Miracle-dz/UniFAR-FTUs huggingface dataset:
Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria

Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC50 values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.
Evaluation of the Effects of Thermal Management on Battery Life in Plug-in Hybrid Electric Vehicles

We develop a simulation model that aims to evaluate the effect of thermal management on battery life. The model consists of two submodels: a thermal model and a battery degradation model. The temperature rise in the battery is calculated using the thermal model, and a temperature profile is obtained under pre-defined driving, charging and stand-by scenarios. The temperature profile and the energy requirement required to achieve a driving profile act as inputs to the degradation sub-model, which is used to predict the battery life. The degradation model is derived from models and test data available in literature, and the model is constructed for aircooled cylindrical LiFePO4 cells based on the Hymotion Prius-conversion configuration. Preliminary results suggest that peak temperatures have the greatest impact on degradation: Thermal management increases life substantially in climates with high peak temperatures (Pheonix) and for more aggressive driving cycles (US06), while thermal management has less influence in climates with lower peak temperatures (Miami) and with gentle driving cycles (UDDS). Use of cabin air vs. outside air for thermal management has minor impact on battery life for the control strategy used, but thermostat control settings are important for lowering peak temperatures and extending battery life. Introduction Plug-in hybrid electric vehicles (PHEVs) have the potential to reduce operating cost, greenhouse gas (GHG) emissions, and petroleum consumption in the transportation sector. One of the most important factors affecting the commercialization of PHEVs is the battery cost, which should be reduced for PHEVs to be cost competitive with other vehicles [2-5]. While reducing the cost, other requirements should also be satisfied such as power, energy, weight, size, and life. Often, improving one of these factors causes an adverse effect in others. If the battery reaches end of life (EOL) before vehicle life, there would be need for battery replacement, which raises the costs for the consumer substantially since the battery is the most expensive part of the vehicle for many electrified vehicles. Although different design choices can lead to different battery EOL criteria [6], EOL is typically defined as the time when 20% capacity loss or 30% internal resistance growth is reached. According to the goals set by US Advanced Battery Consortium (USABC), a PHEV battery is targeted to have 15 years of calendar life and 300,000 cycles of cycle life One of these stress factors that strongly affects degradation rate is temperature. The relationship between degradation and temperature can be formulated by an Arrhenius type behavior where degradation rate increases exponentially with temperature [7]. To achieve these goals, it is necessary to improve battery life by managing the stress factors that affect battery life.
Combinatorial PX‐866 and Raloxifene Decrease Rb Phosphorylation, Cyclin E2 Transcription, and Proliferation of MCF‐7 Breast Cancer Cells

As a potential means to reduce proliferation of breast cancer cells, a multiple‐pathway approach with no effect on control cells was explored. The human interactome being constructed by the Center for Cancer Systems Biology will prove indispensable to understanding composite effects of multiple pathways, but its discovered protein–protein interactions require characterization. Accordingly, we explored the effects of regulators of one protein on downstream targets of the other protein. MCF‐7 estrogen receptor‐positive (ER+) breast cancer cells were treated with raloxifene to upregulate the TGF‐β pathway and PX‐866 to down‐regulate the PI3K/Akt pathway. This resulted in highly significant downstream reduction of cell cycle proliferation in breast cancer cells with no significant proliferation reduction following similar treatment of noncancerous MCF10A breast epithelial cells. Reduced phosphorylation of p107 and substantial reduction of Rb phosphorylation were observed in response. The effects of reduced Rb and p107 phosphorylation were reflected in significant decline in E2F‐1 transcriptional activity, which is dependent on pocket protein phosphorylation status. The reduced proliferation was related to decreased expression of cyclins, including E2F‐1‐regulated Cyclin E2, which was also in response to raloxifene and PX‐866. All combinations of raloxifene and PX‐866 produced significant or highly significant results for reduced MCF‐7 cell proliferation, reduced Cyclin E2 transcription, and reduced Rb phosphorylation. These studies demonstrated that uncontrolled proliferation of ER+ breast cancer cells can be significantly reduced by combinational targeting of two relevant pathways. J. Cell. Biochem. 117: 1688–1696, 2016. © 2015 Wiley Periodicals, Inc.
Irreversible inhibitors of serine, cysteine, and threonine proteases.

F. Vinyl Sulfones and Other Michael Acceptors 4683 G. Azodicarboxamides 4695 IV. Acylating Agents 4695 A. Aza-peptides 4695 B. Carbamates 4699 C. Peptidyl Acyl Hydroxamates 4700 D. â-Lactams and Related Inhibitors 4704 E. Heterocyclic Inhibitors 4714 1. Isocoumarins 4715 2. Benzoxazinones 4722 3. Saccharins 4725 4. Miscellaneous Heterocyclic Inhibitors 4728 V. Phosphonylation Agents 4728 A. Peptide Phosphonates 4728 B. Phosphonyl Fluorides 4734 VI. Sulfonylating Agents 4735 A. Sulfonyl Fluorides 4735 VII. Miscellaneous Inhibitors 4736 VIII. Summary and Perspectives 4737 IX. Acknowledgments 4740 X. Note Added in Proof 4740 XI. References 4740
Development of the Burden Distribution and Gas Flow Model in the Blast Furnace Shaft

It is important to control the burden distribution, which affects the gas flow pattern in the blast furnace. Therefore, a burden distribution analysis model is needed to predict the burden profile. In this study, the burden descent and gas flow models were developed to complete a blast furnace analysis model. A previous study reported two models based on the burden trajectory and stock model. The burden profile that is due to the burden trajectory was calculated using stock model in the upper part of shaft. The entire burden profile, which is classified into five burden types calculated using the descent model, was used for a gas flow calculation as the initial conditions in the gas flow model. The analysis models were developed using a visual basic based spread sheet, and compared with the 1/12 scaled model experiment. In addition, a GUI (Graphic User Interface) was added for the convenience of the operators.
Improving corrosion performance by surface patterning

Based on the idea that hydrophobic (low or non-wettable) surfaces can decrease the contact area between a corrosive solution and a surface, thereby potentially rendering the material more corrosion resistant, the effect of surface patterning on the corrosion behaviour of nickel was investigated. The surface patterning consisted of an array of holes of various diameters (D) and inter-hole spacings (L) that were produced by a laser ablation process. The corrosion behaviour of the patterned surfaces was studied using a potentiodynamic polarization method in a 0.5M H2SO4 electrolyte and compared with that of a polished reference sample. Following the potentiodynamic polarization corrosion test cycle, the corroded surfaces were examined using scanning electron microscopy (SEM) for morphological features and white light interferometry (WLI) to determine the surface roughness. The changes in surface morphology were related to the corrosion behaviour. A relationship was found between D, L, and the corrosion current density (Icorr), whereby the higher the (D/L ) 2 ratio, the higher the Icorr value. The corrosion potential (Ecorr) of all surface patterned samples was lower
Transcranial Magnetic Stimulation in Epilepsy

Transcranial magnetic stimulation (TMS) seems an attractive tool for the study of seizure disorders. It is simple to perform, relatively inexpensive, and generally safe, with the potential to provide noninvasive clinical measurements of neuronal excitability. Applications in patients with epilepsy include investigation of underlying cortical excitability and determination of the effects of antiepileptic drugs (AEDs); preoperative localization of epileptic foci; and functional mapping. Several review articles have been published on the use of TMS for epilepsy (1, 2, 3, 4, 5). Most intriguingly, TMS could become a new seizure treatment modality. The parameters measured by TMS include motor threshold, which is the minimal threshold for motor response in target muscle and motor evoked potential (MEP) amplitude, both measured using single pulses (see Table 1). The cortical silent period (CSP) is a lapse in electromyogram (EMG), when a TMS pulse is given during tonic voluntary muscle contraction; its duration is related to stimulus intensity. Additional parameters are measured with paired-pulse stimulation techniques. For example, intracortical inhibition (ICI), a decrease in MEP amplitude from the first to the second stimulus, is seen when a subthreshold conditioning pulse is followed by a suprathreshold pulse after a 2- to 5-millisecond delay, whereas intracortical facilitation (ICF) occurs when the pulses are 7 to 20 milliseconds apart. TABLE 1 TMS Parameters There is uncertainty concerning the physiologic mechanisms underlying these phenomena. Motor threshold probably reflects cortical and spinal neuronal membrane excitability as well as intracortical synaptic and corticospinal connections (6). MEP reflects the overall pool of potentially excitable neurons; CSP possibly indicates activation of γ-aminobutyric acid (GABAergic) inhibitory interneurons; and ICI and ICF have ill-defined “inhibitory” and “excitatory” mechanisms (4). The currents generated by TMS and their physiological effects are modulated by a wide variety of factors, including coil construction and positioning, brain conductivity, and neuronal orientation. The brain is not an ideal, uniform, conduction medium. Distribution of field strength and flux as well as effects on cortical excitability may be difficult to predict. Positron emission tomography (PET) blood-flow studies, for example, showed multifocal, bilateral activation from unilateral motor cortex stimulation (7).
A critical role for mTORC1 in erythropoiesis and anemia

Red blood cells (RBC) must coordinate their rate of growth and proliferation with the availability of nutrients, such as iron, but the signaling mechanisms that link the nutritional state to RBC growth are incompletely understood. We performed a screen for cell types that have high levels of signaling through mTORC1, a protein kinase that couples nutrient availability to cell growth. This screen revealed that reticulocytes show high levels of phosphorylated ribosomal protein S6, a downstream target of mTORC1. We found that mTORC1 activity in RBCs is regulated by dietary iron and that genetic activation or inhibition of mTORC1 results in macrocytic or microcytic anemia, respectively. Finally, ATP competitive mTOR inhibitors reduced RBC proliferation and were lethal after treatment with phenylhydrazine, an inducer of hemolysis. These results identify the mTORC1 pathway as a critical regulator of RBC growth and proliferation and establish that perturbations in this pathway result in anemia. DOI: http://dx.doi. org/10.7554/eLife.01913. 001
Physcomitrella Patens Dehydrins (PpDHNA and PpDHNC) Confer Salinity and Drought Tolerance to Transgenic Arabidopsis Plants

Dehydrins (DHNs) as a member of late-embryogenesis-abundant (LEA) proteins are involved in plant abiotic stress tolerance. Two dehydrins PpDHNA and PpDHNC were previously characterized from the moss Physcomitrella patens, which has been suggested to be an ideal model plant to study stress tolerance due to its adaptability to extreme environment. In this study, functions of these two genes were analyzed by heterologous expressions in Arabidopsis. Phenotype analysis revealed that overexpressing PpDHN dehydrin lines had stronger stress resistance than wild type and empty-vector control lines. These stress tolerance mainly due to the up-regulation of stress-related genes expression and mitigation to oxidative damage. The transgenic plants showed strong scavenging ability of reactive oxygen species(ROS), which was attributed to the enhancing of the content of antioxidant enzymes like superoxide dismutase (SOD) and catalase (CAT). Further analysis showed that the contents of chlorophyll and proline tended to be the appropriate level (close to non-stress environment) and the malondialdehyde (MDA) were repressed in these transgenic plants after exposure to stress. All these results suggest the PpDHNA and PpDHNC played a crucial role in response to drought and salt stress.
Reinduction with Certolizumab Pegol in Patients with Crohn's Disease Experiencing Disease Exacerbation: 7-Year Data from the PRECiSE 4 Study

Background:Patients with Crohn's disease in whom tumor necrosis factor antagonist therapy fails have limited treatment options, and the benefit of reintroducing the same therapy remains unclear. Here, we report results from PRECiSE 4 (NCT00160706), an open-label extension study of certolizumab pegol in patients who withdrew from the placebo-controlled studies PRECiSE 1 or 2. Methods:Patients eligible for PRECiSE 4 had Crohn's disease exacerbation on placebo or primary or secondary failure to certolizumab pegol in PRECiSE 1 or 2, and received 400 mg certolizumab pegol subcutaneously at weeks 0, 2, and 4 and every 4 weeks thereafter up to 360 weeks. We assessed safety (adverse events) and efficacy (clinical remission) of extended certolizumab pegol therapy. Results:Patients enrolled in PRECiSE 4 (N = 310; mean age, 37 yr; 58% female; 95% white) had a mean Crohn's disease duration of 8.5 years before entering the qualifying studies. At weeks 52, 104, and 156, remission rates were 28.5%, 17.5%, and 12.6% by nonremitter imputation, and 63.8%, 60.0%, and 63.5% by observed cases, with 47.4%, 31.9%, and 23.2% of patients, respectively, remaining on therapy. By study end (7.5 yr), 92.3% of patients discontinued therapy, 49% on account of adverse events. No new safety signals emerged. Incidence rate (new cases)/100 patient-years was 6.11 for serious infections and 1.29 for malignancies. Conclusions:Certolizumab pegol was effective in many patients who previously discontinued certolizumab pegol for lack or loss of response. Thus, discontinuation of therapy may not always be necessary. Safety was consistent with previous findings.
Base-Station Duty-Cycling and Traffic Buffering as a Means to Achieve Green Communications

In this paper, we propose the Base-Station (BS) Discontinuous Transmission (DTX) as the means for saving energy. Traditional proposals utilize DTX at the BS to enable sleep modes under lightly loaded scenarios. However, we propose to shape the traffic to enable more frequent sleep modes at the BS, while ensuring the QoS requirements in terms of application delay are successfully met. The results show that our DTX proposal has a significant potential even under moderately loaded scenarios. The system Energy Efficiency (EE) gain is achieved in our proposal by exploiting the classical Energy-delay tradeoff. We show the performance of our scheme in the presence of realistic system power models proposed within the framework of EARTH project.
Bruton's Tyrosine Kinase Is Required for Activation of Iκb Kinase and Nuclear Factor κb in Response to B Cell Receptor Engagement

Mutations in the gene encoding Bruton's tyrosine kinase (btk) cause the B cell deficiency diseases X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. In vivo and in vitro studies indicate that the BTK protein is essential for B cell survival, cell cycle progression, and proliferation in response to B cell antigen receptor (BCR) stimulation. BCR stimulation leads to the activation of transcription factor nuclear factor (NF)-κB, which in turn regulates genes controlling B cell growth. We now demonstrate that a null mutation in btk known to cause the xid phenotype prevents BCR-induced activation of NF-κB. This defect can be rescued by reconstitution with wild-type BTK. This mutation also interferes with BCR-directed activation of IκB kinase (IKK), which normally targets the NF-κB inhibitor IκBα for degradation. Taken together, these findings indicate that BTK couples IKK and NF-κB to the BCR. Interference with this coupling mechanism may contribute to the B cell deficiencies observed in XLA and xid.
Effects of Outdated Control Information in Control-Plane-Enabled Optical Networks With Path Protection

New signaling suites for a distributed control plane in wavelength division multiplexing (WDM) networks, such as generalized multiprotocol label switching (GMPLS) and automatic switched optical networks (ASON), allow one to cope with the increasing variability of traffic patterns to be supported by operators by providing a means to dynamically set up and release connections. The dissemination of link-state information [usually provided by routing protocols such as open-shortest-path-first traffic engineering (OSPF-TE)] is essential in this kind of control-plane enabled network: in particular, this information has to be continuously updated to allow routing algorithms to efficiently carry out the path computation. Most of the studies on dynamic traffic routing tend to neglect the effect of delays in control-information distribution on routing performance: in particular, even when the control plane is considered as in testbeds, emulators, or some simulations, the analysis of the effects of control plane delays is limited to a small range of values, applicable to well-specified contexts. Applying a very general control-delay representation, we are able to provide a wide-range simulative study to quantify the effect of signaling on routing performance, mainly by using the blocking probability metric. We are able to evaluate the effect of outdated information (1) for a wide interval of control delay values, (2) for a large set of routing scenarios, considering, e.g., unprotected, dedicated, and shared path protection routing, and (3) quantifying the different delay effects in the absence or in the presence of wavelength conversion capabilities.
Irritable bowel syndrome symptom severity improves equally with probiotic and placebo

AIM To determine the effects of Lactobacillus acidophilus NCFM on irritable bowel syndrome (IBS) symptoms and quality of life (QoL). METHODS In this randomized triple-blind trial, adult IBS volunteers who were recruited according to Rome III criteria received 109 or 1010 colony-forming units of NCFM or placebo daily for 12 wk. IBS Symptom Severity Score (IBS-SSS), which constituted the primary outcome, and secondary outcomes, including individual IBS symptoms, IBS-related QoL questionnaire, anxiety and depression, defecation frequency, and stool consistency, were assessed at baseline at the end of the 8-wk run-in period, after 4 and 12 wk of intervention, and after a 4-wk washout. RESULTS A total of 340 of 391 randomized volunteers completed the trial. IBS-SSS improved over 12 wk of treatment in all treatment groups, decreasing by a mean ± SD of 44.0 ± 80.2, 50.8 ± 82.4, and 48.3 ± 72.2 in the placebo, active low-dose, and active high-dose groups, respectively. Similarly, secondary outcomes did not differ between treatment groups. However, in a post hoc analysis of volunteers with moderate to severe abdominal pain at baseline (VAS > 35/100), the treatment significantly reduced the sensation of abdominal pain. Pain scores fell by 20.8 ± 22.8, 29.4 ± 17.9, and 31.2 ± 21.9 in the placebo, active low-dose, and active high-dose groups, respectively (P value for placebo vs combined active doses = 0.0460). CONCLUSION NCFM alleviates moderate to severe abdominal pain, consistent with earlier observations of this strain mitigating visceral pain through increased analgesic receptor expression.
Assessment of Proinflammatory Th 1 Cytokines ( IL 18-IFN ) and Th 2 Cytokine ( IL 13 ) Concentrations in patients with Autoimmune Rheumatic Diseases ( Systemic Lupus Erythematosus , Rheumatoid Artharitis and Systemic Sclerosis )

Objective: Several cytokines play a role in the production of autoantibodies and the pathogenesis of rheumatic diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic sclerosis (SS). This study investigated serum concentration of the proinflammatory Th1 cytokine; IL18 and its inducer IFN, the study also investigated serum concentration of proinflammatory Th2 cytokine; IL13, to explain the role of Th1 and Th2 in the pathogenesis of autoimmune rheumatic diseases (SLE, RA and SS) Patients and methods: IL18, IFN and IL13 levels were evaluated by enzyme linked immunosorbent assay (ELISA). Four groups were included in this study. Group I: Comprised (15) patients of SLE. Group II: Comprised (15) patients of RA. Group III: Comprised (15) patients with SS. Group IV: Control group consisted of (15) sex and age matched healthy controls. Results: Serum levels of IL18 was significantly higher in SLE (3138.200 1413.096 pg/ml)& RA(3336.667 921.839 pg/ml) than control group(86.647 35.370 pg/ml ), while IL18 in SS had no statistically significant difference between patients (103.634 50.593 pg/ml) and control group (86.647 35.370 pg/ml). The cut off level was 257.75 pg/ml . IFN was significantly higher in SLE patients (5.4391.430 IU/ml) and RA patients (2.973 0.598 IU/ml ) than control group(0.580  0.234 IU/ml) ,while IFN in SS had no statistically significant difference (0.592 0.245IU/ml) than control group (0.580  0.234 IU/ml) . The cut off level was1.2 IU/ml . As regard IL13 it was significantly higher in SLE patients (55.6736.892 pg/ml) ,RA patients (59.58712.183 pg/ml) and SS (61.550 12.047 pg/ml) than control group (21.427 7.274 pg/ml ) . The cut off level was 44.4 pg/ml . There was significant positive correlation of IL18/ IL13 and IFN / IL13 ratio in SLE and RA , while significant negative correlation of IL18/ IL13 and IFN / IL13 ratio in SS. Conclusion: There was a significant increase of both Th1 cytokines (IL18 and IFN) and Th2 cytokine (IL13) in SLE and RA with Th1 predominance,while predominance of Th2 cytokine (IL13) in SS than Th1 cytokine (IL18 and IFN). This result suggests that IL18, INF and IL13 could be involved in the pathogenesis of autoimmune rheumatic diseases.