Re-assessing the social climate of physical (in)activity in Canada.

Social-ecological models suggest that a strategy for increasing population physical activity participation is to reconstruct the "social climate" through changing social norms and beliefs about physical activity (PA). In this study, we assessed whether the PA social climate in Canada has changed over a five-year period after controlling for sociodemographic factors and PA levels. Replicating a survey administered in 2018, a sample of adults in Canada (n = 2,507) completed an online survey assessing social climate dimensions, including but not limited to descriptive and injunctive norms. Descriptive statistics were calculated, and binary logistic regressions were conducted to assess the associations of sociodemographic factors and year of the survey with social climate dimensions. Results suggest some social climate constructs are trending in a positive direction between 2018 and 2023. Physical inactivity was considered a serious public health concern by 49% of respondents, second to unhealthy diets (52%). Compared to those who participated in the 2018 survey, participants in 2023 were less likely to see others walking or wheeling in their neighbourhood (OR = 1.58, 95% CI: 1.41, 1.78), but more likely to see people exercising (OR = 0.82, 95% CI: 0.73, 0.92) and kids playing in their neighbourhood (OR = 0.75, 95% CI: 0.66, 0.85). No changes were reported between 2018 and 2023 in individuals' perceptions of whether physical inactivity is due to individual versus external factors (OR = 0.99, 95% CI: 0.87, 1.13). The findings of this work indicate a modest positive shift in some measured components of the social climate surrounding PA although attributing causes for these changes remain speculative.

Honoring the Care Experiences of Chinese Canadian Survivors of Prostate Cancer to Cultivate Cultural Safety and Relationality in Digital Health: Exploratory-Descriptive Qualitative Study.

BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed nonskin cancer for Canadian men and has one of the highest 5-year survival rates, straining systems to provide care. Virtual care can be one way to relieve this strain, but survivors' care needs and technology use are influenced by intersecting social and cultural structures. Cultural adaptation has been posited as an effective method to tailor existing interventions to better serve racialized communities, including Chinese men. However, cultural adaptations may inadvertently draw attention away from addressing structural inequities. OBJECTIVE: This study used qualitative methods to (1) explore the perceptions and experiences of Chinese Canadian PCa survivors with follow-up and virtual care, and (2) identify implications for the cultural adaptation of a PCa follow-up care app, the Ned (no evidence of disease) Clinic. METHODS: An axiology of relational accountability and a relational paradigm underpinned our phenomenologically informed exploratory-descriptive qualitative study design. A community-based participatory approach was used, informed by cultural safety and user-centered design principles, to invite Chinese Canadian PCa survivors and their caregivers to share their stories. Data were inductively analyzed to explore their unmet needs, common experiences, and levels of digital literacy. RESULTS: Unmet needs and technology preferences were similar to broader trends within the wider community of PCa survivors. However, participants indicated that they felt uncomfortable, unable to, or ignored when expressing their needs. Responses spoke to a sense of isolation and reflected a reliance on culturally informed coping mechanisms, such as "eating bitterness," and familial assistance to overcome systemic barriers and gaps in care. Moreover, virtual care was viewed as "better than nothing;" it did not change a perceived lack of focus on improving quality of life or care continuity in survivorship care. Systemic changes were identified as likely to be more effective in improving care delivery and well-being rather than the cultural adaptation of Ned for Chinese Canadians. Participants' desires for care reflected accessibility issues that were not culturally specific to Chinese Canadians. CONCLUSIONS: Chinese Canadian survivors are seeking to strengthen their connections in a health care system that provides privacy and accessibility, protects relationality, and promotes transparency, accountability, and responsibility. Designing "trickle-up" adaptations that address structural inequities and emphasize accessibility, relationality, and privacy may be more effective and efficient at improving care than creating cultural adaptations of interventions.

PDE4 inhibitor eliminates breast cancer stem cells via noncanonical activation of mTOR.

Ineffective cancer treatment is implicated in metastasis, recurrence, resistance to chemotherapy and radiotherapy, and evasion of immune surveillance. All these failures occur due to the persistence of cancer stem cells (CSCs) even after rigorous therapy, thereby rendering them as essential targets for cancer management. Contrary to the quiescent nature of CSCs, a gene profiler array disclosed that phosphatidylinositol-3-kinase (PI3K), which is known to be crucial for cell proliferation, differentiation, and survival, was significantly upregulated in CSCs. Since PI3K is modulated by cyclic adenosine 3',5' monophosphate (cAMP), analyses of cAMP regulation revealed that breast CSCs expressed increased levels of phosphodiesterase 4 (PDE4) in contrast to normal stem cells. In accordance, the effects of rolipram, a PDE4 inhibitor, were evaluated on PI3K regulators and signaling. The efficacy of rolipram was compared with paclitaxel, an anticancer drug that is ineffective in obliterating breast CSCs. Analyses of downstream signaling components revealed a switch between cell survival and death, in response to rolipram, specifically of the CSCs. Rolipram-mediated downregulation of PDE4A levels in breast CSCs led to an increase in cAMP levels and protein kinase A (PKA) expression. Subsequently, PKA-mediated upregulation of phosphatase and tensin homolog antagonized the PI3K/AKT/mTOR pathway and led to cell cycle arrest. Interestingly, direct yet noncanonical activation of mTOR by PKA, circumventing the influence of PI3K and AKT, temporally shifted the fate of CSCs toward apoptosis. Rolipram in combination with paclitaxel indicated synergistic consequences, which effectively obliterated CSCs within a tumor, thereby suggesting combinatorial therapy as a sustainable and effective strategy to abrogate breast CSCs for better patient prognosis.

Synthesis, Fluorescence Spectra, Redox Property and the DNA Binding Studies of 7-phenylacenaphtho[1,2-b]quinoxalin-7-ium chloride: Evidences of the Formation of Neutral Radical Analogue.

Reaction of acenaphthoquinone with N-phenyl-o-phenylenediamine in methanol in presence of HCl yielded 7-phenylacenaphtho[1,2-b]quinoxalin-7-ium chloride, [1][Cl]. [1][Cl] is brightly fluorescencent in dichloromethane (λex = 403 nm and λem = 442, 464, 488 nm) and water (λex = 408 nm and λem = 545 nm). Density functional theory (DFT) and time dependent (TD) DFT calculations on [1](+) at the B3LYP level of the theory elucidated that the origin of the lower energy excitation at around 400 nm is due to π → π(*) transition. [1](+) is redox active and exhibits a reversible cathodic wave at -0.66 V referenced to Fc(+)/Fc couple due to [1](+)/[1](•) redox couple. Electrogenerated neutral radical analogue [1](•) was characterized by electron paramagnetic resonance (EPR), UV-vis spectra and DFT calculations. DNA binding studies using the techniques of UV-vis absorption, fluorescence, circular dichroism (CD) spectra, viscosity, gel electrophoresis, hydrodynamic, isothermal titration calorimetry (ITC) and UV optical melting studies of [1][Cl] revealed that [1](+) is a strong DNA intercalator obeying neighbor exclusion principle. ITC experiment authenticated that the binding of [1](+) to DNA is entropy driven.

The relationship between religious service attendance and coronary heart disease and related risk factors in Saskatchewan, Canada.

Research suggests that attending religious services could provide small yet important protective benefits against coronary heart disease (CHD) and CHD risk factors (e.g., diabetes, hypertension). The extent to which these benefits apply to Canada deserves study because approximately one-third of adult Canadians attend religious services at least monthly. Therefore, the objective of this study is to examine the association between frequency of religious service attendance and prevalence of (1) CHD, (2) diabetes, and (3) hypertension in Canada. We used the Saskatchewan sample (n = 5,442) of the Canadian Community Health Survey (CCHS-4.1) and built multivariable logistic regression models to evaluate associations between religious service attendance and self-reported CHD, diabetes, and hypertension. After controlling for demographic, socioeconomic and health behavior variables, the association between religious service attendance and prevalence of CHD was not significant (OR = 0.82; 95 % CI 0.61-1.11). However, persons who attended religious services more than once a week exhibited lower prevalence odds of diabetes (OR = 0.60; 95 % CI 0.45-0.80) and hypertension (OR = 0.82; 95 % CI 0.68-0.99) compared to persons who attended less than once a year. The findings of this study are the first to suggest religious service attendance may be associated with a lower prevalence of CHD risk factors in Canada.

Attending religious services and its relationship with coronary heart disease and related risk factors in older adults: a qualitative study of church pastors' and parishioners' perspectives.

A qualitative study was undertaken to explain findings of a cross-sectional study of Canadian Community Health Survey (CCHS) 4.1 data showing older persons who attend religious services more than once a week, compared to persons who do not attend at all, have lower prevalences of coronary heart disease (CHD), diabetes and high blood pressure. Twelve semi-structured interviews with ordained pastors and three focus groups with older parishioners from Canadian churches were conducted. Interviews were transcribed and analyzed for emergent themes through a process of direct content analysis. All participants claimed that religious service attendance (RSA): (1) enhances mental health; (2) provides social support and activities; and (3) promotes health and lifestyle behaviours that lower CHD risk. These three themes appear to be underlying mechanisms that help to explain the inverse association between RSA and the prevalence of adverse health outcomes found in the CCHS 4.1 data.

Prevalence of perturbed gut microbiota in pathophysiology of arsenic-induced anxiety- and depression-like behaviour in mice.

Severe toxic effects of arsenic on human physiology have been of immense concern worldwide. Arsenic causes irrevocable structural and functional disruption of tissues, leading to major diseases in chronically exposed individuals. However, it is yet to be resolved whether the effects result from direct deposition and persistence of arsenic in tissues, or via activation of indirect signaling components. Emerging evidences suggest that gut inhabitants play an active role in orchestrating various aspects of brain physiology, as the gut-brain axis maintains cognitive health, emotions, learning and memory skills. Arsenic-induced dysbiosis may consequentially evoke neurotoxicity, eventually leading to anxiety and depression. To delineate the mechanism of action, mice were exposed to different concentrations of arsenic. Enrichment of Gram-negative bacteria and compromised barrier integrity of the gut enhanced lipopolysaccharide (LPS) level in the bloodstream, which in turn elicited systemic inflammation. Subsequent alterations in neurotransmitter levels, microglial activation and histoarchitectural disruption in brain triggered onset of anxiety- and depression-like behaviour in a dose-dependent manner. Finally, to confirm whether the neurotoxic effects are specifically a consequence of modulation of gut microbiota (GM) by arsenic and not arsenic accumulation in the brain, fecal microbiota transplantations (FMT) were performed from arsenic-exposed mice to healthy recipients. 16S rRNA gene sequencing indicated major alterations in GM population in FMT mice, leading to severe structural, functional and behavioural alterations. Moreover, suppression of Toll-like receptor 4 (TLR4) using vivo-morpholino oligomers (VMO) indicated restoration of the altered parameters towards normalcy in FMT mice, confirming direct involvement of the GM in inducing neurotoxicity through the arsenic-gut-brain axis. This study accentuates the potential role of the gut microbiota in promoting neurotoxicity in arsenic-exposed mice, and has immense relevance in predicting neurotoxicity under altered conditions of the gut for designing therapeutic interventions that will target gut dysbiosis to attenuate arsenic-mediated neurotoxicity.

Asprosin-mediated regulation of ovarian functions in mice: An age-dependent study.

Asprosin is a recently discovered adipokine reported to be involved in the modulation of mammalian gonadal functions. Preliminary investigations suggest its role in regulation of ovarian functions in rodents as well as bovids. In addition, increased levels of the adipokine during human ovarian pathophysiologies implicate it in disease progression and severity. The present study evidenced high expression of asprosin in ovaries of juvenile, pubertal and adult mice while expression was significantly low in ageing ovaries. Further, asprosin stimulated expression of markers for ovarian folliculogenesis (Scf, c-Kit, Gdf9, Bmp6, Fshr, Lhr) and steroidogenesis (3ß-Hsd) in adult mice. In addition to exploring concentration-dependent effect of asprosin, the study implicates asprosin as an age-dependent modulator of ovarian functions as treatment of ovaries with asprosin led to upregulation of Fshr, c-Kit, Bmp6, and Gdf9 in both adult and juvenile ovaries, Lhr only in adults while that of Scf only in juvenile ovaries. The current study is first to report an age-dependent expression and role of asprosin in murine ovaries.

Beyond the Body: Using Photovoice to Explore Social Determinants of Diabetes With South Asian Adolescents in the Peel Region of Ontario, Canada.

OBJECTIVES: The higher prevalence of diabetes in the South Asian (SA) population living in Canada spans across generations and is often associated with individual risk factors while undermining the social determinants of health (SDOH). There is a scarcity of studies on the perspectives of SA adolescents with a family history of type 2 diabetes mellitus (T2DM). Learning directly from these adolescents can fill a major gap by providing insight on how the SDOH contribute to disproportionate rates of T2DM in SA immigrant communities. METHODS: In this study, we used Photovoice, which is a community-based participatory research (CBPR) method that involves the use of photography to visually capture the challenges of diabetes prevention from the perspective of those with lived experiences. A group of 15 SA youth were recruited from an adolescent diabetes education program in the Peel Region of Ontario. The youth discussed their images and accompanied written narratives during focus groups. RESULTS: Four themes emerged from the thematic analysis of the photographs and participant narratives that influence the manifestation of T2DM in SA communities: 1) immigration and resettlement stressors; 2) food insecurity; 3) unhealthy school environments; and 4) academic pressures. CONCLUSIONS: Findings suggest the need to address T2DM as a response to unjust conditions and environments rather than as an epidemic entrenched in genetic predisposition, culture, and poor lifestyle choices.

User-Centered Design and Usability of a Culturally Adapted Virtual Survivorship Care App for Chinese Canadian Prostate Cancer Survivors: Qualitative Descriptive Study.

BACKGROUND: Cultural adaptations of digital health innovations are a growing field. However, digital health innovations can increase health inequities. While completing exploratory work for the cultural adaptation of the Ned Clinic virtual survivorship app, we identified structural considerations that provided a space to design digitally connected and collective care. OBJECTIVE: This study used a community-based participatory research and user-centered design process to develop a cultural adaptation of the Ned Clinic app while designing to intervene in structural inequities. METHODS: The design process included primary data collection and qualitative analysis to explore and distill design principles, an iterative design phase with a multidisciplinary team, and a final evaluation phase with participants throughout the design process as a form of member checking and validation. RESULTS: Participants indicated that they found the final adapted prototype to be acceptable, appropriate, and feasible for their use. The changes made to adapt the prototype were not specifically culturally Chinese. Instead, we identified ways to strengthen connections between the survivor and their providers; improve accessibility to resources; and honor participants' desires for relationality, accountability, and care. CONCLUSIONS: We grounded the use of user-centered design to develop a prototype design that supports the acts of caring through digital technology by identifying and designing to resist structures that create health inequities in the lives of this community of survivors. By designing for collective justice, we can provide accessible, feasible, and relational care with digital health through the application of Indigenous and Black feminist ways of being and knowing.

Assessing the effectiveness of "BETTER Women", a community-based, primary care-linked peer health coaching programme for chronic disease prevention: protocol for a pragmatic, wait-list controlled, type 1 hybrid effectiveness-implementation trial.

INTRODUCTION: The Building on Existing Tools to Improve Cancer and Chronic Disease Prevention and Screening in Primary Care (BETTER) programme trains allied health professionals working in primary care settings to develop personalised chronic disease 'prevention prescriptions' with patients. However, maintenance of health behaviour changes is difficult without ongoing support. Sustainable options to enhance the BETTER programme and ensure accessibility to underserved populations are needed. We designed the BETTER Women programme, which uses a digital app to match patients with a trained peer health coach (PHC) who provides ongoing support for health behaviour change after receipt of a BETTER prevention prescription in primary care. METHODS AND ANALYSIS: We will conduct a type 1 hybrid implementation-effectiveness patient-randomised trial. Interested women aged 40-68 years will be recruited from three large, sociodemographically distinct primary care clinics (urban, suburban and rural). Patients will be randomised 1:1 to intervention or wait-list control after receipt of their BETTER prevention prescription. We will aim to recruit 204 patients per group (408 total). Effectiveness will be assessed by the primary outcome of targeted behaviours achieved for each participant at 6 months, consisting of three cancer screening tests (cervical, breast and colorectal) and four behavioural determinants of cancer and chronic disease (diet, smoking, alcohol use and physical activity). Data will be collected through patient survey and clinical chart review, measured at 3, 6 and 12 months. Implementation outcomes will be assessed through patient surveys and interviews with patients, peer health coaches and healthcare providers. An embedded economic evaluation will examine cost per quality-adjusted life-year and per additional health behavioural targets achieved. ETHICS AND DISSEMINATION: This study has been approved by Women's College Hospital Research Ethics Board (REB), the Royal Victoria Regional Health Centre REB and the University of Toronto REB. All participants will provide informed consent prior to enrolment. Participation is voluntary and withdrawal will have no impact on the usual care received from their primary care provider. The results of this trial will be published in peer-reviewed journals and shared via conference presentations. Deidentified datasets will be shared on request, after publication of results. TRIAL REGISTRATION NUMBER: NCT04746859.

Assessing Support for Policy Actions With Co-Benefits for Climate Change and Physical Activity in Canada.

BACKGROUND: Calls to action addressing the interconnections between physical (in)activity and the climate crisis are increasing. The current study aimed to investigate public support for policy actions that potentially have co-benefits for physical activity promotion and climate change mitigation. METHODS: In 2023, a survey through the Angus Reid Forum was completed by 2507 adults living in Canada. Binary logistic regressions were conducted. Separate models were created to reflect support or opposition to the 8 included policy items. Several covariates were included in the models including age, gender, political orientation, physical activity levels, income, urbanicity climate anxiety, and attitudes surrounding physical activity and climate change. The data were weighted to reflect the gender, age, and regional composition of the country. RESULTS: Most individuals living in Canada strongly or moderately supported all actions (ranging from 71% to 85%). Meeting the physical activity guidelines, higher self-reported income, and scoring high on personal experience of climate change were associated with higher odds of supporting the policy actions related to climate actions. CONCLUSIONS: Most adults living in Canada support policies that align with the recommended policy actions related to physical activity and climate change. National campaigns enhancing awareness and understanding of the bidirectional relationship between physical activity and climate change are warranted, and these should consider the consistent demographic differences (eg, gender, age, and political orientation) seen in public support for physical activity-related policies.

Social Media Interventions for Nutrition Education Among Adolescents: Scoping Review.

BACKGROUND: Adolescence is a critical period for reinforcing healthy dietary behaviors and supporting the development of cooking skills. Social media may be an avenue for supporting these behaviors, as it is popular among adolescents and can improve access to nutrition education interventions. This study sought to understand the optimal implementation of effective social media-based nutrition education interventions to inform the implementation of future social media-based nutrition education interventions. OBJECTIVE: A scoping review of the characteristics, feasibility, effectiveness, and factors influencing social media-based nutrition education interventions for adolescents was conducted. METHODS: We searched MEDLINE, Embase, CINAHL, Web of Science, and PsycINFO databases using a predefined search strategy. Primary research articles were independently screened and included if they involved adolescent populations (10-18 years old) and delivered nutrition education through social media. The information on intervention characteristics, feasibility, effectiveness, and factors influencing social media-based nutrition education interventions was extracted. RESULTS: A total of 28 publications out of 20,557 met the eligibility criteria. Twenty-five nutrition interventions were examined by 28 studies. Fourteen interventions used homegrown social media platforms, 8 used Facebook, and 2 used Instagram. Feasibility outcomes were infrequently reported, and the cost of intervention delivery was not reported. Engagement with interventions was variable; high engagement was not required to elicit significant improvements in dietary behaviors. Tailoring interventions, offering practical content, meaningful peer support, and involving families and communities facilitated successful interventions. Strategies to address engagement and technical issues were varied. CONCLUSIONS: Emerging evidence demonstrates that social media interventions for adolescent nutrition are acceptable and improve nutrition outcomes. Future interventions should strengthen peer support components and tailor delivery to specific populations. Further research should examine engagement, adherence, and the impact of interventions on behavioral and physical outcomes. This review is the first to examine the use of social media as the primary medium for nutrition education for adolescent populations. The analysis used in this review argues the importance of peer support in social media-based nutrition interventions and the need for user-centered design of the interventions.

Embedding anti-racism in Schools of Public Health: a pathway to accountability for progress towards equity.

The importance of seeing race as a socially constructed idea continues to produce unfair differences between humans and establishes power relations that lead to injustice and exposure to death. Since the racial justice movement in early 2020, there has been a heightened awareness of, and increased interest in, addressing historic racial disparities across Schools of Public Health (SPH) in Canada. Steps have been taken to recognize systemic racism and increase diversity through structural reforms to advance equity and inclusion; however, addressing racism demands collectively uprooting racist institutional designs still inherent in learning, teaching, research, service, and community engagement. This commentary highlights the need for sustained commitment to establishing longitudinal benchmarks for greater racial equity among students, staff, and faculty; revising curricula to include historic and contemporary narratives of colonialism and slavery; and providing community-engaged learning opportunities as instrumental to dismantle systemic drivers of racial health inequities locally and globally. We also advocate for intersectoral collaboration, mutual learning, and sharing of resources across SPH and partner agencies to accomplish a continual collective agenda for racial health equity and inclusion that is intersectional in Canada, while being held accountable to Indigenous and racialized communities.

RéSUMé: L'importance de voir la race comme une idée socialement construite continue de produire des différences inéquitables entre les gens et d'établir des relations de pouvoir qui mènent à l'injustice et à l'exposition à la mort. Depuis que le mouvement pour la justice raciale s'est enclenché au début de 2020, il existe une conscience aiguë des disparités raciales historiques entre les écoles de santé publique (ESP) du Canada et un intérêt accru pour le redressement de ces disparités. Des mesures ont été prises pour reconnaître le racisme systémique et accroître la diversité par des réformes structurelles visant à promouvoir l'équité et l'inclusion; cependant, pour aborder le racisme, il faut collectivement arracher les modèles institutionnels racistes qui font encore partie intégrante de l'apprentissage, de l'enseignement, de la recherche, des services et de la participation de la communauté. Dans notre commentaire, nous soulignons le besoin d'un engagement soutenu à établir des repères longitudinaux pour une plus grande équité raciale dans la population étudiante, au sein du personnel et dans le corps professoral, à revoir les programmes d'études pour y inclure les discours historiques et contemporains du colonialisme et de l'esclavage, et à offrir des possibilités d'enseignement faisant appel aux communautés, car elles contribueront à démanteler les moteurs systémiques des iniquités raciales en santé à l'échelle locale et mondiale. Nous promulguons aussi la collaboration intersectorielle, l'apprentissage mutuel et le partage des ressources entre les ESP et les organismes partenaires afin de concrétiser un plan d'action collective continue en faveur de l'équité raciale en santé et de l'inclusion ­ un plan qui sera intersectionnel au Canada et qui rendra des comptes aux communautés autochtones et racisées.

ALDH1A1 promotes PARP inhibitor resistance by enhancing retinoic acid receptor-mediated DNA polymerase θ expression.

Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi) have been approved for both frontline and recurrent setting in ovarian cancer with homologous recombination (HR) repair deficiency. However, more than 40% of BRCA1/2-mutated ovarian cancer lack the initial response to PARPi treatment, and the majority of those that initially respond eventually develop resistance. Our previous study has demonstrated that increased expression of aldehyde dehydrogenase 1A1 (ALDH1A1) contributes to PARPi resistance in BRCA2-mutated ovarian cancer cells by enhancing microhomology-mediated end joining (MMEJ) but the mechanism remains unknown. Here, we find that ALDH1A1 enhances the expression of DNA polymerase θ (Polθ, encoded by the POLQ gene) in ovarian cancer cells. Furthermore, we demonstrate that the retinoic acid (RA) pathway is involved in the transcription activation of the POLQ gene. The RA receptor (RAR) can bind to the retinoic acid response element (RARE) located in the promoter of the POLQ gene, promoting transcription activation-related histone modification in the presence of RA. Given that ALDH1A1 catalyzes the biosynthesis of RA, we conclude that ALDH1A1 promotes POLQ expression via the activation of the RA signaling pathway. Finally, using a clinically-relevant patient-derived organoid (PDO) model, we find that ALDH1A1 inhibition by the pharmacological inhibitor NCT-505 in combination with the PARP inhibitor olaparib synergistically reduce the cell viability of PDOs carrying BRCA1/2 mutation and positive ALDH1A1 expression. In summary, our study elucidates a new mechanism contributing to PARPi resistance in HR-deficient ovarian cancer and shows the therapeutic potential of combining PARPi and ALDH1A1 inhibition in treating these patients.

Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ).

Glucocorticoid receptor-α (GRα) and peroxisome proliferator-activated receptor-γ (PPARγ) regulate adipogenesis by controlling the balance between lipolysis and lipogenesis. Here, we show that protein phosphatase 5 (PP5), a nuclear receptor co-chaperone, reciprocally modulates the lipometabolic activities of GRα and PPARγ. Wild-type and PP5-deficient (KO) mouse embryonic fibroblast cells were used to show binding of PP5 to both GRα and PPARγ. In response to adipogenic stimuli, PP5-KO mouse embryonic fibroblast cells showed almost no lipid accumulation with reduced expression of adipogenic markers (aP2, CD36, and perilipin) and low fatty-acid synthase enzymatic activity. This was completely reversed following reintroduction of PP5. Loss of PP5 increased phosphorylation of GRα at serines 212 and 234 and elevated dexamethasone-induced activity at prolipolytic genes. In contrast, PPARγ in PP5-KO cells was hyperphosphorylated at serine 112 but had reduced rosiglitazone-induced activity at lipogenic genes. Expression of the S112A mutant rescued PPARγ transcriptional activity and lipid accumulation in PP5-KO cells pointing to Ser-112 as an important residue of PP5 action. This work identifies PP5 as a fulcrum point in nuclear receptor control of the lipolysis/lipogenesis equilibrium and as a potential target in the treatment of obesity.

Diarrhea and colitis in mice require the Salmonella pathogenicity island 2-encoded secretion function but not SifA or Spv effectors.

We investigated the roles of Salmonella pathogenicity island 2 (SPI-2) and two SPI-2 effectors in Salmonella colitis and diarrhea in genetically resistant BALB/c.D2(Slc11a1) congenic mice with the wild-type Nramp1 locus. Wild-type Salmonella enterica serovar Typhimurium 14028s caused a pan-colitis, and the infected mice developed frank diarrhea with a doubling of the fecal water content. An ssaV mutant caused only a 26% increase in fecal water content, without producing the pathological changes of colitis, and it did not cause weight loss over a 1-week period of observation. However, two SPI-2 effector mutants, the spvB and sifA mutants, and a double spvB sifA mutant caused diarrhea and colitis, even though the sifA mutant was sensitive to killing by bone marrow-derived macrophages from BALB/c.D2 mice and was severely impaired in extraintestinal growth but not in growth in the cecum. These results demonstrate that systemic S. enterica infection and diarrhea/colitis are distinct pathogenic processes and that only the former requires spvB and sifA.