Manipulating insulin signaling to enhance mosquito reproduction

<p>Abstract</p> <p>Backgrond</p> <p>In the mosquito <it>Aedes aegypti </it>the insulin/insulin growth factor I signaling (IIS) cascade is a key regulator of many physiological processes, including reproduction. Two important reproductive events, steroidogenesis in the ovary and yolk synthesis in the fat body, are regulated by the IIS cascade in mosquitoes. The signaling molecule phosphatase and tensin homolog (PTEN) is a key inhibitor of the IIS cascade that helps modulate the activity of the IIS cascade. In <it>Ae. aegypti</it>, six unique splice variants of AaegPTEN were previously identified, but the role of these splice variants, particularly AaegPTEN3 and 6, were unknown.</p> <p>Results</p> <p>Knockdown of AaegPTEN or its specific splice variant AaegPTEN6 (the splice variant thought to regulate reproduction in the ovary and fat body) using RNAi led to a 15–63% increase in egg production with no adverse effects on egg viability during the first reproductive cycle. Knockdown of AaegPTEN3, expressed predominantly in the head, had no effect on reproduction. We also characterized the protein expression patterns of these two splice variants during development and in various tissues during a reproductive cycle.</p> <p>Conclusion</p> <p>Previous studies in a range of organisms, including <it>Drosophila melanogaster </it>and <it>Caenorhabditis elegans</it>, have demonstrated that disruption of the IIS cascade leads to decreased reproduction or sterility. In this study we demonstrate that knockdown of the IIS inhibitor PTEN can actually increase reproduction in the mosquito, at least during the first reproductive cycle.</p

Racial Differences in the Use of Adjuvant Chemotherapy for Breast Cancer in a Large Urban Integrated Health System

Background. Racial differences in breast cancer survival may be in part due to variation in patterns of care. To better understand factors influencing survival disparities, we evaluated patterns of receipt of adjuvant chemotherapy among 2,234 women with invasive, nonmetastatic breast cancer treated at the Henry Ford Health System (HFHS) from 1996 through 2005. Methods. Sociodemographic and clinical information were obtained from linked datasets from the HFHS, Metropolitan Detroit Cancer Surveillance Systems, and U.S. Census. Comorbidity was measured using the Charlson comorbidity index (CCI), and economic deprivation was categorized using a neighborhood deprivation index. Results. African American (AA) women were more likely than whites to have advanced tumors with more aggressive clinical features, to have more comorbidity and to be socioeconomically deprived. While in the unadjusted model, AAs were more likely to receive chemotherapy (odds ratio (OR) 1.22, 95% confidence interval (CI) 1.02–1.46) and to have a delay in receipt of chemotherapy beyond 60 days (OR 1.68, 95% CI, 1.26–1.48), after multivariable adjustment there were no racial differences in receipt (odds ratio (OR) 1.02, 95% confidence interval (CI) 0.73–1.43), or timing of chemotherapy (OR 1.18, 95 CI, 0.8–1.74). Conclusions. Societal factors and not race appear to have an impact on treatment delay among African American women with early breast cancer

The vaccinia chondroitin sulfate binding protein drives host membrane curvature to facilitate fusion

Cellular attachment of viruses determines their cell tropism and species specificity. For entry, vaccinia, the prototypic poxvirus, relies on four binding proteins and an eleven-protein entry fusion complex. The contribution of the individual virus binding proteins to virion binding orientation and membrane fusion is unclear. Here, we show that virus binding proteins guide side-on virion binding and promote curvature of the host membrane towards the virus fusion machinery to facilitate fusion. Using a membrane-bleb model system together with super-resolution and electron microscopy we find that side-bound vaccinia virions induce membrane invagination in the presence of low pH. Repression or deletion of individual binding proteins reveals that three of four contribute to binding orientation, amongst which the chondroitin sulfate binding protein, D8, is required for host membrane bending. Consistent with low-pH dependent macropinocytic entry of vaccinia, loss of D8 prevents virion-associated macropinosome membrane bending, disrupts fusion pore formation and infection. Our results show that viral binding proteins are active participants in successful virus membrane fusion and illustrate the importance of virus protein architecture for successful infection.</p

A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity

Racial Differences in the Use of Adjuvant Chemotherapy for Breast Cancer in a Large Urban Integrated Health System

Background. Racial differences in breast cancer survival may be in part due to variation in patterns of care. To better understand factors influencing survival disparities, we evaluated patterns of receipt of adjuvant chemotherapy among 2,234 women with invasive, nonmetastatic breast cancer treated at the Henry Ford Health System (HFHS) from 1996 through 2005. Methods. Sociodemographic and clinical information were obtained from linked datasets from the HFHS, Metropolitan Detroit Cancer Surveillance Systems, and U.S. Census. Comorbidity was measured using the Charlson comorbidity index (CCI), and economic deprivation was categorized using a neighborhood deprivation index. Results. African American (AA) women were more likely than whites to have advanced tumors with more aggressive clinical features, to have more comorbidity and to be socioeconomically deprived. While in the unadjusted model, AAs were more likely to receive chemotherapy (odds ratio (OR) 1.22, 95% confidence interval (CI) 1.02-1.46) and to have a delay in receipt of chemotherapy beyond 60 days (OR 1.68, 95% CI, 1.26-1.48), after multivariable adjustment there were no racial differences in receipt (odds ratio (OR) 1.02, 95% confidence interval (CI) 0.73-1.43), or timing of chemotherapy (OR 1.18, 95 CI,. Conclusions. Societal factors and not race appear to have an impact on treatment delay among African American women with early breast cancer. Background Despite improvements in available options for breast cancer treatment, there continues to be a considerable gap in survival between African American (AA) and white women with breast cancer Adjuvant chemotherapy and hormonal therapy have had a dramatic impact on breast cancer survival, and in order to optimize longevity, it is critical for patients to receive treatment according to standard clinical guidelines International Journal of Breast Cancer Previous reports on patterns of care have indicated that AA women are less likely to receive standard breast cancer treatment compared with white women We hypothesized that racial disparities in breast cancer survival may be at least in part due to differences in the receipt of standard adjuvant chemotherapy as defined by national treatment guidelines. In order to address this question, we evaluated patterns of breast cancer care provided at the Henry Ford Health System (HFHS), a large integrated health system serving southeastern MI. The goal of this study was to assess patterns of adjuvant chemotherapy administration among women with invasive, nonmetastatic breast cancer comparing AA and white women, and focusing on receipt of standard chemotherapy, duration of treatment, and timing of treatment in relationship to diagnosis. Methods Study Design. This study consisted of a descriptive analysis of adjuvant chemotherapy received by AA and white women diagnosed with invasive, nonmetastatic breast cancer at the HFHS between January 1, 1996 and December 31, 2005. HFHS is a large urban integrated health system located in southeast Michigan founded in 1915 to provide for the health care needs of the city of Detroit and surrounding metropolitan area. HFHS currently consists of 5 hospitals, anchored by Henry Ford Hospital, a 903 bed tertiary care, research and teaching facility; and 36 ambulatory care facilities including 5 sites located within the city of Detroit, and 31 sites located in Wayne (outside of Detroit), Macomb, Oakland, and Washtenaw counties. A single lifetime medical record number (MRN) is used throughout the system to provide continuity of record keeping and medical care. For the purposes of this project, patient sociodemographic, clinical, and treatment information was derived through analyses of linked datasets using the HFHS administrative databases, the Metropolitan Detroit Cancer Surveillance System (MDCSS), and the U.S. Census Bureau. The MDCSS is home for the Detroit SEER registry, which registers all cancers of residents from Wayne, Oakland, and Macomb counties. In the current study, case records were matched from the SEER and HFHS databases using MRN, social security number (SSN), last name, and date of birth. Records that matched for only one variable were manually reviewed to look for character or punctuation errors in other nonmatched fields. Matching resulted in 3,630 record matches. We excluded matches with unknown American Joint Cancer Committee (AJCC) stage (n = 51); first breast surgery at another institution (n = 147); history of a prior malignancy within 6 months of breast cancer diagnosis (n = 52); duplicate records (n = 3); histology code indicating non-breast origin (n = 1); stage IV disease (n = 978), other race (n = 45); no definitive breast surgery (n = 52); and receipt of neoadjuvant chemotherapy (n = 67). These exclusions resulted in a study population of 2,234 (61.5%) white and AA women treated for invasive, nonmetastatic breast cancer at the HFHS. Measurement of Variables. Detailed information on breast cancer treatment, clinical, and socio-demographic data were derived from the HFHS and SEER database and information on neighborhood-level economic deprivation (see deprivation index below) was obtained form the U.S. Census Bureau. All primary breast surgery consisting of lumpectomy (partial mastectomy) or mastectomy (modified radical mastectomy, radical mastectomy, or simple mastectomy) and standard axillary lymph node dissection was performed at the HFHS. Guidelines from the National Comprehensive Cancer Network (NCCN) corresponding to the years of diagnosis were used to define standard adjuvant chemotherapy treatment recommendations according to AJCC stage Patient and clinical characteristics included race (from the medical record listing), age at diagnosis, tumor size, lymph node positivity, histology, grade, and estrogen and progesterone receptor (ER and PR) status. Insurance status was available from the HFHS records and was classified based on the most frequent insurance charged for each treatment visit, and categorized into 3 groups (private, Medicare, and other, including uninsured). Comorbidity was assessed using the Charlson comorbidity index (CCI) a prospectively verified method for classifying comorbid medical conditions which could affect the risk of mortality in longitudinal studies Statistical Analysis. The clinical and sociodemographic characteristics of AA and white women with invasive, nonmetastatic breast cancer were compared by chi-square tests for categorical variables and Student&apos;s t-tests for continuous variables. Separate analyses were conducted to determine racial differences in the use of standard chemotherapy (yes versus no), timing of chemotherapy as determined by the date of diagnosis and the date of chemotherapy initiation (dichotomized using the sample median, 60 days) for cases where detailed chemotherapy records were available and completion of standard chemotherapy (i.e., completing the NCCN recommended number of cycles of treatment). Odds ratios (ORs) for receipt of chemotherapy for AA versus white women and 95% confidence intervals (CIs) were estimated using unconditional logistic regression analyses. Race, age at diagnosis, tumor size, lymph node positivity, hormone receptor status, tumor grade, CCI, deprivation index, and insurance status were assessed individually and in multivariable adjusted models. Unconditional logistic regression was also used to estimate the odds of beginning chemotherapy within 60 days of the date of diagnosis. The analyses consisted of three models, first adjusting for clinical factors only (race, age, tumor size, lymph node positivity, hormone receptor status, tumor grade, and CCI), second adjusting for societal factors (race, deprivation index, and insurance status), and third adjusting for all listed variables. The purpose of performing three different models was to determine whether clinical versus societal factors had a greater impact on racial differences in receipt of adjuvant chemotherapy or in timing of chemotherapy. All regression models were run with and without a clustering correction for census tract. Results There were no significant racial differences in age at diagnosis adjuvant chemotherapy for AA women compared with white women. The average time from diagnosis to initiation of chemotherapy for white women was 67.9 days (S.D. 38.6) compared to 73.2 (S.D. 36.4) for AA women, P = 0.049. When time to adjuvant chemotherapy was stratified at 60 days (the sample median), white women were more likely to be treated prior to 60 days (55%) compared to AA women (43%), P &lt; 0.001. Discussion While breast cancer survival rates continue to improve over time http://seer.cancer.gov/csr/1975 2008/, there remains a marked discrepancy in survival by race, Strengths of this study include the inclusion of women enrolled in a large integrated urban heath care system which provides uniform access to high-quality medical care. In addition, the linked HFHS and SEER database allowed for availability of detailed and accurate clinical, demographic, and treatment data including details on adjuvant chemotherapy received. Our measure of socioeconomic deprivation was a sophisticated measure developed through the linkage with U.S. Census data, however, the derived deprivation index was not based on factors specific to the individual patient such as income, education, or family support, and may therefore be subject to misclassification. In conclusion, race had no direct impact on receipt of adjuvant chemotherapy or timing of chemotherapy among a cohort of women treated at a large urban integrated health care system in Detroit. The fact that AA women were more likely to receive adjuvant chemotherapy in the unadjusted model was largely explained by the more advanced stage at diagnosis among AAs that suggests the need for better screening and access to early treatment interventions. Delay in receipt of chemotherapy among AA women was largely explained by societal factors which likely have a direct effect on access to care. However, the delay was on average less than one week and may not have had significant clinical impact. Nevertheless, it serves to remind health care providers of the importance of making health care accessible to all

Diversity and toxicity of Pseudo-nitzschia species in Monterey Bay : perspectives from targeted and adaptive sampling

Author Posting. © The Author(s), 2018. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Harmful Algae 78 (2018): 129-141, doi:10.1016/j.hal.2018.08.006.Monterey Bay, California experiences near-annual blooms of Pseudo-nitzschia that can affect marine animal health and the economy, including impacts to tourism and commercial/recreational fisheries. One species in particular, P. australis, has been implicated in the most toxic of events, however other species within the genus can contribute to widespread variability in community structure and associated toxicity across years. Current monitoring methods are limited in their spatial coverage as well as their ability to capture the full suite of species present, thereby hindering understanding of HAB events and limiting predictive accuracy. An integrated deployment of multiple in situ platforms, some with autonomous adaptive sampling capabilities, occurred during two divergent bloom years in the bay, and uncovered detailed aspects of population and toxicity dynamics. A bloom in 2013 was characterized by spatial differences in Pseudo39 nitzschia populations, with the low-toxin producer P. fraudulenta dominating the inshore community and toxic P. australis dominating the offshore community. An exceptionally toxic bloom in 2015 developed as a diverse Pseudo-nitzschia community abruptly transitioned into a bloom of highly toxic P. australis within the time frame of a week. Increases in cell density and proliferation coincided with strong upwelling of nutrients. High toxicity was driven by silicate limitation of the dense bloom. This temporal shift in species composition mirrored the shift observed further north in the California Current System off Oregon and Washington. The broad scope of sampling and unique platform capabilities employed during these studies revealed important patterns in bloom formation and persistence for Pseudo-nitzschia. Results underscore the benefit of expanded biological observing capabilities and targeted sampling methods to capture more comprehensive spatial and temporal scales for studying and predicting future events.This work was supported by the National Oceanic and Atmospheric Administration (NA11NOS4780055, NA11NOS4780056, NA11NOS4780030) and a fellowship to H. Bowers from the Packard Foundation

First-In-Human Study in Cancer Patients Establishing the Feasibility of Oxygen Measurements in Tumors Using Electron Paramagnetic Resonance With the OxyChip

Objective: The overall objective of this clinical study was to validate an implantable oxygen sensor, called the ‘OxyChip’, as a clinically feasible technology that would allow individualized tumor-oxygen assessments in cancer patients prior to and during hypoxia-modification interventions such as hyperoxygen breathing. Methods: Patients with any solid tumor at ≤3-cm depth from the skin-surface scheduled to undergo surgical resection (with or without neoadjuvant therapy) were considered eligible for the study. The OxyChip was implanted in the tumor and subsequently removed during standard-of-care surgery. Partial pressure of oxygen (pO2) at the implant location was assessed using electron paramagnetic resonance (EPR) oximetry. Results: Twenty-three cancer patients underwent OxyChip implantation in their tumors. Six patients received neoadjuvant therapy while the OxyChip was implanted. Median implant duration was 30 days (range 4–128 days). Forty-five successful oxygen measurements were made in 15 patients. Baseline pO2 values were variable with overall median 15.7 mmHg (range 0.6–73.1 mmHg); 33% of the values were below 10 mmHg. After hyperoxygenation, the overall median pO2 was 31.8 mmHg (range 1.5–144.6 mmHg). In 83% of the measurements, there was a statistically significant (p ≤ 0.05) response to hyperoxygenation. Conclusions: Measurement of baseline pO2 and response to hyperoxygenation using EPR oximetry with the OxyChip is clinically feasible in a variety of tumor types. Tumor oxygen at baseline differed significantly among patients. Although most tumors responded to a hyperoxygenation intervention, some were non-responders. These data demonstrated the need for individualized assessment of tumor oxygenation in the context of planned hyperoxygenation interventions to optimize clinical outcomes

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Ancient DNA and deep population structure in sub-Saharan African foragers

Multiple lines of genetic and archaeological evidence suggest that there were major demographic changes in the terminal Late Pleistocene epoch and early Holocene epoch of sub-Saharan Africa(1-4). Inferences about this period are challenging to make because demographic shifts in the past 5,000 years have obscured the structures of more ancient populations(3,5). Here we present genome-wide ancient DNA data for six individuals from eastern and south-central Africa spanning the past approximately 18,000 years (doubling the time depth of sub-Saharan African ancient DNA), increase the data quality for 15 previously published ancient individuals and analyse these alongside data from 13 other published ancient individuals. The ancestry of the individuals in our study area can be modelled as a geographically structured mixture of three highly divergent source populations, probably reflecting Pleistocene interactions around 80-20 thousand years ago, including deeply diverged eastern and southern African lineages, plus a previously unappreciated ubiquitous distribution of ancestry that occurs in highest proportion today in central African rainforest hunter-gatherers. Once established, this structure remained highly stable, with limited long-range gene flow. These results provide a new line of genetic evidence in support of hypotheses that have emerged from archaeological analyses but remain contested, suggesting increasing regionalization at the end of the Pleistocene epoch. DNA analysis of 6 individuals from eastern and south-central Africa spanning the past approximately 18,000 years, and of 28 previously published ancient individuals, provides genetic evidence supporting hypotheses of increasing regionalization at the end of the Pleistocene.info:eu-repo/semantics/publishedVersio

Genomic epidemiology reveals multiple introductions of Zika virus into the United States

Zika virus (ZIKV) is causing an unprecedented epidemic linked to severe congenital abnormalities. In July 2016, mosquito-borne ZIKV transmission was reported in the continental United States; since then, hundreds of locally acquired infections have been reported in Florida. To gain insights into the timing, source, and likely route(s) of ZIKV introduction, we tracked the virus from its first detection in Florida by sequencing ZIKV genomes from infected patients and Aedes aegypti mosquitoes. We show that at least 4 introductions, but potentially as many as 40, contributed to the outbreak in Florida and that local transmission is likely to have started in the spring of 2016-several months before its initial detection. By analysing surveillance and genetic data, we show that ZIKV moved among transmission zones in Miami. Our analyses show that most introductions were linked to the Caribbean, a finding corroborated by the high incidence rates and traffic volumes from the region into the Miami area. Our study provides an understanding of how ZIKV initiates transmission in new regions