Resonance effects in the 5σ photoionization of CO

We report vibrational branching ratios and vibrationally resolved photoelectron angular distributions for resonant photoionization of the 5sigma level of CO leading to X^2Σ+CO+. These results were obtained using frozen-core Hartree–Fock photoelectron continuum orbitals. These studies provide a clear quantitative picture of the role of the kσ shape resonance in the observed non-Franck–Condon behavior and useful insight into the interplay between this shape resonance and a valence-like autoionizing resonance around 23 eV

GEC1-kappa Opioid Receptor Binding Involves Hydrophobic Interactions GEC1 has Chaperone-Like Effect

We demonstrated previously that the protein GEC1 (glandular epithelial cell 1) bound to the human κ opioid receptor (hKOPR) and promoted cell surface expression of the receptor by facilitating its trafficking along the secretory pathway. Here we showed that three hKOPR residues (Phe345, Pro346, and Met350) and seven GEC1 residues (Tyr49, Val51, Leu55, Thr56, Val57, Phe60, and Ile64) are indispensable for the interaction. Modeling studies revealed that the interaction was mediated via direct contacts between the kinked hydrophobic fragment in hKOPR C-tail and the curved hydrophobic surface in GEC1 around the S2 β-strand. Intramolecular Leu44-Tyr109 interaction in GEC1 was important, likely by maintaining its structural integrity. Microtubule binding mediated by the GEC1 N-terminal domain was essential for the GEC1 effect. Expression of GEC1 also increased cell surface levels of the GluR1 subunit and the prostaglandin EP3.f receptor, which have FPXXM and FPXM sequences, respectively. With its widespread distribution in the nervous system and its predominantly hydrophobic interactions, GEC1 may have chaperone-like effects for many cell surface proteins along the biosynthesis pathway

Structural Mimicry in Class A G Protein-coupled Receptor Rotamer Toggle Switches

In this study, we tested the hypothesis that a CB1 TMH3-4-5-6 aromatic microdomain, which includes F3.25(190), F3.36(201), W5.43(280), and W6.48(357), is centrally involved in CB1 receptor activation, with the F3.36(201)/W6.48(357) interaction key to the maintenance of the CB1-inactive state. We have shown previously that when F3.36(201), W5.43(280), and W6.48(357) are individually mutated to alanine, a significant reduction in ligand binding affinity is observed in the presence of WIN 55,212-2 and SR141716A but not CP55,940 and anandamide. In the work presented here, we report a detailed functional analysis of the F3.36(201)A, F3.25(190)A, W5.43(280)A, and W6.48(357)A mutant receptors in stable cell lines created in HEK cells for agonist-stimulated guanosine 5′-3-O-(thio)triphosphate (GTPγS) binding and GIRK1/4 channel current effects in Xenopus oocytes where the mutant proteins were expressed transiently. The F3.36(201)A mutation showed statistically significant increases in ligand-independent stimulation of GTPγS binding versus wild type CB1, although basal levels for the W6.48(357)A mutant were not statistically different from wild type CB1. F3.36(201)A demonstrated a limited activation profile in the presence of multiple agonists. In contrast, enhanced agonist activation was produced by W6.48(357)A. These results suggest that a F3.36(201)/W6.48(357)-specific contact is an important constraint for the CB1-inactive state that may need to break during activation. Modeling studies suggest that the F3.36(201)/W6.48(357) contact can exist in the inactive state of CB1 and be broken in the activated state via a χ1 rotamer switch (F3.36(201) trans, W6.48(357) g+) → (F3.36(201) g+, W6.48(357) trans). The F3.36(201)/W6.48(357) interaction therefore may represent a “toggle switch” for activation of CB1

Towards A Molecular Understanding of The Cannabinoid Related Orphan Receptor GPR18: A Focus on Its Constitutive Activity

The orphan G-protein coupled receptor (GPCR), GPR18, has been recently proposed as a potential member of the cannabinoid family as it recognizes several endogenous, phytogenic, and synthetic cannabinoids. Potential therapeutic applications for GPR18 include intraocular pressure, metabolic disorders, and cancer. GPR18 has been reported to have high constitutive activity, i.e., activation/signaling occurs in the absence of an agonist. This activity can be reduced significantly by the A3.39N mutation. At the intracellular (IC) ends of (transmembrane helices) TMH3 and TMH6 in GPCRs, typically, a pair of oppositely charged amino acids form a salt bridge called the “ionic lock”. Breaking of this salt bridge creates an IC opening for coupling with G protein. The GPR18 “ionic lock” residues (R3.50/S6.33) can form only a hydrogen bond. In this paper, we test the hypothesis that the high constitutive activity of GPR18 is due to the weakness of its “ionic lock” and that the A3.39N mutation strengthens this lock. To this end, we report molecular dynamics simulations of wild-type (WT) GPR18 and the A3.39N mutant in fully hydrated (POPC) phophatidylcholine lipid bilayers. Results suggest that in the A3.39N mutant, TMH6 rotates and brings R3.50 and S6.33 closer together, thus strengthening the GPR18 “ionic lock”.This research was supported by a grant from the National Institutes on Drug Abuse KO5 DA021358 to PHR.We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI)Peer reviewe

Taking stock: protocol for evaluating a family planning supply chain intervention in Senegal.

BACKGROUND: In Senegal, only 12% of women of reproductive age in union (WRAU) were using contraceptives and another 29% had an unmet need for contraceptives in 2010-11. One potential barrier to accessing contraceptives is the lack of stock availability in health facilities where women seek them. Multiple supply chain interventions have been piloted in low- and middle-income countries with the aim of improving contraceptive availability in health facilities. However, there is limited evidence on the effect of these interventions on contraceptive availability in facilities, and in turn on family planning use in the population. This evaluation protocol pertains to a supply chain intervention using performance-based contracting for contraceptive distribution that was introduced throughout Senegal between 2012 and 2015. METHODS: This multi-disciplinary research project will include quantitative, qualitative and economic evaluations. Trained researchers in the different disciplines will implement the studies separately but alongside each other, sharing findings throughout the project to inform each other's data collection. A non-randomised study with stepped-wedge design will be used to estimate the effect of the intervention on contraceptive stock availability in health facilities, and on the modern contraceptive prevalence rate among women in Senegal, compared to the current pull-based distribution model used for other commodities. Secondary data from annual Service Provision Assessments and Demographic and Health Surveys will be used for this study. Data on stock availability and monthly family planning consultations over a 4-year period will be collected from 200 health facilities in five regions to perform time series analyses. A process evaluation will be conducted to understand the extent to which the intervention was implemented as originally designed, the acceptability of third-party logisticians within the health system and potential unintended consequences. These will be assessed using monthly indicator data from the implementer and multiple ethnographic methods, including in-depth interviews with key informants and stakeholders at all levels of the distribution system, observations of third-party logisticians and clinic diaries. An economic evaluation will estimate the cost of the intervention, as well as its cost-effectiveness compared to the current supply chain model. DISCUSSION: Given the very limited evidence base, there is an important need for a comprehensive standardised approach to evaluating supply chain management, and distribution specifically. This evaluation will help address this evidence gap by providing rigorous evidence on whether private performance-based contracting for distribution of contraceptives can contribute to improving access to family planning in low- and middle-income countries

Understanding 'missed appointments' for pills and injectables: a mixed methods study in Senegal.

INTRODUCTION: High discontinuation rates of contraceptive methods have been documented in sub-Saharan Africa. However, little is known about gaps within individual episodes of method use, despite their implications for unintended pregnancies. The objective of this mixed methods study was to examine the prevalence of, and explore the factors contributing to, delays in repeat appointments for pills and injectables in Senegal. METHODS: First, we constructed a longitudinal data set of women's contraceptive consultations using routine records from 67 facilities in Senegal. Consultations for pills and injectables were classified as on time, delayed or with unknown delay status based on time since previous appointment. We described the prevalence of delayed appointments and used backward stepwise regression to build a mixed-effects model to investigate risk factors for delay. Second, we conducted workshops with family planning (FP) providers, and indepth interviews and focus group discussions with women of reproductive age, to explore factors contributing to delays. RESULTS: Almost one-third (30%) of appointments for pills and injectables were delayed, resulting in risk of pregnancy. Previous delay, pill use, lower educational level, higher parity, third and subsequent visits, and Islamic faith were independently predictive of delays (p<0.04 for all). Although women's 'forgetfulness' was initially mentioned as the main reason for delays by women and providers, examining the routines around appointment attendance revealed broader contextual barriers to timely refills-particularly widespread covert use, illiteracy, financial cost of FP services and limited availability of FP services. CONCLUSION: Delays in obtaining repeat pills and injections are common among contraceptive users in Senegal, exposing women to unintended pregnancies. Strategies to reduce such delays should move beyond a narrow focus on individual women to consider contraceptive behaviour within the broader socioeconomic and health systems context. In particular, effective interventions addressing low acceptability of contraception and appointment reminder strategies in high illiteracy contexts are needed

Mid-Infrared Spectrophotometric Observations of Fragments B and C of Comet 73P/Schwassmann-Wachmann 3

We present mid-infrared spectra and images from the GEMINI-N (+Michelle) observations of fragments SW3-[B] and SW3-[C] of the ecliptic (Jupiter Family) comet 73P/Schwassmann-Wachmann 3 pre-perihelion. We observed fragment B soon after an outburst event (between 2006 April 16 - 26 UT) and detected crystalline silicates. The mineralogy of both fragments was dominated by amorphous carbon and amorphous pyroxene. The grain size distribution (assuming a Hanner modified power-law) for fragment SW3-[B] has a peak grain radius of a_p ~ 0.5 micron, and for fragment SW3-[C], a_p ~ 0.3 micron; both values larger than the peak grain radius of the size distribution for the dust ejected from ecliptic comet 9P/Tempel 1 during the Deep Impact event (a_p = 0.2 micron. The silicate-to-carbon ratio and the silicate crystalline mass fraction for the submicron to micron-size portion of the grain size distribution on the nucleus of fragment SW3-[B] was 1.341 +0.250 -0.253 and 0.335 +0.089 -0.112, respectively, while on the nucleus of fragment SW3-[C] was 0.671 +0.076 -0.076 and 0.257 +0.039 -0.043, respectively. The similarity in mineralogy and grain properties between the two fragments implies that 73P/Schwassmann-Wachmann 3 is homogeneous in composition. The slight differences in grain size distribution and silicate-to-carbon ratio between the two fragments likely arises because SW3-[B] was actively fragmenting throughout its passage while the activity in SW3-[C] was primarily driven by jets. The lack of diverse mineralogy in the fragments SW3-[B] and SW3-[C] of 73P/Schwassmann-Wachmann 3 along with the relatively larger peak in the coma grain size distribution suggests the parent body of this comet may have formed in a region of the solar nebula with different environmental properties than the natal sites where comet C/1995 O1 (Hale-Bopp) and 9P/Tempel 1 nuclei aggregated.Comment: 31 pages, 5 figure, accepted for publication in A

Dust Morphology and Composition in FU Orionis Systems

FU Orionis stars are a small group of pre–main-sequence stars known for large-amplitude optical variability. These objects also exhibit multiwavelength phenomena suggestive of active accretion from a circumstellar disk. We present high spatial resolution mid-IR imaging and spectroscopy, submillimeter photometry, and 3–4 μm photometry of four FU Ori–class objects, RNO 1B and C, Z CMa, and Par 21, and one object classified as a pre–FU Ori star, V380 Ori. We resolve multiple IR sources and extended emission in the RNO 1B/C system, and we discuss in detail their association with disk activity and the source of the Infrared Astronomical Satellite far-IR and radio maser emission in this field. We derive dust temperatures and masses for all sources and discuss how dust composition and morphology is related to the evolutionary stage of these objects

Critical insights on the demographic concept of "birth spacing": locating Nef in family well-being, bodies, and relationships in Senegal.

Birth spacing has emerged since the early 1980s as a key concept to improve maternal and child health, triggering interest in birth spacing practices in low-income countries, and drawing attention to prevailing norms in favour of long birth intervals in West Africa. In Senegal, the Wolof concept of Nef, which means having children too closely spaced in time, is morally condemned and connotes a resulting series of negative implications for family well-being. While Nef and "birth spacing" intersect in key ways, including acknowledging the health benefits of longer birth intervals, they are not translations of each other, for each is embedded in distinct broader cultural and political assumptions about social relations. Most notably, proponents of the demographic concept of birth spacing assume that the practice of using contraception after childbearing to postpone births could contribute to "empowering" women socially. In Senegal, by contrast, preventing Nef (or short birth intervals) is also viewed as strengthening family well-being by allowing women to care more fully for their family. This paper draws on policy documents and interviews to explore women's and men's understanding of Nef, and in turn critically reflect on the demographic concept of birth spacing. Our findings reinforce the relevance of the concept of birth spacing to engage with women and men around family planning services in Senegal. Accounts of the Nef taboo in Senegal also show that social norms stigmatising short birth intervals can legitimise constraints faced by women on control of their body