Photodissociative Modules that Control Dual-Emission Properties in Donor-π-Acceptor Organoborane Fluorophores.

Donor-π-acceptor fluorophores that consist of an electron-donating amino group and an electron-accepting triarylborane moiety generally exhibit substantial solvatochromism in their fluorescence while retaining high fluorescence quantum yields even in polar media. Herein, we report a new family of this compound class, which bears ortho-P(=X)R2 -substituted phenyl groups (X=O or S) as a photodissociative module. The P=X moiety that intramolecularly coordinates to the boron atom undergoes dissociation in the excited state, giving rise to dual emission from the corresponding tetra- and tricoordinate boron species. The susceptibility of the systems to photodissociation depends on the coordination ability of the P=O and P=S moieties, whereby the latter facilitates dissociation. The intensity ratios of the dual emission bands are sensitive to environmental parameters, including temperature, solution polarity, and the viscosity of the medium. Moreover, precise tuning of the P(=X)R2 group and the electron-donating amino moiety led to single-molecule white emission in solution.

Photobase-Driven Excited-State Intramolecular Proton Transfer (ESIPT) in a Strapped π-Electron System.

We report a new design strategy for an excited-state intramolecular proton transfer (ESIPT) fluorophore that can be used in acidic media. A photobasic pyridine-centered donor-acceptor-donor-type fluorophore is combined with a basic trialkylamine "strap". In the presence of an acid, protonation occurs predominantly at the amine moiety in the ground state. A single-crystal X-ray diffraction analysis confirmed the formation of a pre-organized intramolecular hydrogen-bonded structure between the resulting ammonium moiety and the pyridine ring. Upon excitation, the intramolecular charge-transfer transition increases the basicity of the pyridine moiety in the excited state, resulting in proton transfer from the amine to the pyridine moiety. Consequently, the fluorophore takes on a polymethine-dye character in the ESIPT state, which gives rise to significantly red-shifted emission with an increased fluorescence quantum yield.

Planarized Phenyldithienylboranes: Effects of the Bridging Moieties and π-Extension on the Photophysical Properties and Lewis Acidity.

Two kinds of planarized phenyldithienylboranes, which contain (CH3 )2 C- or CH2 -bridging moieties, were synthesized. The difference of the bridging moieties affects their packing structures and photophysical properties. In particular, the (CH3 )2 C-bridged derivative exhibits a large Stokes shift, unusual for such planarized compounds, that results from a large structural relaxation in the excited state. A series of π-extended derivatives was synthesized, among which a p-(diphenylamino)phenyl-substituted derivative shows large solvatochromism in the fluorescence spectra, while maintaining high quantum yields even in polar solvents. The Lewis acidity of the phenyldithienylborane derivatives was also assessed by titration with pyridine. The Lewis acidity of the boron center is affected not only by the difference in the steric bulk of the bridging moieties, but also by the electronic effect of the substituents introduced at remote positions relative to the boron atom. These results demonstrate the characteristic features of planarized phenyldithienylboranes as building blocks for boron-based π-electron materials.

Prenatal clinical manifestations in individuals with COL4A1/2 variants.

BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

Olefin-Borane Interactions in Donor-π-Acceptor Fluorophores that Undergo Frustrated-Lewis-Pair-Type Reactions.

Olefin-borane π-complexes have been postulated as intermediates for the addition of frustrated Lewis pairs (FLP) to olefins. In the present study, we have employed this weak interaction to modulate the electronic properties of boron-based π-electron materials. A series of donor-π-acceptor (D-π-A) fluorophores that contain an alkenyl-bridged diarylboryl group is synthesized. A crystallographic analysis revealed that the olefin and boron moieties are held in close proximity. Upon addition of a Lewis base to a solution of these D-π-A fluorophores, an FLP-type addition occurs with concurrent significant changes in the absorption and emission properties. The FLP-type reaction shifts the reaction site from the Lewis-acidic boron atom to a carbocationic center, and thereby even facilitates a reaction with bulky Lewis bases. For example, a tricyclohexylphosphine adduct thus generated exhibits temperature-dependent reversible dissociation/association behavior. These results provide a design strategy for stimuli-responsive emissive boron-based materials.

Fluorescent Organic π-Radicals Stabilized with Boron: Featuring a SOMO-LUMO Electronic Transition.

We report on the fluorescence properties of a new class of emissive and stable π-radicals that contain a boron atom at a position distant from the radical center. A fully planarized derivative exhibited an intense red fluorescence with high fluorescence quantum yields (ΦF >0.67) even in polar solvents. To elucidate the origin of this phenomenon, we synthesized another boron-stabilized radical that contains a bulky aryl group on the boron atom. A comparison of these derivatives, as well as with conventional donor-π-acceptor (D-π-A)-type emissive π-radicals, unveiled several characteristic features in their photophysical properties. A theoretical analysis revealed that the SOMO-LUMO electronic transition generates an emissive D1 state. Unlike conventional D-π-A-type π-radicals, this state does not undergo significant structural relaxation. The boron-stabilized π-radicals demonstrated promising potential for organic light-emitting diodes as an emitting material.

Dual Trapping of a Metastable Planarized Triarylborane π-System Based on Folding and Lewis Acid-Base Complexation for Seeded Polymerization.

We report the kinetically controlled supramolecular polymerization of boron-containing π-conjugated molecules, which was enabled by a seeding method based on dual trapping of a metastable state by synergistic intramolecular hydrogen bonding and Lewis acid-based complexation. Planarized triarylborane-based 1, which bears a diamide chain with chiral alkyl groups, was synthesized. Upon cooling, the solution of monomer 1 afforded a supramolecular polymerization in a cooperative manner to form helical supramolecular nanostructures with intense J-type aggregate emission. In the presence of pyridine, the triarylborane moiety formed a Lewis acid-base complex, which enhances the stabilization of the metastable monomeric state. An assembly incompetent structure with a folded diamide chain conformation and a pyridine moiety axially coordinated to the boron atom is responsible for slowing the spontaneous aggregation. The seeding method was successfully applied to the solution to produce homogeneous nanofibers even at a high (millimolar-level) concentration. This unprecedented kinetic control via dual trapping provides an effective method to achieve seed-initiated polymerization under concentrated conditions.

Boron-Doped Polycyclic π-Electron Systems with an Antiaromatic Borole Substructure That Forms Photoresponsive B-P Lewis Adducts.

Heteroatom doping is a powerful strategy to alter the electronic structure of polycyclic aromatic hydrocarbons (PAHs). Especially boron doping endows PAH scaffolds with electron-accepting character and Lewis acidic centers. Herein, we report that embedding a five-membered borole ring into a polycyclic skeleton imparts the π-system with antiaromatic character and thereby induces unique properties and behavior. A series of borole-embedded π-conjugated compounds were synthesized from teraryl precursors via a borylation/intramolecular electrophilic C-H borylation sequence. The obtained compounds exhibit planar structures with distorted geometries around the boron center and form columnar slipped face-to-face π-stacked structures. Among these compounds, a pyrene-fused derivative shows an intense emission with a high quantum yield in solution. This compound also exhibits high Lewis acidity, which reflects the antiaromatic character and strained structure of the borole substructure. This compound forms a Lewis acid-base adduct even with weakly Lewis basic phosphorus-containing polycyclic π-systems. Analyzing the crystal structure of the thus-obtained adduct revealed a complex between the boron- and phosphorus-embedded π-systems with a direct B-P dative bond. This complex undergoes photodissociation in the excited state and exhibits an emission exclusively from the base-free borole-embedded π-system.

Twofold C-H Activation Enables Synthesis of a Diazacoronene-Type Fluorophore with Near Infrared Emission Through Isosteric Replacement.

The synthesis and photophysical properties of a soluble amide-embedded coronene is reported. The key step in this synthesis is the twofold C-H activation of diazaperylene by a rhodium(III)Cp* catalyst. This unprecedented structural motif shows intense fluorescence in the near infrared region with a small Stokes shift and a distinct vibronic structure, which exhibits a slight extent of negative solvatochromism. Comparison of this compound with some relevant compounds revealed the importance of the amide incorporation in the peripheral concave region including an angular position to retain high aromaticity reflecting that of parent coronene. Treatment of this compound with Lewis acid B(C6 F5 )3 formed a bis-adduct, which exhibited enhanced aromaticity as a consequence of the increased double bond character of the amide C-N bonds.

Electron-Deficient Heteroacenes that Contain Two Boron Atoms: Near-Infrared Fluorescence Based on a Push-Pull Effect*.

Electron-deficient heteroacenes that contain two tricoordinate boron atoms in their acene skeletons and planarized phenyl ether moieties at their periphery were synthesized via the borylation of silicon-bridged precursors. X-ray crystallographic analysis revealed quinoidal structures, which give rise to two-step reversible redox processes for both the reduction and oxidation. These compounds exhibit intense absorption and sharp fluorescence bands with vibronic structures in the near-infrared (NIR) region. These properties originate from the push-pull effect along the long axis of the molecule derived from the electron-donating ether moieties and the electron-accepting boron moieties. Of particular note is the NIR emission of the thienothiophene-centered heteroacene, which has a maximum at 952 nm with a narrow band width of 309 cm-1 in cyclohexane. A Franck-Condon analysis revealed the crucial role of the sterically less-hindered thienothiophene spacer in achieving this sharp emission band.

Planarized B,N-phenylated dibenzoazaborine with a carbazole substructure: electronic impact of the structural constraint.

A B,N-diphenyl-5,10-dihydro-dibenzo-1,4-azaborine, in which both phenyl groups on the boron and nitrogen atoms are planarized to generate a carbazole substructure, was synthesized. The structral constraint around the boron and nitrogen atoms alters the π-conjugation mode and thus the photophysical and electrochemical properties. Specifically, this structurally constrained dibenzoazaborine showed an intense blue emission with a narrow full width at half maximum. One of its derivatives exhibited near infrared absorption in the one-electron-oxidized state.

A novel homozygous missense mutation in the SH3-binding motif of STAMBP causing microcephaly-capillary malformation syndrome.

Microcephaly-capillary malformation syndrome is a congenital and neurodevelopmental disorder caused by biallelic mutations in the STAMBP gene. Here we identify the novel homozygous mutation located in the SH3 binding motif of STAMBP (NM_006463.4) (c.707C>T: p.Ser236Phe) through whole-exome sequencing. The case patient was a 2-year-old boy showing severe global developmental delay, progressive microcephaly, refractory seizures, dysmorphic facial features, and multiple capillary malformations. Immunoblot analysis of patient-derived lymphoblastoid cell lines (LCLs) revealed a severe reduction in STAMBP expression, indicating that Ser236Phe induces protein instability. STAMBP interacts with the SH3 domain of STAM and transduces downstream signals from the Jaks-STAM complex. The substitution of Ser236Phe found in the case patient was located in the SH3-binding motif, and we propose the mutation may block STAM binding and subsequently induce STAMBP degradation. Contrary to previously reported STAMBP mutations, the Ser236Phe mutation did not lead to constitutive activation of the PI3K-AKT-mTOR pathway in patient-derived LCLs, as indicated by the expression of phosphorylated S6 ribosomal protein, suggesting that it is not the major pathomechanism underlying the disorder in this patient.

Boron-Stabilized Planar Neutral π-Radicals with Well-Balanced Ambipolar Charge-Transport Properties.

Organic neutral π-monoradicals are promising semiconductors with balanced ambipolar carrier-transport abilities, which arise from virtually identical spatial distribution of their singly occupied and unoccupied molecular orbitals, SOMO(α) and SOMO(ß), respectively. Herein, we disclose a boron-stabilized triphenylmethyl radical that shows outstanding thermal stability and resistance toward atmospheric conditions due to the substantial spin delocalization. The radical is used to fabricate organic Mott-insulator transistors that operate at room temperature, wherein the radical exhibits well-balanced ambipolar carrier transport properties.

A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly.

BACKGROUND: Constitutive activation of the PI3K-AKT-mTOR pathway (mTOR pathway) underlies megalencephaly in many patients. Yet, prevalence of the involvement of the PI3K-AKT-mTOR pathway in patients with megalencephaly remains to be elucidated, and molecular diagnosis is challenging. Here, we have successfully established a combination of genetic and biochemical methods for diagnosis of mTOR pathway-associated megalencephaly, and have attempted to delineate the clinical characteristics of the disorder. METHODS: Thirteen patients with an increased head circumference and neurological symptoms participated in the study. To evaluate the activation of the mTOR pathway, we performed western blot analysis to determine the expression levels of phosphorylated S6 ribosomal protein (phospho-S6 protein) in lymphoblastoid cell lines from 12 patients. Multiplex targeted sequencing analysis for 15 genes involved in the mTOR pathway was performed on 12 patients, and whole-exome sequencing was performed on one additional patient. Clinical features and MRI findings were also investigated. RESULTS: We identified pathogenic mutations in six (AKT3, 1 patient; PIK3R2, 2 patients; PTEN, 3 patients) of the 13 patients. Increased expression of phospho-S6 protein was demonstrated in all five mutation-positive patients in whom western blotting was performed, as well as in three mutation-negative patients. Developmental delay, dysmorphic facial features were observed in almost all patients. Syndactyly/polydactyly and capillary malformations were not observed, even in patients with AKT3 or PIK3R2 mutations. There were no common phenotypes or MRI findings among these patients. CONCLUSIONS: A combination of genetic and biochemical methods successfully identified mTOR pathway involvement in nine of 13 (approximately 70%) patients with megalencephaly, indicating a major contribution of the pathway to the pathogenesis of megalencephaly. Our combined approach could be useful to identify patients who are suitable for future clinical trials using an mTOR inhibitor.

Efficacy of nalfurafine hydrochloride in patients with chronic liver disease with refractory pruritus: A randomized, double-blind trial.

AIMS: Patients with chronic liver disease sometimes develop cholestasis, which induces severe whole-body pruritus that may disrupt daily activities and sleep. To determine the efficacy of nalfurafine hydrochloride (5 µg), which is a selective κ-opioid receptor agonist, in improving pruritus, we undertook a double-blind placebo-controlled study in patients with chronic liver disease with refractory pruritus. Nalfurafine hydrochloride at 2.5 µg was also used to evaluate the dose-response relationship. METHODS: In total, 318 subjects were randomly assigned to receive the placebo or nalfurafine hydrochloride (2.5 or 5 µg) given orally once daily for 84 consecutive days. Pruritus was assessed based on the visual analog scale and pruritus scores. RESULTS: Changes in the visual analog scale at week 4 (last observation carried forward) were significantly greater in the nalfurafine hydrochloride groups at 28.56 and 27.46 mm in the 2.5 µg and 5 µg groups, respectively, compared to 19.25 mm in the placebo group (P = 0.0022 and 0.0056, respectively). The major adverse drug reactions (ADRs) included pollakiuria (including nocturia), somnolence, insomnia (including middle insomnia), and constipation. Most ADRs were mild. CONCLUSIONS: Nalfurafine hydrochloride (2.5 or 5 µg daily) was effective in the treatment of refractory pruritus in patients with chronic liver disease. Furthermore, no clinically significant ADRs were observed at either dose.

Photochemical Intramolecular C-H Addition of Dimesityl(hetero)arylboranes through a [1,6]-Sigmatropic Rearrangement.

A new reaction mode for triarylboranes under photochemical conditions was discovered. Photoirradiation of dimesitylboryl-substituted (hetero)arenes produced spirocyclic boraindanes, where one of the C-H bonds in the ortho-methyl groups of the mesityl substituents was formally added in a syn fashion to a C-C double bond of the (hetero)aryl group. Quantum chemical calculations and laser flash photolysis measurements indicated that the reaction proceeds through a [1,6]-sigmatropic rearrangement. This behavior is reminiscent of the photochemical reaction mode of arylalkenylketones, thus demonstrating the isosteric relation between tricoordinate organoboron compounds and the corresponding pseudo-carbocationic species in terms of pericyclic reactions. Despite the disrupted π-conjugation, the resulting spirocyclic boraindanes exhibited a characteristic absorption band at relatively long wavelengths (λ=370-400 nm).

Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome.

Bainbridge-Ropers syndrome (BRPS) is characterized by severe developmental delay, feeding problems, short stature, characteristic facal appearance including arched eyebrows and anteverted nares, and ulnar deviation of the hands. BRPS is caused by a heterozygous mutation in the additional sex combs-like 3 (ASXL3) gene. We describe a patient with severe developmental delay, feeding problems, short stature, autism, and sleep disturbance with a heterozygous de novo splicing mutation in the ASXL3 gene. Reported disease-causing mutations in ASXL3 are located mostly in the first half of exon 11, analogous to ASXL1 mutations of which result in Bohring-Opitz syndrome (BOS). Our findings suggest that the expression of the truncated ASXL3 protein, including ASXN and ASXH domains, give rise to BRPS, which is distinct from but overlaps with BOS. © 2016 Wiley Periodicals, Inc.

Seizure characteristics of epilepsy in childhood after acute encephalopathy with biphasic seizures and late reduced diffusion.

OBJECTIVE: The aim of this study was to clarify characteristics of post-encephalopathic epilepsy (PEE) in children after acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), paying particular attention to precise diagnosis of seizure types. METHODS: Among 262 children with acute encephalopathy/encephalitis registered in a database of the Tokai Pediatric Neurology Society between 2005 and 2012, 44 were diagnosed with AESD according to the clinical course and magnetic resonance imaging (MRI) findings and were included in this study. Medical records were reviewed to investigate clinical data, MRI findings, neurologic outcomes, and presence or absence of PEE. Seizure types of PEE were determined by both clinical observation by pediatric neurologists and ictal video-electroencephalography (EEG) recordings. RESULTS: Of the 44 patients after AESD, 10 (23%) had PEE. The period between the onset of encephalopathy and PEE ranged from 2 to 39 months (median 8.5 months). Cognitive impairment was more severe in patients with PEE than in those without. Biphasic seizures and status epilepticus during the acute phase of encephalopathy did not influence the risk of PEE. The most common seizure type of PEE on clinical observation was focal seizures (n = 5), followed by epileptic spasms (n = 4), myoclonic seizures (n = 3), and tonic seizures (n = 2). In six patients with PEE, seizures were induced by sudden unexpected sounds. Seizure types confirmed by ictal video-EEG recordings were epileptic spasms and focal seizures with frontal onset, and all focal seizures were startle seizures induced by sudden acoustic stimulation. Intractable daily seizures remain in six patients with PEE. SIGNIFICANCE: We demonstrate seizure characteristics of PEE in children after AESD. Epileptic spasms and startle focal seizures are common seizure types. The specific seizure types may be determined by the pattern of diffuse subcortical white matter injury in AESD and age-dependent reorganization of the brain network.

Homoplasmy of a mitochondrial 3697G>A mutation causes Leigh syndrome.

Herein we report on three siblings with Leigh syndrome (LS) harboring a homoplasmic m.3697G>A mutation (G131S) in the MT-ND1 gene. The siblings' phenotypically normal mother had the same, albeit heteroplasmic, mutation. Complex I deficiency (8% of average control values) was demonstrated in a biceps brachii muscle from one of the patients. Heteroplasmic m.3697G>A has been reported in patients with Leber's hereditary optic neuropathy, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes and Stüve-Wiedemann syndrome. Because all three patients in this series carried m.3697G>A in a homoplasmic manner and had LS, we suggest that homoplasmy of m.3697G>A may cause the LS phenotype.

Fulminant encephalopathy with marked brain edema and bilateral thalamic lesions.

We encountered two children with acute encephalopathy associated with unique clinical manifestations. Both the patients had status epilepticus at onset and neuroimaging studies revealed marked brain edema and bilateral thalamic lesions. Although they were treated with steroids and immunoglobulin, their outcomes were very poor. A thermolabile variant of carnitine palmitoyltransferase II and an elevated interleukin-6 level in cerebrospinal fluid were observed in one patient each. The constellation of clinical and neuroimaging findings in our patients is apparently not consistent with any established subtype of acute encephalopathy/encephalitis.