Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity

During macroautophagy, conjugation of ATG12 to ATG5 is essential for LC3 lipidation and autophagosome formation. Additionally, ATG12 has ATG5-independent functions in diverse processes including mitochondrial fusion and mitochondrial-dependent apoptosis. In this study, we investigated the regulation of free ATG12. In stark contrast to the stable ATG12–ATG5 conjugate, we find that free ATG12 is highly unstable and rapidly degraded in a proteasome-dependent manner. Surprisingly, ATG12, itself a ubiquitin-like protein, is directly ubiquitinated and this promotes its proteasomal degradation. As a functional consequence of its turnover, accumulation of free ATG12 contributes to proteasome inhibitor-mediated apoptosis, a finding that may be clinically important given the use of proteasome inhibitors as anticancer agents. Collectively, our results reveal a novel interconnection between autophagy, proteasome activity, and cell death mediated by the ubiquitin-like properties of ATG12

Association Between Cytokines and Liver Histology in Children with Nonalcoholic Fatty Liver Disease.

BackgroundReliable non-invasive markers to characterize inflammation, hepatocellular ballooning, and fibrosis in nonalcoholic fatty liver disease (NAFLD) are lacking. We investigated the relationship between plasma cytokine levels and features of NAFLD histology to gain insight into cellular pathways driving NASH and to identify potential non-invasive discriminators of NAFLD severity and pattern.MethodsCytokines were measured from plasma obtained at enrollment in pediatric participants in NASH Clinical Research Network studies with liver biopsy-proven NAFLD. Cytokines were chosen a priori as possible discriminators of NASH and its components. Minimization of Akaike Information Criterion (AIC) was used to determine cytokines retained in multivariable models.ResultsOf 235 subjects, 31% had "Definite NASH" on liver histology, 43% had "Borderline NASH", and 25% had NAFLD but not NASH. Total plasminogen activator inhibitor 1 (PAI1) and activated PAI1 levels were higher in pediatric participants with Definite NASH and with lobular inflammation. Interleukin-8 (IL-8) was higher in those with stage 3-4 fibrosis and lobular inflammation. sIL-2rα was higher in children with stage 3-4 fibrosis and portal inflammation. In multivariable analysis, PAI1 variables were discriminators of Borderline/Definite NASH, definite NASH, lobular inflammation and ballooning. IL-8 increased with steatosis and fibrosis severity; sIL-2rα increased with fibrosis severity and portal inflammation. IL-7 decreased with portal inflammation and fibrosis severity.ConclusionsPlasma cytokines associated with histology varied considerably among NASH features, suggesting promising avenues for investigation. Future, more targeted analysis is needed to identify the role of these markers in NAFLD and to evaluate their potential as non-invasive discriminators of disease severity

Immunomodulator expression in trophoblasts from the feline immunodeficiency virus (FIV)-infected cat

<p>Abstract</p> <p>Background</p> <p>FIV infection frequently compromises pregnancy under experimental conditions and is accompanied by aberrant expression of some placental cytokines. Trophoblasts produce numerous immunomodulators that play a role in placental development and pregnancy maintenance. We hypothesized that FIV infection may cause dysregulation of trophoblast immunomodulator expression, and aberrant expression of these molecules may potentiate inflammation and compromise pregnancy. The purpose of this project was to evaluate the expression of representative pro-(TNF-α, IFN-γ, IL-1β, IL-2, IL-6, IL-12p35, IL-12p40, IL-18, and GM-CSF) and anti-inflammatory cytokines (IL-4, IL-5, and IL-10); CD134, a secondary co-stimulatory molecule expressed on activated T cells (FIV primary receptor); the chemokine receptor CXCR4 (FIV co-receptor); SDF-1α, the chemokine ligand to CXCR4; and FIV gag in trophoblasts from early-and late-term pregnancy.</p> <p>Methods</p> <p>We used an anti-cytokeratin antibody in immunohistochemistry to identify trophoblasts selectively, collected these cells using laser capture microdissection, and extracted total RNA from the captured cell populations. Real time, reverse transcription-PCR was used to quantify gene expression.</p> <p>Results</p> <p>We detected IL-4, IL-5, IL-6, IL-1β, IL-12p35, IL-12p40, and CXCR4 in trophoblasts from early-and late-term pregnancy. Expression of cytokines increased from early to late pregnancy in normal tissues. A clear, pro-inflammatory microenvironment was not evident in trophoblasts from FIV-infected queens at either stage of pregnancy. Reproductive failure was accompanied by down-regulation of both pro-and anti-inflammatory cytokines. CD134 was not detected in trophoblasts, and FIV gag was detected in only one of ten trophoblast specimens collected from FIV-infected queens.</p> <p>Conclusion</p> <p>Feline trophoblasts express an array of pro-and anti-inflammatory immunomodulators whose expression increases from early to late pregnancy in normal tissues. Non-viable pregnancies were associated with decreased expression of immunomodulators which regulate trophoblast invasion in other species. The detection of FIV RNA in trophoblasts was rare, suggesting that the high rate of reproductive failure in FIV-infected queens was not a direct result of viral replication in trophoblasts. The influence of placental immune cells on trophoblast function and pregnancy maintenance in the FIV-infected cat requires additional study.</p

Positive Surgical Margins in the 10 Most Common Solid Cancers.

A positive surgical margin (PSM) following cancer resection oftentimes necessitates adjuvant treatments and carries significant financial and prognostic implications. We sought to compare PSM rates for the ten most common solid cancers in the United States, and to assess trends over time. Over 10 million patients were identified in the National Cancer Data Base from 1998-2012, and 6.5 million had surgical margin data. PSM rates were compared between two time periods, 1998-2002 and 2008-2012. PSM was positively correlated with tumor category and grade. Ovarian and prostate cancers had the highest PSM prevalence in women and men, respectively. The highest PSM rates for cancers affecting both genders were seen for oral cavity tumors. PSM rates for breast cancer and lung and bronchus cancer in both men and women declined over the study period. PSM increases were seen for bladder, colon and rectum, and kidney and renal pelvis cancers. This large-scale analysis appraises the magnitude of PSM in the United States in order to focus future efforts on improving oncologic surgical care with the goal of optimizing value and improving patient outcomes

GENDER EQUITY LANDSCAPE IN HIGHER EDUCATION DURING PANDEMIC YEARS: LINKING ORGANIZATIONAL PRACTICES TO TEACHERS’ MORALE AND PRODUCTIVITY

This study sought to ascertain how organizational strategies affected gender equity in a teacher’s morale and productivity among male, female, and nonbinary faculty at Jose Rizal Memorial State University, utilizing a descriptive correlational research design with the use of standardized tests. The frequency count, percent, mean, Chi-square, and Pearson R statistical tests were used to total, tabulate, and further analyze and interpret the results. The findings showed a substantial association, demonstrating how organizational practices have an effect on a teacher's level of morale. The organization may implement leadership development programs to prepare upcoming deans or associate deans for their positions. Organizational practices and faculty production in research were not significantly correlated, however there was a strong correlation between organizational practices and faculty productivity in instruction and community services. Gender equity within an organization can stimulate improvements in instruction and performance in extension but does not lead to research productivity among the faculty of the university. Thus, the deans and associate deans may include in their PPMP the purchase of classroom supplies, equipment, and other audio-visual aids and projection equipment. Furthermore, a staff may be hired in the college to assist the faculty with encoding, designing, and developing instructional materials. On the other hand, gender equality among university teachers does not result in increased productivity in research. The college may conduct action research to explore the factors that may affect the research productivity of the male, female, and nonbinary faculty. Furthermore, the proposed "Action Plan for Monitoring and Evaluating Gender Equity in Institutional Work Plans and Activities" may be utilized to sustain gender equity in educational institutions

Putting the PASS in Class: Peer Mentors’ Identities in Science Workshops on Campus and Online

In this paper, we analyse the introduction of peer mentors into timetabled classes to understand how in-class mentoring supports students’ learning. The peer mentors in this study are high-achieving students who previously completed the same course and who were hired and trained to facilitate Peer Assisted Study Sessions (PASS). PASS gives students the opportunity to deepen their understanding through revision and active learning and are typically held outside of class time. In contrast, our trial embedded peer mentors into classes for a large (~250 students) first-year workshop-based course. We employed a participatory action research methodology to facilitate the peer mentors’ co-creation of the research process. Data sources include peer mentors’ journal entries, student cohort data, and a focus group with teaching staff. We found that during face-to-face workshops, peer mentors role-modelled ideal student behaviour (e.g., asking questions) rather than acting as additional teachers, and this helped students to better understand how to interact effectively in class. The identity of embedded peer mentors is neither that of teachers nor of students, and it instead spans aspects of both as described using a three-part schema comprising (i) identity, (ii) associated roles, and (iii) associated practices. As we moved classes online mid-semester in response to the COVID-19 pandemic, mentors’ identities remained stable, but mentors adjusted their associated roles and practices, including through the technical aspects of their engagement with students. This study highlights the benefits of embedding mentors in classrooms on campus and online