Building a highly efficient Streptomyces super-chassis for secondary metabolite production by reprogramming naturally-evolved multifaceted shifts.

Streptomyces has an extensive array of bioactive secondary metabolites (SMs). Nevertheless, devising a framework for the heterologous production of these SMs remains challenging. We here reprogrammed a versatile plug-and-play Streptomyces super-chassis and established a universal pipeline for production of diverse SMs via understanding of the inherent pleiotropic effects of ethanol shock on jadomycin production in Streptomyces venezuelae. We initially identified and characterized a set of multiplex targets (afsQ1, bldD, bldA, and miaA) that contribute to SM (jadomycin) production when subjected to ethanol shock. Subsequently, we developed an ethanol-induced orthogonal amplification system (EOAS), enabling dynamic and precise control over targets. Ultimately, we integrated these multiplex targets into functional units governed by the EOAS, generating a universal and plug-and-play Streptomyces super-chassis. In addition to achieving the unprecedented titer and yield of jadomycin B, we also evidenced the potential of this super-chassis for production of diverse heterologous SMs, including antibiotic oxytetracycline, anticancer drug doxorubicins, agricultural herbicide thaxtomin A, and plant growth regulator guvermectin, all with the yields of >10 mg/g glucose in a simple mineral medium. Given that the production of SMs all required complexed medium and the cognate yields were usually much lower, our achievement of using a universal super-chassis and engineering pipeline in a simple mineral medium is promising for convenient heterologous production of SMs.

Exploring the Effects of Online Physician Voice Pitch Range and Filled Pauses on Patient Satisfaction in Mobile Health Communication.

The convenience of mobile devices has driven the widespread use of voice technology in mobile health communication, significantly improving the timeliness of online service. However, the issue of listening to therapeutic content, which requires great cognitive effort and may exceed the patient's information processing capacity (i.e., information overload), is of concern. Based on information processing theory, this study reports how online physicians' voice characteristics (pitch range and filled pauses) affect patient satisfaction. We obtained 10,585 mobile voice consultation records of 1,416 doctors from China's largest mHealth platform and analyzed them using audio mining and empirical methods. Results showed that pitch range (ß = 0.0539, p < .01) and filled pauses (ß = 0.0365, p < .01) in doctors' voice positively influenced online patient satisfaction. However, the effect of filled pauses becomes weaker for patients with higher health literacy and higher disease risk. This suggests that there is heterogeneity in the way different patients process audio information. This study provides important insights for guiding online physician behaviors, enhancing patient satisfaction, and improving mobile health platform management.

Association of geriatric nutritional risk index with bone mineral density and osteoporosis in postmenopausal elderly women with T2DM.

BACKGROUND AND OBJECTIVES: To investigate the relationship between geriatric nutritional risk index (GNRI) and osteoporosis (OP) in postmenopausal elderly women with type 2 diabetes mellitus (T2DM). METHODS AND STUDY DESIGN: A total of 141 postmenopausal elderly women with T2DM was divided into OP and normal bone mineral density (BMD) groups, the differences in GRNI levels between the two groups were compared. According to the tertile levels of GRNI, T2DM were divided into three groups (T1, T2, T3 groups), and the differences in OP prevalence and levels of BMD among the three groups were compared. RESULTS: Among postmenopausal elderly women with T2DM, GNRI levels were lower in the OP group compared to the nor-mal BMD group [(103±5.46) vs. (105±5.46), p<0.05)]. With elevated GNRI levels, the BMD levels of femoral, total hip, total body, and lumbar vertebrae (L) were gradually increased, which were higher in the T3 group than in the T1 group (all p< 0.05). GNRI levels were positively correlated with the BMD levels of femoral, spine, total hip, total body, L1, L2, L3, L4, and L1-L4. GNRI was an independent influencing factor for the occurrence of OP (OR=0.887, 95%CI [0.795,0.988]). The ROC curve showed that the GNRI combined with serum ALP and P levels had a high predictive value for OP, with an area under the curve of 0.725 (p<0.01). CONCLUSIONS: In postmenopausal elderly women with T2DM, GNRI was independently and positively correlated with BMD levels. GNRI may be a predictor development of OP.

Development and characterization of a novel mouse anti-canine oncostatin M receptor beta monoclonal antibody.

Oncostatin M receptor beta (OSMRß) mediates signaling of Oncostatin M (OSM) and interleukine-31 (IL-31), two key cytokines involved in many important biological processes including inflammation and cancer progression. More importantly, OSMRß might be a potential biomarker and therapeutic target for some diseases, such as inflammatory bowel disease, pruritus and ovarian cancer. In this study, soluble recombinant canine OSMRß (cOSMRß) was experimentally expressed as a native antigen to develop an effective cOSMRß-specific monoclonal antibody (mAb), 2O2, using hybridoma technology. It was demonstrated that 2O2 is able to detect OSMRß expressed on cell surface using immunofluorescence assay (IFA) and flow cytometry (FACS). This mAb exhibits very high binding affinity to cOSMRß with the KD and half-maximal effective concentration (EC50) values of 2.49 nM and 96.96 ng/ml, respectively. Meanwhile, it didn't show any cross-relativities with feline OSMRß (fOSMRß) and human OSMRß (hOSMRß). Moreover, we determined the binding epitope of 2O2, which localizes in the domain VI (DVI, amino acids 623-734) of cOSMRß. In conclusion, this novel mAb, 2O2, can be used in immunoassays, including IFA, FACS and enzyme-linked immunosorbent assay (ELISA) to facilitate studies in dogs.

Targeting FAM134B-mediated reticulophagy activates sorafenib-induced ferroptosis in hepatocellular carcinoma.

Ferroptosis is a kind of cell death closely related to selective autophagy, such as ferritinophagy, lipophagy, clockophagy and chaperone-mediated autophagy. However, the role of reticulophagy, which specifically degrades endoplasmic reticulum (ER) fragments (also known as ER-phagy), in ferroptosis regulation is still unclear. In this study, we found that sorafenib (ferroptosis inducer) can effectively activate the receptor protein FAM134B-mediated ER-phagy, and FAM134B knockdown not only blocked ER-phagy but also significantly strengthened cellular sensitivity to ferroptosis without affecting macroautophagy. In vivo experiments also yielded similar results. These evidences provided new clues for ferroptosis regulation. Subsequently, bioinformatic analysis combined with RNA binding protein immunoprecipitation and polyribosome fractionation preliminarily indicated that PABPC1 can interact with FAM134B mRNA and promote its translation. Taken together, this study revealed the role of the PABPC1-FAM134B-ER-phagy pathway on ferroptosis, providing important evidence for novel anti-cancer strategies.

Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials.

BACKGROUND: To investigate whether metformin monotherapy or adjunctive therapy improves the prognosis in patients with any type of cancer compared to non-metformin users (age ≥18). METHODS: Databases (Medline, Embase, and the Cochrane Central Register of Controlled Trials) and clinical trial registries ( ClinicalTrials.gov ; the World Health Organization International Clinical Trials Registry Platform) were screened for randomized, controlled trials (RCT) reporting at least progression-free survival (PFS) and/or overall survival (OS). Main outcome measures included hazard ratios (HR), and combined HRs and 95% confidence intervals (CI) were calculated using random-effects models. RESULTS: Of the 8419 records screened, 22 RCTs comprising 5943 participants were included. Pooled HRs were not statistically significant in both PFS (HR 0.97, 95% CI 0.82-1.15, I2 = 50%) and OS (HR 0.98, 95% CI 0.86-1.13, I2 = 33%) for patients with cancer between the metformin and control groups. Subgroup analyses demonstrated that metformin treatment was associated with a marginally significant improvement in PFS in reproductive system cancers (HR 0.86, 95% CI 0.74-1.00) and a significantly worse PFS in digestive system cancers (HR 1.45, 95% CI 1.03-2.04). The PFS or OS was observed consistently across maintenance dose, diabetes exclusion, median follow-up, risk of bias, and combined antitumoral therapies. CONCLUSION: Metformin treatment was not associated with cancer-related mortality in adults compared with placebo or no treatment. However, metformin implied beneficial effects in the PFS of the patients with reproductive system cancers but was related to a worse PFS in digestive system cancers. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42022324672.

Relationship between prevalence and risk of osteoporosis or osteoporotic fracture with non-alcoholic fatty liver disease: A systematic review and meta-analysis.

The aim of this study was to investigate the relationship between prevalence and risks of osteoporosis or osteoporotic fracture and NAFLD. Patients with NAFLD should be monitored regularly for bone mineral density and bone metabolism indicators to prevent osteoporosis or osteoporotic fractures. OBJECTIVES: The aim of this meta-analysis was to investigate the relationship between prevalence and risks of osteoporosis or osteoporotic fracture and non-alcoholic fatty liver disease (NAFLD). METHODS: Five databases, including PubMed, Web of Science, Embase, Scopus and Cochrane Library, were searched since the conception of these databases until December 2021. The cohort studies, cross-sectional analyses or case-control studies evaluating the relationship between osteoporosis or osteoporotic fracture and NAFLD were retrieved from these databases. Relevant data were extracted from the included studies, and a meta-analysis was performed. RESULTS: A total of seven studies were included. The prevalence of osteoporosis or osteoporotic fractures was higher in the NAFLD group than in the non-NAFLD group [OR = 1.17, 95%CI(1.04,1.31)], while the prevalence of osteoporosis was higher in the NAFLD group than in the non-NAFLD group [OR = 1.46, 95%CI (1.21,1.77) and OR = 1.48, 95%CI (1.31,1.68), respectively] in men and women. The risk of osteoporosis or osteoporotic fractures was higher in the NAFLD group than in the non-NAFLD group [OR = 1.33,95%CI (1.24,1.44) and OR = 1.57,95%CI (1.08,2.29), respectively]. The risk of osteoporosis or osteoporotic fractures was higher in male and female NAFLD groups than that in the non-NAFLD group [OR = 1.29, 95%CI(1.14,1.47) and OR = 1.36, 95%CI (1.25,1.48), respectively]. After parameter adjustment, the risk of osteoporosis or osteoporotic fracture was higher in the male NAFLD group than in the non-NAFLD group [OR = 2.10, 95%CI(1.36,3.25)], while no significant difference was found among women [OR = 1.13, 95%CI (0.86,1.48)]. CONCLUSIONS: The prevalence and risk of osteoporosis or osteoporotic fractures were significantly associated with NAFLD in men and women. TRIAL REGISTRATION: PROSPERO 2022 CRD42022304708.

Relationship between iron metabolism and gestational diabetes mellitus: A systemic review and meta analysis.

BACKGROUND AND OBJECTIVES: To investigate the relationship between serum iron metabolism indexes and gestational diabetes mellitus (GDM) using a meta-analysis. METHODS AND STUDY DESIGN: Databases including PubMed, Web of Science, Embase, and Cochrane Library were searched. Prospective cohort or case-control studies evaluating the relationships between serum iron metabolism indexes and GDM were retrieved from these data-bases. The outcome indicators, such as mean ± standard deviation, relative risk (RR), or odds ratio (OR) were extracted. The RR or OR, standard mean difference (SMD), and 95% confidence interval (CI) were used to calculate the combined effect sizes. RESULTS: A total of 32 studies on the relationships between serum iron metabolic indexes and GDM were included. The serum iron [SMD=0.40 mg/dL, 95% CI (0.16, 0.64), p=0.001], ferritin [SMD=0.58 ng/mL, 95% CI (0.35, 0.81), p˂0.001], hemoglobin [SMD=0.48 g/dL, 95% CI (0.28, 0.67), p˂0.001], transferrin saturation [SMD=0.83%, 95% CI (0.15, 1.52), p=0.000], and hepcidin [SMD=0.63 ng/mL, 95% CI (0.09, 1.18), p=0.023] levels were higher in the GDM group than in the non-GDM group, whereas total iron binding ability [SMD = -0.53 µg/dL, 95% CI (-1.05, -0.02), p=0.001] was lower in the GDM group than in the non-GDM group. High serum ferritin [OR=1.92, 95% CI (1.59, 2.32), p˂0.001] and hemoglobin levels [OR=1.30, 95% CI (1.04,1.63), p=0.023] were associated with GDM risk. CONCLUSIONS: Serum iron, ferritin, transferrin saturation, hepcidin, and hemoglobin levels were higher and total iron binding ability was lower in GDM patients than in those without GDM. High serum ferritin and hemoglobin levels were associated with GDM risk.

Full-Scale Clinical Data and Reshaped Intestinal Microbiome on a Short-Term Low-Phosphorus Diet among Healthy Adults.

OBJECTIVES: During the past few decades, phosphorus intake has dramatically increased along with higher protein intake and overuse of inorganic phosphate additives worldwide. The detrimental effects of overconsumption of phosphorus are well recognized for patients with chronic kidney disease (CKD), and dietary phosphorus restriction was recommended for these patients. However, the effects of dietary phosphorus restriction in healthy people have not been fully studied. METHODS: In this open-label crossover study, healthy adult men (n = 12) consumed normal phosphorus diet (NPD, 1,500 mg/d) for five days. After a 10-day washout period, healthy adults took low phosphorus diet (LPD, 500 mg/d) for another five days. On the fifth day of each intervention, blood, urine and saliva samples were collected at ten time points, and fecal specimens were collected for bacterial taxa identification. RESULTS: We found that 24-h mean levels of serum phosphate (Pi), urinary Pi, serum parathyroid hormone and fibroblast growth factor 23 decreased, while serum calcium (Ca) and 1,25-dihydroxy vitamin D increased significantly under LPD compared with those under NPD. Dietary phosphorus intake did not change salivary Pi, urinary Ca, salivary Ca and magnesium (Mg) metabolism. Compared with NPD, LPD increased the relative abundance of beneficial microbes including Bacteroidetes, Ruminococcaceae and Lachnospiraceae, indicating that multiple bacterial metabolic pathways have been shifted. CONCLUSIONS: Full-scale data of dietary phosphorus restriction on Pi, Ca and Mg metabolism in healthy male adults are provided. More importantly, for the first time, dietary phosphorus restriction was found to reshape the intestinal microbiome, which provides information for benefits of dietary phosphorus restriction in healthy people, and potential clues for treating patients with CKD.

Iron down-regulates leptin by suppressing protein O-GlcNAc modification in adipocytes, resulting in decreased levels of O-glycosylated CREB.

We previously reported that iron down-regulates transcription of the leptin gene by increasing occupancy of phosphorylated cAMP response element-binding protein (pCREB) at two sites in the leptin gene promoter. Several nutrient-sensing pathways including O-GlcNAcylation also regulate leptin. We therefore investigated whether O-glycosylation plays a role in iron- and CREB-mediated regulation of leptin. We found that high iron decreases protein O-GlcNAcylation both in cultured 3T3-L1 adipocytes and in mice fed high-iron diets and down-regulates leptin mRNA and protein levels. Glucosamine treatment, which bypasses the rate-limiting step in the synthesis of substrate for glycosylation, increased both O-GlcNAc and leptin, whereas inhibition of O-glycosyltransferase (OGT) decreased O-GlcNAc and leptin. The increased leptin levels induced by glucosamine were susceptible to the inhibition by iron, but in the case of OGT inhibition, iron did not further decrease leptin. Mice with deletion of the O-GlcNAcase gene, either via whole-body heterozygous deletion or through adipocyte-targeted homozygous deletion, exhibited increased O-GlcNAc levels in adipose tissue and increased leptin levels that were inhibited by iron. Of note, iron increased the occupancy of pCREB and decreased the occupancy of O-GlcNAcylated CREB on the leptin promoter. These patterns observed in our experimental models suggest that iron exerts its effects on leptin by decreasing O-glycosylation and not by increasing protein deglycosylation and that neither O-GlcNAcase nor OGT mRNA and protein levels are affected by iron. We conclude that iron down-regulates leptin by decreasing CREB glycosylation, resulting in increased CREB phosphorylation and leptin promoter occupancy by pCREB.

CircBACH1 (hsa_circ_0061395) promotes hepatocellular carcinoma growth by regulating p27 repression via HuR.

In recent years, an increasing number of circular RNAs (circRNAs) have been discovered in hepatocellular carcinoma (HCC). However, the functions of most circRNAs require further investigation. Here, we found that circBACH1 was significantly upregulated in HCC tissues and that high circBACH1 levels were closely associated with poor prognosis. In addition, circBACH1 could promote HCC growth by accelerating cell cycle progression in vitro and in vivo. We next investigated the cellular and molecular mechanisms and discovered that circBACH1 inhibited p27 translation, which influenced cell cycle progression. Moreover, we revealed that circBACH1 could combine directly with HuR using RNA immunoprecipitation assays, pull-down assays, and electrophoretic mobility shift assays. The combination of these molecules facilitated HuR translocation from the nucleus to the cytoplasm according to the fluorescence in situ hybridization and immunofluorescence results. Finally, silencing HuR abrogated circBACH1's inhibition of p27 translation and abolished the circBACH1-induced effect on HCC proliferation. In sum, circBACH1 plays a significant role as an oncogene through the circBACH1/HuR/p27 axis in HCC development.

Altered mast cell activity in response to rhinovirus infection provides novel insight into asthma.

Objective: Human rhinoviruses (RVs) are a type of common respiratory virus capable of inducing an asthma attack. Although mast cells are important effector cells involved in allergic disease, little is known about the direct effects of an RV infection on mast cells. The aim of this study is to investigate mast cell behavior in response to RV infection and gain insight into the effects of RVs on mast cells. Methods: Viral replication, cell viability, apoptosis and cytokine release were quantified in Human mast cell-1 (HMC-1) cells following RV16 infection. Results: The results revealed that the viral RNA copy number increased substantially over time. Intercellular cell adhesion molecule-1 (ICAM-1) transcripts were significantly upregulated from 1.79 to 6.37 times following RV16 infection compared to the controls (p ≤ 0.05). Lactate dehydrogenase (LDH) activity was significantly increased, whereas the cell viability decreased following RV16 infection. Examination of the early cellular response to infection revealed that RV16 increased caspase 3 activity and aggravated apoptotic responses. Furthermore, detection of the innate immune response to RV infection revealed that the release of IL-6, IL-8, TNF-α, and IFN-α by HMC-1 cells increased significantly compared to the control groups. Conclusions: RV infection influences mast cell functionality and promotes the innate immune response of mast cells following viral infection. These results provide a novel insight which mast cells have the potential to be involved in the pathogenesis of RV-induced exacerbations of asthma.

Consumers' satisfaction factors mining and sentiment analysis of B2C online pharmacy reviews.

BACKGROUND: In recent years, online pharmacies have been accepted by increasingly more consumers, and the prospects for online pharmacies are optimistic. This article explores the consumers' satisfaction factors addressed in Business to Customer (B2C) online pharmacy reviews and analyzes the sentiments expressed in the reviews. The goal of this work is to help B2C online pharmacy enterprises identify consumers' concerns, continuously improve the health services level. METHODS: This article was based on the Latent Dirichlet Allocation (LDA) topic model. From a third-party platform-based B2C online pharmacy and a proprietary B2C online pharmacy (JD Pharmacy and J1.COM, respectively), 136,630 pieces of over-the-counter (OTC) drug review data posted from January 1, 2015 to December 31, 2018 were selected as samples and used to explore the satisfaction factors of B2C online pharmacy consumers regarding the entire drug purchasing process. Then, the sentiments expressed in the drug reviews were analyzed with SnowNLP. RESULT: Categorization of the 12 factors identified by LDA showed that 5 factors were related to logistics; these 5 factors, which also included the most drug reviews, made up 38.5% of the reviews. The number of factors related to drug prices was second, with 3 factors, and reviews of drug prices made up 25.5% of the reviews. Customer service and drug effects each had two related factors, and a smaller percentage of these reviews (13.95%) were related to drug effects. Consumers still maintain positive opinions of JD Pharmacy and J1.COM. However, some opinions on logistics and drug prices are expressed. CONCLUSION: The most important task for online pharmacies is to improve logistics. It is better to develop self-built logistics. Both types of B2C online pharmacies can improve consumer viscosity by implementing marketing strategies. With regard to customer service, focusing on improving employees' service attitudes is necessary.

Data Mining of the Reviews from Online Private Doctors.

Background: User-generated content shared in the online health communities (OHCs) is becoming a valuable resource for researchers to understand patients' decision-making behaviors in the management of their health. Many studies have focused on how to obtain useful information from online reviews in OHCs. Introduction: This study focuses on a telemedicine service called Online Private Doctor (OPD), which is offered by a leading Chinese physician review website (PRW). OPD reviews have not received much attention. By data mining the reviews, our goal is to determine what patients are talking about when they use the OPD service and whether they are satisfied with the service or not. Materials and Methods: We used a Python web crawler to collect 41,029 reviews and 84,510 short reviews (labels) of all 5,645 physicians who offered the OPD service on a PRW (haodf.com) in China. Mixed methods (i.e., a literature review, topic discovery, annotation, and a sentiment analysis) were used to determine the information that the OPD reviews are meant to express. Results: We discovered that the OPD reviews can be categorized into four subjects: competence (35.1%), communication (29.4%), treatment (26.0%), and convenience (9.5%). In terms of previously discovered topics, we found that competence, communication, and treatment have been discussed before, but convenience is an emerging subject. The sentiment analysis indicated that 93.67% of the reviews indicated positive emotions, and the area under the receiver operating characteristic (ROC) curve is 0.64. Furthermore, the labels indicated that only 0.72% (603/84,570) of reviews were negative toward the OPD service. The subjects of the labels were distributed according to competence (34.7%), communication (23.8%), treatment (33.5%), and convenience (8.0%). Discussion: The findings of our study suggest that patients who ever used OPD have been quite satisfied with the service. From their reviews, we discovered that OPD has its special characteristics and is convenient. However, it still has some shortcomings, for example, the quality of the phone connection. In terms of both the platform and the doctors, more efforts should be made to make the OPD better and more regulated. Conclusion: OPD is an emerging telemedicine service that still needs more time and space to evolve. For patients, it helps reduce problems such as scheduling and queuing. Therefore, it brings more convenience to people's daily lives. In the future, more attention should be paid to this service, as it is helpful in reducing the uneven distribution of medical resources.

The placental transcriptome of the first-trimester placenta is affected by in vitro fertilization and embryo transfer.

BACKGROUND: The placenta is a highly specialized temporary organ that is related to fetal development and pregnancy outcomes, and epidemiological data demonstrate an increased risk of placental abnormality after in vitro fertilization and embryo transfer (IVF-ET). METHODS: This study examines alterations in the transcriptome profile of first-trimester placentas from IVF-ET pregnancies and analyzes the potential mechanisms that play a role in the adverse perinatal outcomes associated with IVF-ET procedures. Four human placental villi from first-trimester samples were obtained through fetal bud aspiration from patients subjected to IVF-ET due to oviductal factors. An additional four control human placental villi were derived from a group of subjects who spontaneously conceived a twin pregnancy. We analyzed their transcriptomes by microarray. Then, RT-qPCR and immunohistochemistry were utilized to analyze several dysregulated genes to validate the microarray results. Biological functions and pathways were analyzed with bioinformatics tools. RESULTS: A total of 3405 differentially regulated genes were identified as significantly dysregulated (> 2-fold change; P < 0.05) in the IVF-ET placenta in the first trimester: 1910 upregulated and 1495 downregulated genes. Functional enrichment analysis of the differentially regulated genes demonstrated that the genes were involved in more than 50 biological processes and pathways that have been shown to play important roles in the first trimester in vivo. These pathways can be clustered into coagulation cascades, immune response, transmembrane signaling, metabolism, cell cycle, stress control, invasion and vascularization. Nearly the same number of up- and downregulated genes participate in the same biological processes related to placental development and maintenance. Procedures utilized in IVF-ET altered the expression of first-trimester placental genes that are critical to these biological processes and triggered a compensatory mechanism during early implantation in vivo. CONCLUSION: These data provide a potential basis for further analysis of the higher frequency of adverse perinatal outcomes following IVF-ET, with the ultimate goal of developing safer IVF-ET protocols.

[Research progress on compliant characteristics of lower extremity exoskeleton robots].

The lower extremity exoskeleton robot is a wearable device designed to help people suffering from a walking disorder to regain the power of the legs and joints to achieve standing and walking functions. Compared with traditional robots that include rigid mechanisms, lower extremity exoskeleton robots with compliant characteristics can store and release energy in passive elastic elements while minimizing the reaction force due to impact, so it can improve the safety of human-robot interaction. This paper reviews the compliant characteristics of lower extremity exoskeleton robots from the aspects of compliant drive and compliant joint, and introduces the augmentation, assistive, rehabilitation lower extremity exoskeleton robots. It also prospect the future development trend of lower extremity exoskeleton robots.

Developing Embedded Taxonomy and Mining Patients' Interests From Web-Based Physician Reviews: Mixed-Methods Approach.

BACKGROUND: Web-based physician reviews are invaluable gold mines that merit further investigation. Although many studies have explored the text information of physician reviews, very few have focused on developing a systematic topic taxonomy embedded in physician reviews. The first step toward mining physician reviews is to determine how the natural structure or dimensions is embedded in reviews. Therefore, it is relevant to develop the topic taxonomy rigorously and systematically. OBJECTIVE: This study aims to develop a hierarchical topic taxonomy to uncover the latent structure of physician reviews and illustrate its application for mining patients' interests based on the proposed taxonomy and algorithm. METHODS: Data comprised 122,716 physician reviews, including reviews of 8501 doctors from a leading physician review website in China (haodf.com), collected between 2007 and 2015. Mixed methods, including a literature review, data-driven-based topic discovery, and human annotation were used to develop the physician review topic taxonomy. RESULTS: The identified taxonomy included 3 domains or high-level categories and 9 subtopics or low-level categories. The physician-related domain included the categories of medical ethics, medical competence, communication skills, medical advice, and prescriptions. The patient-related domain included the categories of the patient profile, symptoms, diagnosis, and pathogenesis. The system-related domain included the categories of financing and operation process. The F-measure of the proposed classification algorithm reached 0.816 on average. Symptoms (Cohen d=1.58, Δu=0.216, t=229.75, and P<.001) are more often mentioned by patients with acute diseases, whereas communication skills (Cohen d=-0.29, Δu=-0.038, t=-42.01, and P<.001), financing (Cohen d=-0.68, Δu=-0.098, t=-99.26, and P<.001), and diagnosis and pathogenesis (Cohen d=-0.55, Δu=-0.078, t=-80.09, and P<.001) are more often mentioned by patients with chronic diseases. Patients with mild diseases were more interested in medical ethics (Cohen d=0.25, Δu 0.039, t=8.33, and P<.001), operation process (Cohen d=0.57, Δu 0.060, t=18.75, and P<.001), patient profile (Cohen d=1.19, Δu 0.132, t=39.33, and P<.001), and symptoms (Cohen d=1.91, Δu=0.274, t=62.82, and P<.001). Meanwhile, patients with serious diseases were more interested in medical competence (Cohen d=-0.99, Δu=-0.165, t=-32.58, and P<.001), medical advice and prescription (Cohen d=-0.65, Δu=-0.082, t=-21.45, and P<.001), financing (Cohen d=-0.26, Δu=-0.018, t=-8.45, and P<.001), and diagnosis and pathogenesis (Cohen d=-1.55, Δu=-0.229, t=-50.93, and P<.001). CONCLUSIONS: This mixed-methods approach, integrating literature reviews, data-driven topic discovery, and human annotation, is an effective and rigorous way to develop a physician review topic taxonomy. The proposed algorithm based on Labeled-Latent Dirichlet Allocation can achieve impressive classification results for mining patients' interests. Furthermore, the mining results reveal marked differences in patients' interests across different disease types, socioeconomic development levels, and hospital levels.

Systematic Analysis of Lysine Acetylation in the Halophilic Archaeon Haloferax mediterranei.

Lysine acetylation is a reversible and highly regulated post-translational modification that plays a critical role in regulating many aspects of cellular processes, both in bacteria and in eukaryotes. However, this modification has not been systematically studied in archaea. Herein, we report the lysine acetylome of a model haloarchaeon, Haloferax mediterranei. Using immunoaffinity enrichment and LC-MS/MS analysis, we identified 1017 acetylation sites in 643 proteins, accounting for 17.3% of the total proteins in this haloarchaeon. Bioinformatics analysis indicated that lysine acetylation mainly distributes in cytoplasm (94%) and participates in protein biosynthesis and carbon metabolism. Specifically, the acetylation of key enzymes in PHBV biosynthesis further suggested that acetylation plays a key role in the energy and carbon storage. In addition, a survey of the acetylome revealed a universal rule in acetylated motifs: a positively charged residue (K, R, or H) located downstream of acetylated lysine at the positions +1, +2, or +3. Interestingly, we identified acetylation in several replication initiation proteins Cdc6; mutation on the acetylated site of Cdc6A destroyed the Autonomous Replication Sequence (ARS) activity of its adjacent origin oriC1. Our study indicates that lysine acetylation is an abundant modification in H. mediterranei, and plays key roles in the processes of replication, protein biosynthesis, central metabolism, and carbon storage. This acetylome of H. mediterranei provides opportunities to explore the physiological role of acetylation in halophilic archaea.

Understanding Health Care Social Media Use From Different Stakeholder Perspectives: A Content Analysis of an Online Health Community.

BACKGROUND: Health care social media used for health information exchange and emotional communication involves different types of users, including patients, caregivers, and health professionals. However, it is difficult to identify different stakeholders because user identification data are lacking due to privacy protection and proprietary interests. Therefore, identifying the concerns of different stakeholders and how they use health care social media when confronted with huge amounts of health-related messages posted by users is a critical problem. OBJECTIVE: We aimed to develop a new content analysis method using text mining techniques applied in health care social media to (1) identify different health care stakeholders, (2) determine hot topics of concern, and (3) measure sentiment expression by different stakeholders. METHODS: We collected 138,161 messages posted by 39,606 members in lung cancer, diabetes, and breast cancer forums in the online community MedHelp.org over 10 years (January 2007 to October 2016) as experimental data. We used text mining techniques to process text data to identify different stakeholders and determine health-related hot topics, and then analyzed sentiment expression. RESULTS: We identified 3 significantly different stakeholder groups using expectation maximization clustering (3 performance metrics: Rand=0.802, Jaccard=0.393, Fowlkes-Mallows=0.537; P<.001), in which patients (24,429/39,606, 61.68%) and caregivers (12,232/39,606, 30.88%) represented the majority of the population, in contrast to specialists (2945/39,606, 7.43%). We identified 5 significantly different health-related topics: symptom, examination, drug, procedure, and complication (Rand=0.783, Jaccard=0.369, Fowlkes-Mallows=0.495; P<.001). Patients were concerned most about symptom topics related to lung cancer (536/1657, 32.34%), drug topics related to diabetes (1883/5904, 31.89%), and examination topics related to breast cancer (8728/23,934, 36.47%). By comparison, caregivers were more concerned about drug topics related to lung cancer (300/2721, 11.03% vs 109/1657, 6.58%), procedure topics related to breast cancer (3952/13,954, 28.32% vs 5822/23,934, 24.33%), and complication topics (4449/25,701, 17.31% vs 4070/31,495, 12.92%). In addition, patients (9040/36,081, 25.05%) were more likely than caregivers (2659/18,470, 14.39%) and specialists (17,943/83,610, 21.46%) to express their emotions. However, patients' sentiment intensity score (2.46) was lower than those of caregivers (4.66) and specialists (5.14). In particular, for caregivers, negative sentiment scores were higher than positive scores (2.56 vs 2.18), with the opposite among specialists (2.62 vs 2.46). Overall, the proportion of negative messages was greater than that of positive messages related to symptom, complication, and examination. The pattern was opposite for drug and procedure topics. A trend analysis showed that patients and caregivers gradually changed their emotional state in a positive direction. CONCLUSIONS: The hot topics of interest and sentiment expression differed significantly among different stakeholders in different disease forums. These findings could help improve social media services to facilitate diverse stakeholder engagement for health information sharing and social interaction more effectively.

Interferon Beta and Interferon Alpha 2a Differentially Protect Head and Neck Cancer Cells from Vesicular Stomatitis Virus-Induced Oncolysis.

UNLABELLED: Oncolytic viruses (OV) preferentially kill cancer cells due in part to defects in their antiviral responses upon exposure to type I interferons (IFNs). However, IFN responsiveness of some tumor cells confers resistance to OV treatment. The human type I IFNs include one IFN-ß and multiple IFN-α subtypes that share the same receptor but are capable of differentially inducing biological responses. The role of individual IFN subtypes in promoting tumor cell resistance to OV is addressed here. Two human IFNs which have been produced for clinical use, IFN-α2a and IFN-ß, were compared for activity in protecting human head and neck squamous cell carcinoma (HNSCC) lines from oncolysis by vesicular stomatitis virus (VSV). Susceptibility of HNSCC lines to killing by VSV varied. VSV infection induced increased production of IFN-ß in resistant HNSCC cells. When added exogenously, IFN-ß was significantly more effective at protecting HNSCC cells from VSV oncolysis than was IFN-α2a. In contrast, normal keratinocytes and endothelial cells were protected equivalently by both IFN subtypes. Differential responsiveness of tumor cells to IFN-α and -ß was further supported by the finding that autocrine IFN-ß but not IFN-α promoted survival of HNSCC cells during persistent VSV infection. Therefore, IFN-α and -ß differentially affect VSV oncolysis, justifying the evaluation and comparison of IFN subtypes for use in combination with VSV therapy. Pairing VSV with IFN-α2a may enhance selectivity of oncolytic VSV therapy for HNSCC by inhibiting VSV replication in normal cells without a corresponding inhibition in cancer cells. IMPORTANCE: There has been a great deal of progress in the development of oncolytic viruses. However, a major problem is that individual cancers vary in their sensitivity to oncolytic viruses. In many cases this is due to differences in their production and response to interferons (IFNs). The experiments described here compared the responses of head and neck squamous cell carcinoma cell lines to two IFN subtypes, IFN-α2a and IFN-ß, in protection from oncolytic vesicular stomatitis virus. We found that IFN-α2a was significantly less protective for cancer cells than was IFN-ß, whereas normal cells were equivalently protected by both IFNs. These results suggest that from a therapeutic standpoint, selectivity for cancer versus normal cells may be enhanced by pairing VSV with IFN-α2a.