Divergent synthesis of complex withanolides enabled by a scalable route and late-stage functionalization.

Withanolides are a group of naturally occurring C28 steroids based on an ergostane skeleton. They have a high degree of polyoxygenation, and the abundance of O-functional groups has enabled various natural alterations to both the carbocyclic skeleton and the side chain. Consequently, these molecules have intricate structural features that lead to their highly varied display of biological activities including anticancer, anti-inflammatory, and immunomodulating properties. Despite being intriguing leads for further discovery research, synthetic access to the withanolides remains highly challenging-compounds for current biological research are mainly isolated from plants, often inefficiently. Here, we report the divergent synthesis of 11 withanolides in 12 to 20 steps, enabled by a gram-scale route and a series of late-stage functionalizations, most notably a bioinspired photooxygenation-allylic hydroperoxide rearrangement sequence. This approach enables further biological research disconnected from a reliance on minute quantities of the parent natural products or their simple derivatives.

Single-cell transcriptome analysis upon ECM-remodeling meningioma cells.

Meningiomas are the most common tumours that primarily arise in the central nervous system, but their intratumoural heterogeneity has not yet been thoroughly studied. We aimed to investigate the transcriptome characteristics and biological properties of ECM-remodeling meningioma cells. Single-cell RNA sequencing (ScRNA-seq) data from meningioma samples were acquired and used for analyses. We conducted comprehensive bioinformatics analyses, including screening for differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway and Gene Ontology (GO) term enrichment analyses, Gene Set Enrichment Analysis (GSEA), protein-protein interaction (PPI) analysis, and copy number variation (CNV) analysis on single-cell sequencing data from meningiomas. Eighteen cell types, including six meningioma subtypes, were identified in the data. ECM-remodeling meningioma cells (MGCs) were mainly distributed in brain-tumour interface tissues. KEGG and GO enrichment analyses revealed that 908 DEGs were mainly related to cell adhesion, extracellular matrix organization, and ECM-receptor interaction. GSEA analysis demonstrated that homophilic cell adhesion via plasma membrane adhesion molecules was significantly enriched (NES = 2.375, P < 0.001). CNV analysis suggested that ECM-remodeling MGCs showed considerably lower average CNV scores. ECM-remodeling MGCs predominantly localized at the brain-tumour interface area and adhere stably to the basement membrane with a lower degree of malignancy. This study provides novel insights into the malignancy of meningiomas.

Focused Ultrasound Stimulates the Prefrontal Cortex and Prevents MK-801-Induced Psychiatric Symptoms of Schizophrenia in Rats.

BACKGROUND AND HYPOTHESIS: Treatment of schizophrenia remains a major challenge. Recent studies have focused on glutamatergic signaling hypoactivity through N-methyl-D-aspartate (NMDA) receptors. Low-intensity pulsed ultrasound (LIPUS) improves behavioral deficits and ameliorates neuropathology in dizocilpine (MK-801)-treated rats. The aim of this study was to investigate the efficacy of LIPUS against psychiatric symptoms and anxiety-like behaviors. STUDY DESIGN: Rats assigned to 4 groups were pretreated with or without LIPUS for 5 days. The open field and prepulse inhibition tests were performed after saline or MK-801 (0.3 mg/kg) administration. Then, the neuroprotective effects of LIPUS on the MK-801-treated rats were evaluated using western blotting and immunohistochemical staining. STUDY RESULTS: LIPUS stimulation of the prefrontal cortex (PFC) prevented deficits in locomotor activity and sensorimotor gating and improved anxiety-like behavior. MK-801 downregulated the expression of NR1, the NMDA receptor, in rat medial PFC (mPFC). NR1 expression was significantly higher in animals receiving LIPUS pretreatment compared to those receiving only MK-801. In contrast, a significant increase in c-Fos-positive cells in the mPFC and ventral tegmental area was observed in the MK-801-treated rats compared to those receiving only saline; this change was suppressed by pretreatment with LIPUS. CONCLUSIONS: This study provides new evidence for the role of LIPUS stimulation in regulating the NMDA receptor and modulating c-Fos activity, which makes it a potentially valuable antipsychotic treatment for schizophrenia.

Anticonvulsant effect of equilibrative nucleoside transporters 1 inhibitor in a mouse model of Dravet syndrome.

There are limited therapeutic options for patients with Dravet syndrome (DS). The equilibrative nucleoside transporters 1 (ENT1) mediate both the influx and efflux of adenosine across the cell membrane exerted beneficial effects in the treatment of epilepsy. This study aimed to evaluate the anticonvulsant effect of the ENT1 inhibitor in an animal model of DS (Scn1aE1099X/+ mice). J7 (5 mg/kg) treatment was efficacious in elevating seizure threshold in Scn1aE1099X/+ mice after hyperthermia exposure. Moreover, the J7 treatment significantly reduced the frequency of spontaneous excitatory post-synaptic currents (sEPSCs, ~35% reduction) without affecting the amplitude in dentate gyrus (DG) granule cells. Pretreatment with the adenosine A1 receptor (A1R) antagonist, DPCPX, abolished the J7 effects on sEPSCs. These observations suggest that the J7 shows an anticonvulsant effect in hyperthermia-induced seizures in Scn1aE1099X/+ mice. This effect possibly acts on presynaptic A1R-mediated signaling modulation in granule cells.

How to use the Surveillance, Epidemiology, and End Results (SEER) data: research design and methodology.

In the United States (US), the Surveillance, Epidemiology, and End Results (SEER) program is the only comprehensive source of population-based information that includes stage of cancer at the time of diagnosis and patient survival data. This program aims to provide a database about cancer incidence and survival for studies of surveillance and the development of analytical and methodological tools in the cancer field. Currently, the SEER program covers approximately half of the total cancer patients in the US. A growing number of clinical studies have applied the SEER database in various aspects. However, the intrinsic features of the SEER database, such as the huge data volume and complexity of data types, have hindered its application. In this review, we provided a systematic overview of the commonly used methodologies and study designs for retrospective epidemiological research in order to illustrate the application of the SEER database. Therefore, the goal of this review is to assist researchers in the selection of appropriate methods and study designs for enhancing the robustness and reliability of clinical studies by mining the SEER database.

Fundamental and second-order dark soliton solutions of two- and three-component Manakov equations in the defocusing regime.

We present exact multiparameter families of soliton solutions for two- and three-component Manakov equations in the defocusing regime. Existence diagrams for such solutions in the space of parameters are presented. Fundamental soliton solutions exist only in finite areas on the plane of parameters. Within these areas, the solutions demonstrate rich spatiotemporal dynamics. The complexity increases in the case of three-component solutions. The fundamental solutions are dark solitons with complex oscillating patterns in the individual wave components. At the boundaries of existence, the solutions are transformed into plain (nonoscillating) vector dark solitons. The superposition of two dark solitons in the solution adds more frequencies in the patterns of oscillating dynamics. These solutions admit degeneracy when the eigenvalues of fundamental solitons in the superposition coincide.

Controlled Synthesis and Enhanced Gas Sensing Performance of Zinc-Doped Indium Oxide Nanowires.

Indium oxide (In2O3) is a widely used n-type semiconductor for detection of pollutant gases; however, its gas selectivity and sensitivity have been suboptimal in previous studies. In this work, zinc-doped indium oxide nanowires with appropriate morphologies and high crystallinity were synthesized using chemical vapor deposition (CVD). An accurate method for electrical measurement was attained using a single nanowire microdevice, showing that electrical resistivity increased after doping with zinc. This is attributed to the lower valence of the dopant, which acts as an acceptor, leading to the decrease in electrical conductivity. X-ray photoelectron spectroscopy (XPS) analysis confirms the increased oxygen vacancies due to doping a suitable number of atoms, which altered oxygen adsorption on the nanowires and contributed to improved gas sensing performance. The sensing performance was evaluated using reducing gases, including carbon monoxide, acetone, and ethanol. Overall, the response of the doped nanowires was found to be higher than that of undoped nanowires at a low concentration (5 ppm) and low operating temperatures. At 300 °C, the gas sensing response of zinc-doped In2O3 nanowires was 13 times higher than that of undoped In2O3 nanowires. The study concludes that higher zinc doping concentration in In2O3 nanowires improves gas sensing properties by increasing oxygen vacancies after doping and enhancing gas molecule adsorption. With better response to reducing gases, zinc-doped In2O3 nanowires will be applicable in environmental detection and life science.

[Effects of Microplastic Exposure on the Community Structure and Function of Symbiotic Bacteria in Sinularia microclavata].

Microplastics are widely distributed in the marine environment and are harmful to the health of marine organisms (including corals). However, studies on the impact of microplastics on coral have been very limited, and the specific mechanism of their impact is not clear. Therefore, in this study, microplastic PA, which is common in the marine environment, was selected to conduct a 7-day microplastic exposure experiment on Sinularia microclavata. The effects of microplastic exposure at different times on the diversity, community structure, and function of the symbiotic bacterial community of coral were analyzed using high-throughput sequencing technology. The α-diversity of the symbiotic bacterial community of coral first decreased and then increased with the exposure time of microplastics. The analysis of ß-diversity and microbial community composition showed that microplastic exposure caused significant changes in the symbiotic bacterial community of coral, and the bacterial community composition also changed with the exposure time. A total of 49 phyla, 152 classes, 363 orders, 634 families, and 1390 genera were detected. At the phylum level, Proteobacteria was the dominant taxa in all samples, but the relative abundance varied among samples. Microplastic exposure increased the abundance of Proteobacteria, Chloroflexi, Firmicutes, Actinobacteriota, Bacteroidota, and Acidobacteriota. At the genus level, Ralstonia, Acinetobacter, and Delftia were the dominant taxa of symbiotic bacteria of coral after microplastic exposure. PICRUSt functional prediction indicated that functions of the coral symbiotic bacterial community, including signal transduction, cellular community prokaryotes, xenobiotics biodegradation and metabolism, and cell motility, decreased after microplastic exposure on coral. BugBase phenotype predictions indicated that microplastic exposure altered three phenotypes (pathogenic, anaerobic, and oxidative stress-tolerant) of the coral symbiotic bacterial community. FAPROTAX functional predictions indicated that microplastic exposure caused significant changes in functions such as the symbiotic relationship between coral symbiotic bacteria and the host, carbon and nitrogen cycling, and photosynthesis. This study provided basic data on the mechanism of microplastic impacts on corals and microplastics ecotoxicology.

Relationship between Dining Place, Iodine Source, and Iodine Nutrition in School-Age Children: A Cross-Sectional Study in China.

Objective: This study assesses the impact of iodine-rich processed foods and dining places on the iodine nutritional status of children. Methods: School-aged children (SAC) in seven provinces in China were selected by school-based multi-stage sampling. Urinary iodine, salt iodine, and thyroid volume (TVOL) were determined. Questionnaires were used to investigate dining places and iodine-rich processed foods. The water iodine was from the 2017 national survey. Multi-factor regression analysis was used to find correlations between variables. Results: Children ate 78.7% of their meals at home, 15.1% at school canteens, and 6.1% at other places. The percentage of daily iodine intake from water, iodized salt, iodine-rich processed foods, and cooked food were 1.0%, 79.2%, 1.5%, and 18.4%, respectively. The salt iodine was correlated with the urinary iodine and TVOL, respectively (r = 0.999 and -0.997, P < 0.05). The iodine intake in processed foods was weakly correlated with the TVOL (r = 0.080, P < 0.01). Non-iodized salt used in processed foods or diets when eating out had less effect on children's iodine nutrition status. Conclusion: Iodized salt remains the primary source of daily iodine intake of SAC, and processed food has less effect on iodine nutrition. Therefore, for children, iodized salt should be a compulsory supplement in their routine diet.

Cutaneous immune-related adverse events among Taiwanese cancer patients receiving immune checkpoint inhibitors link to a survival benefit.

Cutaneous immune-related adverse events are common in cancer patients receiving immunotherapies but seldom studied in a comprehensive way of collecting all cancer types with comparisons between different immune-oncology drugs and correlation to patient survival. In this retrospective cohort study, we recruited 468 cancer patients receiving immunotherapies in a tertiary referral center in Taiwan and try to determine real-world incidence of cutaneous immune-related adverse events and their associations with the survival rates. Among them, 128 patients (27.4%) had cutaneous immune-related adverse events, with maculopapular eruption (10.6%) and pruritus (10.1%) most frequently identified in the monotherapy group. The incidence of these cutaneous immune-related adverse events was highest in patients receiving pembrolizumab (34.1%, P < .0001). Concurrent usage of molecular-targeted therapy with immunotherapy was associated with a higher incidence (57.8%, P < .0001). The Kaplan-Meier plot and log-rank test showed that patients with any type of immune-related cutaneous adverse events had longer survival time than those without (P < .0001). In conclusion, having either type of cutaneous immune-related adverse event in cancer patients receiving immunotherapies was correlated with a longer overall survival. Prompt diagnosis and suitable treatment are important.

Transcranial Ultrasound Stimulation Reverses Behavior Changes and the Expression of Calcium-Binding Protein in a Rodent Model of Schizophrenia.

Cognitive dysfunctions are a core feature of schizophrenia that may be linked to abnormalities in gamma-aminobutyric-acid (GABA)ergic neurons. Traditional antipsychotics show poor efficacy in treating cognitive symptoms. The purpose of this study was to investigate the restorative role of transcranial ultrasound stimulation (TUS) in counteracting dizocilpine (MK-801)-induced cognitive deficits and GABAergic interneuron dysfunction in a simulation of schizophrenia. Some rats subjected to MK-801 administration were treated with low-intensity pulsed ultrasound (LIPUS) daily for 5 days, while other rats subjected to MK-801 administration received no LIPUS treatment. After LIPUS treatment, the neuroprotective effects of LIPUS in the LIPUS-treated rats were assessed through behavioral analysis, western blotting, and histological observations. Compared with the MK-801-treated group, the MK-801 plus LIPUS-treated rats revealed a preference for novel objects. The MK-801 plus LIPUS-treated rats also exhibited a significant decrease in swim times compared to the MK-801-treated rats. LIPUS stimulation significantly increased hippocampal levels of CB and PV and restored the cell densities of PV + and CB + in the cingulate cortex in the MK-801 plus LIPUS-treated group. In addition, LIPUS stimulation rebalanced the BDNF levels in the hippocampus and medial prefrontal cortex. Our findings indicate that LIPUS improves cognitive deficits and ameliorates neuropathology in MK-801-treated rats. These results suggest that LIPUS may constitute a potential novel therapeutic approach for the treatment of schizophrenia.

Taiwanese dermatological association consensus for the definition, classification, diagnosis, and management of urticaria: A 2021 update.

Urticaria is a prevalent disease with substantial physical, psychological, and economic impacts. With the advent of understandings of the disease and the emerging evidence of treatments, the international guidelines for treating urticaria have been updated in recent years. In order to update the 2014 edition of the Taiwanese Dermatological Association (TDA) consensus of urticaria, a total of 17 dermatologists with extensive experience in urticaria management were invited to and attended the TDA consensus meetings. All the specific aspects of the content were approved by at least 75% of the experts in attendance. Comparing to the former edition, several substantial modifications were made. For diagnosis, D-dimer was added as the recommended routine test in patients with chronic spontaneous urticaria. For pharmacological management, treatment suggestions were simplified. The approved-dosed, the up-dosed second-generation antihistamines, omalizumab, and cyclosporine were listed as the first-line to the fourth-line treatment, respectively. In addition, the management for patients of special considerations, such as the elderly, children, and pregnant women, were all discussed and mentioned in the consensus. We hope the updated TDA consensus can serve as a reference for all physicians and can help the physicians providing up-to-dated managements for these patients.

Photodecarboxylative Amination of Redox-Active Esters with Diazirines.

Diazirines have been recently demonstrated to serve as electrophilic amination reagents that afford diaziridines, versatile heterocycles that are readily transformed into amines, hydrazines, and nitrogen-containing heterocycles. Here, we report the photodecarboxylative amination of redox-active esters with diazirines using inexpensive photoactivators under mild conditions with an enhanced scope for primary substrates. The stability of diazirines to blue light is demonstrated, paving the way for further research into other photochemical amination methods with these unique heterocycles.

Perampanel Reduces Hyperthermia-Induced Seizures in Dravet Syndrome Mouse Model.

Treatment options for Dravet syndrome are limited. The aim of this study was to evaluate the antiepileptic effect of the AMPA receptor antagonist perampanel (PER) on a mouse model of Dravet syndrome (Scn1a E1099X/+ ). We report here that the PER (2 mg/kg) treatment inhibited the spontaneous recurrent seizures and attenuated epileptic activity in Scn1a E1099X/+ mice. In the hyperthermia-induced seizure experiment, PER clearly increased temperature tolerance and significantly ameliorated seizure frequency and discharge duration. PER also demonstrated antiepileptic effects in a cross-over study and a synergistic effect for attenuating heat-induced seizure when given in combination with stiripentol or valproic acid. The results showed that PER effectively decreased the occurrence of spontaneous recurrent seizures and showed significant therapeutic potential for hyperthermia-induced seizures with regard to both susceptibility and severity in a Dravet syndrome mouse model. Potential therapeutic effects of PER for treatment of Dravet syndrome were demonstrated.

Low-Intensity Pulsed Ultrasound Enhances Neurotrophic Factors and Alleviates Neuroinflammation in a Rat Model of Parkinson's Disease.

Low-intensity pulsed ultrasound (LIPUS) has also been reported to improve behavioral functions in Parkinson's disease (PD) animal models; however, the effect of LIPUS stimulation on the neurotrophic factors and neuroinflammation has not yet been addressed. PD rat model was built by injection of 6-hydroxydopamine (6-OHDA) in 2 sites in the right striatum. The levels of neurotrophic factors and lipocalin-2 (LCN2)-induced neuroinflammation were quantified using a western blot. Rotational test and cylinder test were conducted biweekly for 8 weeks. When the 6-OHDA + LIPUS and 6-OHDA groups were compared, the locomotor function of the 6-OHDA + LIPUS rats was significantly improved. After LIPUS stimulation, the tyrosine hydroxylase staining density was significantly increased in the striatum and substantia nigra pars compacta (SNpc) of lesioned rats. Unilateral LIPUS stimulation did not increase brain-derived neurotrophic factor in the striatum and SNpc of lesioned rats. In contrast, unilateral LIPUS stimulation increased glial cell line-derived neurotrophic factor (GDNF) protein 1.98-fold unilaterally in the SNpc. Additionally, LCN2-induced neuroinflammation can be attenuated following LIPUS stimulation. Our data indicated that LIPUS stimulation may be a potential therapeutic tool against PD via enhancement of GDNF level and inhibition of inflammatory responses in the SNpc of the brain.

Cloning and expression analysis of GATA1 gene in Carassius auratus red var.

BACKGROUND: GATA1 is a key transcription factor in the GATA family, and promotes the differentiation and maturation of red blood cell, which is essential for normal hematopoiesis. RESULTS: Our results showed that the cDNA sequence of GATA1 was 2730 bp long encoding 443 amino acids. qRT-PCR analysis demonstrated that GATA1 had the highest expression in testis (T), followed by pituitary (P) and spleen (S). GATA1 gene expression in C. auratus red var. embryo from the neuroblast stage (N) to the embryo hatching (H) changes continuously; and the gene expression levels of nonylphenol (NP)-treated and those of control embryos were significantly different. Moreover, Methylation levels of GATA1 gene in NP-treated embryos were higher than those in control embryos, indicating that NP affected GATA1 methylation. CONCLUSIONS: Our study provides cues for further studying the roles of GATA1 gene in fish development, and suggested a potential molecular mechanism by which NP leads to abnormal development of fish embryos.

Exosomal miR-365a-5p derived from HUC-MSCs regulates osteogenesis in GIONFH through the Hippo signaling pathway.

The pathogenesis of glucocorticoid (GC)-induced osteonecrosis of the femoral head (GIONFH) is still disputed, and abnormal bone metabolism caused by GCs may be an important factor. In vitro, Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) staining were used to evaluate cellular proliferation, and western blotting was used to investigate osteogenesis. In vivo, we used micro-computed tomography (micro-CT), H&E staining, Masson staining, and immunohistochemistry (IHC) analysis to evaluate the impact of exosomes. In addition, the mechanism by which exosomes regulate osteogenesis through the miR-365a-5p/Hippo signaling pathway was investigated using RNA sequencing (RNA-seq), luciferase reporter assays, fluorescence in situ hybridization (FISH), and western blotting. The results of western blotting verified that the relevant genes in osteogenesis, including BMP2, Sp7, and Runx2, were upregulated. RNA-seq and qPCR of the exosome and Dex-treated exosome groups showed that miR-365a-5p was upregulated in the exosome group. Furthermore, we verified that miR-365a-5p promoted osteogenesis by targeting SAV1. Additional in vivo experiments revealed that exosomes prevented GIONFH in a rat model, as shown by micro-CT scanning and histological and IHC analysis. We concluded that exosomal miR-365a-5p was effective in promoting osteogenesis and preventing the development of GIONFH via activation of the Hippo signaling pathway in rats.

Perceptions of Role Transition into Practice among Advanced Practice Providers and Physicians.

This study sought to examine the experiences of advanced practice providers (APPs) as an approach to inform the development of formalized programs for transition into practice and to compare APP (N = 122) and physician (N = 84) perceptions of the novice practitioners' acclimation into a provider role within the first year of practice. Using a cross-sectional survey design, two separate web-based questionnaires were distributed to APPs and physicians. The APPs' perspectives echoed findings of earlier studies with regard to perceived confidence, feelings of anxiety/fear, and inadequacy. In 16 of 23 paired items, physicians and APPs had similar perspectives about confidence/competence after orientation. Significant differences in their perceptions included amount of physician support, time management, length of time to become a fully functional APP, and independence. Better understanding of the perceptions of APPs and physicians can augment APP preparation for a shifting workforce composition and team-based, interprofessional practice designed to meet the population's health care needs.