gebhart/patrepeval huggingface dataset:
Aging-Reversing Properties of Thyrotropin-Releasing Hormone (2013)

Thyrotropin-releasing hormone (TRH) aroused our interest when we were engaged in related experiments, so we decided to study its effects on organs, tissues, and aging-related metabolic and hormonal markers when administered in acute or chronic (oral) doses at various time points in its cyclic circadian pattern. We also wanted to determine what effects, if any, it had on aging processes in two essential systems, namely gonadal-reproductive and kidney-urinary. Our results show positive changes as a result of short-term acute and long-term chronic oral administration of TRH to old mice that included rapid correction to more juvenile levels of most typical aging-related hormonal and metabolic measurements. Remarkably, testes function was maintained by means of a 4-month oral treatment with TRH in aging mice. As we suspected upon seeing a significant increase in testes weight, TRH resulted in maintenance or even reconstitution of testes structure and function when administered in the drinking water. This was demonstrated by the active formation and proliferation of mature spermatogonia and the intensive spermatogenesis in the follicles. The same TRH treatment led to protection for the kidneys from amyloid and hyalin infiltration of tubuli and glomeruli, which typically occurs in aging mice. In fact, we observed massive deposits of amyloid and hyalin material infiltrating the shrunken glomeruli and negatively affecting filtration capacity of the untreated mice, whereas this was barely present in the TRH-treated mice. Advanced hyalin degeneration could also be observed in the tubular vessels of the untreated control mice. These experiments with TRH supplementation show clear aging-delaying and apparently even aging-reversing effects of the neuropeptide, whether it was administered parenterally or orally. TRH, like melatonin, is an anti-aging agent with a broad spectrum of activities that, because of their actions, suggest that TRH has a fundamental role in the regulation of metabolic and hormonal functions.
Overproduction of dihydrofolate reductase and gene amplification in methotrexate-resistant Chinese hamster ovary cells. (1982)

Stable isolates of Chinese hamster ovary cells that are highly resistant to methotrexate have been selected in a multistep selection process. Quantitative immunoprecipitations have indicated that these isolates synthesize dihydrofolate reductase at an elevated rate over its synthesis in sensitive cells. Restriction enzyme and Southern blot analyses with a murine reductase cDNA probe indicate that the highly resistant isolates contain amplifications of the dihydrofolate reductase gene number. Depending upon the parenteral line used to select these resistant cells, they overproduce either a wild-type enzyme or a structurally altered enzyme. Karyotype analysis shows that some of these isolates contain chromosomes with homogeneously staining regions whereas others do not contain such chromosomes.
Sexual Dysfunction in Patients Treated With Atypical Antipsychotics (2008)

Atypical antipsychotics can provide improvement in schizophrenic symptomatology but also may cause side effects, such as erectile dysfunction and decreased libido, which can be problematic for patients. In order to keep patients symptomatically stable and to help alleviate these side effects, clinicians should alter the treatment strategy, possibly by switching medications, to encourage adherence to the medication as well as optimize patients' outcomes. To establish clinically useful standards for switching agents, more studies are needed that focus on gradual cross-titration methods to achieve therapeutic doses for patients.
Constitutive activation of STAT5A and STAT5B regulates IgM secretion in Waldenström's macroglobulinemia (2013)

Activation of the Janus kinase family/signal transducer and activator of transcription (JAK/STAT) signaling pathway has been associated with the pathogenesis and progression of both solid and hematologic malignancies. We have detected constitutive activation of STAT5 in malignant B cells derived from patients with Waldenström's macroglobulinemia (WM). Although short hairpin RNA-mediated knockdown of the STAT5A and STAT5B isoforms did not affect cellular proliferation, loss of STAT5 significantly decreased immunoglobulin M (IgM) secretion. A similar dose-dependent inhibition of IgM secretion was observed when WM cell lines were treated with a small molecule inhibitor of STAT5. These data suggest that STAT5 is involved in regulating IgM production in WM and that inhibition of STAT5 may represent a novel therapeutic strategy for lowering IgM levels in WM patients.
Hive‐stored pollen of honey bees: many lines of evidence are consistent with pollen preservation, not nutrient conversion (2014)

Honey bee hives are filled with stored pollen, honey, plant resins and wax, all antimicrobial to differing degrees. Stored pollen is the nutritionally rich currency used for colony growth and consists of 40-50% simple sugars. Many studies speculate that prior to consumption by bees, stored pollen undergoes long-term nutrient conversion, becoming more nutritious 'bee bread' as microbes predigest the pollen. We quantified both structural and functional aspects associated with this hypothesis using behavioural assays, bacterial plate counts, microscopy and 454 amplicon sequencing of the 16S rRNA gene from both newly collected and hive-stored pollen. We found that bees preferentially consume fresh pollen stored for <3 days. Newly collected pollen contained few bacteria, values which decreased significantly as pollen were stored >96 h. The estimated microbe to pollen grain surface area ratio was 1:1 000 000 indicating a negligible effect of microbial metabolism on hive-stored pollen. Consistent with these findings, hive-stored pollen grains did not appear compromised according to microscopy. Based on year round 454 amplicon sequencing, bacterial communities of newly collected and hive-stored pollen did not differ, indicating the lack of an emergent microbial community co-evolved to digest stored pollen. In accord with previous culturing and 16S cloning, acid resistant and osmotolerant bacteria like Lactobacillus kunkeei were found in greatest abundance in stored pollen, consistent with the harsh character of this microenvironment. We conclude that stored pollen is not evolved for microbially mediated nutrient conversion, but is a preservative environment due primarily to added honey, nectar, bee secretions and properties of pollen itself.
Composition of phospholipids and of phospholipid fatty acids and aldehydes in human red cells (1967)

Improved methods for lipid analysis that have been developed recently were employed to reevaluate the phospholipid composition, the fatty acid and fatty aldehyde composition of the total phospholipid, and the fatty acid composition of the individual phospholipids of normal human red cells. Thirty-three fatty acids and five fatty aldehydes were estimated and tentatively identified in the total phospholipid of normal human red cells. Additional minor components were evident. The major individual phospholipids were isolated by silicic acid thin-layer chromatography and quantified. The fatty acid compositions of phosphatidyl ethanolamine, phosphatidyl serine, lecithin, and sphingomyelin were determined. Each of these phospholipids showed a distinctive and characteristic fatty acid pattern.
Carbamoyl Phosphate Synthetase (Glutamine-Hydrolyzing): Increased Activity in Cancer Cells (1981)

The specific activity of carbamoyl phosphate synthetase (glutamine-hydrolyzing), the first and rate-limiting enzyme of de novo uridine 5'-triphosphate biosynthesis, was increased in 13 transplantable hepatomas, particularly in the rapidly growing tumors (5.7- to 9.5-fold), and the rise was correlated with tumor growth rates. Thus, synthetase activity was linked with both hepatic neoplastic transformation and progression. Synthetase specific activity was so elevated in a transplantable sarcoma (18-fold) and a kidney adenocarcinoma (5-fold). The increased activity should enhance the capacity of the pathway and should confer selective advantages to cancer cells.
Upregulation of the E3 ligase NEDD4-1 by Oxidative Stress Degrades IGF-1 Receptor Protein in Neurodegeneration (2012)

The importance of ubiquitin E3 ligases in neurodegeneration is being increasingly recognized. The crucial role of NEDD4-1 in neural development is well appreciated; however, its role in neurodegeneration remains unexplored. Herein, we report increased NEDD4-1 expression in the degenerated tissues of several major neurodegenerative diseases. Moreover, its expression is upregulated in cultured neurons in response to various neurotoxins, including zinc and hydrogen superoxide, via transcriptional activation likely mediated by the reactive oxygen species (ROS)-responsive FOXM1B. Reduced protein levels of the insulin-like growth factor receptor (IGF-1Rβ) were observed as a consequence of upregulated NEDD4-1 via the ubiquitin-proteasome system. Overexpression of a familial mutant form of superoxide dismutase 1 (SOD1) (G93A) in neuroblastoma cells resulted in a similar reduction of IGF-1Rβ protein. This inverse correlation between NEDD4-1 and IGF-1Rβ was also observed in the cortex and spinal cords of mutant (G93A) SOD1 transgenic mice at a presymptomatic age, which was similarly induced by in vivo-administered zinc in wild-type C57BL/6 mice. Furthermore, histochemistry reveals markedly increased NEDD4-1 immunoreactivity in the degenerating/degenerated motor neurons in the lumbar anterior horn of the spinal cord, suggesting a direct causative role for NEDD4-1 in neurodegeneration. Indeed, downregulation of NEDD4-1 by shRNA or overexpression of a catalytically inactive form rescued neurons from zinc-induced cell death. Similarly, neurons with a NEDD4-1 haplotype are more resistant to apoptosis, largely due to expression of higher levels of IGF-1Rβ.Together, our work identifies a novel molecular mechanism for ROS-upregulated NEDD4-1 and the subsequently reduced IGF-1Rβ signaling in neurodegeneration.
Antiosteogenic effect of arsenic trioxide, cholecalciferol, lovastatin or their combination in vitro (2019)

Pathological formation of bone in non-skeletal soft tissues or heterotopic ossification (HO), for which there is currently no effective treatment, is considered to be mediated by activation of Hedgehog (Hh) signaling pathway. Moreover, the biochemical mechanism of this pathological process is not fully understood. Here, we tested the efficacy of three chemical inhibitors of the Hh signaling pathway, arsenic trioxide (ATO), lovastatin (Lov) and cholecalciferol (Vitamin D) to hamper differentiation of mesenchymal stem cells (MSC) into osteoblasts or osteogenesis. Each of the three Hh inhibitors potently decreased alkaline phosphatase activity, suggesting effective suppression of osteogenic activity in Hh-impaired MSC. Gene expression analysis revealed a significant reduction in mRNA levels of chief Hh signaling marker, Gli1, following administration of Hh small molecule inhibitors. A functional link between Hedgehog and osteogenesis in native MSC cells is further established in studies involving the mix of three Hh inhibitors acting at different checkpoints of the Hh signaling pathway. Thus, a combination of small molecule inhibitors of the Hh pathway at their lower concentrations could be a novel approach for HO prophylaxis with increased efficacy and potentially reduced side effects.
Plasmonics: Merging Photonics and Electronics at Nanoscale Dimensions (2006)

Electronic circuits provide us with the ability to control the transport and storage of electrons. However, the performance of electronic circuits is now becoming rather limited when digital information needs to be sent from one point to another. Photonics offers an effective solution to this problem by implementing optical communication systems based on optical fibers and photonic circuits. Unfortunately, the micrometer-scale bulky components of photonics have limited the integration of these components into electronic chips, which are now measured in nanometers. Surface plasmon-based circuits, which merge electronics and photonics at the nanoscale, may offer a solution to this size-compatibility problem. Here we review the current status and future prospects of plasmonics in various applications including plasmonic chips, light generation, and nanolithography.
BMP-2 induction and TGF-?1 modulation of rat periosteal cell chondrogenesis (2001)

Periosteum contains osteochondral progenitor cells that can differentiate into osteoblasts and chondrocytes during normal bone growth and fracture healing. TGF-beta 1 and BMP-2 have been implicated in the regulation of the chondrogenic differentiation of these cells, but their roles are not fully defined. This study was undertaken to investigate the chondrogenic effects of TGF-beta 1 and BMP-2 on rat periosteum-derived cells during in vitro chondrogenesis in a three-dimensional aggregate culture. RT-PCR analyses for gene expression of cartilage-specific matrix proteins revealed that treatment with BMP-2 alone and combined treatment with TGF-beta 1 and BMP-2 induced time-dependent mRNA expression of aggrecan core protein and type II collagen. At later times in culture, the aggregates treated with BMP-2 exhibited expression of type X collagen and osteocalcin mRNA, which are markers of chondrocyte hypertrophy. Aggregates incubated with both TGF-beta 1 and BMP-2 showed no such expression. Treatment with TGF-beta 1 alone did not lead to the expression of type II or X collagen mRNA, indicating that this factor itself did not independently induce chondrogenesis in rat periosteal cells. These data were consistent with histological and immunohistochemical results. After 14 days in culture, BMP-2-treated aggregates consisted of many hypertrophic chondrocytes within a metachromatic matrix, which was immunoreactive with anti-type II and type X collagen antibodies. In contrast, at 14 days, TGF-beta 1 + BMP-2-treated aggregates did not contain any morphologically identifiable hypertrophic chondrocytes and their abundant extracellular matrix was not immunoreactive to the anti-type X collagen antibody. Expression of BMPR-IA, TGF-beta RI, and TGF-beta RII receptors was detected at all times in each culture condition, indicating that the distinct responses of aggregates to BMP-2, TGF-beta 1 and TGF-beta 1 + BMP-2 were not due to overt differences in receptor expression. Collectively, our results suggest that BMP-2 induces neochondrogenesis of rat periosteum-derived cells, and that TGF-beta 1 modulates the terminal differentiation in BMP-2 induced chondrogenesis.
Relationship between replication and differentiation in cultured human adipocyte precursor cells (1996)

The aim of this study was to investigate the role of cell replication for the differentiation of human adipocyte precursor cells in primary culture. When cells were seeded in a medium supplemented with 10% fetal bovine serum, they started to proliferate within 48 h after exposure, as assessed by cell counting and [3H]thymidine autoradiography. When cells were inoculated in the absence of serum, a significant degree of cell proliferation was not detectable. Histochemical investigations using bromodeoxyuridine incorporation demonstrated that cells replicating their DNA did not accumulate lipid droplets. Inoculating adipocyte precursor cells under completely serum-free conditions resulted in a 30-50% higher expression of lipogenic enzymes such as glycerol-3-phosphate dehydrogenase and lipoprotein lipase than keeping cells in serum-supplemented medium for the initial 16 h. Addition of cytosine arabinoside at concentrations that effectively block mitosis did not interfere with adipocyte development. In conclusion, adipocyte precursor cells from human adipose tissue do not require cell division to enter the differentiation process in vitro. These cells may have already undergone possibly critical cell divisions in vivo and may be in a late stage of adipocyte development.
Hypoxia upregulates glucose transport activity through an adenosine-mediated increase of GLUT1 expression in retinal capillary endothelial cells. (1998)

Elevation of intracellular glucose within retinal vascular cells is believed to be an important causal factor in the development of diabetic retinopathy. The intracellular glucose concentration is regulated by both the rate of glucose metabolism and glucose transport. Because retinal hypoxia often precedes proliferative diabetic retinopathy, we have studied the regulation of the glucose transport system by hypoxia in cultured bovine retinal endothelial cells (BRECs). Because retinal ischemia is known to increase intracellular adenosine levels, which subsequently regulate hypoxia-inducible genes, such as vascular endothelial growth factor and erythropoietin, the role of adenosine and its receptor-mediated pathways has also been evaluated. Hypoxia (0.5% O2, 5% CO2, and 94.5% N2) stimulated GLUT1 mRNA expression in BRECs in a time-dependent manner with an 8.9 +/- 1.5-fold (P < 0.01) increase observed after 12 h. GLUT1 mRNA expression returned to baseline (1.4 +/- 0.3-fold of control) within 12 h after reinstitution of normoxia. N6-Cyclopentyl adenosine (adenosine A1 receptor agonist, Kd = 1 nmol/l) did not affect GLUT1 mRNA expression at concentrations up to 1 micromol/l, while 2-p-(2-carboxyethyl)-phenethyl-amino-5'-N-ethylcarboxamidoadenosine and 5'-(N-ethylcalboxamido)-adenosine (adenosine A2 receptor [A2R] agonists, Kd = 15 and 16 nmol/l, respectively) increased mRNA levels at concentrations as low as 10 nmol/l. Maximal stimulation was 2.3 +/- 0.2- and 2.1 +/- 0.2-fold, respectively (P < 0.01). The adenosine A2a receptor antagonist 8-(3-chlorostyryl)caffeine (CSC) (Kd = 100 nmol/l for A2R) inhibited hypoxia-stimulated GLUT1 mRNA expression by 40 +/- 8% at 100 nmo/l. Hypoxia upregulated GLUT1 protein expression by 3.0 +/- 0.3-fold after 12 h (P < 0.01), but this response was attenuated by CSC (P < 0.05). Hypoxia increased glucose transport activity by 2.1 +/- 0.3-fold (P < 0.001) after 12 h, a response inhibited 65% by CSC (P < 0.01). A protein kinase A (PKA) inhibitor (H89, 20 micromol/l) suppressed hypoxia-induced GLUT1 mRNA expression by 42 +/- 9% (P < 0.01). These data suggest that hypoxia in BRECs upregulates glucose transport activity through an increase of GLUT1 expression that is partially mediated by adenosine, A2R, and the cAMP-PKA pathway.
Medical impedance tomography and process impedance tomography: a brief review (2001)

The resurgence of research into medical electrical impedance tomography about 20 years ago was soon accompanied by a parallel development in process impedance tomography. The interaction between these two research communities was beneficial to both groups. In recent years this interaction has been very much reduced. This paper briefly reviews the history and then the current developments in medical impedance tomography.
Application of fluorescent tracer agent technology to point-of-care gastrointestinal permeability measurement (2016)

Gut dysfunction, often accompanied by increased mucosal permeability to gut contents, frequently accompanies a variety of human intestinal inflammatory conditions. These disorders include inflammatory bowel diseases (e.g., Crohn’s Disease) and environmental enteropathy and enteric dysfunction, a condition strongly associated with childhood malnutrition and stunting in resource poor areas of the world. The most widely used diagnostic assay for gastrointestinal permeability is the lactulose to mannitol ratio (L:M) measurement. These sugars are administered orally, differentially absorbed by the gut, and then cleared from the body by glomerular filtration in the kidney. The amount of each sugar excreted in the urine is measured. The larger sugar, lactulose, is minimally absorbed through a healthy gut. The smaller sugar, mannitol, in contrast, is readily absorbed through both a healthy and injured gut. Thus a higher ratio of lactulose to mannitol reflects increased intestinal permeability. However, several issues prevent widespread use of the L:M ratio in clinical practice. Urine needs to be collected over time intervals of several hours, the specimen then needs to be transported to an analytical laboratory, and sophisticated equipment is required to measure the concentration of each sugar in the urine. In this presentation we show that fluorescent tracer agents with molecular weights similar to those of the sugars, selected from our portfolio of biocompatible renally cleared fluorophores, mimic the L:M ratio test for gut permeability. This fluorescent tracer agent detection technology can be used to overcome the limitations of the L:M assay, and is amenable to point-of-care clinical use.
Fast methods for code search in CELP (1993)

The code excited linear prediction (CELP) technique has the potential for producing high quality synthetic speech at bit rates as low as 4.8 kb/s. Three fast search methods for selecting an optimal excitation sequence from a code book of stochastic vectors are described. The key idea is to inverse-filter the actual speech with the formant and pitch filters to produce a residual error sequence (RES). The residual error is used to identify a neighborhood or a subset of codes for further processing. The first method, called dynamic nearest neighborhood (DNN), attempts to dynamically construct a neighborhood of the K codes of maximum correlation with the residual error. The second method, called nearest fixed neighborhood (NFN), clusters the code book into a fixed number of cells, and code search is performed on the codes of the cell nearest to the RES. The two methods achieve a reduction in the search procedure by a factor of 8-20 times. The third method combines the advantages of the first two methods to attain a reduction from 40 to 50 times. The performance of these techniques and some of their ramifications are addressed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Improved diagnostic approaches to infection/sepsis detection (2005)

Sepsis is a major healthcare problem from the perspective of mortality and economics. Advances in diagnostic detection of infection and sepsis have been slow, but recent advances in both soluble biomarker detection and quantitative cellular measurements promise the availability of improved diagnostic techniques. Though the promise of cytokine measurements reaching clinical practice have not matured, procalcitonin levels are currently available in many countries and appear to offer enhanced diagnostic distinction between bacterial and viral etiologies. Cellular diagnostics is poised to enter clinical laboratory practice in the form of neutrophil CD64 measurements, which offer superior sensitivity and specificity to conventional laboratory assessment of sepsis. Neutrophil CD64 expression is negligible in the healthy state. However, it increases as part of the systemic response to severe infection or sepsis. The combination of cellular proteomics, as in the case of neutrophil CD64 quantification, and selected soluble biomarkers of the inflammatory response, such as procalcitonin or triggering receptor expressed on myeloid cells (TREM)-1, is predicted to remove the current subjectivity and uncertainty in the diagnosis and therapeutic monitoring of infection and sepsis.
Treatment selection in multi-arm, multi-stage clinical trials (2013)

Adaptive designs that are based on group-sequential approaches have the benefit of being efficient as stopping boundaries can be found that lead to good operating characteristics with test decisions based solely on sufficient statistics. The drawback of these so called "pre-planned adaptive" designs is that unexpected design changes are not possible without impacting the error rates. "Flexible adaptive designs", and in particular designs based on p-value combination, on the other hand can cope with a large number of contingencies at the cost of reduced efficiency.