julilili42/papers huggingface dataset:
Significance of SGK1 in the regulation of neuronal function
2010-06-08

The present brief review highlights the putative role of the serum- and glucocorticoid-inducible-kinase-1 (SGK1) in the regulation of neuronal function. SGK1 is genomically upregulated by cell shrinkage and by a variety of hormones including mineralocorticoids and glucocorticoids. The kinase is activated by insulin and growth factors via phosphatidylinositide-3-kinase (PI3-kinase), phosphoinositide-dependent kinase PDK1 and mammalian target of rapamycin mTORC2. SGK1 upregulates ion channels (e.g. SCN5A, ENaC, ASIC1, TRPV5,6, ROMK, Kv1.1-5, KCNEx/KCNQ1-5, GluR6, VSOAC, ClC2, CFTR), carriers (e.g. NHE3, NKCC2, NCC, NaPiIIb, SMIT, GLUT1,4, SGLT1, NaDC, EAAT1-5, SN1, ASCT2, 4F2/LAT, PepT2), and the Na(+)/K(+)-ATPase. SGK1 regulates enzymes (e.g. glycogen-synthase-kinase-3, ubiquitin-ligase Nedd4-2, phosphomannose-mutase-2), and transcription factors (e.g. forkhead transcription factor Foxo3a, β-catenin, nuclear factor-kappa-B (NFB)). SGK1 participates in the regulation of transport, hormone release, neuroexcitability, inflammation, coagulation, cell proliferation and apoptosis. SGK1 contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Presumably, SGK1 contributes to the regulation of diverse cerebral functions (e.g. memory consolidation, fear retention) and the pathophysiology of several cerebral diseases (e.g. Parkinson's disease, schizophrenia, depression, Alzheimer's disease). Despite multiple SGK1 functions, the phenotype of the SGK1 knockout mouse is mild and becomes only apparent under challenging conditions.
High response rate after intratumoral treatment with interleukin‐2
2010-06-08

Abstract BACKGROUND: Systemic high‐dose interleukin‐2 (IL‐2) achieved long‐term survival in a subset of patients with advanced melanoma. The authors reported previously that intratumorally applied IL‐2 induced complete local responses of all metastases in &gt;60% of patients. The objectives of the current study were to confirm those results in a larger cohort and to identify patient or regimen characteristics associated with response. METHODS: Patients with melanoma who had a median of 12 injectable metastases received intratumoral IL‐2 treatments 3 times weekly until they achieved clinical remission. The initial dose of 3 million international units was escalated, depending on the individual patient's tolerance. RESULTS: Forty‐eight of 51 patients were evaluable. Only grade 1/2 toxicity was recorded. A complete response that lasted ≥6 months was documented in 70% of all injected metastases. A complete local response of all treated metastases was achieved in 33 patients (69%), including 11 patients who had between 20 and 100 metastases. Response rates were higher for patients who had stage III disease compared with patients who had stage IV disease. No objective responses of distant untreated metastases were observed. The 2‐year survival rate was 77% for patients with stage IIIB/IIIC disease and 53% for patients with stage IV disease. Efficacy and survival did not differ between patients who had ≥20 lesions and patients who had &lt;20 lesions. CONCLUSIONS: Intratumoral IL‐2 treatment elicited complete local responses in a high percentage of patients. Further studies will be required to investigate the mode of action of this treatment and its impact on survival. Cancer 2010. © 2010 American Cancer Society.
The Bcl-2 Homology Domain 3 Mimetic Gossypol Induces Both Beclin 1-dependent and Beclin 1-independent Cytoprotective Autophagy in Cancer Cells
2010-06-08

Gossypol, a natural Bcl-2 homology domain 3 mimetic compound isolated from cottonseeds, is currently being evaluated in clinical trials. Here, we provide evidence that gossypol induces autophagy followed by apoptotic cell death in both the MCF-7 human breast adenocarcinoma and HeLa cell lines. We first show that knockdown of the Bcl-2 homology domain 3-only protein Beclin 1 reduces gossypol-induced autophagy in MCF-7 cells, but not in HeLa cells. Gossypol inhibits the interaction between Beclin 1 and Bcl-2 (B-cell leukemia/lymphoma 2), antagonizes the inhibition of autophagy by Bcl-2, and hence stimulates autophagy. We then show that knockdown of Vps34 reduces gossypol-induced autophagy in both cell lines, and consistent with this, the phosphatidylinositol 3-phosphate-binding protein WIPI-1 is recruited to autophagosomal membranes. Further, Atg5 knockdown also reduces gossypol-mediated autophagy. We conclude that gossypol induces autophagy in both a canonical and a noncanonical manner. Notably, we found that gossypol-mediated apoptotic cell death was potentiated by treatment with the autophagy inhibitor wortmannin or with small interfering RNA against essential autophagy genes (Vps34, Beclin 1, and Atg5). Our findings support the notion that gossypol-induced autophagy is cytoprotective and not part of the cell death process induced by this compound.
Stem Cell Quiescence in the Hippocampal Neurogenic Niche Is Associated With Elevated Transforming Growth Factor-β Signaling in an Animal Model of Huntington Disease
2010-06-08

Cellular proliferation, differentiation, integration, and survival within the adult neural stem cell niche are altered under pathological conditions, but the molecular cues regulating the biology of this niche are mostly unknown. We examined the hippocampal neural stem cell niche in a transgenic rat model of Huntington disease. In this model, progressive cognitive deficits develop at the age of 9 months, suggesting possible hippocampal dysfunction. We found a disease-associated progressive decline in hippocampal progenitor cell proliferation accompanied by an expansion of the pool of 5-bromo-2-deoxyuridine label-retaining Sox-2-positive quiescent stem cells in the transgenic animals. Increments in quiescent stem cells occurred at the expense of cAMP-responsive element-binding protein-mediated neuronal differentiation and survival. Because elevated levels of transforming growth factor-beta1 (TGF-beta1) impair neural progenitor proliferation, we investigated hippocampal TGF-beta signaling and determined that TGF-beta1 induces the neural progenitors to exit the cell cycle. Although phospho-Smad2, an effector of TGF-beta signaling, is normally absent in subgranular stem cells, it accumulated progressively in Sox2/glial fibrillary acidic protein-expressing cells of the subgranular zone in the transgenic rats. These results indicate that alterations in neurogenesis in transgenic Huntington disease rats occur in successive phases that are associated with increasing TGF-beta signaling. Thus, TGF-beta1 signaling seems to be a crucial modulator of neurogenesis in Huntington disease and may represent a target for future therapy.
Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan as part of a reduced- intensity conditioning regimen for allogeneic hematopoietic cell transplantation in patients with advanced non-Hodgkin lymphoma: results of a phase 2 study
2010-06-08

Abstract Forty patients were enrolled in this phase 2 study combining radioimmunotherapy (RIT) using yttrium-90-ibritumomab-tiuxetan (15 MBq [0.4 mCi]/kg) with reduced-intensity conditioning (RIC) using fludarabine (90 mg/m2) and 2 Gy total body irradiation followed by allogeneic hematopoietic cell transplantation (HCT) from related (n = 13) or unrelated (n = 27) donors for the treatment of advanced non-Hodgkin lymphoma. Diagnoses were follicular lymphoma (n = 17), chronic lymphocytic leukemia (n = 13), mantle cell lymphoma (n = 8), marginal zone lymphoma (n = 1), and lymphoplasmacytic lymphoma (n = 1). Median age was 55 years (range, 34-68 years). All patients were high risk with refractory disease or relapse after preceding autologous HCT. No additional toxicities attributable to RIT were observed. Engraftment was rapid and sustained. Incidences of acute graft-versus-host disease 2-4 and chronic graft-versus-host disease were 43% and 53%, respectively. Kaplan-Meier–estimated nonrelapse mortality was 45% at 2 years. Twenty-two of 40 patients (55%) are alive, resulting in a Kaplan-Meier–estimated 2-year survival of 51% for all, 67% for follicular lymphoma, 49% for chronic lymphocytic leukemia, and 37% for mantle cell lymphoma patients. The combined use of RIT with RIC is feasible with acceptable toxicity, even in elderly and heavily pretreated patients. This study is registered at www.clinicaltrials.gov as #NCT00302757.
Dystonia‐plus syndromes
2010-06-08

Dystonia‐plus syndromes represent a heterogeneous group of diseases, where dystonia is accompanied by other neurological features and gene mutations can be detected frequently. Symptomatic dystonias and complex neurodegenerative diseases with dystonia as part of the clinical presentation are excluded from this category. At present, the following disorders are categorized as dystonia‐plus syndromes: Dopa‐responsive dystonia (DRD) is a mostly pediatric‐onset, neurometabolic disorder with two different modes of inheritance: in its autosomal‐dominant form, heterozygous mutations of GTP‐cyclohydrolase I (GCH1, DYT5) cause DRD with reduced penetrance and excellent and lasting response to levodopa. Autosomal‐recessive (AR) forms of DRD are caused by homozygous or compound heterozygous mutations of the tyrosine hydroxylase ( TH) or the sepiapterin reductase ( SPR ) gene. In AR‐DRD, the phenotype is generally more severe including cognitive deficits and developmental delay. Diagnosis can be confirmed by analysis of CSF pterine metabolites. Alternatively, comprehensive genetic testing yields causative mutations in up to 80% of patients. Myoclonus–dystonia (M‐D) is caused by heterozygous mutations of the epsilon‐sarcoglycan gene ( SGCE ). Dystonia is generally only mild to moderate, and ‘lightning‐like’ myoclonic jerks occur rarely at rest and can be triggered by complex motor tasks like writing and drawing. Both features together with an age at onset below 25 years strongly predict SGCE mutation in M‐D and differentiate this genetic disease from other ‘jerky’ dystonias. The combination of dystonia and parkinsonism can only be rarely observed in non‐degenerative syndromes. Besides DRD, two additional syndromes have been classified. Rapid‐onset dystonia–parkinsonism (RPD, DYT12) is a rare disorder with an abrupt onset of symptoms over minutes to days, prominent bulbar involvement and parkinsonism with a lack of response to levodopa. Patients with this rare phenotype should be screened for mutation in the Na + /K + ATPase alpha3‐subunit ( ATP1A3 ) gene, even if family history is negative. Recently, a novel form of dystonia–parkinsonism (DYT16) has been found to be linked to mutations in the PRKRA gene, whose relation to basal ganglia disorders is yet unknown .
Macrocyclic Gd3+ Chelates Attached to a Silsesquioxane Core as Potential Magnetic Resonance Imaging Contrast Agents: Synthesis, Physicochemical Characterization, and Stability Studies
2010-06-08

Two macrocyclic ligands, 1,4,7,10-tetraazacyclododecane-1-glutaric-4,7,10-triacetic acid (H(5)DOTAGA) and the novel 1,4,7,10-tetraazacyclododecane-1-(4-(carboxymethyl)benzoic)-4,7,10-triacetic acid (H(5)DOTABA), were prepared and their lanthanide complexes (Ln = Gd(3+), Y(3+)) attached to an amino-functionalized T(8)-silsesquioxane. The novel compounds Gadoxane G (GG) and Gadoxane B (GB) possess eight monohydrated lanthanide complexes each, as evidenced by multinuclear ((1)H, (13)C, (29)Si) NMR spectroscopy and high resolution mass spectrometry (HR-MS). Pulsed-field gradient spin echo (PGSE) diffusion (1)H NMR measurements revealed hydrodynamic radii of 1.44 nm and global rotational correlation times of about 3.35 ns for both compounds. With regard to potential MRI contrast agent applications, a variable-temperature (17)O NMR and (1)H nuclear magnetic relaxation dispersion (NMRD) study was carried out on aqueous solutions of the gadolinium(III) complexes of the Gadoxanes and the corresponding monomeric ligands to yield relevant physicochemical properties. The water exchange rates of the inner-sphere water molecules are all very similar (k(ex)(298) between (5.3 +/- 0.5) x 10(6) s(-1) and (5.9 +/- 0.3) x 10(6) s(-1)) and only slightly higher than that reported for the gadolinium(III) complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (H(4)DOTA) (k(ex)(298) = 4.1 x 10(6) s(-1)). Despite their almost identical size and their similar water exchange rates, GB shows a significantly higher longitudinal relaxivity than GG over nearly the whole range of magnetic fields (e.g., 17.1 mM(-1) s(-1) for GB and 12.1 mM(-1) s(-1) for GG at 20 MHz and 25 degrees C). This difference arises from their different local rotational correlation times (tau(lR)(298) = 240 +/- 10 ps and 380 +/- 20 ps, respectively), because of the higher rigidity of the phenyl ring of GB as compared to the ethylene spacer of GG. A crucial feature of these novel compounds is the lability of the silsesquioxane core in aqueous media. The hydrolysis of the Si-O-Si moieties was investigated by (29)Si NMR and PGSE diffusion (1)H NMR spectroscopy, electrospray ionization mass spectrometry (ESI-MS), as well as by relaxivity measurements. Although frozen aqueous solutions (pH 7.0) of GG and GB can be stored at -28 degrees C for at least 10 months without any decomposition, with increasing temperature and pH the hydrolysis of the silsesquioxane core was observed (e.g., t(1/2) = 15 h at pH 7.4 and 55 min at pH 8.1 for GG at 37 degrees C). No change in relaxivity was detected within the first 3 h, since the hydrolysis of the initial Si-O-Si moieties has no influence on the rotational correlation time. However, the further hydrolysis of the silsesquioxane core leads to smaller fragments and therefore to a decrease in relaxivity.
The impact of pregnancy and vaginal delivery on urinary incontinence
2010-06-08

Abstract Objective To identify women who had urinary incontinence (UI) before, during, and after pregnancy, and to determine whether women with symptoms of UI during pregnancy were the same women who had urinary incontinence postpartum. Methods All primigravid women who delivered within 1 year (1999) at the Charité Hospital in Berlin received a questionnaire about UI at 5 different time points during pregnancy and the postpartum period. Results Of 610 eligible women, 411 (67.4%) completed the questionnaire. The prevalence of urinary incontinence increased significantly in the second half of pregnancy (26.3%, P &lt; 0.001). Although the overall number of women who reported UI within 6 weeks after delivery (28.5%) was almost the same as the number reporting UI in the second half of pregnancy, approximately every second women changed from being continent to incontinent and vice versa. Conclusion The group of women who experienced UI postpartum was different from the group that experienced UI before delivery and vice versa. Pregnancy itself may influence pelvic floor function in a different way compared with vaginal delivery.
The Candida albicans cell wall protein Rhd3/Pga29 is abundant in the yeast form and contributes to virulence
2010-06-08

Abstract The glycosylphosphatidylinositol‐modified protein Rhd3/Pga29 of the human pathogen Candida albicans belongs to a family of cell wall proteins that are widespread among Candida species but are not found in other fungi. Pga29 is covalently linked to the β‐1,3‐glucan framework of the cell wall via β‐1,6‐glucan. It is a small and abundant O ‐glycosylated protein and requires the protein‐ O ‐mannosyl transferase Pmt1 for glycosylation. Furthermore, Pga29 is strongly expressed in yeast cells but is downregulated in hyphae. Removal of the PGA29 gene in C. albicans leads to a significant reduction of cell wall mannan; however, Pga29 does not seem to have a major role in maintaining cell wall integrity. In addition, adhesion capacity and hyphae formation appear normal in pga29 deletion mutants. Importantly, the pga29 deletion mutant is less virulent, and infection of reconstituted human epithelium with the pga29 mutant results in a diminished induction of proinflammatory cytokines, such as GM‐CSF, TNF, IL‐6 and IL‐8. We propose that the reduced virulence of the pga29 mutant is a consequence of altered surface properties, resulting in altered fungal recognition. Copyright © 2010 John Wiley &amp; Sons, Ltd.
Transitional fossils and the origin of turtles
2010-06-09

The origin of turtles is one of the most contentious issues in systematics with three currently viable hypotheses: turtles as the extant sister to (i) the crocodile–bird clade, (ii) the lizard–tuatara clade, or (iii) Diapsida (a clade composed of (i) and (ii)). We reanalysed a recent dataset that allied turtles with the lizard–tuatara clade and found that the inclusion of the stem turtle Proganochelys quenstedti and the ‘parareptile’ Eunotosaurus africanus results in a single overriding morphological signal, with turtles outside Diapsida. This result reflects the importance of transitional fossils when long branches separate crown clades, and highlights unexplored issues such as the role of topological congruence when using fossils to calibrate molecular clocks.
Temporal Preparation Decreases Perceptual Latency: Evidence from a Clock Paradigm
2010-06-09

A clock paradigm was employed to assess whether temporal preparation decreases the time to detect the onset of a stimulus—that is, perceptual latency. In four experiments participants watched a revolving clock hand while listening to soft or loud target tones under high or low temporal preparation. At the end of each trial, participants reported the clock hand position at the onset of the target tone. The deviation of the reported clock hand position from the actual position indexed perceptual latency. As expected, perceptual latency decreased with target tone intensity. Most importantly, however, greater temporal preparation decreased perceptual latency in all four experiments, especially for soft tones, which supports rather directly the idea that temporal preparation diminishes the duration of perceptual processing.
Comparative morphology of the head of selected sporophagous and non‐sporophagous aleocharinae (Coleoptera: Staphylinidae): Musculature and hypopharynx‐prementum complex
2010-06-09

Abstract To investigate whether specialization to spore‐ (or pollen‐) feeding in advanced Aleocharinae is mirrored by their head anatomy, we compiled and compared synchrotron X‐ray micro‐tomography datasets for 11 Aleocharinae in conjunction with previous data for two aleocharine and six outgroup species (two nonstaphylinids, four staphylinids). We describe the presence/absence of head muscles and investigate the variability of points of origin by character mapping analyses. Monophyly of Aleocharinae is supported by the absence of M. 48 (M. tentoriobuccalis anterior), and by changes in the origins of Mm. 1, 2, 17, 18, 28, 29, 30. Within Aleocharinae the origins of the labial muscles (Mm. 28–30) have shifted posteriorly to the gula, which might enhance the movement posterad of the hypopharynx and partly compensate for the loss of M. 48. We also analyzed the general organization of the hypopharynx‐prementum complex and the fine structure of the mandibles through SEM studies. In the absence of grinding mandibular molae like those of most mycophagous Coleoptera, seven aleocharine species studied have evolved “pseudomolae” at the ventral side of the mandibles that replace true molae as secondary grinding surfaces. In these species, the hypopharynx is elevated and displaced anteriorly, bearing a bowl‐like depression on its surface that functions as a mortar where spores are ground between the hypopharynx and the mandibles. Two of these species are not yet known to feed on spores or pollen. Another species ( Oxypoda alternans ) is thought to feed on fungus material but bears no pseudomolae on its mandibles. J. Morphol. 271:910–931, 2010. © 2010 Wiley‐Liss, Inc.
GDF-15 Contributes to Proliferation and Immune Escape of Malignant Gliomas
2010-06-10

Abstract Purpose: Growth and differentiation factor (GDF)-15 is a member of the transforming growth factor (TGF)-β family. GDF-15 is necessary for the maintenance of pregnancy but has also been linked to other physiologic and pathologic conditions. Experimental Design: The expression of GDF-15 in glioma cell lines was assessed by quantitative reverse transcriptase-PCR and immunoblot. GDF-15 levels in situ and in the peripheral blood of glioma patients were examined by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. The effects of short hairpin RNA-mediated GDF-15 inhibition on proliferation and immunogenicity of SMA-560 glioma cells were investigated by [methyl-3H]thymidine incorporation and immune-mediated target cell lysis. The impact of GDF-15 on glioma growth in vivo was assessed in syngeneic mice. Results: GDF-15 is expressed by gliomas of different WHO grades as assessed by immunohistochemistry. The high expression of GDF-15 in tumor tissue translates into elevated GDF-15 serum levels in glioblastoma patients compared with healthy controls. GDF-15 mRNA and protein are also detectable in human and mouse glioma cells in vitro. Silencing of GDF-15 by RNA interference reduces the proliferation of malignant glioma cells. Immunologically, the depletion of glioma-derived GDF-15 enhances the susceptibility of mouse glioma cells towards syngeneic natural killer cells and splenocytes. This results in a reduced in vivo tumorigenicity and increased T-cell infiltration of GDF-15–deficient glioma cells in syngeneic mice. Conclusions: Although previous studies focusing on ectopic overexpression of GDF-15 have proposed unclear or antitumorigenic effects of GDF-15 in glioma cells, we here show that GDF-15 at endogenous levels contributes to proliferation and immune escape of malignant gliomas in an immunocompetent host. Clin Cancer Res; 16(15); 3851–9. ©2010 AACR.
Strong Surface Contribution to the Nonlinear Meissner Effect ind-Wave Superconductors
2010-06-10

We demonstrate that in a d-wave superconductor the bulk nonlinear Meissner effect is dominated by a surface effect due to Andreev bound states at low temperatures. The contribution of this surface effect to the nonlinear response coefficient follows a 1/T3 law with the opposite sign compared to the bulk 1/T behavior. The crossover from bulk dominated behavior to surface dominated behavior occurs at a temperature of T/Tc∼1/square root(κ). We present an approximate analytical calculation, which supports our numerical calculations and provides a qualitative understanding of the effect. The effect can be probed by intermodulation distortion experiments.