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Background: Endovascular treatment (EVT) is an established method for managing large vessel occlusion (LVO), but its efficacy in patients with mild stroke (National Institutes of Health Stroke Scale [NIHSS] score < 6) remains debated. Given the clinical problem of early neurological deterioration in approximately 10% of mild stroke patients, understanding the role of EVT in managing these patients is crucial. Our objective was to perform a meta-analysis with trial sequential analysis (TSA) focusing on mild stroke patients with LVO to determine whether EVT offers better outcomes than best medical therapy alone., Methods: A comprehensive search of PubMed, Cochrane, and Embase databases up to 12 December 2023 identified 14 retrospective and prospective cohort studies, including a total of 4436 patients with NIHSS scores less than 6 and presenting with LVO. Studies were categorized into crossover and non-crossover groups to prevent overestimation of the treatment effect. In the crossover group, patients initially treated with BMT were moved to EVT upon clinical deterioration. In the non-crossover group, patients remained in their initially assigned treatment. Meta-analysis and data extraction followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The primary outcome was achieving an excellent functional outcome, defined as a modified Rankin scale (mRS) score of 0-1 at 3 months. Secondary outcomes included good (mRS 0-2) and favorable (mRS 0-3) functional outcomes. Safety outcomes were symptomatic intracerebral hemorrhage (sICH) and mortality at 3 months., Results: In the crossover group, EVT did not significantly improve excellent functional outcomes, and TSA results were inconclusive. Conversely, in the non-crossover group, EVT significantly improved the excellent functional outcome rates at 3 months (65.0% vs. 53.7%; OR 1.62; 95% CI 1.13 to 2.32), supported by TSA. EVT increased the risk of sICH in both crossover and non-crossover groups, while mortality rates did not significantly differ between EVT and BMT groups., Conclusions: Our research indicates that thrombectomy may not significantly help mild stroke patients in recovering functional status and could increase the risk of sICH. The disparity in results between crossover and non-crossover studies highlights the critical need for the prompt identification of patients at risk of early neurological deterioration to minimize negative outcomes. Additional randomized controlled trials are essential to optimize the application of EVT in this patient population.

Oxaliplatin is effective against colorectal cancer (CRC), but resistance hampers treatment. We found upregulated Dickkopf-1 (DKK1, a secreted protein) in oxaliplatin-resistant (OR) CRC cell lines and DKK1 levels increased by more than 2-fold in approximately 50% of oxaliplatin-resistant CRC tumors. DKK1 activates AKT via cytoskeleton-associated protein 4 (CKAP4, a DKK1 receptor), modulating oxaliplatin responses in vitro and in vivo. The leucine zipper (LZ) domain of CKAP4 and cysteine-rich domain 1 (CRD1) of secreted DKK1 are crucial for their interaction and AKT signaling. By utilizing the LZ protein, we disrupted DKK1 signaling, enhancing oxaliplatin sensitivity in OR CRC cells and xenograft tumors. This suggests that DKK1 as a chemoresistant factor in CRC via AKT activation. Targeting DKK1 with the LZ protein offers a promising therapeutic strategy for oxaliplatin-resistant CRC with high DKK1 levels. This study sheds light on oxaliplatin resistance mechanisms and proposes an innovative intervention for managing this challenge., (© 2024. The Author(s).)

Combinational antiretroviral therapy (cART) suppresses human immunodeficiency virus type 1 (HIV-1) viral replication and pathogenesis in acquired immunodeficiency syndrome (AIDS) patients. However, HIV-1 remains in the latent stage of infection by suppressing viral transcription, which hinders an HIV-1 cure. One approach for an HIV-1 cure is the "shock and kill" strategy. The strategy focuses on reactivating latent HIV-1, inducing the viral cytopathic effect and facilitating the immune clearance for the elimination of latent HIV-1 reservoirs. Here, we reported that the H3K4 trimethylation (H3K4me3)-specific demethylase KDM5A/B play a role in suppressing HIV-1 Tat/LTR-mediated viral transcription in HIV-1 latent cells. Furthermore, we evaluated the potential of KDM5-specific inhibitor JQKD82 as an HIV-1 "shock and kill" agent. Our results showed that JQKD82 increases the H3K4me3 level at HIV-1 5' LTR promoter regions, HIV-1 reactivation, and the cytopathic effects in an HIV-1-latent T cell model. In addition, we identified that the combination of JQKD82 and AZD5582, a non-canonical NF-κB activator, generates a synergistic impact on inducing HIV-1 lytic reactivation and cell death in the T cell. The latency-reversing potency of the JQKD82 and AZD5582 pair was also confirmed in peripheral blood mononuclear cells (PBMCs) isolated from HIV-1 aviremic patients and in an HIV-1 latent monocyte. In latently infected microglia (HC69) of the brain, either deletion or inhibition of KDM5A/B results in a reversal of the HIV-1 latency. Overall, we concluded that KDM5A/B function as a host repressor of the HIV-1 lytic reactivation and thus promote the latency and the survival of HIV-1 infected reservoirs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The Coronavirus disease 2019 (COVID-19) is the largest global epidemic in recent time. Chinese medicine has been recognized by the World Health Organization as an effective treatment for COVID-19, but there is still a lack of high-quality randomized, double-blind trials using placebo as the control to support its application, which may hinder its further promotion locally and internationally. Objectives: This study will evaluate the efficacy and safety of Yinqiao Powder-Maxing Ganshi Decoction with variation in relieving major symptoms of mild and moderate COVID-19 by telemedicine. Methods and design: This clinical study is a randomized, double-blind, placebo-controlled trial that applies telemedicine to evaluate the efficacy and safety of Yinqiao Powder-Maxing Ganshi Decoction in the treatment of mild and moderate COVID-19. Eligible subjects will be randomly divided into either treatment or placebo groups for up to 14 days after stratification according to age (A:18-49, B:50-65) and the number of vaccinations (a: ≥3 doses, b: ≤2 doses). The treatment group will receive Yinqiao Powder-Maxing Ganshi Decoction granules along with certain variation based on their symptoms, and the placebo group will receive the same amount of placebo granules. Subjects will be prescribed different additions based on their symptoms and pathogenesis at the inclusion. The oral temperature, oximeter, result of rapid antigen test and symptom score will be recorded by subjects until they have stopped the medication. Subjects are required to have follow-up assessment by video-conference on days 7, 14 and 35. The time for the body temperature returning to normal will be used as the primary outcome. Discussion: This trial will provide scientific evidence on the use of Yinqiao Powder-Maxing Ganshi Decoction for the treatment of COVID-19, and the results would help raise the awareness in Hong Kong and the international community on the use of Chinese herbal medicine for treating COVID-19. Clinical Trial Registration: clinicaltrials.gov, identifier NCT05787327., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sum, Li, Zhang, Hung, Fong, Lin, Chow, Leung, Lo, Chia, Chan and Lin.)

Cognition and behavior could reciprocally impact each other and together determine mental health amid large-scale disasters such as COVID-19. This study reports a six-month cohort study of a population-representative sample of Hong Kong residents (N = 906) from March-August 2021 (T1) to September 2021-February 2022 (T2). Cross-lagged panel analyses reveal that T1 poor behavioral functioning as indicated by high daily routine disruptions is inversely associated with T2 cognitive adaptation as indicated by self-efficacy and meaning-making but not vice versa. T1 routine disruptions but not cognitive adaptation are positively associated with T2 probable depression/anxiety. The positive link between T1 routine disruptions and T2 probable disorders is mediated by poor cognitive adaptation at T2. The present findings suggest that upholding daily behavioral functioning relative to positive states of mind could have a more pivotal role in mental health amid large-scale disasters. Future studies can test interventions that enhance the sustainment of regular daily routines., (© 2023. The Author(s).)

Key Message: The extensive application of CRISPR in cotton was limited due to the labor-intensive transformation process. Thus, we here established a convenient method of CRISPR in cotton by CLCrV-mediated sgRNA delivery., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The prognosis of pancreatic adenocarcinoma (PDAC) remains poor, with a 5-year survival rate of 12%. Although radiotherapy is effective for the locoregional control of PDAC, it does not have survival benefits compared with systemic chemotherapy. Most patients with localized PDAC develop distant metastasis shortly after diagnosis. Upfront chemotherapy has been suggested so that patients with localized PDAC with early distant metastasis do not have to undergo radical local therapy. Several potential tissue markers have been identified for selecting patients who may benefit from local radiotherapy, thereby prolonging their survival. This review summarizes these biomarkers including SMAD4 , which is significantly associated with PDAC failure patterns and survival. In particular, Krüppel-like factor 10 ( KLF10 ) is an early response transcription factor of transforming growth factor ( TGF ) -β . Unlike TGF-β in advanced cancers, KLF10 loss in two-thirds of patients with PDAC was associated with rapid distant metastasis and radioresistance; thus, KLF10 can serve as a predictive and therapeutic marker for PDAC. For patients with resectable PDAC, a combination of KLF10 and SMAD4 expression in tumor tissues may help select those who may benefit the most from additional radiotherapy. Future trials should consider upfront systemic therapy or include molecular biomarker-enriched patients without early distant metastasis.

Background: The development of new therapies for malignant gliomas has been stagnant for decades. Through the promising outcomes in clinical trials of oncolytic virotherapy, there is now a glimmer of hope in addressing this situation. To further enhance the antitumor immune response of oncolytic viruses, we have equipped a modified oncolytic adenovirus (oAds) with a recombinant interferon-like gene (YSCH-01) and conducted a comprehensive evaluation of the safety and efficacy of this modification compared to existing treatments., Methods: To assess the safety of YSCH-01, we administered the oAds intracranially to Syrian hamsters, which are susceptible to adenovirus. The efficacy of YSCH-01 in targeting glioma was evaluated through in vitro and in vivo experiments utilizing various human glioma cell lines. Furthermore, we employed a patient-derived xenograft model of recurrent glioblastoma to test the effectiveness of YSCH-01 against temozolomide., Results: By modifying the E1A and adding survivin promoter, the oAds have demonstrated remarkable safety and an impressive ability to selectively target tumor cells. In animal models, YSCH-01 exhibited potent therapeutic efficacy, particularly in terms of its distant effects. Additionally, YSCH-01 remains effective in inhibiting the recurrent GBM patient-derived xenograft model., Conclusions: Our initial findings confirm that a double-modified oncolytic adenovirus armed with a recombinant interferon-like gene is both safe and effective in the treatment of malignant glioma. Furthermore, when utilized in combination with a targeted therapy gene strategy, these oAds exhibit a more profound effect in tumor therapy and an enhanced ability to inhibit tumor growth at remote sites., Competing Interests: K.J.Z., X.L.F., J.F.G., and X.Y.L. hold ownership interests and own patents of YSCH-01 in Yuansong Biotechnology Co., Ltd. No potential conflicts of interest were disclosed by the other authors., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Objective: To determine the role of ascending aorta dilatation in the relationship between pulse pressure (PP) and left ventricular (LV) hypertrophy., Methods: A total of 1556 Chinese elderly hypertensive patients were retrospectively studied. Transthoracic echocardiography was used to obtain the aortic and cardiac structure measurements. In addition, brachial blood pressure was measured, and total arterial compliance, systemic vascular resistance, arterial elastance, and end-systolic LV elastance were calculated. The participants were divided into four groups according to the status of ascending aortic diameter and PP., Results: LV mass index increased in succession in the four groups, i.e., the group with the normal aorta and lower PP, with the normal aorta and higher PP, with aortic dilatation and lower PP, and with aortic dilatation and higher PP ( P trend < 0.001). Total arterial compliance -1 , arterial elastance, and end-systolic LV elastance were slightly higher in the individuals with normal aorta compared to those with aortic dilatation, regardless of PP being lower or higher ( P < 0.01). Compared to the group with the normal aorta and lower PP, individuals with aortic dilatation had a significantly increased multivariable adjusted risk of LV hypertrophy, and higher PP further exacerbated this risk [aortic dilatation with lower PP (OR = 1.75, 95% CI: 1.01-3.04) and aortic dilatation with higher PP (OR = 3.42, 95% CI: 2.03-5.77)]. In the relation between PP and LV mass index ( β = 0.095, P < 0.001), -41.3% of the total effect was attributable to mediation by ascending aortic diameter ( P < 0.0001)., Conclusions: In Chinese elderly patients with hypertension, ascending aorta dilatation could reduce the influence of elevated PP on LV hypertrophy., (© 2023 JGC All rights reserved; www.jgc301.com.)

Introduction: Acral melanoma is a predominant and aggressive subtype of melanoma in non-Caucasian populations. There is a lack of genotype-driven therapies for over 50% of patients. TRPM1 (transient receptor potential melastatin 1), a nonspecific cation channel, is mainly expressed in retinal bipolar neurons and skin. Nonetheless, the function of TRPM1 in melanoma progression is poorly understood., Objectives: We investigated the association between TRPM1 and acral melanoma progression and revealed the molecular mechanisms by which TRPM1 promotes tumor progression and malignancy., Methods: TRPM1 expression and CaMKII phosphorylation in tumor specimens were tested by immunohistochemistry analysis and scored by two independent investigators. The functions of TRPM1 and CaMKII were assessed using loss-of-function and gain-of-function approaches and examined by western blotting, colony formation, cell migration and invasion, and xenograft tumor growth assays. The effects of a CaMKII inhibitor, KN93, were evaluated using both in vitro cell and in vivo xenograft mouse models., Results: We revealed that TRPM1 protein expression was positively associated with tumor progression and shorter survival in patients with acral melanoma. TRPM1 promoted AKT activation and the colony formation, cell mobility, and xenograft tumor growth of melanoma cells. TRPM1 elevated cytosolic Ca 2+ levels and activated CaMKIIδ (Ca 2+ /calmodulin-dependent protein kinase IIδ) to promote the CaMKIIδ/AKT interaction and AKT activation. The functions of TRPM1 in melanoma cells were suppressed by a CaMKII inhibitor, KN93. Significant upregulation of phospho-CaMKII levels in acral melanomas was related to increased expression of TRPM1. An acral melanoma cell line with high expression of TRPM1, CA11, was isolated from a patient to show the anti-tumor activity of KN93 in vitro and in vivo., Conclusions: TRPM1 promotes tumor progression and malignancy in acral melanoma by activating the Ca 2+/ CaMKIIδ/AKT pathway. CaMKII inhibition may be a potential therapeutic strategy for treating acral melanomas with high expression of TRPM1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Production and hosting by Elsevier B.V.)

Background: Colorectal cancer (CRC), the most common cancer type, causes high morbidity and mortality. Patients who develop drug resistance to oxaliplatin-based regimens have short overall survival. Thus, identifying molecules involved in the development of oxaliplatin resistance is critical for designing therapeutic strategies., Methods: A proteomic screen was performed to reveal altered protein kinase phosphorylation in oxaliplatin-resistant (OR) CRC tumour spheroids. The function of CHK2 was characterised using several biochemical techniques and evident using in vitro cell and in vivo tumour models., Results: We revealed that the level of phospho-CHK2(Thr68) was elevated in OR CRC cells and in ~30% of tumour samples from patients with OR CRC. We demonstrated that oxaliplatin activated several phosphatidylinositol 3-kinase-related kinases (PIKKs) and CHK2 downstream effectors and enhanced CHK2/PARP1 interaction to facilitate DNA repair. A phosphorylation mimicking CHK2 mutant, CHK2T68D, but not a kinase-dead CHK2 mutant, CHK2D347A, promoted DNA repair, the CHK2/PARP1 interaction, and cell growth in the presence of oxaliplatin. Finally, we showed that a CHK2 inhibitor, BML-277, reduced protein poly(ADP-ribosyl)ation (PARylation), FANCD2 monoubiquitination, homologous recombination and OR CRC cell growth in vitro and in vivo., Conclusion: Our findings suggest that CHK2 activity is critical for modulating oxaliplatin response and that CHK2 is a potential therapeutic target for OR CRC., (© 2022. The Author(s).)

Background: In face of large-scale disasters, persons with fewer assets are at greater risk of persistent poorer mental health than persons with more assets. Everyday daily routine disruptions and financial hardship could mediate this association., Methods: This prospective population-representative study in Hong Kong aimed to investigate the relation between assets during the acute phase of COVID-19 (February-August 2020, T1) and persistent probable depression from T1 to March-August 2021 (T2), as well as the mediating effects of daily routine disruptions and financial hardship on the assets-depression association., Results: Low assets at T1 prospectively related to persistent probable depression from T1 to T2. Primary routine disruptions (i.e., healthy eating and sleep) at T1 and financial hardship at T2 were found to fully mediate the association between T1 assets and persistent probable depression., Limitations: Persistent probable depression reported on the PHQ-9 should be further verified with clinical diagnoses/interviews., Conclusions: The COVID-19 pandemic was accompanied by a global economic downturn. Persons who have fewer assets could be at greater risk of depression during this period. Our findings suggest a need to provide behavioral and financial assistance to persons with fewer assets in the short run and a need to ensure that everyone has adequate assets to mitigate the mental health consequences of the COVID-19 pandemic in the long run., (Copyright © 2022. Published by Elsevier B.V.)

Objective: There is a socioeconomic gradient to depression risks, with more pronounced inequality amid macroenvironmental potential traumatic events. Between mid-2019 and mid-2020, the Hong Kong population experienced drastic societal changes, including the escalating civil unrest and the COVID-19 pandemic. We examined the change of the socioeconomic gradient in depression and the potential intermediary role of daily routine disruptions., Method: We conducted repeated territory-wide telephone surveys in July 2019 and July 2020 with 1112 and 2034 population-representative Cantonese-speaking Hong Kong citizens above 15 years old, respectively. Stratified by year, we examined the association between socioeconomic indicators (education attainment, household income, employment status and marital status) and probable depression (nine-item Patient Health Questionnaire [PHQ-9] ⩾ 10) using logistic regression. Differences in the socioeconomic gradient between 2019 and 2020 were tested. Finally, we performed a path analysis to test for the mediating role of daily routine disruptions., Results: Logistic regression showed that higher education attainment in 2019 and being married in 2020 were protective against probable depression. Interaction analysis showed that the inverse association of higher education attainment with probable depression attenuated in 2020 but that of being married increased. Path analysis showed that the mediated effects through daily routine disruptions accounted for 95.9% of the socioeconomic gradient of probable depression in 2020, compared with 13.1% in 2019., Conclusion: From July 2019 to July 2020, the mediating role of daily routine disruptions in the socioeconomic gradient of depression in Hong Kong increased. It is thus implied that infection control measures should consider the relevant potential mental health impacts accordingly.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-κB activation and induction of pro-inflammatory cytokines, though the underlying mechanism for this activation is not fully understood. Our results reveal that the SARS-CoV-2 Nsp14 protein contributes to the viral activation of NF-κB signaling. Nsp14 caused the nuclear translocation of NF-κB p65. Nsp14 induced the upregulation of IL-6 and IL-8, which also occurred in SARS-CoV-2 infected cells. IL-8 upregulation was further confirmed in lung tissue samples from COVID-19 patients. A previous proteomic screen identified the putative interaction of Nsp14 with host Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2), which is known to regulate NF-κB signaling. We confirmed the Nsp14-IMPDH2 protein interaction and identified that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14- mediated NF-κB activation and cytokine induction. Furthermore, IMPDH2 inhibitors (RIB, MPA) or NF-κB inhibitors (bortezomib, BAY 11-7082) restricted SARS-CoV-2 infection, indicating that IMPDH2-mediated activation of NF-κB signaling is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in inducing NF-κB activation through IMPDH2 to promote viral infection., Competing Interests: J-GP and LM-S are listed as inventors on a pending patent application describing the SARS-CoV-2 antibody 1207B4. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Kenney, Park, Fiches, Liu, Zhou, Biswas, Zhao, Que, Santoso, Martinez-Sobrido, Yount and Zhu.)

FACT (FAcilitates Chromatin Transcription) is a heterodimeric protein complex composed of SUPT16H and SSRP1, and a histone chaperone participating in chromatin remodeling during gene transcription. FACT complex is profoundly regulated, and contributes to both gene activation and suppression. Here we reported that SUPT16H, a subunit of FACT, is acetylated in both epithelial and natural killer (NK) cells. The histone acetyltransferase TIP60 contributes to the acetylation of SUPT16H middle domain (MD) at lysine 674 (K674). Such acetylation of SUPT16H is recognized by bromodomain protein BRD4, which promotes protein stability of SUPT16H in both epithelial and NK cells. We further demonstrated that SUPT16H-BRD4 associates with histone modification enzymes (HDAC1, EZH2), and further regulates their activation status and/or promoter association as well as affects the relevant histone marks (H3ac, H3K9me3 and H3K27me3). BRD4 is known to profoundly regulate interferon (IFN) signaling, while such function of SUPT16H has never been explored. Surprisingly, our results revealed that SUPT16H genetic knockdown via RNAi or pharmacological inhibition by using its inhibitor, curaxin 137 (CBL0137), results in the induction of IFNs and interferon-stimulated genes (ISGs). Through this mechanism, depletion or inhibition of SUPT16H is shown to efficiently inhibit infection of multiple viruses, including Zika, influenza, and SARS-CoV-2. Furthermore, we demonstrated that depletion or inhibition of SUPT16H also causes the remarkable activation of IFN signaling in NK cells, which promotes the NK-mediated killing of virus-infected cells in a co-culture system using human primary NK cells. Overall, our studies unraveled the previously un-appreciated role of FACT complex in coordinating with BRD4 and regulating IFN signaling in both epithelial and NK cells, and also proposed the novel application of the FACT inhibitor CBL0137 to treat viral infections., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

This study examined the mediating effects of coping resources in the prospective associations between daily routine disruptions in the acute phase of COVID-19 and persistent probable anxiety and depression. A prospective, population-representative cohort of 1318 Hong Kong Chinese respondents completed a baseline survey between February and July 2020 (T1) and a 1-year follow-up survey between March and August 2021 (T2). Respondents reported demographics and disruptions to primary and secondary daily routines at T1, coping resources (i.e., self-efficacy and meaning making) at T2, and anxiety and depressive symptoms at T1 and T2. We found that 8.1% and 10.0% of respondents reached cutoff scores for probable anxiety and depression respectively at both T1 and T2. Logistic regression showed that T1 daily routine disruptions were positively associated with heightened risk of persistent probable anxiety and depression amid COVID-19. Path analysis showed that 15.3% and 13.1% of the associations of daily routine disruptions with persistent probable anxiety and depression were explained by coping resources, respectively, while the direct routine-outcome associations remained significant. Daily routine disruptions predict higher odds of persistent probable anxiety and depression directly and partially through reducing coping resources. Sustainment of regular daily routines should be advocated and fostered to enhance coping resources and reduce the risk of poorer adjustment among the affected populations amid public health crises., (Copyright © 2022. Published by Elsevier Ltd.)

Background: This study investigated whether subjective unrest-related distress was associated with probable depression during and after the 2019 anti-ELAB movement in Hong Kong., Methods: Population-representative data were collected from 7157 Hong Kong Chinese in four cross-sectional surveys (July 2019-July 2020). Logistic regression examined the association between subjective unrest-related distress and probable depression (PHQ-9 ⩾ 10), stratified by the number of conflicts/protests across the four timepoints., Results: Unrest-related distress was positively associated with probable depression across different numbers of conflicts/protests., Conclusion: Unrest-related distress is a core indicator of probable depression. Public health interventions should target at resolving the distress during seemingly peaceful period after unrest., (© The Author(s) 2022.)

Background and Objective: Periodontitis is a multifactorial chronic inflammatory disease that can lead to the irreversible destruction of dental support tissues. As an epigenetic factor, the expression of circRNA is tissue-dependent and disease-dependent. This study aimed to identify novel periodontitis-associated circRNAs and predict relevant circRNA-periodontitis regulatory network by using recently developed bioinformatic tools and integrating sequencing profiling with clinical information for getting a better and more thorough image of periodontitis pathogenesis, from gene to clinic., Material and Methods: High-throughput sequencing and RT-qPCR were conducted to identify differentially expressed circRNAs in gingival tissues from periodontitis patients. The relationship between upregulated circRNAs expression and probing depth (PD) was performed using Spearman's correlation analysis. Bioinformatic analyses including GO analysis, circRNA-disease association prediction, and circRNA-miRNA-mRNA network prediction were performed to clarify potential regulatory functions of identified circRNAs in periodontitis. A receiver-operating characteristic (ROC) curve was established to assess the diagnostic significance of identified circRNAs., Results: High-throughput sequencing identified 70 differentially expressed circRNAs (68 upregulated and 2 downregulated circRNAs) in human periodontitis (fold change >2.0 and p < .05). The top five upregulated circRNAs were validated by RT-qPCR that had strong associations with multiple human diseases, including periodontitis. The upregulation of circRNAs were positively correlated with PD (R = .40-.69, p < .05, moderate). A circRNA-miRNA-mRNA network with the top five upregulated circRNAs, differentially expressed mRNAs, and overlapped predicted miRNAs indicated potential roles of circRNAs in immune response, cell apoptosis, migration, adhesion, and reaction to oxidative stress. The ROC curve showed that circRNAs had potential value in periodontitis diagnosis (AUC = 0.7321-0.8667, p < .05)., Conclusion: CircRNA-disease associations were predicted by online bioinformatic tools. Positive correlation between upregulated circRNAs, circPTP4A2, chr22:23101560-23135351+, circARHGEF28, circBARD1 and circRASA2, and PD suggested function of circRNAs in periodontitis. Network prediction further focused on downstream targets regulated by circRNAs during periodontitis pathogenesis., (© 2022 The Authors. Journal of Periodontal Research published by John Wiley & Sons Ltd.)

Polyamines are critical metabolites involved in various cellular processes and often dysregulated in cancers. Kaposi's sarcoma-associated Herpesvirus (KSHV), a defined human oncogenic virus, leads to profound alterations of host metabolic landscape to favor development of KSHV-associated malignancies. In our studies, we identified that polyamine biosynthesis and eIF5A hypusination are dynamically regulated by KSHV infection through modulation of key enzymes (ODC1 and DHPS) of these pathways. During KSHV latency, ODC1 and DHPS are upregulated along with increase of hypusinated eIF5A (hyp-eIF5A), while hyp-eIF5A is further induced along with reduction of ODC1 and intracellular polyamines during KSHV lytic reactivation. In return these metabolic pathways are required for both KSHV lytic reactivation and de novo infection. Further analysis unraveled that synthesis of critical KSHV latent and lytic proteins (LANA, RTA) depends on hypusinated-eIF5A. We also demonstrated that KSHV infection can be efficiently and specifically suppressed by inhibitors targeting these pathways. Collectively, our results illustrated that the dynamic and profound interaction of a DNA tumor virus (KSHV) with host polyamine biosynthesis and eIF5A hypusination pathways promote viral propagation, thus defining new therapeutic targets to treat KSHV-associated malignancies., Competing Interests: The authors have declared that no competing interests exist.

The ability of melanoma to acquire metastasis through the induction of angiogenesis is one of the major causes of skin cancer death. Here, it is found that high transcript levels of DEP domain containing 1B (DEPDC1B) in cutaneous melanomas are significantly associated with a poor prognosis. Tissue microarray analysis indicates that DEPDC1B expression is positively correlated with SOX10 in the different stages of melanoma. Consistently, DEPDC1B is both required and sufficient for melanoma growth, metastasis, angiogenesis, and functions as a direct downstream target of SOX10 to partly mediate its oncogenic activity. In contrast to other tumor types, the DEPDC1B-mediated enhancement of melanoma metastatic potential is not dependent on the activities of RHO GTPase signaling and canonical Wnt signaling, but is acquired through secretion of signal peptide, CUB domain and EGF like domain containing 3 (SCUBE3), which is crucial for promoting angiogenesis in vitro and in vivo. Mechanistically, DEPDC1B regulates SCUBE3 protein stability through the competitive association with ubiquitin ligase cell division cycle 16 (CDC16) to prevent SCUBE3 from undergoing degradation via the ubiquitin-proteasome pathway. Importantly, expression of SOX10, DEPDC1B, and SCUBE3 are positively correlated with microvessel density in the advanced stage of melanomas. In conclusion, it is revealed that a SOX10-DEPDC1B-SCUBE3 regulatory axis promotes melanoma angiogenesis and metastasis, which suggests that targeting secreted SCUBE3 can be a therapeutic strategy against metastatic melanoma., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

This study aims to test the associations of nature contact with multiple dimensions of psychological functioning. A total of 90 university employees were randomly assigned to spend their lunch breaks on (1) a 30-min structured protocol of nature contact and (2) a control group for 10 consecutive weekdays. Psychological distress, psychological well-being, and work-related psychological outcomes were assessed at baseline (T1), the day after the 10-day intervention (T2), and three months after the intervention (T3). Mixed-design analyses of variance (ANOVA) were conducted. Overall, significant intervention effects were found in the structured protocol of nature contact on psychological distress, well-being outcomes, and work engagement (all p < 0.05), whereas the 3-month post-intervention effects were non-significant. Our study showed that nature-based activities during lunch breaks could enhance office workers’ mental health in general, but the effects could be short-lived, calling for regular nature-based programs in occupational settings.

A rare subset of HIV-infected individuals, termed elite controllers (ECs), can maintain long-term control over HIV replication in the absence of antiretroviral therapy (ART). To elucidate the biological mechanism of resistance to HIV replication at the molecular and cellular levels, we performed RNA sequencing and identified alternative splicing variants from ECs, HIV-infected individuals undergoing ART, ART-naive HIV-infected individuals, and healthy controls. We identified differential gene expression patterns that are specific to ECs and may influence HIV resistance, including alternative RNA splicing and exon usage variants of the CREM/ICER gene (cyclic AMP [cAMP]-responsive element modulator/inducible cAMP early repressors). The knockout and knockdown of specific ICER exons that were found to be upregulated in ECs resulted in significantly increased HIV infection in a CD4 + T cell line and primary CD4 + T cells. Overexpression of ICER isoforms decreased HIV infection in primary CD4 + T cells. Furthermore, ICER regulated HIV long terminal repeat (LTR) promoter activity in a Tat-dependent manner. Together, these results suggest that ICER is an HIV host factor that may contribute to the HIV resistance of ECs. These findings will help elucidate the mechanisms of HIV control by ECs and may yield a new approach for treatment of HIV. IMPORTANCE A small group of HIV-infected individuals, termed elite controllers (ECs), display control of HIV replication in the absence of antiretroviral therapy (ART). However, the mechanism of ECs' resistance to HIV replication is not clear. In our work, we found an increased expression of specific, small isoforms of ICER in ECs. Further experiments proved that ICER is a robust host factor to regulate viral replication. Furthermore, we found that ICER regulates HIV LTR promoter activity in a Tat-dependent manner. These findings suggest that ICER is related to spontaneous control of HIV infection in ECs. This study may help elucidate a novel target for treatment of HIV.

HIV-1 envelope glycoprotein (Env) interacts with cell surface receptors and induces membrane fusion to enter cells and initiate infection. HIV-1 Env on virions comprises trimers of the gp120 and gp41 subunits. The polar region (PR) in the N-terminus of gp41 is composed of 17 conserved residues, including seven polar amino acids. We have reported that the PR is crucial for Env trimer stability and fusogenicity. Mutations of three highly conserved residues (S534P, T536A, or T538A) in the PR of HIV-1 NL4-3 significantly decrease or eliminate viral infectivity due to defective fusion and increased gp120 shedding. To identify compensatory Env mutations that restore viral infectivity, we infected a CD4 + T-cell line with PR mutants pseudotyped with wild-type (WT) HIV-1 Env or vesicular stomatitis virus envelope glycoprotein (VSV-G). We found that PR mutant-infected CD4 + T-cells produced infectious viruses at 7 days postinfection (dpi). Sequencing of the env cDNA from cells infected with the recovered HIV-1 revealed that the S534P mutant reverted to serine or threonine at residue 534. Interestingly, the combined PR-mutant HIV-1 (S534P/T536A or S534P/T536A/T538A) recovered its infectivity and reverted to S534, but maintained the T536A or T538A mutation, suggesting that HIV-1 replication in CD4 + T-cells can tolerate T536A and T538A Env mutations, but not S534P. Moreover, VSV-G-pseudotyped HIV-1 mutants with a fusion-defective Env also recovered infectivity in CD4 + T-cells through reverted Env mutations. These new observations help define the Env residues critical for HIV-1 infection and demonstrate that Env-defective HIV-1 mutants can rapidly regain replication competency in CD4 + T-cells. IMPORTANCE Our previous mutagenesis study revealed that serine at position 534 of HIV-1 Env is critical for viral infectivity. We found that HIV-1 Env containing serine to proline mutation at position 534 (S534P) are incapable of supporting virus-cell and cell-cell fusion. To investigate whether these mutant viruses can recover infectivity and what amino acid changes account for recovered infectivity, we infected CD4 + T-cells with Env-mutant HIV-1 pseudotyped with WT HIV-1 Env or VSV-G and monitored cultures for the production of infectious viruses. Our results showed that most of the pseudotyped viruses recovered their infectivity within 1-week postinfection, and all the recovered viruses mutated proline at position 534. These observations help define the Env residues critical for HIV-1 replication. Because Env-defective HIV-1 mutants can rapidly regain replication competency in CD4 + T-cells, it is important to carefully monitor viral mutations for biosafety consideration when using HIV-1-derived lentivirus vectors pseudotyped with Env.

Both COVID-19 and unrest are posing a significant threat to population mental health across the globe. This study examined trends of probable depression and anxiety during a time of civil unrest and concurrent COVID-19 in Hong Kong. Four random digit dialing telephone surveys were conducted in July 2019 (n = 1112), February-March 2020 (n = 2003), April-May 2020 (n = 2008), and July-August 2020 (n = 2034). The prevalence of probable depression increased from 25.7% (95% CI: 23.2-28.3) in July 2019 to 28.2% (95% CI: 26.2-30.1) in February-March 2020, and then decreased to 15.3% (95% CI: 14.0-17.0) in April-May 2020 and 13.7% (95% CI: 12.2-15.2) in July-August 2020. The prevalence of probable anxiety was 19.2% (95% CI: 17.5-20.9) in February-March 2020 and then stabilized in April-May 2020 and July-August 2020 (14.1%, 95% CI: 12.0-15.8). Probable depression and anxiety were more prevalent among persons with high relative to low daily routine disruptions. Combined high unrest-COVID-19 stress was associated with probable depression and anxiety across all persons; high unrest stress alone was associated with probable mental disorders at high daily routine disruptions. Civil unrest and COVID-19 are jointly associated with depression and anxiety among Hong Kong citizens. While population mental health improved, daily routine disruptions is a risk factor of mental disorders at every time-point., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The tumor microenvironment plays a critical role in maintaining the immature phenotype of tumor-initiating cells (TIC) to promote cancer. Hepatocellular carcinoma (HCC) is a unique disease in that it develops in the setting of fibrosis and cirrhosis. This pathologic state commonly shows an enrichment of stromal myofibroblasts, which constitute the bulk of the tumor microenvironment and contribute to disease progression. Follistatin-like 1 (FSTL1) has been widely reported as a proinflammatory mediator in different fibrosis-related and inflammatory diseases. Here we show FSTL1 expression to be closely correlated with activated fibroblasts and to be elevated in regenerative, fibrotic, and disease liver states in various mouse models. Consistently, FSTL1 lineage cells gave rise to myofibroblasts in a CCL 4 -induced hepatic fibrosis mouse model. Clinically, high FSTL1 in fibroblast activation protein-positive (FAP + ) fibroblasts were significantly correlated with more advanced tumors in patients with HCC. Although FSTL1 was expressed in primary fibroblasts derived from patients with HCC, it was barely detectable in HCC cell lines. Functional investigations revealed that treatment of HCC cells and patient-derived 3D organoids with recombinant FSTL1 or with conditioned medium collected from hepatic stellate cells or from cells overexpressing FSTL1 could promote HCC growth and metastasis. FSTL1 bound to TLR4 receptor, resulting in activation of AKT/mTOR/4EBP1 signaling. In a preclinical mouse model, blockade of FSTL1 mitigated HCC malignancy and metastasis, sensitized HCC tumors to sorafenib, prolonged survival, and eradicated the TIC subset. Collectively, these data suggest that FSTL1 may serve as an important novel diagnostic/prognostic biomarker and therapeutic target in HCC. SIGNIFICANCE: This study shows that FSTL1 secreted by activated fibroblasts in the liver microenvironment augments hepatocellular carcinoma malignancy, providing a potential new strategy to improve treatment of this aggressive disease., (©2021 American Association for Cancer Research.)

The present meta-analytic review examined the associations between different forms of trauma and mental disorders among prisoners and ex-prisoners. Studies published from 1998 to March 31 2021 were identified by searching PsycINFO, PubMed, Medline and Web of Science. Data were meta-analyzed using a random-effect model. Moderator and mediator analyses were conducted. The protocol was registered in PROSPERO (CRD42020181587). We identified 62 studies (50 non-duplicated samples) with 15,115 (97.86%) prisoners and 330 (2.14%) ex-prisoners in 16 countries. A multi-level meta-analysis found that overall trauma was positively associated with more diagnoses or symptoms of mental disorders (Zr = 0.198, 95% CI = [0.167, 0.229], p < 0.001). Stronger effect sizes were found between childhood trauma (Zr = 0.357, 95% CI = [0.147, 0.568], p < 0.01) and sexual trauma (Zr = 0.326, 95% CI = [0.216, 0.435], p < 0.001) and stress-related disorders. Multilevel moderator analysis showed that effect size was stronger in imprisonment trauma (β = 0.247, 95% CI = [0.177, 0.316], p < 0.01), mixed trauma (β = 0.234, 95% CI = [0.196, 0.272], p < 0.001), and stress-related disorders (β = 0.261, 95% CI = [0.214, 0.307], p < 0.01). Associations between trauma and mental disorders were mediated by social support but not coping. Our findings provide an evidence base for future research on the impact of trauma and inform assessments and interventions in correctional settings., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Objectives: This study examined the association of loneliness with depressive symptoms across various age groups. Loneliness is a significant risk factor for precipitating depressive symptoms. Rumination, a mechanism that underpins depression, can become intense when a person feels lonely. In addition, age is a major factor associated with changes in mental and physical health. Thus, the importance of rumination and age in moderating the loneliness-depression link were investigated., Research Design and Methods: This cross-sectional study was conducted during the acute phase of the coronavirus disease 2019 pandemic in Hong Kong (February 27 to March 17, 2020). A population-representative sample of 1,972 people (1,107 females; 18-92 years of age) was recruited and interviewed via telephone through random digit dialing. This sample included 394 younger adults (18-30 years), 1,106 middle-aged adults (31-64 years), and 472 older adults (65 years or above). Respondents reported depressive symptoms, subjective loneliness, state rumination, and sociodemographic factors., Results: Loneliness and rumination were positively associated with depressive symptoms, and they significantly interacted in predicting cognitive-affective symptoms. Further analysis of age showed that the interaction was significant only in middle-aged adults and older adults. Both rumination and age interacted with loneliness, respectively, in predicting cognitive-affective symptoms., Discussion and Implications: These findings indicate that the strength of the association between loneliness and the cognitive-affective symptoms of depression depends on rumination levels and age. An intervention to regulate rumination offers a feasible direction for health care and social care aimed at improving older adults' mental health., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Purpose: To examine the joint associations of civil unrest and COVID-19 with probable anxiety and depression during the first half of 2020 in Hong Kong. Associations were compared between persons with low or high assets., Methods: A population-representative sample of 4011 Hong Kong Chinese residents aged 15 years or older were recruited between February and May 2020. Respondents reported current anxiety and depressive symptoms, unrest stress, COVID-19 stress, assets (savings and home ownership), and demographics., Results: Stress due to unrest and COVID-19 was associated with higher prevalence of probable anxiety and depression; persons with both stressors had higher prevalence. This pattern was consistent among persons with low or high assets, but the probabilities of mental disorder were substantially higher among persons with fewer assets., Conclusions: The effect of stressors on probable anxiety and depression are cumulative: persons with stress due to civil unrest and to COVID-19 reported more mental disorders than persons with stress due to only one, or none of these factors. Overall high assets appear to buffer the consequences of stressors, lowering the risk of mental disorder., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)

Background: Ocular adverse events are common dose-limiting toxicities in cancer patients treated with HSP90 inhibitors, such as AUY922; however, the pathology and molecular mechanisms that mediate AUY922-induced retinal toxicity remain undescribed., Methods: The impact of AUY922 on mouse retinas and cell lines was comprehensively investigated using isobaric tags for relative and absolute quantitation (iTRAQ)‑based proteomic profiling and pathway enrichment analysis, immunohistochemistry and immunofluorescence staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, MTT assay, colony formation assay, and western blot analysis. The effect of AUY922 on the Transient Receptor Potential cation channel subfamily M member 1 (TRPM1)-HSP90 chaperone complex was characterized by coimmunoprecipitation. TRPM1-regulated gene expression was analyzed by RNAseq analysis and gene set enrichment analysis (GSEA). The role of TRPM1 was assessed using both loss-of-function and gain-of-function approaches., Results: Here, we show that the treatment with AUY922 induced retinal damage and cell apoptosis, dysregulated the photoreceptor and retinal pigment epithelium (RPE) layers, and reduced TRPM1 expression. Proteomic profiling and functional annotation of differentially expressed proteins reveals that those related to stress responses, protein folding processes, regulation of apoptosis, cell cycle and growth, reactive oxygen species (ROS) response, cell junction assembly and adhesion regulation, and proton transmembrane transport were significantly enriched in AUY922-treated cells. We found that AUY922 triggered caspase-3-dependent cell apoptosis, increased ROS production and inhibited cell growth. We determined that TRPM1 is a bona fide HSP90 client and characterized that AUY922 may reduce TRPM1 expression by disrupting the CDC37-HSP90 chaperone complex. Additionally, GSEA revealed that TRPM1-regulated genes were associated with retinal morphogenesis in camera-type eyes and the JAK-STAT cascade. Finally, gain-of-function and loss-of-function analyses validated the finding that TRPM1 mediated the cell apoptosis, ROS production and growth inhibition induced by AUY922., Conclusions: Our study demonstrates the pathology of AUY922-induced retinal toxicity in vivo. TRPM1 is an HSP90 client, regulates photoreceptor morphology and function, and mediates AUY922-induced cytotoxicity., (© 2021. The Author(s).)

Objective: To investigate the Helicobacter pylori ( H. pylori ) eradication rate and improvement of dyspepsia in patients who were newly diagnosed with H. pylori infection and dyspepsia and treated by bismuth-containing quadruple therapy followed by Jing-Hua-Wei-Kang(JHWK). Methods: Patients who were newly diagnosed with dyspepsia and H. pylori infection and treated in 16 medical centers in China between December 1, 2017 and September 30, 2019 were randomly divided into two groups. The experimental group received bismuth-containing quadruple therapy (esomeprazole+amoxicillin+furazolidone+colloidal bismuth pectin capsule, 14 days), followed by JHWK (30 days), and the course of treatment was 44 days in total. In the control group, the administration regimen was bismuth-containing quadruple therapy (esomeprazole+amoxicillin+furazolidone+colloidal bismuth pectin capsule, 14 days). The main outcome measure was H. pylori eradication rate, while the secondary outcome measures were dyspepsia symptom changes and adverse events during the treatment and the 1st month after treatment. Results: A total of 1 054 patients were included in the study. There were 522 cases enrolled in the experimental group, including 224(42.91%) men and 298(57.09%) women, and the age was 53(26, 73) years old; 532 cases enrolled in the control group, including 221(41.54%) men and 311(58.46%) women, and the age was 46(22, 71) years old. Based on PP analysis, it was found that the H. pylori eradication rate in the experimental group was significantly higher than those in the control group (93.85% vs 87.88%, P =0.001). In the group of all enrolled patients, the symptom dyspepsia after H. pylori eradication was significantly improved compared with that before treatment [4(4, 7) vs 15(10, 22), P <0.001], so was the superior and middle abdominal pain [1(1, 4) vs 4(1, 8), P <0.001], the postprandial fullness [1(1, 4) vs 4(4, 9), P <0.001], the early satiety [1(1, 1) vs 4(1, 4), P <0.001], and the heartburn [1(1, 1) vs 1(1, 4), P <0.001]. The symptom dyspepsia after treatment was significantly improved compared with that before treatment in the experimental, the control groups, the successful and the unsuccessful H. pylori eradication groups. The superior and middle abdominal pain after treatment was signifcantly improved than that before treatment [1(1, 2) vs 1(1, 4), P <0.001], so were the postprandial fullness [1(1, 3) vs 1(1, 4), P =0.002] and the dyspepsia[4(4, 7) VS 7(4, 10), P <0.001]. There was no statistically significant difference in the incidence of adverse events between the experimental group and the control group (1.34% vs 0.38%, P =0.09). Conclusions: Compared with bismuth-containing quadruple therapy, bismuth-containing quadruple therapy followed by JHWK significantly improves the H. pylori eradication rate without increasing the incidence of adverse events. H. pylori eradication therapy can improve symptoms of patients with H. pylori infection and dyspepsia.

How flightless animals disperse to remote oceanic islands is a key unresolved question in biogeography. The flightless Pachyrhynchus weevils represent repetitive colonization history in West Pacific islands, which attracted our interests about how some weevils have successfully dispersed in the reverse direction against the sea current. Here, we propose endozoochory as a possible mechanism that the eggs of the weevils might be carried by embedded in the fruits as the food of frugivorous birds. In this study, Pachyrhynchus eggs were embedded in small pieces of persimmon fruits ( Diospyros kaki ) and fed to captive frugivorous birds. After digestion, 83%-100% eggs were retrieved from the feces of a bulbul ( Hypsipetes leucocephalus ) and two thrushes ( Turdus chrysolaus ). The retrieved eggs had hatching rates higher than 84%, which were not different from the control. In contrast, no egg was retrieved from the feces of the frugivorous pigeon ( Treron sieboldii ), which took a longer retention time in the guts. Our study identified that the eggs of Pachyrhynchus weevils are possible to be transported by internal digesting in some bird species., Competing Interests: The authors declare no conflict of interests., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Objective: To explore the risk factors of low cardiac output syndrome (LCOS) after cardiac valvular surgery in elderly patients with valvular disease complicated with giant left ventricle. Methods: This was a retrospective study. The clinical data of patients over 60 years old with giant left ventricle who underwent cardiac valvular surgery in Henan Provincial People's Hospital (Fuwai Central China Cardiovascular Hospital) from January 2016 to January 2020 were collected in this study. Patients were divided into LCOS group and non-LCOS group. The clinical data, preoperative echocardiographic results and surgical data of all patients were collected. Taking LCOS as dependent variable and statistically significant variables in univariate analysis as independent variable, multivariate logistic regression equation was constructed to identify the risk factors of LCOS after cardiac valvular surgery in elderly patients with valvular disease complicated with giant left ventricle. On the basis of logistic regression, the risk factors of continuous variables were put into the regression model for trend test. Results: A total of 112 patients were included, among whom 76 patients were male, the mean age was (65.3±3.8) years. There were 21 cases in LCOS group and 91 cases in non LCOS group. Univariate analysis showed that age≥70 years, preoperative NYHA cardiac function class Ⅳ, preoperative renal dysfunction, preoperative cerebrovascular disease, preoperative LVEF<40%, blood loss/total blood volume>20%, cardiopulmonary bypass (CPB) time>130 minutes and aortic cross-clamp time>90 minutes all had statistically significant differences between the two groups (all P <0.05). Multivariate logistic regression analysis showed that age≥70 years ( OR =5.067, 95% CI 1.320-19.456, P =0.018), preoperative NYHA cardiac function class Ⅳ ( OR =3.100, 95% CI 1.026-9.368, P =0.045), renal dysfunction ( OR =3.627, 95% CI 1.018-12.926, P =0.047), CPB time>130 minutes ( OR =4.539, 95% CI 1.483-13.887, P =0.008) were the independent risk factors of LCOS after cardiac valvular surgery in elderly patients with giant left ventricle. Risk of LCOS was significantly higher in patients aged from 65 to 70 years ( OR =1.784, 95% CI 0.581-5.476) and aged 70 years and above ( OR =4.400, 95% CI 1.171-16.531) than in patients aged from 60 to 65 years. The trend test results showed that the risk of LCOS increased significantly in proportion with the increase of age ( P for trend=0.024). Risk of LCOS was significantly higher in patients with CPB time between 90 and 110 minutes ( OR =1.917, 95% CI 0.356-10.322), 110 and 130 minutes ( OR =1.437, 95% CI 0.114-18.076) and 130 minutes and above ( OR =5.750, 95% CI 1.158-28.551) than in patients with CPB time ≤ 90 minutes ( P for trend=0.009). Conclusions: The risk factors of LCOS after cardiac valvular surgery are age≥70 years, preoperative NYHA cardiac function class Ⅳ, renal dysfunction, CPB time>130 minutes in elderly patients with giant left ventricle.

Hyperglycemia and hyperlipidemia are often observed in individuals with type II diabetes (T2D) and related mouse models. One dysmetabolic biochemical consequence is the non-enzymatic reaction between sugars, lipids, and proteins, favoring protein glycation, glycoxidation, and lipoxidation. Here, we identified oxidative alterations in key components of the major histocompatibility complex (MHC) class II molecule antigen processing and presentation machinery in vivo under conditions of hyperglycemia-induced metabolic stress. These modifications were linked to epitope-specific changes in endosomal processing efficiency, MHC class II-peptide binding, and DM editing activity. Moreover, we observed some quantitative and qualitative changes in the MHC class II immunopeptidome of Ob/Ob mice on a high-fat diet compared with controls, including changes in the presentation of an apolipoprotein B100 peptide associated previously with T2D and metabolic syndrome-related clinical complications. These findings highlight a link between glycation reactions and altered MHC class II antigen presentation that may contribute to T2D complications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study examined prevalences of anxiety and depression and their correlations with daily routines among Hong Kong Chinese during the COVID-19 pandemic. Random digit dialing recruited two population-representative samples of 6029 residents during a period of low infection and limited intervention (survey 1: n = 4021) and high incidence and intensive measures (survey 2: n = 2008). Prevalence of anxiety for survey 1 and survey 2 were 14.9% and 14% and depression were 19.6% and 15.3%, respectively. Increased odds of anxiety and depression were associated with disrupted routines and lower socioeconomic status in both surveys, whereas depression was inversely related to the novel preventive routine of avoiding going to crowded places in survey 1. The prevalences of anxiety and depression were higher than preceding public health/social crises. A heavier burden of psychiatric conditions was evidenced amongst people experiencing disrupted daily routines across different phases of the pandemic and without novel preventive routines in the early phase.

Background: This study examined the associations between components of psychological resilience and mental health at different levels of exposure to COVID-19 stressors., Methods: A population-representative sample of 4,021 respondents were recruited and assessed between February 25th and March 19th, 2020. Respondents reported current anxiety symptoms (7-item Generalized Anxiety Disorder scale [GAD-7]), cognitive components (perceived ability to adapt to change, tendency to bounce back after adversities) and behavioral components (regularity of primary and secondary daily routines) of resilience, worry about COVID-19 infection, and sociodemographics., Results: Logistic regression revealed that cognitive and behavioral components of resilience were not correlated with probable anxiety (GAD-7≥10) among those reporting no worry. Among respondents who were worried, all resilient components were inversely associated with probable anxiety. Specifically, propensity to bounce back and regular primary routines were more strongly related to lower odds of probable anxiety among those reporting lower levels of worry., Limitations: The cross-sectional design limits causal inference. Second, other resilient components and some key daily routines that could be related to better mental health were not assessed. Third, generalizability of the findings to other similar major cities is uncertain because cases and deaths due to COVID-19 in Hong Kong have been comparatively lower., Conclusions: To foster mental health, cultivation of confidence in one's ability to adapt to change and a propensity to bounce back from hardship should be coupled with sustainment of regular daily routines. Such assessment and intervention protocols could be more relevant to those who suffer heightened levels of exposure to COVID-19 stressors., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: This study examined prevalence and correlates of probable depression and suicidal ideation among Hong Kong Chinese residents amidst the anti-extradition bill protests., Methods: Random digit dialing recruited a population-representative sample of Hong Kong residents aged 15 years or older during the first three weeks of July, 2019. Respondents reported current depressive symptoms and suicidal ideation, participation in protest activities, attitudes and perceived stress, disruptions to daily routines, and demographics., Results: Among 1112 respondents, 25.7% reported probable depression, and 9.1% reported suicidal ideation. Multivariable logistic regression showed that persons with higher odds of probable depression had primary education and high disruptions to regular routines of eating, sleep, socializing, and leisure activities. Persons who were at higher odds of suicidal ideation had lower household income, used social media to engage in the protests, and had medium or high disruptions to regular eating and sleep., Conclusions: During the anti-extradition bill protests, the prevalence of probable depression and suicidal ideation were substantially higher than would be expected and higher than during the Umbrella Movement of 2014. Psychiatric morbidity may be a consequence of massive social movements, particularly among persons with limited protective resources whose daily life is disrupted by these events., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This study examined the associations of perceived social capital and income change since the outbreak with probable depression and preventive behaviors during the COVID-19 pandemic in Hong Kong. Random digit dialing recruited a population-representative sample of 3011 Hong Kong Chinese aged ≥ 15 years (mean = 44, 55% females) between February 25 and April 29 2020. Respondents reported social capital (perceived interpersonal trust, social harmony, and sense of belonging), income change since the outbreak (loss vs. gain/no change), depressive symptoms, preventive behaviors, and demographics. Controlling for sociodemographics, lack of perceived interpersonal trust was associated with probable depression and avoiding contact with people with respiratory symptoms. Lack of perceived sense of belonging was associated with probable depression and decreased odds of adopting preventive behaviors. Lack of perceived social harmony was associated with probable depression and increased odds of used face masks among respondents with income loss only. Our results suggest that social capital is related to lower risk of depression and to higher chance of used face masks particularly among those experiencing income loss related to COVID-19. Prevention of mental health problems and promotion of effective preventive behaviors could be implemented by focusing on support for those who are socioeconomically disadvantaged.

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphohydrolase (dNTPase) with a nuclear localization signal (NLS). SAMHD1 suppresses innate immune responses to viral infection and inflammatory stimuli by inhibiting the NF-κB and type I interferon (IFN-I) pathways. However, whether the dNTPase activity and nuclear localization of SAMHD1 are required for its suppression of innate immunity remains unknown. Here, we report that the dNTPase activity, but not nuclear localization of SAMHD1, is important for its suppression of innate immune responses in differentiated monocytic cells. We generated monocytic U937 cell lines stably expressing WT SAMHD1 or mutated variants defective in dNTPase activity (HD/RN) or nuclear localization (mNLS). WT SAMHD1 in differentiated U937 cells significantly inhibited lipopolysaccharide-induced expression of tumor necrosis factor α ( TNF- α) and interleukin-6 ( IL-6 ) mRNAs, as well as IFN- α, IFN- β, and TNF- α mRNA levels induced by Sendai virus infection. In contrast, the HD/RN mutant did not exhibit this inhibition in either U937 or THP-1 cells, indicating that the dNTPase activity of SAMHD1 is important for suppressing NF-κB activation. Of note, in lipopolysaccharide-treated or Sendai virus-infected U937 or THP-1 cells, the mNLS variant reduced TNF- α or IFN- β mRNA expression to a similar extent as did WT SAMHD1, suggesting that SAMHD1-mediated inhibition of innate immune responses is independent of SAMHD1's nuclear localization. Moreover, WT and mutant SAMHD1 similarly interacted with key proteins in NF-κB and IFN-I pathways in cells. This study further defines the role and mechanisms of SAMHD1 in suppressing innate immunity., (© 2020 Qin et al.)

The present study was designed to evaluate the dynamic survival and recurrence of remnant gastric cancer (RGC) after radical resection and to provide a reference for the development of personalized follow-up strategies. A total of 298 patients were analyzed for their 3-year conditional overall survival (COS3), 3-year conditional disease-specific survival (CDSS3), corresponding recurrence and pattern changes, and associated risk factors. The 5-year overall survival (OS) and the 5-year disease-specific survival (DSS) of the entire cohort were 41.2% and 45.8%, respectively. The COS3 and CDDS3 of RGC patients who survived for 5 years were 84.0% and 89.8%, respectively. The conditional survival in patients with unfavorable prognostic characteristics showed greater growth over time than in those with favorable prognostic characteristics (eg, COS3, ≥T3: 46.4%-83.0%, Δ36.6% vs ≤T2: 82.4%-85.7%, Δ3.3%; P < 0.001). Most recurrences (93.5%) occurred in the first 3 years after surgery. The American Joint Committee on Cancer (AJCC) stage was the only factor that affected recurrence. Time-dependent Cox regression showed that for both OS and DSS, after 4 years of survival, the common prognostic factors that were initially judged lost their ability to predict survival (P > 0.05). Time-dependent logistic regression analysis showed that the AJCC stage independently affected recurrence within 2 years after surgery (P < 0.05). A postoperative follow-up model was developed for RGC patients. In conclusion, patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow-up model for RGC patients of different stages, which may affect the design of future clinical trials., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Based on 20,000 records representing c . 11,000 individuals from an 8-year capture-mark-recapture (CMR) study, we tested and confirmed a new case of invariant clutch size (ICS) in a sexually dichromatic lacertid lizard, Takydromus viridipunctatus . In the grassland habitat of the early succession stage, females showed strictly low and invariant clutch size, multiple clutches in a breeding season, high reproductive potential, and annual breeding cycles that correspond to the emergence of male courtship coloration. The hatchlings mature quickly, and join the adult cohort for breeding within a few months, whereas adults show low survival rates and a short lifespan, such that most die within one year. Mortality increased in both sexes during the breeding season, especially in females, indicating an unequal cost of reproduction in survival. These life history characters may be explained by two non-exclusive hypotheses of ICS-arboreal hypothesis and predation hypothesis-within the ecological context of their habitat. Our study highlights a confirmed case of ICS, which adapts well to this r -selected grassland habitat that experiences seasonal fluctuation and frequent disturbance., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2020.)

Objective: To preliminarily investigate the influence of recombinant human growth hormone (rhGH) on the immune function of younger children with severe burn injuries. Methods: A total of 30 younger children with severe burn injuries, conforming to the study criteria, were admitted to our hospital from July 2016 to July 2018. They were enrolled in the prospective, randomized, double-blinded, controlled trial and divided into group rhGH [ n =15, 10 boys and 5 girls, aged (22±10) months] and control group [ n =15, 8 boys and 7 girls, aged (21±7) months] according to the random number table. The patients in control group received anti-shock, anti-infection, and wound caring therapies, etc. On the basis of above-mentioned treatment, the patients in group rhGH were subcutaneously injected with rhGH once every night before bedding, with a dosage of 0.2 IU·kg(-1)·d(-1), from the 3rd day post injury for 7 consecutive days. Before and on the 3rd and 7th day of rhGH treatments, the fasting peripheral venous blood was collected from patients in both groups. Blood glucose level was detected by glucometer. Percentages of CD4(+) T lymphocytes, CD8(+) T lymphocytes, CD3(+) T lymphocytes, CD19(+) B lymphocytes, and ratio of CD4(+) T lymphocytes to CD8(+) T lymphocytes were determined by flow cytometer. Mass concentration of serum immune globulin (Ig) A, IgG, and complement C3 were detected by enzyme-linked immunosorbent assay. Data were processed with Fisher's exact probability test, independent sample t test, analysis of variance for repeated measurement and Bonferroni correction, and Mann-Whitney U test. Results: (1) The blood glucose levels of children in the two groups were similar before and on the 3rd and 7th day of rhGH treatment ( t =0.474, 1.652, 1.997, P >0.05). The glucose levels of children in group rhGH on the 3rd and 7th day of rhGH treatment [(6.9±1.0) and (7.7±1.1) mmol/L] were significantly higher than (5.9±0.9) mmol/L before rhGH treatment ( P <0.05). The glucose level of children in control group on the 7th day of rhGH treatment was significantly higher than that before rhGH treatment ( P <0.05). (2) The percentages of CD4(+) T lymphocytes of children in group rhGH before rhGH treatment and on the 7th day of rhGH treatment were (35.1±2.0)% and (38.5±2.2)%, which were close to (36.2±2.0)% and (33.6±2.2)% in control group, respectively ( t =0.371, 1.553, P >0.05). The percentages of CD4(+) T lymphocytes of children in group rhGH on the 7th day of rhGH treatment[(44.7±2.2)%] was significantly higher than (36.5±2.2)% in control group ( t =2.624, P <0.05). The percentage of CD4(+) T lymphocytes of children in group rhGH on the 7th day of rhGH treatment was significantly higher than that before rhGH treatment ( P <0.05). The percentages of CD4(+) T lymphocytes of children in control group on the 3rd and 7th day of rhGH treatment were both close to the percentage before rhGH treatment ( P >0.05). (3) The percentage of CD8(+) T lymphocytes of children in group rhGH on the 3rd day of rhGH treatment was significantly lower than that in control group ( t =2.107, P <0.05). (4) The ratio of CD4(+) T lymphocytes to CD8(+) T lymphocytes of children in group rhGH on the 7th day of rhGH treatment (2.36±0.20) was significantly higher than 1.72±0.20 in control group ( t =2.285, P <0.05). The ratio of CD4(+) T lymphocytes to CD8(+) T lymphocytes of children in group rhGH on the 7th day of rhGH treatment was significantly higher than 2.04±0.19 before rhGH treatment ( P <0.05). (5) The percentages of CD3(+) T lymphocytes and CD19(+) B lymphocytes of children in the two groups were similar before and on the 3rd and 7th day of rhGH treatment ( t =1.913, 0.552, 1.327, 1.465, 1.587, 0.407, P >0.05). The percentages of CD3(+) T lymphocytes of children in group rhGH on the 3rd and 7th day of rhGH treatment were significantly higher than the percentage before rhGH treatment ( P <0.05). (6) The mass concentration of serum IgA, complement C3, and IgG of children in the two groups was similar before and on the 3rd and 7th day of rhGH treatment ( t =-1.596, -0.100, 1.263, -0.220, 1.378, 1.631, Z =0.228, 0.519, 1.182, P >0.05). The mass concentration of serum IgA and complement C3 of children in group rhGH on the 3rd and 7th day of rhGH treatment was significantly higher than that before rhGH treatment( P <0.05). Conclusions: rhGH has little effect on humoral immunity of younger children with severe burn injuries with limited influence on CD19(+) B lymphocyte, mass concentration of serum IgA, IgG, and complement C3. It may improve the cellular immunity function mainly through promoting the release of CD4(+) T lymphocyte, reducing the release of CD8(+) T lymphocyte. It can be used in clinical treatment of younger children with severe burn injuries.

Objectives: Hip arthritis plays a critical role in the prognosis of ankylosing spondylitis (AS). Dose reduction of tumor necrosis factor inhibitors preserves general improvement of AS, so this study attempted to examine the equivalence between Yisaipu® tapering and conventional therapy for hip arthritis in AS patients, using clinical parameters and magnetic resonance image (MRI)., Methods: AS patients received this etanercept-biosimilar injections (50 mg/week) in the first 12 weeks. Participants in the tapering group were treated with this reagent 50 mg every other week from week 13 to week 24, while the control group kept undergoing full-dose therapy. Clinical and laboratory parameters were assessed at baseline, week 12 and week 24. MRI examination of hip was performed at baseline and week 24., Results: One hundred and thirty-six patients were enrolled, and 80 of them were in the tapering group. Linear mixed model revealed that main effects of tapering group with control group as reference in disease activity parameters were insignificant (p > 0.05). Main effects of baseline with week 24 as reference were significant (p < 0.05), but main effects of week 12 with week 24 as reference were not (p > 0.05). Prevalence of acute inflammatory change in MRI significantly decreased in the tapering group (76.88% vs 20.00%, p < 0.05) and control group (76.79% vs 19.64%, p < 0.05). Influence of both treatments on acute inflammatory change was equivalent (p > 0.05)., Conclusion: Efficacy of Yisaipu® tapering treatment is comparable to the full-dose therapy for hip arthritis in AS patients. Both treatments maintain remission of hip arthritis after patients achieved low disease activity.