Strengthening regional commitment to ensuring access to medical abortion medicines in WHO's South-East Asia region: report of a participatory assessment and workshop.

BACKGROUND: In 2019, the World Health Organization identified improving access to safe abortion as an important priority toward improving sexual and reproductive health and rights and achieving Sustainable Development Goals. One strategy for addressing this priority is strengthening access to medicines for medical abortion. All 11 countries in the South-East Asia Region have some indications for legal abortion and permit post-abortion care. Therefore, strengthening access to medical abortion medicines is a reasonable strategy for improving access to safe abortion for the Region. METHODOLOGY: We applied an adapted version of an existing World Health Organization landscape assessment protocol for the availability of medical abortion medicines at the country-level in the South-East Asia Region. We collected publicly available data on the existence of national health laws, policies, and standard treatment guidelines; inclusion of medical abortion medicines in the national essential medicines list; and marketing authorization status for medical abortion medicines for each country and verified by Ministries of health. The findings were once more presented, discussed and recommendations were formulated during regional technical consultation workshop. Each country teams participated in the process, and subsequently, the suggestions were validated by representatives from Ministries of Health.. RESULTS: Few countries in the Region currently have national policies and guidelines for comprehensive safe abortion. However, either mifepristone-misoprostol in combination or misoprostol alone (for other indications) is included in national essential medicines lists in all countries except Indonesia and Sri Lanka. Few countries earmark specific public funds for procuring and distributing medical abortion commodities. In countries where abortion is legal, the private sector and NGOs support access to medical abortion information and medicines. Several countries only allow registered medical practitioners or specialists to administer medical abortion. CONCLUSION: Following this rapid participatory assessment and technical consultation workshop, the World Health Organization South-East Asia Regional Technical Advisory and Sexual and Reproductive Health and Rights technical committee recommended priority actions for policy and advocacy, service delivery, and monitoring and evaluation, and indicated areas for support.

The Alternating Access Mechanism in Mammalian Multidrug Resistance Transporters and Their Bacterial Homologs.

Multidrug resistance (MDR) proteins belonging to the ATP-Binding Cassette (ABC) transporter group play a crucial role in the export of cytotoxic drugs across cell membranes. These proteins are particularly fascinating due to their ability to confer drug resistance, which subsequently leads to the failure of therapeutic interventions and hinders successful treatments. One key mechanism by which multidrug resistance (MDR) proteins carry out their transport function is through alternating access. This mechanism involves intricate conformational changes that enable the binding and transport of substrates across cellular membranes. In this extensive review, we provide an overview of ABC transporters, including their classifications and structural similarities. We focus specifically on well-known mammalian multidrug resistance proteins such as MRP1 and Pgp (MDR1), as well as bacterial counterparts such as Sav1866 and lipid flippase MsbA. By exploring the structural and functional features of these MDR proteins, we shed light on the roles of their nucleotide-binding domains (NBDs) and transmembrane domains (TMDs) in the transport process. Notably, while the structures of NBDs in prokaryotic ABC proteins, such as Sav1866, MsbA, and mammalian Pgp, are identical, MRP1 exhibits distinct characteristics in its NBDs. Our review also emphasizes the importance of two ATP molecules for the formation of an interface between the two binding sites of NBD domains across all these transporters. ATP hydrolysis occurs following substrate transport and is vital for recycling the transporters in subsequent cycles of substrate transportation. Specifically, among the studied transporters, only NBD2 in MRP1 possesses the ability to hydrolyze ATP, while both NBDs of Pgp, Sav1866, and MsbA are capable of carrying out this reaction. Furthermore, we highlight recent advancements in the study of MDR proteins and the alternating access mechanism. We discuss the experimental and computational approaches utilized to investigate the structure and dynamics of MDR proteins, providing valuable insights into their conformational changes and substrate transport. This review not only contributes to an enhanced understanding of multidrug resistance proteins but also holds immense potential for guiding future research and facilitating the development of effective strategies to overcome multidrug resistance, thus improving therapeutic interventions.

Reproductive inequality among males in the genus Pan.

Reproductive inequality, or reproductive skew, drives natural selection, but has been difficult to assess, particularly for males in species with promiscuous mating and slow life histories, such as bonobos (Pan paniscus) and chimpanzees (Pan troglodytes). Although bonobos are often portrayed as more egalitarian than chimpanzees, genetic studies have found high male reproductive skew in bonobos. Here, we discuss mechanisms likely to affect male reproductive skew in Pan, then re-examine skew patterns using paternity data from published work and new data from the Kokolopori Bonobo Reserve, Democratic Republic of Congo and Gombe National Park, Tanzania. Using the multinomial index (M), we found considerable overlap in skew between the species, but the highest skew occurred among bonobos. Additionally, for two of three bonobo communities, but no chimpanzee communities, the highest ranking male had greater siring success than predicted by priority-of-access. Thus, an expanded dataset covering a broader demographic range confirms that bonobos have high male reproductive skew. Detailed comparison of data from Pan highlights that reproductive skew models should consider male-male dynamics including the effect of between-group competition on incentives for reproductive concessions, but also female grouping patterns and factors related to male-female dynamics including the expression of female choice. This article is part of the theme issue 'Evolutionary ecology of inequality'.

Designing a zero-order energy transition model: How to create a new Starter Data Kit.

The Paris Agreement was signed by 192 Parties, who committed to reducing emissions. Reaching such commitments by developing national decarbonisation strategies requires significant analyses and investment. Analyses for such strategies are often delayed due to a lack of accurate and up-to-date data for creating energy transition models. The Starter Data Kits address this issue by providing open-source, zero-level country datasets to accelerate the energy planning process. There is a strong demand for replicating the process of creating Starter Data Kits because they are currently only available for 69 countries in Africa, Asia, and South America. Using an African country as an example, this paper presents the methodology to create a Starter Data Kit made of tool-agnostic data repositories and OSeMOSYS-specific data files. The paper illustrates the steps involved, provides additional information for conducting similar work in Asia and South America, and highlights the limitations of the current version of the Starter Data Kits. Future development is proposed to expand the datasets, including new and more accurate data and new energy sectors. Therefore, this document provides instructions on the steps and materials required to develop a Starter Data Kit.•The methodology presented here is intended to encourage practitioners to apply it to new countries and expand the current Starter Data Kits library.•It is a novel process that creates data pipelines that feed into a single Data Collection and Manipulation Tool (DaCoMaTool).•It allows for tool-agnostic data creation in a consistent format ready for a modelling analysis using one of the available tools.

Protein dynamics of a light-driven Na+ pump rhodopsin probed using a tryptophan residue near the retinal chromophore.

Direct observation of protein structural changes during ion transport in ion pumps provides valuable insights into the mechanism of ion transport. In this study, we examined structural changes in the light-driven sodium ion (Na+) pump rhodopsin KR2 on the sub-millisecond time scale, corresponding with the uptake and release of Na+. We compared the ion-pumping activities and transient absorption spectra of WT and the W215F mutant, in which the Trp215 residue located near the retinal chromophore on the cytoplasmic side was replaced with a Phe residue. Our findings indicated that atomic contacts between the bulky side chain of Trp215 and the C20 methyl group of the retinal chromophore promote relaxation of the retinal chromophore from the 13-cis to the all-trans form. Since Trp215 is conserved in other ion-pumping rhodopsins, the present results suggest that this residue commonly acts as a mechanical transducer. In addition, we measured time-resolved ultraviolet resonance Raman (UVRR) spectra to show that the environment around Trp215 becomes less hydrophobic at 1 ms after photoirradiation and recovers to the unphotolyzed state with a time constant of around 10 ms. These time scales correspond to Na+ uptake and release, suggesting evolution of a transient ion channel at the cytoplasmic side for Na+ uptake, consistent with the alternating-access model of ion pumps. The time-resolved UVRR technique has potential for application to other ion-pumping rhodopsins and could provide further insights into the mechanism of ion transport.

Structural Pharmacology of Cation-Chloride Cotransporters.

Loop and thiazide diuretics have been cornerstones of clinical management of hypertension and fluid overload conditions for more than five decades. The hunt for their molecular targets led to the discovery of cation-chloride cotransporters (CCCs) that catalyze electroneutral movement of Cl- together with Na+ and/or K+. CCCs consist of two 1 Na+-1 K+-2 Cl- (NKCC1-2), one 1 Na+-1 Cl- (NCC), and four 1 K+-1 Cl- (KCC1-4) transporters in human. CCCs are fundamental in trans-epithelia ion secretion and absorption, homeostasis of intracellular Cl- concentration and cell volume, and regulation of neuronal excitability. Malfunction of NKCC2 and NCC leads to abnormal salt and water retention in the kidney and, consequently, imbalance in electrolytes and blood pressure. Mutations in KCC2 and KCC3 are associated with brain disorders due to impairments in regulation of excitability and possibly cell volume of neurons. A recent surge of structures of CCCs have defined their dimeric architecture, their ion binding sites, their conformational changes associated with ion translocation, and the mechanisms of action of loop diuretics and small molecule inhibitors. These breakthroughs now set the stage to expand CCC pharmacology beyond loop and thiazide diuretics, developing the next generation of diuretics with improved potency and specificity. Beyond drugging renal-specific CCCs, brain-penetrable therapeutics are sorely needed to target CCCs in the nervous system for the treatment of neurological disorders and psychiatric conditions.

Evidence for a credit-card-swipe mechanism in the human PC floppase ABCB4.

ABCB4 is described as an ATP-binding cassette (ABC) transporter that primarily transports lipids of the phosphatidylcholine (PC) family but is also capable of translocating a subset of typical multidrug-resistance-associated drugs. The high degree of amino acid identity of 76% for ABCB4 and ABCB1, which is a prototype multidrug-resistance-mediating protein, results in ABCB4's second subset of substrates, which overlap with ABCB1's substrates. This often leads to incomplete annotations of ABCB4, in which it was described as exclusively PC-lipid specific. When the hydrophilic amino acids from ABCB4 are changed to the analogous but hydrophobic ones from ABCB1, the stimulation of ATPase activity by 1,2-dioleoyl-sn-glycero-3-phosphocholine, as a prime example of PC lipids, is strongly diminished, whereas the modulation capability of ABCB1 substrates remains unchanged. This indicates two distinct and autonomous substrate binding sites in ABCB4.

Utilizing the ACCESS Model to Understand Communication With the Ultraorthodox Community in Beit Shemesh During the First Wave of COVID-19.

INTRODUCTION: The coronavirus pandemic has disproportionately negatively affected the ultraorthodox in Israel. Their unique characteristics and slow adoption of preventative health guidelines resulted in a significant increase in morbidity and mortality. To lower these rates, health and government authority figures employed methods to change the ultraorthodox community health behaviors. METHODOLOGY: This study utilizes the ACCESS model for transcultural nursing to analyze the response by authorities to high infection rates in the large ultraorthodox community in city of Beit Shemesh during the first wave of the outbreak (through early May). RESULTS: The authorities employed all model components to varying degrees and found moderate success in changing health behaviors of the ultraorthodox. DISCUSSION: Employing the ACCESS model as a response to the health care crisis among the ultraorthodox community in Beit Shemesh led to some success in increased compliance, thus lowering morbidity rates. However, not establishing strong respect and rapport hindered the process.

Substrate binding in the bile acid transporter ASBTYf from Yersinia frederiksenii.

Apical sodium-dependent bile acid transporter (ASBT) retrieves bile acids from the small intestine and plays a pivotal role in enterohepatic circulation. Currently, high-resolution structures are available for two bacterial ASBT homologs (ASBTNM from Neisseria meningitides and ASBTYf from Yersinia frederiksenii), from which an elevator-style alternating-access mechanism has been proposed for substrate transport. A key concept in this model is that the substrate binds to the central cavity of the transporter so that the elevator-like motion can expose the bound substrate alternatingly to either side of the membrane during a transport cycle. However, no structure of an ASBT has been solved with a substrate bound in its central cavity, so how a substrate binds to ASBT remains to be defined. In this study, molecular docking, structure determination and functional analysis were combined to define and validate the details of substrate binding in ASBTYf. The findings provide coherent evidence to provide a clearer picture of how the substrate binds in the central cavity of ASBTYf that fits the alternating-access model.

The Effect of Salience on Chinese Pun Comprehension: A Visual World Paradigm Study.

The present study adopted the printed-word visual world paradigm to investigate the salience effect on Chinese pun comprehension. In such an experiment, participants listen to a spoken sentence while looking at a visual display of four printed words (including a semantic competitor, a phonological competitor, and two unrelated distractors). Previous studies based on alphabetic languages have found robust phonological effects (participants fixated more at phonological competitors than distractors during the unfolding of the spoken target words), while controversy remains regarding the existence of a similar semantic effect. A recent Chinese study reported reliable semantic effects in two experiments using this paradigm, suggesting that Chinese participants could actively map the semantic input from the auditory modality with the semantic information retrieved from printed words. In light of their study, we designed an experiment with two conditions: a replication condition to test the validity of using the printed-word world paradigm in Chinese semantic research, and a pun condition to assess the role played by salience during pun comprehension. Indeed, global analyses have revealed robust semantic effects in both experimental conditions, where participants were found more attracted to the semantic competitors than to the distractors with the emergence of target words. More importantly, the local analyses from the pun condition have shown that the participants were more attracted to the semantic competitors related to the salient meaning of the ambiguous word in a pun than to those related to the less salient meanings within 200 ms after target word offset. This finding suggests that the salient meaning of the ambiguous word in a pun is activated and assessed faster than its less salient counterpart. The initial advantage observed in the present study is consistent with the prediction of the graded salience hypothesis rather than the direct access model.

Secondary Active Transporters.

Transport of solutes across biological membranes is essential for cellular life. This process is mediated by membrane transport proteins which move nutrients, waste products, certain drugs and ions into and out of cells. Secondary active transporters couple the transport of substrates against their concentration gradients with the transport of other solutes down their concentration gradients. The alternating access model of membrane transporters and the coupling mechanism of secondary active transporters are introduced in this book chapter. Structural studies have identified typical protein folds for transporters that we exemplify by the major facilitator superfamily (MFS) and LeuT folds. Finally, substrate binding and substrate translocation of the transporters LacY of the MFS and AdiC of the amino acid-polyamine-organocation (APC) superfamily are described.

Education About Dental Hygienists' Roles in Public Dental Prevention Programs: Dental and Dental Hygiene Students' and Faculty Members' and Dental Hygienists' Perspectives.

In 2005, Public Act No. 161 (PA 161) was passed in Michigan, allowing dental hygienists to practice in approved public dental prevention programs to provide services for underserved populations while utilizing a collaborative agreement with a supervising dentist. The aims of this study were to assess how well dental and dental hygiene students and faculty members and practicing dental hygienists have been educated about PA 161, what attitudes and knowledge about the act they have, and how interested they are in additional education about it. University of Michigan dental and dental hygiene students and faculty members, students in other Michigan dental hygiene programs, and dental hygienists in the state were surveyed. Respondents (response rate) were 160 dental students (50%), 63 dental hygiene students (82%), 30 dental faculty members (26%), and 12 dental hygiene faculty members (52%) at the University of Michigan; 143 dental hygiene students in other programs (20%); and 95 members of the Michigan Dental Hygienists' Association (10%). The results showed that the dental students were less educated about PA 161 than the dental hygiene students, and the dental faculty members were less informed than the dental hygiene faculty members and dental hygienists. Responding dental hygiene faculty members and dental hygienists had more positive attitudes about PA 161 than did the students and dental faculty members. Most of the dental hygiene faculty members and dental hygienists knew a person providing services in a PA 161 program. Most dental hygiene students, faculty members, and dental hygienists wanted more education about PA 161. Overall, the better educated about the program the respondents were, the more positive their attitudes, and the more interested they were in learning more.

A current view of serotonin transporters.

Serotonin transporters (SERTs) are largely recognized for one aspect of their function-to transport serotonin back into the presynaptic terminal after its release. Another aspect of their function, however, may be to generate currents large enough to have physiological consequences. The standard model for electrogenic transport is the alternating access model, in which serotonin is transported with a fixed ratio of co-transported ions resulting in net charge per cycle. The alternating access model, however, cannot account for all the observed currents through SERT or other monoamine transporters.  Furthermore, SERT agonists like ecstasy or antagonists like fluoxetine generate or suppress currents that the standard model cannot support.  Here we survey evidence for a channel mode of transport in which transmitters and ions move through a pore. Available structures for dopamine and serotonin transporters, however, provide no evidence for a pore conformation, raising questions of whether the proposed channel mode actually exists or whether the structural data are perhaps missing a transient open state.

The SLC24 family of K⁺-dependent Na⁺-Ca²âº exchangers: structure-function relationships.

The human SLC24 gene family contains five members encoding the NCKX1-5 proteins that function as K(+)-dependent Na⁺-Ca²âº exchangers. NCKX proteins have been shown to play critical roles in retinal rod and cone photoreceptors, olfactory neurons, epidermal melanocytes, and the retinal pigment epithelium. NCKX transcripts are also found in many other tissues, in particular throughout the brain, but their specific physiological roles yet need to be elucidated in most cases. Here, we focus on our current knowledge of NCKX transport function as has been described in detail only for in situ NCKX1 in the outer segments of retinal rod photoreceptors and on structure-function relationships elucidated for the NCKX2 isoform after expression of its (mutated) cDNA in cell lines.

Conformational changes of the bacterial type I ATP-binding cassette importer HisQMP2 at distinct steps of the catalytic cycle.

Prokaryotic solute binding protein-dependent ATP-binding cassette import systems are divided into type I and type II and mechanistic differences in the transport process going along with this classification are under intensive investigation. Little is known about the conformational dynamics during the catalytic cycle especially concerning the transmembrane domains. The type I transporter for positively charged amino acids from Salmonella enterica serovar Typhimurium (LAO-HisQMP2) was studied by limited proteolysis in detergent solution in the absence and presence of co-factors including ATP, ADP, LAO/arginine, and Mg(2+) ions. Stable peptide fragments could be obtained and differentially susceptible cleavage sites were determined by mass spectrometry as Lys-258 in the nucleotide-binding subunit, HisP, and Arg-217/Arg-218 in the transmembrane subunit, HisQ. In contrast, transmembrane subunit HisM was gradually degraded but no stable fragment could be detected. HisP and HisQ were equally resistant under pre- and post-hydrolysis conditions in the presence of arginine-loaded solute-binding protein LAO and ATP/ADP. Some protection was also observed with LAO/arginine alone, thus reflecting binding to the transporter in the apo-state and transmembrane signaling. Comparable digestion patterns were obtained with the transporter reconstituted into proteoliposomes and nanodiscs. Fluorescence lifetime spectroscopy confirmed the change of HisQ(R218) to a more apolar microenvironment upon ATP binding and hydrolysis. Limited proteolysis was subsequently used as a tool to study the consequences of mutations on the transport cycle. Together, our data suggest similar conformational changes during the transport cycle as described for the maltose ABC transporter of Escherichia coli, despite distinct structural differences between both systems.