Increasing The Odds Of Hit Iidentification By Screening Against Receptor Homologs

Increasing the odds of hit identification in screening is of significance for drug discovery. The odds for finding a hit are closely related either to the diversity of libraries or to the availability of focused libraries. There are no truly diverse libraries and it is difficult to design focused libraries without sufficient information. Hence it is helpful to consider alternative approaches that can enhance the odds using existing libraries. Multiple members of a protein family have been considered collectively in inhibitor design, on the basis of the correlation between protein families and ligands derived from specific compound classes. Such a correlation has been exploited in various drug discovery studies and a general receptor-homolog-based screening scheme may be devised. The feasibility of such a scheme in enhancing the odds of hit identification is discussed.Singapore-MIT Alliance (SMA

Analysis on the risks of severe adverse events in rabies post-exposure prophylaxis and appropriate decision-making procedure

Severe adverse events (AEs) following post-exposure rabies vaccination had been occasionally described in previous studies. Once AEs occurred, immediate medical treatment and appropriate change of vaccine and vaccination schedule were of significance. It was also important and challengeable to determine the relationship among adverse reactions, vaccines residues and laboratory tests for patients, to choose a proper vaccine in resumed vaccination, to avoid the reoccurrence of AEs and to ensure adequate immune response. Here, we present steps about how to cope with AEs by giving an example with a two-year-old girl who was identified as category II exposure to rabies, suffered from anaphylaxis after first dose administration with human diploid rabies vaccine (HDCV) so vaccination was temporarily suspended. Dexamethasone was prescribed to her in anti-allergy therapy. Allergy tests indicated that the patient was not sensitive to allergens and heterologous proteins. Vaccine test report showed that residual kanamycin existed in that batch of vaccines. This reminded us to provide her antibiotic skin sensitivity test which found she was allergic to kanamycin. Thus, we could conclude it was the cause of AEs. Then, 0.5 mL lyophilized Purified Vero Cell Rabies Vaccine (PVRV) without any residues was enrolled in the resumed vaccination. To ensure successful immunization, immunogenicity test was also provided which showed adequate immune response (RVNA ≥ 0.5 IU/mL) starting from day14. Besides, no further AEs occurred afterward. This study emphasized the importance of in-depth survey, analysis and implied the necessity to scientifically and properly choose the optimal vaccine for patients and appropriately provide treatments if AEs occurred

Area Postrema Cell Types that Mediate Nausea-Associated Behaviors

Nausea, the unpleasant sensation of visceral malaise, remains a mysterious process. The area postrema is implicated in some nausea responses and is anatomically privileged to detect blood-borne signals. To investigate nausea mechanisms, we built an area postrema cell atlas through single-nucleus RNA sequencing, revealing a few neuron types. Using mouse genetic tools for cell-specific manipulation, we discovered excitatory neurons that induce nausea-related behaviors, with one neuron type mediating aversion imposed by multiple poisons. Nausea-associated responses to agonists of identified area postrema receptors were observed and suppressed by targeted cell ablation and/or gene knockout. Anatomical mapping revealed a distributed network of long-range excitatory but not inhibitory projections with subtype-specific patterning. These studies reveal the basic organization of area postrema nausea circuitry and provide a framework toward understanding and therapeutically controlling nausea

A narrative review to identify promising approaches for digital health interventions to support emotion regulation for adolescents with ADHD

Emotion regulation difficulties affect many adolescents with ADHD, and previous research has highlighted a need for accessible interventions to support them in this domain in real life contexts. Digital health interventions (DHIs) can be embedded in adolescents’ daily lives and thus offer considerable promise for meeting this need. However, there is a lack of information to guide the development of suitable DHIs. The current narrative review synthesises diverse relevant evidence to inform their development, including promising therapeutic approaches and components, as well as other relevant design, development and evaluation considerations. Based on our findings, we recommend therapeutic approaches built on variants of cognitive behavioural therapy that are focused on emotions and their regulation and that additionally consider the latest research on emotion regulation in ADHD. Embedding elements designed to motivate and engage young people in order to support sustained adherence should be explored. The development process should be based on a co-production approach with young people with ADHD. The research described within this report was supported by a Medical Research Foundation (MRF) grant (Reference: MRF-001-0014-RG-MURR-C0932) and AM was additionally supported by a Wellcome Trust Career Development Grant (REF: 225364/Z/22/Z)

Temperature rise test and analysis of high current switchgear in distribution system

As the load of the power system continues to increase, the capacity of switchgear climbs, resulting in that the overheating problems becoming more serious. In order to realise the monitoring of the temperature of the switchgear, the authors need to conduct a thorough analysis of the temperature rise principle of the switchgear firstly. For the purpose of getting the detailed temperature distribution in the switchgear, a series of temperature rise tests were carried out based on the KYN28A-12(Z) overhead line switchgear, and the data were analysed and compared in detail to summarise the factors that affect the temperature distribution in the switchgear

Research on temperature rise of high current switchgear in distribution system

With the increase of the load of the switchgear, the overheating of the switchgear is more and more serious. In this article, the authors give the primary heat sources in the electrical equipment. According to these sources, they explore the reason of why the switchgear can be overheated during operation. Then, they build a 3D model in the Comsol & Multiphysics® and analyse the temperature state of the switchgear from the simulation. They also carry out temperature test on KYN28 switchgear to summarise the laws of the temperature change of the switchgear. Finally, they propose a brief method to monitor the temperature and realise the function of temperature warning to avoid accidents caused by overheating

5-Fluorouracil-loaded poly-l-lactide fibrous membrane for the prevention of intestinal stent restenosis

Restenosis instents is often reported in the longterm treatment of tumor-associated intestinal stenosis because conventional stents lack a sustainable antitumor capability. The aim of this study was to develop a drug-loaded poly-l-lactide fibrous membrane onto the surface of stents for the alleviation of intestinal restenosis. A polydioxanone stent was weft-knitted and then 5-fluorouracil (5-FU)-loaded poly-l-lactide membranes at concentration of 1.6, 6.4, and 12.8 %, respectively, were electro-spun onto the stent surface. The coating membrane morphology, chemical structure, and drug release property in vitro were examined. The antitumor activity in vitro was assessed with MTT assay using a human colorectal cancer cell line HCT-116. The results showed that the chemical structure of the drug was completed through electrospinning process. The drug release behavior was enhanced when the drug loading percentage increased. The 6.4 and 12.8 % membranes had better antitumor effects than pure 5-fluorouracil at half maximal inhibitory concentration (IC50) because of the sustainable drug releasing property of the membranes. In conclusion, the membranes at appropriate drug-loading dose such as 6.4 or 12.8 % had significant for the drug release capabilities and antitumor effect. The coating membrane can find promising clinical applications for the treatment of intestinal cancers in the future.Institute of Textiles and Clothin

Safety, immunogenicity of lyophilized purified vero cell cultured rabies vaccine administered in Zagreb and Essen regimen in post-exposure subjects: A post-marketing, parallel control clinical trial

To compare the safety and immunogenicity of lyophilized PVRV under Zagreb and Essen regimen. A post-marketing parallel control clinical trial was conducted. Totally 240 subjects were assigned to two groups randomly, immunized with lyophilized PVRV under Zagreb and Essen schedule. Solicited adverse events were observed after each dose and unsolicited adverse events were collected. Serum samples were collected on days 0, 7, 14, 42, 180 and 365 to be used to determine immunogenicity level. No severe adverse events (SAE) were observed. The incidence of adverse events under Zagreb and Essen were similar and there was no significant difference between the two groups and within all age groups. Fever and pain were the most frequently reported systemic and local adverse events (AEs) respectively. There were no differences in the GMT and the positive seroconversion rate between these two groups. All participants in the Zagreb group obtained protective effect on day 14, while 99.16% of the subjects obtained in the Essen group. Both groups showed similar enduring immunity. Immunizations under Zagreb and Essen regimens showed similar safety and immunogenicity. For lyophilized PVRV, Zagreb was non-inferior to Essen to patients of all age groups