Airway remodeling in asthma involves the hyperproliferation of airway smooth muscle (ASM) cells. However, the molecular signals that regulate ASM growth are not completely understood. Gq-coupled G ...protein-coupled receptor and receptor tyrosine kinase signaling regulate ASM cell proliferation via activation of phospholipase C, generation of inositol triphosphate (IP
) and diacylglycerol (DAG). Diacylglycerol kinase (DGK) converts DAG into phosphatidic acid (PA) and terminates DAG signaling while promoting PA-mediated signaling and function. Herein, we hypothesized that PA is a pro-mitogenic second messenger in ASM, and DGK inhibition reduces the conversion of DAG into PA resulting in inhibition of ASM cell proliferation. We assessed the effect of pharmacological inhibition of DGK on pro-mitogenic signaling and proliferation in primary human ASM cells. Pretreatment with DGK inhibitor I (DGKI) significantly inhibited platelet-derived growth factor-stimulated ASM cell proliferation. Anti-mitogenic effect of DGKI was associated with decreased mTOR signaling and expression of cyclin D1. Exogenous PA promoted pro-mitogenic signaling and rescued DGKI-induced attenuation of ASM cell proliferation. Finally, house dust mite (HDM) challenge in wild type mice promoted airway remodeling features, which were attenuated in DGKζ
mice. We propose that DGK serves as a potential drug target for mitigating airway remodeling in asthma.
Micrometer-sized gold–silica Janus particles act as an effective stabilizer of emulsions by adsorption at the oil–water interface. The Janus particles were adsorbed at the oil–water interface as a ...monolayer and stabilized near-spherical and nonspherical oil droplets that remained stable without coalescence for longer than one year. Gold and silica surfaces have hydrophobic and hydrophilic features; these surfaces were exposed to oil and water phases, respectively. In contrast, bare silica particles cannot stabilize stable emulsion, and completed demulsification occurred within 2 h. Greater stability of the emulsion for the Janus particle system compared to the silica particle system was achieved by using the adsorption energy of the Janus particles at the oil–water interface; the adsorption energy of the Janus particles is more than 3 orders of magnitude greater than that of silica particles. Suspension polymerization of Janus particle-stabilized vinyl monomer droplets in the absence of any molecular-level emulsifier in aqueous media led to nonspherical microspheres with Janus particles on their surface. Furthermore, polymer microspheres carrying Au femtoliter cups on their surfaces were successfully fabricated by removal of the silica component from the Janus-particle stabilized microspheres.
Sekentei (social appearance) is a Japanese concept that describes a person’s sense of implicit societal pressure to conform to social norms. However, evidence of a relationship between sekentei and ...health outcomes is sparse. This study examined the association between sekentei and cognitive function among community-dwelling older Japanese people. Baseline data were obtained from the Neuron to Environmental Impact across Generations (NEIGE) study conducted in 2017; 526 randomly sampled community-dwelling individuals aged 65–84 years living in Tokamachi, Niigata Prefecture, Japan were analyzed. The 12-item Sekentei Scale was used to assess sekentei. Cognitive function levels were evaluated with the Japanese version of Mini-Mental State Examination (MMSE-J; ranging from 0–30). Approximately 10% and 25% had cognitive decline and mild cognitive impairment, respectively (MMSE-J scores of ≤23 and 24–26, respectively). Multinomial logistic regression analysis showed that both high and low levels of sekentei were associated with lower cognitive function, particularly mild cognitive impairment, after adjusting for sociodemographic factors, health behaviors, health conditions, and genetic factors. The current findings suggest that a moderate level of sekentei consciousness is beneficial for cognitive health, and that sekentei could be an important socio-cultural factor affecting cognitive function.
Background
Progressive supranuclear palsy (PSP) is a neurodegenerative disease and patients with PSP frequently experience depression. However, there have been few reports of patients with major ...depressive disorder as an antecedent diagnosis of PSP. Here, we report a case who presented with a major depressive episode with palilalia and difficulty in opening his eyes as prodromal symptoms of PSP.
Case Presentation
A Japanese man developed his first major depressive episode at the age of 75 years. At 76 years old, the patient developed palilalia and difficulty in opening his eyes, which worsened with anxiety and agitation. His depression symptoms were not alleviated following treatment with several antidepressants. He gradually became less depressed but more apathetic. Subsequently, he experienced falls and developed nuchal and axial rigidity. Magnetic resonance imaging and 123I‐ioflupane single‐photon emission tomography showed predominant midbrain atrophy and postsynaptic striatal dopaminergic degeneration, respectively. He was diagnosed as having symptoms suggestive of PSP at the age of 80 years. The combination of sertraline and aripiprazole reduced his anxiety and agitation. Botulinum toxin treatment provided partial relief for his difficulty in eye opening.
Conclusion
Some patients, such as the current case, develop a major depressive episode at the onset of PSP and present to a psychiatrist. Psychiatrists should therefore be aware of the possibility of a major depressive episode with non‐specific symptoms preceding the onset of the core clinical features of PSP.
The patient's first major depressive episode occurred at the age of 75 years. At the age of 80 years, the patient was diagnosed as having symptoms suggestive of progressive supranuclear palsy with predominant postural instability.
The host-microbiota relationship has evolved to shape mammalian physiology, including immunity, metabolism, and development. Germ-free models are widely used to study microbial effects on host ...processes such as immunity. Here, we find that both germ-free and T cell-deficient mice exhibit a robust sebum secretion defect persisting across multiple generations despite microbial colonization and T cell repletion. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that non-genetic information in the gametes is required for microbial-dependent phenotypic transmission. Accordingly, gene expression in early embryos derived from gametes from germ-free or T cell-deficient mice is strikingly and similarly altered. Our findings demonstrate that microbial- and immune-dependent regulation of non-genetic information in the gametes can transmit inherited phenotypes transgenerationally in mice. This mechanism could rapidly generate phenotypic diversity to enhance host adaptation to environmental perturbations.
Display omitted
•Germ-free and T cell-deficient mice show defects in barrier tissue function•Defects persist transgenerationally via non-genetic inheritance•Immune-microbe-influenced inheritance is transmitted by the germlines of both sexes•The microbiome and immune system impact embryonic gene expression of progeny
Harris et al. describe phenotypic abnormalities in germ-free and T cell-deficient mice that are not acutely correctable and are non-genetically transmitted to progeny. The parental microbe and immune environment impact gametes to alter early embryonic gene expression, thereby influencing barrier and metabolic tissue of progeny through transgenerational non-genetic inheritance.
Schizophrenia is thought to be caused by a combination of genetic and environmental factors; however, its pathogenesis remains largely unknown. Here, we focus on the endothelial tight-junction ...protein claudin-5 (CLDN5), because the
gene is mapped to the schizophrenia-associated 22q11.2 deletion region, and a single nucleotide polymorphism in the
locus is also linked to schizophrenia. We show, by RT-qPCR and immunohistochemistry, that the expressions of CLDN5 mRNA and protein are significantly increased and decreased, respectively, in the schizophrenic prefrontal cortex (PFC) compared with control PFC. These changes were not observed in the schizophrenic visual cortex (VC), and neither the density nor diameter of the CD34-positive microvessels was altered in the schizophrenic PFC or VC. Interestingly, protein kinase A (PKA) was activated in the microvascular and perivascular regions of the schizophrenic PFC, and the pPKA-positive microvascular endothelial cells occasionally exhibited focal loss of CLND5. Since we previously demonstrated that cAMP induced
mRNA expression and size-selective loosening of the endothelial barrier in PKA-independent and -dependent manners, respectively, a similar mechanism could contribute to the discrepancy between mRNA and protein expression of CLDN5 in the schizophrenic PFC. Taken collectively, these findings provide novel insights into the pathophysiology of schizophrenia.
To investigate whether water influx into cerebrospinal fluid (CSF) space is reduced in Alzheimer's patients as previously shown in the transgenic mouse model for Alzheimer's disease.
Ten normal young ...volunteers (young control, 21-30 years old), ten normal senior volunteers (senior control, 60-78 years old, MMSE ≥ 29), and ten Alzheimer's disease (AD) patients (study group, 59-84 years old, MMSE: 13-19) participated in this study. All AD patients were diagnosed by neurologists specializing in dementia based on DSM-IV criteria. CSF dynamics were analyzed using positron emission tomography (PET) following an intravenous injection of 1,000 MBq 15OH2O synthesized on-line.
Water influx into CSF space in AD patients, expressed as influx ratio, (0.755 ± 0.089) was significantly reduced compared to young controls (1.357 ± 0.185; p < 0.001) and also compared to normal senior controls (0.981 ± 0.253, p < 0.05). Influx ratio in normal senior controls was significantly reduced compared to young controls (p < 0.01).
Water influx into the CSF is significantly reduced in AD patients. β-amyloid clearance has been shown to be dependent on interstitial flow and CSF production. The current study indicates that reduction in water influx into the CSF may disturb the clearance rate of β-amyloid, and therefore be linked to the pathogenesis of AD.
UMIN Clinical Trials Registry UMIN000011939.
Abstract
Introduction
Pegfilgrastim is indicated to decrease the incidence of chemotherapy‐induced febrile neutropenia. It is the first granulocyte‐colony stimulating factor approved for prophylactic ...use regardless of carcinoma type and is marketed in Japan as G‐LASTA (Kyowa Kirin Co., Ltd., Tokyo, Japan). MD‐110 is a biosimilar of pegfilgrastim. This phase III, multicenter, open‐label, single‐arm study investigated the efficacy and safety of MD‐110 in early‐stage breast cancer patients receiving neoadjuvant or adjuvant myelosuppressive chemotherapy.
Methods
A total of 101 patients received the study drug. Each patient received docetaxel 75 mg/m
2
and cyclophosphamide 600 mg/m
2
(TC) for four cycles on day 1 of each cycle. MD‐110 (3.6 mg) was administered subcutaneously on day 2 of each cycle. The primary efficacy endpoint was the duration of severe neutropenia during cycle 1 (days with absolute neutrophil count < 500/mm
3
). The safety endpoints were adverse events and the presence of antidrug antibodies.
Results
The mean (SD) duration of severe neutropenia for MD‐110 was 0.2 (0.4) days. The upper limit of the two‐sided 95% confidence interval for the mean duration of severe neutropenia was 0.2 days, below the predefined threshold of 3.0 days. The incidence of febrile neutropenia, the secondary efficacy endpoint, was 6.9% (7/101). Adverse events, occurring in more than 50% of patients, were alopecia, constipation, and malaise, which are common side effects of TC chemotherapy. Antidrug antibodies were negative in all patients.
Conclusion
MD‐110 was effective against chemotherapy‐induced neutropenia. No additional safety concern, compared with the originator, was observed in patients with breast cancer receiving TC chemotherapy.(JapicCTI‐205230).
Systemic sclerosis (SSc) is an intractable connective tissue disease that causes skin and organ fibrosis. Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) affect its ...prognosis. YKL-40 protein impacts inflammation and tissue remodeling. Therefore, we evaluated the utility of YKL-40 blood levels in identifying patients with SSc complicated by PAH, as confirmed by immunohistochemistry (IHC) examination.
We retrospectively analyzed 78 patients with SSc and performed IHC on 7 normal and 7 SSc skin samples in the Japanese population. Age-adjusted YKL-40 serum levels were analyzed.
YKL-40 age percentile was significantly elevated in SSc patients. There was no difference between patients with SSc with and without ILD and PAH. YKL-40 age percentile was greater in patients with PAH complication. YKL-40 immunostaining was negative in normal skin and prominent in the subcutaneous vascular wall of all SSc samples. Receiver operating characteristic (ROC) curve analysis indicated that YKL-40 age percentile correctly differentiated between patients with and without PAH with a sensitivity of 80% and a specificity of 94.1%.
A higher YKL-40 level with PAH may be reflective of angiogenesis due to capillary injury in SSc. YKL-40 may offer a useful and easily applicable diagnostic biomarker of SSc complicated with PAH.
PDF
