1267C>T (p.Arg423∗) variant. These cells replicated the secreted abnormalities seen in serum N-glycosylation, and a portion of the mutant protein appears to relocate to a distinct, non-Golgi compartment, possibly ER exit sites. These cells also show a gene dosage-dependent alteration in the Golgi morphology and reduced intraluminal pH that may account for the altered glycosylation. In summary, we identify a recurrent mutation in SLC37A4 that causes a dominantly inherited congenital disorder of glycosylation characterized by coagulopathy and liver dysfunction with abnormal serum N-glycans.In mammals, sound is detected by mechanosensory hair cells that are activated in response to vibrations at frequency-dependent positions along the cochlear duct. We demonstrate that inner ear supporting cells provide a structural framework for transmitting sound energy through the cochlear partition. Humans and mice with mutations in GAS2, encoding a cytoskeletal regulatory protein, exhibit hearing loss due to disorganization and destabilization of microtubule bundles in pillar and Deiters' cells, two types of inner ear supporting cells with unique cytoskeletal specializations. Failure to maintain microtubule bundle integrity reduced supporting cell stiffness, which in turn altered cochlear micromechanics in Gas2 mutants. Vibratory responses to sound were measured in cochleae from live mice, revealing defects in the propagation and amplification of the traveling wave in Gas2 mutants. We propose that the microtubule bundling activity of GAS2 imparts supporting cells with mechanical properties for transmitting sound energy through the cochlea.The assembly of nascent proteins into multi-subunit complexes is a tightly regulated process that must occur at high fidelity to maintain cellular homeostasis. The ER membrane protein complex (EMC) is an essential insertase that requires seven membrane-spanning and two soluble cytosolic subunits to function. Here, we show that the kinase with no lysine 1 (WNK1), known for its role in hypertension and neuropathy, functions as an assembly factor for the human EMC. WNK1 uses a conserved amphipathic helix to stabilize the soluble subunit, EMC2, by binding to the EMC2-8 interface. Shielding this hydrophobic surface prevents promiscuous interactions of unassembled EMC2 and directly competes for binding of E3 ubiquitin ligases, permitting assembly. Depletion of WNK1 thus destabilizes both the EMC and its membrane protein clients. This work describes an unexpected role for WNK1 in protein biogenesis and defines the general requirements of an assembly factor that will apply across the proteome. Stress responses vary throughout pregnancy and impact of late gestational variable stress (LGVS) with vitamin C supplementation on uterine contractility is barely explored. This study investigates fetal weight outcome and uterine contractile responses to pharmacological agents during LGVS exposure. Twenty four nulliparous pregnant rats were divided into four groups of six. During gestation days 10-19, groups 1 & 2 received normal saline and vitamin C (10mg/kg) respectively. Groups 3 and 4 were exposed to stress (sleep deprivation, predator exposure, immobility, rapid cage changes, noise, and foreign object) with group 4 concurrently supplemented with vitamin C (10mg/kg). Serum cortisol, oxidative bio-markers, fetal weights and contractile responses of excised uterine tissue to acetylcholine (Ach), oxytocin, calcium chloride (CaCl ), potassium chloride (KCl), diclofenac, and magnesium ions were determined. Malondialdehyde activity and cortisol were significantly increased in variable stress only exposed group when compared with control and vitamin C supplemented groups. Fetal body weights, superoxide dismutase and catalase activity were significantly reduced in variable stress only exposed group. Significantly impaired contractile responses to Ach, CaCl & KCl in variable stress only exposed group were modulated in vitamin C supplemented groups. Impaired contractile response to oxytocin was however not reversed. Relaxation responses to diclofenac and magnesium ions were statistically unaltered across groups. Impaired fetal weights and uterine contractile activity to Ach, CaCl and KCl during LGVS was modulated by vitamin C supplementation. Impaired oxytocin contractile activity was however unreversed.Impaired fetal weights and uterine contractile activity to Ach, CaCl2 and KCl during LGVS was modulated by vitamin C supplementation. Impaired oxytocin contractile activity was however unreversed. Reliable biological variation (BV) data are required for the clinical use of tumor markers in the diagnosis and monitoring of treatment effects in cancer. The European Biological Variation Study (EuBIVAS) was established by the EFLM Biological Variation Working Group to deliver BV data for clinically important measurands. selleck chemicals In this study, EuBIVAS-based BV estimates are provided for cancer antigen (CA) 125, CA 15-3, CA 19-9, carcinoembryonic antigen, cytokeratin-19 fragment, alpha-fetoprotein and human epididymis protein 4. Subjects from five European countries were enrolled in the study, and weekly samples were collected from 91 healthy individuals (53 females and 38 males; 21-69 years old) for 10 consecutive weeks. All samples were analyzed in duplicate within a single run. After excluding outliers and homogeneity analysis, the BVs of tumor markers were determined by CV-ANOVA on trend-corrected data, when relevant (Røraas method). Marked individuality was found for all tumor markers. CYFRA 21-1 was the measurand with the highest index of individuality (II) at 0.67, whereas CA 19-9 had the lowest II at 0.07. The CV s of HE4, CYFRA 21-1, CA 19-9, CA 125 and CA 15-3 of pre- and postmenopausal females were significantly different from each other. This study provides updated BV estimates for several tumor markers, and the findings indicate that marked individuality is characteristic. The use of reference change values should be considered when monitoring treatment of patients by means of tumor markers.This study provides updated BV estimates for several tumor markers, and the findings indicate that marked individuality is characteristic. The use of reference change values should be considered when monitoring treatment of patients by means of tumor markers.