Shear stress stimulated apical endocytosis in renal proximal tubule epithelia

The proximal tubule (PT) plays a critical role in the reabsorption of ions, solutes and low molecular weight proteins from the glomerular filtrate. Although the PT has been known to acutely modulate ion reabsorption in response to changes in flow rates of the glomerular filtrate, whether apical endocytosis was regulated in response to changes in flow was unknown. I hypothesized that the fluid shear stress (FSS) caused by the flow of glomerular filtrate on the apical surface of the tubules would stimulate apical endocytosis in PT epithelia. I used a cell culture based parallel plate flow chamber system to test my hypothesis, and used PT cells from opossum, mice and humans in this study. I determined that FSS stimulated a rapidly reversible increase in apical endocytosis of both albumin (Megalin ligand) and dextran (fluid phase marker) in OK cells, which starts within 30 min of exposure to a FSS of 1 dyne/cm2 and the response increases linearly for at least three hours so long as FSS is maintained. This FSS-stimulated increase in endocytosis is clathrin and dynamin mediated. Primary cilia act as the principal mechanosensor in this process, and cause an increase in [Ca2+]i through the release of the ryanodine sensitive pool of calcium from the ER. In addition, purinergic signaling, triggered by the bending of cilia, is also important for both the FSS stimulated Ca2+ and endocytic responses. Lowe syndrome is a rare X linked genetic disease that affects young boys. It is characterized by the loss of OCRL a lipid phosphatase, and causes proteinuria. The FSS stimulated increase in endocytosis is ablated in OCRL depleted human PT cells, and the length of cilia in OCRL depleted cells is also higher. However, the lengthening of cilia is not responsible for the loss of FSS stimulated responses in these cells. This dissertation synthesizes our current understanding of mechanosensitive regulation of endocytic capacity in proximal tubule epithelia, suggests a mechanism that may define the reason for proteinuria in Lowe syndrome patients, and highlights areas of opportunity for future investigations

Prayers to Kāli: practicing radical numinosity

Prayers to Kāli is an invocation of the radical-sacred as a way into decolonization, liberation, and healing. The radical-sacred, as I conceive of it, is broadly to do with the work of retrieving our spiritual dimensions as an inextricable part of queer, and decolonial futurities. The construction and performance of decolonial, queer-feminist theory, and knowledge discourses as fundamentally located in communities of coalition, new modes of resistance and cosmologies, form the theoretical foil of this paper. The broader aim of the paper is to highlight the significance of spiritual, corporeal, and emotional knowledges in the work of decoloniality and dismantling systems of oppression. I locate this exploration within the narrative specifics of contemporary spirit- poetry from Tamil Nadu; a radical, border site where these connections and dimensions of decoloniality, gender, desire, and resistance play out

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Roles of Calreticulin in Protein Folding, Immunity, Calcium Signaling and Cell Transformation

The endoplasmic reticulum (ER) is an organelle that mediates the proper folding and assembly of proteins destined for the cell surface, the extracellular space and subcellular compartments such as the lysosomes. The ER contains a wide range of molecular chaperones to handle the folding requirements of a diverse set of proteins that traffic through this compartment. The lectin-like chaperones calreticulin and calnexin are an important class of structurally-related chaperones relevant for the folding and assembly of many N-linked glycoproteins. Despite the conserved mechanism of action of these two chaperones in nascent protein recognition and folding, calreticulin has unique functions in cellular calcium signaling and in the immune response. The ER-related functions of calreticulin in the assembly of major histocompatibility complex (MHC) class I molecules are well-studied and provide many insights into the modes of substrate and co-chaperone recognition by calreticulin. Calreticulin is also detectable on the cell surface under some conditions, where it induces the phagocytosis of apoptotic cells. Furthermore, mutations of calreticulin induce cell transformation in myeloproliferative neoplasms (MPN). Studies of the functions of the mutant calreticulin in cell transformation and immunity have provided many insights into the normal biology of calreticulin, which are discussed