Visually or auditorily induced seizures involve the activation of nonhippocampal brain areas and hippocampal removal does not alleviate seizures in a mouse model of temporal lobe epilepsy.

Objective: Several studies have attributed epileptic activities in temporal lobe epilepsy (TLE) to the hippocampus; however, the participation of nonhippocampal neuronal networks in the development of TLE is often neglected. Here, we sought to understand how these nonhippocampal networks are involved in the pathology that is associated with TLE disease.

Methods: A kainic acid (KA) model of temporal lobe epilepsy was induced by injecting KA into dorsal hippocampus of C57BL/6J mice.

Quantitative evaluation of traditional Chinese medicine development policy: A PMC index model approach.

Background: Traditional Chinese medicine development policies (TCMDPs) are essential in improving the sustainable development of TCM undertakings, of which transmissions of policy information are closely related to the actual policy effectiveness. However, the inherent components of TCMDPs had not been explored from the structural dimension of policy design.

Methods: Based on the policy modeling consistency (PMC) index model, we constructed a comprehensive evaluation system, including ten first-level and 40 second-level indicators, and focused on the TCMDPs released by the Chinese central government in the past 42 years (1980-2022) to conduct multi-dimensional inspections to TCMDPs by analyzing the overall policy quality, individual scoring performance, and indicators distribution characteristics.

Induced CD45 Proximity Potentiates Natural Killer Cell Receptor Antagonism.

Natural killer (NK) cells are a major subset of innate immune cells that are essential for host defense against pathogens and cancer. Two main classes of inhibitory NK receptors (NKR), KIR and CD94/NKG2A, play a key role in suppressing NK activity upon engagement with tumor cells or virus-infected cells, limiting their antitumor and antiviral activities. Here, we find that single-chain NKR antagonists linked to a VHH that binds the cell surface phosphatase CD45 potentiate NK and T activities to a greater extent than NKR blocking antibodies alone in vitro.

Facile discovery of surrogate cytokine agonists.

Cytokines are powerful immune modulators that initiate signaling through receptor dimerization, but natural cytokines have structural limitations as therapeutics. We present a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics amenable to high-throughput screening. Using VHH and scFv to human interleukin-2/15, type-I interferon, and interleukin-10 receptors, we generated combinatorial matrices of single-chain bispecific ligands that exhibited diverse spectrums of functional activities, including potent inhibition of SARS-CoV-2 by surrogate interferons.

Interleukin-2 superkines by computational design.

Affinity maturation of protein–protein interactions is an important approach in the development of therapeutic proteins such as cytokines. Typical experimental strategies involve targeting the cytokine-receptor interface with combinatorial libraries and then selecting for higher-affinity variants. Mutations to the binding scaffold are usually not considered main drivers for improved affinity.

Robust All-Cellulose Nanofiber Composite from Stack-Up Bacterial Cellulose Hydrogels via Self-Aggregation Forces.

All-cellulose composites are usually prepared by removing impurities and using a surface-selective dissolution approach, which detract significantly from their environment-friendly properties. In this paper, we report an environment-friendly approach to fabricate all-cellulose nanofiber composites from stack-up bacterial cellulose (BC) hydrogels via self-aggregation forces of the hydrogen bond by water-based processing. Structural and mechanical properties of BC-laminated composites have been investigated.

SPOP Promotes Nanog Destruction to Suppress Stem Cell Traits and Prostate Cancer Progression.

Frequent SPOP mutation defines the molecular feature underlying one of seven sub-types of human prostate cancer (PrCa). However, it remains largely elusive how SPOP functions as a tumor suppressor in PrCa. Here, we report that SPOP suppresses stem cell traits of both embryonic stem cells and PrCa cells through promoting Nanog poly-ubiquitination and subsequent degradation.

Biochemical Aspects of PD-L1 Regulation in Cancer Immunotherapy.

PD-L1, frequently expressed in human cancers, engages with PD-1 on immune cells and contributes to cancer immune evasion. As such, antibodies blocking the PD-1/PD-L1 interaction reactivate cytotoxic T cells to eradicate cancer cells. However, a majority of cancer patients fail to respond to PD-1/PD-L1 blockade with unclear underlying mechanism(s).

[Effects of propofol pretreatment on myocardial cell apoptosis and SERCA2 expression in rats with hepatic ischemia/reperfusion].

Introduction: Hepatic ischemia-reperfusion injury is a common pathophysiological process in liver surgery. Whether Propofol can reduce myocardial ischemia-reperfusion injury induced by hepatic ischemia-reperfusion injury in rats, together with related mechanisms, still needs further studies.

Objective: To investigate if propofol would protect the myocardial cells from apoptosis with hepatic ischemia-reperfusion injury.

Effects of basic drugs on prognosis of acute lung injury in mice.

The aim of this study was to investigate the effects of basic drugs that alkalizes blood, on prognosis of acute lung injury in mice. Mice were randomized into three groups: Group normal saline, Group THAM, injected with 3.64% tri-(hydroxymethyl) methylamine (THAM), and Group NaHCO3, injected with 5% NaHCO3 (n=26, each group).

A Role for Tubular Necroptosis in Cisplatin-Induced AKI.

Cell death and inflammation in the proximal tubules are the hallmarks of cisplatin-induced AKI, but the mechanisms underlying these effects have not been fully elucidated. Here, we investigated whether necroptosis, a type of programmed necrosis, has a role in cisplatin-induced AKI. We found that inhibition of any of the core components of the necroptotic pathway-receptor-interacting protein 1 (RIP1), RIP3, or mixed lineage kinase domain-like protein (MLKL)-by gene knockout or a chemical inhibitor diminished cisplatin-induced proximal tubule damage in mice.

Ppm1b negatively regulates necroptosis through dephosphorylating Rip3.

The auto-phosphorylation of murine receptor-interacting protein 3 (Rip3) on Thr 231 and Ser 232 in the necrosome is required to trigger necroptosis. However, how Rip3 phosphorylation is regulated is still largely unknown. Here we identified protein phosphatase 1B (Ppm1b) as a Rip3 phosphatase and found that Ppm1b restricts necroptosis in two settings: spontaneous necroptosis caused by Rip3 auto-phosphorylation in resting cells, and tumour necrosis factor-α (TNF)-induced necroptosis in cultured cells.

[Successful management of massive gastrointestinal bleeding using recombinant factor VIIa in an elderly patient with respiratory and renal failure].

Recombinant activated factor VII (rFVIIa) is a novel therapeutic agent for life-threatening massive gastrointestinal bleeding. We report a case of massive gastrointestinal bleeding in a 78-year-old female patient with respiratory and renal failure. After failure of management of the bleeding with routine pharmacotherapy, we gave the patient rFVIIa injection at the dose of 20 µg/kg and the bleeding was rapidly controlled.

The Gβγ-Src signaling pathway regulates TNF-induced necroptosis via control of necrosome translocation.

Formation of multi-component signaling complex necrosomes is essential for tumor necrosis factor α (TNF)-induced programmed necrosis (also called necroptosis). However, the mechanisms of necroptosis are still largely unknown. We isolated a TNF-resistant L929 mutant cell line generated by retrovirus insertion and identified that disruption of the guanine nucleotide-binding protein γ 10 (Gγ10) gene is responsible for this phenotype.

Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death.

Mixed lineage kinase domain-like protein (MLKL) was identified to function downstream of receptor interacting protein 3 (RIP3) in tumor necrosis factor-α (TNF)-induced necrosis (also called necroptosis). However, how MLKL functions to mediate necroptosis is unknown. By reconstitution of MLKL function in MLKL-knockout cells, we showed that the N-terminus of MLKL is required for its function in necroptosis.

Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis.

Mixed lineage kinase domain-like protein (Mlkl) was recently found to interact with receptor interacting protein 3 (Rip3) and to be essential for tumor necrosis factor (TNF)-induced programmed necrosis (necroptosis) in cultured cell lines. We have generated Mlkl-deficient mice by transcription activator-like effector nucleases (TALENs)-mediated gene disruption and found Mlkl to be dispensable for normal mouse development as well as immune cell development. Mlkl-deficient mouse embryonic fibroblasts (MEFs) and macrophages both showed resistance to necrotic but not apoptotic stimuli.

A role of RIP3-mediated macrophage necrosis in atherosclerosis development.

Necrotic death of macrophages has long been known to be present in atherosclerotic lesions but has not been studied. We examined the role of receptor interacting protein (RIP) 3, a mediator of necrotic cell death, in atherosclerosis and found that RIP3(-/-);Ldlr(-/-) mice were no different from RIP3(+/+);Ldlr(-/-) mice in early atherosclerosis but had significant reduction in advanced atherosclerotic lesions. Similar results were observed in Apoe(-/-) background mice.