Microbial metabolites, short‐chain fatty acids, restrain tissue bacterial load, chronic inflammation, and associated cancer in the colon of mice

The intestinal immune system is regulated by microbes and their metabolites. The roles of gut microbial metabolites in regulating intestinal inflammation and tumorigenesis are incompletely understood. We systematically studied the roles of short‐chain fatty acids (SCFAs) and their receptors (GPR43 or GPR41) in regulating tissue bacterial load, acute versus chronic inflammatory responses, and intestinal cancer development. SCFA receptor‐, particularly GPR43‐, deficient mice were defective in mounting appropriate acute immune responses to promote barrier immunity, and developed uncontrolled chronic inflammatory responses following epithelial damage. Further, intestinal carcinogenesis was increased in GPR43‐deficient mice. Dietary fiber and SCFA administration suppressed intestinal inflammation and cancer in both GPR43‐dependent and independent manners. The beneficial effect of GPR43 was not mediated by altered microbiota but by host tissue cells and hematopoietic cells to a lesser degree. We found that inability to suppress commensal bacterial invasion into the colonic tissue is associated with the increased chronic Th17‐driven inflammation and carcinogenesis in the intestine of GPR43‐deficient mice. In sum, our results reveal the beneficial function of the SCFA‐GPR43 axis in suppressing bacterial invasion and associated chronic inflammation and carcinogenesis in the colon.We found with animal models that dietary fiber, their microbial metabolites, and host receptors for these metabolites potentiate gut barrier immune responses during colon cancer development to decrease bacterial burden and chronic inflammatory responses, resulting in decreased cancer formation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144635/1/eji4232-sup-0002-SuppMat.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144635/2/eji4232-sup-0001-PRC.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144635/3/eji4232.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144635/4/eji4232_am.pd

Treatment‐Resistant Depression and Risk of Suicide

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99660/1/sltb12022.pd

Precision MARS{\tt MARS} Mass Reconstruction of Abell 2744: Synergizing the Largest Strong Lensing and Densest Weak Lensing Datasets from JWST

We present a new high-resolution free-form mass model of Abell 2744, combining both weak-lensing (WL) and strong-lensing (SL) datasets from JWST. The SL dataset comprises 286 multiple images, presenting the most extensive SL constraint to date for a single cluster. The WL dataset, employing photo-$z$ selection, yields a source density of ~ 350 arcmin$^{-2}$, marking the densest WL constraint ever. The combined mass reconstruction enables the highest-resolution mass map of Abell 2744 within the ~ 1.8 Mpc$\times$1.8 Mpc reconstruction region to date, revealing the isosceles triangular structure with two legs of ~ 1 Mpc and a base of ~ 0.6 Mpc. Although our algorithm MAximum-entropy ReconStruction (${\tt MARS}$) is entirely blind to the cluster galaxy distribution, the resulting mass reconstruction remarkably well traces the brightest cluster galaxies with the five strongest mass peaks coinciding with the five most luminous cluster galaxies. We do not detect any unusual mass peaks that are not traced by the cluster galaxies, unlike the findings in previous studies. Our mass model shows the smallest scatters of SL multiple images in both source (~0".05) and image (~0".1) planes, which are lower than the previous studies by a factor of ~ 4. Although ${\tt MARS}$ represents the mass field with an extremely large number of ~ 300,000 free parameters, it converges to a solution within a few hours thanks to our utilization of the deep learning technique. We make our mass and magnification maps publicly available.Comment: 27 pages, 19 figures, 3 tables, Submitted to Ap

Conditional degradation of SDE2 by the Arg/N-End rule pathway regulates stress response at replication forks

Multiple pathways counteract DNA replication stress to prevent genomic instability and tumorigenesis. The recently identified human SDE2 is a genome surveillance protein regulated by PCNA, a DNA clamp and processivity factor at replication forks. Here, we show that SDE2 cleavage after its ubiquitin-like domain generates Lys-SDE2^(Ct), the C-terminal SDE2 fragment bearing an N-terminal Lys residue. Lys-SDE2^(Ct) constitutes a short-lived physiological substrate of the Arg/N-end rule proteolytic pathway, in which UBR1 and UBR2 ubiquitin ligases mediate the degradation. The Arg/N-end rule and VCP/p97^(UFD1-NPL4) segregase cooperate to promote phosphorylation-dependent, chromatin-associated Lys-SDE2^(Ct) degradation upon UVC damage. Conversely, cells expressing the degradation-refractory K78V mutant, Val-SDE2^(Ct), fail to induce RPA phosphorylation and single-stranded DNA formation, leading to defects in PCNA-dependent DNA damage bypass and stalled fork recovery. Together, our study elucidates a previously unappreciated axis connecting the Arg/N-end rule and the p97-mediated proteolysis with the replication stress response, working together to preserve replication fork integrity

With a little help from my friends?: Racial and gender differences in the role of social support in later-life depression medication adherence

Background: Social support has been shown to be an important factor in improving depression symptom outcomes, yet less is known regarding its impact on antidepressant medication adherence. This study sought to evaluate the role of perceived social support on adherence to new antidepressant medication prescriptions in later-life depression. Methods: Data from two prospective observational studies of participants ≥60 years old, diagnosed with depression, and recently prescribed a new antidepressant (N = 452). Perceived social support was measured using a subscale of the Duke Social Support Index and medication adherence was assessed using a validated self-report measure. Results: At four-month follow up, 68% of patients reported that they were adherent to antidepressant medication. Examining the overall sample, logistic regression analysis demonstrated no significant relationship between perceived social support and medication adherence. However, when stratifying the sample by social support, race, and gender, adherence significantly differed by race and gender in those with inadequate social support: Among those with low social support, African-American females were significantly less likely to adhere to depression treatment than white females (OR = 4.82, 95% CI = 1.14–20.28, p = 0.032) and white males (OR = 3.50, 95% CI = 1.03–11.92, p = 0.045). Conclusions: There is a significant difference in antidepressant medication adherence by race and gender in those with inadequate social support. Tailored treatment interventions for low social support should be sensitive to racial and gender differences.The National Institute of Mental Health (5R21MH073002)Veterans Affairs Health Services Research & Development (IIR 04-104-2)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152350/1/Gerlach Kavanagh Watkins Chiang Kim Kales 2017 with_a_little_help_from_my_friends_racial_and_gender_differences_in_the_role_of_social_support_in_laterlife_depression_medicat.pd

Managing suicidal ideation in a breast cancer cohort seeking reconstructive surgery

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135255/1/pon4017_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135255/2/pon4017.pd

Randomized controlled trial of a health plan-level mood disorders psychosocial intervention for solo or small practices

Background: Mood disorders represent the most expensive mental disorders for employer-based commercial health plans. Collaborative care models are effective in treating chronic physical and mental illnesses at little to no net healthcare cost, but to date have primarily been implemented by larger healthcare organizations in facility-based models. The majority of practices providing commercially insured care are far too small to implement such models. Health plan-level collaborative care treatment can address this unmet need. The goal of this study is to implement at the national commercial health plan level a collaborative care model to improve outcomes for persons with mood disorders. Methods/Design A randomized controlled trial of a collaborative care model versus usual care will be conducted among beneficiaries of a large national health plan from across the country seen by primary care or behavioral health practices. At discharge 344 patients identified by health plan claims as hospitalized for unipolar depression or bipolar disorder will be randomized to receive collaborative care (patient phone-based self-management support, care management, and guideline dissemination to practices delivered by a plan-level care manager) or usual care from their provider. Primary outcomes are changes in mood symptoms and mental health-related quality of life at 12 months. Secondary outcomes include rehospitalization, receipt of guideline-concordant care, and work productivity. Discussion This study will determine whether a collaborative care model for mood disorders delivered at the national health plan level improves outcomes compared to usual care, and will inform a business case for collaborative care models for these settings that can reach patients wherever they receive treatment. Trial registration ClinicalTrials.gov Identifier: NCT02041962; registered January 3, 2014

Taking Healthy Steps: rationale, design and baseline characteristics of a randomized trial of a pedometer-based internet-mediated walking program in veterans with chronic obstructive pulmonary disease

Abstract Background Low levels of physical activity are common in patients with chronic obstructive pulmonary disease (COPD), and a sedentary lifestyle is associated with poor outcomes including increased mortality, frequent hospitalizations, and poor health-related quality of life. Internet-mediated physical activity interventions may increase physical activity and improve health outcomes in persons with COPD. Methods/Design This manuscript describes the design and rationale of a randomized controlled trial that tests the effectiveness of Taking Healthy Steps, an Internet-mediated walking program for Veterans with COPD. Taking Healthy Steps includes an uploading pedometer, a website, and an online community. Eligible and consented patients wear a pedometer to obtain one week of baseline data and then are randomized on a 2:1 ratio to Taking Healthy Steps or to a wait list control. The intervention arm receives iterative step-count feedback; individualized step-count goals, motivational and informational messages, and access to an online community. Wait list controls are notified that they are enrolled, but that their intervention will start in one year; however, they keep the pedometer and have access to a static webpage. Discussion Participants include 239 Veterans (mean age 66.7 years, 93.7% male) with 155 randomized to Taking Healthy Steps and 84 to the wait list control arm; rural-living (45.2%); ever-smokers (93.3%); and current smokers (25.1%). Baseline mean St. George’s Respiratory Questionnaire Total Score was 46.0; 30.5% reported severe dyspnea; and the average number of comorbid conditions was 4.9. Mean baseline daily step counts was 3497 (+/- 2220). Veterans with COPD can be recruited to participate in an online walking program. We successfully recruited a cohort of older Veterans with a significant level of disability including Veterans who live in rural areas using a remote national recruitment strategy. Trial registration Clinical Trials.gov NCT01102777http://deepblue.lib.umich.edu/bitstream/2027.42/109506/1/12890_2014_Article_479.pd

Conditional degradation of SDE2 by the Arg/N-End rule pathway regulates stress response at replication forks

Multiple pathways counteract DNA replication stress to prevent genomic instability and tumorigenesis. The recently identified human SDE2 is a genome surveillance protein regulated by PCNA, a DNA clamp and processivity factor at replication forks. Here, we show that SDE2 cleavage after its ubiquitin-like domain generates Lys-SDE2^(Ct), the C-terminal SDE2 fragment bearing an N-terminal Lys residue. Lys-SDE2^(Ct) constitutes a short-lived physiological substrate of the Arg/N-end rule proteolytic pathway, in which UBR1 and UBR2 ubiquitin ligases mediate the degradation. The Arg/N-end rule and VCP/p97^(UFD1-NPL4) segregase cooperate to promote phosphorylation-dependent, chromatin-associated Lys-SDE2^(Ct) degradation upon UVC damage. Conversely, cells expressing the degradation-refractory K78V mutant, Val-SDE2^(Ct), fail to induce RPA phosphorylation and single-stranded DNA formation, leading to defects in PCNA-dependent DNA damage bypass and stalled fork recovery. Together, our study elucidates a previously unappreciated axis connecting the Arg/N-end rule and the p97-mediated proteolysis with the replication stress response, working together to preserve replication fork integrity

Optimizing veteran-centered prostate cancer survivorship care: study protocol for a randomized controlled trial

Abstract Background Although prostate cancer is the most common cancer among veterans receiving care in the Veterans Health Administration (VA), more needs to be done to understand and improve survivorship care for this large population. This study, funded by VA Health Services Research & Development (HSR&D), seeks to address the need to improve patient-centered survivorship care for veterans with prostate cancer. Methods/Design This is a two-armed randomized controlled trial (RCT) with a target enrollment of up to 325 prostate cancer survivors per study arm (total anticipated n = 600). Patients will be recruited from four VA sites. Patient eligibility criteria include age range of 40–80 years, one to ten years post-treatment, and currently experiencing prostate cancer symptom burden. We will compare the “Building Your New Normal” program, a personally-tailored automated telephone symptom management intervention for improving symptom self-management to usual care enhanced with a non-tailored newsletter about symptom management. Primary outcomes include changes in symptom burden, bother, and health services utilization at five and 12 months after enrollment. Secondary outcomes include long-term psychosocial outcomes (e.g. subjective health, perceived cancer control). We will use multivariable regression analysis to evaluate the impact of the intervention on primary and secondary outcomes. We will conduct a process evaluation to understand the effective intervention components and explore possibilities for broader implementation and dissemination. Discussion Our central hypothesis is that intervention group participants will have improved and more confident symptom self-management and prostate cancer quality of life following the intervention and that these outcomes will translate to more efficient use of health services. The study results will provide much needed information about how to optimize the quality of care, and life, of veteran prostate cancer survivors. Trial registration ClinicalTrials.gov ID NCT01900561 ; Registered on 22 July 2013.https://deepblue.lib.umich.edu/bitstream/2027.42/136600/1/13063_2017_Article_1925.pd