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High temperatures applied in the production of plant-based meat analogs (PBMA) lead to the occurrence of Maillard reactions, in which harmful compounds Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL) and acrylamide are formed. However, little research has focused on these compounds in PBMA. In this study, the contents of CML, CEL and acrylamide in 15 commercial-sold PBMA were determined by an ultra-high performance liquid chromatograph coupled with a triple quadrupole tandem mass spectrometer (UHPLC-QqQ-MS/MS). Nutrients (protein, amino acids, fatty acids and sugars) which are related to the formation of these compounds were also studied. The results showed that CML, CEL and acrylamide contents were in the range of 16.46–47.61 mg/kg, 25.21–86.23 mg/kg and 31.81–186.70 μg/kg, respectively. Proteins account for 24.03–53.18% of PBMA. Except for Met + Cys, which is the limiting amino acid of most PBMA, all other indispensable amino acids met the requirements for adults. Besides, PBMA had more n-6 fatty acids than n-3 fatty acids. A correlation analysis showed that proteins and the profiles of amino acid and fatty acid had little influence on CML but significant influence on CEL and acrylamide. The results of the present study can be used as a reference to produce PBMA with higher amounts of nutrients and lower amounts of CML, CEL and acrylamide.

Current IoT applications in indoor air focus mainly on general monitoring. This study proposed a novel IoT application to evaluate airflow patterns and ventilation performance using tracer gas. The tracer gas is a surrogate for small-size particles and bioaerosols and is used in dispersion and ventilation studies. Prevalent commercial tracer-gas-measuring instruments, although highly accurate, are relatively expensive, have a long sampling cycle, and are limited in the number of sampling points. To enhance the spatial and temporal understanding of tracer gas dispersion under the influence of ventilation, a novel application of an IoT-enabled, wireless R134a sensing network using commercially available small sensors was proposed. The system has a detection range of 5–100 ppm and a sampling cycle of 10 s. Using Wi-Fi communication, the measurement data are transmitted to and stored in a cloud database for remote, real-time analysis. The novel system provides a quick response, detailed spatial and temporal profiles of the tracer gas level, and a comparable air change rate analysis. With multiple units deployed as a wireless sensing network, the system can be applied as an affordable alternative to traditional tracer gas systems to identify the dispersion pathway of the tracer gas and the general airflow direction.

To investigate the impact of extrusion parameters on the formation of Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL) and acrylamide in plant-based meat analogues (PBMAs), the content changes and the correlations of compounds related to their formation were studied. The extrusion promoted CML, CEL and acrylamide formation, with more CEL being formed than CML. Variations in the moisture level and barrel temperature exerted a greater influence on the CML, CEL, acrylamide and α-dicarbonyl compounds than the screw speed and the feed rate. An increase in the moisture content led to a decrease in the CEL content, whereas it enhanced CML formation. The impact of moisture on acrylamide formation varied depending on whether low- or high-moisture extrusion was applied. Elevated temperatures promoted the accumulation of CEL, methylglyoxal and 2,3-butanedione while diminishing the accumulation of CML, acrylamide, glyoxal and 3-deoxyglucosone. CML and CEL were positively correlated with glyoxal and methylglyoxal, respectively. CEL and methylglyoxal were negatively correlated with protein and water content, whereas CML, glyoxal and 3-deoxyglucosone displayed positive correlations. In summary, higher moisture levels and feed rates and lower screw speeds and barrel temperatures are advantageous for producing PBMAs with lower CEL and total advanced glycation end-products contents, while lower or higher moisture contents, a lower feed rate and a higher barrel temperature are beneficial to reducing the acrylamide content. [ABSTRACT FROM AUTHOR]

Seed mucilages are potential sources of natural polysaccharides. They are biodegradable, biocompatible, sustainable, renewable, and safe for human consumption. Due to the desirable physicochemical and functional properties (e.g. gelling, thickening, stabilizing, and emulsifying), seed mucilages have attracted extensive attention from researchers for utilization as a promising material for the development of advanced carrier systems. Seed mucilages have been utilized as natural polymers to improve the properties of various carrier systems (e.g. complex coacervates, beads, nanofibers, and gels) and for the delivery of diverse hydrophilic and lipophilic compounds (e.g. vitamins, essential oils, antioxidants, probiotics, and antimicrobial agents) to achieve enhanced stability, bioavailability, bioactivity of the encapsulated molecules, and improved quality attributes of food products. This review highlights the recent progress in seed mucilage-based carrier systems for food and nutraceutical applications. The main contents include (1) sources, extraction methods, and physicochemical and functional characteristics of seed mucilages, (2) application of seed mucilages for the development of advanced carrier systems, (3) major issues associated with carrier fabrication, and (4) mechanisms of carrier development, latest improvements in carrier formulation, carrier efficiency in the delivery of bioactive agents, and application in food and nutraceuticals. Furthermore, major challenges and future perspectives of seed mucilage-based carriers for a commercial application are discussed. [ABSTRACT FROM AUTHOR]

Variants (pathogenic) of the LMNA gene are a common cause of familial dilated cardiomyopathy (DCM), which is characterised by early-onset atrioventricular (AV) block, atrial fibrillation and ventricular tachyarrhythmias (VTs), and progressive heart failure. The unstable internal nuclear lamina observed in LMNA-related DCM is a consequence of the disassembly of lamins A and C. This suggests that LMNA variants produce truncated or alternative forms of protein that alter the nuclear structure and the signalling pathway related to cardiac muscle diseases. To date, the pathogenic mechanisms and phenotypes of LMNA-related DCM have been studied using different platforms, such as patient-specific induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs) and transgenic mice. In this review, point variants in the LMNA gene that cause autosomal dominantly inherited forms of LMNA-related DCM are summarised. In addition, potential therapeutic targets based on preclinical studies of LMNA variants using transgenic mice and human iPSC-CMs are discussed. They include mitochondria deficiency, variants in nuclear deformation, chromatin remodelling, altered platelet-derived growth factor and ERK1/2-related pathways, and abnormal calcium handling. [ABSTRACT FROM AUTHOR]

In recent years, microalgal protein (MP) has gained a lot of interest, and research on its properties and applications is steadily increasing. However, the crude protein derived from microalgae is generally undervalued and has not yet found significant applications in the food industry. There are still many issues that need to be addressed in order to promote the MP industry and make it viable. In this review, about 30 microalgal species commonly used for human consumption are depicted with their safety aspects, and the potential MP production strategies and technologies are evaluated and compared in terms of protein yield efficiency. The latest findings on the nutritional, biological, and techno-functional properties of MP are summarized to identify the potential future applications in food. Apart from that, the challenges and current issues facing the MP industry are addressed, and several technological and strategic approaches are suggested to stimulate more relevant and problem-solving research activities in this area. From the literature review, it can be concluded that MPs have balanced amino acid profiles, high quality, and good bioaccessibility. They also possess various biological activities and diverse physicochemical properties, which could be suitable for different food development needs. However, the disruption of stubborn cell walls and the migration of low sensory scores of microalgae are important challenges for the current MP industry. To increase the sustainability of MP in the human food industry, developing low-cost and large-scale microalgae cultivation strategies, seeking efficient protein purification techniques, and exploring novel applications based on the MP properties are crucial. [ABSTRACT FROM AUTHOR]

Malignant pleural effusions are uncommon in small cell lung carcinoma (SCLC). We report a case of this in an elderly female patient. Her previous history of ductal breast carcinoma, ovarian serous carcinoma, and non-small cell lung carcinoma prompted several possible differential diagnoses. We discuss the importance of cytology specimens in the diagnosis of lung carcinomas, and the cytomorphological features of SCLC with their nuances and subtleties. [ABSTRACT FROM AUTHOR]

COVID-19 continues to spread around the world. This is mainly because new variants of the SARS-CoV-2 virus emerge due to genomic mutations, evade the immune system and result in the effectiveness of current therapeutics being reduced. We previously established a series of detection platforms, comprising computational docking analysis, S-protein-based ELISA, pseudovirus entry, and 3CL protease activity assays, which allow us to screen a large library of phytochemicals from natural products and to determine their potential in blocking the entry of SARS-CoV-2. In this new screen, rutaecarpine (an alkaloid from Evodia rutaecarpa) was identified as exhibiting anti-SARS-CoV-2 activity. Therefore, we conducted multiple rounds of structure-activity-relationship (SAR) studies around this phytochemical and generated several rutaecarpine analogs that were subjected to in vitro evaluations. Among these derivatives, RU-75 and RU-184 displayed remarkable inhibitory activity when tested in the 3CL protease assay, S-protein-based ELISA, and pseudovirus entry assay (for both wild-type and omicron variants), and they attenuated the inflammatory response induced by SARS-CoV-2. Interestingly, RU-75 and RU-184 both appeared to be more potent than rutaecarpine itself, and this suggests that they might be considered as lead candidates for future pharmacological elaboration. [ABSTRACT FROM AUTHOR]

This document explores the use of ultrasound (US) in rheumatology practice, specifically focusing on a new model called Point of Care US (POCUS) in Rheumatology (POCRUS). The authors argue that learning US examination skills can improve diagnostic accuracy and clinical confidence in rheumatology. They propose a probability-directed approach to US, using standardized assessments based on international classification criteria for rheumatic and musculoskeletal diseases. The document acknowledges the support of various organizations in organizing and reporting the findings of an online course on POCRUS. [Extracted from the article]

Abstract Background Mixotrophy can confer a higher growth rate than the sum of photoautotrophy and heterotrophy in many microalgal species. Thus, it has been applied to biodiesel production and wastewater utilization. However, its carbon and energy metabolic mechanism is currently poorly understood. Results To elucidate underlying carbon and energy metabolic mechanism of mixotrophy, Chromochloris zofingiensis was employed in the present study. Photosynthesis and glucose metabolism were found to operate in a dynamic balance during mixotrophic cultivation, the enhancement of one led to the lowering of the other. Furthermore, compared with photoautotrophy, non-photochemical quenching and photorespiration, considered by many as energy dissipation processes, were significantly reduced under mixotrophy. Comparative transcriptome analysis suggested that the intermediates of glycolysis could directly enter the chloroplast and replace RuBisCO-fixed CO2 to provide carbon sources for chloroplast organic carbon metabolism under mixotrophy. Therefore, the photosynthesis rate-limiting enzyme, RuBisCO, was skipped, allowing for more efficient utilization of photoreaction-derived energy. Besides, compared with heterotrophy, photoreaction-derived ATP reduced the need for TCA-derived ATP, so the glucose decomposition was reduced, which led to higher biomass yield on glucose. Based on these results, a mixotrophic metabolic mechanism was identified. Conclusions Our results demonstrate that the intermediates of glycolysis could directly enter the chloroplast and replace RuBisCO-fixed CO2 to provide carbon for photosynthesis in mixotrophy. Therefore, the photosynthesis rate-limiting enzyme, RuBisCO, was skipped in mixotrophy, which could reduce energy waste of photosynthesis while promote cell growth. This finding provides a foundation for future studies on mixotrophic biomass production and photosynthetic metabolism.

Abstract Background Little is known about the progression of obesity from childhood to adolescence. This study aimed to longitudinally examine the obesity status in a cohort of children across their childhood and adolescence, and to identify the factors associated with persistent obesity. Methods The study used data from School Physical Fitness Award Scheme (SPFAS), a population-based programme in Hong Kong primary and secondary schools. Students were included if they participated in the SPFAS in both 2014 (Primary 1 and 2) and 2018 (Primary 5 and 6). Their anthropometric and physical fitness parameters were analyzed. Results A total of 18,863 students were included. The baseline prevalence of obesity was 5.7 %. After 4 years, the prevalence increased to 6.7 %. Among those with obesity at baseline, 35.3 % remained obese after 4 years. The addition of baseline physical fitness level did not improve the prediction for persistent obesity. Conclusions One-third of obese students in junior primary school remained to be obese into adolescence. Their baseline physical fitness level did not improve the predictive value for future obesity. Further studies should investigate the prognostic factors that may influence the natural course of childhood obesity.

Energy storage is essential for balancing the generation and load in power systems. Building a battery energy storage system (BESS) with retired battery packs from electric vehicles (EVs) or plug-in hybrid electric vehicles (PHEVs) is one possible way to subsidize the price of EV/PHEV batteries, and at the same time mitigating forecast error introduced by load and renewable energy sources in power systems. This paper proposes a detailed framework to evaluate end-of-life (EOL) EV/PHEV batteries in BESS application. The framework consists of three parts. A generalized model for battery degradation is first introduced. It is followed by modeling the battery retirement process in its first life. Two vehicle types—EV and PHEV—as well as two retirement modes—nominal and realistic modes—are considered. Finally, the application of the second-life BESS in power systems is modeled in a detailed economic dispatch (ED) problem. This is how second-life BESS’s performance translates into cost savings on power generation. An optimization problem is formulated to maximize total cost savings in power generation over the battery’s second life. This is done by striking a balance between short-term benefit (daily cost savings) and long-term benefit (cost savings through service years). Numerical results validate the effectiveness of the proposed framework/models. They show that battery usage and retirement criterion in its first life directly affect the performance in its second life application. In our case study, EV battery packs possess larger EOL energy capacities and consequently generate more cost savings in the second life. However, the BESS built from retired PHEV batteries has higher cost savings per MWh. It is because, with the proposed degradation model, battery health is better preserved in PHEV applications. Compared to nominal retirement mode, realistic retirement mode results in extra cost savings due to the reduced first-life service years.

Gout is the most common inflammatory arthritis due to deposition of monosodium urate (MSU) crystals in joints and connective tissues. In contrast to joint disease, the majority of extra-articular involvement remains asymptomatic in patients with gout. Achilles tendon is the most common site of involvement and the inflammation elicited by MSU crystals can be falsely attributed to injury or overuse. In addition, tendon or ligament damage secondary to MSU crystal deposition can lead to ligament tear or tendon rupture. However, the diagnosis of gout in patients with extra-articular involvement is often delayed or even missed because tissue sampling is not feasible in routine clinical practice. Advanced imaging techniques using ultrasound and dual-energy computer tomography (DECT) can detect MSU crystal deposition in a non-invasive manner and confirm the diagnosis of gout in patients with extra-articular involvement. The following case demonstrates an atypical presentation of gout causing multiple ligament tears in the ankle and highlights the role of DECT in the diagnosis of gout with extra-articular involvement.

The NOD-like receptors (NLRs) have been shown to be involved in infection and autoinflammatory disease. Previously, we identified a zebrafish NLR, nlrc3-like, required for macrophage homeostasis in the brain under physiological conditions. Here, we found that a deficiency of nlrc3-like leads to decreased bacterial burden at a very early stage of Mycobacterium marinum infection, along with increased production of pro-inflammatory cytokines, such as il-1β and tnf-α. Interestingly, myeloid-lineage specific overexpression of nlrc3-like achieved the opposite effects, suggesting that the impact of nlrc3-like on the host anti-mycobacterial response is mainly due to its expression in the innate immune system. Fluorescence-activated cell sorting (FACS) and subsequent gene expression analysis demonstrated that inflammasome activation-related genes were upregulated in the infected macrophages of nlrc3-like deficient embryos. By disrupting asc, encoding apoptosis-associated speck-like protein containing a CARD, a key component for inflammasome activation, the bacterial burden increased in asc and nlrc3-like double deficient embryos compared with nlrc3-like single deficient embryos, implying the involvement of inflammasome activation in infection control. We also found extensive neutrophil infiltration in the nlrc3-like deficient larvae during infection, which was associated with comparable bacterial burden but increased tissue damage and death at a later stage that could be alleviated by administration of dexamethasone. Our findings uncovered an important role of nlrc3-like in the negative regulation of macrophage inflammasome activation and neutrophil infiltration during mycobacterial infection. This highlights the importance of a balanced innate immune response during mycobacterial infection and provides a potential molecular basis to explain how anti-inflammatory drugs can improve treatment outcomes in TB patients whose infection is accompanied by a hyperinflammatory response.

Curcumin (CUR) has demonstrated promising potential as a therapeutic agent against colorectal cancer (CRC). However, its intrinsic shortcomings, including oxidative instability, sensitivity to gastrointestinal (GI) hydrolytic/enzymatic action, and susceptibility to biotransformation and systemic elimination, have greatly undermined its value for application in clinical settings. The development of carriers, in particular oral formulations, for its efficient delivery has remained an important direction in nutraceutical research. In the present work, CUR-encapsulated nanoparticles were fabricated with zein alone (Zein-CUR) and with zein and a polysaccharide (PS) [gum Arabic (GA), hyaluronic acid (HA) and pectin (PC), respectively] (PS-Zein-CUR). Their physicochemical and biological properties were evaluated in a series of in vitro and in vivo assays. Dynamic light scattering analysis showed an increase in the particle size of the nanoparticles from 129.0 nm (Zein-CUR) to 188.8–346.4 nm (PS-Zein-CUR). The three PS-Zein-CUR formulations had significantly higher (17–22%) CUR encapsulation efficiency (EE) than Zein-CUR. Among them, HA-Zein-CUR exhibited the highest EE and loading capacity. Zeta potential and FTIR spectra indicated the involvement of electrostatic and hydrophobic interactions and hydrogen bonds in the formation of the PS-Zein-CUR. In human CRC cell lines (HCT8, HCT29, and HCT116), the three PS-Zein-CUR and CUR all effectively inhibited cell viability and colony formation (HA-Zein-CUR > PC-Zein-CUR > GA-Zein-CUR/CUR). HA-Zein-CUR and PC-Zein-CUR also resulted in significantly higher cellular uptake of CUR than GA-Zein-CUR and CUR. Simulated GI-digestion assay demonstrated significantly improved controlled-release properties of these two formulations. Further pharmacokinetics and tissue distribution assays in a CRC subcutaneous xenograft model in nude mice corroborated the enhanced pharmacokinetic properties of intragastric administration of HA-Zein-CUR compared with that of free CUR (3 times higher Cmax and 9.18 times higher plasma AUC). HA-Zein-CUR also led to enhanced delivery and accumulation of CUR in major organs/tissues, in particular CRC tumors and colon. These results together support that HA-Zein-CUR has promising potential as an oral agent for the control of CRC.

Background: Hong Kong, a Special Administrative Region of China, recorded its first confirmed coronavirus disease 2019 (COVID-19) case on 23 January 2020. We reviewed the case epidemiology and the various public health measures implemented from January to May 2020. Methods: The epidemiological and clinical characteristics of the cases recorded in different phases of the epidemic were described and compared, and the effectiveness of the public health measures implemented were reviewed using the changes in the daily number of confirmed cases and the interval from symptom onset to hospital admission. Results: Between January and May 2020, 1084 confirmed COVID-19 cases were reported, about 70% of which had a history of travel during the incubation period. The case fatality ratio was 0.4%. The local epidemic progressed through four phases: (1) preparedness and imported infection from mainland China, (2) local transmission, (3) imported infection from overseas countries associated with local transmission, and (4) controlled imported infection with limited local transmission, with an eventual reduction of the daily case number and minimization of the onset-to-admission interval. Various public health measures, including enhanced surveillance, border control, and social distancing, were introduced in phases in response to the prevailing local and global situations. Discussion: The overall containment strategy in Hong Kong led to a stabilization of the number of cases and the absence of a community-wide outbreak during the 4.5 m after the first case was reported. This strategy of containment might serve as an example for future planning of preparedness and response against novel infectious agents.

Abstract Background In the management of operable hilar cholangiocarcinoma (HC) patients with hyperbilirubinemia, preoperative biliary drainage is a measure to bring down the bilirubin to a certain level so as to avoid adverse postoperative outcomes that would otherwise result from hyperbilirubinemia. A cutoff value of bilirubin level in this context is needed but has not been agreed upon without controversy. This retrospective study aimed to identify a cutoff of preoperative bilirubin level that would minimize postoperative morbidity and mortality. Methods Data of patients having hepatectomy with curative intent for HC were analyzed. Discriminative analysis was performed to identify the preoperative bilirubin level that would make a survival difference. The identified level was used as the cutoff to divide patients into two groups. The groups were compared. Results Ninety patients received hepatectomy with curative intent for HC. Their median preoperative bilirubin level was 23 μmol/L. A cutoff preoperative bilirubin level of 75 μmol/L was derived from Youden’s index (sensitivity 0.333; specificity 0.949) and confirmed to be optimal by logistic regression (relative risk 9.250; 95% confidence interval 1.932–44.291; p = 0.005), with mortality shown to be statistically different at 90 days (p = 0.008). Patients were divided into Group A (≤75 μmol/L; n = 82) and Group B (> 75 μmol/L; n = 8). Group B had a higher preoperative bilirubin level (p

Background: Currently there is no guideline based on preoperative clinical parameters for assessing the prognosis of the adjunctive surgery for drug-resistant tuberculosis. Methods: We retrospectively analyzed 138 patients who had undergone surgical resection as a treatment for drug- resistant tuberculosis after 24 months. Four clinical parameters on lesion type, treatment history, body physiological status, and surgery approach were evaluated. Categorical preoperative clinical parameters were analyzed by ordinal logistic regression model when considering postoperative complications as outcomes ordered in terms of severity. Statistically significant parameters were then combined in a single classification system for predicting the outcomes of the adjunctive surgery. Findings: Diffused, progressive bilateral lesions, or active/progressive extra pulmonary tuberculosis (L3), and history of less than 2 months treatment before surgery (T3) were the strongest predicative parameters for postoperative complications and for surgery failure. Classification systems based on the four parameters were found to have a statistically significant effect on postoperative complications and postoperative efficacy. 24- month follow up indicated a high cure rate (above 95.5%) among patients without T3, L3, or severe physiological complications (B3). Interpretation: A classification system based on objective clinical parameters showed predicative value for the prognosis of the adjunctive surgery and could guide management of drug-resistant Tuberculosis.

In Hong Kong, universal varicella vaccination was introduced in July 2014 with a two-dose schedule but the vaccines had been available in the private market since 1996. With data from varicella notification and surveys on immunization coverage, we used the screening method to estimate dose-specific varicella vaccine effectiveness (VE) among preschool children in Hong Kong before universal vaccination. We estimated the VE of one- and two-dose varicella vaccination against all notified varicella as 69.4% (95% confidence interval (95% CI) 69.5–71.2) and 93.4% (95% CI 91.7–94.7), respectively. We found that VE did not decrease with time since receipt. Varicella vaccine was more effective against complications (85.4% [95% CI 48.8–95.8] for one dose and 100% [95% CI –Inf to 100] for two doses) and against hospital admission (75.2% [95% CI 53.4–86.8] for one dose and 93.1% [95% CI 47.1–99.1] for two doses). Lower protection of one-dose varicella vaccine resulted in breakthrough varicella. Under universal vaccination, second-dose varicella vaccine (given as combined measles, mumps, rubella and varicella vaccine) was first scheduled for children when they reach primary one (about 6 years of age) and was recently advanced to 18 months of age. Shortening the interval between the first dose and second dose of varicella vaccination should reduce breakthrough varicella and outbreaks in preschool.

Traditional speed control of permanent magnet synchronous motors (PMSMs) includes a cascaded speed loop with proportional-integral (PI) regulators. The output of this outer speed loop, i.e. electromagnetic torque reference, is in turn fed to either the inner current controller or the direct torque controller. This cascaded control structure leads to relatively slow dynamic response, and more importantly, larger speed ripples. This paper presents a new dual cost function model predictive direct speed control (DCF-MPDSC) with duty ratio optimization for PMSM drives. By employing accurate system status prediction, optimized duty ratios between one zero voltage vector and one active voltage vector are firstly deduced based on the deadbeat criterion. Then, two separate cost functions are formulated sequentially to refine the combinations of voltage vectors, which provide two-degree-of-freedom control capability. Specifically, the first cost function results in better dynamic response, while the second one contributes to speed ripple reduction and steady-state offset elimination. The proposed control strategy has been validated by both Simulink simulation and hardware-in-the-loop (HIL) experiment. Compared to existing control methods, the proposed DCF-MPDSC can reach the speed reference rapidly with very small speed ripple and offset.

Background & Aims: Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by loss-of-function mutations in ATP7B, which encodes a copper-transporting protein. It is characterized by excessive copper deposition in tissues, predominantly in the liver and brain. We sought to investigate whether gene-corrected patient-specific induced pluripotent stem cell (iPSC)-derived hepatocytes (iHeps) could serve as an autologous cell source for cellular transplantation therapy in WD. Methods: We first compared the in vitro phenotype and cellular function of ATP7B before and after gene correction using CRISPR/Cas9 and single-stranded oligodeoxynucleotides (ssODNs) in iHeps (derived from patients with WD) which were homozygous for the ATP7B R778L mutation (ATP7BR778L/R778L). Next, we evaluated the in vivo therapeutic potential of cellular transplantation of WD gene-corrected iHeps in an immunodeficient WD mouse model (Atp7b-/- / Rag2-/- / Il2rg-/-; ARG). Results: We successfully created iPSCs with heterozygous gene correction carrying 1 allele of the wild-type ATP7B gene (ATP7BWT/-) using CRISPR/Cas9 and ssODNs. Compared with ATP7BR778L/R778L iHeps, gene-corrected ATP7BWT/- iHeps restored in vitro ATP7B subcellular localization, its subcellular trafficking in response to copper overload and its copper exportation function. Moreover, in vivo cellular transplantation of ATP7BWT/- iHeps into ARG mice via intra-splenic injection significantly attenuated the hepatic manifestations of WD. Liver function improved and liver fibrosis decreased due to reductions in hepatic copper accumulation and consequently copper-induced hepatocyte toxicity. Conclusions: Our findings demonstrate that gene-corrected patient-specific iPSC-derived iHeps can rescue the in vitro and in vivo disease phenotypes of WD. These proof-of-principle data suggest that iHeps derived from gene-corrected WD iPSCs have potential use as an autologous ex vivo cell source for in vivo therapy of WD as well as other inherited liver disorders. Lay summary: Gene correction restored ATP7B function in hepatocytes derived from induced pluripotent stem cells that originated from a patient with Wilson’s disease. These gene-corrected hepatocytes are potential cell sources for autologous cell therapy in patients with Wilson’s disease.

Chemotherapy is the mainstream treatment modality for invasive breast cancer. Unfortunately, chemotherapy-associated adverse events can result in early termination of treatment. Paradoxical effects of chemotherapy are also sometimes observed, whereby prolonged exposure to high doses of chemotherapeutic agents results in malignant states resistant to chemotherapy. In this study, potential synergism between doxorubicin (DOX) and pulsed electromagnetic field (PEMF) therapy was investigated in: 1) MCF-7 and MDA-MB-231 cells in vitro; 2) MCF-7 tumors implanted onto a chicken chorioallantoic membrane (CAM) and; 3) human patient-derived and MCF-7 and MDA-MB-231 breast cancer xenografts implanted into NOD-SCID gamma (NSG) mice. In vivo, synergism was observed in patient-derived and breast cancer cell line xenograft mouse models, wherein PEMF exposure and DOX administration individually reduced tumor size and increased apoptosis and could be augmented by combined treatments. In the CAM xenograft model, DOX and PEMF exposure also synergistically reduced tumor size as well as reduced Transient Receptor Potential Canonical 1 (TRPC1) channel expression. In vitro, PEMF exposure alone impaired the survival of MCF-7 and MDA-MB-231 cells, but not that of non-malignant MCF10A breast cells; the selective vulnerability of breast cancer cells to PEMF exposure was corroborated in human tumor biopsy samples. Stable overexpression of TRPC1 enhanced the vulnerability of MCF-7 cells to both DOX and PEMF exposure and promoted proliferation, whereas TRPC1 genetic silencing reduced sensitivity to both DOX and PEMF treatments and mitigated proliferation. Chronic exposure to DOX depressed TRPC1 expression, proliferation, and responses to both PEMF exposure and DOX in a manner that was reversible upon removal of DOX. TRPC1 channel overexpression and silencing positively correlated with markers of epithelial-mesenchymal transition (EMT), including SLUG, SNAIL, VIMENTIN, and E-CADHERIN, indicating increased and decreased EMT, respectively. Finally, PEMF exposure was shown to attenuate the invasiveness of MCF-7 cells in correlation with TRPC1 expression. We thus demonstrate that the expression levels of TRPC1 consistently predicted breast cancer sensitivity to DOX and PEMF interventions and positively correlated to EMT status, providing an initial rationale for the use of PEMF-based therapies as an adjuvant to DOX chemotherapy for the treatment of breast cancers characterized by elevated TRPC1 expression levels.

COVID-19, derived from SARS-CoV-2, has resulted in millions of deaths and caused unprecedented socioeconomic damage since its outbreak in 2019. Although the vaccines developed against SARS-CoV-2 provide some protection, they have unexpected side effects in some people. Furthermore, new viral mutations reduce the effectiveness of the current vaccines. Thus, there is still an urgent need to develop potent non-vaccine therapeutics against this infectious disease. We recently established a series of detecting platforms to screen a large library of Chinese medicinal herbs and phytochemicals. Here, we reveal that the ethanolic extract of Evodiae Fructus and one of its components, rutaecarpine, showed promising potency in inhibiting the activity of 3C-like (3CL) protease, blocking the entry of the pseudo-typed SARS-CoV-2 (including wild-type and omicron) into cultured cells. In addition, inflammatory responses induced by pseudo-typed SARS-CoV-2 were markedly reduced by Evodiae Fructus extract and rutaecarpine. Together our data indicate that the herbal extract of Evodiae Fructus and rutaecarpine are potent anti-SARS-CoV-2 agents, which might be considered as a treatment against COVID-19 in clinical applications.

Abstract Background High-sensitivity troponin I (hs-Tnl) and B-type natriuretic peptide (BNP) are promising prognostic markers for coronary artery disease (CAD). This prospective cohort study investigated whether a combination of these cardiac biomarkers with conventional risk factors would add incremental value for the prediction of secondary major adverse cardiovascular events (MACEs) in patients with CAD, with and without type 2 diabetes mellitus (T2DM). Methods Baseline plasma level of hs-Tnl and BNP was measured in 2275 Chinese patients with stable CAD. Patients were monitored for new-onset of MACE over a median of 51 months. Cox proportional hazard model and area under the receiver operating characteristic curve (AUC) were used to assess the association of cardiac biomarkers with MACE and their predictive values in relationship with or without T2DM. Results During the follow up period 402 (18%) patients experienced a new-onset MACE with hs-Tnl and BNP level significantly higher than in those without MACE. In multivariable analyses, patients with elevated hs-Tnl (hazard ratio, 1.75 [95% CI 1.41–2.17]; P

Background: Global dissemination of SARS-CoV-2 Variants of Concern (VOCs) remains a concern. The aim of this study is to describe how mass testing and phylogenetic analysis successfully prevented local transmission of SARS-CoV-2 VOC in a densely populated city with low herd immunity for COVID-19. Methods: In this descriptive study, we conducted contact tracing, quarantine, and mass testing of the potentially exposed contacts with the index case. Epidemiological investigation and phylogeographic analysis were performed. Findings: Among 11,818 laboratory confirmed cases of COVID-19 diagnosed till 13th May 2021 in Hong Kong, SARS-CoV-2 VOCs were found in 271 (2.3%) cases. Except for 10 locally acquired secondary cases, all SARS-CoV-2 VOCs were imported or acquired in quarantine hotels. The index case of this SARS-CoV-2 VOC B.1.351 epidemic, an inbound traveler with asymptomatic infection, was diagnosed 9 days after completing 21 days of quarantine. Contact tracing of 163 contacts in household, hotel, and residential building only revealed 1 (0.6%) secondary case. A symptomatic foreign domestic helper (FDH) without apparent epidemiological link but infected by virus with identical genome sequence was subsequently confirmed. Mass testing of 0.34 million FDHs identified two more cases which were phylogenetically linked. A total of 10 secondary cases were identified that were related to two household gatherings. The clinical attack rate of household close contact was significantly higher than non-household exposure during quarantine (7/25, 28% vs 0/2051, 0%; p

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by MeCP2 mutations. Nonetheless, the pathophysiological roles of MeCP2 mutations in the etiology of intrinsic cardiac abnormality and sudden death remain unclear. In this study, we performed a detailed functional studies (calcium and electrophysiological analysis) and RNA-sequencing-based transcriptome analysis of a pair of isogenic RTT female patient-specific induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs) that expressed either MeCP2wildtype or MeCP2mutant allele and iPSC-CMs from a non-affected female control. The observations were further confirmed by additional experiments, including Wnt signaling inhibitor treatment, siRNA-based gene silencing, and ion channel blockade. Compared with MeCP2wildtype and control iPSC-CMs, MeCP2mutant iPSC-CMs exhibited prolonged action potential and increased frequency of spontaneous early after polarization. RNA sequencing analysis revealed up-regulation of various Wnt family genes in MeCP2mutant iPSC-CMs. Treatment of MeCP2mutant iPSC-CMs with a Wnt inhibitor XAV939 significantly decreased the β-catenin protein level and CACN1AC expression and ameliorated their abnormal electrophysiological properties. In summary, our data provide novel insight into the contribution of activation of the Wnt/β-catenin signaling cascade to the cardiac abnormalities associated with MeCP2 mutations in RTT.

Large-scale renewable photovoltaic (PV) and battery energy storage system (BESS) units are promising to be significant electricity suppliers in the future electricity market. A bidding model is proposed for PV-integrated BESS power plants in a pool-based day-ahead (DA) electricity market, in which the uncertainty of PV generation output is considered. In the proposed model, we consider the market clearing process as the external environment, while each agent updates the bid price through the communication with the market environment for its revenue maximization. A multiagent reinforcement learning (MARL) called win-or-learn-fast policy-hill-climbing (WoLF-PHC) is used to explore optimal bid prices without any information of opponents. The case study validates the computational performance of WoLF-PHC in the proposed model, while the bidding strategy of each participated agent is thereafter analyzed.