Miltefosine reinvigorates exhausted T cells by targeting their bioenergetic state.

T cell exhaustion presents a major challenge for the efficacy of both immune checkpoint inhibitors (ICBs) and chimeric antigen receptor T (CAR-T) cell immunotherapies. To address this issue, we generate hypofunctional CAR-T cells that imitate the exhaustion state. By screening a Food and Drug Administration (FDA)-approved small molecule library using this model, we identify miltefosine as a potent molecule that restores the impaired function of CAR-T cells in a PD-1/PD-L1-independent manner.

Efficacy and Safety of Erzhu Jiedu Decoction Granules in Treating Mid-advanced Hepatitis B Virus-Associated Primary Liver Cancer Patients with Pi (Spleen)-Deficiency and Dampness-Heat Syndrome.

Objective: To assess the efficacy and safety of Erzhu Jiedu Decoction (EZJDD) Granules in treating mid-advanced hepatitis B virus-associated primary liver cancer (HBV-PLC) patients with Pi (Spleen)-deficiency and dampness-heat syndrome.

Methods: From January 2021 to June 2023, a cohort of 132 patients were enrolled and randomly assigned to a control group or a EZJDD group according to the random numbers, with 66 patients in each group. The patients in the control group received conventional treatment for 3 months, followed by a 3-month follow-up.

Prompt Diagnosis and Treatment of Japanese Spotted Fever with an Atypical Triad of Clinical Symptoms: A Case Report.

Japanese spotted fever (JSF) is a neglected and potentially fatal infectious disease. Delays in diagnosis and treatment of JSF are important causes of poor prognosis. We report a case of JSF in a 75-year-old farmer who, following autumn field work in Sichuan, China, presented with an atypical triad of clinical symptoms: high fever, petechial rash, and notably no eschar.

Spatio-temporal distributions of COVID-19 vaccine doses uptake in the Netherlands: a Bayesian ecological modelling analysis.

In the transitioning era towards the COVID-19 endemic, there is still a sizable population that has never been vaccinated against COVID-19 in the Netherlands. This study employs Bayesian spatio-temporal modelling to assess the relative chances of COVID-19 vaccination uptake - first, second, and booster doses - both at the municipal and regional (public health services) levels. Incorporating ecological regression modelling to consider socio-demographic factors, our study unveils a diverse spatio-temporal distribution of vaccination uptake.

Aberrant copper metabolism and hepatic inflammation cause neurological manifestations in a mouse model of Wilson's disease.

Pathogenic germline mutations in the P-type copper-transporting ATPase (ATP7B) gene cause Wilson's disease (WD), a hereditary disorder characterized by disrupted copper metabolism. The Arg778Leu (R778L) mutation in exon 8 is prevalent among individuals with WD in East Asia and is associated with more severe phenotypes. In this study, we generated a WD mouse model harboring R778L mutation (R778L mice) using CRISPR/Cas9.

Modeling X chromosome inactivation using t5iLA naive human pluripotent stem cells.

Background: X chromosome inactivation (XCI) is a critical epigenetic event for dosage compensation of X-linked genes in female mammals, ensuring developmental stability. A robust in vitro model is required for mimicking XCI during the early stages of embryonic development. This methodology article introduces an advanced framework for the in-depth study of XCI using human pluripotent stem cells (hPSCs).

Systematic discovery of DNA-binding tandem repeat proteins.

Tandem repeat proteins (TRPs) are widely distributed and bind to a wide variety of ligands. DNA-binding TRPs such as zinc finger (ZNF) and transcription activator-like effector (TALE) play important roles in biology and biotechnology. In this study, we first conducted an extensive analysis of TRPs in public databases, and found that the enormous diversity of TRPs is largely unexplored.

PLM_Sol: predicting protein solubility by benchmarking multiple protein language models with the updated Escherichia coli protein solubility dataset.

Protein solubility plays a crucial role in various biotechnological, industrial, and biomedical applications. With the reduction in sequencing and gene synthesis costs, the adoption of high-throughput experimental screening coupled with tailored bioinformatic prediction has witnessed a rapidly growing trend for the development of novel functional enzymes of interest (EOI). High protein solubility rates are essential in this process and accurate prediction of solubility is a challenging task.

All-RNA-mediated targeted gene integration in mammalian cells with rationally engineered R2 retrotransposons.

All-RNA-mediated targeted gene integration methods, rendering reduced immunogenicity, effective deliverability with non-viral vehicles, and a low risk of random mutagenesis, are urgently needed for next-generation gene addition technologies. Naturally occurring R2 retrotransposons hold promise in this context due to their site-specific integration profile. Here, we systematically analyzed the biodiversity of R2 elements and screened several R2 orthologs capable of full-length gene insertion in mammalian cells.

Genome editing in plants using the TnpB transposase system.

Unlabelled: The widely used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated nuclease (Cas) system is thought to have evolved from IS200/IS605 transposons. TnpB proteins, encoded by one type of IS200/IS605 transposon, are considered to be the evolutionary ancestors of Cas12 nucleases, which have been engineered to function as RNA-guided DNA endonucleases for genome editing in bacteria and human cells. TnpB nucleases, which are smaller than Cas nucleases, have been engineered for use in genome editing in animal systems, but the feasibility of this approach in plants remained unknown.

A transient transcriptional activation governs unpolarized-to-polarized morphogenesis during embryo implantation.

During implantation, embryos undergo an unpolarized-to-polarized transition to initiate postimplantation morphogenesis. However, the underlying molecular mechanism is unknown. Here, we identify a transient transcriptional activation governing embryonic morphogenesis and pluripotency transition during implantation.

Functional near-infrared spectroscopy-based neurofeedback training regulates time-on-task effects and enhances sustained cognitive performance.

Time-on-task effect is a common consequence of long-term cognitive demand work, which reflects reduced behavioral performance and increases the risk of accidents. Neurofeedback is a neuromodulation method that can guide individuals to regulate their brain activity and manifest as changes in related symptoms and cognitive behaviors. This study aimed to examine the effects of functional near-infrared spectroscopy-based neurofeedback training on time-on-task effects and sustained cognitive performance.

Heterologous survey of 130 DNA transposons in human cells highlights their functional divergence and expands the genome engineering toolbox.

Experimental studies on DNA transposable elements (TEs) have been limited in scale, leading to a lack of understanding of the factors influencing transposition activity, evolutionary dynamics, and application potential as genome engineering tools. We predicted 130 active DNA TEs from 102 metazoan genomes and evaluated their activity in human cells. We identified 40 active (integration-competent) TEs, surpassing the cumulative number (20) of TEs found previously.

Still trouble with bleeding: Risk factors for HCV transmission in men who have sex with men and behavioural trajectories from 2019 to 2021.

Objectives: To identify sexual/sex-associated risk factors for hepatitis C transmission among men who have sex with men (MSM) and visualise behavioural trajectories from 2019 to 2021.

Methods: We linked a behavioural survey to a hepatitis C cohort study (NoCo), established in 2019 across six German HIV/hepatitis C virus (HCV) treatment centres, and performed a case-control analysis. Cases were MSM with recent HCV infection, and controls were matched for HIV status (model 1) or proportions of sexual partners with HIV (model 2).

Platelet-derived TGF-β1 induces functional reprogramming of myeloid-derived suppressor cells in immune thrombocytopenia.

Platelet α-granules are rich in transforming growth factor β1 (TGF-β1), which is associated with myeloid-derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP).

Effect of water film evaporation on the shale gas transmission in inorganic nanopores under viscosity.

Shale gas reservoirs generally have ultra-low water saturation, and the water in reservoirs is closely bound to the walls of inorganic nanopores, forming a water film structure on the hydrophilic surface. When shale gas enters the inorganic nanopores, the water films in the inorganic pores will be removed by evaporation instead of being driven away by the gas, which increases the difficulty of predicting production during shale gas extraction. Based on molecular dynamics simulations, a water film evaporation model is proposed, considering the evaporation of water films during shale gas transport and the influence of water film evaporation on the shale gas transport mechanism.

Light-Quality-Adapted Carotenoid Photoprotection in the Photosystem of .

The photosystem of filamentous anoxygenic phototroph (.) comprises a light-harvesting (LH) complex encircling a reaction center (RC), which intensely absorbs blue-green light by carotenoid (Car) and near-infrared light by bacteriochlorophyll (BChl). To explore the influence of light quality (color) on the photosynthetic activity, we compared the pigment compositions and triplet excitation dynamics of the LH-RCs from .

Identification of Erzhu Jiedu Recipe and its molecular mechanism underlying inhibited human hepatoma cells by UHPLC-Q-Exactive Orbitrap HRMS and network pharmacology.

Ethnopharmacological Relevance: Erzhu Jiedu Recipe (EZJDR) is a formula of traditional Chinese medicine (TCM) for treating hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). However, its effective components and the mechanism of action remain unclear.

Aim Of The Study: To explain how the active compounds of EZJDR suppress the growth of hepatoma cells.

Unlocking CAR T cell potential: Inosine-induced stemness and enhanced potency.

Adenosine (Ado) drives immune suppression in the tumor microenvironment. In this issue of Cancer Cell, Klysz et al. investigate Ado-mediated immunosuppression.