Targeted delivery of anti-cancer drugs by MS2 virus-like particles

Problems associated with poor pharmacokinetics and biodistribution, as well as toxic off-target effects, limit the curative potential of most anti-cancer drugs. This has prompted the development of nanoparticulate drug delivery systems to impart both more favourable pharmacological properties and precise tumour targeting. The vast number of formulations, ranging from fully synthetic delivery systems to ones derived from natural sources, currently undergoing clinical trials or preclinical testing underlines the significance of this field. This project is a proof-of-concept investigation into the feasibility and effectiveness of a novel drug delivery system, based on virus-like particles (VLPs) of the MS2 bacteriophage. Doxorubicin (Dox) and an anti-BCL2 siRNA were used as model drug cargos. They were packaged inside MS2 VLPs either by chemical infusion, or via covalent attachment to an MS2 packaging signal, TR, respectively. An average loading of ~10 molecules of siRNA or ~110 molecules of Dox per VLP was achieved. Packaged cargos remained stably encapsidated; the siRNA was protected from nuclease degradation. VLPs were surface decorated with polyethylene glycol (PEG), and tumour-targeting ligands, human transferrin (Tf) or A9L, an RNA aptamer that targets prostate-specific membrane antigen (PSMA). Extensive PEGylation was achieved (~97% of coat proteins), and each VLP displayed on average ~7 molecules of Tf or ~16 molecules of A9L. PEGylation significantly reduced the non-specific cellular uptake of VLPs, and antibody binding. Further addition of tumour-targeting ligands facilitated the specific delivery of drug cargos to targeted cancer cells in culture, likely via receptor-mediated endocytosis, and induced significant cytotoxicity with an LC50 of ~10 nM for siRNA and ~800 nM for Dox. Importantly, negligible toxic effects were observed in the presence of excess free targeting ligands, or with non-targeted control cell lines. Furthermore, the cellular uptake of VLPs did not appear to induce any off-target effects. MS2 VLPs continue to show promise as a robust, flexible and effective drug delivery system. This project highlights the versatility of VLPs for displaying a range of useful ligands on their surface, as well as packaging various therapeutic cargos, and demonstrated their ability to specifically deliver drugs to targeted cancer cells. Though further studies are required, the work presented here is an important step towards fully realising the potential of this drug delivery system

Pelargonium sidoides root extract for the treatment of acute cough due to lower respiratory tract infection in adults::a feasibility double-blind, placebo-controlled randomised trial

BACKGROUND: Pelargonium sidoides DC (Geraniaceae) root extract, EPs®7630 or "Kaloba®", is a widely used herbal remedy for respiratory infections, with some evidence of effectiveness for acute bronchitis. However, it is not yet widely recommended by medical professionals in the UK. There is a need to undertake appropriately designed randomised trials to test its use as an alternative to antibiotics. The aim was to assess the feasibility of conducting a double-blind randomised controlled trial of Pelargonium sidoides root extract for treatment of acute bronchitis in UK primary care, investigating intervention compliance, patient preference for dosage form and acceptability of patient diaries.STUDY DESIGN: Feasibility double-blind randomised placebo-controlled clinical trial.METHODS: We aimed to recruit 160 patients with cough (≤ 21 days) caused by acute bronchitis from UK general practices. Practices were cluster-randomised to liquid or tablet preparations and patients were individually randomised to Kaloba® or placebo. We followed participants up for 28 days through self-reported patient diaries with telephone support and reviewed medical records at one month. Outcomes included recruitment, withdrawal, safety, reconsultation and symptom diary completion rates. We also assessed treatment adherence, antibiotic prescribing and consumption, mean symptom severity (at days 2-4 after randomisation) and time to symptom resolution. We interviewed 29 patients and 11 health professionals to identify barriers and facilitators to running such a randomised trial.RESULTS: Of 543 patients screened, 261 were eligible, of whom 134 (51%) were recruited and 103 (77%) returned a completed diary. Overall, 41% (41/100) of patients took antibiotics (Kaloba® liquid group: 48% [15/31]; placebo liquid group: 23% [6/26]; Kaloba® tablet group: 48% [9/21]; placebo tablet group: 50% [11/22]). Most patients adhered to the study medication (median 19 out of 21 doses taken in week 1, IQR 18-21 - all arms combined). There were no serious adverse events relating to treatment. Most patients interviewed found study recruitment to be straightforward, but some found the diary too complex.CONCLUSIONS: It was feasible and acceptable to recruit patients from UK primary care to a double-blind placebo-controlled trial of herbal medicine (Kaloba®) for the treatment of acute bronchitis, with good retention and low data attrition.TRIAL REGISTRATION: HATRIC was registered on the ISRCTN registry ( ISRCTN17672884 ) on 16 August 2018, retrospectively registered. The record can be found at http://www.isrctn.com/ISRCTN17672884 .</p

Genetic and pathogenic characterizations of a naturally occurring reassortant and homologous recombinant strain of the classical infectious bursal disease virus re-emerging in chickens in southern China

Infectious bursal disease (IBD) classical virus strain (cIBDV) can cause morbidity and mortality in young chickens with severe long-term immunosuppression. However, since the emergence and widespread prevalence of very virulent strain (vvIBDV) in China from 1991, reports of cIBDV have become rare. A novel reassortant and recombinant strain GXYL211225 (genotype A1aB1a) with segment A originating from the classical strain (A1a) and segment B from the attenuated vaccine strain (B1a) was characterized in the study. Notably, segment A resulted from recombination between the cIBDV strains 150127-0.2 and Faragher52-70, expressing as a backbone from 150127-0.2, where a fragment located at the position of nucleotide (nt) 519-1 410 was replaced by the corresponding region of Faragher52-70. The infection of GXYL211225 caused mortality in SPF chicken embryos, despite lacking the critical amino acid (aa) residues 253H, 279 N and 284A associated with the cellular tropism, and induced significant cytopathic effect (CPE) on a wide range of cells, confirming its natural cell-adapted character. Furthermore, the challenge experiment of GXYL211225 was performed on the commercial Three-yellow chickens of 4-week-old, and with the vvIBDV HLJ-0504-like strain NN1172 and the novel variant (nv) IBDV strain QZ191002 as the comparison. All the challenged birds experienced reduced body-weight gain. QZ191002 infected birds showed no obvious clinical symptoms or mortality, while those of NN1172 and GXYL211225 showed typical IBD symptoms and resulted in 20% (2/10) and 10% (1/10) of mortality rates, respectively. At 7 days post-challenge (dpc), the damages of bursal of Fabricius (BF) varied among groups, with NN1172 causing the most severe lesions, followed by GXYL211225, and then QZ191002. It was also found that the pathogenicity was correlated positively with the viral load, aligning with the histopathological severity in BF. The study confirms the rapid and diverse evolution of the re-emerged classical strains in the field and emphasizes the need to monitor the changes of IBDV on both the genetic and pathogenic aspects for the effective control of the disease

Baichuan 2: Open Large-scale Language Models

Large language models (LLMs) have demonstrated remarkable performance on a variety of natural language tasks based on just a few examples of natural language instructions, reducing the need for extensive feature engineering. However, most powerful LLMs are closed-source or limited in their capability for languages other than English. In this technical report, we present Baichuan 2, a series of large-scale multilingual language models containing 7 billion and 13 billion parameters, trained from scratch, on 2.6 trillion tokens. Baichuan 2 matches or outperforms other open-source models of similar size on public benchmarks like MMLU, CMMLU, GSM8K, and HumanEval. Furthermore, Baichuan 2 excels in vertical domains such as medicine and law. We will release all pre-training model checkpoints to benefit the research community in better understanding the training dynamics of Baichuan 2.Comment: Baichuan 2 technical report. Github: https://github.com/baichuan-inc/Baichuan

A Novel Spatial-Spectra Dynamics-Based Ranking Model for Sorting Time-Varying Functional Networks from Single Subject FMRI Data

Part 7: Fault DiagnosisInternational audienceAccumulating evidence suggests that the brain state has time-varying transitions, potentially implying that the brain functional networks (BFNs) have spatial variability and power-spectra dynamics over time. Recently, ICA-based BFNs tracking models, i.e., SliTICA, real-time ICA, Quasi-GICA, etc., have been gained wide attention. However, how to distinguish the neurobiological BFNs from those representing noise and artifacts is not trivial in tracking process due to the random order of components generated by ICA. In this study, combining with our previous BFNs tracking model, i.e., Quasi-GICA, we proposed a novel spatial-spectra dynamics-based ranking method for sorting time-varying BFNs, called weighted BFNs ranking, which was based on the dynamical properties in both spatial and spectral domains of each BFN. This proposed weighted BFNs ranking model mainly consisted of two steps: first, the dynamic spatial reproducibility (DSR) and dynamic fraction of amplitude low-frequency fluctuations (DFALFF) for each BFN were calculated; then a weighted coefficients-based ranking strategy for merging the DSR and DFALFF of each BFN was proposed, to make the meaningful dynamic BFNs rank ahead. We showed the effective results by this ranking model on the simulated and real data, suggesting that the meaningful dynamical BFNs with both strong properties of DSR and DFALFF across the tracking process were ranked at the top

A Spatial-Temporal Transformer Architecture Using Multi-Channel Signals for Sleep Stage Classification

Sleep stage classification is a fundamental task in diagnosing and monitoring sleep diseases. There are 2 challenges that remain open: (1) Since most methods only rely on input from a single channel, the spatial-temporal relationship of sleep signals has not been fully explored. (2) Lack of sleep data makes models hard to train from scratch. Here, we propose a vision Transformer-based architecture to process multi-channel polysomnogram signals. The method is an end-to-end framework that consists of a spatial encoder, a temporal encoder, and an MLP head classifier. The spatial encoder using a pre-trained Vision Transformer captures spatial information from multiple PSG channels. The temporal encoder utilizing the self-attention mechanism understands transitions between nearby epochs. In addition, we introduce a tailored image generation method to extract features within multi-channel and reshape them for transfer learning. We validate our method on 3 datasets and outperform the state-of-the-art algorithms. Our method fully explores the spatial-temporal relationship among different brain regions and addresses the problem of data insufficiency in clinical environments. Benefiting from reformulating the problem as image classification, the method could be applied to other 1D-signal problems in the future.ISSN:1534-4320ISSN:1558-021

TiO2−x films for bolometer applications: recent progress and perspectives

The bolometer is widely used in military and civilian infrared imaging due to its advantages of non-cooling, small size and portability. Thermosensitive materials seriously affect the performance of bolometers. As a kind of heat-sensitive material, the TiO _2−x material has the advantages of good thermal stability, large-area preparation, and compatibility with the complementary metal-oxide semiconductor (CMOS) process. However, there is almost no review on the application of titanium oxide for bolometers. In this paper, we introduce the bolometer’s main thermal and photoelectric performance parameters and the critical technologies to manufacture the bolometer. Finally, we will particularly emphasize the effects of preparation process parameters of TiO _2 on the performance parameters temperature coefficient of resistance (TCR), 1/ f noise, etc

Numerical Study on the Acoustic Characteristics of an Axial Fan under Rotating Stall Condition

Axial fan is an important piece of equipment in the thermal power plant that provides enough air for combustion of coal. This paper focuses on the aerodynamic noise characteristics of an axial fan in the development from stall inception to stall cells. The aerodynamic noise characteristic of monitoring region in time and frequency domains was simulated employing the large-eddy simulation (LES), with the addition of throttle setting and the Ffowcs Williams-Hawkings (FW-H) noise model. The numerical results show that, under the design condition, the acoustic pressure presents regular periodicity along with the time. The noise energy is concentrated with high energy of the fundamental frequency and high order harmonics. During the stall inception stage, the acoustic pressure amplitude starts fluctuating and discrete frequencies are increased significantly in the low frequency; among them, there are three obvious discrete frequencies: 27.66 Hz, 46.10 Hz and 64.55 Hz. On the rotating stall condition, the fluctuation of the acoustic pressure level and amplitude are more serious than that mentioned above. During the whole evolution process, the acoustic pressure peak is difficult to keep stable all the time, and a sudden increase of the peak value at the 34.5th revolution corresponds to the relative velocity’s first sudden increase at the time when the valve coefficient is 0.780