Additive genetic variation in the craniofacial skeleton of baboons (genus Papio) and its relationship to body and cranial size

Objectives Determining the genetic architecture of quantitative traits and genetic correlations among them is important for understanding morphological evolution patterns. We address two questions regarding papionin evolution: (1) what effect do body and cranial size, age, and sex have on phenotypic (VP) and additive genetic (VA) variation in baboon crania, and (2) how might additive genetic correlations between craniofacial traits and body mass affect morphological evolution? Materials and Methods We use a large captive pedigreed baboon sample to estimate quantitative genetic parameters for craniofacial dimensions (EIDs). Our models include nested combinations of the covariates listed above. We also simulate the correlated response of a given EID to selection on body mass alone. Results Covariates account for 1.2%–91% of craniofacial VP. EID VA decreases across models as more covariates were included. The median genetic correlation estimate between each EID and body mass is 0.33. Analysis of the multivariate response to selection reveals that observed patterns of craniofacial variation in extant baboons cannot be attributed solely to correlated response to selection on body mass, particularly in males. Discussion Because a relatively large proportion of EID VA is shared with body mass variation, different methods of correcting for allometry by statistically controlling for size can alter residual VP patterns. This may conflate direct selection effects on craniofacial variation with those resulting from a correlated response to body mass selection. This shared genetic variation may partially explain how selection for increased body mass in two different papionin lineages produced remarkably similar craniofacial phenotypes

Role of peptidylarginine deiminase 2 (PAD2) in mammary carcinoma cell migration

BACKGROUND: Penetration of the mammary gland basement membrane by cancer cells is a crucial first step in tumor invasion. Using a mouse model of ductal carcinoma in situ, we previously found that inhibition of peptidylarginine deiminase 2 (PAD2, aka PADI2) activity appears to maintain basement membrane integrity in xenograft tumors. The goal of this investigation was to gain insight into the mechanisms by which PAD2 mediates this process. METHODS: For our study, we modulated PAD2 activity in mammary ductal carcinoma cells by lentiviral shRNA-mediated depletion, lentiviral-mediated PAD2 overexpression, or PAD inhibition and explored the effects of these treatments on changes in cell migration and cell morphology. We also used these PAD2-modulated cells to test whether PAD2 may be required for EGF-induced cell migration. To determine how PAD2 might promote tumor cell migration in vivo, we tested the effects of PAD2 inhibition on the expression of several cell migration mediators in MCF10DCIS.com xenograft tumors. In addition, we tested the effect of PAD2 inhibition on EGF-induced ductal invasion and elongation in primary mouse mammary organoids. Lastly, using a transgenic mouse model, we investigated the effects of PAD2 overexpression on mammary gland development. RESULTS: Our results indicate that PAD2 depletion or inhibition suppresses cell migration and alters the morphology of MCF10DCIS.com cells. In addition, we found that PAD2 depletion suppresses the expression of the cytoskeletal regulatory proteins RhoA, Rac1, and Cdc42 and also promotes a mesenchymal to epithelial-like transition in tumor cells with an associated increase in the cell adhesion marker, E-cadherin. Our mammary gland organoid study found that inhibition of PAD2 activity suppresses EGF-induced ductal invasion. In vivo, we found that PAD2 overexpression causes hyperbranching in the developing mammary gland. CONCLUSION: Together, these results suggest that PAD2 plays a critical role in breast cancer cell migration. Our findings that EGF treatment increases protein citrullination and that PAD2 inhibition blocks EGF-induced cell migration suggest that PAD2 likely functions within the EGF signaling pathway to mediate cell migration

Dietary Intake, D3Cr Muscle Mass, and Appendicular Lean Mass in a Cohort of Older Men.

BackgroundWe examined cross-sectional associations between dietary patterns, macronutrient intake, and measures of muscle mass and lean mass in older men.MethodsParticipants in the Osteoporotic Fractures in Men (MrOS) cohort (n = 903; mean ± SD age 84.2 ± 4 years) completed brief Block food frequency questionnaires (May 2014-May 2016); factor analysis was used to derive dietary patterns. The D3-creatine (D3Cr) dilution method was used to measure muscle mass; dual-energy x-ray absorptiometry (DXA) was used to measure appendicular lean mass (ALM). Generalized linear models were used to report adjusted means of outcomes by dietary pattern. Multiple linear regression models were used to determine associations between macronutrients and D3Cr muscle mass and DXA ALM. Multivariable models were adjusted for age, race, clinic site, education, depression, total energy intake, height, and percent body fat.ResultsGreater adherence to a Western dietary pattern (high factor loadings for red meat, fried foods, and high-fat dairy) was associated with higher D3Cr muscle mass (p-trend = .026). Adherence to the Healthy dietary pattern (high factor loadings for fruit, vegetables, whole grains, and lean meats) was not associated with D3Cr muscle mass or DXA ALM. Total protein (β = 0.09, 95% CI = 0.03, 0.14) and nondairy animal protein (β = 0.16, 95% CI = 0.10, 0.21) were positively associated with D3Cr muscle mass. Nondairy animal protein (β = 0.06, 95% CI = 0.002, 0.11) was positively associated with DXA ALM. Associations with other macronutrients were inconsistent.ConclusionsNondairy animal protein intake (within a Western dietary pattern and alone) was positively associated with D3Cr muscle mass in older men

Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity

Inactivation of sterol Δ5,6-desaturase (Erg3p) in the prevalent fungal pathogen Candida albicans is one of several mechanisms that can confer resistance to the azole antifungal drugs. However, loss of Erg3p activity is also associated with deficiencies in stress tolerance, invasive hyphal growth, and attenuated virulence in a mouse model of disseminated infection. This may explain why relatively few erg3-deficient strains have been reported among azole-resistant clinical isolates. In this study, we examined the consequences of Erg3p inactivation upon C. albicans pathogenicity and azole susceptibility in mouse models of mucosal and disseminated infection. While a C. albicans erg3Δ/Δ mutant was unable to cause lethality in the disseminated model, it induced pathology in a mouse model of vaginal infection. The erg3Δ/Δ mutant was also more resistant to fluconazole treatment than the wild type in both models of infection. Thus, complete loss of Erg3p activity confers azole resistance but also niche-specific virulence deficiencies. Serendipitously, we discovered that loss of azole-inducible ERG3 transcription (rather than complete inactivation) is sufficient to confer in vitro fluconazole resistance, without compromising C. albicans stress tolerance, hyphal growth, or pathogenicity in either mouse model. It is also sufficient to confer fluconazole resistance in the mouse vaginal model, but not in the disseminated model of infection, and thus confers niche-specific azole resistance without compromising C. albicans pathogenicity at either site. Collectively, these results establish that modulating Erg3p expression or activity can have niche-specific consequences on both C. albicans pathogenicity and azole resistanc

Planet Hunters VII. Discovery of a New Low-Mass, Low-Density Planet (PH3 c) Orbiting Kepler-289 with Mass Measurements of Two Additional Planets (PH3 b and d)

We report the discovery of one newly confirmed planet ($P=66.06$ days, $R_{\rm{P}}=2.68\pm0.17R_\oplus$) and mass determinations of two previously validated Kepler planets, Kepler-289 b ($P=34.55$ days, $R_{\rm{P}}=2.15\pm0.10R_\oplus$) and Kepler-289-c ($P=125.85$ days, $R_{\rm{P}}=11.59\pm0.10R_\oplus$), through their transit timing variations (TTVs). We also exclude the possibility that these three planets reside in a $1:2:4$ Laplace resonance. The outer planet has very deep ($\sim1.3$), high signal-to-noise transits, which puts extremely tight constraints on its host star's stellar properties via Kepler's Third Law. The star PH3 is a young ($\sim1$ Gyr as determined by isochrones and gyrochronology), Sun-like star with $M_*=1.08\pm0.02M_\odot$, $R_*=1.00\pm0.02R_\odot$, and $T_{\rm{eff}}=5990\pm38$ K. The middle planet's large TTV amplitude ($\sim5$ hours) resulted either in non-detections or inaccurate detections in previous searches. A strong chopping signal, a shorter period sinusoid in the TTVs, allows us to break the mass-eccentricity degeneracy and uniquely determine the masses of the inner, middle, and outer planets to be $M=7.3\pm6.8M_\oplus$, $4.0\pm0.9M_\oplus$, and $M=132\pm17M_\oplus$, which we designate PH3 b, c, and d, respectively. Furthermore, the middle planet, PH3 c, has a relatively low density, $\rho=1.2\pm0.3$ g/cm$^3$ for a planet of its mass, requiring a substantial H/He atmosphere of $2.1^{+0.8}_{-0.3}$ by mass, and joins a growing population of low-mass, low-density planets.Comment: 21 pages, 10 figures, 5 tables, accepted into Ap

Postcode Lotteries in Public Health - The NHS Health Checks Programme in North West London

<p>Abstract</p> <p>Background</p> <p>Postcode lotteries in health refer to differences in health care between different geographic areas. These have been previously associated with clinical services. However there has been little documentation of postcode lotteries relating to preventative health care services. This paper describes a postcode lottery effect in relation to the NHS Health Checks Programme (a national cardiovascular screening programme in England) in eight PCTs in the North West sector of London.</p> <p>Methods</p> <p>A descriptive cross-sectional analysis of the Health Checks Programme was carried out in eight PCTs in North West London using a structured data-collecting instrument.</p> <p>Results</p> <p>The analysis found variation in the implementation of the national Health Checks Programme in terms of: the screening approach taken; the allocated budget (which varied from £69,000 to £1.4 million per 100,000 eligible population); payment rates made to providers of Health Checks; tools used to identify and measure risk of cardiovascular disease and diabetes; monitoring and evaluation; and preventative services available following the health check.</p> <p>Conclusions</p> <p>This study identifies a postcode lottery effect related to a national public health programme. Although it is important to allow enough flexibility in the design of the Health Checks Programme so that it fits in with local factors, aspects of the programme may benefit from greater standardisation or stronger national guidance.</p

Testimony on Pennsylvania SB1306: No Additional Protections for Religious Freedom

On behalf of the Public Rights/Private Conscience Project (PRPCP) at Columbia Law School I offer the following legal analysis of Senate Bill 1306. Overall, the current version of the bill promises to modernize Pennsylvania’s Human Relations Act by expanding antidiscrimination protections in employment to include sexual orientation and gender identity-based discrimination. Were the Pennsylvania legislature to pass SB 1306, the Commonwealth would join twenty-two states that include sexual orientation and nineteen states that include gender identity in their laws assuring equal employment opportunities for their citizens

Rethinking the patient: using Burden of Treatment Theory to understand the changing dynamics of illness

&lt;b&gt;Background&lt;/b&gt; In this article we outline Burden of Treatment Theory, a new model of the relationship between sick people, their social networks, and healthcare services. Health services face the challenge of growing populations with long-term and life-limiting conditions, they have responded to this by delegating to sick people and their networks routine work aimed at managing symptoms, and at retarding - and sometimes preventing - disease progression. This is the new proactive work of patient-hood for which patients are increasingly accountable: founded on ideas about self-care, self-empowerment, and self-actualization, and on new technologies and treatment modalities which can be shifted from the clinic into the community. These place new demands on sick people, which they may experience as burdens of treatment.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Discussion&lt;/b&gt; As the burdens accumulate some patients are overwhelmed, and the consequences are likely to be poor healthcare outcomes for individual patients, increasing strain on caregivers, and rising demand and costs of healthcare services. In the face of these challenges we need to better understand the resources that patients draw upon as they respond to the demands of both burdens of illness and burdens of treatment, and the ways that resources interact with healthcare utilization.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Summary&lt;/b&gt; Burden of Treatment Theory is oriented to understanding how capacity for action interacts with the work that stems from healthcare. Burden of Treatment Theory is a structural model that focuses on the work that patients and their networks do. It thus helps us understand variations in healthcare utilization and adherence in different healthcare settings and clinical contexts