The protein phosphatase PC1 dephosphorylates and deactivates CatC to negatively regulate H2O2 homeostasis and salt tolerance in rice.

Catalase (CAT) is often phosphorylated and activated by protein kinases to maintain hydrogen peroxide (H2O2) homeostasis and protect cells against stresses, but whether and how CAT is switched off by protein phosphatases remains inconclusive. Here, we identified a manganese (Mn2+)-dependent protein phosphatase, which we named PHOSPHATASE OF CATALASE 1 (PC1), from rice (Oryza sativa L.) that negatively regulates salt and oxidative stress tolerance. PC1 specifically dephosphorylates CatC at Ser-9 to inhibit its tetramerization and thus activity in the peroxisome. PC1 overexpressing lines exhibited hypersensitivity to salt and oxidative stresses with a lower phospho-serine level of CATs. Phosphatase activity and seminal root growth assays indicated that PC1 promotes growth and plays a vital role during the transition from salt stress to normal growth conditions. Our findings demonstrate that PC1 acts as a molecular switch to dephosphorylate and deactivate CatC and negatively regulate H2O2 homeostasis and salt tolerance in rice. Moreover, knockout of PC1 not only improved H2O2-scavenging capacity and salt tolerance but also limited rice grain yield loss under salt stress conditions. Together, these results shed light on the mechanisms that switch off CAT and provide a strategy for breeding highly salt-tolerant rice.

Human amniotic mesenchymal stem cells-derived conditioned medium and exosomes alleviate oxidative stress-induced retinal degeneration by activating PI3K/Akt/FoxO3 pathway.

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly, which is primarily attributed to oxidative stress-induced damage to the retinal pigment epithelium (RPE). Human amniotic mesenchymal stem cells (hAMSC) were considered to be one of the most promising stem cells for clinical application due to their low immunogenicity, tissue repair ability, pluripotent potential and potent paracrine effects. The conditional medium (hAMSC-CM) and exosomes (hAMSC-exo) derived from hAMSC, as mediators of intercellular communication, play an important role in the treatment of retinal diseases, but their effect and mechanism on oxidative stress-induced retinal degeneration are not explored. Here, we reported that hAMSC-CM alleviated H2O2-induced ARPE-19 cell death through inhibiting mitochondrial-mediated apoptosis pathway in vitro. The overproduction of reactive oxygen species (ROS), alteration in mitochondrial morphology, loss of mitochondrial membrane potential and elevation of Bax/Bcl2 ratio in ARPE-19 cells under oxidative stress were efficiently reversed by hAMSC-CM. Moreover, it was found that hAMSC-CM protected cells against oxidative injury via PI3K/Akt/FoxO3 signaling. Intriguingly, exosome inhibitor GW4869 alleviated the inhibitory effect of hAMSC-CM on H2O2-induced decrease in cell viability of ARPE-19 cells. We further demonstrated that hAMSC-exo exerted the similar protective effect on ARPE-19 cells against oxidative damage as hAMSC-CM. Additionally, both hAMSC-CM and hAMSC-exo ameliorated sodium iodate-induced deterioration of RPE and retinal damage in vivo. These results first indicate that hAMSC-CM and hAMSC-exo protect RPE cells from oxidative damage by regulating PI3K/Akt/FoxO3 pathway, suggesting hAMSC-CM and hAMSC-exo will be a promising cell-free therapy for the treatment of AMD in the future.

Impact of homocysteine on acute ischemic stroke severity: possible role of aminothiols redox status.

BACKGROUND: Acute ischemic stroke (AIS) is one of the most common cerebrovascular diseases which accompanied by a disruption of aminothiols homeostasis. To explore the relationship of aminothiols with neurologic impairment severity, we investigated four aminothiols, homocysteine (Hcy), cysteine (Cys), cysteinylglycine (CG) and glutathione (GSH) in plasma and its influence on ischemic stroke severity in AIS patients. METHODS: A total of 150 clinical samples from AIS patients were selected for our study. The concentrations of free reduced Hcy (Hcy), own oxidized Hcy (HHcy), free reduced Cys (Cys), own oxidized Cys (cysteine, Cyss), free reduced CG (CG) and free reduced GSH (GSH) were measured by our previously developed hollow fiber centrifugal ultrafiltration (HFCF-UF) method coupled with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The concentration ratio of Hcy to HHcy (Hcy/HHcy), Cys to Cyss (Cys/Cyss) were also calculated. The neurologic impairment severity of AIS was evaluated using National Institutes of Health Stroke Scale (NIHSS). The Spearman correlation coefficient and logistic regression analysis was used to estimate and perform the correlation between Hcy, HHcy, Cys, Cyss, CG, GSH, Hcy/HHcy, Cys/Cyss and total Hcy with NIHSS score. RESULTS: The reduced Hcy and Hcy/HHcy was both negatively correlated with NIHSS score in AIS patients with P = 0.008, r=-0.215 and P = 0.002, r=-0.249, respectively. There was no significant correlation of Cys, CG, GSH, HHcy, Cyss, Cys/Cyss and total Hcy with NIHSS score in AIS patients with P value > 0.05. CONCLUSIONS: The reduced Hcy and Hcy/HHcy, not total Hcy concentration should be used to evaluate neurologic impairment severity of AIS patient.

Ten missteps in the management of inflammatory bowel disease in Asia: An expert report by the Asian Pacific Association of Gastroenterology Working Group on Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is rapidly emerging in the Asia Pacific region. However, there are many challenges in the diagnosis and management of this condition. The Asian Pacific Association of Gastroenterology (APAGE) Working Group on IBD conducted a round table meeting to identify 10 common mistakes in the management of IBD in Asia. To summarize, many physicians still over rely on a definitive histological diagnosis before starting treatment and do not fully establish disease extent such as perianal and proximal gastrointestinal involvement in Crohn's disease (CD) or extent of involvement in ulcerative colitis (UC). It is also essential to actively look for evidence of extra-intestinal manifestations, which may influence choice of therapy. In terms of conventional therapy, underuse of topical 5 aminosalicylates (5-ASAs) in UC and inappropriate dosing of corticosteroids are also important considerations. Acute severe UC remains a life-threatening condition and delay in starting rescue therapy after inadequate response to intravenous steroids is still common. Anti-tumor necrosis factors should be considered first line in all cases of complex perianal fistulizing CD. Most patients with IBD are on potent immunosuppressive therapy and should be screened for latent infections and offered vaccinations according to guidelines. Under-recognition and management of significant complications such as anemia, osteoporosis, malnutrition, and thromboembolism should also be addressed. Colonoscopy is still not properly performed for dysplasia/cancer surveillance and for evaluating post-op recurrence of CD. Another common misstep is inappropriate withdrawal of medications during pregnancy leading to increased complications for the mother and the newborn.

Structure-Guided Discovery of Diverse Cytotoxic Dimeric Xanthones/Chromanones from Penicillium chrysogenum C-7-2-1 and Their Interconversion Properties.

Xanthone-chromanone homo- or heterodimers are regarded as a novel class of topoisomerase (Topo) inhibitors; however, limited information about these compounds is currently available. Here, 14 new (1-14) and 6 known tetrahydroxanthone chromanone homo- and heterodimers (15-20) are reported as isolated from Penicillium chrysogenum C-7-2-1. Their structures and absolute configurations were unambiguously demonstrated by a combination of spectroscopic data, single-crystal X-ray diffraction, modified Mosher's method, and electronic circular dichroism analyses. Plausible biosynthetic pathways are proposed. For the first time, it was discovered that tetrahydroxanthones can convert to chromanones in water, whereas chromone dimerization does not show this property. Among them, compounds 5, 7, 8, and 16 exhibited significant cytotoxicity against H23 cell line with IC50 values of 6.9, 6.4, 3.9, and 2.6 µM, respectively.

H*ads dynamics engineering via bimetallic Pd-Cu@MXene catalyst for enhanced electrocatalytic hydrodechlorination.

Electrocatalytic hydrodechlorination (EHDC) is a promising approach to safely remove halogenated emerging contaminants (HECs) pollutants. However, sluggish production dynamics of adsorbed atomic H (H*ads) limit the applicability of this green process. In this study, bimetallic Pd-Cu@MXene catalysts were synthesized to achieve highly efficient removal of HECs. The alloy electrode (Pd-Cu@MX/CC) exhibited better EHDC performance in comparison to Pd@MX/CC electrode, resulting in diclofenac degradation efficiency of 93.3 ± 0.1%. The characterization analysis revealed that the Pd0/PdII ratio decreased by forming bimetallic Pd-Cu alloy. Density functional theory calculations further demonstrated the electronic configuration modulation of the Pd-Cu@MXene catalysts, optimizing binging energies for H* and thereby facilitating H*ads production and tuning the reduction capability of H*ads. Noteably, the amounts and reduction potential of H*ads for Pd-Cu@MXene catalysts were 1.5 times higher and 0.37 eV lower than those observed for the mono Pd electrode. Hence, the introduction of Cu into the Pd catalyst optimized the dynamics of H*ads production, thereby conferring significant advantages to EHDC reactions. This augmentation was underscored by the successful application of the alloy catalysts supported by MXene in EHDC experiments involving other HECs, which represented a new paradigm for EHDC for efficient recalcitrant pollutant removal by H*ads.

Association of blood urea nitrogen with all-cause and cardiovascular mortality in hyperlipidemia: NHANES 1999-2018.

OBJECTIVE: Although blood urea nitrogen (BUN) has a crucial impact on many diseases, its effect on outcomes in patients with hyperlipidemia remains unknown. The study aimed to investigate the relationships between BUN levels and all-cause and cardiovascular disease (CVD) mortality in individuals with hyperlipidemia. METHODS: This analysis comprised 28,122 subjects with hyperlipidemia from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018. The risk of BUN on mortality was evaluated using weighted Cox regression models. Additionally, to illustrate the dose-response association, the restricted cubic spline (RCS) was used. RESULTS: During the observation period, 4276 participant deaths were recorded, of which 1206 were due to CVD. Compared to patients with hyperlipidemia in the third BUN quintile, the hazard ratios (HRs) for all-cause mortality were 1.26 (95% CIs: 1.09, 1.45) and 1.22 (95% CIs: 1.09, 1.37) for patients in the first and fifth quintiles of BUN, respectively. The HRs for CVD mortality among patients in the fifth quintile of BUN were 1.48 (95% CIs: 1.14, 1.93). BUN levels were found to have a U-shaped association with all-cause mortality and a linear association with CVD mortality using restricted triple spline analysis. CONCLUSIONS: This study revealed that both low and high BUN levels in patients with hyperlipidemia are associated with heightened all-cause mortality. Furthermore, elevated BUN levels are also associated with increased CVD mortality. The findings indicate that patients with hyperlipidemia may face an elevated risk of death if they have abnormal BUN levels.

Ecological momentary assessment of digital food and beverage marketing exposure and impact in young adults: A feasibility study.

Unhealthy food marketing is contributing to the obesity epidemic, but real-time insights into the mechanisms of this relationship are under-studied. Digital marketing is growing and following food and beverage (F&B) brands on social media is common, but measurement of exposure and impact of such marketing presents novel challenges. Thus, this study aimed to evaluate the feasibility of collecting data on exposure and impact of digital F&B marketing (DFM) using a smartphone-based ecological momentary assessment (EMA) methodology. We hypothesized that DFM-induced food cravings would vary based on whether (or not) participants engaged with F&B brands online. Participants were Singapore residents (n = 95, 21-40 years), recruited via telephone from an existing cohort. Participants were asked to upload screenshots of all sightings of online F&B marketing messages for seven days, and answer in-app contextual questions about sightings including whether any cravings were induced. Participants provided a total of 1310 uploads (median 9 per participant, Q1-Q3: 4-21) of F&B marketing messages, 27% of which were provided on Day 1, significantly more than on other days (P < 0.001). Followers of food/beverage brands on social media encountered 25.6 percentage points (95% CI 11.4, 39.7) more marketing messages that induced cravings than participants who were not followers. University education was also associated with more (18.1 percentage points; 95% CI 3.1, 33.1) encounters with marketing messages that induced cravings. It was practical and acceptable to participants to gather insights into digital F&B marketing exposure and impact using EMA in young adults, although a shorter study period is recommended in future studies. Followers of food and beverage brands on social media appear to be more prone to experience cravings after exposure to digital F&B marketing.

p32/OPA1 axis-mediated mitochondrial dynamics contributes to cisplatin resistance in non-small cell lung cancer.

Cisplatin resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). p32 and OPA1 are the key regulators of mitochondrial morphology and function. This study aims to investigate the role of the p32/OPA1 axis in cisplatin resistance in NSCLC and its underlying mechanism. The levels of p32 protein and mitochondrial fusion protein OPA1 are higher in cisplatin-resistant A549/DDP cells than in cisplatin-sensitive A549 cells, which facilitates mitochondrial fusion in A549/DDP cells. In addition, the expression of p32 and OPA1 protein is also upregulated in A549 cells during the development of cisplatin resistance. Moreover, p32 knockdown effectively downregulates the expression of OPA1, stimulates mitochondrial fission, decreases ATP generation and sensitizes A549/DDP cells to cisplatin-induced apoptosis. Furthermore, metformin significantly downregulates the expressions of p32 and OPA1 and induces mitochondrial fission and a decrease in ATP level in A549/DDP cells. The co-administration of metformin and cisplatin shows a significantly greater decrease in A549/DDP cell viability than cisplatin treatment alone. Moreover, D-erythro-Sphingosine, a potent p32 kinase activator, counteracts the metformin-induced downregulation of OPA1 and mitochondrial fission in A549/DDP cells. Taken together, these findings indicate that p32/OPA1 axis-mediated mitochondrial dynamics contributes to the acquired cisplatin resistance in NSCLC and that metformin resensitizes NSCLC to cisplatin, suggesting that targeting p32 and mitochondrial dynamics is an effective strategy for the prevention of cisplatin resistance.

Effect of MVF Combined with FES on Limb Function Recovery and Fine Function Rehabilitation of Hemiplegic Patients after ACI.

Background: This study assesses the efficacy of mirror visual feedback (MVF) combined with functional electrical stimulation (FES) in rehabilitating limb function and fine motor skills in hemiplegic patients after acute cerebral infarction (ACI). Given the limited research in this area, this study aims to provide insights into innovative rehabilitation techniques. Methods: A randomized controlled trial was conducted on 106 post-ACI hemiplegic patients, split into two groups of 53 each. One group received conventional training plus FES, while the other group underwent MVF combined with FES. Key metrics like walking parameters, the modified Lindmark score, center of gravity movement speed, Fugl-Meyer Motor function (FMA) score, fall index, Berg score, and Time-Up-Go Time (TUGT) were measured to evaluate the effectiveness. Results: In the study, significant improvements were observed in the observation group compared to the control group. The Modified Lindmark Scores for sensory function, motor coordination, and total scores in the observation group improved to 6.85±0.72, 15.77±2.25, and 22.62±2.78 respectively post-treatment, surpassing the control group's scores of 5.77±0.68, 13.92±1.87, and 19.69±2.45. In terms of FMA score, fall index, Berg score, and TUGT time, the observation group showed remarkable improvement: the FMA score increased from 43.69±4.51 to 67.25±7.04, the fall index decreased from 55.74±8.76 to 42.08±5.97, the Berg score rose from 31.03±6.28 to 43.11±6.71, and the TUGT time was reduced from 30.78±6.59s to 18.57±3.26s. These changes were significantly better than those in the control group, with all P = .000, indicating statistically significant improvements. Conclusion: The results indicate that the combination of MVF and FES is more effective in improving limb function, hand fine movements, and balance in hemiplegic patients post-ACI compared to FES alone. This suggests that integrating MVF with FES may be a more beneficial approach in stroke rehabilitation. Future research is advised to explore larger sample sizes and long-term effects, offering guidance for developing more effective treatment and rehabilitation plans. This study suggests that integrating mirror visual feedback and functional electrical stimulation into stroke rehabilitation could significantly enhance recovery, potentially influencing clinical practices and rehabilitation policies. Future studies should explore the long-term effects, applicability to diverse patient groups, and cost-effectiveness of these combined therapies.

Synthesis and Antifungal Activity of Chalcone Derivatives Containing 1,3,4-Thiadiazole.

24 chalcone derivatives containing 1,3,4-thiadiazole were synthesized. The results of bioactivity tests indicated that some of the target compounds exhibited superior antifungal activities in vitro. Notably, the EC50 value of D4 was 14.4 µg/mL against Phomopsis sp, which was significantly better than that of azoxystrobin (32.2 µg/mL) and fluopyram (54.2 µg/mL). The in vivo protective activity of D4 against Phomopsis sp on kiwifruit (71.2 %) was significantly superior to azoxystrobin (62.8 %) at 200 µg/mL. The in vivo protective activities of D4 were 74.4 and 57.6 % against Rhizoctonia solani on rice leaf sheaths and rice leaves, respectively, which were slightly better than those of azoxystrobin (72.1 and 49.2 %) at 200 µg/mL. Scanning electron microscopy (SEM) results showed that the mycelial surface collapsed, contracted and grew abnormally after D4 treatment. Finally, the results were further verified by in vivo antifungal assay, fluorescence microscopy (FM) observation, determination of relative conductivity, membrane lipid peroxidation degree assay, and determination of cytoplasmic content leakage. Molecular docking results suggested that D4 could be a potential SDHI.

Promotion of self-directed learning abilities among Chinese medical students through preparing for career calling and enhancing teaching competencies in medical education: a cross-sectional study.

BACKGROUND: Medical students face a heavy burden as they are tasked with acquiring a vast amount of medical knowledge within a limited time frame. Self-directed learning (SDL) has become crucial for efficient and ongoing learning among medical students. However, effective ways to foster SDL ability among Chinese medical students are lacking, and limited studies have identified factors that impact the SDL ability of medical students. This makes it challenging for educators to develop targeted strategies to improve students' SDL ability. This study aims to assess SDL ability among Chinese medical students and examine the effects of career calling and teaching competencies on SDL ability, as well as the possible mechanisms linking them. METHODS: Data were collected from 3614 respondents (effective response rate = 60.11%) using cross-sectional online questionnaires and analyzed using IBM SPSS Statistics 22.0. The questionnaire comprised a Demographic Characteristics Questionnaire, Self-directed Learning Ability Scale (Cronbach's alpha = 0.962), Teaching Competencies Scale, and Career Calling Scale. RESULTS: The average SDL ability score of Chinese medical students was 3.68 ± 0.56, indicating a moderate level of SDL ability. The six factors of the Self-directed Learning Ability Scale-self-reflection, ability to use learning methods, ability to set study plans, ability to set studying objectives, ability to adjust psychological state, and willpower in studying-accounted for 12.90%, 12.89%, 12.39%, 11.94%, 11.34%, and 8.67% of the variance, respectively. Furthermore, career calling was positively associated with SDL learning ability (ß = 0.295, p < 0.001), and SDL learning ability was positively associated with teaching competencies (ß = 0.191, p < 0.01). Simple slope analysis showed that when the level of teaching competencies was higher, the influence of career calling on SDL ability was stronger. CONCLUSIONS: Chinese medical students' SDL ability has room for improvement. Medical students could strengthen their willpower in studying by setting milestones goals with rewards, which could inspire their motivation for the next goals. Teachers should guide students to learn experience to improve students' reflective ability. Educators play a crucial role in bridging the gap between career calling education and SDL ability enhancement, highlighting the significance of optimal teaching competencies. Colleges should focus on strengthening teachers' sense of career calling and teaching competencies.

An Aggregation-Induced Fluorescence Probe for Detection H2S and Its Application in Cell Imaging.

Monitoring hydrogen sulfide (H2S) in living organisms is very important because H2S acts as a regulator in many physiological and pathological processes. Upregulation of endogenous H2S concentration has been shown to be closely related to the occurrence and development of tumors, atherosclerosis, neurodegenerative diseases and diabetes. Herin, a novel fluorescent probe HND with aggregation-induced emission was designed. Impressively, HND exhibited a high selectivity, fast response (1 min) and low detection limit (0.61 µM) for H2S in PBS buffer (10 mM, pH = 7.42). Moreover, the reaction mechanism between HND and H2S was conducted by Job's plot, HR-MS, and DFT. In particular, HND was successfully employed to detect H2S in HeLa cells.

The structural and functional properties of hemp protein isolate-epigallocatechin-3-gallate biopolymer covalent complex during heating.

BACKGROUND: It is well known that hemp proteins have the disadvantages of poor solubility and poor emulsification. To improve these shortcomings, an alkali covalent cross-linking method was used to prepare hemp protein isolate-epigallocatechin-3-gallate biopolymer (HPI-EGCG) and the effects of different heat treatment conditions on the structure and emulsifying properties of the HPI-EGCG covalent complex were studied. RESULTS: The secondary and tertiary structures, solubility, and emulsification ability of the HPI-EGCG complexes were evaluated using particle size, zeta potential, circular dichroism (CD), and fluorescence spectroscopy indices. The results showed that the absolute value of zeta potential of HPI-EGCG covalent complex was the largest, 18.6 mV, and the maximum binding amount of HPI to EGCG was 29.18 µmol g-1 . Under heat treatment at 25-35 °C, the α-helix content was reduced from 1.87% to 0%, and the ß-helix content was reduced from 82.79% to 0% after the covalent binding of HPI and EGCG. The solubility and emulsification properties of the HPI-EGCG covalent complexes were improved significantly, and the emulsification activity index (EAI) and emulsion stability index (ESI) were increased by 2.77-fold and 1.21-fold, respectively. CONCLUSION: A new HPI-EGCG covalent complex was developed in this study to provide a theoretical basis for the application of HPI-EGCG in food industry. © 2023 Society of Chemical Industry.

Natural sesquiterpene quinone/quinols: chemistry, biological activity, and synthesis.

Covering: 2010 to 2021Sesquiterpene quinone/quinols (SQs) are characterized by a C15-sesquiterpenoid unit incorporating a C6-benzoquinone/quinol moiety. Numerous unprecedented carbon skeletons have been constructed with various connection patterns between the two parts. The potent anti-cancer, anti-inflammatory, anti-microbial, anti-viral, and fibrinolytic activities of SQs are associated with their diverse structures. The representative avarol has even entered the stage of clinical phase II research as an anti-HIV agent, and was developed as paramedic medicine against psoriasis. This review provides an overall summary of 558 new natural SQs discovered between 2010 and 2021, including seven groups and sixteen structure-type subgroups, which comprehensively recapitulates their chemical structures, spectral characteristics, source organisms, biological activities, synthesis, and biosynthesis, aiming to expand the application scope of this unique natural product resource.

UNOS Down-Staging Criteria for Liver Transplantation of Hepatocellular Carcinoma: Systematic Review and Meta-Analysis of 25 Studies.

BACKGROUND & AIMS: Down-staging is commonly used to select patients with hepatocellular carcinoma (HCC) beyond Milan criteria (MC) for liver transplantation (LT), but outcomes are heterogenous. We aimed to estimate pooled down-staging success rates, HCC recurrence, and overall survival (OS), stratified by criteria used for baseline tumor burden. METHODS: We searched Pubmed and EMBASE databases from inception until August 2021 for studies reporting down-staging success (reduction of tumor burden to within MC) and outcomes of adult HCC patients. In addition, we performed a pooled analysis using reconstructed individual participant data to obtain robust estimates for OS. RESULTS: We screened 1059 articles and included 25 articles involving 3997 patients. Overall, 55.16% (45.49%-64.46%) underwent successful down-staging, and 31.52% (24.03%-40.11%) received LT (by intention-to-treat analysis [ITT]). Among patients who received LT, 16.01% (11.80%-21.37%) developed HCC recurrence. Comparing studies that used the United Network for Organ Sharing Down-Staging (UNOS-DS) criteria versus studies beyond UNOS-DS or did not specify criteria, down-staging success (by ITT) was 83.21% versus 45.93%, P < .001; the proportion who received LT (by ITT) was 48.61% vs 28.60%, P = .030; and HCC recurrence (among patients who received LT) occurred in 9.06% versus 20.42%, P < .001. Among studies that used UNOS-DS criteria, ITT 1- and 5-year OS from the initiation of down-staging treatment was 86% and 58%, respectively, whereas 1- and 5-year post-LT OS was 94% and 74%, respectively. CONCLUSIONS: Among studies that adhered to UNOS-DS criteria, down-staging was successful in four-fifths of patients, >50% received LT, and post-LT outcomes were excellent. These data provide clinical validation for the utilization of UNOS-DS criteria.

Raising awareness of antimicrobial resistance: development of an 'antibiotic footprint calculator'.

Non-academic partners can be vital in successful public engagement activities on antimicrobial resistance. With collaboration between academic and non-academic partners, we developed and launched an open-access web-based application, the 'antibiotic footprint calculator', in both Thai and English. The application focused on a good user experience, addressing antibiotic overuse and its impact, and encouraging immediate action. The application was unveiled in joint public engagement activities. From 1 Nov 2021 to 31 July 2022 (9 month period), 2554 players estimated their personal antibiotic footprint by using the application.

Efficacy and safety of tirzepatide for treatment of overweight or obesity. A systematic review and meta-analysis.

BACKGROUND: Recent studies suggest that tirzepatide, a dual glucose-dependent insulinotropic-peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA), has significant weight loss effects. This systematic review and meta-analysis aims to assess the efficacy and safety of tirzepatide for weight loss in patients with overweight or obesity. METHODS: Medline, Embase and Cochrane CENTRAL were searched for randomized controlled trials (RCTs) on tirzepatide's weight loss efficacy for these patients. A single arm meta-analysis of proportions estimated primary outcomes, ≥5%, ≥10%, and ≥15% weight loss, and adverse events (AEs); while meta-analysis of means estimated secondary outcomes. Comparative meta-analysis was conducted between tirzepatide and control arms where mean differences and odds ratios were estimated for continuous and dichotomous outcomes respectively. RESULTS: RCTs included in this study revealed that among 5800 patients, 78.22% (95% CI: 72.15% to 83.73%), 55.60% (95% CI: 46.54% to 64.47%), 32.28% (95% CI: 23.17% to 42.12%) achieved ≥5%, ≥10%, and ≥15% weight loss, respectively. Tirzepatide 5 mg demonstrated weight loss superiority relative to placebo (MD: -12.47 kg, 95% CI: -13.94 kg to -11.00 kg) and semaglutide (n = 1409, MD: -1.90 kg, 95% CI: -2.97 kg to -0.83 kg) with dose-dependent increase for 10 mg and 15 mg doses. The comparison between tirzepatide and semaglutide was examined in the SURPASS-2 trial that was included in this systematic review. For AEs, there was increase odds of experiencing gastrointestinal AEs with tirzepatide compared to placebo, but no significant difference with semaglutide. CONCLUSION: Tirzepatide has significant potential as a weight loss drug in patients with overweight and obesity, with little increase in AEs compared to other weight loss drugs. With its ability to concurrently target multiple aspects of metabolic syndrome, it should be considered as the next helm of weight loss therapies.

CRISPRi-microfluidics screening enables genome-scale target identification for high-titer protein production and secretion.

Genome-scale target identification promises to guide microbial cell factory engineering for higher-titer production of biomolecules such as recombinant proteins (r-protein), but challenges remain due to the need not only for comprehensive genotypic perturbation but also in conjunction with high-throughput phenotypic screening strategies. Here, we developed a CRISPRi-microfluidics screening platform to systematically identify crucial gene targets that can be engineered to enhance r-protein secretion in Corynebacterium glutamicum. We created a CRISPR interference (CRISPRi) library containing 46,549 single-guide RNAs, where we aimed to unbiasedly target all genes for repression. Meanwhile, we developed a highly efficient droplet-based microfluidics system integrating the FlAsH-tetracysteine assay that enables screening of millions of strains to identify potential knockdowns conducive to nanobody VHH secretion. Among our highest-ranking candidates are a slew of previously unknown targets involved in transmembrane transport, amino-acid metabolism and redox regulation. Guided by these findings, we eventually constructed a hyperproducer for multiple proteins via combinatorial engineering of redox-response transcription factors. As the near-universal applicability of CRISPRi technology and the FlAsH-based screening platform, this procedure might be expanded to include a varied variety of microbial species and recombinant proteins.

Efficacy and safety profile of angiotensin receptor neprilysin inhibitors in the management of heart failure: a systematic review and meta-analysis of randomized controlled trials.

Several guidelines have recommended the use of angiotensin receptor neprilysin inhibitors (ARNIs) as replacement for angiotensin-converting enzyme inhibitors in the management of heart failure. Till date, there are no reviews done that comprehensively cover different aspects of efficacy and safety parameters. Hence, we have performed a comprehensive systematic review and meta-analysis on role of ARNIs for the management of heart failure patients. Searches were done in Embase, Scopus, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, PubMed Central, Cochrane Library, MEDLINE, Google Scholar, ScienceDirect and Clinicaltrials.gov until June 2022. Risk of bias assessment was done with Cochrane's risk of bias tool. Meta-analysis was carried out using random-effects model. Pooled standardized mean difference (SMD)/mean difference (MD) and/or risk ratio (RR) with 95% confidence intervals (CIs) was reported. In total, we analysed 34 studies, with almost all of them had a high risk of bias. Pooled RR was 0.88 (95% CI: 0.82-0.95) for all-cause mortality, 0.84 (95% CI: 0.77-0.92) for cardiovascular mortality and 0.78 (95% CI: 0.70-0.87) for hospitalization. Pooled MD was 3.74 (95% CI: 1.93-5.55) for left ventricular ejection fraction, -2.16 (95% CI: -3.58 to -0.74) for left atrial volume index, -3.80 (95% CI: -6.60 to -1.00) for left ventricular end-diastolic dimension and -1.16 (95% CI: -1.98 to -0.35) for E/E' ratio. Regarding adverse events, pooled RR was 1.55 (95% CI: 1.31-1.85) for symptomatic hypotension, 0.93 (95% CI: 0.78-1.11) for worsening renal function, 1.09 (95% CI: 0.94-1.26) for hyperkalaemia and 1.29 (95% CI: 0.67-2.50) for angioedema. ARNIs had beneficial efficacy and safety profile on the management of heart failure especially patients with reduced ejection fraction.