Nervous System of Felis Domestica

This 34 page thesis examines the embryology, anatomy and histology of the nervous system of Felis domestica

Janus kinase mutations in mice lacking PU.1 and Spi-B drive B cell leukemia through reactive oxygen species-induced DNA damage

Precursor B cell acute lymphoblastic leukemia (B-ALL) is caused by genetic lesions in developing B cells that function as drivers for the accumulation of additional mutations in an evolutionary selection process. We investigated secondary drivers of leukemogenesis in a mouse model of B-ALL driven by PU.1/Spi-B deletion (Mb1-CreΔPB). Whole-exome-sequencing analysis revealed recurrent mutations in Jak3 (encoding Janus kinase 3), Jak1, and Ikzf3 (encoding Aiolos). Mutations with a high variant-allele frequency (VAF) were dominated by C¡T transition mutations that were compatible with activation-induced cytidine deaminase, whereas the majority of mutations, with a low VAF, were dominated by C¡A transversions associated with 8-oxoguanine DNA damage caused by reactive oxygen species (ROS). The Janus kinase (JAK) inhibitor ruxolitinib delayed leukemia onset, reduced ROS and ROS-induced gene expression signatures, and altered ROS-induced mutational signatures. These results reveal that JAK mutations can alter the course of leukemia clonal evolution through ROS-induced DNA damage

Effect of police enforcement and extreme social inequalities on violence and mental health among women who sell sex: findings from a cohort study in London, UK

OBJECTIVES: To examine legal and social determinants of violence, anxiety/depression among sex workers. METHODS: A participatory prospective cohort study among women (inclusive of transgender) ≥18 years, selling sex in the last 3 months in London between 2018 and 2019. We used logistic generalised estimating equation models to measure associations between structural factors on recent (6 months) violence from clients or others (local residents, strangers), depression/anxiety (Patient Health Questionnaire-4). RESULTS: 197 sex workers were recruited (96% cisgender-women; 46% street-based; 54% off-street) and 60% completed a follow-up questionnaire. Street-based sex workers experienced greater inequalities compared with off-street in relation to recent violence from clients (73% vs 36%); police (42% vs 7%); intimate partner violence (IPV) (56% vs 18%) and others (67% vs 17%), as well as homelessness (65% vs 7%) and recent law enforcement (87% vs 9%). Prevalence of any STI was 17.5% (17/97). For street-based sex workers, recent arrest was associated with violence from others (adjusted OR (aOR) 2.77; 95% CI 1.11 to 6.94) and displacement by police was associated with client violence (aOR 4.35; 95% CI 1.36 to 13.90). Financial difficulties were also associated with client violence (aOR 4.66; 95% CI 1.64 to 13.24). Disability (aOR 3.85; 95% CI 1.49 to 9.95) and client violence (aOR 2.55; 95% CI 1.10 to 5.91) were associated with anxiety/depression. For off-street sex workers, financial difficulties (aOR 3.66; 95% CI 1.64 to 8.18), unstable residency (aOR 3.19; 95% CI 1.36 to 7.49), IPV (aOR 3.77; 95% CI 1.30 to 11.00) and alcohol/drug use were associated with client violence (aOR 3.16; 95% CI 1.26 to 7.92), while always screening and refusing clients was protective (aOR 0.36; 95% CI 0.15 to 0.87). Disability (aOR 5.83; 95% CI 2.34 to 14.51), unmet mental health needs (aOR 3.08; 95% CI 1.15 to 8.23) and past eviction (aOR 3.99; 95% CI 1.23 to 12.92) were associated with anxiety/depression. CONCLUSIONS: Violence, anxiety/depression are linked to poverty, unstable housing and police enforcement. We need to modify laws to allow sex workers to work safely and increase availability of housing and mental health services

Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer

IntroductionAccumulating evidence suggests that both levels and activity of the estrogen receptor (ER) and the progesterone receptor (PR) are dramatically influenced by growth-factor receptor (GFR) signaling pathways, and that this crosstalk is a major determinant of both breast cancer progression and response to therapy. The phosphatidylinositol 3-kinase (PI3K) pathway, a key mediator of GFR signaling, is one of the most altered pathways in breast cancer. We thus examined whether deregulated PI3K signaling in luminal ER+ breast tumors is associated with ER level and activity and intrinsic molecular subtype.MethodsWe defined two independent molecular signatures of the PI3K pathway: a proteomic (reverse-phase proteomic array) PI3K signature, based on protein measurement for PI3K signaling intermediates, and a PI3K transcriptional (mRNA) signature based on the set of genes either induced or repressed by PI3K inhibitors. By using these signatures, we scored each ER+ breast tumor represented in multiple independent expression-profiling datasets (four mRNA, n = 915; one protein, n = 429) for activation of the PI3K pathway. Effects of PI3K inhibitor BEZ-235 on ER expression and activity levels and cell growth were tested by quantitative real-time PCR and cell proliferation assays.ResultsWithin ER+ tumors, ER levels were negatively correlated with the PI3K activation scores, both at the proteomic and transcriptional levels, in all datasets examined. PI3K signature scores were also higher in ER+ tumors and cell lines of the more aggressive luminal B molecular subtype versus those of the less aggressive luminal A subtype. Notably, BEZ-235 treatment in four different ER+ cell lines increased expression of ER and ER target genes including PR, and treatment with IGF-I (which signals via PI3K) decreased expression of ER and target genes, thus further establishing an inverse functional relation between ER and PI3K. BEZ-235 had an additional effect on tamoxifen in inhibiting the growth of a number of ER+ cell lines.ConclusionsOur data suggest that luminal B tumors have hyperactive GFR/PI3K signaling associated with lower ER levels, which has been correlated with resistance to endocrine therapy. Targeting PI3K in these tumors might reverse loss of ER expression and signaling and restore hormonal sensitivity

An epigenomic approach to therapy for tamoxifen-resistant breast cancer

Tamoxifen has been a frontline treatment for estrogen receptor alpha (ERα)-positive breast tumors in premenopausal women. However, resistance to tamoxifen occurs in many patients. ER still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ERα remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ERα signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ERα signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ERα gene by the BET protein BRD3/4, and facilitates ERα gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ERα signaling pathway and the growth of Tam-R breast cancer cells in culture. Using a Tam-R breast cancer xenograft mouse model, we demonstrated in vivo anti-breast cancer activity by JQ1 and a strong long-lasting effect of combination therapy with JQ1 and the ER degrader fulvestrant. Taken together, we provide evidence that the epigenomic proteins BRD3/4 and WHSC1 are essential regulators of estrogen receptor signaling and are novel therapeutic targets for treatment of Tam-R breast cancer

More on FOX News: FOXA1 on the horizon of estrogen receptor function and endocrine response

Estrogen receptor α (ER) is a major driver of breast cancer and the target of endocrine therapy. Full disclosure of the cofactors regulating ER interactions with chromatin and its transcriptional regulatory activity is still elusive. Novel genome-wide profiling tools have mapped ER binding events in breast cancer cells and delineated cofactors important in ER activity. Among these, the Forkhead protein FOXA1 is emerging as a key factor dictating global chromatin structure and the transcriptional function of ER in breast and non-breast cancer cells. The significance of FOXA1 in the chromatin interactions and transcriptional regulation of both estrogen- and tamoxifen-bound ER, and in supporting tamoxifen-resistant cell growth, may impact current endocrine therapies

It takes two: Evidence for reduced sexual conflict over parental care in a biparental canid

In biparental systems, sexual conflict over parental investment predicts that the parent providing care experiences greater reproductive costs. This inequality in parental contribution is reduced when offspring survival is dependent on biparental care. However, this idea has received little empirical attention. Here, we determined whether mothers and fathers differed in their contribution to care in a captive population of coyotes (Canis latrans). We performed parental care assays on 8 (n = 8 males, 8 females) mated pairs repeatedly over a 10-week period (i.e., 5–15 weeks of litter age) when pairs were first-time breeders (2011), and again as experienced breeders (2013). We quantified consistent individual variation (i.e., repeatability) in 8 care behaviors and examined within- and among-individual correlations to determine if behavioral plasticity within or parental personality across seasons varied by sex. Finally, we extracted hormone metabolites (i.e., cortisol and testosterone) from fecal samples collected during gestation to describe potential links between hormonal mechanisms and individual consistency in parental behaviors. Parents differed in which behaviors were repeatable: mothers demonstrated consistency in provisioning and pup-directed aggression, whereas fathers were consistent in pup checks. However, positive within-individual correlations for identical behaviors (e.g., maternal versus paternal play) suggested that the rate of change in all behaviors except provisioning was highly correlated between the sexes. Moreover, positive among-individual correlations among 50% of identical behaviors suggested that personality differences across parents were highly correlated. Lastly, negative among-individual correlations among pup-directed aggression, provisioning, and gestational testosterone in both sexes demonstrated potential links between preparental hormones and labile parental traits. We provide novel evidence that paternal contribution in a biparental species reaches near equivalent rates of their partners

Local Response in Health Emergencies: Key Considerations for Addressing the COVID-19 Pandemic in Informal Urban Settlements

This paper highlights the major challenges and considerations for addressing COVID-19 in informal settlements. It discusses what is known about vulnerabilities and how to support local protective action. There is heightened concern about informal urban settlements because of the combination of population density and inadequate access to water and sanitation, which makes standard advice about social distancing and washing hands implausible. There are further challenges to do with the lack of reliable data and the social, political and economic contexts in each setting that will influence vulnerability and possibilities for action. The potential health impacts of COVID-19 are immense in informal settlements, but if control measures are poorly executed these could also have severe negative impacts. Public health interventions must be balanced with social and economic interventions, especially in relation to the informal economy upon which many poor urban residents depend. Local residents, leaders and communitybased groups must be engaged and resourced to develop locally appropriate control strategies, in partnership with local governments and authorities. Historically, informal settlements and their residents have been stigmatized, blamed, and subjected to rules and regulations that are unaffordable or unfeasible to adhere to. Responses to COVID-19 should not repeat these mistakes. Priorities for enabling effective control measures include: collaborating with local residents who have unsurpassed knowledge of relevant spatial and social infrastructures, strengthening coordination with local governments, and investing in improved data for monitoring the response in informal settlements

Low-latency gravitational wave alert products and their performance in anticipation of the fourth LIGO-Virgo-KAGRA observing run

Multi-messenger searches for binary neutron star (BNS) and neutron star-black hole (NSBH) mergers are currently one of the most exciting areas of astronomy. The search for joint electromagnetic and neutrino counterparts to gravitational wave (GW)s has resumed with Advanced LIGO (aLIGO)'s, Advanced Virgo (AdVirgo)'s and KAGRA's fourth observing run (O4). To support this effort, public semi-automated data products are sent in near real-time and include localization and source properties to guide complementary observations. Subsequent refinements, as and when available, are also relayed as updates. In preparation for O4, we have conducted a study using a simulated population of compact binaries and a Mock Data Challenge (MDC) in the form of a real-time replay to optimize and profile the software infrastructure and scientific deliverables. End-to-end performance was tested, including data ingestion, running online search pipelines, performing annotations, and issuing alerts to the astrophysics community. In this paper, we present an overview of the low-latency infrastructure as well as an overview of the performance of the data products to be released during O4 based on a MDC. We report on expected median latencies for the preliminary alert of full bandwidth searches (29.5 s) and for the creation of early warning triggers (-3.1 s), and show consistency and accuracy of released data products using the MDC. This paper provides a performance overview for LVK low-latency alert structure and data products using the MDC in anticipation of O4