HBO1 determines SMAD action in pluripotency and mesendoderm specification.

TGF-ß signaling family plays an essential role to regulate fate decisions in pluripotency and lineage specification. How the action of TGF-ß family signaling is intrinsically executed remains not fully elucidated. Here, we show that HBO1, a MYST histone acetyltransferase (HAT) is an essential cell intrinsic determinant for TGF-ß signaling in human embryonic stem cells (hESCs). HBO1-/- hESCs fail to response to TGF-ß signaling to maintain pluripotency and spontaneously differentiate into neuroectoderm. Moreover, HBO1 deficient hESCs show complete defect in mesendoderm specification in BMP4-triggered gastruloids or teratomas. Molecularly, HBO1 interacts with SMAD4 and co-binds the open chromatin labeled by H3K14ac and H3K4me3 in undifferentiated hESCs. Upon differentiation, HBO1/SMAD4 co-bind and maintain the mesoderm genes in BMP4-triggered mesoderm cells while lose chromatin occupancy in neural cells induced by dual-SMAD inhibition. Our data reveal an essential role of HBO1, a chromatin factor to determine the action of SMAD in both human pluripotency and mesendoderm specification.

A novel online calculator based on clinical features and hematological parameters to predict total skin clearance in patients with moderate to severe psoriasis.

BACKGROUND: Treatment responses to biologic agents vary between patients with moderate to severe psoriasis; while some patients achieve total skin clearance (TSC), a proportion of patients may only experience partial improvement. OBJECTIVE: This study was designed to identify potential predictors for achieving TSC in psoriasis patients treated with IL-17 inhibitors. It also aimed to develop an easy-to-use calculator incorporating these factors by the nomogram to predict TSC response. METHODS: A total of 381 patients with psoriasis receiving ixekizumab were included in the development cohort and 229 psoriasis patients who initiated secukinumab treatment were included in the validation cohort. The study endpoint was achieving TSC after 12 weeks of IL-17 inhibitors treatment, defined as the 100% improvement in Psoriasis Area and Severity Index (PASI 100). Multivariate Cox regression analyses and LASSO analysis were performed to identify clinical predictors and blood predictors respectively. RESULTS: The following parameters were identified as predictive factors associated with TSC: previous biologic treatment, joint involvement, genital area affected, early response (PASI 60 at week 4), neutrophil counts and uric acid levels. The nomogram model incorporating these factors achieved good discrimination in the development cohort (AUC, 0.721; 95% CI 0.670-0.773) and validation cohort (AUC, 0.715; 95% CI 0.665-0.760). The calibration curves exhibited a satisfactory fit, indicating the accuracy of the model. Furthermore, the decision curve analysis confirmed the clinical utility of the nomogram, highlighting its favorable value for practical application. Web-based online calculator has been developed to enhance the efficiency of clinical applications. CONCLUSIONS: This study developed a practical and clinically applicable nomogram model for the prediction of TSC in patients with moderate to severe psoriasis. The nomogram model demonstrated robust predictive performance and exhibited significant clinical utility. Trial registration A multi-center clinical study of systemic treatment strategies for psoriasis in Chinese population;ChiCTR2000036186; Registered 31 August 2020; https://www.chictr.org.cn/showproj.html?proj=58256 .

CBX4 contributes to HIV-1 latency by forming phase-separated nuclear bodies and SUMOylating EZH2.

The retrovirus HIV-1 integrates into the host genome and establishes a latent viral reservoir that escapes immune surveillance. Molecular mechanisms of HIV-1 latency have been studied extensively to achieve a cure for the acquired immunodeficiency syndrome (AIDS). Latency-reversing agents (LRAs) have been developed to reactivate and eliminate the latent reservoir by the immune system. To develop more promising LRAs, it is essential to evaluate new therapeutic targets. Here, we find that CBX4, a component of the Polycomb Repressive Complex 1 (PRC1), contributes to HIV-1 latency in seven latency models and primary CD4+ T cells. CBX4 forms nuclear bodies with liquid-liquid phase separation (LLPS) properties on the HIV-1 long terminal repeat (LTR) and recruits EZH2, the catalytic subunit of PRC2. CBX4 SUMOylates EZH2 utilizing its SUMO E3 ligase activity, thereby enhancing the H3K27 methyltransferase activity of EZH2. Our results indicate that CBX4 acts as a bridge between the repressor complexes PRC1 and PRC2 that act synergistically to maintain HIV-1 latency. Dissolution of phase-separated CBX4 bodies could be a potential intervention to reactivate latent HIV-1.

(±)-Hypernumqulins A-H: Eight pairs of unexpected [2+2] cycloaddition sesquiterpenoid alkaloid with 6/6/6/4/10 ring system from Hypericum monogynum L.

(±)-Hypernumqulins A-H (1-8), eight pairs of enantiomeric quinoline alkaloids fused with an isopentenyl and a germacrane-type sesquiterpenoid, featuring an unprecedented skeleton with 6/6/6/4/10 ring system, were isolated from Hypericum monogynum L. under the guidance of molecular networking strategy. Their structures including absolute configuration were elucidated by NMR spectroscopy analysis, X-ray crystallography and quantum chemical calculation. The proposed [2+2] cycloaddition may play a key biogenic step in building the unexpected skeleton. Most of the isolates exhibited cytotoxicity with IC50 values ranging from 2.82 ± 0.03 to 45.25 ± 1.26 µM against MCF-7, A549 or SGC7901 cells. Furthermore, compounds (±)-1 and (-)-1 could induce apoptosis by upregulating the protein expression level of Bax and downregulating of Bcl-2 in MCF-7 cells. These findings provided the first example of germacrane sesquiterpene quinoline alkaloids, and supported the possibilities for the development of new anti-tumor agents.

Who will name new plant species? Temporal change in the origins of taxonomists in China.

Discovery rates of new plant species need to be accelerated because many species will be extinct before they are formally described. Current studies have focused on where new species may occur and their characteristics. However, who will actually discover and describe these new species has received limited attention. Here, we used 31 576 vascular plant species distributed and described in China as a case study to explore the temporal patterns of the nationalities of the taxonomists. We found that most recently described species are endemic species, and there has been an increasing proportion of species descriptions by resident Chinese taxonomists over time. The proportion of species described by resident taxonomists reached an average of 80.8% between 1977 and 2018. By contrast, species discoveries by non-resident experts, often non-endemic species, showed signs of levelling off. Our study underscores an urgent need for training of, support for and collaboration with resident taxonomists in megadiverse countries with a high potential of discovering undescribed plant species.

Learning curve of laparoscopic inguinal hernia repair: systematic review, meta-analysis, and meta-regression.

BACKGROUND: Laparoscopic inguinal hernia repair has a long learning curve. It can be a technically challenging procedure and initially presents an unfamiliar view of inguinal anatomy. The aim of this review was to evaluate published literature relating to the learning curve of laparoscopic inguinal hernia repair and identify the number of cases required for proficiency. The secondary aim was to compare outcomes between surgeons before and after this learning curve threshold had been attained. METHODS: A systematic literature search was conducted in databases of PubMed, Medline, Embase, Web of Science, and Cochrane Library, to identify studies that evaluated the learning curve of laparoscopic inguinal hernia repair. A meta-regression analysis was undertaken to identify the number of cases to achieve surgical proficiency, and a meta-analysis was performed to compare outcomes between cases that were undertaken during a surgeon's learning phase and experienced phase of the curve. RESULTS: Twenty-two studies were included in this review, with 19 studies included in the meta-regression analysis, and 11 studies included in the meta-analysis. Mixed-effects Poisson regression demonstrated that there was a non-linear trend in the number of cases required to achieve surgical proficiency, with a 2.7% year-on-year decrease. The predicted number of cases to achieve surgical proficiency in 2020 was 32.5 (p < 0.01). The meta-analysis determined that surgeons in their learning phase may experience a higher rate of conversions to open (OR 4.43, 95% CI 1.65, 11.88), postoperative complications (OR 1.61, 95% CI 1.07, 2.42), and recurrences (OR 1.32, 95% CI 0.40, 4.30). CONCLUSION: Laparoscopic inguinal hernia repair has a well-defined learning curve. While learning surgeons demonstrated reasonable outcomes, supervision during this period may be appropriate given the increased risk of conversion to open surgery. These data may benefit learning surgeons in the skill development of minimally invasive inguinal hernia repairs.

Preoperative estimation of the survival of patients with unresectable hepatocellular carcinoma achieving complete response after conventional transcatheter arterial chemoembolization: assessments of clinical and LI-RADS MR features.

PURPOSE: To identify the associations of clinical and magnetic resonance (MR) features with overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC) achieving complete response (CR) after conventional transcatheter arterial chemoembolization (TACE) and to further develop an individual nomograph to estimate the survival probability. MATERIALS AND METHODS: A total of 112 patients with unresectable HCC treated with TACE as first-line treatment were retrospectively evaluated. Potential risk factors associated with OS were identified by univariate and multivariate Cox analyses. The survival model was developed by multivariate Cox proportional hazard model. The area under the receiver operating characteristic curve was calculated to assess the performance of each marker and of the whole model. Discrimination was performed using Kaplan-Meier curves, and the survival curves were compared by the log-rank test. A nomogram derived from the survival model was established. RESULTS: Multivariate Cox analyses indicated that nonsmooth tumor margin, peritumoral enhancement, fat sparing in solid mass, and Barcelona clinic liver cancer (BCLC) stage were independent risk indicators associated with OS. The survival model showed acceptable diagnostic power, with an area under the curve (AUC) of 0.687. Kaplan-Meier curves demonstrated that the model discriminated well, as the high-risk and low-risk groups had median survival times of 21.6 months and 34.8 months, respectively (log-rank test, P = 0.01). CONCLUSIONS: Nonsmooth tumor margin, peritumoral enhancement, fat sparing in solid mass, and BCLC stage were potential biomarkers to evaluate the survival with favorable performance and discriminate HCC patients with CR under conventional TACE treatment.

Clinical features and outcomes of 31 children with congenital hypothyroidism missed by neonatal screening.

OBJECTIVE: To investigate the clinical features and outcomes of children with congenital hypothyroidism (CH) missed by neonatal screening. METHODS: The clinical and laboratory date of 31 children with CH missed by neonatal screening from February 2015 to February 2022 in Guangzhou Women and Children's Medical Center were retrospectively analyzed. Whole-exome high-throughput sequencing analysis was performed in 17 patients. RESULTS: Among the 31 patients, 19 cases (61.3%) were preterm, 12 cases (38.7%) were term neonates. The median value of gestation age was 36 (26-40) weeks, birth weight was 2.35 (0.75-3.70) kg, diagnosed age was 20 d (7 d-4 years), dry blood spot thyrotropin was 4.18 (0.34-8.97) mU/L. Nine cases (29.0%) were same-sex twins and 4 cases (12.9%) had a family history of hypothyroidism. The initial clinical symptoms were growth retardation in 11 cases (35.5%), prolonged jaundice in 7 cases (22.6%), short stature, abdominal distension, fetal edema and goiter in 1 case (3.2%), respectively. Genetic analysis of the 17 children showed that DUOX2 gene mutations were detected in 10 cases (6 cases with biallelic mutations and 4 cases with monoallelic mutations), of whom 3 had a family history of hypothyroidism. A total of 22 patients were reevaluated at the age of 2-3 years, of whom 17 cases (77.3%) were transient CH and 5 cases (22.7%) were permanent CH. Among the 10 cases with DUOX2 gene mutations, 6 cases were transient CH, 1 case was permanent CH, and 3 cases (< 3 years old) were still under treatment with L-thyroxine. CONCLUSIONS: False negative results on neonatal screening for CH often occurs in preterm birth, low birth weight, same-sex twins, family history of hypothyroidism, and DUOX2 defects are the common molecular pathogenesis, most of whom are transient CH. Thyroid function should be evaluated in time for children with unexplained slow growth and delayed jaundice regression.

Vitamin C-dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition.

Hematopoietic stem cells (HSCs)/progenitor cells (HPCs) are generated from hemogenic endothelial cells (HECs) during the endothelial-to-hematopoietic transition (EHT); however, the underlying mechanism remains poorly understood. Here, using an array of approaches, including CRSPR/Cas9 gene knockouts, RNA-Seq, ChIP-Seq, ATAC-Seq etc., we report that vitamin C (Vc) is essential in HPC generation during human pluripotent stem cell (hPSC) differentiation in defined culture conditions. Mechanistically, we found that the endothelial cells generated in the absence of Vc fail to undergo the EHT because of an apparent failure in opening up genomic loci essential for hematopoiesis. Under Vc deficiency, these loci exhibited abnormal accumulation of histone H3 trimethylation at Lys-27 (H3K27me3), a repressive histone modification that arose because of lower activities of demethylases that target H3K27me3. Consistently, deletion of the two H3K27me3 demethylases, Jumonji domain-containing 3 (JMJD3 or KDM6B) and histone demethylase UTX (UTX or KDM6A), impaired HPC generation even in the presence of Vc. Furthermore, we noted that Vc and jmjd3 are also important for HSC generation during zebrafish development. Together, our findings reveal an essential role for Vc in the EHT for hematopoiesis, and identify KDM6-mediated chromatin demethylation as an important regulatory mechanism in hematopoietic cell differentiation.

Estimating Residual Life Distributions of Complex Operational Systems Using a Remaining Maintenance Free Operating Period (RMFOP)-Based Methodology.

Recent developments in the area of condition monitoring research have been targeted towards predicting machinery health condition for the purpose of preventative maintenance. Typically, published research uses data collected from rotating components (bearings, cutting tools, etc.) working in an idealized lab environment as the case study for prognosis algorithm validations. However, the operational implementation in industry is still very sporadic, mainly owing to the lack of proper data allowing sufficiently mature development of comprehensive methodologies. The prognosis methodology presented herein bridges the gap between academic research and industrial implementations by employing a novel time period for prognosis and implementing random coefficients regression models. The definition of the remaining maintenance-free operating period (RMFOP) is proposed first, which helps to transform the usefulness of the degradation data that is readily available from data short of failure. Degradation patterns are subsequently extracted from the original degradation data, before fitting into either of two regression models (linear or exponential). The system residual life distributions are then computed and updated by estimating the parameter statistics within the model. This RMFOP-based methodology is validated using real-world degradation data collected from multiple operational railway switch systems across Great Britain. The results indicate that both the linear model and the exponential model can produce residual life distributions with a sufficient prediction accuracy for this specific application. The exponential model gives better predictions, the accuracy of which also improves as more of system life percentage has elapsed. By using the RMFOP methodology, switch system health condition affected by an incipient overdriving fault is recognized and predicted.

Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium.

Cortisol, a physiologic glucocorticoid (GC), is essential for growth and differentiation of the airway epithelium. Epithelial function influences inflammation in chronic respiratory diseases. Synthetic GCs, including inhaled corticosteroids, exert anti-inflammatory effects in airway epithelium by transactivation of genes and by inhibition of proinflammatory cytokine release. We examined the effect of cortisol on the actions of synthetic GCs in the airway epithelium, demonstrating that cortisol acts like a partial agonist at the GC receptor (GR), limiting GC-induced GR-dependent transcription in the BEAS-2B human bronchial epithelial cell line. Cortisol also limited the inhibition of granulocyte macrophage colony-stimulating factor release by synthetic GCs in TNF-α-activated BEAS-2B cells. The relevance of these findings is supported by observations on tracheal epithelium obtained from mice treated for 5 d with systemic GC, showing limitations in selected GC effects, including inhibition of IL-6. Moreover, gene transactivation by synthetic GCs was compromised by standard air-liquid interface (ALI) growth medium cortisol concentration (1.4 µM) in the ALI-differentiated organotypic culture of primary human airway epithelial cells. These findings suggest that endogenous corticosteroids may limit certain actions of synthetic pharmacological GCs and contribute to GC insensitivity, particularly when corticosteroid levels are elevated by stress.-Prodanovic, D., Keenan, C. R., Langenbach, S., Li, M., Chen, Q., Lew, M. J., Stewart, A. G. Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium.

[Characteristics of DUOXA2 gene mutation in children with congenital hypothyroidism].

OBJECTIVE: To investigate the characteristics of DUOXA2 gene mutation and the genotype-phenotype relationship in children with congenital hypothyroidism (CH) in Guangzhou, China. METHODS: A total of 20 CH patients with suspected thyroid dyshormonogenesis who had no DUOX2 gene mutation were enrolled. These patients who were born between 2011 and 2012 were screened and diagnosed with CH in the Guangzhou Newborn Screening Center. PCR and direct sequencing were used to analyze DUOXA2 gene mutation. RESULTS: Among the 20 patients, 2 had p.Y246X/p.Y246X homozygous mutation; 4 had monoallelic heterozygous mutation, among whom 2 carried the known pathogenic mutation c.413-414insA, 1 carried p.Y246X, and 1 carried a novel mutation, p.G79R. Reevaluation was performed at the age of 2-3 years, and the results showed that the two patients with p.Y246X/p.Y246X homozygous mutation were manifested as transient and mild permanent CH, respectively. Among the four patients with monoallelic heterozygous mutation, the one who carried p.Y246X mutation was manifested as typical permanent CH, and the other three were manifested as transient CH. CONCLUSIONS: DUOXA2 gene mutation is a common molecular pathogenic basis for CH children with suspected thyroid dyshormonogenesis in Guangzhou, and most of them are manifested as transient CH. There is no association between DUOXA2 genotypes and phenotypes. The novel mutation p.G79R is probably a pathogenic mutation.

Endoplasmic reticulum stress mechanisms and exercise intervention in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a metabolic disease primarily characterized by insulin resistance (IR) and insufficient insulin secretion. The unfolded protein response (UPR) overactivation induced by endoplasmic reticulum stress (ERS) appears to play a key role in this process, although the exact pathogenesis of T2DM is not fully understood. Studies have demonstrated that appropriate exercise can regulate ERS in the heart, liver, pancreas, skeletal muscle, and other body tissues leading to an improvement in diabetes and its complications. However, the exact mechanism remains unclear. By analyzing the relationship between ERS, T2DM pathology, and exercise intervention, this review concludes that exercise can increase insulin sensitivity, inhibit IR, promote insulin secretion and alleviate T2DM by regulating ERS. This paper specifically reviews the signaling pathways by which ERS induces diabetes, the mechanisms of exercise regulation of ERS in diabetes, and the varying effects of different types of exercise on diabetes improvement through ERS mechanisms. Physical exercise is an effective non-pharmacological intervention for T2DM. Thus, further exploration of how exercise regulates ERS in diabetes could refine "precision exercise medicine" for diabetes and identify new drug targets.

The associations between high-levels of urine benzophenone-type UV filters (BPs) and changes in serum lipid concentrations.

Little is known about the potential health impacts of benzophenone-type UV filters (BPs) exposure among the general population. In our study conducted in Wuxi, China, we investigated the associations between the concentrations of eight BP-derivatives and five target lipid molecules. We collected basic information, serum, and urine samples from 120 residents aged 9 to 80 in Wuxi. We determined BPs in urine samples and lipid levels in serum samples. Generalized linear models were used to evaluate the differences in ln-transformed serum target lipids levels (µg/L) with different urine BPs quartiles compared to the lowest quartile. Benzophenone-4 (BP-4) had the highest detection rate (95.0%) and geometric mean concentration (1.96 µg/L) among all the BP-derivatives in our study population. The exposure levels of BPs were generally higher in females than in males. Participants in the 9-17 and 18-50 age groups exhibited greater levels of exposure to BPs than those in the 51-80 age group. We observed statistically significant changes in LysoPC (18:0), LysoPE (18:0), ΣLPL, and ΣTL concentrations between the highest and lowest quartiles of BP-4. Similar changes were found in LysoPE (18:0) concentration between the highest and lowest quartiles of ΣBP-3 and ΣBPs. High urine BP concentrations were associated with variations in our target serum lipids involved in neurological and metabolic disorders, and posed a potential health risk. Future studies are warranted to further validate and elucidate our findings.

Effect of laparoscopic sleeve gastrectomy versus laparoscopic Roux-en-Y gastric bypass on body composition.

BACKGROUND: There is limited data with respect to body composition changes for laparoscopic sleeve gastrectomy (SG) and laparoscopic Roux-en-Y gastric bypass (RYGB). The objective of this study was to analyse changes in body composition between these two procedures during the first year after bariatric surgery. METHODS: A prospective study was performed in patients undergoing bariatric surgery at two tertiary hospitals between 2017 and 2023. Body composition was assessed with dual-energy x-ray absorptiometry immediately before surgery, and at 1-, 6-, 12-, 18- and 24-months post-operatively, with a subgroup analysis performed for patients who undertook a scan at 18- and 24-months. Total weight loss (TWL), body mass index (BMI), fat mass (FM), lean body mass (LBM) and bone mineral content (BMC) parameters were compared between SG and RYGB. RESULTS: Forty-five patients were included in this series (SG n = 30, RYGB n = 15). There was a significant reduction in mean %TWL of 26.94 ± 8.86% and mean BMI of 11.12 ± 3.70 kg/m2 over 12-months. LBM accounted for 17.8% of TWL over 12-months, SG and RYGB did not differ in terms of loss of FM or LBM. For both procedures, the loss of LBM appeared to plateau at 6-months post-operatively. The only statistically significant finding between the two procedures was that RYGB resulted in an additional 0.06 kg loss compared with SG. CONCLUSION: SG and RYGB have been shown to have comparable weight loss and body composition changes in the short-to-medium term following surgery. LBM reduction was most significant in the early post-operative period across the entire cohort.

Recent Progress of Wide Bandgap Perovskites towards Two-Terminal Perovskite/Silicon Tandem Solar Cells.

Perovskite/silicon tandem solar cells have garnered considerable interest due to their potential to surpass the Shockley-Queisser limit of single-junction Si solar cells. The rapidly advanced efficiencies of perovskite/silicon tandem solar cells benefit from the significant improvements in perovskite technology. Beginning with the evolution of wide bandgap perovskite cells towards two-terminal (2T) perovskite/silicon tandem solar cells, this work concentrates on component engineering, additives, and interface modification of wide bandgap perovskite cells. Furthermore, the advancements in 2T perovskite/silicon tandem solar cells are presented, and the influence of the central interconnect layer and the Si cell on the progression of the tandem solar cells is emphasized. Finally, we discuss the challenges and obstacles associated with 2T perovskite/silicon tandem solar cells, conducting a thorough analysis and providing a prospect for their future.

Association between systemic immune inflammation index, systemic inflammation response index and adult psoriasis: evidence from NHANES.

Background: The systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI) are both novel biomarkers and predictors of inflammation. Psoriasis is a skin disease characterized by chronic inflammation. This study aimed to investigate the potential association between SII, SIRI, and adult psoriasis. Methods: Data of adults aged 20 to 80 years from the National Health and Nutrition Examination Survey (NHANES) (2003-2006, 2009-2014) were utilized. The K-means method was used to group SII and SIRI into low, medium, and high-level clusters. Additionally, SII or SIRI levels were categorized into three groups: low (1st-3rd quintiles), medium (4th quintile), and high (5th quintile). The association between SII-SIRI pattern, SII or SIRI individually, and psoriasis was assessed using multivariate logistic regression models. The results were presented as odds ratios (ORs) and confidence intervals (CIs). Restricted cubic spline (RCS) regression, subgroup, and interaction analyses were also conducted to explore the potential non-linear and independent relationships between natural log-transformed SII (lnSII) levels or SIRI levels and psoriasis, respectively. Results: Of the 18208 adults included in the study, 511 (2.81%) were diagnosed with psoriasis. Compared to the low-level group of the SII-SIRI pattern, participants in the medium-level group had a significantly higher risk for psoriasis (OR = 1.40, 95% CI: 1.09, 1.81, p-trend = 0.0031). In the analysis of SII or SIRI individually, both SII and SIRI were found to be positively associated with the risk of psoriasis (high vs. low group OR = 1.52, 95% CI: 1.18, 1.95, p-trend = 0.0014; OR = 1.48, 95% CI: 1.12, 1.95, p-trend = 0.007, respectively). Non-linear relationships were observed between lnSII/SIRI and psoriasis (both p-values for overall < 0.05, p-values for nonlinearity < 0.05). The association between SII levels and psoriasis was stronger in females, obese individuals, people with type 2 diabetes, and those without hypercholesterolemia. Conclusion: We observed positive associations between SII-SIRI pattern, SII, SIRI, and psoriasis among U.S. adults. Further well-designed studies are needed to gain a better understanding of these findings.

Autophagy is essential for human myelopoiesis.

Emergency myelopoiesis (EM) is essential in immune defense against pathogens for rapid replenishing of mature myeloid cells. During the EM process, a rapid cell-cycle switch from the quiescent hematopoietic stem cells (HSCs) to highly proliferative myeloid progenitors (MPs) is critical. How the rapid proliferation of MPs during EM is regulated remains poorly understood. Here, we reveal that ATG7, a critical autophagy factor, is essential for the rapid proliferation of MPs during human myelopoiesis. Peripheral blood (PB)-mobilized hematopoietic stem/progenitor cells (HSPCs) with ATG7 knockdown or HSPCs derived from ATG7-/- human embryonic stem cells (hESCs) exhibit severe defect in proliferation during fate transition from HSPCs to MPs. Mechanistically, we show that ATG7 deficiency reduces p53 localization in lysosome for a potential autophagy-mediated degradation. Together, we reveal a previously unrecognized role of autophagy to regulate p53 for a rapid proliferation of MPs in human myelopoiesis.

Short-term efficacy and safety of biologics and Janus kinase inhibitors for patients with atopic dermatitis: A systematic review and meta-analysis.

Background: In recent years, biologics targeting key cytokines and Janus kinase (JAK) inhibitors have demonstrated favorable efficacy and safety outcomes for atopic dermatitis (AD) therapy. To evaluate the short-term efficacy and safety of AD therapy involving biologics, JAK inhibitors, and their combination with topical corticosteroids (TCS) for patients with AD, we conducted this systematic review and meta-analysis. Using eligible randomized clinical trials (RCTs) of 12 or 16 weeks of treatment with systemic medications and 4 weeks of topical treatment for AD. Methods: PubMed, Web of Science, ScienceDirect, and the Cochrane Library were searched from inception up to October 25, 2023. English-language randomized clinical trials (RCTs) of 12 or 16 weeks of treatment with systemic medications and 4 weeks of topical treatment for AD were included. Titles, abstracts, and articles were screened in duplicate. Of 7261 citations, 37 studies were included. The data were analyzed using Review Manager 5.4 and the outcomes were measured by the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), the pruritus Numerical Rating Scale (NRS), as well as instances of adverse events (AE), and serious AE (SAE), which were presented as risk ratio (RR) with a 95 % confidence interval (CI). The efficacy of the biological therapies was analyzed with the percentage of patients who have achieved EASI 75, EASI 90, IGA 0/1 and pruritus NRS4, while the safety of treatments was evaluated in terms of the number of patients who had ≥1 AE and who had at least one SAE. Results: A total of 37 studies with 43 cohorts that examined 9 medications and placebo and involved 18172 participants were included. Compared with the placebo, all biologics and JAK inhibitors were associated with a higher response rate in efficacy outcomes, while systematic administration was presented by dupilumab 200 mg subcutaneously every 2 weeks with superior improvement in EASI 90 (RR 9.50, 95 % CI 2.31-39.03) and IGA0/1 (RR 17.00, 95 % CI 2.33-123.78), upadacitinib 30 mg once daily in EASI 75 (RR 5.14, 95 % CI 4.20-6.31) and Pruritus NRS4 (RR 5.73, 95 % CI 4.44-7.39), and external use was presented by ruxolitinib 1.5 % twice daily orally in EASI 75 (RR 4.14, 95 % CI 3.06-5.61) and Pruritus NRS4 (RR 4.08, 95 % CI 2.86-5.81), and most of doses led to a better safety profile. Most doses of baricitinib, dupilumab, tralokinumab, and upadacitinib in combination with TCS demonstrated good efficacy as compared with the control groups (placebo + TCS). However, patients receiving baricitinib at a dosage of 2 mg daily (RR 1.23, 95 % CI 1.02-1.49) and 4 mg daily (RR 1.39, 95 % CI 1.22-1.58) in combination with TCS, exhibited a higher incidence of one or more SAE as compared with those taking placebo + TCS. Conclusion: Our research has revealed that ruxolitinib and dupilumab are effective and safe treatments for mild to moderate AD and moderate to severe AD, respectively. Additionally, the combination of dupilumab and TCS demonstrates greater efficacy and safety compared to baricitinib, tralokinumab, and upadacitinib with TCS as a background treatment for moderate to severe AD. We suggest that the use of topical JAK inhibitors could be a potential alternative to TCS when used in combination with systemic medications, as a novel approach to treat AD. Insufficient different data sources caused by partial interventions were only mentioned in a few articles and low event rates in safety analyses may lead to the results being biased. Further studies directly comparing existing and novel treatments are needed and will be included in forthcoming updates of this review. Our findings could form a useful foundation for developing a new generation of treatment guidelines for AD.

C. tropicalis promotes CRC by down-regulating tumor cell-intrinsic PD-1 receptor via autophagy.

Background: The programmed cell death 1 (PD-1) receptor is an immune checkpoint molecule that induces immune tolerance and mediates the immune escape of tumor cells. It is mainly expressed in immune cells such as T cells, B cells and monocytes. In recent years, studies have shown that tumor cell-intrinsic PD-1 plays different roles in the development of melanoma, Liver cancer and lung cancer. However, the expression and function of PD-1 in colon cancer cells has not been reported. Our previous studies have found that Candida tropicalis (C. tropicalis) can promote CRC tumor growth and chemotherapy resistance to oxaliplatin by regulating mismatch repair system. Whether C. tropicalis participates in the progression of CRC and immunotherapy resistance through regulating the tumor cell-intrinsic PD-1 remains to be further elucidated. Methods & Results: In this study, we first found that high concentrations of C. tropicalis promote tumor growth in cell cultures and xenografts. In addition, we proved that colon cancer cell lines express PD-1 receptors. Knockdown of PD-1 enhanced SW480 viability in-vitro, while overexpression of PD-1 diminished cell viability. Moreover, blocking antibody against PD-1 promotes tumor growth both in SW480 cells and mice CRC xenografts in an adaptive immune-independent manner. We also demonstrated that high concentrations of C. tropicalis can down-regulate tumor cell-intrinsic PD-1 expression in colon cancer cells. CRC cell growth induced by C. tropicalis is partially offset in the presence of PD-1 overexpression. This shows that C. tropicalis promotes CRC progression via controlling the expression of tumor cell-intrinsic PD-1. Mechanistically, we found that C. tropicalis modulates the expression of PD-1 via increasing the autophagy traffic in colon cancer cells. Combining autophagy inhibitor with C. tropicalis treatment partly blocked the CRC tumor growth and reversed the downregulation of PD-1. Conclusion: This study shows that PD-1 is a tumor suppressor in CRC. C. tropicalis can down-regulate tumor cell-intrinsic PD-1 expression via enhancing tumor cells autophagy levels to promote CRC progression. It may provide a new idea and mechanism for answering why the immune monoclonal antibody treatment is ineffective in cancer patients.