gebhart/patrepeval huggingface dataset:
Pathophysiological mechanisms of obesity and hypertension in mouse models of Bardet‐Biedl syndrome (2006)

Bardet-Biedl syndrome (BBS) is a genetic disorder with the cardinal features of obesity, retinopathy and polydactyly. We have developed mouse BBS models for BBS2, BBS4 and BBS6 whose phenotypes closely resemble that of humans. We sought to use these models to dissect the mechanisms involved in the metabolic and cardiovascular disorders associated with BBS. We found that BBS null mice develop obesity due to both hyperphagia and decrease activity. Obesity in the BBS knockout mice is associated with high circulating levels of the adipocyte-derived hormone, leptin even at an early age (5–6 weeks old) when no difference in body weight could be detected. Administration of exogenous leptin caused a significant decrease in body weight and food intake in the wild type mice, but leptin failed to reduce appetite or body weight in Bbs2−/ −, Bbs4−/ − and Bbs6−/ −mice. This indicates that loss of leptin action in the central nervous system may be important for the development of obesity associated with BBS. Next we compared arterial pressure between wild type and BBS null mice. Bbs4−/ − and Bbs6−/ − mice exhibited ~12 mmHg higher arterial pressure than their wild type controls. However, Bbs2−/ − mice had normal arterial pressure. Increased sympathetic nerve activity (SNA) is considered to be an important mechanism of obesity-associated hypertension. Using multifiber recording, we found that Bbs4v/− and Bbs6−/ − mice have higher baseline renal SNA as compared to the wild type mice but the Bbs2−/ − mice did not, consistent with the normal arterial pressure findings. All 3 mouse models of BBS exhibit obesity however only 2 exhibit hypertension. Our data also suggest a role for the renal SNA in the hypertension associated with BBS.
Characterization of aCorynebacteriumStrain That Can Grow in Medium Containing up to 2 M Nitrate (2008)

ABSTRACT A gram-positive bacterium, identified as Corynebacterium K37, was isolated from the waste effluent of a dairy farm. The bacterium thrived and expressed nitrate-reducing activity at nitrate concentrations of up to 2 M, and reduced nitrate concentration from 0.4 M to 11.4 mM and also from 0.4 M to 23.4 mM in aerobic and anaerobic fed-batch cultures, respectively. Cells of K37 were able to utilize a variety of carbon sources for nitrate reduction with little or no accumulation of nitrite. In aerobic cultures, the residual nitrite was minimal and it was completely reduced after prolonged incubation. Growth on acetate or pyruvate in anaerobic cultures resulted in lower nitrite reductase activities and concomitant higher residual nitrite concentrations than did growth on ethanol or glucose, suggesting that diminished electron availability was a factor in the accumulation of residual nitrite. The bacterium also survived in 2 M concentrations of NaCl, KCl, and CaCl2. Corynebacterium sp. K37 may be useful in bioremediation of high nitrate pollution in contaminated soils and water.
Industrial Agents as a Key Enabler for Realizing Industrial Cyber-Physical Systems: Multiagent Systems Entering Industry 4.0 (2020)

Industrial agents (IAs) [1] are multiagent-based systems (MASs) [2] that, for many years, have been advocated as a promising and realistic solution for an emerging set of industrial challenges. In the past, MASs fell into the scope of enterprise agility [3]-[8], and now, more than ever, pertain to the industrial digital transformation and sustainability spheres. MAS technology is being applied to several industrial applications in the cyber-physical system (CPS) context, namely, in smart production, smart electric grids, smart logistics, and smart health care [9]. To understand the future potential of IAs, one must first have a sufficiently concise view of the past and present efforts, i.e., understand their early applications and current directions. Such a view is necessary because, over the last decades, the concept of the IA has proven to be a bit of a moving target, adjusting to the needs, visions, and technologies of each era.
Classics in Chemical Neuroscience: Fluoxetine (Prozac) (2013)

Fluoxetine (Prozac) was the first major breakthrough for the treatment of depression since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) nearly 30 years earlier. It was the first selective serotonin reuptake inhibitor (SSRI) approved by the United States Food and Drug Administration, offering superior efficacy and reduced side effects relative to TCAs and MAOIs. Though a debate remains regarding the exact mechanism by which the clinical efficacy of fluoxetine is manifested, the importance of fluoxetine and related SSRIs to the field is unquestionable. The trade name Prozac has permeated popular culture, helping to raise awareness of depression and to diminish the prevalence of long-standing stigmas associated with this illness. In this Review, we will showcase the history and importance of fluoxetine to neuroscience in general, as well as for the treatment of depression, and review the synthesis, pharmacology, drug metabolism, and adverse effects of fluoxetine.
An improved method for determining snowmelt onset dates over Arctic sea ice using scanning multichannel microwave radiometer and Special Sensor Microwave/Imager data (2001)

Ablation of snow over sea ice is an important physical process affecting the Arctic surface energy balance. An improved understanding of the spatial and temporal variations in snowmelt onset could be utilized to improve climate simulations in the Arctic, as well as monitor the Arctic for signs of climate change. Utilizing an updated approach for monitoring snowmelt onset over Arctic sea ice, spatial variability in passive microwave derived snowmelt onset dates is examined from 1979 through 1998. The improved technique, termed the advanced horizontal range algorithm (AHRA), utilizes temporal variations in 18/19 GHz and 37 GHz passive microwave horizontal brightness temperatures obtained from the scanning multichannel microwave radiometer (SMMR) and the Special Sensor Microwave/Imager (SSM/I) to identify snowmelt onset. A qualitative assessment of spatial variability in snowmelt onset discusses the 1979 through 1998 mean snowmelt onset pattern, and it also illustrates that there are significant variations in snowmelt onset on an annual basis. Principal component analysis of the snowmelt onset dates suggests snowmelt onset variability is dominated by a zone of abnormally early (late) snowmelt onset near the Siberian coast and another zone of abnormally late (early) snowmelt onset near Baffin Bay. Statistical analysis between the first principal component and March‐June monthly averaged Arctic Oscillation values implies that variations in snowmelt onset are related to alterations in the phase of the spring Arctic Oscillation.
Cellular L-arginine pools modulate c-di-GMP turnover and biofilm formation in Pseudomonas putida (2020)

&amp;lt;p&amp;gt;The intracellular second messenger cyclic diguanylate (c-di-GMP) is broadly conserved in bacteria, where it influences processes such as virulence, stress resistance and biofilm development. In the plant-beneficial bacterium &amp;lt;em&amp;gt;Pseudomonas putida&amp;lt;/em&amp;gt; KT2440, the response regulator with diguanylate cyclase activity CfcR is the main contributor to c-di-GMP levels in the stationary phase of growth. When overexpressed, CfcR increases c-di-GMP levels and gives rise to a pleiotropic phenotype that includes enhanced biofilm formation and crinkly colony morphology. Our group has previously reported that insertion mutants in &amp;lt;em&amp;gt;argG&amp;lt;/em&amp;gt; and &amp;lt;em&amp;gt;argH&amp;lt;/em&amp;gt;, the genes that encode the last two enzymes in the arginine biosynthesis pathway, do not display the crinkly colony morphology phenotype and show decreased c-di-GMP levels even in the presence of &amp;lt;em&amp;gt;cfcR&amp;lt;/em&amp;gt; in multicopy (Ramos-Gonz&amp;amp;#225;lez, M.I. &amp;lt;em&amp;gt;et al.&amp;lt;/em&amp;gt; 2016. Front. Microbiol. 7, 1093). Here we present results indicating that L-arginine acts both as an environmental and as a metabolic signal that influences the lifestyles of &amp;lt;em&amp;gt;P. putida&amp;lt;/em&amp;gt; through the modulation of c-di-GMP levels and changes in the expression of structural elements of biofilms. Exogenous L-arginine partially restores c-di-GMP levels in arginine biosynthesis mutants, a response that is transduced through CfcR and possibly (an)other diguanylate cyclase(s). At least three periplasmic binding proteins, each forming part of an amino acid transport system, contribute in different ways to the response to external L-arginine. We propose that the turnover of the second messenger c-di-GMP is modulated by the state of global arginine pools in the cell resulting both from anabolism and from uptake.&amp;lt;/p&amp;gt;
FELLOW EYE CHANGES IN PATIENTS WITH NONISCHEMIC CENTRAL RETINAL VEIN OCCLUSION (2015)

Fellow eye changes detectable on adaptive optics scanning light ophthalmoscope fluorescein angiography reflect subclinical pathology difficult to detect using conventional imaging technologies. These changes may help elucidate the pathogenesis of nonischemic CRVO and help identify eyes at increased risk of future occlusion.
Electron spin resonance spectrum of the xanthen radical anion (1975)

The radical anions of xanthen and several of its derivatives have been prepared by the action of potassium on a solution of the parent compound in dimethoxyethane at –70°. The e.s.r. spectra of these species are reported and compared with the results of MO calculations. It is suggested that the xanthen radical anion is not symmetrical but that the electron is localised on one of the benzene rings and jumps rapidly between the two sites. The radicals decompose at higher temperatures to yield other radicals some of which have been identified.
ORM-6151: A First-in-Class, Anti-CD33 Antibody-Enabled GSPT1 Degrader for AML (2022)

Targeted protein degradation (TPD) molecules have expanded the breadth of therapeutic options through both their catalytic mechanism of action and ability to degrade previously "undruggable" target proteins. Prior reports of small-molecule GSPT1 degraders such as CC-90009 in AML demonstrate potent anti-tumor cytotoxicity, but with a potentially narrow therapeutic index. To increase the efficacy vs. tolerability window of TPDs and improve drug delivery, we introduce TPD-Squared (TPD2TM), a dual-targeted protein degradation approach of combining the catalytic mechanism of targeted protein degradation with the precision of tumor-targeting therapeutic antibodies. We generated conjugates using a CD33-targeting antibody (OR000283) produced by engineering the FAb (H&L) sequences from gemtuzumab onto an IgG1 Fc with N297A variant to inhibit Fc-γR binding. Medicinal chemistry optimization of linker-payloads led to the identification of ORM-6151, which is composed of SMol006, a highly potent GSPT1 degrader conjugated to OR000283 via a novel β-glucoronide releasable linker. ORM-6151 treatment in CD33-expressing cell lines showed picomolar activity with 10-1000-fold greater potency compared to several GSPT1 degrader molecules including CC-90009 or Mylotarg, and had robust activity in Mylotarg-resistant lines (AML193 and Kasumi6). ORM-6151 also exhibited picomolar potency in in vitro cytotoxicity to primary relapsed/refractory AML patient blasts, with better potency than CC-90009 and Mylotarg. Moreover, ORM-6151 showed minimal cytotoxic activity to healthy hematopoietic progenitor cells, with 10-10,000 fold less toxicity than CC-90009 or Mylotarg. We evaluated ORM-6151 in several in vivo xenograft models and observed robust efficacy, following a single treatment at doses as low as 1 mg/kg. In the MV4-11 xenograft model, treatment with ORM-6151 demonstrated superior activity than CC-90009. The tumor growth inhibition correlated with the degree and duration of GSPT1 depletion and changes in expression of previously described integrated stress response biomarker genes. In summary, ORM-6151 is a promising, potential therapy for AML and currently in preclinical development as a first-in-class targeted protein degrader therapy with CD33-targeted delivery. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal
Pharmacological Assessment of &lt;i&gt;γ&lt;/i&gt;-Secretase Activity from Rodent and Human Brain (2012)

γ-Secretase is involved in the final processing of the amyloid precursor protein into a heterogeneous pool of β-amyloid (Aβ) peptides. Current Alzheimer’s disease drug discovery efforts include targeting γ-secretase activity in brain to attenuate production of the neurotoxic Aβ species. The resulting pharmacology may be affected by species-specific differences in the γ-secretase core complex or its associated proteins. Therefore, we utilized partially purified γ-secretase membranes derived from the brains of different species, including human cortex, to quantitatively assess the de novo production of both Aβ42 and Aβ40 following treatment with known γ-secretase inhibitors and modulators. We determined that the inhibitory activity of a Notch-1 sparing γ-secretase inhibitor and the modulatory activity of two classes of γ-secretase modulators were equipotent at affecting the production of Aβ across rodent and human brain membrane preparations. Additionally, the observed modulator-specific Aβ profile in isolated brain membranes across species was similar to that observed in HeLa cell membranes, and the brain and CSF of guinea pigs following oral administration. By utilizing rapidly purified γ-secretase, we were able to probe and compare the complex pharmacology of γ-secretase in the brain across common rodent species and human cortex.
A Systematic Study of Unsaturation in Lipid Nanoparticles Leads to Improved mRNA Transfection In Vivo (2020)

Abstract Lipid nanoparticles (LNPs) represent the leading concept for mRNA delivery. Unsaturated lipids play important roles in nature with potential for mRNA therapeutics, but are difficult to access through chemical synthesis. To systematically study the role of unsaturation, modular reactions were utilized to access a library of 91 amino lipids, enabled by the synthesis of unsaturated thiols. An ionizable lipid series (4A3) emerged from in vitro and in vivo screening, where the 4A3 core with a citronellol‐based (Cit) periphery emerged as best. We studied the interaction between LNPs and a model endosomal membrane where 4A3‐Cit demonstrated superior lipid fusion over saturated lipids, suggesting its unsaturated tail promotes endosomal escape. Furthermore, 4A3‐Cit significantly improved mRNA delivery efficacy in vivo through Selective ORgan Targeting (SORT), resulting in 18‐fold increased protein expression over parent LNPs. These findings provide insight into how lipid unsaturation promotes mRNA delivery and demonstrate how lipid mixing can enhance efficacy.
Effect of Hydrogen Dioxide Treatment on the Osteogenic Potential of Duck-beak Bone-derived Natural Bioceramic Microparticles (2017)

As an alternative material to the autogenous bone, duck-beak bone particle for bone substitute have been attracting great attention due to their biological properties. To deliver the most favorable outcome of medical treatment, it is essential to study the effect of various processing methods of the duck-beak bone. In this study, we compared the two deproteinizing agents for manufacturing duck-beak bone. Group 1 was treated by a conventional chemical agent (ethylenediamine) and Group 2 by hydrogen dioxide (H<sub>2</sub>O<sub>2</sub>). In vitro and in vivo experiments were conducted in parallel to compare the cytocompatibility and osteogenic capability between two processing methods. For in vitro tests, human adipose-derived mesenchymal stem cells (hAD-MSCs) were planted onto each sample and their attachment and growing were evaluated. For in vivo biocompatibility and osteogenic properties, the samples were applied on the critical-sized calvarial bone defect of rats. Group 2 showed significantly higher cell attachment but Group1 showed slightly higher cell proliferation. In in vivo tests, all groups have shown biocompatibility and increased level of osteogenic potential. However, Group 2 had significantly higher bone regeneration (p<0.05). This experiment confirmed that H<sub>2</sub>O<sub>2</sub> can be an optimal processing method for duck-beak bone particle.
Expanded grand canonical and Gibbs ensemble Monte Carlo simulation of polymers (1996)

A novel formalism is presented for simulation of polymers in expanded grand canonical and expanded Gibbs ensembles. Molecular creation and destruction attempts are replaced by transition attempts between states of a tagged chain of variable length. Results are presented for expanded grand canonical simulations of hard-core chain fluids in the bulk and in a slit pore and for expanded Gibbs ensemble simulations of vapor–liquid equilibria for square-well chains.
An investigation of perceived sharpness and sharpness metrics (2005)

Sharpness is an important attribute that contributes to the overall impression of image quality. As digital photography becomes more and more popular, digital photo enhancement has been a topic of great interest. In this paper, we investigate two issues related to digital photo sharpness. 1) How do we quantitatively measure the sharpness of a digital image? 2) What is the preferred sharpness of a digital image, and what is the relation between preferred sharpness and sharpness detection threshold? Both issues are of practical use to the digital photography market. First, we present the design and properties of three sharpness metrics to answer the first question. Next, we describe psychophysical experiments to investigate the second question. It is found that 1) the sharpness metric Digital Sharpness Scale (DSS) and Average Edge Transition Slope (AETS) are highly correlated to the perceived sharpness; 2) Both DSS and AETS predict sharpness equality with acceptable error; 3) the sharpness detection threshold is relatively consistent across subjects and across image contents, compared with the sharpness preference; 4) the average level of preferred sharpness is consistently higher than the detection threshold across image contents and across subjects, which implies that observers in general prefer a sharpened image to the original image; and 5) the preferred level of sharpness has a strong dependency on image content.
Polymer Gel Templating of Free-Standing Inorganic Monoliths for Photocatalysis (2009)

We have developed a simple, low-cost process to fabricate free-standing porous metal oxide monoliths. Various swollen polymers and hydrogels possessing an open network structure are infiltrated with pure liquid metal alkoxide. Hydrolysis followed by chemical or thermal degradation of the polymer leads to bulk porous monoliths, TiO2 and SiO2 as initial examples. The titania solids were subsequently employed as photocatalysts under UV light and monitored for adsorption. The materials show efficient reusable photocatalytic ability as compared to pure-phase nanoparticle titanium oxide.
A Battery Digital Twin Based on Neural Network for Testing SoC/SoH Algorithms (2022)

Lithium ion cells are the preferred solution for the growing world of mobile applications. To avoid working conditions that can accelerate irreversible degradation reactions, two parameters must always be known, namely State of Charge (SoC) and State of Health (SoH). Since SoC and SoH cannot be measured directly with sensors on cells, they must be derived from the observation of voltage and current at the accessible connections. The literature on algorithms for SoC-SoH estimation is very rich and new advanced ones are continuously developed. However, the testing of algorithms on real batteries is very time consuming due to the need of many charge-discharge cycles in order to observe aging effects. These operations can take months in the lab. In this paper we present a Battery Digital Twin (BDT) that outputs a realistic voltage signal as a function of SoC and SoH inputs. The voltage signals produced by the BDT can later be used to feed SoC/SoH estimation algorithms. The BDT is thus a simulator for fast testing of battery parameter estimation algorithms. This paper presents a BDT developed in the Matlab-Simulink-Simscape environment. The non-linear Open Circuit Voltage (OCV) generator as a function of SoC/SoH is based on a feed forward Neural Network (NN) trained with real data from a publicly available repository. The internal complex impedance can assume fixed circuit configurations derived from typical Nyquist plots or can be dynamically adjusted by other trained NN as non-linear function of SoC/SoH.
IFN signaling and neutrophil degranulation transcriptional signatures are induced during SARS-CoV-2 infection (2020)

The novel virus SARS-CoV-2 has infected more than 14 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Limited information on the underlying immune mechanisms that drive disease or protection during COVID-19 severely hamper development of therapeutics and vaccines. Thus, the establishment of relevant animal models that mimic the pathobiology of the disease is urgent. Rhesus macaques infected with SARS-CoV-2 exhibit disease pathobiology similar to human COVID-19, thus serving as a relevant animal model. In the current study, we have characterized the transcriptional signatures induced in the lungs of juvenile and old rhesus macaques following SARS-CoV-2 infection. We show that genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. We demonstrate that Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. In contrast, pathways involving VEGF are downregulated in lungs of old infected macaques. Using samples from humans with SARS-CoV-2 infection and COVID-19, we validate a subset of our findings. Finally, neutrophil degranulation, innate immune system and IFN gamma signaling pathways are upregulated in both tuberculosis and COVID-19, two pulmonary diseases where neutrophils are associated with increased severity. Together, our transcriptomic studies have delineated disease pathways to improve our understanding of the immunopathogenesis of COVID-19 to facilitate the design of new therapeutics for COVID-19.