gebhart/patrepeval huggingface dataset:
Leishmania donovani Dipeptidylcarboxypeptidase Inhibitor as a Potential Oral Treatment for Visceral Leishmaniasis (2022)

Chemotherapy is the key intervention to control visceral leishmaniasis (VL), a neglected tropical disease. Current regimens include not only a few drugs but also present several drawbacks, including moderate to severe toxicity, cost, long-term administration, patient compliance, and growing drug resistance. Thus, the need for better treatment options against VL is a priority. In an endeavor to find an orally active and affordable antileishmanial agent, we evaluated the therapeutic potential of compounds belonging to the (2<i>Z</i>,2'<i>Z</i>)-3,3'-(ethane-1,2-diylbis(azanediyl))bis(1-(4-halophenyl)-6-hydroxyhex-2-en-1-ones) series, identified as inhibitor(s) of Leishmania donovani dipeptidylcarboxypeptidase, a novel drug target. Among them, compound 3c exhibited best <i>in vivo</i> antileishmanial efficacy via both intraperitoneal and oral routes. Therefore, the present study led to the identification of compound 3c as the lead candidate for treating VL.
Maribavir Versus Valganciclovir for Pre-Emptive Treatment of Cytomegalovirus Viremia: A Randomized, Dose-Ranging, Phase 2 Study Among Hematopoietic Stem Cell Transplant and Solid Organ Transplant Recipients (2017)

Background: Cytomegalovirus (CMV) infection/disease is associated with substantial morbidity and mortality among hematopoietic stem cell transplant (SCT) and solid organ transplant (SOT) recipients. Current anti-CMV therapy is associated with significant side effects, including myelosuppression and renal toxicity. Maribavir (MBV) is a potent and selective orally bioavailable anti-CMV agent. This Phase 2 study (EudraCT 2010-024247-32) assessed safety, tolerability, and anti-CMV activity of pre-emptive MBV versus valganciclovir (VGC) among hematopoietic SCT and SOT recipients. Methods: SCT and SOT recipients aged ≥18 years with 1000-100,000 CMV DNA copies/mL in blood/plasma and no documented CMV organ disease were randomized 1:1:1:1 to receive oral MBV 400, 800, or 1200 mg twice daily (BID), or VGC (Weeks 1-3: 900 mg BID, after Week 3: 900 mg once daily; adjusted for renal function), for up to 12 weeks. Primary safety analysis focused on incidence of treatment-emergent adverse events (TEAEs). Primary efficacy endpoint was proportion of patients with confirmed undetectable plasma CMV DNA within 3 and 6 weeks of treatment ("responders"). Treatment effect estimates were calculated for the pooled MBV group versus VGC and compared statistically; no statistical tests were performed on safety endpoints. Results: Between May 2012 and July 2014, 159/161 randomized patients received study drug (119 MBV [58 SOT], 40 VGC [19 SOT]); median (range) age 58 (18-76) years. Efficacy results are shown in the table.Tabled 1 Most TEAEs were mild-to-moderate in severity. Gastrointestinal AEs (nausea/vomiting/diarrhea) occurred more frequently in those receiving MBV (20-23%) versus VGC (10-15%); dysgeusia occurred more frequently with MBV (40%) versus VGC (3%) but with no apparent dose effect. Neutropenia (ANC <1000/mm3) occurred less frequently with MBV (5%) versus VGC (18%). Conclusion: MBV 400-1200 mg BID had similar efficacy to VGC at clearing CMV viremia among SCT and SOT recipients, with a similar treatment effect across MBV doses. MBV was generally well tolerated with a safety profile similar to previous studies having less treatment-emergent neutropenia compared with VGC. MBV may increase immunosuppressant drug levels, therefore monitoring and dose adjustment of immunosuppressant drugs are typically considered.
Study of Creative Manufacturing Practice to a Physically Handicapped Student (2004)

Recently, a barrier-free environment has been needed in various fields. The educational improvements for disabled students have been carrying out at a number of higher education institutions. In this study, integrated manufacturing practice to a physically handicapped student was tried through the manufacture of Scotch-yoke mechanism. It was found that a physically handicapped student could gain manufacturing experience, enjoying the progress of this work.
A Collagen–Poly(Vinyl Alcohol) Nanofiber Scaffold for Cartilage Repair (2011)

Articular cartilage has a limited capacity for self-repair. Untreated injuries of cartilage may lead to osteoarthritis. This problem demands new effective methods to reconstruct articular cartilage. Mesenchymal stem cells (MSCs) have the proclivity to differentiate along multiple lineages giving rise to new bone, cartilage, muscle, or fat. This study was an animal model for autologous effects of transplantation of MSCs with a collagen-poly(vinyl alcohol) (PVA) scaffold into full-thickness osteochondral defects of the stifle joint in the rabbit as an animal model. A group of 10 rabbits had a defect created experimentally in the full thickness of articular cartilage penetrated into the subchondral space in the both stifle joints. The defect in the right stifle was filled with MSCs/collagen-PVA scaffold (group I), and in the left stifle, the defect was left without any treatment as the control group (group II). Specimens were harvested at 12 weeks after implantation, examined histologically for morphologic features, and stained immunohistochemically for type-II collagen. Histology observation showed that the MSCs/collagen-PVA repair group had better chondrocyte morphology, continuous subchondral bone, and much thicker newly formed cartilage compared with the control group at 12 weeks post operation. There was a significant difference in histological grading score between these two groups. The present study suggested that the hybrid collagen-PVA scaffold might serve as a new way to keep the differentiation of MSCs for enhancing cartilage repair.
P4‐078: REPRESENTATION OF BLOOD FLOW IN PERFORATING BASAL GANGLIA ARTERIES OF PATIENTS WITH CEREBRAL SMALL VESSEL DISEASE (CSVD) AT 7 TESLA MRI (2019)

Interest in the small vessels’ pathology is growing because of its contribution to cognitive impairment (Pantoni et al., 2009) and its possible interaction with AD-related pathology (Boyle et al., 2018). CSVD affects vessels (small arteries & veins, arterioles and capillaries), including the perforating arteries of the basal ganglia. Because of their small dimension, in vivo analysis of blood flow in these arteries is challenging. We applied an innovative 2D-Flow sequence at 7 Tesla MRI (Bouvy et al., 2016) in order to assess the blood flow velocity and pulsatility index (PI) of these arteries in 20 CSVD patients (mean [SD] age 71 [9] years, 65% male) and 28 healthy elderly controls (70 [9] years, 62% male). Vascular risk factors, cerebral spinal fluid (CSF) biomarkers (e.g. tau and b-amyloid 42) and Apolipoprotein E status were also available in this cohort. Furthermore, we obtained MRI measures of 8 participants approximately a year from baseline. We hypothesize to observe a relation between these measures, age and vascular risk factors. We will then compare CSVD subtypes, i.e. hypertensive arteriopathy and cerebral amyloid angiopathy, and expect to find differences between groups in both blood velocity and vascular stiffness (measured by PI) of the basal ganglia perforating arteries. We will further characterize the development of these parameters over time.
A new validated mathematical model of the Wnt signalling pathway predicts effective combinational therapy by sFRP and Dkk (2012)

The Wnt signalling pathway controls cell proliferation and differentiation, and its deregulation is implicated in different diseases including cancer. Learning how to manipulate this pathway could substantially contribute to the development of therapies. We developed a mathematical model describing the initial sequence of events in the Wnt pathway, from ligand binding to β-catenin accumulation, and the effects of inhibitors, such as sFRPs (secreted Frizzled-related proteins) and Dkk (Dickkopf). Model parameters were retrieved from experimental data reported previously. The model was retrospectively validated by accurately predicting the effects of Wnt3a and sFRP1 on β-catenin levels in two independent published experiments (R(2) between 0.63 and 0.91). Prospective validation was obtained by testing the model's accuracy in predicting the effect of Dkk1 on Wnt-induced β-catenin accumulation (R(2)≈0.94). Model simulations under different combinations of sFRP1 and Dkk1 predicted a clear synergistic effect of these two inhibitors on β-catenin accumulation, which may point towards a new treatment avenue. Our model allows precise calculation of the effect of inhibitors applied alone or in combination, and provides a flexible framework for identifying potential targets for intervention in the Wnt signalling pathway.
SILVER NANOPARTICLES AND GOLD METALLODENDRIMERS: FROM MOLECULAR PRECURSORS TO NANOMATERIALS (2008)

The increased interest in the synthesis of new metal-based nanomaterials stems from the fact that new electronic, optical or magnetic properties can be reached at this length scale. These properties can be tuned depending on the size and the shape of the new nanomaterials. By the use of our experience in gold and silver organometallic and coordination chemistry we have carried out the synthesis of metal nanoparticles and nanometer sized metallodendrimers through chemical methods. The first research line makes use of the organometallic silver precursor [Ag(C6F5)] that under mild conditions and in the presence of stabilizers, permits the synthesis of small size silver nanoparticles. This organometallic method leads to Ag nanoparticles stabilized in different substrates such as organic ligands (amines), polymers (PVP, cellulose acetate) or inorganic SiO2 (see Figure 1). Moreover, alkylamine capped silver nanoparticles (ca. 10 nm) display high antimicrobial activity against some representative microorganisms.[1] We have also focused on the synthesis and study of a series of gold metallodendrimers. These new materials are based on PPI or PAMAM dendrimers functionalized with peripheral PPh2 groups what permits the coordination of Au(I) fragments. Depending on the dendrimer
Convex Lens-Induced Confinement for Imaging Single Molecules (2010)

Fluorescence imaging is used to study the dynamics of a wide variety of single molecules in solution or attached to a surface. Two key challenges in this pursuit are (1) to image immobilized single molecules in the presence of a high level of fluorescent background and (2) to image freely diffusing single molecules for long times. Strategies that perform well by one measure often perform poorly by the other. Here, we present a simple modification to a wide-field fluorescence microscope that addresses both challenges and dramatically improves single-molecule imaging. The technique of convex lens-induced confinement (CLIC) restricts molecules to a wedge-shaped gap of nanoscale depth, formed between a plano-convex lens and a planar coverslip. The shallow depth of the imaging volume leads to 20-fold greater rejection of background fluorescence than is achieved with total internal reflection fluorescence (TIRF) imaging. Elimination of out-of-plane diffusion leads to an approximately 10,000-fold longer diffusion-limited observation time per molecule than is achieved with confocal fluorescence correlation spectroscopy. The CLIC system also provides a new means to determine molecular size. The CLIC system does not require any nanofabrication, nor any custom optics, electronics, or computer control.
Pathway-Activity Likelihood Analysis and Metabolite Annotation for Untargeted Metabolomics Using Probabilistic Modeling (2020)

<b>Motivation</b>: Untargeted metabolomics comprehensively characterizes small molecules and elucidates activities of biochemical pathways within a biological sample. Despite computational advances, interpreting collected measurements and determining their biological role remains a challenge. <b>Results</b>: To interpret measurements, we present an inference-based approach, termed Probabilistic modeling for Untargeted Metabolomics Analysis (PUMA). Our approach captures metabolomics measurements and the biological network for the biological sample under study in a generative model and uses stochastic sampling to compute posterior probability distributions. PUMA predicts the likelihood of pathways being active, and then derives probabilistic annotations, which assign chemical identities to measurements. Unlike prior pathway analysis tools that analyze differentially active pathways, PUMA defines a pathway as <i>active</i> if the likelihood that the path generated the observed measurements is above a particular (user-defined) threshold. Due to the lack of "ground truth" metabolomics datasets, where all measurements are annotated and pathway activities are known, PUMA is validated on synthetic datasets that are designed to mimic cellular processes. PUMA, on average, outperforms pathway enrichment analysis by 8%. PUMA is applied to two case studies. PUMA suggests many biological meaningful pathways as active. Annotation results were in agreement to those obtained using other tools that utilize additional information in the form of spectral signatures. Importantly, PUMA annotates many measurements, suggesting 23 chemical identities for metabolites that were previously only identified as isomers, and a significant number of additional putative annotations over spectral database lookups. For an experimentally validated 50-compound dataset, annotations using PUMA yielded 0.833 precision and 0.676 recall.
Sensor Systems using Tunable Micro-Electro-Mechanical Systems Vertical Cavity Surface Emitting Lasers (MEMS-VCSELs) from the Visible to the Mid-infrared (2019)

MEMS-VCSELs enable fractional tuning ranges of >11%, wavelength repetition rates >1MHz, and dynamic single-mode operation. These properties promise an economical optical source for imaging, metrology, and spectroscopy in applications from the visible to the mid-infrared.
Allelic Diversity in the Serum Amyloid A2 Gene and Amyloid A Amyloidosis in a Breeding Colony of Zebra Finches (Taeniopygia guttata) (2019)

A high incidence of amyloid A (AA) amyloidosis was observed in the research breeding colony of zebra finches at our institution. Some birds with hepatic AA amyloidosis were asymptomatic for comorbid conditions frequently associated with the development of AA amyloidosis, whereas other birds with comorbid conditions failed to develop AA amyloidosis, suggesting a potential genetic component to the disease. Sequencing the <i>SAA2</i> gene from 20 birds yielded 18 distinct sequences that coded for 5 isoforms of the protein. Most of the amino acid substitutions are unlikely to affect the protein's structure or function, but 2 changes-R52L and V84M-were predicted to be disruptive. In particular, R52 is highly conserved across vertebrates, with only arginine or lysine found at this position in reported sequences to date. The atypical R52L substitution occurred in 2 otherwise healthy birds with hepatic AA amyloidosis, supporting the idea that this change is pathogenic.
P1‐464: ALZHEIMER'S DISEASE‐ASSOCIATED NEURODEGENERATION IS RELATED TO ABNORMAL BIOMARKER LEVELS OF CEREBROVASCULAR DISEASE AND AMYLOID (2018)

Biomarkers for Alzheimer's disease (AD) sequentially become abnormal, prior to clinical diagnosis, and culminate in cortical atrophy. Although not typically considered a core feature of AD, cerebrovascular disease may promote AD-related neurodegeneration and clinical outcomes. The purpose of this study was to examine the differences in cortical thickness and cortical thinning rate by clinical diagnosis (normal control (NC), mild cognitive impairment (MCI), or AD) or amyloid and cerebrovascular disease (CVD) burden. Subjects from the Alzheimer's Disease Neuroimaging Initiative underwent longitudinal AV45 PET and MR imaging to quantify amyloid, white matter hyperintensities (WMHs), and cortical thickness, respectively. AV45 SUVR was estimated as the ratio of cortical regions to a composite white matter reference region. White matter hyperintensity volume, an indication of CVD, was derived using spatial and contextual prior probabilities. Cortical thickness in AD-associated regions was measured with the FreeSurfer longitudinal processing stream. Thresholds for abnormal biomarker levels were determined as the upper 95%CI of the mean in normal controls for amyloid and log-transformed WMH and the prevalence of biomarker abnormality by diagnosis was tested. Linear mixed-effects models tested for differences in cortical thickness or cortical thinning rate. Individuals with AD had lower cortical thickness than those with MCI, who, in turn, had lower cortical thickness than NCs (significant main effect of Diagnosis), but individuals with AD had the slowest the slowest rate of cortical thinning over time (significant Diagnosis-Time interaction). To investigate the apparent decrease with AD, individuals were categorized by biomarker abnormality. The proportion of individuals with abnormal amyloid and WMH increased across diagnostic groups in the expected direction, but note approximately 15% of the AD group do not have elevated amyloid (Table 1). Cortical thickness was significantly lower in individuals with abnormally high amyloid compared to normal amyloid, but cortical thinning rate was only significantly different from zero given abnormally high WMH volume (Figure 1). Cortical thinning rate over time, shown by abnormal biomarker profiles. Profiles of multiple, abnormal biomarkers provide more insight into variations in the AD pathophysiological process compared to single biomarkers or clinical diagnosis. Importantly, abnormally high WMH volume is associated with neurodegeneration over time in key AD-associated regions after adjusting for amyloid.
The synthesizer generator (1984)

Programs are hierarchical compositions of formulae satisfying structural and extra-structural relationships. A program editor can use knowledge of such relationships to detect and provide immediate feedback about violations of them. The Synthesizer Generator is a tool for creating such editors from language descriptions. An editor designer specifies the desired relationships and the feedback to be given when they are violated, as well as a user interface; from the specification, the Synthesizer Generator creates a full-screen editor for manipulating programs in the language.
Rfx6 promotes the differentiation of peptide-secreting enteroendocrine cells while repressing genetic programs controlling serotonin production (2019)

ABSTRACT Objective Enteroendocrine cells (EECs) of the gastro-intestinal tract sense gut luminal factors and release peptide hormones or serotonin (5-HT) to coordinate energy uptake and storage. Our goal is to decipher the gene regulatory networks controlling EECs specification from enteroendocrine progenitors. In this context, we studied the role of the transcription factor Rfx6 which had been identified as the cause of Mitchell-Riley syndrome characterized by neonatal diabetes and congenital malabsorptive diarrhea. We previously reported that Rfx6 was essential for pancreatic beta cell development and function, however, the role of Rfx6 in EECs differentiation remained to be elucidated. Methods We examined the molecular, cellular and metabolic consequences of constitutive and conditional deletion of Rfx6 in the embryonic and adult mouse intestine. We performed single cell and bulk RNA-Seq to characterize EECs diversity and identify Rfx6-regulated genes. Results Rfx6 is expressed in the gut endoderm; later it is turned on in, and restricted to, enteroendocrine progenitors and persists in hormone-positive EECs. In the embryonic intestine, the constitutive lack of Rfx6 leads to gastric heterotopia, suggesting a role in the maintenance of intestinal identity. In the absence of intestinal Rfx6, EECs differentiation is severely impaired both in the embryo and adult. However, the number of serotonin-producing enterochromaffin cells and mucosal 5-HT content are increased. Concomitantly, Neurog3-positive enteroendocrine progenitors accumulate. Combined analysis of single-cell and bulk RNA-Seq data revealed that enteroendocrine progenitors differentiate in two main cell trajectories, the enterochromaffin (EC) cells and the Peptidergic Enteroendocrine (PE) cells, whose differentiation programs are differentially regulated by Rfx6. Rfx6 operates upstream of Arx , Pax6 and Isl1 to trigger the differentiation of peptidergic EECs such as GIP-, GLP-1- or CCK-secreting cells. On the contrary, Rfx6 represses Lmx1a and Tph1 , two genes essential for serotonin biosynthesis. Finally, we identified transcriptional changes uncovering adaptive responses to the prolonged lack of enteroendocrine hormones and leading to malabsorption and lower food efficiency ratio in Rfx6-deficient mouse intestine. Conclusion These studies identify Rfx6 as an essential transcriptional regulator of EECs specification and shed light on the molecular mechanisms of intestinal failures in human RFX6-deficiencies such as Mitchell-Riley syndrome.
New North American species of earthworms of the family Megascolecidae (1937)

Among the more interesting specimens of Oligochaeta in the collections of the writer are some that were taken in Oregon and that belong to new species of the genera Megascolides McCoy and Plutellus I.Perrier.
Leptin (2000)

The discovery of the adipose-derived hormone leptin has generated enormous interest in the interaction between peripheral signals and brain targets involved in the regulation of feeding and energy balance. Plasma leptin levels correlate with fat stores and respond to changes in energy balance. It was initially proposed that leptin serves a primary role as an anti-obesity hormone, but this role is commonly thwarted by leptin resistance. Leptin also serves as a mediator of the adaptation to fasting, and this role may be the primary function for which the molecule evolved. There is increasing evidence that leptin has systemic effects apart from those related to energy homeostasis, including regulation of neuroendocrine and immune function and a role in development.
Traumatic Brain Injury and Stem Cells: An Overview of Clinical Trials, the Current Treatments and Future Therapeutic Approaches (2020)

Traumatic brain injury represents physical damage to the brain tissue that induces transitory or permanent neurological disabilities. The traumatic injury activates an important inflammatory response, followed by a cascade of events that lead to neuronal loss and further brain damage. Maintaining proper ventilation, a normal level of oxygenation, and adequate blood pressure are the main therapeutic strategies performed after injury. Surgery is often necessary for patients with more serious injuries. However, to date, there are no therapies that completely resolve the brain damage suffered following the trauma. Stem cells, due to their capacity to differentiate into neuronal cells and through releasing neurotrophic factors, seem to be a valid strategy to use in the treatment of traumatic brain injury. The purpose of this review is to provide an overview of clinical trials, aimed to evaluate the use of stem cell-based therapy in traumatic brain injury. These studies aim to assess the safety and efficacy of stem cells in this disease. The results available so far are few; therefore, future studies need in order to evaluate the safety and efficacy of stem cell transplantation in traumatic brain injury.
Action research literature 2008—2010: Themes and trends (2010)

This is the fourth in a series of two-yearly reviews of action research books and edited collections. After an overview of the general action research literature I gather together other relevant literature under the following headings: educational action research, appreciative inquiry, community research and engagement, rural and regional development, organizational and systemic applications, and action learning. The review concludes with a brief examination of other relevant literature, and a tentative look to the future of action research.