The tumor suppressor NF2 modulates TEAD4 stability and activity in Hippo signaling via direct interaction.

As an output effector of the Hippo signaling pathway, the TEAD transcription factor and co-activator YAP play crucial functions in promoting cell proliferation and organ size. The tumor suppressor NF2 has been shown to activate LATS1/2 kinases and interplay with the Hippo pathway to suppress the YAP-TEAD complex. However, whether and how NF2 could directly regulate TEAD remains unknown. We identified a direct link and physical interaction between NF2 and TEAD4. NF2 interacted with TEAD4 through its FERM domain and C-terminal tail and decreased the protein stability of TEAD4 independently of LATS1/2 and YAP. Furthermore, NF2 inhibited TEAD4 palmitoylation and induced the cytoplasmic translocation of TEAD4, resulting in ubiquitination and dysfunction of TEAD4. Moreover, the interaction with TEAD4 is required for NF2 function to suppress cell proliferation. These findings reveal an unanticipated role of NF2 as a binding partner and inhibitor of the transcription factor TEAD, shedding light on an alternative mechanism of how NF2 functions as a tumor suppressor through the Hippo signaling cascade.

The punctilious RNA polymerase II core promoter.

The signals that direct the initiation of transcription ultimately converge at the core promoter, which is the gateway to transcription. Here we provide an overview of the RNA polymerase II core promoter in bilateria (bilaterally symmetric animals). The core promoter is diverse in terms of its composition and function yet is also punctilious, as it acts with strict rules and precision. We additionally describe an expanded view of the core promoter that comprises the classical DNA sequence motifs, sequence-specific DNA-binding transcription factors, chromatin signals, and DNA structure. This model may eventually lead to a more unified conceptual understanding of the core promoter.

UV-A radiation increases biomass yield by enhancing energy flow and carbon assimilation in the edible cyanobacterium Nostoc sphaeroides.

Ultraviolet (UV) A radiation (315-400 nm) is the predominant component of solar UV radiation that reaches the Earth's surface. However, the underlying mechanisms of the positive effects of UV-A on photosynthetic organisms have not yet been elucidated. In this study, we investigated the effects of UV-A radiation on the growth, photosynthetic ability, and metabolome of the edible cyanobacterium Nostoc sphaeroides. Exposures to 5-15 W m-2 (15-46 µmol photons m-2 s-1) UV-A and 4.35 W m-2 (20 µmol photons m-2 s-1) visible light for 16 days significantly increased the growth rate and biomass production of N. sphaeroides cells by 18%-30% and 15%-56%, respectively, compared to the non-UV-A-acclimated cells. Additionally, the UV-A-acclimated cells exhibited a 1.8-fold increase in the cellular nicotinamide adenine dinucleotide phosphate (NADP) pool with an increase in photosynthetic capacity (58%), photosynthetic efficiency (24%), QA re-oxidation, photosystem I abundance, and cyclic electron flow (87%), which further led to an increase in light-induced NADPH generation (31%) and ATP content (83%). Moreover, the UV-A-acclimated cells showed a 2.3-fold increase in ribulose-1,5-bisphosphate carboxylase/oxygenase activity, indicating an increase in their carbon-fixing capacity. Gas chromatography-mass spectrometry-based metabolomics further revealed that UV-A radiation upregulated the energy-storing carbon metabolism, as evidenced by the enhanced accumulation of sugars, fatty acids, and citrate in the UV-A-acclimated cells. Therefore, our results demonstrate that UV-A radiation enhances energy flow and carbon assimilation in the cyanobacterium N. sphaeroides.IMPORTANCEUltraviolet (UV) radiation exerts harmful effects on photo-autotrophs; however, several studies demonstrated the positive effects of UV radiation, especially UV-A radiation (315-400 nm), on primary productivity. Therefore, understanding the underlying mechanisms associated with the promotive effects of UV-A radiation on primary productivity can facilitate the application of UV-A for CO2 sequestration and lead to the advancement of photobiological sciences. In this study, we used the cyanobacterium Nostoc sphaeroides, which has an over 1,700-year history of human use as food and medicine, to explore its photosynthetic acclimation response to UV-A radiation. As per our knowledge, this is the first study to demonstrate that UV-A radiation increases the biomass yield of N. sphaeroides by enhancing energy flow and carbon assimilation. Our findings provide novel insights into UV-A-mediated photosynthetic acclimation and provide a scientific basis for the application of UV-A radiation for optimizing light absorption capacity and enhancing CO2 sequestration in the frame of a future CO2 neutral, circular, and sustainable bioeconomy.

Maize functional requirements drive the selection of rhizobacteria under long-term fertilization practices.

Rhizosphere microbiomes are pivotal for crop fitness, but the principles underlying microbial assembly during root-soil interactions across soils with different nutrient statuses remain elusive. We examined the microbiomes in the rhizosphere and bulk soils of maize plants grown under six long-term (≥ 29 yr) fertilization experiments in three soil types across middle temperate to subtropical zones. The assembly of rhizosphere microbial communities was primarily driven by deterministic processes. Plant selection interacted with soil types and fertilization regimes to shape the structure and function of rhizosphere microbiomes. Predictive functional profiling showed that, to adapt to nutrient-deficient conditions, maize recruited more rhizobacteria involved in nutrient availability from bulk soil, although these functions were performed by different species. Metagenomic analyses confirmed that the number of significantly enriched Kyoto Encyclopedia of Genes and Genomes Orthology functional categories in the rhizosphere microbial community was significantly higher without fertilization than with fertilization. Notably, some key genes involved in carbon, nitrogen, and phosphorus cycling and purine metabolism were dominantly enriched in the rhizosphere soil without fertilizer input. In conclusion, our results show that maize selects microbes at the root-soil interface based on microbial functional traits beneficial to its own performance, rather than selecting particular species.

Synthesis and biological evaluation of triazolones/oxadiazolones as novel urease inhibitors.

Urease is the main virulence factor of infectious gastritis and gastric ulcers. Urease inhibitors are regarded as the first choice for the treatment of such diseases. Based on the triazolone/oxadiazolone skeleton, a urea-like fragment being able to specifically bind the urease activity pocket and prevent urea from hydrolysis, we designed and synthesized 45 triazolones/oxadiazolones as urease inhibitors. Eight compounds were proved to show excellent inhibitory activity against Helicobacter pylori urease, being more potency than the clinically used urease inhibitor acetohydroxamic acid. The most active inhibitor with IC50 value of 1.2 µM was over 20-fold higher potent than the positive control. Enzymatic kinetic assays showed that these novel inhibitors reversibly inhibited urease with a mixed competitive mechanism. Molecular dockings provided evidence for the observations in enzyme assays. Furthermore, these novel inhibitors were proved as drug-like compounds with very low cytotoxicity to mammalian cells and favorable water solubility. These results suggested that triazolone and oxadiazolone were promising scaffolds for the design and discovery of novel urease inhibitors, and were expected as good candidates for further drug development.

Development of Macromolecular Cryoprotectants for Cryopreservation of Cells.

Cryopreservation is a common way for long-term storage of therapeutical proteins, erythrocytes, and mammalian cells. For cryoprotection of these biosamples to keep their structural integrity and biological activities, it is essential to incorporate highly efficient cryoprotectants. Currently, permeable small molecular cryoprotectants such as glycerol and dimethyl sulfoxide dominate in cryostorage applications, but they are harmful to cells and human health. As acting in the extracellular space, membrane-impermeable macromolecular cryoprotectants, which exert remarkable membrane stabilization against cryo-injury and are easily removed post-thaw, are promising candidates with biocompatibility and feasibility. Water-soluble hydroxyl-containing polymers such as poly(vinyl alcohol) and polyol-based polymers are potent ice recrystallization inhibitors, while polyampholytes, polyzwitterions, and bio-inspired (glyco)polypeptides can significantly increase post-thaw recovery with reduced membrane damages. In this review, the synthetic macromolecular cryoprotectants are systematically summarized based on their synthesis routes, practical utilities, and cryoprotective mechanisms. It provides a valuable insight in development of highly efficient macromolecular cryoprotectants with valid ice recrystallization inhibition activity for highly efficient and safe cryopreservation of cells.

Depressive disorder and elevated risk of bell's palsy: a nationwide propensity score-weighting study.

BACKGROUND: Prior studies have reported a potential relationship between depressive disorder (DD), immune function, and inflammatory response. Some studies have also confirmed the correlation between immune and inflammatory responses and Bell's palsy. Considering that the pathophysiology of these two diseases has several similarities, this study investigates if DD raises the risk of developing Bell's palsy. METHODS: This nationwide propensity score-weighting cohort study utilized Taiwan National Health Insurance data. 44,198 patients with DD were identified as the DD cohort and 1,433,650 adult subjects without DD were identified as the comparison cohort. The inverse probability of treatment weighting (IPTW) strategy was used to balance the differences of covariates between two groups. The 5-year incidence of Bell's palsy was evaluated using the Cox proportional-hazard model, presenting results in terms of hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The average age of DD patients was 48.3 ± 17.3 years, and 61.86% were female. After propensity score-weighting strategy, no significant demographic differences emerged between the DD and comparison cohort. The Cox proportional hazards model revealed a statistically significant adjusted IPTW-HR of 1.315 (95% CI: 1.168-1.481) for Bell's palsy in DD patients compared to comparison subjects. Further independent factors for Bell's palsy in this model were age (IPTW-HR: 1.012, 95% CI: 1.010-1.013, p < 0.0001), sex (IPTW-HR: 0.909, 95% CI: 0.869-0.952, p < 0.0001), hypertension (IPTW-HR: 1.268, 95% CI: 1.186-1.355, p < 0.0001), hyperlipidemia (IPTW-HR: 1.084, 95% CI: 1.001-1.173, p = 0.047), and diabetes (IPTW-HR: 1.513, 95% CI: 1.398-1.637, p < 0.0001) CONCLUSION: This Study confirmed that individuals with DD face an elevated risk of developing Bell's palsy. These findings hold significant implications for both clinicians and researchers, shedding light on the potential interplay between mental health and the risk of certain physical health outcomes.

Impact of hemodialysis on efficacies of the antiplatelet agents in coronary artery disease patients complicated with end-stage renal disease.

It is controversial whether hemodialysis affects the efficacy of the antiplatelet agents. We aimed to investigate the impact of hemodialysis on efficacies of the antiplatelet agents in coronary artery disease (CAD) patients complicated with end-stage renal disease (ESRD). 86 CAD patients complicated with ESRD requiring hemodialysis were consecutively enrolled. After 5-day treatment with aspirin and clopidogrel or ticagrelor, the platelet aggregations induced by arachidonic acid (PLAA) or adenosine diphosphate (PLADP), and the P2Y12 reaction unit (PRU) were measured before and after hemodialysis. The propensity matching score method was adopted to generate a control group with normal renal function from 2439 CAD patients. In patients taking aspirin, the PLAA remained unchanged after hemodialysis. In patients taking clopidogrel, the PLADP (37.26 ± 17.04 vs. 31.77 ± 16.09, p = 0.029) and corresponding clopidogrel resistance (CR) rate (23 [48.9%] vs. 14 [29.8%], p = 0.022) significantly decreased after hemodialysis, though PRU remained unchanged. Subgroup analysis indicated that PLADP significantly decreased while using polysulfone membrane (36.8 ± 17.9 vs. 31.1 ± 14.5, p = 0.024). In patients taking ticagrelor, PLADP, and PRU remained unchanged after hemodialysis. ESRD patients had higher incidences of aspirin resistance (AR) and CR compared to those with normal renal function (AR: 16.1% vs. 0%, p = 0.001; CR: 48.4% vs. 24.8%, p = 0.024). Hemodialysis does not have negative effect on the efficacies of aspirin, clopidogrel and ticagrelor in ESRD patients with CAD. ESRD patients have higher incidences of AR and CR compared with those with normal renal function.Trial registration ClinicalTrials.gov Identifier: NCT03330223, first registered January 4, 2018.

Medication use patterns in pregnant women with psoriasis: A nationwide study in Taiwan.

BACKGROUND: Psoriasis, an autoimmune skin condition, affects 2%-4% of the global population, with significant prevalence among women of childbearing age. Pregnancy presents challenges in managing psoriasis due to hormonal changes and treatment safety concerns. Understanding treatment patterns in pregnant women is crucial, given limited real-world evidence. OBJECTIVES: Explore the utilization patterns of medications among pregnant women diagnosed with psoriasis within a real-world data, utilizing data sourced from a nationwide database in Taiwan. METHODS: This nationwide study utilized Taiwan's National Health Insurance (NHI) database and Birth Certificate Application. It included registered pregnant women diagnosed with psoriasis from 2005 to 2014. Medication usage was tracked three years before conception to three years after delivery. Medications were categorized based on Anatomical Therapeutic Chemical (ATC) codes, and statistical analyses were conducted using SAS software. RESULTS: A total of 30,267 pregnant women with psoriasis were studied. 11,651 (38.49%) mothers had received at least one prescription during follow-up (exposed group), and >60% had never received medication (unexposed group). Demographics and comorbidities were similar between these two groups. Topical corticosteroids were the most prescribed treatment, followed by phototherapy, with systemic drugs and biologics less common. During the study period, 11,096 women with psoriasis had used topical corticosteroids, 3,376 had used non-steroidal topical agents, 218 had used systemic agents or biologics, and 519 had received treatment with phototherapy. Medication usage declined during pregnancy, reaching its lowest in the third trimester but rebounded postpartum. CONCLUSIONS: Psoriasis medications, systemic, biological, or topical, were largely discontinued during pregnancy, sometimes up to 2 years before and extending postpartum. Research is needed to understand its impact on maternal and child health.

Association between amiodarone use and risk of cataract: a population-based active-comparator study.

BACKGROUND: Despite previous concerns about ocular side effects related to amiodarone, the relationship between amiodarone and cataract remains uncertain. Therefore, this study aimed to assess the potential association between amiodarone use and the subsequent risk of cataract, taking into account potential confounders. METHODS: This population-based, active comparator-controlled cohort study utilized the data from the Taiwan National Health Insurance program and involved adults over 40 years old between 2001 and 2013. We analyzed 12 055 new amiodarone users and contrasted them with a propafenone user cohort. The primary outcome was the incidence of cataract. Inverse-probability treatment-weighting (IPTW) was further used to eliminate the potential confounding effects, and Cox proportional-hazard regression analyses were performed to calculate the risk of cataract. Serial subgroup analyses were also performed. RESULTS: In the main analysis, amiodarone users did not exhibit a significant causal relationship in both full cohort [adjusted hazard ratio (aHR): 0.994, 95% confidence interval (CI): 0.913-1.082] and IPTW cohort (IPTW-aHR 0.977, 95% CI: 0.900-1.060). Furthermore, it is important to highlight a significantly reduced risk of cataract among patients with heart failure (IPTW-aHR 0.708, 95% CI: 0.554-0.905) and during the 2-year follow-up period (IPTW-aHR 0.889, 95% CI: 0.794-0.996), implying potential advantages linked to the use of amiodarone. CONCLUSIONS: The study found no increased risk of cataract with amiodarone, one of the most frequently used antiarrhythmic medications, compared to the use of propafenone. Future research is recommended to explore potential mechanisms and their implications for clinical practice.

Longitudinal effects of sexual minority stigma on depressive symptoms among young men who have sex with men: Distinguish between and within person effects.

BACKGROUND: Young men who have sex with men (YMSM) may experience high levels of sexual minority stigma (SMS) and depressive symptoms (DS) over the world and in China. However, there is a lack of studies investigating the longitudinal effects of SMS on DS of YMSM, especially focusing on YMSM and separating the between-person and within-person effects. This study aimed to fill the said gaps. METHODS: Study data were derived from a prospective cohort of 349 YMSM from central China (Wuhan, Changsha, Nanchang), the baseline survey was started in 2017 with one follow-up visit every year. SMS and DS were measured three times using valid and reliable instruments. The cross-lagged panel model (CLPM) and the random intercept CLPM (RI-CLPM) were used to examine the between-person and within-person concurrent and lagged effects, respectively. RESULTS: Findings of CLPM revealed bidirectional associations between SMS and DS over time. RI-CLPM suggested that at the between-person level, SMS was significantly associated with DS, echoing the results of CLPM. However, this reciprocal relationship has not been found at the within-person level. CONCLUSION: The associations between SMS and DS among YMSM at the population level is more significant than that at the individual level. We suggest that interventions should be against the adverse effects of cultural marginalization and systemic change the social concepts to reduce the amount of SMS in society.

PacBio single-molecule long-read sequencing provides new insights into the complexity of full-length transcripts in oriental river prawn, macrobrachium nipponense.

BACKGROUND: Oriental river prawn (Macrobrachium nipponense) is one of the most dominant species in shrimp farming in China, which is a rich source of protein and contributes to a significant impact on the quality of human life. Thus, more complete and accurate annotation of gene models are important for the breeding research of oriental river prawn. RESULTS: A full-length transcriptome of oriental river prawn muscle was obtained using the PacBio Sequel platform. Then, 37.99 Gb of subreads were sequenced, including 584,498 circular consensus sequences, among which 512,216 were full length non-chimeric sequences. After Illumina-based correction of long PacBio reads, 6,599 error-corrected isoforms were identified. Transcriptome structural analysis revealed 2,263 and 2,555 alternative splicing (AS) events and alternative polyadenylation (APA) sites, respectively. In total, 620 novel genes (NGs), 197 putative transcription factors (TFs), and 291 novel long non-coding RNAs (lncRNAs) were identified. CONCLUSIONS: In summary, this study offers novel insights into the transcriptome complexity and diversity of this prawn species, and provides valuable information for understanding the genomic structure and improving the draft genome annotation of oriental river prawn.

Anti-angiogenic effect of exo-LncRNA TUG1 in myocardial infarction and modulation by remote ischemic conditioning.

The successful use of exosomes in therapy after myocardial infarction depends on an improved understanding of their role in cardiac signaling and regulation. Here, we report that exosomes circulating after myocardial infarction (MI) carry LncRNA TUG1 which downregulates angiogenesis by disablement of the HIF-1α/VEGF-α axis and that this effect can be counterbalanced by remote ischemic conditioning (RIC). Rats with MI induced through left coronary artery ligation without (MI model) and with reperfusion (ischemia/reperfusion I/R model) were randomized to RIC, or MI (I/R) or sham-operated (SO) control. Data from one cohort study and one randomized-controlled trial of humans with MI were also utilized, the former involving patients who had not received percutaneous coronary intervention (PCI) and the latter patients with PCI. Exosome concentrations did not differ between intervention groups (RIC vs. control) in rats (MI and I/R model) as well as humans (with and without PCI). However, MI and I/R exosomes attenuated HIF-1α, VEGF-α, and endothelial function. LncRNA TUG1 was increased in MI and I/R exosomes, but decreased in SO and RIC exosomes. HIF-1α expression was downregulated with MI and I/R exosomes but increased with RIC exosomes. Exosome inhibition suppressed HIF-1α upregulation through RIC exosomes. VEGF-α was identified as HIF-1α-regulated target gene. Knockdown of HIF-1α decreased VEGF-α, endothelial cell capability, and tube formation. Overexpression of HIF-1α exerted opposite effects. Transfection and co-transfection of 293 T cells with exosome-inhibitor GW4869 and HIF-1α inhibitor si-HIF-1α confirmed the exosomal-LncRNA TUG1/HIF-1α/VEGF-α pathway. LncRNA TUG1 is a potential therapeutic target after MI with or without reperfusion through PCI.

The optimal intravesical maintenance chemotherapy scheme for the intermediate-risk group non-muscle-invasive bladder cancer.

OBJECTIVE: Although the current European Association of Urology(EAU) guideline recommends that patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC) should accept intravesical chemotherapy or Calmette-Guerin (BCG) for no more than one year after transurethral resection of bladder tumor(TURBT), there is no consensus on the optimal duration of chemotherapy. Hence, we explored the optimal duration of maintenance intravesical chemotherapy in patients with intermediate-risk NMIBC. SUBJECTS AND METHODS: This was a real-world single-center retrospective cohort study. In total 158 patients with pathologically confirmed intermediate-risk NMIBC were included, who were divided into 4 subgroups based on the number of instillations given. We used Cox regression analysis and survival analysis chart to explore the 3-yr recurrence outcomes of tumor.The optimal duration was determined by receive operating characteristic curve (ROC). RESULTS: The median follow-up was 5.2 years. Compared with instillation for 1-2 months, the Hazard Ratios(HR) values of instillation for less than 1 month, maintenance instillation for 3-6 months and > 6 months were 3.57、1.57 and 0.22(95% CI 1.27-12.41;0.26-9.28;0.07-0.80, P = 0.03;0.62;0.02, respectively). We found a significant improvement in 3-yr relapse-free survival in intermediate-risk NMIBC patients who maintained intravesical instillation chemotherapy for longer than 6 months, and the best benefit was achieved with 10.5 months of maintenance chemotherapy by ROC. CONCLUSIONS: In our scheme, the optimal duration of intravesical instillation with pirrubicin is 10.5 months. This new understanding provides valuable experience for the precise medical treatment model of intermediate-risk NMIBC.

Common pathogenic bacteria-induced reprogramming of the host proteinogenic amino acids metabolism.

Apart from cancer, metabolic reprogramming is also prevalent in other diseases, such as bacterial infections. Bacterial infections can affect a variety of cells, tissues, organs, and bodies, leading to a series of clinical diseases. Common Pathogenic bacteria include Helicobacter pylori, Salmonella enterica, Mycobacterium tuberculosis, Staphylococcus aureus, and so on. Amino acids are important and essential nutrients in bacterial physiology and support not only their proliferation but also their evasion of host immune defenses. Many pathogenic bacteria or opportunistic pathogens infect the host and lead to significant changes in metabolites, especially the proteinogenic amino acids, to inhibit the host's immune mechanism to achieve its immune evasion and pathogenicity. Here, we review the regulation of host metabolism, while host cells are infected by some common pathogenic bacteria, and discuss how amino acids of metabolic reprogramming affect bacterial infections, revealing the potential adjunctive application of amino acids alongside antibiotics.

Flexible Azo-Polyimide-Based Smart Surface with Photoregulatable Surface Micropatterns: Toward Rewritable Information Storage and Wrinkle-Free Device Fabrication.

Stimulus-sensitive materials are of great fascination in surface and interface science owing to their dynamically tunable surface properties and/or morphologies. Herein, we have synthesized an azobenzene-containing polyimide (azo-PI) with enhanced chain flexibility for the fabrication of photosensitive surface patterns on a film/substrate wrinkle system or wrinkle-free devices. The phototriggered cis-trans isomerization kinetics of azobenzene groups in the novel azo-PI with various chain structures were systematically investigated. On the basis of the characteristics of stress relaxation that azobenzene reversible cis-trans isomerization induces in the wrinkled azo-PI film/substrate system, a variety of rewritable visual surface patterns with high resolution and a long legibility time (>30 days) could be easily constructed via visible-light irradiation, enabling the wrinkled azo-PI surfaces to be used as rewritable information storage media. Meanwhile, because of the visible-light irradiation strategy, these photoresponsive surfaces could find potential application in the fabrication of wrinkle-free flexible devices. This study not only sheds light on the influence of the azo-polymer chain structure on its photoresponsive behavior but also provides a versatile strategy for realizing tailor-made smart surface patterns on multilayer functional devices.

Tetrandrine synergizes with MAPK inhibitors in treating KRAS-mutant pancreatic ductal adenocarcinoma via collaboratively modulating the TRAIL-death receptor axis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies lacking effective therapies. KRAS mutations that occur in over 90% of PDAC are major oncogenic drivers of PDAC. The MAPK signaling pathway plays a central role in KRAS-driven oncogenic signaling. However, pharmacological inhibitors of the MAPK pathway are poorly responded in KRAS-mutant PDAC, raising a compelling need to understand the mechanism behind and to seek new therapeutic solutions. Herein, we perform a screen utilizing a library composed of 800 naturally-derived bioactive compounds to identify natural products that are able to sensitize KRAS-mutant PDAC cells to the MAPK inhibition. We discover that tetrandrine, a natural bisbenzylisoquinoline alkaloid, shows a synergistic effect with MAPK inhibitors in PDAC cells and xenograft models. Mechanistically, pharmacological inhibition of the MAPK pathway exhibits a double-edged impact on the TRAIL-death receptor axis, transcriptionally upregulating TRAIL yet downregulating its agonistic receptors DR4 and DR5, which may explain the limited therapeutic outcomes of MAPK inhibitors in KRAS-mutant PDAC. Of great interest, tetrandrine stabilizes DR4/DR5 protein via impairing ubiquitination-mediated protein degradation, thereby allowing a synergy with MAPK inhibition in inducing apoptosis in KRAS-mutant PDAC. Our findings identify a new combinatorial approach for treating KRAS-mutant PDAC and highlight the role of TRAIL-DR4/DR5 axis in dictating the therapeutic outcome in KRAS-mutant PDAC.

Screening differentially expressed genes and the pathogenesis in atopic dermatitis using bioinformatics.

Atopic dermatitis (AD) is a common chronic skin inflammation. It was to screen differentially expressed genes (DEGs) and related biological functional pathways in atopic dermatitis (AD) by bioinformatics methods, and to understand the pathogenesis of AD. gene chip datasets GSE120721 and GSE32924 in the public database NCBI Gene Expression Omnibus (GEO) were adopted. Differential expression analysis between the patient group and controls was performed by applying the zero-code differential expression analysis tool GEO2R, and a few DEGs were screened. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out. In addition, the STRING online database was employed to predict the potential relationship among DEGs, the protein-protein interaction network (PPI) was drawn, and the module analysis of PPI was performed using the Cytoscape plugin MCODE. 233 DEGs were screened out, including 134 up-regulated genes and 99 down-regulated genes. GO analysis suggested that these DEGs were mainly involved in biological processes (BP), cellular components (CC), and molecular function (MF). KEGG analysis displayed that these DEGs were mainly involved in NF-kappa B signaling, cell cycle, T cell receptor signaling, and other pathways. PPI analysis indicated that there were complex interactions among DEGs, and module analysis further revealed the important roles of DEGs in regulating immune response, inflammatory response, and skin barrier function. The above findings provide a valuable reference for the development of new treatment options.

Identification of (N-aryl-N-arylsulfonyl)aminoacetohydroxamic acids as novel urease inhibitors and the mechanism exploration.

Thirty-three (N-aryl-N-arylsulfonyl)aminoacetohydroxamic acids were synthesized in an effort to develop novel urease inhibitors. Among these compounds, 2-(N-(3-nitrophenyl)-N-(4-tert-butylphenylsulfonyl))aminoacetohydroxamic acid (e2) exhibited excellent inhibitory activity against Helicobacter pylori urease with no perceptible cytotoxicity to mammalian cells. Compound e2 showed over 690-fold higher potency than the clinical used urease inhibitor acetohydroxamic acid, reversibly inhibiting urease with a mixed mechanism. Molecular modeling revealed that (N-aryl-N-arylsulfonyl)aminoacetohydroxamic acids may possibly bind Ni ions and two hydrophobic regions with a 'Y'-like shape.

Skin sequelae in patients with infantile hemangioma: a systematic review.

Infantile hemangioma (IH) is the most common vascular tumor in infancy. Although IHs can regress spontaneously, some problematic IHs still need treatment. However, either treated or untreated IHs may leave skin sequelae which can cause permanent disfigurement. Many studies evaluated the short-term efficacy of different kinds of treatment, but now, few studies are focusing on long-term skin sequelae. The objectives of our systemic review were to identify skin sequelae of IH thoroughly, determine specific factors associated with long-term IH sequelae, and learn how to improve these sequelae. We searched the following electronic databases: PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov. Three independent authors assessed the articles, and we reported this systemic review following PRISMA guidelines. Of 4448 articles initially identified, 62 underwent full-text review, and 17 met inclusion criteria. The overall rate of sequelae ranged from 5.3 to 93.5%. Factors associated with skin sequelae included patients' demographics, hemangioma characteristics, and treatment factors. What is Known: • Infantile hemangioma is the most common vascular tumor during infancy. • Infantile hemangiomas can regress spontaneously but either treated or untreated patients may leave permanent skin sequelae. What is New: • Skin sequelae in involuted Infantile hemangiomas are very common. • It is significant to prevent, recognize, and improve skin sequelae of infantile hemangiomas.