Dynamics and functions of lipid droplets.

Lipid droplets are storage organelles at the centre of lipid and energy homeostasis. They have a unique architecture consisting of a hydrophobic core of neutral lipids, which is enclosed by a phospholipid monolayer that is decorated by a specific set of proteins. Originating from the endoplasmic reticulum, lipid droplets can associate with most other cellular organelles through membrane contact sites. It is becoming apparent that these contacts between lipid droplets and other organelles are highly dynamic and coupled to the cycles of lipid droplet expansion and shrinkage. Importantly, lipid droplet biogenesis and degradation, as well as their interactions with other organelles, are tightly coupled to cellular metabolism and are critical to buffer the levels of toxic lipid species. Thus, lipid droplets facilitate the coordination and communication between different organelles and act as vital hubs of cellular metabolism.

Key steps in ERAD of luminal ER proteins reconstituted with purified components.

Misfolded proteins of the endoplasmic reticulum (ER) are retrotranslocated into the cytosol, polyubiquitinated, and degraded by the proteasome, a process called ER-associated protein degradation (ERAD). Here, we use purified components from Saccharomyces cerevisiae to analyze the mechanism of retrotranslocation of luminal substrates (ERAD-L), recapitulating key steps in a basic process in which the ubiquitin ligase Hrd1p is the only required membrane protein. We show that Hrd1p interacts with substrate through its membrane-spanning domain and discriminates misfolded from folded polypeptides. Both Hrd1p and substrate are polyubiquitinated, resulting in the binding of Cdc48p ATPase complex. Subsequently, ATP hydrolysis by Cdc48p releases substrate from Hrd1p. Finally, ubiquitin chains are trimmed by the deubiquitinating enzyme Otu1p, which is recruited and activated by the Cdc48p complex. Cdc48p-dependent membrane extraction of polyubiquitinated proteins can be reproduced with reconstituted proteoliposomes. Our results suggest a model for retrotranslocation in which Hrd1p forms a membrane conduit for misfolded proteins.

Quality Control of Protein Complex Assembly by a Transmembrane Recognition Factor.

The inner nuclear membrane (INM) is continuous with the endoplasmic reticulum (ER) but harbors a distinctive proteome essential for nuclear functions. In yeast, the Asi1/Asi2/Asi3 ubiquitin ligase complex safeguards the INM proteome through the clearance of mislocalized ER membrane proteins. How the Asi complex selectively targets mislocalized proteins and coordinates its activity with other ER functions, such as protein biogenesis, is unclear. Here, we uncover a link between INM proteome identity and membrane protein complex assembly in the remaining ER. We show that lone proteins and complex subunits failing to assemble in the ER access the INM for Asi-mediated degradation. Substrates are recognized by direct binding of Asi2 to their transmembrane domains for subsequent ubiquitination by Asi1/Asi3 and membrane extraction. Our data suggest a model in which spatial segregation of membrane protein complex assembly and quality control improves assembly efficiency and reduces the levels of orphan subunits.

Quality Control of ER Membrane Proteins by the RNF185/Membralin Ubiquitin Ligase Complex.

Misfolded proteins in the endoplasmic reticulum (ER) are degraded by ER-associated degradation (ERAD). Although ERAD components involved in degradation of luminal substrates are well characterized, much less is known about quality control of membrane proteins. Here, we analyzed the degradation pathways of two short-lived ER membrane model proteins in mammalian cells. Using a CRISPR-Cas9 genome-wide library screen, we identified an ERAD branch required for quality control of a subset of membrane proteins. Using biochemical and mass spectrometry approaches, we showed that this ERAD branch is defined by an ER membrane complex consisting of the ubiquitin ligase RNF185, the ubiquitin-like domain containing proteins TMUB1/2 and TMEM259/Membralin, a poorly characterized protein. This complex cooperates with cytosolic ubiquitin ligase UBE3C and p97 ATPase in degrading their membrane substrates. Our data reveal that ERAD branches have remarkable specificity for their membrane substrates, suggesting that multiple, perhaps combinatorial, determinants are involved in substrate selection.

Order through destruction: how ER-associated protein degradation contributes to organelle homeostasis.

The endoplasmic reticulum (ER) is a large, dynamic, and multifunctional organelle. ER protein homeostasis is essential for the coordination of its diverse functions and depends on ER-associated protein degradation (ERAD). The latter process selects target proteins in the lumen and membrane of the ER, promotes their ubiquitination, and facilitates their delivery into the cytosol for degradation by the proteasome. Originally characterized for a role in the degradation of misfolded proteins and rate-limiting enzymes of sterol biosynthesis, the many branches of ERAD now appear to control the levels of a wider range of substrates and influence more broadly the organization and functions of the ER, as well as its interactions with adjacent organelles. Here, we discuss recent mechanistic advances in our understanding of ERAD and of its consequences for the regulation of ER functions.

Retrotranslocation of a misfolded luminal ER protein by the ubiquitin-ligase Hrd1p.

Misfolded, luminal endoplasmic reticulum (ER) proteins are retrotranslocated into the cytosol and degraded by the ubiquitin/proteasome system. This ERAD-L pathway requires a protein complex consisting of the ubiquitin ligase Hrd1p, which spans the ER membrane multiple times, and the membrane proteins Hrd3p, Usa1p, and Der1p. Here, we show that Hrd1p is the central membrane component in ERAD-L; its overexpression bypasses the need for the other components of the Hrd1p complex. Hrd1p function requires its oligomerization, which in wild-type cells is facilitated by Usa1p. Site-specific photocrosslinking indicates that, at early stages of retrotranslocation, Hrd1p interacts with a substrate segment close to the degradation signal. This interaction follows the delivery of substrate through other ERAD components, requires the presence of transmembrane segments of Hrd1p, and depends on both the ubiquitin ligase activity of Hrd1p and the function of the Cdc48p ATPase complex. Our results suggest a model for how Hrd1p promotes polypeptide movement through the ER membrane.

Integration of genomic and ecological methods inform management of an undescribed, yet highly exploited, sardine species.

Assessing genetic diversity within species is key for conservation strategies in the context of human-induced biotic changes. This is important in marine systems, where many species remain undescribed while being overfished, and conflicts between resource-users and conservation agencies are common. Combining niche modelling with population genomics can contribute to resolving those conflicts by identifying management units and understanding how past climatic cycles resulted in current patterns of genetic diversity. We addressed these issues on an undescribed but already overexploited species of sardine of the genus Harengula. We find that the species distribution is determined by salinity and depth, with a continuous distribution along the Brazilian mainland and two disconnected oceanic archipelagos. Genomic data indicate that such biogeographic barriers are associated with two divergent intraspecific lineages. Changes in habitat availability during the last glacial cycle led to different demographic histories among stocks. One coastal population experienced a 3.6-fold expansion, whereas an island-associated population contracted 3-fold, relative to the size of the ancestral population. Our results indicate that the island population should be managed separately from the coastal population, and that a Marine Protected Area covering part of the island population distribution can support the viability of this lineage.

The bHLH transcription factor OsPRI1 activates the Setaria viridis PEPC1 promoter in rice.

Photosynthetic efficiency is reduced by the dual role of Rubisco, which acts either as a carboxylase or as an oxygenase, the latter leading to photorespiration. C4 photosynthesis evolved as a carbon-concentrating mechanism to reduce photorespiration. To engineer C4 into a C3 plant, it is essential to understand how C4 genes, such as phosphoenolpyruvate carboxylase (PEPC1), are regulated to be expressed at high levels and in a cell-specific manner. Yeast one-hybrid screening was used to show that OsPRI1, a rice bHLH transcription factor involved in iron homeostasis, binds to the Setaria viridis PEPC1 promoter. This promoter drives mesophyll-specific gene expression in rice. The role of OsPRI1 in planta was characterized using a rice line harbouring SvPEPC1pro ::GUS. We show that OsPRI1 activates the S. viridis PEPC1 promoter by binding to an N-box in the proximal promoter, and that GUS activity is highly reduced in SvPEPC1pro ::GUS lines when OsPRI1 is mutated. Cross-species comparisons showed that the SvPRI1 homolog binds to the SvPEPC1 promoter but the maize ZmPRI1 does not bind to the ZmPEPC1 promoter. Our results suggest that elements of the iron homeostasis pathway were co-opted to regulate PEPC1 gene expression during the evolution of some but not all C4 species.

Adjunctive low-voltage area ablation for patients with atrial fibrillation: An updated meta-analysis of randomized controlled trials.

BACKGROUND: The efficacy and safety of adjunctive low-voltage area (LVA) ablation on outcomes of catheter ablation (CA) for atrial fibrillation (AF) remains uncertain. METHODS: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) comparing CA with versus without LVA ablation for patients with AF. Risk ratios (RR) with 95% confidence intervals (CI) were pooled with a random-effects model. Our primary endpoint was recurrence of atrial tachyarrhythmia (ATA), including AF, atrial flutter, or atrial tachycardia. We used R version 4.3.1 for all statistical analyses. RESULTS: Our meta-analysis included 10 RCTs encompassing 1780 patients, of whom 890 (50%) were randomized to LVA ablation. Adjunctive LVA ablation significantly reduced recurrence of ATA (RR 0.76; 95% CI 0.67-0.88; p < .01) and reduced the number of redo ablation procedures (RR 0.54; 95% CI 0.35-0.85; p < .01), as compared with conventional ablation. Among 691 (43%) patients with documented LVAs on baseline substrate mapping, adjunctive LVA ablation substantially reduced ATA recurrences (RR 0.57; 95% CI 0.38-0.86; p < .01). There was no significant difference between groups in terms of periprocedural adverse events (RR 0.78; 95% CI 0.39-1.56; p = .49). CONCLUSIONS: Adjunctive LVA ablation is an effective and safe strategy for reducing recurrences of ATA among patients who undergo CA for AF.

Gastric dysplasia in random biopsies: the influence of Helicobacter pylori infection and alcohol consumption in the presence of a lesion.

BACKGROUND: Gastric dysplasia in the absence of an endoscopically defined lesion is rare, usually either a false positive diagnosis or a previously unidentified precancerous lesion during esophagogastroduodenoscopy (EGD). AIMS: Evaluate factors associated with the presence of an endoscopically visible lesion during follow-up in patients with histologic diagnosis of gastric dysplasia in random biopsies. METHODS: Retrospective cohort study including patients referred to our institution for gastric dysplasia in random biopsies during Index EGD. Endoscopic evaluation was performed with a high-definition endoscope using narrow band imaging (HD EGD-0). If no lesion was detected, endoscopic surveillance (HD EGD-FU) was conducted within 6 months for high grade dysplasia (HGD) or 12 months for low grade (LGD) or indefinite for dysplasia (IFD). RESULTS: From a total sample of 96 patients, 5 (5.2%) presented with an endoscopically visible lesion during HD EGD-0, while 10 lesions (10.4%) were identified during HD EGD-FU. Patients with Helicobacter pylori infection at Index EDG and with regular alcohol consumption (≥25 g/day) were 8 and 4 times more likely to have an endoscopically visible lesion on HD EGD-FU (p = 0.012 and p = 0.047). In binary logistic regression, both factors were independent predictors of the presence of gastric lesion on HD EGD-FU (OR 9.284, p = 0.009 and OR 5.025, p = 0.033). CONCLUSIONS: The presence of an endoscopically visible lesion after the histologic diagnosis of gastric dysplasia in random biopsies was more frequent during HD EGD-FU. H. pylori infection at Index EGD and regular alcohol consumption were significant predictors of the presence of gastric lesion on HD EGD-FU.

BEST-J Score: Validation of a Predicting Model for Delayed Bleeding After Gastric Endoscopic Submucosal Dissection on a European Sample.

BACKGROUND: Delayed bleeding (DB) is a possible adverse event following gastric endoscopic submucosal dissection (ESD). The BEST-J score was created as a risk prediction model for DB following gastric ESD, but is yet to be validated in Western populations. AIMS: We aimed to validate the BEST-J score on a European sample and to perform a subgroup analysis according to histological classification. METHODS: Retrospective study of all consecutive patients undergoing gastric ESD on a European Endoscopic Unit. DB was defined as hemorrhage with clinical symptoms and confirmed by emergency endoscopy from the time of completion to 28 days after ESD. BEST-J score was calculated in each patient and confronted with the outcome (DB). RESULTS: Final sample included 161 patients. From these, 10 (6.2%) presented DB following ESD, with a median time to bleeding of 7 days (IQR 6.8). BEST-J score presented an excellent accuracy predicting DB in our sample, with an AUC = 0.907 (95%CI 0.801-1.000; p < 0.001). Subgroup analysis by histological classification proved that the discriminative power was still excellent for each grade: low-grade dysplasia-AUC = 0.970 (p < 0.001); high-grade dysplasia-AUC = 0.874 (p < 0.001); early gastric cancer-AUC = 0.881 (p < 0.001). The optimal cut-off value to predict DB was a BEST-J score ≥ 3, which matches the cut-off value for high-risk of bleeding in the original investigation. CONCLUSIONS: The BEST-J score still presents excellent accuracy in risk stratification for post-ESD bleeding in European individuals. Thus, this score may help to guide which patients benefit the most from prophylactic therapies following gastric ESD in this setting.

Dissonance-Based Eating Disorder Prevention for Body-Dissatisfied Brazilian Cisgender Gay and Bisexual Men: A Randomized Controlled Trial With a 1-Year Follow-Up.

OBJECTIVE: Gay and bisexual men are at an increased risk for eating disorders (EDs) and muscle dysmorphia (MD) compared with their heterosexual counterparts. Existing dissonance-based (DB) EDs prevention programs for this population have been evaluated in the United States; however, these programs have not been evaluated in the Brazilian context. Thus, we investigated the feasibility, acceptability, and efficacy of a DB ED prevention program (i.e., the PRIDE Body Project) among Brazilian cisgender gay and bisexual men. METHOD: Eligible men were randomly assigned to either a DB intervention (n = 74) condition or an assessment-only control (AOC) condition (n = 75). Participants completed measures assessing ED and MD risk and protective factors at baseline, post-intervention, 1-month, 6-month, and 1-year follow-up. Those in the intervention condition also completed acceptability measures. RESULTS: Feasibility and acceptability ratings were highly favorable. Regarding efficacy, post-intervention results were not significant, except for self-objectification, which showed a significantly greater decrease in the DB condition compared with the AOC condition at all time-points of follow-ups (Cohen's d = -0.31 to -0.76). At follow-up, the DB condition showed significantly greater decreases in appearance-ideal internalization, drive for muscularity, self-objectification, ED and MD symptoms at 1-month, 6-month, and 1-year follow-ups (d = -0.33 to -0.92) compared with the AOC condition. Significant increases were observed in the DB compared with the AOC condition for body appreciation at 1-month, 6-month, and 1-year follow-ups (d = 0.31-0.81). DISCUSSION: Results support the feasibility, acceptability, and efficacy of the PRIDE Body Project up to 1-year in Brazilian cisgender gay and bisexual men. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials (ReBEC; available at http://www.ensaiosclinicos.gov.br/) number of registration: RBR-62fctqz.

Preoperative Levosimendan in Patients With Severe Left Ventricular Dysfunction Undergoing Isolated Coronary Artery Bypass Grafting: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To verify the impact of preoperative levosimendan on patients with severe left ventricular dysfunction (ejection fraction <35%) undergoing isolated coronary artery bypass grafting. DESIGN: A meta-analysis. SETTING: Hospitals. PARTICIPANTS: The authors included 1,225 patients from 6 randomized controlled trials. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors performed a meta-analysis of trials that compared preoperative levosimendan with placebo or no therapy, reporting efficacy and safety endpoints. Statistical analyses used mean differences and risk ratios (RR), with a random effects model. Six studies were included, comprising 1,225 patients, of whom 615 (50.2%) received preoperative levosimendan, and 610 (49.8%) received placebo/no therapy. Preoperative levosimendan showed a lower risk of all-cause mortality (RR 0.31; 95% CI 0.16-0.60; p < 0.01; I2 = 0%), postoperative acute kidney injury (RR 0.44; 95% CI 0.25-0.77; p < 0.01; I2 = 0%), low-cardiac-output syndrome (RR 0.45; 95% CI 0.30-0.66; p < 0.001; I2 = 0%), and postoperative atrial fibrillation (RR 0.49; 95% CI 0.25-0.98; p = 0.04; I2 = 85%) compared to control. Moreover, levosimendan significantly reduced the need for postoperative inotropes and increased the cardiac index at 24 hours postoperatively. There were no differences between groups for perioperative myocardial infarction, hypotension, or any adverse events. CONCLUSION: Preoperative levosimendan in patients with severe left ventricular dysfunction undergoing isolated coronary artery bypass grafting was associated with reduced all-cause mortality, low-cardiac-output syndrome, acute kidney injury, postoperative atrial fibrillation, and the need for circulatory support without compromising safety.

Association of morbidity, mortality, and average daily gain with transfer of passive immunity in dairy-beef crossbred calves up to 60 d of life.

Adequate transfer of passive immunity (TPI) is a cornerstone for a proper health status of calves. In the literature, there is limited information on the prevalence of failure of TPI in dairy-beef crossbred calves and its impact on morbidity, mortality, and average daily gain (ADG) during the preweaning period. Therefore, this study aimed to evaluate the association between TPI with morbidity, mortality, and ADG in pre-weaned dairy-beef crossbred calves. A total of 1,055 newborn dairy-beef crossbred calves were enrolled upon arrival at a calf-raising facility in California from January to August 2021. Farm of origin, genetic breed group, sex, and body weight were recorded upon arrival. Blood was collected at 24 ± 1 h post-arrival to evaluate serum IgG concentration, serum total protein (TP), and packed cell volume. Morbidity (diarrhea and respiratory treatment records) and mortality were recorded daily until 60 d of life. Calves were grouped into 2 genetic breed groups: Holstein x Beef (Ho x Be, 49.6%) and Jersey × Beef crossbred calves (Je × Be, 50.4%). Descriptive statistics and Cox proportional hazard models were created to evaluate the association of TPI categories for serum IgG (TPI-IgG: poor: < 10.0 g/L, fair: 10.0 - 17.9 g/L, good: 18.0 - 24.9 g/L, and excellent: ≥ 25.0 g/L) and TP (TPI-TP: poor: < 5.1 g/dL, fair: 5.1 - 5.7 g/dL, good: 5.8 - 6.1 g/dL, and excellent: ≥ 6.2 g/dL), sex, and genetic breed group with morbidity and mortality. Additionally, a mixed linear regression was performed to evaluate the association of sex, genetic breed group, and TPI categories with ADG. Overall morbidity and mortality were 84.8% (n = 895) and 2.5% (n = 26). Calves classified as TPI-IgG excellent were associated with the lowest (43.2% less) hazard of being treated compared with TPI-IgG poor calves. For mortality, dairy-beef crossbred calves with TPI-IgG excellent were associated with a reduction of 82.0% in the hazard of dying compared with TPI-IgG poor. The TPI-IgG poor and TPI-IgG fair calves were associated with a decreased ADG of 101.0 and 98.8 g/d, respectively, in comparison with TPI-IgG good calves. Average daily gain of TPI-IgG good and TPI-IgG excellent calves were not different. In our study, dairy-beef crossbred calves enrolled may have endured challenging conditions that increased morbidity. This reinforces the importance of high IgG levels to decrease morbidity and mortality and maximize ADG in dairy-beef crossbred calves raising systems. Further research should evaluate the long-term effects of TPI categories on the health and performance of dairy-beef crossbred calves.

C4 Phosphoenolpyruvate Carboxylase: Evolution and transcriptional regulation.

Photosynthetic phosphoenolpyruvate carboxylase (PEPC) catalyses the irreversible carboxylation of phosphoenolpyruvate (PEP), producing oxaloacetate (OAA). This enzyme catalyses the first step of carbon fixation in C4 photosynthesis, contributing to the high photosynthetic efficiency of C4 plants. PEPC is also involved in replenishing tricarboxylic acid cycle intermediates, such as OAA, being involved in the C/N balance. In plants, PEPCs are classified in two types: bacterial type (BTPC) and plant-type (PTPC), which includes photosynthetic and non-photosynthetic PEPCs. During C4 evolution, photosynthetic PEPCs evolved independently. C4 PEPCs evolved to be highly expressed and active in a spatial-specific manner. Their gene expression pattern is also regulated by developmental cues, light, circadian clock as well as adverse environmental conditions. However, the gene regulatory networks controlling C4 PEPC gene expression, namely its cell-specificity, are largely unknown. Therefore, after an introduction to the evolution of PEPCs, this review aims to discuss the current knowledge regarding the transcriptional regulation of C4 PEPCs, focusing on cell-specific and developmental expression dynamics, light and circadian regulation, as well as response to abiotic stress. In conclusion, this review aims to highlight the evolution, transcriptional regulation by different signals and importance of PEPC in C4 photosynthesis and its potential as tool for crop improvement.

Validation and measurement invariance of the Compulsive Exercise Test among Brazilian and American young adults.

PURPOSE: To evaluate compulsive exercise, researchers often rely on the widely used Compulsive Exercise Test (CET). However, the measure has shown unstable factor structure in several validation studies and is not available in Portuguese for use in Brazil. We aimed to describe the translation and cultural adaptation of the CET to Brazilian Portuguese, to test several factor structures among Brazilian and US samples of men and women, to test measurement invariance across countries, and to evaluate its internal consistency. Furthermore, we sought to evaluate convergent validity, correlating the CET with a measure of eating disorder symptoms, and to compare compulsive exercise symptoms between countries. METHODS: Four models of the latent structure of the CET were tested using confirmatory factor analyses (CFAs), three-factor structure with 15 items, three-factor structure with 18 items, four-factor structure with 21 items, and the original five-factor structure with 24 items, in a sample of 1,531 young adults (601 Brazilians and 930 Americans), aged 18-35 years. RESULTS: A series of CFAs demonstrated that the three-factor structure with 15 items showed a better fit to the data. This model demonstrated good convergent validity and internal consistency. Results from the CET multigroup CFA showed evidence for the invariance at the configural, metric, and scalar levels across Brazilians and Americans. Furthermore, significant differences were found between Brazilians and Americans, with Brazilians demonstrating higher scores on the Avoidance and rule-driven behavior and Mood improvement subscales, whereas US participants scored higher on the Weight control exercise subscale. CONCLUSIONS: Results support the three-factor structure with 15 items to be used as a measure of compulsive exercise among Brazilians and Americans, allowing cross-cultural comparisons between these countries. LEVEL OF EVIDENCE: Level V, Cross-sectional, Psychometric study.

Energy metabolism and respirometry of lambs fed sun or shade dried hays of banana crop residues.

We aimed to evaluate the effects of different drying methods for banana residues on the energy metabolism and respirometry of growing lambs. Twenty Santa Inês x Dorper lambs were fed five experimental diets: Tifton 85 grass hay (Control), shade-dried banana leaf hay (LH Shade), shade-dried pseudostem banana hay (PH Shade), sun-dried banana leaf hay (LH Sun), and sun-dried banana pseudostem hay (PH Sun). Nutrient intake and digestibility were assessed in metabolic cages, whereas O2 consumption and CO2, methane, and heat production were measured in a respirometry chamber with animals fed at maintenance and ad libitum levels. Nutrient and energy intake was not influenced by diet. Pseudostem hay had higher apparent digestibility of dry matter (71.5%), organic matter (72.4%), and neutral detergent fiber (58.0%). However, this led to greater energy loss in the form of methane (12.1%). The banana residue hays and drying methods did not alter oxygen consumption, CO2 production, or heat production of animals fed ad libitum or during maintenance. On the other hand, the use of leaf hay resulted in a reduction of 24.7% in enteric methane production of animals fed ad libitum. The inclusion of pseudostem hay is recommended in sheep feedlot diet. This residue provided greater use of DM, however promoted a greater loss of energy in the form of methane, resulting in similar energy consumption. The drying methods did not reduce the availability of nutrients and the sun drying method is recommended, since it is a faster drying method.

Predicting residual neoplasia after a non-curative gastric ESD: validation and modification of the eCura system in the Western setting: the W-eCura score.

OBJECTIVE: To evaluate the risk factors for lymph node metastasis (LNM) after a non-curative (NC) gastric endoscopic submucosal dissection (ESD) and to validate and eventually refine the eCura scoring system in the Western setting. Also, to assess the rate and risk factors for parietal residual disease. DESIGN: Retrospective multicentre multinational study of prospectively collected registries from 19 Western centres. Patients who had been submitted to surgery or had at least one follow-up endoscopy were included. The eCura system was applied to assess its accuracy in the Western setting, and a modified version was created according to the results (W-eCura score). The discriminative capacities of the eCura and W-eCura scores to predict LNM were assessed and compared. RESULTS: A total of 314 NC gastric ESDs were analysed (72% high-risk resection (HRR); 28% local-risk resection). Among HRR patients submitted to surgery, 25% had parietal disease and 15% had LNM in the surgical specimen. The risk of LNM was significantly different across the eCura groups (areas under the receiver operating characteristic curve (AUC-ROC) of 0.900 (95% CI 0.852 to 0.949)). The AUC-ROC of the W-eCura for LNM (0.916, 95% CI 0.870 to 0.961; p=0.012) was significantly higher compared with the original eCura. Positive vertical margin, lymphatic invasion and younger age were associated with a higher risk of parietal residual lesion in the surgical specimen. CONCLUSION: The eCura scoring system may be applied in Western countries to stratify the risk of LNM after a gastric HRR. A new score is proposed that may further decrease the number of unnecessary surgeries.

EGAD! There is an ERAD doppelganger in the Golgi.

Disposal of membrane proteins in the late secretory pathway is thought to be exclusively facilitated by ESCRT-dependent lysosomal degradation. In this issue of The EMBO Journal, Schmidt et al define a previously uncharacterized endosome and Golgi-associated degradation (EGAD) pathway. This pathway, which has remarkable similarities to ERAD in the endoplasmic reticulum, operates in post-ER organelles via the proteasome and contributes to lipid homeostasis in eukaryotic cells.

Efficacy and safety of the dual GIP and GLP-1 receptor agonist tirzepatide for weight loss: a meta-analysis of randomized controlled trials.

OBJECTIVES: Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for type 2 diabetes. We performed a meta-analysis to assess tirzepatide's weight reduction efficacy and safety. METHODS: We searched PubMed, Embase, and Cochrane for randomized controlled trials published from inception to July 2022, comparing tirzepatide with placebo for the co-primary endpoints of absolute and percent change in weight. Mean difference (MD) and odds ratio (OR) were calculated for continuous and binary outcomes, respectively. Review Manager 5.4.1 and RStudio were used for the statistical analysis, and RoB-2 (Cochrane) to assess the risk of bias. RESULTS: Of 397 search results, 6 studies (4036 participants) ranging from 12 to 72 weeks were included. Pooled analysis showed that tirzepatide 5 mg, 10 mg, and 15 mg were more effective than placebo, with MD in body weight of -7.7 kg (95% CI -11.0, -4.4; p < 0.001), -11.6 kg (95% CI -18.8, -4.3; p = 0.002), and -11.8 kg (95% CI -17.4, -6.2; p < 0.001), respectively, and MD in percent change in weight of -8.1% (95% CI -11.0, -5.2; p < 0.001), -11.9% (95% CI -18.1, -5.6; p < 0.001), and -12.4% (95% CI -17.2, -7.5; p < 0.001), respectively. Tirzepatide also reduced BMI and waist circumference. Adverse events were more common with tirzepatide with respect to nausea (OR 4.2; 95% CI 2.4, 7.5; p < 0.001), vomiting (OR 7.0; 95% CI 4.3, 11.4; p < 0.001), and diarrhea (OR 2.8; 95% CI 1.6, 4.9; p < 0.001) (15 mg dose), when compared with placebo. CONCLUSIONS: The results support that tirzepatide leads to substantial weight reduction and constitutes a valuable therapeutic option for weight management, despite an increase in gastrointestinal symptoms. PROTOCOL REGISTRATION: CRD42022348576.