Viral proteases activate the CARD8 inflammasome in the human cardiovascular system.

Nucleotide-binding oligomerization domain (NBD), leucine-rich repeat (LRR) containing protein family (NLRs) are intracellular pattern recognition receptors that mediate innate immunity against infections. The endothelium is the first line of defense against blood-borne pathogens, but it is unclear which NLRs control endothelial cell (EC) intrinsic immunity. Here, we demonstrate that human ECs simultaneously activate NLRP1 and CARD8 inflammasomes in response to DPP8/9 inhibitor Val-boro-Pro (VbP). Enterovirus Coxsackie virus B3 (CVB3)-the most common cause of viral myocarditis-predominantly activates CARD8 in ECs in a manner that requires viral 2A and 3C protease cleavage at CARD8 p.G38 and proteasome function. Genetic deletion of CARD8 in ECs and human embryonic stem cell-derived cardiomyocytes (HCMs) attenuates CVB3-induced pyroptosis, inflammation, and viral propagation. Furthermore, using a stratified endothelial-cardiomyocyte co-culture system, we demonstrate that deleting CARD8 in ECs reduces CVB3 infection of the underlying cardiomyocytes. Our study uncovers the unique role of CARD8 inflammasome in endothelium-intrinsic anti-viral immunity.

Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis.

Electron transport chain (ETC) biogenesis is tightly coupled to energy levels and availability of ETC subunits. Complex III (CIII), controlling ubiquinol:ubiquinone ratio in ETC, is an attractive node for modulating ETC levels during metabolic stress. Here, we report the discovery of mammalian Co-ordinator of mitochondrial CYTB (COM) complexes that regulate the stepwise CIII biogenesis in response to nutrient and nuclear-encoded ETC subunit availability. The COMA complex, consisting of UQCC1/2 and membrane anchor C16ORF91, facilitates translation of CIII enzymatic core subunit CYTB. Subsequently, microproteins SMIM4 and BRAWNIN together with COMA subunits form the COMB complex to stabilize nascent CYTB. Finally, UQCC3-containing COMC facilitates CYTB hemylation and association with downstream CIII subunits. Furthermore, when nuclear CIII subunits are limiting, COMB is required to chaperone nascent CYTB to prevent OXPHOS collapse. Our studies highlight CYTB synthesis as a key regulatory node of ETC biogenesis and uncover the roles of microproteins in maintaining mitochondrial homeostasis.

Hip Hemiarthroplasty: The Misnomer of a Narrow Femoral Canal and the Cost Implications.

Objective Hemiarthroplasty has been identified as the treatment of choice for displaced intracapsular femoral neck fractures. A modular prosthesis is sometimes preferred for its sizing options in narrow femoral canals, despite its higher cost and no advantage in clinical outcomes. Thus, in this study, we investigated the factors affecting surgeons' choice of prosthesis, hypothesizing that modular hemiarthroplasty is overused for narrow femoral canals compared to monoblock hip hemiarthroplasty. Methods A retrospective study of a regional level 1 trauma center was conducted. Patients who had sustained femoral neck fractures from March 2013 to December 2016 were included in this study. Inclusion criterion was modular hemiarthroplasty for a narrow femoral canal. A matched group of patients who underwent monobloc hemiarthroplasty (MH) was created through randomization. The main outcome measurements were sex, age, Dorr classification, and femoral head size. We measured the protrusion of the greater trochanter beyond the level of the lateral femoral cortex postoperatively. Modular hemiarthroplasty patients were templated on radiographs using TraumaCad for Stryker Exeter Trauma Stem (ETS®). Results In total, 533 hemiarthroplasty procedures were performed, of which 27 were modular for a narrow femoral canal. The ratio of modular to monobloc was 1:18. Average head size was 46.7 mm ± 3.6 mm for monobloc and 44.07 ± 1.5 for modular (P= 0.001). There were four malaligned stems in the monobloc group versus 14 in the modular group (P= 0.008). Unsatisfactory lateralization was noted in 18 patients (7 mm ± 2.9 mm) in the modular group compared with 8 (4.7 mm ± 3.9 mm) in the monobloc group (P= 0.029). Dorr classification was A or B in 24 patients in the modular group and 18 in the monobloc group (P = 0.006). Templating revealed that modular was not required in 25 patients. Conclusions As per our findings, it was determined that patients with a narrow femoral canal intraoperatively should not receive modular hemiarthroplasty. This is especially true for female patients with small femoral head and narrow femoral canal dimensions (Dorr A and B). They would require extensive careful planning. Surgical techniques should be explored through education intraoperatively to achieve lateralization during femoral stem preparation. This may avoid prolonged anesthetic time and achieve potential cost savings.