Explore the vast range of titles available.

Protein prenylation is believed to be catalyzed by three heterodimeric enzymes: FTase, GGTase1 and GGTase2. Here we report the identification of a previously unknown human prenyltransferase complex consisting of an orphan prenyltransferase α-subunit, PTAR1, and the catalytic β-subunit of GGTase2, RabGGTB. This enzyme, which we named GGTase3, geranylgeranylates FBXL2 to allow its localization at cell membranes, where this ubiquitin ligase mediates the polyubiquitylation of membrane-anchored proteins. In cells, FBXL2 is specifically recognized by GGTase3 despite having a typical carboxy-terminal CaaX prenylation motif that is predicted to be recognized by GGTase1. Our crystal structure analysis of the full-length GGTase3–FBXL2–SKP1 complex reveals an extensive multivalent interface specifically formed between the leucine-rich repeat domain of FBXL2 and PTAR1, which unmasks the structural basis of the substrate-enzyme specificity. By uncovering a missing prenyltransferase and its unique mode of substrate recognition, our findings call for a revision of the ‘prenylation code’.

BRCA1-associated protein 1 (BAP1) regulates calcium flux in the endoplasmic reticulum to facilitate the execution of apoptosis, unveiling a new facet of the role of BAP1 as an environmental tumour suppressor. A new role for BAP1 in tumour suppression BAP1 is a tumour suppressor associated with germline mutations in several malignancies including uveal melanoma and mesothelioma. BAP1 tumour suppressor activity has previously been linked to its nuclear role in maintaining genome integrity. Here, the authors reveal a new role for BAP1 in the endoplasmic reticulum, where it regulates calcium flux to facilitate the execution of apoptosis. Loss of BAP1 function prevents apoptosis in transformed cells with accumulated DNA damage. The results unveil a new facet of the role of BAP1 as an environmental tumour suppressor. BRCA1-associated protein 1 ( BAP1 ) is a potent tumour suppressor gene that modulates environmental carcinogenesis 1 , 2 , 3 . All carriers of inherited heterozygous germline BAP1 -inactivating mutations ( BAP1 +/− ) developed one and often several BAP1 −/− malignancies in their lifetime 4 , mostly malignant mesothelioma, uveal melanoma 2 , 5 , and so on 6 , 7 , 8 , 9 , 10 . Moreover, BAP1 -acquired biallelic mutations are frequent in human cancers 8 , 11 , 12 , 13 , 14 . BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity 15 , 16 , 17 . The possible activity of BAP1 in the cytoplasm is unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination 18 , indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. Here we discover that BAP1 localizes at the endoplasmic reticulum. Here, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), modulating calcium (Ca 2+ ) release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1 +/− carriers cause reduction both of IP3R3 levels and of Ca 2+ flux, preventing BAP1 +/− cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in BAP1 +/− carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene–environment interaction in human carcinogenesis.

Background Several anthropometric indices, such as body mass index and waist circumference, have been used as clinical screening tools for the prediction of nonalcoholic fatty liver disease (NAFLD). To further refine these clinical tools for NAFLD, the body roundness index (BRI) has recently been evaluated. In this systematic review and meta-analysis, the objective was to evaluate the relationship and predictive capability of the BRI in identifying NAFLD. Methods A comprehensive search was conducted in PubMed, Embase, Web of Science, and Scopus up to December 31, 2024. Eligibility criteria included observational studies on adults (≥ 18 years old) with measured BRI and its association with NAFLD. The Joanna Briggs Institute tool was used for risk of bias assessment. Meta-analyses used random-effects models to pool data on mean difference, odds ratio, sensitivity, specificity, and the area under the curve (AUC), with heterogeneity and publication bias assessed. Results Ten studies involving 59,466 participants were included. The pooled mean difference in BRI between the NAFLD and non-NAFLD groups was 1.73 (95% confidence interval [CI]: 1.31–2.15). The pooled sensitivity and specificity of BRI for diagnosing NAFLD were 0.806 and 0.692, respectively. The pooled AUC for BRI was 0.803 (95% CI: 0.775–0.830), indicating good diagnostic accuracy. Unlike subgroup analysis by country, subgroup analysis by sex showed no significant differences. Higher BRI values were associated with increased odds of NAFLD (pooled OR = 2.87, 95% CI: 1.39; 5.96). Studies provided mixed results on the predictive ability of BRI compared to other indices like body mass index, mostly favoring BRI over conventional indices. Conclusion BRI demonstrates a good diagnostic performance for NAFLD, suggesting it may be a valuable clinical tool for NAFLD assessment. Further research is necessary to validate these findings and strengthen the evidence base.

Carriers of heterozygous germline BAP1 mutations ( BAP1 +/− ) develop cancer. We studied plasma from 16 BAP1 +/− individuals from 2 families carrying different germline BAP1 mutations and 30 BAP1 wild-type ( BAP1 WT ) controls from these same families. Plasma samples were analyzed by liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS), ultra-performance liquid chromatography triple quadrupole mass spectrometry (UPLC-TQ-MS), and gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We found a clear separation in the metabolic profile between BAP1 WT and BAP1 +/− individuals. We confirmed the specificity of the data in vitro using 12 cell cultures of primary fibroblasts we derived from skin punch biopsies from 12/46 of these same individuals, 6 BAP1 +/− carriers and 6 controls from both families. BAP1 +/− fibroblasts displayed increased aerobic glycolysis and lactate secretion, and reduced mitochondrial respiration and ATP production compared with BAP1 WT . siRNA-mediated downregulation of BAP1 in primary BAP1 WT fibroblasts and in primary human mesothelial cells, led to the same reduced mitochondrial respiration and increased aerobic glycolysis as we detected in primary fibroblasts from carriers of BAP1 +/− mutations. The plasma and cell culture results were highly reproducible and were specifically and only linked to BAP1 status and not to gender, age or family, or cell type, and required an intact BAP1 catalytic activity. Accordingly, we were able to build a metabolomic model capable of predicting BAP1 status with 100% accuracy using data from human plasma. Our data provide the first experimental evidence supporting the hypothesis that aerobic glycolysis, also known as the ‘Warburg effect’, does not necessarily occur as an adaptive process that is consequence of carcinogenesis, but rather that it may also predate malignancy by many years and facilitate carcinogenesis.

Non-alcoholic fatty liver disease (NAFLD), which approximately affects a quarter of the world’s population, has become a major public health concern. Although usually associated with excess body weight, it may also affect normal-weight individuals, a condition termed as lean/non-obese NAFLD. The prevalence of lean/non-obese NAFLD is around 20% within the NAFLD population, and 5% within the general population. Recent data suggest that individuals with lean NAFLD, despite the absence of obesity, exhibit similar cardiovascular- and cancer-related mortality compared to obese NAFLD individuals and increased all-cause mortality risk. Lean and obese NAFLD individuals share several metabolic abnormalities, but present dissimilarities in genetic predisposition, body composition, gut microbiota, and susceptibility to environmental factors. Current treatment of lean NAFLD is aimed at improving overall fitness and decreasing visceral adiposity, with weight loss strategies being the cornerstone of treatment. Moreover, several drugs including PPAR agonists, SGLT2 inhibitors, or GLP-1 receptor agonists could also be useful in the management of lean NAFLD. Although there has been an increase in research regarding lean NAFLD, there are still more questions than answers. There are several potential drugs for NAFLD therapy, but clinical trials are needed to evaluate their efficacy in lean individuals.

Diabetic foot ulcers (DFUs) are a serious complication of diabetes mellitus (DM), affecting around 25% of individuals with DM. Primary treatment of a DFU involves wound off-loading, surgical debridement, dressings to provide a moist wound environment, vascular assessment, and appropriate antibiotics through a multidisciplinary approach. Three-dimensional (3D) printing technology is considered an innovative tool for the management of DFUs. The utilization of 3D printing technology in the treatment of DFU involves the modernization of traditional methods and the exploration of new techniques. This review discusses recent advancements in 3D printing technology for the application of DFU care, and the development of personalized interventions for the treatment of DFUs. We searched the electronic database for the years 2019-2024. Studies related to the use of 3D printing technology in Diabetic foot were included. A total of 25 identified articles based on database search and citation network analysis. After removing duplicates, 18 articles remained, and three articles that did not meet the inclusion criteria were removed after reading the title/abstract. A total of 97 relevant articles were included during the reading of references. In total, 112 articles were included. 3D printing technology offers unparalleled advantages, particularly in the realm of personalized treatment. The amalgamation of traditional treatment methods with 3D printing has yielded favorable outcomes in decelerating the progression of DFUs and facilitating wound healing. However, there is a limited body of research regarding the utilization of 3D printing technology in the domain of DFUs.

As mediators of innate immunity, neutrophils respond to chemoattractants by adopting a highly polarized morphology. Efficient chemotaxis requires the formation of one prominent pseudopod at the cell front characterized by actin polymerization, while local inhibition suppresses the formation of rear and lateral protrusions. This asymmetric control of signaling pathways is required for directional migration along a chemotactic gradient. Here, we identify the MAGUK protein p55/MPP1 as a mediator of the frontness signal required for neutrophil polarization. We developed a p55 knockout $({\\rm p}55^{-/-})$ mouse model, and demonstrate that ${\\rm p}55^{-/-}$ neutrophils form multiple transient pseudopods upon chemotactic stimulation, and do not migrate efficiently in vitro. Upon agonist stimulation, p55 is rapidly recruited to the leading edge of neutrophils in mice and humans. Total F-actin polymerization, along with Rac1 and RhoA activation, appear to be normal in ${\\rm p}55^{-/-}$ neutrophils. Importantly, phosphorylation of Akt is significantly decreased in ${\\rm p}55^{-/-}$ neutrophils upon chemotactic stimulation. The activity of immunoprecipitated phosphatidylinositol 3-kinase γ (PI3Kγ), responsible for chemoattractant-induced synthesis of PIP₃ and Akt phosphorylation, is unperturbed in ${\\rm p}55^{-/-}$ neutrophils. Although the total amount of PIP₃ is normal in ${\\rm p}55^{-/-}$ neutrophils, PIP₃ is diffusely localized and forms punctate aggregates in activated ${\\rm p}55^{-/-}$ neutrophils, as compared to its accumulation at the leading edge membrane in the wild type neutrophils. Together, these results show that p55 is required for neutrophil polarization by regulating Akt phosphorylation through a mechanism that is independent of PI3Kγ activity.

Levosulpiride is the levorotatory enantiomer of sulpiride used in dyspeptic syndromes of various etiologies. The prokinetic effect of levosulpiride is mediated through the blockade of enteric inhibitory dopaminergic type 2 (D2) receptors. The antagonism of central D2 receptors leads to both therapeutic (e.g. antiemetic effect due to D2 receptor blockade in the chemoreceptor trigger zone) and adverse (including hyperprolactinemia) effects. Dopamine is the main endogenous inhibitor of prolactin synthesis and secretion in the anterior pituitary. Levosulpiride causes significant elevation of serum prolactin levels in significant number of patients. The resultant hyperprolactinemia often manifests as distressing menstrual abnormalities and galactorrhoea in females. A significant number of patients who use levosulpiride develop serum prolactin levels of > 200 ng/mL that goes against the classical textbook teaching where pituitary tumor is supposed to be the mostly likely cause. Careful drug history in patients presenting with high serum prolactin levels will be of great help in reaching the exact diagnosis and avoiding unnecessary brain imaging.

Tumor‐induced osteomalacia (TIO) is a curable condition when the tumor is correctly located and completely removed. These tumors are, however, small and located in regions that make surgical removal difficult and sometimes risky in some patients. Experience of radiofrequency ablation (RFA) in the management of TIO is limited. We describe 3 patients with TIO who were treated in our hospital with RFA. They had suspected lesions in surgically difficult locations and were subjected to single sessions of RFA. The response was documented in terms of improvement in symptoms, normalization of hypophosphatemia and hyperphosphaturia, and disappearance of uptake on follow‐up Ga68 DOTANOC PET/CT imaging. All 3 patients had a clinical and biochemical profile consistent with TIO. The first patient (patient 1) had an intensely Ga68 DOTANOC avid lesion involving the roof of right acetabulum. The second patient (patient 2) had a Ga68 DOTANOC avid intramuscular lesion in left pectineus muscle and the third patient (patient 3) had a Ga68 DOTANOC avid expansile osteolytic lesion involving the angle and ramus of right mandible. All 3 patients achieved complete biochemical as well as clinical remission with single sessions of RFA. Six months after the procedure, Ga68 DOTANOC imaging revealed the absence of uptake at the previous sites, corroborating with the clinical improvement and normalization of hypophosphatemia and hyperphosphaturia. In conclusion, although surgical resection is the standard of care, RFA can be used successfully for treating patients with TIO. It can be an effective, less invasive, and safe modality of treatment in those patients where resection of the lesion is not possible because of inaccessible anatomical location or comorbidity that prohibits surgery. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Background and Aim Type 2 diabetes (T2D) in associated with higher prevalence and worse outcomes of nonalcoholic fatty liver disease (NAFLD). However, data regarding the prevalence of clinically relevant liver fibrosis (CRLF) in Indian individuals with T2D are scarce. We investigated the prevalence of, and factors associated with, CRLF in Indians with T2D. Methods We conducted a prospective study of 601 consecutive adults with T2D. Steatosis was diagnosed using ultrasonography. Liver stiffness measurement (LSM) by transient elastography of ≥8.0 kPa was taken as cutoff suggesting CRLF. Individuals with LSM > 13.0 kPa underwent dynamic magnetic resonance imaging (MRI) of liver for detecting changes consistent with cirrhosis. Results The prevalence of steatosis was 84.2%. Higher body mass index (BMI, P = 0.022), alanine aminotransferase (ALT; P = 0.001), and lower high‐density lipoprotein (HDL; P = 0.002) were independent factors associated with steatosis. The prevalence of CRLF was 28.2%. Higher BMI (P = 0.001), aspartate aminotransferase (AST; P < 0.0001), gamma‐glutamyl transpeptidase (GGT; P < 0.0001), and concomitant hypertension (P = 0.03) were independent factors associated with CRLF. Elevated ALT and AST (≥40 units/L) levels were present in 70.6 and 51.6% individuals with CRLF, respectively. Thirty‐one (7.2%) individuals had LSM > 13.0 kPa. Among them, 25 individuals underwent dynamic MRI of liver, which revealed features consistent with cirrhosis in 18 patients. Conclusion CRLF, an established risk factor for cirrhosis and overall mortality, affects at least one out of four (25%) Indians with T2D. These results support screening of all patients with T2D and NAFLD for liver fibrosis. Type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) often coexist. T2D promotes the progression of NAFLD to more severe liver pathologies. We found high prevalence of clinically relevant liver fibrosis in individuals with T2D and NAFLD.