Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21

Traditionally, well-defined three-dimensional structure has been thought to be essential for protein function. However, myriad biological functions are performed by highly dynamic, intrinsically disordered proteins (IDPs). IDPs often fold upon binding their biological targets and frequently show 'binding diversity' by targeting multiple ligands. We sought to understand the physical basis of IDP binding diversity and report here that the cyclin-dependent kinase (Cdk) inhibitor p21(Cip1) adaptively binds to and inhibits the various Cdk-cyclin complexes that regulate eukaryotic cell division. Using results from NMR spectroscopy and biochemical and cellular assays, we show that structural adaptability of a helical subdomain within p21, termed LH, enables two other subdomains, D1 and D2, to specifically bind conserved surface features of the cyclin and Cdk subunits, respectively, within otherwise structurally distinct Cdk-cyclin complexes. Adaptive folding upon binding is likely to mediate the diverse biological functions of the thousands of IDPs present in eukaryotes.     

B Cells Regulate Neutrophilia during Mycobacterium tuberculosis Infection and BCG Vaccination by Modulating the Interleukin-17 Response

We have previously demonstrated that B cells can shape the immune response to Mycobacterium tuberculosis, including the level of neutrophil infiltration and granulomatous inflammation at the site of infection. The present study examined the mechanisms by which B cells regulate the host neutrophilic response upon exposure to mycobacteria and how neutrophilia may influence vaccine efficacy. To address these questions, a murine aerosol infection tuberculosis (TB) model and an intradermal (ID) ear BCG immunization mouse model, involving both the μMT strain and B cell-depleted C57BL/6 mice, were used. IL (interleukin)-17 neutralization and neutrophil depletion experiments using these systems provide evidence that B cells can regulate neutrophilia by modulating the IL-17 response during M. tuberculosis infection and BCG immunization. Exuberant neutrophilia at the site of immunization in B cell-deficient mice adversely affects dendritic cell (DC) migration to the draining lymph nodes and attenuates the development of the vaccine-induced Th1 response. The results suggest that B cells are required for the development of optimal protective anti-TB immunity upon BCG vaccination by regulating the IL-17/neutrophilic response. Administration of sera derived from M. tuberculosis-infected C57BL/6 wild-type mice reverses the lung neutrophilia phenotype in tuberculous μMT mice. Together, these observations provide insight into the mechanisms by which B cells and humoral immunity modulate vaccine-induced Th1 response and regulate neutrophila during M. tuberculosis infection and BCG immunization.     

Endémie bilharzienne à Schistosoma mansoni à la vallée du Kou : caractérisation du système de transmission et impact socioéconomique

Schistosomiasis is one of the waterborne diseases which benefit from environmental and behavioral changes induced by the mobilization of surface water resources in Sahelian countries, such as Burkina Faso. Studies have established the existence of human schistosomiasis in the Kou valley, one of the oldest hydro-agricultural zones in the country. However, the role of population behavior in the transmission pattern of this disease and its socioeconomic impact in this valley are poorly understood. It is in response to these questions that this study was undertaken. The objectives of this study were to identify activities that exposed most of the Valley's population to infection by schistosomiasis, and to contribute knowledge on the consequences of this disease. The study was conducted in the cold dry season at the Kou Valley, located in the South Sudanese area of Burkina Faso. It has adopted the strategy of direct observation to examine host–parasites interactions. The study of the socioeconomic consequences of the infection has been first to identify subjects that actually carry the parasite by screening the population by the Kato–Katz method. These were then subjected to a questionnaire. Data were analyzed using Epi Info 6.4. This work has revealed six activities at risk of infection for the residents of the Valley with an increased risk of factor for rice farming, household activities and swimming. In view of these activities, women and young people seem to be most vulnerable to infection. This disease causes significant economic losses as a function of socio-professional categories of infected persons.     

ETMB-RBF: Discrimination of Metal-Binding Sites in Electron Transporters Based on RBF Networks with PSSM Profiles and Significant Amino Acid Pairs

Background

Cellular respiration is the process by which cells obtain energy from glucose and is a very important biological process in living cell. As cells do cellular respiration, they need a pathway to store and transport electrons, the electron transport chain. The function of the electron transport chain is to produce a trans-membrane proton electrochemical gradient as a result of oxidation–reduction reactions. In these oxidation–reduction reactions in electron transport chains, metal ions play very important role as electron donor and acceptor. For example, Fe ions are in complex I and complex II, and Cu ions are in complex IV. Therefore, to identify metal-binding sites in electron transporters is an important issue in helping biologists better understand the workings of the electron transport chain.

Methods

We propose a method based on Position Specific Scoring Matrix (PSSM) profiles and significant amino acid pairs to identify metal-binding residues in electron transport proteins.

Results

We have selected a non-redundant set of 55 metal-binding electron transport proteins as our dataset. The proposed method can predict metal-binding sites in electron transport proteins with an average 10-fold cross-validation accuracy of 93.2% and 93.1% for metal-binding cysteine and histidine, respectively. Compared with the general metal-binding predictor from A. Passerini et al., the proposed method can improve over 9% of sensitivity, and 14% specificity on the independent dataset in identifying metal-binding cysteines. The proposed method can also improve almost 76% sensitivity with same specificity in metal-binding histidine, and MCC is also improved from 0.28 to 0.88.

Conclusions

We have developed a novel approach based on PSSM profiles and significant amino acid pairs for identifying metal-binding sites from electron transport proteins. The proposed approach achieved a significant improvement with independent test set of metal-binding electron transport proteins.     

The Application of the Grey Disaster Model to Forecast Epidemic Peaks of Typhoid and Paratyphoid Fever in China

Objective

The objectives of this study were to forecast epidemic peaks of typhoid and paratyphoid fever in China using the grey disaster model, to evaluate its feasibility of predicting the epidemic tendency of notifiable diseases.

Methods

According to epidemiological features, the GM(1,1) model and DGM model were used to build the grey disaster model based on the incidence data of typhoid and paratyphoid fever collected from the China Health Statistical Yearbook. Model fitting accuracy test was used to evaluate the performance of these two models. Then, the next catastrophe date was predicted by the better model.

Results

The simulation results showed that DGM model was better than GM(1,1) model in our data set. Using the DGM model, we predicted the next epidemic peak time will occur between 2023 to 2025.

Conclusion

The grey disaster model can predict the typhoid and paratyphoid fever epidemic time precisely, which may provide valuable information for disease prevention and control.     

The Risk of Cancer in Patients with Generalized Anxiety Disorder: A Nationwide Population-Based Study

Objective

To evaluate the risk of cancer among patients with generalized anxiety disorder (GAD) in a nationwide population-based dataset.

Methods

We recruited newly-diagnosed GAD patients aged 20 years or older without antecedent cancer from the Taiwan National Health Insurance Research database between 2000–2010. Standardized incidence ratios (SIRs) of cancers were calculated in GAD patients, and the subgroup of GAD patients diagnosed by psychiatric specialists.

Results

A total of 559 cancers developed among 19,793 GAD patients with a follow-up of 89,485 person-years (median follow-up of 4.34 years), leading to a significantly increased SIR of 1.14 [95% confidence interval (CI) 1.05–1.24]. Male GAD patients had a significantly increased SIR overall (1.30, 95% CI 1.15–1.46) and for lung and prostate cancer (1.77, 95% CI 1.33–2.30 and 2.17, 95% CI 1.56–2.93, respectively). Patients over 80 years of age also had a significantly increased SIR (1.56, 95% CI 1.25–1.92), especially in males. However, psychiatrist-diagnosed GAD patients did not show increased cancer risk relative to the general population, perhaps due to having fewer physical comorbidities than non-psychiatrist-diagnosed GAD patients.

Conclusion

This study found that overall cancer risk is elevated among patients with GAD. The risk of lung and prostate cancer also increased in male patients with GAD. This increased cancer risk may be due to physical comorbidities and surveillance bias. Further prospective study is necessary to confirm these findings.     

Changes in Forest Soil Properties in Different Successional Stages in Lower Tropical China

Background

Natural forest succession often affects soil physical and chemical properties. Selected physical and chemical soil properties were studied in an old-growth forest across a forest successional series in Dinghushan Nature Reserve, Southern China.

Methodology/Principal Findings

The aim was to assess the effects of forest succession change on soil properties. Soil samples (0–20 cm depth) were collected from three forest types at different succession stages, namely pine (Pinus massoniana) forest (PMF), mixed pine and broadleaf forest (PBMF) and monsoon evergreen broadleaf forest (MEBF), representing early, middle and advanced successional stages respectively. The soil samples were analyzed for soil water storage (SWS), soil organic matter (SOM), soil microbial biomass carbon (SMBC), pH, NH₄ ⁺-N, available potassium (K), available phosphorus (P) and microelements (available copper (Cu), available zinc (Zn), available iron (Fe) and available boron (B)) between 1999 and 2009. The results showed that SWS, SOM, SMBC, Cu, Zn, Fe and B concentrations were higher in the advanced successional stage (MEBF stage). Conversely, P and pH were lower in the MEBF but higher in the PMF (early successional stage). pH, NH₄ ⁺-N, P and K declined while SOM, Zn, Cu, Fe and B increased with increasing forest age. Soil pH was lower than 4.5 in the three forest types, indicating that the surface soil was acidic, a stable trend in Dinghushan.

Conclusion/Significance

These findings demonstrated significant impacts of natural succession in an old-growth forest on the surface soil nutrient properties and organic matter. Changes in soil properties along the forest succession gradient may be a useful index for evaluating the successional stages of the subtropical forests. We caution that our inferences are drawn from a pseudo-replicated chronosequence, as true replicates were difficult to find. Further studies are needed to draw rigorous conclusions regarding on nutrient dynamics in different successional stages of forest.