Search

Sanders, D, Taylor, RJ, Myers, T, and Akubat, I. A field-based cycling test to assess predictors of endurance performance and establishing training zones. J Strength Cond Res 34(12): 3482-3488, 2020-This study evaluates the relationship between a field-based 8-minute time trial (8MTT) and physiological endurance variables assessed with an incremental laboratory test. Second, lactate thresholds assessed in the laboratory were compared with estimated functional threshold power (FTP) from the 8MTT. Nineteen well-trained road cyclists (aged 22 ± 2 years, height 185.9 ± 4.5 cm, body mass 72.8 ± 4.6 kg, V[Combining Dot Above]O2max 64 ± 4 ml·min·kg) participated. Linear regression revealed that mean 8MTT power output (PO) was strongly to very strongly related to PO at 4 mmol·L, PO at initial rise of 1.00 mmol·L, PO at Dmax and modified (mDmax) (r = 0.61-0.82). Mean 8MTT PO was largely to very largely different compared with PO at fixed blood lactate concentration of 2 mmol·L (ES = 3.20) and 4 mmol·L (ES = 1.90), PO at initial rise 1.00 mmol·L (ES = 2.33), PO at Dmax (ES = 3.47) and mDmax (ES = 1.79) but only trivially different from maximal PO (Wmax) (ES = 0.09). The 8MTT based estimated FTP was moderate to very largely different compared with PO at initial rise of 1 mmol·L (ES = 1.37), PO at Dmax (ES = 2.42), PO at mDmax (ES = 0.77) and PO at 4 mmol·L (ES = 0.83). Therefore, even though the 8MTT can be valuable as a performance test in cycling shown through its relationships with predictors of endurance performance, coaches should be cautious when using FTP and PO at laboratory-based thresholds interchangeably to inform training prescription.

The concept of "double jeopardy"-being both older and Black-describes how racism and ageism together shape higher risks for coronavirus exposure, COVID-19 disease, and poor health outcomes for older Black adults. Black people and older adults are the two groups most affected by COVID-19 morbidity and mortality. Double jeopardy, as a race- and age-informed analysis, demonstrates how Black race and older age are associated with practices and policies that shape key life circumstances (e.g., racial residential segregation, family and household composition) and resources in ways that embody elevated risk for COVID-19. The concept of double jeopardy underscores long-standing race- and age-based inequities and social vulnerabilities that produce devastating COVID-19 related deaths and injuries for older Black adults. Developing policies and actions that address race- and age-based inequities and social vulnerabilities can lower risks and enhance protective factors to ensure the health of older Black Americans during the COVID-19 pandemic.

Objectives: Discrimination is associated with several negative social, economic, and health consequences. Past research focuses on the impact of discrimination while less is known about both the type and correlates of discrimination, particularly among older adults., Methods: Using the National Survey of American Life, we used latent class analysis to identify discrimination typologies (frequency and type) among African Americans aged 55 and older. We then used multinomial logistic regression to identify demographic correlates of discrimination types, including a statistical interaction between gender and educational attainment., Results: We identified three discrimination typologies. Increasing age was associated with lower probability of belonging to the high discrimination and disrespect and condescension subtypes. Men and non-Southern residents were most likely to belong in the high discrimination subtype. Higher levels of education increased the probability of belonging in the high discrimination and disrespect and condescension subtypes for older men, but not women., Discussion: Older African American men, particularly those with more education, are vulnerable to both high-frequency discrimination and discrimination characterized by disrespect and condescension. This finding suggests that, for men with more years of education, increased exposure to discrimination reflects efforts to maintain social hierarchies (male target hypothesis)., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

There is growing diversity within the Black population in the U.S., but limited understanding of ethnic and nativity differences in the mental health treatment needs of Black women. This study examined differences in the prevalence of psychiatric disorders, their persistence, and unmet treatment needs among Black women in the U.S. Data were from the National Survey of American Life, a nationally representative survey that assessed lifetime and twelve-month mood, anxiety, and substance use disorders according to the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) criteria, and mental health service use among those meeting disorder criteria. One in three African American women met criteria for a lifetime disorder, compared to one in three Caribbean women born within the U.S. and one in five Caribbean women born outside the U.S. About half of African American women with a lifetime disorder had a persistent psychiatric disorder, compared to two in five Caribbean women born within the U.S. and two in three Caribbean women born outside the U.S. African Americans had more persisting dysthymia and panic disorder and less persisting social phobia compared to foreign-born Caribbean women. Of the three groups, Caribbean women born within the U.S. were most likely to seek mental health treatment during their lifetime. These results demonstrate, despite a lower prevalence of psychiatric disorders in Black women, that there is a great likelihood their disorders will be marked by persistence and underscores the need for culturally specific treatment approaches. As Black immigrants in the United States are increasing in number, adequate mental health services are needed.

We developed a simple method of analyzing the strontium (Sr) and calcium (Ca) content of intact eggshell samples in support of a broader study of how dietary Sr uptake impacts waterfowl eggshell quality. We used wavelength dispersive - x-ray fluorescence spectrometry (WD-XRF) to analyze eggshell pieces ranging in size from ∼6-mm 2 fragments to intact half-shells. We verified this approach on a subset of reference shells by subjecting the same region and volume of shell material from which x-ray signals were measured to analysis by inductively-coupled plasma mass spectrometry (ICP-MS). An analysis of the sources of analytical uncertainty yielded total internal error estimates of ±0.3 and 5% relative for Ca and Sr, respectively, on the basis of which the chemistry of intact shell material analyzed by WD-XRF in this study is compared. The total external errors associated with the WD-XRF results of this study in relation to certified reference material (National Institute of Standards and Technology [NIST] 1400 [a bone ash]) are ±9 and 13.5% relative for Ca and Sr, respectfully (95% CL). Our results demonstrate this method is acceptably accurate and precise for many wildlife management applications. WD-XRF analysis is a quick and inexpensive alternative to traditional methods for determining eggshell Sr and Ca that require acid digestion, allowing for generation of larger datasets that might otherwise be cost-prohibitive, while preserving sample material intact., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

Cancer stem cells (CSCs) are cells within tumors that maintain the ability to self-renew, drive tumor growth, and contribute to therapeutic resistance and cancer recurrence. In this study, we investigate the role of Zinc finger and SCAN domain containing 4 (ZSCAN4) in human head and neck squamous cell carcinoma (HNSCC). The murine Zscan4 is involved in telomere maintenance and genomic stability of mouse embryonic stem cells. Our data indicate that the human ZSCAN4 is enriched for, marks and is co-expressed with CSC markers in HNSCC. We show that transient ZSCAN4 induction for just 2 days increases CSC frequency both in vitro and in vivo and leads to upregulation of pluripotency and CSC factors. Importantly, we define for the first time the role of ZSCAN4 in altering the epigenetic profile and regulating the chromatin state. Our data show that ZSCAN4 leads to a functional histone 3 hyperacetylation at the promoters of OCT3/4 and NANOG, leading to an upregulation of CSC factors. Consistently, ZSCAN4 depletion leads to downregulation of CSC markers, decreased ability to form tumorspheres and severely affects tumor growth. Our study suggests that ZSCAN4 plays an important role in the maintenance of the CSC phenotype, indicating it is a potential therapeutic target in HNSCC.

Taylor, RJ, Sanders, D, Myers, T, and Akubat, I. Reliability and validity of integrated external and internal load ratios as measures of fitness in academy rugby union players. J Strength Cond Res 34(6): 1723-1730, 2020-This study aimed to assess the relationships between integrated ratios of external and internal load measures and aerobic fitness in 3 different training exercise protocols. Twelve academy rugby union players (aged; 17.6 ± 0.44 years, height; 179.4 ± 6.3 cm, body mass 83.3 ± 9.7 kg) performed a lactate threshold/V[Combining Dot Above]O2max test (LT/V[Combining Dot Above]O2max) followed by 3 exercise protocols; 760 m continuous shuttle running (20 m shuttle run at 9 km·h), sprint interval training (SIT: 6 × 6 seconds sprint with 54 seconds recovery), and a small-sided game (SSG: 6 vs. 6, 10 minutes on a 39 × 51 m pitch) on 2 occasions. A LT/V[Combining Dot Above]O2max test was used to determine velocity at lactate threshold (vLT) and at the onset of blood lactate accumulation (vOBLA), maximal oxygen uptake (V[Combining Dot Above]O2max) and the heart rate-blood lactate profile for the calculation of internal load (individualized training impulse or iTRIMP). The total distance (TD), PlayerLoad, metabolic power (MP), high-speed distance >15 km·h (HSD), very high-speed distance >18 km·h (VHSD) and individualized high-speed distance based on each player's vOBLA (iHSD) for the 3 exercise protocols were measured using Micro Electro Mechanical Systems/Global Positioning System technology. Bayesian analysis was used to assess the ratios validity and reliability. Ratios demonstrated large-to-very large associations with vOBLA (Rho = 0.64-0.76), vLT (Rho = 0.63-0.71). Reliability of the ratios ranged from 7.06 to 36.28% (coefficient of variation [CV]%). The results suggest that integrated load ratios from the SIT and SSG protocols provide a measure which is reliable with large-to-very large associations to submaximal aerobic fitness in rugby union.

Background: Despite research on the dramatic changes in marriage, there is a dearth of research on the correlates of marriage and romantic involvement among older African Americans. This is an important omission because although the marriage decline is universal, African Americans show the steepest decline in marriage rates., Methods: Based on data from the National Survey of American Life, multinomial logistic regression analysis is used to identify demographic and health correlates of: 1) being married or cohabiting, 2) having a romantic involvement, 3) not having a romantic involvement but desiring one, and lastly, 4) not having and not desiring a romantic involvement., Results: Four in 10 older African Americans are either married or cohabiting, 11% are unmarried but romantically involved, 9.5% are unmarried and not romantically involved but open to the possibility of a relationship, and 38% neither have nor desire a romantic involvement. More men than women are married or cohabiting, a gap that increases with advanced age. Across all age groups, African American women are more likely than their male counterparts to report that they neither have nor desire a romantic relationship., Conclusion: Almost as many older African Americans do not want a romantic relationship as those who are married/cohabiting. Findings support social exchange theories and the importance of an unbalanced sex ratio. Furthermore, the results suggest that singlehood among older African Americans (especially women) is not necessarily an involuntary status. Nonetheless, this group is at higher risk of economic and health problems as they age., Competing Interests: The authors have declared that no competing interests exist.

In utero electroporation (IUE) is a powerful tool for testing the role of genes in neuronal migration and function, but this technique suffers from high degrees of variability. Such variability can result from inconsistent surgery, developmental gradients along both rostral-caudal and medial-lateral axes, differences within littermates and from one litter to another. Comparisons between control and experimental electroporations rely on section matching, which is inherently subjective. These sources of variability are cumulative, leading to difficult to interpret data and an increased risk of both false positives and false negatives. To address these limitations, we developed two tools: (1) a new plasmid, termed Double UP, which combines LoxP-flanked reporters and limiting Cre dosages to generate internal controls, and (2) an automated program for unbiased and precise quantification of migration. In concert, these tools allow for more rigorous and objective experiments, while decreasing the mice, time, and reagents required to complete studies., (Copyright © 2020 Taylor, Carrington, Gerlach, Taylor, Richters and Dent.)

Background & Aims: Biopsy-confirmed liver fibrosis is a prognostic factor for patients with nonalcoholic fatty liver disease (NAFLD). We performed a systematic review to quantify the prognostic value of fibrosis stage in patients with NAFLD and the subgroup of patients with nonalcoholic steatohepatitis (NASH) and to assess the evidence that change in fibrosis stage is a surrogate endpoint., Methods: We searched the MEDLINE, Embase, Cochrane Library, and trial registry databases through August 2018 for prospective or retrospective cohort studies of liver-related clinical events and outcomes in adults with NAFLD or NASH. We collected data on mortality (all cause and liver related) and morbidity (cirrhosis, liver cancer, and all liver-related events) by stage of fibrosis, determined by biopsy, for patients with NAFLD or NASH. Using fibrosis stage 0 as a reference population, we calculated fibrosis stage-specific relative risk (RR) and 95% confidence interval (CI) values for mortality and morbidities. We performed fixed-effect and random-effect model meta-analyses. Metaregression was used to examine associations among study design (prospective vs retrospective cohort), overall risk of bias (medium or high), and mean duration of follow-up (in years)., Results: Our meta-analysis included 13 studies, comprising 4428 patients with NAFLD; 2875 of these were reported to have NASH. Compared with no fibrosis (stage 0), unadjusted risk increased with increasing stage of fibrosis (stage 0 vs 4): all-cause mortality RR, 3.42 (95% CI, 2.63-4.46); liver-related mortality RR, 11.13 (95% CI, 4.15-29.84); liver transplant RR, 5.42 (95% CI, 1.05-27.89); and liver-related events RR, 12.78 (95% CI, 6.85-23.85). The magnitude of RR did not differ significantly after adjustment for confounders, including age or sex in the subgroup of NAFLD patients with NASH. Three studies examined the effects of increasing fibrosis on quality of life had inconsistent findings., Conclusions: In a systematic review and meta-analysis, we found biopsy-confirmed fibrosis to be associated with risk of mortality and liver-related morbidity in patients with NAFLD, with and without adjustment for confounding factors and in patients with reported NASH. Further studies are needed to assess the association between fibrosis stage and patient quality of life and establish that change in liver fibrosis stage is a valid endpoint for use in clinical trials., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Psychiatric disorders impose significant personal, social, and financial costs for individuals, families, and the nation. Despite a large amount of research and several journals focused on psychiatric conditions, there is a paucity of research on psychiatric disorders among Black Americans (i.e., African Americans and Black Caribbeans), particularly older Black Americans. The present literature review examines research on psychiatric disorders among older Black Americans and provides a broad overview of research findings that are based on nationally representative studies. Collectively, this research finds: (1) older African Americans have lower rates of psychiatric disorders than younger African Americans; (2) family support is not protective of psychiatric disorders, whereas negative interaction with family members is a risk factor; (3) everyday discrimination is a risk factor for psychiatric disorders; (4) both older African Americans and African American across the adult age range have lower prevalence rates of psychiatric disorders than non-Latino whites; (5) Black Caribbean men have particularly high rates of depression, posttraumatic stress disorder, and suicide attempts; and (6) a significant proportion of African American older adults with mental health disorders do not receive professional help. This literature review also discusses the "Race Paradox" in mental health, the Environmental Affordances Model, and the importance of investigating ethnicity differences among Black Americans. Future research directions address issues that are directly relevant to the Black American population and include the following: (1) understanding the impact of mass incarceration on the psychiatric disorders of prisoners' family members, (2) assessing the impact of immigration from African countries for ethnic diversity within the Black American population, (3) examining the impact of racial identity and racial socialization as potential protective factors for psychiatric morbidities, and (4) assessing racial diversity in life-course events and their impact on mental health., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Social isolation is a major problem in the United States that has adverse impacts on health and well-being. However, few studies investigate social isolation among African Americans or the impact of social isolation on psychiatric disorders. This study addresses this gap by investigating the impact of objective (absence of contact with others) and subjective (lacking feelings of closeness to others) social isolation on psychiatric disorders among African Americans. The sample includes 3,570 African Americans from the National Survey of American Life. Regression models were used to test the impact of objective and subjective isolation on 12-month MDD, any 12-month DSM disorder and number of 12-month DSM disorders. Analyses indicated that subjective isolation from family only, friends only, and both groups were associated with greater odds of meeting criteria for 12-month MDD, any 12-month disorder and number of 12-month DSM disorders. However, objective isolation was unrelated to either measure of psychiatric disorder. Study findings indicate that affective characteristics of social isolation (feelings of closeness with family and friends) are more significant for psychiatric disorders than are objective features (social contact). Our discussion notes that the connections between subjective and objective social isolation and psychiatric disorders are complex and potentially reciprocally associated with one another. Clinical practice should focus on both possible associations., Competing Interests: Conflict-of-Interest Statement The authors declare that they have no conflict of interest.

This study examined racial and ethnic differences in professional service use by older African Americans, Black Caribbeans, and Non-Hispanic Whites in response to a serious personal problem. The analytic sample (N = 862) was drawn from the National Survey of American Life. Findings indicated that African Americans and Black Caribbeans were less likely to use services than Whites. Type and race of providers seen varied by respondents' race and ethnicity. Among respondents who did not seek professional help, reasons for not seeking help varied by ethnicity. Study findings are discussed in relation to practice implications.

Dictyostelium discoideum is gaining increasing attention as a model organism for the study of calcium binding and calmodulin function in basic biological events as well as human diseases. After a short overview of calcium-binding proteins, the structure of Dictyostelium calmodulin and the conformational changes effected by calcium ion binding to its four EF hands are compared to its human counterpart, emphasizing the highly conserved nature of this central regulatory protein. The calcium-dependent and -independent motifs involved in calmodulin binding to target proteins are discussed with examples of the diversity of calmodulin binding proteins that have been studied in this amoebozoan. The methods used to identify and characterize calmodulin binding proteins is covered followed by the ways Dictyostelium is currently being used as a system to study several neurodegenerative diseases and how it could serve as a model for studying calmodulinopathies such as those associated with specific types of heart arrythmia. Because of its rapid developmental cycles, its genetic tractability, and a richly endowed stock center, Dictyostelium is in a position to become a leader in the field of calmodulin research., Competing Interests: The authors declare no conflict of interest.

Social isolation is a significant social problem in the United States that many health and welfare organizations have begun to acknowledge and address. Unfortunately, extremely little research focuses on social isolation among ethnic minority populations. This study investigated the association between social isolation from family and friends and the mental health of African Americans and Black Caribbeans. Using data from the National Survey of American Life (2001-2003), we explore 2 indicators of mental health: depressive symptoms (CES-D) and serious psychological distress (Kessler 6). The negative binomial regression analysis examined both objective isolation (infrequent contact) and subjective isolation (lack of emotional closeness) from family and friends. Overall study findings indicated that infrequent contact (objective social isolation) and diminished emotional closeness (subjective social isolation) from family and friends were associated with higher levels of depressive symptoms and serious psychological distress for both African Americans and Black Caribbeans. The addition of subjective social isolation to regression models attenuated the association between objective social isolation and depressive symptoms for both groups. However, the addition of subjective social isolation attenuated the association between serious psychological distress for African Americans but not for Black Caribbeans. These findings contribute to the very limited, but growing body of research on the negative association between social isolation and the mental and physical health of ethnic minorities. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Early blight is an economically important foliar disease of potato in the United States. Because of the lack of resistant potato cultivars, fungicides are applied extensively to obtain adequate control. To manage early blight, standard protectant fungicides and single-site mode-of-action "specialty" fungicides are applied either alone or incorporated into a fungicide rotation program. Control efficacy at two crop growth stages (tuber initiation/early bulking and late bulking/tuber maturation) and the overall tuber yield response to standard and specialty fungicides were assessed using network metaanalytic models. Control efficacy of fungicides ranged from moderate to very high (>30 to 75%) compared with the nontreated control. For both potato growth stages, specialty fungicides performed better than standard protectant fungicides. Furthermore, control efficacy of both fungicides was higher (3 to 9%) at late bulking and tuber maturation when compared with early bulking crop growth stage. Specialty fungicide programs increased overall tuber yields by 4 and 9% over standard fungicides and nontreated control, respectively. Based on the results, more precise fungicide use recommendations and fungicide programs can be developed for early blight management.

The signaling protein calmodulin (CaM) undergoes a well-known change in secondary structure upon binding Ca 2+ , but the structural plasticity of the Ca 2+ -free apo state is linked to CaM functionality. Variable temperature studies of apo -CaM indicate two structural transitions at 46 and 58 °C that are assigned to melting of the C- and N-terminal domains, respectively, but the molecular mechanism of domain unfolding is unknown. We report temperature-jump time-resolved infrared (IR) spectroscopy experiments designed to target the first steps in the C-terminal domain melting transition of human apo -CaM. A comparison of the nonequilibrium relaxation of apo -CaM with the more thermodynamically stable holo -CaM, with 4 equiv of Ca 2+ bound, shows that domain melting of apo -CaM begins on microsecond time scales with α-helix destabilization. These observations enable the assignment of previously reported dynamics of CaM on hundreds of microsecond time scales to thermally activated melting, producing a complete mechanism for thermal unfolding of CaM.

Objectives: Social isolation is a major risk factor for poor physical and mental health among older adults. This study investigates the correlates of objective social isolation among older African Americans, Black Caribbean immigrants, and non-Hispanic Whites., Methods: The analysis is based on the older subsample (n = 1,439) of the National Survey of American Life. There are eight indicators of objective social isolation: no contact with neighbors, neighborhood groups, friends, family members, religious congregation members, not being married and no romantic involvement, living alone, and not being a parent., Results: Very few older Americans are socially isolated from family and friends. Non-Hispanic Whites are more likely than both African Americans and Black Caribbeans to live alone, to be childless, and have limited contact with religious congregation members. For both African Americans and Black Caribbeans, being female is protective against social isolation, but for both populations, men are more likely to be married or have a romantic partner. For African Americans, residing in the South is also protective against social isolation., Discussion: This analysis provides greater clarity on racial and ethnic differences in social isolation among older adults, as well as within-group differences in objective social isolation among African Americans and Black Caribbeans., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The development of a commercial fusion power plant presents a unique set of challenges associated with the complexity of the systems, the integration of novel technologies, the likely diversity and distribution of the organizations involved, and the scale of resources required. These challenges are reviewed and compared to those for other complex engineering systems. A framework for creating a digital environment that integrates research, test, design and operational data is discussed and is based on combining the integrated nuclear digital environment (INDE), proposed recently for nuclear fission power plants, with the hierarchical pyramid of test and simulation used in the aerospace industry. The framework offers the opportunity to plan modelling strategies that allow large design domains to be explored prior to optimizing a detailed design for construction; and in this context, the relationship between measurements and predictions are explored. The use of the framework to guide the socio-technical activity associated with a distributed and collaborative design process is discussed together with its potential benefits and the technology gaps that need to be addressed in order to realize them. These benefits include shorter development times, reduced costs and improvements in credibility, operability, reliability and safety., Competing Interests: The authors have no competing interests., (© 2019 The Authors.)

Objective: We report an association between lower cranial nerve (CN IX/X) vascular compression at the brainstem with laryngeal symptoms utilizing a stepwise algorithm that systematically evaluates and eliminates all other common etiologies. Our experiences with retromastoid craniectomy with lower cranial nerve (LCN) decompression versus non-neurosurgical treatments are detailed., Study Design: Retrospective chart review at a tertiary care academic medical center with follow-up telephone survey., Methods: Baseline demographics, clinical characteristics, quality-of-life surveys, and treatment outcomes were recorded for patients with laryngeal symptoms associated with LCN compression at the brainstem., Results: Forty-nine patients demonstrated LCN compression at the brainstem on imaging and presented with chief complaints of dysphonia (25 of 49, 51%), chronic cough (19 of 49, 39%), dysphoric breathing (3 of 49, 6%), and dysphagia (2 of 49, 4%). Poor initial scores were noted for Voice-Related Quality of Life (V-RQOL), Reflux Symptom Index, and Glottal Closure Index. Twenty-four patients underwent LCN decompression, of which 21 of 24 (88%) reported partial, near-complete, or complete improvement. Major perioperative complications occurred in four of 24 patients (17%). Patients who had undergone decompression were more likely to obtain complete/near-complete symptom resolution (10 of 24 patients, 42%) compared to those undergoing conservative treatments (2 of 25 patients, 8%) (P = 0.02). V-RQOL scores improved more in surgical patients [mean change score, 33.0 (standard deviation [SD], 31.2) than nonsurgical patients (mean change score 9.6, SD 20.9) (P = 0.03) (mean follow-up 3.0 years, SD 2.0)., Conclusion: Lower cranial nerve compression at the brainstem should be considered when all other etiologies are excluded. Retromastoid craniectomy with LCN decompression demonstrates an acceptable safety profile., Level of Evidence: 4 Laryngoscope, 129:2105-2111, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

The widely expressed G-protein coupled receptors (GPCRs) are versatile signal transducer proteins that are attractive drug targets but structurally challenging to study. GPCRs undergo a number of conformational rearrangements when transitioning from the inactive to the active state but have so far been believed to adopt a fairly conserved inactive conformation. Using 19 F NMR spectroscopy and advanced molecular dynamics simulations we describe a novel inactive state of the adenosine 2A receptor which is stabilised by the aminotriazole antagonist Cmpd-1. We demonstrate that the ligand stabilises a unique conformation of helix V and present data on the putative binding mode of the compound involving contacts to the transmembrane bundle as well as the extracellular loop 2., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: Black Caribbeans in the United States have been the victims of major discrimination (e.g. unfairly fired, denied a promotion, denied housing). What is not known is the degree to which they also experience more routine forms of everyday discrimination such as receiving poor restaurant service, being perceived as dishonest, and being followed in stores. This paper investigates the distribution and correlates of everyday discrimination among a national sample of black Caribbeans in the U.S., Design: This analysis used the black Caribbean sub-sample (n = 1,621) of the National Survey of American Life. Demographic and immigration status correlates of ten items from the Everyday Discrimination Scale were investigated: being treated with less courtesy, treated with less respect, receiving poor restaurant service, being perceived as not smart, being perceived as dishonest, being perceived as not as good as others, and being feared, insulted, harassed, or followed in stores., Results: Roughly one out of ten black Caribbeans reported that, on a weekly basis, they were treated with less courtesy and other people acted as if they were better than them, were afraid of them, and as if they were not as smart. Everyday discrimination was more frequent for black Caribbeans who were male, never married, divorced/separated, earned higher incomes, and who were second or third generation immigrants. Black Caribbeans attributed the majority of the discrimination they experienced to their race., Conclusion: To our knowledge, this is the first study to provide an in-depth investigation of everyday discrimination among the black Caribbean population. It provides the frequency, types and correlates of everyday discrimination reported by black Caribbeans in the United States. Understanding the frequency and types of discrimination is important because of the documented negative impacts of everyday discrimination on physical and mental health.

The F-BAR family of proteins play important roles in many cellular processes by regulating both membrane and actin dynamics. The CIP4 family of F-BAR proteins is widely recognized to function in endocytosis by elongating endocytosing vesicles. However, in primary cortical neurons, CIP4 concentrates at the tips of extending lamellipodia and filopodia and inhibits neurite outgrowth. Here, we report that the highly homologous CIP4 family member, FBP17, induces tubular structures in primary cortical neurons and results in precocious neurite formation. Through domain swapping and deletion experiments, we demonstrate that a novel polybasic region between the F-BAR and HR1 domains is required for membrane bending. Moreover, the presence of a poly-PxxP region in longer splice isoforms of CIP4 and FBP17 largely reverses the localization and function of these proteins. Thus, CIP4 and FBP17 function as an antagonistic pair to fine-tune membrane protrusion, endocytosis, and neurite formation during early neuronal development., (© 2019 Taylor et al.)

We examined the sociodemographic and religious involvement correlates of church support networks in a nationally representative sample of African Americans across the adult life span. Data from the National Survey of American Life was used for analysis. Ordinary least squares regression was conducted to identify correlates of frequency of contact, subjective closeness, provision and receipt of overall support, receipt of emotional support, and negative interactions with church members. We also investigated differences in church support networks separately for men and women. Religious involvement was positively associated with church support network indicators (i.e., frequency of contact). Church support network indicators also varied by age, gender, education, family income, marital status, and region. The findings indicate that for many African Americans, church members are an integral component of their support networks and underscore the importance of social integration in church networks for social support exchanges. Moreover, these church support network characteristics are patterned by sociodemographic characteristics., (© 2019 Wiley Periodicals, Inc.)

Passwords might unlock more than our computer accounts. A New York Times Magazine described anecdotes of people who infused their passwords with autobiographical information [Urbina, I. (2014, November 20). The Secret Life of Passwords. New York Times. Retrieved from https://www.nytimes.com/2014/11/19/magazine/the-secret-life-of-passwords.html ]. We suspected people infused their passwords with autobiographical information so they could privately remember that information. Across two studies we took a systematic approach to address the extent to which people infused passwords with autobiographical information and the functions that information served. We also examined the self-reported consequences of people infusing their passwords with autobiographical information. Across both studies, 41.6-71.1% of people infused their passwords with autobiographical memories; in Study 2, 9.3% of people infused their passwords with episodic future thoughts. People who infused their password with autobiographical information reported that information served identity, social, and directive functions, and they created their password to remember that information. These studies show that people do not simply use passwords to unlock their computer accounts. Some people might use passwords as mementos to cue autobiographical information.

Chronic wounds are projected to reach epidemic proportions worldwide because of the aging population and the increasing incidence of diabetes. Despite extensive research, infection remains one of the leading sources of complications in chronic wounds, resulting in improper healing, biofilm formation, and lower extremity amputation. To address the limitations of standard treatments, we have developed a hydrogel wound dressing with self-tuning moisture control that incorporates a novel antimicrobial agent to eliminate and prevent infection. 3D-printing of a hydrogel dressing with dual porosity resulted in a new dressing with greater flexibility, increased water uptake, and more rapid swelling than bulk hydrogel dressings. Additionally, gallium maltolate (GaM) was incorporated into the dressing to investigate the efficacy of this antimicrobial agent. Loading profiles, release kinetics, and the bactericidal activity against Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus ) of GaM were investigated in vitro to identify target profiles that supported infection control. Finally, GaM-loaded hydrogel dressings were evaluated in vivo , utilizing a murine splinted-wound model that was inoculated with S. aureus . In comparison to an untreated control, GaM dressings markedly reduced the wound bacterial load without compromising wound closure rates. Overall, this work demonstrates the utility of a 3D-printed hydrogel dressing as an antimicrobial dressing to control infection in chronic wounds.

Gram-negative bacteria are surrounded by an inner cytoplasmic membrane and by an outer membrane, which serves as a protective barrier to limit entry of many antibiotics. The distinctive properties of the outer membrane are due to the presence of lipopolysaccharide 1 . This large glycolipid, which contains numerous sugars, is made in the cytoplasm; a complex of proteins forms a membrane-to-membrane bridge that mediates transport of lipopolysaccharide from the inner membrane to the cell surface 1 . The inner-membrane components of the protein bridge comprise an ATP-binding cassette transporter that powers transport, but how this transporter ensures unidirectional lipopolysaccharide movement across the bridge to the outer membrane is unknown 2 . Here we describe two crystal structures of a five-component inner-membrane complex that contains all the proteins required to extract lipopolysaccharide from the membrane and pass it to the protein bridge. Analysis of these structures, combined with biochemical and genetic experiments, identifies the path of lipopolysaccharide entry into the cavity of the transporter and up to the bridge. We also identify a protein gate that must open to allow movement of substrate from the cavity onto the bridge. Lipopolysaccharide entry into the cavity is ATP-independent, but ATP is required for lipopolysaccharide movement past the gate and onto the bridge. Our findings explain how the inner-membrane transport complex controls efficient unidirectional transport of lipopolysaccharide against its concentration gradient.

Background: Understanding the real-world effect of pneumococcal conjugate vaccines (PCVs) on pneumonia mortality is crucial because of the expectation that increased PCV use will substantially reduce the burden of pneumonia deaths in children younger than 5 years. However, few post-vaccine introduction studies have estimated the benefits of PCV use on childhood mortality and results have been inconsistent. Therefore, we set out to assess the effect of introduction of ten-valent pneumococcal conjugate vaccine (PCV10) on pneumonia mortality in children in Brazil., Methods: In this retrospective observational study, we used publicly available mortality data of children aged 3-59 months in Brazil. We separated data by age group (3-11 months, 3-23 months, and 3-59 months) and stratified data by three different socioeconomic factors of Brazilian municipalities (in 2010): Human Development Index, proportion of children living in extreme poverty, and proportion of mothers with no primary education. We first examined long-term trends in childhood pneumonia mortality in Brazil (from 1980 to 2014). We then assessed the effect of PCV10-introduced in Brazil in 2010-both nationally and in municipalities stratified by socioeconomic status, with a synthetic control approach as our primary analytical method., Findings: Between 1980 and 2010, a period during which Brazil's Human Development Index rose substantially, national pneumonia mortality in children younger than 5 years decreased from about 150 to 15 deaths per 100 000 children younger than 5 years. Despite rapid uptake of PCV10 after its introduction in 2010, we observed a further vaccine-associated decline of about 10% in national childhood pneumonia mortality with our primary analytical method, with a high degree of uncertainty in the estimates. We observed larger reductions in municipal childhood pneumonia mortality in all three age groups (3-11 months, 3-23 months, and 3-59 months) in municipalities with a high percentage of extreme childhood poverty and mothers with no primary education, with the largest decrease observed in children aged 3-23 months in municipalities with low maternal education (24%, 95% credible interval 7-35)., Interpretation: The large reduction observed from 1980 to 2010 in national pneumonia mortality in children younger than 5 years underscores that improvements in nutrition, hygiene, education, and health care have an important role in reducing pneumonia mortality. Although the PCV-associated reduction in childhood pneumonia mortality at the national level was modest, we found that PCV led to larger reductions in low-income municipalities. Similarly, large benefits might occur when PCVs are introduced in other low-income settings., Funding: Bill & Melinda Gates Foundation and National Institute of Allergy and Infectious Diseases., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Simple hydroxamic acids such as acteohydroxamic acid (AHA) have been identified as suitable reagents for the control of Pu and Np in advanced separation processes for nuclear fuel reprocessing such as the Advanced PUREX or UREX based recycle processes, due to their ability to strip the tetravalent form of Pu and Np from tri-butyl phosphate into nitric acid. However, both free and metal bound hydroxamates are known to undergo acid catalysed hydrolysis at low pH, the kinetics of which must be characterised before implementation of PUREX/UREX based reprocessing flowsheets. In support of this implementation, a comprehensive thermodynamic and kinetic model that describes both the complex speciation and hydrolysis of AHA in the presence of Np(iv) has been developed. The model has two unique features: (i) in the case of the hydrolysis reaction kinetics, the model includes the hydrolysis of not only free AHA but also both the mono- and bishydroxamato-Np(iv) complexes; (ii) for the associated speciation calculations, the model explicitly includes the ionic strength dependence of not only the mono- and bishydroxamato-Np(iv) complexes but also the mono- and bisnitrato neptunium(iv) and monohydroxoneptunium(iv) complexes. For the latter three species, respective SIT coefficients of Δε1,NO3 = -0.13 ± 0.03 kg mol-1, , Δε2,NO3 = -0.37 ± 0.13 kg mol-1, Δε1,OH = -0.36 kg mol-1 and log10 K01,OH = -1.23 were also determined. Using experimental data from a series of kinetic studies on the Np(iv)-AHA system, this model has been used to determine the rate constants for hydrolysis of mono- and bis-acetohydroxamatoneptunium(iv) at 25 °C for the first time. These were found to be 3.5 × 10-5 ± 2.5 × 10-5 dm3 mol-1 s-1 and 1.9 × 10-3 ± 1.3 × 10-3 dm3 mol-1 s-1, respectively. Comparison of these values with the rate constants for hydrolysis of free AHA indicates that complexation of AHA with Np(iv) increases the rate of hydroxamate hydrolysis - an observation that we attribute to the electron withdrawing effect of the metal centre within the Np(iv)-AHA complex increasing the susceptibility of the AHA carbonyl carbon to nucleophilic attack, the accepted first step in its mechanism of hydrolysis.

Background: The synthetic control model is a powerful tool to quantify the population-level impact of vaccines because it can adjust for trends unrelated to vaccination using a composite of control diseases. Because vaccine impact studies are often conducted using smaller, subnational datasets, we evaluated the performance of synthetic control models with sparse time series data. To obtain more robust estimates of vaccine impacts from noisy time series, we proposed a possible alternative approach, STL+PCA method (seasonal-trend decomposition plus principal component analysis), which first extracts smoothed trends from the control time series and uses them to adjust the outcome., Methods: Using both the synthetic control and STL+PCA models, we estimated the impact of 10-valent pneumococcal conjugate vaccine on pneumonia hospitalizations among cases <12 months and 80+ years of age during 2004-2014 at the subnational level in Brazil. We compared the performance of these models using simulation analyses., Results: The synthetic control model was able to adjust for trends unrelated to 10-valent pneumococcal conjugate vaccine in larger states but not in smaller states. Simulation analyses showed that the estimates obtained with the synthetic control approach were biased when there were fewer cases, and only 4% of simulations had credible intervals covering the true estimate. In contrast, the STL+PCA analysis had 90% lower bias and had 95% of simulations, with credible intervals covering the true estimate., Conclusions: Estimates from the synthetic control model might be biased when data are sparse. The STL+PCA model provides more accurate evaluations of vaccine impact in smaller populations.

mRNA translation in axons enables neurons to introduce new proteins at sites distant from their cell body. mRNA-protein interactions drive this post-transcriptional regulation, yet knowledge of RNA binding proteins (RBP) in axons is limited. Here we used proteomics to identify RBPs interacting with the axonal localizing motifs of Nrn1 , Hmgb1 , Actb , and Gap43 mRNAs, revealing many novel RBPs in axons. Interestingly, no RBP is shared between all four RNA motifs, suggesting graded and overlapping specificities of RBP-mRNA pairings. A systematic assessment of axonal mRNAs interacting with hnRNP H1, hnRNP F, and hnRNP K, proteins that bound with high specificity to Nrn1 and Hmgb1 , revealed that axonal mRNAs segregate into axon growth-associated RNA regulons based on hnRNP interactions. Axotomy increases axonal transport of hnRNPs H1, F, and K, depletion of these hnRNPs decreases axon growth and reduces axonal mRNA levels and axonal protein synthesis. Thus, subcellular hnRNP-interacting RNA regulons support neuronal growth and regeneration., (© 2018 Lee et al.)

Aims: There is a continuing debate as to whether cardiac resynchronization therapy-defibrillation (CRT-D) is superior to CRT-pacing (CRT-P), particularly in patients with non-ischaemic cardiomyopathy (NICM). We sought to quantify the clinical outcomes after primary prevention of CRT-D and CRT-P and identify whether these differed according to the aetiology of cardiomyopathy., Methods and Results: Analyses were undertaken in the total study population of patients treated with CRT-D (n = 551) or CRT-P (n = 999) and in propensity-matched samples. Device choice was governed by the clinical guidelines in the United Kingdom. In univariable analyses of the total study population, for a maximum follow-up of 16 years (median 4.7 years, interquartile range 2.4-7.1), CRT-D was associated with a lower total mortality [hazard ratio (HR) 0.72] and the composite endpoints of total mortality or heart failure (HF) hospitalization (HR 0.72) and total mortality or hospitalization for major adverse cardiac events (MACE; HR 0.71) (all P < 0.001). After propensity matching (n = 796), CRT-D was associated with a lower total mortality (HR 0.72) and the composite endpoints (all P < 0.01). When further stratified according to aetiology, CRT-D was associated with a lower total mortality (HR 0.62), total mortality or HF hospitalization (HR 0.63), and total mortality or hospitalization for MACE (HR 0.59) (all P < 0.001) in patients with ischaemic cardiomyopathy (ICM). There were no differences in outcomes between CRT-D and CRT-P in patients with NICM., Conclusion: In this study of real-world clinical practice, CRT-D was superior to CRT-P with respect to total mortality and composite endpoints, independent of known confounders. The benefit of CRT-D was evident in ICM but not in NICM.

Classically, the unfolded protein response (UPR) safeguards secretory pathway proteostasis. The most ancient arm of the UPR, the IRE1-activated spliced X-box binding protein 1 (XBP1s)-mediated response, has roles in secretory pathway maturation beyond resolving proteostatic stress. Understanding the consequences of XBP1s activation for cellular processes is critical for elucidating mechanistic connections between XBP1s and development, immunity, and disease. Here, we show that a key functional output of XBP1s activation is a cell type-dependent shift in the distribution of N-glycan structures on endogenous membrane and secreted proteomes. For example, XBP1s activity decreased levels of sialylation and bisecting GlcNAc in the HEK293 membrane proteome and secretome, while substantially increasing the population of oligomannose N-glycans only in the secretome. In HeLa cell membranes, stress-independent XBP1s activation increased the population of high-mannose and tetraantennary N-glycans, and also enhanced core fucosylation. mRNA profiling experiments suggest that XBP1s-mediated remodeling of the N-glycome is, at least in part, a consequence of coordinated transcriptional resculpting of N-glycan maturation pathways by XBP1s. The discovery of XBP1s-induced N-glycan structural remodeling on a glycome-wide scale suggests that XBP1s can act as a master regulator of N-glycan maturation. Moreover, because the sugars on cell-surface proteins or on proteins secreted from an XBP1s-activated cell can be molecularly distinct from those of an unactivated cell, these findings reveal a potential new mechanism for translating intracellular stress signaling into altered interactions with the extracellular environment., Competing Interests: The authors declare no conflict of interest.

Fundamental questions regarding collagen biosynthesis, especially with respect to the molecular origins of homotrimeric versus heterotrimeric assembly, remain unanswered. Here, we demonstrate that the presence or absence of a single cysteine in type-I collagen's C-propeptide domain is a key factor governing the ability of a given collagen polypeptide to stably homotrimerize. We also identify a critical role for Ca 2+ in non-covalent collagen C-propeptide trimerization, thereby priming the protein for disulfide-mediated covalent immortalization. The resulting cysteine-based code for stable assembly provides a molecular model that can be used to predict, a priori, the identity of not just collagen homotrimers, but also naturally occurring 2:1 and 1:1:1 heterotrimers. Moreover, the code applies across all of the sequence-diverse fibrillar collagens. These results provide new insight into how evolution leverages disulfide networks to fine-tune protein assembly, and will inform the ongoing development of designer proteins that assemble into specific oligomeric forms.

The survival of Gram-negative bacteria depends on assembly of the asymmetric outer membrane, which creates a barrier that prevents entry of toxic molecules including antibiotics. The outer leaflet of the outer membrane is composed of lipopolysaccharide, which is made at the inner membrane and pushed across a protein bridge that spans the inner and outer membranes. We have developed a fluorescent assay to follow lipopolysaccharide (LPS) transport across a bridge linking proteoliposomes that mimic the inner and outer membranes. We show that LPS is delivered to the leaflet of the outer membrane proteoliposome that corresponds to the outer leaflet of the membrane in a cell. Transport stops long before substrates at the inner membrane are exhausted. Using mutants of the transport machinery, we find that the final amount of LPS delivered into the membrane depends on the affinity of the outer membrane translocon for LPS. Furthermore, ATP hydrolysis depends on delivery of LPS into the outer membrane. Therefore, the transport process is regulated by the outer membrane translocon causing ATP hydrolysis in the inner membrane proteoliposome to stop. Negative feedback from the outer membrane to the inner membrane provides a mechanism for long distance control over LPS transport.

Background Experimental evidence indicates that left ventricular ( LV ) apical pacing is hemodynamically superior to nonapical LV pacing. Some studies have shown that an LV apical lead position is unfavorable in cardiac resynchronization therapy. We sought to determine whether an apical LV lead position influences cardiac mortality after cardiac resynchronization therapy. Methods and Results In this retrospective observational study, the primary end point of cardiac mortality was assessed in relation to longitudinal (basal, midventricular, or apical) and circumferential (anterior, lateral, or posterior) LV lead positions, as well as right ventricular (apical or septal), assigned using fluoroscopy. Lead positions were assessed in 1189 patients undergoing cardiac resynchronization therapy implantation over 15 years. After a median follow-up of 6.0 years (interquartile range: 4.4-7.7 years), an apical LV lead position was associated with lower cardiac mortality than a nonapical position (adjusted hazard ratio: 0.74; 95% confidence interval, 0.56-0.99) after covariate adjustment. There were no differences in total mortality or heart failure hospitalization. Death from pump failure was lower with apical than nonapical positions (adjusted hazard ratio: 0.69; 95% confidence interval, 0.51-0.94). Compared with a basal position, an apical LV position was also associated with lower risk of sudden cardiac death (adjusted hazard ratio: 0.34; 95% confidence interval, 0.13-0.93). No differences emerged between circumferential LV lead positions or right ventricular positions with respect to any end point. Conclusions In recipients of cardiac resynchronization therapy, an apical LV lead position was associated with better long-term cardiac survival than a nonapical position. This effect was due to a lower risk of pump failure and sudden cardiac death.

Background: Despite experiencing conditions associated with higher risk for depression and psychological distress, the mental health of rural African Americans remains understudied. This brief report examines the association between sociodemographic characteristics, self-rated health, and material hardship, and depressive symptoms and psychological distress among rural African Americans., Method: Data are from the rural African American subsample (N = 250) of the National Survey of American Life (NSAL; 2001-2003). The Center for Epidemiological Studies-Depression Scale (CES-D) was used to assess depressive symptoms. Psychological distress was measured using the Kessler 6 (K6). Negative binominal regression analyses were performed., Results: Rural African Americans reporting more material hardship and poorer self-rated physical health had higher levels of depressive symptoms and psychological distress compared to counterparts with less hardship and better self-rated health. Findings also suggest rural African American women had more depressive symptoms compared to male peers. Older rural African Americans and African Americans with fewer years of education had more symptoms of psychological distress than their respective counterparts., Limitations: Though the NSAL represents the only national probability survey on African Americans' mental health; the timeliness of the data, collected between 2001 and 2003 is a limitation., Conclusions: Material hardship and worse self-rated health emerged as risk factors for depression and psychological distress among this population. This suggests the need for systems of care and integrated healthcare models across service providers within rural African American communities to promote adequate screening, intervention, and referrals related to economic, physical, and mental health needs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Dickkopf (Dkk) family proteins are important regulators of Wnt signaling pathways, which play key roles in many essential biological processes. Here, we report the first detailed structural and dynamics study of a full-length mature Dkk protein (Dkk4, residues 19-224), including determination of the first atomic-resolution structure for the N-terminal cysteine-rich domain (CRD1) conserved among Dkk proteins. We discovered that CRD1 has significant structural homology to the Dkk C-terminal cysteine-rich domain (CRD2), pointing to multiple gene duplication events during Dkk family evolution. We also show that Dkk4 consists of two independent folded domains (CRD1 and CRD2) joined by a highly flexible, nonstructured linker. Similarly, the N-terminal region preceding CRD1 and containing a highly conserved N X I(R/K) sequence motif was shown to be dynamic and highly flexible. We demonstrate that Dkk4 CRD2 mediates high-affinity binding to both the E1E2 region of low-density lipoprotein receptor-related protein 6 (LRP6 E1E2) and the Kremen1 (Krm1) extracellular domain. In contrast, the N-terminal region alone bound with only moderate affinity to LRP6 E1E2, consistent with binding via the conserved N X I(R/K) motif, but did not interact with Krm proteins. We also confirmed that Dkk and Krm family proteins function synergistically to inhibit Wnt signaling. Insights provided by our integrated structural, dynamics, interaction, and functional studies have allowed us to refine the model of synergistic regulation of Wnt signaling by Dkk proteins. Our results indicate the potential for the formation of a diverse range of ternary complexes comprising Dkk, Krm, and LRP5/6 proteins, allowing fine-tuning of Wnt-dependent signaling., (© 2018 Patel et al.)

Most Gram-negative bacteria assemble lipopolysaccharides (LPS) on their surface to form a permeability barrier against many antimicrobials. LPS is synthesized at the inner membrane and then transported to the outer leaflet of the outer membrane. Although the overall LPS structure is conserved, LPS molecules can differ in composition at the species and strain level. Some bacteria also regulate when to modify phosphates on LPS at the inner membrane in order to become resistant to cationic antimicrobial peptides. The multi-protein Lpt trans-envelope machine, which transports LPS from the inner to the outer membrane, must therefore handle a variety of substrates. The most poorly understood step in LPS transport is how the ATP-binding cassette LptB 2 FG transporter extracts LPS from the inner membrane. Here, we define residue K34 in LptG as a site within the structural cavity of the Escherichia coli LptB 2 FG transporter that interacts electrostatically with phosphates on unmodified LPS. Alterations to this residue cause transport defects that are suppressed by the activation of the BasSR two-component signaling system, which results in modifications to the LPS phosphates. We also show this residue is part of a larger site in LptG that differentially contributes to the transport of unmodified and modified LPS., (© 2018 John Wiley & Sons Ltd.)

Background: Early clinical severity assessments during the 2009 influenza A H1N1 pandemic (pH1N1) overestimated clinical severity due to selection bias and other factors. We retrospectively investigated how to use data from the International Network for Strategic Initiatives in Global HIV Trials, a global clinical influenza research network, to make more accurate case fatality ratio (CFR) estimates early in a future pandemic, an essential part of pandemic response., Methods: We estimated the CFR of medically attended influenza (CFRMA) as the product of probability of hospitalization given confirmed outpatient influenza and the probability of death given hospitalization with confirmed influenza for the pandemic (2009-2011) and post-pandemic (2012-2015) periods. We used literature survey results on health-seeking behavior to convert that estimate to CFR among all infected persons (CFRAR)., Results: During the pandemic period, 5.0% (3.1%-6.9%) of 561 pH1N1-positive outpatients were hospitalized. Of 282 pH1N1-positive inpatients, 8.5% (5.7%-12.6%) died. CFRMA for pH1N1 was 0.4% (0.2%-0.6%) in the pandemic period 2009-2011 but declined 5-fold in young adults during the post-pandemic period compared to the level of seasonal influenza in the post-pandemic period 2012-2015. CFR for influenza-negative patients did not change over time. We estimated the 2009 pandemic CFRAR to be 0.025%, 16-fold lower than CFRMA., Conclusions: Data from a clinical research network yielded accurate pandemic severity estimates, including increased severity among younger people. Going forward, clinical research networks with a global presence and standardized protocols would substantially aid rapid assessment of clinical severity., Clinical Trials Registration: NCT01056354 and NCT01056185

Northern bobwhites (Colinus virginianus) have been declining across the range of the species primarily due to habitat loss and habitat fragmentation. There is increasing concern regarding effects related to elevated environmental contaminants, including pesticides and metals. Elevated concentrations of some metals are known to have adverse effects on reproduction, development, and survival in birds; however, little research has been conducted on metal exposure in wild bobwhites. We analyzed metal concentrations in the feathers of 60 bobwhites from 3 ecoregions in Texas and evaluated differences between age-class, gender, and location with the objective of determining if bobwhites in Texas are at increased risk of exposure to elevated metal concentrations. We found feather Pb concentrations above the established effect threshold of 4.0 µg/g dry weight at which sublethal and reproductive effects have been reported in birds. More than 25% (n = 16) of the samples analyzed had Pb concentrations above the effect threshold, including four that were five times above the threshold. We also observed slightly elevated feather Cd concentrations, above 0.1 µg/g dry weight, in 17% (n = 11) of the bobwhites analyzed. On average, juvenile bobwhites had higher concentrations of Ba, Co, Fe, Mn, Sr, and V compared to adults (p < 0.05). Additionally, concentrations of Al, Be, Co, Fe, Hg, Ni, Se, Sr, and Tl differed significantly between sampling locations, indicating a potential relationship between metal levels and local agricultural practices. The results of our study indicate a potential risk of sublethal effects of Pb and to a lesser extent Cd in bobwhites in Texas.

The aim of this study was to determine the sensitivity of selected subjective and objective monitoring assessments in detecting changes in group and individual responses to low and high load bouts of high intensity intermittent exercise. In a counterbalanced crossover design, Thirteen Academy Rugby Union players (mean ± SD: age: 18 ± 1 years) performed a low load (15 min) and a high load (90 min) bout of high intensity intermittent exercise (Loughborough Intermittent Shuttle Test) one week apart. Monitoring assessments were performed immediately prior to and 20 h following each trial. Subjective self-report Well-being Questionnaire (WQ) items showed small to large deteriorations following the high load compared to low load ( d = 0.4⁻1.5, p = 0.03⁻0.57). A very large increase in resting HR (HR rest ) ( d = 2.1, p = 0.02), moderate decrease in heart rate variability (HRV) indices ( d = 0.7, p = 0.04 and d = 0.7, p = 0.01 for the natural logarithm of the standard deviation of R-R intervals (ln SDNN) and the root square of the mean squared differences of successive R-R intervals (rMSSD), respectively) and no change in countermovement jump ( d = 0.0, p = 0.97) were evident following the high load compared to low load. Individual WQ responses revealed 7/9, 7/9, 6/9, 6/9, 5/9, 3/9 and 1/9 participants reported deteriorations in recovery, sleep quality, motivation, muscle soreness, fatigue, stress and appetite, respectively, following the high load compared to low load. Individual analysis indicated a negative response following the high load compared to low load in HR rest , ln SDNN and ln rMSSD for 4/6, 2/6 and 1/6 participants, respectively. Selected WQ items detected group and individual responses to high load and low load highlighting their potential utility. However, objective assessments lacked the sensitivity to detect small individual changes.

Background: African American men in the USA experience poorer aging-related health outcomes compared to their White counterparts, partially due to socioeconomic disparities along racial lines. Greater exposure to socioeconomic strains among African American men may adversely impact health and aging at the cellular level, as indexed by shorter leukocyte telomere length (LTL). This study examined associations between socioeconomic factors and LTL among African American men in midlife, a life course stage when heterogeneity in both health and socioeconomic status are particularly pronounced., Methods: Using multinomial logistic regression, we examined associations between multiple measures of SES and tertiles of LTL in a sample of 92 African American men between 30 to 50 years of age., Results: Reports of greater financial strain were associated with higher odds of short versus medium LTL (odds ratio (OR)=2.21, p = 0.03). Higher income was associated with lower odds of short versus medium telomeres (OR=0.97, p = 0.04). Exploratory analyses revealed a significant interaction between educational attainment and employment status (χ 2  = 4.07, p = 0.04), with greater education associated with lower odds of short versus long telomeres only among those not employed (OR=0.10, p = 0.040)., Conclusion: Cellular aging associated with multiple dimensions of socioeconomic adversity may contribute to poor aging-related health outcomes among African American men. Subjective appraisal of financial difficulty may impact LTL independently of objective dimensions of SES. Self-appraised success in fulfilling traditionally masculine gender roles, including being an economic provider, may be a particularly salient aspect of identity for African American men and have implications for cellular aging in this population.

This study investigated ethnic and nativity differences in the chronicity and treatment of psychiatric disorders of African American and Caribbean Black men in the U.S. Data were analyzed from the National Survey of American Life, a population-based study which included 1859 self-identified Black men (1222 African American, 176 Caribbean Black men born within the U.S., and 461 Caribbean Black men born outside the U.S.). Lifetime and twelve-month prevalence of DSM-IV mood, anxiety, and substance use disorders (including Bipolar I and Dysthmia), disorder chronicity, and rate of mental health services use among those meeting criteria for a lifetime psychiatric disorder were examined. Logistic regression models were employed to determine ethnic differences in chronicity, and treatment utilization for disorders. While rates of DSM-IV disorders were generally low in this community sample of Black men, their disorders were chronic and remained untreated. Caribbean Black men born in the U.S. had higher prevalence of Post-Traumatic Stress Disorder, Major Depressive Disorder, and Alcohol Abuse Disorder compared with African American men. Foreign born Caribbean Black men experienced greater chronicity in Social Phobia and Generalized Anxiety Disorder compared to other Black Men. Utilization of mental health service was low for all groups of Black Men, but lowest for the foreign born Caribbean Black men. Results underscore the large unmet needs of both African American and Caribbean Black men in the United States. Results also highlight the role of ethnicity and nativity in mental disorder chronicity and mental health service utilization patterns of Black men.

Saturation transfer difference (STD) NMR spectroscopy is one of the most popular ligand-based NMR techniques for the study of protein-ligand interactions. This is due to its robustness and the fact that it is focused on the signals of the ligand, without any need for NMR information on the macromolecular target. This technique is most commonly applied to systems involving different types of ligands (e.g., small organic molecules, carbohydrates or lipids) and a protein as the target, in which the latter is selectively saturated. However, only a few examples have been reported where membrane mimetics are the macromolecular binding partners. Here, we have employed STD NMR spectroscopy to investigate the interactions of the neurotransmitter dopamine with mimetics of lipid bilayers, such as nanodiscs, by saturation of the latter. In particular, the interactions between dopamine and model lipid nanodiscs formed either from charged or zwitterionic lipids have been resolved at the atomic level. The results, in agreement with previous isothermal titration calorimetry studies, show that dopamine preferentially binds to negatively charged model membranes, but also provide detailed atomic insights into the mode of interaction of dopamine with membrane mimetics. Our findings provide relevant structural information for the design of lipid-based drug carriers of dopamine and its structural analogues and are of general applicability to other systems., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: In several inflammatory disorders, altered peripheral blood mononuclear leukocyte (PBML) glucocorticoid (GC) receptor isoform expression has been associated with GC resistance and disease severity. However, it is unclear if PBML GC receptor isoforms are expressed differentially and are associated with worsened disease severity in chronic rhinosinusitis (CRS)., Methods: PBMLs were isolated from control (n = 8), CRS without nasal polyps (CRSsNP) (n = 8), atopic CRS with nasal polyps (CRSwNP) (n = 8), non-atopic CRSwNP (n = 8), and allergic fungal rhinosinusitis (AFRS) (n = 8) patients. Demographics, atopic status, asthmatic status, 22-item Sino-Nasal Outcome Test (SNOT-22) scores, Lund-Kennedy nasal endoscopy scores, Lund-Mackay sinus computed tomography (CT) scores, Kennedy Osteitis scores, and GC utilization 6 months postoperatively were collected. Intracellular immunostaining was then performed for functional GC receptor α (GCRα) and nonfunctional GC receptor β (GCRβ), followed by flow cytometry analysis of geometric mean fluorescent intensity (MFI) and the percentage of cells expressing each GC receptor isoform., Results: Compared to controls, each CRS subtype had decreased PBML GCRα and GCRα:GCRβ MFI expression, but no difference in GCRβ expression. Decreasing PBML GCRα in AFRS was associated with increasing Lund-Mackay sinus CT scores (r = -0.880, p =0.004). No significant associations were found between GC receptor isoform expression and other clinical measures., Conclusion: CRS patients have reduced functional PBML GCRα expression and decreased GCRα:GCRβ compared to controls. Reductions in GCRα in AFRS are associated with worsening Lund-Mackay sinus CT scores. The clinical implications of decreased functional GC receptor expression merits further investigation., (© 2018 ARS-AAOA, LLC.)