A Cation–π Interaction between Extracellular TEA and an Aromatic Residue in Potassium Channels

Open-channel blockers such as tetraethylammonium (TEA) have a long history as probes of the permeation pathway of ion channels. High affinity blockade by extracellular TEA requires the presence of an aromatic amino acid at a position that sits at the external entrance of the permeation pathway (residue 449 in the eukaryotic voltage-gated potassium channel Shaker). We investigated whether a cation–{pi} interaction between TEA and such an aromatic residue contributes to TEA block using the in vivo nonsense suppression method to incorporate a series of increasingly fluorinated Phe side chains at position 449. Fluorination, which is known to decrease the cation–{pi} binding ability of an aromatic ring, progressively increased the inhibitory constant Ki for the TEA block of Shaker. A larger increase in Ki was observed when the benzene ring of Phe449 was substituted by nonaromatic cyclohexane. These results support a strong cation–{pi} component to the TEA block. The data provide an empirical basis for choosing between Shaker models that are based on two classes of reported crystal structures for the bacterial channel KcsA, showing residue Tyr82 in orientations either compatible or incompatible with a cation–{pi} mechanism. We propose that the aromatic residue at this position in Shaker is favorably oriented for a cation–{pi} interaction with the permeation pathway. This choice is supported by high level ab initio calculations of the predicted effects of Phe modifications on TEA binding energy

Activation of G protein-coupled receptors entails cysteine modulation of agonist binding

The increase of the affinity of agonists with an increase in pH and experiments using thiol-specific reagents indicate that G protein-coupled receptors contain an ionizable cysteine residue at the ligand binding site. Since treatment of receptors with reducing agents produces functional activation and potentiates agonist stimulation, it is likely that this free sulfhydryl modulates receptor activation. We have derived a two-state acid-base model for cysteine modulation of ligand binding which leads to a description of ligand efficacy. We have shown that pH-dependent binding of agonists is closely correlated with measurements of ligand efficacy at the 5-HT2A receptor. In general, efficacy is determined by the preference of a ligand for the base of the receptor. Efficacy may also be described in thermodynamic terms as the coupling free energy involving a ligand and the acid and base states of the receptor. Molecular modeling of the third transmembrane domain of the 5-HT2A receptor, which contains a conserved cysteine, shows that efficacy is determined by the difference between the electrostatic interaction energies of a ligand with the acid and base forms of the receptor model. The difference in interaction energy between the two forms of cysteine makes the largest contribution to this electrostatic interaction energy difference. Therefore, the cysteine makes the largest contribution to ligand efficacy. Using this approach, we can distinquish between the efficacies of agonists with varying molecular structures and account for the differences between the properties of agonists and antagonists

Matrix concentration inequalities via the method of exchangeable pairs

This paper derives exponential concentration inequalities and polynomial moment inequalities for the spectral norm of a random matrix. The analysis requires a matrix extension of the scalar concentration theory developed by Sourav Chatterjee using Stein's method of exchangeable pairs. When applied to a sum of independent random matrices, this approach yields matrix generalizations of the classical inequalities due to Hoeffding, Bernstein, Khintchine and Rosenthal. The same technique delivers bounds for sums of dependent random matrices and more general matrix-valued functions of dependent random variables.Comment: Published in at http://dx.doi.org/10.1214/13-AOP892 the Annals of Probability (http://www.imstat.org/aop/) by the Institute of Mathematical Statistics (http://www.imstat.org

Toward a New Technology and Policy Program (TPP) Curriculum

The mission of the MIT Technology and Policy Program (TPP) is: “Provide an integrative education to scientists and engineers who wish to lead in the development and implementation of responsible strategies and policies for exploitation of technology for the benefit of their communities” (Hastings, 2000). Embedded in the TPP mission statement are several educational requirements: (1) a comprehensive and diverse set of solid analytical skills needed to develop and assess strategies and policies, (2) the flexibility to manage the conflicting interests and values that are present at all stages of the policy process, and (3) the ability to provide leadership at each stage in the policy process. With these concepts in mind, the TPP Curriculum Development Committee will work to place TPP at the forefront of educating the “leaders (researchers and practitioners) of the fields of technology and policy studies” (Hastings, 2000)

Economic evaluation of mobile phone text message interventions to improve adherence to HIV therapy in Kenya

A surge in mobile phone availability has fueled low cost short messaging service (SMS) adherence interventions. Multiple systematic reviews have concluded that some SMS-based interventions are effective at improving antiretroviral therapy (ART) adherence, and they are hypothesized to improve retention in care. The objective of this study was to evaluate the cost-effectiveness of SMS-based adherence interventions and explore the added value of retention benefits

A multicountry randomized controlled trial of comprehensive maternal nutrition supplementation initiated before conception: the Women First trial.

Background: Reported benefits of maternal nutrition supplements commenced during pregnancy in low-resource populations have typically been quite limited. Objectives: This study tested the effects on newborn size, especially length, of commencing nutrition supplements for women in low-resource populations ≥3 mo before conception (Arm 1), compared with the same supplement commenced late in the first trimester of pregnancy (Arm 2) or not at all (control Arm 3). Methods: Women First was a 3-arm individualized randomized controlled trial (RCT). The intervention was a lipid-based micronutrient supplement; a protein-energy supplement was also provided if maternal body mass index (kg/m2) was(DRC), Guatemala, India, and Pakistan. The primary outcome was length-for-age z score (LAZ), with all anthropometry obtainedDRC, outcomes were determined for all 4 sites from WHO newborn standards (non-gestational-age-adjusted, NGAA) as well as INTERGROWTH-21st fetal standards (3 sites, gestational age-adjusted, GAA). Results: A total of 7387 nonpregnant women were randomly assigned, yielding 2451 births with NGAA primary outcomes and 1465 with GAA outcomes. Mean LAZ and other outcomes did not differ between Arm 1 and Arm 2 using either NGAA or GAA. Mean LAZ (NGAA) for Arm 1 was greater than for Arm 3 (effect size: +0.19; 95% CI: 0.08, 0.30, P = 0.0008). For GAA outcomes, rates of stunting and small-for-gestational-age were lower in Arm 1 than in Arm 3 (RR: 0.69; 95% CI: 0.49, 0.98, P = 0.0361 and RR: 0.78; 95% CI: 0.70, 0.88, P \u3c 0.001, respectively). Rates of preterm birth did not differ among arms. Conclusions: In low-resource populations, benefits on fetal growth-related birth outcomes were derived from nutrition supplements commenced before conception or late in the first trimester. This trial was registered at clinicaltrials.gov as NCT01883193

Trends and determinants of stillbirth in developing countries: results from the Global Network\u27s Population-Based Birth Registry.

BACKGROUND: Stillbirth rates remain high, especially in low and middle-income countries, where rates are 25 per 1000, ten-fold higher than in high-income countries. The United Nations\u27 Every Newborn Action Plan has set a goal of 12 stillbirths per 1000 births by 2030 for all countries. METHODS: From a population-based pregnancy outcome registry, including data from 2010 to 2016 from two sites each in Africa (Zambia and Kenya) and India (Nagpur and Belagavi), as well as sites in Pakistan and Guatemala, we evaluated the stillbirth rates and rates of annual decline as well as risk factors for 427,111 births of which 12,181 were stillbirths. RESULTS: The mean stillbirth rates for the sites were 21.3 per 1000 births for Africa, 25.3 per 1000 births for India, 56.9 per 1000 births for Pakistan and 19.9 per 1000 births for Guatemala. From 2010 to 2016, across all sites, the mean stillbirth rate declined from 31.7 per 1000 births to 26.4 per 1000 births for an average annual decline of 3.0%. Risk factors for stillbirth were similar across the sites and included maternal age \u3c 20 years and age \u3e 35 years. Compared to parity 1-2, zero parity and parity \u3e 3 were both associated with increased stillbirth risk and compared to women with any prenatal care, women with no prenatal care had significantly increased risk of stillbirth in all sites. CONCLUSIONS: At the current rates of decline, stillbirth rates in these sites will not reach the Every Newborn Action Plan goal of 12 per 1000 births by 2030. More attention to the risk factors and treating the causes of stillbirths will be required to reach the Every Newborn Action Plan goal of stillbirth reduction. TRIAL REGISTRATION: NCT01073475

Interactions Between Zooplankton and Karenia brevis in the Gulf of Mexico.

Blooms of the toxic dinoflagellate K. brevis are common in the Gulf of Mexico, yet no in situ studies of the interactions between zooplankton and K. brevis in the Gulf of Mexico have been conducted. Zooplankton numerical abundance, biomass and taxonomic composition of nonbloom and K. brevis bloom stations within the ECOHAB study area were compared. At nonbloom stations, the most important determinant species were Parvolcalanus crassirostris, Oithona colcarva and Paracalanus quasimodo at the 5-m isobath and P. quasimodo, O. colcarva and Oikopleura dioka at the 25-m isobath. There was considerable overlap between the 5 and 25-m isobaths, with 9 species contributing to the top 90% of numerical abundance at both isobaths. Within K. brevis blooms Acartia tonsa, Centropages velificatus, Temora turbinata, Evadne tergestina, O. colcarva, O. dioika, and P. crassirostris were consistently dominant. Variations between non-bloom and bloom assemblages were evident, including variations in numerical abundance and biomass and the reduction in numerical abundance of 3 key species. Calculated grazing pressure proved insufficient to terminate K. brevis blooms, despite occasional grazing hot spots

A national audit of current cardiac device policies from radiotherapy centres across the UK

Aims: The number of patients with cardiac implantable electronic devices (permanent pacemakers and implantable cardioverter defibrillators) undergoing radiotherapy treatment is increasing. The aims of this audit were to establish current UK practice regarding the management of patients with implanted cardiac devices undergoing radiotherapy and to compare this practice with current ‘gold standard’ evidence-based guidelines. Materials and methods: All UK radiotherapy departments were contacted and asked to provide their current cardiac implantable electronic device policy or to indicate if there was no current policy. A proforma was created to analyse these polices and to compare with current best practice. Results: In total, 47/67 (70%) radiotherapy departments responded and 45 departmental policies were submitted; 31/45 (69%) policies defined the radiotherapy tolerance dose to permanent pacemakers and 14/45 (31%) defined the monitoring procedure for patients in line with current best practice. Only 5/45 (11%) policies defined the radiotherapy tolerance dose to implantable cardioverter defibrillators and 12/45 (27%) defined the monitoring procedure in line with current best practice. Conclusion: Most UK cardiac device policies do not reflect current best evidence. Policies are based on research carried out in 1994 by the American Association of Physicists in Medicine. This evidence does not account for advances in cardiac implantable electronic device technology. Further research is urgently needed to establish the effect of radiotherapy on these devices