Cisplatin-Chelated Iminodiacetic Acid-Conjugated Hyaluronic Acid Nanogels for the Treatment of Malignant Pleural Mesothelioma in Mice.

Malignant pleural mesothelioma (MPM) is one of the intractable cancers that require a more effective therapeutic strategy for clinical practice. Hyaluronic acid (HA) nanogels were prepared by the chelation of cisplatin (CDDP) with different molecular weights of iminodiacetic acid-conjugated hyaluronic acid (HA-IDA). The sizes of the 100, 850, and 2000 kDa HA nanogels were 33, 43, and 44 nm, respectively.

Diurnal shift of mouse activity by the deficiency of an ageing-related gene Lmna.

Nuclear lamina is a fundamental structure of the cell nucleus and regulates a wide range of molecular pathways. Defects of components of the nuclear lamina cause ageing-like physiological disorders, called laminopathy. Generally, ageing and diseases are often associated with perturbation of various time-of-day-dependent regulations, but it remains elusive whether laminopathy induces any changes of the circadian clock and physiological rhythms.

A behavioural correlate of the synaptic eligibility trace in the nucleus accumbens.

Reward reinforces the association between a preceding sensorimotor event and its outcome. Reinforcement learning (RL) theory and recent brain slice studies explain the delayed reward action such that synaptic activities triggered by sensorimotor events leave a synaptic eligibility trace for 1 s. The trace produces a sensitive period for reward-related dopamine to induce synaptic plasticity in the nucleus accumbens (NAc).

RAP80 suppresses the vulnerability of R-loops during DNA double-strand break repair.

Single-stranded DNA (ssDNA) arising as an intermediate of cellular processes on DNA is a potential vulnerability of the genome unless it is appropriately protected. Recent evidence suggests that R-loops, consisting of ssDNA and DNA-RNA hybrids, can form in the proximity of DNA double-strand breaks (DSBs) within transcriptionally active regions. However, how the vulnerability of ssDNA in R-loops is overcome during DSB repair remains unclear.

The interaction of secreted phospholipase A2-IIA with the microbiota alters its lipidome and promotes inflammation.

Secreted phospholipase A2-IIA (sPLA2-IIA) hydrolyzes phospholipids to liberate lysophospholipids and fatty acids. Given its poor activity toward eukaryotic cell membranes, its role in the generation of proinflammatory lipid mediators is unclear. Conversely, sPLA2-IIA efficiently hydrolyzes bacterial membranes.

Group IIA secreted phospholipase A2 controls skin carcinogenesis and psoriasis by shaping the gut microbiota.

Besides promoting inflammation by mobilizing lipid mediators, group IIA secreted phospholipase A2 (sPLA2-IIA) prevents bacterial infection by degrading bacterial membranes. Here, we show that, despite the restricted intestinal expression of sPLA2-IIA in BALB/c mice, its genetic deletion leads to amelioration of cancer and exacerbation of psoriasis in distal skin. Intestinal expression of sPLA2-IIA is reduced after treatment with antibiotics or under germ-free conditions, suggesting its upregulation by gut microbiota.

Decrease in MAP3Ks expression enhances the cell death caused by hyperthermia.

Purpose: Hyperthermia is a promising anticancer treatment modality. However, the molecular mechanism underlying the thermal sensitivity of tumor cells is largely unknown. The aim of this study was to clarify how biochemical changes triggered by heat stimulate antitumor activity.

Star-Polymer-DNA Gels Showing Highly Predictable and Tunable Mechanical Responses.

Dynamically crosslinked gels are appealing materials for applications that require time-dependent mechanical responses. DNA duplexes are ideal crosslinkers for building such gels because of their excellent sequence addressability and flexible tunability in bond energy. However, the mechanical responses of most DNA gels are complicated and unpredictable.

mTOR-AKT Signaling in Cellular Clock Resetting Triggered by Osmotic Stress.

The circadian clock oscillates in a cell-autonomous manner with a period of ∼24 h, and the phase is regulated by various time cues such as light and temperature through multiple clock input pathways. We previously found that osmotic and oxidative stress strongly affected the circadian period and phase of cellular rhythms, and triple knockout of apoptosis signal-regulating kinase (ASK) family members, , and , abolished the phase shift (clock resetting) induced by hyperosmotic pulse treatment. We aimed at exploring a key molecule(s) and signaling events in the clock input pathway dependent on ASK kinases.

Heart Rate Modeling and Prediction Using Autoregressive Models and Deep Learning.

Physiological time series are affected by many factors, making them highly nonlinear and nonstationary. As a consequence, heart rate time series are often considered difficult to predict and handle. However, heart rate behavior can indicate underlying cardiovascular and respiratory diseases as well as mood disorders.

Fine-tuning of polyaspartamide derivatives with alicyclic moieties for systemic mRNA delivery.

Development of efficient delivery vehicles for in vitro transcribed mRNA (IVT mRNA) is currently a major challenge in nanomedicines. For systemic mRNA delivery, we developed a series of cationic amphiphilic polyaspartamide derivatives (PAsp(DET/R)s) carrying various alicyclic (R) moieties with diethylenetriamine (DET) in the side chains to form mRNA-loaded polyplexes bearing stability under physiological conditions and possessing endosomal escape functionality. While the size and ζ-potential of polyplexes were comparable among various PAsp(DET/R)s, the transfection efficiencies of polyplexes were considerably varied due to difference in the R moieties of PAsp(DET/R)s and were described by an octanol-water (or buffer at pH 7.

Hepatocellular carcinoma diagnosis using a novel electrochemiluminescence immunoassay targeting serum IgM-free AIM.

Background: Recent increases in the number of patients with non-alcoholic steatohepatitis (NASH) warrant the identification of biomarkers for early detection of hepatocellular carcinoma (HCC) associated with NASH (NASH-HCC). IgM-free apoptosis inhibitor of macrophage (AIM), which generally associates with IgM in blood and exerts its biological function by dissociation from IgM, may serve as an effective biomarker for NASH-HCC. Here, we established a fully automatic and high-throughput electrochemiluminescence immunoassay (ECLIA) to measure IgM-free AIM and investigated its efficacy in diagnosing NASH-HCC and viral HCC.

Dynamic Stabilization of Unit Polyion Complexes Incorporating Small Interfering RNA by Fine-Tuning of Cationic Block Length in Two-Branched Poly(ethylene glycol)--poly(l-lysine).

To stabilize small interfering RNA (siRNA) in the bloodstream for systemic RNAi therapeutics, we previously fabricated ultrasmall siRNA nanocarriers that were sub-20 nm in hydrodynamic diameter, named as unit polyion complexes (uPICs), using two-branched poly(ethylene glycol)--poly(l-lysine) (bPEG-PLys). The blood retention time of uPICs is dramatically increased in the presence of free bPEG-PLys, suggesting dynamic stabilization of uPICs by free bPEG-PLys based on their equilibrium. Herein, we examined how the degree of polymerization of PLys (DP) affected the dynamic stability of uPICs in the bloodstream during prolonged circulation.

Bridging mRNA and Polycation Using RNA Oligonucleotide Derivatives Improves the Robustness of Polyplex Micelles for Efficient mRNA Delivery.

Polyplex for messenger RNA (mRNA) delivery requires strong yet reversible association between mRNA and polycation for extracellular robustness and selective intracellular disintegration. Herein, RNA oligonucleotide (OligoRNA) derivatives that bridge mRNA and polycation are developed to stabilize polyplex micelles (PMs). A set of the OligoRNAs introduced with a polyol moiety in their 5' end is designed to hybridize to fixed positions along mRNA strand.

High salt exacerbates acute kidney injury by disturbing the activation of CD5L/apoptosis inhibitor of macrophage (AIM) protein.

The influence of excess salt intake on acute kidney injury (AKI) has not been examined precisely except for some clinical data, unlike in chronic kidney disease. Here, we addressed the influence of high salt (HS) on AKI and its underlying mechanisms in terms of the activity of circulating apoptosis inhibitor of macrophage (AIM, also called CD5L) protein, a facilitator of AKI repair. HS loading in mice subjected to ischemia/reperfusion (IR) resulted in high mortality with advanced renal tubular obstruction and marked exacerbation in biomarkers of proximal renal tubular damage.

Mechanical actions of dendritic-spine enlargement on presynaptic exocytosis.

Synaptic transmission involves cell-to-cell communication at the synaptic junction between two neurons, and chemical and electrical forms of this process have been extensively studied. In the brain, excitatory glutamatergic synapses are often made on dendritic spines that enlarge during learning. As dendritic spines and the presynaptic terminals are tightly connected with the synaptic cleft, the enlargement may have mechanical effects on presynaptic functions.

Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin.

Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during "osteocytogenesis" is poorly understood. Here we show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites.

Associations of work-related stress and total sleep time with cholesterol levels in an occupational cohort of Japanese office workers.

Objective: The aim of the study was to investigate the associations of total sleep time (TST) and occupational stress based on the Brief Job Stress Questionnaire (BJSQ) with cholesterol levels in an occupational cohort of Japanese office workers.

Methods: The present study is a secondary analysis of a subset of participants from a randomized controlled trial. Participants were 179 employees from 5 companies in Tokyo who participated as the intervention group in a 3-month lifestyle intervention study among office workers with metabolic syndrome or at risk of metabolic syndrome.

Intraperitoneal Administration of a Cisplatin-Loaded Nanogel through a Hybrid System Containing an Alginic Acid-Based Nanogel and an Cross-Linkable Hydrogel for Peritoneal Dissemination of Ovarian Cancer.

Intraperitoneal chemotherapy demonstrates potential applicability in the treatment of peritoneally disseminated ovarian cancer because the disseminated tumors can directly receive exposure to high concentrations of anticancer drugs. However, a considerable proportion of drugs, particularly micromolecular and hydrophilic drugs, such as cisplatin (CDDP), are often excreted through glomerular filtration for a short period. To effectively deliver CDDP into peritoneally disseminated ovarian cancer tissues, we developed an alginate (AL)-based hybrid system in which a CDDP-loaded AL nanogel (AL/CDDP-nanogel) was encapsulated in an injectable AL-hydrogel cross-linked with calcium ions.

Block catiomer with flexible cationic segment enhances complexation with siRNA and the delivery performance in vitro.

RNA interference (RNAi) by small interfering RNAs (siRNAs) is a promising therapeutic approach. Because siRNA has limited intracellular access and is rapidly cleared , the success of RNAi depends on efficient delivery technologies. Particularly, polyion complexation between block catiomers and siRNA is a versatile approach for constructing effective carriers, such as unit polyion complexes (uPIC), core-shell polyion complex (PIC) micelles and vesicular siRNAsomes, by engineering the structure of block catiomers.