POPULARITY
10 episodes with pcna
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6 episodes with pcna
Mary Furto of Counselor Top 40 supplier PCNA (asi/66887) gives an overview of several consumer trends to watch in the months to come, and presents promotional product ideas in line with those trends.
Hormones affect metabolism and heart health, and the changes throughout a woman's lifetime have long standing effects on cardiovascular disease. Guest Priya Vellanki, MD, MS discusses the importance of understanding reproductive history of patients including PCOS and gestational diabetes.PCNA article: Cardiovascular Health in Women: Beyond the Basics: https://pcna.net/cardiovascular-health-in-women-beyond-the-basics/See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
While you can't change your genetics, what you do can impact your risk for cardiovascular disease. Guest Mary Nejedly, RN, MS, NP-BC, discusses employee health programs, community presentations, and engagement strategies to help patients understand and improve their health.PCNA resource: CVD Screening Toolkit: https://pcna.net/clinical-resources/provider-tools/cvd-screening-toolkit/See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
Learn about the latest in remote monitoring strategies--including managing the additional data streams--for patients with heart failure and other diseases. Guest Kim Newlin, RN, CNS, ANP-C. BMAD trial: https://www.acc.org/Latest-in-Cardiology/Articles/2023/03/01/22/45/mon-830am-bmad-acc-2023Heart failure risk score: https://www.jacc.org/doi/10.1016/j.jchf.2023.09.014PCNA heart failure patient education: https://pcna.net/clinical-resources/patient-handouts/heart-failure-tools-and-handout/PCNA heart failure resources for HCPs: https://pcna.net/clinical-resources/provider-tools/heart-failure-provider-tools/PCNA professional development (search 'heart failure'): https://pcna.net/professional-development/online-learning/See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
What is the role of a nurse navigator--whether or not that is your job title? Guest Susan Bush, RN, BSN, CCRP, FPCNA, describes how these individuals can help patients with heart failure and other diseases find information, resources, support, and much more. PCNA heart failure resources for patients: https://pcna.net/clinical-resources/patient-handouts/heart-failure-tools-and-handout/PCNA heart failure resources for professionals: https://pcna.net/clinical-resources/provider-tools/heart-failure-provider-tools/American Association of Heart Failure Nurses: https://www.aahfn.org/See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
Team-based cared for patients with heart failures and related comorbidities is an effective management practice, helping support patients in both inpatient settings and beyond. Guest Anita Rich, DNP, RN, CHFN, CDCES, describes how to instill confidence in team members, be an effective change agent, and inspire hope in these complex patients. PCNA membership: https://pcna.net/member-center/join-pcna/Heart Failure Nurse Certification: https://www.aahfn.org/mpage/certificationboard2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001063See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
Why have we not found the cure for cancer yet? Neil deGrasse Tyson, Chuck Nice, and Gary O'Reilly explore paradigm shifts in cancer treatment, molecular biology, and a promising new cancer drug AOH1996 with City of Hope cancer researcher Dr. Linda Malkas. NOTE: StarTalk+ Patrons can listen to this entire episode commercial-free.Thanks to our Patrons Willie Bass, Nicholas A Jones, Edwin Goel, Joe Gibbs, Shane Alexander, Keith Goodman, and James Kuntz for supporting us this week.Photo Credit: Dr. Cecil Fox (Photographer), Public domain, via Wikimedia Commons
Today, we are talking with Neil about two fundamental priorities for Polyconcept: sustainability and how deeply sustainability permeates all of their decisions at PCNA, and technology through the lens of making distributors' lives easier.
Utilizing team- and patient-based care makes a significant impact on our patients, including those with hypertension and diabetes. Guest Thomas Hinneh, MScIH, BScN, RN, shares his experience and inspiration from his work in Ghana, with takeaways we all can utilize in clinical practice.PCNA diabetes tools for patients: https://pcna.net/clinical-resources/patient-handouts/diabetes-tools-and-handouts/PCNA diabetes resources for HCPs: https://pcna.net/clinical-resources/provider-tools/diabetes-provider-tools/PCNA hypertension tools for patients: https://pcna.net/clinical-resources/patient-handouts/hypertension-patient-tools-and-handouts/HI Foundation Ghana: https://hifoundationgh.org/ See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
The following question refers to Section 4.7 of the 2021 ESC CV Prevention Guidelines. The question is asked by student Dr. Shivani Reddy, answered first by NP Carol Patrick, and then by expert faculty Dr. Eileen Handberg.Dr. Handberg is an Adult Nurse Practitioner, Professor of Medicine, and Director of the Cardiovascular Clinical Trials Program in the Division of Cardiovascular Medicine at the University of Florida. She has served as Chair of the Cardiovascular Team Section and the Board of Trustees with the ACC and is the President Elect for the PCNA.The CardioNerds Decipher The Guidelines Series for the 2021 ESC CV Prevention Guidelines represents a collaboration with the ACC Prevention of CVD Section, the National Lipid Association, and Preventive Cardiovascular Nurses Association.Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #34 Ms. BW presents after her best friend was diagnosed with hypertension and is interested in measuring her own blood pressure. According to the ESC Guidelines, what BP screening approach is recommended for making a diagnosis of hypertension? ARepeated measurements in one visitBA single measurement in a single visitCRepeated measurements in more than one visit DReported patient history Answer #34 Explanation The correct answer is C – Repeated measurements in more than one visit.It is recommended to base the diagnosis of hypertension on repeated office BP measurements on more than one visit except when hypertension is severe (e.g., Grade 3—defined as SBP > 180 and/ or DBP >110mmHg—and especially in high-risk patients) (Class I, LOE C). In addition to recommending repeat measurements across visits, the guidelines provide a number of considerations for appropriately measuring blood pressure, such as taking measurements when seated in a quiet environment for 5 minutes and measuring in both arms at the first visit and using the higher-level value arm for visits thereafter (see Table 14 on page 3283).Additionally, home blood pressure monitoring is recommended as an alternative to repeated office measurements. Blood pressure measurements are taken with a semiautomated, validated cuff for 3 consecutive days – and 6-7 days being preferred – in the morning and at night, averaged over that period. Notably, home blood pressure thresholds for the diagnosis of hypertension are lower than for that of in-office measurements, with a daytime systolic of 135mmHg or diastolic of 85mmHg given as the level at which hypertension is diagnosed, as opposed to 140mmHg and 90mmHg for systolic and diastolic levels, respectively, given for in-office diagnosis.Main TakeawayWith the exception of those with severely elevated blood pressures, the diagnosis of hypertension requires repeated measurements across multiple office visits.Guideline Loc.Sections 4.7.1 and 4.7.2, Table 13 and 14, Figure 14 CardioNerds Decipher the Guidelines - 2021 ESC Prevention SeriesCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor RollCardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron!
This year, a renewed focus on operations, sourcing, and technology has emerged for suppliers. At skucamp in Austin, Texas, we held an interview on stage with three of the industry's largest supplier leaders: Neil Ringle, CEO at PCNA, Dan Pantano, President and CEO at alphabroder prime, and CJ Schmidt, President and CEO at Hit Promotional Products.
科學家們的早期研究發現，一種新藥物能殺死惡性實體腫瘤，而不傷害其它細胞。 這種新分子針對的是存在於大多數癌症中的一種蛋白質——增殖細胞核抗原（PCNA），它有助於腫瘤在體內生長和繁殖，在過去被認為是“不可成藥”靶點。 但這種藥物在實驗室中對70種不同的癌細胞進行了測試，包括來自乳腺癌、前列腺癌、腦癌、卵巢癌、宮頸癌、皮膚癌和肺癌的癌細胞; 被發現對這些癌細胞都有效。 該新葯是美國最大的癌症中心之一洛杉磯希望之城醫院（City of Hope Hospital）20年研發的結晶，代號為AOH1996，是以2005年死於致命性兒童癌症、年僅9歲的Anna Olivia Healy的名字命名的。 發表在《細胞化學生物學》雜誌上的最新研究顯示，這種新藥已在70多種癌細胞系和幾種正常人體細胞上進行了測試。 藥效分子通過破壞癌細胞的正常繁殖週期、阻止DNA受損細胞的分裂以及阻止有缺陷的DNA複製，來選擇性地殺死癌細胞。 該藥物目前正在希望之城進行第一期人體臨床試驗，由希望之城分子診斷和實驗治療系教授Linda 博士帶領研究團隊。 Linda 博士解釋了藥效分子如何選擇性地破壞癌細胞中的DNA複製和修復，而使健康細胞不受影響。 早在馬里蘭大學醫學院學習期間，Linda 博士遇到了安娜的父親，當時安娜正處於生命的最後階段。 Linda 博士正在研究乳腺癌，但安娜的父親問她是否可以為神經母細胞瘤（好發於兒童的惡性腫瘤）做點什麼，並給她的實驗室寫了一張2.5萬美元的支票。 Linda 博士說，那一刻改變了她的一生，她想為那個小女孩做一些特別的事情。 這也是該項研究命名的由來。 下一步，研究人員將進一步瞭解其作用機制，以改進正在進行的人體臨床試驗。
An estimated 8.5 million adults over the age of 40 have PAD, yet up to half have no symptoms. Guest Lola Coke, PhD, ACNS-BC, FAHA, FPCNA, FAAN, describes how the disease disproportionately impacts individuals who are Black, Latinx, and Native American, and how clinician awareness can make a positive difference in effective diagnosis and management.PAD Patient education tools (PCNA): https://pcna.net/clinical-resources/patient-handouts/peripheral-artery-disease-tools-and-handouts/PAD Screening Toolkit, Activity Program: https://pcna.net/clinical-resources/provider-tools/peripheral-artery-disease-provider-tools/See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.13.548953v1?rss=1 Authors: Kim, S., Kang, N., Ra, J. S., Park, S. H., Myung, K., Lee, K.-y. Abstract: Replication stresses are the major source of break-induced replication (BIR). Here, we show that in alternative lengthening of telomeres (ALT) cells, replication stress-induced polyubiquitinated PCNA (polyUb-PCNA) triggers BIR at telomeres and the common fragile site (CFS). Consistently, depleting RAD18, a PCNA ubiquitinating enzyme, reduces the occurrence of ALT-associated PML bodies (APBs) and mitotic DNA synthesis at telomeres and CFS, both of which are mediated by BIR. In contrast, inhibiting USP1, an Ub-PCNA deubiquitinating enzyme, results in an increase in the above phenotypes in a RAD18- and UBC13 (the PCNA polyubiquitinating enzyme)-dependent manner. Furthermore, deficiency of ATAD5, which facilitates USP1 activity and unloads PCNAs, augments recombination-associated phenotypes. Mechanistically, telomeric polyUb-PCNA accumulates SLX4, a nuclease scaffold, at telomeres through its ubiquitin-binding domain and increases telomere damage. Consistently, APB increase induced by Ub-PCNA depends on SLX4 and SLX4-associated nucleases. Taken together, our results identified the polyUb-PCNA-SLX4 axis as a trigger for directing BIR. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Stephanie Little, MSN, RNC-OB, C-EFM, examines cardio-obstetrics, a growing field focused on the link of CVD in patients who are pregnant, post-partum, or have had pregnancy-related health issues. The conversation also includes information about professional development throughout the nursing career, and a review of the importance of nutrition on heart health.PCNA CE Course: https://pcna.net/online-course/reducing-maternal-mortality-through-comprehensive-antenatal-and-postnatal-cardiovascular-care/PCNA online courses: https://pcna.net/professional-development/online-learning/See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
Hypertension prevention and management is a keystone strategy in reducing CVD risk globally, and guest Eileen Handberg, PhD, ANP-BC, FAHA, FACC, FPCNA, compels nurses to continue to play key leadership roles in this endeavor. Dr. Handberg also shares the importance of involvement in professional associations.PCNA patient ed tools: https://pcna.net/clinical-resources/patient-handouts/hypertension-patient-tools-and-handouts/AHA Blood Pressure Toolkit: https://www.heart.org/en/health-topics/high-blood-pressure/high-blood-pressure-toolkit-resourcesINVEST Trial: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2800790/See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
The following question refers to Section 4.6 of the 2021 ESC CV Prevention Guidelines. The question is asked by Student Dr. Shivani Reddy, answered first by Johns Hopkins Cardiology Fellow Dr. Rick Ferraro, and then by expert faculty Dr. Eileen Handberg. Dr. Handberg is an Adult Nurse Practitioner, Professor of Medicine, and Director of the Cardiovascular Clinical Trials Program in the Division of Cardiovascular Medicine at the University of Florida. She has served as Chair of the Cardiovascular Team Section and the Board of Trustees with the ACC and is the President for the PCNA. The CardioNerds Decipher The Guidelines Series for the 2021 ESC CV Prevention Guidelines represents a collaboration with the ACC Prevention of CVD Section, the National Lipid Association, and Preventive Cardiovascular Nurses Association. Question #22 Mr. HC is a 50-year-old man presenting for a routine clinic visit. He is not sure the last time he had a lipid panel drawn, and would like one today, but ate lunch just prior to your appointment – a delicious plate of 50% fruits and vegetables, 25% lean meats, and 25% whole grains as you had previously recommended. True or False: Mr. HC should return another day to obtain a fasting lipid panel. TRUE FALSE Answer #22 Answer choices TRUE FALSE Explanation This statement is False. A non-fasting lipid panel is appropriate for risk stratification and lipid evaluation in most patients per the ESC guidelines. While no level of evidence in provided in the ESC guidelines, this recommendation is consistent with AHA/ACC cholesterol guidelines, which have also largely moved away from fasting lipid panels for most patients and give a Class 1 (LOE B) recommendation to obtaining a fasting or nonfasting plasma lipid profile for ASCVD estimation and baseline LDL-C in adults 20 years of age or older. The ESC recommendation is based upon large trials showing that results of fasting and non-fasting panels are largely similar. This is similar to the AHA/ACC guidelines, which note non-fasting and fasting LDL-C change minimal over time following a normal meal, while HDL-C and tryiglycerides appear to have similar prognostic significance with cardiovascular outcomes in fasting or nonfasting states. A fasting lipid panel should be considered in those with hypertriglyceridemia, metabolic syndrome, and diabetes mellitus, as consumption of food or drink can have direct and immediate effects on TG and blood glucose values. Main Takeaway A non-fasting lipid panel is appropriate for the majority of patients undergoing lipid evaluation and cardiovascular risk stratification. Guideline Loc. Section 4.6.1 CardioNerds Decipher the Guidelines - 2021 ESC Prevention Series CardioNerds Episode Page CardioNerds Academy Cardionerds Healy Honor Roll CardioNerds Journal Club Subscribe to The Heartbeat Newsletter! Check out CardioNerds SWAG! Become a CardioNerds Patron!
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.21.537900v1?rss=1 Authors: Wen, B., Zheng, H.-X., Deng, D.-X., Zhang, Z.-D., Heng, J.-H., Liao, L.-D., Xu, L.-Y., Li, E.-M. Abstract: The translesion DNA synthesis (TLS) pathway mediated by proliferating cell nuclear antigen (PCNA) monoubiquitination is an essential mechanism by which cancer cells bypass DNA damage caused by DNA replication stress to maintain genomic stability and cell survival. Chromatin assembly factor 1 subunit A (CHAF1A) traditionally promotes histone assembly during DNA replication. Here, we revealed that CHAF1A is a novel regulator of the TLS pathway. High expression of CHAF1A is significantly associated with poor prognosis in cancer patients. CHAF1A promotes fork restart under DNA replication stress and maintains genome integrity. CHAF1A enhances the interaction between PCNA and E3 ubiquitin protein ligase RAD18 and promotes PCNA monoubiquitination, thereby promoting the recruitment of Y-family DNA polymerase Pol {eta} and enhancing cancer cell resistance to stimuli that trigger replication fork blockade. Mechanistically, CHAF1A-mediated PCNA monoubiquitination is independent of CHAF1A-PCNA interaction. CHAF1A interacts with both RAD18 and replication protein A2 (RPA2), mediating RAD18 binding on chromatin in response to DNA replication stress. Taken together, these findings improve our understanding of the mechanisms that regulate the TLS pathway and provide insights into the relationship between CHAF1A and the malignant progression of cancers. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Holly Brown and AJ Dickson of Top 40 supplier PCNA (asi/78897) talk about how the company's Proud Path initiative has grown in the last year and what they have in store for the future.
In this second of a three-part content series, in partnership with the Medical Alley, we explore the topic of advocacy for patients with obesity. Guests Starlin Haydon-Greatting and Garth Reynolds join Medical Alley's Frank Jaskulke to discuss the barriers to medical coverage for obesity treatment. This episode follows the first podcast, hosted by PCNA, which examined obesity's impacts on cardiovascular disease.Take this short survey to provide feedback on this episode (Thank you in advance): https://forms.gle/111fpVjWhpYEZZVs6See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.07.531331v1?rss=1 Authors: Pabba, M. K., Ritter, C., Chagin, V. O., Stear, J. H., Loerke, D., Kolobynina, K., Prorok, P., Schmid, A. K., Leonhardt, H., Rohr, K., Cardoso, M. C. Abstract: Chromatin has been shown to undergo diffusional motion, which is affected during gene transcription by RNA polymerase activity. However, the relationship between chromatin mobility and other genomic processes remains unclear. Hence, we set out to label the DNA directly in a sequence unbiased manner and followed labeled chromatin dynamics in interphase human cells expressing GFP-tagged PCNA, a cell cycle marker and core component of the DNA replication machinery. We detected decreased chromatin mobility during the S-phase compared to G1 and G2 phases using automated particle tracking. To gain insight into the dynamical organization of the genome during DNA replication, we determined labeled chromatin domain sizes and analyzed their motion in replicating cells. By correlating chromatin mobility proximal to the active sites of DNA synthesis, we showed that chromatin motion was locally constrained at the sites of DNA replication. Furthermore, inhibiting DNA synthesis led to increased loading of DNA polymerases. This was accompanied by accumulation of the single-stranded DNA binding protein on the chromatin and activation of DNA helicases further restricting local chromatin motion. We, therefore, propose that it is the loading of replisomes but not their catalytic activity that reduces the dynamics of replicating chromatin segments in the S-phase as well as their accessibility and probability of interactions with other genomic regions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.03.531045v1?rss=1 Authors: Adelman, J. W., Rosas, S., Schumacher, M., Mokry, R., Terhune, S. S., Ebert, A. Abstract: Human cytomegalovirus (HCMV) is a highly prevalent viral pathogen that typically presents asymptomatically in healthy individuals despite lifelong latency. However, in 10-15% of congenital cases, this beta-herpesvirus demonstrates direct effects on the central nervous system, including microcephaly, cognitive/learning delays, and hearing deficits. HCMV has been widely shown to infect neural progenitor cells, but the permissiveness of fully differentiated neurons to HCMV is controversial and chronically understudied, despite potential associations between HCMV infection with neurodegenerative conditions. Using a model system representative of the human forebrain, we demonstrate that induced pluripotent stem cell (iPSC)-derived, excitatory glutamatergic and inhibitory GABAergic neurons are fully permissive to HCMV, demonstrating complete viral replication, competent virion production, and spread within the culture. Interestingly, while cell proliferation was not induced in these post-mitotic neurons, HCMV did increase expression of proliferative markers Ki67 and PCNA suggesting alterations in cell cycle machinery. These finding are consistent with previous HCMV-mediated changes in various cell types and implicate the ability of the virus to alter proliferative pathways to promote virion production. HCMV also induces significant structural changes in forebrain neurons, such as the formation of syncytia and retraction of neurites. Finally, we demonstrate that HCMV disrupts calcium signaling and decreases neurotransmission, with action potential generation effectively silenced after 15 days post infection. Taken together, our data highlight the potential for forebrain neurons to be permissive to HCMV infection in the CNS, which could have significant implications on overall brain health and function. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Medical Alley and the Preventive Cardiovascular Nurses Association have partnered on a three-part content series focusing on obesity . In this first podcast episode, hosted by PCNA, Dr. Erin Ferranti joins host Geralyn Warfield to discuss the impacts obesity has on cardiovascular disease, and also examines the roles that social determinants of health play. The second podcast will include a patient and a healthcare provider for a discussion on advocacy for patients with obesity. Be sure to register for a webinar March 2, which will conclude the three-part content series. That webinar will focus on obesity's impact on mental health. Learn more or register at medicalalley.org.
In this second of a three-part content series, in partnership with the Preventive Cardiovascular Nurses Association, we explore the topic of advocacy for patients with obesity. Guests Starlin Haydon-Greatting and Garth Reynolds join our Frank Jaskulke to discuss the barriers to medical coverage for obesity treatment. This episode follows the first podcast, hosted by PCNA, which examined obesity's impacts on cardiovascular disease. Be sure to register for our webinar on March 2, which is the culmination of this series on obesity. The topic of obesity's impact on mental health will be explored by our panel of experts. Learn more and register at medicalalley.org.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.23.529672v1?rss=1 Authors: Yang, Y., Yu, C., Le, Y., Gong, W., Ju, J., Zhang, G., Ji, P., Zuo, R., Liu, Z., Zhang, P., Hou, R., Fu, Y. Abstract: Proliferation and migration of epidermal stem cells (EpSCs) are essential for epithelialization during skin wound healing. Angiopoietin-like 4 (ANGPTL4) has been reported to play an important role in wound healing, but the mechanisms involved are not fully understood. Here we investigate the contribution of ANGPTL4 to full-thickness wound re-epithelialization and the underlying mechanisms using Angptl4 knockout mice. Immunohistochemical staining reveals that ANGPTL4 is significantly upregulated in the basal layer cells of the epidermis around the wound during cutaneous wound healing. ANGPTL4 deficiency impairs wound healing. H & E staining shows that ANGPTL4 deficiency significantly reduces the thickness, length and area of regenerated epidermis postwounding. Immunohistochemical staining for markers of EpSCs (alpha 6 integrin and beta 1 integrin) and cell proliferation (PCNA) shows that the number and proliferation of EpSCs in the basal layer of the epidermis are reduced in ANGPTL4-deficient mice. In vitro studies show that ANGPTL4 deficiency impedes EpSC proliferation, causes cell cycle arrest at the G1 phase and reduced the expression of cyclins D1 and A2, which can be reversed by ANGPTL4 overexpression. ANGPTL4 deletion suppresses EpSC migration, which is also rescued by ANGPTL4 overexpression. Overexpression of ANGPTL4 in EpSCs accelerates cell proliferation and migration. Collectively, our results indicate that ANGPTL4 promotes EpSCs proliferation by upregulating cyclins D1 and A2 expression and accelerating cell cycle transition from G1 to S phase, and ANGPTL4 promotes skin wound re-epithelialization by stimulating EpSC proliferation and migration. Our study reveals a novel mechanism underlying EpSC activation and re-epithelialization during cutaneous wound healing. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.21.529372v1?rss=1 Authors: Han, Y., Liu, Y., Tian, X., Zhang, X., Liu, D., Yan, C. Abstract: Aortic aneurysm (AA) is a potentially fatal disease with the possibility of rupture, causing high mortality rates with no effective drugs for the treatment of AA. The mechanism of AA, as well as its therapeutic potential to inhibit aneurysm expansion, has been minimally explored. Small non-coding RNA (miRNAs and miRs) is emerging as a new fundamental regulator of gene expression. This study aimed to explore the role and mechanism of miR-193a-5p in abdominal aortic aneurysms (AAA). In AAA vascular tissue and Angiotensin II (Ang II)-treated vascular smooth muscle cells (VSMCs), the expression of miR-193a-5 was determined using real-time quantitative PCR (RT-qPCR). Western blotting was used to detect the effects of miR-193a-5p on PCNA, CCND1, CCNE1, and CXCR4. To detect the effect of miR-193a-5p on the proliferation and migration of VSMCs, CCK-8, and EdU immunostaining, flow cytometry, wound healing, and Transwell Chamber analysis were performed. In vitro results suggest that overexpression of miR-193a-5p inhibited the proliferation and migration of VSMCs, and its inhibition aggravated their proliferation and migration. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.17.529005v1?rss=1 Authors: He, H., Yang, J., He, Y., Li, Z., Fu, C., Zhang, D., Li, M., Lu, A., Dong, J., Liu, J., Gu, H., Shen, S. Abstract: Ulva prolifera is the dominant species of "green tide", and has higher tolerance to environmental stresses such as temperature. However, the molecular mechanisms are still unclear. Here, transcriptome analysis, Western blot and RT-qPCR analysis of U. prolifera suggested that, under temperature stresses (4{degrees}C, 36{degrees}C), the expression of PCNA and CyclinA was promoted, and the MAPK signaling was activated. Besides, the results showed that PCNA interacted with CyclinA. Interestingly, the expression of miR-2916, which was predicted to bind PCNA at -552~-772, was negatively correlated with the expression of PCNA under temperature stresses (4{degrees}C, 36{degrees}C). In addition, the results showed that low temperature (4{degrees}C) had no obvious effect on the survival, the formation of cell walls, and the division of protoplasts. However, high temperature (36{degrees}C) had obvious effect on them. PCNA inhibitors increased the sensitivity of the protoplasts under temperature stresses. Together, our results suggested PCNA regulating the proliferation in response to the temperature stress of U. prolifera was associated with miR-2916/PCNA/CyclinA/MAPK pathway. In conclusion, the study preliminarily illuminates the molecular mechanism in response to temperature stress of U. prolifera, and may provide a new insight for prevention of green tide. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
At skucamp, the leaders of three of the industry's largest suppliers joined Catherine Graham, commonsku's Co-founder and CEO on stage to answer audience questions and discuss the state of the industry now and their perspective on the future. The panel featured David Nicholson - Vice Chairman at PCNA, Dan Pantano, President & CEO at AlphaBroder Prime, and Jonathan Isaacson, Chairman, and CEO at Gemline.
VIDEOS: EXCLUSIVE: UNDERTAKER EXPLAINS “MYSTERIOUS” CLOTTING PHENOMENON! | Louder with Crowder (part 2) Society is going to COLLAPSE -Neil Oliver ( 5:24) Fear Psychosis and the Cult of Safety – Why are People so Afraid? – Academy of Ideas (13:25) Dietary supplement found to improve concentration levels University of Granada, November 3, 2022 The research group from the University of Granada (UGR) has tested the effects of a multi-ingredient dietary nootropic on concentration levels and cognitive performance. Nootropics are cognitive enhancers that have traditionally been used in the treatment of cognitive pathologies. Leading this study was Lucas Jurado Fasoli—a researcher from the Scientific Unit of Excellence in Exercise, Nutrition and Health (UCEENS) at the Sport and Health Joint University Institute (iMUDS). He explains that, traditionally, nootropics have been drugs, with their corresponding side-effects. “To address the issue of potential side-effects, different dietary nootropics have emerged as an alternative way to enhance cognitive performance. And these, as is the case in this study, are used by healthy individuals in activities such as preparing for competitive exams or video-game competitions,” explains Jurado Fasoli. The results of the study showed that the acute intake of this multi-ingredient nootropic decreases the response time across different cognitive tests: in processing speed, inhibitory control, working memory, and cognitive flexibility. It also increases accuracy in tests involving processing speed, inhibitory control, and cognitive flexibility. The supplement contains L-tyrosine, acetyl L-carnitine, sodium citicoline, alpha-GPC, taurine, caffeine, mango leaf extract and huperzia serrata leaf. These results were accompanied by an increase in positive emotions and a decrease in negative emotions and depression. And, importantly, the favorable effects of this nootropic did not appear to have any effect on the heart-rate of participants. Previous studies have shown that supplementation with the combination of caffeine and taurine, L-theanine, tyrosine, and mango leaves extract can improve the RT in different cognitive and computerized tests. In this study, we showed that a dietary multi-ingredient nootropic improves the processing speed of information in young healthy adults. This effect could be due to the synergic effects of different dietary ingredients included in the nootropic. Also, it could be partially explained by the central nervous system activation and alertness enhancement effect of caffeine, which could increase the processing speed and decrease the RT. The inclusion of L-theanine as a dietary ingredient in the nootropic counteracts the potential effects derived from a high dose of caffeine on anxiety, psychological stress, blood pressure, and HR, which completely agrees with our results. A sample comprising 26 young adults (50:50 male/female, with an average age of 25) participated in the study. They were required to undertake various cognitive tests twice, separated by 48 hours, having ingested either the multi-ingredient dietary nootropic or a placebo (randomized and triple-blinded across the sample). Thirty minutes after ingestion, measurements were taken of processing speed, inhibitory control, working memory, cognitive flexibility, creativity, and verbal fluency. Different emotions were also evaluated and the participants' heart-rate was recorded while they undertook the tests. Consuming more magnesium associated with lower risk of mortality during years following heart attack Wageningen University and Research (Netherlands), October 31, 2022 A study of people with a history of heart attack found that those who consumed more magnesium lived longer than those whose intake was low. Having a high magnesium intake, defined as greater than 320 milligrams (mg) per day, was associated with a 28% lower risk of dying from cardiovascular disease and a 22% lower risk of death from any cause compared to a low intake, defined as less than 283 mg per day. The protective effect of magnesium was even stronger in patients who were being treated with diuretic drugs. In this group, the risk of mortality from cardiovascular disease was 45% lower among those with high magnesium compared to those with low magnesium. “Little is known about magnesium intake and long-term mortality risk in cardiovascular disease patients,” authors Ilse Evers and colleagues noted. “Magnesium requirements may be different in cardiovascular disease patients because of alterations in the cardiovascular system, comorbidities and/or medication use.” The study included 4,365 participants in the Alpha Omega Cohort, an ongoing follow-up of participants in the earlier 40-month Alpha Omega Trial. The Alpha Omega Trial included men and women between the ages of 60 and 80 years who had experienced a heart attack within 10 years prior to enrolling between 2002 and 2006. Dietary questionnaire responses obtained at enrollment provided information concerning magnesium intake from food and non-food sources. Mortality was ascertained through 2018. The findings were published in Frontiers in Cardiovascular Medicine. Calorie restriction promotes longevity through effects on mitochondrial network Harvard School of Public Health, October 27 2022. Research reported in Cell Metabolism helps explain the effects of calorie restriction and activation of AMP-activated protein kinase (AMPK, an energy-sensing protein) on longevity. Harvard researchers have determined that AMPK and calorie restriction promote homeostasis and plasticity of networks formed by the cells' power plants known as mitochondria. Mitochondria networks change shape according to energy demand, however, this ability declines with age. “Dynamic remodeling of mitochondrial networks by fusion and fission promotes maintenance of cellular homeostasis,” explain Heather J. Weir and colleagues at the Harvard T. H. Chan School of Public Health. “Dysregulation of mitochondrial dynamics and aberrant mitochondrial morphology are hallmarks of aging and are thought to contribute to the pathology of numerous age-related pathologies including Alzheimer's and Parkinson's disease.” By restricting calories in the diet of roundworms or using a strain of roundworm in which an AMPK subunit is activated, the researchers found that the roundworms maintained a youthful fused mitochondrial network shape with age. The youthful networks lengthen life by communicating with peroxisomes within the cells to alter fat metabolism. “Low-energy conditions such as dietary restriction and intermittent fasting have previously been shown to promote healthy aging,” Dr Weir commented. “Our work shows how crucial the plasticity of mitochondria networks is for the benefits of fasting. If we lock mitochondria in one state, we completely block the effects of fasting or dietary restriction on longevity.” Electroacupuncture found to ease nausea and vomiting in ICU patients recovering from chemotherapy Narbonne Hospital (France), October 28, 2022 Refractory vomiting is just one of many complications endured by patients confined to intensive care units (ICU) due to chemotherapy and other major medical treatments. But relief may be coming in the form of transcutaneous electroacupuncture (TEA) therapy that can alleviate the worst symptoms of persistent vomiting. Earlier studies have shown that TEA can reduce episodes of nausea and vomiting attributed to chemotherapy treatments, recently concluded medical operations, and pregnancy. It is growing popular as an alternative to anti-emetic medication. The TEA treatment consisted of two electrodes attached on either side of the Neiguan (PC 6) pressure point, also known as the pericardium meridian. The researchers employed a standard neuromuscular transmission monitor to stimulate the acupuncture point for 30 minutes. The overall incidence of nausea or vomiting within the first 24 hours after TEA was 50 percent. After the 24-hour mark, 30 percent of the patients perceived nausea, and 20 percent experienced vomiting. Ninety percent of patients reported suppression of nausea/vomiting immediately after undergoing TEA. During a six-hour period after TEA, 60 percent of patients did not sense nausea or experience vomiting. Between six to 24 hours after TEA, 60 percent of patients remained free from nausea or vomiting episodes. Two patients who experienced nausea were given a second TEA session that remedied all symptoms.TEA itself was free from any complication and side effects. The Mindfulness Skill That Is Crucial for Stress A new study suggests that practicing acceptance helps reduce our stress more than simple mindful awareness. Carnegie Mellon University, October 28, 2022 In this study, researchers randomly assigned 137 stressed adults of various ages and ethnicities to one of three programs: an eight-week Mindfulness-Based Stress Reduction (MBSR) course, where they learned to mindfully pay attention to their present-moment experiences in an accepting, nonjudgmental way; an MBSR course without instructions on acceptance; or no course. The courses included many lessons—for example, how to pay attention to your breath and your body sensations, and how to eat food or take a walk mindfully—as well as practice time outside of class. Before, during, and afterwards, participants reported five times daily about how stressed they felt in the moment and whether they'd experienced a stressful event since their last report.In response to stress, many people today are turning to meditation or mindfulness apps (myself included). But not all mindfulness practice is equally effective for combating stress, a new study suggests. It's possible that some of our practices may be missing a vital ingredient: acceptance. Though all of the groups experienced less stress and fewer incidents of feeling stressed over time, the people who took the full MBSR course had a significantly steeper improvement than the other two groups. “Learning how to accept your present-moment experience is really important for reducing stress,” says Emily Lindsay, one of the study's coauthors. “It seems to be a key element of mindfulness training.” Mindfulness practices that specifically emphasize acceptance teach us a nonjudgmental attitude toward our experiences—meaning, learning not to label our thoughts, feelings, or experiences as good or bad, and trying not to change or resist them in any way. While many mindfulness courses include instructions in acceptance as par for the course, those that don't may not be as effective. People who learn to accept and not just notice their experiences become less prone to mind-wandering, which has been tied to well-being, and less reactive to stress—meaning, they show reductions in systolic blood pressure, the stress hormone cortisol, and feelings of stress in a stressful situation. Her recent study adds to these results by monitoring participants daily, helping to show that acceptance makes a difference in everyday life situations and not just in the laboratory. Accepting stress helps people to stop focusing only on what's wrong and to notice other feelings, sensations, and thoughts occurring at the same time, enabling them to see the “bigger picture.” Acceptance is not about acquiescing to your fate, though —like getting a diagnosis of a terminal illness and just accepting that you're going to die. That kind of “acceptance” leads to worse outcomes. Nor is it about accepting poor treatment from other people. It's more about accepting your internal experience—your thoughts and feelings—which informs you about how to respond to your external circumstances in a wiser way. For example, if you feel angry and accept your anger in the moment, it may prevent you from lashing out at someone and help you see that your feelings aren't their fault Eat more trifoliate oranges to keep your prostate healthy Korean Institute of Oriental Medicine, October 26, 2022 Compared to younger individuals, older men are at a higher risk of developing benign prostatic hyperplasia (BPH) or an enlarged prostate. A study published in the journal BMC Complementary and Alternative Medicine reveals a compelling reason for men to eat trifoliate oranges, as extracts from the fruit were proven effective in preventing the onset of BPH and cease its progression. The trifoliate orange (Poncirus trifoliata), also known as the hardy orange, is a citrus fruit native to China. It is grown in parts of the US and Europe for use in jellies, marmalades, and jams despite its notoriously bitter taste. It has been used as an ingredient in Traditional Chinese Medicine since ancient times, and current studies have shown its importance in maintaining prostate health. As the word “benign” in its name implies, BPH is relatively harmless. In fact, some consider it a normal part of the aging process among males. It can, however, be extremely inconvenient as its symptoms can make the vital act of urinating difficult. It can also cause a constant feeling of needing to pee even at night; in most cases, sufferers may find themselves unable to sleep properly because of this particular symptom. The researchers in the aforementioned looked at the trifoliate orange as a possible treatment for BPH. In particular, the study investigated the extract from Ponciri Fructus (PFE), the young fruit of the trifoliate orange, and its protective effects on the development of the BPH. In the study, the researchers induced BPH in a rat model by injecting testosterone propionate (TP) and corn oil every day for four weeks. PFE was administered via oral gavage at a dose level of 200 mg/kg, one hour before these injections over the same duration. At the end of the study, the rats were sacrificed and examined for markers of BPH. Specifically, the researchers took note of relative prostate weight, the levels of testosterone and dihydrotestosterone (DHT), common factors influencing the development of BPH. At the end of the study, the researchers noticed reductions in relative prostate weight, the level of testosterone and DHT in serum and prostatic tissue, prostatic hyperplasia, and the expression of PCNA. They also noted higher levels of antioxidant enzymes.
Episode 307 - Lotus is joined by the special guest ManCaveGaming to discuss the grand return of Cyrodiil PvP with the hardware update to PCNA datacenters and what it entails for the PvP community! | Timestamps: 00:00(Intro) - 02:45(Cyrodiil Discussion) - 45:00(Tales) An action-packed show full of game news, tales, opinions, and listener emails for The Elder Scrolls Online by Zenimax Online Studios! And remember, if you'd like to send in your own letter to the show email us directly at TalesofTamrielPodcast@gmail.com! If you wish to support Tales of Tamriel, consider supporting us over at our Patreon Page, Patreon.com/UESP! You can also support us by leaving us a review on iTunes, or by telling a friend about us! We hope you enjoyed this episode of Tales of Tamriel and be sure to come back next week! Learn more about your ad choices. Visit megaphone.fm/adchoices
The following question refers to Section 4.6 of the 2021 ESC CV Prevention Guidelines. The question is asked by student Dr. Shivani Reddy, answered first by NP Carol Patrick, and then by expert faculty Dr. Eileen Handberg. Dr. Handberg is an Adult Nurse Practitioner, Professor of Medicine, and Director of the Cardiovascular Clinical Trials Program in the Division of Cardiovascular Medicine at the University of Florida. She has served as Chair of the Cardiovascular Team Section and the Board of Trustees with the ACC and is the President Elect for the PCNA. The CardioNerds Decipher The Guidelines Series for the 2021 ESC CV Prevention Guidelines represents a collaboration with the ACC Prevention of CVD Section, the National Lipid Association, and Preventive Cardiovascular Nurses Association. Question #10 Ms. DW is a 67-year-old woman with a history of coronary artery disease and prior percutaneous coronary intervention in 2019 with a drug-eluting stent to the proximal left anterior descending artery. They have transitioned to your clinic from a previous provider, and their LDL is 134 mg/dL. What would be the ESC recommended goal LDL-C level for this patient? A.
The Top 40 supplier launched ProudPath this week, which it is hoping will be a comprehensive, turnkey platform that will help promo distributors communicate their environmental and social efforts with confidence.
In this episode of Hello, Print Friend Miranda speaks with Paul Mullowney, a Master Printer and professor at PCNA. We'll talk about his familial ties to printmaking. Big names like Sol le Wit, John Cage, and Kathan Brown to name a few, traveling around the world through printmaking, weathering the storms of recessions, and giving back to the community you belong to. The Mullowney Printing Company Website http://www.mullowneyprinting.com Mullowney Printing Instagram https://www.instagram.com/mullowneyprinting/?hl=en Shop Talk www.patreon.com/helloprintfriend YOUTUBE www.youtube.com/channel/UCOMIT3guY5PjHj1M7GApouw MERCH www.teepublic.com/user/helloprintfriend WEBSITE www.helloprintfriend.com instagram www.instagram.com/helloprintfriend print gallery helloprintfriend.com/print-gallery ✨patreon✨ www.patreon.com/helloprintfriend Our sponsor Speedball www.speedballart.com
In this week's cover paper of Oncotarget (Volume 12, Issue 12), entitled, "Frame-shift mediated reduction of gain-of-function p53 R273H and deletion of the R273H C-terminus in breast cancer cells result in replication-stress sensitivity," researchers used the CRISPR-Cas9 tool to analyze a p53 mutation in triple-negative breast cancer. The researchers from the City University of New York, Columbia University, and Weill Cornell Medical College wrote that both the C-terminal domain (CTD) and oligomerization domain (OD) of mtp53 R273H proteins are intact, and it is not clear if these regions are responsible for chromatin-based DNA replication activities. To examine the ability of mtp53 R273H to influence cell proliferation, DNA replication, and cell cycle progression of breast cancer cells, the researchers used the CRISPR-Cas9 tool to edit the C-terminal regions of the mtp53 gene. “CRISPR-Cas9 sgRNA editing of the C-terminal regions of the endogenous mtp53 gene were carried out so as to delete gene sequences that correspond to the OD and CTD regions.” The team generated breast cancer cells and edited CTD and OD regions of mtp53 R273H using the CRISPR-Cas9 tool. They then treated the cell populations with thymidine—to block cells at G1/S phase in the cell cycle. The researchers then compared the status and proliferation of the variants with the original cell line and observed changes in total cell lysates by western blot analysis. “We examined how changes in the level of mtp53 R273H level and/or deletion of the CTD, or OD plus CTD, region influenced cell proliferation, cell cycle progression, and chromatin association of mtp53, RPA, PCNA and MCM2.” Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.27975 DOI - https://doi.org/10.18632/oncotarget.27975 Full text - https://www.oncotarget.com/article/27975/text/ Correspondence to - Jill Bargonetti - bargonetti@genectr.hunter.cuny.edu Keywords - mutant p53, gain-of-function, oligomerization, DNA replication, frame-shift, breast cancer About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget YouTube - https://www.youtube.com/c/OncotargetYouTube/ LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957
It's Friday morning which means it's time for your weekly dose of the Promo UPFront Podcast with Kirby Hasseman and Bill Petrie! This week the Majors of Mezcal talk about FedEx entering the world of promotional products (sort of), work from home injuries, Untuckit's partnership with PCNA, Miller Lite's genius “Vax Time Tees,” Norm Hullinger leaving alphabroder for Bella+Canvas, an epic “Party in the Back” where Kirby explores Bill's bizarre love of footwear, and so much more! A huge thanks to one of the true innovators in the industry for sponsoring this fine broadcast: PromoPulse!
Pedro Mota is Vice President, Marketing, for Porsche Cars North America, Inc. (PCNA), headquartered in Atlanta. PCNA is the exclusive U.S. importer of the Porsche 911, 718 Boxster and 718 Cayman; Panamera; Cayenne, and Macan. In this exclusive video, Hagerty will sit down with Mota to discuss his love of cars, what’s on the horizon for PCNA, and where he’s driving to next.
Kim Newlin! Kim Newlin is currently practicing as a Cardiovascular Clinical Nurse Specialist and Adult Nurse Practitioner at Sutter Roseville Medical Center in Roseville, California. She first earned a BS in Exercise Physiology at University of California at Davis, then completed the RN and CNS program at the University of California, San Francisco, and the Gerontology/Adult Nurse Practitioner post-master's program through the University of Massachusetts at Boston. Kim is the Director of Cardiovascular Services, which includes oversight of the Cath Lab, Interventional Radiology, Cardiac and Pulmonary Rehab and the Heart Health Clinic. She continues to see patients in the Heart Health clinic which she established in 2011. Kim developed the first Care Transitions Program in the Sutter Sacramento region, both of which have significantly improved the patient experience during the transition home and reduced readmissions back to the hospital by focusing on improving medication reconciliation, creating a realistic transitional care plan and helping patients and families obtain the appropriate post acute care. She also mentors new and seasoned nurses and works on a variety of process improvement programs within the hospital and the region. Kim's Three Tips for Aging Thoughtfully: 1. Move every day. It doesn't need to be fancy. You don't need expensive clothes – you don't need to go to the gym. Just make it a priority. Fit it into your day however you have to. It doesn't need to be more than 30 minutes, and it's really never too late to start. So, if you don't do anything now – anything more than you're doing now is better. 2. Choose to be a mindful eater. From everything to when you're buying the food, to when you're making your meals and when you are putting it in your mouth. Realizing that food becomes a part of you and can make all the difference in your daily energy, your mood, your weight and really your health. 3. Find a daily stress relief that does not cost money or require you to travel. Kim mentions the book: Salt, Fat, Acid, Heat: Mastering the Element of Good Cooking Heart Healthy Links from Kim! There is not a lack of literature out there, so I recommend talking to a health care professional and doing some reading on trustworthy sites with good, easy to read information: (CDC, https://www.cdc.gov/nutrition/index.html and PCNA: https://pcna.net/clinical-resources/patient-handouts/heart-healthy-toolbox/ Two good articles with a lot of research are: https://www.onlinejacc.org/content/69/9/1172: Trending Cardiovascular Nutrition Controversies https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2018/07/25/13/51/a-clinicians-guide-for-trending-cardiovascular-nutrition: Cardiovascular Nutrition: Current Controversies Physical Activity Guidelines: https://www.hhs.gov/fitness/be-active/physical-activity-guidelines-for-americans/index.html --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app Support this podcast: https://anchor.fm/agethoughtfully/support
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.11.247064v1?rss=1 Authors: Li, M., Sengupta, B., Benkovic, S. J., Lee, T. H., Hedglin, M. Abstract: Translesion DNA synthesis (TLS) enables DNA replication through damaging modifications to template DNA and requires monoubiquitination of the PCNA sliding clamp by the Rad6/Rad18 complex. This posttranslational modification is critical to cell survival following exposure to DNA damaging agents and is tightly regulated to restrict TLS to damaged DNA. RPA, the major single strand DNA (ssDNA) binding protein, forms filaments on ssDNA exposed at TLS sites and plays critical yet undefined roles in regulating PCNA monoubiquitination. Here, we utilize kinetic assays and single molecule FRET microscopy to monitor PCNA monoubiquitination and Rad6/Rad18 complex dynamics on RPA filaments, respectively. Results reveal that a Rad6/Rad18 complex is recruited to an RPA filament via Rad18-RPA interactions and randomly translocates along the filament. These translocations promote productive interactions between the Rad6/Rad18 complex and the resident PCNA, significantly enhancing monoubiquitination. These results illuminate critical roles of RPA in the specificity and efficiency of PCNA monoubiquitination. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.24.219980v1?rss=1 Authors: Kulik, A. A., Maruszczak, K. K., Thomas, D. C., Nabi, N. L. A., Carr, M., Bingham, R. J., Cooper, C. D. O. Abstract: Polymerase {delta}-interacting protein 2 (POLDIP2, PDIP38) is a multifaceted, moonlighting protein, involved in binding protein partners from many different cellular processes, including mitochondrial metabolism, DNA replication and repair, and reactive oxygen species generation. POLDIP2 is found in multiple cellular compartments, potentially shuttled depending on its role. How POLDIP2 binds to and coordinates many different proteins is currently unknown. Towards this goal, we present the crystal structure of the mitochondrial fragment of POLDIP2 to 2.8 [A]. POLDIP2 exhibited a compact two-domain {beta}-strand-rich globular structure, confirmed by circular dichroism and small angle X-ray scattering approaches. POLDIP2 comprised canonical DUF525 (ApaG) and YccV-like domains, but with the conserved domain linker packed tightly, resulting in an extended YccV module. A central channel through POLDIP2 was observed which we hypothesise could influence structural changes potentially mediated by redox conditions, following observation of a modified cysteine residue in the channel. Unstructured regions were rebuilt by ab initio modelling to generate a model of full length POLDIP2. Molecular dynamics simulations revealed a highly dynamic N-terminal region tethered to the YccV-domain by an extended linker, potentially facilitating interactions with distal binding partners. Finally we build models of POLDIP2 interacting in complex with two of its partners in genome stability, PrimPol and PCNA. These indicate that dynamic flexibility of the POLDIP2 N-terminal and loop regions are critical to mediate protein-protein interactions. Copy rights belong to original authors. Visit the link for more info
In this episode, we're looking at the decade ahead through the lens of the supplier and are joined by David Nicholson, the President of Top 40 supplier PNCA, parent company of Leed's, Bullet, Trimark, and JournalBooks, and Jonathan Isaacson, President, and CEO of Top 40 supplier The Gem Group, the parent company of Gemline.
What impact is the 2019 Novel Coronavirus in China having on the North American promo products industry? How will it affect the supply chain, shipment timing and costs, planning, business travel overseas, and even human health? Larry Whitney, Top 40 supplier Polyconcept North America’s (PCNA, asi/78897) director of global compliance, is an expert on overseas sourcing and manufacturing. In this exclusive podcast, he offers insights into those pressing questions.
In today's skucast, Bobby Lehew sits down with Kate Boyce who is the new Vice President and General Manager of Trimark, the apparel division of PCNA. Kate comes to PCNA with over 20 years of apparel experience in the retail industry, most recently from Dick's Sporting Goods where she was Vice President of Merchandising for Outerwear and Outdoor Apparel.
Commentary by Dr. Valentin Fuster
Commentary by Dr. Valentin Fuster
Michele Bell, ASI’s Editorial Director, interviewed Neil Ringel – the new CEO of Counselor Top 40 supplier Polyconcept – and PCNA President David Nicholson on Ringel’s plans for the company, his take on the industry overall and how his previous 23-year tenure at Staples prepared him for his new role as the head of the billion dollar global promo entity. PCNA was the #3 supplier on Counselor’s 2018 Top 40 list, with $606.3 million in North American promo sales.
Can You Help Me Fight The Fossils? Read More About Patreon here EVne.ws/patreon Read today’s show notes on https://www.evnewsdaily.com Good morning, good afternoon and good evening wherever you are in the world, welcome to EV News Daily for Tuesday 29th January 2019. It’s Martyn Lee here and I’ve been through every EV story I can find today, and picked out the ones I think you need to know about. Thank you to MYEV.com for helping make this show, they’ve built the first marketplace specifically for Electric Vehicles. It’s a totally free marketplace that simplifies the buying and selling process, and help you learn about EVs along the way too. NISSAN LEAF SOFTWARE UPDATE LETTER From James: "Thank you for your continued patience whilst I have been investigating this for you. I have confirmed that as of today we have finalised and released a bulletin to our dealership network with instructions on how to complete a software update for your Nissan Leaf. The software developed will ensure the maximisation if the quick charge performance whilst also ensuring the ongoing protection of the battery. The software has now been rolled out to all of our Nissan franchised dealership with in the UK and can now be applied to all suitable vehicles. If you would like to make contact with your local Nissan dealership they will be able to book your vehicle in to have this software applied. If you have any questions or need any help in getting your vehicle booked in please do not hesitate to contact me. Kind regards Amber" Joseph says "This is presumably 5SH2A to 5SH2C update. I called my local dealership and they confirmed they have received the bulletin but their system has not yet received the software for the update but this is likely to happen in the next day or so." HYUNDAI KONA ELECTRIC GETS PRICED IN U.S: SEL, LIMITED, ULTIMATE "Hyundai has officially announced the pricing breakdowns for the three versions of Kona Electric to be sold in the U.S." says Eric Loveday at InsideEVs.com. SEL - $36,450 (equivalent to Bolt) Limited - $41,150 Ultimate - $44,650 (cooled seats, HUD) https://insideevs.com/hyundai-kona-electric-gets-officially-priced-in-u-s/ ARE TESLA VEHICLES ALREADY SHIPPING EQUIPPED WITH AUTOPILOT 3.0? Staying with InsideEVs: "YouTuber Erik Strait (DAErik) is wrapped up in all sorts of Tesla-related business. One of his tasks is tracking Tesla inventory. With the help of his friend David, he discovered the Tesla Autopilot 2.0 update ahead of its official launch." reports Steven Loveday: "According to Erik and David, they claim they have an early indication that Tesla Autopilot 3.0 (or really Autopilot 4.0) is on the way. Erik and David believe the feature may be shipping on some cars already. Now, they’ve stumbled upon an AP4 code, which they believe may apply to the upcoming Autopilot 3.0 technology. The feature, they believe, will use additional hardware that will eventually work to provide Full Self-Driving features. This timing would make sense since Tesla could assure that the new hardware and update is already present in vehicles shipped to Europe. Additionally, the company’s earnings call is this week, so a big announcement would be advantageous for sure." https://insideevs.com/video-tesla-autopilot-3-0-shipping-early-2-radars/ NEW 2019 RENAULT CLIO GOES UPMARKET IN FIRST INTERIOR IMAGES "Renault has revealed the interior of its new, fifth-generation Clio, with the supermini's exterior design due to be unveiled tomorrow " says Rachael Burgess for Autocar: "The Clio will distinguish itself from rivals by being one of the most technologically advanced models in its class when it launches at the Geneva motor show. the Clio will be available with a 9.3in portrait-angled touchscreen, said to be inspired by that of the much larger and pricier Espace (not sold in the UK). There's also a 10.0in digital instrument binnacle that can display sat-nav instructions. Last year, then Renault boss Carlos Ghosn announced the French car maker would launch eight electric vehicles in the next five years. However, a fully electric variant of the Clio is not expected to be one of them. That’s because Renault executives are worried it would steal sales from its existing Zoe electric supermini. The Zoe was the best-selling electric car in Europe in 2017." https://www.autocar.co.uk/car-news/new-cars/new-2019-renault-clio-goes-upmarket-first-interior-images PORSCHE ANNOUNCES THREE YEARS OF ELECTRIFY AMERICA CHARGING FOR TAYCAN OWNERS Porsche Cars North America, Inc. (PCNA) today announced an agreement with Electrify America, LLC to provide the first all-electric Porsche, the Taycan, with three years of charging at Electrify America public stations across the country. This charging benefit will be included in the price of the Taycan. In addition, Porsche U.S. dealers will install their own fast-charge kiosks. Porsche will also offer home charging technology. Taken together, these three components will make up a comprehensive power network for the Taycan when it launches late this year. Electrify America highway and metro stations, and many Porsche dealers, will offer DC fast charging at rates up to 350 kilowatts. Using 800 volt technology and the combined charging system (CCS) plug, the Taycan will be able to add more than 60 miles of range in four minutes – the fastest in today's automotive market. Taycan buyers will receive three years of unlimited 30-minute charging at Electrify America locations, comprised of more than 300 highway stations in 42 states as well as more than 180 sites in 17 metro areas. Each location will have an average of five charging dispensers, with some having as many as 10. The Electrify America highway stations will have a minimum of two 350 kW chargers per site, with additional chargers delivering up to 150kW. The highway stations will be spaced along multiple routes and no more than 120 miles from each other. Nationally, the distance between highway stations will average 70 miles. Charging dispensers at metro locations will be able to charge at speeds up to 150 kW. https://www.prnewswire.com/news-releases/porsche-cars-north-america-announces-three-years-of-electrify-america-charging-for-taycan-owners-300785029.html PON ELECTRIFIES CATERPILLAR DIGGER CAT 323F "Norway’s Pon Equipment joint hands with Caterpillar to electrify their digger Cat 323F. The electric excavator is currently biting its time testing but is set to show at a fair this May." reports Electrive: "Codenamed Z-line (for zero emission), this version of the Cat 323F is a 25 ton machine that handles itself all-electrically. While the machine looks like a regular Cat 323F, it got green stickers that qualifies it as the eco option. It obviously got no air filter and no exhaust pad. Inside, the entire engine has been replaced with an electric motor, controllers and heavy duty batteries. The Li-ion battery is said to be large enough for 5 – 7 hours in operation and charges quickly as there is the possibility of fast charging at a 400 or 1000V power supply. It took the Pon engineers eleven months to electrify the heavy-duty machine during which they worked closely with Caterpillar. They made adjustments to the software and some to the excavator." https://www.electrive.com/2018/01/24/pon-electrifies-caterpillar-digger-cat-323f/?fbclid=IwAR3pRXRCATJe0BBYlkB-oK6LClY_S2Vm1whhmlQatFkb98un2I8suk1oVTE EUROPCAR MOBILITY GROUP ADDS 85 ZOES TO ITS UK CAR-SHARING The UK’s leading low-emission car sharing club has reaffirmed the suitability of the all-electric Renault ZOE for its growing operation as its parent company, Europcar Mobility Group, orders a further 85 of the award-winning supermini. E-Car Club – ecarclub.co.uk – has taken a number of units, supporting its expansion across the UK, from East London to St Andrews, Scotland. Through the innovative scheme, E-Car Club provides the public with a low-cost, hassle-free and environmentally friendly alternative to private car ownership and customers can hire a Renault ZOE from only £4.50 per hour, including power and insurance. The majority of E-Car Club’s newly acquired, 40 kWh Renault ZOEs, will be used for a brand new scheme in North Solihull, which sees the popular EV available to members at nine locations throughout the region’s residential areas. Local drivers can hire any of the new ZOEs, one of which has been wrapped in a distinctive ‘ECO Jungle’ livery, by simply signing up online. Completely self-service, bookings can be made via the E-Car Club website 24 hours a day, 365 days a year with customers gaining access to a ZOE simply by scanning their membership card against the windscreen. Drivers then unplug the ZOE from the onsite charger to experience all the benefits of all-electric motoring. COMMUNITY And thanks to MYEV.com they’ve set us another Question Of The Week. Keep your comments coming in on email and YouTube… What new car announcement would do the most for EV publicity – an 250mph EV hypercar, a go-anywhere truck or a truly affordable small family car? I want to say a heartfelt thank you to the 178 patrons of this podcast whose generosity means I get to keep making this show, which aims to entertain and inform thousands of listeners every day about a brighter future. 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Anne Simon joins the TWiV team to talk about plant viruses, including plum pox virus that devastates nut and stone fruit trees, and a geminivirus protein that regulates viral DNA synthesis. Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Rich Condit, Brianne Barker, and Anne Simon Click arrow to play Download TWiV 512 (62 MB .mp3, 103 min) Subscribe (free): iTunes, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode Support Viruses Gordon Conference3:38 Potyvirus (ViralZone) Plum pox (Wikipedia) History, biology, management of plum pox (Mich St Ext) Papaya ring spot virus (Bus Man) Geminivirus (ViralZone) Geminivirus rep impairs PCNA SUMOylation (J Virol) Image credit Letters read on TWiV 512 Timestamps by Jolene. Thanks! Weekly Science Picks Brianne - Why are so many genes unstudied? (Zimmerand Yong) Alan - Unveiling the RNA World Rich - Spaghetti mystery solved (PNAS paper) Dickson - Science Fair Vincent - A PhD Lab Coat Ceremony Listener Picks Stephen - Flu vaccine myth rant by Crislip Jolene - Research Matters in PLoS Path and PLoS Biology Nicholas - Charity Matters app Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv
Sonos has joined a buying group. ADT posts huge revenue. Control4's PCNA gets 1,000 registered users.
Sonos has joined a buying group. ADT posts huge revenue. Control4's PCNA gets 1,000 registered users.
Jennifer Carver, Award Winning Field Sales Manager for PCNA, shares how she survived sexual abuse in her childhood and became a successful sales professional. Jennifer also shares sales tips for business professionals and how her childhood experiences impact her life today. Kim shares the importance of noticing and changing the stories that we tell ourselves, and how those stories can hold us back in our life and career.
Joining Mark Graham for an interview with David Nicholson, President of Polyconcept North America. PCNA is one of the industry’s largest and most influential suppliers. Under David’s leadership, Polyconcept has grown into a $ ½ billion organization. It’s been a staggering run. On July 18, the industry learned that Polyconcept was acquired by Charlesbank Capital Partners, a private equity firm focused on middle market companies. This acquisition marked the end of a successful 11-year partnership with Investcorp. The 2005 acquisition, which consisted of PF Concept in Europe and Leed's in the United States, marked the formation of Polyconcept. In our episode, we will talk to David about the reasons for the acquisition, what it means for Polyconcept and the industry as a whole.
Francisco Blanco, Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia - SPAIN speaks on "Structure of the p15 /PCNA complex and implications for clamp sliding on the Dna during replication and repair". This seminar has been recorded by ICGEB Trieste
This podcast with Dr. Sam Cohen and hosted by Dr. Peter Hall concerns the publication of a STP committee chaired by Dr. Charles Wood concerning the role of increased cell proliferation in the evaluation of the mode of action of carcinogenesis, particularly for nongenotoxic chemicals. Dr. Cohen emphasizes the importance of attention to details in assessing cell proliferation, with different approaches necessary for various tissues and circumstances. He also emphasizes that the focus is on the number of cell replications, not necessarily the rate, and that it is the tissue stem cell population that is critical. For nongenotoxic chemicals the mode of action always involves an increase in cell proliferation, and this can be utilized in designing a short (e.g. 90 days) study to screen for carcinogenesis in rodents. Such a screen requires a labeling index (BrdU, Ki-67, PCNA) in addition to standard histopathology. If positive, additional short term studies can be performed to evaluate the dose response in detail and to determine the mode of action and its relevance to humans. Ultimately, this could replace the standard 2 year bioassay. Click here to read the full article.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 05/06
Mon, 16 Mar 2015 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/18234/ https://edoc.ub.uni-muenchen.de/18234/1/Tomi_Nils-Sebastian.pdf Tomi, Nils-Sebastian ddc:570, ddc:500, Fakultät für Biolog
Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 07/07
Ziel dieser Arbeit war es, mittels Licht- und Rasterelektronenmikroskopie sowie immunhistochemischen Methoden, die Morphologie der Hornhaut im tierartlichen Vergleich an Hand unserer Haussäugetiere detailliert zu beschreiben. Für die Untersuchungen wurden die Hornhäute von 28 Schweinen, 11 Rindern, 2 Ziegen, 6 Pferden, 4 Hunden und 5 Katzen verwendet. Speziesspezifische Besonderheiten wurden bildlich dokumentiert und zur Verdeutlichung tabellarisch dargestellt. Die Hornhaut unserer Haussäugetiere baut sich aus dem Hornhautepithel, dem Stroma, der Descemetschen Membran und dem Hornhautendothel auf. Eine Bowmansche Membran konnte nicht dargestellt werden. Die Fleischfresser besitzen verglichen mit den Huftieren eine deutlich dünnere Hornhaut. Insbesondere das dreischichtige Epithel (Stratum basale, Stratum intermedium und Stratum superficiale) besteht bei den Fleischfressern aus einer kleineren Anzahl an Zelllagen. Die Cytokeratine 1, 2 und 3, als Bestandteile des Zytoskeletts, konnten immunhistochemisch bei allen untersuchten Tierarten, insbesondere im Stratum superficiale des Hornhautepithels, nachgewiesen werden. Das vom Zentrum aus an Höhe abnehmende Hornhautepithel lässt unter dem Rasterelektronenmikroskop auf der Oberfläche der polygonalen Epithelzellen feine Membranausstülpungen erkennen, die sich beim Fleischfresser in Form von kurzen Microvilli darstellen. Das Pferd, Rind und Schwein weisen längere Microplicae auf, die bei der Ziege einzelne ringförmige Kringel bilden. Eine beim Pferd und bei den Wiederkäuern auch epithelial zu findende Pigmentierung, lässt sich im Stroma tierartenübergreifend im Bereich des Limbus erkennen. Mit Ausnahme des anterioren Bereichs weisen die im Stroma liegenden Keratozyten einen geordneten, parallelen Verlauf auf. Tierartliche Unterschiede liegen in der Ausbildung der Descemetschen Membran vor. Das Pferd besitzt die dickste Descemetsche Membran, wohingegen das Schwein die am schwächsten ausgebildete Membran vorweist. Endothelial produziertes Kollagen Typ VIII bildet einen Bestandteil der hexagonalen Gitterstruktur der Descemetschen Membran, wodurch die Elastizität der Hornhaut möglicherweise mitbestimmt wird. Der Nachweis von Elastin ist hingegen im Hornhautgewebe negativ verlaufen. Das einschichtige Hornhautendothel besteht aus Zellen von hexagonaler Form. Es konnte gezeigt werden, dass die Endothelzellen das Membranprotein AQP1 enthalten, das auch in den Keratozyten in tierartlicher Variation exprimiert wird. Hingegen kann das AQP5 ausschließlich im Hornhautepithel identifiziert werden. Durch APQ1 und APQ5 wird der für die Transparenz der Hornhaut wichtige relative Dehydratationszustand aufrecht erhalten. Mit Claudin-1 konnte im Hornhautepithel und -endothel ein tight junctions-bildendes Zellverbindungsprotein markiert werden. Mit Antikörpern gegen p63 sowie PCNA und PHH3 wurde untersucht, wie sich die Hornhaut erneuert. Die Ergebnisse machen deutlich, dass eine Zellerneuerung überwiegend epithelial stattfindet. Limbal befindet sich bei allen untersuchten Tierarten im Stratum basale ein Stammzellreservoir, das bei den Fleischfressern entlang des Hornhautepithels durch einzelne p63-positive Zellen ergänzt wird. Die mittels PCNA und PHH3 dargestellten mitotischen Zellen sind ebenfalls im Stratum basale lokalisiert.
Commentary by Dr. Valentin Fuster
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 15/19
Urocortine (Ucn) gehören zur Familie des Corticotropin-Releasing-Hormons und sind wichtige Modulatoren der Stressantwort, der Angstkontrolle und der assoziierten Erkrankungen, wie z. B. der Depression. Während Ucn1 mit gleicher Affinität an den CRF1- und CRF2-Rezeptor bindet, sind Ucn2 und Ucn3 spezifische Liganden für den CRF2-Rezeptor. Zusätzlich zum Zentralen Nervensystem sind Urocortine in verschiedenen peripheren Organen exprimiert – so auch in der Nebenniere. Mit Hilfe sechs verschiedener Knock-out Modelle, in denen Urocortine in unterschiedlichen Kombinationen deletiert wurden, wurden potentielle Urocortin-abhängige Effekte auf die Nebenniere der Maus untersucht. Dabei wurde mit Hilfe von HE-Färbungen die Struktur, mit Färbungen gegen PCNA als Proliferationsmarker die Zellteilungen und mit RT-PCR die Expressionslevel wichtiger Schlüsselenzyme der Steroidbiosynthese und der Katecholaminsynthese ermittelt. Während in Single KO Mäusen nur geringe Effekte detektierbar waren, zeigten sich in Double und Triple KO Mäuse im Vergleich zu Wildtyp Mäusen ausgeprägte Änderungen der untersuchten Parameter, so dass eine funktionelle Redundanz innerhalb der Urocortine vermutet werden kann. Um die spezifische Wirkung einer organspezifischen Überexpression von Ucn2 zu untersuchen, wurden Mäuse auf der Basis des Cre-Lox-Systems gezüchtet, die abhängig vom Promotor des Steroidogenic Factor 1-Gens (SF1), d. h. vor allem in der Nebenniere und in den Gonaden, Ucn2 überexprimieren (Ucn2 OE Mäuse mit dem Genotyp R26+/stopUcn2 SF1-Cre+/-). Zusätzlich zu den oben genannten Messungen wurden Hormonkonzentrationen im Plasma unter Basal-Bedingungen, nach einem ACTH-Stimulationstest und nach einem Restraint-Stress-Test bestimmt. Es zeigte sich, dass die Überexpression von Ucn2 mit einer erniedrigten Steroidbiosynthese in der Nebenniere assoziiert ist. Zudem konnten geschlechtsspezifische Unterschiede beobachtet werden – so zeigten weibliche Ucn2 OE Mäuse vor allem Änderungen unter Basal-Bedingungen und nach ACTH-Stimulation, wobei bei männlichen Tieren nur nach Restraint-Stress eine reduzierte Stressantwort im Vergleich zu den Kontrolltieren auftrat. Zusammenfassend kann aus diesen in vivo Studien der Schluss gezogen werden, dass ein intraadrenales Regulationssystem existiert, das durch die Balance aller Urocortine und deren Rezeptoren geschlechtsspezifisch die Struktur und Funktion der Nebenniere beeinflusst.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 03/06
Thu, 12 Nov 2009 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/11549/ https://edoc.ub.uni-muenchen.de/11549/1/Ertongur_Sabahat_Isin.pdf Ertongur, Sabahat Isin ddc:570, ddc:500, Fakultät für Biologie
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 03/06
DNA lesions arising from environmental and endogenous sources induce various cellular responses including cell cycle arrest, DNA repair and apoptosis. Although detailed insights into the biochemical mechanisms and composition of DNA repair pathways have been obtained from in vitro experiments, a better understanding of the interplay and regulation of these pathways requires DNA repair studies in living cells. In this study we employed laser microirradiation and photobleaching techniques in combination with specific mutants and inhibitors to analyze the real-time accumulation of proteins at laser-induced DNA damage sites in vivo, thus unravelling the mechanisms underlying the coordination of DNA repair in living cells. The immediate and faithful recognition of DNA lesions is central to cellular survival, but how these lesions are detected within the context of chromatin is still unclear. In vitro data indicated that the DNA-damage dependent poly(ADP-ribose) polymerases, PARP-1 and PARP-2, are involved in this crucial step of DNA repair. With specific inhibitors, mutations and photobleaching analysis we could reveal a complex feedback regulated mechanism for the recruitment of the DNA damage sensor PARP-1 to microirradiated sites. Activation of PARP-1 results in localized poly(ADP-ribosyl)ation and amplifies a signal for the subsequent rapid recruitment of the loading platform XRCC1 which coordinates the assembly of the repair machinery. Using similar techniques we could demonstrate the immediate and transient binding of the RNA Polymerase II cofactor PC4 to DNA damage sites, which depended on its single strand binding capacity. This establishes an interesting link between DNA repair and transcription. We propose a role for PC4 in the early steps of the DNA damage response, recognizing and stabilizing single stranded DNA (ssDNA) and thereby facilitating DNA repair by enabling repair factors to access their substrates. After DNA lesions have been successfully detected they have to be handed over to the repair machinery which restores genome integrity. Efficient repair requires the coordinated recruitment of multiple enzyme activities which is believed to be controlled by central loading platforms. As laser microirradiation induces a variety of different DNA lesions we could directly compare the recruitment kinetics of the two loading platforms PCNA and XRCC1 which are involved in different repair pathways side by side. We could demonstrate that PCNA and XRCC1 show distinct recruitment and binding kinetics with the immediate and fast recruitment of XRCC1 preceding the slow and continuous recruitment of PCNA. Introducing consecutively multiple DNA lesions within a single cell, we further demonstrated that these different recruitment and binding characteristics have functional consequences for the capacity of PCNA and XRCC1 to respond to successive DNA damage events. To further study the role of PCNA and XRCC1 as loading platforms in DNA repair, we extended our analysis to their respective interaction partners DNA Ligase I and III. Although these DNA Ligases are highly homologous and catalyze the same enzymatic reaction, they are not interchangeable and fulfil unique functions in DNA replication and repair. With deletion and mutational analysis we could identify domains mediating the specific recruitment of DNA Ligase I and III to distinct repair pathways through their interaction with PCNA and XRCC1. We conclude that this specific targeting may have evolved to accommodate the particular requirements of different repair pathways (single nucleotide replacement vs. synthesis of short stretches of DNA) and thus enhances the efficiency of DNA repair. Interestingly, we found that other PCNA-interacting proteins exhibit recruitment kinetics similar to DNA Ligase I, indicating that PCNA not only serves as a central loading platform during DNA replication, but also coordinates the recruitment of multiple enzyme activities to DNA repair sites. Accordingly, we found that the maintenance methyltransferase DNMT1, which is known to associate with replication sites through binding to PCNA, is likewise recruited to DNA repair sites by PCNA. We propose that DNMT1, like in DNA replication, preserves methylation patterns in the newly synthesized DNA, thus contributing to the restoration of epigenetic information in DNA repair. In summary, we found immediate and transient binding of repair factors involved in DNA damage detection and signalling, while repair factors involved in the later steps of DNA repair, like damage processing, DNA ligation and restoration of epigenetic information, showed a slow and persistent accumulation at DNA damage sites. We conclude that DNA repair is not mediated by binding of a preassembled repair machinery, but rather coordinated by the sequential recruitment of specific repair factors to DNA damage sites.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06
Genomic integrity largely depends on the accurate replication and faithful transmission of the genetic information to the progeny each time a cell divides. To ensure the fidelity of these fundamental processes, highly sophisticated protein networks have evolved. This study investigated how the diverse mechanisms for maintaining genomic integrity are integrated and coordinated at the replication fork. In the first part, the roles of post-translational modifications with ubiquitin and SUMO in regulating replication through DNA lesions were investigated. Previous work in S. cerevisiae showed that post-translational modifications of the replication factor PCNA control DNA repair activities of the replisome. PCNA is a homotrimeric ring-shaped protein that encircles DNA and confers processivity to DNA polymerases during DNA synthesis. Moreover, being devoid of enzymatic activity, PCNA is perfectly suited to act as a platform for recruitment of factors to the replication fork, including DNA repair enzymes, chromatin remodelers and replication regulators. PCNA modifications by ubiquitin govern two distinct modes of lesion bypass, either channeling the repair processes into error-prone translesion synthesis by recruiting specialized polymerases, or promoting an error-free mechanism involving a template switch to the sister chromatid. In addition, PCNA-modification by SUMO inhibits the third major bypass mechanism, namely recombinational repair, by recruiting the anti-recombinogenic helicase Srs2. In this study, the importance and universality of PCNA-modifications could be demonstrated by showing that PCNA ubiquitylation in human and chicken cells is well conserved. Interestingly, SUMO modification appeared less preserved, indicating that the pathways controlled by PCNA modifications are used to different degrees throughout species. A further finding of this thesis was the identification of DNA polymerase
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06
Eine akkurate DNA-Replikation ist notwendig, um die Stabilität der genetischen Information zu gewährleisten. Dieser Prozess wird durch DNA-Läsionen erschwert, die durch eine Vielzahl von Ursachen entstehen und häufig nicht vor dem Erreichen der S-Phase repariert werden können. Nicht nur kann durch Läsionen geschädigte DNA häufig nicht dupliziert werden, angehaltene Replikationsgabeln können auch zusammenbrechen und so zu DNA-Strangbrüchen führen. Die Funktion des RAD6-pathways liegt darin, die Umgehung (Bypass) von DNA-Läsionen während der Replikation zu ermöglichen, wodurch eine Toleranz gegenüber Schädigungen der DNA erreicht wird. In dieser Arbeit wurde die Regulation des RAD6-vermittelten Bypass von DNA-Läsionen durch posttranslationale Ubiquitin- und SUMO-Modifikationen des Replikationsfaktors PCNA untersucht. PCNA bildet einen trimeren Ring um die DNA und verstärkt durch Bindung der replikativen Polymerase deren Assoziation zur DNA und somit die Prozessivität der Replikation. Als DNA gebundener Faktor des Replikations-komplexes ohne katalytische Aktivität ist PCNA ideal geeignet, um durch seine Modifikation Replikations-assoziierte Prozesse zu regulieren. Die Ubiquitinierung von PCNA durch Enzyme des RAD6-pathways erfolgt als spezifische Antwort auf DNA-Läsionen während der Replikation und ermöglicht deren Bypass. Dabei bewirken unterschiedliche Ubiquitin-Modifikationen verschiedene Arten des Bypass. Die Mono-Ubiquitin-Modifikation führt zum Einsatz von speziellen Transläsions-Polymerasen, die eine größere Toleranz für geschädigte DNA haben, aber auch für die Entstehung von Mutationen verantwortlich sind. Einen mechanistisch anderen Bypass von DNA-Schäden bewirkt die Modifikation von PCNA mit einer Lysin K63-verknüpften Multi-Ubiquitinkette. Für diesen wird wahrscheinlich der neureplizierte, unbeschädigte Schwester-Strang als Vorlage benutzt. Unabhängig von Schädigungen der DNA wird PCNA während der S-Phase zusätzlich mit dem ubiquitin-ähnlichen Protein SUMO modifiziert. Dies führt zu einer Interaktion mit der Helikase Srs2, die als Antagonist zu dem zentralen Rekombinationsprotein Rad51 wirkt. Dadurch wird spezfisch die homologe Rekombination zwischen Schwesterchromatiden an der Rekombinationsgabel inhibiert, nicht jedoch andere Rekombinationsereignisse, wie. z.B. Rekom-bination zwischen homologen Chromosomen. Deshalb ist es wahrscheinlich, dass spezifisch die Replikationsgabel durch PCNA-SUMO-Srs2 geschützt wird, um schädliche Rekombination oder Rekombinationsstrukturen zu vermeiden, die mit Replikations-assoziierten Prozessen interferieren. Ubiquitin- und SUMO-Modifikation regulieren demnach unabhängige Prozesse. Interessanterweise haben diese aber eine verwandte Funktion im Bypass von DNA-Läsionen während der Replikation. Die Inhibition der Schwesterchromatid-Rekombination durch PCNA-SUMO-Srs2 lenkt den Bypass von DNA-Läsionen in einen durch PCNA-Ubiquitinierung gesteuerten Mechanismus.
Pathogenic events leading to in-stent restenosis (ISR) are still incompletely understood. Among others, inflammation, immune reactions, deregulated cell death and growth have been suggested. Therefore, atherectomy probes from 21 patients with symptomatic ISR were analyzed by immunohistochemistry for pathogen burden and compared to primary target lesions from 20 stable angina patients. While cytomegalovirus, herpes simplex virus, Epstein-Barr virus and Helicobacter pylori were not found in ISR, acute and/or persistent chlamydial infection were present in 6/21 of these lesions (29%). Expression of human heat shock protein 60 was found in 8/21 of probes (38%). Indicated by distinct signals of CD68, CD40 and CRP, inflammation was present in 5/21 (24%), 3/21 (14%) and 2/21 (10%) of ISR cases. Cell density of ISR was significantly higher than that of primary lesions ( 977 +/- 315 vs. 431 +/- 148 cells/mm(2); p < 0.001). There was no replicating cell as shown by Ki67 or PCNA. TUNEL+ cells indicating apoptosis were seen in 6/21 of ISR specimens (29%). Quantitative analysis revealed lower expression levels for each intimal determinant in ISR compared to primary atheroma (all p < 0.05). In summary, human ISR at the time of clinical presentation is characterized by low frequency of pathogen burden and inflammation, but pronounced hypercellularity, low apoptosis and absence of proliferation. Copyright (C) 2004 S. Karger AG, Basel.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 01/06
Das Protein Ubiquitin kann posttranslational an Proteine geknüpft werden. Dieser Vorgang ist für den Abbau von Proteinen durch das Proteasom notwendig.Neben dieser Funktion hat die Modifikation mit Ubiquitin noch weitere Funktionen,die nicht zum Abbau des Proteins führen.Ubiquitin- ähnlichen Proteine,wie beispielsweise SUMO,sind ebenfalls nicht direkt am Proteinabbau beteiligt.Die Konsequenz der Modifikation,und das Zusammenspiel Ubiquitin-ähnlicher-Systeme mit dem Ubiquitin-System sind bisher allerdings wenig verstanden. PCNA (Proliferating Cell Nuclear Antigen)ist eine zentrale Komponente der DNA-Replikation und DNA-Reparatur.Im Rahmen dieser Arbeit konnte gezeigt werden,daß PCNA über drei verschiedene posttranslationale Modifikationen reguliert wird.In der S-Phase des Zellzyklus wird PCNA durch SUMO modifiziert.Nach DNA-Schädigung wird PCNA dagegen durch Komponenten des RAD6 -DNA-Reparaturwegs mono-oder multiubiquitiniert. Alle drei Modifikationen finden am gleichen,zwischen eukaryontischen Spezies kon servierten Lysin statt.Der RAD6 -DNA-Reparaturweg reguliert postreplikative DNA-Reparatur.Eine Schlüsselstellung innerhalb dieses Reparaturwegs nehmen zwei Ubiquitin-konjugierende Enzyme,RAD6 sowie das Heterodimer UBC13/MMS2,die über die RING-Finger Prote ine RAD18 bzw.RAD5 an das Chromatin rekrutiert werden,ein.Interessanterweise interagiert neben PCNA auch das SUMO-konjugierende Enzym UBC9 mit den beiden RING-Finger Proteinen sowie mit PCNA selbst und ist so ebenfalls mit dem RAD6 -Reparaturweg assoziiert.Nach DNA-Schädigung wird PCNA von RAD6/RAD18 monoubiquitiniert.Alternativ kann PCNA durch das hierfür zusätzlich notwendige Heterodimer UBC13/MMS2 und das RING-Finger- Protein RAD5 mit speziellen,Lysin-63-verknüpften Ubiquitinketten, multiubiquitiniert werden.PCNA-Ubiquitinierung ist essentiell für DNA- Reparatur,da eine PCNA-Mutante,die nicht mehr modifiziert wird,starke Sensitivität gegenüber DNA-Schädigung besitzt. Es konnte gezeigt werden,daß die verschiedenen Modifikationen unterschiedlich auf die Funktionen von PCNA einwirken können. SUMOylierung von PCNA wirkt inhibierend auf RAD6 -abhängige DNA- Reparatur.PCNA-Multiubiquitinierung durch Lysin-63-verknüpfte Ubiquitinketten aktiviert PCNA in dem UBC13/MMS2/RAD5-abhängigen Zweig RAD6 -abhängiger DN A -Reparatur,der fehlerfrei arbeitet.PCNA- Monoubiquitinierung scheint dagegen den fehlerhaften Zweig RAD6 - abhängiger DNA-Reparatur zu aktivieren.ˇ
Objectives: DNA sequences are very rich in short repeats and their pattern can be altered by point mutations. We wanted to investigate the effect of single nucleotide polymorphism (SNP) on the pattern of short DNA repeats and its biological consequences. Methods: Analysis of the pattern of short DNA repeats of the Thy-1 sequence with and without SNP. Searching for DNA-binding factors in any region of significance. Results: Comparing the pattern of short repeats in the Thy-1 gene sequences of Turkish patients with ataxia telangiectasia (AT) with the `wild type' sequence from the DNA database, we identified a missing 8-bp repeat element due to an SNP in position 1271 (intron II) in AT-DNA sequences. Only the mutated sequence had the potential for the formation of a stem loop in DNA or pre-mRNA. In super-shift experiments we found that DNA oligomers covering the area of this SNP formed a complex with proteins amongst which we identified the proliferating cell nuclear antigen (PCNA) protein. Conclusion: SNPs have the potential to alter DNA or pre-mRNA conformation. Although no SNP-depeding formation of the DNA-protein complex was evident, future investigations could reveal differential molecular mechanisms of cellular regulation. Copyright (C) 2001 S. Karger AG, Basel.
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