Chronological transitions of hepatocyte growth factor treatment effects in spinal cord injury tissue.

Inflammatory responses are known to suppress neural regeneration in patients receiving stem cell-based regenerative therapy for spinal cord injury (SCI). Consequently, pathways involved in neurogenesis and immunomodulation, such as the hepatocyte growth factor (HGF)/MET signaling cascade, have garnered significant attention. Notably, various studies, including our own, have highlighted the enhanced recovery of locomotor functions achieved in SCI animal models by combining HGF pretreatment and human induced stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation. However, these studies implicitly hypothesized that the functionality of HGF in SCI would be time consistent and did not elucidate its dynamics. In the present article, we investigated the time-course of the effect of HGF on SCI, aiming to uncover a more precise mechanism for HGF administration, which is indispensable for developing crystallizing protocols for combination therapy. To this end, we performed a detailed investigation of the temporal variation of HGF using the RNA-seq data we obtained in our most recent study. Leveraging the time-series design of the data, which we did not fully exploit previously, we identified three components in the effects of HGF that operate at different times: early effects, continuous effects, and delayed effects. Our findings suggested a concept where the three components together contribute to the acceleration of neurogenesis and immunomodulation, which reinforce the legitimacy of empirically fine-tuned protocols for HGF administration and advocate the novel possibility that the time-inconsistent effects of HGF progressively augment the efficacy of combined therapy.

A set-theoretic definition of cell types with an algebraic structure on gene regulatory networks and application in annotation of RNA-seq data.

The emergence of single-cell RNA sequencing (RNA-seq) has radically changed the observation of cellular diversity. Although annotations of RNA-seq data require preserved properties among cells of an identity, annotations using conventional methods have not been able to capture universal characters of a cell type. Analysis of expression levels cannot be accurately annotated for cells because differences in transcription do not necessarily explain biological characteristics in terms of cellular functions and because the data themselves do not inform about the correct mapping between cell types and genes. Hence, in this study, we developed a new representation of cellular identities that can be compared over different datasets while preserving nontrivial biological semantics. To generalize the notion of cell types, we developed a new framework to manage cellular identities in terms of set theory. We provided further insights into cells by installing mathematical descriptions of cell biology. We also performed experiments that could correspond to practical applications in annotations of RNA-seq data.

Subarachnoid hemorrhage triggers neuroinflammation of the entire cerebral cortex, leading to neuronal cell death.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a fatal disease, with early brain injury (EBI) occurring within 72 h of SAH injury contributes to its poor prognosis. EBI is a complicated phenomenon involving multiple mechanisms. Although neuroinflammation has been shown to be important prognosis factor of EBI, whether neuroinflammation spreads throughout the cerebrum and the extent of its depth in the cerebral cortex remain unknown. Knowing how inflammation spreads throughout the cerebrum is also important to determine if anti-inflammatory agents are a future therapeutic strategy for EBI. METHODS: In this study, we induced SAH in mice by injecting hematoma into prechiasmatic cistern and created models of mild to severe SAH. In sections of the mouse cerebrum, we investigated neuroinflammation and neuronal cell death in the cortex distal to the hematoma injection site, from anterior to posterior region 24 h after SAH injury. RESULTS: Neuroinflammation caused by SAH spread to all layers of the cerebral cortex from the anterior to the posterior part of the cerebrum via the invasion of activated microglia, and neuronal cell death increased in correlation with neuroinflammation. This trend increased with the severity of the disease. CONCLUSIONS: Neuroinflammation caused by SAH had spread throughout the cerebrum, causing neuronal cell death. Considering that the cerebral cortex is responsible for long-term memory and movement, suppressing neuroinflammation in all layers of the cerebral cortex may improve the prognosis of patients with SAH.

The GADD45G/p38 MAPK/CDC25B signaling pathway enhances neurite outgrowth by promoting microtubule polymerization.

GADD45G, one of the genes containing the human-specific conserved deletion enhancer-sequence (hCONDEL), has contributed to the evolution of the human cerebrum, but its function in human neurons has not been established. Here, we show that the GADD45G/p38 MAPK/CDC25B signaling pathway promotes neurite outgrowth in human neurons by facilitating microtubule polymerization. This pathway ultimately promotes dephosphorylation of phosphorylated CRMP2 which in turn promotes microtubule assembly. We also found that GADD45G was highly expressed in developing human cerebral specimens. In addition, RK-682, which is the inhibitor of a phosphatase of p38 MAPK and was found in Streptomyces sp., was shown to promote microtubule polymerization and neurite outgrowth by enhancing p38 MAPK/CDC25B signaling. These in vitro and in vivo results indicate that GADD45G/p38 MAPK/CDC25B enhances neurite outgrowth in human neurons.

Transplantation of iPSC-derived corneal endothelial substitutes in a monkey corneal edema model.

OBJECTIVE: In order to provide regenerative therapy for millions of patients suffering from corneal blindness globally, we derived corneal endothelial cell substitute (CECSi) cells from induced pluripotent stem cells (iPSCs) to treat corneal edema due to endothelial dysfunction (bullous keratopathy). METHODS AND RESULTS: We developed an efficient xeno-free protocol to produce CECSi cells from both research grade (Ff-MH09s01 and Ff-I01s04) and clinical grade (QHJI01s04) iPSCs. CECSi cells formed a hexagonal confluent monolayer with Na, K-ATPase alpha 1 subunit expression (ATP1A1), tight junctions, N-cadherin adherence junction formation, and nuclear PITX2 expression, which are all characteristics of corneal endothelial cells. CECSi cells can be cryopreserved, and thawed CECSi cell suspensions also expressed N-cadherin and ATP1A1. Residual undifferentiated iPSCs in QHJI01s04-derived CECSi cells was below 0.01%. Frozen stocks of Ff-I01s04- and QHJI01s04-derived CECSi cells were transported, thawed and transplanted into a monkey corneal edema model. CECSi-transplanted eyes significantly reduced corneal edema compared to control group. CONCLUSION: Our results show a promising approach to provide bullous keratopathy patients with an iPS-cell-based cell therapy to recover useful vision.

Food allergy in nursery children of Kawasaki city, Japan.

BACKGROUND: Food allergies are often life threatening. In order to establish appropriate food allergy measures in nursery children, it is important to analyze local epidemiological data on the food allergy prevalence in nursery children. However, no such data are currently available for the city of Kawasaki, Japan. OBJECTIVE: The present study retrospectively evaluated food allergy prevalence among nursery children in Kawasaki city. METHODS: Data from children with food allergies requiring food avoidance in the nurseries of Kawasaki city between 2007 and 2016 were evaluated. RESULTS: From 2007 to 2016, the prevalence of food allergies among nursery children in Kawasaki city increased from 2.7% to 5.3%. The increase of food allergy prevalence was higher in 2-5 year-old children than in 0-1 year-old children (2.0% to 4.7% vs. 5.3% to 7.0%, respectively). The top five most common food allergies were hen's egg (73.0%), cow's milk (29.3%), nuts (9.7%), soy (8.9%), and wheat (6.5%). Hen's egg was consistently identified as a causative food of food allergy in more than 70% (73.0-89.1%) of food avoidance cases over the 10 year period. The increase of egg allergy prevalence was higher in 2-5 year-old children than in 0-1 year-old children (1.7% to 3.2% vs. 5.2% to 6.0%, respectively). CONCLUSIONS: Food allergies, to hen's egg in particular, have increased considerably among nursery children in the city of Kawasaki, Japan, and that increase was higher among older children.

Prospective surveillance for atypical pathogens in children with community-acquired pneumonia in Japan.

A total of 141 children with community-acquired pneumonia (CAP) were studied prospectively to determine the causative microorganisms. Microbial investigations included examination of postnasal swabs, cultures, polymerase chain reaction (PCR), and serology. The atypical pathogens occurring most frequently were Mycoplasma pneumoniae (58 patients [41.1%]), Chlamydia pneumoniae (4 patients [2.8%]), and concurrent occurrence of both pathogens (1 patient [0.7%]). Patients aged under 4 years showed a relatively lower rate of atypical bacterial etiology compared with those aged 4 years or older. Major bacterial pathogens were detected in 89 patients (atypical pathogens were detected in 28 patients simultaneously), including Streptococcus pneumoniae in 34 patients, Haemophilus influenzae in 60, Moraxella catarrhalis in 48, and multiple pathogens in 42. In patients suspected of having atypical pneumonia, macrolides are recommended.