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Chien-Yu Cheng,1,2 Mao-Song Tsai,3 Chia-Jui Yang,3,4 Shu-Hsing Cheng,1,5 Hsin-Yun Sun,6 Shu-Fang Chang,7 Li-Hsin Su,7 Yi-Ching Su,6 Chien-Ching Hung,6,8–10 Sui-Yuan Chang7,11 For the Taiwan HIV Study Group 1Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan; 2School of Public Health, National Yang-Ming University, Taipei, Taiwan; 3Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan; 4School of Medicine, National Yang-Ming University, Taipei, Taiwan; 5School of Public Health, Taipei Medical University, Taipei, Taiwan; 6Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; 7Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan; 8Department of Parasitology, National Taiwan University College of Medicine, Taipei, Taiwan; 9Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; 10China Medical University, Taichung, Taiwan; 11Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan Background: Increasing trends of resistance-associated mutations (RAMs) to non-nucleoside reverse-transcriptase inhibitors (nNRTIs) have raised concerns about the effectiveness of the regimens in the national HIV treatment programs in resource-limited countries. We aimed to retrospectively investigate the incidence and patterns of emergent RAMs of HIV-1 in HIV-positive adults experiencing virological failure to first-line nNRTI-containing combination antiretroviral therapy (cART) in Taiwan. Patients and methods: Between June 2012 and March 2016, 1138 antiretroviral-naïve HIV-positive adults without baseline RAMs who initiated nNRTI-containing regimens were included for analysis. Virological failure was defined as plasma viral load (PVL) ≥200 copies/mL after 6 months of cART or confirmed PVL ≥200 copies/mL after achieving PVL

Ovarian clear cell carcinoma (OCCC) frequently develops resistance to platinum-based therapies, which is regarded as an aggressive subtype. However, metabolic changes in paclitaxel resistance remain unclear. Herein, we present the metabolic alternations of paclitaxel resistance in bioenergetic profiling in OCCC. Paclitaxel-resistant OCCC cells were developed and metabolically active with oxygen consumption rates (OCR) compared to parental cells. Metabolite profiling analysis revealed that paclitaxel-resistant OCCC cells reduced intracellular ATP and GTP influx rates, increasing the NADH/NAD+ ratio. We further demonstrated that paclitaxel-resistant OCCC cells led to characteristic alternations of metabolite levels in energy-requiring and energy-releasing steps of glycolysis and their corresponding glycolytic enzymes. Copy number alterations and RNA sequencing analysis demonstrated that ATP-binding cassette (ABC) transporters and solute carrier (SLC) transporter genes involved in glycolysis metabolism and molecular transport were enriched in paclitaxel-resistant OCCC cells. We first identified that Hexokinase 2 (HK2) expression is upregulated in paclitaxel-resistant OCCC cells to determine the quantity of glucose entering glycolysis. Utilizing proteolysis-targeting chimera (PROTAC) HK2 degraders, we also found that paclitaxel sensitivity, viability, and oxygen consumption rates under paclitaxel treatment were restored by HK2 degraders treatment, and decreased downstream expression of the ABC and SLC transporters was shown in OCCC cells. Taken together, these findings highlight the paclitaxel resistance in OCCC elucidates metabolic alternation, including ABC- and SLC- drug transporters, thereby affecting glycolysis metabolism in response to paclitaxel resistance, and HK2 may become a novel potential therapeutic target for paclitaxel resistance., 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 Masson SAS.. All rights reserved.)

Ventilator-induced lung injury is a serious complication in mechanically ventilated patients. Neddylation, the post-translational modification of neural precursor cell-expressed developmentally down-regulated 8 (NEDD8) conjugation, regulates numerous biological functions. However, its involvement and therapeutic significance in ventilator-induced lung injury remains unknown. Therefore, this study aimed to examine the kinetics and contribution of activated neddylation and the impact of neddylation inhibition in mice subjected to high tidal volume (HTV) ventilation in vivo and human pulmonary alveolar epithelial cells stimulated through cyclic stretching (CS) in vitro. The neddylation and expression of ubiquitin conjugating enzyme 3 (UBA3), a NEDD8-activating enzyme (NAE) catalytic subunit, were time-dependently upregulated in HTV-ventilated mice. Additionally, the NAE inhibitor MLN4924 considerably attenuated acute lung injury induced by HTV ventilation, manifesting as reduced inflammation and oxidative stress. Furthermore, MLN4924 effectively reduced the secretion of inflammatory cytokines from Ly6C high monocytes and neutrophils, subsequently decreasing endothelial permeability. Moreover, our study revealed an upregulation of the neddylation pathway, oxidative stress, and apoptosis during CS of alveolar epithelial cells. However, blockade of neddylation via MLN4924 or through UBA3 knockdown suppressed this upregulation. Overall, the inhibition of neddylation may alleviate HTV-induced acute lung injury by preventing CS-induced damage to alveolar epithelial cells. This indicates that the neddylation pathway plays a critical role in the progression of ventilator-induced lung injury. These findings may provide a new therapeutic target for treating ventilator-induced lung injury., 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. Published by Elsevier Inc.)

Colorectal cancer (CRC) has become a prevalent and deadly malignancy over the years. Drug resistance remains a major challenge in CRC treatment, significantly affecting patient survival rates. Obesity is a key risk factor for CRC development, and accumulating evidence indicates that increased secretion of adipokines, including Visfatin, under obese conditions contributes to the development of resistance in CRC to various therapeutic methods. Amphiregulin (AREG) is a member of the epidermal growth factor (EGF) family, which activates the EGF receptor (EGFR), influencing multiple tumorigenic characteristics of cancers. Abnormal expression levels of AREG in cancer cells have been associated with resistance to anti-EGFR therapy in patients. However, it remains unclear whether this abnormal expression also impacts CRC resistance to other chemotherapeutic drugs. The aim of this study is to examine whether AREG expression levels could be affected in CRC cells under Visfatin stimulation, thereby initiating the development of resistance to 5-fluororacil (5-FU). Through our results, we found that Visfatin indeed increases AREG expression, reducing the sensitivity of HCT-116 CRC cells to 5-FU cytotoxicity. Moreover, AREG upregulation is regulated by STAT3-CREB transcription factors activated by JNK1/2 and p38 signaling. This study highlights the significant role of AREG upregulation in CRC cells in initiating chemotherapeutic resistance to 5-FU under Visfatin stimulation. These findings provide a deeper understanding of drug resistance development in CRC under obese conditions and offer new insights into the correlation between an abnormal increase in AREG levels and the development of 5-FU-resistance in CRC cells, which should be considered in future clinical applications.

Background: Treatment of articular cartilage injury remains a challenging clinical problem in orthopedics. Chitosan-derived biomaterial could be a potential adjuvant treatment to improve cartilage repair. In the current study, we examined the effects of two potential chitosan-derived materials on cartilage regeneration of osteochondral defects in rabbits., Methods: An osteochondral defect was created over the rabbit knee and treated using three approaches: group A received no material (n = 24), group B received chitosan membranes with glucose absorption (CGA; n = 25), and group C received chitosan-glucose derivative membranes obtained via the Maillard reaction (CGMR; n = 25). Cartilage repair over the osteochondral defect was analyzed 12 weeks post-surgery via histological analysis, immunostaining, and reverse transcription-qualitative polymerase chain reaction (RT-qPCR) for type-I and type-II collagen mRNA., Results: According to histological analysis, CGMR-treated defects showed significantly improved modified O'Driscoll scoring when compared with no material- and CGA-treated defects (20.9 ± 4.3 vs. 13.00 ± 2.5 and 17.7 ± 4.6, p < 0.001). Moreover, group C exhibited higher intensity of type-II collagen immunohistochemical staining over the regenerated cartilage than groups A and B, along with increased expression of type-II collagen mRNA by RT-qPCR., Conclusions: CGMR might improve cartilage regeneration in osteochondral defects., (© 2024. The Author(s).)

Background: Concurrent with population ageing, falls have become a significantly more challenging public health issue among older adults. Three years of data collected recently from a nursing home in northern Taiwan reveals an increasing trend in fall density that is primarily associated with aging, physiological decline, chronic diseases, polypharmacy, osteoporosis, and lack of exercise. The percentage of nursing home residents at high risk of falls is currently at 12.6%, and the fall rate has been reported as reaching as high as 30% annually., Purpose: A fall prevention program was implemented to reduce the fall incidence rate to 18%, with secondary goals of improving fall prevention awareness, behavior, self-efficacy, lower limb muscle strength, balance, and gait by 10% on average, respectively, between pre-test and post-test., Resolution: From September 30, 2023 to February 29, 2024, a health promotion activity and fall prevention exercise course were implemented using an interdisciplinary team collaboration model over a six-week period, providing individualized exercise for the participants., Results: The study included 20 older adults with an average age of 88 years. Most (90%; n = 18) had chronic diseases, 25% (n = 5) were on more than nine medications, 70% (n = 14) had reduced bone mass, and 40% (n = 8) were at high risk of falls, with a fall incidence rate of 30% during the immediately preceding year. Post-intervention, the fall incidence rate dropped to 5%, fall prevention awareness, behavior, and self-efficacy increased by 18.3%, and lower limb muscle strength, balance, and gait improved by 11.7%. The post-test results in fall prevention awareness, behavioral changes, self-efficacy, and lower limb strength, balance, and gait were all significantly better than pre-test results, with all results achieving statistical significance., Conclusions: The project results support the positive effects of the developed intervention effectively on elderly physical fitness and fall risk, providing valuable insights for the implementation of fall prevention strategies in nursing homes.

Background: Viral neutralization (NT) assays can be used to determine the immune status of patients or assess the potency of candidate vaccines or therapeutic monoclonal antibodies (mAbs). Focus reduction neutralization test (FRNT) is a conventional neutralization test (cVNT) with superior specificity for measurement of neutralizing antibodies against a specific virus. Unfortunately, the application of FRNT to the chikungunya virus (CHIKV) involves a highly pathogenic bio-agent requiring biosafety level 3 (BSL3) facilities, which inevitably imposes high costs and limits accessibility. In this study, we evaluated a safe surrogate virus neutralization test (sVNT) that uses novel CHIKV replicon particles (VRPs) expressing eGFP and luciferase (Luc) to enable the rapid detection and quantification of neutralizing activity in clinical human serum samples., Methods: This unmatched case-control validation study used serum samples from laboratory-confirmed cases of CHIKV (n = 19), dengue virus (DENV; n = 9), Japanese encephalitis virus (JEV; n = 5), and normal individuals (n = 20). We evaluated the effectiveness of sVNT, based on mosquito cell-derived CHIK VRPs (mos-CHIK VRPs), in detecting (eGFP) and quantifying (Luc) neutralizing activity, considering specificity, sensitivity, and reproducibility. We conducted correlation analysis between the proposed rapid method (20 h) versus FRNT assay (72 h). We also investigated the correlation between sVNT and FRNT in NT titrations in terms of Pearson's correlation coefficient (r) and sigmoidal curve fitting., Results: In NT screening assays, sVNT-eGFP screening achieved sensitivity and specificity of 100%. In quantitative neutralization assays, we observed a Pearson's correlation coefficient of 0.83 for NT50 values between sVNT-Luc and FRNT., Conclusions: Facile VRP-based sVNT within 24 h proved highly reliable in the identification and quantification of neutralizing activity against CHIKV in clinical serum samples., (© 2024. The Author(s).)

Background: This study aimed to determine whether a cognitive test the Mini-Mental State Examination (MMSE) and the Ascertain Dementia 8 (AD8) instrument applied in combination could improve the accuracy of dementia detection in a community setting., Methods: Study participants were recruited from a community-based integrated screening program in Tainan, Taiwan. Participants completed the AD8 and were administered the Chinese version of the MMSE by psychologists. In addition, the presence of dementia was determined by neurologists based on the 2011 National Institute on Aging-Alzheimer's Association guidelines. Logistic regression analysis determined whether the combination of these two tests provided any additional information for dementia detection than either test alone. Receiver operating characteristic (ROC) curve analyses were conducted to explore the performances of different screening modalities in detecting dementia., Result: In total, 282 participants with an average age of 69.31 ± 10.27 years were enrolled. The prevalence of dementia among participants aged ≥65 years was 9.29 %. The sensitivity and specificity of the AD8 applied alone for detecting dementia were 64.71 % and 87.89 %, respectively, and of the MMSE applied alone, after adjusting for education level, were 41.18 % and 84.50 %, respectively. Using a cutoff score of 21 for the MMSE resulted in sensitivity of 77.78 % and specificity of 73.58 %. The AD8 and MMSE when combined in parallel yielded 88.89 % sensitivity and 70.16 % specificity. The serial use of the AD8 followed by the MMSE yielded 50 % sensitivity and 93.02 % specificity. Except for when an MMSE cutoff value of 26 was applied, the sensitivity of all examined modalities was poor and specificity was moderate for detecting mild cognitive impairment. ROC curve analysis revealed that the parallel application of the MMSE and AD8 (area under the ROC curve [AUC]: 82.3 % [75.1 %-89.4 %]) resulted in better dementia detection accuracy than the AD8 alone (AUC: 73.3 % [60.7 %-85.9 %]), the MMSE alone (AUC: 77.4 % [67.6 %-87.3 %]), or serial test administration (AUC: 67.6 % [53.4 %-81.8 %])., Conclusion: This study successfully demonstrated that the MMSE and AD8 combination for dementia screening could improve detection accuracy in a community setting., Competing Interests: Declaration of competing interest 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 The Authors. Published by Elsevier Inc. All rights reserved.)

We investigated 2 acute cases and 1 previous case of Seoul hantavirus infection in workers in a feeder rodent breeding farm in Taiwan. Prevalence of hantavirus IgG among the tested feeder rats was 37.5%. Appropriate prevention measures, including using disinfection protocols and personal protective equipment, are crucial to lowering risk.

Active learning and peer instruction contribute to positive learning outcomes. We developed a 25-week, question-based program for first-year medical students (MS1). Senior students developed weekly question and answer sets. Second-year peer educators helped MS1s learn to collaboratively problem solve by working through the questions and answer explanations. Controlling for average MCAT 2015 score, attendance significantly correlated with improved academic performance in basic science coursework (beta = 0.196, p  < .001) and one organ systems module (beta = 0.104, p  = .033). Academic outcomes and an 83% sustained participation rate point to the benefits of peer-led, positive learning environments., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s) under exclusive licence to International Association of Medical Science Educators 2024.)

Type 2 diabetes mellitus (T2DM) presents a challenge for individuals today, affecting their health and life quality. Besides its known complications, T2DM has been found to contribute to bone/mineral abnormalities, thereby increasing the vulnerability to bone fragility/fractures. However, there is still a need for appropriate diagnostic approaches and targeted medications to address T2DM-associated bone diseases. This study aims to investigate the relationship between changes in gut microbiota, T2DM, and osteoporosis. To explore this, a T2DM rat model was induced by combining a high-fat diet and low-dose streptozotocin treatment. Our findings reveal that T2DM rats have lower bone mass and reduced levels of bone turnover markers compared to control rats. We also observe significant alterations in gut microbiota in T2DM rats, characterized by a higher relative abundance of Firmicutes (F) and Proteobacteria (P), but a lower relative abundance of Bacteroidetes (B) at the phylum level. Further analysis indicates a correlation between the F/B ratio and bone turnover levels, as well as between the B/P ratio and HbA1c levels. Additionally, at the genus level, we observe an inverse correlation in the relative abundance of Lachnospiraceae . These findings show promise for the development of new strategies to diagnose and treat T2DM-associated bone diseases., Competing Interests: The authors have declared that no competing interests exist.

Bone defects are a common clinical issue, but therapeutic efficiency can be challenging in cases of more considerable traumas or elderly patients with degenerated physiological metabolism. To address this issue, a more suitable cell-biomaterial construct promoting bone regeneration has been extensively investigated, with the chitosan scaffold being considered a potential candidate. In this study, chitosan was crosslinked with different doses of glucose (CTS-10~50%Glc) using a modified Maillard reaction condition to develop a more appropriate cell-biomaterial construct. Mouse MC3T3-E1 pre-osteoblasts were seeded onto the scaffolds to examine their osteoinductive capability. The results showed that CTS-Glc scaffolds with higher glucose contents effectively improved the adhesion and survival of mouse MC3T3-E1 pre-osteoblasts and promoted their differentiation and mineralization. It was further demonstrated that the membrane integrin α5 subunit of pre-osteoblasts is the primary adhesion molecule that communicates with CTS-Glc scaffolds. After that, Akt signaling was activated, and then bone morphogenetic protein 4 was secreted to initiate the osteoinduction of pre-osteoblasts. The prepared CTS-Glc scaffold, with enhanced osteoinduction capability and detailed mechanism elucidations, offers a promising candidate material for advancing bone tissue engineering and clinical regenerative medicine. As a result, this study presents a potential tool for future clinical treatment of bone defects., (© 2023 Wiley Periodicals LLC.)

The (pro)renin receptor ((P)RR) is an essential component of the renin-angiotensin system (RAS) as a specific single-pass transmembrane receptor for prorenin and renin and has now emerged as a multifunctional protein implicated in a wide variety of developmental and physio-pathological processes and pathways. The (P)RR may be of pathological significance in metabolic syndrome. The (P)RR has received much consideration; substantial efforts have been made to understand the localization, regulation, and function of the (P)RR at both a molecular and system level. (P)RR regulation of cell function depends on whether it is intact or cleaved into its constituent forms. Therefore, the present chapter describes immunohistochemical approaches to examine the expression of (P)RR in various organs. It was shown that different molecular forms of (P)RR could be present in different tissue compartments in almost all organs. Among them, the liver has high PRR activity. Our findings could elucidate more detailed distribution of different (P)RR molecular forms in different organs, which could provide useful information to further investigate the pathophysiological mechanisms of the development of various diseases in the future.

In 2015 and 2016, two Barramundi ( Lates calcarifer ) farms in Singapore reported a disease outbreak characterized by lethargic behavior, pronounced inappetence, generalized skin lesions, erosions of the fins and tail, and ultimately high mortality in their fish. Next-generation sequencing and PCR confirmed presence of a novel virus belonging to the Alloherpesviridae family, Lates calcarifer herpesvirus (LCHV), which was subsequently isolated and cultured. We characterize, for the first time, the complete genome of two cultured LCHV isolates. The genome contains a long unique region of approximately 105,000 bp flanked by terminal repeats of approximately 24,800 bp, of which the first 8.2 kb do not show any similarity to described genomes in the Alloherpesviridae family. The two cultured isolates share 89% nucleotide identity, and their closest relatives are the viruses belonging to the genus Ictalurivirus . Experimental infections using one of the cultured LCHV isolates resulted in identical clinical signs as originally described in the index farm, both in intraperitoneal-injection infected fish and cohabitant fish, with mortality in both groups. Histopathological analysis showed pronounced abnormalities in the gills. Virus culture and PCR analysis confirmed the replication of LCHV in the infected fish, and thus Koch's postulates were fulfilled.

Background: Metabolic disorder is noted for pacing-induced cardiomyopathy. The benefits of His bundle pacing over right ventricular (RV) pacing in preventing pacing-induced cardiomyopathy from a metabolic perspective are yet to be fully understood., Method and Results: Three pig groups were established for this study: sham control, RV pacing (RV pacing for 6 months), and His pacing (RV pacing for 6 months, followed by His bundle pacing for 3 months). Complete atrioventricular block was created in the last 2 groups. Left ventricular function and dyssynchrony were assessed via echocardiography, while proteins linked to metabolism, endoplasmic reticulum stress, and inflammation in left ventricular myocardium were examined. The RV pacing group had significantly more left ventricular mechanical dyssynchrony compared with the other groups. The RV pacing group exhibited triglyceride and diacylglycerol accumulation in cardiomyocytes and higher expression of binding immunoglobulin protein and tumor necrosis factor-α than the other groups. Additionally, the expression of CD36 was activated, while the expression of hormone-sensitive lipase was downregulated in the RV pacing group compared with the His pacing and sham control groups. Furthermore, the expressions of GLUT4 and pyruvate dehydrogenase were higher in the RV pacing group than the sham control and His pacing groups. Notably, the abnormal fatty acid and glucose metabolic pathways in the left ventricular myocardium during RV pacing could be corrected by His bundle pacing., Conclusions: His bundle pacing can mitigate the abnormal metabolism disorders, endoplasmic reticulum stress, and inflammation induced during RV pacing and may contribute to the superiority of conduction system pacing over RV pacing in reducing heart failure hospitalization.

Bladder cancer is becoming one of the most common malignancies across the world. Although treatment strategy has been continuously improved, which has led to cisplatin-based chemotherapy becoming the standard medication, cancer recurrence and metastasis still occur in a high proportion of patients because of drug resistance. The high efficacy of regorafenib, a broad-spectrum kinase inhibitor, has been evidenced in treating a variety of advanced cancers. Hence, this study investigated whether regorafenib could also effectively antagonize the survival of cisplatin-resistant bladder cancer and elucidate the underlying mechanism. Two types of cisplatin-resistant bladder cancer cells, T24R1 and T24R2, were isolated from T24 cisplatin-sensitive bladder cancer cells. These cells were characterized, and T24R1- and T24R2-xenografted tumor mice were created to examine the therapeutic efficacy of regorafenib. T24R1 and T24R2 cells exhibited higher expression levels of epithelial-mesenchymal transition (EMT) and stemness markers compared to the T24 cells, and regorafenib could simultaneously inhibit the viability and the expression of EMT/stemness markers of both T24R1 and T24R2 cells. Moreover, regorafenib could efficiently arrest the cell cycle, promote apoptosis, and block the transmigration/migration capabilities of both types of cells. Finally, regorafenib could significantly antagonize the growth of T24R1- and T24R2-xenografted tumors in mice. These results demonstrated the therapeutic efficacy of regorafenib in cisplatin-resistant bladder cancers. This study, thus, provides more insights into the mechanism of action of regorafenib and demonstrates its great potential in the future treatment of cisplatin-resistant advanced bladder cancer patients.

We detected African swine fever virus (ASFV) from a wild boar in Singapore. In <72 hours, we confirmed and reported ASFV p72 genotype II, CD2v serogroup 8, and IGR-II variant by using a combination of real-time PCR and whole-genome sequencing. Continued biosurveillance will be needed to monitor ASFV in Singapore.

In Singapore, 10 captive lions tested positive for SARS-CoV-2 by real-time PCR. Genomic analyses of nanopore sequencing confirmed human-to-animal transmission of the SARS-CoV-2 Delta variant. Viral genomes from the lions and zookeeper shared a unique spike protein substitution, S:A1016V. Widespread SARS-CoV-2 transmission among humans can increase the likelihood of anthroponosis.

Background: The main objective of this study was to investigate the risk of falls among middle-aged and older adults with dynapenic abdominal obesity., Methods: A systematic literature search was conducted to review and analyze relevant studies. Dynapenia was measured by handgrip strength, and abdominal obesity was measured by waist circumference. The search keywords included "older people" OR "elderly" OR "middle age" AND "dynapenia" AND "abdominal obesity" AND "fall." The search was not limited by time and included articles published up until April 2023. The literature search process followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, involving extraction and examination of the retrieved relevant articles. Systematic literature searches were performed in databases such as Embase, PubMed, MEDLINE, CINAHL, and Cochrane Library., Results: This study collected a total of eight articles with a combined sample size of 15,506 participants. The findings revealed that the average follow-up period for falls was 6.6 years (SD = 3.67). The overall results of the study showed that individuals with dynapenic abdominal obesity had a higher risk of falls compared to those without dynapenic abdominal obesity (RR = 6.91, 95% CI: 5.42-8.80). Subgroup analysis demonstrated that both prospective studies (HR = 6.61; 95% CI = 4.29-10.20) and retrospective studies (OR = 7.37; 95% CI = 5.13-10.59) consistently found a higher risk of falls among individuals with dynapenic abdominal obesity. However, there was no significant difference in fall risk between community-dwelling individuals with dynapenic abdominal obesity and hospitalized individuals with dynapenic abdominal obesity (Q between x 2 = 0.29, p = 0.58). Additionally, there was no difference in fall risk between individuals with dynapenic abdominal obesity residing in Europe and Latin America compared to those residing in Asia (Q between x 2 = 0.05, p = 0.81). It was worth noting that male individuals with dynapenic abdominal obesity had a higher risk of falls compared to females (Q between x 2 = 4.73, p = 0.03)., Conclusions: Empirical studies have demonstrated that individuals with dynapenic abdominal obesity have a higher risk of falls. Therefore, healthcare professionals should conduct early fall risk assessments and develop effective preventive strategies specifically targeted at individuals with dynapenic abdominal obesity.

Background: Babesia is a protozoal, tick-borne parasite that can cause life-threatening disease in humans, wildlife and domestic animals worldwide. However, in Southeast Asia, little is known about the prevalence and diversity of Babesia species present in wildlife and the tick vectors responsible for its transmission. Recently, a novel Babesia species was reported in confiscated Sunda pangolins (Manis javanica) in Thailand. To investigate the presence of this parasite in Singapore, we conducted a molecular survey of Babesia spp. in free-roaming Sunda pangolins and their main ectoparasite, the Amblyomma javanense tick., Methods: Ticks and tissue samples were opportunistically collected from live and dead Sunda pangolins and screened using a PCR assay targeting the 18S rRNA gene of Babesia spp. DNA barcoding of the cytochrome oxidase subunit I (COI) mitochondrial gene was used to confirm the species of ticks that were Babesia positive., Results: A total of 296 ticks and 40 tissue samples were obtained from 21 Sunda pangolins throughout the 1-year study period. Babesia DNA was detected in five A. javanense ticks (minimum infection rate = 1.7%) and in nine different pangolins (52.9%) located across the country. Phylogenetic analysis revealed that the Babesia 18S sequences obtained from these samples grouped into a single monophyletic clade together with those derived from Sunda pangolins in Thailand and that this evolutionarily distinct species is basal to the Babesia sensu stricto clade, which encompasses a range of Babesia species that infect both domestic and wildlife vertebrate hosts., Conclusions: This is the first report documenting the detection of a Babesia species in A. javanense ticks, the main ectoparasite of Sunda pangolins. While our results showed that A. javanense can carry this novel Babesia sp., additional confirmatory studies are required to demonstrate vector competency. Further studies are also necessary to investigate the role of other transmission pathways given the low infection rate of ticks in relation to the high infection rate of Sunda pangolins. Although it appears that this novel Babesia sp. is of little to no pathogenicity to Sunda pangolins, its potential to cause disease in other animals or humans cannot be ruled out., (© 2023. The Author(s).)

Background Lifestyle and metabolic diseases influence the severity and pathogenesis of cardiovascular disease through numerous mechanisms, including regulation via posttranslational modifications. A specific posttranslational modification, the addition of O -linked β- N acetylglucosamine ( O -GlcNAcylation), has been implicated in molecular mechanisms of both physiological and pathologic adaptations. The current study aimed to test the hypothesis that in cardiomyocytes, sustained protein O -GlcNAcylation contributes to cardiac adaptations, and its progression to pathophysiology. Methods and Results Using a naturally occurring dominant-negative O -GlcNAcase (dnOGA) inducible cardiomyocyte-specific overexpression transgenic mouse model, we induced dnOGA in 8- to 10-week-old mouse hearts. We examined the effects of 2-week and 24-week dnOGA overexpression, which progressed to a 1.8-fold increase in protein O- GlcNAcylation. Two-week increases in protein O -GlcNAc levels did not alter heart weight or function; however, 24-week increases in protein O -GlcNAcylation led to cardiac hypertrophy, mitochondrial dysfunction, fibrosis, and diastolic dysfunction. Interestingly, systolic function was maintained in 24-week dnOGA overexpression, despite several changes in gene expression associated with cardiovascular disease. Specifically, mRNA-sequencing analysis revealed several gene signatures, including reduction of mitochondrial oxidative phosphorylation, fatty acid, and glucose metabolism pathways, and antioxidant response pathways after 24-week dnOGA overexpression. Conclusions This study indicates that moderate increases in cardiomyocyte protein O -GlcNAcylation leads to a differential response with an initial reduction of metabolic pathways (2-week), which leads to cardiac remodeling (24-week). Moreover, the mouse model showed evidence of diastolic dysfunction consistent with a heart failure with preserved ejection fraction. These findings provide insight into the adaptive versus maladaptive responses to increased O- GlcNAcylation in heart.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Isolinderalactone (ILL), a sesquiterpene isolated from the root extract of Lindera aggregata , has been reported to exhibit anti-proliferative and anti-metastatic activities in various cancer cell lines. However, the mechanisms associated with its antitumor effects on CRC cells remain unclear. ILL treatment significantly suppressed proliferation and induced cell cycle G2/M arrest in CRC cells by inhibiting the expression of cyclin B, p-cdc2, and p-cdc25c and up-regulating the expression of p21. In addition, ILL induced mitochondria-associated apoptosis through the up-regulation of cleaved -caspase-9 and -3 expression. ILL induced autophagy by increasing the levels of LC3B in CRC cells, which was partially rescued by treatment with an autophagy inhibitor (chloroquine). Furthermore, ILL increases the accumulation of reactive oxygen species (ROS) and activates the MAPK pathway. Application of the ROS scavenger, N-acetyl cysteine (NAC), effectively inhibited ILL toxicity and reversed ILL-induced apoptosis, cell cycle arrest, autophagy, and ERK activation. Taken together, these results suggest that ILL induces G2/M phase arrest, apoptosis, and autophagy and activates the MAPK pathway via ROS-mediated signaling in human CRC cells.

Harvesting osmotic energy through nanofluidic devices with diverse materials has received considerable attention in recent years. Often, a small testing area on a membrane was chosen to assess its power performance by calculating power density as output power per effective area. Since the choice of this testing area is arbitrary, and it is usually quite small, the result obtained can be too optimistic. There is a need to come up with a common standard so that the performance of a device/membrane can be assessed reasonably. In this study, we systematically investigate the power density as a function of testing area in nanoporous anodic-aluminum-oxide membranes. Through changing the aperture size of substrates, we clearly show that the obtained power density decreases drastically with increasing testing area. For instance, the power density acquired from the testing area of μm 2 -scale can be five orders of magnitude larger than that from the pristine membrane of cm 2 -scale. We also advance simulations by building a 3D model to simulate osmotic-driven ion transport in the multichannel system. The result of modeling agrees with our experimental observation that the power density decreases with increasing number of channels, and the ionic concentration profile reveals that the concentration polarization becomes serious as the number of channels increases. Our result highlights the importance of effective area on testing the power performance in nanofluidic devices.

Background: Toxoplasma gondii is traditionally known as a parasite of felids, with possible infection in intermediate hosts such as dogs and humans, and thus a disease of public health significance. Published data on the prevalence of toxoplasmosis in dogs and cats in Singapore is scanty, and this paper documents a suspect clinical case of toxoplasmosis in a free-roaming puppy trapped from an offshore island of Singapore., Case Presentation: A 12-week-old puppy presented with hindlimb weakness and sarcopenia, with rapidly progressing ascending paralysis and respiratory distress, one week after trapping. Toxoplasmosis was suspected after indirect fluorescence antibody testing (IFAT) revealed anti-T. gondii antibodies. The puppy responded quickly to clindamycin treatment and was discharged from hospital after 10 days., Conclusion: While rare and undocumented, veterinary clinicians in Singapore are advised to also include toxoplasmosis infection as a differential diagnosis in dogs presenting with similar clinical signs. This is especially so for dogs which have access to the outdoors., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Aim: We explored the performance of demographic characteristics, physiological state, cognitive function, sensory function, and biomarkers when used as predictors of frailty for patients with schizophrenia., Design: A cross-sectional study design was adopted., Methods: Demographic data and data on physiological state, cognitive function, sensory function, biochemical indices, and frailty status of patients with schizophrenia were collected. The data were analysed using descriptive statistics, a chi-square test, one-factor analysis of variance, and logistic regression., Results: The results revealed that frailty was prevalent among patients with lower educational attainment, longer hospital stay, higher skeletal muscle mass, higher basal metabolic rate, lower cognitive function, the use of tranquillisers and sleeping pills, and the use of assistive equipment as well as having fallen in the past year. In addition, cognitive function (p < 0.05), use of a wheelchair (p < 0.05), and use of an assistive walker (p < 0.001) were used as predictors of frailty condition of patients with schizophrenia., Patient Contribution: Patients with schizophrenia have higher risk of having complications than patients with other chronic illnesses. Therefore, medical staff should regularly assess the levels of frailty risk to help patients with schizophrenia., (© 2023 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

Background: Point-of-care diagnostic devices, such as lateral-flow assays, are becoming widely used by the public. However, efforts to ensure correct assay operation and result interpretation rely on hardware that cannot be easily scaled or image processing approaches requiring large training datasets, necessitating large numbers of tests and expert labeling with validated specimens for every new test kit format., Methods: We developed a software architecture called AutoAdapt POC that integrates automated membrane extraction, self-supervised learning, and few-shot learning to automate the interpretation of POC diagnostic tests using smartphone cameras in a scalable manner. A base model pre-trained on a single LFA kit is adapted to five different COVID-19 tests (three antigen, two antibody) using just 20 labeled images., Results: Here we show AutoAdapt POC to yield 99% to 100% accuracy over 726 tests (350 positive, 376 negative). In a COVID-19 drive-through study with 74 untrained users self-testing, 98% found image collection easy, and the rapidly adapted models achieved classification accuracies of 100% on both COVID-19 antigen and antibody test kits. Compared with traditional visual interpretation on 105 test kit results, the algorithm correctly identified 100% of images; without a false negative as interpreted by experts. Finally, compared to a traditional convolutional neural network trained on an HIV test kit, the algorithm showed high accuracy while requiring only 1/50th of the training images., Conclusions: The study demonstrates how rapid domain adaptation in machine learning can provide quality assurance, linkage to care, and public health tracking for untrained users across diverse POC diagnostic tests., (© 2023. The Author(s).)

Background: The growing population of older adults worldwide is associated with an extended life expectancy and an increasing proportion of older adults with dynapenia. Most research on dynapenia has involved only populations of older adults living in the community; little research has examined the effects of risk factors on sleep quality among older adults with dynapenia residing in assisted living facilities., Aim: This study examined the relationships among physical function, nutrition, cognitive function, depression, and sleep quality among older adults with dynapenia residing in assisted living facilities., Methods: In this cross-sectional study, data on physical function, nutrition, cognitive function, depression, and sleep quality was collected from 178 older adults with dynapenia residing in assisted living facilities, who were selected using purposive sampling. Descriptive statistical analysis, independent-sample t tests, chi-squared tests, and logistic regression analysis were performed using SPSS 25.0., Results: The statistical analyses revealed correlations between sleep quality and age (t = 2.37, p < 0.05), level of education (χ 2  = 3.85, p < 0.05), grip strength (t = 3.40, p < 0.01), activities of daily living (t = 4.29, p < 0.001), instrumental activities of daily living (t = 2.23, p < 0.001), calf circumference (t = 2.89, p < 0.01), Mini Nutritional Assessment scores (t = 2.29, p < 0.05), Mini Mental State Exam (MMSE) scores (t = 4.50, p < 0.001), and Geriatric Depression Scale (GDS) scores (t = - 4.20, p < 0.001). Calf circumference (OR = 0.8, 95% CI = 0.650.97, p < 0.05), GDS score (OR = 1.42, 95% CI = 1.05-1.92, p < 0.05), and MMSE score (OR = 0.85, 95% CI = 0.73-0.97, p < 0.05) were related to sleep quality among the sample population., Conclusion: Physical function, nutrition, cognitive function, and depression affect the sleep quality of older adults with dynapenia residing in assisted living facilities. Facility nurses must regularly assess these aspects of their patients to ensure that facility-dwelling older adults can maintain their physical function and improve their health to improve the quality of their sleep., (© 2023. The Author(s).)

Rabbit haemorrhagic disease (RHD) is a significant and debilitating viral disease affecting lagomorphs. In September 2020, Singapore reported its first cases of RHD virus (RHDV) infection in domesticated rabbits. The initial findings reported that the outbreak strain belonged to genotype GI.2 (RHDV2/RHDVb), and epidemiological investigations could not identify the definitive source of the virus origin. Further recombination detection and phylogenetic analyses of the Singapore outbreak strain revealed that the RHDV was a GI.2 structural (S)/GI.4 non-structural (NS) recombinant variant. Sequence analyses on the National Centre for Biotechnology Information (NCBI) database showed high homology to recently emerged Australian variants, which were prevalent in local Australian lagomorph populations since 2017. Time-structured and phylogeographic analyses for the S and NS genes revealed a close genetic relationship between the Singapore RHDV strain and the Australian RHDV variants. More thorough epidemiological inquiries are necessary to ascertain how an Australian RHDV was introduced into the Singapore rabbit population, and opportune development of RHDV diagnostics and vaccines will be important to safeguard lagomorphs from future RHDV infection and disease management., Competing Interests: The authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: Natural products in diet have shown a potential role in the prevention and treatment of cancer. Ginger (Zingiber officinale Roscoe) is a great candidate because of its properties of anti-inflammatory, antioxidant, and anti-cancer, but little is known about its effect on head and neck cancer. 6-Shogaol is an active compound derived from Ginger. Thus, this study aimed to investigate the possible anticancer effects of 6-shogaol, a major ginger derivate, on head and neck squamous cell carcinomas (HNSCCs) and the underlying mechanisms. Material and Methods: Two HNSCC cell lines, SCC4 and SCC25, were used in this study. Both SCC4 and SCC25 cells were kept as control or treated with 6-shogaol for 8 and 24 hours and then the cell apoptosis and cell cycle progression of treated cells were examined by PI and Annexin V-FITC double stain and flow cytometry analysis. The Cleaved caspase 3, phosphorylations of ERK1/2 and p38 kinases were examined by Western blot analysis. Results: The results showed that 6-shogaol significantly initiated the G2/M phase arrest of the cell cycle and apoptosis to inhibit the survival of both cell lines. Moreover, these responses could be regulated by ERK1/2 and p38 signaling. And, finally, we also demonstrated that 6-shogaol could enhance the cytotoxicity of cisplatin in HNSCC cells. Conclusion: Our data provided new insights to understand the potential pharmaceutical efficacy of a ginger derivate, 6-shogaol, in antagonizing HNSCC survival. The present study suggests that 6-shogaol is a potential novel candidate for anti-HNSCCs therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The spread of chikungunya virus (CHIKV) is reaching pandemic levels, and vaccines and antivirals to control CHIKV infection have yet to be approved. Virus-like particles (VLPs), a self-assembled native multi-subunit protein structure, could potentially be used as an antigen for serological detection and vaccine development. In the current study, we describe the production of novel CHIKV VLPs from mosquitoes using a Baculovirus/Mosquito (BacMos) system in a simple Biosafety Level-2 laboratory. Substantial envelope and capsid protein secretions were detected in culture medium. Co-fractionation of CHIKV E2, E1, and capsid proteins via sucrose gradient ultracentrifugation provided evidence of VLP formation. Transmission electron microscopy and dynamic light scattering analysis revealed the formation of VLPs in the form of spherical particles with a diameter of roughly 40 nm in transduced cells and culture medium. VLP-based IgM capture ELISA in CHIKV patient sera revealed native epitopes on the VLPs. These non-purified VLPs were shown to act as an antigen in CHIKV-specific IgM capture ELISA. The immunization of CHIKV-VLPs alone in mice induced a balance CHIKV-specific IgG2a/IgG1 antibodies and neutralized antibody responses. The study provides support for the hypothesis that mosquito cell-derived CHIKV VLPs could serve as a novel antigen for serological detection and the development of vaccines against CHIKV infection. KEY POINTS: • CHIKV VLPs secreted from BacMos-CHIKV 26S-transduced mosquito cell. • This CHIKV VLPs potentially serve as an alternative capture antigen for MAC-ELISA. • Unadjuvanted CHIK VLPs induce CHIKV-specific IgG and NT responses in mice., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Continual learning is an emerging research branch of deep learning, which aims to learn a model for a series of tasks continually without forgetting knowledge obtained from previous tasks. Despite receiving a lot of attention in the research community, temporal-based continual learning techniques are still underutilized. In this paper, we address the problem of temporal-based continual learning by allowing a model to continuously learn on temporal data. To solve the catastrophic forgetting problem of learning temporal data in task incremental scenarios, in this research, we propose a novel method based on attentive recurrent neural networks, called Temporal Teacher Distillation (TTD). TTD solves the catastrophic forgetting problem in an attentive recurrent neural network based on three hypotheses, namely Rotation Hypothesis, Redundant Hypothesis, and Recover Hypothesis. Rotation Hypothesis and Redundant hypotheses could cause the attention shift phenomenon, which degrades the model performance on the learned tasks. Moreover, not considering the Recover Hypothesis increases extra memory usage in continuously training different tasks. Therefore, the proposed TTD based on the above hypotheses complements the inadequacy of the existing methods for temporal-based continual learning. For evaluating the performance of our proposed method in task incremental setting, we use a public dataset, WIreless Sensor Data Mining (WISDM), and a synthetic dataset, Split-QuickDraw-100. According to experimental results, the proposed TTD significantly outperforms state-of-the-art methods by up to 14.6% and 45.1% in terms of accuracy and forgetting measures, respectively. To the best of our knowledge, this is the first work that studies continual learning in real-world incremental categories for temporal data classification with attentive recurrent neural networks and provides the proper application-oriented scenario., 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 Elsevier Ltd. All rights reserved.)

Aim: This study was to explore the relationship of older adults' demographic information, physiological indices, and stages of frailty with their risk of falling., Methods: In the cross-sectional study, a total of 221 older adults with the mean age 74.9 (SD = 6.8) years old were surveyed by senior fitness test., Results: Results were observed in terms of participants' physical fitness, with significant differences being observed in the correlations of left-hand grip strength ( t = 5.05, p < .000), right-hand grip strength ( t = 6.03, p < .000), and total grip strength ( t = 5.70, p < .000), time up and go test ( t = -6.25, p < .000), and 30-sec chair stand test ( t = 7.19, p < .000) with the risk of falling. According to the logistic regression analysis results, long-term medication (OR = 0.12, 95% CI =0.02-0.62, p < .01) and right-hand grip strength (OR = 0.86, 95% CI =0.76-0.97, p < .01) are the main predictors of older adults' risk of falling., Conclusions: Older females with low education, history of falls, weaker grip strengths; taking longer to finish the TUG test; and standing fewer times during the 30-second chair stand test were at risk of fall. In prediction, older people using long-term medication were at lower risk of falling, and the greater the hand grip strength was, the lower the fall risk was. According to the research results, nursing personnel must develop care programs and improve older adults' risk of falls., Competing Interests: The authors of this manuscript declare no competing financial interests related to this work. Meanwhile, the authors declare that they have no competing interests., (Copyright © 2022 Yan-Cheng Lee et al.)

African horse sickness (AHS) is a highly infectious and often fatal disease caused by 9 serotypes of the orbivirus African horse sickness virus (AHSV). In March 2020, an AHS outbreak was reported in Thailand in which AHSV serotype 1 was identified as the causative agent. Trivalent live attenuated vaccines serotype 1, 3, and 4 were used in a targeted vaccination campaign within a 50-km radius surrounding the infected cases, which promptly controlled the spread of the disease. However, AHS-like symptoms in vaccinated horses required laboratory diagnostic methods to differentiate infected horses from vaccinated horses, especially for postvaccination surveillance. We describe a real-time reverse transcription PCR-based assay for rapid characterization of the affecting field strain. The development and validation of this assay should imbue confidence in differentiating AHS-vaccinated horses from nonvaccinated horses. This method should be applied to determining the epidemiology of AHSV in future outbreaks.

Uncontrolled and sustained inflammation disrupts the wound-healing process and produces excessive reactive oxygen species, resulting in chronic or impaired wound closure. Natural antioxidants such as plant-based extracts and natural polysaccharides have a long history in wound care. However, they are hard to apply to wound beds due to high levels of exudate or anatomical sites to which securing a dressing is difficult. Therefore, we developed a complex coacervate-based drug carrier with underwater adhesive properties that circumvents these challenges by enabling wet adhesion and controlling inflammatory responses. This resulted in significantly accelerated wound healing through balancing the pro- and anti-inflammatory responses in macrophages. In brief, we designed a complex coacervate-based drug carrier (ADC) comprising oligochitosan and inositol hexaphosphate to entrap and release antioxidant proanthocyanins (PA) in a sustained way. The results from in vitro experiments demonstrated that ADC is able to reduce LPS-stimulated pro-inflammatory responses in macrophages. The ability of ADC to reduce LPS-stimulated pro-inflammatory responses in macrophages is even more promising when ADC is encapsulated with PA (ADC-PA). Our results indicate that ADC-PA is able to polarize macrophages into an M2 tissue-healing phenotype via up-regulation of anti-inflammatory and resolution of inflammatory responses. Treatment with ADC-PA around the wound beds fine-tunes the balance between the numbers of inducible nitric oxide synthase-positive (iNOS+) and mannose receptor-negative (CD206-) M1 and iNOS-CD206+ M2 macrophages in the wound microenvironment compared to controls. Achieving such a balance between the numbers of iNOS+CD206- M1 and iNOS-CD206+ M2 macrophages in the wound microenvironment has led to significantly improved wound closure in mouse models of diabetes, which exhibit severe impairments in wound healing. Together, our results demonstrate for the first time the use of a complex coacervate-based drug delivery system to promote timely resolution of the inflammatory responses for diabetic wound healing by fine-tuning the functions of macrophages.

The resistance of renal cell carcinoma (RCC) to sunitinib impedes the success of chemotherapy in cancer treatment. Although several sunitinib resistance mechanisms have been proposed, little is known concerning the impact of obesity and adipokines in RCC cells. The upregulation of sterol-regulatory element-binding protein-1 (SREBP-1) has been reported to modulate the progression of tumor cells. The present study investigated the effect of visfatin on sunitinib-induced cytotoxicity in RCC cells through SREBP-1 expression. We found that visfatin-induced Akt and p70S6K activation increased SREBP-1 expression in 786-O cells. The visfatin-induced SREBP-1 mRNA and protein levels were attenuated through the inactivation of Akt and p70S6K by pharmacological inhibitors. In addition, the SREBP-1 knockdown using siRNA enhanced the cytotoxic effects of sunitinib. Our results also revealed the roles of simvastatin in attenuating the effects of visfatin on 786-O cells by inhibiting the production of reactive oxygen species. In particular, simvastatin co-treatment increased the cell cytotoxicity of sunitinib in visfatin-treated 786-O cells, which were associated with down-regulation of SREBP-1 expression. Our results suggest an important role of SREBP-1 in visfatin-induced drug resistance of RCC cells to sunitinib. The cytotoxic mechanism of simvastatin on RCC cells may provide a new strategy to improve therapeutic outcomes for the RCC treatment.

The main purpose of this study was to investigate the relationship between sarcopenia and injury events (falls, fractures, hospitalization, disability, and death). This study systemically searched the literature from Embase, PubMed, MEDLINE, CINAHL, and Cochrane Library and analyzed the collected literature using the random effects model to demonstrate the relationship between sarcopenia and injury events. This study followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and collected a total of 38 prospective studies, and the results showed that, when compared to robust individuals, the risk of injury events for older individuals with sarcopenia was significantly higher for fractures (HR = 9.66, CI: 5.07-18.38), hospital admissions (HR = 11.80, CI: 4.86-28.65), and death (HR = 9.57, CI: 3.17-28.94). In consideration of the negative impact of sarcopenia on the subsequent health of older adults, professional nursing personnel should assess older adults for sarcopenia as early as possible and propose relevant care policies to further reduce negative health impacts.

Blood reflux and metabolic regulation play important roles in chronic venous disease (CVD) development. Histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) serve as repressors that inhibit metabolic signaling, which is induced by proatherogenic flow to promote aortic endothelial cell (EC) dysfunction and atherosclerosis. The aim of this study was to elucidate the relationship between blood reflux and epigenetic factors HDACs and DNMTs in CVD. Human varicose veins with different levels of blood reflux versus normal veins with normal venous flow were examined. The results show that HDAC-1, -2, -3, -5, and -7 are overexpressed in the endothelium of varicose veins with blood reflux. Blood reflux-induced HDACs are enhanced in the varicose veins with a longer duration time of blood reflux. In contrast, these HDACs are rarely expressed in the endothelium of the normal vein with normal venous flow. Similar results are obtained for DNMT1 and DNMT3a. Our findings suggest that the epigenetic factors, HDACs and DNMTs, are induced in venous ECs in response to blood reflux but are inhibited in response to normal venous flow. Blood reflux-induced HDACs and DNMTs could inhibit metabolic regulation and promote venous EC dysfunction, which is highly correlated with CVD pathogenesis.

Ginger extracts have been shown to have health-promoting pharmacological activity and beneficial effects, including antioxidant and anticancer properties. The extraction of ginger by natural deep eutectic solvents (NaDES) has been shown to enhance bioactivity, but the cytotoxicity of NaDES extracts needs to be further determined. Signaling through the CXC chemokine receptor 4 (CXCR4) expressed on colorectal cancer (CRC) cells has a pivotal role in tumor cell chemosensitivity. Oxaliplatin is a third-generation platinum compound used as an effective chemotherapeutic drug for CRC treatment. However, whether ginger extract and oxaliplatin could induce a synergistic cytotoxic effect in oxaliplatin-resistant CRC cells through modulating CXCR4 expression is not known. In this study, oxaliplatin-resistant HCT-116 (HCT-116/R) cells were generated first. Ginger was extracted using the NaDES mixture betaine/lactate/water (1:2:2.5). Lactobacillus reuteri fermentation of NaDES-ginger extract increased the total polyphenol content (12.42 mg gallic acid/g in non-fermented NaDES-ginger extract and 23.66 mg gallic acid/g in fermented NaDES-ginger extract). It also increased the antioxidant activity by about 20−30% compared to non-fermented NaDES-ginger extract. In addition, it achieved low cytotoxicity to normal colonic mucosal cells and enhanced the anticancer effect on HCT-116/R cells. On the other hand, the inhibition of NF-κB activation by fermented NaDES-ginger extract significantly decreased the CXCR4 expression (p < 0.05) in HCT-116/R cells. The inactivation of NF-κB by pharmacological inhibitor pyrrolidine dithiocarbamate further enhanced the fermented NaDES-ginger extract-reduced CXCR4 expression levels (p < 0.05). Moreover, fermented NaDES-ginger extract could synergistically increase the cytotoxicity of oxaliplatin by inhibiting CXCR4 expression and inactivating NF-κB, resulting in HCT-116/R cell death. These findings demonstrate that fermented NaDES-ginger extract reduces the NF-kB-mediated activation of CXCR4 and enhances oxaliplatin-induced cytotoxicity in oxaliplatin-resistant CRC cells.

Oral cancer, constituted up to 90% by squamous cell carcinomas, is a significant health burden globally. Grape seed proanthocyanidins (PA) have been suggested as a potential chemopreventive agent for oral cancer. However, their efficacy can be restricted due to the low bioavailability and bioaccessibility. Inspired by sandcastle worm adhesive, we adapted the concept of complex coacervation to generate a new type of drug delivery platform. Complex coacervates are a dense liquid phase formed by the associative separation of a mixture of oppositely charged polyelectrolytes, can serve as a drug delivery platform to protect labile cargo. In this study, we developed a complex coacervates-based delivery of PA. The release kinetics was measured, and anticancer effects were determined in two human tongue squamous cell carcinoma cell lines. The results showed that complex coacervate successfully formed and able to encapsulate PA. Additionally, PA were steadily released from the system in a pH-dependent manner. The drug delivery system could significantly inhibit the cell proliferation, migration, and invasion of cancer cells. Moreover, it could markedly reduce the expression of certain matrix metalloproteinases (MMP-2, 9, and 13) crucial to metastatic processes. We also found that suppression of protein kinase B (Akt) pathway might be the underlying mechanism for these anticancer activities. Taken together, complex coacervates-based delivery of PA can act as an effective anticancer approach for oral cancer therapy., 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 © 2022 Liu, Wee, Luo, Chang, Jia, Feng, Huang, Lin and Wang.)

Real-world experience with low-level viraemia (LLV) and its impact remain less reported among people living with HIV (PLWH) who receive antiretroviral therapy (ART) containing second-generation integrase strand transferase inhibitors, including dolutegravir and bictegravir. This retrospective cohort study included virally suppressed PLWH who achieved plasma HIV-RNA viral load (PVL) <50 copies/mL for ≥6 months and were switched to either dolutegravir- or bictegravir-based ART. Incidence rates of developing LLV events (PVL, 50-200 copies/mL) and virologic failure (VF) (PVL ≥1000 copies/mL) were compared between the dolutegravir and bictegravir cohorts. A total of 623 and 862 PLWH switched to dolutegravir-based and bictegravir-based ART, respectively, were included. The incidence rate of developing LLV was 6.2 per 100 person-years of follow-up (PYFU) in the bictegravir cohort and 3.8 per 100 PYFU in the dolutegravir cohort [incidence rate ratio (IRR) = 1.63, 95% confidence interval (CI), 0.90-2.95; P = 0.08], while rates of VF were 0.69 per 100 PYFU and 0.95 per 100 PYFU, respectively, in the bictegravir and dolutegravir cohorts (IRR = 0.72, 95% CI 0.12-3.39; P = 0.34). Presence of LLV events was not associated with subsequent VF in multivariate analysis. Secondary analysis also demonstrated that resistance-associated mutations (RAMs) to nucleoside reverse transcriptase inhibitors (NRTIs) before switch were not associated with adverse virologic outcomes in either cohort. In conclusion, among virally suppressed PLWH, the incidences of developing LLV or VF were similar after switch to dolutegravir- or bictegravir-based ART. Pre-existing RAMs to NRTIs or LLV events were not associated with subsequent VF., Competing Interests: Declaration of Competing Interest CCH has received research support from Merck, Gilead Sciences and ViiV and speakers’ honoraria from Gilead Sciences and ViiV, and has served on advisory boards for Gilead Sciences and ViiV; HYS has received research support from Gilead Sciences. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Rabbit haemorrhagic disease (RHD) is a highly contagious viral disease affecting lagomorphs. The first documented cases of RHD in Singapore occurred in adult pet European rabbits in September 2020. Singapore subsequently declared the outbreak resolved in December 2020. Epidemiological investigations ruled out introductions via importation of infected rabbits and contaminated feed. The source could not be definitively determined. However, the findings suggested that the incident involved both inter- and intra-household transmission and veterinary clinic-household transmission. This incident demonstrated the importance of sustained application of biosecurity measures, epidemiological investigations including active case finding, control measures such as expedient vaccine dissemination and risk communications. It showed that even without a wild lagomorph population, an urbanized city-state like Singapore could still encounter emerging diseases such as RHD. Given its social impact on rabbit owners, the National Parks Board, Singapore and private veterinarians worked together to communicate with rabbit owners in order to urge them to adopt biosecurity measures and to address their concerns., (© 2021 Wiley-VCH GmbH.)

Coix lacryma-jobi var. ma-yuen L. Gramineae is widely cultivated in Taiwan. Literature regarding the molecular action mechanism of coixol on tyrosinase and the application of coicis seed extracts to the processing of facial masks is still lacking. Solvent extractability analysis revealed that most of the polyphenolics in coicis seeds were water soluble (3.17 ± 0.12 to 3.63 ± 0.07 μg/mLGAE). In contrast, the methanolic extract contained the most flavonoids (0.06 ± 0.00~0.26 ± 0.03 μg/mL QE) and coixol (11.43 ± 0.13~12.83 ± 0.14 μg/mL), showing potent antioxidant capability. Additionally, the contents of coixenolide (176.77 ± 5.91 to 238.60 ± 0.21 μg/g), phytosterol (52.45 ± 2.05 to 58.23 ± 1.14 mg/g), and polysaccharides (3.42 ± 0.10 to 4.41 ± 0.10 mg/g) were rather high. The aqueous extract (10 μg/mL) and the ethanolic extract (1 mg/mL) showed no cytotoxicity to B16F10 melanocytes. More attractively, the ethanolic extract at 1 mg/mL caused 48.4% inhibition of tyrosinase activity in B16F10 melanocytes, and 50.7% on human tyrosinase (hTyr) fragment 369-377. Conclusively, the coicis seed extracts containing abundant nutraceuticals with promising anti-hTyr activity and moisturizing capability can serve as good ingredients for facial mask processing.