Investigation on the binding behavior of human α1-acid glycoprotein with Janus Kinase inhibitor baricitinib: Multi-spectroscopic and molecular simulation methodologies.

Baricitinib is a Janus Kinase (JAK) inhibitor that is primarily used to treat moderately to severely active rheumatoid arthritis in adults and has recently been reported for the treatment of patients with severe COVID-19. This paper describes the investigation of the binding behavior of baricitinib to human α1-acid glycoprotein (HAG) employing a variety of spectroscopic techniques, molecular docking and dynamics simulations. Baricitinib can quench the fluorescence from amino acids in HAG through a mix of dynamic and static quenching, according to steady-state fluorescence and UV spectra observations, but it is mainly static quenching at low concentration. The binding constant (Kb) of baricitinib to HAG at 298 K was at the level of 104 M-1, indicating a moderate affinity of baricitinib to HAG. Hydrogen bonding and hydrophobic interactions conducted the main effect, according to thermodynamic characteristics, competition studies between ANS and sucrose, and molecular dynamics simulations. For the change in HAG conformation, the results of multiple spectra showed that baricitinib was able to alter the secondary structure of HAG as well as increase the polarity of the microenvironment around the Trp amino acid. Furthermore, the binding behavior of baricitinib to HAG was investigated by molecular docking and molecular dynamics simulations, which validated experimental results. Also explored is the influence of K+, Co2+, Ni2+, Ca2+, Fe3+, Zn2+, Mg2+ and Cu2+plasma on binding affinity.

Relative validity of a Diet Risk Score (DRS) for Chinese American adults

ObjectiveThe objective of this study was to evaluate the relative validity of the nine-item Diet Risk Score (DRS) among Chinese American adults using Healthy Eating Index (HEI)-2015 scores. We provide insights into the application of the Automated Self-Administered 24-Hour Dietary Assessment Tool (ASA24) for this population, and report on lessons learned from carrying out participant recruitment during the COVID-19 pandemic.MethodsThirty-three Chinese American adults (mean age=40;36% male) were recruited from the community and through ResearchMatch. Participants completed the DRS and two 24-hour food records, which were entered into the ASA 24-Hour Dietary Assessment Tool (ASA24) by community health workers (CHWs). HEI-2015 scores were calculated from each food record and an average score was obtained for each participant. One-way analysis of variance and Spearman correlations were used to compare total and component scores between the DRS and HEI-2015.ResultsMean HEI-2015 score was 56.7/100 (SD 10.6) and mean DRS score was 11.8/27 (SD 4.7), with higher scores reflecting better and worse diets, respectively. HEI-2015 and DRS scores were inversely correlated (r=−0.43, p<0.05). The strongest correlations were between HEI-2015 Total Vegetables and DRS Vegetables (r=−0.5, p<0.01), HEI-2015 Total Vegetables and Green Vegetables (r=−0.43, p=0.01) and HEI-2015 Seafood/Plant Protein and DRS Fish (r=−0.47, p<0.01). The inability to advertise and recruit for the study in person at community centres due to pandemic restrictions impeded the recruitment of less-acculturated individuals. A lack of cultural food items in the ASA24 database made it difficult to record dietary intake as reported by participants.ConclusionThe DRS can be a valuable tool for physicians to identify and reach Chinese Americans at risk of cardiometabolic disease.

Lack of STAT6 enhances murine acute lung injury through NLRP3/p38 MAPK signaling pathway in macrophages.

BACKGROUND: Signal transducer and activator of transcription 6 (STAT6) is an intracelluar transcriotion factor and NLRP3 (Nod-like receptor containing a pyrin domain 3) is a component of NLRP3 inflammasome in pyroptotic cells. There was increased activation of STAT6 and expression of NLRP3 in mice with murine acute lung injury (ALI). However, it is unknown their roles in the development of murine ALI. We in this study, investigated the effects of STAT6 signaling on murine ALI and pyroptosis in STAT6 knock-out (KO) mice and macrophages. RESULTS: STAT6 was activated in the lung tissues of mice 2 days after intratracheal treatmemt with 5 mg/kg LPS. Lack of STAT6 expression in KO mice induced more severe lung inflammation, associated with elevated neutrophil influx and expression of TNF-alpha, IL-6 and IL-1beta in the inflamed lung tissues. In addition, the expression of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD), p-p38 MAPK (p38 mitogen-activated protein kinase) and ratio of LC3-II/I (microtubule-associated protein-1 light chain-3) was increased, accompanied with the increased polarization of Siglec-F(-) subtype macrophages in KO mice with ALI. Further studies in bone marrow-derived macrophages (BMDMs) revealed that lack of STAT6 increased the expression of NLRP3 and p-p38 MAPK, in association with elevated expression of TNF-alpha, IL-1beta and Calreticulin in LPS-treated KO BMDMs. CONCLUSIONS: Lack of STAT6 exacerbated murine ALI through improving the expression of NLRP3 and activation of p38 MAPK in macrophages. STAT6 has an immune suppressive role in the development of ALI and would be a promising therapeutic target in the treatment of ALI and possibly among patients with acute respiratory distress syndrome (ARDS).

A Social Media-Based Intervention Improves Glycemic Control in a Low-Income Older Immigrant Population

Purpose: Access to in-person diabetes self-management education (DSME) programs is limited in underserved immigrant communities. In this report, we examined the feasibility, acceptability, and potential efficacy of a social media-based DSME intervention in low-income older Chinese immigrants with type 2 diabetes (T2D). Methods: This was a single-group study in 30 Chinese immigrants with T2D living in NYC. The intervention included 24 culturally and linguistically tailored DSME videos. Over 12 weeks, participants received 2 brief videos each week via WeChat, a free social media app popular among Chinese immigrants. Feasibility was defined as ability to achieve: 1) the recruitment goal (n=30);2) >80% retention;and 3) >80% watch rate. Acceptability was assessed via a satisfaction survey at 6 months. HbA1c was collected at baseline and 6 months Results: Recruitment was completed prior to the NYC COVID-19 lockdown. Despite COVID-19, the intervention continued without interruption. Participants were mostly female (70.0%), married (63.3%), with limited English proficiency (86.7%), and a mean age of 61.2 (SD=6.7) years old. Most reported an annual household income of < $25,000 (84.0%) and an education of high school or less (63.3%). Thirty participants were recruited within 2 months, 93.3% were retained at 6 months, and a video watch rate of 92.2% was achieved. The mean baseline HbA1c was 7.4% (SD=1.2) and declined by 0.6% (95% CI: 0.3%-0.9%, p=0.001) to 6.8% (SD=0.8) at 6 months. Participants expressed high satisfaction (96.4%), and all strongly agreed or agreed that they preferred this video-based DSME to face-to-face visits. Conclusions: This pilot study demonstrated that a social media-based DSME intervention is feasible, acceptable, and potentially efficacious in an aging low-income immigrant population with T2D. These findings provide timely implications in the era of COVID-19, suggesting older low-income immigrants can be engaged in mHealth interventions.

Challenges of conducting a remote behavioral weight loss study: Lessons learned and a practical guide.

OBJECTIVES: To describe challenges and lessons learned in conducting a remote behavioral weight loss trial. METHODS: The Personal Diet Study is an ongoing randomized clinical trial which aims to compare two mobile health (mHealth) weight loss approaches, standardized diet vs. personalized feedback, on glycemic response. Over a six-month period, participants attended dietitian-led group meetings via remote videoconferencing and were encouraged to self-monitor dietary intake using a smartphone app. Descriptive statistics were used to report adherence to counseling sessions and self-monitoring. Challenges were tracked during weekly project meetings. RESULTS: Challenges in connecting to and engaging in the videoconferencing sessions were noted. To address these issues, we provided a step-by-step user manual and video tutorials regarding use of WebEx, encouraged alternative means to join sessions, and sent reminder emails/texts about the WebEx sessions and asking participants to join sessions early. Self-monitoring app-related issue included inability to find specific foods in the app database. To overcome this, the study team incorporated commonly consumed foods as "favorites" in the app database, provided a manual and video tutorials regarding use of the app and checked the self-monitoring app dashboard weekly to identify nonadherent participants and intervened as appropriate. Among 135 participants included in the analysis, the median attendance rate for the 14 remote sessions was 85.7% (IQR: 64.3%-92.9%). CONCLUSIONS: Experience and lessons shared in this report may provide critical and timely guidance to other behavioral researchers and interventionists seeking to adapt behavioral counseling programs for remote delivery in the age of COVID-19.

Comparative study of the lymphocyte change between COVID-19 and non-COVID-19 pneumonia cases suggesting uncontrolled inflammation might not be the main reason of tissue injury (preprint)

Background: The corona virus disease 2019 (COVID-19) shows unusually high transmission rate and unique clinical characteristics, with key pathological mechanism remaining unclear. Here, we analysed the laboratory data based on clinical samples from COVID-19 patients, in parallel comparison with non-COVID-19 pneumonia cases, in an attempt to elucidate the key pathological features of COVID-19 during its infection of the human body. Methods: We analysed biochemical indices and lymphocyte subpopulation in COVID-19 patients, and compare these data from non-COVID-19 pneumonia cases. Correlation analysis was performed between leukocyte subgroups count and biochemical indexes in COVID-19 patients. Results: The study enrolled 110 patients, comprising 88 COVID-19 patients and 22 non-COVID-19 pneumonia cases. We observed significant differences, including abnormal biochemical indices (CRP, LDH, AST, eGFR, and sodium ion concentration) and reduced lymphocyte subsets count, between the COVID-19 patients and non-COVID-19-caused pneumonia cases. Correlation analysis indicates that the count for lymphocyte subsets-but not that for neutrophils and monocytes-exhibits a significant negative correlation with biochemical indices relating to organ injury, in the COVID-19 infected patients. Conclusions: The study indicates significantly different clinical features between 2019 novel coronavirus (2019-nCoV)-caused and non-2019-nCoV-caused pneumonia, especially in terms of lymphocytopenia and organ injury. Notably, correlation analysis demonstrates that tissue damage in COVID-19 patients is attributed to virus infection itself rather than uncontrolled inflammatory responses ("cytokine storm"). These findings provide new insights for developing efficient therapeutic strategies against COVID-19 infection.