gebhart/patrepeval huggingface dataset:
Chronic inflammation in Alzheimer’s disease offers therapeutic opportunities (2001)

Postmortem studies have revealed a state of chronic inflammation in affected regions of the brain in Alzheimer's disease (AD). Chronic inflammation can be damaging to host cells and the brain may be particularly vulnerable as neurons are not replaced. Evidence suggests that the inflammation is killing neurons in AD brain, so anti-inflammatory agents might slow the process of the disease. More than 20 epidemiological studies have shown that persons taking nonsteroidal anti-inflammatory drugs (NSAIDs) have a greatly reduced incidence of AD. In one clinical trial, indomethacin appeared to halt the progression of memory loss in AD patients. NSAIDs inhibit synthesis of prostaglandins, which are fringe players in the inflammatory process. Agents that would block the more important actors, such as the complement system, activated microglia and inflammatory cytokines, might have important therapeutic benefits in AD as well as in other conditions, such as heart disease and stroke, where inflammation also plays a deleterious role.
Supplementary Figure 2 from Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in <i>EGFR</i>-Mutant Lung Cancer (2023)

&lt;p&gt;Supplementary Figure S2. Comparison of WZ4002 + crizotinib and WZ4002 + trametinib combinations in TKI resistant cell lines. HCC827 GR6 and HCC827 + HGF were treated with DMSO control (Media), 100 nM WZ4002, 30 nM trametinib, 100 nM crizotinib or WZ4002 combinations weekly. Positive wells were tallied weekly (mean +/- SD, n = 3 biological replicates of 60 wells each). Arrow indicates that confluence was not reached at 9 weeks.&lt;/p&gt;
Functionalized spirolactones by photoinduced dearomatization of biaryl compounds (2019)

The idea of using biaryl structures to generate synthetic building blocks such as spirolactones is attractive because biaryl structures are abundant in biomass waste streams. However, the inertness of aromatic rings of biaryls makes it challenging to transform them into functionalized structures. In this work, we developed photoinduced dearomatization of nonphenolic biaryl compounds to generate spirolactones. We demonstrate that dearomatization can be performed <i>via</i> either aerobic photocatalysis or anaerobic photooxidation to tolerate specific synthetic conditions. In both pathways, dearomatization is induced by electrophilic attack of the carboxyl radical. The resulting spirodiene radical is captured by either oxygen or water in aerobic and anaerobic systems, respectively, to generate the spirodienone. These methods represent novel routes to synthesize spirolactones from the biaryl motif.
The Discovery of Macrocyclic XIAP Antagonists from a DNA-Programmed Chemistry Library, and Their Optimization To Give Lead Compounds with in Vivo Antitumor Activity (2015)

Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.
CHAPTER 8. Novel Therapeutic Agents from Bacterial Toxins (2013)

Bacterial protein toxins are causative agents of multiple healthcare issues and yet are also components of strategies leading the therapeutic fight against a range of debilitating conditions. Chapter 8 provides an insight into the biology of key exemplar toxic proteins and describes how understanding the structure of such proteins can lead to the design of new therapeutics with novel mechanisms of action. Focusing the discussion on examples of cytotoxic proteins (in particular diphtheria toxin and pseudomonas exotoxin A) and non-cytotoxins (in particular botulinum neurotoxin), the possibility for using recombinant DNA techniques to create families of novel proteins is described. After approximately 30 years of investigation into the applications of bacterial toxins to treat human disease, there is clinical evidence of the success of this strategy and a number of additional examples are moving through pre-clinical and clinical investigation. Indeed, in a number of cases, bacterial toxins, or novel agents derived from fragments of bacterial toxins, are first line therapy options.
Towards optical quality yttrium aluminum garnet (YAG) fibers: recent efforts at AFRL/RX (2010)

Traditional silica fibers currently are unlikely to be able to sustain the powers needed for future Air Force applications. The low thermal conductivity of silica makes it difficult to control thermal gradients within the fibers resulting in failure or degradation in beam quality. While some of these problems can be ameliorated by using longer fibers, this results in problems with nonlinear effects such as stimulated Raman and Brillouin scattering (SRS and SBS). Yttrium aluminum garnet (Y3Al5O12, YAG) has the potential for overcoming these problems due to 1) higher thermal conductivity, 2) reduced thermal lensing, and 3) higher SBS threshold. Polycrystalline YAG has been demonstrated to be a highly efficient and economical laser host material in slab form. Polycrystalline YAG can be doped more uniformly and at higher levels than single-crystals with no dopant loss by zone refinement, has higher fracture toughness than single-crystals, and supports higher power densities. Despite the anticipated advantages, polycrystalline YAG has never been demonstrated in high-power fiber lasers. The development and characterization of YAG fibers for high energy laser applications is the primary goal of our research. Recent results in the processing of optical quality polycrystalline YAG fibers will be presented and discussed.
Supplementary Table 1 from IGFBP2/FAK Pathway Is Causally Associated with Dasatinib Resistance in Non–Small Cell Lung Cancer Cells (2023)

&lt;p&gt;PDF - 35KB, Combination Index for dasatinib and FAK inhibitor PF562271.&lt;/p&gt;
Long-Term Lead Performance for Vagus Nerve Stimulation: Low Rate of Complications and Failures (2020)

Background: Vagus nerve stimulation (VNS) has been shown to improve cardiac function and heart failure symptoms. The VITARIA System provides chronic stimulation through a self-sizing, atraumatic lead placed around the cervical vagus nerve. The lead is identical to the predecessor M304 lead, which has been implanted in patients since 2009 for treatment of epilepsy and depression. Its long-term performance has not been previously reported. Methods: All leads implanted in the United States for any indication were included in this analysis. All available data on lead explants, replacements, and customer complaints were used to identify failures. Lead survival was defined as likelihood of the implanted lead remaining implanted and performing as intended. Results: The M304 lead has been part of 31,000 implantations, with 72,100 device-years of patient exposure. In 11,000 patients, 99.4% of leads remained implanted and performing as intended after 1 year. At 7 years, 95.7% of leads performed as intended. Lead failure is rare, with common causes being infection (0.87%) and vocal cord dysfunction (0.68%). Conclusions: The M304 VNS lead has been used for neuromodulation in over 30,000 patients for over 70,000 device-years. Cumulative lead survival has exceeded design requirements and has low rates of complications and failures.
Applications of seismic interferometry to seismic field data (2007)

In seismic interferometry one extracts the Green’s function of a system from fluctuations in the system. This makes it possible to retrieve the waves that propagate between receivers, as if one of the receivers acts as a source. Examples are presented of this principle to field data. One can show that in seismic interferometry one can retrieve the Green’s function that has different boundary conditions than the physical system has. It is shown how this can be used to unravel the building response from its coupling to the subsurface, and how this principle can be exploited to suppress surface-related multiples in marine seismics. As another example, we present the propagation of P-wave and S-waves down a vertical borehole extracted from incoherent man-made noise, and how shear-wave splitting can be extracted from these measurements. Finally we show how drill-bit noise can be used for imaging when the vibrations in the drill stem have not been recorded.
Preparation of Tremorine and Gemini Surfactant Precursors with Cationic Ethynyl‐Bridged Digold Catalysts (2016)

Tremorine and precursors of gemini surfactants were synthesised in a one-pot, three-step, double-catalytic A<sup>3</sup> coupling reaction and characterised by structural and spectroscopic methods. The cationic [Au<sup>I</sup> (L1)]SbF<sub>6</sub> complex is a more active catalyst compared to neutral L2- and L3-Au<sup>I</sup> bis(trifluoromethanesulfonyl)imidate complexes (L1, L2=Buchwald-type biaryl phosphane; L3=triphenylphosphine) in promoting the double A<sup>3</sup> coupling of ethynyltrimethylsilane, secondary amines (cyclic, aliphatic, or aromatic) and formaldehyde. The solvent influences the catalytic performance by desilylation of silyl acetylene or deactivation of the catalyst by a halide anion. Acetylide-bridged cationic digold(I) L1 and L2 complexes were isolated and characterised by means of single-crystal X-ray structure analysis and their spectroscopic properties. Iodine in the acetylene reagent deactivates the Au<sup>I</sup> catalyst by formation of the less active iodido-bridged cationic digold(I) L1 complex, which was fully characterised by single-crystal X-ray crystal structure analysis and spectroscopy. The nature of the phosphine ligand of the gold complexes used as catalyst affects the stability and activity of the formed cationic ethynyl-bridged Au<sup>I</sup><sub>2</sub> -L intermediates, isolation of which lends support to the proposed double A<sup>3</sup> coupling mechanism.
Additional analog computer simulation of transfer functions (1975)

Two single operational amplifier analog computer simulations of a class of voltage transfer functions having negative real poles are derived using Rathore's decomposition. The procedure reported is such that the functions with distinct negative real poles can be realized with either polarity, while the remaining functions of the class considered can be realized with one particular polarity only.
Synthesis of Heterocyclic Analogues of Tamoxifen asPotential Antiestrogens (1997)

The synthesis of(E/Z )-1-aryl-2-phenyl-1-(2-thienyl/selenophen-2-yl)but-1-enes, derived from2-phenyl-1-(2-thienyl/selenophen-2-yl)butan-1-ones, is described;the key steps in the synthesis involve the reaction of thebutan-1-ones with 4-(2-morpholinoethoxy)phenyl bromide, followedby dehydration of the resulting carbinols to give the targetcompounds which are separated by fractionalrecrystallisation.
A Novel Approach of Daunorubicin Application on Formation of Proliferative Retinopathy Using a Porous Silicon Controlled Delivery System: Pharmacodynamics (2015)

Daunorubicin-loaded pSi particles can safely reside in the vitreous for at least 3 months. The pSi-based delivery expanded the therapeutic window of DNR by a factor of 862 and drove down the minimum effective concentration by a factor of 175.
Inhibitors of Glycine Transporter-1: Potential Therapeutics for the Treatment of CNS Disorders (2016)

Glycine acts as an inhibitory neurotransmitter at glycine receptor (GlyR)-enriched synapses and as an obligatory co-agonist at the N-methyl-D-aspartate (NMDA) receptor, where it facilitates neuronal excitation. Two high-affinity and substrate selective transporters, glycine transporter-1 and glycine transporter-2 (GlyT-1 and GlyT-2), regulate extracellular glycine concentrations within the CNS and as such, play critical roles in maintaining a balance between inhibitory and excitatory neurotransmission. GlyT-1 inhibition has been extensively examined as a potential means by which to treat several CNS disorders that include schizophrenia, depression, anxiety, obsessive compulsive disorder (OCD), and addiction. More recently, preclinical studies have emerged that indicate the approach may also promote neuroprotection, provide a pharmacotherapeutic strategy for autism spectrum disorders (ASDs), and treat symptomology associated with pain, Parkinson's disease, and epilepsy. This review examines the pharmacological aspects of GlyT-1 inhibition and describes drug discovery and development efforts toward the identification of novel inhibitors.
Rano otkrivanje raka u Hrvatskoj (2010)

Introduction: A well organized and conducted program of cancer screening at the population level should be scientifically based, cost-effective at long term, and designed on the good practice examples.Appropriate diagnosis and treatment should be warranted by high rate of target population inclusion, while appropriate diagnosis and treatment should be warranted for those with positive findings.Aim: The aim is to present implementation of the national programs of early detection of breast and colon cancer in Croatia.Results: In the first cycle screening for breast cancer (since the end of 2006), a total of 720,981 women were invited for mammography, of which 58.5% presented for screening, with more than 1500 cases of breast cancer detected.A total of 808,913 tests were distributed for colon cancer screening from the end of 2007 to the beginning of 2010, of which only 19.9% were returned, 7.7% of these positive.Colonoscopy yielded 77.5% of pathologic findings, including 388 (5.99%) carcinomas, 2492 (38.46%) polyps, 1641 hemorrhoids and 998 diverticula. Conclusion:In Croatia, the public health service has made maximal use of all its resources in the national programs of early cancer detection.Great efforts and time, along with continuous education of all those involved in the program, have been invested in preparatory activities, organization and coordination of the program, contacts and collaboration with family physicians, specialist units, mass media, regional and local authorities, partnership with non-governmental societies, monitoring, evaluation and quality control.
Structural insights into the human niacin receptor HCA2-Gi signalling complex (2023)

The hydroxycarboxylic acid receptor 2 (HCA2) agonist niacin has been used as treatment for dyslipidemia for several decades albeit with skin flushing as a common side-effect in treated individuals. Extensive efforts have been made to identify HCA2 targeting lipid lowering agents with fewer adverse effects, despite little being known about the molecular basis of HCA2 mediated signalling. Here, we report the cryo-electron microscopy structure of the HCA2-G<sub>i</sub> signalling complex with the potent agonist MK-6892, along with crystal structures of HCA2 in inactive state. These structures, together with comprehensive pharmacological analysis, reveal the ligand binding mode and activation and signalling mechanisms of HCA2. This study elucidates the structural determinants essential for HCA2 mediated signalling and provides insights into ligand discovery for HCA2 and related receptors.
Arsenic Exposure, Diabetes Prevalence, and Diabetes Control in the Strong Heart Study (2012)

This study evaluated the association of arsenic exposure, as measured in urine, with diabetes prevalence, glycated hemoglobin, and insulin resistance in American Indian adults from Arizona, Oklahoma, and North and South Dakota (1989-1991). We studied 3,925 men and women 45-74 years of age with available urine arsenic measures. Diabetes was defined as a fasting glucose level of 126 mg/dL or higher, a 2-hour glucose level of 200 mg/dL or higher, a hemoglobin A1c (HbA1c) of 6.5% or higher, or diabetes treatment. Median urine arsenic concentration was 14.1 µg/L (interquartile range, 7.9-24.2). Diabetes prevalence was 49.4%. After adjustment for sociodemographic factors, diabetes risk factors, and urine creatinine, the prevalence ratio of diabetes comparing the 75th versus 25th percentiles of total arsenic concentrations was 1.14 (95% confidence interval: 1.08, 1.21). The association between arsenic and diabetes was restricted to participants with poor diabetes control (HbA1c ≥8%). Arsenic was positively associated with HbA1c levels in participants with diabetes. Arsenic was not associated with HbA1c or with insulin resistance (assessed by homeostatic model assessment to quantify insulin resistance) in participants without diabetes. Urine arsenic was associated with diabetes control in a population from rural communities in the United States with a high burden of diabetes. Prospective studies that evaluate the direction of the relation between poor diabetes control and arsenic exposure are needed.
Quantitative Comparison of Trace Organonitrate Explosives Detection by GC-MS and GC-ECD2 Methods with Emphasis on Sensitivity (2011)

Quantitative analysis of organonitrate explosive standards was performed by gas chromatography (GC) with dual electron capture detection (ECD2) and electron-impact ionization quadrupole mass spectrometry (EI-MS) in selected ion monitoring (SIM) detection mode. A comparison of method conditions and performance parameters, including minimum detectable limit (MDL) by compound, is presented in this technical note. The GC-ECD2 method shows an improved 30–250X sensitivity to dinitroaromatics, trinitroaromatics and RDX, in clean noise-limited backgrounds, and the GC-MS method reveals a sensitivity increase of 2–1 0X to high volatility mononitroaromatics, the ability to detect target analytes in complex matrices, and identify unknown compounds by mass-to-charge determination.
The GABA system, a new target for medications against cognitive impairment—Associated with neuroactive steroids (2023)

The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA-A receptor modulating stress and sex steroids (steroid-PAMs) such as allopregnanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA-A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hepatic encephalopathy. Here we describe disorders affected by steroid-PAMs and opportunities to treat these adverse effects of steroid-PAMs with novel GAMSAs.
Introduction to Chemokines (2003)

The chemokine superfamily consists of a group of small (approximately 8-to 12-kDa) peptides that are characterized by the presence of four conserved cysteines in their primary amino acid sequence (1). Chemokines have been divided into two main subfamilies based on the arrangement of two N-terminal cysteine residues, CXC and CC, depending on whether the ﬁrst two cysteine residues are separated by a single amino acid (CXC) or are adjacent (CC). Two other classes of chemokines have more recently been described: lymphotactin (C) and fractalkine (CX3C). Lymphotactin (also referred to as XCL1) lacks cysteines 1 and 3 of the typical chemokine structure, whereas fractalkine contains three amino acids between the ﬁrst two cytsteines and is also the only membrane-bound chemokine by means of a mucin-like stalk. The predominant function of chemokines is to induce the migration and activation of leukocytes, including neutrophils, monocytes, lymphocytes, eosinophils, and dendritic cells. These chemoattractant molecules exert their biological effect by forming gradients around the producing cells. The responding cells expressing appropriate chemokine receptors are then able to migrate under the inﬂuence of an established chemokine gradient (2). Hence,2 Zlotnik Tabl e 1CX C,C, CX3C ,an dCC Chem okin e/R ecep to rFam iliesSy stem at icn ame H uman chro m osom eH uman ligan dM ouse ligan dCh emok in e re cept orCX Cch emok in e/re cept orfa m ilyCX CL1 4q21 .1
Self-Supervised Learning from Automatically Separated Sound Scenes (2021)

Real-world sound scenes consist of time-varying collections of sound sources, each generating characteristic sound events that are mixed together in audio recordings. The association of these constituent sound events with their mixture and each other is semantically constrained: the sound scene contains the union of source classes and not all classes naturally co-occur. With this motivation, this paper explores the use of unsupervised automatic sound separation to decompose unlabeled sound scenes into multiple semantically-linked views for use in self-supervised contrastive learning. We find that learning to associate input mixtures with their automatically separated outputs yields stronger representations than past approaches that use the mixtures alone. Further, we discover that optimal source separation is not required for successful contrastive learning by demonstrating that a range of separation system convergence states all lead to useful and often complementary example transformations. Our best system incorporates these unsupervised separation models into a single augmentation front-end and jointly optimizes similarity maximization and coincidence prediction objectives across the views. The result is an unsupervised audio representation that rivals state-of-the-art alternatives on the established shallow AudioSet classification benchmark.
Structural Basis for Inactivating Mutations and pH-dependent Activity of Avian Sarcoma Virus Integrase (1998)

Crystallographic studies of the catalytic core domain of avian sarcoma virus integrase (ASV IN) have provided the most detailed picture so far of the active site of this enzyme, which belongs to an important class of targets for designing drugs against AIDS. Recently, crystals of an inactive D64N mutant were obtained under conditions identical to those used for the native enzyme. Data were collected at different pH values and in the presence of divalent cations. Data were also collected at low pH for the crystals of the native ASV IN core domain. In the structures of native ASV IN at pH 6.0 and below, as well as in all structures of the D64N mutants, the side chain of the active site residue Asx-64 (Asx denotes Asn or Asp) is rotated by approximately 150 degrees around the Calpha---Cbeta bond, compared with the structures at higher pH. In the new structures, this residue makes hydrogen bonds with the amide group of Asn-160, and thus, the usual metal-binding site, consisting of Asp-64, Asp-121, and Glu-157, is disrupted. Surprisingly, however, a single Zn2+ can still bind to Asp-121 in the mutant, without restoration of the activity of the enzyme. These structures have elucidated an unexpected mechanism of inactivation of the enzyme by lowering the pH or by mutation, in which a protonated side chain of Asx-64 changes its orientation and interaction partner.