The policy case for designating EMS teams for vulnerable patient populations: Evidence from an intervention in Boston.

This study documents more than five years of analysis that drove the policy case, deployment, and retrospective evaluation for an innovative service model that enables Boston Emergency Medical Services (EMS) to respond quickly and effectively to investigation incidents in an area of heavy need in Boston. These investigation incidents are typically calls for service from passers-by or other third-party callers requesting that Boston EMS check in on individuals, often those who may appear to have an altered mental status or to be unhoused. First, this study reports the pre-intervention analytics in 2017 that built the policy case for service segmentation, a new Community Assistance Team designated "Squad 80" that primarily responds to investigation incidents in one broad area of the city with high rates of substance abuse and homelessness, helping patients who often refuse ambulance transport connect to social services. Second, this study reports a post-intervention, observational evaluation of its operational advantages and trade-offs. We observe that incidents involving the Community Assistance Team have significantly shorter response times and result in fewer transports to emergency departments than investigation incidents not involving the unit, leading to fewer ambulance unit-hours utilized across the system. This study documents the descriptive analytics that built the successful policy case for a substantive change in the healthcare-delivery supply chain in Boston and how this change offers operational advantages. It is written to be an accessible guide to the analysts and policy makers considering emergency services segmentation, an important frontier in equitable public-service delivery.

Policy-Relevant Indicators of Urban Emergency Medical Services COVID-19-Patient Encounters.

In the first two years of the COVID-19 pandemic, members of Boston Emergency Medical Services, the City of Boston's municipal ambulance service, had 7,689 encounters with confirmed-positive Boston residents. As COVID-19 virus strains continue to infect residents in Boston and across the country, understanding the correlation between population positivity, EMS encounters, and hospitalizations can inform healthcare response. This study examines urban virus-surveillance indicators that can serve as an early warning of the volume of Emergency Medical Services (EMS) encounters with COVID-19 positive patients and subsequently how EMS encounters with confirmed COVID-19 patients can serve as an early indicator of future hospital-demand surges. With daily data from Boston EMS and three other public agencies, we evaluate the relationship between five indicators and confirmed Boston EMS COVID-19 encounters by estimating separate Auto Regressive Integrated Moving Average models and cross-correlating their residuals. This study finds a significant and positive correlation between new COVID-19 cases citywide and EMS encounters 6 days later (p < 0.01), as well as between confirmed EMS encounters with COVID-19 patients and the number of intensive care unit beds occupied 7- and 18 -days later (p < 0.01). This study provides city health leadership needed clarity on the specific ordering and associated time lag in which infections in the population increase, EMS members encounter positive patients, and hospitals deliver care.

MoVIT: a tomographic reconstruction framework for 4D-CT.

4D computed tomography (4D-CT) aims to visualise the temporal dynamics of a 3D sample with a sufficiently high temporal and spatial resolution. Successive time frames are typically obtained by sequential scanning, followed by independent reconstruction of each 3D dataset. Such an approach requires a large number of projections for each scan to obtain images with sufficient quality (in terms of artefacts and SNR). Hence, there is a clear trade-off between the rotation speed of the gantry (i.e. time resolution) and the quality of the reconstructed images. In this paper, the MotionVector-based Iterative Technique (MoVIT) is introduced which reconstructs a particular time frame by including the projections of neighbouring time frames as well. It is shown that such a strategy improves the trade-off between the rotation speed and the SNR. The framework is tested on both numerical simulations and on 4D X-ray CT datasets of polyurethane foam under compression. Results show that reconstructions obtained with MoVIT have a significantly higher SNR compared to the SNR of conventional 4D reconstructions.

Evaluation of cacao projects in Colombia: The case of the rural Productive Partnerships Project (PAAP).

Identifying the effectiveness of agricultural interventions is a challenge faced by many international aid initiatives. This article reports on our efforts to document the success of agricultural aid interventions. The study is focused on evaluating cacao projects in Colombia, specifically on assessing the success of the rural Productive Partnerships Project (PAAP). The two approaches used to assess the project's success included the degree of accomplishment of four of the PAAP project's objectives and a measurement of the project performance at the local level, for which an existing performance index was utilized. Quantitative data were obtained from the project's evaluation platform developed by the PAAP project coordinators. Based on our first evaluation approach, we found that the four project objectives evaluated were not fully accomplished. While our results using the performance index provide baseline data for upcoming work assessing cacao projects' performance, the absence of precedent information constrained its interpretation. Finally, the paper offers feasible, affordable, and practical recommendations that could benefit future program planning and evaluation of international aid interventions, particularly on cacao projects worldwide.

Instruments measuring spirituality in clinical research: a systematic review.

INTRODUCTION: Numerous instruments have been developed to assess spirituality and measure its association with health outcomes. This study's aims were to identify instruments used in clinical research that measure spirituality; to propose a classification of these instruments; and to identify those instruments that could provide information on the need for spiritual intervention. METHODS: A systematic literature search in MEDLINE, CINHAL, PsycINFO, ATLA, and EMBASE databases, using the terms "spirituality" and "adult$," and limited to journal articles was performed to identify clinical studies that used a spiritual assessment instrument. For each instrument identified, measured constructs, intended goals, and data on psychometric properties were retrieved. A conceptual and a functional classification of instruments were developed. RESULTS: Thirty-five instruments were retrieved and classified into measures of general spirituality (N = 22), spiritual well-being (N = 5), spiritual coping (N = 4), and spiritual needs (N = 4) according to the conceptual classification. Instruments most frequently used in clinical research were the FACIT-Sp and the Spiritual Well-Being Scale. Data on psychometric properties were mostly limited to content validity and inter-item reliability. According to the functional classification, 16 instruments were identified that included at least one item measuring a current spiritual state, but only three of those appeared suitable to address the need for spiritual intervention. CONCLUSIONS: Instruments identified in this systematic review assess multiple dimensions of spirituality, and the proposed classifications should help clinical researchers interested in investigating the complex relationship between spirituality and health. Findings underscore the scarcity of instruments specifically designed to measure a patient's current spiritual state. Moreover, the relatively limited data available on psychometric properties of these instruments highlight the need for additional research to determine whether they are suitable in identifying the need for spiritual interventions.

Perception of organic farmers towards organic agriculture and role of extension.

The sustainability of organic agriculture is associated with the farmers' experience, quality of information provided, management of risks, and compliance with legislation. The objectives of this study were to identify the sources used by the organic farmers to gain information related to organic production, and to assess organic farmers' perceived attitudes towards extension services. To address the research objectives, in-depth semi-structured interviews were conducted with 10 organic farmers in central Pennsylvania. The interviews were digitally recorded and transcribed verbatim, categorized and coded, then thematically analyzed using an interpretive description methodology. The results showed that the extension services were not identified as a primary source of information that was frequently used by the organic farmers. Other organic farmers and organizationa for organic agriculture were the two primary sources of informaiton. The organic farmers were very adept at building social capital in seeking informaiton to address their issues and problems. The primary challenges faced by the organic farmers were the control of insects and weeds, and weather-related issues. The results highlighted that in addition to identifying viable information sources, factors such as adaptive capacities to climate change and certification were key to successful production in organic systems. The present study provides rich and deep information on how farmers perceive organic agriculture and extension services. The outcome of the research undertaken will enable planners, policy makers and the related Cooperative Extension personnel to better understand perceptions of the farmers to devise viable and workable policies and plans that address the concerns and challenges of the farmers.

Primary and secondary supportive partnerships among HIV-positive and HIV-negative middle-aged and older gay men.

This study describes the primary and secondary partnerships of aging gay men participating in the Understanding Patterns of Healthy Aging Among Men Who Have Sex with Men substudy of the Multicenter AIDS Cohort Study and examines differences in the prevalence of these relationship structures by HIV status while adjusting for age, education, and race/ethnicity. Relationships were compared within the following structural categories: "only a primary partnership", "only a secondary partnership", "both a primary and secondary relationship", or "neither a primary nor secondary relationship". There were 1,054 participants (51.9% HIV negative/48.1% HIV positive) included in the study. Participants had a median age of 62.0 years (interquartile range: 56.0-67.0) and most reported being non-Hispanic white (74.6%) and college educated (88.0%). Of the 1,004 participants with available partnership status data, 384 (38.2%) reported no primary or secondary partnerships, 108 (10.8%) reported secondary-only partnership, 385 (38.3%) reported primary-only partnership, and 127 (12.6%) reported both primary and secondary partnerships. Of participants who reported primary partnerships only, the prevalence rates (PRs) were lower among those 62 years and older, HIV positive, black non-Hispanic and Hispanics. Of participants who reported only having a secondary partnership, the PRs were higher among those 62 years and older and HIV positive. Of participants who did not report having either a primary or secondary partnership, the PRs were higher among those 62 years and older, HIV positive, and black non-Hispanic compared with their respective referent groups. There was no significant difference in PRs of having both primary and secondary partnerships by age category, HIV status, race/ethnicity, and education. This study aimed to fill a knowledge gap in the literature regarding both primary and secondary supportive partnerships among aging HIV-positive and HIV-negative gay men.

Prevalence and correlates of sexual behavior and risk management among HIV-positive adults over 50.

BACKGROUND: This study examined the prevalence and correlates of sexual behavior, sexual risk, and behavioral risk reduction strategies among a diverse sample of HIV-positive adults over age 50. METHODS: Individual surveys were conducted with 914 HIV-positive adults age 50 and over (640 male, 264 female, 10 transgender) living in New York City. RESULTS: Over half the sample reported sexual activity in the past 3 months, and one-third of sexually active participants reported unprotected anal or vaginal sex in that time period. Sexually active participants were more likely to be younger and male, but did not differ on physical health status. Participants reported a range of risk-management strategies, including 100% condom use (49% of sexually active participants), serosorting (17%), and strategic positioning (4%). The prevalence of strategies differed by gender/sexual identity subgroups. In multivariate modeling, unprotected sex was significantly associated with recent substance use and loneliness. CONCLUSIONS: Older HIV-positive adults are sexually active, and engage in both high-risk and risk-management behaviors. Loneliness emerged as the dominant risk factor in this sample. Findings provide meaningful implications for HIV prevention interventions targeting this population.

Loneliness and HIV-related stigma explain depression among older HIV-positive adults.

Advances in the treatment of HIV have resulted in a large growing population of older adults with HIV. These aging adults face added social, psychological, and physical challenges associated with the aging process. Correlations between depression, loneliness, health, and HIV/AIDS-related stigma have been studied, but there is little evaluation of these associations among HIV-positive adults over the age of 50. Data for these analyses were taken from the Research on Older Adults with HIV study of 914 New York City-based HIV-positive men and women over the age of 50. In total, 39.1% of participants exhibited symptoms of major depression (CES-D > 23). Multivariate modeling successfully explained 42% of the variance in depression which was significantly related to increased HIV-associated stigma, increased loneliness, decreased cognitive functioning, reduced levels of energy, and being younger. These data underscore the need for service providers and researchers to assert more aggressive and innovative efforts to resolve both psychosocial and physical health issues that characterize the graying of the AIDS epidemic in the USA. Data suggest that focusing efforts to reduce HIV-related stigma and loneliness may have lasting effects in reducing major depressive symptoms and improving perceived health.

Why do they leave? Factors associated with job termination among personal assistant workers in home care.

Recruiting and retaining an adequate number of personal support workers in home care is both challenging and essential to allowing elders to age in place. A mixed-method, longitudinal study examined turnover in a sample of 261 personal support workers in Maine; 70 workers (26.8%) left their employment in the first year of the study. Logistic regression analysis indicated that younger age and lack of health insurance were significant predictors of turnover. Analysis of telephone interviews revealed three overarching themes related to termination: job not worthwhile, personal reasons, and burnout. Implications of study findings for gerontological social workers are outlined.

MUC1 and estrogen receptor alpha gene polymorphisms in dry eye patients.

Dry eye syndrome is a collection of common disorders of multifactorial etiology. Although the epidemiology of dry eye has been well studied, reports of genetic patterns that might influence susceptibility to dry eye are few. We reported that the frequency of non-Sjögren's aqueous-deficient dry eye patients expressing only the MUC1/A splice variant of the mucin MUC1 may be lower than that of a normal control group [Imbert, Y., Darling, D.S., Jumblatt, M.M., Foulks, G.N., Couzin, E.G., Steele, P.S., Young, W.W., Jr., 2006. MUC1 splice variants in human ocular surface tissues: possible differences between dry eye patients and normal controls. Exp. Eye Res. 83, 493-501]. Also, He et al. [He, Y., Li, X., Bao, Y., Sun, J., Liu, J., 2006. The correlation of polymorphism of estrogen receptor gene to dry eye syndrome in postmenopausal women. Yan. Ke. Xue. Bao. 22, 233-236] reported a difference between Chinese dry eye and control groups in the frequency of a polymorphism in estrogen receptor alpha (ERalpha). In the present study we determined the statistical significance and generality of these observations and tested if the MUC1 splice variant difference between subject groups reflected a difference in the MUC1 variable number of tandem repeat (VNTR) size class. There was a perfect correlation between the MUC1/A or MUC1/B splice variant pattern and the SNP genotype frequency of the SNP (rs4072037) controlling that splicing event. In contrast, western and Southern blotting indicated that MUC1 VNTR size class corresponded to the MUC1 SNP genotype in only 80% of cases. We determined the status of the MUC1 SNP in normal and dry eye populations all of whom were female Caucasians. The MUC1 SNP genotype frequency of the normal control group was statistically different from both the non-Sjögren's aqueous-deficient dry eye group with ocular surface staining (P=0.017) and the evaporative dry eye group (P=0.015). We also tested SNP rs2234693 to analyze the polymorphism in the ERalpha gene and found no significant difference in the SNP genotype frequency between the control group and either of the dry eye subtypes. Thus, among Caucasians there is no evidence for an association of the ERalpha gene polymorphism with dry eye syndrome as previously described in a Chinese population. In conclusion, the etiologies of evaporative dry eye and non-Sjögren's aqueous-deficient dry eye are known to be different. However, our results suggest that both of these subtypes of dry eye disease may share a common mechanism or factor related to MUC1 genotypic differences that affects susceptibility to ocular surface damage. This altered susceptibility may not be related to the MUC1 VNTR size class. Therefore, mechanisms influencing protection of the ocular surface against inflammation and damage in different types of dry eye disease warrant further investigation particularly in relation to MUC1 genotype.

A MicroRNA gene is hosted in an intron of a schizophrenia-susceptibility gene.

Schizophrenia (SZ) is a neuropsychiatric disorder that affects about 1% of the adult population. Numerous genes have been implicated in SZ susceptibility. MicroRNAs (miRNA) are small RNA molecules that regulate the translation of mRNAs via interactions with their 3' untranslated regions. Identification of known miRNA targets on all human genes indicated that miRNA-346 targets SZ susceptibility genes listed in the SchizophreniaGene database twice as frequently as expected relative to other genes in the genome. The gene encoding this miRNA, miR-346, is located in intron 2 of the glutamate receptor ionotropic delta 1 (GRID1) gene, which has been previously implicated in SZ susceptibility. We used quantitative real-time PCR to determine the expression levels of miR-346 and GRID1 using brain RNA samples from the Stanley Array Collection, Stanley Medical Research Institute. Expression of both miR-346 and GRID1 is lower in SZ patients than that in normal controls (P=0.017 and 0.086, respectively). However, the expression of miR-346 and GRID1 is less correlated in SZ patients than in bipolar patients or in normal controls. This study implicates the importance of a miRNA in SZ.

Training needs of extension agents' regarding organic agriculture in Saudi Arabia.

The purpose of this study was to investigate the needs of extension agents for training on organic agriculture (OA) in the Riyadh Region. Fifty-five percent (n = 69) of extension agents were selected to collect data through an electronic survey. Results indicated that extension agents in the Riyadh Region cited on job training as a main source for acquiring knowledge in OA. Agents expressed interest in receiving training in OA in general, OA marketing, and transitioning to OA. The most useful resources were field days at organic farms, OA training sessions at colleges, and attending OA trial plots. There were no differences in the level of interest in training; however, there were significant differences between individuals in terms of their experience in OA, job responsibility for providing information related to OA, and area of specialization in their job. This study recommends developing professional training programs based on the current knowledge of extension agents.

Association of Sult4A1 SNPs with psychopathology and cognition in patients with schizophrenia or schizoaffective disorder.

A number of genes located on chromosome 22q11-13, including catechol-O-methyltransferase (COMT), are potential schizophrenia susceptibility genes. Recently, the sulfotransferase-4A1 (Sult4A1) locus within chromosome 22q13 was reported to be linked to schizophrenia in a family TDT study. Sult4A1 is related to metabolism of monoamines, particularly dopamine and norepinephrine, both of which have been implicated in the pathophysiology of the psychopathology and cognitive dysfunction components of schizophrenia. An available, prospectively collected data base was interrogated to determine how three Sult4A1 SNPs: rs138060, rs138097, and rs138110, previously shown to be associated with schizophrenia might be associated with psychopathology, cognition, and quality of life in a sample of 86 Caucasian patients with schizophrenia or schizoaffective disorder. The majority of patients met criteria for treatment resistant schizophrenia and had been drug-free for one week or longer at the time of evaluation. The major findings were: 1) patients heterozygous (T/G) for rs138060 had significantly worse Brief Psychiatric Rating Scale (BPRS) Total and anxiety/depression sub-scale scores, and higher Scale for the Assessment of Positive Symptoms (SAPS) Total scores than G/G homozygous patients; and 2) patients heterozygous (A/G) for rs138097 demonstrated significantly worse performance on neuropsychological testing, specifically on tests of executive function and working memory, compared to patients homozygous for the G and A alleles. RS138110 was unrelated to psychopathology and cognition. These results provide the first evidence of how genetic variation in Sult4A1 may be related to clinical symptoms and cognitive function in schizophrenia, and permit future studies to attempt to replicate these potentially important findings.

Genetic predictors of antipsychotic response to lurasidone identified in a genome wide association study and by schizophrenia risk genes.

Biomarkers which predict response to atypical antipsychotic drugs (AAPDs) increases their benefit/risk ratio. We sought to identify common variants in genes which predict response to lurasidone, an AAPD, by associating genome-wide association study (GWAS) data and changes (Δ) in Positive And Negative Syndrome Scale (PANSS) scores from two 6-week randomized, placebo-controlled trials of lurasidone in schizophrenia (SCZ) patients. We also included SCZ risk SNPs identified by the Psychiatric Genomics Consortium using a polygenic risk analysis. The top genomic loci, with uncorrected p<10-4, include: 1) synaptic adhesion (PTPRD, LRRC4C, NRXN1, ILIRAPL1, SLITRK1) and scaffolding (MAGI1, MAGI2, NBEA) genes, both essential for synaptic function; 2) other synaptic plasticity-related genes (NRG1/3 and KALRN); 3) the neuron-specific RNA splicing regulator, RBFOX1; and 4) ion channel genes, e.g. KCNA10, KCNAB1, KCNK9 and CACNA2D3). Some genes predicted response for patients with both European and African Ancestries. We replicated some SNPs reported to predict response to other atypical APDs in other GWAS. Although none of the biomarkers reached genome-wide significance, many of the genes and associated pathways have previously been linked to SCZ. Two polygenic modeling approaches, GCTA-GREML and PLINK-Polygenic Risk Score, demonstrated that some risk genes related to neurodevelopment, synaptic biology, immune response, and histones, also contributed to prediction of response. The top hits predicting response to lurasidone did not predict improvement with placebo. This is the first evidence from clinical trials that SCZ risk SNPs are related to clinical response to an AAPD. These results need to be replicated in an independent sample.

Computational insights into the inhibition of ß-haematin crystallization by antimalarial drugs.

During the red blood cell phase of their life cycle, malaria parasites digest their host's haemoglobin, with concomitant release of potentially toxic iron(iii) protoporphyrin IX (FePPIX). The parasites' strategy for detoxification of FePPIX involves its crystallization to haemozoin, such that the build-up of free haem in solution is avoided. Antimalarial drugs of both historical importance and current clinical use are known to be capable of disrupting the growth of crystals of ß-haematin, which is the synthetic equivalent of haemozoin. Hence, the disruption of haemozoin crystal growth is implicated as a possible mode of action of such drugs. However, the details of ß-haematin crystal poisoning at the molecular level have yet to be fully elucidated. In this study, we have used a combination of density functional theory (DFT) and molecular modelling to examine the possible modes of action of ten different antimalarial drugs, including quinine-type aliphatic alcohols, amodiaquine-type phenols, and chloroquine-type aliphatic diamines. The DFT calculations indicate that each of the drugs can form at least one molecular complex with FePPIX. These complexes have 1 : 1 or 2 : 1 FePPIX : drug stoichiometries and all of them incorporate Fe-O bonds, formed either by direct coordination of a zwitterionic form of the drug, or by deprotonation of water. Most of the drugs can form more than one such complex. We have used the DFT model structures to explore the possible formation of a monolayer of each drug-haem complex on four of the ß-haematin crystal faces. In all cases, the drug complexes can form a monolayer on the fast-growing {001} and {011} faces, but not on the slower growing {010} and {100} faces. Additional modelling of the chloroquine and quinidine complexes shows that individual molecules of these species can also obstruct the growth of new layers on other crystal faces. The implications of these observations for antimalarial drug development are discussed.

Evidence for two schizophrenia susceptibility genes on chromosome 22q13.

OBJECTIVE: Previous linkage scans and meta-analyses for schizophrenia susceptibility loci failed to include the most distal portion of chromosome 22q. Accordingly, 27 families having individuals affected with schizophrenia and schizophrenia-spectrum disorders were analyzed using a set of highly informative markers covering all of chromosome 22q. METHODS: Microsatellite and single nucleotide polymorphism markers were evaluated by nonparametric linkage, parametric linkage, and transmission disequilibrium testing of 22q. RESULTS: The maximum nonparametric logarithm of odd scores were 2.9 (P=0.0016) for schizophrenia and 2.7 (P=0.003) for a broader disease definition that included schizotypal personality disorder-both at 44.5 cM within the Sult4A1 locus. Parametric models assuming dominant modes of inheritance and genetic heterogeneity gave maximum multipoint logarithm of odd scores for the broader disease definition at the Sult4A1 locus of 3.3 (P=0.0006) and single point logarithm of odd scores of 3.1-4.8 for Sult4A1 markers (P=0.000015-0.0005). A distal locus, centered at 61 cM, shows a maximum nonparametric logarithm of odd scores of 1.5 (P=0.072) for the broader disease definition. Transmission disequilibrium testing for three adjacent microsatellite markers located near the distal linkage peak revealed significant values for marker D22s526 for schizophrenia (P=0.0016-0.14) and for broader disease definitions including schizotypal personality disorder (P=0.0002-0.0003), and both schizotypal personality disorder plus schizoaffective disorder (P=0.00001-0.000077). CONCLUSION: At least two separable, but closely linked, loci within 22q13 influencing susceptibility to schizophrenia-spectrum disorders, might be possible.

Psychosocial adaptations to dual sensory loss in middle and late adulthood.

Concurrent losses of hearing and vision function, or dual sensory loss, affect a large number of individuals of all ages and particularly older adults. Dual sensory loss may present at any age as a result of genetic defect, accident, injury, disease, or environmental insult; however, most persons develop this condition as a result of age-related disease processes that rarely result in total deafness or blindness. This condition has wide-ranging implications for physical and psychological functioning and quality of life. In this article, we review the prevalence and causes of dual impairment and its effects on functioning for both individuals affected and their families. We examine psychosocial coping and adaptation to this condition using biopsychosocial-spiritual and ecological models and discuss various strategies for coping and adaptation. The impact of larger societal forces on psychosocial adaptation is presented, followed by recommendations for how rehabilitation and other professionals can meet the challenge of dual sensory loss that awaits us with the aging of the population.

The impact of assistive device use on disability and depression among older adults with age-related vision impairments.

OBJECTIVE: One can conceptualize adaptive technology as a resource used by disabled older adults in order to maintain competence in everyday life. This study examined the independent relationships between optical and adaptive device utilization and change in functional disability and depression among older adults with age-related vision impairments. METHODS: We interviewed older adults (n = 438) with a recent vision impairment applying for vision rehabilitation services both pre-service and at the 6-month follow-up. We conducted hierarchical regression analyses with functional disability and depressive symptoms as criteria. In order to identify their independent direct effects, we entered optical and adaptive device use into the final step, preceded by Time 1 criterion scores, demographics, baseline disability or depression (depending on criterion), and total rehabilitation service hours. RESULT: Optical, but not adaptive, device use was significantly associated with declines in functional disability and depressive symptoms over time. DISCUSSION: We propose that these differential effects result from the fact that optical devices optimize residual vision and thus allow for greater continuity in the way tasks are accomplished (i.e., reading still performed visually), whereas use of adaptive aids (e.g., talking books) involves learning new methods in order to compensate for lost functions and thus is not as desirable either functionally or psychologically.

Structural and Functional Analysis of a Talin Triple-Domain Module Suggests an Alternative Talin Autoinhibitory Configuration.

Talin plays an important role in regulating integrin-mediated signaling. Talin function is autoinhibited by intramolecular interactions between the integrin-binding F3 domain and the autoinhibitory domain (R9). We determined the crystal structure of a triple-domain fragment, R7R8R9, which contains R9 and the RIAM (Rap1-interacting adaptor molecule) binding domain (R8). The structure reveals a crystallographic contact between R9 and a symmetrically related R8 domain, representing a homodimeric interaction in talin. Strikingly, we demonstrated that the α5 helix of R9 also interacts with the F3 domain, despite no interdomain contact involving the α5 helix in the crystal structure of an F2F3:R9 autoinhibitory complex reported previously. Mutations on the α5 helix significantly diminish the F3:R9 association and lead to elevated talin activity. Our results offer biochemical and functional evidence of the existence of a new talin autoinhibitory configuration, thus providing a more comprehensive understanding of talin autoinhibition, regulation, and quaternary structure assembly.