Extending the Grading of Recommendations Assessment, Development and Evaluation (GRADE) in Traditional Chinese Medicine (TCM): The GRADE-TCM.

AIM: To extend and form the "Grading of Recommendations Assessment, Development and Evaluation in Traditional Chinese Medicine" (GRADE-TCM). METHODS: Methodologies were systematically reviewed and analyzed concerning evidence-based TCM guidelines worldwide. A survey questionnaire was developed based on the literature review and open-end expert interviews. Then, we performed expert consensus, discussion meeting, opinion collection, external examination, and the GRADE-TCM was formed eventually. RESULTS: 265 Chinese and English TCM guidelines were included and analyzed. Five experts completed the open-end interviews. Ten methodological entries were summarized, screened and selected. One round of consensus was conducted, including a total of 22 experts and 220 valid questionnaire entries, concerning 1) selection of the GRADE, 2) GRADE-TCM upgrading criteria, 3) GRADE-TCM evaluation standard, 4) principles of consensus and recommendation, and 5) presentation of the GRADE-TCM and recommendation. Finally, consensus was reached on the above 10 entries, and the results were of high importance (with voting percentages ranging from 50 % to 81.82 % for "very important" rating) and strong reliability (with the Cr ranging from 0.93 to 0.99). Expert discussion meeting (with 40 experts), opinion collection (in two online platforms) and external examination (with 14 third-party experts) were conducted, and the GRADE-TCM was established eventually. CONCLUSION: GRADE-TCM provides a new extended evidence-based evaluation standard for TCM guidelines. In GRADE-TCM, international evidence-based norms, characteristics of TCM intervention, and inheritance of TCM culture were combined organically and followed. This is helpful for localization of the GRADE in TCM and internationalization of TCM guidelines.

Edible Insects: A New Sustainable Nutritional Resource Worth Promoting.

Edible insects are a highly nutritious source of protein and are enjoyed by people all over the world. Insects contain various other nutrients and beneficial compounds, such as lipids, vitamins and minerals, chitin, phenolic compounds, and antimicrobial peptides, which contribute to good health. The practice of insect farming is far more resource-efficient compared to traditional agriculture and animal husbandry, requiring less land, energy, and water, and resulting in a significantly lower carbon footprint. In fact, insects are 12 to 25 times more efficient than animals in converting low-protein feed into protein. When it comes to protein production per unit area, insect farming only requires about one-eighth of the land needed for beef production. Moreover, insect farming generates minimal waste, as insects can consume food and biomass that would otherwise go to waste, contributing to a circular economy that promotes resource recycling and reuse. Insects can be fed with agricultural waste, such as unused plant stems and food scraps. Additionally, the excrement produced by insects can be used as fertilizer for crops, completing the circular chain. Despite the undeniable sustainability and nutritional benefits of consuming insects, widespread acceptance of incorporating insects into our daily diets still has a long way to go. This paper provides a comprehensive overview of the nutritional value of edible insects, the development of farming and processing technologies, and the problems faced in the marketing of edible insect products and insect foods to improve the reference for how people choose edible insects.

Genomic and phenotypic-based safety assessment and probiotic properties of Streptococcus thermophilus FUA329, a urolithin A-producing bacterium of human milk origin.

Streptococcus thermophilus FUA329, a urolithin A-producing bacterium, is isolated from human breast milk. The complete genome sequence of FUA329 did not contain any plasmids and at least 20 proteins were related to extreme environment resistance. Phenotypic assay results demonstrated that FUA329 was susceptible to 12 kinds of antibiotics and did not exhibit any hemolytic or nitrate reductase activity. Three free radical scavenging assays revealed that FUA329 have high antioxidant capability. FUA329 exhibited a cell surface hydrophobicity of 52.58 ± 1.17% and an auto-aggregation rate of 18.69 ± 2.48%. Moreover, FUA329 demonstrated a survival rate of over 60% in strong acid and bile salt environments, indicating that FUA329 may be stable colonization in the gastrointestinal tract. Additionally, we firstly found 3 potential proteins and 11 potential genes of transforming ellagic acid to urolithins in FUA329 genome. The above results indicate that FUA329 has credible safety and probiotic properties, as well as the potential to be developed as a new generation of urolithin A-producing probiotics.

Research on spatial and temporal differences of carbon emissions and influencing factors in eight economic regions of China based on LMDI model.

With the gradual increase of international willingness to reach the carbon peak and carbon neutrality, this paper decomposes the influencing factors of China's carbon emission changes from 2008 to 2019 using the Logarithmic Mean Divisia Index model (LMDI), and analyzes the contribution amount and rate of each influencing factor. The results found that: for the whole country, the cumulative growth of carbon emissions during the study period is about 416,484.47 (104 tons), among which the economic growth effect plays a major role in promoting, with a cumulative contribution rate of 284.16%; The increase in regulation intensity and the optimization of industrial structure, however, suppress carbon emissions well, with a cumulative contribution rate of about - 199.21% and - 64.75%, respectively, during the study period. For economic regions, the cumulative influence direction of each driver is the same as that of the whole country, while the population size effect in the northeast economic region and the regulation input effect in the eastern coastal economic region act in the opposite direction from other economic regions, and the carbon emission reduction direction of the energy intensity effect varies from one economic region to another. Accordingly, this paper proposes policy recommendations to enhance regulatory intensity, optimize industrial and energy consumption structure, implement localized emission reduction strategies, and promote synergistic emission reduction in economic zones.

Global trends and forecasts of breast cancer incidence and deaths.

Breast cancer (BC) is one of the major public health challenges worldwide. Studies that address the new evidence on trends of BC are of great importance for preventing and controlling the occurrence and development of diseases and improving health. The aim of this study was to analyze the outcomes for the global burden of disease (GBD), incidence, deaths, and risk factors for BC from 1990 to 2019, and predict the GBD of BC until 2050 to inform global BC control planning efforts. In this study, the results show that the regions with low levels of socio-demographic index (SDI) will have the largest disease burden of BC in the future. The leading global risk factor for death attributable to BC in 2019 was metabolic risks, followed by behavioral risks. This study supports the worldwide urgent need for comprehensive cancer prevention and control strategies to reduce exposure, early screening, and improve treatment to effectively reduce the GBD of BC.

The impact of Water Ecological Civilization City Pilot on urban green innovation: the case of China.

As an essential part of ecological civilization, water ecological civilization has significant influence on the green and sustainable development of cities. Under the background of China's Water Ecological Civilization City Pilot (WECCP), based on data from 275 cities in China from 2007 to 2019 by using the difference-in-differences (DID) model, we empirically analyzed the influence of the WECCP establishment on urban green innovation and explored the impact mechanism in depth using a mediating effect model, which aimed to verify whether the "Porter hypothesis" holds true in China. The result indicated that the WECCP had made a remarkable contribution to enhancing urban green innovation in the pilot cities. Further research found that the input mechanism played an important mediating role. In addition, the heterogeneity test indicated that cities in the central region, at low administrative levels, and in the first batch of pilots gained more from the policy establishment. This paper has theoretical implications for understanding the derived innovation benefits of the environmental policy, practical implications for identifying new drivers of urban innovation, and provides related experience for the country to further promote and expand water ecological civilization construction and useful policy inspiration for other developing countries to formulate ecological and environmental policies.

Study on the measurement of industrial eco-efficiency, spatial distribution and influencing factors in Yangtze River Economic Belt.

Nowadays, China insists on the strategy of ecological priority and green development, and the Yangtze River Economic Belt is a pioneering demonstration belt for the construction of ecological civilization in China. Promoting industrial ecological efficiency is of great significance to Chinese sustainable development and high-quality economic development. Based on the provincial panel data of 11 provinces and cities in the Yangtze River Economic Belt region from 2011 to 2020, we use the super-efficient slacks-based measure of efficiency SBM model to measure the industrial eco-efficiency of the Yangtze River Economic Belt, reveal the spatial differences in industrial eco-efficiency of different provincial units, and explore the industrial eco-efficiency. The results show that: (1) from the perspective of the Yangtze River Economic Belt as a whole, industrial eco-efficiency is on a stable upward trend, but the efficiency level is not high, and there is more room for improvement; (2) in terms of the spatial distribution of industrial eco-efficiency in the Yangtze River Economic Belt, there are significant differences, with industrial eco-efficiency in the downstream region being higher than that in the midstream region and the upstream region, and the lowest in the midstream region, while in terms of the spatial distribution pattern, the industrial eco-efficiency of 11 provinces and cities in the Yangtze River Economic Belt eco-efficiency has a significant positive spatial autocorrelation; (3) in terms of influencing factors, economic development level, factor endowment, and foreign investment can significantly influence industrial eco-efficiency in the Yangtze River Economic Belt. The study's result helps provide theoretical guidance and practical reference for promoting the green and ecological development of industries in the Yangtze River Economic Belt.

Threshold Effect of Environmental Regulation and Green Innovation Efficiency: From the Perspective of Chinese Fiscal Decentralization and Environmental Protection Inputs.

In the context of China's 14th Five-Year Plan and 2035 visionary goals of national economic and social development, to achieve the national dual carbon goals, an innovation-driven green development strategy must be implemented, and the relationship between environmental regulation and green innovation efficiency must be clarified. Based on the DEA-SBM model, in this study, we measured the green innovation efficiency of 30 provinces and cities in China from 2011 to 2020 by introducing environmental regulation as the core explanatory variable, and two threshold variables, environmental protection input and fiscal decentralization, to empirically analyze the threshold effect of environmental regulation on green innovation efficiency. We found that: (1) The green innovation efficiency of 30 provinces and municipalities in China is spatially distributed as strong in the east and weak in the west. (2) A double-threshold effect exists with environmental protection input as the threshold variable. Environmental regulation showed an inverted N-shaped relationship of first inhibiting, then promoting, and finally inhibiting green innovation efficiency. (3) A double-threshold effect exists with fiscal decentralization as the threshold variable. Environmental regulation showed an inverted N-shaped relationship of inhibiting, promoting, and then inhibiting green innovation efficiency. The study results provide theoretical guidance and practical reference for China to achieve the dual carbon goal.

Using transcriptomics, proteomics and phosphoproteomics as new approach methodology (NAM) to define biological responses for chemical safety assessment.

Omic-based technologies are of particular interest and importance for hazard identification and health risk characterization of chemicals. Their application in the new approach methodologies (NAMs) anchored on cellular toxicity pathways is based on the premise that any apical health endpoint change must be underpinned by some alterations at the omic levels. In the present study we examined the cellular responses to two chemicals, caffeine and coumarin, by generating and integrating multi-omic data from multi-dose and multi-time point transcriptomic, proteomic and phosphoproteomic experiments. We showed that the methodology presented here was able to capture the complete chain of events from the first chemical-induced changes at the phosphoproteome level, to changes in gene expression, and lastly to changes in protein abundance, each with vastly different points of departure (PODs). In HepG2 cells we found that the metabolism of lipids and general cellular stress response to be the dominant biological processes in response to caffeine and coumarin exposure, respectively. The phosphoproteomic changes were detected early in time, at very low doses and provided a fast, adaptive cellular response to chemical exposure with 7-37-fold lower points of departure comparing to the transcriptomics. Changes in protein abundance were found much less frequently than transcriptomic changes. While challenges remain, our study provides strong and novel evidence supporting the notion that these three omic technologies can be used in an integrated manner to facilitate a more complete understanding of pathway perturbations and POD determinations for risk assessment of chemical exposures.

Disparities in Online Use Behaviours and Chinese Digital Inclusion: A 10-Year Comparison.

This study focuses on the disparities in Chinese online use behaviours (frequency and diversity) based on educational background and socioeconomic status over 10 years to reveal the Chinese digital inclusion process. We used the China Family Panel Studies (CFPS) 2010 and 2018 panels and considered the time and cohort effects separately. Ordinary least squares analysis revealed usage frequency. The generalized partial proportional odds model demonstrated participants' prioritization of online study, work, entertainment, and social activity. The results show that the profile of the individuals with the most time spent online has changed from those with high education and income levels to mid-range education and income levels. Individuals with high education and income levels prefer to use the internet for studying and working. There are no clear preference differences between entertainment and social activities amongst most educational backgrounds and socioeconomic statuses. Regarding frequency of internet use, digital inclusion has spread downwards from the upper to the middle classes. Regarding diverse internet uses, upper-class individuals prefer to conduct capital-enhancing activities, and youth remain the main force for diverse online activities; however, over time, middle-aged groups have increased their capital-enhancing activities, and older adults have increased their digital social activities.

Effectiveness of a nurse-led coaching of self-care agency intervention for elderly patients with total laryngectomy: study protocol for a randomised controlled trial.

INTRODUCTION: Due to functional defects and structural destruction after total laryngectomy, patients experienced the poor quality of life, especially for elderly. The barriers to accessing self-care in elderly patients were considered to result from complex and multifaceted interactions of biologic and social factors. Therefore, specific efforts to improve elderly patients' quality of life are needed. The purpose of our study is to verify nurse-led coaching of elderly patient self-care approaches, which can reduce logistic burden of patients and obtain the successful functional rehabilitation ultimately. METHODS AND ANALYSIS: Elderly patients (n=60) scheduled for total laryngectomy will be randomly divided into the intervention group and the control group. Patients in the control group received routinely nursing during hospitalisation and thereby at home after discharge received conventional family care without regular supervision of nurses. Patients in the intervention group will receive a series of self-care intervention based on the transtheoretical model during hospitalisation. During home after discharge, nurses will additionally evaluate and supervise the self-care effect of patients. The two groups of patients' self-care agency, self-efficacy, quality of life and nutritional status will be recorded separately at different time points. Primary outcome is the improvement of patients' self-care agency, and secondary outcome is the improvements of patients' self-efficacy, quality of life, nutritional states and 3-month unplanned readmission rate. ETHICS AND DISSEMINATION: The Ethics Committee of Hubei Cancer Hospital has approved this protocol (KYLLBA2020006). The findings of the trial will be disseminated through peer-reviewed journals, national or international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2100043731.

Bioequivalence evaluation and food effect assessment of Lisinopril/amlodipine tablets in healthy Chinese subjects under fasting and fed conditions.

PURPOSE: The combination of lisinopril and amlodipine has a marked additional effect on blood pressure and fewer side effects than individual monotherapy. This study was conducted to compare the pharmacokinetic parameters and evaluate the bioequivalence between two Lisinopril/amlodipine tablets in healthy Chinese subjects. METHODS: A single center, randomized, open-label, single-dose, two-period crossover bioequivalence study was designed in healthy Chinese subjects under both fasting and fed conditions. Blood samples were collected before drug administration and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 24, 36, 48, 72, 96, 144, 168 h after administration. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine the plasma concentration of lisinopril and amlodipine. Maximum concentration (Cmax) and area under the concentration-time curve (AUC) were used to evaluate bioequivalence. Adverse events were recorded. RESULTS: Ninety-two healthy subjects were enrolled, and 75 completed the study. The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ of lisinopril and amlodipine under both fasting and fed conditions fell within the conventional bioequivalence criteria of 0.80-1.25. A high-fat meal appeared to decrease the Cmax and AUC of lisinopril. No severe adverse events were observed. CONCLUSION: The trial demonstrated that the test and the reference lisinopril/amlodipine tablets were bioequivalent and well tolerated in Chinese people under fasting and fed conditions. TRIAL REGISTRATION: Clinical Trails.gov identifier, NCT04885660 (retrospectively registered in 13/05/ 2021).

Contrasting influences of biogeophysical and biogeochemical impacts of historical land use on global economic inequality.

Climate change has significant implications for macro-economic growth. The impacts of greenhouse gases and anthropogenic aerosols on economies via altered annual mean temperature (AMT) have been studied. However, the economic impact of land-use and land-cover change (LULCC) is still unknown because it has both biogeochemical and biogeophysical impacts on temperature and the latter differs in latitudes and disturbed land surface types. In this work, based on multi-model simulations from the Coupled Model Intercomparison Project Phase 6, contrasting influences of biogeochemical and biogeophysical impacts of historical (1850-2014) LULCC on economies are found. Their combined effects on AMT result in warming in most countries, which harms developing economies in warm climates but benefits developed economies in cold climates. Thus, global economic inequality is increased. Besides the increased AMT by the combined effects, day-to-day temperature variability is enhanced in developing economies but reduced in developed economies, which further deteriorates global economic inequality.

Heavy metal leaching behaviour and long-term environmental risk assessment of cement-solidified municipal solid waste incineration fly ash in sanitary landfill.

Cement solidification is a commonly used pre-treatment method for municipal solid waste incineration fly ash (MSWIFA) prior to sanitary landfill. However, the long-term environmental risk of cement-solidified MSWIFA blocks in the exposed scenario of zoning sanitary landfill remains unclear. In this study, the leaching characteristics of different heavy metals in cement-solidified MSWIFA blocks under deionized water and acid rain scenarios were firstly investigated. The leaching control mechanisms of heavy metals were also explored and applied to established mechanical models for the estimation of long-term environmental risk. Results revealed that Pb leaching from cement-solidified MSWIFA blocks was controlled by diffusion; Cu, Cr and As leaching was mainly controlled by surface wash-off and diffusion; and Ni leaching was mainly controlled by diffusion and dissolution. Additionally, the established bulk diffusion, first-order reaction/diffusion and diffusion/dissolution models could accurately fit the abovementioned three types of heavy metals with different leaching control mechanisms (R2 > 0.95). Under acid rain scenarios， according to the prediction results of the calibrated models, the cumulative leaching amount of Pb in 718 d was higher than the limit in GB16889-2008, the cumulative leaching amount of Cu, Cr, As and Ni did not exceed the limit in GB 16889-2008 even in 50 years. Therefore, the long-term environmental risk was relatively high for Pb but was low for Cu, Cr, As and Ni in cement-solidified MSWIFA blocks. This finding could be attributed to the strong alkali environment of cement-solidified MSWIFA blocks (pH > 12) that induced Pb salts (e.g. Pb(OH)2 and PbSO4) dissolution. Therefore, the removal of partially soluble Pb salts from freshly made cement-solidified MSWIFA blocks by water or natural rainwater (e.g. without final cover system) washing in the initial landfilling stage (e.g. the leachate drainage system remains functional) is an effective countermeasure to reduce the environmental risks in zoning sanitary landfill.

The Costs and Benefits of Two Secondary Symbionts in a Whitefly Host Shape Their Differential Prevalence in the Field.

Insects commonly harbor maternally inherited intracellular symbionts in nature, and the microbial partners often exert influence on host reproduction and fitness to promote their prevalence. Here, we investigated composition of symbionts and their biological effects in the invasive Bemisia tabaci MED species of a whitefly complex. Our field surveys revealed that populations of the MED whitefly, in addition to the primary symbiont Portiera, mainly contain two secondary symbionts Hamiltonella, which is nearly fixed in the host populations, and Cardinium with infection frequencies ranging from 0 to 86%. We isolated and established Cardinium-positive and Cardinium-free whitefly lines with a similar nuclear genetic background from a field population, and compared performance of the two whitefly lines. The infection of Cardinium incurred significant fitness costs on the MED whitefly, including reduction of fecundity and egg viability as well as delay in development. We then selectively removed Hamiltonella from the Cardinium-free whitefly line and compared performance of two whitefly lines, one harboring both Portiera and Hamiltonella and the other harboring only Portiera. While depletion of Hamiltonella had little or only marginal effects on the fecundity, developmental rate, and offspring survival, the Hamiltonella-free whitefly line produced very few female offspring, often reducing the progeny female ratio from about 50% to less than 1%. Our findings indicate that the varying costs and benefits of the association between these two symbionts and the MED whitefly may play an important role in shaping their differential prevalence in the field.

Water quality criteria and ecological risk assessment for ammonia in the Shaying River Basin, China.

Current Chinese surface water environmental quality standard GB3838-2002 for ammonia fails to take water quality factors and native organism distributions in different basins into consideration. In this study, ammonia toxicity tests were performed using three aquatic organisms native to the Shaying River Basin (China). Published ammonia toxicity data with pH and temperature, and toxicity data acquired in this study were used to establish water quality criteria. The final criterion maximum concentration (CMC) and criterion continuous concentration (CCC) for the Shaying River Basin were 5.09 and 1.36 (mg total ammonia nitrogen (TAN))/L (pH 7 and 20 °C), respectively. In addition, based on the corresponding relationship between ammonia toxicity and temperature and pH, the ecological risk assessment of ammonia was conducted in different seasons for the Shaying River using a tiered approach of both hazard quotient (HQ) and the joint probability (JPC) methods. Two methods gave consistent results: the ecological risks of ammonia to aquatic species in the Shaying River Basin were severe and the risk could be ranked as wet season > flat season > dry season. It is therefore indicating that monitoring, evaluation, and early warning of ammonia pollution need to be taken to prevent and control the risks posed by ammonia pollution, especially for wet season (because of high temperatures and pH) or flat season (because of high pH values). We hope the present work could provide valuable information to manage and control ammonia pollution in the Shaying River Basin.

Where Skilled Nursing Facility Residents Get Acute Care: Is the Emergency Department the Medical Home?

OBJECTIVES: This study aimed to characterize the distribution of acute care visits among Medicare beneficiaries receiving skilled nursing facility (SNF) services. METHODS: We conducted a cross-sectional analysis of a 20% sample of continuously enrolled Medicare beneficiaries in the 2012 Chronic Condition Warehouse data set. Beneficiaries were grouped by the number of days of SNF services, and acute care visits were categorized as "before SNF," "during SNF," or "after SNF." RESULTS: Among the 10,717,786 Medicare beneficiaries analyzed, 384,312 (3.6%) had at least one SNF stay. DISCUSSION: Beneficiaries who received SNF services had a higher proportion of acute care visits made to emergency departments (EDs) than beneficiaries who did not receive SNF services. Also, a higher proportion of acute care visits were made to EDs by beneficiaries after a SNF stay in comparison to residents actively residing in a SNF. The acute care capabilities of SNFs and post-SNF transitions of care to the community setting are discussed.

Low initial trough concentration of rituximab is associated with unsatisfactory response of first-line R-CHOP treatment in patients with follicular lymphoma with grade 1/2.

For follicular lymphoma (FL) with grade 1/2, the complete response (CR) rate of the first-line R-CHOP treatment was significantly low. In this study, we assessed the rationality of the administration of rituximab for FL patients with grade 1/2 based on concentration-response relationship analyses. Thus, we conducted a prospective pharmacokinetic (PK) study in 68 FL patients with grades 1-3 treated with R-CHOP at 21-day intervals. Plasma rituximab concentrations were quantified using ELISA and the population PK modeling was established with Phoenix® NLMETM. The first cycle trough concentration (C1-trough) of rituximab was a significant independent risk factor for achieving CR in matched-pair logistic regression analysis, rather than the concentrations in later cycles; the recommendatory minimum optimal C1-trough was 13.60 µg/mL. Patients with grade 1/2 had significantly lower C1-trough compared with grade 3 (12.21 µg/mL vs. 23.45 µg/mL, P < 0.001), only 30% patients with grade 1/2 could reach 13.60 µg/mL, compared with 91.67% in patients with grade 3, which was in accord with its unsatisfactory CR rates (43.33% vs. 76.32%). The stage indicating the tumor burden (the target) was a crucial influence factor for C1-trough, accounting for 40.70% of its variability, 70% patients with grade 1/2 were stage IV in this study, since the systemic therapy only started at the disseminated disease stage. The initial dose of 1800 mg was recommended by Monte Carlo simulation for patients with grade 1/2. In summary, low C1-trough accounted for low-grade FL's unsatisfactory CR rate, designing the first dosage of rituximab should be a very important component of individualized therapy for FL.

CD4-binding obstacles in conformational transitions and allosteric communications of HIV gp120.

As the only exposed viral protein at the membrane surface of HIV, envelope glycoprotein gp120 is responsible for recognizing host cells and mediating virus-cell membrane fusion. Available structures of gp120 indicate that it exhibits two distinct conformational states, called closed and open states. Although experimental data demonstrates that CD4 binding stabilizes open state of gp120, detailed structural dynamics and kinetics of gp120 during this process remain elusive. Here, two open-state gp120 simulation systems, one without any ligands (ligand-free) and the other complexed with CD4 (CD4-bound), were subjected to microsecond-scale molecular dynamics simulations following the conformational transitions and allosteric pathways of gp120 evaluated by using the Markov state model and a network-based method, respectively. Our results provide an atomic-resolution description of gp120 conformational transitions, suggesting that gp120 is intrinsically dynamic from the open state to closed state, whereas CD4 binding blocks these transitions. Consistent with experimental structures, five metastable conformations with different orientations of the V1/V2 region and V3 loop have been extracted. The binding of CD4 significantly enhances allosteric communications from the CD4-binding site to V3 loop and ß20-21 hairpin, resulting in high-affinity interactions with coreceptors and activation of the conformational transitions switcher, respectively. This study will facilitate the structural understanding of the CD4-binding effects on conformational transitions and allosteric pathways of gp120.

DriverML: a machine learning algorithm for identifying driver genes in cancer sequencing studies.

Although rapid progress has been made in computational approaches for prioritizing cancer driver genes, research is far from achieving the ultimate goal of discovering a complete catalog of genes truly associated with cancer. Driver gene lists predicted from these computational tools lack consistency and are prone to false positives. Here, we developed an approach (DriverML) integrating Rao's score test and supervised machine learning to identify cancer driver genes. The weight parameters in the score statistics quantified the functional impacts of mutations on the protein. To obtain optimized weight parameters, the score statistics of prior driver genes were maximized on pan-cancer training data. We conducted rigorous and unbiased benchmark analysis and comparisons of DriverML with 20 other existing tools in 31 independent datasets from The Cancer Genome Atlas (TCGA). Our comprehensive evaluations demonstrated that DriverML was robust and powerful among various datasets and outperformed the other tools with a better balance of precision and sensitivity. In vitro cell-based assays further proved the validity of the DriverML prediction of novel driver genes. In summary, DriverML uses an innovative, machine learning-based approach to prioritize cancer driver genes and provides dramatic improvements over currently existing methods. Its source code is available at https://github.com/HelloYiHan/DriverML.