Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in ...multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects’ fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/− mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/− mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/− mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.
Abstract
The second most significant detection of the Planck Sunyaev−Zel’dovich survey, PLCK G287.0+32.9 (
z
= 0.385), boasts two similarly bright radio relics and a radio halo. One radio relic is ...located
NW of the X-ray peak and the other
Mpc to the SE. This large difference suggests that a complex merging scenario is required. A key missing puzzle for the merging scenario reconstruction is the underlying dark matter distribution in high resolution. We present a joint Subaru Telescope and
Hubble Space Telescope
weak-lensing analysis of the cluster. Our analysis shows that the mass distribution features four significant substructures. Of the substructures, a primary cluster of mass
dominates the weak-lensing signal. This cluster is likely to be undergoing a merger with one (or more) subcluster whose mass is approximately a factor of 10 lower. One candidate is the subcluster of mass
located
to the SE. The location of this subcluster suggests that its interaction with the primary cluster could be the source of the NW radio relic. Another subcluster is detected
Mpc to the SE of the X-ray peak with mass
. This SE subcluster is in the vicinity of the SE radio relic and may have created the SE radio relic during a past merger with the primary cluster. The fourth subcluster,
, is NW of the X-ray peak and beyond the NW radio relic.
Human respiratory syncytial virus (HRSV) has three surface glycoproteins: small hydrophobic (SH), attachment (G) and fusion (F), encoded by three consecutive genes (SH-G-F). A 270-nt fragment of the ...G gene is used to genotype HRSV isolates. This study genotyped and investigated the variability of the gene and amino acid sequences of the three surface proteins of HRSV strains collected from 1987 to 2005 from one center. Sixty original clinical isolates and 5 prototype strains were analyzed. Sequences containing SH, F and G genes were generated, and multiple alignments and phylogenetic trees were analyzed. Genetic variability by protein domains comparing virus genotypes was assessed. Complete sequences of the SH-G-F genes were obtained for all 65 samples: HRSV-A = 35; HRSV-B = 30. In group A strains, genotypes GA5 and GA2 were predominant. For HRSV-B strains, the genotype GB4 was predominant from 1992 to 1994 and only genotype BA viruses were detected in 2004-2005. Different genetic variability at nucleotide level was detected between the genes, with G gene being the most variable and the highest variability detected in the 270-nt G fragment that is frequently used to genotype the virus. High variability (>10%) was also detected in the signal peptide and transmembrane domains of the F gene of HRSV A strains. Variability among the HRSV strains resulting in non-synonymous changes was detected in hypervariable domains of G protein, the signal peptide of the F protein, a not previously defined domain in the F protein, and the antigenic site #216; in the pre-fusion F. Divergent trends were observed between HRSV -A and -B groups for some functional domains. A diverse population of HRSV -A and -B genotypes circulated in Houston during an 18 year period. We hypothesize that diverse sequence variation of the surface protein genes provide HRSV strains a survival advantage in a partially immune-protected community.
ABSTRACT In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5′ untranslated region (5′UTR) of the ...interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.–14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation.
Osteocytes are the terminally differentiated cell type of the osteoblastic lineage and have important functions in skeletal homeostasis. Although the transcriptional regulation of osteoblast ...differentiation has been well characterized, the factors that regulate differentiation of osteocytes from mature osteoblasts are poorly understood. Here we show that miR-23a∼27a∼24-2 (miR-23a cluster) promotes osteocyte differentiation. Osteoblast-specific miR-23a cluster gain-of-function mice have low bone mass associated with decreased osteoblast but increased osteocyte numbers. By contrast, loss-of-function transgenic mice overexpressing microRNA decoys for either miR-23a or miR-27a, but not miR24-2, show decreased osteocyte numbers. Moreover, RNA-sequencing analysis shows altered transforming growth factor-β (TGF-β) signalling. Prdm16, a negative regulator of the TGF-β pathway, is directly repressed by miR-27a with concomitant alteration of sclerostin expression, and pharmacological inhibition of TGF-β rescues the phenotypes observed in the gain-of-function transgenic mice. Taken together, the miR-23a cluster regulates osteocyte differentiation by modulating the TGF-β signalling pathway through targeting of Prdm16.
HIV infection is associated with deficits in category fluency, but the underlying cognitive mechanisms of such impairments have not been determined. Considering the preferential disruption of the ...structure and function of frontostriatal circuits in HIV disease, the present study evaluated the hypothesis that HIV-associated category fluency deficits are driven by impaired switching. Study participants were 96 HIV-infected individuals and 43 demographically comparable healthy comparison volunteers who were administered a standard measure of animal fluency and an alternating category fluency task (i.e., fruits and furniture) in a randomized order. Consistent with prior research on letter fluency, HIV infection was associated with greater impairments in switching, but not semantic clustering within the animal fluency task. Moreover, a significant interaction was observed whereby the HIV-associated deficits in switching were exacerbated by the explicit demands of the alternating fluency task. Across both fluency tasks, switching demonstrated generally small correlations with standard clinical measures of executive functions, working memory, and semantic memory. Collectively, these findings suggest that HIV-associated category fluency deficits are driven by switching impairments and related cognitive abilities (e.g., mental flexibility), perhaps reflecting underlying neuropathology within prefrontostriatal networks.
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