p62/SQSTM1 is required for cell survival of apoptosis-resistant bone metastatic prostate cancer cell lines

BACKGROUND: Bone marrow stromal cell (BMSC) paracrine factor(s) can induce apoptosis in bone metastatic prostate cancer (PCa) cell lines. However, the PCa cells that escape BMSC-induced apoptosis can upregulate cytoprotective autophagy. METHODS: C4-2, C4-2B, MDA PCa 2a, MDA PCa 2b, VCaP, PC3, or DU145 PCa cell lines were grown in BMSC conditioned medium and analyzed for mRNA and/or protein accumulation of p62 (also known as sequestome-1/SQSTM1), Microtubule-associated protein 1 light chain 3B (LC3B), or lysosomal-associated membrane protein 1 (LAMP1) using quantitative polymerase chain reaction (QPCR), Western blot, or immunofluorescence. Small interfering RNA (siRNA) was used to determine if p62 is necessary PCa cell survival. RESULTS: BMSC paracrine signaling upregulated p62 mRNA and protein in a subset of the PCa cell lines. The PCa cell lines that were insensitive to BMSC-induced apoptosis and autophagy induction had elevated basal p62 mRNA and protein. In the BMSC-insensitive PCa cell lines, siRNA knockdown of p62 was cytotoxic and immunostaining showed peri-nuclear clustering of autolysosomes. However, in the BMSC-sensitive PCa cell lines, p62 siRNA knockdown was not appreciably cytotoxic and did not affect autolysosome subcellular localization. CONCLUSIONS: A pattern emerges wherein the BMSC-sensitive PCa cell lines are known to be osteoblastic and express the androgen receptor, while the BMSC-insensitive PCa cell lines are characteristically osteolytic and do not express the androgen receptor. Furthermore, BMSC-insensitive PCa may have evolved a dependency on p62 for cell survival that could be exploited to target and kill these apoptosis-resistant PCa cells in the bone

Gettysburg College Sustainability Proposal

In the fall of 2011, the Environmental Studies capstone class led by Professor Rutherford Platt was asked to write Gettysburg College’s first Sustainability Plan. The goal of the plan was to develop specific sustainable practices for the campus that were related to the three pillars of sustainability: economic, social, and environmental, and how integrating diligent sustainable practices into each of these respected pillars will result in a more conscious campus, community, and future. In 2010, Gettysburg College turned to the Sustainability Tracking Assessment and Rating System (STARS) to quantify the institution’s sustainability efforts, providing a self-check mechanism to encourage sustainability applications to all aspects of the College. The American College and University Presidents’ Climate Commitment was signed in 2007 by former Gettysburg College President Katherine Haley Will, declaring that Gettysburg College would become carbon neutral by 2032. Gettysburg College has made large strides in the search for sustainability, and aims to continue its dedication to furthering sustainable practice. The following plan outlines the six priority areas identified by the Capstone class: progress of the American College and University Presidents’ Climate Commitment, Dining Services, campus green space, community outreach, integration of sustainability into the Gettysburg College Curriculum, and the Sustainability Advisory Committee. The first priority area identified was monitoring and upholding the American College and University Presidents’ Climate Commitment (ACUPCC). Though creating new sustainability initiatives on campus is the driving force towards an increasingly sustainable college and community, it is imperative that these goals be carried out in full to maximize beneficial returns. In order to reach carbon neutrality, Gettysburg College hopes to increase energy efficiency in buildings, incorporate renewable energy sources on campus, and mitigate remaining emissions through the purchase of carbon offsets. To further the College’s progress, it is proposed that Gettysburg College continue its energy-efficient appliance purchasing policy, as well as create a policy to offset all greenhouse gas emissions generated by air travel for students study abroad. As stated by the ACUPCC, a Sustainability Committee should take responsibility for the updates and progress reports required to meet the goal of carbon neutrality. The second priority area identified was sustainability in Dining Services. Gettysburg College is home to 2,600 students, all of whom require three full meals a day. Dining Services accounts for a large fraction of Gettysburg College’s sustainability efforts, already implementing sustainability through composting, buying local produce, and using biodegradable products. The proposed on-campus sales cuts of non-reusable to-go items, a change in campus mentality on food waste, and improved composting practices will translate to an increasingly sustainable campus, as well as a well-fed campus body. The third priority was maintaining green space on campus. Ranked as the 23rd most beautiful campus in the United States by The Best Colleges, Gettysburg College utilizes campus green space to create an atmosphere that is conducive to activity as well as tranquility. The plan proposes that Gettysburg College and its grounds facilities continue their exceptional efforts, focusing on increasing the use of the student garden, creating a new rain garden or social area on campus, and converting unnecessary parking lots into green space. As these additions are completed, they must be introduced to the student body and faculty alike to assure these areas are known and utilized. The fourth priority was utilizing community outreach to spread awareness of sustainability initiatives on and off campus. To connect the sustainability-geared changes proposed in this plan, community outreach at Gettysburg College is assessed to estimate how well these initiatives are communicated and promoted to both potential and enrolled students, faculty, and other concerned parties. To evaluate the efficiency of communication at Gettysburg College, a quantitative assessment is presented to measure the ease of finding the sustainability webpage, the quality of sustainability-related topics available on the webpage, and quality of webpage design. The webpage is in need of improved text to image ratios, locations of sustainability topics, and data displays. Despite not having a link to the sustainability webpage on the Gettysburg College homepage, sustainability events should be covered and presented on the rotational news feed found on the homepage to maximize outreach to interested parties or simply to add to the definition of Gettysburg College. The fifth priority was integrating sustainability into the Curriculum to build a culture on campus that values academic rigor, supports students as they cultivate intellectual and civic passions, and promotes the development of healthy social relationships and behaviors. The proposed Sustainability Committee on Sustainability in the Curriculum (SCC) will hold sustainability workshops for faculty with the aim to instill sustainability into all academic disciplines, providing all Gettysburg graduates with a means to approach their professional careers in a fashion that is conscious of sustainability. The sixth and last priority was the Sustainability Advisory Committee. Established in 2007, the Sustainability Advisory Committee is currently under review, but it is recommended that the committee restructure itself in accordance with the new Sustainability Committee Bylaws. These bylaws aim to define the purposes, membership, governance, and involvement with the college. With a clearly defined set of goals and methodology, the Sustainability Advisory Committee will be able to improve the solidarity of the sustainability movement on campus as a whole. By following the propositions laid out in the Gettysburg College Sustainability Plan, the student body, faculty, and community alike will become a part of a multi-faceted progression toward a more sustainable future

Biological resurfacing in a canine model of hip osteoarthritis

[Figure: see text]

Concert recording 2017-04-23b

[Track 1]. Slowing down. I. Rotations in an emergency [Track 2]. II. Under the city [Track 3]. III. Forfeit [Track 4]. IV. Something comfortable to fall into / Jeremiah Flannery

Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice

Background: Cancer cachexia is largely irreversible, at least via nutritional means, and responsible for 20–40% of cancer-related deaths. Therefore, preventive measures are of primary importance; however, little is known about muscle perturbations prior to onset of cachexia. Cancer cachexia is associated with mitochondrial degeneration; yet, it remains to be determined if mitochondrial degeneration precedes muscle wasting in cancer cachexia. Therefore, our purpose was to determine if mitochondrial degeneration precedes cancer-induced muscle wasting in tumour-bearing mice. Methods: First, weight-stable (MinStable) and cachectic (MinCC) ApcMin/+ mice were compared with C57Bl6/J controls for mRNA contents of mitochondrial quality regulators in quadriceps muscle. Next, Lewis lung carcinoma (LLC) cells or PBS (control) were injected into the hind flank of C57Bl6/J mice at 8 week age, and tumour allowed to develop for 1, 2, 3, or 4 weeks to examine time course of cachectic development. Succinate dehydrogenase stain was used to measure oxidative phenotype in tibialis anterior muscle. Mitochondrial quality and function were assessed using the reporter MitoTimer by transfection to flexor digitorum brevis and mitochondrial function/ROS emission in permeabilized adult myofibres from plantaris. RT-qPCR and immunoblot measured the expression of mitochondrial quality control and antioxidant proteins. Data were analysed by one-way ANOVA with Student–Newman–Kuels post hoc test. Results: MinStable mice displayed ~50% lower Pgc-1α, Pparα, and Mfn2 compared with C57Bl6/J controls, whereas MinCC exhibited 10-fold greater Bnip3 content compared with C57Bl6/J controls. In LLC, cachectic muscle loss was evident only at 4 weeks post-tumour implantation. Oxidative capacity and mitochondrial content decreased by ~40% 4 weeks post-tumour implantation. Mitochondrial function decreased by ~25% by 3 weeks after tumour implantation. Mitochondrial degeneration was evident by 2 week LLC compared with PBS control, indicated by MitoTimer red/green ratio and number of pure red puncta. Mitochondrial ROS production was elevated by ~50 to ~100% when compared with PBS at 1–3 weeks post-tumour implantation. Mitochondrial quality control was dysregulated throughout the progression of cancer cachexia in tumour-bearing mice. In contrast, antioxidant proteins were not altered in cachectic muscle wasting. Conclusions: Functional mitochondrial degeneration is evident in LLC tumour-bearing mice prior to muscle atrophy. Contents of mitochondrial quality regulators across ApcMin/+ and LLC mice suggest impaired mitochondrial quality control as a commonality among pre-clinical models of cancer cachexia. Our data provide novel evidence for impaired mitochondrial health prior to cachectic muscle loss and provide a potential therapeutic target to prevent cancer cachexia

The Lantern, 2017-2018

On Dissociation • Untouchable • After Rocket Man • The Science Fair • Cardinal Rule at Stephen J. Memorial • Quentin & Sylvie • Cabello • The Get Out • Painting Day • Black, White and Grey • Family Pruning • How to Remove a Stain • Becoming Ourselves • Wonderbread U • Overture • Pescadero • Gross • Stage Fright • Lucky Daddy • Sarah • Rumble • Silvermine • The Green Iguana • A Poem for Ghost Children • A Poem for Lost Boys • Mother • Drop of Grease • Don\u27t Wanna be White • I • Amelia Earhart Disappeared Into My Vagina: An Ode to Cunts, Menstrual Cups and All Things Woman • Suburban Summer • Nightmares and Dreams Induced by My Mother • Teacups, Skins, etc. • Three Thoughts About My Bedroom • Dear Siri • 2 Queens (Beyonce in Reference to Sonia Sanchez) • Voyeurs • In Front of the Bathroom Mirror • To a Rose • Howl • Mice • Mirror • Language Accordion Volcano Mouth • Lucky Woman • Butterscotch • To Persephone • Wolf • Notes Never Passed • Topple • Bust • Kyoto • Identity • Sunflower • Tornabuoni Bubbles • Olympia • Decayed Hall • Perspectivehttps://digitalcommons.ursinus.edu/lantern/1186/thumbnail.jp

Association Between Whole Blood-Derived Mitochondrial Dna Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia)

Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection

Chronic infections are an increasing problem due to the aging population and the increase in antibiotic resistant organisms. Therefore, understanding the host-pathogen interactions that result in chronic infection is of great importance. Here, we investigate the molecular basis of chronic bacterial cystitis. We establish that introduction of uropathogenic E. coli (UPEC) into the bladders of C3H mice results in two distinct disease outcomes: resolution of acute infection or development of chronic cystitis lasting months. The incidence of chronic cystitis is both host strain and infectious dose-dependent. Further, development of chronic cystitis is preceded by biomarkers of local and systemic acute inflammation at 24 hours post-infection, including severe pyuria and bladder inflammation with mucosal injury, and a distinct serum cytokine signature consisting of elevated IL-5, IL-6, G-CSF, and the IL-8 analog KC. Mice deficient in TLR4 signaling or lymphocytes lack these innate responses and are resistant, to varying degrees, to developing chronic cystitis. Treatment of C3H mice with the glucocorticoid anti-inflammatory drug dexamethasone prior to UPEC infection also suppresses the development of chronic cystitis. Finally, individuals with a history of chronic cystitis, lasting at least 14 days, are significantly more susceptible to redeveloping severe, chronic cystitis upon bacterial challenge. Thus, we have discovered that the development of chronic cystitis in C3H mice by UPEC is facilitated by severe acute inflammatory responses early in infection, which subsequently are predisposing to recurrent cystitis, an insidious problem in women. Overall, these results have significant implications for our understanding of how early host-pathogen interactions at the mucosal surface determines the fate of disease

Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission

Abstract Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).</jats:p