Search

Blood lipid traits are treatable and heritable risk factors for heart disease, a leading cause of mortality worldwide. Although genome-wide association studies (GWASs) have discovered hundreds of variants associated with lipids in humans, most of the causal mechanisms of lipids remain unknown. To better understand the biological processes underlying lipid metabolism, we investigated the associations of plasma protein levels with total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol in blood. We trained protein prediction models based on samples in the Multi-Ethnic Study of Atherosclerosis (MESA) and applied them to conduct proteome-wide association studies (PWASs) for lipids using the Global Lipids Genetics Consortium (GLGC) data. Of the 749 proteins tested, 42 were significantly associated with at least one lipid trait. Furthermore, we performed transcriptome-wide association studies (TWASs) for lipids using 9,714 gene expression prediction models trained on samples from peripheral blood mononuclear cells (PBMCs) in MESA and 49 tissues in the Genotype-Tissue Expression (GTEx) project. We found that although PWASs and TWASs can show different directions of associations in an individual gene, 40 out of 49 tissues showed a positive correlation between PWAS and TWAS signed p values across all the genes, which suggests high-level consistency between proteome-lipid associations and transcriptome-lipid associations.

Health professions students, including occupational therapy students, often have limited exposure to unhoused populations, which may alter their attitudes and self-efficacy to participate in their care. In turn, this could reduce access and quality of care for these marginalized groups. The purpose of this study was to evaluate the impact of a phased multimodal learning approach on interprofessional health sciences students' attitudes and self-efficacy in providing care to unhoused individuals. A pre-posttest single group design was used to evaluate a didactic presentation, poverty simulation, and street-based experiential learning experience. Findings revealed significant differences in students' (N=257) attitudes and self-efficacy in providing care, and many students reported this as an "eye-opening experience." This learning approach evoked a strong emotional response, improved attitudes and self-efficacy, and has implications for future advocacy efforts related to caring for unhoused populations.

Comparison of microbial strains for tolerance to and catabolism of lignin stream constituents toward evaluating microbial hosts for lignin bioconversion.

Water is an increasingly precious resource in California as years of drought, climate change, pollution, as well as an expanding population have all stressed the state's drinking water supplies. Currently, there are increasing concerns about whether regulated and unregulated contaminants in drinking water are linked to a variety of human-health outcomes particularly in socially disadvantaged communities with a history of health risks. To begin to address this data gap by broadly assessing contaminant mixture exposures, the current study was designed to collect tapwater samples from communities in Gold Country, the San Francisco Bay Area, two regions of the Central Valley (Merced/Fresno and Kern counties), and southeast Los Angeles for 251 organic chemicals and 32 inorganic constituents. Sampling prioritized low-income areas with suspected water quality challenges and elevated breast cancer rates. Results indicated that mixtures of regulated and unregulated contaminants were observed frequently in tapwater throughout the areas studied and the types and concentrations of detected contaminants varied by region, drinking-water source, and size of the public water system. Multiple exceedances of enforceable maximum contaminant level(s) (MCL), non-enforceable MCL goal(s) (MCLG), and other health advisories combined with frequent exceedances of benchmark-based hazard indices were also observed in samples collected in all five of the study regions. Given the current focus on improving water quality in socially disadvantaged communities, our study highlights the importance of assessing mixed-contaminant exposures in drinking water at the point of consumption to adequately address human-health concerns (e.g., breast cancer risk). Data from this pilot study provide a foundation for future studies across a greater number of communities in California to assess potential linkages between breast cancer rates and tapwater contaminants.

The copy number of a plasmid is linked to its functionality, yet there have been few attempts to optimize higher-copy-number mutants for use across diverse origins of replication in different hosts. We use a high-throughput growth-coupled selection assay and a directed evolution approach to rapidly identify origin of replication mutations that influence copy number and screen for mutants that improve Agrobacterium-mediated transformation (AMT) efficiency. By introducing these mutations into binary vectors within the plasmid backbone used for AMT, we observe improved transient transformation of Nicotiana benthamiana in four diverse tested origins (pVS1, RK2, pSa and BBR1). For the best-performing origin, pVS1, we isolate higher-copy-number variants that increase stable transformation efficiencies by 60-100% in Arabidopsis thaliana and 390% in the oleaginous yeast Rhodosporidium toruloides. Our work provides an easily deployable framework to generate plasmid copy number variants that will enable greater precision in prokaryotic genetic engineering, in addition to improving AMT efficiency.

Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals of increasing concern to human health. PFAS contamination in water systems has been linked to a variety of sources including hydrocarbon fire suppression activities, industrial and military land uses, agricultural applications of biosolids, and consumer products. To assess PFAS in California tap water, we collected 60 water samples from inside homes in four different geographic regions, both urban and rural. We selected mostly small water systems with known history of industrial chemical or pesticide contamination and that served socioeconomically disadvantaged communities. Thirty percent of the tap water samples (18) had a detection of at least one of the 32 targeted PFAS and most detections (89 %) occurred in heavily industrialized Southeast Los Angeles (SELA). The residents of SELA are predominately Latino and low-income. Concentrations of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) ranged from 6.8 to 13.6 ng/L and 9.4-17.8 ng/L, respectively in SELA and were higher than State (PFOA: 0.007 ng/L; PFOS: 1.0 ng/L) and national health-based goals (zero). To look for geographic patterns, we mapped potential sources of PFAS contamination, such as chrome plating facilities, airports, landfills, and refineries, located near the SELA water systems; consistent with the multiple potential sources in the area, no clear spatial associations were observed. The results indicate the importance of systematic testing of PFAS in tap water, continued development of PFAS regulatory standards and advisories for a greater number of compounds, improved drinking-water treatments to mitigate potential health threats to communities, especially in socioeconomically disadvantaged and industrialized areas.

While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ∼70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model.

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular landscape is not fully established. Utilizing an integrative multi-omics approach, and leveraging data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we show profound sexual dimorphism in the scWAT of sedentary rats and in the dynamic response of this tissue to ExT. Specifically, the scWAT of sedentary females displays -omic signatures related to insulin signaling and adipogenesis, whereas the scWAT of sedentary males is enriched in terms related to aerobic metabolism. These sex-specific -omic signatures are preserved or amplified with ExT. Integration of multi-omic analyses with phenotypic measures identifies molecular hubs predicted to drive sexually distinct responses to training. Overall, this study underscores the powerful impact of sex on adipose tissue biology and provides a rich resource to investigate the scWAT response to ExT.

Abstract Recombinant adeno-associated viral vectors (rAAV) are a powerful tool for gene delivery but have a limited DNA carrying capacity. Efforts to expand this genetic payload have focused on engineering the vector components, such as dual trans-splicing vectors which double the delivery size by exploiting the natural concatenation of rAAV genomes in host nuclei. We hypothesized that inefficient dual vector transduction could be improved by modulating host factors which affect concatenation. Since factors mediating concatenation are not well defined, we performed a genome-wide screen to identify host cell regulators. We discover that Homologous Recombination (HR) is inhibitory to dual vector transduction. We demonstrate that depletion or inhibition of HR factors BRCA1 and Rad51 significantly increase reconstitution of a large split transgene by increasing both concatenation and expression from rAAVs. Our results define roles for DNA damage repair in rAAV transduction and highlight the potential for pharmacological intervention to increase genetic payload of rAAV vectors.

Background: Drug overdose and organo-phosphorous (OP) poisoning are one of the most common forms of deliberate self-harm (DSH) in our society. Some drugs and OP compounds have well-described electrocardiographic (ECG) manifestations in the event of toxicity. This study aims to determine the clinical implications of an electrocardiogram (ECG) in patients with an alleged history of DSH (drug overdose and/or OP poisoning) presenting to the ED. Methodology: We conducted this retrospective study over one and a half years (October 2018 to April 2020). Demographical data, clinical presentations, and ECG findings were extracted from the hospital’s electronic database, coded, and analyzed. Results: Our study population included 364 (0.32%) patients with DSH (OP poisoning and drug overdose), of which the majority (n-224; 61.5%) had presented with a drug overdose. The mean age of the cohort was 33.9 (SD: 13.1) years, with a female preponderance (n-222; 60.9%). The most common presenting complaints were vomiting (n-180; 49.5%), other gastrointestinal complaints (n-146; 40.1%), and giddiness (n-122; 33.5%). At the presentation to ED, the majority had a qSOFA ≥2 (n-212; 58.3%). The most common drugs noted to be consumed singly included benzodiazepines (n-42, 11.5%), paracetamol (n-38; 10.4%), and tricyclic antidepressant (n-20; 5.5%). Polydrug intoxication was seen in 68 (18.7%), and co-ingestion with OP was seen in 26 (7.2%) patients. ECG changes (QTc prolongation) were noted in 187 (51.4%: p-value 0.003) patients. All patients were advised to be admitted after initial stabilization and emergency management; however, 73 (20.1%) patients left the ED against medical advice. During their hospital stay, seven (1.9%) patients succumbed to their illness. Conclusion: Middle-aged female patients are more prone to DSH, with gastrointestinal complaints as the most common presenting symptom. In patients with drug overdose or OP poisoning, ECG changes (QTc prolongation) were noted in the majority of the study population.

Abstract Science is integral to society because it can inform individual, government, corporate, and civil society decision-making on issues such as public health, new technologies or climate change. Yet, public distrust and populist sentiment challenge the relationship between science and society. To help researchers analyse the science-society nexus across different geographical and cultural contexts, we undertook a cross-sectional population survey resulting in a dataset of 71,922 participants in 68 countries. The data were collected between November 2022 and August 2023 as part of the global Many Labs study “Trust in Science and Science-Related Populism” (TISP). The questionnaire contained comprehensive measures for individuals’ trust in scientists, science-related populist attitudes, perceptions of the role of science in society, science media use and communication behaviour, attitudes to climate change and support for environmental policies, personality traits, political and religious views and demographic characteristics. Here, we describe the dataset, survey materials and psychometric properties of key variables. We encourage researchers to use this unique dataset for global comparative analyses on public perceptions of science and its role in society and policy-making.

Abstract Background Reducing the environmental impact of foods consumed is important for meeting climate goals. We aimed to conduct a randomised controlled trial to test whether ecolabels reduce the environmental impact of food selected in worksite cafeterias, alone or in combination with increased availability of more sustainable meal options. Methods Worksite cafeterias (n = 96) were randomised to one of three study groups, with 54 included for final analysis. One group was intended to increase the availability of meat-free options, but no change was implemented. Therefore, this group was treated as part of the control, creating two groups: (1) control (no ecolabels) (n = 35), and (2) ecolabels (n = 19). Regression analysis assessed the primary outcome of total environmental impact of hot meals sold over a 6-week period. Secondary outcome analyses explored the individual environmental indicators that composed the total environmental impact score (i.e., greenhouse gas emissions, biodiversity loss, eutrophication, and water scarcity). The mean weekly environmental impact scores of hot meal options over the full 12-week trial period were assessed using hierarchical mixed effects models. Results There was no significant effect of the intervention on the environmental impact scores of meals sold (mean difference between control and intervention sites: -1.4%, 95%CI: -33.6%, + 30.8%). There was no evidence of an effect in mean weekly environmental impact score (-5.4%, 95%CI: -12.6%, + 2.5%), nor in any of the four individual environmental indicators (greenhouse gas emissions: -3.6%, 95%CI: -30.7%, 34.3%; biodiversity loss: 2.0%, 95%CI: -25.8%, 40.2%; eutrophication: -2.4%, 95%CI: -29.3%, 34.7%; water scarcity: -0.4%, 95%CI: -28.7%, 39.1%). Conclusions Ecolabels may not be an effective tool to shift consumer behaviour in worksite cafeterias towards meals with lower environmental impact. Trial registration The study was pre-registered prospectively on ISRCTN ( https://www.isrctn.com/ISRCTN10268258 ; 06/01/2022).

Science fiction conventions are places where individuals with an interest in diverse genres and mediums can engage with a community that bridges the world of science fiction and fact. Many of these conventions provide a science "track" where science experts share their expertise and research on scientific findings and applications of science with science fiction enthusiasts. This study explored science fiction conference attendees' (n = 241) interest in science, as well as how attendees (n = 172) plan to utilize science shared at science track sessions. Survey responses were analyzed within "STEM career" groups by comparing science track and non-science track attendees, and documenting what science track attendees plan to do with the information gained at a science track session. There were no differences in how science track attendees and non-science track attendees with STEM careers reported their interest in science. For the attendees that did not report having a career related to STEM, science track participants reported higher interest scores than non-science track attendees. Over half of the science track attendees (66%) shared they will apply what they learned from a science track session to their own personal context. Furthermore, the demographics of the survey respondents may suggest that science fiction conventions are an untapped science learning environment connecting to a younger, more diverse community. Overall, recognizing the benefit of science fiction conventions is crucial to provide spaces for accessible venues of science communication to foster an interest in science for a diverse, public audience.

The prevalence of autism spectrum disorder (ASD) has risen significantly in the past two decades. Unfortunately, there is a shortage of mental health providers who have specialized training in delivering evidenced-based services to this population. Early intensive behavioral intervention (EIBI) is an evidenced-based treatment recommended for toddlers with ASD, and school psychologists are uniquely positioned to help children with ASD receive it. However, many school psychologists do not receive adequate training in this subspecialty. This paper makes recommendations to school psychology training programs about how to add or improve training in this subspecialty based on the results of an Office of Special Education Programs grant-funded ASD training program which involved collaboration between a NASP-approved and APA-accredited school psychology training program and a community-based early intensive behavioral intervention (EIBI) clinic. The grant supported development of an interdisciplinary didactic and clinical training program to increase the ASD knowledge, skills, and competencies of school psychology graduate students, with the broader goals of developing a replicable training model and increasing the workforce of trained providers for this underserved population. Fifteen graduate students completed the training program. Outcomes related to trainee knowledge, skills, and competencies, trainee satisfaction, and lessons learned over time analyzed within a logic model that guided the project's development and execution can be informative for other school psychology programs undertaking training in this subspecialty.

IntroductionUrology residency prepares trainees for independent practice. The optimal operative chief resident year experience to prepare for practice is undefined. We analyzed the temporal arc of cases residents complete during their residency compared to their chief year in a multi-institutional cohort.MethodsAccreditation Council for Graduate Medical Education case logs of graduating residents from 2010 to 2022 from participating urology residency programs were aggregated. Resident data for 5 categorized index procedures were recorded: (1) general urology, (2) endourology, (3) reconstructive urology, (4) urologic oncology, and (5) pediatric urology. Interactions were tested between the trends for total case exposure in residency training relative to the chief resident year.ResultsFrom a sample of 479 resident graduates, a total of 1,287,433 total cases were logged, including 375,703 during the chief year (29%). Urologic oncology cases had the highest median percentage completed during chief year (56%) followed by reconstructive urology (27%), general urology (24%), endourology (17%), and pediatric urology (2%). Across the study period, all categories of cases had a downward trend in median percentage completed during chief year except for urologic oncology. However, only trends in general urology (slope of -0.68, P = .013) and endourology (slope of -1.71, P ≤ .001) were significant.ConclusionsOver 50% of cases completed by chief residents are urologic oncology procedures. Current declining trends indicate that residents are being exposed to proportionally fewer general urology and endourology cases during their chief year prior to entering independent practice.

Abstract Purpose Healthcare providers often lack training and education in caring for gender diverse youth. We aimed to explore changes in provider confidence and behaviors following the implementation of an online learning course focused on gender affirming care for youth. Methods An asynchronous, online training consisting of 2 modules was made available in October 2021. Participants were asked to complete 3 surveys for each module they completed: a pre-survey, a post-survey, and a 3-month follow-up survey. Surveys included demographic data and an assessment of provider confidence and self-reported behaviors related to the provision of gender affirming care for adolescents that were in line with the objectives outlined in each module. Paired sample t-tests were used to compare participant confidence at all timepoints. Results Participants (n = 487) completed at least one survey from one module. There was notable diversity in provider types, including mental health providers (n = 86, 17.7%), community health workers (n = 71, 14.6%), and medical students or health professionals (n = 61, 12.5%). Participants were significantly more confident in all aspects of care provision when comparing pre-surveys and post-surveys (p

Abstract Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. Currently, there is no means to non-invasively identify NRF2 activation in living subjects. Here, we show that positron emission tomography imaging with the system xc − radiotracer, [18F]FSPG, provides a sensitive and specific marker of NRF2 activation in orthotopic, patient-derived, and genetically engineered mouse models of NSCLC. We found a NRF2-related gene expression signature in a large cohort of NSCLC patients, suggesting an opportunity to preselect patients prior to [18F]FSPG imaging. Furthermore, we reveal that system xc − is a metabolic vulnerability that can be therapeutically targeted with an antibody-drug conjugate for sustained tumour growth suppression. Overall, our results establish [18F]FSPG as a predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.

Abstract Background Presently incurable, metastatic breast cancer is estimated to occur in as many as 30% of those diagnosed with early-stage breast cancer. Timely and accurate identification of those at risk for developing metastasis using validated biomarkers has the potential to have profound impact on overall survival rates. Our primary goal was to conduct a systematic review and synthesize the existing body of scientific knowledge on the candidate genes and their respective single nucleotide polymorphisms associated with metastasis-related outcomes among patients diagnosed with breast cancer. This knowledge is critical to inform future hypothesis-driven and validation research aimed at enhancing clinical decision-making for breast cancer patients. Methods Using PRISMA guidelines, literature searches were conducted on September 13th, 2023, using PubMed and Embase databases. The systematic review protocol was registered with INPLASY (DOI: https://doi.org/10.37766/inplasy2024.8.0014 ). Covidence software was used to facilitate the screening and article extraction processes. Peer-reviewed articles were selected if authors reported on single nucleotide polymorphisms directly associated with metastasis among adults diagnosed with breast cancer. Findings We identified 451 articles after 44 duplicates were removed resulting in 407 articles to be screened for study inclusion. Three reviewers completed the article screening process which resulted in 86 articles meeting the study inclusion criteria. Sampling varied across studies with the majority utilizing a case-control design (n = 75, 87.2%), with sample sizes ranging from 23 to 1,017 participants having mean age 50.65 ± 4.50 (min-max: 20–75). The synthesis of this internationally generated evidence revealed that the scientific area on the underlying biological contributions to breast cancer metastasis remains predominantly exploratory in nature (n = 74, 86%). Of the 12 studies with reported power analyses, only 9 explicitly stated the power values which ranged from 47.88 to 99%. Discussion Understanding the underlying biological mechanisms contributing to metastasis is a critical component for precision oncological therapeutics and treatment approaches. Current evidence investigating the contribution of SNPs to the development of metastasis is characterized by underpowered candidate gene studies. To inform individualized precision health practices and improve breast cancer survival outcomes, future hypothesis-driven research is needed to replicate these associations in larger, more diverse datasets.

Abstract BerryPortraits (Phenotyping of Ripening Traits) is open source Python-based image-analysis software that rapidly detects and segments berries and extracts morphometric data on fruit quality traits such as berry color, size, shape, and uniformity. Utilizing the YOLOv8 framework and community-developed, actively-maintained Python libraries such as OpenCV, BerryPortraits software was trained on 512 postharvest images (taken under controlled lighting conditions) of phenotypically diverse cranberry populations (Vaccinium macrocarpon Ait.) from the two largest public cranberry breeding programs in the U.S. The implementation of CIELAB, an intuitive and perceptually uniform color space, enables differentiation between berry color and berry brightness, which are confounded in classic RGB color channel measurements. Furthermore, computer vision enables precise and quantifiable color phenotyping, thus facilitating inclusion of researchers and data analysts with color vision deficiency. BerryPortraits is a phenotyping tool for researchers in plant breeding, plant genetics, horticulture, food science, plant physiology, plant pathology, and related fields. BerryPortraits has strong potential applications for other specialty crops such as blueberry, lingonberry, caneberry, grape, and more. As an open source phenotyping tool based on widely-used python libraries, BerryPortraits allows anyone to use, fork, modify, optimize, and embed this software into other tools or pipelines.

Abstract Background Breast cancer, one of the most common forms of cancer, is associated with the highest cancer-related mortality among women worldwide. In comparison to other types of breast cancer, patients diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst outcome because current therapies do not produce long-lasting responses. Hence, innovative therapies that produce persisting responses are a critical need. We previously discovered that hyperactivating purinergic receptors (P2RXs) by increasing extracellular adenosine triphosphate (eATP) concentrations enhances TNBC cell lines’ response to chemotherapy. Heparan sulfate inhibits multiple extracellular ATPases, so it is a molecule of interest in this regard. In turn, heparanase degrades polysulfated polysaccharide heparan sulfate. Importantly, previous work suggests that breast cancer and other cancers express heparanase at high levels. Hence, as heparan sulfate can inhibit extracellular ATPases to facilitate eATP accumulation, it may intensify responses to chemotherapy. We postulated that heparanase inhibitors would exacerbate chemotherapy-induced decreases in TNBC cell viability by increasing heparan sulfate in the cellular microenvironment and hence, augmenting eATP. Methods We treated TNBC cell lines MDA-MB 231, Hs 578t, and MDA-MB 468 and non-tumorigenic immortal mammary epithelial MCF-10A cells with paclitaxel (cytotoxic chemotherapeutic) with or without the heparanase inhibitor OGT 2115 and/or supplemental heparan sulfate. We evaluated cell viability and the release of eATP. Also, we compared the expression of heparanase protein in cell lines and tissues by immunoblot and immunohistochemistry, respectively. In addition, we examined breast-cancer-initiating cell populations using tumorsphere formation efficiency assays on treated cells. Results We found that combining heparanase inhibitor OGT 2115 with chemotherapy decreased TNBC cell viability and tumorsphere formation through increases in eATP and activation of purinergic receptors as compared to TNBC cells treated with single-agent paclitaxel. Conclusion Our data shows that by preventing heparan sulfate breakdown, heparanase inhibitors make TNBC cells more susceptible to chemotherapy by enhancing eATP concentrations.

Abstract Centrioles define centrosome structure and function. Deregulation of centriole numbers can cause developmental defects and cancer. The p53 tumor suppressor limits the growth of cells lacking or harboring additional centrosomes and can be engaged by the “mitotic surveillance” or the “PIDDosome pathway”, respectively. Here, we show that early B cell progenitors frequently present extra centrioles, ensuing their high proliferative activity and related DNA damage. Extra centrioles are efficiently cleared during B cell maturation. In contrast, centriole loss upon Polo-like kinase 4 (Plk4) deletion causes apoptosis and arrests B cell development. This defect can be rescued by co-deletion of Usp28, a critical component of the mitotic surveillance pathway, that restores cell survival and maturation. Centriole-deficient mature B cells are proliferation competent and mount a humoral immune response. Our findings imply that progenitor B cells are intolerant to centriole loss but permissive to centriole amplification, a feature potentially facilitating their malignant transformation.

States and school districts in the USA have begun to create and implement curriculum to promote elementary students' nascent STEM-related interests and to generate their initial knowledge of careers in those fields. Evaluating the efficacy of such interventions warrants valid and reliable tools, which are not presently available for middle childhood (ages 6-11) aged students in lower elementary school (approximately grades 2 to 4). This research study describes the creation and validation of the "STEM Future-Career Interest Survey (STEM Future-CIS)," a survey informed by extant inventories (i.e., "Student Attitudes toward Science," "Technology," "Engineering," and "Math Survey" and "STEM Career Interest Survey") and grounded in the constructs of interest, self-efficacy beliefs, outcome expectations, and personal goals (i.e., social cognitive career theory or SCCT) to better understand the knowledge and interest in S-T-E-M fields for grades 2-4. From two rounds of student and teacher interviews and pilots punctuated by periods of expert review, 804 students (grades 2-4 in the southeastern U.S.) participated in the "STEM Future-CIS." By employing exploratory and confirmatory factor analyses among four models, results affirmed SCCT constructs as a model for how middle childhood aged students conceive their interest to engage in future career considerations in 25 items and four validated factors of "math/science interest," "engineering interest," "technology interest," and "future self." Sampled students were able to report technology and engineering interests; however, they experienced difficulty in differentiating math and science subject areas and the related future career opportunities in engineering and technology.

Purpose of reviewThere is growing consensus that eliciting CD8 + T cells in addition to antibodies may be required for an effective HIV vaccine for both prevention and cure. Here, we review key qualities of vaccine-elicited CD8 + T cells as well as major CD8 + T cell-based delivery platforms used in recent HIV vaccine clinical trials.Recent findingsMuch progress has been made in improving HIV immunogen design and delivery platforms to optimize CD8 + T cell responses. With regards to viral vectors, recent trials have tested newer chimp and human adenovirus vectors as well as a CMV vector. DNA vaccine immunogenicity has been increased by delivering the vaccines by electroporation and together with adjuvants as well as administering them as part of a heterologous regimen. In preclinical models, self-amplifying RNA vaccines can generate durable tissue-based CD8 + T cells. While it may be beneficial for HIV vaccines to recapitulate the functional and phenotypic features of HIV-specific CD8 + T cells isolated from elite controllers, most of these features are not routinely measured in HIV vaccine clinical trials.SummaryIdentifying a vaccine capable of generating durable T cell responses that target mutationally vulnerable epitopes and that can rapidly intercept infecting or rebounding virus remains a challenge for HIV. Comprehensive assessment of HIV vaccine-elicited CD8 + T cells, as well as comparisons between different vaccine platforms, will be critical to advance our understanding of how to design better CD8 + T cell-based vaccines for HIV.

We examine the properties of diesel boiling range ethers made from coupling of alcohols produced by oligomerization of ethanol (Guerbet alcohols) for their utility as low-carbon liquid fuel blendstocks. Basic properties of boiling point, flash point, freezing point, density and viscosity are well suited for blending into diesel fuels. For the mixture of ethers the lightest component, di-n-butyl ether, can be present at up to 20 vol% while still having adequately high flashpoint for safe handling. Soot formation tendency (as yield sooting index) is well below that of conventional diesel. The ethers have similar compatibility with elastomers as conventional diesel, based on Hansen solubility parameter analysis. Oxidation stability was assessed for 30 vol% blends of individual ethers in a conventional diesel fuel using a long-term storage test. Over 6 weeks we observed no formation of peroxides or degradation. n-alkyl ethers with carbon number of 8 or higher have cetane number over 100, which is outside the defined range of cetane number, while branched ethers are over 70. The ethers also blend antagonistically into conventional diesel for cetane number, meaning that the blend cetane value is lower than predicted based on a linear by volume, mass, or mole model. We show that aromatics and naphthenes likely act as radical scavengers to slow or shut down autoignition of the highly reactive ethers at low to medium blend levels. Overall, diesel boiling range ethers show significant promise as high quality low-net carbon diesel blendstocks.