The impact of the Southern Annular Mode on future changes in Southern Hemisphere rainfall

A robust positive trend in the Southern Annular Mode (SAM) is projected for the end of the 21st century under the Representative Concentration Pathway 8.5 scenario, which results in rainfall decreases in the midlatitudes and increases in the high latitudes in the Southern Hemisphere (SH). We find that this SAM trend also increases rainfall over the SH subtropics in austral summer but not in winter, leading to a pronounced wintertime poleward expansion of the subtropical dry zone. These dynamically driven rainfall changes by the SAM appear to oppose the thermodynamically driven projected rainfall changes in the SH subtropics and midlatitudes, whereas the two components reinforce each other in the high latitudes. However, we show that most climate models fall short in capturing the observed SAM component driven by the El Nino-Southern Oscillation and associated rainfall in the austral warm seasons, which limits our confidence in quantifying the contribution of the SAM to projected rainfall changes.11145Ysciescopu

The Personalization of Clopidogrel Antiplatelet Therapy: The Role of Integrative Pharmacogenetics and Pharmacometabolomics

Dual antiplatelet therapy of aspirin and clopidogrel is pivotal for patients undergoing percutaneous coronary intervention. However, the variable platelets reactivity response to clopidogrel may lead to outcome failure and recurrence of cardiovascular events. Although many genetic and nongenetic factors are known, great portion of clopidogrel variable platelets reactivity remain unexplained which challenges the personalization of clopidogrel therapy. Current methods for clopidogrel personalization include CYP2C19 genotyping, pharmacokinetics, and platelets function testing. However, these methods lack precise prediction of clopidogrel outcome, often leading to insufficient prediction. Pharmacometabolomics which is an approach to identify novel biomarkers of drug response or toxicity in biofluids has been investigated to predict drug response. The advantage of pharmacometabolomics is that it does not only predict the response but also provide extensive information on the metabolic pathways implicated with the response. Integrating pharmacogenetics with pharmacometabolomics can give insight on unknown genetic and nongenetic factors associated with the response.This review aimed to review the literature on factors associated with the variable platelets reactivity response to clopidogrel, as well as appraising current methods for the personalization of clopidogrel therapy. We also aimed to review the literature on using pharmacometabolomics approach to predict drug response, as well as discussing the plausibility of using it to predict clopidogrel outcome

A Mobile Web App to Improve Health Screening Uptake in Men (ScreenMen): Utility and Usability Evaluation Study.

BACKGROUND: Globally, the uptake of health screening is suboptimal, especially in men and those of younger age. In view of the increasing internet access and mobile phone ownership, ScreenMen, a mobile Web app, was developed to improve health screening uptake in men. OBJECTIVE: This study aimed to evaluate the utility and usability of ScreenMen. METHODS: This study used both qualitative and quantitative methods. Healthy men working in a banking institution were recruited to participate in this study. They were purposively sampled according to job position, age, education level, and screening status. Men were asked to use ScreenMen independently while the screen activities were being recorded. Once completed, retrospective think aloud with playback was conducted with men to obtain their feedback. They were asked to answer the System Usability Scale (SUS). Intention to undergo screening pre- and postintervention was also measured. Qualitative data were analyzed using a framework approach followed by thematic analysis. For quantitative data, the mean SUS score was calculated and change in intention to screening was analyzed using McNemar test. RESULTS: In total, 24 men participated in this study. On the basis of the qualitative data, men found ScreenMen useful as they could learn more about their health risks and screening. They found ScreenMen convenient to use, which might trigger men to undergo screening. In terms of usability, men thought that ScreenMen was user-friendly and easy to understand. The key revision done on utility was the addition of a reminder function, whereas for usability, the revisions done were in terms of attracting and gaining users' trust, improving learnability, and making ScreenMen usable to all types of users. To attract men to use it, ScreenMen was introduced to users in terms of improving health instead of going for screening. Another important revision made was emphasizing the screening tests the users do not need, instead of just informing them about the screening tests they need. A Quick Assessment Mode was also added for users with limited attention span. The quantitative data showed that 8 out of 23 men (35%) planned to attend screening earlier than intended after using the ScreenMen. Furthermore, 4 out of 12 (33%) men who were in the precontemplation stage changed to either contemplation or preparation stage after using ScreenMen with P=.13. In terms of usability, the mean SUS score of 76.4 (SD 7.72) indicated that ScreenMen had good usability. CONCLUSIONS: This study showed that ScreenMen was acceptable to men in terms of its utility and usability. The preliminary data suggested that ScreenMen might increase men's intention to undergo screening. This paper also presented key lessons learned from the beta testing, which is useful for public health experts and researchers when developing a user-centered mobile Web app

Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation

Due to their high affinity and specificity, aptamers have been widely used as effective inhibitors in clinical applications. However, the ability to activate protein function through aptamer-protein interaction has not been well-elucidated. To investigate their potential as target-specific agonists, we used SELEX to generate aptamers to the insulin receptor (IR) and identified an agonistic aptamer named IR-A48 that specifically binds to IR, but not to IGF-1 receptor. Despite its capacity to stimulate IR autophosphorylation, similar to insulin, we found that IR-A48 not only binds to an allosteric site distinct from the insulin binding site, but also preferentially induces Y1150 phosphorylation in the IR kinase domain. Moreover, Y1150-biased phosphorylation induced by IR-A48 selectively activates specific signaling pathways downstream of IR. In contrast to insulin-mediated activation of IR, IR-A48 binding has little effect on the MAPK pathway and proliferation of cancer cells. Instead, AKT S473 phosphorylation is highly stimulated by IR-A48, resulting in increased glucose uptake both in vitro and in vivo. Here, we present IR-A48 as a biased agonist able to selectively induce the metabolic activity of IR through allosteric binding. Furthermore, our study also suggests that aptamers can be a promising tool for developing artificial biased agonists to targeted receptors.111615Ysciescopu

Aiding first incident responders using a decision support system based on live drone feeds

In case of a dangerous incident, such as a fire, a collision or an earthquake, a lot of contextual data is available for the first incident responders when handling this incident. Based on this data, a commander on scene or dispatchers need to make split-second decisions to get a good overview on the situation and to avoid further injuries or risks. Therefore, we propose a decision support system that can aid incident responders on scene in prioritizing the rescue efforts that need to be addressed. The system collects relevant data from a custom designed drone by detecting objects such as firefighters, fires, victims, fuel tanks, etc. The drone autonomously observes the incident area, and based on the detected information it proposes a prioritized based action list on e.g. urgency or danger to incident responders

Influence of the initial chemical conditions on the rational design of silica particles

The influence of the water content in the initial composition on the size of silica particles produced using the Stöber process is well known. We have shown that there are three morphological regimes defined by compositional boundaries. At low water levels (below stoichiometric ratio of water:tetraethoxysilane), very high surface area and aggregated structures are formed; at high water content (>40 wt%) similar structures are also seen. Between these two boundary conditions, discrete particles are formed whose size are dictated by the water content. Within the compositional regime that enables the classical Stöber silica, the structural evolution shows a more rapid attainment of final particle size than the rate of formation of silica supporting the monomer addition hypothesis. The clearer understanding of the role of the initial composition on the output of this synthesis method will be of considerable use for the establishment of reliable reproducible silica production for future industrial adoption

Spiral ligament fibrocyte-derived MCP-1/CCL2 contributes to inner ear inflammation secondary to nontypeable H. influenzae-induced otitis media

<p>Abstract</p> <p>Background</p> <p>Otitis media (OM), one of the most common pediatric infectious diseases, causes inner ear inflammation resulting in vertigo and sensorineural hearing loss. Previously, we showed that spiral ligament fibrocytes (SLFs) recognize OM pathogens and up-regulate chemokines. Here, we aim to determine a key molecule derived from SLFs, contributing to OM-induced inner ear inflammation.</p> <p>Methods</p> <p>Live NTHI was injected into the murine middle ear through the tympanic membrane, and histological analysis was performed after harvesting the temporal bones. Migration assays were conducted using the conditioned medium of NTHI-exposed SLFs with and without inhibition of MCP-1/CCL2 and CCR2. qRT-PCR analysis was performed to demonstrate a compensatory up-regulation of alternative genes induced by the targeting of MCP-1/CCL2 or CCR2.</p> <p>Results</p> <p>Transtympanic inoculation of live NTHI developed serous and purulent labyrinthitis after clearance of OM. THP-1 cells actively migrated and invaded the extracellular matrix in response to the conditioned medium of NTHI-exposed SLFs. This migratory activity was markedly inhibited by the viral CC chemokine inhibitor and the deficiency of MCP-1/CCL2, indicating that MCP-1/CCL2 is a main attractant of THP-1 cells among the SLF-derived molecules. We further demonstrated that CCR2 deficiency inhibits migration of monocyte-like cells in response to NTHI-induced SLF-derived molecules. Immunolabeling showed an increase in MCP-1/CCL2 expression in the cochlear lateral wall of the NTHI-inoculated group. Contrary to the <it>in vitro </it>data, deficiency of MCP-1/CCL2 or CCR2 did not inhibit OM-induced inner ear inflammation <it>in vivo</it>. We demonstrated that targeting MCP-1/CCL2 enhances NTHI-induced up-regulation of MCP-2/CCL8 in SLFs and up-regulates the basal expression of CCR2 in the splenocytes. We also found that targeting CCR2 enhances NTHI-induced up-regulation of MCP-1/CCL2 in SLFs.</p> <p>Conclusions</p> <p>Taken together, we suggest that NTHI-induced SLF-derived MCP-1/CCL2 is a key molecule contributing to inner ear inflammation through CCR2-mediated recruitment of monocytes. However, deficiency of MCP-1/CCL2 or CCR2 alone was limited to inhibit OM-induced inner ear inflammation due to compensation of alternative genes.</p

Individual variation in levels of haptoglobin-related protein in children from Gabon

Background: Haptoglobin related protein (Hpr) is a key component of trypanosome lytic factors (TLF), a subset of highdensity lipoproteins (HDL) that form the first line of human defence against African trypanosomes. Hpr, like haptoglobin (Hp) can bind to hemoglobin (Hb) and it is the Hpr-Hb complexes which bind to these parasites allowing uptake of TLF. This unique form of innate immunity is primate-specific. To date, there have been no population studies of plasma levels of Hpr, particularly in relation to hemolysis and a high prevalence of ahaptoglobinemia as found in malaria endemic areas. Methods and Principal Findings: We developed a specific enzyme-linked immunosorbent assay to measure levels of plasma Hpr in Gabonese children sampled during a period of seasonal malaria transmission when acute phase responses (APR), malaria infection and associated hemolysis were prevalent. Median Hpr concentration was 0.28 mg/ml (range 0.03-1.1). This was 5-fold higher than that found in Caucasian children (0.049 mg/ml, range 0.002-0.26) with no evidence of an APR. A general linear model was used to investigate associations between Hpr levels, host polymorphisms, parasitological factors and the acute phase proteins, Hp, C-reactive protein (CRP) and albumin. Levels of Hpr were associated with Hp genotype, decreased with age and were higher in females. Hpr concentration was strongly correlated with that of Hp, but not CRP