Brain-wide correspondence of neuronal epigenomics and distant projections.

Single-cell analyses parse the brain's billions of neurons into thousands of 'cell-type' clusters residing in different brain structures1. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use.

Topical Melatonin Exerts Immunomodulatory Effect and Improves Dermatitis Severity in a Mouse Model of Atopic Dermatitis.

Oral melatonin supplement has been shown to improve dermatitis severity in children with AD, but the mechanism of the effect is unclear, and it is uncertain whether melatonin has a direct immunomodulatory effect on the dermatitis. Topical melatonin treatment was applied to DNCB-stimulated Balb/c mice, and gross and pathological skin findings, serum IgE, and cytokine levels in superficial lymph nodes were analyzed. Secretion of chemokines and cell proliferative response after melatonin treatment in human keratinocyte HaCaT cells were also studied. We found that in DNCB-stimulated Balb/c mice, topical melatonin treatment improved gross dermatitis severity, reduced epidermal hyperplasia and lymphocyte infiltration in the skin, and decreased IP-10, CCL27, IL-4, and IL-17 levels in superficial skin-draining lymph nodes. Melatonin also reduced cytokine-induced secretion of AD-related chemokines IP-10 and MCP-1 and decreased IL-4-induced cell proliferation in HaCaT cells. Melatonin seems to have an immunomodulatory effect on AD, with IP-10 as a possible target, and topical melatonin treatment is a potentially useful treatment for patients with AD.

Decorating Bacteria with a Therapeutic Nanocoating for Synergistically Enhanced Biotherapy.

Disorders in the gut microbiota have been implicated in various diseases, such as inflammatory bowel diseases, diabetes, and cancers. Oral microecologics are of great importance due to their ability to directly intervene the gut microbiome as well as their noninvasiveness and low side effects, while have suffered from low bioavailability and a single therapeutic effect. Here, probiotics are coated with a therapeutic nanocoating for synergistically enhanced biotherapy, a method inspired by the robust protective and therapeutic effectiveness of silkworm cocoon. With its transition from a random coil to ß-sheet conformation, silk fibroin can self-assemble onto the surface of bacteria. By a simple layer-by-layer procedure, an entire nanocoating can be formed along with a near quantitative coating ratio and almost uninfluenced bacterial viability. Thanks to its protective barrier role and innate pharmaceutical activity, silk fibroin nanocoating endows the coated bacteria with a markedly improved survival against gastric insults and a synergistically enhanced therapeutic effect in a murine model of intestinal mucositis. This work demonstrates how therapeutic elements can be combined with probiotics via a simple coating strategy and proposes an alternative to enhance bioavailability and treatment efficacy of oral microecologics.

Acupuncture Combined with Hydrotherapy in Diabetes Patients with Mild Lower-Extremity Arterial Disease: A Prospective, Randomized, Nonblinded Clinical Study.

BACKGROUND The aim of this pragmatic study was to explore the intervention of acupuncture combined with hydrotherapy and perceived effects in type 2 diabetic patients with recently diagnosed, mild, lower-extremity arterial disease (LEAD) in comparison with a control group. MATERIAL AND METHODS One hundred twenty-six diabetes patients who were diagnosed mild LEAD according to ankle-brachial blood pressure index (ABPI) and peripheral neuropathy symptom were randomly assigned to either an experimental (n=64) or control group (n=62). The experimental group attended and completed (1) a 30-min session of acupuncture in certain selected points, and (2) a 30-min hydrotherapy exercise every 2 days for 15 weeks. The outcome parameters were assessed at baseline, after intervention, and at 6-week follow-up. RESULTS The intervention was associated with an improvement in leg flow conductance and partial physical capacities, including chair-sit-and-reach, the walking impairment questionnaire (WIQ), and physical component summary score (PCS), compared to the control group. The treatment benefits were sustained throughout the 6-week follow-up endpoint. There was no difference in fasting glucose levels, Hb1Ac, blood pressure, or BMI after the intervention. At the endpoint of 6-week follow-up, acupuncture plus hydrotherapy appeared to reduce inflammatory response by decreasing IL-6, TNF-α, malondialdehyde, and SOD, and increasing glutathione. CONCLUSIONS Acupuncture plus hydrotherapy, without significant glycemic-controlling effects in the type 2 diabetic patients with mild LEAD, exerts a measurable benefit in disease-specific physical functions and health-related quality of life. Our results suggest that the combined therapy regulates the inflammatory process and oxidative stress and contributes to immune protection.

Identification of Herb Pairs in Esophageal Cancer.

BACKGROUND: Chinese herbal medicine (CHM) is used widely to treat various diseases, including cancer. However, effective herb pairs for treating specific cancer types have so far not been identified. Here, we aimed to calculate the survival benefits of herb pairs by cluster analysis, association rules, and survival evaluation in patients with esophageal cancer (EC) treated with CHM. PATIENTS AND METHODS: 59 patients with EC who received 176 prescriptions including 178 types of herbs were enrolled into the study. The herb pairs were identified by both cluster analysis and association rules. Overall survival (OS) was estimated by the Kaplan-Meier method. RESULTS: Eight groups of herb pairs were identified by cluster analysis, and 4 groups of herb pairs were identified by association rules. Of these, 3 groups of herb pairs were identified by both methods. OS estimation showed that the pair of chicken gizzard-membrane/Astragalus was associated with improved survival in patients with EC treated with CHM. CONCLUSION: Patients who received prescriptions containing the pair of chicken gizzard-membrane and Astragalus had improved OS compared with patients who received prescriptions lacking this pair.

IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes.

Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp® Simulator, and GastroPlus™) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (Foral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foral was also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. Foral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.

IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2: An introduction to the simulation exercise and overview of results.

Orally administered drugs are subject to a number of barriers impacting bioavailability (Foral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp®, and GastroPlus™) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details. 43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.). Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, Foral and relative AUC (Frel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations. A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.

[Response of Inflow Water Quality to Land Use Pattern in Northern Watershed of Lake Erhai].

The inherent relationship between land use pattern and inflow water quality is essential for nonpoint source pollution study. Response of inflow river quality to land use pattern in Northern part of Lake Erhai Watershed was analyzed in aspects of land use composition and configuration using spatial analysis and statistical analysis methods. The results indicated that as land use composition indexes, average slope and vegetation area percentage had significant relationship with TN and TP of inflow rivers. As land use configuration indexes, patch density, patch density of agriculture land and landscape shape index of water had significant relationship with TP and NH4+-N of inflow rivers. Response of inflow river quality to land use pattern was better at class level than at landscape level. Water quality response indicators were TP in rainy season and NH4+-N in dry season, of which regression adjustment coefficient R2 was 0.761 and 0.978, respectively. Response of inflow river quality to land use pattern was better in dry season than in rainy season, and the water quality response indicators were TN, TP and NH4+-N. Improving vegetation coverage and agriculture land intensive degree and avoiding human disturb to natural water area especially in dry season were suggested in nonpoint source pollution control of northern watershed of Lake Erhai Watershed. Later research on relationship between land use configuration and inflow river quality should better be at class level.

[Analysis on traditional Chinese medicine prescriptions treating cancer-related anorexia syndrome based on grey system theory combined with multivariate analysis method and discovery of new prescriptions].

Cancer-related anorexia syndrome (CACS) is one of the main causes for death at present as well as a syndrome seriously harming patients' quality of life, treatment effect and survival time. In current clinical researches, there are fewer reports about empirical traditional Chinese medicine(TCM) prescriptions and patent prescriptions treating CACS, and prescription rules are rarely analyzed in a systematic manner. As the hidden rules are not excavated, it is hard to have an innovative discovery and knowledge of clinical medication. In this paper, the grey screening method combined with the multivariate statistical method was used to build the ″CACS prescriptions database″. Based on the database, totally 359 prescriptions were selected, the frequency of herbs in prescription was determined, and commonly combined drugs were evolved into 4 new prescriptions for different syndromes. Prescriptions of TCM in treatment of CACS gave priority to benefiting qi for strengthening spleen, also laid emphasis on replenishing kidney essence, dispersing stagnated liver-qi and dispersing lung-qi. Moreover, interdependence and mutual promotion of yin and yang should be taken into account to reflect TCM's holism and theory for treatment based on syndrome differentiation. The grey screening method, as a valuable traditional Chinese medicine research-supporting method, can be used to subjectively and objectively analyze prescription rules; and the new prescriptions can provide reference for the clinical use of TCM for treating CACS and the drug development.

[Relationship Between Agricultural Land and Water Quality of Inflow River in Erhai Lake Basin].

We studied the relationship between agricultural land and water quality of inflow river in Erhai Lake Basin, by means of spatial and statistical analysis, from the perspective of comprehensive agricultural land and the area percentage of different types of agricultural land. The obtained results indicated that inflow water quality showed a significant spatial difference, the inflow TP pollution in the western inflow rivers of Erhai Basin was serious. The major pollution indicators in the northern and southern inflow rivers (except for D3) were organic matter and nitrogen. The area percentage of agricultural land had a significantly indicative effect on the water quality of inflow river. The area percentage of comprehensive agricultural land negatively correlated with permanganate index, NH4(+) -N, TN and TP contents in wet season, the correlation coefficients were - 0.859, - 0.565, - 0.693, - 0.181. It negatively correlated with permanganate index and NH4(+) -N content in dry season, the correlation coefficients were - 0.384, - 0.328. It had positive relationships with and TN, TP content in dry season, the correlation coefficients were 0.221 and 0.146. The area percentage of different types of agricultural land had an obviously indicative effect on the inflow water quality. Farmland positively correlated with TN and TP contents both in wet and dry seasons. The correlation coefficients between farmland and TN, TP were 0.252, 0.581 in rainy season and were 0.149, 0.511 in dry season. It had positive and negative relationships with permanganate index, NH4(+) -N content in wet season and dry season, respectively. The correlation coefficients between farmland and permanganate index, NH4(+) -N were 0.388, 0.053 in rainy season and were -0.137, -0.147 in dry season. Forest land exhibited an opposite performance to that of farmland. The correlation coefficients between forest land and TN, TP, permanganate index, NH4(+) -N were - 0.526, - 0.275, - 0.469, -0.155 in rainy season and were -0.012, -0.100, 0.282, 0.151 in dry season. Fishpond had a weakly indicative effect on TN and TP contents. Meadowland and orchard had a similar performance with that of farmland in wet season, but were opposite to that of farmland in dry season. Therefore, management for farmland, meadowland and orchard in the north and south during wet season should be emphasized during the agricultural nonpoint source control in Erhai Lake Basin.

Spatial and temporal variations of crop fertilization and soil fertility in the loess plateau in china from the 1970s to the 2000s.

Increased fertilizer input in agricultural systems during the last few decades has resulted in large yield increases, but also in environmental problems. We used data from published papers and a soil testing and fertilization project in Shaanxi province during the years 2005 to 2009 to analyze chemical fertilizer inputs and yields of wheat (Triticum aestivum L.) and maize (Zea mays L.) on the farmers' level, and soil fertility change from the 1970s to the 2000s in the Loess Plateau in China. The results showed that in different regions of the province, chemical fertilizer NPK inputs and yields of wheat and maize increased. With regard to soil nutrient balance, N and P gradually changed from deficit to surplus levels, while K deficiency became more severe. In addition, soil organic matter, total nitrogen, alkali-hydrolysis nitrogen, available phosphorus and available potassium increased during the same period. The PFP of N, NP and NPK on wheat and maize all decreased from the 1970s to the 2000s as a whole. With the increase in N fertilizer inputs, both soil total nitrogen and alkali-hydrolysis nitrogen increased; P fertilizer increased soil available phosphorus and K fertilizer increased soil available potassium. At the same time, soil organic matter, total nitrogen, alkali-hydrolysis nitrogen, available phosphorus and available potassium all had positive impacts on crop yields. In order to promote food safety and environmental protection, fertilizer requirements should be assessed at the farmers' level. In many cases, farmers should be encouraged to reduce nitrogen and phosphate fertilizer inputs significantly, but increase potassium fertilizer and organic manure on cereal crops as a whole.

Effect of methamidophos and urea application on microbial communities in soils as determined by microbial biomass and community level physiological profiles.

In this study, we evaluated the effect of the application by two agrochemicals, methamidophos (O,S-dimethyl phosphoroamidothioate) and urea, on microbial diversity in soil, using the combined approaches of soil microbial biomass analysis and community level physiological profiles (CLPPs). The results showed that both a low and a high level of methamidophos application (CS2 and CS3) and urea application (CS4) significantly decreased microbial biomass C (Cmic) by 41-83% compared with the control (CS1). The soil organic C (Corg) values of CS3 and CS4 were significantly higher and lower by 24% and 14%, respectively, than that of CS1. Similarly to Cmic, the values of Cmic/Corg of the three applied soils which decreased were lower by 31-84% than that of CS1. In contrast, the respiration activity of the three applied soils were significantly higher than the control. Agrochemical application also significantly increased the soil total of N and P (Ntol and Ptol) and decreased the Corg/Ntol and Corg/Ptol values. The CLPPs results showed that the AWCD (average well color development) of the three applied soils were significantly higher than that of CS1 during the incubation period. Substrate richness, Shannon and Simpson indices of microbial communities under chemical stresses, increased significantly. In addition, the CFU (colony-forming unit) numbers of methamidophos metabolized bacteria in CS2 and CS3 also increased significantly by 86.1% and 188.9% compared with that of CS1. The combined results suggest that agrochemicals reduce microbial biomass and enhance functional diversities of soil microbial communities; meanwhile, some species of bacteria may be enriched in soils under methamidophos stress.

Phosphorus fractions and the effect of pH on the phosphorus release of the sediments from different trophic areas in Taihu Lake, China.

The sediment characteristics, different phosphorus (P) fraction concentrations and the effect of pH on P release were investigated in a shallow eutrophic lake in China. The total phosphorus (TP) concentrations in the sediments ranged greatly from 420 to 3408 mg kg(-1) and inorganic P (IP) was the main P fraction. For the heavily eutrophic sediment, IP mainly consisted of NaOH-P; while for the mesotrophic sediments, IP mainly consisted of HCl-P. The rate of P release decreased as pH increased from 2 to 6. But it increased as pH increased from 8 to 12. It is suggested that high pH promoted the release of NaOH-P, and low pH promoted the release of HCl-P, and there was no P release occurring in the neutral condition.

[Phosphate adsorption characteristics onto the sediments from shallow lakes in the middle and lower reaches of the Yangtze River].

Adsorption isotherms and kinetics of phosphate onto the 11 sediments taken from shallow lakes in the middle and lower reaches of the Yangtze River were determined in laboratory, and the effect of physical and chemical properties of the sediments on its phosphate adsorption characteristics was also analyzed. The results indicate that: (1) The process of phosphate adsorption onto sediments mainly occurred within 0-10 h, the maximum adsorption rates occurred within 0-0.5 h, and then attends to a dynamic equilibrium; (2) Between the NAP and its organic matter, CEC, total phosphorus, inorganic phosphorus, organic phosphorus, Fe/Al-phosphorus and total nitrogen have remarkable positive correlation; between the maximum adsorption of phosphate and its CEC, inorganic phosphorus, organic matter and total phosphorus have remarkable negative correlation; between the total maximum adsorption of phosphate and its organic matter, CEC, total phosphorus, inorganic phosphorus, organic phosphorus, Fe/Al-phosphorus and total nitrogen have remarkable positive correlation; (3) As regards water quality of the shallow lakes in the middle and lower reaches of the Yangtze River at present, its sediment exists desorption. Between the adsorption-desorption equilibrium concentrations of phosphate onto the sediments and its organic matter, CEC, total nitrogen, the total phosphorus and the content of every form phosphorous have a remarkable positive correlation. Even the sediment from heavily polluted lake also has the tendency to release phosphate into the overlying water in this study.