cssi/SciSciGPT-SciSciNet huggingface dataset:
In vivo testing of Mycophenolic acid (MPA) in primary pancreatic cancer (PaCa) xenografts

2213 Background: Pancreatic cancer (PaCa) is an almost universally fatal disease, and new therapeutic alternatives are needed. Mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF) is a known inosine mono phosphate dehydrogenase inhibitor (IMPDH) and is clinically used as an immune-suppressive agent following organ transplantation. Preliminary studies from our group testing a panel of 2,000 non-antitumor approved agents evidenced that MPA had activity in vitro against PaCa cell lines. In this study we performed a preclinical study to determine pharmacodynamic (PD) markers and to explore the activity of MPA in in vivo models of PaCa. Methods : MPA was tested in vitro against a panel of pancreatic cancer cell lines in the range of 0-10uM by MTT assay. In a novel patient derived PaCa xenograft model, we studied MPA in vivo in 6 xenografts derived directly from patient tumors. Combination therapy with gemcitabine plus MPA was done on selected, gemcitabine-resistant cases to evaluate the modulation in activity of the drugs. Mice were treated daily with 125mg/Kg MPA ip. The efficacy of treatment was measured by determining the tumor growth inhibition at 28 days. PD markers of MPA were assessed using western blotting and immunohistochemistry of target proteins. GTP pools in in vitro samples and pharmacokinetics of the MPA levels in mouse was done using HPLC-tandem mass spectrometry. Fine needle aspirate (FNA)-based ex vivo testing was conducted exposing acquired cells to MPA mimicking in vitro conditions. Results : MPA confirmed in vitro antitumor activity in a broader panel of PaCa cell lines. Two cell lines showing differential response were selected for PD studies. In order to investigate the mechanism and the involvement of IMPDH inhibition in the effect mediated by MPA on those cell lines in vitro , guanosine replenishment was done and the response was read using MTT. Nucleotidal GTP pools in the cells were taken as a marker of IMPDH inhibition and showed a decrease with increasing MPA dosage in vitro . The cell lines also showed a decrease in VEGF suggesting a potential anti-angiogenic effect by MPA. Single-agent MPA treatment in vivo in 6 patient-derived xenografts showed differential efficacy, with two cases being sensitive and four being resistant. Ex vivo and pharmacodynamic testing was conducted to characterize the basis of those differences. A decrement in VEGF protein was observed in vivo and encouraging combination data was documented. Conclusions: MPA showed activity in a subset of PaCa direct xenografts, making it a candidate drug for further development in PaCa . Pharmacodynamic studies suggest that this efficacy may at least be mediated by an antiangiogenic effect. Updated pharmacodynamic, pharmacokinetic and tumor permeability data using magnetic resonance imaging will be presented in the meeting.
Rare corneal complication following selective laser trabeculoplasty.

Abstract Purpose This case report describes two glaucoma patients who underwent selective laser trabeculoplasty (SLT) and developed a rare post-procedure corneal complication and subsequent permanent corneal distortions and reduced acuity. Observations Both patients experienced early post-procedure corneal edema, reduced visual acuity, and pain. Each patient was treated with topical steroids with resolution of the edema, but each patient had irregular corneal astigmatism which was not present pre-operatively and did not resolve. Conclusions and importance There are very few reported cases of post-SLT corneal edema and these typically resolve without long-term complications. The following two cases represent an uncommon adverse event of irregular corneal astigmatism despite resolution of the corneal edema. The exact mechanism of these corneal effects is not known. Practitioners should inform patients of this rare, but possible complication following SLT and consider extra precautions in patients susceptible to corneal edema.
Passivity based control of the compass gait biped

Abstract In this paper we discuss the passivity based control of the two-link robot known as the Compass Gait Biped. Starting from a narrow region of initial conditions, the compass gait biped is capable of locomotion down shallow inclines without actuation or feedback control of any kind. We will discuss some feedback control strategies that can exploit these passive dynamics by shaping the energy of the system. Using potential energy shaping we can make the passive limit cycle slope invariant. We also discuss the use of switching control to address the sensitivity to initial conditions and robustness to disturbances.
Pathogenesis of urinary tract infections. Host defenses

Host defenses in the urinary tract constitute a highly complex and efficient system of physical, chemical, genetic, and immunologic measures aimed at limiting the presence of bacteria in the urinary tract. These mechanisms vary in their roles at different anatomical levels and are directed at eliminating bacteria and preventing their ascent to the upper tract. A detailed description is provided of anticolonization and antiadherence mechanisms that may fail for a variety of congenital and acquired reasons. Major defects in host defenses such as obstruction, stasis, calculi, and diabetes are discussed together with the pathogenesis of urinary tract infection in adults with radiologically normal urinary tracts.
Epidemiology of vaccine-preventable diseases in Japan: considerations for pre-travel advice for the 2019 Rugby World Cup and 2020 Summer Olympic and Paralympic Games.

Introduction In 2019 and 2020, Japan will host two international sporting events estimated to draw a combined 22 million visitors. Mass gatherings like these ones increase the risk of spread of infectious disease outbreaks and international transmission. Pre-travel advice reduces that risk. Methods To assist ministries of health and related organizations in developing pre-travel advice, we summarized national surveillance data in Japan (2000-2016, to the extent available) for rubella, invasive pneumococcal disease, measles, non-A and non-E viral hepatitis, hepatitis A, invasive Haemophilus influenzae disease, tetanus, typhoid fever, invasive meningococcal disease, Japanese encephalitis, influenza, varicella, mumps and pertussis by calculating descriptive statistics of reported cases and reviewing trends. (See Annex A for details of reviewed diseases.). Results Our findings showed notable incidences of rubella (1.78 per 100 000 person-years), influenza (243.5 cases per sentinel site), and mumps (40.1 per sentinel site); seasonal increases for influenza (November-May) and Japanese encephalitis (August-November); and a geographical concentration of Japanese encephalitis in western Japan. Measles cases decreased from 11 013 in 2008 to 35 in 2015, but outbreaks (n = 165 cases) associated with importation occurred in 2016. Though invasive meningococcal disease incidence was only 0.03 per 100 000, international transmission occurred at a mass gathering in Japan in 2015. Discussion Ministries of health and related organizations should use these findings to develop targeted pre-travel advice for travellers to the 2019 Rugby World Cup and the 2020 Summer Olympic and Paralympic Games, especially for mumps, measles, rubella, influenza, and meningitis. Travellers with increased exposure risk should also be advised about hepatitis A and Japanese encephalitis.
A Multi-Phase-Field Anisotropic Damage-Plasticity Model for Crystalline Rocks

Many engineering applications, such as geological disposal of nuclear waste, require reliable predictions on the thermo-hydro-mechanical responses of porous media exposed to extreme environments. This presentation will discuss the relevant modeling techniques designed specifically for such environmental conditions. In particular, we will provide an overview of the coupling method of crystal plasticity and multi-phase-field model designed to replicate the thermal- and rate-dependent damage-plasticity of crystalline rock. Special emphasis is placed on capturing the intrinsic anisotropy of salt grain in 3D with respect to damage behavior and plastic flow by incorporating the crystallographic information of salt.
Neutralizing Antibody Responses to Homologous and Heterologous H1 and H3 Influenza A Strains After Vaccination With Inactivated Trivalent Influenza Vaccine Vary With Age and Prior-year Vaccination.

Background Prior influenza immunity influences the homologous neutralizing antibody responses elicited by inactivated influenza vaccines (IIV), but neutralizing antibody responses to heterologous strains have not been extensively characterized. Methods We analyzed neutralizing antibody titers in individuals aged 1-88 who received the 2009-2010 season IIV before infection by or vaccination against the 2009 pandemic H1N1 virus. Neutralization titers to homologous and heterologous past, recent, and advanced H1 and H3 strains, as well as H2, H5, and H7 strains, were measured using influenza hemagglutinin pseudoviruses. We performed exploratory analyses based on age, prior-year IIV, and prevaccination titer, without controlling for Type I errors. Results IIV elicited neutralizing antibodies to past and advanced H1 and H3 strains, as well as to an H2 strain in individuals who were likely infected early in life. The neutralization of avian subtype viruses was rare, and there was no imprinting of neutralization responses to novel avian subtype viruses based on the influenza group. Compared to adults, children had higher seroresponse rates to homologous and heterologous strains, and their sera generated larger antigenic distances among strains. Seroresponse rates to homologous and heterologous strains were lower in subjects vaccinated with prior-year IIV, though postimmunization titers were generally high. Conclusions IIV elicited neutralizing antibodies to heterologous H1 and H3 strains in all ages groups, but titers and seroresponse rates were usually higher in children. Prior-year vaccination with the same strains tended to blunt IIV neutralization responses to all strains in young and old age groups, yet postimmunization titers were high.
A review of the potential impacts of climate change on bulk power system planning and operations in the United States

Abstract Climate change might impact various components of the bulk electric power system, including electricity demand; transmission; and thermal, hydropower, wind, and solar generators. Most research in this area quantifies impacts on one or a few components and does not link these impacts to effects on power system planning and operations. Here, we advance the understanding of how climate change might impact the bulk U.S. power system in three ways. First, we synthesize recent research to capture likely component-level impacts of climate change in the United States. Second, given the interconnected nature of the electric power system, we assess how aggregated component-level impacts might affect power system planning and operations. Third, we outline an agenda for future research on climate change impacts on power system planning and operations. Although component-level impacts vary in their magnitude, collectively they might significantly affect planning and operations. Most notably, increased demand plus reduced firm capacity across generation types might require systems to procure significant additional capacity to maintain planning reserve margins, and regional declines in renewable resources might need to be offset by increasing zero-carbon investment to meet decarbonization targets. Aggregated impacts might also affect operations, e.g., through shifts in dispatching and increased operational reserve requirements. Future research should aggregate component-level impacts at operational timescales, quantify impacts on wind and solar variability, and contextualize climate change impacts within ongoing shifts in the electric power system.
Multiple myeloma: The case for ORIF and inferior alveolar nerve grafting

Abstract Multiple myeloma is a plasma cell malignancy occurring most commonly in the fifth decades of life. Often skeletal lesions precipitate back pain, which lead to identification to osteolytic lesions in the spine. While mandibular involvement in multiple myeloma has been reported in the past, it is an uncommon and historically has been managed with radiation and chemotherapy. In this case report, we explore a unique presentation of multiple myeloma that resulted in both pathologic fracture and effacement of the left inferior alveolar nerve. Rather than manage the long-term complications of MRONJ and osteoradionecrosis, surgery was elected as the initial therapy, followed by medical management. The fracture was treated with open reduction and internal fixation by reconstruction plate. The nerve was reconstructed with a cadaveric nerve graft. Both procedures were completed intraorally during a single surgical intervention. The site healed without complication and patient experienced compete recovery of form, function, and sensation. Currently, the patient is undergoing medical therapy and tolerating it well.
Imaging ionomer in fuel cell catalyst layers with synchrotron nano transmission x-ray microscopy

Abstract This work presents a novel characterization method for distinguishing ionomer phase within porous composite catalyst layer. Quantifying ionomer distribution in a catalyst layer of polymer electrolyte fuel cells (PEFCs) is critical to understanding the morphological and transport properties of this key component. Current methods to image ionomer rely on staining it with heavy ions, such as cesium, Cs, to enable detection with hard X-rays, however if the catalyst layer contains electrocatalyst, such as platinum, Pt, then the challenge is to distinguish between Cs-stained ionomer and Pt. These two materials have very similar X-ray attenuation coefficients. Using synchrotron transmission x-ray microscopy (TXM) and two energy imaging, above and below Pt electrocatalyst absorption edge, the ionomer distribution is quantified. The method is applied to a PEFC catalyst layer and compared against the method of single energy imaging, which is not able to separate the two phases.
A Practical Review of Proteasome Pharmacology

The ubiquitin proteasome system (UPS) degrades individual proteins in a highly regulated fashion and is responsible for the degradation of misfolded, damaged, or unneeded cellular proteins. During the past 20 years, investigators have established a critical role for the UPS in essentially every cellular process, including cell cycle progression, transcriptional regulation, genome integrity, apoptosis, immune responses, and neuronal plasticity. At the center of the UPS is the proteasome, a large and complex molecular machine containing a multicatalytic protease complex. When the efficiency of this proteostasis system is perturbed, misfolded and damaged protein aggregates can accumulate to toxic levels and cause neuronal dysfunction, which may underlie many neurodegenerative diseases. In addition, many cancers rely on robust proteasome activity for degrading tumor suppressors and cell cycle checkpoint inhibitors necessary for rapid cell division. Thus, proteasome inhibitors have proven clinically useful to treat some types of cancer, especially multiple myeloma. Numerous cellular processes rely on finely tuned proteasome function, making it a crucial target for future therapeutic intervention in many diseases, including neurodegenerative diseases, cystic fibrosis, atherosclerosis, autoimmune diseases, diabetes, and cancer. In this review, we discuss the structure and function of the proteasome, the mechanisms of action of different proteasome inhibitors, various techniques to evaluate proteasome function in vitro and in vivo, proteasome inhibitors in preclinical and clinical development, and the feasibility for pharmacological activation of the proteasome to potentially treat neurodegenerative disease.
A Proposal of Conducting Bioequivalence Trials with Gastric pH Modulators for Two Oral Formulations Demonstrating Different Dissolution Profiles at Elevated pH

In this paper, a special case for bioequivalence evaluation of oral formulations is discussed. Drug formulations with different forms of active moieties (e.g., free base and salt) may yield different dissolution characteristics and, thus, differ in absorption at elevated gastric pH. However, routine bioequivalence trials using subjects with normal gastric pH (i.e., ~ 1) may fail to identify these differences because dissolution/absorption profiles of the two formulations at normal gastric pH are similar. In the case of palbociclib, it is confirmedthat the free base and salt formulations showed different absorption in patients with different gastric pH. Significant reduction in drug absorption was observed only in patients with elevated gastric pH using free base formulation. The discovery that the free base had significantly reduced absorption hinged on the inclusion of enough patients with elevated gastric pH to detect a difference in a bioequivalence trial. This raises a concern, as demonstrated through simulation, that dissolution/absorption differences in other formulations could be missed in routine bioequivalence trials. Aside from differences in active pharmaceutical ingredients (APIs), other factors, such as changes in excipients or manufacturing methods, may also lead to exposure differences between formulations at elevated gastric pH. For formulations containing different forms of the same active moiety or the same API and showing different dissolution profiles at elevated pH (i.e., pH ~ 4-6.8), evaluation of bioequivalence with gastric pH modulators (e.g., a H2 blocker) in addition to routine bioequivalence assessments may help to ensure therapeutic equivalence in patients with elevated gastric pH.
Pulmonary vein isolation in a patient with achalasia and megaesophagus.

Atrioesophageal fistula (AEF) is a rare but life-threatening complication of catheter ablation of atrial fibrillation (AF), thought to occur in as many as 0.03%–0.08% of cases.1 It is not known if patients with existing esophageal disorders, particularly those that dilate the esophagus, are at higher risk of AEF after pulmonary vein isolation (PVI). Achalasia is an inflammatory and neurodegenerative disorder of the esophagus characterized by increased tone and failure of relaxation of the lower esophageal sphincter as well as absent peristalsis of the esophageal body, often leading to progressive esophageal dilation and megaesophagus. Here we present a case of a 73-year-old man with symptomatic paroxysmal AF and achalasia and marked esophageal dilation despite Heller myotomy who underwent PVI with Cryoballoon (Medtronic, Minneapolis, MN), pharmacologic esophageal protection, and a multisensor esophageal temperature (ET) monitor.
Thermophysical properties of thorium mononitride from 298 to 1700 K

Abstract Nitride fuel forms offer higher actinide density, melting point, and thermal conductivity compared to traditional oxide fuels, and such properties afford a reduction in core size for comparable reactor designs. Preliminary findings show that additions of thorium mononitride (ThN) into uranium mononitride (UN) greatly improves the thermomechanical and neutronic performance of the fuel. This study is part of a series of experiments designed to precisely characterize the properties of thorium mononitride, for which little data is available in the published literature. The purpose of this work was to create high purity, dense (>92%) monoliths of ThN for use in thermophysical property measurements. This was achieved by traditional cold pressing and high temperature sintering under inert atmospheres. Sintered test specimens were used for the measurement of the coefficient of thermal expansion, heat capacity, thermal diffusivity, and thermal conductivity of ThN as a function of temperature from 298 to 1700 K. The thermal conductivity of ThN was found to exceed that of UN by up to a factor of 5 in temperatures relevant to the operation of nuclear reactors. The results of this work will facilitate more detailed thermodynamic, mechanical, and neutronic modeling of mixed UN and ThN fuel forms to aid in the design of thorium nitride reactors and fuel cycles.
Importance of Early Diagnosis in Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) can lead to long-term systolic dysfunction, especially among black women. Hypertensive disorders of pregnancy (HDP) are the strongest risk factor for PPCM, but controversy remains on whether HDP predict a favorable outcome. Women with HDP are also often diagnosed with PPCM earlier than those without HDP. Our objective is to determine recovery of systolic function in patients with PPCM stratified by HDP, timing of diagnosis, and race. We conducted a retrospective cohort study of 220 patients (55% black) diagnosed with PPCM. Patients with PPCM and HDP were diagnosed earlier postpartum than patients without HDP (P=0.013), an effect that was most pronounced in nonblack patients. Rates of left ventricular ejection fraction (LVEF) recovery were similar among PPCM patients with and without HDP (68.4% versus 62.6%, P=0.425). In contrast, patients with PPCM diagnosed after 1-month postpartum had lower rates of LVEF recovery than patients diagnosed <1-month postpartum (53.7% versus 69.9%, P=0.035). LVEF at time of diagnosis is a strong predictor of LVEF recovery, and patients with PPCM diagnosed after 1-month postpartum had lower baseline LVEF compared to patients presenting earlier (P=0.041). The presence of HDP does not correlate with LVEF recovery in our racially diverse PPCM cohort. In contrast, early diagnosis portends a favorable outcome. Early diagnosis is associated with higher LVEF at presentation, likely explaining the improved outcomes in these women. These findings underscore the need for early monitoring and diagnosis, especially in at-risk and underserved populations.
Primary Idiopathic Complex Aphthosis: Diagnosis and Successful Treatment with Montelukast in a 44-Year-Old Filipino Female.

Recurrent aphthous stomatitis (RAS) is an oral condition characterized by frequent attacks of painful oral ulcers. Complex aphthosis (CA) is a severe form of RAS described as the almost constant presence of ≥3 oral ulcers with or without genital aphthosis. Management of primary CA varies, but most patients warrant the use of systemic agents. Because of prolonged treatment, it is preferred to use systemic medications with the least side effects. Herein, we present a case of a primary idiopathic CA. Workup and examination were done to exclude Adamantiades-Behcet's disease and other diseases. The patient was shifted to montelukast after poor tolerance to colchicine. Favorable control of CA was noted during the 5-month follow-up period while the patient was on montelukast.
Validation and application of dynamic biplane radiography to study in vivo ankle joint kinematics during high-demand activities.

Abstract Ankle ligament injuries are the most common musculoskeletal injury in physically active populations. Failure to restore native kinematics post-injury often leads to long-term consequences including chronic instability and arthritis. Using traditional motion capture, it is difficult to distinguish independent motions of the tibiotalar and subtalar joints to assess the effects of injury, surgical repair, and rehabilitation on ankle joint complex (AJC) kinematics. Therefore, the aims of this study were to determine the accuracy of dynamic biplane radiography for determining in vivo AJC kinematics and arthrokinematics, and to identify sport-related movements that require the largest AJC range of motion (ROM) during support. Two subjects had three to five 1.0 mm diameter tantalum beads implanted into the tibia, fibula, talus, and calcaneus during lateral ankle ligament repair. Six months after surgery, the subjects executed seven movements while biplane radiographs were collected. Bone motion was tracked using radiostereophotogrammetric analysis (RSA) as a “gold standard”, and compared to a volumetric CT model-based tracking algorithm that matched digitally reconstructed radiographs to the original biplane radiographs. Over all movements, the average tibiotalar, subtalar and tibiofibular RMS errors were 0.5 mm ± 0.2 mm, 0.8 mm ± 0.5 mm and 0.8 mm ± 0.3 mm in translation and 1.4° ± 0.4°, 1.5° ± 0.5° and 1.7° ± 0.6° in rotation, respectively. Tibiotalar joint space was determined with an average precision of 0.5 mm. ROM results indicate that jumping and a forward-to-backward push-off movement are the best of the seven sport-related movements evaluated for eliciting full ROM kinematics.
Dépasser la survie pour atteindre l’ordinaire: Destiny de Pierrette Fleutiaux

Destiny, the final book of acclaimed French author Pierrette Fleutiaux, is a plight for the migrants cause and an invitation to the return of the value of hospitality. Step by step, the eponymous p...
Anisotropic Slab Scattering: Oblique Incidence Case

A heuristic uniform theory of diffraction (UTD) corner and wedge diffraction coefficient for predicting electromagnetic scattering by a thin lossless anisotropic slab when illuminated by an oblique incident field is presented. A previous proposed formulation has been modified to handle both normal and oblique incident cases. The formulation is valid for both uniaxial and biaxial media.
Electrical doping in halide perovskites

Electrical doping (that is, intentional engineering of carrier density) underlies most energy-related and optoelectronic semiconductor technologies. However, for the intensely studied halide perovskite family of semiconductors, reliable doping remains challenging, owing to, for example, compensation from and facile migration of intrinsic defects. In this Review, we first discuss the underlying fundamentals of semiconductor doping and then investigate different doping strategies in halide perovskites, including intrinsic defect, extrinsic defect and charge transfer doping, from an experimental as well as a theoretical perspective. We outline the advantages and pitfalls of different characterization techniques to assess doping and examine the impact of doping on optoelectronic properties. Finally, we highlight challenges that need to be overcome to gain control over the electronic properties of this important material class. Halide perovskites exhibit outstanding semiconductor properties and are a key component of a variety of devices, including solar cells and light-emitting diodes. This Review discusses electrical doping strategies for halide perovskites and takes a critical look at the challenges that need to be overcome to control the electronic properties of these semiconducting materials.
NUMERICAL SIMULATION ON UNSTEADY STATE HEAT TRASFER OF WORK ROLLS DURING CONTINUOUS HOT STRIP ROLLING

The spreading properties of unsteady state temperature wave,heating flux wave and heating shock phenomena during continuous hot slab rolling have been numerically simulated for three types of commonly used composite rolls by use of various coordinate systems and user-defined functions based on Fluent 6.3 software.The results indicate that the temperature wave can be divided into a high-frequency and low-frequency unsteady state temperature wave to describe the temperature distribution and spreading properties in rolls.It is found that the wave amplitude of the high-frequency temperature wave will quickly decrease with the increase of propagation depth,and its propagation depth of maximum impact is less than 7.5 mm.But,under the same rolling conditions,the amplitude attenuation of the low-frequency temperature wave is slower,and its propagation depth of impact is more than 20 mm.The heating shock decreases rapidly with the increase of distance from the surface of work roll.The heating shock depth is the deepest for the high speed steel composite roll,but the shallowest for the high nicked chromium cast iron composite roll under the same rolling conditions. The absorbed and resided heat by work-rolls during each slab hot rolling is down,but the dissipated heat by rolls is up with rolled slab number increasing.
Dynamic Graph Learning Based on Graph Laplacian

The purpose of this paper is to infer a global (collective) model of time-varying responses of a set of nodes as a dynamic graph, where the individual time series are respectively observed at each of the nodes. The motivation of this work lies in the search for a connectome model which properly captures brain functionality upon observing activities in different regions of the brain and possibly of individual neurons. We formulate the problem as a quadratic objective functional of observed node signals over short time intervals, subjected to the proper regularization reflecting the graph smoothness and other dynamics involving the underlying graph’s Laplacian, as well as the time evolution smoothness of the underlying graph. The resulting joint optimization is solved by a continuous relaxation and an introduced novel gradient-projection scheme. We apply our algorithm to a real-world dataset comprising recorded activities of individual brain cells. The resulting model is shown to not only be viable but also efficiently computable.
Phase I Study of Entinostat in Combination with Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer.

Lessons learned Entinostat at the selected dose levels in combination with a standard dose of enzalutamide showed a promising safety profile in this small phase I study BACKGROUND: Entinostat inhibits prostate cancer (PCa) growth and suppresses Treg cell function in vitro and in vivo. Methods This was a phase I study to explore the safety and preliminary efficacy of entinostat (3 and 5 mg orally per week) in combination with enzalutamide in castration resistant PCa (CRPC). The study was carried out in an open-label two-cohort design. Patients who had developed disease progression on or were eligible for enzalutamide were enrolled in the study. The safety profile of the combination therapy, Prostate specific antigen (PSA) levels, the pharmacokinetics of enzalutamide after entinostat administration, peripheral T-cell subtype (including Treg quantitation), and mononuclear cell (PBMC) histone H3 acetylation were analyzed. Results Six patients with metastatic CRPC were enrolled. There was no noticeable increment of fatigue related to entinostat. Toxicities possibly or probably related to entinostat or the combination therapy included grade 3 anemia 1/6 (17%), grade 2 white blood cell (WBC) decrease 1/6 (17%), and other self-limiting grade 1 adverse events (AEs). Median duration of treatment with entinostat was 18 weeks. Entinostat did not affect the steady plasma concentration of enzalutamide. Increased PBMC histone H3 acetylation was observed in blood samples. No evident T-cell subtype changes were detected, including in Treg quantitation. Conclusion Entinostat 5 mg weekly in combination with enzalutamide showed an acceptable safety profile in this small phase I study. A planned phase II part of the trial was terminated because of sponsor withdrawal.
Capture of CO2 and Water While Driving for Use in the Food and Agricultural Systems

This white paper proposes research on the design and evaluation of an integrated system assembled to the vehicle with no energy penalty where a sequence of processes, cooling, heating, mass transfer, and compression, will take place while driving. The increasing demand for fresh produce has led to an expansion of the US urban agriculture industry (greenhouses) which uses carbon dioxide (CO2) enrichment from burning fossil fuels to increase plant productivity and to shorten the plant growth time. The demand for CO2 and water in greenhouses is massive (2.81 kg CO2eq/kg produce, 22 L water/kg produce), and alternate CO2 and water delivery sources are essential to make post-harvest food processing technologies such as dense-phase CO2 pasteurization of beverages more sustainable. Internal combustion engines (ICE) have an average efficiency of about 30%, with 30% of the thermal energy wasted in the exhaust gases. A typical passenger vehicle emits about 4.6 metric tons of CO2 and 21,000 l of water per year into the environment. Although multiple carbon capture technologies exist, the size of these plants is large, their unit operations are fixed, and the use of novel materials is limited. In this white paper, we propose to retrofit the wasted energy in a car’s exhaust to capture, concentrate, store, and deliver liquid CO2 and water for agricultural and food systems. Preliminary thermodynamic and exergy analysis indicates that this is feasible. Specially designed heat and mass transfer units with novel materials and 3D printing technology could be easily deployed and used while driving to mitigate the global warming problem while addressing the needs of agricultural systems.
Health Aspects of Physical Education

(1937). Health Aspects of Physical Education. The Journal of Health and Physical Education: Vol. 8, No. 10, pp. 591-632.
Reducing the cost and effort of computer-aided test program development

Hewlett-Packard's marketing research over the past several years reveals that the chief concern of computer-aided test (CAT) managers is to reduce the cost and effort of program development. CAT software tools and techniques for rapidly developing high-performance test programs at lower costs and with less effort are discussed. Functional test manager (FTM) and interactive test generator (ITG) software packages work together to provide a very easy functional test software solution. FTM provides a wide range of capability designed to help automate functional test applications. ITG is a very easy-to-use tool for generating instrument control and measurement procedure software. It makes it possible to generate the instrument control portion of functional test programs without having to search through manuals looking for instrument control mnemonics. >
Characterization of the Ld-restricted cytotoxic T-lymphocyte epitope in the mouse hepatitis virus nucleocapsid protein.

Abstract The mouse hepatitis virus (MHV) JHM strain (JHMV) produces primary demyelination in the central nervous system associated with acute encephalomyelitis. Humoral and cellular immune responses both participate in controlling the development of chronic MHV-induced demyelination. A subset of the CD8+ cytotoxic T lymphocytes (CTL) induced by immunization of BALB/c (H-2d) mice with JHMV is specific for the viral nucleocapsid protein. This CTL population recognizes an epitope located within the carboxy-terminal 149 amino acids in association with the Ld class I molecule (S. A. Stohlman, S. Kyuwa, M. Cohen, C. Bergmann, J. P. Polo, J. Yeh, R. Anthony, and J. G. Keck, Virology 189:217-224, 1992). Using a panel of vaccinia virus recombinants expressing truncated forms of the nucleocapsid protein and a series of overlapping synthetic peptides, we mapped the response to 15 amino acids. This sequence, encompassing the MHV epitope, contains the Ld-specific binding motif. The predicted 9-mer peptide (residues 318 to 326: APTAGAFFF) was sufficient and highly active in sensitizing target cells for CTL recognition when either added exogenously or synthesized intracellularly. Cross-reactivity of JHMV nucleocapsid protein-specific CTL with six other MHV strains indicated that natural sequence variations within the 9-mer epitope are tolerated in positions 4 and 5, whereas all other amino acids are conserved. These data define a novel 9-mer Ld-restricted CTL epitope which represents the first MHV CTL epitope. Characterization of this epitope provides a molecular basis to study the role of nucleocapsid protein-specific CTL in the clearance of JHMV from the central nervous system.
Alternating Product Ciphers: A Case for Provable Security Comparisons

We formally study iterated block ciphers that alternate between two sequences of independent and identically distributed (i.i.d.) rounds. It is demonstrated that, in some cases the effect of alternating increases security, while in other cases the effect may strictly decrease security relative to the corresponding product of one of its component sequences. As this would appear to contradict conventional wisdom based on the ideal cipher approximation, we introduce new machinery for provable security comparisons. The comparisons made here simultaneously establish a coherent ordering of security metrics ranging from key-recovery cost to computational indistinguishability.
Cyclic nucleotide-gated channels: shedding light on the opening of a channel pore.

Few proteins have been described functionally in such detail as ion channels. All ion channels open and close their ion-conducting pores, a process referred to as gating. The recent crystallization of the P-loop-containing channel KcsA has cast channel function in a new light. Results relating to a variety of P-loop-containing channels are converging on a common mechanism in which separation of the inner helices that line the pore results in channel opening. At the same time, differences — some subtle and some perhaps more profound — have emerged between channel types. Here we highlight the evidence for a specific conformational change during the gating of cyclic nucleotide-gated channels, and compare and contrast this evidence to that obtained for other channels.
A Really Big Picture View of Social Intelligence

Daniel Goleman, author of the widely read book titled Emotional Intelligence, has written a new book, Social Intelligence: The New Science of Human Relationships, which deals with a topic that has ...
Configural learning in humans : The transverse patterning problem

Most learning theorists concur that some sort of configural representation system is required for animals to solve certain compound discriminations. Transverse patterning (A+ vs. B−, B+ vs. C−, C+ vs. A−) is one example of a problem that requires a configurai solution. It has been reported in the past that adult humans are unable to solve this problem (Berch & Israel, 1971; Franks, 1976). We investigated the generality of these reports. Moreover, we examined whether a stepwise approach to training this problem would facilitate learning and at what stage in training subjects adopt a configurai strategy. We found that college-aged adults had little difficulty solving the transverse patterning problem, and that their learning was greatly facilitated by using the stepwise approach described by Alvarado and Rudy (1989). Moreover, we found that subjects seem to adopt a configural strategy when faced with ambiguous stimulus pairs even when an elemental strategy would suffice. These results provide insight into how humans solve configurai problems and also suggest some direct tests of the role of the hippocampus in configural associations.
Fibrinogen γ′ chain binds thrombin exosite II

Summary. A high-affinity thrombin-binding site in an alternately processed fibrinogen variant, the γA/γ′ isoform, is characterized in this report. The binding site has been shown to be situated between γ′ 414 and 427, and Tyr418 and 422 in this part of the γ′ chain are known to be sulfated. A synthetic peptide corresponding to the γ′ chain carboxyl terminus is shown to bind thrombin with a Kd = 0.63 ± 0.16 µmol L−1. Maximum binding of this peptide requires negative charges on Tyr418 and 422. Competitive binding studies with hirudin peptides, heparin and DNA aptamers specific for thrombin exosites I or II indicate thrombin binds to the γ′ peptide via exosite II. Thus, thrombin binding to the γ′ chain leaves exosite I and the active site accessible to substrates. This may explain why fibrin-bound thrombin can retain enzymatic activity, and why fibrin-bound thrombin is heparin-resistant.
Reaction kinetics of Mo(a7S3, a5S2, a5DJ, a5GJ) with O2

Abstract The gas phase reactivities of Mo ( a 7 S 3 , a 5 S 2 , a 5 D J , a 5 G J ) with O2 with O2 in the temperature range 297–620 K are reported. Mo atoms were produced by the photodissociation of Mo(CO)6 and MoCl4 and detected by laser-induced fluorescence. The disappearance rates of all states are found to be pressure independent with argon buffer gas. The disappearance rate constants of the s 1 d 5 a 7 S 3 , a 5 S 2 and a 5 G J states are on the order of the gas kinetic rate constant. The s2d4a5DJ states are not as reactive and are found to be temperature dependent. Results are discussed in terms of the different electron configurations of the states.
Development of a method for detecting trace metals in aqueous solutions based on the coordination chemistry of hexahydrotriazines

The detection of trace amounts (<10 ppb) of heavy metals in aqueous solutions is described using 1,3,5-hexahydro-1,3,5-triazines (HTs) as chemical indicators and a low cost fluorimeter-based detection system. This method takes advantage of the inherent properties of HTs to coordinate strongly with metal ions in solution, a fundamental property that was studied using a combination of analytical tools (UV-Vis titrations, 1H-NMR titrations and computational modeling). Based on these fundamental studies that show significant changes in the HT UV signature when a metal ion is present, HT compounds were used to prepare indicator strips that resulted in significant fluorescence changes when a metal was present. A portable and economical approach was adopted to test the concept of utilizing HTs to detect heavy metals using a fluorimeter system that consisted of a low-pressure mercury lamp, a photo-detector, a monolithic photodiode and an amplifier, which produces a voltage proportional to the magnitude of the visible fluorescence emission. Readings of the prepared HT test strips were evaluated by exposure to two different heavy metals at the safe threshold concentration described by the U.S. Environmental Protection Agency (EPA) for Cr3+ and Ag2+ (100 μg L−1 and 6.25, respectively). This method of detection could be used to the presence of either metal at these threshold concentrations.
The impact of service failures on customer loyalty: The moderating role of affective commitment

This purpose of this study was to investigate the negative impact of service failures on customer loyalty. More specifically, we examined the moderating role of affective commitment on post‐failure attitudes and loyalty intentions under two service failure conditions: a successful and poor service recovery. Our findings indicate that emotionally‐bonded customers might feel “betrayed” when a service failure occurs, thus resulting in sharp decrease in post‐recovery attitudes. Conversely, this negativity effect was limited to poor service recovery among consumers with low affective commitment. Customers with lower levels of emotional bonding with the service provider were more “forgiving” when the service recovery was effectively handled. Poor service recovery led to more ambivalent post‐failure attitudes irrespective of the degree of affective commitment between the customer and the service provider. Finally, the results suggest that affective commitment might reduce the spill‐over effects of service failures to future loyalty behaviors. The implications for retention management strategies are briefly discussed.
Thread placement on the Intel Paragon: modeling and experimentation

In multicomputer architectures where communication latency is distance independent, thread placement is expected to have a limited impact on an application's performance. In this paper, the impact of thread placement on application performance is demonstrated on a wormhole routed multicomputer, the Intel Paragon. A communication intensive synthetic workload is used to "stress test" the effects of contention on communication latency induced by thread placement. It is shown by means of experimentation and modeling that appropriate thread placement patterns minimizing contention in the system's interconnection network improve performance. The analytic model and the experimental observations are in good agreement. >
Singularity cancellation in boundary integral equations for axisymmetric Stokes flow

The boundary element method (BEM) provides a scheme for solving boundary integral equations numerically by dividing the boundary into elements and approximating the unknown variables over these elements by means of shape functions. In recent years this method has developed into a powerful tool for solving engineering problems. One difficulty that arises in solving problems by the boundary element method is the computation of integrals that exist only in the sense of the Cauchy principal value. Singular kernels appear in integrals that are on or near the diagonal of the matrices that result from the discretization of the boundary, and the solution is very sensitive to the accurate calculation of these integrals. For axisymmetric creeping flow problems (i.e., at zero Reynolds numbers’s2) the singularities are of order l/r and logr. Integration through the logarithmic singularity is easily performed by logarithmic Gauss quadrature. In Cartesian co-ordinates the calculation of the l/r-singular integrals has been overcome by the use of the rigid body motion m e t h ~ d . ~ However, in axisymmetric creeping flow, rigid body motion cannot be imposed in the radial direction. Other modes of motion, analogous to rigid body motion, have been suggested by Sarihan and Mukherjee? Bakr’ and Rizzo and Shippy.6 For certain problems the principal value of singular integral can even be evaluated analytically.’ However, because of the complexity of the kernel functions (combinations of elliptic integrals of the first and second kinds), general analytical integration cannot be performed. Recently, Guiggiani and Cassilini’ reported the direct calculation of Cauchy principal value integrals using standard and logarithmic Gauss quadrature. Telles’ used a mapping technique to eliminate the singularity. We will show here that these singularities cancel out directly in axisymmetric BEM by means of algebraic simplification for arbitrary elements and mappings. It is more practical to cancel out the l/r-singularities and obtain non-singular expressions rather than to calculate them individually using other techniques. We begin by presenting the boundary integral equations that describe creeping flow of an incompressible Newtonian fluid. Then we show how these equations ‘simplify’ for axisymmetric flow. Finally we show how the singularities cancel for any order elements.
Does consumption of mega-doses of ascorbic acid pose a hemolytic risk to persons with sickle cell trait and sickle cell anemia?

Abstract Based on the occurrence of inherently high levels of erythrocyte copper in individuals with either sickle cell trait or sickle cell anemia and the demonstrated capacity of ascorbic acid to markedly enhance the hemolytic capacity of copper, it is proposed that persons with these hereditary blood disorders who ingest mega-doses of ascorbic acid may experience enhanced hemolytic changes.