PharmBERT: a domain-specific BERT model for drug labels.

Human prescription drug labeling contains a summary of the essential scientific information needed for the safe and effective use of the drug and includes the Prescribing Information, FDA-approved patient labeling (Medication Guides, Patient Package Inserts and/or Instructions for Use), and/or carton and container labeling. Drug labeling contains critical information about drug products, such as pharmacokinetics and adverse events. Automatic information extraction from drug labels may facilitate finding the adverse reaction of the drugs or finding the interaction of one drug with another drug. Natural language processing (NLP) techniques, especially recently developed Bidirectional Encoder Representations from Transformers (BERT), have exhibited exceptional merits in text-based information extraction. A common paradigm in training BERT is to pretrain the model on large unlabeled generic language corpora, so that the model learns the distribution of the words in the language, and then fine-tune on a downstream task. In this paper, first, we show the uniqueness of language used in drug labels, which therefore cannot be optimally handled by other BERT models. Then, we present the developed PharmBERT, which is a BERT model specifically pretrained on the drug labels (publicly available at Hugging Face). We demonstrate that our model outperforms the vanilla BERT, ClinicalBERT and BioBERT in multiple NLP tasks in the drug label domain. Moreover, how the domain-specific pretraining has contributed to the superior performance of PharmBERT is demonstrated by analyzing different layers of PharmBERT, and more insight into how it understands different linguistic aspects of the data is gained.

HNRNPA2B1 stabilizes NFATC3 levels to potentiate its combined actions with FOSL1 to mediate vasculogenic mimicry in GBM cells.

BACKGROUND: Vasculogenic mimicry (VM) is an enigmatic physiological feature that influences blood supply within glioblastoma (GBM) tumors for their sustained growth. Previous studies identify NFATC3, FOSL1 and HNRNPA2B1 as significant mediators of VEGFR2, a key player in vasculogenesis, and their molecular relationships may be crucial for VM in GBM. AIMS: The aim of this study was to understand how NFATC3, FOSL1 and HNRNPA2B1 collectively influence VM in GBM. METHODS: We have investigated the underlying gene regulatory mechanisms for VM in GBM cell lines U251 and U373 in vitro and in vivo. In vitro cell-based assays were performed to explore the role of NFATC3, FOSL1 and HNRNPA2B1 in GBM cell proliferation, VM and migration, in the context of RNA interference (RNAi)-mediated knockdown alongside corresponding controls. Western blotting and qRT-PCR assays were used to examine VEGFR2 expression levels. CO-IP was employed to detect protein-protein interactions, ChIP was used to detect DNA-protein complexes, and RIP was used to detect RNA-protein complexes. Histochemical staining was used to detect VM tube formation in vivo. RESULTS: Focusing on NFATC3, FOSL1 and HNRNPA2B1, we found each was significantly upregulated in GBM and positively correlated with VM-like cellular behaviors in U251 and U373 cell lines. Knockdown of NFATC3, FOSL1 or HNRNPA2B1 each resulted in decreased levels of VEGFR2, a key growth factor gene that drives VM, as well as the inhibition of proliferation, cell migration and extracorporeal VM activity. Chromatin immunoprecipitation (ChIP) studies and luciferase reporter gene assays revealed that NFATC3 binds to the promoter region of VEGFR2 to enhance VEGFR2 gene expression. Notably, FOSL1 interacts with NFATC3 as a co-factor to potentiate the DNA-binding capacity of NFATC3, resulting in enhanced VM-like cellular behaviors. Also, level of NFATC3 protein in cells was enhanced through HNRNPA2B1 binding of NFATC3 mRNA. Furthermore, RNAi-mediated silencing of NFATC3, FOSL1 and HNRNPA2B1 in GBM cells reduced their capacity for tumor formation and VM-like behaviors in vivo. CONCLUSION: Taken together, our findings identify NFATC3 as an important mediator of GBM tumor growth through its molecular and epistatic interactions with HNRNPA2B1 and FOSL1 to influence VEGFR2 expression and VM-like cellular behaviors.

[Factors associated with the care needs of the older adults based on different disability levels].

OBJECTIVE: To identify the factors associated with the care needs of the older adults aged 65-105 by age groups, and to compare these factors across different age groups. METHODS: A total of 12 244 older adults from the Chinese longitudinal healthy longevity survey (CLHLS) conducted in 2018 were included in the analyses. The participants were categorized into three age groups: young-old (aged 65-79), middle-old (aged 80-89), and oldest-old (aged 90-105). The level of disability was measured by the disability index (DI) in four dimensions, reflecting their care needs. Potential factors associated with care needs were selected based on the health ecological model (HEM), including perspectives of personal characteristics, behavioral characteristics, interpersonal network, living and working conditions, and policy environment. Multifactor analysis was performed using multinomial Logistic regression. RESULTS: Among China ' s 12 244 older adults, 43.4% had medium or high care needs. Factors for higher care needs of older adults included higher age, higher number of chronic diseases, no exercise habit, excessive sleep duration (≥9 h/d), depressive tendency, living with children or spouse, and uneducated (all P < 0.05). In addition, the young-old group who were past smokers (OR=2.009, 95% CI: 1.019-3.959), were past drinkers (OR=2.213, 95% CI: 1.141-4.291), and reported self-perceived poverty (OR=2.051, 95% CI: 1.189-3.540), had higher level of care needs. The middle-old group who were female (OR=1.373, 95% CI: 1.038-1.817), never drank alcohol (OR=1.551, 95% CI: 1.059-2.269), and were lack of medical insurance (OR=1.598, 95% CI: 1.053-2.426), and had higher level of care needs. The oldest-old group who were female (medium care needs vs. low care needs: OR=1.412, 95% CI: 1.062-1.878; high care needs vs. low care needs: OR=1.506, 95% CI: 1.137-1.993), reported self-perceived poverty (OR=2.064, 95% CI: 1.282-3.323), and were lack of medical insurance (OR=1.621, 95% CI: 1.148-2.291), and had higher level of care needs. CONCLUSION: The identical factors associated with care needs across different age groups include age, chronic disease, exercise, sleep, depression, living arrangement, and education. Smoking, alcohol consumption, and economic status are specific factors among the young-old group of the older adults, while gender and medical insurance are specific factors among the middle-old and the oldest-old group of the older adults. We recommend conducting prospective cohort studies and intervention studies among specific age groups on the above factors to provide reliable evidence for policy formulation.

Fine-tuning BERT for automatic ADME semantic labeling in FDA drug labeling to enhance product-specific guidance assessment.

Product-specific guidances (PSGs) recommended by the United States Food and Drug Administration (FDA) are instrumental to promote and guide generic drug product development. To assess a PSG, the FDA assessor needs to take extensive time and effort to manually retrieve supportive drug information of absorption, distribution, metabolism, and excretion (ADME) from the reference listed drug labeling. In this work, we leveraged the state-of-the-art pre-trained language models to automatically label the ADME paragraphs in the pharmacokinetics section from the FDA-approved drug labeling to facilitate PSG assessment. We applied a transfer learning approach by fine-tuning the pre-trained Bidirectional Encoder Representations from Transformers (BERT) model to develop a novel application of ADME semantic labeling, which can automatically retrieve ADME paragraphs from drug labeling instead of manual work. We demonstrate that fine-tuning the pre-trained BERT model can outperform conventional machine learning techniques, achieving up to 12.5% absolute F1 improvement. To our knowledge, we were the first to successfully apply BERT to solve the ADME semantic labeling task. We further assessed the relative contribution of pre-training and fine-tuning to the overall performance of the BERT model in the ADME semantic labeling task using a series of analysis methods, such as attention similarity and layer-based ablations. Our analysis revealed that the information learned via fine-tuning is focused on task-specific knowledge in the top layers of the BERT, whereas the benefit from the pre-trained BERT model is from the bottom layers.

Leveraging GPT-4 for food effect summarization to enhance product-specific guidance development via iterative prompting.

Food effect summarization from New Drug Application (NDA) is an essential component of product-specific guidance (PSG) development and assessment, which provides the basis of recommendations for fasting and fed bioequivalence studies to guide the pharmaceutical industry for developing generic drug products. However, manual summarization of food effect from extensive drug application review documents is time-consuming. Therefore, there is a need to develop automated methods to generate food effect summary. Recent advances in natural language processing (NLP), particularly large language models (LLMs) such as ChatGPT and GPT-4, have demonstrated great potential in improving the effectiveness of automated text summarization, but its ability with regard to the accuracy in summarizing food effect for PSG assessment remains unclear. In this study, we introduce a simple yet effective approach,iterative prompting, which allows one to interact with ChatGPT or GPT-4 more effectively and efficiently through multi-turn interaction. Specifically, we propose a three-turn iterative prompting approach to food effect summarization in which the keyword-focused and length-controlled prompts are respectively provided in consecutive turns to refine the quality of the generated summary. We conduct a series of extensive evaluations, ranging from automated metrics to FDA professionals and even evaluation by GPT-4, on 100 NDA review documents selected over the past five years. We observe that the summary quality is progressively improved throughout the iterative prompting process. Moreover, we find that GPT-4 performs better than ChatGPT, as evaluated by FDA professionals (43% vs. 12%) and GPT-4 (64% vs. 35%). Importantly, all the FDA professionals unanimously rated that 85% of the summaries generated by GPT-4 are factually consistent with the golden reference summary, a finding further supported by GPT-4 rating of 72% consistency. Taken together, these results strongly suggest a great potential for GPT-4 to draft food effect summaries that could be reviewed by FDA professionals, thereby improving the efficiency of the PSG assessment cycle and promoting generic drug product development.

Predictive value of ellipsoid zone-related angle parameters in primary surgery of large macular hole: a case control study.

BACKGROUND: To explore the predictive value of Ellipsoid Zone (EZ) -related angle parameters for the outcome of primary macular hole surgery. METHODS: This was a retrospective study. Patients diagnosed with large macular hole (MH) (minimum diameter > 500 µm) between 2018 and 2021 were enrolled. All patients underwent 25-gauge pars plana vitrectomy, internal limiting membrane (ILM) peeling and air tamponade. Spectral-domain OCT (SD-OCT) and best corrected visual acuity (BCVA) were measured in preoperative and 2-week post-operative. Classic and angle related parameters were measured via ImageJ. Angle regularity (AR) were defined as the standard deviation of the angle parameters in vertical and horizontal direction. RESULTS: Seventy-six eyes were included for analysis; 24 eyes showed an unclosed macular hole at the 2-week postoperative and 52 eyes showed a closed hole. Preoperatively, MLD (P < 0.001), BD (P = 0.009) and diameter of EZ/ELM disruption (P = 0.002 and 0.025) in patients failed to close the hole after primary surgery were significantly larger than those succeeded. EZ-MH (P = 0.018), EZ-NFL (P = 0.006), EZ-GCL (P = 0.004), EZ-INL (P = 0.002), EZ-OPL (P = 0.009) and EZ-ONL (P = 0.011) angles were smaller in patients with unclosed hole. AR of the EZ-NFL (P = 0.009), EZ-GCL (P = 0.009), EZ-OPL (P = 0.023), EZ-ONL (P = 0.048) and Basal-NFL (P = 0.030) angles among the unclosed patients were significantly larger than those of the closed group. EZ-NFL (P = 0.015), EZ-GCL (P = 0.004), EZ-INL (P < 0.001), EZ-OPL (P < 0.001), EZ-ONL (P < 0.001), Basal (P = 0.023) and Basal-NFL (P < 0.001) angles of hole-unclosed patients enlarged significantly after the surgery. CONCLUSIONS: Patients with large macular holes and an increased EZ-related angle and angle AR are more likely to experience unsuccessful outcomes following primary MH surgery. Therefore, EZ-related angles hold potential as valuable parameters for predicting the surgical outcome.

Potential dynamic changes of single-season rice planting suitability across China.

As an important food crop in China, changes in suitable areas for rice planting are critical to agricultural production. In this study, the maximum entropy model (MaxEnt) was utilized to pick the main climatic factors affecting single-season rice planting distribution and project the potential changes under RCP4.5 and RCP8.5 scenarios. It was clear that rice planting distribution was significantly affected by annual total precipitation, the accumulated temperature during a period in which daily temperature was ≥ 10 °C, the moisture index, total precipitation during April-September, and continuous days during the period of daily temperature ≥ 18 °C, with their contribution being 97.6%. There was a continuous decrease in the area of good and high suitability for rice planting projected from 2021-2040 to 2061-2080, with a respective value ranging from 1.49 × 106 km2 to 0.93 × 106 km2 under the RCP4.5 scenario and from 1.42 × 106 km2 to 0.66 × 106 km2 under RCP8.5 scenarios. In 2081-2100, there was a bit increase in the area of good and high suitability under the RCP4.5 scenario. The most significant increases in good and high suitability were detected in Northeast China, while obvious decreases were demonstrated in the Yangtze River Basin which might be exposed to extreme temperature threat. The spatial potential planting center was characterized by the largest planting area in 25°N-37°N and 98°E-134°E. The north boundary and center of rice cultivation arose to 53.5°N and 37.52°N, respectively. These potential distributions for single-season rice under future climate change can provide a theoretical basis for optimizing rice planting layout, improving cultivation, and adjusting variety and management systems in response to climate change.

The burden and sexual dimorphism with nonalcoholic fatty liver disease in Asian children: A systematic review and meta-analysis.

BACKGROUND: Despite substantial attention paid to the epidemic of nonalcoholic fatty liver disease (NAFLD) in adults, data on the burden and sexual dimorphism of NAFLD in Asian children have not yet been synthesized. METHODS: We conducted a literature search of 735 references up to April 2021. Pooled analyses, stratified analyses and meta-regression were all performed. RESULTS: Thirty-three study populations were finally included. Nine of them comprising 20 595 children showed an overall NAFLD prevalence of 5.53% (95% CI 3.46%-8.72%), in which, 36.64% (95% CI, 27.99%-46.26%) NAFLD subjects had elevated levels of ALT. The prevalence rate of NAFLD increased about 1.6-fold from 2004 to 2010 to the last decade. Male predominant trends were observed in paediatric NAFLD (boys: 8.18%, 95% CI 4.93%-13.26%; girls: 3.60%, 95% CI 1.60%-7.87%). Moreover, meta-analysis showed that after 10 years of age, boys were more prone to have NAFLD than girls (OR = 1.75; P = .0012). In addition, the pooled prevalence of NAFLD increased sequentially in normal-weight (1.49%, 95% CI 0.88%-2.51%, n = 2610), overweight (16.72%, 95% CI 7.07%-34.65%, n = 1265) and obese children (50.13%, 95% CI 41.99%-58.27%, n = 6434 individuals). After full covariate adjustment, the multivariate meta-regression also showed that boy percentage (P = .0396) and body mass index (P < .0001) were positively correlated with prevalent NAFLD. CONCLUSIONS: In Asia, paediatric NAFLD is becoming prevalent over the recent decades, particularly among obese children and boys after 10 years old. The hormonal and chromosomal origins of paediatric NAFLD dimorphism need further investigation.

Reversible stability of colloids switched by CO2 based on polyhexamethylene guanidine.

The stability of a colloid, including emulsion and polymer latex, can be destroyed irreversibly by the addition of salt. Using the CO2 stimulus, amines can be converted into organic ammonium salts reversibly, which can access the switching of colloids. Polyhexamethylene guanidine (PHMG), was chosen as a switchable amine. The conductivity of PHMG aqueous solution switched by adding and removing CO2. Surface tension measurements verified that, under CO2, the critical micelle concentration of sodium dodecyl benzene sulfonate (SDBS) decreased from 1.0 × 10-3 to 5.0 × 10-4 M with the addition of PHMG. The crude oil emulsion containing SDBS and PHMG was destroyed and restored reversibly by the treatment with CO2 and N2. The polystyrene latex also occurred an obvious stratification after sparging with CO2 and returned a homogeneous phase upon bubbling N2. This study is intended to pave the way for colloids which has reversible stability in response to CO2 stimulation.

Current status and challenges in the drug treatment for fibrotic nonalcoholic steatohepatitis.

Currently, nonalcoholic steatohepatitis (NASH) is one of the most common forms of chronic hepatitis, increasing the burden of health care worldwide. In patients with NASH, the fibrosis stage is the most predictive factor of long-term events. However, there are still no drugs approved by the Food and Drug Administration of the United States for treating biopsy-proven NASH with fibrosis or cirrhosis. Although some novel drugs have shown promise in preclinical studies and led to improvement in terms of hepatic fat content and steatohepatitis, a considerable proportion of them have failed to achieve histological endpoints of fibrosis improvement. Due to the large number of NASH patients and adverse clinical outcomes, the search for novel drugs is necessary. In this review, we discuss current definitions for the evaluation of treatment efficacy in fibrosis improvement for NASH patients, and we summarize novel agents in the pipeline from different mechanisms and phases of trial. We also critically review the challenges we face in the development of novel agents for fibrotic NASH and NASH cirrhosis.

Screening varices in patients with HBV-related cirrhosis on antiviral therapy: Platelet alone or together with LSM.

BACKGROUND & AIMS: Non-invasive assessment criteria to rule out high-risk varices (HRV) in compensated hepatitis B virus (HBV) cirrhosis on antiviral therapy remains unclear. METHODS: HBV-related compensated cirrhotic patients who underwent screening endoscopy during antiviral therapy were enrolled and randomly divided into the derivation and validation sets. HRV were defined as medium to large varices or small varices with red signs. Univariate and multivariate logistic analysis were used to determine the parameters associated with HRV. RESULTS: A total of 436 HBV-related compensated cirrhotic patients screened for varices were enrolled, the median duration of antiviral therapy was 4 years (IQR: 2.5-5.5 years). In the derivation set (N = 290, 17.2% with HRV), only platelet (PLT) count (OR = 0.972, 95% CI 0.961-0.984, P < .05) was independently associated with HRV, whereas liver stiffness measurement was not associated with the presence of HRV. With a PLT count cut-off value of 105 × 109 /L, unnecessary endoscopies could be spared in 56.9% patients, with a 3.6%. risk of missing HRV. In the validation cohort (N = 146, 16.4% with HRV), the proportion of patients that could safely spare endoscopies (61.0%) identified by this PLT count cut-off value was higher than that obtained by using Baveno VI criteria (34.9%), with an acceptable risk of missing HRV (3.4%). CONCLUSION: Compared with the 'Baveno VI criteria or beyond' criteria, PLT count higher than 105 × 109 /L could safely spare more screening endoscopies without increasing the risk of missing HRV in patients with HBV-related compensated cirrhosis on antiviral therapy.

Electrical and thermal performances of epoxy-based micro-nano hybrid composites at different electric fields and temperatures.

This paper investigates the electrical and thermal properties of pure epoxy resin (EP) and its micro-nano hybrid composites (20 wt% micro-AlN fillers with 1 wt% and 3 wt% nano-Al2O3fillers; 50% micro-AlN with 3% nano-Al2O3fillers) for power electronic packaging applications. Electrical properties such as space charge distribution, electrical conductivity and surface potential decay are measured. The thermal performance of the fabricated samples is estimated using thermal analysis devices. The hybrid composite consisting of 20 wt% micro-AlN and 1 wt% nano-Al2O3fillers exhibits the least space charge accumulation, higher thermal conductivity and better thermal stability. However, the excessive addition adversely affects space charge and electrical conductivity properties. The micro-nano hybrid composites significantly exhibit higher electrical conductivity than pure EP. The microfiller addition from 20 wt% to 50 wt% significantly improves the thermal conductivity of the EP. The reduced space charge injection and accumulation in the hybrid micro-nano composites are attributed to the enhancement of the injection barrier and reduction of the charge carrier traps in these materials. A theoretical mechanism of the charge dynamics inside the samples under different test conditions is proposed to support the experimental results.

Family interaction among young Chinese breast cancer survivors.

BACKGROUND: Family interaction is an important factor contributing to the quality of survivorship among breast cancer survivors. The dearth of studies involving young females with breast cancer has limited the understanding of family interaction in this increasingly large population. METHODS: The aim of this study was to explore family interaction patterns among young Chinese breast cancer survivors. We conducted in-depth interviews with seventeen young breast cancer survivors (YBCSs) in China between May 2019 and December 2019. A content analysis was performed to identify the characteristics of family interaction in this population. Conceptualizations of feminism and social support were used to guide the data analysis. RESULTS: Family interaction patterns were categorized into 5 domains from the perceptions of Chinese YBCSs: (1) adjustment of parenthood (changes in child-rearing approaches, perception of children's care) (2) ambivalence towards intimacy (desire for intimate relationships, perceived relationship insecurity); (3) concerns regarding fertility; (4) return to work (coping with gratitude and guilt by working, readapting to family and society by working); (5) activation of the support system in a large family (instrumental support from core family members, instrumental, informational, and appraisal support from relatives). CONCLUSIONS: The study provides a deeper understanding of the interactions between young breast cancer survivors and their family members in China. These findings can support health professionals in developing female-sensitive, culturally specific interventions to assist Chinese YBCSs and their families in increasing positive interactions and family resilience as well as quality of life. In addition, the findings are highly applicable to other female cancer survivors and their vulnerable families exposed to similar social and cultural contexts.

Coordinated histone modifications and chromatin reorganization in a single cell revealed by FRET biosensors.

The dramatic reorganization of chromatin during mitosis is perhaps one of the most fundamental of all cell processes. It remains unclear how epigenetic histone modifications, despite their crucial roles in regulating chromatin architectures, are dynamically coordinated with chromatin reorganization in controlling this process. We have developed and characterized biosensors with high sensitivity and specificity based on fluorescence resonance energy transfer (FRET). These biosensors were incorporated into nucleosomes to visualize histone H3 Lys-9 trimethylation (H3K9me3) and histone H3 Ser-10 phosphorylation (H3S10p) simultaneously in the same live cell. We observed an anticorrelated coupling in time between H3K9me3 and H3S10p in a single live cell during mitosis. A transient increase of H3S10p during mitosis is accompanied by a decrease of H3K9me3 that recovers before the restoration of H3S10p upon mitotic exit. We further showed that H3S10p is causatively critical for the decrease of H3K9me3 and the consequent reduction of heterochromatin structure, leading to the subsequent global chromatin reorganization and nuclear envelope dissolution as a cell enters mitosis. These results suggest a tight coupling of H3S10p and H3K9me3 dynamics in the regulation of heterochromatin dissolution before a global chromatin reorganization during mitosis.

Influence of weight management on the prognosis of steatohepatitis in chronic hepatitis B patients during antiviral treatment.

BACKGROUND: Although concomitant nonalcoholic steatohepatitis (NASH) is common in chronic hepatitis B (CHB), the impact of viral factors on NASH and the outcome of CHB patients concomitant with NASH remain unclear. We aimed to investigate the outcomes of NASH in CHB patients receiving antiviral treatment. METHODS: In the post-hoc analysis of a multicenter trial, naïve CHB patients receiving 72-week entecavir treatment were enrolled. We evaluated the biochemical, viral and histopathological responses of these patients. The histopathological features of NASH were also evaluated, using paired liver biopsies at baseline and week 72. RESULTS: A total of 1000 CHB patients were finally enrolled for analysis, with 18.2% of whom fulfilling the criteria of NASH. A total of 727 patients completed entecavir antiviral treatment and received the second biopsy. Serum HBeAg loss, HBeAg seroconversion and HBV-DNA undetectable rates were similar between patients with or without NASH (P > 0.05). Among patients with NASH, the hepatic steatosis, ballooning, lobular inflammation scores and fibrosis stages all improved during follow-up (all P < 0.001), 46% (63/136) achieved NASH resolution. Patients with baseline body mass index (BMI) ≥ 23 kg/m2 (Asian criteria) [odds ratio (OR): 0.414; 95% confidence interval (95% CI): 0.190-0.899; P = 0.012] and weight gain (OR: 0.187; 95% CI: 0.050-0.693; P = 0.026) were less likely to have NASH resolution. Among patients without NASH at baseline, 22 (3.7%) developed NASH. Baseline BMI ≥ 23 kg/m2 (OR: 12.506; 95% CI: 2.813-55.606; P = 0.001) and weight gain (OR: 5.126; 95% CI: 1.674-15.694; P = 0.005) were predictors of incident NASH. CONCLUSIONS: Lower BMI and weight reduction but not virologic factors determine NASH resolution in CHB. The value of weight management in CHB patients during antiviral treatment deserves further evaluation.

Tunable Viscoelastic Properties of Sodium Polyacrylate Solution via CO2-Responsive Switchable Water.

Upon stimulus by CO2, CO2-switchable viscoelastic fluids experience a deliberate transition between non-viscous and highly viscous solution states. Despite attracting considerable recent attention, most such fluids have not been applied at a large- scale due to their high costs and/or complex synthesis processes. Here, we report the development of CO2-switchable viscoelastic fluids using commercially available sodium polyacrylate (NaPAA) and N,N-dimethyl ethanol amine (DMEA)-based switchable water. Upon bubbling CO2, into the solutions under study, DMEA molecules are protonated to generate quaternary ammonium salts, resulting in pronounced decreases in solutions viscosity and elasticity due to the influence of increased ionic strength on NaPAA molecular conformations. Upon removal of CO2 via introduction of N2, quaternary salts are deprotonated to tertiary amines, allowing recovery of fluid viscosity and elasticity to near the initial state. This work provides a simple approach to fabricating CO2-switchable viscoelastic fluids, widening the potential use of CO2 in stimuli-responsive applications.

The Prevalence of Lean/Nonobese Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIM: The prevalence of lean/nonobese nonalcoholic fatty liver disease (NAFLD) ranges widely in studies. Thus, here, we aimed to perform a meta-analysis on NAFLD prevalence in the lean or nonobese population to give clarity. MATERIALS AND METHODS: PubMed, Embase, and the Cochrane Library databases were systematically searched to identify studies reporting NAFLD prevalence in the lean/nonobese population. Lean or nonobese was defined by body mass index cutoffs reported by authors in original studies. NAFLD prevalence based on community, population, or health checkups was combined with random-effect model after logit transformation. Subgroup analysis and meta-regression were further performed to investigate the heterogenicity. RESULTS: A total of 45 studies were enrolled in the final analysis, with 55,936 lean/nonobese subjects included, among whom 7351 NAFLD patients were diagnosed. Overall, the pooled NAFLD prevalence of the lean or nonobese population was 10.2% (95% confidence interval: 7.6%-13.6%) and 15.7% (95% confidence interval: 12.5%-19.6%), respectively. Compared with western studies, the NAFLD prevalence in the lean or nonobese population was lower in eastern studies. In addition, the NAFLD prevalence in both the lean and nonobese population showed a general upward trend during recent years. The prevalence was similar in community-based and health checkup-based studies. Lean/nonobese NAFLD patients had significantly lower rates of hypertension, lower uric acid and fasting plasma glucose, and a higher level of high-density lipoprotein than nonlean/obese patients. CONCLUSIONS: The prevalence of NAFLD in the lean/nonobese population is not rare in either the western or eastern regions of the world. This meta-analysis of prevalence assessment and clinical characteristics should enable higher confidence in more specific interventions and health care standards for these patients.

Bound states of different pulses based on third-order dispersion.

Bound states of double pulses with different wavelengths are observed in a Tm-doped passively mode-locked fiber laser with near-zero net cavity group-velocity dispersion and strong third-order dispersion. The double pulses in the bound states exhibit different pulse durations and peak powers. Simulations show that the two pulses experience different compressing and broadening processes during the intra-cavity evolution. This demonstration reveals the existence of a new form of bound states and enriches the nonlinear dynamics of multi-pulse mode locking.

A variable DNA recognition site organization establishes the LiaR-mediated cell envelope stress response of enterococci to daptomycin.

LiaR is a 'master regulator' of the cell envelope stress response in enterococci and many other Gram-positive organisms. Mutations to liaR can lead to antibiotic resistance to a variety of antibiotics including the cyclic lipopeptide daptomycin. LiaR is phosphorylated in response to membrane stress to regulate downstream target operons. Using DNA footprinting of the regions upstream of the liaXYZ and liaFSR operons we show that LiaR binds an extended stretch of DNA that extends beyond the proposed canonical consensus sequence suggesting a more complex level of regulatory control of target operons. We go on to determine the biochemical and structural basis for increased resistance to daptomycin by the adaptive mutation to LiaR (D191N) first identified from the pathogen Enterococcus faecalis S613. LiaR(D191N) increases oligomerization of LiaR to form a constitutively activated tetramer that has high affinity for DNA even in the absence of phosphorylation leading to increased resistance. Crystal structures of the LiaR DNA binding domain complexed to the putative consensus sequence as well as an adjoining secondary sequence show that upon binding, LiaR induces DNA bending that is consistent with increased recruitment of RNA polymerase to the transcription start site and upregulation of target operons.

Photo-thermal effect enhances the efficiency of radiotherapy using Arg-Gly-Asp peptides-conjugated gold nanorods that target αvß3 in melanoma cancer cells.

BACKGROUND: Thermotherapy has been known to be one of the most effective adjuvants to radiotherapy (RT) in cancer treatment, but it is not widely implemented clinically due to some limitations, such as, inadequate temperature concentrations to the tumor tissue, nonspecific and non-uniform distribution of heat. So we constructed arginine-glycine-aspartate peptides-conjugated gold nanorods (RGD-GNRs) that target the alpha(v) beta(3) Integrin (αvß3) and investigate whether the photo-thermal effect of RGD-GNRs by near infrared radiation (NIR) could enhance the efficiency of RT in melanoma cancer cells. RESULTS: RGD-GNRs could be seen both on the surface of the cell membranes and cytoplasm of A375 cells with high expression of αvß3. After exposed to 808 nm NIR, RGD-GNRs with various concentrations could be rapidly heated up. Compared to other treatments, flow cytometric analysis indicated that RT + NIR + RGD-GNRs increased apoptosis (p < 0.001) and decreased the proportion of cells in the more radioresistant S phase (p = 0.014). Treated with NIR + RGD-GNRs, the radiosensitivity was also significantly enhanced (DMFSF2: 1.41). CONCLUSION: Results of the current study showed the feasibility of using RGD-GNRs for synergetic RT with photo-thermal therapy. And it would greatly benefit the therapeutic effects of refractory or recurrent malignant cancers.