Factors influencing terrestriality in primates of the Americas and Madagascar.

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (body mass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use.

The nuclear lamina binds the EBV genome during latency and regulates viral gene expression.

The Epstein Barr virus (EBV) infects almost 95% of the population worldwide. While typically asymptomatic, EBV latent infection is associated with several malignancies of epithelial and lymphoid origin in immunocompromised individuals. In latently infected cells, the EBV genome persists as a chromatinized episome that expresses a limited set of viral genes in different patterns, referred to as latency types, which coincide with varying stages of infection and various malignancies. We have previously demonstrated that latency types correlate with differences in the composition and structure of the EBV episome. Several cellular factors, including the nuclear lamina, regulate chromatin composition and architecture. While the interaction of the viral genome with the nuclear lamina has been studied in the context of EBV lytic reactivation, the role of the nuclear lamina in controlling EBV latency has not been investigated. Here, we report that the nuclear lamina is an essential epigenetic regulator of the EBV episome. We observed that in B cells, EBV infection affects the composition of the nuclear lamina by inducing the expression of lamin A/C, but only in EBV+ cells expressing the Type III latency program. Using ChIP-Seq, we determined that lamin B1 and lamin A/C bind the EBV genome, and their binding correlates with deposition of the histone repressive mark H3K9me2. By RNA-Seq, we observed that knock-out of lamin A/C in B cells alters EBV gene expression. Our data indicate that the interaction between lamins and the EBV episome contributes to the epigenetic control of viral gene expression during latency, suggesting a restrictive function of the nuclear lamina as part of the host response against viral DNA entry into the nucleus.

Introducing Porosity into Refractory Molybdenum Boride through Controlled Decomposition of a Metastable Mo-Al-B Precursor.

The high temperatures typically required to synthesize refractory compounds preclude the formation of high-energy morphological features, including nanoscopic pores that are beneficial for applications, such as catalysis, that require higher surface areas. Here, we demonstrate a low-temperature multistep pathway to engineer mesoporosity into a catalytic refractory material. Mesoporous molybdenum boride, α-MoB, forms through the controlled thermal decomposition of nanolaminate-containing sheets of the metastable MAB (metal-aluminum-boron) phase Mo2AlB2 and amorphous alumina. Upon heating, the Mo2AlB2 layers of the Mo2AlB2-AlOx nanolaminate, which is derived from MoAlB, begin to bridge and decompose, forming inclusions of alumina in a framework of α-MoB. The alumina can be dissolved in aqueous sodium hydroxide in an autoclave, forming α-MoB with empty and accessible pores. Statistical analysis of the morphologies and dimensions of the pores reveals a correlation with grain size, which relates to the pathway by which the alumina inclusions form. The transformation of Mo2AlB2 to α-MoB is topotactic due to crystal structure relationships, resulting in a high density of stacking faults that can be modeled to account for the observed experimental diffraction data. Porosity was validated by comparing surface areas and demonstrating catalytic viability for the hydrogen evolution reaction.

Unexpected Multi-Step Transformation of AgCuS to AgAuS During Nanoparticle Cation Exchange.

Cation exchange reactions can modify the compositions of colloidal nanoparticles, providing easy access to compounds or nanoparticles that may not be accessible directly. The most common nanoparticle cation exchange reactions replace monovalent cations with divalent cations or vice versa, but some monovalent-to-monovalent exchanges have been reported. Here, we dissect the reaction of as-synthesized AgCuS nanocrystals with Au+ to form AgAuS, initially hypothesizing that Au+ could be selective for Cu+ (rather than for Ag+) based on a known Au+-for-Cu+ exchange and the stability of the targeted AgAuS product. Unexpectedly, we found this system and the putative cation exchange reaction to be much more complex than anticipated. First, the starting AgCuS nanoparticles, which match literature reports, are more accurately described as a hybrid of Ag and a variant of AgCuS that is structurally related to mckinstryite Ag5Cu3S4. Second, the initial reaction of Ag-AgCuS with Au+ results in a galvanic replacement to transform the Ag component to a AuyAg1-y alloy. Third, continued reaction with Au+ initiates cation exchange with Cu+ in AuyAg1-y-AgCuS to form AuyAg1-y-Ag3CuxAu1-xS2 and then AuyAg1-y-AgAuS, which is the final product. Crystal structure relationships among mckinstryite-type AgCuS, Ag3CuxAu1-xS2, and AgAuS help to rationalize the transformation pathway. These insights into the reaction of AgCuS with Au+ reveal the potential complexity of seemingly simple nanoparticle reactions and highlight the importance of thorough compositional, structural, and morphological characterization before, during, and after such reactions.

An interdomain helix in IRE1α mediates the conformational change required for the sensor's activation.

The unfolded protein response plays an evolutionarily conserved role in homeostasis, and its dysregulation often leads to human disease, including diabetes and cancer. IRE1α is a major transducer that conveys endoplasmic reticulum stress via biochemical signals, yet major gaps persist in our understanding of how the detection of stress is converted to one of several molecular outcomes. It is known that, upon sensing unfolded proteins via its endoplasmic reticulum luminal domain, IRE1α dimerizes and then oligomerizes (often visualized as clustering). Once assembled, the kinase domain trans-autophosphorylates a neighboring IRE1α, inducing a conformational change that activates the RNase effector domain. However, the full details of how the signal is transmitted are not known. Here, we describe a previously unrecognized role for helix αK, located between the kinase and RNase domains of IRE1α, in conveying this critical conformational change. Using constructs containing mutations within this interdomain helix, we show that distinct substitutions affect oligomerization, kinase activity, and the RNase activity of IRE1α differentially. Furthermore, using both biochemical and computational methods, we found that different residues at position 827 specify distinct conformations at distal sites of the protein, such as in the RNase domain. Of importance, an RNase-inactive mutant, L827P, can still dimerize with wildtype monomers, but this mutation inactivates the wildtype molecule and renders leukemic cells more susceptible to stress. We surmise that helix αK is a conduit for the activation of IRE1α in response to stress.

Tumour-directed microenvironment remodelling at a glance.

The tissue microenvironment supports normal tissue function and regulates the behaviour of parenchymal cells. Tumour cell behaviour, on the other hand, diverges significantly from that of their normal counterparts, rendering the microenvironment hostile to tumour cells. To overcome this problem, tumours can co-opt and remodel the microenvironment to facilitate their growth and spread. This involves modifying both the biochemistry and the biophysics of the normal microenvironment to produce a tumour microenvironment. In this Cell Science at a Glance article and accompanying poster, we outline the key processes by which epithelial tumours influence the establishment of the tumour microenvironment. As the microenvironment is populated by genetically normal cells, we discuss how controlling the microenvironment is both a significant challenge and a key vulnerability for tumours. Finally, we review how new insights into tumour-microenvironment interactions has led to the current consensus on how these processes may be targeted as novel anti-cancer therapies.

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 and B-Cell Growth Transformation Induce Lipogenesis through Fatty Acid Synthase.

Latent membrane protein 1 (LMP1) is the major transforming protein of Epstein-Barr virus (EBV) and is critical for EBV-induced B-cell transformation in vitro Several B-cell malignancies are associated with latent LMP1-positive EBV infection, including Hodgkin's and diffuse large B-cell lymphomas. We have previously reported that promotion of B cell proliferation by LMP1 coincided with an induction of aerobic glycolysis. To further examine LMP1-induced metabolic reprogramming in B cells, we ectopically expressed LMP1 in an EBV-negative Burkitt's lymphoma (BL) cell line preceding a targeted metabolic analysis. This analysis revealed that the most significant LMP1-induced metabolic changes were to fatty acids. Significant changes to fatty acid levels were also found in primary B cells following EBV-mediated B-cell growth transformation. Ectopic expression of LMP1- and EBV-mediated B-cell growth transformation induced fatty acid synthase (FASN) and increased lipid droplet formation. FASN is a crucial lipogenic enzyme responsible for de novo biogenesis of fatty acids in transformed cells. Furthermore, inhibition of lipogenesis caused preferential killing of LMP1-expressing B cells and significantly hindered EBV immortalization of primary B cells. Finally, our investigation also found that USP2a, a ubiquitin-specific protease, is significantly increased in LMP1-positive BL cells and mediates FASN stability. Our findings demonstrate that ectopic expression of LMP1- and EBV-mediated B-cell growth transformation leads to induction of FASN, fatty acids, and lipid droplet formation, possibly pointing to a reliance on lipogenesis. Therefore, the use of lipogenesis inhibitors could be used in the treatment of LMP1+ EBV-associated malignancies by targeting an LMP1-specific dependency on lipogenesis.IMPORTANCE Despite many attempts to develop novel therapies, EBV-specific therapies currently remain largely investigational, and EBV-associated malignancies are often associated with a worse prognosis. Therefore, there is a clear demand for EBV-specific therapies for both prevention and treatment of virus-associated malignancies. Noncancerous cells preferentially obtain fatty acids from dietary sources, whereas cancer cells will often produce fatty acids themselves by de novo lipogenesis, often becoming dependent on the pathway for cell survival and proliferation. LMP1- and EBV-mediated B-cell growth transformation leads to induction of FASN, a key enzyme responsible for the catalysis of endogenous fatty acids. Preferential killing of LMP1-expressing B cells following inhibition of FASN suggests that targeting LMP-induced lipogenesis is an effective strategy in treating LMP1-positive EBV-associated malignancies. Importantly, targeting unique metabolic perturbations induced by EBV could be a way to explicitly target EBV-positive malignancies and distinguish their treatment from EBV-negative counterparts.

Effect of reversal of residual neuromuscular blockade on the amplitude of motor evoked potentials: a randomized controlled crossover study comparing sugammadex and placebo.

PURPOSE: To compare the amplitude changes in motor evoked potentials (MEP) with reversal of residual neuromuscular blockade using sugammadex or placebo in patients with cervical myelopathy. METHODS: In this prospective randomized double-blind, placebo-controlled crossover trial, 38 patients with cervical myelopathy undergoing posterior cervical decompression and fusion were randomized to either sugammadex (2mg/kg) or placebo. The primary outcome measure was the increase in amplitude of the MEP in the first dorsal interossei (FDI) muscle at 3 min. Mann-Whitney U test was used to analyze the primary outcome measure. RESULTS: There was a significant increase in the amplitude of MEP at 3 min with sugammadex when compared to placebo group. The median (IQR) increase in MEP amplitude (µV) at 3 min from the left FDI in sugammadex and placebo group was 652.9 (142:1650) and 20.6 (-183.5:297.5) (p <0.001), respectively. Corresponding values from right FDI were 2153.4 (1400:4536.8) and 55(-65.2:480.8) (p=<0.001). CONCLUSION: Our study showed that there was a 200% increase in the MEP amplitude in the first dorsal interosseous muscle at 3 min following reversal of residual neuromuscular blockade with sugammadex. By ensuring that maximal MEP amplitude is recorded at baseline, early commencement of neuromonitoring can be achieved. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: The study was registered at http://clinicaltrials.gov , ID NCT03087513, Feb 5th 2018.

A Gamified Personalized Normative Feedback App to Reduce Drinking Among Sexual Minority Women: Randomized Controlled Trial and Feasibility Study.

BACKGROUND: Sexual minority women disproportionately engage in heavy drinking and shoulder the burden of alcohol dependence. Although several intensive interventions are being developed to meet the needs of treatment-seeking sexual minority women, there remains a lack of preventive interventions to reduce drinking and its consequences among women not yet motivated to reduce their alcohol consumption. OBJECTIVE: We aimed to examine the feasibility and efficacy of reducing alcohol-related risks via personalized normative feedback (PNF) on alcohol use and coping delivered within LezParlay, a social media-inspired digital competition designed to challenge negative stereotypes about lesbian, bisexual, and queer (LBQ)-identified sexual minority women. METHODS: Feasibility was assessed by examining engagement with LezParlay outside the context of an incentivized research study, assessing the characteristics of the LBQ women taking part, and examining the competition's ability to derive risk-reducing actual norms as well as levels of acceptability and perceived benefits reported by participants. Intervention efficacy was examined by randomizing a subsample of 499 LBQ alcohol consumers (ie, drinkers) already taking part in the competition to receive sexual identity-specific PNF on alcohol use and coping, alcohol use only, or control topics over only 2 rounds of play. Changes in alcohol use and negative consequences were examined 2 and 4 months after the delivery of treatment PNF. RESULTS: A total of 2667 diverse LBQ women played ≥1 round of LezParlay. The competition attracted large numbers of moderate and heavy drinkers; however, risk-reducing actual norms could still be derived from competition rounds and featured in PNF. Efficacy results revealed that drinkers who received PNF on alcohol use and both alcohol use and coping had similar reductions in their weekly drinks (P=.003; P<.001), peak drinks (P<.001; P<.001), and negative consequences (P<.001; P<.001) relative to those who received PNF on control topics at the 2-month follow-up. However, at the 4-month follow-up, reductions in alcohol consumption outcomes faded among those who received alcohol PNF only (weekly: P=.06; peak: P=.11), whereas they remained relatively robust among those who received PNF on both alcohol use and coping (weekly: P=.02; peak: P=.03). Finally, participants found the competition highly acceptable and psychologically beneficial as a whole. CONCLUSIONS: The LezParlay competition was found to be a feasible and efficacious means of reducing alcohol-related risks in this population. Our findings demonstrate the utility of correcting sexual identity-specific drinking and coping norms to reduce alcohol-related risks among LBQ women and suggest that this approach may also prove fruitful in other stigmatized health disparity populations. To engage these populations in the real world and expand the psychological benefits associated with PNF, our findings also point to packaging PNF within a broader, culturally tailored competition designed to challenge negative group stereotypes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03884478; https://clinicaltrials.gov/ct2/show/NCT03884478. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/24647.

Evaluating Non-response Bias in a Parent-Based College Alcohol Intervention.

Background: The purpose of this study was to address a dearth in the literature on non-response bias in parent-based interventions (PBIs) by investigating parenting constructs that might be associated with whether a parent volunteers to participate in a no-incentive college drinking PBI. Method: Incoming first-year students (N = 386) completed an online questionnaire that included items assessing plausible predictors of participation in a PBI (students' drinking, perceptions of parents' harm-reduction and zero-tolerance alcohol communication, whether parents allowed alcohol, and changes in parents' alcohol rules). Four months later, all parents of first-year students at the study university were invited to join the PBI, which was described as a resource guide to teach them how to help their student navigate the college transition and prepare them for life at their university. Results: Parents who signed up for the intervention used greater harm-reduction communication than those who did not sign up, were more likely to have allowed alcohol use, and signing up was significantly associated with student reports that fathers became less strict toward drinking after high school. Students' drinking and zero-tolerance communication did not significantly differ between the groups. Conclusion: Results indicate that non-response bias can be an issue when utilizing a real-world, non-RCT recruitment approach to invite parents into a PBI (i.e., non-incentivized, inviting all parents). Findings suggest that more comprehensive recruitment strategies may be required to increase parent diversity in PBIs.

Fermented food consumption in wild nonhuman primates and its ecological drivers.

OBJECTIVES: Although fermented food use is ubiquitous in humans, the ecological and evolutionary factors contributing to its emergence are unclear. Here we investigated the ecological contexts surrounding the consumption of fruits in the late stages of fermentation by wild primates to provide insight into its adaptive function. We hypothesized that climate, socioecological traits, and habitat patch size would influence the occurrence of this behavior due to effects on the environmental prevalence of late-stage fermented foods, the ability of primates to detect them, and potential nutritional benefits. MATERIALS AND METHODS: We compiled data from field studies lasting at least 9 months to describe the contexts in which primates were observed consuming fruits in the late stages of fermentation. Using generalized linear mixed-effects models, we assessed the effects of 18 predictor variables on the occurrence of fermented food use in primates. RESULTS: Late-stage fermented foods were consumed by a wide taxonomic breadth of primates. However, they generally made up 0.01%-3% of the annual diet and were limited to a subset of fruit species, many of which are reported to have mechanical and chemical defenses against herbivores when not fermented. Additionally, late-stage fermented food consumption was best predicted by climate and habitat patch size. It was more likely to occur in larger habitat patches with lower annual mean rainfall and higher annual mean maximum temperatures. DISCUSSION: We posit that primates capitalize on the natural fermentation of some fruits as part of a nutritional strategy to maximize periods of fruit exploitation and/or access a wider range of plant species. We speculate that these factors contributed to the evolutionary emergence of the human propensity for fermented foods.

Food availability, plant diversity, and vegetation structure drive behavioral and ecological variation in Endangered Coimbra-Filho's titi monkeys.

There is wide variability in primate behavior and ecology. Understanding how frugivorous primates behave under different habitat fragmentation levels is key for effective conservation and management of species and their habitats. We evaluated the seasonality in activity budget, diet, and ranging behavior of two groups of Endangered Coimbra-Filho's titi monkeys (Callicebus coimbrai). One group inhabited a 14-ha forest fragment, whereas the other lived in a 522-ha fragment. We measured the monthly density of trees and lianas available as food sources over 8 months. We also collected behavioral and group location data every 5 min, from dawn to dusk, using the scan sampling method. The two forest fragments differed seasonally in the number of fruiting food-resource available. In the 14-ha fragment, we found that the time spent by titi monkeys feeding, foraging, resting, and traveling differed seasonally. In the 522-ha fragment, titi monkeys exhibited seasonal differences in time spent sleeping, socializing, foraging, and revisiting food sources. In both titi monkey groups, diets varied seasonally. Our findings indicate that Coimbra-Filho's titi monkeys can exhibit behavioral flexibility in their activity budgets, diets, and movement patterns. Such flexibility is important for this species to survive in fragmented habitats and may be linked to three key factors: species-specific resource availability, plant species diversity, and the vegetation structure of each forest fragment.

Mechanical Signaling in the Mammary Microenvironment: From Homeostasis to Cancer.

It is becoming increasingly appreciated that biophysical influences on tissues are at least as important as biochemical influences in regulating normal development and homeostasis. Furthermore, diseases of aberrant tissue homeostasis such as cancers are driven by the abnormal biophysics of cancerous tissues. The mammary gland, a mechanoresponsive tissue, is exquisitely sensitive to changes in its mechanical microenvironment. Forces play an important role in normal mammary development, lactation, and involution, as well as in mammary neoplasia. As such the mechanical influences on normal tissue homeostasis and neoplasia are easily studied in this tissue. Here, we discuss the role of mechanical forces in these developmental and homeostatic processes and highlight insights gained from new findings in the field of mammary mechanobiology. We also discuss the potential for harnessing these insights into novel anticancer therapy approaches that halt tumor progression, with opportunities to revolutionize cancer care and outcomes for patients.

Temporal, Sex-Specific, Social Media-Based Alcohol Influences during the Transition to College.

BACKGROUND: The transition to college is an important developmental phase, usually met with increased social desirability, access to alcohol, and new peer groups. Recently, research has utilized social media as a predictor of events during college, but few have assessed how social media can influence alcohol use during the transition to college. Methods: Participants (N = 320) were recruited prior to entering their first year of college. Participants were 18 years old, 60.7% were women, with 46.3% identifying as White, 16.5% Hispanic, 14.9% Asian, 9.5% Black, and 7.6% other. Each participant was assessed three times: prior to matriculation, first semester, and second semester of their freshman year. We assessed the effect of exposure to alcohol content via social media on long-term trajectories of alcohol use. We also assessed self-reported sex as a moderator. Results: Exposure to alcohol content (over and above one's own posting of alcohol content) was associated with greater frequency of drinking during the transition to college. In the multi-group model, exposure to alcohol content was associated with greater drinking prior to matriculation for men. However, for women, exposure to alcohol content was associated with greater alcohol use in the first semester of college. Conclusion: Our results indicate exposure to alcohol-related media content is a strong predictor, over and above one's own positing, of increased drinking, and this effect varies by sex and point in time. Our results lend support for more tailored and time-specific prevention programming for incoming freshmen that should integrate social media normative feedback.

Uncovering Tumor-Stroma Inter-relationships Using MALDI Mass Spectrometry Imaging.

Tumorigenesis involves a complex interplay between genetically modified cancer cells and their adjacent normal tissue, the stroma. We used an established breast cancer mouse model to investigate this inter-relationship. Conditional activation of Rho-associated protein kinase (ROCK) in a model of mammary tumorigenesis enhances tumor growth and progression by educating the stroma and enhancing the production and remodeling of the extracellular matrix. We used peptide matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to quantify the proteomic changes occurring within tumors and their stroma in their regular spatial context. Peptides were ranked according to their ability to discriminate between the two groups, using a receiver operating characteristic tool. Peptides were identified by liquid chromatography tandem mass spectrometry, and protein expression was validated by quantitative immunofluorescence using an independent set of tumor samples. We have identified and validated four key proteins upregulated in ROCK-activated mammary tumors relative to those expressing kinase-dead ROCK, namely, collagen I, α-SMA, Rab14, and tubulin-ß4. Rab14 and tubulin-ß4 are expressed within tumor cells, whereas collagen I is localized within the stroma. α-SMA is predominantly localized within the stroma but is also expressed at higher levels in the epithelia of ROCK-activated tumors. High expression of COL1A, the gene encoding the pro-α 1 chain of collagen, correlates with cancer progression in two human breast cancer genomic data sets, and high expression of COL1A and ACTA2 (the gene encoding α-SMA) are associated with a low survival probability (COLIA, p = 0.00013; ACTA2, p = 0.0076) in estrogen receptor-negative breast cancer patients. To investigate whether ROCK-activated tumor cells cause stromal cancer-associated fibroblasts (CAFs) to upregulate expression of collagen I and α-SMA, we treated CAFs with medium conditioned by primary mammary tumor cells in which ROCK had been activated. This led to abundant production of both proteins in CAFs, clearly highlighting the inter-relationship between tumor cells and CAFs and identifying CAFs as the potential source of high levels of collagen 1 and α-SMA and associated enhancement of tissue stiffness. Our research emphasizes the capacity of MALDI-MSI to quantitatively assess tumor-stroma inter-relationships and to identify potential prognostic factors for cancer progression in human patients, using sophisticated mouse cancer models.

Clustering of IRE1α depends on sensing ER stress but not on its RNase activity.

The sensors of the unfolded protein response react to endoplasmic reticulum (ER) stress by transient activation of their enzymatic activities, which initiate various signaling cascades. In addition, the sensor IRE1α exhibits stress-induced clustering in a transient time frame similar to activation of its endoRNase activity. Previous work had suggested that the clustering response and RNase activity of IRE1α are functionally linked, but here we show that they are independent of each other and have different behaviors and modes of activation. Although both clustering and the RNase activity are responsive to luminal stress conditions and to depletion of the ER chaperone binding protein, RNase-inactive IRE1α still clusters and, conversely, full RNase activity can be accomplished without clustering. The clusters formed by RNase-inactive IRE1α are much larger and persist longer than those induced by ER stress. Clustering requires autophosphorylation, and an IRE1α mutant whose RNase domain is responsive to ligands that bind the kinase domain forms yet a third type of stress-independent cluster, with distinct physical properties and half-lives. These data suggest that IRE1α clustering can follow distinct pathways upon activation of the sensor.-Ricci, D., Marrocco, I., Blumenthal, D., Dibos, M., Eletto, D., Vargas, J., Boyle, S., Iwamoto, Y., Chomistek, S., Paton, J. C., Paton, A. W., Argon, Y. Clustering of IRE1α depends on sensing ER stress but not on its RNase activity.

#recovery: Understanding recovery from the lens of recovery-focused blogs posted by individuals with lived experience.

OBJECTIVE: Definitions of eating disorder (ED) recovery have primarily focused on symptom management (i.e., weight regain, reduced/absent ED behaviors, and normalized ED thoughts). Notwithstanding the importance of these approaches, there are arguably additional considerations in ED recovery. In order to get a more comprehensive understanding of recovery, it is necessary to turn to individuals with lived experience. Here, we examine how individuals with lived experience of an ED conceptualize and define recovery in narrative, recovery-focused blogs and consider how this understanding may contribute to definitions of recovery in the field. METHOD: Inductive thematic analysis was used to examine 168 blogs posted by at least 120 unique authors (95% women; 36% reporting anorexia nervosa diagnosis) to 10 moderated, ED websites. RESULTS: Results from the thematic analysis yielded seven themes: recovery as (1) existing in contrast to the ED, (2) existing in a broader context, (3) subjective, (4) a choice, (5) a complex, nonlinear process, (6) transformative, and (7) overcoming. DISCUSSION: The present findings are consistent with previous qualitative research, suggesting that recovery is multifaceted and encompasses more than just symptom management. Notably, bloggers highlighted that recovery may not be equally attainable for all individuals, citing numerous social justice issues in the conceptualization of recovery. This multifaceted and intersectional view of recovery is consistent with consumer models of recovery. We argue that a dimensional model of recovery may be a good starting framework for researchers and clinicians to develop a more comprehensive definition of recovery.

Interplay between CCR7 and Notch1 axes promotes stemness in MMTV-PyMT mammary cancer cells.

BACKGROUND: Breast cancer is the major cause of cancer-related mortality in women. It is thought that quiescent stem-like cells within solid tumors are responsible for cancer maintenance, progression and eventual metastasis. We recently reported that the chemokine receptor CCR7, a multi-functional regulator of breast cancer, maintains the stem-like cell population. METHODS: This study used a combination of molecular and cellular assays on primary mammary tumor cells from the MMTV-PyMT transgenic mouse with or without CCR7 to examine the signaling crosstalk between CCR7 and Notch pathways. RESULTS: We show for the first time that CCR7 functionally intersects with the Notch signaling pathway to regulate mammary cancer stem-like cells. In this cell subpopulation, CCR7 stimulation activated the Notch signaling pathway, and deletion of CCR7 significantly reduced the levels of activated cleaved Notch1. Moreover, blocking Notch activity prevented specific ligand-induced signaling of CCR7 and augmentation of mammary cancer stem-like cell function. CONCLUSION: Crosstalk between CCR7 and Notch1 promotes stemness in mammary cancer cells and may ultimately potentiate mammary tumor progression. Therefore, dual targeting of both the CCR7 receptor and Notch1 signaling axes may be a potential therapeutic avenue to specifically inhibit the functions of breast cancer stem cells.

PDIA6 regulates insulin secretion by selectively inhibiting the RIDD activity of IRE1.

Protein disulfide isomerase A6 (PDIA6) interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme (IRE)-1 and inhibits their unfolded protein response signaling. In this study, shRNA silencing of PDIA6 expression in insulin-producing mouse cells reduced insulin production (5-fold) and, consequently, glucose-stimulated insulin secretion (3-4-fold). This inhibition of insulin release was independent of the PDIA6-PERK interaction or PERK activity. Acute inhibition of PERK did not change the short-term response of ß cells to glucose. Rather, PDIA6 affected insulin secretion by modulating one of the activities of IRE1. At 11 mM glucose and lower, the regulated IRE1-dependent decay (RIDD) of the mRNA activity of IRE1 was activated, but not its X-box binding protein (XBP)-1 splicing activity. In the absence of PDIA6, RIDD activity toward insulin transcripts was enhanced up to 4-fold, as shown by molecular assays in cultured cells and the use of a fluorescent reporter in intact islets. Such physiologic activation of IRE1 by glucose contrasted with IRE1 activation by chemical stress, when both IRE1 activities were induced. Thus, whereas the stimulus determines the quality of IRE1 signaling, PDIA6 attenuates multiple enzymatic activities of IRE1, maintaining its signaling within a physiologically tolerable range.

Tissue-selective expression of a conditionally-active ROCK2-estrogen receptor fusion protein.

The serine/threonine kinases ROCK1 and ROCK2 are central mediators of actomyosin contractile force generation that act downstream of the RhoA small GTP-binding protein. As a result, they have key roles in regulating cell morphology and proliferation, and have been implicated in numerous pathological conditions and diseases including hypertension and cancer. Here we describe the generation of a gene-targeted mouse line that enables CRE-inducible expression of a conditionally-active fusion between the ROCK2 kinase domain and the hormone-binding domain of a mutated estrogen receptor (ROCK2:ER). This two-stage system of regulation allows for tissue-selective expression of the ROCK2:ER fusion protein, which then requires administration of estrogen analogues such as tamoxifen or 4-hydroxytamoxifen to elicit kinase activity. This conditional gain-of-function system was validated in multiple tissues by crossing with mice expressing CRE recombinase under the transcriptional control of cytokeratin14 (K14), murine mammary tumor virus (MMTV) or cytochrome P450 Cyp1A1 (Ah) promoters, driving appropriate expression in the epidermis, mammary or intestinal epithelia respectively. Given the interest in ROCK signaling in normal physiology and disease, this mouse line will facilitate research into the consequences of ROCK activation that could be used to complement conditional knockout models. Birth Defects Research (Part A) 106:636-646, 2016. © 2016 Wiley Periodicals, Inc.