MAFLD criteria are better than MASLD criteria at predicting the risk of chronic kidney disease.

INTRODUCTION AND OBJECTIVES: Fatty liver disease is a multisystem disease. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a more accurate indicator of chronic kidney disease (CKD) than nonalcoholic fatty liver disease (NAFLD). However, the relationship between recently defined metabolic dysfunction-associated steatotic liver disease (MASLD) and CKD is currently unclear. The objective of this cross-sectional study was to investigate the prevalence of CKD and albuminuria among individuals diagnosed with either MAFLD or MASLD. PATIENTS AND METHODS: This study involved 5,492 participants who provided biochemical marker and liver ultrasound data from the U.S. National Health and Nutrition Examination Survey (2017-2020). Multiple logistic regression analyses were conducted to assess the independent associations of nonoverlapping MAFLD and MASLD with the presence of CKD or albuminuria (urinary albumin-to-creatinine ratio ≥ 3 mg/mmol). RESULTS: MAFLD and MASLD were identified in 47 % and 44.5 % of the participants, respectively. Individuals with MAFLD had a greater prevalence of CKD (29.60% vs. 26.56 %, P < 0.05) and albuminuria (29.60% vs. 26.56 %, P < 0.05) than did those with MASLD. Importantly, after adjusting for factors such as sex, age, ethnicity, and alcohol use, it was demonstrated that individuals in the MAFLD-only group had a 4.73-fold greater likelihood of having prevalent CKD than those in the MASLD-only group (P < 0.03). CONCLUSIONS: The MAFLD criteria better identify patients with CKD than do the MASLD criteria. Therefore, it is suggested that the MASLD criteria be reconsidered, as currently, the justification for changing from MAFLD to MASLD criteria may not be appropriate.

Size and fixation options of dorsoulnar fragments in distal radius fractures.

PURPOSE: This study aimed to investigate the influence of size and fixation options of dorsoulnar fragments on the clinical outcomes of distal radius fractures (DRFs). METHODS: This retrospective analysis was performed on 94 patients with DFR accompanied by dorsoulnar fragments, spanning the period from October 2018 to November 2022. Mean follow-up was 15.5 (range, 12-20) months. Patients were divided into small- (<5 %, n = 28), middle- (5-15 %, n = 50), and large- (>15 %, n = 16) sized groups according to articular involvement of dorsoulnar fragments determined by three-dimensional (3D) computed tomography (CT) modeling. Subdivision also took place for the presence of postoperative fragment displacement (>2 mm) and fixation methods including volar locking plate (VLP), VLP combined with dorsal hollow compression screw (VDS), and VLP combined with dorsal low-profile mini plate (VDP). The radiographic parameters (volar tilt, radial inclination, and radial height) and functional outcome measures of wrist range of motion, wrist function (DASH, PRWE), and wrist pain (VAS) were evaluated and compared between groups. RESULTS: Fracture healing was observed in all patients at final follow-up. No instances of dorsoulnar fragment displacement were observed in patients undergoing VDS and VDP treatment and the incidence of the dorsoulnar fragment displacement was 35 % (n = 8) in small-sized group, 21 % (n = 7) in middle-sized group, and 7 % (n = 1) in large-sized group when patients were treated with VLP. In small-sized group, no significant differences were found between patients with and without dorsoulnar fragment displacement in dorsiflexion restriction (10.6 ± 2.8°, 9.1 ± 2.3°, P = 0.159), pronosupination restriction (9.6 ± 2.1°, 8.6 ± 1.7°, P = 0.188), DASH (11.5 ± 4.1, 10.7 ± 3.2, P = 0.562), PRWE (11.9 ± 4.2, 10.6 ± 3.6, P = 0.425), and VAS (1.1 ± 1.1, 0.9 ± 1.0, P = 0.528). In middle-sized combined with large-sized group, the functional outcome measures of dorsiflexion restriction (12.5 ± 3.7°, 9.8 ± 2.9°, P = 0.022), DASH (14.6 ± 5.2, 11.4 ± 3.7, P = 0.030), and PRWE (15.0 ± 4.5, 11.3 ± 3.9, P = 0.016) were superior in patients without dorsoulnar fragment displacement. In patients treated with VLPs, no significant differences were found in dorsiflexion restriction (9.8 ± 2.5°, 10.8 ± 3.5°, 9.4 ± 2.5°, P = 0.299), pronosupination restriction (9.2 ± 1.9°, 10.1 ± 2.8°, 8.9 ± 1.5°, P = 0.200), DASH (11.1 ± 3.5, 12.9 ± 4.3, 11.1 ± 3.6, P = 0.162), PRWE (11.1 ± 3.9, 12.8 ± 4.2, 10.8 ± 3.9, P = 0.188), and VAS (1.0 ± 1.0, 1.4 ± 1.1, 0.9 ± 0.9, P = 0.151) between small-sized, middle-sized, and large-sized groups. In middle-sized group, no significant differences were found in dorsiflexion restriction (10.8 ± 3.5°, 9.4 ± 2.2°, 9.4 ± 2.4°, P = 0.316); pronosupination restriction (10.1 ± 2.8°, 8.8 ± 1.9°, 9.0 ± 2.5°, P = 0.314), DASH (12.9 ± 4.3, 10.3 ± 3.7, 10.5 ± 3.7, P = 0.133), PRWE (12.8 ± 4.2, 10.4 ± 3.8, 10.6 ± 4.1, P = 0.199), and VAS (1.4 ± 1.1, 0.8 ± 0.7, 1.0 ± 1.1, P = 0.201) between subgroups of VLP, VDS, and VDP. No significant differences were found in radiographic parameters between all groups compared. CONCLUSION: This study indicated that the strict reduction and fixation of a dorsoulnar fragment might be not essential when its articular involvement was less than 5 %. The volar locking plate (VLP) fixation was commonly effective in treating distal radius fractures accompanied by a dorsoulnar fragment involving over 15 % of the articular surface. Additionally, the use of an additional dorsal hollow compression screw or a dorsal low-profile mini plate can get good wrist function in the early-term follow-up when the dorsoulnar fragment involve 5-15 % of the articular surface.

Electro-oxidative three-component cascade coupling of isocyanides with elemental sulfur and amines for the synthesis of 2-aminobenzothiazoles.

2-Aminobenzothiazoles are commonly encountered in various functional compounds. Herein, we disclose an electro-oxidative three-component reaction for the effective synthesis of 2-aminobenzothiazoles under mild conditions, utilizing non-toxic and abundant elemental sulfur as the sulfur source. Both aliphatic amines and aryl amines demonstrate good compatibility at room temperature, highlighting the broad functional group tolerance of this approach. Additionally, elemental selenium demonstrated reactivities comparable to those of elemental sulfur.

Modified Ileal Conduit for Pelvic Lipomatosis: Technique Description and Outcome.

INTRODUCTION: To present the surgical technique and clinical outcomes of modified ileal conduit for pelvic lipomatosis (PL). METHODS: From 2020 to 2022, we prospectively enrolled 9 patients with PL undergoing modified ileal conduit. The patient characteristics, perioperative variables, and follow-up outcomes as well as the description of surgical technique were reported. RESULTS: All 9 patients successfully completed the operation. Two patients had perioperative complications of Clavien-Dindo grade I. The mean operation time and bleeding volumes were 253±51.4 min and 238.9±196.9 ml, with a mean postoperative follow-up time of 13.0±5.6 months. The postoperative 3-month and 1-year creatinine values were significantly decreased versus the preoperative (P=0.006 and P=0.024). The postoperative 3-month and 1-year eGFR values were significantly increased comapred with those before operation (P=0.0002 and P=0.018). The separation value of left renal pelvis collection system after operation were significantly reduced compared with preoperative evaluation (P=0.023 at 3 month and P=0.042 at 1 year) and so was the right side (P=0.019 and P=0.023). CONCLUSION: Modified ileal conduit is safe and feasible for PL. A large sample cohort with long-term follow-up is needed to evaluate the clinical outcomes of PL.

Mapping human tissues with highly multiplexed RNA in situ hybridization.

In situ transcriptomic techniques promise a holistic view of tissue organization and cell-cell interactions. There has been a surge of multiplexed RNA in situ mapping techniques but their application to human tissues has been limited due to their large size, general lower tissue quality and high autofluorescence. Here we report DART-FISH, a padlock probe-based technology capable of profiling hundreds to thousands of genes in centimeter-sized human tissue sections. We introduce an omni-cell type cytoplasmic stain that substantially improves the segmentation of cell bodies. Our enzyme-free isothermal decoding procedure allows us to image 121 genes in large sections from the human neocortex in <10 h. We successfully recapitulated the cytoarchitecture of 20 neuronal and non-neuronal subclasses. We further performed in situ mapping of 300 genes on a diseased human kidney, profiled >20 healthy and pathological cell states, and identified diseased niches enriched in transcriptionally altered epithelial cells and myofibroblasts.

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

In-depth theoretical analysis of the influence of an external electric field on charge transport parameters.

It is important to develop materials with environmental stability and long device shelf life for use in organic field-effect transistors (OFETs). The microscopic, molecular-level nature of the organic layer in OFETs is not yet well understood. The stability of geometric and electronic structures and the regulation of the external electric field (EEF) on the charge transport properties of four typical homogeneous organic semiconductors (OSCs) were investigated by density functional theory (DFT). The results showed that under the EEF, the structural changes in single-bond linked oligomers were more sensitive and complex than those of condensed molecules, and there were non-monotonic changes in their reorganization energy (λ) during charge transport under an EEF consisting of decreases and then increases (Series D). The change in λ under an EEF can be preliminarily and qualitatively determined by the change in the frontier molecular orbitals (FMOs) - the number of C-atoms with nonbonding characteristics. For single-bonded molecules, the transfer integral is basically unchanged under a low EEF, but it will greatly change at a high EEF. Because the structure and properties of the molecule will greatly change under different EEFs, the effect of an EEF should be fully considered when determining the intrinsic mobility of OSCs, which could cause a deviation 0.3-20 times in mobility. According to detailed calculations, one heterogeneous oligomer, TH-BTz, was designed. Its λ can be greatly reduced under an EEF, and the change in the energy level of FMOs can be adjusted to different degrees. This study provides a reasonable idea for verification of the experimental mobility value and also provides guidance for the directional design of stable high-mobility OSCs.

Cell-free DNA methylation profiles enable early detection of colorectal and gastric cancer.

Colorectal cancer (CRC) and gastric cancer (GC) rank the top five common and lethal cancers worldwide. Early detection can significantly reduce the mortality of CRC and GC. However, current clinical screening methods including invasive endoscopic techniques and noninvasive fecal occult blood test screening tests/fecal immunochemical test have shown low sensitivity or unsatisfactory patient's compliance. Aberrant DNA methylation occurs frequently in tumorigenesis and cell-free DNA (cfDNA) methylation has shown the potential in multi-cancer detection. Herein, we aimed to explore the value of cfDNA methylation in the gastrointestinal cancer detection and develop a noninvasive method for CRC and GC detection. We applied targeted methylation sequencing on a total of 407 plasma samples from patients diagnosed with CRC, GC, and noncancerous gastrointestinal benign diseases (Non-Ca). By analyzing the methylation profiles of 34 CRC, 62 GC and 107 Non-Ca plasma samples in the training set (n=203), we identified 40,110 gastrointestinal cancer-specific markers and 63 tissue of origin (TOO) prediction markers. A new integrated model composed of gastrointestinal cancer detection and TOO prediction for three types of classification of CRC, GC and Non-Ca patients was further developed through logistic regression algorithm and validated in an independent validation set (n=103). The model achieved overall sensitivities of 83% and 81.3% at specificities of 81.5% and 80% for identifying gastrointestinal cancers in the test set and validation set, respectively. The detection sensitivities for GC and CRC were respectively 81.4% and 83.3% in the cohort of the test and validation sets. Among these true positive cancer samples, further TOO prediction showed accuracies of 95.8% and 95.8% for GC patients and accuracies of 86.7% and 93.3% for CRC patients, in test set and validation set, respectively. Collectively, we have identified novel cfDNA methylation biomarkers for CRC and GC detection and shown the promising potential of cfDNA as a noninvasive gastrointestinal cancer detection tool.

Unmet needs in biomarkers for autoimmune pancreatitis diagnosis.

Autoimmune pancreatitis (AIP) is a rare chronic autoimmune disorder. The diagnosis of AIP mainly depends on histopathology, imaging and response to treatment. Serum immunoglobulin 4 (IgG4) is used only as collateral evidence in diagnostic criteria for AIP because of its moderate sensitivity. Serum IgG4 levels are normal in 15%-37% of type 1 AIP and most of type 2 AIP patients. In these patients, the indeterminate imaging and histopathology may lead to the difficulty in definitive diagnosis of AIP. Therefore, discovery of new biomarkers is important for AIP diagnosis. Here, we provide some views on the progression and challenges in identifying novel serological biomarkers in AIP diagnosis.

Photoredox-Catalyzed Alkylarylation of N-Aryl Bicyclobutyl Amides with α-Carbonyl Alkyl Bromides: Access to 3-Spirocyclobutyl Oxindoles.

A visible-light-induced radical alkylarylation of N-aryl bicyclobutyl amides with α-carbonyl alkyl bromides for the synthesis of functionalized 3-spirocyclobutyl oxindoles is described in which ß-selective radical addition of the alkyl radical to N-aryl bicyclobutyl amides forms a key radical intermediate followed by interception with intrinsic arene functional group. This approach can be applicable to a wide range of α-carbonyl alkyl bromides, including primary, secondary, and tertiary α-bromoalkyl esters, ketones, nitriles, and nitro compounds.

Enhancing Light Outcoupling Efficiency via Anisotropic Low Refractive Index Electron Transporting Materials for Efficient Perovskite Light-Emitting Diodes.

Thanks to the extensive efforts toward optimizing perovskite crystallization properties, high-quality perovskite films with near-unity photoluminescence quantum yield are successfully achieved. However, the light outcoupling efficiency of perovskite light-emitting diodes (PeLEDs) is impeded by insufficient light extraction, which poses a challenge to the further advancement of PeLEDs. Here, an anisotropic multifunctional electron transporting material, 9,10-bis(4-(2-phenyl-1H-benzo[d]imidazole-1-yl)phenyl) anthracene (BPBiPA), with a low extraordinary refractive index (ne ) and high electron mobility is developed for fabricating high-efficiency PeLEDs. The anisotropic molecular orientations of BPBiPA can result in a low ne of 1.59 along the z-axis direction. Optical simulations show that the low ne of BPBiPA can effectively mitigate the surface plasmon polariton loss and enhance the photon extraction efficiency in waveguide mode, thereby improving the light outcoupling efficiency of PeLEDs. In addition, the high electron mobility of BPBiPA can facilitate balanced carrier injection in PeLEDs. As a result, high-efficiency green PeLEDs with a record external quantum efficiency of 32.1% and a current efficiency of 111.7 cd A-1 are obtained, which provides new inspirations for the design of electron transporting materials for high-performance PeLEDs.

A silver-mediated radical process of ß-keto sulfones for the synthesis of 2,3-diacyl furans.

A facile and efficient method for constructing 2,3-diacyl trisubstituted furans via a silver-mediated radical process of ß-keto sulfones is developed. The reaction mechanism has been carefully investigated, revealing that the transformation proceeds through a radical pathway, leading to moderate to good yields of desired products.

Comprehensive Analysis of the Expression of Cell Adhesion Molecules Genes in Hepatocellular Carcinoma and their Prognosis, and Biological Significance.

BACKGROUND: Collagen-related cell adhesion molecules (CAMs) are a major component of the extracellular matrix (ECM) and often accumulate in the liver during chronic liver disease or hepatocellular carcinoma (HCC). In this study we identified several promising collagens related to CAMs that may be of clinical use for the diagnosis and prognosis of HCC. METHODS: We obtained multi-omics data including RNA sequencing (RNA-Seq) data, microarray data, proteomic data from the TCGA, GEO databases, GTEx, and NODE. Bioinformatics analyses were then performed to investigate correlations between the expression patterns of significant genes and HCC. Tumor tissue and para-cancerous tissue samples from HCC patients were also used to validate the results using RT-PCR. RESULTS: A literature research and LASSO-COX analysis identified three significant collagen-related CAM genes: SERPINH1, DCN, and ITGB1. Immunohistochemistry images in the Human Protein Atlas Project database showed that SERPINH1 and ITGB1 proteins were moderately or highly expressed in HCC tumor tissues compared to para-cancerous tissue, whereas DCN expression was lower in HCC tumor tissue. These results were validated by RT-PCR. Low- and high-risk groups of HCC patients were distinguished by the logistic panel in the TCGA database. These showed significantly different prognosis, clinicopathological features, and immune cell infiltration. Logistic regression was used to construct predictive models based on the individual expression levels of DCN, SERPINH1, and ITGB1. These showed highly accurate diagnostic ability (AUC = 0.987). CONCLUSIONS: The current findings suggest that the collagen-related CAMs DCN, SERPINH1, and ITGB1 may be potential therapeutic targets in HCC. Logistic panels of DCN, SERPINH1 and ITGB1 could serve as non-invasive and effective diagnostic biomarkers for HCC. CLINICAL TRIAL REGISTRATION: Identifier: NCT03189992. Registered on June 4, 2017. Retrospectively registered (https://clinicaltrials.gov/).

Polychromatic and collimated lights generated by nondegenerate four-wave mixing in cesium vapor.

We demonstrate the generation of polychromatic and collimated lights at 456 nm, 459 nm, and 761 nm based on cesium (133Cs) 6S1/2 - 6P3/2 - 8S1/2 - 7P3/2, 7P1/2, 6P1/2 - 6S1/2 multi-diamond-type atomic system via two-photon excitation with two IR pump lasers at 852 nm and 795 nm. The 456 nm, 459 nm (7P3/2, 7P1/2 → 6S1/2) collimated blue lights result from the self-seeded four-wave mixing process (FWM), and the 761 nm coherent light (8S1/2 → 6P1/2) is from a seeded FWM process with the injection of a third laser at 895 nm. We measure the dependency of generated polychromatic fields on the temperature of 133Cs vapor cell and the powers of input lasers, clearly demonstrating the competition between the self-seeded FWM and seeded FWM, as they share the same excitation path. This work is helpful to further produce entangled multi-color photons for quantum communication.

Effects of mindfulness-based interventions on cardiovascular risk factors: An umbrella review of systematic reviews and meta-analyses.

OBJECTIVE: Reviews have shown that mindfulness-based interventions (MBIs) were effective in improving cardiovascular risk factors (CVRFs), but the results were contradictory. This umbrella review aimed to summarize and grade the existing reviews on CVRFs associated with MBIs. METHODS: The protocol of this umbrella review had been registered in PROSPERO (CRD42022356812). PubMed, Web of science, Embase, The Cochrane Library, Scopus, Medline, PsycINFO and CINAHL were searched from database inception to 20 July 2022. The quality of evidence was assessed through GRADE. RESULTS: Twenty-seven reviews with 14,923 participants were included. Overall, 45% of reviews had low heterogeneity (I2 < 25%). For the quality of evidence, 31% were rated very low, 42% were rated low, 17% were rated moderate and 10% were rated high. MBIs significantly improved systolic blood pressure [SMD -5.53 mmHg (95% CI -7.81, -3.25)], diastolic blood pressure [SMD -2.13 mmHg (95% CI -2.97, -1.30)], smoking [Cohen's d 0.42 (95% CI 0.20, 0.64)], glycosylated hemoglobin [MD 0.01 (95% CI -0.43, -0.07)], binge eating behavior [SMD -6.49 (95% CI -10.80, -2.18)], depression [SMD -0.72 (95% CI -1.23, -0.21)] and stress [SMD -0.67 (95% CI -1.00, -0.34)]. CONCLUSIONS: In conclusion, this umbrella review provided evidence for the role of MBIs in the improvement of CVRFs.

Inflammatory recruitment of healthy hematopoietic stem and progenitor cells in the acute myeloid leukemia niche.

Inflammation in the bone marrow (BM) microenvironment is a constitutive component of leukemogenesis in acute myeloid leukemia (AML). Current evidence suggests that both leukemic blasts and stroma secrete proinflammatory factors that actively suppress the function of healthy hematopoietic stem and progenitor cells (HSPCs). HSPCs are also cellular components of the innate immune system, and we reasoned that they may actively propagate the inflammation in the leukemic niche. In two separate congenic models of AML we confirm by evaluation of the BM plasma secretome and HSPC-selective single-cell RNA sequencing (scRNA-Seq) that multipotent progenitors and long-lived stem cells adopt inflammatory gene expression programs, even at low leukemic infiltration of the BM. In particular, we observe interferon gamma (IFN-γ) pathway activation, along with secretion of its chemokine target, CXCL10. We show that AML-derived nanometer-sized extracellular vesicles (EVAML) are sufficient to trigger this inflammatory HSPC response, both in vitro and in vivo. Altogether, our studies indicate that HSPCs are an unrecognized component of the inflammatory adaptation of the BM by leukemic cells. The pro-inflammatory conversion and long-lived presence of HSPCs in the BM along with their regenerative re-expansion during remission may impact clonal selection and disease evolution.

Therapeutic management of metabolic dysfunction associated steatotic liver disease.

The incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) have been steadily increasing worldwide, with a huge societal and economic burden. Recently, NAFLD and non-alcoholic steatohepatitis have been renamed and redefined as metabolic dysfunction associated steatotic liver disease (MASLD) and steatohepatitis (Metabolic Dysfunction Associated Steatohepatitis (MASH)), which result from an imbalance between metabolic and inflammatory stress (mainly as a consequence of adipose tissue dysfunction and insulin resistance) and the defence and repair mechanisms of the steatotic liver. Once MASLD progresses to end-stage of liver disease, treatment efficacy becomes limited and may require liver transplantation. Early detection and intervention are crucial. Lifestyle modification is consequently the cornerstone of its management. Timely consideration of bariatric surgeries should be given to patients meeting specific criteria. A multidisciplinary approach is warranted, starting from the concept that MASLD/MASH is at the centre of the cardiovascular-liver-metabolic syndrome. In some cases, pharmacological treatment can complement lifestyle modification. Several drugs used to treat the cardiometabolic co-morbidities have some potential efficacy in slowing Down disease progression, and some have demonstrated efficacy on histological endpoints that are likely to translate into long-term clinical benefits. Optimising the use of these drugs within their licenced indications is thus paramount for patients with MASLD. Several MASH-specific drugs are on the horizon and are likely to enrich our therapeutic armamentarium in the near future, particularly in non-cirrhotic stages of the disease. Much work still needs to be done to understand the specific features of MASH cirrhosis and develop efficacious treatments for this disease stage.

Multidimensional Optimization of Saccharomyces cerevisiae for Carotenoid Overproduction.

Microbial synthesis of carotenoids is a highly desirable alternative to plant extraction and chemical synthesis. In this study, we investigated multidimensional strategies to improve the carotenoid synthesis in the industrial workhorse of Saccharomyces cerevisiae. First, we rewired the yeast central metabolism by optimizing non-oxidative glycolysis pathway for an improved acetyl-CoA supply. Second, we restricted the consumption of farnesyl pyrophosphate (FPP) by the down-regulation of squalene synthase using the PEST degron. Third, we further explored the human lipid binding/transfer protein saposin B (hSapB)-mediated metabolic sink for an enhanced storage of lipophilic carotenoids. Last, the copper-induced GAL expression system was engineered to function in the yeast-peptone-dextrose medium for an increased biomass accumulation. By combining the abovementioned strategies, the final engineered yeast produced 166.79 ± 10.43 mg/l ß-carotene in shake flasks, which was nearly 5-fold improvement of the parental carotenoid-producing strain. Together, we envision that multidimensional strategies reported here might be applicable to other hosts for the future industrial development of carotenoid synthesis from renewable feedstocks.