A significant proportion of the human genome codes for transcription factors. Balanced activity of transcriptional activators and repressors is essential for normal development and differentiation. ...Previously we reported that a classical C
2H
2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3–ZNF651 corepressor complex. It is suggested that CBFA2T3–ZNF651 and CBFA2T3–ZNF652 repressor complexes perform functionally similar roles in a tissue-specific manner.
MINT-
7555667:
CBFA2T3 (uniprotkb:
O75081)
physically interacts (MI:
0915) with
ZNF651 (uniprotkb:
Q9UFB7) by
anti tag co-immunoprecipitation (MI:
0007)
Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the ...sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies.
Abstract
We present a study of the far-infrared (IR) properties of a stellar mass selected sample of 1.5 < z < 3 galaxies with log (M
*/M⊙) > 9.5 drawn from the Great Observatories Origins Deep ...Survey (GOODS) Near Infrared Camera and Multi-Object Spectrometer (NICMOS) Survey (GNS), the deepest H-band Hubble Space Telescope survey of its type prior to the installation of Wide Field Camera 3 (WFC3). We use far-IR and submm data from the Photoconductor Array Camera and Spectrometer (PACS) and Spectral and Photometric Imaging Receiver (SPIRE) instruments on-board Herschel, taken from the PACS Evolutionary Probe (PEP) and Herschel Multi-Tiered Extragalactic Survey (HerMES) key projects, respectively. We find a total of 22 GNS galaxies, with median log (M
*/M⊙) = 10.8 and z = 2.0, associated with 250 μm sources detected with signal-to-noise ratio (SNR) > 3. We derive mean total IR luminosity log L
IR(L⊙) = 12.36 ± 0.05 and corresponding star formation rate (SFR)IR + UV = (280 ± 40) M⊙ yr−1 for these objects, and find them to have mean dust temperature T
dust ≈ 35 K. We find that the SFR derived from the far-IR photometry combined with ultraviolet (UV)-based estimates of unobscured SFR for these galaxies is on average more than a factor of 2 higher than the SFR derived from extinction-corrected UV emission alone, although we note that the IR-based estimate is subject to substantial Malmquist bias. To mitigate the effect of this bias and extend our study to fainter fluxes, we perform a stacking analysis to measure the mean SFR in bins of stellar mass. We obtain detections at the 2-4σ level at SPIRE wavelengths for samples with log (M
*/M⊙) > 10. In contrast to the Herschel detected GNS galaxies, we find that estimates of SFRIR + UV for the stacked samples are comparable to those derived from extinction-corrected UV emission, although the uncertainties are large. We find evidence for an increasing fraction of dust obscured star formation with stellar mass, finding , which is likely a consequence of the mass-metallicity relation.
Glutathione levels are decreased in the substantia nigra of patients with Parkinson's disease. We studied whether glutathione depletion contributes to dopaminergic cell death using a specific ...inhibitor of glutathione biosynthesis, L-buthionine sulfoximine (BSO). We found no significant reduction of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta (SNpc) when BSO was administered systemically to preweanling mice or locally to the SNpc of adult rats. However, the combination of BSO with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in preweanling mice and the combination of nigral injections of BSO with intrastriatal injections of MPP+ (1-methyl-4-phenylpyridinium), the active metabolite of MPTP in adult rats, potentiated the toxic effects of MPTP and MPP+ on nigral neurones. Our data show that glutathione depletion can result in cell death if the nigrostriatal system is metabolically compromised.
Tubular aggregates (TAs) are aggregates of densely packed tubules in human skeletal muscle fibers with particular histochemical and ultrastructural features that most probably arise from the ...sarcoplasmic reticulum. Some studies have shown an additional mitochondrial origin of TAs. We studied the histopathological spectrum and clinical features in a large cohort of patients with TAs in their muscle biopsy (106 biopsies), derived from our muscle biopsy archive (15,412 biopsies in total). In particular, we examined light microscopic, enzyme histochemical, immunohistochemical and ultrastructural features in the muscle biopsies, as well as the patients' clinical data. We found TAs in 0.5% of all muscle biopsies. Based on the size of TAs, we identified two sub-groups: (1) myopathies with large TAs (29 biopsies) in type 2 fibers and sometimes also in type 1 fibers, absence of any other associated disorder, and a familial history in half of the cases, and (2) myopathies with small TAs (77 biopsies), exclusively in type 2 fibers, presence of another associated disease in the majority of patients and mostly no familial history. In the sub-group with large TAs, we observed a high variability of ultrastructural changes. The most frequent clinical symptom in both groups was limb muscle weakness. No significant differences in clinical presentation, age at onset or disease duration at the time of biopsy were found between the two groups. In conclusion, myopathies with TAs can be sub-divided into a group with large TAs, probably corresponding to the so-called primary TA myopathies, and into a group with small TAs as a feature of another underlying condition.
Can We Close the Discussion on PFO-Closure? Litmathe, Jens; Haarmeier, Thomas; Zizlsperger, Leopold ...
Hellenic journal of cardiology,
2015 May-Jun, Letnik:
56, Številka:
3
Journal Article
Synphilin-1 has been identified as an interacting protein of alpha-synuclein, Parkin, and LRRK2, proteins which are mutated in familial forms of Parkinson’s disease (PD). Subsequently, synphilin-1 ...has also been shown to be an intrinsic component of Lewy bodies in sporadic PD. In order to elucidate the role of synphilin-1 in the pathogenesis of PD, we generated transgenic mice overexpressing wild-type and mutant (R621C) synphilin-1 driven by a mouse prion protein promoter. Transgenic expression of both wild-type and the R621C variant synphilin-1 resulted in increased dopamine levels of the nigrostriatal system in 3-month-old mice. Furthermore, we found pathological ubiquitin-positive inclusions in cerebellar sections and dark-cell degeneration of Purkinje cells. Both transgenic mouse lines showed significant reduction of motor skill learning and motor performance. These findings suggest a pathological role of overexpressed synphilin-1 in vivo and will help to further elucidate the mechanisms of protein aggregation and neuronal cell death.
Profound endourological skills are required for optimal postoperative outcome parameters after transurethral resection of the prostate (TURP). We investigated the Karl Storz (Tuttlingen, Germany) ...UroTrainer for virtual simulation training of the TURP.
Twenty urologists underwent a virtual reality (VR) TURP training. After a needs analysis, performance scores and self-rated surgical skills were compared before and after the curriculum, the realism of the simulator was assessed, and the optimal level of experience for VR training was evaluated. Statistical testing was done with SPSS 25.
Forty percent of participants indicated frequent intraoperative overload during real-life TURP and 80% indicated that VR training might be beneficial for endourological skills development, underlining the need to advance classical endourological training. For the complete cohort, overall VR performance scores (P = 0.022) and completeness of resection (P < 0.001) significantly improved. Self-rated parameters including identification of anatomical structures (P = 0.046), sparing the sphincter (P = 0.002), and handling of the resectoscope (P = 0.033) became significantly better during the VR curriculum. Participants indicated progress regarding handling of the resectoscope (70%), bleeding control (55%), and finding the correct resection depth (50%). Although overall realism and handling of the resectoscope was good, virtual bleeding control and correct tissue feedback should be improved in future VR simulators. Seventy percent of participants indicated 10 to 50 virtual TURP cases to be optimal and 80% junior residents to be the key target group for VR TURP training.
There is a need to improve training the TURP and VR simulators might be a valuable supplement, especially for urologists beginning with the endourological desobstruction of the prostate.
The neuropathological hallmark of the autosomal dominantly inherited, neurodegenerative disorder Huntington's disease is progressive striatal loss starting several years prior to symptom ...manifestation. Magnetic resonance (MR) imaging has been widely used to detect altered structure in premanifest and early Huntington's disease. Given that neurodegeneration is likely preceded by substantial neuronal dysfunction, we used in vivo sodium MR imaging, which has been shown to be sensitive to cell death and viability, to investigate cellular and metabolic integrity of Huntington's disease brain tissue.
We studied a total of thirteen healthy controls and thirteen Huntington's disease gene carriers (11 manifest and 2 premanifest). The manifest Huntington's disease group was subdivided into stages 1 and 2 according to their Total Functional Capacity scores. Clinical total motor and cognitive scores, as well as calibrated sodium and T1-weighted MR images were obtained with a 4T Siemens MR scanner. Sodium images were acquired by means of a constant time imaging technique with an ultra-short “echo time”. T1-weighted MR images were further analysed with voxel-based morphometry. The absolute total sodium concentration and grey matter values were measured in several Huntington's disease‐specific and also non-specific areas. Statistical analysis of variance and Pearson correlation were applied.
In Huntington's disease subjects, we found an increase of total sodium concentration of the entire brain compared to controls. Increased total sodium concentration values were found in structurally affected, but also in some non-affected, regions. The highest total sodium concentration values were found in the bilateral caudate, which was associated with caudate grey matter atrophy and CAG repeat length. In all Huntington's disease subjects we further found a profound increase of total sodium concentration in the putamen, pallidum, thalamus, hippocampus, insula, precuneus and occipital cortex compared to controls. No change of total sodium concentration was observed in the amygdala, pre- and postcentral gyrus, frontal and temporal cortices or in the cerebellum.
This is the first in vivo sodium MR imaging study carried out on a 4T MR scanner in Huntington's disease gene carriers demonstrating a significant enhancement in sodium concentration in the bilateral striatum, a key region in Huntington's disease, and also in other disease-related atrophic areas. Sodium MR imaging may provide a deeper insight into the pathophysiological mechanisms of tissue degeneration in Huntington's disease, presenting potential to detect changes preceding neurodegeneration.
► First sodium MRI to investigate total sodium concentration of brain tissue in HD. ► Enhanced sodium concentration in HD related atrophic structures. ► Highest sodium concentration in the HD key region striatum. ► Striatal sodium content increased along with severity of clinical manifestation. ► Results may reflect cellular and metabolic changes.
Purpose
To investigate differences in standard preoperative inflammatory markers in patients with urothelial carcinoma (UC) and variant histologies undergoing radical cystectomy (RC) and determine ...its impact on survival.
Methods
Patients undergoing RC at an academic high-volume center were retrospectively analyzed. Preoperatively taken CRP, leukocytes, hemoglobin (Hb), and thrombocytes were analyzed as routine inflammatory biomarkers. Log-rank tests and Kruskal–Wallis analysis were used to calculate for differences in survival and in blood levels of biomarkers.
Results
886 patients with complete follow-up and UC or variant histology underwent RC at our institution between 2004 and 2019. Although variant histology presents with significantly higher t stage than UC, cancer-specific survival (CSS) of UC (1-year-CSS: 93%) is not significantly different to variant histology of UC with squamous differentiation (UCSD, 1-year-CSS: 81%), squamous cell carcinoma (SCC, 1-year-CSS: 82%), and adenocarcinoma (AC, 1-year-CSS: 81%). In UC, alterations in all biomarkers except leukocytes beyond routine cut-off values were associated with poor survival (
p
< 0.01), whereas Hb beyond cut-off values are associated with poor prognosis in SCC (
p
< 0.05). CRP levels are significantly elevated in UCSD and SCC at time of surgery compared to UC (
p
< 0.05).
Conclusion
Inflammatory biomarkers reveal distinctive patterns across UC and variant histologies of bladder cancer. As inflammation might play an important role in cancer progression, further research is warranted to understand those molecular mechanisms and their potential therapeutic impact in variant histology of bladder cancer.
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