An ATP13A1-assisted topogenesis pathway for folding multi-spanning membrane proteins.

Many multi-spanning membrane proteins contain poorly hydrophobic transmembrane domains (pTMDs) protected from phospholipid in mature structure. Nascent pTMDs are difficult for translocon to recognize and insert. How pTMDs are discerned and packed into mature, muti-spanning configuration remains unclear. Here, we report that pTMD elicits a post-translational topogenesis pathway for its recognition and integration. Using six-spanning protein adenosine triphosphate-binding cassette transporter G2 (ABCG2) and cultured human cells as models, we show that ABCG2's pTMD2 can pass through translocon into the endoplasmic reticulum (ER) lumen, yielding an intermediate with inserted yet mis-oriented downstream TMDs. After translation, the intermediate recruits P5A-ATPase ATP13A1, which facilitates TMD re-orientation, allowing further folding and the integration of the remaining lumen-exposed pTMD2. Depleting ATP13A1 or disrupting pTMD-characteristic residues arrests intermediates with mis-oriented and exposed TMDs. Our results explain how a "difficult" pTMD is co-translationally skipped for insertion and post-translationally buried into the final correct structure at the late folding stage to avoid excessive lipid exposure.

Effects and mechanism of sub-freezing storage on water holding capacity and tenderness of beef.

In order to explore the effect of sub-freezing storage on water holding capacity and tenderness of beef, four treatments were compared in this study: sub-freezing (-7 °C) fast sub-freezing (-38 °C until the core temperature achieved to -7 °C), superchilling (-1 °C) and fast frozen (-38 °C until the core temperature achieved to -18 °C) with the latter two treatments serving as the controls. The differences in muscle fiber structure, water distribution, protein oxidation and cytoskeletal protein degradation were studied. The results demonstrated that compared with other treatments, the fast sub-freezing treatment resulted in less structural damage to the muscle fibers and had better water holding capacity. Both sub-freezing and fast sub-freezing treatments inhibited protein oxidation compared with superchilling, but the former treatment's level of protein oxidation was higher than that in fast sub-freezing treatment during long-term storage (42 weeks). In addition, the structural proteins in the sub-freezing and fast sub-freezing treatments underwent faster degradation during long-term storage and therefore the meat was more tender compared with the fast frozen treatment. The results indicate that the fast sub-freezing treatment can be potentially applied in beef storage.

Improvement of coronary stent visualization using ultra-high-resolution photon-counting detector CT.

OBJECTIVES: This study aimed to compare the image quality and diagnostic performance of standard-resolution (SR) and ultra-high-resolution (UHR) coronary CT angiography (CCTA) based on photon-counting detector CT (PCD-CT) of coronary stents and explore the best reconstruction kernel for stent imaging. METHODS: From July 2023 to September 2023, patients were enrolled to undergo CCTA using a dual-source PCD-CT system after coronary angioplasty with stent placement. SR images with a slice thickness/increment of 0.6/0.4 mm were reconstructed using a vascular kernel (Bv48), while UHR images with a slice thickness/increment of 0.2/0.2 mm were reconstructed using vascular kernels of six sharpness levels (Bv48, Bv56, Bv60, Bv64, Bv72, and Bv76). The in-stent lumen diameters were evaluated. Subjective image quality was also evaluated by a 5-point Likert scale. Invasive coronary angiography was conducted in 12 patients (25 stents). RESULTS: Sixty-nine patients (68.0 [61.0, 73.0] years, 46 males) with 131 stents were included. All UHR images had significantly larger in-stent lumen diameter than SR images (p < 0.001). Specifically, UHR-Bv72 and UHR-Bv76 for in-stent lumen diameter (2.17 [1.93, 2.63] mm versus 2.20 [1.93, 2.59] mm) ranked the two best kernels. The subjective analysis demonstrated that UHR-Bv72 images had the most pronounced effect on reducing blooming artifacts, showcasing in-stent lumen and stent demonstration, and diagnostic confidence (p < 0.001). Furthermore, SR and UHR-Bv72 images showed a diagnostic accuracy of 78.3% (95% confidence interval [CI]: 56.3%-92.5%) and 88.0% (95%CI: 68.8%-97.5%), respectively. CONCLUSION: UHR CCTA by PCD-CT leads to significantly improved visualization and diagnostic performance of coronary stents, and Bv72 is the optimal reconstruction kernel showing the stent struts and in-stent lumen. CLINICAL RELEVANCE STATEMENT: The significantly improved visualization of coronary stents using ultra-high resolution CCTA could increase the diagnostic accuracy for in-stent restenosis and avoid unnecessary invasive quantitative coronary angiography, thus changing the clinical management for patients after percutaneous coronary intervention. KEY POINTS: Coronary stent imaging is challenging with energy-integrating detector CT due to "blooming artifacts." UHR images using a PCD-CT enhanced coronary stent visualization. UHR coronary stent imaging demonstrated improved diagnostic accuracy in clinical settings.

CT radiomic features reproducibility of virtual non-contrast series derived from photon-counting CCTA datasets using a novel calcium-preserving reconstruction algorithm compared with standard non-contrast series: focusing on epicardial adipose tissue.

PURPOSE: We aimed to evaluate the reproducibility of computed tomography (CT) radiomic features (RFs) about Epicardial Adipose Tissue (EAT). The features derived from coronary photon-counting computed tomography (PCCT) angiography datasets using the PureCalcium (VNCPC) and conventional virtual non-contrast (VNCConv) algorithm were compared with true non-contrast (TNC) series. METHODS: RFs of EAT from 52 patients who underwent PCCT were quantified using VNCPC, VNCConv, and TNC series. The agreement of EAT volume (EATV) and EAT density (EATD) was evaluated using Pearson's correlation coefficient and Bland-Altman analysis. A total of 1530 RFs were included. They are divided into 17 feature categories, each containing 90 RFs. The intraclass correlation coefficients (ICCs) and concordance correlation coefficients (CCCs) were calculated to assess the reproducibility of RFs. The cutoff value considered indicative of reproducible features was > 0.75. RESULTS: the VNCPC and VNCConv tended to underestimate EATVs and overestimate EATDs. Both EATV and EATD of VNCPC series showed higher correlation and agreement with TNC than VNCConv series. All types of RFs from VNCPC series showed greater reproducibility than VNCConv series. Across all image filters, the Square filter exhibited the highest level of reproducibility (ICC = 67/90, 74.4%; CCC = 67/90, 74.4%). GLDM_GrayLevelNonUniformity feature had the highest reproducibility in the original image (ICC = 0.957, CCC = 0.958), exhibiting a high degree of reproducibility across all image filters. CONCLUSION: The accuracy evaluation of EATV and EATD and the reproducibility of RFs from VNCPC series make it an excellent substitute for TNC series exceeding VNCConv series.

A signature based on circadian rhythm-associated genes for the evaluation of prognosis and the tumour microenvironment in HNSCC.

The morbidity and mortality rates of head and neck squamous cell carcinoma (HNSCC) remain high worldwide. Therefore, there is an urgent need to identify a new prognostic biomarker to guide the personalized treatment of HNSCC patients. Increasing evidence suggests that circadian rhythm genes play an important role in the development and progression of cancer. We aimed to explore the value of circadian rhythm genes in predicting prognosis and guiding the treatment of HNSCC. We first obtained a list of circadian rhythm genes from previous research. The sequencing data were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Finally, univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox proportional hazard analysis were performed to develop a prognostic signature (Circadian Rhythm-Related Gene Prognostic Index, CRRGPI) consisting of nine circadian rhythm genes. The signature exhibited good performance in predicting overall survival. Patients with low CRRGPI scores had lower metabolic activities and an active antitumour immunity ability. Additionally, a clinical cohort was used to further evaluate the ability of the CRRGPI to predict the efficacy of immune checkpoint inhibitors. In conclusion, the novel circadian rhythm-related gene signature can provide a precise prognostic evaluation with the potential capacity to guide individualized treatment regimens for HNSCC patients.

Circadian clock-related genome-wide mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity.

BACKGROUND: Circadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can contribute to inflammatory diseases such as Ulcerative colitis (UC). This Mendelian Randomization (MR) analysis applies genetic tools to represent the aggregated statistical results of exposure to circadian rhythm disorders and UC and its comorbidities, allowing for causal inferences. METHODS: Summary statistics of protein, DNA methylation and gene expression quantitative trait loci in individuals of European ancestry (pQTL, mQTL, and eQTL, respectively) were used. Genetic variants located within or near 152 circadian clock-related genes and closely related to circadian rhythm disorders were selected as instrumental variables. Causal relationships with UC and its comorbidities were then estimated through employed Summary data-based Mendelian Randomization (SMR) and Inverse-Variance-Weighted MR (IVW-MR). RESULTS: Through preliminary SMR analysis, we identified a potential causal relationship between circadian clock-related genes and UC along with its comorbidities, which was further confirmed by IVW-MR analysis. Our study identified strong evidence of positive correlation involving seven overlapping genes (CSNK1E, OPRL1, PIWIL2, RORC, MAX, PPP5C, and AANAT) through MWAS and TWAS in UC, four overlapping genes (OPRL1, CHRNB2, FBXL17, and SIRT1) in UC with PSC, and three overlapping genes (ARNTL, USP7, and KRAS) in UC with arthropathy. CONCLUSIONS: This SMR study demonstrates the causal effect of circadian rhythm disorders in UC and its comorbidities. Furthermore, our investigation pinpointed candidate genes that could potentially serve as drug targets.

A review on the research progress and application of compressed hydrogen in the marine hydrogen fuel cell power system.

The urgency to mitigate greenhouse gas emissions from maritime vessels has intensified due to the increasingly stringent directives set forth by the International Maritime Organization (IMO). These directives specifically address energy efficiency enhancements and emissions reduction within the shipping industry. In this context, hydrogen is the much sought after fuel for all the global economies and its applications, for transportation and propulsion in particular, is crucial for cutting down carbon emissions. Nevertheless, the realization of hydrogen-powered vessels is confronted by substantial technical hurdles that necessitate thorough examination. This study undertakes a comprehensive analysis encompassing diverse facets, including distinct variations of hydrogen fuel cells, hydrogen internal combustion engines, safety protocols associated with energy storage, as well as the array of policies and commercialization endeavors undertaken globally for the advancement of hydrogen-propelled ships. By amalgamating insights from these multifaceted dimensions, this paper adeptly encapsulates the myriad challenges intrinsic to the evolution of hydrogen-fueled maritime vessels, while concurrently casting a forward-looking gaze on their prospective trajectory.

Assessing the causal associations of sleep apnea with mental health and socioeconomic status: a bidirectional two-sample Mendelian randomization.

OBJECTIVE: Traditional observational research has suggested a connection between socioeconomic position, mental health, and sleep apnea (SA), but the specifics of this connection are still unclear. Using the Mendelian randomization approach, we intended to evaluate the potential causal link between mental health, socioeconomic status, and SA. METHODS: Our research employed summary statistics data from large-scale genome-wide association studies (GWAS) on mental health, socioeconomic status, and SA. In the main study, the connection between mental health, socioeconomic status, and SA was examined using the inverse variance weighted approach. In addition, as a supplement, we also used other Mendelian randomization methods, including MR Egger, weighted median, simple mode, and weighted mode. RESULTS: The primary analysis showed that educational attainment, including longer years of schooling, college or university degree, and higher intelligence was associated with a lower risk of SA (OR = 0.750, 95%CI = 0.653-0.862; OR = 0.558, 95%CI = 0.423-0.735; OR = 0.871, 95%CI = 0.760-0.999, respectively), while social deprivation was associated with a higher risk of SA (OR = 1.821, 95%CI = 1.075-3.085). And the income was not associated with the risk of sleep apnea (OR = 0.877, 95%CI = 0.682-1.129). In mental health exposure, major depressive disorder was associated with a higher risk of sleep apnea (OR = 1.196, 95%CI = 1.015-1.409), while attention-deficit hyperactivity disorder, bipolar disorder, and schizophrenia were not associated with the risk of sleep apnea (OR = 1.064, 95%CI = 0.958-1.181; OR = 1.030, 95%CI = 0.942-1.127; OR = 0.990, 95%CI = 0.957-1.025, respectively). Reverse MR analysis failed to find a causal effect from SA on mental health and socioeconomic status. CONCLUSIONS: This MR investigation offers proof of a possible causal relationship between SA, socioeconomic level, and mental health.

LPVS guidance and adaptive event-triggered control for an underactuated surface vessel with the prevention of obstacle's vicious maneuvering.

This paper investigates the adaptive neural event-triggered control for an underactuated surface vessel (USV), considering constraints of the obstacle's vicious maneuvering and the limited communication channel. In the algorithm, a novel logical phantom virtual ship (LPVS) guidance principle is developed to generate the global path following reference and the obstacle avoidance order in the simulation results, where the corresponding operation comply to the suggestion in international regulations for prevention collision at sea (COLREGs). The improved design of velocity obstacle (VO) method can guarantee its predictive capability to prevent the obstacle's vicious maneuvering. As for the control module, the adaptive event-triggered control algorithm is proposed by employing the robust neural damping technique and the input event-triggered mechanism. And the derived adaptive law can effectively solve perturbations from the gain uncertainty and the external disturbances. Through the theoretical analysis, all signals of the closed-loop control system are with the semi-globally uniform ultimate bounded (SGUUB) stability. The simulation experiments have been presented to verify the obstacle avoidance effectiveness and the burden-some superiority of the algorithm.

Fuzhengjiedu formula exerts protective effect against LPS-induced acute lung injury via gut-lung axis.

BACKGROUND: Acute lung injury (ALI) is distinguished by rapid and severe respiratory distress and prolonged hypoxemia. A traditional Chinese medicine (TCM), known as the Fuzhengjiedu formula (FZJDF), has been shown to have anti-inflammatory benefits in both clinical and experimental studies. The precise underlying processes, nevertheless, are yet unclear. PURPOSE: This study sought to enlighten the protective mechanism of FZJDF in ALI through the standpoint of the gut-lung crosstalk. METHODS: The impact of FZJDF on lipopolysaccharide (LPS)-induced ALI murine model were investigated, and the lung injury score, serum interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) expression were measured to confirm its anti-inflammatory effects. Additionally, gut microbiota analysis and serum and fecal samples metabolomics were performed using metagenomic sequencing and high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry, respectively. RESULTS: FZJDF significantly induced histopathological changes caused by LPS-induced ALI as well as downregulated the serum concentration of IL-1ß and TNF-α. Furthermore, FZJDF had an effect in gut microbiota disturbances, and linear discriminant effect size analysis identified signal transduction, cell motility, and amino acid metabolism as the potential mechanisms of action in the FZJDF-treated group. Several metabolites in the LPS and FZJDF groups were distinguished by untargeted metabolomic analysis. Correlations were observed between the relative abundance of microbiota and metabolic products. Comprehensive network analysis revealed connections among lung damage, gut microbes, and metabolites. The expression of glycine, serine, glutamate, cysteine, and methionine in the lung and colon tissues was dysregulated in LPS-induced ALI, and FZJDF reversed these trends. CONCLUSION: This study revealed that FZJDF considerably protected against LPS-induced ALI in mice by regulating amino acid metabolism via the gut-microbiota-lung axis and offered thorough and in-depth knowledge of the multi-system linkages of systemic illnesses.

Correlation analysis of cardiopulmonary exercise test indices and conditions of overweight patients with obstructive sleep apnea: a retrospective study

ABSTRACT BACKGROUND: The cardiopulmonary function of patients with obstructive sleep apnea (OSA) is significantly lower than that of patients with simple snoring and is significantly related to the severity of OSA. Currently, only a few studies have been conducted on cardiopulmonary exercise testing in overweight patients with OSA. OBJECTIVE: To analyze the correlation between cardiopulmonary exercise test (CPET) indices and the condition of overweight patients with OSA. DESIGN AND SETTING: Retrospective study in Guangdong Provincial Hospital of Chinese Medicine. METHODS: This study included 73 hospitalized overweight patients. The patients were divided into no, mild, moderate, and severe OSA groups. Differences in the CPET indices among the four groups were compared. The correlation between the CPET indices and conditions was analyzed. RESULTS: No, mild, moderate, and severe OSA groups had 18 men and 5 women, 11 men and 3 women, 12 men and 2 women, and 21 men and 1 woman, respectively (P > 0.05). No significant difference was observed in resting pulmonary function among the four groups (P > 0.05). In the CPET, the anaerobic threshold, maximum oxygen uptake, and oxygen pulse were significantly lower in the severe OSA group than those in the normal OSA group (P < 0.05). Moreover, CPET indices negatively correlated with the apnea-hypopnea index. CONCLUSION: Changes in CPET indices occurred earlier than changes in resting pulmonary function in patients with OSA. CPET might be a potential method for evaluating the severity of OSA combined with overweight status.

Effects of different protein phosphorylation levels on the tenderness of different ultimate pH beef.

This study investigated the relationship between tenderness and protein phosphorylation levels of normal ultimate pH (pHu, 5.4-5.8, NpHu), intermediate pHu (5.8-6.2, IpHu) and high pHu (≥6.2, HpHu) Longissimus lumborum from beef. During 21 d of ageing, the HpHu group had the lowest Warner-Bratzler shear force (WBSF) values, while the IpHu group showed the highest and even after 21 days of ageing still had high levels. In the late stage of the 24 h post-mortem period the faster degradation rate of troponin T and earlier activation of caspase 9 in the HpHu group were the key reasons for the lower WBSF compared with the NpHu and IpHu groups. The activity of caspase 3 cannot explain the tenderness differences between IpHu and HpHu groups, since their activities did not show any difference. At 24 h post-mortem, 17 common differential phosphorylated peptides were detected among pHu groups, of which nine were associated with pHu and WBSF. The higher phosphorylation level of glycogen synthase may have caused the delay of meat tenderization in the IpHu group.

Correlation analysis of cardiopulmonary exercise test indices and conditions of overweight patients with obstructive sleep apnea: a retrospective study.

BACKGROUND: The cardiopulmonary function of patients with obstructive sleep apnea (OSA) is significantly lower than that of patients with simple snoring and is significantly related to the severity of OSA. Currently, only a few studies have been conducted on cardiopulmonary exercise testing in overweight patients with OSA. OBJECTIVE: To analyze the correlation between cardiopulmonary exercise test (CPET) indices and the condition of overweight patients with OSA. DESIGN AND SETTING: Retrospective study in Guangdong Provincial Hospital of Chinese Medicine. METHODS: This study included 73 hospitalized overweight patients. The patients were divided into no, mild, moderate, and severe OSA groups. Differences in the CPET indices among the four groups were compared. The correlation between the CPET indices and conditions was analyzed. RESULTS: No, mild, moderate, and severe OSA groups had 18 men and 5 women, 11 men and 3 women, 12 men and 2 women, and 21 men and 1 woman, respectively (P > 0.05). No significant difference was observed in resting pulmonary function among the four groups (P > 0.05). In the CPET, the anaerobic threshold, maximum oxygen uptake, and oxygen pulse were significantly lower in the severe OSA group than those in the normal OSA group (P < 0.05). Moreover, CPET indices negatively correlated with the apnea-hypopnea index. CONCLUSION: Changes in CPET indices occurred earlier than changes in resting pulmonary function in patients with OSA. CPET might be a potential method for evaluating the severity of OSA combined with overweight status.

Effect of resveratrol on skeletal slow-twitch muscle fiber expression via AMPK/PGC-1α signaling pathway in bovine myotubes.

The purpose of this study was to evaluate the impact of resveratrol on slow-twitch muscle fiber expression in bovine myotubes. The results revealed that resveratrol enhanced slow myosin heavy chain (MyHC) and suppressed fast MyHC protein expression, accompanied by increased MyHC I/IIa and decreased MyHC IIx/IIb mRNA levels in bovine myotubes (P < 0.05). Resveratrol also enhanced the activities of succinic dehydrogenase (SDH), malate dehydrogenase (MDH) and the mitochondrial DNA (mtDNA) content, but reduced lactate dehydrogenase (LDH) activity (P < 0.05). Meanwhile, the protein and gene expression of AMPK, SIRT1 and PGC-1α were upregulated by resveratrol (P < 0.05). Furthermore, PGC-1α inhibitor SR-18292 could attenuate resveratrol-induced muscle fiber conversion from fast-twitch to slow-twitch. These results suggest that resveratrol might promote muscle fiber type transition from fast-twitch to slow-twitch through the AMPK/PGC-1α signaling pathway and mitochondrial biogenesis in bovine myotubes.

Effects of dietary resveratrol supplementation in cattle on the anti-oxidative capacity and meat quality of beef steaks under high­oxygen packaging.

The effects of dietary resveratrol supplementation on beef quality and antioxidant capacity under high­oxygen packaging were studied. Twelve cattle were selected and fed a total mixed ration (Control, CON) or supplemented with resveratrol (5 g/cattle/day, RES) for 120 days. The antioxidant capacity and meat quality of beef under high­oxygen modified atmosphere packaging (HiOx-MAP, 80%O2/20%CO2) and overwrap packaging (OW) were evaluated during storage. Compared to the CON, RES enhanced antioxidant enzyme activity in serum and muscle, and increased the expression of Nrf2 and its downstream target genes (P < 0.05), which decreased the lipid and protein oxidation of steaks during storage (P < 0.05). The RES resulted in a* values increasing throughout storage (P < 0.05) and lower MetMb% than CON steaks (P < 0.05) in HiOx-MAP. The water-holding capacity (WHC) was improved and Warner-Bratzler shear force (WBSF) was reduced (P < 0.05) in RES steaks during storage. Thus dietary resveratrol increased beef antioxidant capacity under HiOx-MAP and improved meat quality, and can be used as a potential method to elevate beef quality and reduce the oxidation under HiOx-MAP.

Comparative analysis of immune checkpoint inhibitors in first-line treatment of esophageal squamous cell carcinoma: a network meta-analysis.

Aim: To evaluate the efficacy and safety of first-line immunochemotherapy in the treatment of advanced esophageal squamous cell carcinoma (CRD42021287033). Methods: PubMed, Embase, Cochrane Library and Web of Science were systematically searched to obtain randomized controlled trials, and the outcome indicators of the reports were compared and analyzed. Results: A total of 3163 patients from five reported randomized controlled trials were included in the meta-analysis. The results showed the comprehensive benefits of toripalimab combined with chemotherapy, in terms of overall survival (hazard ratio: 0.59; 95% CI: 0.43-0.81) and progression-free survival (hazard ratio: 0.58; 95% CI: 0.46-0.73). Conclusion: Toripalimab combined with chemotherapy may be a better choice for first-line immunochemotherapy, although this needs to be verified by clinical studies.

The treatment of cancer is an issue of importance to the general public. A number of drugs are available to treat cancer, including those that enhance the body's natural defense. Such drugs are also the first choice for cancer of the esophagus, which cannot be removed surgically. In this study, we analyzed five different first-choice drugs in different ways, including how long the patient survives and how long the patient lives without their disease getting worse. We found that toripalimab, which strengthens the body's natural defense, may be the best combination choice for use in combination with chemotherapy. Although further studies are needed to increase the reliability of the conclusions, we preliminarily consider that this drug is particularly promising.

The clinical efficacy of type 2 monoclonal antibodies in eosinophil-associated chronic airway diseases: a meta-analysis.

Background: Anti-type 2 inflammation therapy has been proposed as a treatment strategy for eosinophil-associated chronic airway disorders that could reduce exacerbations and improve lung function. We performed a meta-analysis of randomized controlled trials to assess the effectiveness of type 2 monoclonal antibodies (anti-T2s) for eosinophil-associated chronic airway disorders. Methods: PubMed, Embase, Web of Science, and Cochrane Library were searched from their inception to 21 August 2022. Randomized clinical trials evaluating the effectiveness of anti-T2s versus placebo in the treatment of chronic airway diseases were selected. The outcomes were exacerbation rate and change in pre-bronchodilator forced expiratory volume in 1 s (FEV1) from baseline. The Cochrane Risk of Bias Assessment Tool 1.0 was used to evaluate the risk of bias, and the random-effects or fixed-effect model were used to pool the data. Results: Thirty-eight articles concerning forty-one randomized clinical trials with 17,115 patients were included. Compared with placebo, anti-T2s therapy yielded a significant reduction in exacerbation rate in COPD and asthma (Rate Ratio (RR)=0.89, 95%CI, 0.83-0.95, I2 = 29.4%; RR= 0.59, 95%CI, 0.52-0.68, I2 = 83.9%, respectively) and improvement in FEV1 in asthma (Standard Mean Difference (SMD)=0.09, 95%CI, 0.08-0.11, I2 = 42.6%). Anti-T2s therapy had no effect on FEV1 improvement in COPD (SMD=0.05, 95%CI, -0.01-0.10, I2 = 69.8%). Conclusion: Despite inconsistent findings across trials, anti-T2s had a positive overall impact on patients' exacerbation rate in asthma and COPD and FEV1 in asthma. Anti-T2s may be effective in treating chronic airway illnesses related to eosinophils. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022362280.

UBE4A catalyzes NRF1 ubiquitination and facilitates DDI2-mediated NRF1 cleavage.

The transcription factor nuclear factor erythroid 2 like 1 (NFE2L1 or NRF1) regulates constitutive and inducible expression of proteasome subunits and assembly chaperones. The precursor of NRF1 is integrated into the endoplasmic reticulum (ER) and can be retrotranslocated from the ER to the cytosol where it is processed by ubiquitin-directed endoprotease DDI2. DDI2 cleaves and activates NRF1 only when NRF1 is highly polyubiquitinated. It remains unclear how retrotranslocated NRF1 is primed with large amount of ubiquitin and/or very long polyubiquitin chain for subsequent processing. Here, we report that E3 ligase UBE4A catalyzes ubiquitination of retrotranslocated NRF1 and promotes its cleavage. Depletion of UBE4A reduces the amount of ubiquitin modified on NRF1, shortens the average length of polyubiquitin chain, decreases NRF1 cleavage efficiency and causes accumulation of non-cleaved, inactivated NRF1. Expression of a UBE4A mutant lacking ligase activity impairs the cleavage, likely due to a dominant negative effect. UBE4A interacts with NRF1 and the recombinant UBE4A can promote ubiquitination of retrotranslocated NRF1 in vitro. In addition, knocking out UBE4A reduces transcription of proteasomal subunits in cells. Our results indicate that UBE4A primes NRF1 for DDI2-mediated activation to facilitate expression of proteasomal genes.

A Meta-analysis of Total Neoadjuvant Therapies Combining Chemoradiotherapy with Induction or Consolidated Chemotherapy for Locally Advanced Rectal Cancer.

OBJECTIVE: Total neoadjuvant therapy (TNT) combining chemoradiotherapy (CRT) with chemotherapy (CT) was a novel pre-surgical approach to cancer treatment. This meta-analysis aimed to compare the clinical outcomes between neoadjuvant CRT (nCRT) with induction CT and nCRT with consolidated CT in locally advanced rectal cancer (LARC) patients. METHOD: In July 2022, a literature search was conducted using the following public databases: PubMed, MEDLINE, Embase, the Cochrane Library, and Web of Science, retrieved all relevant articles comparing nCRT-combining induction CT with nCRT-combining-consolidated CT treatments for LARC patients. RESULTS: Four eligible studies were identified, including a total of 995 LARC patients: 473 in the nCRT with consolidated CT group and 522 in the nCRT with induction CT group. The organ preservation (OP) rate of the nCRT with consolidated CT group was higher than that of the nCRT with induction CT group (RR [relative risk]: 1.53; 95% CI (confidence interval): 1.09-2.14). The pathological complete response (PCR, RR: 1.22; 95% CI 0.37-2.17), the 3-year disease-free survival (DFS, RR 1.02; 95% CI 0.71-1.46), the local recurrence (LR, RR 0.98; 95% CI 0.52-1.85), rates of R0 resection (RR 0.74; 95% CI 0.55-1.10), compliance (RR 0.52; 95% CI 0.12-2.26), and grade 3--4 toxicities (RR 0.78; 95% CI 0.57-1.06) were all similar between the two groups. CONCLUSION: In this meta-analysis of TNT regimens for rectal cancer, consolidative CT following nCRT was associated with similar PCR, 3-year DFS, LR, R0 resection, compliance, and grade 3-4 toxicities compared to induction CT prior to nCRT but a higher rate of organ preservation.