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At least 379 records · Page 21

Artificial neural network algorithms for pulse shape discrimination and recovery of piled-up pulses in organic scintillators

We developed two neural-network (NN)-based algorithms (fully-connected neural network (Fc-NN) and recurrent neural network (RNN)) to perform pulse shape discrimination (PSD) and identification of piled-up pulses produced by organic scintillators, upon interaction with neutrons and gamma rays. We tested the algorithms on measured and verification sets of data and compared their classification performances to standard approaches. At a high acquisition count rate (100,000 counts per second, cps), in the presence of a gamma-to-neutron ratio of approximately 400–1, the proposed NN-based algorithm achieves a fraction of misclassified neutron, gamma, and piled-up pulses of approximately 1%, 1.8%, and 0.6%, respectively. Compared to the traditional approach, it exhibits 3×, 14×, and 11× improved (lower) miscalculation rates for neutron, gamma, and piled-up pulses, respectively. Here, we also demonstrate the capability of NN-based algorithms of successfully recovering and identifying neutron and gamma ray compositions from piled-up pulses in challenging, high pulse count rate conditions.

42 ENGINEERING↗

Experimental and analytical study of the hydrodynamic and single and two-phase convective heat transfer performance of flexible PDMS microchannels with micropillar arrays

Various copper and silicon based thermal management systems are used in the cooling of electronics. However, the rigid nature of these materials along with their high thermal and electrical conductivity pose a difficulty in developing direct contact embedded flexible cooling systems that can offer robust cooling performance. The low density, thermal stability, chemical inertness, and electrical insulation of Polydimethylsiloxane (PDMS) make it an ideal material to develop lightweight direct contact thermal management systems for electronics. Its ease of fabrication with tunable flexibility provides the opportunity to go beyond traditional electronics and develop advanced active and passive thermal management systems for a wide–range of applications in foldable and wearable electronics, liquid cooling garments, microgravity, and electric motors. In this study, a flexible PDMS based microchannel with micropillar arrays, which enhance the thermal performance of the device through capillary-assisted flow, has been developed. The hydrodynamic and convection heat transfer performance of three PDMS wick pillar geometries, ranging from a porosity of 0.8–0.91, are investigated and compared under single-phase and two-phase conditions. Dielectric coolant FC-3283 is employed and permeability measurements are made for mass fluxes ranging from 53 kg/m 2 s to 369 kg/m 2 s. Given its conformability, the device demonstrates a deviation from Darcy’s Law, within the laminar regime, with an increasing permeability with mass flux at the rate of ~0.5–0.8 Darcy/(kg/m 2 s). A semi-analytical model has been developed and reported to quantify the conformability of the device. The heat transfer performance is experimentally evaluated using the same dielectric fluid for mass flux ranging from 105 kg/m 2 s to 420 kg/m 2 s with heat fluxes ranging from 1.5 W/cm 2 to 16 W/cm 2 . Heat transfer coefficients of up to 7000 W/m 2 K are observed, which are comparable to copper and silicon microchannels. The effect of porosity on the single phase thermal performance has been evaluated against the pumping power to provide a basis for thermal management system design. Finally, high-speed imaging is performed to study the two-phase flow characteristics to provide insight into the vapor formation and removal.

42 ENGINEERING↗

VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells

Research highlights: {yields} Bone marrow-derived mast cells (BMMCs) secrete functional VEGF but do not degranulate after Cobalt chloride-induced hypoxia. {yields} CoCl{sub 2}-induced VEGF secretion in mast cells occurs by a Ca{sup 2+}-insensitive but brefeldin A and Tetanus toxin-sensitive mechanism. {yields} Trolox and N-acetylcysteine inhibit hypoxia-induced VEGF secretion but only Trolox inhibits Fc{epsilon}RI-dependent anaphylactic degranulation in mast cells. {yields} Src family kinase Fyn activation after free radical production is necessary for hypoxia-induced VEGF secretion in mast cells. -- Abstract: Mast cells (MC) have an important role in pathologic conditions such as asthma and chronic obstructive pulmonary disease (COPD), where hypoxia conduce to deleterious inflammatory response. MC contribute to hypoxia-induced angiogenesis producing factors such as vascular endothelial growth factor (VEGF), but the mechanisms behind the control of hypoxia-induced VEGF secretion in this cell type is poorly understood. We used the hypoxia-mimicking agent cobalt chloride (CoCl{sub 2}) to analyze VEGF secretion in murine bone marrow-derived mast cells (BMMCs). We found that CoCl{sub 2} promotes a sustained production of functional VEGF, able to induce proliferation of endothelial cells in vitro. CoCl{sub 2}-induced VEGF secretion was independent of calcium rise but dependent on tetanus toxin-sensitive vesicle-associated membrane proteins (VAMPs). VEGF exocytosis required free radicals formation and the activation of Src family kinases. Interestingly, an important deficiency on CoCl{sub 2}-induced VEGF secretion was observed in Fyn kinase-deficient BMMCs. Moreover, Fyn kinase was activated by CoCl{sub 2} in WT cells and this activation was prevented by treatment with antioxidants such as Trolox and N-acetylcysteine. Our results show that BMMCs are able to release VEGF under hypoxic conditions through a tetanus toxin-sensitive mechanism, promoted by free radicals-dependent Fyn kinase activation.

60 APPLIED LIFE SCIENCES↗

Static pressure accelerates ox-LDL-induced cholesterol accumulation via SREBP-1-mediated caveolin-1 downregulation in cultured vascular smooth muscle cells

Research highlights: {yields} Vertical static pressure accelerates ox-LDL-induced cholesterol accumulation in cultured vascular smooth muscle cells. {yields} Static pressure induces SREBP-1 activation. {yields} Static pressure downregulates the expressions of caveolin-1 by activating SREBP-1. {yields} Static pressure also downregulates the transcription of ABCA1 by activating SREBP-1. {yields} Static pressure increases ox-LDL-induced cholesterol accumulation by SREBP-1-mediated caveolin-1 downregulation in vascular smooth muscle cells cultured in vitro. -- Abstract: Objective: To investigate the effect of static pressure on cholesterol accumulation in vascular smooth muscle cells (VSMCs) and its mechanism. Methods: Rat-derived VSMC cell line A10 treated with 50 mg/L ox-LDL and different static pressures (0, 60, 90, 120, 150, 180 mm Hg) in a custom-made pressure incubator for 48 h. Intracellular lipid droplets and lipid levels were assayed by oil red O staining and HPLC; The mRNA levels of caveolin-1 and ABCA1, the protein levels of caveolin-1 SREBP-1 and mature SREBP-1 were respectively detected by RT-PCR or western blot. ALLN, an inhibitor of SREBP metabolism, was used to elevate SREBP-1 protein level in VSMCs treated with static pressure. Results: Static pressures significantly not only increase intracellular lipid droplets in VSMCs, but also elevate cellular lipid content in a pressure-dependent manner. Intracellular free cholesterol (FC), cholesterol ester (CE), total cholesterol (TC) were respectively increased from 60.5 {+-} 2.8 mg/g, 31.8 {+-} 0.7 mg/g, 92.3 {+-} 2.1 mg/g at atmosphere pressure (ATM, 0 mm Hg) to 150.8 {+-} 9.4 mg/g, 235.9 {+-} 3.0 mg/g, 386.7 {+-} 6.4 mg/g at 180 mm Hg. At the same time, static pressures decrease the mRNA and protein levels of caveolin-1, and induce the activation and nuclear translocation of SREBP-1. ALLN increases the protein level of mature SREBP-1 and decreases caveolin-1 expression, so that cellular lipid levels were upregulated. Conclusion: Static pressures stimulate ox-LDL-induced cholesterol accumulation in cultured VSMCs through decreasing caveolin-1 expression via inducing the maturation and nuclear translocation of SREBP-1.

60 APPLIED LIFE SCIENCES↗

Regulation of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling during late stage osteoclast differentiation

Highlights: Black-Right-Pointing-Pointer Calcineurin/NFAT inhibitors FK506 and VIVIT treated human PBMC derived osteoclasts in vitro. Black-Right-Pointing-Pointer Differential regulation of ITAM receptors and adaptor molecules by calcineurin/NFAT inhibitors. Black-Right-Pointing-Pointer FK506 and VIVIT suppress ITAM factors during late phase osteoclast differentiation. -- Abstract: Osteoclasts are specialised bone resorptive cells responsible for both physiological and pathological bone loss. Osteoclast differentiation and activity is dependent upon receptor activator NF-kappa-B ligand (RANKL) interacting with its receptor RANK to induce the transcription factor, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway has been identified as a co-stimulatory pathway in osteoclasts. Osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells (TREM2) are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FcR{gamma}) and DNAX-activating protein 12 kDa (DAP12) respectively to induce calcium signalling. Treatment with calcineurin-NFAT inhibitors, Tacrolimus (FK506) and the 11R-VIVIT (VIVIT) peptide, reduces NFATc1 expression consistent with a reduction in osteoclast differentiation and activity. This study aimed to investigate the effects of inhibiting calcineurin-NFAT signalling on the expression of ITAM factors and late stage osteoclast genes including cathepsin K (CathK), Beta 3 integrin ({beta}3) and Annexin VIII (AnnVIII). Human peripheral blood mononuclear cells (PBMCs) were differentiated with RANKL and macrophage-colony stimulating factor (M-CSF) over 10 days in the presence or absence of FK506 or VIVIT. Osteoclast formation (as assessed by tartrate resistant acid phosphatase (TRAP)) and activity (assessed by dentine pit resorption) were significantly reduced with treatment. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that FK506 treatment significantly (p < 0.05) reduced the expression of NFATc1, CathK, OSCAR, FcR{gamma}, TREM2 and DAP12 during the terminal stage of osteoclast formation. VIVIT treatment significantly (p < 0.05) decreased CathK, OSCAR, FcR{gamma}, and AnnVIII, gene expression. This data suggest FK506 and VIVIT act differently in targeting the calcineurin-NFAT signalling cascade to suppress key mediators of the ITAM pathway during late stage osteoclast differentiation and this is associated with a reduction in both osteoclast differentiation and activity.

60 APPLIED LIFE SCIENCES↗

Tetravalent anti-CD20/CD3 bispecific antibody for the treatment of B cell lymphoma

Bispecific antibodies (bsAbs) are second generation antibodies for therapeutic application in immunotherapy. One of the major strategies of the bsAb platform is the recruitment of immune effector T cells by incorporating an anti-CD3 domain. A bispecific T-cell engager (BiTE), with one end having an affinity for CD3 and the other end with affinity for CD19, has been approved in the US and Europe for the treatment of acute lymphoblastic leukemia. However, due to their small size and lack of Fc region, these single-chain variable fragment (scFv) bsAbs have short half-lives in vivo. Additionally, poor solubility, structural instability, and low production yields have also become major challenges in the bulk production process. To overcome these challenges, we have engineered a tetravalent bsAb with bivalent binding specificity for the CD20 and CD3 antigen in an immunoglobulin G (IgG) format. The fusion of the anti-CD3 scFvs to the CD20 antibody via a linker-hinge domain (LHD) results in improved antibody stabilization and properties. Here we demonstrate this antibody's highly efficient cancer cell elimination in a dose-dependent manner in a CD20-expressing B lymphoblastoid cell line in vitro. Our data suggest the potential clinical application of this bsAb for the treatment of CD20-expressing B cell malignancies. - Highlights: • A bispecific antibody (bsAb) can increase immunotherapeutic efficacy. • A tetravalent bsAb with binding specificity for the CD20 and CD3 antigens is proposed. • A linker-hinge domain (LHD) within the bsAb results in improved antibody properties.

60 APPLIED LIFE SCIENCES↗

Analysis and quality control of carbohydrates in therapeutic proteins with fluorescence HPLC

Conbercept is an Fc fusion protein with very complicated carbohydrate profiles which must be carefully monitored through manufacturing process. Here, we introduce an optimized fluorescence derivatization high-performance liquid chromatographic method for glycan mapping in conbercept. Compared with conventional glycan analysis method, this method has much better resolution and higher reproducibility making it excellent for product quality control.

60 APPLIED LIFE SCIENCES↗

Life, death and tolerance

Highlights: • CD95 triggers death as well as non-death activities - e.g. proliferation, invasion and inflammation. • The CD95-Fc fusion protein, APG101, can serve as a tool to manipulate CD95-mediated non-death and death events. • The manipulation of the new immunological Annexin checkpoint system has an impact on peripheral tolerance towards apoptotic cells.

60 APPLIED LIFE SCIENCES↗

Fluorographite-co-polydimethylsiloxane coated polyvinylidene-fluoride membrane for desalination of highly saline water with humic acid in direct contact membrane distillation

Highlights: • Surface modifications by FGi particles with PDMS binder of PVDF microporous membranes shown improvement in DCMD. • LEP with DI water & performance of M2-M4 modified membranes in DCMD was enhanced with 1M NaCl & 10 ppm HA feed solution. • Amphiphobicity was evidenced by CA with low surface tension liquids upto 38 dyne/cm as well as with canola oil. • EDX analysis proved enhancement in FC ratio and membrane surface analysis lead to understand enhanced performance in DCMD. Membranes with amphiphobic properties are crucial for desalination of concentrated saline water with organic foulant by membrane distillation. In this research, we coated Fluorographite (FGi) particles on polyvinylidene-fluoride (PVDF) flat sheet membranes with 0.8% v/v polydimethylsiloxane (PDMS) as binder by filtration coating method. We evaluated its amphiphobicity via contact angles which were observed by DI water, canola oil and organic solutions as mimicking for oleophobicity. Surface modifications by FGi particles on the surface of membranes was introduced with PDMS binder which brought bifunctionality of amphiphobicity to enhance hydrophobicity and oleophobicity. We also investigated performance of coated membranes in direct contact membrane distillation (DCMD) with 1 molar concentrated NaCl solution along with humic acid being organic foulant and compared with virgin membrane (M1 membrane) and Liquid entry pressure (LEP) was also evaluated. LEP was measured by dynamic method which shown considerable improvement in coated membranes. M3 membrane showed overall better performance in terms of salt rejection higher than 99.87% and flux as compared to M1 membrane. Furthermore, the evaluation of surface characterizations was done by FESEM with EDX, AFM and FTIR. Surface morphology confirmed the coating of FGi on membrane surface while EDX evidenced increase in atomic percent of fluorine in turn F:C ratio.

54 ENVIRONMENTAL SCIENCES↗

Redox-active dinuclear oxorhenium(V) pyrazolate complexes

Four new structurally similar dinuclear oxorhenium(V) complexes, [{Re(O)X(PPh 3 )} 2 (μ-O)(μ-4-x'-pz) 2 ], where pz = pyrazolate anion, X = X' = Cl (1) and Br (4), X = Cl, X' = Br (2), and X = Br, X' = Cl (3), have been synthesized and characterized. Little variation in spectroscopic features – 1 H NMR, IR, UV–Vis – exists among the four complexes. All complexes possess a bent Re-O-Re core as well as distorted octahedral coordination geometry around the rhenium centers. Finally, a reversible one-electron electrochemical process is observed at approximately 0.84 V vs. Fc + /Fc in all four complexes; however, changing the terminal halide from chloride to bromide slightly destabilizes the oxidized Re(VI) center.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Performance analysis of hybrid power configurations: Impact on primary energy intensity, carbon dioxide emissions, and life cycle costs

In this work, utilization of Natural gas and Hydrogen to support current and future building energy needs to offset the total electric demand while improving the grid resiliency and energy efficiency was investigated. Demand side energy management will play an important role in efficiently managing the available energy resources. Performance assessment of different power generation and energy management configurations is presented in this paper. Development of solutions in addressing grid resiliency by providing the ability to design suitable configurations for meeting individual building energy needs is discussed. Primary movers (PM) such as internal combustion engines (ICE) and fuel cells (FC) along with small scale auxiliary renewable energy source such as photovoltaics (PV) were considered. Key attributes of total carbon foot-print, life cycle costs including capital and operational expenditure, electric grid offset or peak shaving capability, thermal energy availability and its further potential to offset total electric demand, and primary energy intensity are analyzed and discussed in detail.

08 HYDROGEN↗

Cost of a potential hydrogen-refueling network for heavy-duty vehicles with long-haul application in Germany 2050

Long-distance road-freight transport emits a large share of Germany's greenhouse gas (GHG) emissions. A potential solution for reducing GHG emissions in this sector is to use green hydrogen in fuel cell electric vehicles (FC-HDV) and establish an accompanying hydrogen refueling station (HRS) network. In this paper, we apply an existing refueling network design model to a HDV-HRS network for Germany until 2050 based on German traffic data for heavy-duty trucks and estimate its costs. Comparing different fuel supply scenarios (pipeline vs. on-site), the on-site scenario results show a network consisting of 137 stations at a cost of 8.38 billion € per year in 2050 (0.40 € per vehicle km), while the centralized scenario with the same amount of stations shows a cheaper cost with 7.25 billion euros per year (0.35 € per vehicle km). Finally, the hydrogen cost (LCOH) varies from 5.59 €/kg (pipeline) to 6.47 €/kg (on-site) in 2050.

08 HYDROGEN↗

Fabric evolution and dilatancy within anisotropic critical state theory guided and validated by DEM

Fabric, expressed by means of an evolving deviatoric fabric tensor F, plays a very important role in the anisotropic mechanical response of granular materials. The Anisotropic Critical State Theory (ACST) addresses fabric anisotropy by rendering dilatancy a function of F, in addition to other state variables. In this paper, 3D DEM is used to guide the specific grain-level definition of F, the formulation of its continuum evolution equation and its effect on anisotropic dilatancy within ACST. DEM provides stress-ratio and shear strain variations as input for ACST analytical calculations of evolving fabric tensor and dilatancy, which are then favourably compared with totally independent direct measurements of these quantities by DEM. Furthermore, dilatancy is shown to be strongly affected by the contact normal-based fabric tensor Fc, whose evolution is best described by a continuum equation within ACST that includes dilatancy and a quantity related to particle orientation-based fabric tensor Fp. The aforementioned favourable comparison of the results for fabric tensor and dilatancy obtained independently by ACST and DEM, confirms the validity of the core framework of ACST irrespective of any constitutive model that addresses the deviatoric stress-strain relations.

58 GEOSCIENCES↗

Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD

Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitopedependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCsandmediatestrong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinantsoftheepitope-drivenprotectionandVOCevasion.WhileEH3represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 micefrom lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

60 APPLIED LIFE SCIENCES↗

Spatially limited antiferromagnetic order in a cluster glass compound Tb2Ni0.90Si2.94

In the present study, the synthesis of a new ternary intermetallic compound Tb2Ni0:90Si2:94 has been reported. The detailed studies on structure, static and dynamical magnetic properties of the compound have been investigated by means of powder x-ray diffraction, compositional analysis, dc & ac magnetization, non-equilibrium dynamics, heat capacity and neutron diffraction measurements. The dc & ac magnetic susceptibility reveal that the compound undergoes spin cluster-glass behaviour below 9.9 K. The frequency dependence of the freezing temperature have been analyzed on the basis of dynamic scaling laws such as power-law divergence and Vogel-Fulcher law, which further con rm the cluster-glass state formation for the compound. A detailed study on non-equilibrium dynamical behaviour associated with cluster-glass state has been carried out through magnetic relaxation behaviour along with magnetic memory effect in zero-field-cooled (ZFC) as well as field-cooled (FC) conditions and associated aging effect. The zero-field neutron diffraction study reveals the presence of a spatially limited antiferromagnetic phase in addition to the magnetically frustrated cluster-glass state. This result has also been supported through zero-field heat capacity studies. The variation in local electronic environment among the magnetic rare- earth ions caused by the structural disorder associated with Ni/Si ions have been argued to be responsible for the coexistence of different magnetic phases.

36 MATERIALS SCIENCE↗

Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET

A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to targeted therapies in patients with non–small cell lung cancer. In this study, we sequentially screened a panel of BsAbs in a combinatorial approach to select the optimal bispecific molecule. The BsAbs were derived from different EGFR and MET parental monoclonal antibodies. Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity toward MET. Hits were identified and further screened based on their potential to induce untoward cell proliferation and cross-phosphorylation of EGFR by MET via receptor colocalization in the absence of ligand. After the final step, we selected the EGFR and MET arms for the lead BsAb and added low fucose Fc engineering to generate amivantamab (JNJ-61186372). The crystal structure of the anti-MET Fab of amivantamab bound to MET was solved, and the interaction between the two molecules in atomic details was elucidated. Amivantamab antagonized the hepatocyte growth factor (HGF)-induced signaling by binding to MET Sema domain and thereby blocking HGF β-chain—Sema engagement. The amivantamab EGFR epitope was mapped to EGFR domain III and residues K443, K465, I467, and S468. Furthermore, amivantamab showed superior antitumor activity over small molecule EGFR and MET inhibitors in the HCC827-HGF in vivo model. Based on its unique mode of action, amivantamab may provide benefit to patients with malignancies associated with aberrant EGFR and MET signaling.

59 BASIC BIOLOGICAL SCIENCES↗

Exchange interaction at the interface of Fe-NiO nanocomposites

Fe-NiO nanocomposites with Fe to NiO ratio 20:80, 30:70 and 50:50 were prepared by a chemical route. X-ray diffraction and TEM measurements showed the presence of {alpha}-Fe and NiO phases in the prepared nanocomposites having an average crystallite size 17 nm. HRTEM image showed a structurally disordered phase at the Fe-NiO interface. Moessbauer spectra of the nanocomposites consist of a doublet along with a sextet corresponding to relaxed and blocked {alpha}-Fe phases, respectively. The dc magnetization measurements in field-cooled condition show a shift of hysteresis loop and an enhancement of coercive field at low temperature confirming the presence of exchange bias at Fe-NiO interfaces. The irreversibility observed in the FC and ZFC magnetization measurements also points to exchange bias effect. -- Graphical abstract: Fe-NiO nanocomposites exhibited some structural disordered region at the interface as revealed by HRTEM. A prominent shift in the hysteresis loops in field cooled condition confirmed the presence of exchange bias at Fe-NiO interfaces. The irreversibility observed in M-T measurements also points to exchange bias effect. Display Omitted

77 NANOSCIENCE AND NANOTECHNOLOGY↗