Construction and characterization of infectious hepatitis C virus chimera containing structural proteins directly from genotype 1b clinical isolates

AbstractHCV genotype is a major determinant of clinical outcome, and GT1b HCV infection is the most difficult to treat and also the predominant genotype in East Asia and Europe. We developed 1b/JFH-1 inter-genotypic recombinants containing the structural genes (Core, E1, E2), p7 and the 1stTMD of NS2 directly from GT1b clinical isolates. Through a cloning selection strategy, we obtained 4 functional clones from 3 cases of GT1b patients' sera, which could produce infectious viruses in Huh7.5.1 cells. Sequencing analysis of recovered viruses from serial passage and reverse genetics revealed that adaptive mutations in the GT1b-originated region were enough for the enhancement of infectivity. A monoclonal antibody to E2 and original patient sera could efficiently block 3 of the viruses (26C3mt, 52B6mt and 79L9) while had little effect on 26C6mt viruses. The availability of 1b/JFH-1 chimeric viruses will be important for studies of isolate-specific neutralization and useful in evaluating antiviral therapies

Controllable synthesis of one-dimensional isolated Ni 0.5 Zn 0.5 Fe 2 O 4 microtubes for application as catalyst support in RF heated reactors

One-dimensional isolated Ni0.5Zn0.5Fe2O4 microtubes have been prepared via a template assisted sol–gel method. Temperature dependence of the structural and magnetic properties was studied via XRD, N2 adsorption, SEM, TEM, and VSM. An increase in calcination temperature from 873 to 1273 K caused a decrease in the specific surface area from 80.7 to 17.0 m2/g due to an increase of the grain size from 25.3 to 112 nm. All samples demonstrated anomalous coercivity behavior due to mechanical stresses acting on their domain walls. The porous microtubes calcined at 1073 K have a mean external diameter of 3.7 μm with a length-to-diameter ratio exceeding 12. The microtubes calcined at 973 K have the highest coercivity of 88.1 Oe and demonstrated the largest specific heating rate of 4.36 W/g in a radiofrequency field at 295 kHz

Peroxisome Proliferator-Activated Receptors Associated with Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming a major cause of chronic liver disease worldwide. Concurrent to an increase in NAFLD prevalence, there is an increase in the obesity epidemic and the correlated insulin-resistant state. It is a challenge to diagnose NAFLD because many patients are asymptomatic until the later stages of disease. The most common symptoms include fatigue, malaise, and discomfort in the right upper quadrant. The major and most accurate tool to clinically diagnose NAFLD is a liver biopsy, followed by histological analysis. However, this procedure is invasive and often carries a high risk of complications. Currently, there are no officially approved medications for the treatment of NAFLD. Although lifestyle modifications with proper diet and exercise have been shown to be beneficial, this has been difficult to achieve and sustain for many patients. Effective pharmacological treatments are still lacking; therefore, additional research to identify novel drugs is clearly warranted. PPARs are promising drug targets for the management of NAFLD and its related conditions of type 2 diabetes mellitus and cardiovascular disease. In this review, we provide an overview of recent studies on the association of PPARs and NAFLD

DNA binding mechanism revealed by high resolution crystal structure of Arabidopsis thaliana WRKY1 protein

WRKY proteins, defined by the conserved WRKYGQK sequence, are comprised of a large superfamily of transcription factors identified specifically from the plant kingdom. This superfamily plays important roles in plant disease resistance, abiotic stress, senescence as well as in some developmental processes. In this study, the Arabidopsis WRKY1 was shown to be involved in the salicylic acid signaling pathway and partially dependent on NPR1; a C-terminal domain of WRKY1, AtWRKY1-C, was constructed for structural studies. Previous investigations showed that DNA binding of the WRKY proteins was localized at the WRKY domains and these domains may define novel zinc-binding motifs. The crystal structure of the AtWRKY1-C determined at 1.6 Å resolution has revealed that this domain is composed of a globular structure with five β strands, forming an antiparallel β-sheet. A novel zinc-binding site is situated at one end of the β-sheet, between strands β4 and β5. Based on this high-resolution crystal structure and site-directed mutagenesis, we have defined and confirmed that the DNA-binding residues of AtWRKY1-C are located at β2 and β3 strands. These results provided us with structural information to understand the mechanism of transcriptional control and signal transduction events of the WRKY proteins

TeacherLM: Teaching to Fish Rather Than Giving the Fish, Language Modeling Likewise

Large Language Models (LLMs) exhibit impressive reasoning and data augmentation capabilities in various NLP tasks. However, what about small models? In this work, we propose TeacherLM-7.1B, capable of annotating relevant fundamentals, chain of thought, and common mistakes for most NLP samples, which makes annotation more than just an answer, thus allowing other models to learn "why" instead of just "what". The TeacherLM-7.1B model achieved a zero-shot score of 52.3 on MMLU, surpassing most models with over 100B parameters. Even more remarkable is its data augmentation ability. Based on TeacherLM-7.1B, we augmented 58 NLP datasets and taught various student models with different parameters from OPT and BLOOM series in a multi-task setting. The experimental results indicate that the data augmentation provided by TeacherLM has brought significant benefits. We will release the TeacherLM series of models and augmented datasets as open-source.Comment: 5 figures, 15 page

Fair Abstractive Summarization of Diverse Perspectives

People from different social and demographic groups express diverse perspectives and conflicting opinions on a broad set of topics such as product reviews, healthcare, law, and politics. A fair summary should provide a comprehensive coverage of diverse perspectives without underrepresenting certain groups. However, current work in summarization metrics and Large Language Models (LLMs) evaluation has not explored fair abstractive summarization. In this paper, we systematically investigate fair abstractive summarization for user-generated data. We first formally define fairness in abstractive summarization as not underrepresenting perspectives of any groups of people and propose four reference-free automatic metrics measuring the differences between target and source perspectives. We evaluate five LLMs, including three GPT models, Alpaca, and Claude, on six datasets collected from social media, online reviews, and recorded transcripts. Experiments show that both the model-generated and the human-written reference summaries suffer from low fairness. We conduct a comprehensive analysis of the common factors influencing fairness and propose three simple but effective methods to alleviate unfair summarization. Our dataset and code are available at https://github.com/psunlpgroup/FairSumm.Comment: 19 pages, 10 figure

Hydrogen Sulfide Mediates K+ and Na+ Homeostasis in the Roots of Salt-Resistant and Salt-Sensitive Poplar Species Subjected to NaCl Stress

Non-invasive micro-test techniques (NMT) were used to analyze NaCl-altered flux profiles of K+, Na+, and H+ in roots and effects of NaHS (a H2S donor) on root ion fluxes in two contrasting poplar species, Populus euphratica (salt-resistant) and Populus popularis (salt-sensitive). Both poplar species displayed a net K+ efflux after exposure to salt shock (100 mM NaCl), as well as after short-term (24 h), and long-term (LT) (5 days) saline treatment (50 mM NaCl, referred to as salt stress). NaHS (50 μM) restricted NaCl-induced K+ efflux in roots irrespective of the duration of salt exposure, but K+ efflux was not pronounced in data collected from the LT salt stress treatment of P. euphratica. The NaCl-induced K+ efflux was inhibited by a K+ channel blocker, tetraethylammonium chloride (TEA) in P. popularis root samples, but K+ loss increased with a specific inhibitor of plasma membrane (PM) H+-ATPase, sodium orthovanadate, in both poplar species under LT salt stress and NaHS treatment. This indicates that NaCl-induced K+ loss was through depolarization-activated K+ channels. NaHS caused increased Na+ efflux and a corresponding increase in H+ influx for poplar roots subjected to both the short- and LT salt stress. The NaHS-enhanced H+ influx was not significant in P. euphratica samples subjected to short term salt stress. Both sodium orthovanadate and amiloride (a Na+/H+ antiporter inhibitor) effectively inhibited the NaHS-augmented Na+ efflux, indicating that the H2S-enhanced Na+ efflux was due to active Na+ exclusion across the PM. We therefore conclude that the beneficial effects of H2S probably arise from upward regulation of the Na+/H+ antiport system (H+ pumps and Na+/H+ antiporters), which promote exchange of Na+ with H+ across the PM and simultaneously restricted the channel-mediated K+ loss that activated by membrane depolarization

The efficacy of mitochondrial targeting antiresistant epirubicin liposomes in treating resistant leukemia in animals

Ying Men*, Xiao-Xing Wang*, Ruo-Jing Li, Yan Zhang, Wei Tian, Hong-Juan Yao, Rui-Jun Ju, Xue Ying, Jia Zhou, Nan Li, Liang Zhang, Yang Yu, Wan-Liang LuState Key Laboratory of Natural and Biomimetic Drugs, and School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China*These authors contributed equally to this manuscriptBackground: Multidrug resistance (MDR) of cancers can be circumvented by inducing programmed cell death, which is known as apoptosis. Mitochondria play a crucial role in apoptosis. Mitochondria-specific therapy would provide an efficient strategy for treating resistant cancers.Design and methods: A strategy was proposed here to overcome MDR by designing cancer mitochondria-specific drug-loaded liposomes, namely, antiresistant epirubicin mitosomes, aimed at treating resistant leukemia by targeting mitochondria. Evaluations were performed on human chronic leukemia K562, MDR K562/ADR cells, and female BALB/c nude mice xenografted with MDR K562/ADR cells. The liposomes were characterized through assays of cytotoxicity, mitochondrial targeting, caspase-9 and caspase-3, antitumor activities, and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) analysis.Results: The average size of antiresistant epirubicin mitosomes was in the range of 105–115 nm. Antiresistant epirubicin mitosomes were effective in inhibiting proliferation of MDR K562/ADR cells in vitro and selectively accumulated into the mitochondria. Caspase-9 and caspase-3 activity was increased after applying antiresistant epirubicin mitosomes. In xenografted resistant MDR K562/ADR tumor in nude mice, antiresistant tumor effect of antiresistant epirubicin mitosomes was evidently observed. Apoptotic inducing effects by antiresistant epirubicin mitosomes were noticeably evidenced via mitochondrial pathway.Conclusions: Antiresistant epirubicin mitosomes had significant inhibitory effect against resistant leukemia in vitro and in vivo, hence providing a promising strategy for improving therapeutic efficacy in resistant human leukemia.Keywords: mitosomes, mitochondria signaling pathway, nude mic