We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS ...patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40–64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington’s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
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•Pathogenic expansions in the HTT gene are a rare cause of FTD/ALS spectrum diseases•Autopsies showed both the expected TDP-43 pathology of FTD/ALS and polyQ inclusions•HTT repeat expansions were not seen in healthy subjects or Lewy body dementia cases•Clinicians should screen FTD/ALS patients for HTT repeat expansions
Using large-scale whole-genome sequencing, Dewan et al. identify pathogenic HTT repeat expansions in patients diagnosed with FTD/ALS neurodegenerative disorders. Autopsies confirm the TDP-43 pathology expected in FTD/ALS and show polyglutamine inclusions within the frontal cortices but no striatal degeneration. These data broaden the phenotype resulting from HTT repeat expansions.
Endoplasmic reticulum-associated degradation (ERAD) is a protein quality control pathway of fundamental importance to cellular homeostasis. Although multiple ERAD pathways exist for targeting ...topologically distinct substrates, all pathways require substrate ubiquitination. Here, we characterize a key role for the UBE2G2 Binding Region (G2BR) of the ERAD accessory protein ancient ubiquitous protein 1 (AUP1) in ERAD pathways. This 27-amino acid (aa) region of AUP1 binds with high specificity and low nanomolar affinity to the backside of the ERAD ubiquitin-conjugating enzyme (E2) UBE2G2. The structure of the AUP1 G2BR (G2BRAUP1) in complex with UBE2G2 reveals an interface that includes a network of salt bridges, hydrogen bonds, and hydrophobic interactions essential for AUP1 function in cells. The G2BRAUP1 shares significant structural conservation with the G2BR found in the E3 ubiquitin ligase gp78 and in vitro can similarly allosterically activate ubiquitination in conjunction with ERAD E3s. In cells, AUP1 is uniquely required to maintain normal levels of UBE2G2; this is due to G2BRAUP1 binding to the E2 and preventing its rapid degradation. In addition, the G2BRAUP1 is required for both ER membrane recruitment of UBE2G2 and for its activation at the ER membrane. Thus, by binding to the backside of a critical ERAD E2, G2BRAUP1 plays multiple critical roles in ERAD.
'This research aims to empirically analyze the spatial distribution of bank-branch networks in Canada. We study the market structure (both industrial and geographic concentrations) within the ...networks' own or adjacent postal areas. Our empirical framework considers branch density (the ratio of the total number of branches to the area size) by employing a spatial two-way fixed-effects model. Our main finding is that there are no effects associated with market structure; however, there are strong spatial socioeconomic effects from the networks' own and nearby areas. In addition, we also study the effect of spatial competition from rival banks: we find that large banks and small banks tend to avoid markets dominated by their competitors'--Abstract.
Diatoms are photosynthetic secondary endosymbionts found throughout marine and freshwater environments, and are believed to be responsible for around one-fifth of the primary productivity on Earth. ...The genome sequence of the marine centric diatom Thalassiosira pseudonana was recently reported, revealing a wealth of information about diatom biology. Here we report the complete genome sequence of the pennate diatom Phaeodactylum tricornutum and compare it with that of T. pseudonana to clarify evolutionary origins, functional significance and ubiquity of these features throughout diatoms. In spite of the fact that the pennate and centric lineages have only been diverging for 90 million years, their genome structures are dramatically different and a substantial fraction of genes (∼40%) are not shared by these representatives of the two lineages. Analysis of molecular divergence compared with yeasts and metazoans reveals rapid rates of gene diversification in diatoms. Contributing factors include selective gene family expansions, differential losses and gains of genes and introns, and differential mobilization of transposable elements. Most significantly, we document the presence of hundreds of genes from bacteria. More than 300 of these gene transfers are found in both diatoms, attesting to their ancient origins, and many are likely to provide novel possibilities for metabolite management and for perception of environmental signals. These findings go a long way towards explaining the incredible diversity and success of the diatoms in contemporary oceans.
The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a ...hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.
Risk factors for postoperative ileus after cesarean delivery Hennebery, Ruth B.; Burke, Christine A.; Bank, Tracy Caroline ...
American journal of obstetrics & gynecology MFM,
November 2022, 2022-11-00, 20221101, Letnik:
4, Številka:
6
Journal Article
Recenzirano
Despite extensive data regarding risk factors for postoperative ileus in the general and colorectal surgery literature, few studies have identified risk factors specific to the obstetrical ...population.
This study aimed to identify factors associated with postoperative ileus following cesarean delivery.
This retrospective case–control study identified women who underwent cesarean delivery at a single hospital between January 2000 and January 2020 and subsequently developed postoperative ileus. Cases were matched in a 1:2 ratio with controls who underwent cesarean delivery and did not develop postoperative ileus. They were matched by age (±1 year) and body mass index (±1 kg/m2). Demographics, common comorbidities, obstetrical history, and delivery characteristics were analyzed.
A total of 147 cases and 294 controls were identified. Cases and controls were similar in terms of parity, number of previous cesarean deliveries, labor preceding their cesarean delivery, incidence of chorioamnionitis, and presurgical diagnosis of hypothyroidism or chronic hypertension. Cases tended to have a diagnosis of preeclampsia (cases 23.1% vs controls 10.5%; P<.001) and were more likely to have been exposed to magnesium sulfate (cases 34.0% vs controls 15.0%; P<.001). Surgical considerations that were common in cases were exposure to general anesthesia (cases 37.4% vs controls 4.1%; P<.001), midline vertical skin incisions (cases 13.6% vs controls 1.4%; P<.001), classical hysterotomy (cases 8.8% vs controls 1.7%; P=.001), estimated blood loss >1000 mL (cases 44.4% vs controls 11.6%; P<.001), transfusion of blood products (cases 25.8% vs controls 2.0%; P<.001), and hysterectomy at the time of cesarean delivery (cases 6.1% vs controls 0.7%; P=.001). After a multivariable modeling using stepwise logistic regression of all variables found to be statistically significant, transfusion of blood products, estimated blood loss >1000 mL, and exposure to general anesthesia were the remaining surgical factors associated with the development of ileus. These variables reflect both the complexity and most likely the duration of surgery that was required, although we note that we did not have operative time as a variable to explore. Preeclampsia was also identified as a comorbidity linked to the development of ileus.
A diagnosis of preeclampsia, exposure to general anesthesia, estimated blood loss >1 L, and transfusion of blood products were identified as potential risk factors for postcesarean ileus.
This study is the first to demonstrate that macrophage migration inhibitory factor (MIF), an immune system 'inflammatory' cytokine that is released by the developing otocyst, plays a role in ...regulating early innervation of the mouse and chick inner ear. We demonstrate that MIF is a major bioactive component of the previously uncharacterized otocyst-derived factor, which directs initial neurite outgrowth from the statoacoustic ganglion (SAG) to the developing inner ear. Recombinant MIF acts as a neurotrophin in promoting both SAG directional neurite outgrowth and neuronal survival and is expressed in both the developing and mature inner ear of chick and mouse. A MIF receptor, CD74, is found on both embryonic SAG neurons and adult mouse spiral ganglion neurons. Mif knockout mice are hearing impaired and demonstrate altered innervation to the organ of Corti, as well as fewer sensory hair cells. Furthermore, mouse embryonic stem cells become neuron-like when exposed to picomolar levels of MIF, suggesting the general importance of this cytokine in neural development.
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