Nancemacmillan5342

Streptococcus pyogenes (Group A streptococcus; GAS) is an important human pathogen responsible for mild to severe, life-threatening infections. GAS expresses a wide range of virulence factors, including the M family proteins. The M proteins allow the bacteria to evade parts of the human immune defenses by triggering the formation of a dense coat of plasma proteins surrounding the bacteria, including IgGs. However, the molecular level details of the M1-IgG interaction have remained unclear. Here, we characterized the structure and dynamics of this interaction interface in human plasma on the surface of live bacteria using integrative structural biology, combining cross-linking mass spectrometry and molecular dynamics (MD) simulations. We show that the primary interaction is formed between the S-domain of M1 and the conserved IgG Fc-domain. In addition, we show evidence for a so far uncharacterized interaction between the A-domain and the IgG Fc-domain. Both these interactions mimic the protein G-IgG interface of group C and G streptococcus. These findings underline a conserved scavenging mechanism used by GAS surface proteins that block the IgG-receptor (FcγR) to inhibit phagocytic killing. We additionally show that we can capture Fab-bound IgGs in a complex background and identify XLs between the constant region of the Fab-domain and certain regions of the M1 protein engaged in the Fab-mediated binding. Our results elucidate the M1-IgG interaction network involved in inhibition of phagocytosis and reveal important M1 peptides that can be further investigated as future vaccine targets.In a human immunodeficiency virus (HIV) clinic for children and their families in Eswatini, we sought to understand the use of antibiotics and identify specific areas for improvement. We performed a retrospective patient chart review as part of a quality improvement (QI) initiative to assess antimicrobial use before and after implementation of a standardized antimicrobial guide. For each prescribing period, 100 random patient encounters were selected for review if the indication for antibiotics, duration, and dose were consistent with World Health Organization (WHO) guidelines. Two physicians reviewed each encounter using a structured abstraction tool, with a third resolving discrepancies. Results were analyzed using a chi-square test of proportions and a structured survey was performed to assess perceptions of the guide. After the implementation of an antimicrobial guide, there was a significant decrease in the proportion of clinic visits with an antibiotic prescribed (p less then 0.001). Incorrect indication for antimicrobial use decreased from 20.4% in the initial period to 10.31% and 10.2% but did not reach significance (p = .0621) in the subsequent periods after implementation. Incorrect dose/duration decreased from 10.47% in the initial period to 7.37% and 3.1% in the subsequent periods, but this was also was not significant (p = 0.139). All prescribers who completed the survey felt that it positively impacted their prescribing. Our study found that an antimicrobial guide reduced and improved the prescription of antimicrobials, demonstrating practical solutions can have a lasting impact on prescribing in low resource settings.Bistability is a common mechanism to ensure robust and irreversible cell cycle transitions. Whenever biological parameters or external conditions change such that a threshold is crossed, the system abruptly switches between different cell cycle states. Experimental studies have uncovered mechanisms that can make the shape of the bistable response curve change dynamically in time. Here, we show how such a dynamically changing bistable switch can provide a cell with better control over the timing of cell cycle transitions. Moreover, cell cycle oscillations built on bistable switches are more robust when the bistability is modulated in time. Our results are not specific to cell cycle models and may apply to other bistable systems in which the bistable response curve is time-dependent.Galectin-1 (gal-1) is a carbohydrate-binding lectin with important functions in angiogenesis, immune response, hemostasis and inflammation. Comparable functions are exerted by platelet factor 4 (CXCL4), a chemokine stored in the α-granules of platelets. Previously, gal-1 was found to activate platelets through integrin αIIbβ3. Both gal-1 and CXCL4 have high affinities for polysaccharides, and thus may mutually influence their functions. The aim of this study was to investigate a possible synergism of gal-1 and CXCL4 in platelet activation. Platelets were treated with increasing concentrations of gal-1, CXCL4 or both, and aggregation, integrin activation, P-selectin and phosphatidyl serine (PS) exposure were determined by light transmission aggregometry and by flow cytometry. To investigate the influence of cell surface sialic acid, platelets were treated with neuraminidase prior to stimulation. Gal-1 and CXCL4 were found to colocalize on the platelet surface. Stimulation with gal-1 led to integrin αIIbβ3 activation and to robust platelet aggregation, while CXCL4 weakly triggered aggregation and primarily induced P-selectin expression. Co-incubation of gal-1 and CXCL4 potentiated platelet aggregation compared with gal-1 alone. Whereas neither gal-1 and CXCL4 induced PS-exposure on platelets, prior removal of surface sialic acid strongly potentiated PS exposure. In addition, neuraminidase treatment increased the binding of gal-1 to platelets and lowered the activation threshold for gal-1. However, CXCL4 did not affect binding of gal-1 to platelets. Taken together, stimulation of platelets with gal-1 and CXCL4 led to distinct and complementary activation profiles, with additive rather than synergistic effects.Phenomenological relations such as Ohm's or Fourier's law have a venerable history in physics but are still scarce in biology. This situation restrains predictive theory. Here, we build on bacterial "growth laws," which capture physiological feedback between translation and cell growth, to construct a minimal biophysical model for the combined action of ribosome-targeting antibiotics. Our model predicts drug interactions like antagonism or synergy solely from responses to individual drugs. We provide analytical results for limiting cases, which agree well with numerical results. We systematically refine the model by including direct physical interactions of different antibiotics on the ribosome. In a limiting case, our model provides a mechanistic underpinning for recent predictions of higher-order interactions that were derived using entropy maximization. We further refine the model to include the effects of antibiotics that mimic starvation and the presence of resistance genes. We describe the impact of a starvation-mimicking antibiotic on drug interactions analytically and verify it experimentally. Our extended model suggests a change in the type of drug interaction that depends on the strength of resistance, which challenges established rescaling paradigms. selleck compound We experimentally show that the presence of unregulated resistance genes can lead to altered drug interaction, which agrees with the prediction of the model. While minimal, the model is readily adaptable and opens the door to predicting interactions of second and higher-order in a broad range of biological systems.A new algorithmic approach to personality prototyping based on Big Five traits was applied to a large representative and longitudinal German dataset (N = 22,820) including behavior, personality and health correlates. We applied three different clustering techniques, latent profile analysis, the k-means method and spectral clustering algorithms. The resulting cluster centers, i.e. the personality prototypes, were evaluated using a large number of internal and external validity criteria including health, locus of control, self-esteem, impulsivity, risk-taking and wellbeing. The best-fitting prototypical personality profiles were labeled according to their Euclidean distances to averaged personality type profiles identified in a review of previous studies on personality types. This procedure yielded a five-cluster solution resilient, overcontroller, undercontroller, reserved and vulnerable-resilient. Reliability and construct validity could be confirmed. We discuss wether personality types could comprise a bridge between personality and clinical psychology as well as between developmental psychology and resilience research.To tackle China's rapidly aging population, a policy was framed by using overlapping generations (OLG) model and computable general equilibrium (CGE) model; the main objective was to successfully implement "second-child policy" and "delayed retirement age" for female or male workers. The 2012 census data was obtained from National Bureau of Statistics of China. Our research findings suggest that the economy can be improved in the short-term by delaying retirement age; however, Chinese economy would improve tremendously in the long run by implementing second-child policy. Compared to delayed retirement age, second-child policy would be more effective in improving the economy in China. In terms of industrial output, the three policies have a greater influence on labor-intensive industries, such as agriculture, light industry, finance, and service sector; the impact is less significant on construction and heavy industry. In terms of industrial import and export, these three policies have greatly influenced following industries finance, electric power, and fossil energy. From a monetary perspective, these three policies can significantly improve household income; these three policies did not significantly impact both government and corporate incomes.The social-ecological effects of agricultural intensification are complex. We explore farmers' perceptions about the impacts of their land management and the impact of social information flows on their management through a case study in a farming community in Navarra, Spain, that is undergoing agricultural intensification due to adoption of large scale irrigation. We found that modern technology adopters are aware that their management practices often have negative social-ecological implications; by contrast, more traditional farmers tend to recognize their positive impacts on non-material benefits such as those linked with traditions and traditional knowledge, and climate regulation. We found that farmers' awareness about nature contributions to people co-production and their land management decisions determine, in part, the structure of the social networks among the farming community. Since modern farmers are at the core of the social network, they are better able to control the information flow within the community. This has important implications, such as the fact that the traditional farmers, who are more aware of their impacts on the environment, rely on information controlled by more intensive modern farmers, potentially jeopardizing sustainable practices in this region. We suggest that this might be counteracted by helping traditional farmers obtain information tailored to their practices from outside the social network.

Postoperative acute kidney injury (po-AKI) is frequently observed after major vascular surgery and impacts on mortality rates. Early identification of po-AKI patients using the novel urinary biomarkers insulin-like growth factor-binding-protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) might help in early identification of individuals at risk of AKI and enable timely introduction of preventative or therapeutic interventions with the aim of reducing the incidence of po-AKI. We investigated whether biomarker-based monitoring would allow for early detection of po-AKI in patients undergoing abdominal aortic interventions.

In an investigator-initiated prospective single-center observational study in a tertiary care academic center, adult patients with emergency/ elective abdominal aortic repair were included. Patients were tested for concentrations of urinary (TIMP-2) x (IGFBP7) at baseline, after surgical interventions (PO), and in the mornings of the first postoperative day (POD1). The primary endpoint was a difference in urinary (TIMP-2) x (IGFBP7) levels at POD1 in patients with/ without po-AKI (all KDIGO stages, po-AKI until seven days after surgery).