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Efficacy of a T Cell-Biased Adenovirus Vector as a Zika Virus Vaccine

Zika virus (ZIKV) is a major public health concern due to the risk of congenital Zika syndrome in developing fetuses and Guillain-Barre syndrome in adults. Currently, there are no approved vaccines available to protect against infection. Adenoviruses are safe and highly immunogenic vaccine vectors capable of inducing lasting humoral and cellular immune responses. Here, we developed two Adenovirus (Ad) vectored Zika virus vaccines by inserting a ZIKV prM-E gene expression cassette into human Ad types 4 (Ad4-prM-E) and 5 (Ad5-prM-E). Immune correlates indicate that Ad5-prM-E vaccination induces both an anti-ZIKV antibody and T-cell responses whereas Ad4-prM-E vaccination only induces a T-cell response. In a highly lethal challenge in an interferon α/β receptor knockout mice, 80% of Ad5 vaccinated animals and 33% of Ad4 vaccinated animals survived a lethal ZIKV challenge, whereas no animals in the sham vaccinated group survived. In an infection model utilizing immunocompetent C57BL/6 mice that were immunized and then treated with a blocking anti-IFNAR-1 antibody immediately before ZIKV challenge, 100% of Ad4-prM-E and Ad5-prM-E vaccinated mice survived. This indicates that Ad4-prM-E vaccination is protective without the development of detectable anti-ZIKV antibodies. The protection seen in these highly lethal mouse models demonstrate the efficacy of Ad vectored vaccines for use against ZIKV

Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix.

Metastasis requires tumor cells to navigate through a stiff stroma and squeeze through confined microenvironments. Whether tumors exploit unique biophysical properties to metastasize remains unclear. Data show that invading mammary tumor cells, when cultured in a stiffened three-dimensional extracellular matrix that recapitulates the primary tumor stroma, adopt a basal-like phenotype. Metastatic tumor cells and basal-like tumor cells exert higher integrin-mediated traction forces at the bulk and molecular levels, consistent with a motor-clutch model in which motors and clutches are both increased. Basal-like nonmalignant mammary epithelial cells also display an altered integrin adhesion molecular organization at the nanoscale and recruit a suite of paxillin-associated proteins implicated in invasion and metastasis. Phosphorylation of paxillin by Src family kinases, which regulates adhesion turnover, is similarly enhanced in the metastatic and basal-like tumor cells, fostered by a stiff matrix, and critical for tumor cell invasion in our assays. Bioinformatics reveals an unappreciated relationship between Src kinases, paxillin, and survival of breast cancer patients. Thus adoption of the basal-like adhesion phenotype may favor the recruitment of molecules that facilitate tumor metastasis to integrin-based adhesions. Analysis of the physical properties of tumor cells and integrin adhesion composition in biopsies may be predictive of patient outcome

GeorgeOral Immunization of Rhesus Macaques with Adenoviral HIV Vaccines Using Enteric-coated Capsules

Targeted delivery of vaccine candidates to the gastrointestinal (GI) tract holds potential for mucosal immunization, particularly against mucosal pathogens like the human immunodeficiency virus (HIV). Among the different strategies for achieving targeted release in the GI tract, namely the small intestine, pH sensitive enteric coating polymers have been shown to protect solid oral dosage forms from the harsh digestive environment of the stomach and dissolve relatively rapidly in the small intestine by taking advantage of the luminal pH gradient. We developed an enteric polymethacrylate formulation for coating hydroxy-propyl-methyl-cellulose (HPMC) capsules containing lyophilized Adenoviral type 5 (Ad5) vectors expressing HIV-1 gag and a string of six highly-conserved HIV-1 envelope peptides representing broadly cross-reactive CD4+ and CD8+ T cell epitopes. Oral immunization of rhesus macaques with these capsules primed antigen-specific mucosal and systemic immune responses and subsequent intranasal delivery of the envelope peptide cocktail using a mutant cholera toxin adjuvant boosted cellular immune responses including, antigen-specific intracellular IFN-γ-producing CD4+ and CD8+ effector memory T cells in the intestine. These results suggest that the combination of oral adenoviral vector priming followed by intranasal protein/peptide boosting may be an effective mucosal HIV vaccination strategy for targeting viral antigens to the GI tract and priming systemic and mucosal immunity

Healthcare outcomes in undocumented immigrants undergoing two emergency dialysis approaches

BACKGROUND: Current estimates suggest 6,500 undocumented end-stage renal disease (ESRD) patients in the United States are ineligible for scheduled hemodialysis and require emergent dialysis. In order to remain in compliance with Emergency Medicaid, an academic health center altered its emergency dialysis criteria from those emphasizing interdialytic interval to a set emphasizing numerical thresholds. We report the impact of this administrative change on the biochemical parameters, utilization, and adverse outcomes in an undocumented patient cohort. METHODS: This retrospective case series examines 19 undocumented ESRD patients during a 6-month transition divided into three 2-month periods (P1, P2, P3). In P1, patients received emergent dialysis based on interdialytic interval and clinical judgment. In P2 (early transition) and P3 (equilibrium), patients were dialyzed according to strict numerical criteria coupled with clinical judgment. RESULTS: Emergent criteria-based dialysis (P2 and P3) was associated with increased potassium, blood urea nitrogen (BUN), and acidosis as compared to P1 (p < 0.05). Overnight hospitalizations were more common in P2 and P3 (p < 0.05). More frequent adverse events were noted in P2 as compared to P1 and P3, with an odds ratio (OR) for the composite endpoint (intubation, bacteremia, myocardial infarction, intensive care unit admission) of 48 (5.9 - 391.2) and 16.5 (2.5 - 108.6), respectively. Per-patient reimbursement-to-cost ratios increased during criteria-based dialysis periods (P1: 1.49, P2: 2.3, P3: 2.49). DISCUSSION: Strict adherence to criteria-based dialysis models increases biochemical abnormalities while improving Medicaid reimbursement for undocumented immigrants. Alternatives to emergent dialysis are required which minimize cost, while maintaining dignity, safety, and quality of life.

Helsinki Stroke Model Is Transferrable With "Real-World" Resources and Reduced Stroke Thrombolysis Delay to 34 min in Christchurch

Background: Christchurch hospital is a tertiary hospital in New Zealand supported by five general neurologists with after-hours services provided mainly by onsite non-neurology medical residents. We assessed the transferrability and impact of the Helsinki Stroke model on stroke thrombolysis door-to-needle time (DNT) in Christchurch hospital. Methods: Key components of the Helsinki Stroke model were implemented first in 2015 with introduction of patient pre-notification and thrombolysis by the computed tomography (CT) suite, followed by implementation of direct transfer to CT on ambulance stretcher in May 2017. Data from the prospective thrombolysis registry which began in 2012 were analyzed for the impact of these interventions on median DNT. Results: Between May and December 2017, 46 patients were treated with alteplase, 25 (54%) patients were treated in-hours (08:00-17:00 non-public holiday weekdays) and 21 (46%) patients were treated after-hours. The in-hours, after-hours, and overall median (interquartile range) DNTs were 34 (28-43), 47 (38-60), and 40 (30-51) minutes. The corresponding times in 2012-2014 prior to interventions were 87 (68-106), 86 (72-116), and 87 (71-112) minutes, representing median DNT reduction of 53, 39, and 47 minutes, respectively (p-values <0.01). The interventions also resulted in significant reductions in the overall median door-to-CT time (from 49 to 19 min), CT-to-needle time (32 to 20 min) and onset-to-needle time (168 to 120 min). Conclusion: The Helsinki stroke model is transferrable with real-world resources and reduced stroke DNT in Christchurch by over 50%.Peer reviewe

Trajectories of Depressive Symptoms Among a Population of HIV-Infected Men and Women in Routine HIV Care in the United States

Depressive symptoms vary in severity and chronicity. We used group-based trajectory models to describe trajectories of depressive symptoms (measured using the Patient Health Questionnaire-9) and predictors of trajectory group membership among 1493 HIV-infected men (84%) and 292 HIV-infected women (16%). At baseline, 29% of women and 26% of men had depressive symptoms. Over a median of 30 months of follow-up, we identified four depressive symptom trajectories for women (labeled “low” [experienced by 56% of women], “mild/moderate” [24%], “improving” [14%], and “severe” [6%]) and five for men (“low” [61%], “mild/moderate” [14%], “rebounding” [5%], “improving” [13%], and “severe” [7%]). Baseline antidepressant prescription, panic symptoms, and prior mental health diagnoses were associated with more severe or dynamic depressive symptom trajectories. Nearly a quarter of participants experienced some depressive symptoms, highlighting the need for improved depression management. Addressing more severe or dynamic depressive symptom trajectories may require interventions that additionally address mental health comorbidities

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance

The clustering of intermediate redshift quasars as measured by the Baryon Oscillation Spectroscopic Survey

We measure the quasar two-point correlation function over the redshift range 2.2<z<2.8 using data from the Baryon Oscillation Spectroscopic Survey. We use a homogeneous subset of the data consisting of 27,129 quasars with spectroscopic redshifts---by far the largest such sample used for clustering measurements at these redshifts to date. The sample covers 3,600 square degrees, corresponding to a comoving volume of 9.7(Gpc/h)^3 assuming a fiducial LambdaCDM cosmology, and it has a median absolute i-band magnitude of -26, k-corrected to z=2. After accounting for redshift errors we find that the redshift space correlation function is fit well by a power-law of slope -2 and amplitude s_0=(9.7\pm 0.5)Mpc/h over the range 3<s<25Mpc/h. The projected correlation function, which integrates out the effects of peculiar velocities and redshift errors, is fit well by a power-law of slope -1 and r_0=(8.4\pm 0.6)Mpc/h over the range 4<R<16Mpc/h. There is no evidence for strong luminosity or redshift dependence to the clustering amplitude, in part because of the limited dynamic range in our sample. Our results are consistent with, but more precise than, previous measurements at similar redshifts. Our measurement of the quasar clustering amplitude implies a bias factor of b~3.5 for our quasar sample. We compare the data to models to constrain the manner in which quasars occupy dark matter halos at z~2.4 and infer that such quasars inhabit halos with a characteristic mass of ~10^{12}Msun/h with a duty cycle for the quasar activity of 1 per cent.Comment: 20 pages, 18 figures. Minor modifications to match version accepted by journa