IRCCS San Raffaele Scientific Institute Showcase

The composition of the secretome depends on the combined action of cargo receptors that facilitate protein transport and sequential checkpoints that restrict it to native conformers. Acting after endoplasmic reticulum (ER)-resident chaperones, ERp44 retrieves its clients from downstream compartments. To guarantee efficient quality control, ERp44 should exit the ER as rapidly as its clients, or more. Here, we show that appending ERp44 to different cargo proteins increases their secretion rates. ERp44 binds the cargo receptor ER-Golgi intermediate compartment (ERGIC)-53 in the ER to negotiate preferential loading into COPII vesicles. Silencing ERGIC-53, or competing for its COPII binding with 4-phenylbutyrate, causes secretion of Prdx4, an enzyme that relies on ERp44 for intracellular localization. In more acidic, zinc-rich downstream compartments, ERGIC-53 releases its clients and ERp44, which can bind and retrieve non-native conformers via KDEL receptors. By coupling the transport of cargoes and inspector proteins, cells ensure efficiency and fidelity of secretion.

eIF4B silencing (siRNA) experiment and assessment of the protein levels of CDKL5, XIAP and alpha-tubulin

Identifying reproducible brain-based stratifications across independent cohorts is critical for parsing heterogeneity in Major Depressive Disorder (MDD), yet robust profiles spanning micro- and macroscales remain poorly defined. We applied stability-based clustering to cortical thickness (CT) data from 1531 MDD individuals in UK Biobank (UKB), with replication in 144 inpatients from IRCCS San Raffaele Hospital (HSR). Two stable clusters emerged (normalized stability = 0.125) that generalized to a hold-out UKB sample with 96.5% accuracy (majority-cluster baseline = 59.5%). The clusters differed in widespread CT, largely reflected in global CT, with one showing cortical thinning, childhood trauma, and diabetes comorbidity. A two-cluster structure was independently replicated in HSR (normalized stability = 0.29), with a broadly similar cortical topography, although systematic CT differences between cohorts limited direct cross-cohort comparability. The clinical correlates identified in UKB did not replicate after correction for multiple comparisons. In UKB, mapping the CT differences between strata onto Neurosynth meta-analytic activation patterns revealed a ventral-dorsal gradient linked with emotion regulation, interoceptive, and motivational processes. Spatial correlations with 19 neurotransmitter receptors and transporters obtained from positron emission tomography identified the dopamine transporter as the dominant contributor in UKB, and the histamine H3 receptor in HSR. These findings provide a reproducible framework linking CT-based clusters in MDD to multiscale biological organization, although their clinical relevance warrants further investigation.

In this study we determined the effect of glucose concentration and beta-hydroxybutyrate (BHB) on T cell phenotype, metabolism and function. The purpose was to determine potential effect on the systemic inflammatory response (T2D) and autoimmunity (T1D).

These files include the raw data that have generated the figures of the paper

Supplementary Table I. Demographic, clinical, laboratory and histopathologic results in the univariate and multivariate analysis. Supplementary Table II. Demographic, clinical, laboratory and histopathologic findings in overlap cases.

Auditory cueing modulates brain activity associated with improved motor performance in pwPD, thus reduces bradykinesia. The following file is provided to increase trasparency. It contains processed kinematic variables.

Supplementary Fig 1. Workflow illustrating tumors distribution according to dermoscopic, confocal and histologic diagnoses. Supplementary Fig 2. A) Dermoscopy showing brown pseudonetwork with defined borders, interpreted as solar lentigo. B-C) Reflectance confocal microscopy (RCM) revealing LM features, specifically: B) RCM at epidermal layer showing perifollicular and interfollicular dendritic cells. C) RCM at dermal-epidermal layer showing medusa-head like structure. Supplementary Fig 3. Double negative LM case: A) Dermoscopy showing multiple grey dots. B) RCM at epidermal layer showing honeycombed pattern with focal mottled pigmentation. C) RCM at dermal-epidermal layer showing abundant melanophages. Supplementary Fig 4. Double negative BCC case: A) Dermoscopy showing brown-red background. B) RCM at epidermal layer showing honeycombed pattern with focal mottled pigmentation. C) RCM at dermal-epidermal layer showing aspecific structures.

BACKGROUND: Major noncardiac surgery is associated with high rates of postoperative myocardial injury and other complications. Remote ischemic preconditioning (RIPC) was reported to decrease these complication rates. However, such supportive evidence lacks robustness. METHODS: In a multinational, double-blind trial, we randomly assigned adult high-risk patients undergoing noncardiac surgical procedures to receive RIPC or sham RIPC after the induction of general anesthesia and before surgery. RIPC involved three 5-minute ischemic cycles, each followed by 5 minutes of reperfusion, using a blood pressure cuff inflated to 200 mm Hg. The primary end point was the rate of myocardial injury, defined by an increase in postoperative troponin levels above the highest 99th percentile of reference values. Secondary outcomes included myocardial infarction, stroke, acute kidney injury, need for intensive care unit, length of hospital stay, and 30-day all-cause mortality. RESULTS: We recruited 1213 patients in 25 hospitals and 8 countries. We randomly assigned 599 patients to RIPC and 614 to sham RIPC. The most frequent surgical procedures were abdominal or intrathoracic surgeries (406 patients [33.6%]). RIPC was applied to the upper limb in 1014 patients (84.8%) and to the lower limb in 182 patients (15.2%). Postoperative myocardial injury occurred in 215 of 566 patients (38.0%) in the RIPC group and in 223 of 596 patients (37.4%) in the sham RIPC group (relative risk, 1.02 [95% CI, 0.88–1.18; P=0.84). There were no significant differences in the rate of any secondary outcomes. We observed 11 episodes of limb petechiae (10 [1.7%] in the RIPC group versus one [0.2%] in the sham RIPC group) and 34 (6.0%) hospital readmissions in the RIPC group versus 20 (3.5%) in the sham RIPC group. CONCLUSIONS: Among adult patients undergoing noncardiac surgery, RIPC did not reduce myocardial injury or other postoperative complications. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02427867.

BACKGROUND Patients undergoing cardiac surgery often receive red-cell transfusions, along with the associated risks and costs. Early intraoperative normovolemic hemodilution (i.e., acute normovolemic hemodilution [ANH]) is a blood-conservation technique that entails autologous blood collection before initiation of cardiopulmonary bypass and reinfusion of the collected blood after bypass weaning. More data are needed on whether ANH reduces the number of patients receiving allogeneic red-cell transfusion. METHODS In a multinational, single-blind trial, we randomly assigned adults from 32 centers and 11 countries who were undergoing cardiac surgery with cardiopulmonary bypass to receive ANH (withdrawal of ≥650 ml of whole blood with crystalloids replacement if needed) or usual care. The primary outcome was the transfusion of at least one unit of allogeneic red cells during the hospital stay. Secondary outcomes were death from any cause within 30 days after surgery or during the hospitalization for surgery, bleeding complications, ischemic complications, and acute kidney injury. RESULTS A total of 2010 patients underwent randomization; 1010 were assigned to ANH and 1000 to usual care. Among patients with available data, 274 of 1005 (27.3%) in the ANH group and 291 of 997 (29.2%) in the usual-care group received at least one allogeneic red-cell transfusion (relative risk, 0.93; 95% confidence interval, 0.81 to 1.07; P = 0.34). Surgery for postoperative bleeding was performed in 38 of 1004 patients (3.8%) in the ANH group and 26 of 995 patients (2.6%) in the usual-care group. Death within 30 days or during hospitalization occurred in 14 of 1008 patients (1.4%) in the ANH group and 16 of 997 patients (1.6%) in the usual care group. Safety outcomes were similar in the two groups. CONCLUSIONS Among adults undergoing cardiac surgery, ANH did not reduce the number of patients receiving allogeneic red-cell transfusion. (Funded by the Italian Ministry of Health; ANH ClinicalTrials.gov number, NCT03913481.)