gebhart/patrepeval huggingface dataset:
QM and QM/MM studies of the phosphoryl transfer reaction catalyzed by a cyclin-dependent kinase (CDKs) (2004)

The regulation of the eukaryotic cell cycle depends on the action of several related Ser/Thr protein kinases called cyclin-dependent kinases (CDKs), which are transiently activated at specific stages of the cycle, and which are also very promising targets for therapeutic intervention. A key step in the mechanism of action of CDKs is the transfer of g-phosphate from ATP to a serine or threonine residue of the substrate. In the present study we have used both QM and QM/MM methods to investigate this enzymic reaction. In this way, we have been able to define a possible reaction pathway for the phosphate transfer reaction, and est. the role of mech. and electrostatic effects in the catalysis. An improvement of the understanding of phosphorylation in CDKs family might eventually lead to the design of new inhibitors based on the enzymic reaction transition state (TS). [on SciFinder (R)]
Effect of Mass Balancing on Cell Performance and Electrochemical Investigation of Sn–Ni Alloy as Anode for Li-Ion Capacitors (2020)

Lithium-ion capacitors (LICs) have been attracting research interest over the past years as promising electrochemical energy devices because they show higher energy densities than supercapacitors and higher power densities than batteries. In this study, we synthesized an Sn–Ni alloy by electrodeposition and applied it as an anode for LICs. To optimize the full-cell configuration, we controlled the mass balancing between the loading amounts of active materials in the cathode and anode with different mass ratios of 16:1, 8:1, and 4:1. In addition, the Sn–Ni alloy was investigated using electrochemical impedance spectroscopy under different depth of discharge (DOD) levels. The LICs assembled with a mass ratio of 4:1 between the cathode and anode exhibited good cyclability, rate performance, energy, and power density. This study not only improved the cycle performance of LICs full cell by mass balancing, but also revealed the relationship between the electrochemical characteristics of LICs and DOD levels of the Sn–Ni anode.
Basis for N-acetyllactosamine-mediated inhibition of enteropathogenic Escherichia coli localized adherence (2006)

In a previous article, the authors reported that exposing wild-type enteropathogenic Escherichia coli (EPEC) to chemically synthesized N-acetyllactosamine glycosides covalently coupled to BSA (LacNAc-BSA) inhibited localized adherence (LA) by these organisms and also caused them to lose their bundle-forming pili (BFP), the filamentous surface appendages responsible for their LA phenotype. This effect has now been further investigated by screening a panel of LacNAc-BSA-related glycosides for their ability to inhibit EPEC LA, which revealed that LacNAc-BSA retained its status as the most effective inhibitor of EPEC LA. It was also shown that LacNAc-BSA did not cause the loss of BFP in an EPEC strain containing a non-polar mutation in the bfpF gene and, as a consequence, unable to retract its BFP. LacNAc-BSA also effectively inhibited LA of the bfpF mutant EPEC. Taken together, these observations suggest that, as well as triggering BfpF-mediated BFP retraction, LacNAc-BSA likely functions as a competitive inhibitor of EPEC binding to LacNAc-related receptors on host cells. Moreover, transmission electron microscopy revealed that LacNAc conjugated to gold nanoparticles bound specifically to BFP. This observation indicated that either the major BFP structural subunit (BfpA) itself or, possibly, an accessory protein co-assembled with BfpA into the BFP filaments, contains a LacNAc-specific EPEC adhesin. The results suggest a mechanism whereby the initial binding of EPEC to LacNAc-like receptors on host cells triggers BfpF-mediated BFP retraction. This could then expedite the intimate adherence phase of the multi-step EPEC colonization process by drawing the organisms closer to the host-cell plasma membrane.
Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa (2014)

RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).
Resolution and purification of three distinct factors produced by Krebs ascites cells which have differentiation-inducing activity on murine myeloid leukemic cell lines. (1988)

The use of different myeloid leukemic cell lines (WEHI-3B D+ and M1) and different sources of factors has led to discrepancies concerning the identity of factors capable of inducing differentiation in leukemic cells. We have biochemically fractionated medium conditioned by one such source (Krebs II ascites cells) and assayed fractions for their bone marrow colony-stimulating activity as well as their differentiation-inducing activity for WEHI-3B D+ and M1 cells. This resulted in the resolution of four distinct molecular species with differentiation-inducing activity. One activity was purified to homogeneity and shown by a variety of biochemical, biological, and receptor-binding criteria to be authentic granulocyte colony-stimulating factor (G-CSF). A second activity was identified as granulocyte-macrophage colony-stimulating factor (GM-CSF). Two other activities termed LIF-A and LIF-B (leukemia inhibitory factor) were shown to probably be different glycosylation variants of the same protein and one of these (LIF-A) was purified 12,000-fold to homogeneity. G-CSF induced differentiation in both WEHI-3B D+ and at higher concentrations M1 cells while GM-CSF weakly induced differentiation in WEHI-3B D+ cells. LIF-A had no colony-stimulating activity and induced differentiation in and inhibited the proliferation of only M1 cells. Each factor bound to a unique cell surface receptor with no evidence of direct cross-reactivity.
Hypothermia in the Combat Trauma Population (2022)

Hypothermia, including a single recorded low temperature in the patient care record, was associated with worse outcomes in this combat trauma population. Prehospital intubation was most strongly associated with developing hypothermia. Prehospital warming interventions were not associated with a reduction in hypothermia risk. Our dataset suggests that current methods for prehospital warming are inadequate.
Predictors of clonal evolution in metastatic colorectal cancer patients. (2015)

3604 Background: Concordance of somatic mutations between primary and metastatic colorectal tumors is high in colorectal cancer (CRC), circulating cell-free DNA (cfDNA) accurately reflects the mutation status of metastatic disease. Intervening treatment and metastatic dissemination may result in clonal evolution from pre-existing intratumoral heterogeneity, with the resulting discordance in minor clones.Methods: Patients (pts) were prospectively consented for collection of cfDNA from plasma samples for sequencing on a 54-gene platform optimized for very low allele frequencies (Guardant360), with concurrent sequencing of clinically available and macrodissected historic FFPE tissue (50-gene Ion-Torrent panel), both performed in CLIA-compliant labs. Eligible cases had plasma and tissue sequencing where the modal mutation was present with ≥ 1% and ≥ 5% allele frequencies, respectively. Minor clones were defined as those with an allele frequency < 10% of the highest detected allele frequency in the sample.Results: 61 pts were enrolled after a median of two prior lines of therapy for metastatic disease, with plasma collected a median of 12.6 months after FFPE tissue (18 metastatic/44 primary tumor tissue). 213 mutations were detected on both tissue DNA and cfDNA, with at least one mutation detected in all cases; 54% of the mutations were present in both samples, with 32% of the mutations uniquely present in the plasma. Microsatellite instability (P = 0.025), intervening treatment with oxaliplatin (P = 0.04) or cetuximab/panitumumab (P < 0.001), but not irinotecan or bevacizumab, were associated with the detection of new minor clones. There was no association with reference tissue source, time from tissue collection, location nor number of metastatic sites.Minor clones represented 30% of the detected mutations and were concordant for only 11%, in contrast to 84% concordance for major clones (P < 0.0001). .Conclusions: Intervening chemotherapy and microsatellite instability results in the appearance of new minor clones in potentially clinically relevant genes in more than half of metastatic CRC pts. Based on this small data set, development of minor clones may be dependent on exposure to specific cytotoxic or molecular drugs.
Biological structure and function emerge from scaling unsupervised learning to 250 million protein sequences (2021)

In the field of artificial intelligence, a combination of scale in data and model capacity enabled by unsupervised learning has led to major advances in representation learning and statistical generation. In the life sciences, the anticipated growth of sequencing promises unprecedented data on natural sequence diversity. Protein language modeling at the scale of evolution is a logical step toward predictive and generative artificial intelligence for biology. To this end, we use unsupervised learning to train a deep contextual language model on 86 billion amino acids across 250 million protein sequences spanning evolutionary diversity. The resulting model contains information about biological properties in its representations. The representations are learned from sequence data alone. The learned representation space has a multiscale organization reflecting structure from the level of biochemical properties of amino acids to remote homology of proteins. Information about secondary and tertiary structure is encoded in the representations and can be identified by linear projections. Representation learning produces features that generalize across a range of applications, enabling state-of-the-art supervised prediction of mutational effect and secondary structure and improving state-of-the-art features for long-range contact prediction.
Recombinant ADAMTS13 Improves Neurological Outcome in Experimental Stroke in Mice. (2009)

Abstract Abstract 3134 Poster Board III-71 Ischemic stroke is a leading cause of death and disability and each year, about 795,000 people experience a new or recurrent stroke in the United States. The only FDA approved therapy available for stroke is tissue plasminogen activator (tPA), which converts inactive plasminogen into plasmin and then catalyzes the digestion of fibrin into soluble degradable products facilitating clot lysis. Although tPA was approved by the FDA, experiments in mice revealed side effects including increased risk of hemorrhage and induction of blood brain barrier breakdown. Therefore, there is a need for an alternative candidate drug. von Willebrand factor (VWF) is an adhesion molecule that plays an important role in platelet adhesion and cohesion at sites of vascular injury both at arterial and venous shear rates. The activity of VWF is modulated by ADAMTS13 (A Disintegrin-like And Metalloprotease with Thrombospondin type I repeats-13) which cleaves VWF to smaller less active forms. Recently, it was demonstrated that deficiency of VWF protects mice from ischemic stroke in the middle cerebral artery occlusion model (MCAO) (Kleinschnitz et al., Blood, 2009.). This observation is in agreement with our previous findings presented at the 2008 ASH meeting. In addition, we have shown that deficiency of ADAMTS13 in mice aggravates consequences of ischemic stroke in the MCAO model. In this study, we evaluated the therapeutic potential of recombinant human ADAMTS13 (r-hu ADAMTS13) in prevention of stroke. We have previously shown that r-hu ADAMTS13 was effective in reducing platelet plug size in the ferric chloride arterial injury model in mice (Chauhan et al., JEM, 2006). We infused r-hu ADAMTS13 prior to reperfusion in wild-type (WT) mice that underwent one hour of middle cerebral artery occlusion. After 24 hours, WT mice infused with r-hu ADAMTS13 had approximately 30% smaller infarctions (P&lt;0.05) compared to control (WT infused with vehicle). Additionally, we did not detect cerebral hemorrhage in the mice infused with r-hu ADAMTS13. To test whether the reduction in infarct volume actually improves functional outcome, we performed the tape removal test, a technique that assesses sensory and motor impairments in forepaw function. Twenty-four hours after surgery, mice that underwent one hour MCAO showed an increase in the time needed to remove adhesive tape from the contralateral and ipsilateral paws compared to sham-operated mice. Interestingly, treatment with r-hu ADAMTS13 significantly shortened the time to remove the adhesive tape when compared to vehicle treated mice (P &lt; 0.05), indicating a profound improvement in sensorimotor performance of the r-hu ADAMTS13 treated mice. Taken together, these results show a protective role of ADAMTS13 and therapeutic effect of r-hu ADAMTS13 when infused after cerebral ischemia. Our findings suggest that recombinant ADAMTS13 could be considered as a new agent for prevention and/or treatment of stroke. Disclosures Dockal: Baxter: Employment. Scheiflinger:Baxter Bioscience: Employment.
Data from Conophylline Inhibits Hepatocellular Carcinoma by Inhibiting Activated Cancer-associated Fibroblasts Through Suppression of G Protein–coupled Receptor 68 (2023)

&lt;div&gt;Abstract&lt;p&gt;Treatment of hepatocellular carcinoma (HCC) is currently challenging. Cancer-associated fibroblasts (CAFs) promote the malignancy of HCC cells via production of cytokines. Conophylline (CnP), a vinca alkaloid obtained from &lt;i&gt;Ervatamia microphylla&lt;/i&gt; leaves, has been reported to suppress activation of hepatic stellate cells and liver fibrosis in rats. We examined the efficacy of CnP in suppressing tumor growth in HCC. Specifically, we investigated whether CnP could inhibit CAFs, which were derived from HCC tissues &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;. Same as previous reports, CAFs promoted proliferative and invasive ability of HCC cells. CnP suppressed α-smooth muscle actin expression of CAFs, and inhibited their cancer-promoting effects. CnP significantly suppressed CAFs producting cytokines such as IL6, IL8, C-C motif chemokine ligand 2, angiogenin, and osteopontin (OPN). Combined therapy with sorafenib and CnP against HCC cells and CAFs &lt;i&gt;in vivo&lt;/i&gt; showed to inhibit tumor growth the most compared with controls and single treatment with CnP or sorafenib. Transcriptome analysis revealed that GPR68 in CAFs was strongly suppressed by CnP. The cancer-promoting effects of cytokines were eliminated by knockdown of GPR68 in CAFs. CnP inhibited the HCC-promoting effects of CAFs by suppressing several HCC-promoting cytokines secreted by CAFs expressing GPR68. Combination therapy with CnP and existing anticancer agents may be a promising strategy for treating refractory HCC associated with activated CAFs.&lt;/p&gt;&lt;/div&gt;
Terabit bandwidth-adaptive transmission using low-complexity format-transparent digital signal processing (2014)

In this paper, we propose a low-complexity format-transparent digital signal processing (DSP) scheme for next generation flexible and energy-efficient transceiver. It employs QPSK symbols as the training and pilot symbols for the initialization and tracking stage of the receiver-side DSP, respectively, for various modulation formats. The performance is numerically and experimentally evaluated in a dual polarization (DP) 11 Gbaud 64QAM system. Employing the proposed DSP scheme, we conduct a system-level study of Tb/s bandwidth-adaptive superchannel transmissions with flexible modulation formats including QPSK, 8QAM and 16QAM. The spectrum bandwidth allocation is realized in the digital domain instead of turning on/off sub-channels, which improves the performance of higher order QAM. Various transmission distances ranging from 240 km to 6240 km are demonstrated with a colorless detection for hardware complexity reduction.
Bloodless Off Pump Coronary Artery Bypass Grafting, Treatment of Choice for Jehova's Witness Patients (2012)

Jehovah's witnesses (JW) belong to a religious group refusing to accept blood transfusion Surgical treatment remains a challenge in this subset of patients. From 1945, JW introduced a ban on accepting blood transfusions, even in life-threatening situations while autologous blood must also be refused if it is predeposited-thus excluding preoperative autodonation. However, autologous blood is acceptable if it is not separated from the patients' circulation at any time. The invasive nature of coronary artery bypass grafting (CABG), the associated decrease of body temperature and the use of cardiopulmonary bypass (CPB) are major reasons for increased blood loss and high incidence for blood transfusions during and after this procedures. Allogenic blood transfusions are often given and considered necessary in such operations, in spite of increased mortality, morbidity and major adverse outcomes resulting from transfusion. Reduction in the use of blood products should therefore be a general desire for every patient due to the associated risk factors. The evolution of less invasive cardiac surgical approaches, such as CABG without CPB (OPCAB) may contribute to a further reduction of blood transfusion and although these minimally invasive techniques may benefit every patient, they might be particularly valuable for JW. In this report, we present our initial experience in JW patient undergoing OPCAB and the way to use patient blood management for improved surgical outcome in such patient.
Parameter Design of a Coaxial Cable Insulation Manufacturing Process Using Axiomatic Design and the Taguchi Method (2008)

Abstract In modern industries, the development of communication mediums requires high-frequency communication networks in which signal reduction by dielectric loss is increased. Accordingly, the need for an insulator with low permittivity also has grown, making the production of highly foamed insulators now necessary. Considering the mechanical and electrical properties of such insulators, benefits can be seen in multiresponse problems with higher densities of uniform-specific cell size. In this paper, we describe the applicability of a highly foamed polyolefin extrusion process to the manufacturing of insulation for coaxial cable. Moreover, a combination of axiomatic design and the Taguchi method was utilized for solving the multiresponse problem. Through this technique, we propose a new method for optimizing multiresponse problems. Development of manufacturing processes for insulating coaxial cable, and responses for each process variable, become possible with this method. Keywords: Axiomatic designFoam extrusionFoamed insulationTaguchi method ACKNOWLEDGMENT This work was financially supported by LS Cable Ltd., South Korea.
Abstract 1864: <i>In vivo</i> efficacy of the PAK4 allosteric modulator KPT-9274 against a triple-negative breast cancer model (2016)

Abstract The p21-activated kinases (PAK) belong to a family of serine threonine kinases that promote cell survival and play an important role in cell proliferation, cell cycle regulation and cell shape determination. There are six mammalian PAK proteins which can be subdivided into two groups by sequence homology and mode of activation- Group A PAKs consisting of PAK 1, 2 and 3 and Group B PAKs consisting of PAK 4, 5 and 6. We have found that PAK4 protein levels are elevated in breast cancer, including Her2 positive and triple negative breast cancers, while it is expressed at low levels in normal mammary tissue, making it an attractive drug target. PAK inhibitors are being tested for effectiveness against solid tumors, but generation of highly specific PAK4 inhibitors has been a challenge. Furthermore, PAK4 has been reported to have kinase-independent functions. Therefore inhibiting its kinase activity alone might not be sufficient in blocking its tumorigenic potential. Our lab has previously reported the effectiveness of PAK4 allosteric modulators (PAM; KPT-8752 and KPT-9274) against multiple breast cancer cell lines. These novel PAK4 inhibitors reduce steady state protein levels and were able to block cell growth, cell migration and induce apoptosis in breast cancer cell lines, without affecting the control cells. Here, we tested the efficacy of the orally bioavailable PAM, KPT-9274 against tumors formed by the triple negative breast cancer cell line, MDA-MB-231. Following six weeks of treatment with orally administered KPT-9274 (150mg/kg bidx4), there was almost a five-fold reduction in tumor volume and tumor weight in the treatment group as compared to the control group. The treatment did not significantly affect mice body weight. After six weeks of treatment, the tumors were excised and analyzed for PAK4 levels. We observed a significant decrease in PAK4 levels in excised tumors from the treatment group as compared to those from the control group. PAK1 levels were monitored to see any off-target effects, but their levels were unchanged. Our results indicate that PAK4 plays a key functional role in triple negative breast cancer and treatment with an orally administered KPT-9274 was capable of specifically binding and inhibiting PAK4, and consequently reducing tumor growth. Future studies analyzing the effects of KPT-9274 in blocking PAK4 mediated functions that promote tumorigenesis are ongoing. Additional studies of the effectiveness of KPT-9274 on mammary fat pad tumors formed by MDA-MB-231 and the ER positive cell line, MCF7 are under investigation. Citation Format: Chetan Rane, William Senapedis, Erkan Baloglu, Sharon Shacham, Audrey G. Minden. In vivo efficacy of the PAK4 allosteric modulator KPT-9274 against a triple-negative breast cancer model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1864.
Crystal structure of 3,4-dihydro-6-(3'-methylbenzyl)-2-[(1-methylpropyl) thio]-4-oxopyrimidine (S-DABO 618), C16H20N2OS and of 3,4- dihydro-2-[(1-methylpropyl)thio]-6-(2-naphthylmethyl)-4-oxopyrimidine (DATNO 774), C19H20N2OS, two HIV-1 reverse transcriptase inhibitors (1998)

Article Crystal structure of 3,4-dihydro-6-(3'-methylbenzyl)-2-[(1-methylpropyl) thio]-4-oxopyrimidine (S-DABO 618), C16H20N2OS and of 3,4- dihydro-2-[(1-methylpropyl)thio]-6-(2-naphthylmethyl)-4-oxopyrimidine (DATNO 774), C19H20N2OS, two HIV-1 reverse transcriptase inhibitors was published on April 1, 1998 in the journal Zeitschrift für Kristallographie - New Crystal Structures (volume 213, issue 1-4).
Orthopedic trauma reduces renal hemodynamics in the STZ‐induced diabetic rat (2012)

Diabetes is an independent risk factor for the development of acute renal dysfunction following orthopedic trauma (OT). Whether OT affects renal hemodynamics has yet to be investigated. The hypothesis tested in this study was that OT reduces renal hemodynamics in type 1 diabetes. Male lean Zucker rats (12 wks) were divided into 4 treatment groups (n=4/gp): non‐diabetic without trauma (ND‐NT), non‐diabetic with trauma (ND‐T), STZ‐induced diabetic without trauma (D‐NT) and STZ‐induced diabetic with trauma (D‐T). Four wks after induction of diabetes, animals were implanted with catheters and OT was induced by soft tissue injury and local injection of bone components in both hind limbs. Animals were placed in metabolic cages for 12hrs to collect urine and urine albumin excretion (UAE) was measured by ELISA. 24 hrs post‐trauma, glomerular filtration rate (GFR) was measured in conscious rats. Our results show that diabetes after 4 wks causes a reduction in GFR compared to controls. However, OT caused a greater reduction in GFR in diabetics than controls. Our data suggest that OT compromises renal function in the setting of type 1 diabetes. Group Body Weight (g) Glucose (mg/dL) UAE (mg/day) GFR/KW (ml/min/g) ND‐NT 396±25 81±6 0.5±0.1 1.37±0.09 ND‐T 415±20 85±4 1.2±0.7 1.52±0.08 D‐NT 298±12 358±27 3.3±0.6 1.17±0.08 D‐T 330±14 366±15 4.6±0.3 1.06±0.07 Avg±SEM; P&lt;0.05 vs. ND‐NT; P&lt;0.05 vs. ND‐T