Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression.

Transposable elements (TEs) are widespread genetic parasites known to be kept under tight transcriptional control. Here, we describe a functional connection between the mouse-orthologous "nuclear exosome targeting" (NEXT) and "human silencing hub" (HUSH) complexes, involved in nuclear RNA decay and the epigenetic silencing of TEs, respectively. Knocking out the NEXT component ZCCHC8 in embryonic stem cells results in elevated TE RNA levels. We identify a physical interaction between ZCCHC8 and the MPP8 protein of HUSH and establish that HUSH recruits NEXT to chromatin at MPP8-bound TE loci. However, while NEXT and HUSH both dampen TE RNA expression, their activities predominantly affect shorter non-polyadenylated and full-length polyadenylated transcripts, respectively. Indeed, our data suggest that the repressive action of HUSH promotes a condition favoring NEXT RNA decay activity. In this way, transcriptional and post-transcriptional machineries synergize to suppress the genotoxic potential of TE RNAs.

The oncogenic kinase TOPK upregulates in psoriatic keratinocytes and contributes to psoriasis progression by regulating neutrophils infiltration.

BACKGROUND: T-LAK cell-oriented protein kinase (TOPK) strongly promotes the malignant proliferation of cancer cells and is recognized as a promising biomarker of tumor progression. Psoriasis is a common inflammatory skin disease featured by excessive proliferation of keratinocytes. Although we have previously reported that topically inhibiting TOPK suppressed psoriatic manifestations in psoriasis-like model mice, the exact role of TOPK in psoriatic inflammation and the underlying mechanism remains elusive. METHODS: GEO datasets were analyzed to investigate the association of TOPK with psoriasis. Skin immunohistochemical (IHC) staining was performed to clarify the major cells expressing TOPK. TOPK conditional knockout (cko) mice were used to investigate the role of TOPK-specific deletion in IMQ-induced psoriasis-like dermatitis in mice. Flow cytometry was used to analyze the alteration of psoriasis-related immune cells in the lesional skin. Next, the M5-induced psoriasis cell model was used to identify the potential mechanism by RNA-seq, RT-RCR, and western blotting. Finally, the neutrophil-neutralizing antibody was used to confirm the relationship between TOPK and neutrophils in psoriasis-like dermatitis in mice. RESULTS: We found that TOPK levels were strongly associated with the progression of psoriasis. TOPK was predominantly increased in the epidermal keratinocytes of psoriatic lesions, and conditional knockout of TOPK in keratinocytes suppressed neutrophils infiltration and attenuated psoriatic inflammation. Neutrophils deletion by neutralizing antibody greatly diminished the suppressive effect of TOPK cko in psoriasis-like dermatitis in mice. In addition, topical application of TOPK inhibitor OTS514 effectively attenuated already-established psoriasis-like dermatitis in mice. Mechanismly, RNA-seq revealed that TOPK regulated the expression of some genes in the IL-17 signaling pathway, such as neutrophils chemokines CXCL1, CXCL2, and CXCL8. TOPK modulated the expression of neutrophils chemokines via activating transcription factors STAT3 and NF-κB p65 in keratinocytes, thereby promoting neutrophils infiltration and psoriasis progression. CONCLUSIONS: This study identified a crucial role of TOPK in psoriasis by regulating neutrophils infiltration, providing new insights into the pathogenesis of psoriasis.

Transplant of fecal microbiota from healthy young mice relieves cognitive defects in late-stage diabetic mice by reducing metabolic disorders and neuroinflammation.

Fecal microbiota transplant (FMT) is becoming as a promising area of interest for treating refractory diseases. In this study, we investigated the effects of FMT on diabetes-associated cognitive defects in mice as well as the underlying mechanisms. Fecal microbiota was prepared from 8-week-aged healthy mice. Late-stage type 1 diabetics (T1D) mice with a 30-week history of streptozotocin-induced diabetics were treated with antibiotics for 7 days, and then were transplanted with bacterial suspension (100 µL, i.g.) once a day for 14 days. We found that FMT from healthy young mice significantly alleviated cognitive defects of late-stage T1D mice assessed in Morris water maze test. We revealed that FMT significantly reduced the relative abundance of Gram-negative bacteria in the gut microbiota and enhanced intestinal barrier integrity, mitigating LPS translocation into the bloodstream and NLRP3 inflammasome activation in the hippocampus, thereby reducing T1D-induced neuronal loss and astrocytic proliferation. FMT also reshaped the metabolic phenotypes in the hippocampus of T1D mice especially for alanine, aspartate and glutamate metabolism. Moreover, we showed that application of aspartate (0.1 mM) significantly inhibited NLRP3 inflammasome activation and IL-1ß production in BV2 cells under a HG/LPS condition. We conclude that FMT can effectively relieve T1D-associated cognitive decline via reducing the gut-brain metabolic disorders and neuroinflammation, providing a potential therapeutic approach for diabetes-related brain disorders in clinic.

Topical application of TOPK inhibitor OTS514 suppresses psoriatic progression by inducing keratinocytes cell cycle arrest and apoptosis.

T-LAK cell-oriented protein kinase (TOPK) potently promotes malignant proliferation of tumour cells and is considered as a maker of tumour progression. Psoriasis is a common inflammatory skin disease characterized by abnormal proliferation of keratinocytes. However, the role of TOPK in psoriasis has not been well elucidated. This study aims to investigate the expression and role of TOPK in psoriasis, and the role of TOPK inhibitor in psoriasis attenuation. Gene Expression Omnibus datasets derived from psoriasis patients and psoriatic model mice were screened for analysis. Skin specimens from psoriasis patients were collected for TOPK immunohistochemical staining to investigate the expression and localization of TOPK. Next, psoriatic mice model was established to further confirm TOPK expression pattern. Then, TOPK inhibitor was applied to investigate the role of TOPK in psoriasis progression. Finally, cell proliferation assay, apoptosis assay and cell cycle analysis were performed to investigate the potential mechanism involved. Our study showed that TOPK was upregulated in the lesions of both psoriasis patients and psoriatic model mice, and TOPK levels were positively associated with psoriasis progression. TOPK was upregulated in psoriatic lesions and expressed predominantly by epidermal keratinocytes. In addition, TOPK levels in epidermal keratinocytes were positively correlated with epidermal hyperplasia. Furthermore, topical application of TOPK inhibitor OTS514 obviously alleviated disease severity and epidermal hyperplasia. Mechanismly, inhibiting TOPK induces G2/M phase arrest and apoptosis of keratinocytes, thereby attenuating epidermal hyperplasia and disease progression. Collectively, this study identifies that upregulation of TOPK in keratinocytes promotes psoriatic progression, and inhibiting TOPK attenuates epidermal hyperplasia and psoriatic progression.

Protective effects and mechanisms of N-acetylcysteine on indomethacin-induced intestinal injury in a porcine model.

This study aimed to investigate the effect of N-acetylcysteine (NAC) on indomethacin (IDMT)-induced intestinal injury in a piglet model and explore the underlying molecular mechanisms. Piglets were randomly divided into 3 treatment groups: (1) control group; (2) IDMT group; (3) NAC+IDMT group. The results showed that NAC administration significantly increased the average daily gain of piglets, attenuated the intestine hyperemia, and restored normal jejunal morphology. Further studies indicated that NAC administration significantly increased plasma citrulline concentration and jejunal villin expression, but decreased the content of proinflammatory cytokines in plasma and jejunum of IDMT-stimulated piglets. NAC administration selectively decreased the proportion of eosinophils but not neutrophils in plasma. Furthermore, NAC administration significantly increased the activities of superoxide dismutase and catalase in plasma but decreased the concentrations of hydrogen peroxide (plasma) and malondialdehyde (plasma and jejunum), as well as the activity of myeloperoxidase (jejunum) when comparing NAC+IDMT group with IDMT group. Gene Ontology analysis showed that the significantly enriched molecular function term was "ubiquitin-like protein ligase binding" for NAC+IDMT versus IDMT differentially regulated genes. In the biological process category, differentially regulated genes of NAC+IDMT versus IDMT were mainly enriched in immune-related terms. The major enrichments for differentially regulated proteins (DRPs) of NAC+IDMT versus IDMT were terms involved in lipid metabolism and immune response. KEGG pathway enrichment analysis showed that "arginine biosynthesis" was a significant enrichment term for the DRPs of NAC+IDMT versus IDMT. Further studies demonstrated that NAC administration up-regulated argininosuccinate synthase 1 mRNA expression and down-regulated arginase mRNA expression in the jejunum of IDMT-stimulated piglets. Moreover, the content of nitric oxide was restored to a normal level with the reduction of nitric oxide synthase activity. NAC administration ameliorated intestinal injury in IDMT-challenged piglets by enhancing antioxidant and anti-inflammatory functions and modulating arginine metabolism in the small intestine.

The RNA exosome shapes the expression of key protein-coding genes.

The ribonucleolytic exosome complex is central for nuclear RNA degradation, primarily targeting non-coding RNAs. Still, the nuclear exosome could have protein-coding (pc) gene-specific regulatory activities. By depleting an exosome core component, or components of exosome adaptor complexes, we identify ∼2900 transcription start sites (TSSs) from within pc genes that produce exosome-sensitive transcripts. At least 1000 of these overlap with annotated mRNA TSSs and a considerable portion of their transcripts share the annotated mRNA 3' end. We identify two types of pc-genes, both employing a single, annotated TSS across cells, but the first type primarily produces full-length, exosome-sensitive transcripts, whereas the second primarily produces prematurely terminated transcripts. Genes within the former type often belong to immediate early response transcription factors, while genes within the latter are likely transcribed as a consequence of their proximity to upstream TSSs on the opposite strand. Conversely, when genes have multiple active TSSs, alternative TSSs that produce exosome-sensitive transcripts typically do not contribute substantially to overall gene expression, and most such transcripts are prematurely terminated. Our results display a complex landscape of sense transcription within pc-genes and imply a direct role for nuclear RNA turnover in the regulation of a subset of pc-genes.

Unusual Secondary Metabolites from the Mangrove Ecosystems: Structures, Bioactivities, Chemical, and Bio-Syntheses.

Mangrove ecosystems are widely distributed in the intertidal zone of tropical and subtropical estuaries or coasts, containing abundant biological communities, for example, mangrove plants and diverse groups of microorganisms, featuring various bioactive secondary metabolites. We surveyed the literature from 2010 to 2022, resulting in a collection of 134 secondary metabolites, and classified them into two major families in terms of the biological sources and 15 subfamilies according to the chemical structures. To highlight the structural diversity and bioactivities of the mangrove ecosystem-associated secondary metabolites, we presented the chemical structures, bioactivities, biosynthesis, and chemical syntheses.

Uncommon Capnosane Diterpenes with Neuroprotective Potential from South China Sea Soft Coral Sarcophyton boettgeri.

The first investigation of the South China Sea soft coral Sarcophyton boettgeri afforded five new capnosane diterpenes, sarboettgerins A-E (1-5), together with one known related compound, pavidolide D (6). Their structures, including absolute configurations, were elucidated by the extensive spectroscopic analysis, 13C NMR calculations, and X-ray diffraction. Among them, new compounds 1-5 were featured by the rarely encountered Z-geometry double bond Δ1 within the 5/11-fused bicyclic capnosane carbon framework. Plausible biogenetic relationships of all isolates were proposed, and they might give an insight into future biomimetic synthesis of these novel compounds. In an in vitro bioassay, compound 5 displayed potent anti-neuroinflammatory activity against LPS-induced NO release in BV-2 microglial cells, which might be developed as a new type of potential neuroprotective agent in future.

Over 1-year duration and age difference of SARS-CoV-2 antibodies in convalescent COVID-19 patients.

Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglouilin G (IgG) and immunoglouilin M (IgM) antibodies have been widely used to assist clinical diagnosis. Our previous study reported a discrepancy in SARS-CoV-2 antibody response between male and female coronavirus disease 2019 (COVID-19) patients. However, the duration and discrepancy between ages as well as sexes of SARS-CoV-2 antibody in convalescent COVID-19 patients have not been clarified. In this study, a total of 538 health-examination individuals who were confirmed with SARS-CoV-2 infection a year ago were enrolled. Blood samples were collected and detected for IgM and IgG antibodies. Among these convalescent patients, 12.80% were detected positive for IgM antibodies. The positive rates for IgM antibody were close between sexes: for males, this is 9.17% and for females 13.75%. However, the IgG antibody was detected positive in as much as 82.90% convalescent patients and the positive rates were nearly the same between males (82.57%) and females (82.98%). Besides this, the level of IgM and IgG antibodies showed no difference between male and female convalescent patients. The level of IgG antibodies showed a significant difference between ages. The elder patients (over 35 years old) maintained a higher level of IgG antibody than the younger patients (under or equal 35 years old) after recovering for 1 year. In addition, IgG antibody was more vulnerable to disappear in younger patients than in elder patients. Overall, our study identified over 1-year duration of SARS-CoV-2 antibody and age difference of IgG antibody response in convalescent COVID-19 patients. These findings may provide new insights into long-term humoral immune response, vaccines efficacy and age-based personalized vaccination strategies.

Genome sequencing and functional annotation of Bacillus sp. strain BS-Z15 isolated from cotton rhizosphere soil having antagonistic activity against Verticillium dahliae.

In the present study, antagonistic activity of bacterial strain BS-Z15, was evaluated against Verticillium dahlia. The fermented broth of BS-Z15 inhibited the growth of Verticillium dahliae. The genome of strain BS-Z15 had a total size of 4,068,702 base pairs and contained 4318 genes, of which 4196 are coding sequences and 122 are non-coding RNA. Among these genes, nine genomic islands, 86 tRNAs, 13 sRNAs, and one prophage was determined. With the help of annotation databases, most unigene functions were identified. At the same time, genomic comparison between BS-Z15 and 12 Bacillus members showed that the genes of BS-Z15 were closely related to the Bacillus group, and were conserved between the two groups, including most of the genes associated with fungal antagonism. BS-Z15 contains genes involved in a variety of antagonistic mechanisms, including genes encoding or synthesizing mycosubtilin, chitinases (but not CHIA and CHIB), glycoside hydrolases, iron nutrients, and antibiosis. However, it only contained the complete mycosubtilin- and bacilibactin-related operators in the reported main antifungal gene cluster of B. subtilis. Mycosubtilin and bacilibactin may be the main active antifungal substance. Besides, some genes could encode products related to biofilm production, which may be related to the colonization ability of the strain in plant rhizospheres. The complete genome of B. subtilis BS-Z15 provided new insights into the potential metabolites it produces related to its biocontrol activity.

Sinueretone A, a Diterpenoid with Unprecedented Tricyclo[12.1.0.05,9]pentadecane Carbon Scaffold from the South China Sea Soft Coral Sinularia erecta.

A novel diterpenoid, sinueretone A (1), featuring an unprecedented tricyclo[12.1.0.05,9]pentadecane carbon framework, along with two new (2 and 3) and one known (4) casbane diterpenoids were isolated from the South China Sea soft coral Sinularia erecta. The structures of the new compounds, especially their absolute stereochemistry, were established by extensive spectroscopic analysis, various quantum chemical calculations, and/or X-ray diffraction analyses. A plausible biogenetic relationship of 1-4 was proposed, which gave an insight for future biomimetic synthesis of the novel compounds. In a bioassay, compounds 1 and 2 displayed interesting anti-inflammatory activity by the inhibition of lipopolysaccharide-induced tumor necrosis factor-α protein release.

Unusual polyoxygenated casbane diterpenoids from the South China Sea soft coral Sinularia erecta.

A further systematically chemical investigation of the South China Sea soft coral Sinularia erecta led to the discovery of two rare casbane diterpenoids with an uncommon 8,10-peroxide bridge, sinuereperoxides B (1) and C (2), five new casbanes with other oxygenated patterns (3-7), and seven known casbanes (8-14). The structures and absolute configurations of 1-7 were established by extensive spectroscopic data analyses, X-ray diffraction analysis, and/or quantum chemical calculations. In bioassay, compounds 2, 7, 11 and 12 exhibited considerable anti-inflammatory activity by the inhibition of TNF-α release, with IC50 values of 33.8 µM, 5 µM, 9.9 µM and 8 µM.

The Feasibility and Effectiveness of Wearable Sensor Technology in the Management of Elderly Diabetics with Foot Ulcer Remission: A Proof-Of-Concept Pilot Study with Six Cases.

AIMS: Using specials wearable sensors, we explored changes in gait and balance parameters, over time, in elderly patients at high risk of diabetic foot, wearing different types of footwear. This assessed the relationship between gait and balance changes in elderly diabetic patients and the development of foot ulcers, in a bid to uncover potential benefits of wearable devices in the prognosis and management of the aforementioned complication. METHODS: A wearable sensor-based monitoring system was used in middle-elderly patients with diabetes who recently recovered from neuropathic plantar foot ulcers. A total of 6 patients (age range: 55-80 years) were divided into 2 groups: the therapeutic footwear group (n = 3) and the regular footwear (n = 3) group. All subjects were assessed for gait and balance throughout the study period. Walking ability and gait pattern were assessed by allowing participants to walk normally for 1 min at habitual speed. The balance assessment program incorporated the "feet together" standing test and the instrumented modified Clinical Test of Sensory Integration and Balance. Biomechanical information was monitored at least 3 times. RESULTS: We found significant differences in stride length (p < 0.0001), stride velocity (p < 0.0001), and double support (p < 0.0001) between the offloading footwear group (OG) and the regular footwear group on a group × time interaction. The balance test embracing eyes-open condition revealed a significant difference in Hip Sway (p = 0.004), COM Range ML (p = 0.008), and COM Position (p = 0.004) between the 2 groups. Longitudinally, the offloading group exhibited slight improvement in the performance of gait parameters over time. The stride length (odds ratio 3.54, 95% CI 1.34-9.34, p = 0.018) and velocity (odds ratio 3.13, 95% CI 1.19-8.19, p = 0.033) of OG patients increased, converse to the double-support period (odds ratio 6.20, 95% CI 1.97-19.55, p = 0.002), which decreased. CONCLUSIONS: Special wearable devices can accurately monitor gait and balance parameters in patients in real time. The finding reveals the feasibility and effectiveness of advanced wearable sensors in the prevention and management of diabetic foot ulcer and provides a solid background for future research. In addition, the development of foot ulcers in elderly diabetic patients may be associated with changes in gait parameters and the nature of footwear. Even so, larger follow-up studies are needed to validate our findings.

The comparative efficacies of intravenous administration and intra-articular injection of tranexamic acid during anterior cruciate ligament reconstruction for reducing postoperative hemarthrosis: a prospective randomized study.

BACKGROUND: Hemarthrosis after anterior cruciate ligament (ACL) reconstruction can create many adverse joint effects. Tranexamic acid (TXA) can be used to minimize hemarthrosis and associated pain after ACL reconstruction. We aimed to compare the efficacies of intravenous (IV) administration and intra-articular (IA) injection of TXA during ACL reconstruction for reducing postoperative hemarthrosis. METHODS: A total of 120 patients who underwent arthroscopic ACL reconstruction were included in this prospective and randomized study. All patients were randomized into three groups: IV group, IA group and placebo group. Patients in the IV group received intravenously administered TXA (15 mg/kg in 100 mL of saline solution) 10 min before tourniquet release; patients in the IA group received intra-articular TXA (15 mg/kg in 100 mL of saline solution) injected via the drainage tube; and patients in the placebo group received an equivalent volume of normal saline administered into the knee joint cavity and intravenously. Drainage tubes were removed 24 h after surgery, and all enrolled patients experienced a 4-week follow-up period. The drain output volume, visual analogue scale (VAS) score, patellar circumference, hemarthrosis grade and Lysholm score of all patients were recorded. RESULTS: Both the IV group and the IA group had significantly lower drain output volumes at day 1, lower VAS scores at weeks 1 and 2, smaller patellar circumferences at weeks 1 and 2, and lower hemarthrosis grades at weeks 1 and 2 than the placebo group (p < 0.05). There were no significant differences in drain output volume, VAS score, patellar circumference or hemarthrosis grade between the IV group and the IA group at any time point (p > 0.05). No obvious differences in Lysholm score were observed between any pair of groups at week 4 (p > 0.05)). Neither infection nor deep vein thrombosis occurred in any group. CONCLUSIONS: Both intravenous administration and intra-articular injection can reduce intra-articular hemarthrosis, joint pain and swelling during ACL reconstruction. No significant difference in the efficacies of reducing hemarthrosis, joint pain and swelling was found between intravenous administration and intra-articular injection. TRIAL REGISTRATION: The study was registered by the Chinese Clinical Trial Registry (The comparative efficacies of intravenous administration and intra-articular injection of tranexamic acid during anterior cruciate ligament reconstruction; ChiCTR-INR-17012217 ; August 1, 2017).

Disordered Eating Attitudes Among University Students: The Role of Psychological Distress.

OBJECTIVE: The aim of this study was to explore the relationship between psychological distress and disordered eating attitudes. METHODS: The study design was cross-sectional study. The 12-item General Health Questionnaire (ghq-12) and Eating Attitude Test-26 (eat-26) were used to measure psychological distress and disordered eating attitudes, respectively. The data were analyzed using spss version 20.0 Software (spss Inc, ii, Chicago, il, usa). Description statistics were used for height, weight, bmi), age, eat-26 scores and ghq-12 scores. Pearson's correlation analysis was performed to explore the relationship between the eat-26 scores and the ghq-12 scores. RESULTS: The overall prevalence of disordered eating attitudes was 4.6%. The mean ghq-12 score in subjects with disordered eating attitude was higher than that of the control group (P < .05) in both the male and female groups. CONCLUSION: Our study suggested that psychological distress is associated with disordered eating attitudes. Bmi and gender turned out to not be correlated with disordered eating attitude. The findings of this study revealed that university students who have psychological distress also have a tendency toward disordered eating attitudes.

Cadmium uptake and transfer by Sedum plumbizincicola using EDTA, tea saponin, and citric acid as activators.

Sedum plumbizincicola (S. plumbizincicola) is known as a sufficient plant for phytoremediation of cadmium (Cd) polluted soils. This study aimed to investigate the effects of ethylene diamine tetraacetic acid (EDTA), tea saponin (TS), and citric acid (CA) on Cd uptake and translocation by S. plumbizincicola. To do so, using a pot experiment, we set four concentration levels of activators (1, 3, 5, and 10 mmol L-1) and a control (CK). Results showed that none of the applied activators had significant impact on soil pH. Except for CA-10, the concentration of available Cd in Cd polluted soils increased by 65.8-72.9% compared with CK. The EDTA-1, CA-1, and TS-5 treatments caused significant increases of 52.3, 67.2, and 38.4%, respectively, in the biomass of aerial parts of S. plumbizincicola (p < 0.05) compared with CK. Except for CA-3, activators increased Cd accumulation in the aerial parts of plants by 47-124% compared with CK. Of all activators, EDTA-3 caused the highest Cd accumulation of 6.64 g pot-1 in the aerial plant tissues followed by CA-10 (6.25 g pot-1) and TS-1 (5.48 g pot-1). Finally, our results suggested that the application of S. plumbizincicola together with different activators sufficiently reduced soil total Cd by 4.64-48.4% compared with CK. These findings suggest that appropriate application of EDTA, TS, and CA can promote phytoremediation of Cd contaminated soils by hyper-accumulators. In particular, the combined use of EDTA and S. plumbizincicola is an affordable and promising strategy for remediation of Cd contaminated soil.Novelty statement: Sedum plumbizincicola (S. plumbizincicola) is a well-known hyper-accumulator plant for remediation of cadmium (Cd) and zinc (Zn) contaminated soils. In addition, low molecular rganic acids and macromolecular chelating agents can improve the solubility and leaching of soil heavy metals. In the present work, we examined the combined effects of three activators (EDTA, tea saponin, and citric acid) with S. plumbizincicola to remediate a Cd contaminated soil in Anhui Province, East China. Our results indicated the effectiveness of these activators to increase soil available Cd, as well as improving the biomass of S. plumbizincicola and its Cd uptake. We believe that this study provides an efficient approach to increase the uptake of Cd by S. plumbizincicola, restoring Cd contaminated soils. Nevertheless, excessive activators may have adverse effects on soil aggregates and soil microorganisms. Therefore, it is necessary to control the amount of chelating agents and subsequently the deterioration of soil quality.

New cembrane-type diterpenoids from the South China Sea soft coral Sinularia crassa and their α-glucosidase inhibitory activity.

A detailed chemical research of the soft coral Sinularia crassa collected from the South China Sea yielded a series of cembrane-type diterpenoids, including four new cembranoids, namely sinulacrassins A - C (1, (+)-2, (+)-4) and ent-xishaflavalin G ((+)-3), along with five known analogs ((-)-3, 5-8). Their structures were elucidated by detailed spectroscopic analysis, chemical methods, and the comparison with those literature data. The absolute configuration of 1 was established by time-dependent density functional theory electronic circular dichroism (TDDFT/ECD) calculation, and the absolute configuration of (+)-2 was determined using the modified Mosher's method. The bioassay results revealed that (+)-2 and 5 were novel α-glucosidase inhibitors with IC50 values of 10.65 ± 0.16 and 30.31 ± 1.22 µM, respectively. In addition, (+)-2 and 5 were nontoxic towards human normal hepatocyte (LO2) cells at 100 µM. The present results highlighted the unusual coexistence of α and ß configurations of C-1 in cembranoids from soft coral in the Order Alcyonacea, and provided new chemotype for the development of α-glucosidase inhibitors used in anti-diabetes treatment.

Clinical and economic outcomes of remotely delivered cognitive behaviour therapy versus treatment as usual for repeat unscheduled care users with severe health anxiety: a multicentre randomised controlled trial.

BACKGROUND: It is challenging to engage repeat users of unscheduled healthcare with severe health anxiety in psychological help and high service costs are incurred. We investigated whether clinical and economic outcomes were improved by offering remote cognitive behaviour therapy (RCBT) using videoconferencing or telephone compared to treatment as usual (TAU). METHODS: A single-blind, parallel group, multicentre randomised controlled trial was undertaken in primary and general hospital care. Participants were aged ≥18 years with ≥2 unscheduled healthcare contacts within 12 months and scored >18 on the Health Anxiety Inventory. Randomisation to RCBT or TAU was stratified by site, with allocation conveyed to a trial administrator, research assessors masked to outcome. Data were collected at baseline, 3, 6, 9 and 12 months. The primary outcome was change in HAI score from baseline to six months on an intention-to-treat basis. Secondary outcomes were generalised anxiety, depression, physical symptoms, function and overall health. Health economics analysis was conducted from a health service and societal perspective. RESULTS: Of the 524 patients who were referred and assessed for trial eligibility, 470 were eligible and 156 (33%) were recruited; 78 were randomised to TAU and 78 to RCBT. Compared to TAU, RCBT significantly reduced health anxiety at six months, maintained to 9 and 12 months (mean change difference HAI -2.81; 95% CI -5.11 to -0.50; P = 0.017). Generalised anxiety, depression and overall health was significantly improved at 12 months, but there was no significant change in physical symptoms or function. RCBT was strictly dominant with a net monetary benefit of £3,164 per participant at a willingness to pay threshold of £30,000. No treatment-related adverse events were reported in either group. CONCLUSIONS: RCBT may reduce health anxiety, general anxiety and depression and improve overall health, with considerable reductions in health and informal care costs in repeat users of unscheduled care with severe health anxiety who have previously been difficult to engage in psychological treatment. RCBT may be an easy-to-implement intervention to improve clinical outcome and save costs in one group of repeat users of unscheduled care. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov on 19 Nov 2014 with reference number NCT02298036.