate descriptions of ...phytoplankton communities and their metabolic activities 6. We therefore measured distributions and activities of cyanobacteria and small photosynthetic eukaryotes throughout the euphotic zone on a zonal transect through the South Pacific Ocean, focusing on the ultraoligotrophic waters of the South Pacific Gyre (SPG). Bulk rates of CO2 fixation were low (0.1 µmol C l−1 d−1) but pervasive throughout both the surface mixed-layer (upper 150 m), as well as the deep chlorophyll a maximum of the core SPG. Chloroplast 16S rRNA metabarcoding, and single-cell 13CO2 uptake experiments demonstrated niche differentiation among the small eukaryotes and picocyanobacteria. Prochlorococcus abundances, activity, and growth were more closely associated with the rims of the gyre. Small, fast-growing, photosynthetic eukaryotes, likely related to the Pelagophyceae, characterized the deep chlorophyll a maximum. In contrast, a slower growing population of photosynthetic eukaryotes, likely comprised of Dictyochophyceae and Chrysophyceae, dominated the mixed layer that contributed 65–88% of the areal CO2 fixation within the core SPG. Small photosynthetic eukaryotes may thus play an underappreciated role in CO2 fixation in the surface mixed-layer waters of ultraoligotrophic ecosystems.
The wheat flour tortilla (WFT) is a Mexican food product widely consumed in the world, despite lacking fiber and micronutrients. Ramón seed flour (RSF) is an underutilized natural resource rich in ...fiber, minerals and bioactive compounds that can be used to improve properties of starchy foods, such as WFT. The study evaluated the impact of partial replacement of wheat flour with RSF on the physicochemical, sensory, rheological and nutritional properties and antioxidant capacity (AC) of RSF-containing flour tortilla (RFT). Results indicated that RFT (25% RSF) had higher dietary fiber (4.5 times) and mineral (8.8%; potassium 42.8%, copper 33%) content than WFT. Two sensory attributes were significantly different between RTF and WFT, color intensity and rollability. RFT was soft and it was accepted by the consumer. Phenolic compounds (PC) and AC were higher in RFT (11.7 times, 33%-50%, respectively) than WFT. PC identification by ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-QTOF-MS) showed that phenolic acids esterified with quinic acid, such as chlorogenic and other caffeoyl and coumaroyl derivatives were the major PC identified in RSF, resveratrol was also detected. These results show that RSF can be used as an ingredient to improve nutritional and antioxidant properties of traditional foods, such as the WFT.
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