Mathematical Modeling of Cytotoxic Lymphocyte-Mediated Immune Response to Hepatitis B Virus Infection

Nowak's model of the human immunodeficiency virus (HIV) infection has been extensively and successfully used to simulate the interaction between HIV and cytotoxic lymphocyte- (CTL-) mediated immune response. However, this model is not available for hepatitis B virus (HBV) infection. As the enhanced recruitment of virus-specific CTLs into the liver has been an important novel concept in the pathogenesis of hepatitis B, we develop a specific mathematical model analyzing the relationship between HBV and the CTL-mediated immune response, and the indicator of the liver cell damage, alanine aminotransferase (ALT). The stability condition of the complete recovery equilibrium point at which HBV will be eliminated entirely from the body is discussed. A different set of parameters is used in the simulation, and the results show that the model can interpret the wide variety of clinical manifestations of HBV infection. The model suggests that a rapid and vigorous CTL response is required for resolution of HBV infection

High-Resolution Structure of the N-Terminal Endonuclease Domain of the Lassa Virus L Polymerase in Complex with Magnesium Ions

Lassa virus (LASV) causes deadly hemorrhagic fever disease for which there are no vaccines and limited treatments. LASV-encoded L polymerase is required for viral RNA replication and transcription. The functional domains of L–a large protein of 2218 amino acid residues–are largely undefined, except for the centrally located RNA-dependent RNA polymerase (RdRP) motif. Recent structural and functional analyses of the N-terminal region of the L protein from lymphocytic choriomeningitis virus (LCMV), which is in the same Arenaviridae family as LASV, have identified an endonuclease domain that presumably cleaves the cap structures of host mRNAs in order to initiate viral transcription. Here we present a high-resolution crystal structure of the N-terminal 173-aa region of the LASV L protein (LASV L173) in complex with magnesium ions at 1.72 Å. The structure is highly homologous to other known viral endonucleases of arena- (LCMV NL1), orthomyxo- (influenza virus PA), and bunyaviruses (La Crosse virus NL1). Although the catalytic residues (D89, E102 and K122) are highly conserved among the known viral endonucleases, LASV L endonuclease structure shows some notable differences. Our data collected from in vitro endonuclease assays and a reporter-based LASV minigenome transcriptional assay in mammalian cells confirm structural prediction of LASV L173 as an active endonuclease. The high-resolution structure of the LASV L endonuclease domain in complex with magnesium ions should aid the development of antivirals against lethal Lassa hemorrhagic fever

Roles of Scaling and Instruction Tuning in Language Perception: Model vs. Human Attention

Recent large language models (LLMs) have revealed strong abilities to understand natural language. Since most of them share the same basic structure, i.e. the transformer block, possible contributors to their success in the training process are scaling and instruction tuning. However, how these factors affect the models' language perception is unclear. This work compares the self-attention of several existing LLMs (LLaMA, Alpaca and Vicuna) in different sizes (7B, 13B, 30B, 65B), together with eye saccade, an aspect of human reading attention, to assess the effect of scaling and instruction tuning on language perception. Results show that scaling enhances the human resemblance and improves the effective attention by reducing the trivial pattern reliance, while instruction tuning does not. However, instruction tuning significantly enhances the models' sensitivity to instructions. We also find that current LLMs are consistently closer to non-native than native speakers in attention, suggesting a sub-optimal language perception of all models. Our code and data used in the analysis is available on GitHub

Accessible tourism: Tourists with physical disability - segmentation based on perceived travel barriers

Purpose: This study aims to explore the heterogeneity of the tourist market for people with a physical disability (PwPD) based on travel barriers, to serve them better, from a tourism marketing perspective. Design/methodology/approach: A market segmentation analysis was conducted on a sample of 480 PwPD in Sichuan Province, China, based on their perceived travel barriers. Data were obtained through three on-site and four online surveys. A four-step factor-item mixed segmentation, including factor analysis, cluster analysis, discriminant analysis and chi-square tests, was applied to examine the differences among PwPD tourist market segments in terms of various demographic characteristics, disability conditions (e.g. duration of disabilities and causes of impairment) and travel features (e.g. travel frequency and tourist destinations). Findings: This study revealed that the PwPD tourist market is heterogeneous due to individual perceived travel barriers. Three market segments were identified, namely, the Explorer Moderates group, the Explorer Minimals group and the Explorer Intensives group. Additionally, the three market segments were found to have significant differences in terms of travel barriers, demographic characteristics, travel features and disability conditions. Practical implications: This research provides suggestions for authorities and private entities to optimize the layout of accessible facilities in public areas for the benefit of all. It also offers crucial implications for tourism marketers to determine the key facets of marketing, for travel organizers to evolve the organization of travel groups for PwPD, and for practitioners to provide personalized tourism services. Originality/value: To the best of the authors’ knowledge, this study is the first to apply perceived travel barriers as a market segmentation criterion in understanding PwPD as a heterogeneous travel market. The findings of this study initially expand the scope of application of the travel barrier model and deepen understanding of the Chinese PwPD tourist market from a marketing perspective. The study results elucidated the heterogeneity and characteristics of this market through a four-step factor-item mixed segmentation approach, offering new insights into the behaviors and experiences of travelers with disabilities

Development of a novel detection technology for drug resistance mutation sites of Mycobacterium tuberculosis using Luminex liquid chip technology

Purpose: To develop a novel detection technology for drug-resistance mutation sites of Mycobacterium tuberculosis (MTB) using a Luminex liquid chip.Methods: Using polymerase chain reaction (PCR) amplification and hybridization analysis, MTB infection and drug-resistant mutation sites of the first-line and second-line anti-MTB drugs were simultaneously identified. A novel detection method was applied to analyze the wild-type standard strains of MTB and 33 clinical samples, and the results were compared with Sanger sequencing results for PCR products.Results: It was revealed that the sensitivity (100 %) and specificity (100 %) of the novel detection method for 31 samples were satisfactory, and all mutation sites were correctly detected. Compared with traditional PCR and culture-based drug sensitivity test, the novel detection method increased the speed of identification of drug-resistant TB, reduced clinicians' workload, and decreased treatment cost. Among 31 samples, 12.90 % were resistant to isoniazid (4/31), 35.48 % to rifampicin (11/31), and 12.90 % to ofloxacin (p < 0.05). Furthermore, 2 (6.45 %) samples were resistant to both isoniazid and rifampicin, 2 (6.45 %) samples to both rifampicin and ofloxacin, and 1 (3.22 %) sample to both isoniazid and ofloxacin, and 1 (3.22%) sample to all the three drugs (p < 0.05).Conclusion: Development and wide application of this novel detection method will facilitate the treatment of MTB, thus reducing the spread of drug-resistant MTB, and improving the prevention and treatment of MTB

A Detection Method of Rice Process Quality Based on the Color and BP Neural Network

Abstract. This paper proposed a detection method of rice process quality using the color and BP neural network. A rice process quality detection device based on computer vision technology was designed to get rice image, a circle of the radius R in the abdomen of the rice was determined as a color feature extraction area, and which was divided into five concentric sub-domains by the average area, the average color of each sub-region H was extraction as the color feature values described in the surface process quality of rice, and then the 5 color feature values as input values were imported to the BP neural network to detection the surface process quality of rice. The results show that the average accuracy of this method is 92.50% when it was used to detect 4 types of rice of different process quality

Multilingual Pretraining and Instruction Tuning Improve Cross-Lingual Knowledge Alignment, But Only Shallowly

Despite their strong ability to retrieve knowledge in English, current large language models show imbalance abilities in different languages. Two approaches are proposed to address this, i.e., multilingual pretraining and multilingual instruction tuning. However, whether and how do such methods contribute to the cross-lingual knowledge alignment inside the models is unknown. In this paper, we propose CLiKA, a systematic framework to assess the cross-lingual knowledge alignment of LLMs in the Performance, Consistency and Conductivity levels, and explored the effect of multilingual pretraining and instruction tuning on the degree of alignment. Results show that: while both multilingual pretraining and instruction tuning are beneficial for cross-lingual knowledge alignment, the training strategy needs to be carefully designed. Namely, continued pretraining improves the alignment of the target language at the cost of other languages, while mixed pretraining affect other languages less. Also, the overall cross-lingual knowledge alignment, especially in the conductivity level, is unsatisfactory for all tested LLMs, and neither multilingual pretraining nor instruction tuning can substantially improve the cross-lingual knowledge conductivity

Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors

Small molecular PD‐1 inhibitors are lacking in current immuno‐oncology clinic. PD‐1/PD‐L1 antibody inhibitors currently approved for clinical usage block interaction between PD‐L1 and PD‐1 to enhance cytotoxicity of CD8+ cytotoxic T lymphocyte (CTL). Whether other steps along the PD‐1 signaling pathway can be targeted remains to be determined. Here, we report that methylene blue (MB), an FDA‐approved chemical for treating methemoglobinemia, potently inhibits PD‐1 signaling. MB enhances the cytotoxicity, activation, cell proliferation, and cytokine‐secreting activity of CTL inhibited by PD‐1. Mechanistically, MB blocks interaction between Y248‐phosphorylated immunoreceptor tyrosine‐based switch motif (ITSM) of human PD‐1 and SHP2. MB enables activated CTL to shrink PD‐L1 expressing tumor allografts and autochthonous lung cancers in a transgenic mouse model. MB also effectively counteracts the PD‐1 signaling on human T cells isolated from peripheral blood of healthy donors. Thus, we identify an FDA‐approved chemical capable of potently inhibiting the function of PD‐1. Equally important, our work sheds light on a novel strategy to develop inhibitors targeting PD‐1 signaling axis