Development of assisted reproductive technologies for Mus spretus†.

The genus Mus consists of many species with high genetic diversity. However, only one species, Mus musculus (the laboratory mouse), is common in biomedical research. The unavailability of assisted reproductive technologies (ARTs) for other Mus species might be a major reason for their limited use in laboratories.

Noncovalent Stabilization of Vesicular Polyion Complexes with Chemically Modified/Single-Stranded Oligonucleotides and PEG--guanidinylated Polypeptides for Intracavity Encapsulation of Effector Enzymes Aimed at Cooperative Gene Knockdown.

For the simultaneous delivery of antisense oligonucleotides and their effector enzymes into cells, nanosized vesicular polyion complexes (PICs) were fabricated from oppositely charged polyion pairs of oligonucleotides and poly(ethylene glycol) (PEG)--polypeptides. First, the polyion component structures were carefully designed to facilitate a multimolecular (or secondary) association of unit PICs for noncovalent (or chemical cross-linking-free) stabilization of vesicular PICs. Chemically modified, single-stranded oligonucleotides (SSOs) dramatically stabilized the multimolecular associates under physiological conditions, compared to control SSOs without chemical modifications and duplex oligonucleotides.

The small compound, TD-198946, protects against intervertebral degeneration by enhancing glycosaminoglycan synthesis in nucleus pulposus cells.

Degeneration of the nucleus pulposus (NP) might serve as a trigger for intervertebral disc degeneration (IDD). A recent drug screening study revealed that the thienoindazole derivative, TD-198946, is a novel drug for the treatment of osteoarthritis. Because of the environmental and functional similarities between articular cartilage and intervertebral disc, TD-198946 is expected to prevent IDD.

Understanding paraxial mesoderm development and sclerotome specification for skeletal repair.

Pluripotent stem cells (PSCs) are attractive regenerative therapy tools for skeletal tissues. However, a deep understanding of skeletal development is required in order to model this development with PSCs, and for the application of PSCs in clinical settings. Skeletal tissues originate from three types of cell populations: the paraxial mesoderm, lateral plate mesoderm, and neural crest.

Computational Characteristics of the Striatal Dopamine System Described by Reinforcement Learning With Fast Generalization.

Generalization is the ability to apply past experience to similar but non-identical situations. It not only affects stimulus-outcome relationships, as observed in conditioning experiments, but may also be essential for adaptive behaviors, which involve the interaction between individuals and their environment. Computational modeling could potentially clarify the effect of generalization on adaptive behaviors and how this effect emerges from the underlying computation.

Selective intracellular delivery of perfluorocarbon nanodroplets for cytotoxicity threshold reduction on ultrasound-induced vaporization.

Background: Phase-change nanodroplets (PCNDs), which are liquid perfluorocarbon nanoparticles, have garnered much attention as ultrasound-responsive nanomedicines. The vaporization phenomenon has been employed to treat tumors mechanically. However, the ultrasound pressure applied to induce vaporization must be low to avoid damage to nontarget tissues.

Signaling models for dopamine-dependent temporal contiguity in striatal synaptic plasticity.

Animals remember temporal links between their actions and subsequent rewards. We previously discovered a synaptic mechanism underlying such reward learning in D1 receptor (D1R)-expressing spiny projection neurons (D1 SPN) of the striatum. Dopamine (DA) bursts promote dendritic spine enlargement in a time window of only a few seconds after paired pre- and post-synaptic spiking (pre-post pairing), which is termed as reinforcement plasticity (RP).

Identification of GLUT12/SLC2A12 as a urate transporter that regulates the blood urate level in hyperuricemia model mice.

Recent genome-wide association studies have revealed some genetic loci associated with serum uric acid levels and susceptibility to gout/hyperuricemia which contain potential candidates of physiologically important urate transporters. One of these novel loci is located upstream of and , suggesting that variations in these genes increase the risks of hyperuricemia and gout. We herein focused on encoding a transporter, GLUT12, the physiological function of which remains unclear.

Photo-reactive oligodeoxynucleotide-embedded nanovesicles (PROsomes) with switchable stability for efficient cellular uptake and gene knockdown.

A photo-responsive nanovesicle is fabricated by polyion complex (PIC) formation between poly(ethylene glycol) (PEG)-block-polypeptides and photo-reactive oligodeoxynucleotides (PROs)/anti-sense oligonucleotides (ASOs). The ultraviolet (UV) light triggers reversible crosslinking between PROs and ASOs in the vesicular membrane, providing the nanovesicle with switchable stability under physiological conditions. The resulting nanovesicle allows efficient cellular internalization, leading to significant UV-triggered gene knockdown in cultured cells.

Crucial Role of AIM/CD5L in the Development of Glomerular Inflammation in IgA Nephropathy.

Background: IgA nephropathy (IgAN) begins with aberrant IgA deposition in glomeruli, progresses to IgM/IgG/complement codeposition, and results in chronic inflammation and glomerular damage. However, the mechanism that drives such phlogogenic cascade has been unclear. Recently, apoptosis inhibitor of macrophage (AIM) protein was shown to modulate macrophages' function in various pathologic conditions, thereby profoundly affecting the progression of renal disorders, including AKI.

Genomic profiling of multiple primary cancers including synchronous lung adenocarcinoma and bilateral malignant mesotheliomas: Identification of a novel BAP1 germline variant.

We report a case with a rare combination of synchronous lung adenocarcinoma and bilateral malignant pleural mesotheliomas in a 70-year-old male without asbestos exposure. He metachronously developed peritoneal malignant mesothelioma, intrahepatic cholangiocarcinoma, urothelial carcinoma of the bladder and prostatic adenocarcinoma. Immunohistochemistry revealed complete loss of BAP1 expression in all seven lesions.

Hedgehog Activation Regulates Human Osteoblastogenesis.

Two genetic diseases, Gorlin syndrome and McCune-Albright syndrome (MAS), show completely opposite symptoms in terms of bone mineral density and hedgehog (Hh) activity. In this study, we utilized human induced pluripotent stem cell (iPSC)-based models of the two diseases to understand the roles of Hh signaling in osteogenesis. Gorlin syndrome-derived iPSCs showed increased osteoblastogenesis and mineralization with Hh signaling activation and upregulation of a set of transcription factors in an osteogenic culture, compared with the isogenic control.

Association Between Electroencephalogram-Derived Sleep Measures and the Change of Emotional Status Analyzed Using Voice Patterns: Observational Pilot Study.

Background: Measuring emotional status objectively is challenging, but voice pattern analysis has been reported to be useful in the study of emotion.

Objective: The purpose of this pilot study was to investigate the association between specific sleep measures and the change of emotional status based on voice patterns measured before and after nighttime sleep.

Methods: A total of 20 volunteers were recruited.

RNF8 promotes high linear energy transfer carbon-ion-induced DNA double-stranded break repair in serum-starved human cells.

The cell-killing effect of radiotherapy largely depends on unrepaired DNA double-stranded breaks (DSBs) or lethal chromosome aberrations induced by DSBs. Thus, the capability of DSB repair is critically important for the cancer-cell-killing effect of ionizing radiation. Here, we investigated the involvement of the DNA damage signaling factors ataxia telangiectasia mutated (ATM), ring finger protein 8 (RNF8), and RNF168 in quiescent G0/G1 cells, which are expressed in the majority of cell populations in tumors, after high linear energy transfer (LET) carbon-ion irradiation.

Group V secreted phospholipase A plays a protective role against aortic dissection.

Aortic dissection is a life-threatening aortopathy involving separation of the aortic wall, whose underlying mechanisms are still incompletely understood. Epidemiological evidence suggests that unsaturated fatty acids improve cardiovascular health. Here, using quantitative RT-PCR, histological analyses, magnetic cell sorting and flow cytometry assays, and MS-based lipidomics, we show that the activity of a lipid-metabolizing enzyme, secreted phospholipase A group V (sPLA-V), protects against aortic dissection by endogenously mobilizing vasoprotective lipids.

Gene regulatory landscape in osteoblast differentiation.

The development of osteoblasts, a bone-forming cell population, occurs in conjunction with development of the skeleton, which creates our physical framework and shapes the body. In the past two decades, genetic studies have uncovered the molecular framework of this process-namely, transcriptional regulators and signaling pathways coordinate the cell fate determination and differentiation of osteoblasts in a spatial and temporal manner. Recently emerging genome-wide studies provide additional layers of understanding of the gene regulatory landscape during osteoblast differentiation, allowing us to gain novel insight into the modes of action of the key regulators, functional interaction among the regulator-bound enhancers, epigenetic regulations, and the complex nature of regulatory inputs.

The Balance between the Hemostatic Effect and Immune Response of Hyaluronan Conjugated with Different Chain Lengths of Inorganic Polyphosphate.

Inorganic polyphosphate (PolyP) is a potential hemostatic material. However, the effect of PolyP chain length on the immune response and hemostatic function remains to be established. We have developed PolyP-conjugated hyaluronans (HA-PolyPs) with three different short-chain PolyPs ( = 13, 40, and 100 phosphate units).

High-throughput functional evaluation of BRCA2 variants of unknown significance.

Numerous nontruncating missense variants of the BRCA2 gene have been identified, but there is a lack of convincing evidence, such as familial data, demonstrating their clinical relevance and they thus remain unactionable. To assess the pathogenicity of variants of unknown significance (VUSs) within BRCA2, here we develop a method, the MANO-B method, for high-throughput functional evaluation utilizing BRCA2-deficient cells and poly (ADP-ribose) polymerase (PARP) inhibitors. The estimated sensitivity and specificity of this assay compared to those of the International Agency for Research on Cancer classification system is 95% and 95% (95% confidence intervals: 77-100% and 82-99%), respectively.

Proliferation-associated long noncoding RNA, TMPO-AS1, is a potential therapeutic target for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer compared with luminal or epidermal growth factor receptor 2 subtypes, thus effective therapeutic options for TNBC are yet to be developed. Nowadays, oncogenic long noncoding RNAs (lncRNAs) are applied to cancer management as a new class of therapeutic targets. We previously showed that thymopoietin antisense transcript 1 (TMPO-AS1) is a proliferation-associated lncRNA that contributes to hormone-dependent breast cancer progression by stabilizing estrogen receptor-α mRNA.

Activation of inflammation and resolution pathways of lipid mediators in synovial fluid from patients with severe rheumatoid arthritis compared with severe osteoarthritis.

Background: The upregulation of the cyclooxygenase and lipoxygenase pathways of arachidonic acid is thought to be involved in the development of rheumatoid arthritis. Recently, the presence of specialized pro-resolving lipid mediators in synovial tissues from patients with osteoarthritis has been reported.

Objective: To clarify the quantitative and qualitative changes in lipid mediators in the synovium of severe rheumatoid arthritis patients, we compared the profiles of lipid mediators in synovial fluid obtained from patients with severe rheumatoid arthritis and from those with severe osteoarthritis.

Secreted Phospholipase PLA2G2D Contributes to Metabolic Health by Mobilizing ω3 Polyunsaturated Fatty Acids in WAT.

Polyunsaturated fatty acids (PUFAs) confer health benefits by preventing inflammation and obesity and by increasing thermogenesis in brown and beige adipocytes. As well as being supplied exogenously as nutrients, PUFAs are largely stored in membrane glycerophospholipids and released by phospholipase As (PLAs). However, the molecular identity of the PLA subtype(s) that supplies endogenous PUFAs for metabolic homeostasis remains unclear.

Installation of a Thermoswitchable Hydrophobic Domain into a Unimer Polyion Complex for Enhanced Cellular Uptake of siRNA.

Whereas small siRNA nanocarriers with a size of 10-20 nm exert high tissue-permeability, they encounter the challenge of inefficient adsorption on the cell surface, resulting in poor cellular uptake of siRNA. To solve this dilemma, this study aims to control the hydrophobicity of a small siRNA nanocarrier, unimer polyion complex (uPIC), with a size of ∼10 nm. The uPICs are fabricated to consist of a single pair between siRNA and a smart triblock copolymer comprising hydrophilic poly(2-ethyl-2-oxazoline) (PEtOx), thermoswitchable poly(2--propyl-2-oxazoline) (PnPrOx), and cationic poly(l-lysine) (PLL).

LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover.

Objective: Non-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic variant in the lysophosphatidylinositol acyltransferase 1 (, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes.