Investigation of spatiotemporal distribution and formation mechanisms of ozone pollution in eastern Chinese cities applying convolutional neural network.

Severe ground-level ozone (O3) pollution over major Chinese cities has become one of the most challenging problems, which have deleterious effects on human health and the sustainability of society. This study explored the spatiotemporal distribution characteristics of ground-level O3 and its precursors based on conventional pollutant and meteorological monitoring data in Zhejiang Province from 2016 to 2021. Then, a high-performance convolutional neural network (CNN) model was established by expanding the moment and the concentration variations to general factors. Finally, the response mechanism of O3 to the variation with crucial influencing factors is explored by controlling variables and interpolating target variables. The results indicated that the annual average MDA8-90th concentrations in Zhejiang Province are higher in the northern and lower in the southern. When the wind direction (WD) ranges from east to southwest and the wind speed (WS) ranges between 2 and 3 m/sec, higher O3 concentration prone to occur. At different temperatures (T), the O3 concentration showed a trend of first increasing and subsequently decreasing with increasing NO2 concentration, peaks at the NO2 concentration around 0.02 mg/m3. The sensitivity of NO2 to O3 formation is not easily affected by temperature, barometric pressure and dew point temperature. Additionally, there is a minimum [Formula: see text] at each temperature when the NO2 concentration is 0.03 mg/m3, and this minimum [Formula: see text] decreases with increasing temperature. The study explores the response mechanism of O3 with the change of driving variables, which can provide a scientific foundation and methodological support for the targeted management of O3 pollution.

Initial ribociclib plus endocrine therapy for HR+/HER2- advanced breast cancer in pre- and postmenopausal Chinese women: Primary results from a phase 2 randomized study.

BACKGROUND: The MONALEESA­7 and ­2 phase 3 randomized trials demonstrated a statistically significant progression­free survival (PFS) and overall survival (OS) benefit with initial ribociclib + endocrine therapy (ET) versus placebo + ET in pre­ and postmenopausal patients with hormone receptor­positive (HR+)/human epidermal growth factor receptor 2­negative (HER2−) advanced breast cancer (ABC), respectively. Similar trends were observed in Asian subgroup analyses. This phase 2 bridging study of initial ET + ribociclib enrolled pre­ and postmenopausal patients with HR+/HER2­ ABC from China and was conducted to demonstrate consistency of PFS results in a Chinese population relative to the global MONALEESA­7 and ­2 studies. METHODS: Patients were randomized (1:1) to ET (nonsteroidal aromatase inhibitor + goserelin for premenopausal patients; letrozole for postmenopausal patients) + either ribociclib or placebo. The primary endpoint was investigator­assessed PFS. RESULTS: As of April 25, 2022, the median follow­up was 34.7 months in both cohorts. In the premenopausal cohort, median PFS was 27.6 months in the ribociclib arm (n = 79) versus 14.7 months in the placebo arm (n = 77) (hazard ratio 0.67 [95% CI: 0.45, 1.01]). In the postmenopausal cohort, median PFS was not reached in the ribociclib arm versus 18.5 months in the placebo arm (n = 77 in each arm) (hazard ratio 0.40 [95% CI: 0.26, 0.62]). Data also suggested improvements in secondary efficacy endpoints, although OS data were not mature. The safety profile in this population was consistent with that in global studies. CONCLUSIONS: These data demonstrate a favorable benefit­risk profile for ribociclib + ET in Chinese patients.

Functional cure induced by tenofovir alafenamide plus peginterferon-alpha-2b in young children with chronic hepatitis B: a case series study.

BACKGROUND AND AIMS: Data on the safety and effectiveness of tenofovir alafenamide (TAF) plus peginterferon-alpha (Peg-IFN-α) in children with chronic hepatitis B (CHB) are lacking. The current study aimed to present the characteristics of four pediatric CHB patients who obtained a functional cure by using TAF and Peg-IFN-α. METHODS: In this case series study initiated in May 2019, ten children who had no clinical symptoms or signs received response-guided (HBV DNA undetectable, hepatitis B e antigen [HBeAg] loss or seroconversion, and hepatitis B surface antigen [HBsAg] loss or seroconversion) and functional cure-targeted (HBsAg loss or seroconversion) TAF (25 mg/d, orally) plus Peg-IFN-α-2b (180 µg/1.73m2, subcutaneously, once weekly) in combination (9/10) or sequential (1/10) therapy. The safety and effectiveness of these treatments were monitored. RESULTS: As of April 2024, four out of ten children obtained a functional cure after a mean of 31.5 months of treatment, and the other six children are still undergoing treatment. These four cured children, aged 2, 4, 8, and 6 years, were all HBeAg-positive and had alanine aminotransferase levels of 80, 47, 114, and 40 U/L; HBV DNA levels of 71200000, 93000000, 8220, and 96700000 IU/mL; and HBsAg levels of 39442.8, 15431.2, 22, and 33013.1 IU/mL, respectively. During treatment, all the children (10/10) experienced mild or moderate adverse events, including flu-like symptoms, anorexia, fatigue, and cytopenia. Notably, growth retardation (8/10) was the most significant adverse event; and it occurred in three cured children (3/4) treated with combination therapy and was present to a low degree in the other cured child (1/4) treated with sequential therapy. Fortunately, all three cured children recovered to or exceeded the normal growth levels at 9 months posttreatment. CONCLUSIONS: TAF plus Peg-IFN-α-2b therapy is potentially safe and effective for pediatric CHB patients, which may provide important insights for future clinical practice and study designs targeting functional cures for children with CHB.

Residual kinematic deviations of the shoulder during humeral elevation after conservative treatment for mid-shaft clavicle fractures.

Despite residual functional deficits clinically observed in conservatively treated mid-shaft clavicle fractures, no study has reported a quantitative assessment of the treatment effects on the kinematics of the shoulder complex during functional movement. Using computerised motion analysis, the current study quantified the 3D residual kinematic deviations or strategies of the shoulder complex bones during multi-plane elevations in fifteen patients with conservatively treated mid-shaft clavicle fractures and fifteen healthy controls. Despite residual clavicular malunion, the patients recovered normal shoulder kinematics for arm elevations up to 60° in all three tested planes. For elevations beyond 60°, normal clavicle kinematics but significantly increased scapular posterior tilt relative to the trunk was observed in the patient group, leading to significantly increased clavicular protraction and posterior tilt relative to the scapula (i.e., AC joint). Slightly different changes were found in the sagittal plane, showing additional changes of increased scapular upward rotations at 90° and 120° elevations. Similar kinematic changes were also found on the unaffected side, indicating a trend of symmetrical bilateral adaptation. The current results suggest that shoulder kinematics in multi-plane arm elevations should be monitored for any compromised integrated motions of the individual bones following conservative treatment. Rehabilitation strategies, including muscle strengthening and synergy stability training, should also consider compensatory kinematic changes on the unaffected side to improve the bilateral movement control of the shoulder complex during humeral elevation.

Previously Unrecognized and Potentially Consequential Challenges Facing Hsp90 Inhibitors in Cancer Clinical Trials.

Targeting the Hsp90 chaperone machinery in various cancers with 200 mono- or combined- therapy clinical trials since 1999 has yet yielded any success of FDA approval. Blames for the failures were unanimously directed on the Hsp90 inhibitors or tumors or both. However, analyses of recent cellular and genetic studies together with the Hsp90 data from the Human Protein Atlas database suggest that the vast variations in Hsp90 expression among different organs in patients might have been the actual cause. It is evident now that Hsp90ß is the root of dose-limiting toxicity (DLT), whereas Hsp90α is a buffer of penetrated Hsp90 inhibitors. The more Hsp90α, the safer Hsp90ß and the lower DTL are for the host. Unfortunately, the dramatic variations of Hsp90, from total absence in eye, muscle, pancreas and heart to abundance in reproduction organs, lung, liver and gastrointestinal track, would cause the selection of any fair toxicity biomarker and an effective maximum tolerable dose (MTD) of Hsp90 inhibitor extremely challenging. In theory, a safe MTD for the organs with high Hsp90 could harm the organs with low Hsp90. In reverse, a safe MTD for organs with low or undetectable Hsp90 would have little impact on the tumors, whose cells exhibit 3-7% Hsp90 over 2-3% Hsp90 in normal cells. Moreover, not all tumor cell lines tested follow the "inhibitor binding-client protein degradation" paradigm. It is likely why the oral Hsp90 inhibitor TAS-16 (Pimitespib), which bypasses blood circulation and other organs, showed some beneficiary efficacy by conveniently hitting tumors along the gastrointestinal track. The critical question is what the next step will be for Hsp90 chaperone as a cancer therapeutic target.

FACT mediates the depletion of macroH2A1.2 to expedite gene transcription.

The histone variant macroH2A is generally linked to transcriptionally inactive chromatin, but how macroH2A regulates chromatin structure and functions in the transcriptional process remains elusive. This study reveals that while the integration of human macroH2A1.2 into nucleosomes does not affect their stability or folding dynamics, it notably hinders the maintenance of facilitates chromatin transcription's (FACT's) function. We show that FACT effectively diminishes the stability of macroH2A1.2-nucleosomes and expedites their depletion subsequent to the initial unfolding process. Furthermore, we identify the residue S139 in macroH2A1.2 as a critical switch to modulate FACT's function in nucleosome maintenance. Genome-wide analyses demonstrate that FACT-mediated depletion of macroH2A-nucleosomes allows the correct localization of macroH2A, while the S139 mutation reshapes macroH2A distribution and influences stimulation-induced transcription and cellular response in macrophages. Our findings provide mechanistic insights into the intricate interplay between macroH2A and FACT at the nucleosome level and elucidate their collective role in transcriptional regulation and immune response of macrophages.

Combined application of Er:YAG laser and low-level laser in non-surgical treatment of periodontitis.

BACKGROUND: To compare the efficacy of combined treatment of Er:YAG laser (ERL) and low-level laser therapy (LLLT) with single laser applications, and scaling and root planing (SRP) for non-surgical periodontal treatment. METHODS: In a randomized controlled trial, 25 non-smoking Stage II or Stage III periodontitis patients were recruited. The four intraoral quadrants were randomly assigned to four different treatments: (1) combined application with ERL plus SRP plus LLLT; (2) ERL plus SRP; (3) SRP plus LLLT; and (4) SRP. We assessed periodontal indexes, including probing depth (PD), clinical attachment level (CAL), bleeding index (BI), and plaque index (PLI), along with three cytokines (IL-1ß, TNF-α, IL-10) from gingival crevicular fluid and red complex pathogens from subgingival dental plaque at baseline, 3 months, and 6 months. RESULTS: For initial moderate pockets (4 mm ≤ PD ≤ 6 mm), quadrants treated with ERL+SRP+LLLT, ERL+SRP, and SRP+LLLT exhibited greater PD improvement compared to the control (SRP) quadrants at the 3-month follow-up (1.25 ± 1.06, 1.23 ± 1.12, 1.00 ± 1.21 vs. 0.98 ± 1.21 mm) and the 6-month follow-up (1.35 ± 1.06, 1.23 ± 1.17, 1.35 ± 0.98 vs. 0.98 ± 1.23 mm) (p = 0.002). Quadrants treated with ERL+SRP+LLLT and SRP+LLLT showed more CAL gain means than the control quadrants at the 3-month follow-up (0.96 ± 1.42, 0.61 ± 1.39 vs. 0.55 ± 1.57 mm) and the 6-month follow-up (0.84 ± 1.54, 0.89 ± 1.49 vs. 0.48 ± 1.68 mm) (p = 0.008). For initial deep pockets (PD ≥ 7 mm), the ERL+SRP+LLLT quadrants had more PD improvement and CAL gain compared to the control quadrants at follow-up. There were no significant differences in BI, PLI, inflammatory cytokines, and periodontal pathogens among the four groups. CONCLUSION: The combined application of ERL and LLLT demonstrated potential efficacy in reducing PD, particularly for deep pockets. PLAIN LANGUAGE SUMMARY: To compare the therapy effect of combined use of Er:YAG laser (ERL) and low level laser therapy (LLLT) with single laser applications, and traditional periodontal treatment (SRP). A total of 25 non smoking patients with periodontitis were involved, and their mouths were divided into four sections, each receiving a different treatment: ERL+SRP+LLLT, ERL+SRP, SRP+LLLT, and SRP. Clinical indexes and laboratory indicators were assessed at baseline, 3 months, and 6 months. After six months, for initial moderate pockets, combined laser group and single laser group showed better improvements than traditional group in reducing the depth of periodontal pockets and increasing attachment levels. But for initial deep pockets, only combined laser group showed better improvement than traditional group. There were no significant differences in bleeding, plaque, inflammation, or harmful bacterial levels among the groups. These findings suggest that the integration of Er:YAG laser and low level laser therapy into standard periodontal treatment may enhance the treatment's benefits in reducing pocket depth, especially for severe conditions.

Impact mechanisms of various surfactants on the biodegradation of phenanthrene in soil: Bioavailability and microbial community responses.

The present study was conducted to systematically explore the mechanisms underlying the impact of various surfactants (CTAB, SDBS, Tween 80 and rhamnolipid) at different doses (10, 100 and 1000 mg/kg) on the biodegradation of a model polycyclic aromatic hydrocarbon (PAH) by indigenous soil microorganisms, focusing on bioavailability and community responses. The cationic surfactant CTAB inhibited the biodegradation of phenanthrene within the whole tested dosage range by decreasing its bioavailability and adversely affecting soil microbial communities. Appropriate doses of SDBS (1000 mg/kg), Tween 80 (100, 1000 mg/kg) and rhamnolipid at all amendment levels promoted the transformation of phenanthrene from the very slow desorption fraction (Fvslow) to bioavailable fractions (rapid and slow desorption fractions, Frapid and Fslow), assessed via Tenax extraction. However, only Tween 80 and rhamnolipid at these doses significantly improved both the rates and extents of phenanthrene biodegradation by 22.1-204.3 and 38.4-76.7 %, respectively, while 1000 mg/kg SDBS had little effect on phenanthrene removal. This was because the inhibitory effects of anionic surfactant SDBS, especially at high doses, on the abundance, diversity and activity of soil microbial communities surpassed the bioavailability enhancement in dominating biodegradation. In contrast, the nonionic surfactant Tween 80 and biosurfactant rhamnolipid enhanced the bioavailability of phenanthrene for degradation and also that to specific degrading bacterial genera, which stimulated their growth and increased the abundance of the related nidA degradation gene. Moreover, they promoted the total microbial/bacterial biomass, community diversity and polyphenol oxidase activity by providing available substrates and nutrients. These findings contribute to the design of suitable surfactant types and dosages for mitigating the environmental risk of PAHs and simultaneously benefiting microbial ecology in soil through bioremediation.

miR-93-5p impairs autophagy-lysosomal pathway via TET3 after subarachnoid hemorrhage.

Intact autophagy-lysosomal pathway (ALP) in neuronal survival is crucial. However, it remains unclear whether ALP is intact after subarachnoid hemorrhage (SAH). Ten-eleven translocation (TET) 3 primarily regulates genes related to autophagy in neurons in neurodegenerative diseases. This study aims to investigate the role of TET3 in the ALP following SAH. The results indicate that the ALP is impaired after SAH, with suppressed autophagic flux and an increase in autophagosomes. This is accompanied by a decrease in TET3 expression. Activation of TET3 by α-KG can improve ALP function and neural function to some extent. Silencing TET3 in neurons significantly inhibited the ALP function and increased apoptosis. Inhibition of miR-93-5p, which is elevated after SAH, promotes TET3 expression. This suggests that the downregulation of TET3 after SAH is, at least in part, due to elevated miR-93-5p. This study clarifies the key role of TET3 in the functional impairment of the ALP after SAH. The preliminary exploration revealed that miR-93-5p could lead to the downregulation of TET3, which could be a new target for neuroprotective therapy after SAH.

A multi-modal framework improves prediction of tissue-specific gene expression from a surrogate tissue.

BACKGROUND: Tissue-specific analysis of the transcriptome is critical to elucidating the molecular basis of complex traits, but central tissues are often not accessible. We propose a methodology, Multi-mOdal-based framework to bridge the Transcriptome between PEripheral and Central tissues (MOTPEC). METHODS: Multi-modal regulatory elements in peripheral blood are incorporated as features for gene expression prediction in 48 central tissues. To demonstrate the utility, we apply it to the identification of BMI-associated genes and compare the tissue-specific results with those derived directly from surrogate blood. FINDINGS: MOTPEC models demonstrate superior performance compared with both baseline models in blood and existing models across the 48 central tissues. We identify a set of BMI-associated genes using the central tissue MOTPEC-predicted transcriptome data. The MOTPEC-based differential gene expression (DGE) analysis of BMI in the central tissues (including brain caudate basal ganglia and visceral omentum adipose tissue) identifies 378 genes overlapping the results from a TWAS of BMI, while only 162 overlapping genes are identified using gene expression in blood. Cellular perturbation analysis further supports the utility of MOTPEC for identifying trait-associated gene sets and narrowing the effect size divergence between peripheral blood and central tissues. INTERPRETATION: The MOTPEC framework improves the gene expression prediction accuracy for central tissues and enhances the identification of tissue-specific trait-associated genes. FUNDING: This research is supported by the National Natural Science Foundation of China 82204118 (D.Z.), the seed funding of the Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province (2020E10004), the National Institutes of Health (NIH) Genomic Innovator Award R35HG010718 (E.R.G.), NIH/NHGRI R01HG011138 (E.R.G.), NIH/NIA R56AG068026 (E.R.G.), NIH Office of the Director U24OD035523 (E.R.G.), and NIH/NIGMS R01GM140287 (E.R.G.).

Targeting colorectal cancer with Herba Patriniae and Coix seed: Network pharmacology, molecular docking, and in vitro validation.

BACKGROUND: Herba Patriniae and Coix seed (HC) constitute a widely utilized drug combination in the clinical management of colorectal cancer (CRC) that is known for its diuretic, anti-inflammatory, and swelling-reducing properties. Although its efficacy has been demonstrated in a clinical setting, the active compounds and their mechanisms of action in CRC treatment remain to be fully elucidated. AIM: To identify the active, CRC-targeting components of HC and to elucidate the mechanisms of action involved. METHODS: Active HC components were identified and screened using databases. Targets for each component were predicted. CRC-related targets were obtained from human gene databases. Interaction targets between HC and CRC were identified. A "drug-ingredient-target" network was created to identify the core components and targets involved. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to elucidate the key pathways involved. Molecular docking between core targets and key components was executed. In vitro experiments validated core monomers. RESULTS: Nineteen active components of HC were identified, with acacetin as the primary active compound. The predictive analysis identified 454 targets of the active compounds in HC. Intersection mapping with 2685 CRC-related targets yielded 171 intervention targets, including 30 core targets. GO and KEGG analyses indicated that HC may influence the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Molecular docking showed that acacetin exhibited an optimal interaction with AKT1, identifying PI3K, AKT, and P53 as key genes likely targeted by HC during CRC treatment. Acacetin inhibited HT-29 cell proliferation and migration, as well as promoted apoptosis, in vitro. Western blotting analysis revealed increased p53 and cleaved caspase-3 expression and decreased levels of p-PI3K, p-Akt, and survivin, which likely contributed to CRC apoptosis. CONCLUSION: Acacetin, the principal active compound in the HC pair, inhibited the proliferation and migration of HT-29 cells and promoted apoptosis through the PI3K/Akt/p53 signaling pathway.

The "blownknee" patient's stress fracture of distal tibial component after unilateral TKA: A case report.

RATIONALE: Periprosthetic fractures (PPF) are rare complications of total knee arthroplasty (TKA). The most common PPF after TKA is supracondylar femoral fracture, which is a relatively rare complication that is usually associated with high-energy trauma, with a reported incidence ranging from 0.4 to 1.7% according to the AOANJRR. However, in TKA patients, it is rarer that the stress fracture around the tibial prosthesis occurs due to changes in the lower limb force line, increasing weight-bearing, and changes in walking gait. PATIENT CONCERNS: A 68-year-old woman visited our hospital with "both knees had aggravated pain and deformity for 8 years." TKA was performed first on the left knee and the patient was discharged within 1 week. Three months later, the patient complained of pain in the upper middle 1/3 part of the medial tibia for 2 weeks, which gradually worsened and affected weight-bearing. DIAGNOSES: Physical examination showed that the left knee joint presented varus deformity, and the right valgus deformity, which diagnosed as osteoarthritis of both knees and was so-called "blownknee". The disease was initially diagnosed as osteoarthritis of both knees on first admission and PPF of the tibia in second. INTERVENTIONS: Three operations were performed on this patient. The first was TKA of the left knee, the second was open reduction and internal fixation of the PPF of the tibia 3 months after the first operation, and the third was TKA of the right knee. OUTCOMES: Until now, the patient has had no recurrent PPF, and the fracture is healing from the last X-ray. LESSONS: Clinicians should be aware of the possibility of PPF after TKA, especially in such patients, the most preferred surgical treatment method was open reduction and internal fixation of fractures using locking plates, and if the PPF with loosened implants, Revision TKA, or megaprosthesis was the better choice.

A prospective multicentre study evaluating the performance of the modified simple biliary atresia scoring system in predicting biliary atresia.

PURPOSE: Early diagnosis of biliary atresia (BA) is critical for best outcomes, but is challenged by overlapping clinical manifestations with other causes of obstructive jaundice in neonates. We evaluate the performance of the modified Simple BA Scoring System (SBASS) in diagnosing BA. METHODS: We performed a prospective, cross-sectional study on infants with cholestatic jaundice (June 2021-December 2022). Modified SBASS scoring was applied and compared to the eventual diagnosis (as per intraoperative cholangiogram (IOC) and liver histopathology). The score (0-6), consists of gall bladder length < 1.6 cm (+ 1), presence of triangular cord sign (+ 1), conjugated bilirubin:total bilirubin ratio > 0.7(+ 2), gamma-glutamyl transferase (GGT) ≥ 200 U/L (+ 2). RESULTS: 73 were included: Fifty-two (71%) had BA. In the non-BA group, 6 (28%) had percutaneous cholangiography (PTC) while 15 (72%) had intraoperative cholangiogram (IOC). At a cut-off of 3, the modified SBASS showed sensitivity of 96.2%, specificity of 61.9% and overall accuracy of 86.3% in diagnosing BA. Area under receiver operating characteristic curve was 0.901. GGT had the highest sensitivity (94.2%), while triangular cord sign showed the highest specificity at 95.2%. CONCLUSION: The SBASS provides a bedside, non-invasive scoring system for exclusion of BA in infantile cholestatic jaundice and reduces the likelihood of negative surgical explorations.

Poor sleep duration and E-cigarette/Cigarette use among US adults with cardiovascular diseases: findings from the 2022 BRFSS cross-sectional study.

BACKGROUND: Studies have explored the connections between tobacco use, sleep and cardiovascular disease (CVD) risks in adults, but no study has examined the link between tobacco use and sleep among adults with CVDs. This study explores the association between tobacco use (cigarette only, e-cigarette only, and dual use) and poor sleep duration among adults with CVDs. METHODS: A sample of 47,180 US adults with CVDs (myocardial infarction, coronary heart disease, or stroke) was drawn from the 2022 Behavioral Risk Factor Surveillance System (BRFSS) cross-sectional survey. Poor/inadequate sleep (< 7 h/24-hour) was defined based on National Sleep Foundation recommendations. Logistic regression models assessed tobacco use status across seven categories (i.e., non-use [reference], current [past-month use] cigarette only, current e-cigarettes only, current dual use, former cigarette only, former e-cigarette only, and former dual use) with inadequate sleep, adjusting for demographics and health conditions. RESULTS: Overall, 40% of US adults with a history of CVD reported inadequate sleep. Current cigarette, e-cigarette, and dual use were associated with a relatively higher proportion of inadequate sleep duration. Unweighted findings revealed a significant association between current cigarette use (OR = 1.35, 95%CI: 1.26-1.44), e-cigarette use (1.40 [1.19-1.63]) and dual use (1.50 [1.27-1.77]) and increased odds of reporting inadequate sleep among adults with CVDs. Weighted analysis showed only a significant link between current cigarette use and inadequate sleep (1.34 [1.17-1.54]). CONCLUSIONS: Current cigarette use is associated with poor sleep in adults with CVDs. Unweighted findings suggested a similar association for e-cigarettes. Interventions targeting smoking cessation may offer promising avenues for improving sleep health and reducing the burden on adults with CVDs.

Corrigendum: Extracellular HSP90α interacts with ER stress to promote fibroblasts activation through PI3K/AKT pathway in pulmonary fibrosis.

[This corrects the article DOI: 10.3389/fphar.2021.708462.].

ALKBH5 governs human endoderm fate by regulating the DKK1/4-mediated Wnt/ß-catenin activation.

N6-methyladenonsine (m6A) is ubiquitously distributed in mammalian mRNA. However, the precise involvement of m6A in early development has yet to be fully elucidated. Here, we report that deletion of the m6A demethylase ALKBH5 in human embryonic stem cells (hESCs) severely impairs definitive endoderm (DE) differentiation. ALKBH5-/- hESCs fail to undergo the primitive streak (PS) intermediate transition that precedes endoderm specification. Mechanistically, we show that ALKBH5 deficiency induces m6A hypermethylation around the 3' untranslated region (3'UTR) of GATA6 transcripts and destabilizes GATA6 mRNA in a YTHDF2-dependent manner. Moreover, GATA6 binds to the promoters of critical regulatory genes involved in Wnt/ß-catenin signaling transduction, including the canonical Wnt antagonist DKK1 and DKK4, which are unexpectedly repressed upon the dysregulation of GATA6 mRNA metabolism. Remarkably, DKK1 and DKK4 both exhibit a pleiotropic effect in modulating the Wnt/ß-catenin cascade and guard the endogenous signaling activation underlying DE formation as potential downstream targets of the ALKBH5-GATA6 regulation. Here, we unravel a role of ALKBH5 in human endoderm formation in vitro by modulating the canonical Wnt signaling logic through the previously unrecognized functions of DKK1/4, thus capturing a more comprehensive role of m6A in early human embryogenesis.

Systematic review and meta-analysis of ROSA vs. conventional therapy for intracerebral hemorrhage.

The purpose of this systematic review and meta-analysis was to evaluate the perioperative and short-term results of the Robot of Stereotactic Assistance (ROSA) compared to traditional approaches in individuals with intracerebral hemorrhage (ICH). We will perform a comprehensive computerized search of PubMed, CNKI, Embase, and Google Scholar to identify relevant literature on ROSA vs. conventional therapy for intracerebral hemorrhage, covering publications from the inception of each database until July 2024. This study will include both English and Chinese language studies. Literature screening will adhere strictly to inclusion and exclusion criteria, focusing on randomized controlled trials (RCTs) and cohort studies. The ROBINS-I tool is utilized for evaluating bias risk in non-RCTs. Analysis of the data from the studies included will be conducted with Review Manager 5.4.1. The final analysis included 7 retrospective cohort studies and 1 randomized controlled study, involving a total of 844 patients. Among these, 433 patients underwent ROSA, while 411 received conventional treatment (conservative treatment, conventional craniotomy, or stereotactic frame-assisted surgery). Compared to conventional therapy, patients treated with ROSA showed improvements in operative time, postoperative rebleeding, postoperative extubation time, and intracranial infection. Nonetheless, there was no notable contrast in mortality or central hyperthermia outcomes between the two treatments. ROSA is a safe and viable option for treating patients with cerebral hemorrhage, showing significant advantages in terms of surgery duration, postoperative rebleeding, time to remove the breathing tube, and intracranial infection compared to conservative treatment, traditional craniotomy, or stereotactic surgery.

Integration of biological and information technologies to enhance plant autoluminescence.

Autoluminescent plants have been genetically modified to express the fungal bioluminescence pathway (FBP). However, a bottleneck in precursor production has limited the brightness of these luminescent plants. Here, we demonstrate the effectiveness of utilizing a computational model to guide a multiplex five-gene-silencing strategy by an artificial microRNA array to enhance caffeic acid and hispidin levels in plants. By combining loss-of-function-directed metabolic flux with a tyrosine-derived caffeic acid pathway, we achieved substantially enhanced bioluminescence levels. We successfully generated eFBP2 plants that emit considerably brighter bioluminescence for naked-eye reading by integrating all validated DNA modules. Our analysis revealed that the luminous energy conversion efficiency of the eFBP2 plants is currently very low, suggesting that luminescence intensity can be improved in future iterations. These findings highlight the potential to enhance plant luminescence through the integration of biological and information technologies.

Are behavioral interventions a better choice for atopic dermatitis patients? A meta-analysis of 6 randomized controlled trials

Abstract Background The treatment for atopic dermatitis (AD) has been the focus of clinical research, and behavioral intervention is considered an indispensable treatment method. To our knowledge, no relevant meta-analysis has evaluated the effects of behavioral interventions on atopic dermatitis. Objectives To evaluate the effects of behavioral interventions on atopic dermatitis. Methods The authors searched PubMed, EMBASE, and Cochrane CENTRAL to retrieve relevant RCTs (up to Feb 2022). The search strategy involved a combination of related keywords. The Cochrane Q and I2 statistics were used to assess heterogeneity. Results Six RCTs involving seven reports with 246 patients were included. The results suggested that behavioral interventions could relieve eczema severity (correlation coefficient [r = −0.39]; p < 0.001) and scratching severity significantly (r = −0.19; p = 0.017), while not affect itching intensity (r = −0.02; p = 0.840). A sensitivity analysis confirmed the robustness of the results. Study limitations An important limitation of this study was the insufficient number of RCTs and the limited sample size. In addition, the study lacked a control group receiving a type of intervention other than the experimental protocol. Another limitation was the short duration of follow-up. Conclusions This study suggests that behavioral interventions could be effective in treating atopic dermatitis by reducing eczema and scratching severity. Additionally, habit-reversal behavioral therapy may be more effective for treating atopic dermatitis.

TDMPP activation of estrogen receptor 2a regulates smc2 and p53 signaling to interfere with liver development in zebrafish (Danio rerio).

Tris (2,6-dimethylphenyl) phosphate (TDMPP), a novel organic phosphorus flame retardant (OPFR), has been found to have estrogenic activity. Estrogens are critical in regulating various biological responses during liver development. However, the effects of TDMPP on zebrafish liver development remain largely unexplored. Here, we utilized a chemical genetic screening approach to assess the estrogenic effects of TDMPP on liver development and to elucidate the underlying molecular mechanism. Our findings revealed that zebrafish larvae exposed to environmentally relevant concentrations of TDMPP (0.05 and 0.5 µM) exhibited concentration-dependent liver impairments, including reduced liver size, histopathological changes, and hepatocyte apoptosis. In addition, E2 caused similar adverse effects to TDMPP, but the pharmacological blockade of estrogen synthesis alleviated the effects on liver development. Chemical inhibitors and morpholino knockdown assays indicated that the reduction of esr2a blocked TDMPP-induced liver impairments, which was further confirmed in the esr2a-/- mutant line. Subsequently, transcriptomic analysis showed that the estrogen receptor activated by TDMPP inhibited the expression of smc2, which was linked to the suppression of liver development through p53 activation. Consistently, overexpression of smc2 and inhibition of p53 evidently rescued hepatic damages induced by TDMPP. Taken together, the above findings identified esr2a, downstream smc2, and p53 as important regulators for the estrogenic effects of TDMPP on liver development. Our work fills crucial gaps in the current knowledge of TDMPP's hepatotoxicity, providing new insights into the adverse effects of TDMPP and the molecular mechanisms of action. These findings underscore the need for further ecological risk assessment and regulatory considerations.