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Biallelic mutations in POLR3A have been associated with childhood-onset hypomyelinating leukodystrophies and adolescent-to-adult-onset spastic ataxia, the latter of which has been linked to the intronic variant c.1909 + 22G>A. We report a case of adult-onset spastic ataxia in a 75-year-old man, being a compound heterozygous carrier of this variant, whose brain and spinal cord were for the first time investigated by neuropathological examination. We describe prominent degeneration of the posterior columns, spinocerebellar tracts, and anterior corticospinal tracts of the spinal cord in a pattern resembling Friedreich's ataxia, with a notable lack of significant white matter pathology throughout the brain, in marked contrast with childhood-onset cases. Immunohistochemical examination for the POLR3A protein demonstrated no apparent differences in localization or staining intensity between the proband and an age-matched control subject. We demonstrate the clinicopathologic description of POLR3A-related neurodegenerative disease and also mention the differential diagnosis of the childhood-onset hypomyelinating leukodystrophy and late-onset spastic ataxia phenotypes.

A novel sodium complex [Na2(L)2(Phen)2(H2O)2]·2(H2O) (L = 3-hydroxyquinoline-4-carboxylic acid anion; Phen = 1,10-phenanthroline) is synthesized by solvothermal approach and is structurally determined by single-crystal X-ray diffraction. The title complex crystallizes in the orthorhombic system of the Pbcn space group. The strong π⋯π stacking and hydrogen bonding interactions produce three-dimensional (3D) chains. A series of properties of the title complex were tested by solid-state photoluminescence, CIE analysis and solid-state diffuse reflectance. The results show that the title complex is a blue light emitter, CIE (x = 0.1542, y = 0.0211) and has an energy bandwidth of 1.607 eV. A novel sodium complex is synthesized via solvothermal approach, which is characteristic of an isolated structure. At the same time, it displays a narrow and intense photoluminescence emission band in the blue region and has an energy bandwidth of 1.607 eV.

Distal hereditary motor neuropathy (dHMN) is an inherited neuromuscular disease characterized by symmetric distal weakness and atrophy without sensory changes. There are about thirty known genes associated with dHMN, but together they explain only about a third of cases. Mutations in the sigma non-opioid intracellular receptor 1 gene (SIGMAR1) have been linked to autosomal recessive dHMN with pyramidal signs in several families. This phenotype can mimic amyotrophic lateral sclerosis (ALS). We report a 39-year-old man who was referred to our ALS clinic with distal motor weakness and hyperreflexia. Whole exome sequencing identified two novel variants in the SIGMAR1 gene in the proband. Targeted Sanger sequencing of asymptomatic family members confirmed that each carried one of these two variants. Our findings expand the number of known SIGMAR1 pathogenic variants associated with dHMN, which should be clinically distinguished from ALS.

We report herein seven novel lanthanide metal–organic frameworks (Ln-MOFs), [M(L27)(DMA)(H2O)·XH2O]n (TCZ-M), (M = Nd, Sm, Eu, Gd, Tb, Dy, Ho), (X = 2 or 3) (H3L27 = 2,7-bis(4-benzoic acid)-N-(4-benzoic acid)carbazole, DMA = N,N-dimethylacetamide, TCZ = “T”-shape carbazole-based MOFs, L27 = fully deprotonated H3L273− ligand). X-ray crystallography showed that all the TCZ-M (M = Nd, Sm, Eu, Gd, Tb, Dy, Ho) are isomorphous and possess a 3,6-connected three-dimensional (3D) framework with a point symbol of {4·62}2{42·610·83}. The photoluminescence measurement indicates that TCZ-Eu shows reddish-orange emission bands and TCZ-Sm shows both visible and near-infrared (NIR) emission bands. Magnetic susceptibility measurements show deviations from the Curie law mainly owing to the split of the ground term due to the ligand field and spin–orbit coupling in TCZ-Eu and TCZ-Sm. The magnetic properties of TCZ-M (M = Nd, Gd, Tb, Dy, Ho) are also investigated, and the results indicate a ferromagnetic interaction between the Tb3+ magnetic centers in TCZ-Tb and the antiferromagnetic interactions in TCZ-M (M = Nd, Gd, Dy, Ho).

The three-dimensional (3D) porous cobalt(II) metal-organic framework (MOF), [Co3(L)2(DMA)2(MeOH)2·4(DMA)·6(MeOH)]n (1) [L = fully deprotonated 2,7-bis(4-benzoic acid)-N-(4-benzoic acid) carbazole, DMA = N,N-dimethylacetamide], was synthesized by hydrothermal reaction. Based on X-ray single-crystal diffraction, structural analysis indicates that complex 1 crystallizes in the monoclinic C2/c space group. Complex 1 possesses a 3,6-connected three-dimensional (3D) topological structure with a point symbol of {42·6}2{44·62·87·102} when a trinuclear CoII cluster was regarded as 6-connected node and the organic ligands could be regarded as 3-connected linkers between the 6-connected nodes. The framework structure exhibits a one-dimension (1D) channel with an accessible void of 4223.0 A3, amounting to 42.8 % of the total unit-cell volume (9862.0 A3). Moreover, the magnetic properties of complex 1 were studied.

Herein we report five porous luminescent coordination polymers (CPs), namely, [Zn3(L27)2(DMA)6(H2O)4]n (TCZ-001), [Zn3(L27)2(DMA)6(CH3CH2OH)2]n (TCZ-002), [Zn3(L27)2(DMA)6(CH3OH)]n (TCZ-003), [Cd3(L27)2(DMA)6(H2O)2]n (TCZ-004), and [Cd9(L27)6DMA13(4,4′-BPY)2(OH)2(H2O)13.5]n (TCZ-005) [H3L27 = 2,7-bis(4-benzoic acid)-N-(4-benzoic acid) carbazole, DMA = N,N-dimethylacetamide, 4,4′-BPY = 4,4′-bipyridine, TCZ = “T”-shape carbazole-based polymers, L27 = fully deprotonated H3L273− ligand]. All of the five CPs were assembled from a novel luminescent carbazole-based ligand. X-ray crystallography showed that TCZ-001 is a 3-connected one-dimensional (1D) chain structure with a {42·6} topology. TCZ-002 possesses a 3,6-connected three-dimensional (3D) framework with a point symbol of {42·6}2{44·62·87·102}. TCZ-003 displays a 3,6-connected two-dimensional 2D network with a Schlafli symbol of {411·64}·{43}2, which is a new topology. TCZ-004 features a 3,6-connected 2D net with a {43}2·{46·66·83} topology. In TCZ-005, the structure can be classified into two groups: one of the two groups is a 3-connected 1D chain structure with a {42·6} topology, similar to TCZ-001; the other one possesses a 3,3,3,4-connected network with a Schlafli symbol of {42·63·8}{42·6}3. The structure of TCZ-005 could be described as an SP 1-periodic net (4,4)(0,2) in the 1D_2D.ttd database. TCZ-001, TCZ-003 and TCZ-004 show a remarkable response to the Ni2+ concentration in DMA, H2O or EtOH. Some of Zn2+ ions were replaced by Ni2+ ions and the rate of the transmetalation depended on the concentration of Ni2+ ions. Also, changing part of the metal node would transform the colour of emitted light. Additionally, the colour of the luminescence displays a linear correlation with the Ni2+ concentration range from 0.005 to 0.35 M (mol L−1). Besides selective sensing of Ni2+, TCZ-004 can also be utilized to detect Eu3+ in DMA solution. Thus, several potential sensory probe materials for Ni2+ and Eu3+ detection in DMA solution have been obtained.

Lysophosphatidylserines (lyso-PSs) are a class of signaling lipids that regulate immunological and neurological processes. The metabolism of lyso-PSs remains poorly understood in vivo. Recently, we determined that ABHD12 is a major brain lyso-PS lipase, implicating lyso-PSs in the neurological disease polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract (PHARC), which is caused by null mutations in the ABHD12 gene. Here, we couple activity-based profiling with pharmacological and genetic methods to annotate the poorly characterized enzyme ABHD16A as a phosphatidylserine (PS) lipase that generates lyso-PS in mammalian systems. We describe a small-molecule inhibitor of ABHD16A that depletes lyso-PSs from cells, including lymphoblasts derived from subjects with PHARC. In mouse macrophages, disruption of ABHD12 and ABHD16A respectively increases and decreases both lyso-PSs and lipopolysaccharide-induced cytokine production. Finally, Abhd16a(-/-) mice have decreased brain lyso-PSs, which runs counter to the elevation in lyso-PS in Abhd12(-/-) mice. Our findings illuminate an ABHD16A-ABHD12 axis that dynamically regulates lyso-PS metabolism in vivo, designating these enzymes as potential targets for treating neuroimmunological disorders.

Objective To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM).

PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts) is a recently described autosomal-recessive neurodegenerative disease caused by mutations in the α-β-hydrolase domain-containing 12 gene (ABHD12). Only five homozygous ABHD12 mutations have been reported and the pathogenesis of PHARC remains unclear. We evaluated a woman who manifested short stature as well as the typical features of PHARC. Sequence analysis of ABHD12 revealed a novel heterozygous c.1129A>T (p.Lys377*) mutation. Targeted comparative genomic hybridization detected a 59-kb deletion that encompasses exon 1 of ABHD12 and exons 1-4 of an adjacent gene, GINS1, and includes the promoters of both genes. The heterozygous deletion was also carried by the patient's asymptomatic mother. Quantitative reverse transcription-PCR demonstrated ∼50% decreased expression of ABHD12 RNA in lymphoblastoid cell lines from both individuals. Activity-based protein profiling of serine hydrolases revealed absence of ABHD12 hydrolase activity in the patient and 50% reduction in her mother. This is the first report of compound heterozygosity in PHARC and the first study to describe how a mutation might affect ABHD12 expression and function. The possible involvement of haploinsufficiency for GINS1, a DNA replication complex protein, in the short stature of the patient and her mother requires further studies.

In this study, the dissipation of two antibiotics, sulfamethoxazole (SMX) and trimethoprim (TRM), in three soils under both aerobic and anaerobic conditions are evaluated. Under aerobic conditions, SMX dissipated rapidly through biodegradation but TRM was more persistent. Within the first 20 days in biologically active soils, >50% of the SMX was lost from the clay loam and loamy sand soils, and >80% loss was noted in the loam soil. Anaerobic dissipation of both compounds was more rapid than aerobic dissipation. The addition of manure to the soil only slightly increased the initial dissipation rate of the two compounds. Little effect was found on glucose mineralisation in soil following the addition of SMX and TRM, even as mixtures at high concentrations.

An Enterobacter strain (GY-1) with high activity of decolorization of Reactive Black 5 (RB 5) was isolated from textile wastewater treating sludge. The kinetic characteristics of dye decolorization by the strain GY-1 were determined quantitatively using the diazo dye, RB 5. Effects of different operation parameters (inoculum size, pH, temperature and salinity) and various electron donors on decolorization of the azo dye by GY-1 were systematically investigated to reveal the primary factors that determine the performance of the azo dye decolorization. The decolorization of RB 5 was attributed to extracellular enzymes. A kinetic model was established giving the dependence of decolorization rate on cell mass concentration (first order). Decolorization rate increased with increasing temperature from 20 to 35 °C, which can be predicted by Arrhenius equation with the activation energy (Ea) of 8.50 kcal mol−1 and the frequency factor (A0) of 6.28 × 107 mg l g MLSS−1 h−1. Michaelis–Menten kinetics and Eadie–Hofstee plot were used to determine Vmax, 1.05 mg l−1 h−1 and Km, 24.06 mg l−1.

Background: Recently, mutations in the transient receptor potential cation channel, subfamily V, member 4 gene ( TRPV4 ) have been reported in Charcot-Marie-Tooth Type 2C (CMT2C) with vocal cord paresis. Other mutations in this same gene have been described in separate families with various skeletal dysplasias. Further clarification is needed of the different phenotypes associated with this gene. Methods: We performed clinical evaluation, electrophysiology, and genetic analysis of the TRPV4 gene in 2 families with CMT2C. Results: Two multigenerational families had a motor greater than sensory axonal neuropathy associated with variable vocal cord paresis. The vocal cord paresis varied from absent to severe, requiring permanent tracheotomy in 2 subjects. One family with mild neuropathy also manifested pronounced short stature, more than 2 SD below the average height for white Americans. There was one instance of dolichocephaly. A novel S542Y mutation in the TRPV4 gene was identified in this family. The other family had a more severe, progressive, motor neuropathy with sensory loss, but less remarkable short stature and an R315W mutation in TRPV4 . Third cranial nerve involvement and sleep apnea occurred in one subject in each family. Conclusion: CMT2C with axonal neuropathy, vocal cord paresis, and short stature is a unique syndrome associated with mutations in the TRPV4 gene. Mutations in TRPV4 can cause abnormalities in bone, peripheral nerve, or both and may result in highly variable orthopedic and neurologic phenotypes.

An X-linked myopathy was recently associated with mutations in the four-and-a-half-LIM domains 1 (FHL1) gene. We identified a family with late onset, slowly progressive weakness of scapuloperoneal muscles in three brothers and their mother. A novel missense mutation in the LIM2 domain of FHL1 (W122C) co-segregated with disease in the family. The phenotype was less severe than that in other reported families. Muscle biopsy revealed myopathic changes with FHL1 inclusions that were ubiquitin- and desmin-positive. This mutation provides additional evidence for X-linked myopathy caused by a narrow spectrum of mutations in FHL1, mostly in the LIM2 domain. Molecular dynamics (MD) simulations of the newly identified mutation and five previously published missense mutations in the LIM2 domain revealed no major distortions of the protein structure or disruption of zinc binding. There were, however, increases in the nonpolar, solvent-accessible surface area in one or both of two clusters of residues, suggesting that the mutant proteins have a variably increased propensity to aggregate. Review of the literature shows a wide range of phenotypes associated with mutations in FHL1. However, recognizing the typical scapuloperoneal phenotype and X-linked inheritance pattern will help clinicians arrive at the correct diagnosis.

Familial cerebral cavernous malformation (CCM) is an autosomal dominant disorder producing vascular anomalies throughout the central nervous system associated with seizures and hemorrhagic stroke. Linkage analysis has shown evidence for at least three genetic loci underlying this disorder with a founder mutation in the Mexican/Hispanic community. We report the first family of Chinese ethnic origin with CCM having a novel mutation in the CCM1 gene. The mutation in exon 19 causes a premature stop codon (Q698X) predicted to produce a truncated Krev1 interaction-trapped 1 (KRIT1) protein. Members of the family with this mutation have a wide range in age of onset with seizures, ataxia, spinal cord vascular malformation, headaches and skin lesions. An additional unrelated sporadic subject with brain lesions compatible with CCM as well as vascular skin findings suggesting the blue rubber bleb nevus (BRBN) syndrome has no mutation detected in the CCM1 gene. These findings expand the phenotype of and demonstrate further evidence for the heterogeneity in the CCM syndrome.

Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia, sometimes associated with monosomy 7. Here, in the four-generation family UW-AP, linkage analysis revealed four regions that provided the maximal LOD scores possible, one of which was in a commonly microdeleted chromosome 7q region. Exome sequencing identified a missense mutation (c.2640C>A, p.His880Gln) in the sterile alpha motif domain containing 9-like gene (SAMD9L) that completely cosegregated with disease. By targeted sequencing of SAMD9L, we subsequently identified a different missense mutation (c.3587G>C, p.Cys1196Ser) in affected members of the first described family with AP syndrome, Li-AP. Neither variant is reported in the public databases, both affect highly conserved amino acid residues, and both are predicted to be damaging. With time in culture, lymphoblastic cell lines (LCLs) from two affected individuals in family UW-AP exhibited copy-neutral loss of heterozygosity for large portions of the long arm of chromosome 7, resulting in retention of only the wild-type SAMD9L allele. Newly established LCLs from both individuals demonstrated the same phenomenon. In addition, targeted capture and sequencing of SAMD9L in uncultured blood DNA from both individuals showed bias toward the wild-type allele. These observations indicate in vivo hematopoietic mosaicism. The hematopoietic cytopenias that characterize AP syndrome and the selective advantage for clones that have lost the mutant allele support the postulated role of SAMD9L in the regulation of cell proliferation. Furthermore, we show that AP syndrome is distinct from the dyskeratoses congenita telomeropathies, with which it shares some clinical characteristics.