Mouse p202 is a disease locus for lupus and a dominant‐negative inhibitor of AIM2 inflammasome activation. A human homolog of p202 has not been identified so far. Here, we report a novel transcript ...isoform of human IFI16‐designated IFI16‐β, which has a domain architecture similar to that of mouse p202. Like p202, IFI16‐β contains two HIN domains, but lacks the pyrin domain. IFI16‐β is ubiquitously expressed in various human tissues and cells. Its mRNA levels are also elevated in leukocytes of patients with lupus, virus‐infected cells, and cells treated with interferon‐β or phorbol ester. IFI16‐β co‐localizes with AIM2 in the cytoplasm, whereas IFI16‐α is predominantly found in the nucleus. IFI16‐β interacts with AIM2 to impede the formation of a functional AIM2‐ASC complex. In addition, IFI16‐β sequesters cytoplasmic dsDNA and renders it unavailable for AIM2 sensing. Enforced expression of IFI16‐β inhibits the activation of AIM2 inflammasome, whereas knockdown of IFI16‐β augments interleukin‐1β secretion triggered by dsDNA but not dsRNA. Thus, cytoplasm‐localized IFI16‐β is functionally equivalent to mouse p202 that exerts an inhibitory effect on AIM2 inflammasome.
Synopsis
IFI16‐β, a novel transcript isoform of IFI16 is a functional homolog of mouse p202 and inhibits the AIM2 inflammasome. IFI16‐β impedes AIM2‐ASC complex formation and blocks cytoplasmic dsDNA sensing of AIM2.
IFI16‐β shows a similar domain architecture than mouse p202.
IFI16‐β associates with STING and is a weak inducer of type I interferons.
IFI16‐β inhibits AIM2 inflammasome activation, and blocks its binding to cytoplasmic dsDNA.
IFI16‐β, a novel transcript isoform of IFI16 is a functional homolog of mouse p202 and inhibits the AIM2 inflammasome. IFI16‐β impedes AIM2‐ASC complex formation and blocks cytoplasmic dsDNA sensing of AIM2.
Abstract
STING is a core adaptor in innate nucleic acid sensing in mammalian cells, on which different sensing pathways converge to induce type I interferon (IFN) production. Particularly, STING is ...activated by 2′3′-cGAMP, a cyclic dinucleotide containing mixed phosphodiester linkages and produced by cytoplasmic DNA sensor cGAS. Here, we reported on a novel transcript isoform of STING designated STING-β that dominantly inhibits innate nucleic acid sensing. STING-β without transmembrane domains was widely expressed at low levels in various human tissues and viral induction of STING-β correlated inversely with IFN-β production. The expression of STING-β declined in patients with lupus, in which type I IFNs are commonly overproduced. STING-β suppressed the induction of IFNs, IFN-stimulated genes and other cytokines by various immunostimulatory agents including cyclic dinucleotides, DNA, RNA and viruses, whereas depletion of STING-β showed the opposite effect. STING-β interacted with STING-α and antagonized its antiviral function. STING-β also interacted with TBK1 and prevented it from binding with STING-α, TRIF or other transducers. In addition, STING-β bound to 2′3′-cGAMP and impeded its binding with and activation of STING-α, leading to suppression of IFN-β production. Taken together, STING-β sequesters 2′3′-cGAMP second messenger and other transducer molecules to inhibit innate nucleic acid sensing dominantly.
To determine the prevalence of mitochondrial diseases (MD) in Hong Kong (HK) and to evaluate the clinical characteristics and genetic landscape of MD patients in the region.
This study ...retrospectively reviewed the phenotypic and molecular characteristics of MD patients from participating public hospitals in HK between January 1985 to October 2020. Molecularly and/or enzymatically confirmed MD cases of any age were recruited via the Clinical Analysis and Reporting System (CDARS) using relevant keywords and/or International Classification of Disease (ICD) codes under the HK Hospital Authority or through the personal recollection of treating clinicians among the investigators.
A total of 119 MD patients were recruited and analyzed in the study. The point prevalence of MD in HK was 1.02 in 100,000 people (95% confidence interval 0.81-1.28 in 100,000). 110 patients had molecularly proven MD and the other nine were diagnosed by OXPHOS enzymology analysis or mitochondrial DNA depletion analysis with unknown molecular basis. Pathogenic variants in the mitochondrial genome (72 patients) were more prevalent than those in the nuclear genome (38 patients) in our cohort. The most commonly involved organ system at disease onset was the neurological system, in which developmental delay, seizures or epilepsy, and stroke-like episodes were the most frequently reported presentations. The mortality rate in our cohort was 37%.
This study is a territory-wide overview of the clinical and genetic characteristics of MD patients in a Chinese population, providing the first available prevalence rate of MD in Hong Kong. The findings of this study aim to facilitate future in-depth evaluation of MD and lay the foundation to establish a local MD registry.
Kinetically inert metal complexes have arisen as promising alternatives to existing platinum and ruthenium chemotherapeutics. Reported herein, to our knowledge, is the first example of a ...substitutionally inert, Group 9 organometallic compound as a direct inhibitor of signal transducer and activator of transcription 3 (STAT3) dimerization. From a series of cyclometalated rhodium(III) and iridium(III) complexes, a rhodium(III) complex emerged as a potent inhibitor of STAT3 that targeted the SH2 domain and inhibited STAT3 phosphorylation and dimerization. Significantly, the complex exhibited potent anti‐tumor activities in an in vivo mouse xenograft model of melanoma. This study demonstrates that rhodium complexes may be developed as effective STAT3 inhibitors with potent anti‐tumor activity.
Saving your skin: A rhodium(III) complex is the first example of a substitutionally inert, Group 9 organometallic compound which serves as a direct inhibitor of the signal transducer and activator of transcription 3 (STAT3) dimerization. The rhodium(III) complex inhibited STAT3 activity in vitro and in vivo and showed potent and selective anticancer activity against melanoma cell lines and melanoma xenografts in an in vivo mouse model.
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•3D printable polypropylene-based conductive filament (<0.01Ωm) has been achieved.•Electrical and UV stress tests demonstrated stability of printed conductors.•Practical plastic ...thermometer and flex sensor were 3D printed.
3D printing is a unique technology that potentially offers a high degree of freedom for the customization of practical products that incorporate electrical components, such as sensors in wearable applications. The availability of inexpensive, reliable, electrically conductive material will be indispensable in the fabrication of such circuits and sensors before the full potential of 3D printing for customized products incorporating electrical elements can be realized. To date, 3D printable conductive filaments with sufficiently high conductivities to fabricate practical circuits remain lacking for fused deposition modeling. Herein, we describe the fabrication, characterization, stress testing, and application of a low-cost thermoplastic conductive composite that has been processed into filament form for 3D printing. Results from stress tests show that the electrical properties of our composites are stable under exposure to sunlight over 1 month and there was no observable degradation in electrical resistance when used at 12V (AC) for 7 days. Practical circuits were 3D printed using filaments with resistivity of ∼5×10−3Ωm, and powered up with a 9V battery. A plastic thermometer and a flex sensor were prototyped to illustrate the potential of this material for sensing applications, for example, in customized wearables.
Background
Psychotic disorders are associated with a high rate of relapse. In addition to medication non‐adherence, some psychosocial factors have been found to be predictive of relapse (e.g., poor ...premorbid adjustment, high expressed emotion and substance misuse). Impairments in cognitive functions including general memory functioning, set shifting, attention, processing speed and working memory have also been indicative of a subsequent psychotic episode. As clinical appointments do not always allow for timely or accurate detection of these early warning signs, the ReMind app is developed to explore potential relapse predictors and enhance the process of relapse monitoring.
Aim
The ReMind app aims (1) to assess whether verbal or visual working memory predicts psychotic relapse in 1 year and (2) to determine whether social factors such as stressful life events, level of expressed emotion and medication adherence also predict relapse in 1 year.
Methods
This is a one‐year prospective follow‐up study involving 176 remitted patients diagnosed with schizophrenia or non‐affective psychoses. Monthly relapse predictor assessments will be conducted via ReMind throughout the one‐year study duration. These assessments include neurocognitive tasks and psychosocial questionnaires.
Results
Recruitment began in August 2017 and is still ongoing. Preliminary user feedback suggested an overall positive experience with the app.
Conclusion
The ReMind app presents a step forward to the identification and sensitive detection of reliable psychosis relapse predictors. With its anticipated success, it may offer an alternative means of monitoring relapse for the Chinese‐speaking population in the future.
Contrasting the well-described effects of early intervention (EI) services for youth-onset psychosis, the potential benefits of the intervention for adult-onset psychosis are uncertain. This paper ...aims to examine the effectiveness of EI on functioning and symptomatic improvement in adult-onset psychosis, and the optimal duration of the intervention.
360 psychosis patients aged 26-55 years were randomized to receive either standard care (SC,
= 120), or case management for two (2-year EI,
= 120) or 4 years (4-year EI,
= 120) in a 4-year rater-masked, parallel-group, superiority, randomized controlled trial of treatment effectiveness (Clinicaltrials.gov: NCT00919620). Primary (i.e. social and occupational functioning) and secondary outcomes (i.e. positive and negative symptoms, and quality of life) were assessed at baseline, 6-month, and yearly for 4 years.
Compared with SC, patients with 4-year EI had better Role Functioning Scale (RFS) immediate interaction estimate = 0.008, 95% confidence interval (CI) = 0.001-0.014,
= 0.02 and extended social network (interaction estimate = 0.011, 95% CI = 0.004-0.018,
= 0.003) scores. Specifically, these improvements were observed in the first 2 years. Compared with the 2-year EI group, the 4-year EI group had better RFS total (
= 0.01), immediate (
= 0.01), and extended social network (
= 0.05) scores at the fourth year. Meanwhile, the 4-year (
= 0.02) and 2-year EI (
= 0.004) group had less severe symptoms than the SC group at the first year.
Specialized EI treatment for psychosis patients aged 26-55 should be provided for at least the initial 2 years of illness. Further treatment up to 4 years confers little benefits in this age range over the course of the study.
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus in Asia that causes severe disease. Despite its clinical importance, treatment options for SFTSV ...infection remains limited. The SFTSV glycoprotein Gn plays a major role in mediating virus entry into host cells and is therefore a potential antiviral target. In this study, we employed an in silico structure-based strategy to design novel cyclic antiviral peptides that target the SFTSV glycoprotein Gn. Among the cyclic peptides, HKU-P1 potently neutralizes the SFTSV virion. Combinatorial treatment with HKU-P1 and the broad-spectrum viral RNA-dependent RNA polymerase inhibitor favipiravir exhibited synergistic antiviral effects in vitro. The in silico peptide design platform in this study may facilitate the generation of novel antiviral peptides for other emerging viruses.
Purpose
Survivorship in children with cancer comes at a cost of developing chronic treatment-related complications. Yet, it is still an under-researched area in Asia, which shares the largest ...proportion of the global childhood cancer burden given its vast population. This systematic review summarizes existing literature on clinically ascertained health outcomes in Asian survivors of childhood cancer.
Methods
A search was conducted on Ovid Medline and EMBASE for studies that focused on survivors of childhood cancer from countries in East and Southeast Asia; adopted post-treatment clinical ascertainment of organ-specific toxicities or/and secondary malignancy. Studies were excluded if health outcomes were assessed during the acute treatment.
Results
Fifty-nine studies, enrolling a total of 13,442 subjects, were conducted on survivors of leukemia (34%), CNS tumor (14%), and cohorts of survivors with heterogeneous cancer diagnoses (52%). The studies used different medical evaluation methods to assess cardiovascular (15%), metabolic and infertility (32%), and neurological/neurocognitive (20%) outcomes in survivors. The collective findings suggest potential differences in the prevalence of certain late effects (e.g., secondary malignancy and obesity) among Asian and non-Asian populations, which may reflect differences in treatment regimens, practice, genetic variations, or/and socioeconomic disparity.
Conclusions
We recommend developing collaborative initiatives to build a regional repository of systematically assessed health outcomes and biospecimens to investigate treatment, social-environmental and genetic predictors, and interventions for late effects in this population.
Implications for Cancer Survivors
The existing types of chronic health problems identified in this review suggest the need for active screening, better access to survivorship care, and promotion of protective health behavior in Asia.
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