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•A biodegradable biopolymeric matrix of chitosan-starch was developed.•Steam sterilization of the matrix increased its swelling equilibrium.•Macrobeads supported the survival of ...bacteria at high levels for more than a year.•Bacterial release from macrospheres was gradual both in water and soil.•The developed material showed potential as a support for biofertilizers.
The study examines the use of macrobeads for the controlled-release of bacteria. Macrobeads were prepared by an easy dripping-technique using 20/80 wt/wt chitosan-starch blends and sodium tripolyphosphate as cross-linking agent. The resulting polymeric matrix was examined by SEM, XRD, TGA, and solid-RMN. The swelling-equilibrium, thermal behaviour, crystallinity, and size of macrobeads were affected by the autoclave-sterilization. The diameter of the sterilized xerogel was c.a. 1.6 mm. The results suggested that ionotropic-gelation and neutralization were the mechanisms underlying hydrogel formation. Plant growth-promoting bacteria (PGPB) were loaded into macrobeads separately or co-inoculated. Bacteria loaded macrobeads were dried and stored. Bacteria survived at least 12 months in orders of 109 CFU of A. brasilense/g and 108 CFU of P. fluorescens/g. Bacterial release in sterile saline solution tended to a super Case-II transport mechanism. Polymeric-matrix release efficiently both PGPB in natural soils, which uncovers their potential for the formulation of novel and improved biofertilizers.
The WHO Director-General has issued a call for action to eliminate cervical cancer as a public health problem. To help inform global efforts, we modelled potential human papillomavirus (HPV) ...vaccination and cervical screening scenarios in low-income and lower-middle-income countries (LMICs) to examine the feasibility and timing of elimination at different thresholds, and to estimate the number of cervical cancer cases averted on the path to elimination.
The WHO Cervical Cancer Elimination Modelling Consortium (CCEMC), which consists of three independent transmission-dynamic models identified by WHO according to predefined criteria, projected reductions in cervical cancer incidence over time in 78 LMICs for three standardised base-case scenarios: girls-only vaccination; girls-only vaccination and once-lifetime screening; and girls-only vaccination and twice-lifetime screening. Girls were vaccinated at age 9 years (with a catch-up to age 14 years), assuming 90% coverage and 100% lifetime protection against HPV types 16, 18, 31, 33, 45, 52, and 58. Cervical screening involved HPV testing once or twice per lifetime at ages 35 years and 45 years, with uptake increasing from 45% (2023) to 90% (2045 onwards). The elimination thresholds examined were an average age-standardised cervical cancer incidence of four or fewer cases per 100 000 women-years and ten or fewer cases per 100 000 women-years, and an 85% or greater reduction in incidence. Sensitivity analyses were done, varying vaccination and screening strategies and assumptions. We summarised results using the median (range) of model predictions.
Girls-only HPV vaccination was predicted to reduce the median age-standardised cervical cancer incidence in LMICs from 19·8 (range 19·4–19·8) to 2·1 (2·0–2·6) cases per 100 000 women-years over the next century (89·4% 86·2–90·1 reduction), and to avert 61·0 million (60·5–63·0) cases during this period. Adding twice-lifetime screening reduced the incidence to 0·7 (0·6–1·6) cases per 100 000 women-years (96·7% 91·3–96·7 reduction) and averted an extra 12·1 million (9·5–13·7) cases. Girls-only vaccination was predicted to result in elimination in 60% (58–65) of LMICs based on the threshold of four or fewer cases per 100 000 women-years, in 99% (89–100) of LMICs based on the threshold of ten or fewer cases per 100 000 women-years, and in 87% (37–99) of LMICs based on the 85% or greater reduction threshold. When adding twice-lifetime screening, 100% (71–100) of LMICs reached elimination for all three thresholds. In regions in which all countries can achieve cervical cancer elimination with girls-only vaccination, elimination could occur between 2059 and 2102, depending on the threshold and region. Introducing twice-lifetime screening accelerated elimination by 11–31 years. Long-term vaccine protection was required for elimination.
Predictions were consistent across our three models and suggest that high HPV vaccination coverage of girls can lead to cervical cancer elimination in most LMICs by the end of the century. Screening with high uptake will expedite reductions and will be necessary to eliminate cervical cancer in countries with the highest burden.
WHO, UNDP, UN Population Fund, UNICEF–WHO–World Bank Special Program of Research, Development and Research Training in Human Reproduction, Canadian Institute of Health Research, Fonds de recherche du Québec–Santé, Compute Canada, National Health and Medical Research Council Australia Centre for Research Excellence in Cervical Cancer Control.
The neuroethology of friendship Brent, Lauren J.N.; Chang, Steve W.C.; Gariépy, Jean-François ...
Annals of the New York Academy of Sciences,
20/May , Letnik:
1316, Številka:
1
Journal Article
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Friendship pervades the human social landscape. These bonds are so important that disrupting them leads to health problems, and difficulties forming or maintaining friendships attend neuropsychiatric ...disorders like autism and depression. Other animals also have friends, suggesting that friendship is not solely a human invention but is instead an evolved trait. A neuroethological approach applies behavioral, neurobiological, and molecular techniques to explain friendship with reference to its underlying mechanisms, development, evolutionary origins, and biological function. Recent studies implicate a shared suite of neural circuits and neuromodulatory pathways in the formation, maintenance, and manipulation of friendships across humans and other animals. Health consequences and reproductive advantages in mammals additionally suggest that friendship has adaptive benefits. We argue that understanding the neuroethology of friendship in humans and other animals brings us closer to knowing fully what it means to be human.
Human interleukin-12 (hIL-12) is a cytokine with anticancer activity, but its systemic application is limited by toxic inflammatory responses. We assessed the safety and biological effects of an ...hIL-12 gene, transcriptionally regulated by an oral activator. A multicenter phase 1 dose-escalation trial (NCT02026271) treated 31 patients undergoing resection of recurrent high-grade glioma. Resection cavity walls were injected (day 0) with a fixed dose of the hIL-12 vector (Ad-RTS-hIL-12). The oral activator for hIL-12, veledimex (VDX), was administered preoperatively (assaying blood-brain barrier penetration) and postoperatively (measuring hIL-12 transcriptional regulation). Cohorts received 10 to 40 mg of VDX before and after Ad-RTS-hIL-12. Dose-related increases in VDX, IL-12, and interferon-γ (IFN-γ) were observed in peripheral blood, with about 40% VDX tumor penetration. Frequency and severity of adverse events, including cytokine release syndrome, correlated with VDX dose, reversing promptly upon discontinuation. VDX (20 mg) had superior drug compliance and 12.7 months median overall survival (mOS) at mean follow-up of 13.1 months. Concurrent corticosteroids negatively affected survival: In patients cumulatively receiving >20 mg versus ≤20 mg of dexamethasone (days 0 to 14), mOS was 6.4 and 16.7 months, respectively, in all patients and 6.4 and 17.8 months, respectively, in the 20-mg VDX cohort. Re-resection in five of five patients with suspected recurrence after Ad-RTS-hIL-12 revealed mostly pseudoprogression with increased tumor-infiltrating lymphocytes producing IFN-γ and programmed cell death protein 1 (PD-1). These inflammatory infiltrates support an immunological antitumor effect of hIL-12. This phase 1 trial showed acceptable tolerability of regulated hIL-12 with encouraging preliminary results.
The activity of voltage-gated sodium channels has long been linked to disorders of neuronal excitability such as epilepsy and chronic pain. Recent genetic studies have now expanded the role of sodium ...channels in health and disease, to include autism, migraine, multiple sclerosis, cancer as well as muscle and immune system disorders. Transgenic mouse models have proved useful in understanding the physiological role of individual sodium channels, and there has been significant progress in the development of subtype selective inhibitors of sodium channels. This review will outline the functions and roles of specific sodium channels in electrical signalling and disease, focusing on neurological aspects. We also discuss recent advances in the development of selective sodium channel inhibitors.
Context. The origin and dynamical evolution of star clusters is an important topic in stellar astrophysics. Several models have been proposed in order to understand the formation of bound and unbound ...clusters and their evolution, and they can be tested by examining the kinematical and dynamical properties of clusters over a wide range of ages and masses. Aims. We use the Gaia-ESO Survey products to study four open clusters (IC 2602, IC 2391, IC 4665, and NGC 2547) that lie in the age range between 20 and 50 Myr. Methods. We employ the gravity index γ and the equivalent width of the lithium line at 6708 Å together with effective temperature Teff and the metallicity of the stars in order to discard observed contaminant stars. Then we derive the cluster radial velocity dispersions σc, the total cluster mass Mtot, and the half mass radius rhm. Using the Gaia-DR1 TGAS catalogue, we independently derive the intrinsic velocity dispersion of the clusters from the astrometric parameters of cluster members. Results. The intrinsic radial velocity dispersions derived by the spectroscopic data are higher than those derived from the TGAS data, possibly due to the different masses of the considered stars. Using Mtot and rhm we derive the virial velocity dispersion σvir and we find that three out of four clusters are supervirial. This result is in agreement with the hypothesis that these clusters are dispersing, as predicted by the “residual gas expulsion” scenario. However, recent simulations show that the virial ratio of young star clustersmay be overestimated if it is determined using the global velocity dispersion, since the clusters are not fully relaxed.
The purpose of this study was to determine if localized delivery of IL-12 encoded by a replication-incompetent adenoviral vector engineered to express IL-12 via a RheoSwitch Therapeutic System
(RTS
) ...gene switch (Ad-RTS-IL-12) administered intratumorally which is inducibly controlled by the oral activator veledimex is an effective approach for glioma therapy. Mice bearing 5-10-day-old intracranial GL-261 gliomas were intratumorally administered Ad-RTS-mIL-12 in which IL-12 protein expression is tightly controlled by the activator ligand, veledimex. Local tumor viral vector levels concomitant with veledimex levels, IL-12-mRNA expression, local and systemic cytokine expression, tumor and systemic flow cytometry and overall survival were studied. Ad-RTS-mIL-12+veledimex elicited a dose-related increase in tumor IL-12 mRNA and IL-12 protein and discontinuation of veledimex resulted in a return to baseline levels. These changes correlated with local immune and antitumor responses. Veledimex crossed the blood-brain barrier in both orthotopic GL-261 mice and cynomolgus monkeys. We have demonstrated that this therapy induced localized controlled production of IL-12 which correlates with an increase in tumor-infiltrating lymphocytes (TILs) leading to the desired biologic response of tumor growth inhibition and regression. At day 85 (study termination), 65% of the animals that received veledimex at 10 or 30 mg/m
/day were alive and tumor free. In contrast, the median survival for the other groups were: vehicle 23 days, bevacizumab 20 days, temozolomide 33 days and anti-PD-1 37 days. These findings suggest that the controlled intratumoral production of IL-12 induces local immune cell infiltration and improved survival in glioma, thereby demonstrating that this novel regulated immunotherapeutic approach may be an effective form of therapy for glioma.
Cortical folding mainly takes place in the third trimester of pregnancy and may therefore be influenced by preterm birth. The aim of this study was to evaluate the development of specific cortical ...structures between early age (around 30weeks postmenstrual age) and term-equivalent age (TEA, around 40weeks postmenstrual age) in 71 extremely preterm infants, and to associate this to clinical characteristics and neurodevelopmental outcome at two years of age. First, analysis showed that the central sulcus (CS), lateral fissure (LF) and insula (INS) were present at early MRI in all infants, whereas the other sulci (post-central sulcus PCS, superior temporal sulcus STS, superior SFS and inferior IFS frontal sulcus) were only seen in part of the infants. Relative growth from early to TEA examination was largest in the SFS. A rightward asymmetry of the surface area was seen in development between both examinations except for the LF, which showed a leftward asymmetry at both time points. Second, lower birth weight z-score, multiple pregnancy and prolonged mechanical ventilation showed negative effects on cortical folding of the CS, LF, INS, STS and PCS, mainly on the first examination, suggesting that sulci developing the earliest were the most affected by clinical factors. Finally, in this cohort, a clear association between cortical folding and neurodevelopmental outcome at two years corrected age was found, particularly for receptive language.
•This article focuses on reviewing modeling and simulation effort in metal additive manufacturing taking places at U.S. Department of Energy national laboratories.•An integrated computational ...approach from process-structure-properties-performance is necessary to ultimately enable engineering and optimization to specific performance requirements.•Models and simulation tools from processing to performance are being developed at multiple lengths scales to account for the complex structure of additive manufactured metals and to understand their performance response.
We have determined how most of the transcriptional regulators encoded in the eukaryote Saccharomyces cerevisiae associate with genes across the genome in living cells. Just as maps of metabolic ...networks describe the potential pathways that may be used by a cell to accomplish metabolic processes, this network of regulator-gene interactions describes potential pathways yeast cells can use to regulate global gene expression programs. We use this information to identify network motifs, the simplest units of network architecture, and demonstrate that an automated process can use motifs to assemble a transcriptional regulatory network structure. Our results reveal that eukaryotic cellular functions are highly connected through networks of transcriptional regulators that regulate other transcriptional regulators.
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