Cisplatin drug delivery using gold-coated iron oxide nanoparticles for enhanced tumour targeting with external magnetic fields

The platinum-based chemotherapeutic drug cisplatin is highly effective in the treatment of solid tumours, but its use is restricted by poor bioavailability, severe dose-limiting side effects and rapid development of drug resistance. In light of this we have tethered the active component of cisplatin to goldcoated iron oxide nanoparticles to improve its delivery to tumours and increase its efficacy. Iron oxide nanoparticles (FeNPs) were synthesised via a co-precipitation method before gold was reduced onto the surface (Au@FeNPs). Aquated cisplatin was used to attach {Pt(NH3)2} to the nanoparticles by a thiolated polyethylene glycol linker forming the desired product (Pt@Au@FeNP). The nanoparticles were characterised by dynamic light scattering, scanning transmission electron microscopy, UV–Vis spectrophotometry, inductively coupled plasma mass spectrometry and electron probe microanalysis. The nanoparticles increase in size as they are constructed, with the synthesised FeNPs having a diameter of 5– 50 nm, which increases to 20–80 nm for the Au@FeNPs, and to 60–120 nm for the Pt@Au@FeNPs. Nanoparticle drug loading was found to be 7.9 10 4 moles of platinum per gram of gold. The FeNPs appear to have little inherent cytotoxicity, whereas the Au@FeNPs are as active as cisplatin in the A2780 and A2780/cp70 cancer cell lines. More importantly the Pt@Au@FeNPs are up to 110-fold more cytotoxic than cisplatin. Finally, external magnets were used to demonstrate that the nanoparticles could be accumulated in specific regions and that cell growth inhibition was localised to those areas

Early weight gain trajectories in first episode anorexia:Predictors of outcome for emerging adults in outpatient treatment

Plain English summary A key feature of anorexia nervosa (AN) is an unhealthily low body weight. Previous studies show that more weight gained early in inpatient treatment leads to better outcomes. This study tried to see if this was also true for outpatients receiving treatment for the first time. All participants were emerging adults between the ages of 16 and 25 who had been ill for less than 3 years. Weight was recorded across the first 12 weekly treatment sessions. Statistics showed that the patients fit roughly into four different groups in early treatment, each with different starting weights and rates of weight gain in the first 12 treatment sessions. The group a patient belonged to could sometimes be predicted by vomiting behaviours, level of depression, and patients’ perception of parental tolerance and expectations at the start of treatment. Out of the four groups, three did relatively well 1 year later, but one small group of patients did not. This small group had a higher starting weight than many of the other groups but did not gain any weight across the first 12 sessions. These patients could benefit from a change or increase in the amount or intensity of treatment after the first 12 treatment session

Transformative Sea-level Rise Research and Planning: Establishing a University, Tribal, and Community Partnership for a Resilient California North Coast

Sea-level rise (SLR) is and will continue to be a pressing issue in the rural, North Coast region of California, especially since nearby Wigi (or Humboldt Bay) is experiencing one of the fastest rates of relative SLR on the U.S. West Coast. In this paper, we argue that SLR presents a transformative opportunity to rekindle environmental relationships and reshape the future of the California North Coast and beyond. As the preeminent higher education institution of the region, Cal Poly Humboldt has the responsibility to be a leader in education, research, and planning for climate resilience. We describe efforts of the Cal Poly Humboldt Sea Level Rise Institute to establish a university-Tribal-community partnership that braids together different approaches and ways of knowing to develop research and planning that supports a resilient California North Coast. Since Wigi is projected to experience the effects of SLR sooner than the rest of the state, the North Coast region is poised to act as an incubator for new ideas and solutions, including Indigenous knowledge systems, and to play a role in influencing equitable, resilient, and transformative SLR adaptation processes in other parts of the state and the world. This will require developing programming and expertise in specific disciplinary areas, but, more importantly, will require the development of opportunities and spaces for various disciplines, ways of knowing, and sectors (e.g. Tribal nations, academia, government, NGOs, private companies, and community groups) to converge and bring the best of what they have to address climate-induced challenges and opportunities

Response of Southeast Asian rice root architecture and anatomy phenotypes to drought stress

Drought stress in Southeast Asia greatly affects rice production, and the rice root system plays a substantial role in avoiding drought stress. In this study, we examined the phenotypic and genetic correlations among root anatomical, morphological, and agronomic phenotypes over multiple field seasons. A set of >200 rice accessions from Southeast Asia (a subset of the 3000 Rice Genomes Project) was characterized with the aim to identify root morphological and anatomical phenotypes related to productivity under drought stress. Drought stress resulted in slight increases in the basal metaxylem and stele diameter of nodal roots. Although few direct correlations between root phenotypes and grain yield were identified, biomass was consistently positively correlated with crown root number and negatively correlated with stele diameter. The accessions with highest grain yield were characterized by higher crown root numbers and median metaxylem diameter and smaller stele diameter. Genome-wide association study (GWAS) revealed 162 and 210 significant SNPs associated with root phenotypes in the two seasons which resulted in identification of 59 candidate genes related to root development. The gene OsRSL3 was found in a QTL region for median metaxylem diameter. Four SNPs in OsRSL3 were found that caused amino acid changes and significantly associated with the root phenotype. Based on the haplotype analysis for median metaxylem diameter, the rice accessions studied were classified into five allele combinations in order to identify the most favorable haplotypes. The candidate genes and favorable haplotypes provide information useful for the genetic improvement of root phenotypes under drought stress

An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice

Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Herein, we show that the ribonucleoside analog β-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (β-D-N4-hydroxycytidine-5′-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple coronaviruses and oral bioavailability highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Changes in Mycobacterium tuberculosis Genotype Families Over 20 Years in a Population-Based Study in Northern Malawi

BACKGROUND: Despite increasing interest in possible differences in virulence and transmissibility between different genotypes of M. tuberculosis, very little is known about how genotypes within a population change over decades, or about relationships to HIV infection. METHODS AND PRINCIPAL FINDINGS: In a population-based study in rural Malawi we have examined smears and cultures from tuberculosis patients over a 20-year period using spoligotyping. Isolates were grouped into spoligotype families and lineages following previously published criteria. Time trends, HIV status, drug resistance and outcome were examined by spoligotype family and lineage. In addition, transmissibility was examined among pairs of cases with known epidemiological contact by assessing the proportion of transmissions confirmed for each lineage, on the basis of IS6110 RFLP similarity of the M tuberculosis strains. 760 spoligotypes were obtained from smears from 518 patients from 1986-2002, and 377 spoligotypes from cultures from 347 patients from 2005-2008. There was good consistency in patients with multiple specimens. Among 781 patients with first episode tuberculosis, the majority (76%) had Lineage 4 ("European/American") strains; 9% had Lineage 3 ("East-African/Indian"); 8% Lineage 1 ("Indo-Oceanic"); and 2% Lineage 2 ("East-Asian"); others unclassifiable. Over time the proportion of Lineage 4 decreased from >90% to 60%, with an increase in the other 3 lineages (p<0.001). Lineage 1 strains were more common in those with HIV infection, even after adjusting for age, sex and year. There were no associations with drug resistance or outcome, and no differences by lineage in the proportion of pairs in which transmission was confirmed. CONCLUSIONS: This is the first study to describe long term trends in the four M. tuberculosis lineages in a population. Lineage 4 has probably been longstanding in this population, with relatively recent introductions and spread of Lineages1-3, perhaps influenced by the HIV epidemic

Last Men Standing: Chlamydatus Portraits and Public Life in Late Antique Corinth

Notable among the marble sculptures excavated at Corinth are seven portraits of men wearing the long chlamys of Late Antique imperial office. This unusual costume, contemporary portrait heads, and inscribed statue bases all help confirm that new public statuary was created and erected at Corinth during the 4th and 5th centuries. These chlamydatus portraits, published together here for the first time, are likely to represent the Governor of Achaia in his capital city, in the company of local benefactors. Among the last works of the ancient sculptural tradition, they form a valuable source of information on public life in Late Antique Corinth

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure