Body mass index and risk of diabetes mellitus in the Asia-Pacific region

Few prospective data from the Asia Pacific region are available relating body mass index to the risk of diabetes. Our objective was to provide reliable age, sex and region specific estimates of the associations between body mass index and diabetes. Twenty-seven cohort studies from Asia, New Zealand and Australia, including 154,989 participants, contributed 1,244,793 person-years of follow-up. Outcome data included a combination of incidence of diabetes (based on blood glucose measurements) and fatal diabetes events. Hazard ratios were calculated from Cox models, stratified by sex and cohort, and adjusted for age at risk and smoking. During follow-up (mean = 8 years), 75 fatal diabetes events and 242 new cases of diabetes were documented. There were continuous positive associations between baseline body mass index and risk of diabetes with each 2 kg/m2 lower body mass index associated with a 27% (23-30%) lower risk of diabetes. The associations were stronger in younger age groups, and regional comparisons demonstrated slightly stronger associations in Asian than in Australasian cohorts (P = 0.04). This overview provides evidence of a strong continuous association between body mass index and diabetes in the Asia Pacific region. The results indicate considerable potential for reduction in incidence of diabetes with population-wide lowering of body mass index in this region.     

A synergy between mechanosensitive calcium- and membrane-binding mediates tension-sensing by C2-like domains

When nuclear membranes are stretched, the peripheral membrane enzyme cytosolic phospholipase A2 (cPLA₂) binds via its calcium-dependent C2 domain (cPLA₂-C2) and initiates bioactive lipid signaling and tissue inflammation. More than 150 C2-like domains are encoded in vertebrate genomes. How many of them are mechanosensors and quantitative relationships between tension and membrane recruitment remain unexplored, leaving a knowledge gap in the mechanotransduction field. In this study, we imaged the mechanosensitive adsorption of cPLA₂ and its C2 domain to nuclear membranes and artificial lipid bilayers, comparing it to related C2-like motifs. Stretch increased the Ca²⁺ sensitivity of all tested domains, promoting half-maximal binding of cPLA₂ at cytoplasmic resting-Ca²⁺ concentrations. cPLA₂-C2 bound up to 50 times tighter to stretched than to unstretched membranes. Our data suggest that a synergy of mechanosensitive Ca²⁺ interactions and deep, hydrophobic membrane insertion enables cPLA₂-C2 to detect stretched membranes with antibody-like affinity, providing a quantitative basis for understanding mechanotransduction by C2-like domains.

Eicosanoids are powerful bioactive lipids generated by the enzymatic oxidation of the polyunsaturated fatty acid arachidonic acid (AA). Among other functions (1), eicosanoids participate in mechanotransduction, for example, during bone load sensing in mammals and osmotic wound detection in zebrafish (2, 3). The rate-limiting step of eicosanoid synthesis is the cleavage of AA from nuclear and endoplasmic reticulum (ER) membranes by the inflammatory lipid hydrolase cPLA₂. Recently, this enzyme emerged as a nuclear membrane (NM) mechanosensor that detects cell swelling and confinement (2, 4–6). Together with Ca²⁺, NM-stretch promotes the bilayer adsorption of cPLA₂ via its C2-domain, which allows the enzyme to hydrolyze AA from phospholipids. Lipoxygenases (ALOX5, ALOX12, etc.), cyclooxygenases (PTGS1 and PTGS2), and other enzymes convert AA into the eicosanoids, which include the leukotrienes, prostaglandins, and other bioactive lipids.There are more than 150 vertebrate proteins with C2-like domains, which include both classic C2 domains, such as those in protein kinase C (PKC) and cPLA₂, as well as the structurally related PLAT (Polycystin-1, Lipoxygenase, Alpha-Toxin) domain as in ALOX5 and ALOX12. Classic C2 domains form a β-sandwich composed of eight β-strands, whereas PLAT domains form a β-sandwich composed of two β-sheets and four β-strands. The mechanosensitivity of these Ca²⁺-dependent membrane-interaction motifs has not been systematically investigated. Therefore, it is currently difficult to predict which C2-like domains act as membrane tension sensors and what the distinguishing features of mechanosensitive C2-like domains are. To gain quantitative insights into this, we decided to focus on a representative group of two classical C2-domains and two PLAT domains, namely, dr cPla₂-C2 and hs cPLA₂-C2 (Danio rerio and Homo sapiens), hs PKCγ-C2 (H. sapiens), dr Alox5a-PLAT (D. rerio), and dr Alox12-PLAT (D. rerio).cPLA₂-C2’s calcium-binding loops (CBRs) contain Ca²⁺-binding residues and two clusters of exposed hydrophobic amino acids that promote membrane-binding and penetration. The Ca²⁺ ions neutralize negative surface charges of lipid headgroups, whereas CBR1 and CBR3 deeply insert into the lipid bilayer and interact with lipid hydrocarbons (7–11). Like cPLA₂-C2, ALOX5-PLAT binds to zwitterionic membranes via hydrophobic membrane insertion and electrostatic interactions (11, 12), whereas the binding mechanism of ALOX12-PLAT is less clear. PKCγ-C2 binds phosphatidylserine (PS)-rich membranes primarily via electrostatic interactions (13). Electron paramagnetic resonance and molecular dynamics studies of the related PKCα-C2 domain underline that compared to cPLA₂-C2, PKCs interact more shallowly with membranes (7, 14, 15).Here, we purified the fluorescent protein fusions of these domains from bacteria and analyzed their adsorption to stretched and unstretched artificial bilayers at different Ca²⁺- and C2-like domain concentrations. As an artificial membrane system, we chose giant unilamellar vesicles (GUVs) generated by a nylon net hydration technique. GUV bilayers are basically flat and thus represent much better the topology of large cell organelles (e.g., the nucleus) than the highly curved, small unilamellar vesicles (SUVs, <100 nm) often used for spectroscopic measurements of membrane–protein interactions. Osmotic swelling enabled the confocal imaging of stretch-dependent domain adsorption to many GUVs in parallel (i.e., under the same conditions), which is hard to achieve via one-by-one stretching methods (e.g., micropipette). The resultant robustness of our assay allowed us to define distinguishing features of mechanosensitive C2-like domains.     

Differences in Timely Antenatal Care Between First and Second-Generation Migrants in the Netherlands

To assess whether there are differences in the timing of first antenatal care visit between 1st and 2nd-generation migrants, and if so, how such differences could be explained. The study has been conducted in the framework of Generation R Study, a multi-ethnic population-based study conducted in Rotterdam, the Netherlands. The study population consists of 845 women of the six largest ethnic groups. Data were derived from the electronic antenatal charts of the participating midwives and from written questionnaires. Logistic regression analyses have been carried out to investigate whether difference could be explained by need, predisposing and enabling factors. More first than second generation women enter antenatal care after 14 weeks of pregnancy (28.1 vs. 18.7 %). Women who were not likely to adopt healthy behaviour regarding pregnancy—such as timely taking folic acid—equally were not inclined to enter antenatal care early in pregnancy. The role of Dutch language mastery was limited. Given our results, first generation women are less likely to receive timely health educational advice or to benefit from screening opportunities than second generation women. Future studies should pay more attention to adequate assessment of proficiency of the host language.     

The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice

Group II metabotropic glutamate receptor agonists have been suggested as potential anti‐psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non‐competitive N‐methyl‐d ‐aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome‐wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in Gria1^?/? mice during rewarded alternation performance in the T‐maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in Gria1^?/? mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non‐competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function.     

The burden of COPD in Africa: a literature review and prospective survey of the availability of spirometry for COPD diagnosis in Africa

Objectives  To ascertain the known burden of chronic obstructive pulmonary disease (COPD) in Africa and of spirometry use to indicate the possibility of further unpublished data becoming shortly available.
Method  Literature review.
Results  Screening of 132 articles yielded 22 relevant articles, of which only six used spirometry based data. A total of 106 physicians in 34 countries were contacted and only 23 reported satisfactory use and availability of spirometry.
Conclusions  Current estimates of COPD burden in Africa are based on an unreliably small dataset. Acquisition of further data will require substantial investment in lung function equipment and training.     

Atropisomerism transforming anti-cancer drug discovery

Atropisomerism is a stereochemical phenomenon that describes how groups are arranged in space as a result of their impeded rotation around a single bond. It is one of the frequently underappreciated conformational kinds of chirality. A significant role for atropisomers in drug discovery and development has been established via substantial study on the characteristics of molecules exhibiting this form of chirality. According to studies on the target selectivity of anti-cancer drugs, it was identified that atropisomers of specific compounds could be examined to modulate the selectivity of promiscuous inhibitors, which are a key target in cancer therapy. Conversely, it was discovered that these deliberate rigidifications of possible molecules along an axis of chirality gave an abundant possibility of acquiring more tailored anti-cancer action. Atropisomerism plays a significant role in altering pharmacodynamic and pharmacokinetic properties and thereby the success of any proposed drug candidate. It is thus necessary to anticipate the impact of stereogenic centres in such compounds on cancer drug development. Hence, herein we review atropisomeric anti-cancer moieties which have been investigated based on their target proteins, origin and isomerism. The insights offered herein would be extremely useful in anti-cancer drug design, pave way for new avenues to development promising potent agents to combat this life-threatening disease.