Modular Synthesis of Tripeptide Analogs with an Aminobitriazole Skeleton Using Diynyl Benziodoxolone as a Trivalent Platform.

A new synthesis method of tripeptide analogs with an aminobitriazole skeleton was proposed. The method involves assembling three amino acid-derived modules at the amino group site and onto a triisopropylsilyl diynyl benziodoxolone by copper-catalyzed electrophilic diynylation of amino acid-derived sulfonamides, chemoselective azide-alkyne cycloadditions with amino acid-derived azides, and deprotection. Various complex aminobitriazoles substituted with pyrene, nucleoside, and -acetylglucosamine were also synthesized.

The protective role of conjunctival goblet cell mucin sialylation.

Gel-forming mucins secreted by conjunctival goblet cells have been implicated in the clearance of allergens, pathogens, and debris. However, their roles remain incompletely understood. Here we show that human and mouse conjunctival goblet cell mucins have Alcian blue-detectable sialic acids, but not sulfates in the steady state.

Late-stage diversification strategy for synthesizing ynamides through copper-catalyzed diynylation and azide-alkyne cycloaddition.

A late-stage diversification strategy for synthesizing ynamides has been developed. This strategy was enabled by the copper-catalyzed direct electrophilic diynylation of sulfonamides with a novel triisopropylsilyl diynyl benziodoxolone, deprotection, and the late-stage chemoselective copper-catalyzed azide-alkyne cycloaddition sequence, which yields various complex molecule-derived ynamides with pyrene, amino acid, nucleoside, and -acetylglucosamine as substituents.

Differentiation of enteric neural crest cells transplanted from SOX10-Venus mouse embryonic stem cells into the gut of the endothelin receptor B null mouse model.

Purpose: Failure of enteric neural crest-derived cells (ENCCs) to correctly colonize the embryonic gut results in Hirschsprung's disease (HD). Embryonic stem cells (ESCs) have the potential to differentiate into all tissue-specific cells and lineages, including ENCCs. We investigated the cellular differentiation of ESCs from Sox10-Venus mice into both control and endothelin receptor-B knockout (Ednrb KO) mouse gut to assess each region.

Synthesis of 4-Imidazolidinones from Diamides and Ethynyl Benziodoxolones via Double Michael-Type Addition: Ethynyl Benziodoxolones as Electrophilic Ynol Synthons.

The moiety of 4-imidazolidinone is an important structural motif in organic synthesis and medicinal chemistry. We present the synthesis of 4-imidazolidinones from various diamides with ethynyl benziodoxolones through double Michael-type addition, which is an unprecedented reaction mode for hypervalent alkynyl iodine compounds. -2,5-Disubstituted 4-imidazolidinones were diastereoselectively synthesized from amino acid derived diamides.

Impaired mitochondrial accumulation and Lewy pathology in neuron-specific FBXO7-deficient mice.

Parkinson's disease, the second most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons. FBXO7 (F-box protein only 7) (PARK15) mutations cause early-onset Parkinson's disease. FBXO7 is a subunit of the SCF (SKP1/cullin-1/F-box protein) E3 ubiquitin ligase complex, but its neuronal relevance and function have not been elucidated.

Impaired GATE16-mediated exocytosis in exocrine tissues causes Sjögren's syndrome-like exocrinopathy.

Sjögren's syndrome (SjS) is a chronic autoimmune disease characterized by immune cell infiltration of the exocrine glands, mainly the salivary and lacrimal glands. Despite recent advances in the clinical and mechanistic characterization of the disease, its etiology remains largely unknown. Here, we report that mice with a deficiency for either Atg7 or Atg3, which are enzymes involved in the ubiquitin modification pathway, in the salivary glands exhibit a SjS-like phenotype, characterized by immune cell infiltration with autoantibody detection, acinar cell death, and dry mouth.

Ablation of fatty acid desaturase 2 (FADS2) exacerbates hepatic triacylglycerol and cholesterol accumulation in polyunsaturated fatty acid-depleted mice.

Deficiency of polyunsaturated fatty acids (PUFAs) is known to induce hepatic steatosis. However, it is not clearly understood which type of PUFA is responsible for the worsening of steatosis. This study observed a marked accumulation of hepatic triacylglycerol and cholesterol in fatty acid desaturase 2 knockout (FADS2 ) mice lacking both C18 and ≥ C20 PUFAs that were fed a PUFA-depleted diet.

Ependymal ciliary motion and their role in congenital hydrocephalus.

Purpose: Since a case of hydrocephalus in humans considered to be caused by ciliary dysfunction was first reported by Greenstone et al. in 1984, numerous papers on the correlation between ciliary function and hydrocephalus have been published.

Methods: We reviewed the published literature on primary ciliary dyskinesia in humans causing hydrocephalus, focusing on articles specifically examining the relation between ciliary function and hydrocephalus and its treatment.

Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer.

Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11) cells are not fully understood. To characterize IL-11 cells in vivo, we generate Il11 reporter mice.

Ligand-Enabled Copper-Catalyzed -Alkynylation of Sulfonamide with Alkynyl Benziodoxolone: Synthesis of Amino Acid-Derived Ynamide.

Ynamides are versatile building blocks in organic synthesis. However, the synthesis of amino acid-derived ynamides is difficult but in high demand. Herein, we disclose the copper-catalyzed Csp-N coupling of sulfonamide, including amino acid and peptide derivatives, to give ynamides by using alkynyl benziodoxolones with broad functional group tolerance under mild reaction conditions.

N-Alkenylation of hydroxamic acid derivatives with ethynyl benziodoxolone to synthesize cis-enamides through vinyl benziodoxolones.

The stereoselective synthesis of cis-β-N-alkoxyamidevinyl benziodoxolones (cis-β-N-RO-amide-VBXs) from O-alkyl hydroxamic acids in the presence of an ethynyl benziodoxolone-acetonitrile complex (EBX-MeCN) is reported herein. The reaction was performed under mild conditions including an aqueous solvent, a mild base, and room temperature. The reaction tolerated various O-alkyl hydroxamic acids derived from carboxylic acids, such as amino acids, pharmaceuticals, and natural products.

Homeostatic p62 levels and inclusion body formation in CHCHD2 knockout mice.

Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurones, but the relationship between impaired autophagy and Lewy bodies (LBs) remains unknown. α-Synuclein and p62, components of LBs, are the defining characteristic of Parkinson's disease (PD). Until now, we have analyzed mice models and demonstrated p62 aggregates derived from an autophagic defect might serve as 'seeds' and can potentially be a cause of LB formation.

Synthesis of Phenol-Derived cis-Vinyl Ethers Using Ethynyl Benziodoxolone.

The stereoselective synthesis of cis-β-phenoxyvinyl benziodoxolones (cis-β-phenol-VBXs) from an ethynyl benziodoxolone-acetonitrile complex (EBX-MeCN) and various phenols is reported herein. The reaction tolerates different phenol derivatives, including complex natural products, and can be conducted under mild conditions. The synthesis was performed in an aqueous solvent in the absence and presence of a catalytic amount of a base.

Low bone mineral density due to secondary hyperparathyroidism in the mouse model of Fabry disease.

Low bone mineral density (BMD)-diagnosed as osteoporosis or osteopenia-has been reported as a new characteristic feature of Fabry disease; however, the mechanism underlying the development of low BMD is unknown. We previously revealed that a mouse model of Fabry disease [] exhibits impaired functioning of medullary thick ascending limb (mTAL), leading to insufficient Ca reabsorption and hypercalciuria. Here, we investigated bone metabolism in mice without marked glomerular or proximal tubular damage.

Characterization of starvation-induced autophagy in cerebellar Purkinje cells of pHluorin-mKate2-human LC3B transgenic mice.

We generated a new transgenic mouse model that expresses a pHluorin-mKate2 fluorescent protein fused with human LC3B (PK-LC3 mice) for monitoring autophagy activity in neurons of the central nervous system. Histological analysis revealed fluorescent puncta in neurons of the cerebral cortex, hippocampus, cerebellar Purkinje cells, and anterior spinal regions. Using CLEM analysis, we confirmed that PK-LC3-positive puncta in the perikarya of Purkinje cells correspond to autophagic structures.

Aging-related motor function and dopaminergic neuronal loss in C57BL/6 mice.

Aging-related dopaminergic neuronal loss and its motor phenotypes are well known. Excessive loss of dopaminergic neurons leads to Parkinson's disease (PD), the most common neurodegenerative disorder characterized by the loss of nigrostriatal dopamine-producing neurons. In mice, however, aging-related dopaminergic neuronal loss and its consequences for motor function are poorly understood.

Loss of Parkin contributes to mitochondrial turnover and dopaminergic neuronal loss in aged mice.

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons. PARK2 mutations cause early-onset Parkinson's disease (EO-PD). PARK2 encodes an E3 ubiquitin ligase, Parkin.

Synthesis of -β-Amidevinyl Benziodoxolones from the Ethynyl Benziodoxolone-Chloroform Complex and Sulfonamides.

The synthesis of -β-amidevinyl benziodoxolones from the ethynyl benziodoxolone-chloroform complex and sulfonamides is reported. Evidence indicates that highly reactive unsubstituted ethynyl benziodoxolone undergoes Michael addition of sulfonamides, including sterically demanding acyclic amino acid derivatives. The synthesis of selectively deuterated -β-amidevinyl benziodoxolones and investigation of ethynyl-λ-iodane reactivity are also described.

Hlf marks the developmental pathway for hematopoietic stem cells but not for erythro-myeloid progenitors.

Before the emergence of hematopoietic stem cells (HSCs), lineage-restricted progenitors, such as erythro-myeloid progenitors (EMPs), are detected in the embryo or in pluripotent stem cell cultures in vitro. Although both HSCs and EMPs are derived from hemogenic endothelium, it remains unclear how and when these two developmental programs are segregated during ontogeny. Here, we show that hepatic leukemia factor (Hlf) expression specifically marks a developmental continuum between HSC precursors and HSCs.

Induced Pluripotent Stem Cells Reprogrammed with Three Inhibitors Show Accelerated Differentiation Potentials with High Levels of 2-Cell Stage Marker Expression.

Although pluripotent stem cells can generate various types of differentiated cells, it is unclear why lineage-committed stem/progenitor cells derived from pluripotent stem cells are decelerated and why the differentiation-resistant propensity of embryonic stem cell (ESC)/induced pluripotent stem cell (iPSC)-derived cells is predominant compared with the in vivo equivalents derived from embryonic/adult tissues. In this study, we demonstrated that iPSCs reprogrammed and maintained with three chemical inhibitors of the fibroblast growth factor 4-mitogen-activated protein kinase cascade and GSK3β (3i) could be differentiated into all three germ layers more efficiently than the iPSCs reprogrammed without the 3i chemicals, even though they were maintained with 3i chemicals once they were reprogrammed. Although the iPSCs reprogrammed with 3i had increased numbers of Zscan4-positive cells, the Zscan4-positive cells among iPSCs that were reprogrammed without 3i did not have an accelerated differentiation ability.

Synthesis, Characterization, and Reactivity of an Ethynyl Benziodoxolone (EBX)-Acetonitrile Complex.

The synthesis of a crystalline ethynyl-1,2-benziodoxol-3(1 H)-one (EBX)-acetonitrile complex is described. EBX has been widely used as an active species for a variety of reactions; however, its high instability has so far prevented its isolation. The EBX-acetonitrile is self-assembled into a double-layered honeycomb structure through weak hypervalent iodine secondary interactions and hydrogen bonding.

Periostin deletion suppresses late-phase response in mouse experimental allergic conjunctivitis.

Background: To investigate the potential roles of periostin (POSTN), an extracellular matrix preferentially expressed in Th2-skewed conditions in the pathophysiology of allergic conjunctivitis.

Methods: The roles of POSTN in ragweed-induced experimental allergic conjunctivitis (RW-EAC) were evaluated using both POSTN-knockout (KO) and congenic BALB/c wild-type mice. Histological analysis was carried out to enumerate eosinophils/basophils in the conjunctival tissue.