α1-COP modulates plasmodesmata function through sphingolipid enzyme regulation.

Callose, a ß-1,3-glucan plant cell wall polymer, regulates symplasmic channel size at plasmodesmata (PD) and plays a crucial role in a variety of plant processes. However, elucidating the molecular mechanism of PD callose homeostasis is limited. We screened and identified an Arabidopsis mutant plant with excessive callose deposition at PD and found that the mutated gene was α1-COP, a member of the coat protein I (COPI) coatomer complex. We report that loss of function of α1-COP elevates the callose accumulation at PD by affecting subcellular protein localization of callose degradation enzyme PdBG2. This process is linked to the functions of ERH1, an inositol phosphoryl ceramide synthase, and glucosylceramide synthase through physical interactions with the α1-COP protein. Additionally, the loss of function of α1-COP alters the subcellular localization of ERH1 and GCS proteins, resulting in a reduction of GlcCers and GlcHCers molecules, which are key sphingolipid (SL) species for lipid raft formation. Our findings suggest that α1-COP protein, together with SL modifiers controlling lipid raft compositions, regulates the subcellular localization of GPI-anchored PDBG2 proteins, and hence the callose turnover at PD and symplasmic movement of biomolecules. Our findings provide the first key clue to link the COPI-mediated intracellular trafficking pathway to the callose-mediated intercellular signaling pathway through PD.

Protective Effect of Vaccine Doses and Antibody Titers Against SARS-CoV-2 Infection in Kidney Transplant Recipients.

Patients undergoing kidney transplantation have a poor response to vaccination and a higher risk of disease progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The effectiveness of vaccine doses and antibody titer tests against the mutant variant in these patients remains unclear. We retrospectively analyzed the risk of SARS-CoV-2 infection in a single medical center according to vaccine doses and immune responses before the outbreak. Among 622 kidney transplant patients, there were 77 patients without vaccination, 26 with one dose, 74 with two doses, 357 with three, and 88 with four doses. The vaccination status and infection rate proportion were similar to the general population. Patients undergoing more than three vaccinations had a lower risk of infection (odds ratio = 0.6527, 95% CI = 0.4324-0.9937) and hospitalization (odds ratio = 0.3161, 95% CI = 0.1311-0.7464). Antibody and cellular responses were measured in 181 patients after vaccination. Anti-spike protein antibody titer of more than 1,689.3 BAU/mL is protective against SARS-CoV-2 infection (odds ratio = 0.4136, 95% CI = 0.1800-0.9043). A cellular response by interferon-γ release assay was not correlated with the disease (odds ratio = 1.001, 95% CI = 0.9995-1.002). In conclusion, despite mutant strain, more than three doses of the first-generation vaccine and high antibody titers provided better protection against the omicron variant for a kidney transplant recipient.

Design, synthesis, evaluation and optimization of potent IRAK4 inhibitors alleviating production of inflammatory cytokines in LPS-induced SIRS model.

Interleukin-1 receptor associated kinase-4 (IRAK4) has emerged as a therapeutic target for inflammatory and autoimmune diseases. Through reversing the amide of CA-4948 and computer aided structure-activity relationship (SAR) studies, a series of IRAK4 inhibitors with oxazolo[4,5-b]pyridine scaffold were identified. Compound 32 showed improved potency (IC50 = 43 nM) compared to CA-4948 (IC50 = 115 nM), but suffered from hERG inhibition (IC50 = 5.7 µM). Further optimization led to compound 42 with reduced inhibition of hERG (IC50 > 30 µM) and 13-fold higher activity (IC50 = 8.9 nM) than CA-4948. Importantly, compound 42 had favorable in vitro ADME and in vivo pharmacokinetic properties. Furthermore, compound 42 significantly reduced LPS-induced production of serum TNF-α and IL-6 cytokines in the mouse model. The overall profiles of compound 42 support it as a lead for the development of IRAK4 inhibitors for the treatment of inflammatory and autoimmune disorders.

Efficacy and safety profile of dupilumab for the treatment of atopic dermatitis in children and adolescents: A systematic review and meta-analysis.

BACKGROUND: Dupilumab is the first biologic approved for the treatment of moderate-to-severe atopic dermatitis (AD) in children and adolescents. Previous systematic reviews explored the effectiveness and safety of dupilumab in adults with AD. However, the underlying mechanisms of AD can vary among different age groups, emphasizing the need for separate investigation into the use of dupilumab in children and adolescents with AD. OBJECTIVE: To evaluate the efficacy and safety of dupilumab in children and adolescents with AD based on evidence from clinical trials and observational studies. METHODS: The process of meta-analysis was conducted according to preferred reporting items for systematic reviews and meta-analyses guidelines. RESULTS: Seven clinical trials and 11 observational studies involving 1275 children and adolescents with AD were eligible for quantitative analysis. Overall, the pooled percentages of eczema area and severity index (EASI) 50, EASI 75, EASI 90, EASI 100, and investigator's global assessment (IGA) 0/1 were 72.9% (95% CI: 61.6%-81.9%), 57.4% (48.1%-66.2%), 31.3% (24.0%-39.7%), 29.7% (23.3%-37.0%), and 35.2% (29.3%-41.5%). With prolonged treatment time, an increase was seen in the pooled rate of EASI response, indicating that dupilumab may provide sustained benefits for children and adolescents over the long term. The reported adverse events were primarily mild and manageable, with an overall incidence rate of 7.2% across clinical trials and 7.6% across observational studies. CONCLUSION: Dupilumab was an effective and safe treatment option for children and adolescents with AD, with positive results observed from long-term use and an acceptable safety profile. More long-term, high-quality, controlled studies in different regions are needed for further verification.

A meta-analysis of the effectiveness of antibacterial bone cement in the treatment of diabetic foot skin wound infections.

A meta-analysis research was implemented to appraise the effect of antibiotic bone cement (ABC) in treating infected diabetic foot wounds (IDFWs). Inclusive literature research till April 2023 was done and 1237 interconnected researches were revised. The 15 selected researches enclosed 895 IDFWs persons were in the utilized researchers' starting point, 449 of them were utilizing ABC, and 446 were in the control group. Odds ratio and 95% confidence intervals were utilized to appraise the consequence of ABC in treating IDFWs by the contentious approach and a fixed or random model. ABC had significantly lower wound healing time (MD, -9.83; 95% CI, -12.45--7.20, p < 0.001), and time to bacterial conversion of the wound (MD, -7.30; 95% CI, -10.38--4.32, p < 0.001) compared to control in IDFWs persons. However, caution needs to be taken when interacting with its values since there was a low sample size of most of the chosen research found for the comparisons in the meta-analysis.

Design, synthesis, and structure-activity relationship of novel RIPK2 inhibitors.

The NOD1/2 (nucleotide-binding oligomerization domain-containing protein 1/2) signaling pathways are involved in innate immune control and host defense. NOD dysfunction can result in a variety of autoimmune disorders. NOD-induced generation of inflammatory cytokines is mediated by receptor-interacting protein kinase 2 (RIPK2), which has been considered as a promising therapeutic target. Herein, we disclose the design, synthesis, and SAR study of a series of RIPK2 inhibitors. The lead compound 17 displayed a high affinity for RIPK2 (Kd = 5.9 nM) and was capable of inhibiting RIPK2 kinase function in an ADP-Glo assay. In vitro DMPK studies showed that compound 17 had good metabolic stability and no CYP inhibition. Compound 17 effectively suppressed inflammatory cytokine production in both cells and animal model.

Discovery, optimization and evaluation of isothiazolo[5,4-b]pyridine derivatives as RIPK1 inhibitors with potent in vivo anti-SIRS activity.

Receptor-interacting protein kinase-1 (RIPK1) is involved in the necroptosis pathway, which regulates inflammatory signaling and cell death in a variety of diseases, including inflammatory and neurodegenerative disorders. We identified a novel hit compound 36 by a cell-based screening assay (anti-necroptosis EC50 = 58 nM). Starting from compound 36, we designed a series of scaffolds to improve anti-necroptosis activity, physicochemical properties and metabolic stability. The isothiazolo[5,4-b]pyridine backbone proved to be a promising scaffold which provided a number of potent necroptosis inhibitors. Compound 56, for example, effectively blocked necroptosis in both human and mouse cells (EC50 = 1-5 nM). A binding assay showed that compound 56 potently binds to RIPK1 (Kd = 13 nM), but not RIPK3 (Kd > 10,000 nM). Kinase functional assay (ADP-Glo) confirmed that compound 56 inhibits RIPK1 phosphorylation with an IC50 at 5.8 nM. Importantly, compound 56 displayed excellent cross-species liver microsomal metabolic stability (t1/2 > 90 min). Furthermore, compound 56 exhibited favorable in vitro safety profiles in hERG and CYP assays. Finally, pre-treatment with 56 significantly reduced hypothermia and lethal shock in the systemic inflammatory response syndrome mice model. Taken together, compound 56 represented a promising prototype for the development of therapeutic agent to treat inflammation-related diseases.

Nomograms predicting the overall survival and cancer-specific survival of patients with stage IIIC1 cervical cancer.

BACKGROUND: To explore the factors that affect the prognosis of overall survival (OS) and cancer-specific survival (CSS) of patients with stage IIIC1 cervical cancer and establish nomogram models to predict this prognosis. METHODS: Data from patients in the Surveil-lance, Epidemiology, and End Results (SEER) programme meeting the inclusion criteria were classified into a training group, and validation data were obtained from the First Affiliated Hospital of Anhui Medical University from 2010 to 2019. The incidence, Kaplan-Meier curves, OS and CSS of patients with stage IIIC1 cervical cancer in the training group were evaluated. Nomograms were established according to the results of univariate and multivariate Cox regression models. Harrell's C-index, calibration plots, receiver operating characteristic (ROC) curves and decision-curve analysis (DCA) were calculated to validate the prediction models. RESULTS: The incidence of pelvic lymph node metastasis, a high-risk factor for the prognosis of cervical cancer, decreased slightly over time. Eight independent prognostic variables were identified for OS, including age, race, marriage status, histology, extension range, tumour size, radiotherapy and surgery, but only seven were identified for CSS, with marriage status excluded. Nomograms of OS and CSS were established based on the results. The C-indexes for the nomograms of OS and CSS were 0.687 and 0.692, respectively, using random sampling of SEER data sets and 0.701 and 0.735, respectively, using random sampling of external data sets. The AUCs for the nomogram of OS were 0.708 and 0.705 for the SEER data sets and 0.750 and 0.750 for the external data sets, respectively. In addition, AUCs of 0.707 and 0.709 were obtained for the nomogram of CSS when validated using SEER data sets, and 0.788 and 0.785 when validated using external data sets. Calibration plots for the nomograms were almost identical to the actual observations. The DCA also indicated the value of the two models. CONCLUSIONS: Eight independent prognostic variables were identified for OS. The same factors predicted CSS, with the exception of the marriage status. Both OS and CSS nomograms had good predictive and clinical application value after validation. Notably, tumour size had the largest contribution to the OS and CSS nomograms.

Graphene production by cracking.

In recent years, graphene has found its use in numerous industrial applications due to its unique properties. While its impermeable and conductive nature can replace currently used anticorrosive toxic pigments in coating systems, due to its large strength to weight ratio, graphene can be an important component as a next-generation additive for automotive, aerospace and construction applications. The current bottlenecks in using graphene and graphene oxide and other two-dimensional materials are the availability of cost-effective, high-quality materials and their effective incorporation (functionalization and dispersion) into the product matrices. On overcoming these factors, graphene may attract significant demands in terms of volume consumption. Graphene can be produced on industrial scales and through cost-effective top-down routes such as chemical, electrochemical and/or high-pressure mechanical exfoliation. Graphene, depending on end applications, can be chemically tuned and modified via functionalization so that easy incorporation into product matrices is possible. This paper discusses different production methods and their impact on the quality of graphene produced in terms of energy input. Graphene with an average thickness below five layers was produced by both methods with varied defects. However, a higher yield of graphene with a lower number of layers was produced via the high-pressure exfoliation route. This article is part of a discussion meeting issue 'A cracking approach to inventing new tough materials: fracture stranger than friction'.

Design, synthesis, and evaluation of novel CXCR4 antagonists based on an aminoquinoline template.

The chemokine receptor CXCR4 has been explored as a drug target due to its involvement in pathological conditions such as HIV infection and cancer metastasis. Here we report the structure-activity relationship study of novel CXCR4 antagonists based on an aminoquinoline template. This template is devoid of the chiral center in the classical tetrahydroquinoline (THQ) ring moiety and therefore can be easily synthesized. A number of potent CXCR4 antagonists were identified, exemplified by compound 3, which demonstrated excellent binding affinity with CXCR4 receptor (IC50 = 57 nM) and inhibited CXCL12 induced cytosolic calcium increase (IC50 = 0.24 nM). Furthermore, compound 3 potently inhibited CXLC12/CXCR4 mediated cell migration in a transwell invasion assay. The simplified synthetic approach combined with good physicochemical properties (e.g. MW 362, clogP 2.1, PSA 48, pKa 7.0 for compound 3) demonstrate the potential of this aminoquinoline template as a novel scaffold to develop CXCR4 antagonists.

Endoscopic magnet placement into subadventitial tunnels for augmenting the lower esophageal sphincter using submucosal endoscopy: ex vivo and in vivo study in a porcine model (with video).

BACKGROUND AND AIMS: Endolumenal therapies serve as a treatment option for GERD. This study aimed to determine if magnets could be placed endoscopically using the adventitial layer to create a subadventitial space near the esophagogastric junction to augment the lower esophageal sphincter using submucosal endoscopy. METHODS: This study consisted of 2 phases, ex vivo and in vivo, with domestic pig esophagus. A long submucosal tunnel was made at the mid to lower esophagus. The muscularis propria was incised by a needle-knife within the submucosal tunnel. A subadventitial tunnel was made by biliary balloon catheter blunt dissection, and a magnet was deployed in the subadventitial space. The same maneuver was done within the opposing esophageal wall, with magnet placement in the opposing subadventitial space. RESULTS: Submucosal tunnels and subadventitial tunnels were successful without perforation ex vivo in all attempts and in 9 of 10 cases, respectively. Magnets were deployed in the subadventitial space in 7 cases. Magnets connected and separated with atraumatic endoscope passage into the stomach and reconnected when the endoscope was withdrawn under fluoroscopy in 5 of 7 cases (71.4%). In vivo submucosal tunnels and subadventitial tunnels were successful in all 5 cases, and magnet augmentation was functionally active in 4 cases (80%). CONCLUSION: Subadventitial tunnels were feasible and could represent a new working space for endoscopic treatment. Endoscopic placement of magnets within the subadventitial space may be an attractive alternative endolumenal therapy for GERD.

Cervical invasion, lymphovascular space invasion, and ovarian metastasis as predictors of lymph node metastasis and poor outcome on stages I to III endometrial cancers: a single-center retrospective study.

BACKGROUND: The aim of this study is to determine pathological factors that increase the risk of LNM and indicate poor survival of patients diagnosed with endometrial cancer and treated with surgical staging. METHOD: Between January 2010 and November 2018, we enrolled 874 eligible patients who received staging surgery in the First Affiliated Hospital of Anhui Medical University. The roles of prognostic risk factors, such as age, histological subtype, tumor grade, myometrial infiltration, tumor diameter, cervical infiltration, lymphopoiesis space invasion (LVSI), CA125, and ascites, were evaluated. Multivariable logistic regression models were used to identify the predictors of LNM. Kaplan-Meier and COX regression models were utilized to study the overall survival. RESULTS: Multivariable regression analysis confirmed cervical stromal invasion (OR 3.412, 95% CI 1.631-7.141; P < 0.01), LVSI (OR 2.542, 95% CI 1.061-6.004; P = 0.04) and ovarian metastasis (OR 6.236, 95% CI 1.561-24.904; P = 0.01) as significant predictors of nodal dissemination. Furthermore, pathological pattern (P = 0.03), myometrial invasion (OR 2.70, 95% CI 1.139-6.40; P = 0.01), and lymph node metastasis (OR 9.675, 95% CI 3.708-25.245; P < 0.01) were independent predictors of decreased overall survival. CONCLUSIONS: Cervical invasion, lymphopoiesis space invasion, and ovarian metastasis significantly convey the risk of LNM. Pathological type, myometrial invasion, and lymph node metastasis are all important predictors of survival and should be scheduled for completion when possible in the surgical staging procedure.

Callose balancing at plasmodesmata.

In plants, communication and molecular exchanges between different cells and tissues are dependent on the apoplastic and symplastic pathways. Symplastic molecular exchanges take place through the plasmodesmata, which connect the cytoplasm of neighboring cells in a highly controlled manner. Callose, a ß-1,3-glucan polysaccharide, is a plasmodesmal marker molecule that is deposited in cell walls near the neck zone of plasmodesmata and controls their permeability. During cell differentiation and plant development, and in response to diverse stresses, the level of callose in plasmodesmata is highly regulated by two antagonistic enzymes, callose synthase or glucan synthase-like and ß-1,3-glucanase. The diverse modes of regulation by callose synthase and ß-1,3-glucanase have been uncovered in the past decades through biochemical, molecular, genetic, and omics methods. This review highlights recent findings regarding the function of plasmodesmal callose and the molecular players involved in callose metabolism, and provides new insight into the mechanisms maintaining plasmodesmal callose homeostasis.

Diverse Transformation of Vinyl Azides with 2,2,6,6-Tetramethyl- N-oxopiperidinium.

A 2,2,6,6-tetramethyl- N-oxopiperidinium (TEMPO+)-mediated three-component diverse transformation of vinyl azides under metal-free conditions is described. The reaction protocols are operationally simple and conducted at ambient temperature, allowing to access various TEMPO-trapped ketones, amides, and α-alkoxyalkyl azides. Preliminary mechanistic studies indicate that an alkene radical cation-mediated radical-radical cross-coupling C-O bond formation could be involved.

Transcription factor-mediated cell-to-cell signalling in plants.

Plant cells utilize mobile transcription factors to transmit intercellular signals when they perceive environmental stimuli or initiate developmental programmes. Studies on these novel cell-to-cell signals have accumulated multiple pieces of evidence showing that non-cell-autonomous transcription factors play pivotal roles in most processes related to the formation and development of plant organs. Recent studies have explored the evolution of mobile transcription factors and proposed mechanisms for their trafficking through plasmodesmata, where a selective system exists to facilitate this process. Mobile transcription factors contribute to the diversity of the intercellular signalling network, which is also established by peptides, hormones, and RNAs. Crosstalk between mobile transcription factors and other intercellular molecules leads to the development of complex biological signalling networks in plants. The regulation of plasmodesmata appears to have been another major step in controlling the intercellular trafficking of transcription factors based on studies of many plasmodesmal components. Furthermore, diverse omics approaches are being successfully applied to explore a large number of candidate transcription factors as mobile signals in plants. Here, we review these fascinating discoveries to integrate current knowledge of non-cell-autonomous transcription factors.

Polyphenolic Platform Ameliorated Sanshool for Skin Photoprotection.

Natural evolution has nurtured a series of active molecules that play vital roles in physiological systems, but their further applications have been severely limited by rapid deactivation, short cycle time, and potential toxicity after isolation. For instance, the instability of structures and properties has greatly descended when sanshool is derived from Zanthoxylum xanthoxylum. Herein, natural polyphenols are employed to boost the key properties of sanshool by fabricating a series of nanoparticles (NPs). The intracellular evaluation and in vivo animal model are conducted to demonstrate the decreased photodamage score and skin-fold thickness of prepared NPs, which can be attributed to the better biocompatibility, improved free radical scavenging, down-regulated apoptosis ratios, and reduced DNA double-strand breaks compared to naked sanshool. This work proposes a novel strategy to boost the key properties of naturally occurring active molecules with the assistance of natural polyphenol-based platforms.

Clinical and Dosimetric Results of Proton or Photon Radiation Therapy for Large (>5 cm) Hepatocellular Carcinoma: A Retrospective Analysis.

PURPOSE: Our purpose was to report the clinical and dosimetric attributes of patients with large unresectable hepatocellular carcinoma (HCC) undergoing proton or photon radiation therapy. METHODS AND MATERIALS: We retrospectively analyzed the outcomes and dosimetric indices of 159 patients with >5 cm nonmetastatic HCC who underwent definitive radiation therapy using either protons (N = 105) or photons (N = 54) between 2014 and 2018. Additional photon plans were performed in the 105 proton-treated patients using the same dose prescription criteria for intragroup dosimetric comparison. RESULTS: After a median follow-up of 47 months, patients with biologically effective dose (BED10) ≥ 75 Gy exhibited significantly better local control (LC; 2-year: 85.6% vs 20.5%; P < .001), progression-free survival (PFS; median, 7.4 vs 3.2 months; P < .001), and overall survival (OS; median, 18.1 vs 7.3 months; P < .001) compared with those with BED10 < 75 Gy. Notably, proton-treated patients had a significantly higher BED10 (96 vs 67 Gy; P < .001) and improved LC (2-year: 88.5% vs 33.8%; P < .001), PFS (median, 7.4 vs 3.3 months; P = .001), and OS (median, 18.9 vs 8.3 months; P < .001) than those undergoing photon radiation therapy. Furthermore, patients treated with protons had significantly lower V1 of the liver (P < .001), mean upper gastrointestinal tract dose (P < .001), and mean splenic dose (P < .001), with significantly decreased incidences of radiation-induced liver disease (P = .007), grade ≥3 upper gastrointestinal bleeding (P = .001), and grade ≥3 lymphopenia (P = .003). On multivariate analysis, proton radiation therapy consistently correlated with superior LC (P < .001), PFS (P < .001), and OS (P < .001). In intragroup dosimetric comparison, photon plans demonstrated significantly higher mean liver dose (P < .001) compared with actually delivered proton treatments, and 72 (69%) of them had mean liver dose exceeding 28 Gy, which necessitated target dose de-escalation. CONCLUSIONS: In the context of large HCC radiation therapy, a higher target BED10 was associated with improved outcomes. Notably, proton therapy has demonstrated the capability to deliver ablative doses while also being accompanied by fewer instances of severe toxicity.

Oral small-molecule tyrosine kinase 2 and phosphodiesterase 4 inhibitors in plaque psoriasis: a network meta-analysis.

Background: Orally administered small-molecule drugs including tyrosine kinase 2 (TYK2) inhibitors and phosphodiesterase 4 (PDE4) inhibitors are new candidates for systemic therapy in plaque psoriasis. However, no previous articles evaluated the benefit and risk profile of TYK2 and PDE4 inhibitors in psoriasis. Objectives: The objective of this study was to compare the efficacy and safety of oral small-molecule drugs, including TYK2 and PDE4 inhibitors, in treating moderate-to-severe plaque psoriasis. Methods: PubMed, Embase, and Cochrane library were searched for eligible randomized clinical trials (RCTs). Response rates for a 75% reduction from baseline in Psoriasis Area and Severity Index (PASI-75) and Physician's Global Assessment score of 0 or 1 (PGA 0/1) were used for efficacy assessment. Safety was evaluated with the incidence of adverse events (AEs). A Bayesian multiple treatment network meta-analysis (NMA) was performed. Results: In total, 13 RCTs (five for TYK2 inhibitors and eight for PDE4 inhibitors) involving 5274 patients were included. The study found that deucravacitinib at any dose (except for 3 mg QOD), ropsacitinib (200 and 400 mg QD), and apremilast (20 and 30 mg BID) had higher PASI and PGA response rates than placebo. In addition, deucravacitinib (3 mg BID, 6 mg QD, 6 mg BID, and 12 mg QD), and ropsacitinib (400 mg QD) showed superior efficacy than apremilast (30 mg BID). In terms of safety, deucravacitinib or ropsacitinib at any dose did not lead to a higher incidence of AEs than apremilast (30 mg BID). The ranking analysis of efficacy revealed that deucravacitinib 12 mg QD and deucravacitinib 3 mg BID had the highest chance of being the most effective oral treatment, followed by deucravacitinib 6 mg BID and ropsacitinib 400 mg QD. Conclusions: Oral TYK2 inhibitors demonstrated satisfactory performance in treating psoriasis, surpassing apremilast at certain doses. More large-scale, long-term studies focusing on novel TYK2 inhibitors are needed. Systematic review registration: PROSPERO (ID: CRD42022384859), available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022384859, identifier CRD42022384859.