Search

Abstract Background The COVID-19 pandemic and subsequent lockdown measures had serious implications for community-dwelling older people with dementia. While the short-term impacts of the pandemic on this population have been well studied, there is limited research on its long-term impacts. Quantifying the long-term impacts may provide insights into whether healthcare adaptations are needed after the acute phase of the pandemic to balance infection prevention measures with healthcare provision. This study aims to examine patterns of psychotropic drug prescriptions and general practice consultations in community-dwelling older people with dementia during the first two years of the pandemic. Methods We utilised routine electronic health records from three Dutch academic general practice research networks located in the North, East, and South, between 2019 and 2021. We (1) compared the weekly prescription rates of five groups of psychotropic drugs and two groups of tracer drugs, and weekly general practice consultation rates per 1000 participants, between the first two years of the pandemic and the pre-pandemic phase, (2) calculated changes in these rates during three lockdowns and two relaxation phases relative to the corresponding weeks in 2019, and (3) employed interrupted time series analyses for the prescription rates. Analyses were performed for each region separately. Results The study population sizes in the North, East, and South between 2019 and 2021 were 1726 to 1916, 93 to 117, and 904 to 960, respectively. Data from the East was excluded from the statistical analyses due to the limited sample size. During the first two years of the pandemic, the prescription rates of psychotropic drugs were either lower or similar to those in the pre-pandemic phase, with differences varying from -2.6‰ to -10.2‰. In contrast, consultation rates during the pandemic were higher than in the pre-pandemic phase, increasing by around 38‰. Conclusions This study demonstrates a decrease in psychotropic drug prescriptions, but an increase in general practice consultations among community-dwelling older people with dementia during the first two years of the pandemic. However, reasons for the decrease in psychotropic drug prescriptions are unclear due to limited information on the presence of neuropsychiatric symptoms and the appropriateness of prescribing.

Abstract Non-small cell lung cancer (NSCLC) ranks as one of the leading causes of cancer-related deaths worldwide. Despite the prominence and effectiveness of kinase-target therapies in NSCLC treatment, these drugs are suitable for and beneficial to a mere ~30% of NSCLC patients. Consequently, the need for novel strategies addressing NSCLC remains pressing. Deubiquitinases (DUBs), a group of diverse enzymes with well-defined catalytic sites that are frequently overactivated in cancers and associated with tumorigenesis and regarded as promising therapeutic targets. Nevertheless, the mechanisms by which DUBs promote NSCLC remain poorly understood. Through a global analysis of the 97 DUBs’ contribution to NSCLC survival possibilities using The Cancer Genome Atlas (TCGA) database, we found that high expression of Josephin Domain-containing protein 2 (JOSD2) predicted the poor prognosis of patients. Depletion of JOSD2 significantly impeded NSCLC growth in both cell/patient-derived xenografts in vivo. Mechanically, we found that JOSD2 restricts the kinase activity of LKB1, an important tumor suppressor generally inactivated in NSCLC, by removing K6-linked polyubiquitination, an action vital for maintaining the integrity of the LKB1-STRAD-MO25 complex. Notably, we identified the first small-molecule inhibitor of JOSD2, and observed that its pharmacological inhibition significantly arrested NSCLC proliferation in vitro/in vivo. Our findings highlight the vital role of JOSD2 in hindering LKB1 activity, underscoring the therapeutic potential of targeting JOSD2 in NSCLC, especially in those with inactivated LKB1, and presenting its inhibitors as a promising strategy for NSCLC treatment.

Abstract Background Studies focusing on patterns of psychotropic drug prescriptions (PDPs) for subpopulations of community-dwelling older people with dementia are lacking. Objective The aim of this study was to identify the longitudinal patterns of PDPs in subpopulations. Methods This retrospective study used electronic health records from general practitioners (GPs) in the Netherlands. People (N = 1278) firstly diagnosed with dementia between 2013 and 2015, aged 65 years or older, were selected and categorized into four subpopulations: community-dwelling (CD) group throughout follow-up, ultimately admitted to nursing homes (NH) group, ultimately died (DIE) group, and ultimately deregistered for unclear reasons (DeR) group. Generalised estimating equations were used to estimate the patterns of psychotropic drug prescriptions, after the diagnosis of dementia for a five-year follow-up, and 0–3 months before institutionalisation or death. Results Over the five-year follow-up, antipsychotic prescriptions increased steadily in CD (OR = 1.07 [1.04–1.10]), NH (OR = 1.10 [1.04–1.15]), and DIE (OR = 1.05 [1.02–1.08]) groups. Similarly, prescriptions of antidepressants also showed upward trends in CD (OR = 1.04 [1.02–1.06]), NH (OR = 1.10 [1.02–1.18]), and DIE (OR = 1.04 [1.00–1.08]) groups. The other psychotropic drugs did not show clear changes over time in most of the subpopulations. In the three months before institutionalisation, antipsychotic prescriptions increased (OR = 2.12 [1.26–3.57]) in the NH group compared to prior periods. Likewise, before death, prescriptions of antipsychotics (OR = 1.74 [1.28–2.38]) and hypnotics and sedatives (OR = 2.11 [1.54–2.90]) increased in the DIE group, while anti-dementia drug prescriptions decreased (OR = 0.42 [0.26–0.69]). Conclusions After community-dwelling older people are diagnosed with dementia, all subpopulations’ prescriptions of antipsychotics and antidepressants increase continuously during the follow-up. While we cannot judge whether these prescriptions are appropriate, GPs might consider a more reluctant use of psychotropic drugs and use alternative psychosocial interventions. Additionally, antipsychotic prescriptions rise considerably shortly before institutionalisation or death, which might reflect that older people experience more neuropsychiatric symptoms during this period.

Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation in vitro and in vivo. Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples. Collectively, this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression, which may provide a potential intervention target for YAP/TAZ-related CCA patients.

The non-linearly curved coastal zone is very long and wide. The traditional satellite can’t cover the whole coastal zone in a single scan. So, the method of matching imaging combining the adjustment of satellite attitude and the scanning of the swing mirror are proposed. Firstly, based on the position of feature points of the coastal zone, the attitude when the optical axis of the satellite always points to the feature points is calculated. According to the width of the sea and land on both sides of the coastline, the parameters of the swing mirror of wide-swath whiskbroom payloads are analyzed. Secondly, the velocity vector model considering time-varying satellite attitude and the dynamic scanning of the swing mirror is constructed. The schemes of matching imaging such as adjustments of yaw angle and detector are developed. Finally, the precise experiment is designed to verify the correctness of the matching imaging. The experimental results show that the resolution of the matching imaging is less than 1 pixel and its modulation transfer function (MTF) is greater than the human eye’s minimum MTF of 0.026. The method of matching imaging using the adjustment of satellite attitude and the scanning of the swing mirror can realize wide imaging along the coastline and improve the temporal resolution at the same time.

The rolling shutter effect decreases the accuracy of the attitude measurement of star trackers when they work in rolling shutter exposure mode, especially under dynamic conditions. To solve this problem, a rolling shutter effect correction method based on particle swarm optimization is proposed. Firstly, a collinear reverse installation method between the star tracker and the satellite is proposed, which simplifies the relationship between the velocity of the star centroid and the star tracker angular velocity. Next, the centroid error model is obtained by the star centroid velocity. Based on the centroid error model and angular distance invariance, the loss function of the centroid error is proposed. Then, the particle swarm optimization algorithm is used to determine the star tracker angular velocity by minimizing the loss function. Finally, the simulation and experiments are carried out to verify the proposed method. The experimental results show that the convergence times of the algorithm are less than 50 and the root mean square error (RMSE) of the angular velocity is better than 0.02°/s when the angular velocity of the star tracker is no more than 5°/s.

Summary: The recently identified novel cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) activates the downstream adaptor protein stimulator of interferon genes (STING) by catalysing the synthesis of cyclic GMP-AMP. This in turn initiates an innate immune response through the release of various cytokines, including type I interferon. Foreign DNA (microbial infection) or endogenous DNA (nuclear or mitochondrial leakage) can serve as cGAS ligands and lead to the activation of cGAS-STING signalling. Therefore, the cGAS-STING pathway plays essential roles in infectious diseases, sterile inflammation, tumours, and autoimmune diseases. In addition, cGAS-STING signalling affects the progression of liver inflammation through other mechanisms, such as autophagy and metabolism. In this review, we summarise recent advances in our understanding of the role of cGAS-STING signalling in the innate immune modulation of different liver diseases. Furthermore, we discuss the therapeutic potential of targeting the cGAS-STING pathway in the treatment of liver diseases.

Metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastatic-associated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin α V function, which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples. Intriguingly, c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both in vitro and in vivo. Additionally, IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis. KEY WORDS: Slug, c-Met, Drug resistance, Ovarian cancer, XL184

In order to reduce energy consumption of the centralized chilled-water cooling system in large buildings, a dynamic control strategy was proposed for cooling plants by modelling and optimization. Combined with the chilled water flow model, this paper analyzed the parallel operation characteristics of the chillers and takes the load distribution as one of the control parameters. Based on the measured data of a typical cooling system that has undergone preliminary energy-saving transformation, the residual neural network is applied to model the relationship among energy consumption, controllable parameters and environmental parameters, and the residual neural network outperforms multi-layer perceptron and support vector regression. To minimize the total energy consumption, the gray wolf optimizer was introduced to optimize the controllable variables of the cooling system. Compared with the energy consumption before optimization, the simulation energy consumption after optimization decreased 10.45% on average, while the energy saving rate is only 7.9% with equal chilled water supply temperature of parallel chillers. [ABSTRACT FROM AUTHOR]