The rockefeller university

ARPP-16, ARPP-19, and ENSA are inhibitors of protein phosphatase PP2A. ARPP-19 and ENSA phosphorylated by Greatwall kinase inhibit PP2A during mitosis. ARPP-16 is expressed in striatal neurons where basal phosphorylation by MAST3 kinase inhibits PP2A and regulates key components of striatal signaling. The ARPP-16/19 proteins were discovered as substrates for PKA, but the function of PKA phosphorylation is unknown. We find that phosphorylation by PKA or MAST3 mutually suppresses the ability of the other kinase to act on ARPP-16. Phosphorylation by PKA also acts to prevent inhibition of PP2A by ARPP-16 phosphorylated by MAST3. Moreover, PKA phosphorylates MAST3 at multiple sites resulting in its inhibition. Mathematical modeling highlights the role of these three regulatory interactions to create a switch-like response to cAMP. Together, the results suggest a complex antagonistic interplay between the control of ARPP-16 by MAST3 and PKA that creates a mechanism whereby cAMP mediates PP2A disinhibition.

Background: The purpose of this study was to determine the utilization and live birth rates of assisted reproductive technology (ART) modalities among various racial and ethnic groups in recent years. Methods: We reviewed ART data reported to the Society for Assisted Reproductive Technologies Clinic Outcome Reporting System (SART CORS) for autologous ART and third-party ART (3ART) cycles which involved donor oocytes, sperm, embryos and gestational carrier, performed in the U.S. between 2004 and 2013. To gauge demand by various racial/ethnic groups for ART services, we examined fertility rates and demographics of the entire U.S. birth cohort over the same time interval. Results: Of 1,132,844 autologous ART cycles 335,462 resulted in a live birth (29.6%). An additional, 217,030 3ART cycles resulted in 86,063 live births (39.7%). Hispanic and Black women demonstrated high fertility and lower utilization rates of autologous ART and 3ART. Caucasian and Asian women exhibited lower fertility rates and higher autologous ART and 3ART utilization. Autologous ART resulted in higher live birth rates among Caucasian and Hispanic women and lower rates among Asian and especially Black women. 3ART improved live birth rates in all races/ethnicities, though Black women experienced lower live birth rates with most modalities. Spontaneous abortion rates were higher among Black women following autologous ART and some 3ART modalities than those among Caucasian women. Conclusion: Utilization of ART is inversely related to fertility rates. Autologous ART produces lower live birth rates among Asian and Black women. 3ART results in relatively low live birth rates among Black women.

Membrane scission is essential for intracellular trafficking. While BAR domain proteins such as endophilin have been reported in dynamin-independent scission of tubular membrane necks, the cutting mechanism has yet to be deciphered. Here, we combine a theoretical model, in vitro, and in vivo experiments revealing how protein scaffolds may cut tubular membranes. We demonstrate that the protein scaffold bound to the underlying tube creates a frictional barrier for lipid diffusion; tube elongation thus builds local membrane tension until the membrane undergoes scission through lysis. We call this mechanism friction-driven scission (FDS). In cells, motors pull tubes, particularly during endocytosis. Through reconstitution, we show that motors not only can pull out and extend protein-scaffolded tubes but also can cut them by FDS. FDS is generic, operating even in the absence of amphipathic helices in the BAR domain, and could in principle apply to any high-friction protein and membrane assembly.

Skin barrier abnormalities have been suggested to play an essential role in initiation of early atopic dermatitis (AD). Antigen penetration through a compromised barrier likely leads to increased innate immune responses, antigen-presenting cell stimulation, and priming of overt cutaneous disease. In a T(H)2-promoting environment, T-cell/B-cell interactions occurring in regional lymph nodes lead to excessive IgE switch. Concurrent redistribution of memory T cells into the circulation not only leads to exacerbation of AD through T-cell skin infiltration but also spreads beyond the skin to initiate the atopic march, which includes food allergy, asthma, and allergic rhinitis. Possible primary interventions to prevent AD are focusing on improving skin barrier integrity, including supplementing barrier function with moisturizers. As for secondary prophylaxis in children with established AD, this can be stratified into prevention of disease exacerbations by using proactive approaches (with either topical corticosteroids or topical calcineurin inhibitors) in mild AD cases or the prevention of other atopic disorders that will probably mandate systemic immunosuppression in severe AD cases.

The pathophysiology of hidradenitis suppurativa (HS) is not well understood. Some of our knowledge comes from clinical and epidemiological observations, along with studies of the histopathology and immunohistochemistry of affected skin. More recently, cutaneous molecular studies and transcriptomic analyses have provided additional information regarding inflammatory processes. The chronic cutaneous inflammation, systemic symptoms, and associated comorbidities suggest that HS should be classified as an immune-mediated disease, rather than a primary infectious disease. As such, a proposed integrated disease pathway is presented. At a fundamental level, there appears to be a primary abnormality in the pilosebaceous-apocrine unit, which leads to follicular occlusion, perifollicular cyst development that traps commensal microbes, and rupture into the dermis.This can trigger an exaggerated response of the cutaneous innate immune system. Initially this is an acute event, but ongoing intermittent disease activity can lead to recurrent inflammatory nodules and dermal tunnels. Once underway, the cutaneous inflammation is very difficult to turn off, leading to suppurative inflammation in whole anatomic regions.As the disease progresses, we propose that there is recruitment of the systemic immune system perpetuating the chronic cutaneous inflammatory process.There remains much to be done to understand the pathogenesis and immune signature of this challenging disease. (C) 2017 Frontline Medical Communications

1. Community indicators are used to assess the state of ecological communities and to guide management. They are usually calculated from monitoring data, often collected annually. Since any given community indicator provides a univariate summary of complex multivariate phenomena, different changes in the community may lead to the same response in the indicator. Sampling variation can also mask ecologically important trends. 2. This study addresses these challenges for community indicators, with a focus on the large fish indicator (LFI), internationally used to report status of marine fish communities. The LFI expresses 'large' fish biomass as a proportion of total fish biomass and is calculated from species-size-abundance data collected on trawl surveys. We develop new methods to decompose the contributions of species, sampling locations and season to trends over time in the LFI, and highlight consequences for assessment and management. 3. Our results showed that both species and locations made divergent contributions to overall trends in the LFI indicator, with contributions differing by several orders of magnitude and in sign. Only small proportions of species and locations drove overall LFI trends, and their contributions changed with season (spring and autumn surveys). To assess significance of component trends, a resampling method was developed. Our method can be generalized and applied to many other community indicators based on survey data. 4. Synthesis and applications. Our new method for decomposing community indicators and generating confidence intervals makes it possible to extract much more information on what drives a 'headline' indicator, providing a solution to challenges arising from multiple possible interpretations of changes in the indicator and from sampling variation. Analysis of the effects of indicator components on headline indicator values is recommended, because the results allow assessors and managers to identify and interpret how divergent factors (e.g. species, sampling locations and seasons) contribute to the headline indicator value.

Maternal aggression is behavior displayed by post-partum lactating female mice toward unfamiliar conspecifics, presumably as a defense against infanticide. A variety of perinatal stressors can impair maternal care in adulthood. Previous studies on associations between developmental perturbations and maternal aggression have produced mixed results. To address this issue, we employed a proxy for developmental instability, namely fluctuating asymmetry (FA) to further elucidate the relationship between low temperature stress and maternal aggression. FA, small, random deviations from perfect symmetry in bilateral characters is used as a quantitative measure of stress during ontogeny. Dams were either maintained in standard laboratory temperatures (21 +/- 2 degrees C), or cold temperatures (8 +/- 2 degrees C) during gestation. During lactation, their progeny either remained in the temperature condition in which they were gestated or were transferred to the other temperature condition. Four individual measures of FA, a composite of these measures, and three measures of maternal aggression were assessed in the female progeny in adulthood. Exposure to low temperatures during both pre- and early post-natal development increased composite FA and reduced all three measures of maternal aggression compared to controls. Exposure to low temperatures during the pre- or post-natal period alone did not induce either high FA or altered maternal aggression. Certain measures of FA and nest defense were negatively correlated. Our results suggest that low temperatures experienced during gestation and lactation may have important fitness costs. Low maternal aggression toward infanticidal conspecifics is likely to limit the number of offspring surviving into adulthood. Overall, FA appears to be a reliable indicator of chronic developmental stress with implications for fitness.

The spontaneous emergence of collective flows is a generic property of active fluids and often leads to chaotic flow patterns characterised by swirls, jets, and topological disclinations in their orientation field. However, the ability to achieve structured flows and ordered disclinations is of particular importance in the design and control of active systems. By confining an active nematic fluid within a channel, we find a regular motion of disclinations, in conjunction with a well defined and dynamic vortex lattice. As pairs of moving disclinations travel through the channel, they continually exchange partners producing a dynamic ordered state, reminiscent of Ceilidh dancing. We anticipate that this biomimetic ability to self-assemble organised topological disclinations and dynamically structured flow fields in engineered geometries will pave the road towards establishing new active topological microfluidic devices.

Using a microfluidic trap, we study the behavior of individual phospholipid vesicles in contact with fatty acids. We show that spontaneous fatty acids insertion inside the bilayer is controlled by the vesicle size, osmotic pressure difference across the membrane and fatty acids concentration in the external bath. Depending on these parameters, vesicles can grow spherically or become unstable and fragment into several daughter vesicles. We establish the phase diagram for vesicle growth and we derive a simple thermodynamic model that reproduces the time evolution of the vesicle volume. Finally, we show that stable growth can be achieved on an artificial cell expressing a simple set of bacterial cytoskeletal proteins, paving the way toward artificial cell reproduction.

Adenylyl cyclases (ACs) generate cAMP, a second messenger of utmost importance that regulates a vast array of biological processes in all kingdoms of life. However, almost nothing is known about how AC activity is regulated through protein degradation mediated by ubiquitination or other mechanisms. Here, we show that transcriptional regulator interacting with the PHD-bromodomain 1 (TRIP-Br1, Sertad1), a newly identified protein with poorly characterized functions, acts as an adaptor that bridges the interaction of multiple AC isoforms with X-linked inhibitor of apoptosis protein (XIAP), a RING-domain E3 ubiquitin ligase. XIAP ubiquitinates a highly conserved Lys residue in AC isoforms and thereby accelerates the endocytosis and degradation of multiple AC isoforms in human cell lines and mice. XIAP/TRIP-Br1-mediated degradation of ACs forms part of a negative-feedback loop that controls the homeostasis of cAMP signaling in mice. Our findings reveal a previously unrecognized mechanism for degrading multiple AC isoforms and modulating the homeostasis of cAMP signaling.