gebhart/patrepeval huggingface dataset:
Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma (2001)

Genetic alteration is considered a probable cause of malignant lymphoma. Folate and methionine metabolism play essential roles in DNA synthesis and DNA methylation, and their metabolic pathways might thus affect disease susceptibility. In the present study, 2 polymorphisms were evaluated for a folate metabolic enzyme, methylenetetrahydrofolate reductase (MTHFR), and one was evaluated for methionine synthase (MS). The 2 polymorphisms, MTHFR677 C-->T and MTHFR1298 A-->C, are reported to reduce the enzyme activity, which causes intracellular accumulation of 5,10-methylenetetrahydrofolate and results in a reduced incidence of DNA double-strand breakage. The MS2756 A-->G polymorphism also reduces the enzyme activity and results in the hypomethylation of DNA. To evaluate the association between malignant lymphoma susceptibility and these polymorphisms, hospital-based case-control study was conducted in Aichi Cancer Center. Ninety-eight patients with histologically confirmed lymphoma and 243 control subjects without cancer were evaluated. Unconditional logistic regression analyses revealed a higher susceptibility with the MTHFR677 CC and the MTHFR1298 AA genotypes (odds ratio, 2.26; 95% confidence interval, 1.26-4.02) when those harboring at least one variant allele in either polymorphism of MTHFR were defined as the reference. For the MS polymorphism, the MS2756 GG genotype also showed a higher susceptibility (odds ratio, 3.83; 95% CI, 1.21-12.1) than those with MS2756 AA or AG types. The significance was not altered when these 3 polymorphisms were evaluated in combination, and the results suggest that folate and methionine metabolism play important roles in the occurrence of malignant lymphomas. Further studies to confirm the association and detailed biologic mechanisms are now required.
[3H]U69,593 binding in guinea-pig brain: comparison with [3H]ethylketazocine binding at the κ-opioid sites (1988)

[3H]U69,593 and [3H]ethylketazocine (mu + delta suppressed) binding was measured in homogenates of guinea-pig brain. Both ligands bind with high affinity to a single class of opioid sites. The relative equilibrium dissociation constant (KD) for [3H]U69,593 is 1.15 nM, while [3H]ethylketazocine has a KD value of 0.33 nM. Their respective maximum binding capacities are 4.49 and 4.48 pmol/g of wet tissue. Various mu-selective, delta-selective, kappa-selective, and nonselective opioids were tested in competition studies against the binding of [3H]U69,593 or [3H]ethylketazocine (in the presence of mu- and delta-blockers) to measure their relative affinity. [D-Ala2, MePhe4,Gly5-ol]enkephalin (mu-selective) has low affinity (600-3000 nM) and [D-Pen2,D-Pen5]enkephalin and [D-Ser2, Leu5, Thr6]enkephalin (delta-selective) have very low affinities (greater than 20,000 nM) at the sites labelled with [3H]U69,593 or [3H]ethylketazocine. On the other hand, unlabelled U69,593, U50,488H, and tifluadom (all three kappa-selective substances) display high affinity (1-5 nM) at those sites. Nonselective opioids, such as bremazocine, levorphanol, and ethylketazocine show similar affinities at the sites labelled with [3H]U69,593 and at the sites labelled with [3H]ethylketazocine. These data indicate that [3H]U69,593 is a selective high-affinity ligand for the same sites that are labelled with [3H]ethylketazocine (in the presence of mu- and delta-blockers) and that these are kappa-sites.
New vitamin D3 derivatives with unexpected antiproliferative activity: 1-(hydroxymethyl)-25-hydroxyvitamin D3 homologs (1992)

Surprisingly, both of the synthetic 1-(hydroxymethyl)-25-hydroxyvitamin D3 diastereomers (-)-2 and (+)-3 retained the antiproliferative activity of natural calcitriol in murine keratinocytes. Preliminary studies indicated, however, that both of these synthetic diastereomers were less than 0.1% as effective as calcitriol for binding to the 1,25-(OH)2-D3 receptor and that they were less than 0.1% as potent as calcitriol for calbindin-D28K induction in organ-cultured embryonic chick duodenum. 1-(Hydroxymethyl)-25-hydroxyvitamin D3 homologs (-)-2 and (+)-3 were synthesized in a convergent manner by combining enantiomerically pure C,D-ring ketone 12 with highly enantiomerically enriched A-ring phosphine oxides (-)-11a and (+)-11b. These A-ring chirons were prepared starting from thermal [2 + 4] cycloaddition of 3-bromo-2-pyrone and acrolein.
Temperature dependence of the photostimulated luminescence of X-irradiate BaFBr:Eu2+ (1990)

The temperature dependence of the luminescence from Eu 2+ activators in BaFBr:Eu2+ photostimulated between 10 and 300 K in the optical absorptions of F centres produced by room temperature X-irradiation, revealed two thermally-activated processes. The photostimulated luminescence (PSL) increases sharply in intensity when excited between 60 and 100 K. After the low-temperature PSL is exhausted by continuous F centre excitation, it can be almost entirely regained by warming the crystal to 300 K. This thermal cycle can be repeated several times. It is shown by EPR that no Eu3+ is formed upon X-irradiation at 300 K. These results are explained with a model for the PSL mechanism which involves a loose aggregate of Eu2+, F, and hole centres.
Hypophosphatasia: Enzyme Replacement Therapy (Asfotase Alfa) Decreases TNSALP Substrate Accumulation And Improves Functional Outcomes In Affected Adolescents And Adults. (2012)

1Shriners Hospital for Children, St. Louis, MO USA; 2Duke University, Durham, NC; 3University of Manitoba, Winnipeg, Manitoba, Canada; 4Shriners Hospital, St. Louis, MO; 5University of Manitoba, Winnipeg, Manitoba, Canada; 6Alexion Pharmaceuticals, Cambridge, MA; 7Corresponding Author: Nerissa Kreher, MD, Alexion Pharmaceuticals, 55 Cambridge Parkway, Ste 800, Cambridge,MA 02142 USA, 617-674-5739; email:Nerissa.Kreher@alxn.com Whyte MP1, Kishnani PS2, Greenberg CR3, Madson K4, Mack K4, Weber T2, Mhanni A5, Plotkin H6, Kreher N6, Landy H6, Nerissa Kreher7 SHORT COMMUNICATION
Lens Connexins α3Cx46 and α8Cx50 Interact with Zonula Occludens Protein-1 (ZO-1) (2003)

Connexin alpha1Cx43 has previously been shown to bind to the PDZ domain-containing protein ZO-1. The similarity of the carboxyl termini of this connexin and the lens fiber connexins alpha3Cx46 and alpha8Cx50 suggested that these connexins may also interact with ZO-1. ZO-1 was shown to be highly expressed in mouse lenses. Colocalization of ZO-1 with alpha3Cx46 and alpha8Cx50 connexins in fiber cells was demonstrated by immunofluorescence and by fracture-labeling electron microscopy but showed regional variations throughout the lens. ZO-1 was found to coimmunoprecipitate with alpha3Cx46 and alpha8Cx50, and pull-down experiments showed that the second PDZ domain of ZO-1 was involved in this interaction. Transiently expressed alpha3Cx46 and alpha8Cx50 connexins lacking the COOH-terminal residues did not bind to the second PDZ domain but still formed structures resembling gap junctions by immunofluorescence. These results indicate that ZO-1 interacts with lens fiber connexins alpha3Cx46 and alpha8Cx50 in a manner similar to that previously described for alpha1Cx43. The spatial variation in the interaction of ZO-1 with lens gap junctions is intriguing and is suggestive of multiple dynamic roles for this association.
Superhydrophobic Materials for Tunable Drug Release: Using Displacement of Air To Control Delivery Rates (2012)

We have prepared 3D superhydrophobic materials from biocompatible building blocks, where air acts as a barrier component in a porous electrospun mesh to control the rate at which drug is released. Specifically, we fabricated poly(ε-caprolactone) electrospun meshes containing poly(glycerol monostearate-co-ε-caprolactone) as a hydrophobic polymer dopant, which results in meshes with a high apparent contact angle. We demonstrate that the apparent contact angle of these meshes dictates the rate at which water penetrates into the porous network and displaces entrapped air. The addition of a model bioactive agent (SN-38) showed a release rate with a striking dependence on the apparent contact angle that can be explained by this displacement of air within the electrospun meshes. We further show that porous electrospun meshes with higher surface area can be prepared that release more slowly than control nonporous constructs. Finally, the entrapped air layer within superhydrophobic meshes is shown to be robust in the presence of serum, as drug-loaded meshes were efficacious against cancer cells in vitro for >60 days, thus demonstrating their applicability for long-term drug delivery.
A Smoothing Regularizer for Feedforward and Recurrent Neural Networks (1996)

We derive a smoothing regularizer for dynamic network models by requiring robustness in prediction performance to perturbations of the training data. The regularizer can be viewed as a generalization of the first-order Tikhonov stabilizer to dynamic models. For two layer networks with recurrent connections described by the training criterion with the regularizer is where Φ = {U, V, W} is the network parameter set, Z(t) are the targets, I(t) = {X(s), s = 1,2, …, t} represents the current and all historical input information, N is the size of the training data set, [Formula: see text] is the regularizer, and λ is a regularization parameter. The closed-form expression for the regularizer for time-lagged recurrent networks is where ‖ ‖ is the Euclidean matrix norm and γ is a factor that depends upon the maximal value of the first derivatives of the internal unit activations f(). Simplifications of the regularizer are obtained for simultaneous recurrent nets (τ ↦ 0), two-layer feedforward nets, and one layer linear nets. We have successfully tested this regularizer in a number of case studies and found that it performs better than standard quadratic weight decay.
Effects of ATP-induced leg vasodilation on Vo2 peakand leg O2extraction during maximal exercise in humans (2006)

During maximal whole body exercise VO2 peak is limited by O2 delivery. In turn, it is though that blood flow at near-maximal exercise must be restrained by the sympathetic nervous system to maintain mean arterial pressure. To determine whether enhancing vasodilation across the leg results in higher O2 delivery and leg VO2 during near-maximal and maximal exercise in humans, seven men performed two maximal incremental exercise tests on the cycle ergometer. In random order, one test was performed with and one without (control exercise) infusion of ATP (8 mg in 1 ml of isotonic saline solution) into the right femoral artery at a rate of 80 microg.kg body mass-1.min-1. During near-maximal exercise (92% of VO2 peak), the infusion of ATP increased leg vascular conductance (+43%, P<0.05), leg blood flow (+20%, 1.7 l/min, P<0.05), and leg O2 delivery (+20%, 0.3 l/min, P<0.05). No effects were observed on leg or systemic VO2. Leg O2 fractional extraction was decreased from 85+/-3 (control) to 78+/-4% (ATP) in the infused leg (P<0.05), while it remained unchanged in the left leg (84+/-2 and 83+/-2%; control and ATP; n=3). ATP infusion at maximal exercise increased leg vascular conductance by 17% (P<0.05), while leg blood flow tended to be elevated by 0.8 l/min (P=0.08). However, neither systemic nor leg peak VO2 values where enhanced due to a reduction of O2 extraction from 84+/-4 to 76+/-4%, in the control and ATP conditions, respectively (P<0.05). In summary, the VO2 of the skeletal muscles of the lower extremities is not enhanced by limb vasodilation at near-maximal or maximal exercise in humans. The fact that ATP infusion resulted in a reduction of O2 extraction across the exercising leg suggests a vasodilating effect of ATP on less-active muscle fibers and other noncontracting tissues and that under normal conditions these regions are under high vasoconstrictor influence to ensure the most efficient flow distribution of the available cardiac output to the most active muscle fibers of the exercising limb.
Bispecific antibody generated with sortase and click chemistry has broad antiinfluenza virus activity (2014)

Bispecific antibodies have therapeutic potential by expanding the functions of conventional antibodies. Many different formats of bispecific antibodies have meanwhile been developed. Most are genetic modifications of the antibody backbone to facilitate incorporation of two different variable domains into a single molecule. Here, we present a bispecific format where we have fused two full-sized IgG antibodies via their C termini using sortase transpeptidation and click chemistry to create a covalently linked IgG antibody heterodimer. By linking two potent anti-influenza A antibodies together, we have generated a full antibody dimer with bispecific activity that retains the activity and stability of the two fusion partners.
A signal-arrest-release sequence mediates export and control of the phage P1 endolysin (2004)

The Lyz endolysin of bacteriophage P1 was found to cause lysis of the host without a holin. Induction of a plasmid-cloned lyz resulted in lysis, and the lytic event could be triggered prematurely by treatments that dissipate the proton-motive force. Instead of requiring a holin, export was mediated by an N-terminal transmembrane domain (TMD) and required host sec function. Exported Lyz of identical SDS/PAGE mobility was found in both the membrane and periplasmic compartments, indicating that periplasmic Lyz was not generated by the proteolytic cleavage of the membrane-associated form. In gene fusion experiments, the Lyz TMD directed PhoA to both the membrane and periplasmic compartments, whereas the TMD of the integral membrane protein FtsI restricts Lyz to the membrane. Thus, the N-terminal domain of Lyz is both necessary and sufficient not only for export of this endolysin to the membrane but also for its release into the periplasm. The unusual N-terminal domain, rich in residues that are weakly hydrophobic, thus functions as a signal-arrest-release sequence, which first acts as a normal signal-arrest domain to direct the endolysin to the periplasm in membrane-tethered form and then allows it to be released as a soluble active enzyme in the periplasm. Examination of the protein sequences of related bacteriophage endolysins suggests that the presence of an N-terminal signal-arrest-release sequence is not unique to Lyz. These observations are discussed in relation to the role of holins in the control of host lysis by bacteriophage encoding a secretory endolysin.
In vivo circumvention of human colon carcinoma resistance to bleomycin. (1992)

Metabolic inactivation of bleomycin (BLM) by cysteine proteinase-like enzymes is thought to be a major mechanism of BLM tumor resistance. We now report that the human colon carcinoma COLO-205 is highly resistant to BLM and that E-64, a cysteine proteinase inhibitor, sensitizes COLO-205 to BLM. Treatment of COLO-205-bearing nude mice with either E-64 (40 mg/kg) or BLM (10 mg/kg) alone did not inhibit COLO-205 growth. However, pretreatment with E-64 prior to BLM prevented these xenografts from growing. Analysis by high performance liquid chromatography of in vivo BLM metabolism following [3H]BLM A2 treatment of COLO-205-bearing nude mice showed a different metabolic profile among the various organs and the tumor. Whereas [3H]BLM A2 was the only major radioactive peak detected in sera and tumors, several metabolites, including deamido-BLM A2, were found in kidney, liver, and lung as early as 15 min. Pretreatment of mice with E-64 inhibited tumor, kidney, and lung BLM A2 metabolism. Furthermore, pretreatment with E-64 increased BLM A2 accumulation in tumors (6.1-fold), kidney (4.0-fold), lung (2.8-fold), liver (1.8-fold), and serum (1.7-fold). E-64 pretreatment did not enhance the major toxicity of BLM, pulmonary fibrosis, as determined by both lung hydroxyproline levels and histopathology. Thus, the cysteine proteinase inhibitor E-64 affects the metabolic fate and the levels of accumulation of BLM in vivo. These results demonstrate that resistance of human COLO-205 tumors to BLM can be circumvented by E-64 without enhancement of the major side effect of BLM, suggesting a possible clinical use of this combination therapy.
The role of thymic stromal lymphopoietin in the immunopathogenesis of atopic dermatitis (2011)

Atopic dermatitis (AD), a skin disease characterized by pruritus and chronic inflammation, results from a complex interplay between environmental and genetic factors. Thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine, is believed to propagate AD lesions through T helper 2 (Th2) polarization. This paper describes the immunologic mechanisms involving TSLP in the generation of allergic disease. Specifically in AD, TSLP has been shown to be an inducer of myeloid dendritic cells, Th2 responses, mast cells, and natural killer T cells, thereby leading to cytokine secretion and the development of AD. We hope that further understanding of the TSLP pathway and its role in the pathogenesis of AD will lead to improved clinical management of AD in the future.
New Concepts about the Mast Cell (1993)

Most physicians and immunologists, if they think of the mast cell at all, regard it as something of a pariah. Other cells of hematopoietic origin, such as neutrophils, macrophages, and platelets, are clearly important in host defense, hemostasis, or both. In contrast, the contributions of the mast cell to pathologic conditions come to mind much more readily than any role it may have in the maintenance of health. Indeed, some would argue that an entire branch of medicine -- allergy -- deals in large part with the adverse effects produced by activation of the mast cell and the basophil, a . . .
Toxicity Profile of Lisdexamfetamine Dimesylate in Three Independent Rat Toxicology Studies (2007)

Lisdexamfetamine dimesylate (LDX) is a d-amphetamine prodrug developed for the treatment of attention-deficit/hyperactivity disorder. The toxicity profile of orally administered LDX has been evaluated in rats. In an acute study, LDX doses of 60 mg/kg and higher caused increased motor activity. At 1000 mg/kg, one rat died and another was euthanized. In a 7-day repeat-dose study, all rats dosed with LDX (14 per dose group for each sex) showed increased activity; 10 male rats and 11 female rats at 300 mg/kg/day and 3 female rats at 100 mg/kg/day were euthanized because of self-mutilation and 1 male rat at 300 mg/kg/day was found dead. In a 28-day study, only rats at 80 mg/kg showed signs of self-mutilation and thin body condition. In both the 7- and 28-day studies, LDX caused significant changes in some blood chemistry parameters (e.g. blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase) and organ weights (e.g. particularly heart, liver, brain, and spleen). Overall, no apparent treatment-related histopathologic changes were observed. Toxicokinetic assessments indicated that as the dose of LDX was increased, rats were exposed to increasing levels of LDX and d-amphetamine. The extent of exposure to LDX and d-amphetamine increased after repeated-dose in the 28-day study. The findings of the repeat-dose studies indicate that the toxicity profile in rats administered LDX orally is comparable to that for d-amphetamine; however, the apparent lethal dose of LDX in rats is more than five times higher than the LD(50) of orally administered d-amphetamine, supporting a putative protective effect of conjugating amphetamine with lysine.
Design, analysis, and performance of a silicon photonic traveling wave Mach-Zehnder modulator (2015)

Silicon photonics is a technology platform for integrating passive and active optical devices. The ability to use existing CMOS-VLSI foundry processes to fabricate integrated optics enables large volume production at low costs while maintaining compatibility with electronic integrated circuits. With the recent explosion in network traffic, large datacenters are demanding higher and higher intra-datacenter transmission speeds over distances of up to 20 km. For this application, optical interconnects are more energy efficient and are able to satisfy the bandwidth demands of the foreseeable future. Optical modulators are an essential component of these communication links and immense research is dedicated to developing efficient high bitrate devices. It is desirable to have high bitrate transmission over a single channel because it simplifies multiplexing (e.g., fewer wavelengths and parallel fibers) which can increase costs. The work presented in this thesis uses the silicon photonic platform to realize an integrated Mach-Zehnder modulator (MZM) suitable for datacenter communication links.A series push-pull traveling wave MZM is designed using T-shaped extensions to increase the microwave index. The modulator is designed to have a characteristic impedance close to 50 Ohms for matching with common microwave drivers and terminations. In addition, the group velocities of the microwave and optical wave are closely matched to optimize the electro-optic bandwidth. A 37 GHz -3 dB electro-optic bandwidth was measured at 1 V reverse bias. The DC Vpi was measured to be 7 V in the most efficient arm, corresponding to a VpiLpi of 2.8 V-cm. For on-off keying modulation, open eye diagrams are visible up to 60 Gbps. Error-free operation with a bit error rate (BER) &lt; 1E-12 was measured up to 45 Gbps, the limit of our photo-receiver. Eye diagrams with a clear opening were observed up to 70 Gbps using analog signal processing to compensate for the limitation of our bit pattern generator. The device was further characterized using digital-signal-processing to dispense the analog bandwidth limitations of the entire communication link to the digital domain. Using PAM-4 and PAM-8 modulation formats, 112 Gbps transmission on 2 km (5 km with PAM-8) of SMF fiber is achieved below the pre-forward-error-correction (FEC) BER threshold of 3.8E-3, corresponding to a post-FEC BER of &lt; 1E10-15. The best case energy consumed by the modulator is estimated to be 0.18 pJ/bit. The ability to generate 100 Gbps modulation in a single wavelength, as achieved in this work, is one of the main waypoints in realizing 400 Gbps and 1 Tbps short reach interconnects.
Clostridium aldenense sp. nov. and Clostridium citroniae sp. nov. Isolated from Human Clinical Infections (2006)

One hundred eight isolates were previously identified in our laboratory as Clostridium clostridioforme by colonial and cellular morphology, as well as biochemical tests. Recent studies have indicated that there are actually three different species in this C. clostridioforme group: C. hathewayi, C. bolteae, and C. clostridioforme. Our isolates were reexamined using biochemical and enzymatic tests and molecular methods. Forty-six isolates were reidentified as C. hathewayi, 34 as C. bolteae, five as C. clostridioforme, and one as C. symbiosum. Twenty-two strains were identified only to the genus level by 16S rRNA gene sequencing, and although they are microscopically and morphologically indistinguishable from the above-mentioned three species, they are phenotypically different and only 96 to 98% similar by gene sequencing. Twenty of these 22 strains were indole positive and formed two novel species. We propose Clostridium aldenense sp. nov. and Clostridium citroniae sp. nov. as names for these new species. They are differentiated from each other by results for raffinose, rhamnose, alpha-galactosidase, and beta-galactosidase: positive, negative, positive, and positive, respectively, for the former species and negative, positive, negative, and negative, respectively, for the latter species. The type strain of C. aldenense is RMA 9741 (ATCC BAA-1318; CCUG 52204), and the type strain of C. citroniae is RMA 16102 (ATCC BAA-1317; CCUG 52203).