gebhart/patrepeval huggingface dataset:
COVID-19: Drug Targets and Potential Treatments (2020)

Currently, humans are immersed in a pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which threatens public health worldwide. To date, no drug or vaccine has been approved to treat the severe disease caused by this coronavirus, COVID-19. In this paper, we will focus on the main virus-based and host-based targets that can guide efforts in medicinal chemistry to discover new drugs for this devastating disease. In principle, all CoV enzymes and proteins involved in viral replication and the control of host cellular machineries are potentially druggable targets in the search for therapeutic options for SARS-CoV-2. This Perspective provides an overview of the main targets from a structural point of view, together with reported therapeutic compounds with activity against SARS-CoV-2 and/or other CoVs. Also, the role of innate immune response to coronavirus infection and the related therapeutic options will be presented.
Effect of Dehydroepiandrosterone on Bone Mass, Serum Lipids, and Dimethylbenz(a)anthracene-Induced Mammary Carcinoma in the Rat* (1997)

The present study investigated the effect of dehydroepiandrosterone (DHEA) on bone mass and serum lipids in the rat with dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma. The animals received DHEA once daily, percutaneously, at the dose of 5, 10, or 20 mg for 9 months following a single dose of 20 mg DMBA at 50-52 days of age. Bone mineral content (BMC) and bone mineral density (BMD) of total skeleton, lumbar spine, and femur were measured by dual energy x-ray absorptiometry. A 9-month treatment with DHEA increased BMC and BMD of total skeleton by 14.2% to 14.5% (all P < 0.01) and 6.7% to 8.3% (all P < 0.01), respectively. Similarly, femoral BMC and BMD were stimulated by 13.6% to 14.7% (all P < 0.05) and by 8.1% to 9.5% (all P < 0.01), respectively. In addition, BMD of lumbar spine was increased by 10.4% to 10.8% (all P < 0.05), whereas the 9.4% to 11.1% increment in BMC of lumbar spine was not statistically significant. Treatment with DHEA led to 26% (NS), 60% (P < 0.01), and 62% (P < 0.01) decreases in serum triglyceride levels at the same doses. On the other hand, no significant change in serum cholesterol concentrations was observed. Two hundred and seventy-nine days after DMBA administration, the incidence of mammary carcinoma had decreased from 95% in control animals to 73% (P < 0.05), 57% (P < 0.01), and 38% (P < 0.01) at the daily percutaneous doses of 5, 10, and 20 mg of DHEA, respectively. Moreover, the mean tumor number per tumor-bearing animal and the mean tumor area per tumor-bearing animal were also reduced by the same treatments. DHEA increased serum total alkaline phosphatase activity and decreased urinary calcium excretion, but had no effect on the urinary ratio of hydroxyproline to creatinine and urinary phosphorus excretion. These data show that DHEA exerts a stimulatory effect on bone mass and an inhibitory effect on serum triglycerides, as well as a preventive effect on the development of mammary carcinoma induced by DMBA in the rat. Such data suggest that while decreasing the risk of breast cancer, DHEA replacement therapy could also exert beneficial effects on the bone and lipid metabolism in women receiving DHEA replacement therapy.
Substrate recognition by class I lysyl-tRNA synthetases: A molecular basis for gene displacement (1999)

Lysyl-tRNA synthetases (LysRSs) are unique amongst the aminoacyl-tRNA synthetases in being composed of unrelated class I and class II enzymes. To allow direct comparison between the two types of LysRS, substrate recognition by class I LysRSs was examined. Genes encoding both an archaeal and a bacterial class I enzyme were able to rescue an Escherichia coli strain deficient in LysRS, indicating their ability to functionally substitute for a class II LysRS in vivo. In vitro characterization showed lysine activation and recognition to be tRNA-dependent, an attribute of several class I, but not class II, aminoacyl-tRNA synthetases. Examination of tRNA recognition showed that class I LysRSs recognize the same elements in tRNALys as their class II counterparts, namely the discriminator base (N73) and the anticodon. This sequence-specific recognition of the same nucleotides in tRNALys by the two unrelated types of enzyme suggests that tRNALys predates at least one of the LysRSs in the evolution of the translational apparatus. The only observed variation in recognition was that the G2.U71 wobble pair of spirochete tRNALys acts as antideterminant for class II LysRS but does not alter class I enzyme recognition. This difference in tRNA recognition strongly favors the use of a class I-type enzyme to aminoacylate particular tRNALys species and provides a molecular basis for the observed displacement of class II by class I LysRSs in certain bacteria.
Alpha-hemolysin contributes to the pathogenicity of piliated digalactoside-binding Escherichia coli in the kidney: efficacy of an alpha-hemolysin vaccine in preventing renal injury in the BALB/c mouse model of pyelonephritis (1991)

Digalactoside-binding (Gal-Gal) pili and alpha-hemolysin of Escherichia coli have been implicated as important virulence determinants in the pathogenesis of human ascending, nonobstructive pyelonephritis. The pathogenic significance of these determinants was evaluated in vitro and in the BALB/c mouse pyelonephritis model by employing wild-type, avirulent laboratory, and genetically defined cosmids, transformants, and recombinant strains. In vitro data suggest that the cytolytic activity of hemolysin is significantly (P less than 0.05) enhanced among digalactoside-binding strains which agglutinate erythrocytes. The basis of increased hemolysis is related presumably to more efficient delivery of the toxin to target lipid substrate in the host plasma membrane. Intravesicular administration of bacteria that express both digalactoside binding and hemolysin generally resulted in greater mortality and renal parenchymal injury in mice than strains that expressed none or only one of these determinants. Analyses convincingly demonstrate that digalactoside-binding pili are correlated with upper urinary tract colonization and that hemolysin is correlated with septicemia and renal parenchymal damage. These determinants collectively constitute the minimal virulence factors to produce disease in this model. Their efficacy as vaccines for the prevention of pyelonephritis was also assessed. A purified Gal-Gal pilus vaccine prevented (P less than 0.05) subsequent colonization by a challenge wild-type strain that exhibited homologous pili. The hemolysin vaccine did not abrogate subsequent bacterial renal colonization on challenge, but it did protect (P less than 0.05) mice which survived challenge from subsequent renal injury compared with those in the saline control group. The combination of these determinants was also protective. The combination of Gal-Gal pili and hemolysin in a vaccine preparation represents a potentially worthwhile strategy for human immunoprophylaxis against pyelonephritis by interdicting several steps in the pathogenesis of a bacterial mucosal infection.
Homologous recombination between a defective virus and a chromosomal sequence in mammalian cells. (1985)

Replacement of the early region of simian virus 40 results in virus that cannot replicate in a normal host, CV-1 cells, but can replicate in COS cells, a derivative of CV-1 cells that constitutively express simian virus 40 tumor antigen (T antigen). However, passage of such an early replacement simian virus 40 mutant in COS cells results in the emergence of virus that can propagate in CV-1 cells. Analysis of this virus revealed that the mutant rescued the integrated T-antigen gene from the COS cell genome. Comparison of the sequence of the recovered virus with that of the viral DNA resident in COS cells (strain 776) and the mutant used in our studies (derived from strain 777) proves that the mutant virus acquired the T-antigen gene from the COS cell chromosome via homologous recombination. Most probably this process was mediated by a direct genetic exchange.
Distal symmetric polyneuropathy: A definition for clinical research (2005)

The objective of this report was to develop a case definition of distal symmetric polyneuropathy to standardize and facilitate clinical research and epidemiologic studies. A formalized consensus process was employed to reach agreement after a systematic review and classification of evidence from the literature. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms; and single abnormalities on examination are less sensitive than multiple abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides the most accurate diagnosis of distal symmetric polyneuropathy. A set of case definitions was rank ordered by likelihood of disease. The highest likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic studies. A modest likelihood of polyneuropathy (useful for field or epidemiologic studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A lower likelihood of polyneuropathy occurs when electrodiagnostic studies and signs are discordant. For research purposes, the best approach to defining distal symmetric polyneuropathy is a set of case definitions rank ordered by estimated likelihood of disease. The inclusion of this formalized case definition in clinical and epidemiologic research studies will ensure greater consistency of case selection.
Sequence analysis of two porcine rotaviruses differing in growth in vitro and in pathogenicity: distinct VP4 sequences and conservation of NS53, VP6 and VP7 genes (1994)

The VP4, VP7, NS53 and VP6 genes of two porcine rotavirus variants which differ in their in vitro growth properties and pathogenicity have been cloned and sequenced. The VP4 genes show only 67.2% nucleic acid and 70.6% amino acid identity. The VP4 gene of one variant (4S) is closely related to that of the bovine UK rotavirus strain, whereas the VP4 gene of the other variant (4F) is only distantly related to known VP4 genes and is likely to represent a new P serotype. In contrast the NS53 (VP5), VP6 and VP7 genes of the 4F and 4S variants show greater than 99% nucleotide and amino acid identity, indicating that the two viruses are genetically related by a reassortment event. The implications for the role of VP4 in the determination of in vitro growth characteristics and pathogenicity are discussed.
Spectral-domain optical coherence tomography: Removal of autocorrelation using an optical switch (2006)

A novel spectral-domain optical coherence tomography (SD-OCT), in which the self-interferogram of the object wave and the standard SD-OCT interferogram are acquired asynchronously using an optical switch in the reference arm, is presented. After Fourier transformation, the autocorrelation of the object is removed simply by subtraction from the standard SD-OCT image. The measured sensitivity is 103.5dB at z=0.115mm, and it gradually reduces to 84.1dB at z=3.275mm. The axial resolution is 15μm in the air. In vivo images of human skin are presented to demonstrate the performance of autocorrelation removal.
A phase II study of docetaxel in patients with metastatic squamous cell carcinoma of the head and neck (1999)

This study was designed to evaluate the activity, safety and tolerance of docetaxel (D) in a selected population with metastatic squamous cell carcinoma of the head and neck (SCCHN). Twenty-four patients with no prior palliative therapy were enrolled and received D 100 mg m(-2) by 1 h of infusion, every 3 weeks. All but two patients had been evaluated for efficacy on lung metastatic sites. No prophylactic administration of anti-emetics or growth factors was given. A pharmacokinetic study was performed in 22 patients. Twenty-one patients were assessable for response and 24 for toxicity. One hundred and four cycles were administered with a median of 4.5 (range 1-9) per patient. The median cumulative dose was 449 mg m(-2). Partial responses were achieved in five patients with a median duration of 18.7 weeks (range 13.1-50.3). The overall response rate was 20.8% with a median duration of 11.0 weeks (range 2.4-52.6). The most frequent side-effect was neutropenia (79.2% grade IV) but with a short duration (median 4 days) and no febrile neutropenia. The incidence of moderate/severe fluid retention was 29.2% with one treatment discontinuation. Other toxicities (all grades) were common (skin 75%, asthenia 50%, infection 29.2%, nausea 16.7%, diarrhoea 12.5%, stomatitis 16.7%, vomiting 8.3% and HSR 8.3%). A mean clearance of 19.6 l h(-1) m(-2) and an area under the curve of 6.00 microg ml(-1) h(-1) was found in the pharmacokinetic analysis. Docetaxel is active in this selected population with metastatic SCCHN, with a good tolerance.
Content-based classification, search, and retrieval of audio (1996)

Many audio and multimedia applications would benefit from the ability to classify and search for audio based on its characteristics. The audio analysis, search, and classification engine described here reduces sounds to perceptual and acoustical features. This lets users search or retrieve sounds by any one feature or a combination of them, by specifying previously learned classes based on these features, or by selecting or entering reference sounds and asking the engine to retrieve similar or dissimilar sounds.
Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease (2019)

As biologic, epidemiologic, and clinical trial data have demonstrated, inflammation is a key driver of atherosclerosis. Circulating biomarkers of inflammation, including high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), are associated with increased risk of cardiovascular events independent of cholesterol and other traditional risk factors. Randomized trials have shown that statins reduce hsCRP, and the magnitude of hsCRP reduction is proportional to the reduction in cardiovascular risk. Additionally, these trials have demonstrated that many individuals remain at increased risk due to persistent elevations in hsCRP despite significant reductions in low-density lipoprotein cholesterol (LDL-C) levels. This "residual inflammatory risk" has increasingly become a viable pharmacologic target. In this review, we summarize the data linking inflammation to atherosclerosis with a particular focus on residual inflammatory risk. Additionally, we detail the results of Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), which showed that directly reducing inflammation with an IL-1β antagonist reduces cardiovascular event rates independent of LDL-C. These positive data are contrasted with neutral evidence from CIRT in which low-dose methotrexate neither reduced the critical IL-1β to IL-6 to CRP pathway of innate immunity, nor reduced cardiovascular event rates.
A rat model of post-traumatic stress disorder reproduces the hippocampal deficits seen in the human syndrome (2012)

Despite recent progress, the causes and pathophysiology of post-traumatic stress disorder (PTSD) remain poorly understood, partly because of ethical limitations inherent to human studies. One approach to circumvent this obstacle is to study PTSD in a valid animal model of the human syndrome. In one such model, extreme and long-lasting behavioral manifestations of anxiety develop in a subset of Lewis rats after exposure to an intense predatory threat that mimics the type of life-and-death situation known to precipitate PTSD in humans. This study aimed to assess whether the hippocampus-associated deficits observed in the human syndrome are reproduced in this rodent model. Prior to predatory threat, different groups of rats were each tested on one of three object recognition memory tasks that varied in the types of contextual clues (i.e., that require the hippocampus or not) the rats could use to identify novel items. After task completion, the rats were subjected to predatory threat and, one week later, tested on the elevated plus maze (EPM). Based on their exploratory behavior in the plus maze, rats were then classified as resilient or PTSD-like and their performance on the pre-threat object recognition tasks compared. The performance of PTSD-like rats was inferior to that of resilient rats but only when subjects relied on an allocentric frame of reference to identify novel items, a process thought to be critically dependent on the hippocampus. Therefore, these results suggest that even prior to trauma PTSD-like rats show a deficit in hippocampal-dependent functions, as reported in twin studies of human PTSD.
Thermal Conductivity of Wilcox and Frio Sandstones in South Texas (Gulf of Mexico Basin) (1996)

Thermal conductivity and petrographic data are presented for verifying mechanistic models of sandstone thermal conductivity. We measured the thermal conductivity of 83 Wilcox and Frio sandstones from south Texas in the Gulf of Mexico sedimentary basin, and correlated conductivity to petrographic variables. Thermal conductivities of water-saturated sandstones at 20°C (68°F) and 3 MPa (435 psi) were measured on core plugs using a divided-bar apparatus. Thermal conductivity ranges from 2.06 to 5.73 W/m/K over a porosity range of 2.4 to 29.6%. Because of a higher quartz content, Wilcox sandstones at a given porosity are more conductive than Frio sandstones. A grain-matrix conductivity of 5.9 W/m/K is estimated for Wilcox sandstones; matrix conductivity is adequately described with an arithmetic mixing model. Thermal conductivities of clean ( 35% of the solids) sandstones, the dependence on quartz content can be dropped and thermal conductivities can be predicted with a linear decrease in conductivity with increasing porosity. These sandstones appear isotropic with respect to thermal conductivity.
Detecting putative orthologs (2003)

We developed an algorithm that improves upon the common procedure of taking reciprocal best blast hits(rbh) in the identification of orthologs. The method-reciprocal smallest distance algorithm (rsd)-relies on global sequence alignment and maximum likelihood estimation of evolutionary distances to detect orthologs between two genomes. rsd finds many putative orthologs missed by rbh because it is less likely than rbh to be misled by the presence of a close paralog.
Antigen Trafficking and Accessory Cell Function in Respiratory Epithelial Cells (1999)

We investigated accessory cell function, antigen (Ag) trafficking, and uptake of immune complexes in isolated nasal epithelial cells (NEC) and airway epithelial cells (AEC), as well as in the two respiratory epithelial cell lines A549 and BEAS-2B. The NEC and AEC were capable of supporting Ag-specific as well as phytohemagglutinin-induced and anti-CD3 antibody-induced T-cell proliferation. We colocalized fluorescein isothiocyanate (FITC)-labeled Ags with human leukocyte antigen (HLA)-DR in A549 and BEAS-2B, utilizing laser confocal microscopy. Respiratory epithelial cells stimulated and unstimulated with interferon (IFN)-gamma were pulsed with FITC-labeled Ags for varying periods and evaluated for their ability to internalize Ag. In the unstimulated cells, intracellular punctate staining was evident at 60 min and persisted up to 120 min. In the IFN-gamma-stimulated cells (100 U/ml for 48 h), uptake occurred at 30 min, was maximal at 60 min, and diminished at 120 min. We conducted kinetic studies in the A549 and BEAS-2B cells, utilizing electron microscopy with colloidal gold-conjugated Ags (Au-OVA). At 15 min, Au-OVA was evident in the early compartments resembling the compartment of uncoupling of receptor and ligand. At 30 min, multivesicular bodies were labeled with Au-OVA, and by 60 min Au-OVA was present in the primary and secondary lysosomes. The FITC-labeled Ags colocalized with an early endosomal marker (anti-cathepsin D), a late endosomal marker (M6PR), a lysosomal marker (CD63), and with 3-(2, 4-dinitroanilino)-3'-aminomethyldipropylamine, a marker of acidic vesicles. The BEAS-2B and A549 cells, and NEC and AEC, expressed surface Fcgamma receptor and internalized IgG immune complexes. The NEC and AEC also expressed the costimulatory molecules CD80 and CD86 as determined with flow cytometry, the reverse transcription-polymerase chain reaction for RNA, and immunohistochemistry, and T-cell proliferation could be blocked by treating NEC and AEC with anti-CD80 and anti-CD86 antibodies. Our findings suggest that respiratory epithelial cells may have a role in local Ag presentation.
Modulation of synaptic transmission in the rat ventral septal area by the pharmacological activation of metabotropic glutamate receptors (2000)

The ventral septal area (VSA) is considered to be critically involved in the control of the height and duration of fever. The major excitatory input to this region of the brain is glutamatergic, and the aim of this study was to investigate possible modulation of this synapse by metabotropic glutamate (mGlu) receptors. Whole-cell patch recordings were made from individual VSA neurons voltage-clamped at -60 mV. Activation of either group I or group II mGlu receptors (by bath application of 3,5-dihydroxyphenylglycine (DHPG) or (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), respectively) produced a long-lasting depression of synaptic transmission which in both cases was insensitive to the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5). In contrast, application of (S)-2-amino-4-phosphonobutyric acid (L-AP4), a group III mGlu receptor agonist, had a biphasic effect on synaptic transmission in the VSA, first eliciting a transient depression of transmission during drug application, followed by a marked and sustained potentiation of synaptic transmission upon drug washout. The response elicited by L-AP4 was dependent on NMDA receptor activation, as in the presence of D-AP5 the potentiation was replaced by an underlying long-term depression (LTD) of transmission. These data provide the first evidence that metabotropic glutamate receptor agonists can induce both NMDA receptor-dependent and -independent modulation of synaptic transmission in the VSA.
A high pressure-resistance micropump using active and normally-closed valves (2002)

A novel micropump that has two active and normally-closed valves was developed using micromachine technology. This micropump can pump in forward and backward direction, and hold the fluid without consuming energy even when the fluid source has some pressure. This normally-closed valve is manufactured in the way of filling up silicone rubber paste after bonding glass substrate and silicon substrate. This silicone rubber works as a "gate" for shutting off the flow. Therefore, high pressure-resistance micropump is realized with no influence of fabrication error. In this paper, basic characteristics of this micropump about flow rate, outlet pressure and pressure-resistance are described.