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In this study, functionally graded ZrB2–B4C–SiC–LaB6 composite materials (FGMs) with potential applications in hypersonic aircraft thermal protection systems were fabricated using spark plasma sintering. A systematic study of the thermal conductivity of the FGM, the conductivity of respective FGM layers, and the equivalent non-graded composites, was performed from room temperature up to 450 °C. The results suggest that the thermal conductivity of the FGMs (in the through-thickness direction) and their equivalent non-graded composites ranged between 25 and 34.9 W/mK, which was ∼60 % less than ZrB2. While the overall thermal conductivity of the FGM and equivalent non-graded composites were similar, in the FGM, the topmost layer with high ZrB2-content displayed up to 245 % higher thermal conductivity than the bottom layer with high B4C content. A systematic comparison between experimentally determined conductivity and relevant thermal conductivity models was conducted.

Abstract There is increased concern about perverse incentives, quantitative performance metrics, and hyper-competition for funding and faculty positions in US academia. Recipients of the prestigious National Science Foundation Graduate Research Fellowships (n = 244) from Civil and Environmental Engineering (45.5%) and Computer Science and Engineering (54.5%) were anonymously surveyed to create a baseline snapshot of their perceptions, behaviors and experiences. NSF Fellows ranked scientific advancement as the top metric for evaluating academics followed by publishing in high-impact journals, social impact of research, and publication/citation counts. The self-reported rate of academic cheating was 16.7% and of research misconduct was 3.7%. Thirty-one percent of fellows reported direct knowledge of graduate peers cheating, and 11.9% had knowledge of research misconduct by colleagues. Only 30.7% said they would report suspected misconduct. A majority of fellows (55.3%) felt that mandatory ethics trainings left them unprepared for dealing with ethical issues. Fellows stated academic freedom, flexible schedules and opportunity to mentor students were the most positive aspects of academia, whereas pressures for funding, publication, and tenure were cited as the most negative aspects. These data may be useful in considering how to better prepare STEM graduate trainees for academic careers.

Abstract Zinc Finger transcription factors are crucial in modulating various cellular processes, including differentiation. Chromatin reader Zinc Finger MYND (Myeloid, Nervy, and DEAF-1) type containing 8 (ZMYND8), an All-Trans Retinoic Acid (ATRA)-responsive gene, was previously shown to play a crucial role in promoting the expression of neuronal-lineage committed genes. Here, we report that ZMYND8 promotes neuronal differentiation by positively regulating canonical MAPT protein-coding gene isoform, a key player in the axonal development of neurons. Additionally, ZMYND8 modulates gene-isoform switching by epigenetically silencing key regulatory regions within the MAPT gene, thereby suppressing the expression of non-protein-coding isoforms such as MAPT213. Genetic deletion of ZMYND8 led to an increase in the MAPT213 that potentially suppressed the parental MAPT protein-coding transcript expression related to neuronal differentiation programs. In addition, ectopic expression of MAPT213 led to repression of MAPT protein-coding transcript. Similarly, ZMYND8-driven transcription regulation was also observed in other neuronal differentiation-promoting genes. Collectively our results elucidate a novel mechanism of ZMYND8-dependent transcription regulation of different neuronal lineage committing genes, including MAPT, to promote neural differentiation.

[Background] Exposure to waterborne lead during the Flint Water Crisis during April 2014-October 2015 is believed to have caused increased special education enrollment in Flint children. [Method] This retrospective population-based cohort study utilized de-identified data for children under six years of age who had their blood lead tested during 2011 to 2019, and special education outcomes data for children enrolled in public schools for corresponding academic years (2011-12 to 2019-20) in Flint, Detroit (control city) and the State of Michigan. Trends in the following crisis-related covariates were also evaluated: waterborne contaminants, poverty, nutrition, city governance, school district policies, negative community expectations, media coverage and social media interactions. [Results] Between 2011 and 2019, including the 2014-15 crisis period, the incidence of elevated blood lead in Flint children (≥ 5µg/dL) was always at least 47% lower than in the control city of Detroit (p < .0001) and was also never significantly higher than that for all children tested in Michigan (p = 0.33). Nonetheless, special education enrollment in Flint spiked relative to Detroit and Michigan (p < .0001). There is actually an inverse relationship between childhood blood lead and special education enrollment in Flint. [Conclusion] This study failed to confirm any positive association between actual childhood blood lead levels and special education enrollment in Flint. Negative psychological effects associated with media predictions of brain damage could have created a self-fulfilling prophecy via a nocebo effect. The findings demonstrate a need for improved media coverage of complex events like the Flint Water Crisis.

We know that many factors contribute to the exacerbation of cancer health disparities. These inequities observed in adulthood may have originated from behaviors occurring in early adolescence. We believe that increasing awareness of cancer prevention in youth may help reduce future disparities. Our community partners identified a need for youth-oriented cancer prevention and helped design the pilot Youth Ambassadors Reaching Out (YARO) program. YARO provided cancer prevention and health disparities education and exposure to health careers to 73 middle school students between 2012-2016. YARO included didactic sessions (health disparities, smoking prevention, physical activity, nutrition), a cancer center tour, and Photovoice project. Students were encouraged to serve as ambassadors by sharing lessons learned with others. Participants demonstrated increases in cancer prevention knowledge during the program. Evaluation data revealed that students served as ambassadors by sharing information with others about healthy behaviors, improving their own health habits, and volunteering in their communities.

Purpose: Rates of loneliness and obesity have increased in recent decades. Loneliness and obesity independently have been found to be risk factors for negative physical and mental health outcomes. This study examined the rates and interrelationships of loneliness, body mass index (BMI), and health care utilization in a primary care setting. Methods: A cross-sectional survey of adult patients presenting for outpatient care at 7 family medicine clinical practices in Pennsylvania was conducted. Survey questions included self-reported measures of loneliness, height/weight, number of health care visits, and potential confounders (eg, sociodemographic variables, health status). Bivariate and multivariable linear regression models were used to analyze associations among loneliness, BMI, and health care utilization. Results: In all, 464 eligible patients returned surveys for an overall response rate of 26%. Mean (standard deviation) loneliness score was 4.2 (1.7), mean BMI was 30.4 (7.6), and mean number of visits in year prior was 2.7 (3.6). On bivariate analysis, BMI was positively associated with loneliness (effect estimate: 0.50; P = 0.03). On multivariable analysis, BMI was negatively associated with attending religious services and self-reported physical health and positively associated with self-reported mental health (P < 0.05 for all), but not associated with loneliness. While not associated with loneliness, health care utilization was negatively associated with Hispanic ethnicity, marital status, and self-reported physical health (P < 0.05 for all). Conclusions: Given the detrimental effects loneliness and obesity have on health outcomes, it might be prudent for health care providers to prioritize health concerns for their patients by assessing loneliness and counseling regarding associated risks, particularly in patients with obesity.

Abstract The major challenge in chemotherapy lies in the gain of therapeutic resistance properties of cancer cells. The relatively small fraction of chemo-resistant cancer cells outgrows and are responsible for tumor relapse, with acquired invasiveness and stemness. We demonstrate that zinc-finger MYND type-8 (ZMYND8), a putative chromatin reader, suppresses stemness, drug resistance, and tumor-promoting genes, which are hallmarks of cancer. Reinstating ZMYND8 suppresses chemotherapeutic drug doxorubicin-induced tumorigenic potential (at a sublethal dose) and drug resistance, thereby resetting the transcriptional program of cells to the epithelial state. The ability of ZMYND8 to chemo-sensitize doxorubicin-treated metastatic breast cancer cells by downregulating tumor-associated genes was further confirmed by transcriptome analysis. Interestingly, we observed that ZMYND8 overexpression in doxorubicin-treated cells stimulated those involved in a good prognosis in breast cancer. Consistently, sensitizing the cancer cells with ZMYND8 followed by doxorubicin treatment led to tumor regression in vivo and revert back the phenotypes associated with drug resistance and stemness. Intriguingly, ZMYND8 modulates the bivalent or poised oncogenes through its association with KDM5C and EZH2, thereby chemo-sensitizing the cells to chemotherapy for better disease-free survival. Collectively, our findings indicate that poised chromatin is instrumental for the acquisition of chemo-resistance by cancer cells and propose ZMYND8 as a suitable epigenetic tool that can re-sensitize the chemo-refractory breast carcinoma.

Freshwater scarcity is increasing across many parts of the globe; to meet this demand, seawater desalination is the best choice, and the electrical energy consumption is escalating due to urbanization and industrialization. Sustainable production of electricity and freshwater can be met by an integrating photovoltaic-thermal (PVT) module with stepped solar still (SSS). The present study focuses on the theoretical modeling of the PVT-SSS desalination system for evaluating thermal efficiency, energy efficiency, freshwater productivity, and electrical power generation. The solar still productivity will be influenced by the depth of water, insulation thickness, glass cover material, thickness and inclination, and operational factors like preheating the input water supply and water salinity. A comparative analysis has been made of summer, winter, and rainy climatic conditions of Vellore town (12.9165° N, 79.1325° E), Tamil Nadu. In the present work, a thermodynamic model based on mass and energy balance is developed for the PVT-SSS system, and it is solved by a numerical method. A Runge-Kutta technique of 4th order is employed using a Python program for solving the thermodynamic simulation model. The results from the model depict that for summer, winter, and rainy climatic seasons, the freshwater productivity of PV/T-SSS was determined to be 12.18 kg/m2day, 6.67 kg/m2day, and 2.77 kg/m2day. Also, it is found that electrical efficiency for summer, winter, and rainy seasons is 8.91%, 9.135%, and 9.53%, respectively. A maximum and minimum freshwater production of 1668 kg/m2 and 1218 kg/m2 are observed for a depth of 2 cm and 5 cm, respectively.

Group medical visits (GMVs) for patients with chronic pain are becoming more accessible and have been shown to be successful in furthering patient education on multidisciplinary, nonopioid interventions. Unfortunately, evidence suggests that many group visit models lack sustainability due to recruitment issues and retention rates. Additionally, most of the studies surrounding GMVs are located in primarily urban health centers, potentially limiting their generalizability. This study aims to identify patient interest in and barriers to GMVs for chronic pain and to explore how chronic pain impacts daily lives for GMV content optimization in a nonurban population. Nineteen participants age 18 to 65 years participated in semistructured phone interviews to generate a thematic analysis. Participants received their care from family practitioners at a suburban multiclinic academic medical group and were being prescribed at least 50 morphine milligram equivalents (MME) at the time of recruitment. Analysis generated two themes: (1) Participants expressed specific interest in GMVs with few barriers identified, and (2) Pain has a negative impact on mental health and most aspects daily life, creating a foundation for discussion in GMVs. Findings support significant patient interest in group medical visits for chronic pain, but careful planning is necessary to address patient needs, expectations, and barriers in order to ensure GMV sustainability.

Background Self-rated health (SRH) is a common measure of overall health. However, little is known about multilevel correlates of physical and mental SRH. Methods Patients attending primary care clinics completed a survey before their appointment, which we linked to community data from American Community Survey and other sources (n = 455). We conducted multilevel logistic regression to assess correlates of excellent/very good versus good/fair/poor physical and mental SRH. Results 43.9% of participants had excellent/very good physical SRH, and 55.2% had excellent/very good mental SRH. Physical SRH was associated with age (odds ratio[OR] = 0.82 per 10 years; 95% confidence interval[CI] = 0.72-0.93) and community correlates, including retail establishment density (OR = 0.94, 95% CI = 0.90-0.99) and percent of students eligible for free/reduced lunch (OR = 1.60, 95% CI = 1.08-2.38) (all P

H2B monoubiquitination is implicated in oncogenesis. Here, the authors show that UBR7 PHD finger is a H2BK120 monoubiquitin ligase that acts a tumour suppressor in breast cancer by suppressing gene expression for EMT, while promoting expression of CDH4 which restrain WNT/β-cat pathway.

Introduction/Objectives: Screening guidelines for breast, cervical, and colorectal cancer (CRC) are less clear for older adults due to the potential harms that may result from screening. Understanding older adults’ attitudes and perceptions, especially racial/ethnic minority and underserved adults, of cancer screening can help health care providers determine how best to communicate with older adults about cancer screening and screening cessation. The objective of this study was to determine how older adults primarily from minority/underserved backgrounds perceive cancer screening and overscreening. Methods: Four focus groups (n = 39) were conducted with adults (>=65 years of age) in 3 community settings in south-central Pennsylvania. Two focus groups were conducted in Spanish and translated to English upon transcription. Focus group data was managed and analyzed using QSR NVivo 12. Inductive thematic analysis was used to analyze the data where themes emerged following the coding process. Results: The focus group participants had an average age of 74 years and were primarily female (74%) and Hispanic (69%), with 69% reporting having less than a high school degree. Four key themes were identified from the focus groups: (1) importance of tailored and targeted education/information; (2) impact of physician/patient communication; (3) impact of barriers and facilitators to screening on cancer screening cessation; and (4) awareness of importance of screening. Participants were more likely to be agreeable to screening cessation if they received specific information regarding their health status and previous medical history from their physician as to why screening should be stopped and told by their physician that the screening decision is up to them. Conclusions: Older adults prefer individualized information from their physician in order to justify screening cessation but are against incorporating life expectancy into the discussion. Future research should focus on developing interventions to test the effectiveness of culturally tailored screening cessation messages for older adults.

The number of cases of aggressive prostate cancer is increasing. Differentiating between aggressive and indolent cases has resulted in increased difficulty for the physician and patient to decide on the best treatment option. Due to this challenge, efforts are underway to profile genetic risk for prostate cancer aggressiveness, which may help physicians and patients at risk for developing aggressive prostate cancer to select an appropriate treatment option. This study explores patients’ interest in receiving genetic results, preference for how genetic risk information should be communicated, and willingness to share results with adult male first-degree relatives (FDRs). A nine-item survey was adapted to assess their beliefs and attitudes about genetic testing for prostate cancer aggressiveness. In addition, participants ( n = 50) responded to hypothetical scenarios and questions associated with perceived importance of risk disclosure, preferences for receiving genetic risk information, and sharing of results with FDRs. As the hypothetical risk estimate for aggressive prostate cancer increased, patients’ willingness to receive genetic risk information increased. This study found that most patients preferred receiving genetic risk education in the form of a DVD (76%), one-page informational sheet (75%), or educational booklet (70%). Almost all patients (98%) reported that they would be willing to share their test results with FDRs. The results of this study highlight prostate cancer patients’ desire to receive and share genetic risk information. Future research should focus on assessing the long-term benefits of receiving genetic information for prostate cancer patients and implications of sharing this information with FDRs.

Summary: The transcriptional co-activator p300 is essential for p53 transactivation, although its precise role remains unclear. We report that p53 activates the acetyltransferase activity of p300 through the enhancement of p300 autoacetylation. Autoacetylated p300 accumulates near the transcription start sites accompanied by a similar enrichment of activating histone marks near those sites. Abrogation of p53-p300 interaction by a site-directed peptide inhibitor abolished p300-mediated histone acetylation, suggesting a crucial role played by the activation in p53-mediated gene regulation. Gain-of-function mutant p53, known to impart aggressive proliferative properties in tumor cells, also activates p300 autoacetylation. The same peptide abolished many of the gain-of-function properties of mutant p53 as well. Reversal of gain-of-function properties of mutant p53 suggests that molecules targeting the p53-p300 interface may be good candidates for anti-tumor drugs. : Molecular Biology; Molecular Mechanism of Gene Regulation; Cancer Subject Areas: Molecular Biology, Molecular Mechanism of Gene Regulation, Cancer

Abstract Background Asthma is a complex, heterogeneous disorder with similar presenting symptoms but with varying underlying pathologies. Exhaled breath condensate (EBC) is a relatively unexplored matrix which reflects the signatures of respiratory epithelium, but is difficult to normalize for dilution. Methods Here we explored whether internally normalized global NMR spectrum patterns, combined with machine learning, could be useful for diagnostics or endotype discovery. Nuclear magnetic resonance (NMR) spectroscopy of EBC was performed in 89 asthmatic subjects from a prospective cohort and 20 healthy controls. A random forest classifier was built to differentiate between asthmatics and healthy controls. Clustering of the spectra was done using k-means to identify potential endotypes. Results NMR spectra of the EBC could differentiate between asthmatics and healthy controls with 80% sensitivity and 75% specificity. Unsupervised clustering within the asthma group resulted in three clusters (n = 41,11, and 9). Cluster 1 patients had lower long-term exacerbation scores, when compared with other two clusters. Cluster 3 patients had lower blood eosinophils and higher neutrophils, when compared with other two clusters with a strong family history of asthma. Conclusion Asthma clusters derived from NMR spectra of EBC show important clinical and chemical differences, suggesting this as a useful tool in asthma endotype-discovery.

A citizen science collaboration between Flint residents, the Virginia Tech “Flint Water Study” team, and others helped to uncover the Flint Lead-in-Drinking Water Crisis and a community-wide outbreak of 'Legionella'. The resulting Federal Emergency declaration in January 2016 resulted in more than $600 million in relief funding, an acknowledged case of environmental injustice, and resignations/indictments of some public officials. But after responsible government entities apologized and attempted to make amends and help with the recovery, some “citizen scientists” began making public statements that were in direct conflict with public health messaging of scientific authorities. A general state of science anarchy resulted, which created further distrust and confusion. Some practices employed were consistent with a concept of “citizen engineering,” which aims to “undermine engineering [and science] expertise” in the name of “democratizing” science. “Citizen Engineers” view concepts of scientific rigor and objectivity as justification for abuse of power by authorities and scientists, and they embrace biases and conflicts of interest that scientists aspire to guard against. While there are ethical guidelines for professional scientists on research misconduct, no such framework exists for policing instances of unethical behavior by citizen scientists. Possible abuses of citizen science documented in Flint explored in this case study include: 1) collection of non-representative data that created unjustified fear among residents about the safety of water used for bathing and showering, 2) perceived financial conflicts of interest, and 3) falsification of data to obtain relief resources, support lawsuits, gain media attention, or support erroneous scientific conclusions. We also report the journey of an aspiring citizen scientist who openly acknowledged mistakes, made the “right” decision in relation to handling an ethical dilemma, and who was then publicly attacked for doing so. This experience highlights challenges to the practice of citizen science, especially during high profile emergency interventions and disasters involving environmental injustice.

Obesity has become a serious issue affecting millions of Americans, especially in the southern United States. One avenue for addressing obesity is the workplace setting. This formative research study examined the feasibility of an obesity prevention worksite intervention in the barbershop for African American barbershop owners (employers) and barbers (employees). The study proposes an intervention where the owner of the barbershop would be trained to educate his barbers about obesity prevention. Twenty in-depth interviews were conducted with the owners ( n = 5) and barbers ( n = 15) of five barbershops in Statesboro, Georgia, to determine the feasibility of the intervention. The results of this study indicated that the owners and barbers all felt that the intervention was feasible and could be implemented in the barbershop. The owners and barbers felt that obesity was an important issue in their community. Additional themes identified include program benefits, empowerment of owners and barbers, and motivational components to help produce healthy habits. The owners felt comfortable educating their barbers about obesity prevention, and the barbers were receptive toward the idea of being educated by their employer. In order for this intervention to be implemented and effective, it must be tailored to fit within the barbershop environment. This intervention addresses known health disparities that exist in the African American community and underscores the need for additional worksite health promotion programs in medically underserved communities.

Mithramycin (MTR) is a clinically approved DNA-binding antitumor antibiotic currently in Phase 2 clinical trials at National Institutes of Health for treatment of osteosarcoma. In view of the resurgence in the studies of this generic antibiotic as a human medicine, we have examined the binding properties of MTR with the integral component of chromatin – histone proteins – as a part of our broad objective to classify DNA-binding molecules in terms of their ability to bind chromosomal DNA alone (single binding mode) or both histones and chromosomal DNA (dual binding mode). The present report shows that besides DNA, MTR also binds to core histones present in chromatin and thus possesses the property of dual binding in the chromatin context. In contrast to the MTR–DNA interaction, association of MTR with histones does not require obligatory presence of bivalent metal ion like Mg2+. As a consequence of its ability to interact with core histones, MTR inhibits histone H3 acetylation at lysine 18, an important signature of active chromatin, in vitro and ex vivo. Reanalysis of microarray data of Ewing sarcoma cell lines shows that upon MTR treatment there is a significant down regulation of genes, possibly implicating a repression of H3K18Ac-enriched genes apart from DNA-binding transcription factors. Association of MTR with core histones and its ability to alter post-translational modification of histone H3 clearly indicates an additional mode of action of this anticancer drug that could be implicated in novel therapeutic strategies.

Intracellular regulatory pathways are replete with protein-protein and protein-DNA interactions, offering attractive targets for therapeutic interventions. So far, most drugs are targeted toward enzymes and extracellular receptors. Protein-protein and protein-DNA interactions have long been considered as “undruggable„. Protein-DNA interactions, in particular, present a difficult challenge due to the repetitive nature of the B-DNA. Recent studies have provided several breakthroughs; however, a design methodology for these classes of inhibitors is still at its infancy. A dominant motif of these macromolecular interactions is an α-helix, raising possibilities that an appropriate conformationally-constrained α-helical peptide may specifically disrupt these interactions. Several methods for conformationally constraining peptides to the α-helical conformation have been developed, including stapling, covalent surrogates of hydrogen bonds and incorporation of unnatural amino acids that restrict the conformational space of the peptide. We will discuss these methods and several case studies where constrained α-helices have been used as building blocks for appropriate molecules. Unlike small molecules, the delivery of these short peptides to their targets is not straightforward as they may possess unfavorable cell penetration and ADME properties. Several methods have been developed in recent times to overcome some of these problems. We will discuss these issues and the prospects of this class of molecules as drugs.