Emergence and migration of trunk neural crest cells in a snake, the California Kingsnake (Lampropeltis getula californiae)

<p>Abstract</p> <p>Background</p> <p>The neural crest is a group of multipotent cells that emerges after an epithelial-to-mesenchymal transition from the dorsal neural tube early during development. These cells then migrate throughout the embryo, giving rise to a wide variety derivatives including the peripheral nervous system, craniofacial skeleton, pigment cells, and endocrine organs. While much is known about neural crest cells in mammals, birds, amphibians and fish, relatively little is known about their development in non-avian reptiles like snakes and lizards.</p> <p>Results</p> <p>In this study, we show for the first time ever trunk neural crest migration in a snake by labeling it with DiI and immunofluorescence. As in birds and mammals, we find that early migrating trunk neural crest cells use both a ventromedial pathway and an inter-somitic pathway in the snake. However, unlike birds and mammals, we also observed large numbers of late migrating neural crest cells utilizing the inter-somitic pathway in snake.</p> <p>Conclusions</p> <p>We found that while trunk neural crest migration in snakes is very similar to that of other amniotes, the inter-somitic pathway is used more extensively by late-migrating trunk neural crest cells in snake.</p

Optimization of a Langmuir-Taylor detector for lithium

This paper describes the construction and optimization of a Langmuir-Taylor detector for lithium, using a rhenium ribbon. The absolute detection probability of this very sensitive detector is measured and the dependence of this probability with oxygen pressure and surface temperature is studied. Sources of background signal and their minimization are also discussed in details. And a comparison between our data concerning the response time of the detector and literature values is given. A theoretical analysis has been made: this analysis supports the validity of the Saha-Langmuir law to relate the ionization probability to the work function. Finally, the rapid variations of the work function with oxygen pressure and temperature are explained by a chemical equilibrium model.Comment: 11 pages, 7 figures, to appear in Rev. Sci. Instru

Automated Security Analysis of IoT Software Updates

IoT devices often operate unsupervised in ever-changing environments for several years. Therefore, they need to be updated on a regular basis. Current approaches for software updates on IoT, like the recent SUIT proposal, focus on granting integrity and confidentiality but do not analyze the content of the software update, especially the IoT application which is deployed to IoT devices. To this aim, in this paper, we present IoTAV, an automated software analysis framework for systematically verifying the security of the applications contained in software updates w.r.t. a given security policy. Our proposal can be adopted transparently by current IoT software updates workflows. We prove the viability of IoTAV&nbsp;by testing our methodology on a set of actual RIOT OS applications. Experimental results indicate that the approach is viable in terms of both reliability and performance, leading to the identification of 26 security policy violations in 31 real-world RIOT applications

Structural snapshots of the reaction coordinate for O-GlcNAc transferase

Visualization of the reaction coordinate undertaken by glycosyltransferases has remained elusive, but is critical for understanding this important class of enzyme. Using substrates and substrate mimics, we describe structural snapshots of all species along the kinetic pathway for human O-GlcNAc transferase, an intracellular enzyme that catalyzes installation of a dynamic post-translational modification. The structures reveal key features of the mechanism and show that substrate participation is important during catalysis

Omega-3 Fatty Acid and Iron Supplementation Alone, but Not in Combination, Lower Inflammation and Anemia of Infection in Mycobacterium tuberculosis-Infected Mice

Progressive inflammation and anemia are common in tuberculosis (TB) and linked to poor clinical outcomes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have inflammation-resolving properties, whereas iron supplementation in TB may have limited efficacy and enhance bacterial growth. We investigated effects of iron and EPA/DHA supplementation, alone and in combination, on inflammation, anemia, iron status markers and clinical outcomes in Mycobacterium tuberculosis-infected C3HeB/FeJ mice. One week post-infection, mice received the AIN-93 diet without (control) or with supplemental iron (Fe), EPA/DHA, or Fe+EPA/DHA for 3 weeks. Mice supplemented with Fe or EPA/DHA had lower soluble transferrin receptor, ferritin and hepcidin than controls, but these effects were attenuated in Fe+EPA/DHA mice. EPA/DHA increased inflammation-resolving lipid mediators and lowered lung IL-1α, IFN-γ, plasma IL-1β, and TNF-α. Fe lowered lung IL-1α, IL-1β, plasma IL-1β, TNF-α, and IL-6. However, the cytokine-lowering effects in the lungs were attenuated with Fe+EPA/DHA. Mice supplemented with EPA/DHA had lower lung bacterial loads than controls, but this effect was attenuated in Fe+EPA/DHA mice. Thus, individually, post-infection EPA/DHA and iron supplementation lowered systemic and lung inflammation and mitigated anemia of infection in TB, but not when combined. EPA/DHA also enhanced bactericidal effects and could support inflammation resolution and management of anemia

Omega-3 long-chain polyunsaturated fatty acids promote antibacterial and inflammation-resolving effects in Mycobacterium tuberculosis-infected C3HeB/FeJ mice, dependent on fatty acid status

AbstractNon-resolving inflammation is characteristic of tuberculosis (TB). Given their inflammation-resolving properties,n-3 long-chain PUFA (n-3 LCPUFA) may support TB treatment. This research aimed to investigate the effects ofn-3 LCPUFA on clinical and inflammatory outcomes ofMycobacterium tuberculosis-infected C3HeB/FeJ mice with either normal or lown-3 PUFA status before infection. Using a two-by-two design, uninfected mice were conditioned on either ann-3 PUFA-sufficient (n-3FAS) or -deficient (n-3FAD) diet for 6 weeks. One week post-infection, mice were randomised to eithern-3 LCPUFA supplemented (n-3FAS/n-3+ andn-3FAD/n-3+) or continued onn-3FAS orn-3FAD diets for 3 weeks. Mice were euthanised and fatty acid status, lung bacterial load and pathology, cytokine, lipid mediator and immune cell phenotype analysed.n-3 LCPUFA supplementation inn-3FAS mice lowered lung bacterial loads (P= 0·003), T cells (P= 0·019), CD4+T cells (P= 0·014) and interferon (IFN)-γ(P< 0·001) and promoted a pro-resolving lung lipid mediator profile. Compared withn-3FAS mice, then-3FAD group had lower bacterial loads (P= 0·037), significantly higher immune cell recruitment and a more pro-inflammatory lipid mediator profile, however, significantly lower lung IFN-γ, IL-1α, IL-1βand IL-17, and supplementation in then-3FAD group provided no beneficial effect on lung bacterial load or inflammation. Our study provides the first evidence thatn-3 LCPUFA supplementation has antibacterial and inflammation-resolving benefits in TB when provided 1 week after infection in the context of a sufficientn-3 PUFA status, whilst a lown-3 PUFA status may promote better bacterial control and lower lung inflammation not benefiting fromn-3 LCPUFA supplementation

Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC The Phase 2 CONDOR Randomized Clinical Trial

IMPORTANCE: Dual blockade of programmed death ligand 1(PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. OBJECTIVE :To assess safety and objective response rate of durvalumab combined with tremelimumab. DESIGN, SETTING, AND PARTICIPANTS: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. INTERVENTIONS: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. MAIN OUTCOMES AND MEASURES: Safety and tolerability and efficacy measured by objective response rate. RESULTS: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%1339%) in the combination arm (n =129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. CONCLUSIONS AND RELEVANCE: In patients with R/M HNSCC and low or no PD-Lt tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC).

Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab - for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a ≥ 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score ≥ 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians\u27 understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S

A pragmatic effectiveness study of 10-session cognitive behavioural therapy (CBT-T) for eating disorders: Targeting barriers to treatment provision

Objective Ten‐session cognitive behavioural therapy (CBT‐T) for transdiagnostic eating disorders targets several barriers to treatment, including cost, therapist expertise, and lengthy wait lists. Method We used a case series design to investigate the effectiveness of CBT‐T delivered by trainee psychologists in a postgraduate training clinic. Participants were randomly allocated to commence treatment either immediately or after a 4‐week waitlist period. CBT‐T was delivered to 52 patients, by six different trainees under supervision. Measures of eating disorder cognitions and behaviours, quality of life, and general psychopathology were examined in completer and intention‐to‐treat analyses using multilevel modelling. Last observation carried forward was applied for abstinence, remission, and good outcome analyses to aid comparison with prior studies. Results Significant improvements, associated with medium to large effect sizes, were found for eating disorder cognitions, behaviours quality of life, and negative affect from baseline to posttreatment, and at 1‐ and 3‐month follow‐up. Attrition (38.5%) was comparable with other treatment studies. Conclusion Results provide evidence for the effectiveness of CBT‐T delivered by trainee psychologists for transdiagnostic eating disorder patients, thus tackling some important barriers for treatment. Longer follow‐up, randomised controlled trial designs, and moderator analyses will provide more robust evidence about which patients do best with a shorter therapy