gebhart/patrepeval huggingface dataset:
Plexin-B2 Regulates the Proliferation and Migration of Neuroblasts in the Postnatal and Adult Subventricular Zone (2012)

In the postnatal forebrain, the subventricular zone (SVZ) contains a pool of undifferentiated cells, which proliferate and migrate along the rostral migratory stream (RMS) to the olfactory bulb and differentiate into granule cells and periglomerular cells. Plexin-B2 is a semaphorin receptor previously known to act on neuronal proliferation in the embryonic brain and neuronal migration in the cerebellum. We show here that, in the postnatal and adult CNS, Plexin-B2 is expressed in the subventricular zone lining the telencephalic ventricles and in the rostral migratory stream. We analyzed Plxnb2(-/-) mice and found that there is a marked reduction in the proliferation of SVZ cells in the mutant. Plexin-B2 expression is downregulated in the olfactory bulb as interneurons initiate radial migration. BrdU labeling and GFP electroporation into postnatal SVZ, in addition to time-lapse videomicroscopy, revealed that neuroblasts deficient for Plexin-B2 migrate faster than control ones and leave the RMS more rapidly. Overall, these results show that Plexin-B2 plays a role in postnatal neurogenesis and in the migration of SVZ-derived neuroblasts.
Difference between the epicondylar and cylindrical axis of the knee. (2007)

Locating the true flexion-extension axis of the knee can play an important role in component placement in a total knee arthroplasty, especially using contemporary computer-assisted surgical navigation. We determined if the commonly used transepicondylar axis is an accurate and reproducible substitute for the flexion-extension axis. Twenty-three fresh-frozen cadaveric distal femurs with intact soft tissue were imaged with computed tomography and reconstructed in three-dimensional virtual space. The transepicondylar axis was compared with a line equidistant from the articular surface of each femoral condyle. Measures were performed by three observers three times for each specimen. Interobserver and intraobserver variations were small, but the differences between axes were approximately 5 degrees. The difference between axes decreased when projected from three-dimensional space to traditional two-dimensional planes (coronal and transverse), explaining why this discrepancy has not been previously documented. The greater difference in three-dimensional space may account for midrange instability reported in total knee arthroplasty. The increased accuracy afforded by computer-assisted surgical navigation in total knee arthroplasty may be lost and increased malposition of components may occur if this discrepancy between reference axes is not appreciated and addressed.
The highly selective CRF2 receptor antagonist K41498 binds to presynaptic CRF2 receptors in rat brain (2002)

1. Novel analogues of antisauvagine-30 (aSvg-30), a selective antagonist for CRF(2) receptors, have been synthesized and characterized in vitro and in vivo. 2. The analogues were tested for their ability to compete for [(125)I-Tyr(0)]Svg binding and to inhibit Svg-stimulated adenylate cyclase activity in human embryonic kidney (HEK) 293 cells, permanently transfected with cDNA coding for the human CRF(1) (hCRF(1)), hCRF(2alpha) and hCRF(2beta) receptor. One analogue [D-Phe(11), His(12), Nle(17)]Svg(11-40), named K41498, showed high affinity binding to hCRF(2alpha) (K(i)=0.66+/-0.03 nM) and hCRF(2beta) (K(i)=0.62+/-0.01 nM) but not the hCRF(1) receptor (k(i)=425+50 nM) and decreased Svg-stimulated cAMP accumulation in hCRF(2) expressing cells. In conscious Wistar-Kyoto rats, K41498 (1.84 microg, i.v.) antagonized the hypotensive response to systemic urocortin (1.4 microg, i.v.), but did not block the pressor response to centrally administered urocortin (2.35 microg, i.c.v.). 3. K41498 was subsequently radio-iodinated, and in autoradiographic studies, specific (sensitive to rat urocortin, astressin and aSvg30, but insensitive to antalarmin) binding of (125)I-K41498 (100 pM) was detected in the heart and in selected brain regions including the nucleus tractus solitarius (NTS), spinal trigeminal nucleus, lateral septum and around the anterior and middle cerebral arteries. 4. Following unilateral nodose ganglionectomy, binding of (125)I-K41498 was reduced by 65% in the ipsilateral NTS, indicative of presynaptic CRF(2) receptors on vagal afferent terminals. 5. These data demonstrate that K41498 is a useful tool to study native CRF(2) receptors in the brain and periphery.
Glycogen Synthase Kinase 3 Is an Insulin-Regulated C/EBPα Kinase (1999)

CCAAT/enhancer binding protein alpha (C/EBPalpha) is a transcription factor involved in creating and maintaining the adipocyte phenotype. We have shown previously that insulin stimulates dephosphorylation of C/EBPalpha in 3T3-L1 adipocytes. Studies to identify the insulin-sensitive sites of phosphorylation reveal that a C/EBPalpha peptide (amino acids H215 to K250) is phosphorylated on T222, T226, and S230 in vivo. The context of these phosphoamino acids implicates glycogen synthase kinase 3 (GSK3), whose activity is known to be repressed in response to insulin, as a potential kinase for phosphorylation of T222 and T226. Accordingly, GSK3 phosphorylates the predicted region of C/EBPalpha on threonine in vitro, and GSK3 uses C/EBPalpha as a substrate in vivo. In addition, the effect of pharmacological agents on GSK3 activity correlates with regulation of C/EBPalpha phosphorylation. Treatment of 3T3-L1 adipocytes with the phosphatidylinositol 3-kinase inhibitor wortmannin results in phosphorylation of C/EBPalpha, whereas treatment with the GSK3 inhibitor lithium results in dephosphorylation of C/EBPalpha. Collectively, these data indicate that insulin stimulates dephosphorylation of C/EBPalpha on T222 and T226 through inactivation of GSK3. Since dephosphorylation of C/EBPalpha in response to lithium is blocked by okadaic acid, strong candidates for the T222 and T226 phosphatase are protein phosphatases 1 and 2a. Treatment of adipocytes with insulin alters the protease accessibility of widespread sites within the N terminus of C/EBPalpha, consistent with phosphorylation causing profound conformational changes. Finally, phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes.
Neural stem cells and cell replacement therapy: making the right cells (2004)

The past few years have seen major advances in the field of NSC (neural stem cell) research with increasing emphasis towards its application in cell-replacement therapy for neurological disorders. However, the clinical application of NSCs will remain largely unfeasible until a comprehensive understanding of the cellular and molecular mechanisms of NSC fate specification is achieved. With this understanding will come an increased possibility to exploit the potential of stem cells in order to manufacture transplantable NSCs able to provide a safe and effective therapy for previously untreatable neurological disorders. Since the pathology of each of these disorders is determined by the loss or damage of a specific neural cell population, it may be necessary to generate a range of NSCs able to replace specific neurons or glia rather than generating a generic NSC population. Currently, a diverse range of strategies is being investigated with this goal in mind. In this review, we focus on the relationship between NSC specification and differentiation and discuss how this information may be used to direct NSCs towards a particular fate.
Cardiac CT Improves Outcomes in Stable Coronary Heart Disease: Results of Recent Clinical Trials (2017)

CCTA is now an established technique for the assessment of coronary artery disease. Recent 'test and treat' randomised controlled trials have shown that CCTA guided changes in management can improve clinical outcomes.
Replicative Senescence: the Human Fibroblast Comes of Age (1990)

Human diploid fibroblasts undergo replicative senescence predominantly because of arrest at the G 1 /S boundary of the cell cycle. Senescent arrest resembles a process of terminal differentiation that appears to involve repression of proliferation-promoting genes with reciprocal new expression of antiproliferative genes, although post-transcriptional factors may also be involved. Identification of participating genes and clarification of their mechanisms of action will help to elucidate the universal cellular decline of biological aging and an important obverse manifestation, the rare escape of cells from senescence leading to immortalization and oncogenesis.
Proteolytic Processing Yields Two Secreted Forms of Sonic hedgehog (1995)

Sonic hedgehog (Shh) is expressed in tissues with known signalling capacities, such as the notochord, the floor plate of the central nervous system, and the zone of polarizing activity in the limb. Several lines of evidence indicate that Shh is involved in floor plate induction, somite patterning, and regulation of anterior-posterior polarity in the vertebrate limb. In this report, we investigate the biochemical behavior of Shh in a variety of expression systems and embryonic tissues. Expression of mouse Shh in Xenopus oocytes, COS cells, and baculovirus-infected insect cells demonstrates that in addition to signal peptide cleavage and N-linked glycosylation, chicken and mouse Shh proteins undergo additional proteolytic processing to yield two peptides with molecular masses of approximately 19 kDa (amino terminus) and 27 kDa (carboxy terminus), both of which are secreted. In transfected COS cells, we show that the 19-kDa peptide does not accumulate significantly in the medium unless heparin or suramin is added, suggesting that this peptide associates with the cell surface or extracellular matrix. This retention appears to depend on sequences in the carboxy-terminal part of the peptide. Finally, detection of the 19-kDa product in a variety of mouse and chicken embryonic tissues demonstrates that the proteolytic processing observed in cell culture is a normal aspect of Shh processing in embryonic development. These results raise the possibility that amino- and carboxyl-terminal regions of Shh may have distinct functions in regulating cell-cell interactions in the vertebrate embryo.
Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats (2011)

Anemia of chronic inflammation (ACI) is the most frequent anemia in hospitalized patients and is associated with significant morbidity. A major underlying mechanism of ACI is the retention of iron within cells of the reticuloendothelial system (RES), thus making the metal unavailable for efficient erythropoiesis. This reticuloendothelial iron sequestration is primarily mediated by excess levels of the iron regulatory peptide hepcidin down-regulating the functional expression of the only known cellular iron export protein ferroportin resulting in blockade of iron egress from these cells. Using a well-established rat model of ACI, we herein provide novel evidence for effective treatment of ACI by blocking endogenous hepcidin production using the small molecule dorsomorphin derivative LDN-193189 or the protein soluble hemojuvelin-Fc (HJV.Fc) to inhibit bone morphogenetic protein-Smad mediated signaling required for effective hepcidin transcription. Pharmacologic inhibition of hepcidin expression results in mobilization of iron from the RES, stimulation of erythropoiesis and correction of anemia. Thus, hepcidin lowering agents are a promising new class of pharmacologic drugs to effectively combat ACI.
Reelin receptors ApoER2 and VLDLR are expressed in distinct spatiotemporal patterns in developing mouse cerebral cortex (2014)

In mammalian developing brain, neuronal migration is regulated by a variety of signaling cascades, including Reelin signaling. Reelin is a glycoprotein that is mainly secreted by Cajal-Retzius neurons in the marginal zone, playing essential roles in the formation of the layered neocortex via its receptors, apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR). However, the precise mechanisms by which Reelin signaling controls the neuronal migration process remain unclear. To gain insight into how Reelin signaling controls individual migrating neurons, we generated monoclonal antibodies against ApoER2 and VLDLR and examined the localization of Reelin receptors in the developing mouse cerebral cortex. Immunohistochemical analyses revealed that VLDLR is localized to the distal portion of leading processes in the marginal zone (MZ), whereas ApoER2 is mainly localized to neuronal processes and the cell membranes of multipolar cells in the multipolar cell accumulation zone (MAZ). These different expression patterns may contribute to the distinct actions of Reelin on migrating neurons during both the early and late migratory stages in the developing cerebral cortex.
Chronic exposure to anabolic steroids induces the muscle expression of oxytocin and a more than fiftyfold increase in circulating oxytocin in cattle (2011)

Molecular mechanisms in skeletal muscle associated with anabolic steroid treatment of cattle are unclear and we aimed to characterize transcriptional changes. Cattle were chronically exposed (68 ± 20 days) to a steroid hormone implant containing 200 mg trenbolone acetate and 20 mg estradiol (Revalor-H). Biopsy samples from 48 cattle (half treated) from longissimus dorsi (LD) muscle under local anesthesia were collected. Gene expression levels were profiled by microarray, covering 16,944 unique bovine genes: 121 genes were differentially expressed (DE) due to the implant (99.99% posterior probability of not being false positives). Among DE genes, a decrease in expression of a number of fat metabolism-associated genes, likely reflecting the lipid storage activity of intramuscular adipocytes, was observed. The expression of IGF1 and genes related to the extracellular matrix, slow twitch fibers, and cell cycle (including SOX8, a satellite cell marker) was increased in the treated muscle. Unexpectedly, a very large 21- (microarray) to 97 (real time quantitative PCR)-fold higher expression of the mRNA encoding the neuropeptide hormone oxytocin was observed in treated muscle. We also observed an ∼50-fold higher level of circulating oxytocin in the plasma of treated animals at the time of biopsy. Using a coexpression network strategy OXTR was identified as more likely than IGF1R to be a major mediator of the muscle response to Revalor-H. A re-investigation of in vivo cattle LD muscle samples during early to mid-fetal development identified a >128-fold increased expression of OXT, coincident with myofiber differentiation and fusion. We propose that oxytocin may be involved in mediating the anabolic effects of Revalor-H treatment.
Non-Clinical Study Examining AAV8.TBG.hLDLR Vector-Associated Toxicity in Chow-Fed Wild-Type and LDLR +/− Rhesus Macaques (2017)

Vectors based on adeno-associated virus serotype 8 (AAV8) have been evaluated in several clinical trials of gene therapy for hemophilia B with encouraging results. In preparation for a Phase 1 clinical trial of AAV8 gene therapy for the treatment of homozygous familial hypercholesterolemia (HoFH), the safety of the clinical candidate vector, AAV8.TBG.hLDLR, was evaluated in wild-type rhesus macaques and macaques heterozygous for a nonsense mutation in the low-density lipoprotein receptor (LDLR) gene (LDLR+/−). Intravenous infusion of 1.25 × 1013 GC/kg of AAV8.TBG.hLDLR expressing the human version of LDLR was well tolerated and associated with only mild histopathology that was restricted to the liver and sporadic, low-level, and transient elevations in transaminases. Some animals developed T cells to both capsid and the hLDLR transgene, although these adaptive immune responses were most evident at the early time points from peripheral blood and in mononuclear cells derived from the liver. This toxicology study supports the safety of AAV8.TBG.hLDLR for evaluation in HoFH patients, and provides some context for evaluating previously conducted clinical trials of AAV8 in patients with hemophilia.
Interleukin-6 Signaling Pathway and Its Role in Kidney Disease: An Update (2017)

Interleukin-6 (IL-6) is a pleiotropic cytokine that not only regulates the immune and inflammatory response but also affects hematopoiesis, metabolism, and organ development. IL-6 can simultaneously elicit distinct or even contradictory physiopathological processes, which is likely discriminated by the cascades of signaling pathway, termed classic and trans-signaling. Besides playing several important physiological roles, dysregulated IL-6 has been demonstrated to underlie a number of autoimmune and inflammatory diseases, metabolic abnormalities, and malignancies. This review provides an overview of basic concept of IL-6 signaling pathway as well as the interplay between IL-6 and renal-resident cells, including podocytes, mesangial cells, endothelial cells, and tubular epithelial cells. Additionally, we summarize the roles of IL-6 in several renal diseases, such as IgA nephropathy, lupus nephritis, diabetic nephropathy, acute kidney injury, and chronic kidney disease.
A pilot study on a new anchoring mechanism for surgical applications based on mucoadhesives (2010)

In order to minimize the invasiveness of laparoscopic surgery, different techniques are emerging from research to clinical practice. Whether the incision is performed on the outside - as in Single Port Laparoscopy (SPL) - or on the inside - as in Natural Orifice Transluminal Endoscopic Surgery (NOTES) - of the patient's body, inserting and operating all the instruments from a single access site seems to be the next challenge in surgery. Magnetic guidance has been recently proposed for controlling surgical tools deployed from a single access. However, the exponential drop of magnetic field with distance makes this solution suitable only for the upper side of the abdominal cavity in nonobese patients. In the present paper we introduce a polymeric anchoring mechanism to lock surgical assistive tools inside the gastric cavity, based on the use of mucoadhesive films. Mucoadhesive properties of four formulations, with different chemical components and concentration, are evaluated by using both in vitro and ex vivo test benches on porcine stomach samples. Hydration of mucoadhesive films by contact with the aqueous mucous layer is analyzed by means of in vitro swelling tests, whereas optimal preloading conditions and adhesion performances, in terms of detachment force, supported weight and size are investigated ex vivo. Mucoadhesion is observed with all the four formulations. For a contact area of 113 mm(2), the maximum normal and shear detachment forces withstood by the adhesive film are 2,6 N and 1 N respectively. These values grow up to 12,14 N and 4,5 N when the contact area increases to 706 mm(2). Lifetime of the bonding on the inner side of the stomach wall was around two hours. Mucoadhesive anchoring represents a fully biocompatible and safe approach to deploy multiple assistive surgical tools on mucosal tissues by minimizing the number of access ports. This technique has been quantitatively assessed ex vivo for anchoring on the inner wall of the gastric cavity or in gastroscopic surgery. By properly varying the chemical formulation, this approach can be extended to other cavities of the human body.
Post-Operative Iron Carboxymaltose May Have an Effect on Haemoglobin Levels in Cardiothoracic Surgical Patients on the ICU - an Observational Pilot Study about Anaemia Treatment with Intravenous Iron (2018)

Anaemia was prevalent in 86.2% of patients upon ICU admission. 429 patients were screened for iron deficiency anaemia. 95 patients were eligible, 35 were treated with IVI. An increase of +0.4 g/dl in Hb levels 7 days after IVI compared to -0.1 g/dl in non-treated anaemic patients was observed. The number of RBC transfusions, ICD codes related to infections and infectious parameters were similar between groups. <b>Conclusions:</b> IVI treatment was safe and resulted in higher median Hb levels. Randomized controlled trials are required to support the hypotheses of this study.
Melanin concentration in normal human retinal pigment epithelium. Regional variation and age-related reduction. (1986)

Melanin concentrations were analyzed in the pigment epithelium of 61 postmortem normal human eyes from donors 14-97 yr of age. The content of soluble melanin in the pigment epithelium declined with age from the highest values of 95 micrograms/mg in the 14-50 yr age group to the lowest values of 22 micrograms/mg dry weight in the over 70 yr age group. In 16 of these eyes, regional measurements revealed that melanin concentrations were lowest in the macula-perimacular area (a region 5-8 mm in diameter centered on the fovea), were higher in the mid-periphery, and were highest in the far periphery. In the macular region, melanin concentrations were similarly low at all ages, whereas, in the mid- and far-peripheral regions, melanin concentrations decreased with age. These studies demonstrate age-related reductions and regional variations in melanin concentrations in the pigment epithelium of postmortem normal human eyes, and establish a baseline for future comparison with donor eyes from patients with hereditary retinal degenerations.
Synthesis of various 5‐substituted uracils (1990)

Abstract Several Pd‐catalyzed coupling reactions have been evaluated for the synthesis of 5‐substituted uracils. A convenient reaction, further developed by us, is the Suzuki Pd(0)‐catalyzed coupling between arylboronic acids and aryl bromides or iodides in weakly alkaline medium. However, all attempts to use 5‐bromo‐ or 5‐iodouracil as the aryl halide failed. On the other hand, couplings between 2,4‐di‐ t ‐butoxy‐5‐bromopyrimidine and various arylboronic acids were successful. In cases when the arylboronic acids were not available, it was better to reverse the coupling functionalities and use 2,4‐di‐ t ‐butoxy‐5‐pyrimidineboronic acid and arylbromides. A large number of 5‐aryluracils were prepared in this way. They were obtained in almost quantitative yields by dealkylation of the 5‐aryl‐2,4‐di‐ t ‐butoxypyrimidines. However, a great drawback of these procedures is the highly allergenic properties of 2,4‐dichloro‐5‐bromopyrimidine, which is an intermediate in the synthesis of 2,4‐di‐ t ‐butoxy‐5‐bromopyrimidine and 2,4‐di‐ t ‐butoxy‐5‐pyrimidineboronic acid. In order to avoid this intermediate the coupling between 5‐bromo‐2,4‐ditrimethylsilyloxypyrimidine and arylboronic acids were attempted but failed. Also attemptes to prepare 2,4‐di‐trimethylsilyloxy‐5‐pyrimidineboronic acid failed due to migration of a silyl group to the 5‐position upon halogen‐metal exchange. We therefore turned to the use of tin derivatives instead of boronic acids in the coupling reaction, which can be carried out under neutral conditions. Thus 5‐(1‐methyl‐2‐pyrrolyl)uracil, which could not be prepared from 2‐bromo‐1‐methylpyrrole and 2,4‐di‐ t ‐butoxy‐5‐pyrimidineboronic acid was obtained through the Pd(0)‐catalyzed coupling of 1‐methyl‐2‐trimethylstannylpyrrole and 2,4‐di‐ t ‐butoxy‐5‐bromopyrimidine followed by dealkylation. However, the great advantage with the tin derivatives was that 5‐bromo‐2,4‐ditrimethylsilyloxypyrimidine could be used in the coupling with aryltin derivatives giving 5‐aryluracils in reasonable yields. We also tried to use unprotected 5‐halouracils in the coupling reactions. We were unsuccessful with the 5‐bromo derivative. However, with 5‐iodouracil coupling was achieved in some cases.