Explore the vast range of titles available.

Administration of a widely used 5‐hydroxytryptamine receptor (5HT3AR) antagonist (ondansetron) potently inhibited the development of experimentally induced opioid dependence and withdrawal responses in mice and humans. However, in several studies examining withdrawal symptoms in subjects with chronic opioid use disorders (OUDs), ondansetron exhibited reduced or absent efficacy. Because attenuation of opioid withdrawal symptomatology is mediated within the brain, this study examined single‐dose ondansetron pharmacokinetics in the blood and brain of mice. We demonstrate that ondansetron concentrations in the brain (Cbrain ng/mg) are 1000‐fold lower than the blood concentrations (Cblood ng/ml) and decrease rapidly after ondansetron administration; and that a large percentage of brain ondansetron remains in the ventricular fluid. These results indicate that the ondansetron dose, and the time window between ondansetron and opioid administration, and when withdrawal is assessed are critical considerations for clinical studies involving subjects with chronic OUD. The pharmacokinetic results and the dosing considerations discussed here can be used to improve the design of subsequent clinical trials, which will test whether a more prolonged period of ondansetron administration can provide a desperately needed therapy that can prevent the development of neonatal opioid withdrawal syndrome in babies born to mothers with chronic OUD.

Background Respiratory virus infections are important causes of morbidity and mortality among pediatric and adult patients. These viruses infect respiratory epithelial cells, where they may induce specific metabolite alterations. As a proof-of-concept, we investigate the novel use of liquid chromatography (LC) combined with quadrupole time-of-flight mass spectrometry (Q-TOF) for the study of host cell metabolite alterations to diagnose and differentiate respiratory viruses. Methods We studied nasopharyngeal swab samples positive for respiratory viruses by the eSensor Respiratory Viral Panel (GenMark Diagnostics, Carlsbad, CA). Banked, frozen samples (−80°C) stored in viral transport media were retrieved and thawed. Aliquots of 100 μL were centrifuged at 13.3 × g for 15 minutes, and the filtrate was analyzed by Agilent 6545 Quadrupole LC/Q-TOF (Agilent Technologies, Santa Clara, CA). Compounds were separated using a novel column arrangement based on hydrophobicity and charge using a quaternary solvent manager, followed by accurate mass analysis by LC/Q-TOF. Agilent Mass Profiler 3D principal component analysis was performed, and compound identification was completed using the METLIN metabolite database. Results A total of 235 specimens were tested by LC/Q-TOF, including 195 positive specimens [including adenovirus, coronavirus, influenza A H1N1 and H3N2, influenza B, human metapneumovirus, parainfluenza viruses 1, 2, 3, and 4, respiratory syncytial virus (RSV), and rhinovirus] as well as 40 negative clinical specimens. LC/Q-TOF primary component analysis (PCA) allowed preliminary identification of key metabolites that distinguished all virus-positive specimens compared with the negative group, and differentiated respiratory viruses from one another including between influenza A 2009 H1N1 and H3N2 subtypes (Figure 1). Conclusion Preliminary data from our LC/Q-TOF analysis show that respiratory viruses exhibit different host cell metabolomic profiles that allow viral differentiation to the species level, and for influenza A virus, the subtype level. This metabolomic approach has substantial potential for diagnostic applications in infectious diseases directly from patient samples, and may be eventually adapted for point-of-care testing. Disclosures All authors: No reported disclosures.

Prior work shows western US forest wildfire activity increased abruptly in the mid-1980s. Large forest wildfires and areas burned in them have continued to increase over recent decades, with most of the increase in lightning-ignited fires. Northern US Rockies forests dominated early increases in wildfire activity, and still contributed 50% of the increase in large fires over the last decade. However, the percentage growth in wildfire activity in Pacific northwestern and southwestern US forests has rapidly increased over the last two decades. Wildfire numbers and burned area are also increasing in non-forest vegetation types. Wildfire activity appears strongly associated with warming and earlier spring snowmelt. Analysis of the drivers of forest wildfire sensitivity to changes in the timing of spring demonstrates that forests at elevations where the historical mean snow-free season ranged between two and four months, with relatively high cumulative warm-season actual evapotranspiration, have been most affected. Increases in large wildfires associated with earlier spring snowmelt scale exponentially with changes in moisture deficit, and moisture deficit changes can explain most of the spatial variability in forest wildfire regime response to the timing of spring. This article is part of the themed issue ‘The interaction of fire and mankind’.

Nasopharyngeal carcinoma is characterised by distinct geographical distribution and is particularly prevalent in east and southeast Asia. Epidemiological trends in the past decade have shown that its incidence has declined gradually but progressively, and mortality has been reduced substantially. These findings probably reflect lifestyle and environmental changes, enhanced understanding of the pathogenesis and risk factors, population screening, advancements in imaging techniques, and individualised comprehensive chemoradiotherapy strategies. In particular, plasma Epstein-Barr virus (EBV) DNA has been used for population screening, prognostication, predicting treatment response for therapeutic adaptation, and disease surveillance. Moreover, the widespread application of intensity-modulated radiotherapy and optimisation of chemotherapy strategies (induction, concurrent, adjuvant) have contributed to improved survival with reduced toxicities. Among the existing developments in novel therapeutics, immune checkpoint therapies have achieved breakthroughs for treating recurrent or metastatic disease and represent a promising future direction in nasopharyngeal carcinoma.

Government policies during the COVID-19 pandemic have drastically altered patterns of energy demand around the world. Many international borders were closed and populations were confined to their homes, which reduced transport and changed consumption patterns. Here we compile government policies and activity data to estimate the decrease in CO2 emissions during forced confinements. Daily global CO2 emissions decreased by –17% (–11 to –25% for ±1σ) by early April 2020 compared with the mean 2019 levels, just under half from changes in surface transport. At their peak, emissions in individual countries decreased by –26% on average. The impact on 2020 annual emissions depends on the duration of the confinement, with a low estimate of –4% (–2 to –7%) if prepandemic conditions return by mid-June, and a high estimate of –7% (–3 to –13%) if some restrictions remain worldwide until the end of 2020. Government actions and economic incentives postcrisis will likely influence the global CO2 emissions path for decades.COVID-19 pandemic lockdowns have altered global energy demands. Using government confinement policies and activity data, daily CO2 emissions have decreased by ~17% to early April 2020 against 2019 levels; annual emissions could be down by 7% (4%) if normality returns by year end (mid-June).

We aimed to improve the outcomes for locoregionally advanced nasopharyngeal carcinoma by testing the feasibility and safety of the addition of bevacizumab to chemoradiotherapy. We enrolled patients older than 18 years with stage IIB–IVB nasopharyngeal carcinoma from 19 centres in North America and Hong Kong. Treatment consisted of three cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m2) both given on days 1, 22, and 43 of radiation (70 Gy) with intensity-modulated radiation therapy delivered over 33 days on a daily basis, Monday through Friday. Patients then received three cycles of bevacizumab (15 mg/kg) and cisplatin (80 mg/m2), both given on days 64, 85, and 106 after radiation, and three cycles of fluorouracil (1000 mg/m2 per day), given on days 64–67, 85–88, and 106–109 after radiation. The primary endpoint was the occurrence of treatment-related grade 4 haemorrhage or any grade 5 adverse event in the first year. Analyses were done with all eligible patients who started protocol treatment. The trial is registered at ClinicalTrials.gov, number NCT00408694. From Dec 13, 2006, to Feb 5, 2009, we enrolled 46 patients, of whom 44 were eligible for analysis. We recorded no grade 3–4 haemorrhages or grade 5 adverse events; nine patients (20%) had a treatment-related grade 1–2 haemorrhage. Nine patients had one or more grade 4 blood or bone marrow-related complication (grade 4 leucopenia was noted in six patients, grade 4 lymphopenia in five, grade 4 neutrophils in five, and grade 4 anaemia in one). One patient had two grade 4 infections with grade 3–4 neutrophils. One patient reported grade 4 tinnitus, one patient reported grade 4 thrombosis, one reported grade 4 radiation mucositis, and two reported grade 4 pharyngolaryngeal pain. With a median follow-up of 2·5 years (IQR 2·1–2·9), the estimated 2 year locoregional progression-free interval was 83·7% (95% CI 72·6–94·9), the 2 year distant metastasis-free interval was 90·8% (82·2–99·5), the 2 year progression-free survival was 74·7% (61·8–87·6), and 2 year overall survival was 90·9% (82·3–99·4). The addition of bevacizumab to standard chemoradiation treatment for patients with nasopharyngeal carcinoma is feasible, and might delay the progression of subclinical distant disease. National Cancer Institute, USA.

Engineering bioelectronic components and set-ups that mimic natural systems is extremely challenging. Here we report the design of a protein-only redox film inspired by the architecture of bacterial electroactive biofilms. The nanowire scaffold is formed using a chimeric protein that results from the attachment of a prion domain to a rubredoxin (Rd) that acts as an electron carrier. The prion domain self-assembles into stable fibres and provides a suitable arrangement of redox metal centres in Rd to permit electron transport. This results in highly organized films, able to transport electrons over several micrometres through a network of bionanowires. We demonstrate that our bionanowires can be used as electron-transfer mediators to build a bioelectrode for the electrocatalytic oxygen reduction by laccase. This approach opens opportunities for the engineering of protein-only electron mediators (with tunable redox potentials and optimized interactions with enzymes) and applications in the field of protein-only bioelectrodes. A protein-only redox film inspired by the architecture of bacterial electroactive biofilms has been developed. The film is formed using a rubredoxin–prion domain chimeric protein. The prion domains self-assemble into fibres that are decorated with rubredoxin. This results in highly organized films, able to transport electrons over several microns, and wire enzymes to electrodes.

Kinesin-8 proteins are microtubule motors that are often involved in regulation of mitotic spindle length and chromosome alignment. They move towards the plus ends of spindle microtubules and regulate the dynamics of these ends due, at least in some species, to their microtubule depolymerization activity. Plasmodium spp. exhibit an atypical endomitotic cell division in which chromosome condensation and spindle dynamics in the different proliferative stages are not well understood. Genome-wide shared orthology analysis of Plasmodium spp. revealed the presence of two kinesin-8 motor proteins, kinesin-8X and kinesin-8B. Here we studied the biochemical properties of kinesin-8X and its role in parasite proliferation. In vitro, kinesin-8X has motility and depolymerization activities like other kinesin-8 motors. To understand the role of Plasmodium kinesin-8X in cell division, we used fluorescence-tagging and live cell imaging to define its location, and gene targeting to analyse its function, during all proliferative stages of the rodent malaria parasite P. berghei life cycle. The results revealed a spatio-temporal involvement of kinesin-8X in spindle dynamics and an association with both mitotic and meiotic spindles and the putative microtubule organising centre (MTOC). Deletion of the kinesin-8X gene revealed a defect in oocyst development, confirmed by ultrastructural studies, suggesting that this protein is required for oocyst development and sporogony. Transcriptome analysis of Δkinesin-8X gametocytes revealed modulated expression of genes involved mainly in microtubule-based processes, chromosome organisation and the regulation of gene expression, supporting a role for kinesin-8X in cell division. Kinesin-8X is thus required for parasite proliferation within the mosquito and for transmission to the vertebrate host.

During viral infections, antibodies and T cells act together to prevent pathogen spread and remove virus-infected cells. Virus-specific adaptive immunity can, however, also trigger pathological processes characterized by localized or systemic inflammatory events. The protective and/or pathological role of virus-specific T cells in SARS-CoV-2 infection has been the focus of many studies in COVID-19 patients and in vaccinated individuals. Here, we review the works that have elucidated the function of SARS-CoV-2-specific T cells in patients and in vaccinated individuals. Understanding whether SARS-CoV-2-specific T cells are more linked to protection or pathogenesis is pivotal to define future therapeutic and prophylactic strategies to manage the current pandemic.