Purkinje cell-specific deficiency in SEL1L-hrd1 endoplasmic reticulum-associated degradation causes progressive cerebellar ataxia in mice.

Recent studies have identified multiple genetic variants of SEL1L-HRD1 endoplasmic reticulum-associated degradation (ERAD) in humans with neurodevelopmental disorders and locomotor dysfunctions, including ataxia. However, the relevance and importance of SEL1L-HRD1 ERAD in the pathogenesis of ataxia remain unexplored. Here, we showed that SEL1L deficiency in Purkinje cells leads to early-onset progressive cerebellar ataxia with progressive loss of Purkinje cells with age.

A reference genome for the Andean cavefish Trichomycterus rosablanca (Siluriformes, Trichomycteridae): Building genomic resources to study evolution in cave environments.

Animals living in caves are of broad relevance to evolutionary biologists interested in understanding the mechanisms underpinning convergent evolution. In the Eastern Andes of Colombia, populations from at least two distinct clades of Trichomycterus catfishes (Siluriformes) independently colonized cave environments and converged in phenotype by losing their eyes and pigmentation. We are pursuing several research questions using genomics to understand the evolutionary forces and molecular mechanisms responsible for repeated morphological changes in this system.

SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex.

The SEL1L-HRD1 protein complex represents the most conserved branch of endoplasmic reticulum (ER)-associated degradation (ERAD). Despite recent advances in both mouse models and humans, in vivo evidence for the importance of SEL1L in the ERAD complex formation and its (patho-)physiological relevance in mammals remains limited. Here we report that SEL1L variant p.

Muscle-specific ER-associated degradation maintains postnatal muscle hypertrophy and systemic energy metabolism.

The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum (ER) is largely unknown. Here, we report that the SEL1L-HRD1 ER-associated degradation (ERAD) complex, the primary molecular machinery that degrades misfolded proteins in the ER, is vital to maintain postnatal muscle growth and systemic energy balance. Myocyte-specific SEL1L deletion blunts the hypertrophic phase of muscle growth, resulting in a net zero gain of muscle mass during this developmental period and a 30% reduction in overall body growth.

Perturbation of endoplasmic reticulum proteostasis triggers tissue injury in the thyroid gland.

Defects in endoplasmic reticulum (ER) proteostasis have been linked to diseases in multiple organ systems. Here we examined the impact of perturbation of ER proteostasis in mice bearing thyrocyte-specific knockout of either HRD1 (to disable ER-associated protein degradation [ERAD]) or ATG7 (to disable autophagy) in the absence or presence of heterozygous expression of misfolded mutant thyroglobulin (the most highly expressed thyroid gene product, synthesized in the ER). Misfolding-inducing thyroglobulin mutations are common in humans but are said to yield only autosomal-recessive disease - perhaps because misfolded thyroglobulin protein might undergo disposal by ERAD or ER macroautophagy.

SEL1L-HRD1 interaction is prerequisite for the formation of a functional HRD1 ERAD complex.

The SEL1L-HRD1 protein complex represents the most conserved branch of endoplasmic reticulum (ER)-associated degradation (ERAD); however, definitive evidence for the importance of SEL1L in HRD1 ERAD is lacking. Here we report that attenuation of the interaction between SEL1L and HRD1 impairs HRD1 ERAD function and has pathological consequences in mice. Our data show that variant ( ) previously identified in Finnish Hound suffering cerebellar ataxia is a recessive hypomorphic mutation, causing partial embryonic lethality, developmental delay, and early-onset cerebellar ataxia in homozygous mice carrying the bi-allelic variant.

The mechanisms to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes.

Endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-phagy are two principal degradative mechanisms for ER proteins and aggregates, respectively; however, the crosstalk between these two pathways under physiological settings remains unexplored. Using adipocytes as a model system, here we report that SEL1L-HRD1 protein complex of ERAD degrades misfolded ER proteins and limits ER-phagy and that, only when SEL1L-HRD1 ERAD is impaired, the ER becomes fragmented and cleared by ER-phagy. When both are compromised, ER fragments containing misfolded proteins spatially coalesce into a distinct architecture termed Coalescence of ER Fragments (CERFs), consisted of lipoprotein lipase (LPL, a key lipolytic enzyme and an endogenous SEL1L-HRD1 substrate) and certain ER chaperones.

Identification of circular dorsal ruffles as signal platforms for the AKT pathway in glomerular podocytes.

Circular dorsal ruffles (CDRs) are rounded membrane ruffles induced by growth factors to function as precursors of the large-scale endocytosis called macropinocytosis. In addition to their role in cellular uptake, recent research using cell line systems has shown that CDRs/macropinocytosis regulate the canonical AKT-mTORC1 growth factor signaling pathway. However, as CDRs have not been observed in tissues, their physiological relevance has remained unclear.

Integration of ER protein quality control mechanisms defines β cell function and ER architecture.

Three principal ER quality-control mechanisms, namely, the unfolded protein response, ER-associated degradation (ERAD), and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the 3 pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in β cells. SEL1L-HRD1 ERAD deficiency in β cells triggers activation of autophagy, at least in part, via IRE1α (an endogenous ERAD substrate).

Damage control in orthopaedical and traumatology.

In Orthopedics, damage control is indicated in patients with pelvic and/or long bone fractures associated with hemodynamic instability. It is inappropriate to perform a complex definitive reduction and fixation surgery for severely injured trauma patients with hemodynamic instability. In these cases, it is recommended to perform minimally invasive procedures that temporarily stabilize the fractures and bleeding control.

Correction: Prion Protein Misfolding Affects Calcium Homeostasis and Sensitizes Cells to Endoplasmic Reticulum Stress.

[This corrects the article DOI: 10.1371/journal.pone.

Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes.

Throughout evolution, proinsulin has exhibited significant sequence variation in both C-peptide and insulin moieties. As the proinsulin coding sequence evolves, the gene product continues to be under selection pressure both for ultimate insulin bioactivity and for the ability of proinsulin to be folded for export through the secretory pathway of pancreatic β-cells. The substitution proinsulin-R(B22)E is known to yield a bioactive insulin, although R(B22)Q has been reported as a mutation that falls within the spectrum of mutant -gene-induced diabetes of youth.

Hemodynamically unstable pelvic fracture: A damage control surgical algorithm that fits your reality.

Pelvic fractures occur in up to 25% of all severely injured trauma patients and its mortality is markedly high despite advances in resuscitation and modernization of surgical techniques due to its inherent blood loss and associated extra-pelvic injuries. Pelvic ring volume increases significantly from fractures and/or ligament disruptions which precludes its inherent ability to self-tamponade resulting in accumulation of hemorrhage in the retroperitoneal space which inevitably leads to hemodynamic instability and the lethal diamond. Pelvic hemorrhage is mainly venous (80%) from the pre-sacral/pre-peritoneal plexus and the remaining 20% is of arterial origin (branches of the internal iliac artery).

Endoplasmic reticulum-associated degradation is required for nephrin maturation and kidney glomerular filtration function.

Podocytes are key to the glomerular filtration barrier by forming a slit diaphragm between interdigitating foot processes; however, the molecular details and functional importance of protein folding and degradation in the ER remain unknown. Here, we show that the SEL1L-HRD1 protein complex of ER-associated degradation (ERAD) is required for slit diaphragm formation and glomerular filtration function. SEL1L-HRD1 ERAD is highly expressed in podocytes of both mouse and human kidneys.

Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling.

β Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying β cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying β cell-specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for β cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of β cell maturation and identity.

Dataset on audio records of animals from the northeast Andes of Colombia II: The vertebrate sounds of Santander department.

Colombia holds one of the most spectacular biodiversity of the world. Yet, vast aspects of this biodiversity are still poorly inventoried. One of the least known aspects of Colombia's biodiversity is the sound produced by its animals, even for the most conspicuous ones, the vertebrates.

Selective EMC subunits act as molecular tethers of intracellular organelles exploited during viral entry.

Although viruses must navigate the complex host endomembrane system to infect cells, the strategies used to achieve this is unclear. During entry, polyomavirus SV40 is sorted from the late endosome (LE) to the endoplasmic reticulum (ER) to cause infection, yet how this is accomplished remains enigmatic. Here we find that EMC4 and EMC7, two ER membrane protein complex (EMC) subunits, support SV40 infection by promoting LE-to-ER targeting of the virus.

NOTCH3 is non-enzymatically fragmented in inherited cerebral small-vessel disease.

The small-vessel disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) arises from mutations in the human gene encoding NOTCH3 and results in vascular smooth muscle cell degeneration, stroke, and dementia. However, the structural changes in NOTCH3 involved in CADASIL etiology are unclear. Here, we discovered site-specific fragmentation of NOTCH3 protein in pathologically affected vessels of human CADASIL-affected brains.

A new species of (Gymnophiona, Caeciliidae) from the Magdalena valley region of Colombia.

A new species of the genus (Caeciliidae) from the western foothills of the Serranía de los Yariguíes in Colombia is described. is similar to and but differs from these species in having fewer primary annular grooves and a shorter body length. With this new species, the currently recognized species in the genus are increased to 35.

Procedure Time Comparison between Radial Versus Femoral Access in ST-Segment Elevation Acute Myocardial Infarction Patients Undergoing Emergent Percutaneous Coronary Intervention: A Meta-analysis of Controlled Randomized Trials.

Introduction: There are inconclusive data about the potential delay of procedure time in emergent percutaneous coronary intervention (PCI) by radial compared with femoral approach in patients with ST-segment elevation myocardial infarction (STEMI).

Aims: The purpose of the current study is to conduct a comprehensive meta-analysis of controlled randomized trials (CRTs) comparing the procedure time in STEMI patients undergoing emergent PCI with radial versus femoral access.

Methods: Formal search of CRTs through electronic databases (Medline and PubMed) was performed from January 1990 to October 2014 without language restrictions.

When intravascular ultrasound becomes indispensable in percutaneous coronary intervention of a chronic total occlusion.

Percutaneous coronary intervention of chronic total occlusion is a particular interventional area which requires high level of operator's experience and the support of additional tools based on intracoronary image such as intravascular ultrasound in many cases to clarify difficulties during procedures and to increase success rate. Implantation of long stents in many cases, the presence of stump ambiguity, and the use of specific techniques in this kind of interventions, such as reverse controlled antegrade and retrograde subintimal tracking (CART) and reverse CART make necessary in many cases the use of intravascular ultrasound for a better understanding of the situation, for reducing eventual complications and increasing procedural success rate. We made a review of literature related to most challenging situations in which the use of intravascular ultrasound during chronic total occlusion percutaneous coronary intervention becomes rather indispensable to safely continue and finish the procedure.