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Onychomatricoma (OM) is a rare nail unit tumor with a characteristic presentation of fingerlike projections arising from the nail matrix. Due to the lack of transcriptome information, the mechanisms underlying its development are largely unknown.To characterize molecular features involved in the disease pathogenesis.Digital spatial profiling (DSP) was conducted in 2 cases of OM and normal control nail units. Based on the histological evaluation, we selectively profiled 69 regions of interest covering epithelial and stromal compartments of each tissue section. Dermoscopic and histopathologic findings were reviewed in 6 cases. Single-cell RNA sequencing of nail units and DSP were combined to define cell type contributions of OM.We identified 173 genes upregulated in stromal compartments of OM compared to onychodermis, specialized nail mesenchyme. Gene ontology analysis of the upregulated genes suggested the role of Wnt pathway activation in OM pathogenesis. We also found PLA2G2A, a known modulator of Wnt signaling, is strongly and specifically expressed in the OM stroma. The potential role of Wnt pathway was further supported by strong nuclear localization of β-catenin in OM. Compared to the nail matrix epithelium, only a few genes were increased in OM epithelium. Deconvolution of nail unit cell types showed that onychofibroblasts are the dominant cell-type in OM stroma.Integrated spatial and single-cell multi-omics concluded that OM is a tumor that derives a significant proportion of its origin from onychofibroblasts and is associated with upregulation of Wnt signals, which play a key role in the disease pathogenesis.

Both the accumulation of Amyloid-β (Aβ) in plaques and phosphorylation of Tau protein (p-Tau) in neurofibrillary tangles have been identified as two major symptomatic features of Alzheimer's disease (AD). Despite of critical role of Aβ and p-Tau in AD progress, the interconnection of signalling pathways that Aβ induces p-Tau remains elusive. Herein, we observed that a popular AD model mouse (APP/PS1) and Aβ-injected mouse showed an increase in p-Tyr42 Rho in hippocampus of brain. Low concentrations of Aβ (1 μM) induced RhoA-mediated Ser422 phosphorylation of Tau protein (p-Ser422 Tau), but reduced the expression of ATP citrate lyase (ACL) in the HT22 hippocampal neuronal cell line. In contrast, high concentrations of Aβ (10 μM) along with high levels of superoxide production remarkably attenuated accumulation of p-Ser422 Tau, but augmented ACL expression and activated sterol regulatory element-binding protein 1 (SREBP1), leading to cellular senescence. Notably, a high concentration of Aβ (10 μM) induced nuclear localization of p-Tyr42 Rho, which positively regulated NAD kinase (NADK) expression by binding to the NADK promoter. Furthermore, severe AD patient brain showed high p-Tyr42 Rho levels. Collectively, our findings indicate that both high and low concentrations of Aβ are detrimental to neurons via distinct two p-Tyr42 RhoA-mediated signalling pathways in Ser422 phosphorylation of Tau and ACL expression., Graphical abstract Image 1, Highlights • Aβ stimulates at least two signalling pathways depending on its concentrations. • p-Tyr42 RhoA is critical for the two signalling pathways. • Low concentration of Aβ induces p-Ser422 Tau. • High concentration of Aβ induces ACL expression along with highly producing superoxide. • In particular, p-Tyr42 RhoA translocalizes to nucleus, where it regulates expression of NAD kinase (NADK).

Glial cells are receiving much attention since they have been recognized as important regulators of many aspects of brain function and disease. Recent evidence has revealed that two different glial cells, astrocytes and microglia, control synapse elimination under normal and pathological conditions via phagocytosis. Astrocytes use the MEGF10 and MERTK phagocytic pathways, and microglia use the classical complement pathway to recognize and eliminate unwanted synapses. Notably, glial phagocytosis also contributes to the clearance of disease-specific protein aggregates, such as β-amyloid, huntingtin, and α-synuclein. Here we reivew recent findings showing that glial cells are active regulators in brain functions through phagocytosis and that changes in glial phagocytosis contribute to the pathogenesis of various neurodegenerative diseases. A better understanding of the cellular and molecular mechanisms of glial phagocytosis in healthy and diseased brains will greatly improve our current approach in treating these diseases.

Circadian (24-hr) rhythms influence virtually every aspect of mammalian physiology. The main rhythm generation center is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and work over the past several years has revealed that rhythmic gene transcription and post-translational processes are central to clock timing. In addition, rhythmic translation control has also been implicated in clock timing; however the precise cell signaling pathways that drive this process are not well known. Here we report that a key translation activation cascade, the mammalian target of rapamycin (mTOR) pathway, is under control of the circadian clock in the SCN. Using phosphorylated S6 ribosomal protein (pS6) as a marker of mTOR activity, we show that the mTOR cascade exhibits maximal activity during the subjective day, and minimal activity during the late subjective night. Importantly, expression of S6 was not altered as a function of circadian time. Rhythmic S6 phosphorylation was detected throughout the dorsoventral axis of the SCN, thus suggesting that rhythmic mTOR activity was not restricted to a subset of SCN neurons. Rather, rhythmic pS6 expression appeared to parallel the expression pattern of the clock gene period1 (per1). Using a transgenic per1 reporter gene mouse strain, we found a statistically significant cellular level correlation between pS6 and per1 gene expression over the circadian cycle. Further, photic stimulation triggered a coordinate upregulation of per1 and mTOR activation in a subset of SCN cells. Interestingly, this cellular level correlation between mTOR activity and per1 expression appears to be specific, since a similar expression profile for pS6 and per2 or c-FOS was not detected. Finally, we show that mTOR activity is downstream of the ERK/MAPK signal transduction pathway. Together these data reveal that mTOR pathway activity is under the control of the SCN clock, and suggests that mTOR signaling may contribute to distinct aspects of the molecular clock timing process.

The development of epilepsy is often associated with marked changes in central nervous system cell structure and function. Along these lines, reactive gliosis and granule cell axonal sprouting within the dentate gyrus of the hippocampus are commonly observed in individuals with temporal lobe epilepsy (TLE). Here we used the pilocarpine model of TLE in mice to screen the proteome and phosphoproteome of the dentate gyrus to identify molecular events that are altered as part of the pathogenic process. Using a two-dimensional gel electrophoresis-based approach, followed by liquid chromatography-tandem mass spectrometry, 24 differentially expressed proteins, including 9 phosphoproteins, were identified. Functionally, these proteins were organized into several classes, including synaptic physiology, cell structure, cell stress, metabolism and energetics. The altered expression of three proteins involved in synaptic physiology, actin, profilin 1 and α-synuclein was validated by secondary methods. Interestingly, marked changes in protein expression were detected in the supragranular cell region, an area where robust mossy fibers sprouting occurs. Together, these data provide new molecular insights into the altered protein profile of the epileptogenic dentate gyrus and point to potential pathophysiologic mechanisms underlying epileptogenesis.

Reductive alkylation and reductive methylation of aromatic primary amines with carbonyls and 37% formaldehyde using decaborane in one-pot way gave the corresponding tertiary amines in high yields. The reaction condition was extended for the reduction of nitroaromatic using decaborane and Pd/C followed by the reductive alkylation and reductive methylation using decaborane to give the corresponding tertiary amines in high yields.

Amines (primary and secondary) were methylated to the corresponding tertiary amine using 37% formaldehyde and decaborane in methanol at room temperature under nitrogen in high yields.

Decaborane reduces α-halocarbonyl compounds to the corresponding dehalogenated products in the presence of Pd/C in methanol at room temperature efficiently and chemoselectively.

The reactions of iodouracils having a formamidine or acetamidine moiety 1 with various acetylenes 2 in DMF at 120°C using potassium carbonate and a catalytic amount of palladium acetate gave a mixture of pyrido[2,3- d ]pyrimidine derivatives in good to high yields. Addition of lithium chloride to the reaction solution resulted in a change of reaction selectivity.

RAB3A, a Ras-related GTP-binding protein, is found in a rat neuronal cytosol in the form of complex with RabGDI or located on the synaptic vesicles and it cycles between the cytosol and the membranes. However, the regulatory mechanism of the translocation of Rab3A has not been clearly understood. To understand the mechanism of the translocation of Rab3A from the cytosol to the membranes, we examined which membranenous phospholipid is required for the translocation of Rab3A. Phosphatidic acid (PA) was found to be required for the translocation of Rab3A to the membranes and GTPgammaS stimulated the translocation of Rab3A.

Decaborane was found to be an effective agent for the chemoselective reduction of ketones to alcohols in the presence of pyrrolidine and cerium(III) chloride heptahydrate in methanol.

Decaborane was found to be an effective agent for the chemoselective reduction of ketones to alcohols in the presence of pyrrolidine and cerium(III) chloride heptahydrate in methanol.

Decaborane reduces α-halocarbonyl compounds to the corresponding dehalogenated products in the presence of Pd/C in methanol at room temperature efficiently and chemoselectively.

Amines (primary and secondary) were methylated to the corresponding tertiary amine using 37% formaldehyde and decaborane in methanol at room temperature under nitrogen in high yields.

Azides were converted to the corresponding carbamates using a system of 20 mol% of decaborane (B10H14) and 20 weight% of 10% Pd/C in methanol in the presence of di-tert-butyl dicarbonate at rt in high yields and to the corresponding amines using a system of 10 mol% of decaborane and 20 weight% of 10% Pd/C in methanol in the absence of di-tert-butyl dicarbonate at rt in high yields.

Recently, considerable attention is focused on anti-carcinogenic phytochemicals, particularly those derived from medicinal or edible plants. [6]-Paradol, a pungent phenolic compound present in certain Zingiberaceae plants, is known to have antimicrobial and analgesic activities. The compound has been reported to attenuate promotion of skin carcinogenesis and TPA-induced ear edema in female ICR mice, and to induce apoptosis in cultured human promyelocytic leukemia (HL-60) cells. In this study, we performed several biochemical studies to evaluate and compare the cancer chemopreventive potential of [6]-paradol and its synthetic derivatives. [6]-Paradol and its synthetic nonpungent analog, [6]-dehydroparadol significantly decreased the incidence and the multiplicity of skin tumors initiated by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application of [6]-paradol and its derivatives inhibited TPA-induced ear edema and H2O2 production and myeloperoxidase activity in the dorsal skin of mice. Induction of TPA-induced mouse epidermal ornithine decarboxylase (ODC) activity and H2O2- and UV-induced formation of oxidized DNA bases in vitro were also attenuated by the above compounds. These results indicate that [6]-paradol and its derivatives possess the cancer chemopreventive potential.

The reactions of iodouracils having a formamidine or acetamidine moiety 1 with various acetylenes 2 in DMF at 120°C using potassium carbonate and a catalytic amount of palladium acetate gave a mixture of pyrido[2,3- d ]pyrimidine derivatives in good to high yields. Addition of lithium chloride to the reaction solution resulted in a change of reaction selectivity.