Rapid Distribution Research Articles

Relationship between HLA genetic variations, COVID-19 vaccine antibody response, and risk of breakthrough outcomes

The rapid global distribution of COVID-19 vaccines, with over a billion doses administered, has been unprecedented. However, in comparison to most identified clinical determinants, the implications of individual genetic factors on antibody responses post-COVID-19 vaccination for breakthrough outcomes remain elusive. Here, we conducted a population-based study including 357,806 vaccinated participants with high-resolution HLA genotyping data, and a subset of 175,000 with antibody serology test results. We confirmed prior findings that single nucleotide polymorphisms associated with antibody response are predominantly located in the Major Histocompatibility Complex region, with the expansive HLA-DQB1*06 gene alleles linked to improved antibody responses. However, our results did not support the claim that this mutation alone can significantly reduce COVID-19 risk in the general population. In addition, we discovered and validated six HLA alleles (A*03:01, C*16:01, DQA1*01:02, DQA1*01:01, DRB3*01:01, and DPB1*10:01) that independently influence antibody responses and demonstrated a combined effect across HLA genes on the risk of breakthrough COVID-19 outcomes. Lastly, we estimated that COVID-19 vaccine-induced antibody positivity provides approximately 20% protection against infection and 50% protection against severity. These findings have immediate implications for functional studies on HLA molecules and can inform future personalised vaccination strategies.

Modulation of Oxidative Stress and Neuroinflammation by Cannabidiol (CBD): Promising Targets for the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia globally. Although the direct cause of AD remains under debate, neuroinflammation and oxidative stress are critical components in its pathogenesis and progression. As a result, compounds like cannabidiol (CBD) are being increasingly investigated for their ability to provide antioxidant and anti-inflammatory neuroprotection. CBD is the primary non-psychotropic phytocannabinoid derived from Cannabis sativa. It has been found to provide beneficial outcomes in a variety of medical conditions and is gaining increasing attention for its potential therapeutic application in AD. CBD is not psychoactive and its lipophilic nature allows its rapid distribution throughout the body, including across the blood–brain barrier (BBB). CBD also possesses anti-inflammatory, antioxidant, and neuroprotective properties, making it a viable candidate for AD treatment. This review outlines CBD’s mechanism of action, the role of oxidative stress and neuroinflammation in AD, and the effectiveness and limitations of CBD in preclinical models of AD.

Soft-gluon corrections in [formula omitted] production

We study higher-order QCD corrections for the associated production of a top-antitop quark pair and a W boson (tt¯W production) in proton-proton collisions. We calculate approximate NNLO (aNNLO) and approximate N3LO (aN3LO) cross sections, with second-order and third-order soft-gluon corrections added to the exact NLO QCD result, and we also include electroweak (EW) corrections through NLO. We calculate uncertainties from scale dependence, which are reduced at higher orders, and from parton distributions, and we also provide separate results for tt¯W+ and tt¯W− production. We compare our results to recent measurements from the LHC, and we find that the aN3LO QCD + NLO EW predictions provide improved agreement with the data. We also calculate differential distributions in top-quark transverse momentum and rapidity and find significant enhancements from the higher-order corrections. This is the first calculation of soft-gluon corrections in single-particle-inclusive kinematics for a 2→3 process where all final-state particles are massive.

A direct probe of Λ potential in nuclear medium

Using the Liège intranuclear-cascade model together with the ablation model ABLA, an investigation is conducted into the effects of Λ potential in Λ-nucleus and Λ-hypernucleus-nucleus collisions across various beam energies. The findings show that the angle and transverse-momentum distributions of scattered Λ hyperon, the scattering cross section of the Λ hyperon in Λ-nucleus collisions as well as the rapidity distribution of Λ hyperon in Λ-hypernucleus-nucleus collisions are significantly influenced by the strength of the Λ potential in these scattering reactions across various beam energies. These demonstrations, unhindered by the uncertainties of Λ and hypernuclei productions in nuclear medium, allow for a direct investigation of the Λ potential, especially its momentum dependence. The criticality of probing the Λ potential is closely associated with the resolution of the “hyperon puzzle” in neutron stars.

Correlation of the hyperon potential stiffness with hyperon constituents in neutron stars and heavy-ion collisions

The breaking of SU(6) symmetry to a more general flavor SU(3) symmetry could serve as a potential explanation for the “hyperon puzzle” of neutron stars by adjusting the hyperon potentials. Specifically, when the soft relativistic mean-field (RMF) Λ hyperon potentials fall within the domains of chiral SU(3) interactions NLO13 with two-body forces, the maximum mass of neutron stars is expected to be lower than 2.0 M⊙, whereas it can exceed 2.0M⊙ if the RMF Λ hyperon potentials are sufficiently stiff to be consistent with those from chiral SU(3) interactions NLO13 with three-body forces. In our investigation involving these two types of Λ hyperon potentials, we explore how the hyperon yields and flows are affected in heavy-ion collisions. We find that the inclusion of hyperon potentials results in better agreement of the Λ directed flows with data but without clear differentiation in the stiffness of the hyperon potentials. Similarly negligent is the disparity in the rapidity distributions of the Λ collective flows predicted by the stiff and soft hyperon potentials. In contrast, the Λ collective flows beyond the central rapidity region turn out to be sensitive to the stiffness of the RMF equation of state (EOS) with the preference of a soft RMF EOS to a stiff one. Notably, the transverse momentum distributions of Λ hyperon production are sensitive to both the stiffness of the RMF EOS and Λ hyperon potential at high transverse momenta.

Investigation of Fourier transform infrared spectroscopy potential in cotton fiber micronaire measurement and distribution

Cotton micronaire is an essential fiber quality attribute that characterizes both fiber maturity and fineness components. Micronaire and other attributes are measured on fiber lint routinely in laboratories under controlled environmental conditions following a well-established high-volume instrument protocol. In this study, the attenuated total reflection Fourier transform infrared spectroscopy, characterizing fundamental group vibrations in fiber cellulose from 4000 to 400 cm−1, and using an attenuated total reflection device, was explored for fiber micronaire assessment, especially for seed cotton locule fibers that were mingled with nonlint materials, and varied in fiber maturity within a naturally variable sample. Partial least squares multivariate regression models and the algorithmic infrared maturity approach were developed and then applied to predict micronaire values of validation samples and independent seed cotton samples for comparison. Unlike partial least squares models that showed worse in the coefficient of determination, bias, and percentage of samples within the 95% agreement range for independent samples than for validation samples, the algorithmic infrared maturity approach indicated a similarity in the coefficient of determination, bias, and percentage of samples within the 95% agreement range between the validation samples and independent samples. In particular, the algorithmic infrared maturity approach avoided the need to re-calibrate the model with new samples. Therefore, the development of a robust and effective Fourier transform infrared technique combined with the infrared maturity approach for rapid laboratory micronaire assessment and distribution demonstrated a great potential for its extension to the early micronaire testing in remote/breeding locations, and also to regular cotton fibers, processed cotton yarns and fabrics.

Response of yield and quality of Japonica rice to different gradients of moisture deficit at grain-filling stage in cold regions

Abstract Water stress significantly affects on rice yield and quality. Eight Japonica varieties from the first and second accumulated temperature zones of Heilongjiang Province were used as materials and four moisture gradients (0, −10, −25 and −40 kPa) were conducted at the grain-filling stage to clarify the effect of water stress on the rice yield and quality in cold regions. The results showed that the rice yield was reduced due to the decrease in the seed setting rate. Rice chalkiness was significantly increased by drought stress, especially under −10 kPa. The protein content of most varieties was significantly reduced and taste quality was increased under −25 to −40 kPa. The effect on protein components increased with increasing drought stress. The gel consistency decreased and the average chain length of amylopectin was less affected by drought. With an increase in moisture deficit, the rapid viscosity analyzer characteristics and chain length distribution of amylopectin showed a trend of first increasing and then decreasing or decreasing and then increasing. The response of starch to mild and severe drought varied. Our study provides a theoretical basis for the efficient utilization of water and high quality and yield of Japonica rice.

High-energy QCD dynamics from bottom flavor fragmentation at the Hi-Lumi LHC

We study the inclusive production of hadrons with bottom flavor at the LHC and its luminosity upgrade. We describe the collinear fragmentation of singly b-flavored hadrons, B mesons and Λb\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\Lambda _b$$\\end{document} baryons, via the KKSS07 determination of fragmentation functions, while for charmed B mesons, Bc(1S0)\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$B_c(^1S_0)$$\\end{document} and Bc(3S1)\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$B_c(^3S_1)$$\\end{document} particles, we employ the novel ZCFW22 set, built on the basis of state-of-the-art nonrelativistic QCD inputs. We use the Jethad multimodular working environment to analyze rapidity and transverse-momentum distributions for observables sensitive to the associated emission of two hadrons or a hadron-plus-jet system. Our reference formalism is the NLL/NLO+\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm{NLL/NLO^+}$$\\end{document} hybrid collinear and high-energy factorization, where the standard collinear description is improved by the inclusions of energy logarithms resummed up to the next-to-leading approximation and beyond. We provide corroborating evidence that b-flavor emissions act as fair stabilizers of the high-energy resummation, thus serving as valuable tools for precision studies of high-energy QCD. As a bonus, we highlight that the predicted production-rate hierarchy between noncharmed b-hadrons and charmed Bc(1S0)\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$B_c(^1S_0)$$\\end{document} mesons is in line with recent LHCb estimates. This serves as simultaneous benchmark both for the hybrid factorization and for the single-parton fragmentation mechanism based on initial-scale inputs calculated via the nonrelativistic QCD effective theory.

GIS Constructed Water Monitoring Network System Via IOT

Monitoring the quality of water plays a vital role in the advancement towards intelligent and smart agriculture. It also facilitates the seamless transition to automated monitoring of essential components of human daily needs, as new technologies continue to be developed and adopted in both agricultural and human daily life, particularly in relation to water. Assessing water stress requires accurate measurement of water usage [1]. The objective of this study is to optimize the distribution strategy and achieve more efficient and rapid distribution, while also making better use of technology to address the urgent need for water conservation. One of the criteria for the second filtering phase, which utilized a realtime data collection system, focused on the implementation of water quality monitoring and characterization methods. Water measurement sensors and the Internet of Things (IoT) can provide immediate information on water flow and pressure rates. This information is crucial for the analysis and surveillance of water [2]. At the RCEW campus, online smart water monitoring is imperative to ensure a more efficient and sustainable use of water. By combining the Internet of Things and geographic information systems (GIS), an online smart water monitoring prototype was developed specifically for RCEW [3]. This cutting-edge technology has proven to be highly successful in providing real-time information on water parameters, saving both time and money, while enabling the continuous study of water consumption patterns. This innovative technology seamlessly integrates IoT and GIS for effective water surveillance [4,5].

RNA Control via Redox‐Responsive Acylation

AbstractIncorporating stimuli‐responsive components into RNA constructs provides precise spatiotemporal control over RNA structures and functions. Despite considerable advancements, the utilization of redox‐responsive stimuli for the activation of caged RNAs remains scarce. In this context, we present a novel strategy that leverages post‐synthetic acylation coupled with redox‐responsive chemistry to exert control over RNA. To achieve this, we design and synthesize a series of acylating reagents specifically tailored for introducing disulfide‐containing acyl adducts into the 2′‐OH groups of RNA (“cloaking”). Our data reveal that these acyl moieties can be readily appended, effectively blocking RNA catalytic activity and folding. We also demonstrate the traceless release and reactivation of caged RNAs (“uncloaking”) through reducing stimuli. By employing this strategy, RNA exhibits rapid cellular uptake, effective distribution and activation in the cytosol without lysosomal entrapment. We anticipate that our methodology will be accessible to laboratories engaged in RNA biology and holds promise as a versatile platform for RNA‐based applications.

RNA Control via Redox-Responsive Acylation.

Incorporating stimuli-responsive components into RNA constructs provides precise spatiotemporal control over RNA structures and functions. Despite considerable advancements, the utilization of redox-responsive stimuli for the activation of caged RNAs remains scarce. In this context, we present a novel strategy that leverages post-synthetic acylation coupled with redox-responsive chemistry to exert control over RNA. To achieve this, we design and synthesize a series of acylating reagents specifically tailored for introducing disulfide-containing acyl adducts into the 2'-OH groups of RNA ("cloaking"). Our data reveal that these acyl moieties can be readily appended, effectively blocking RNA catalytic activity and folding. We also demonstrate the traceless release and reactivation of caged RNAs ("uncloaking") through reducing stimuli. By employing this strategy, RNA exhibits rapid cellular uptake, effective distribution and activation in the cytosol without lysosomal entrapment. We anticipate that our methodology will be accessible to laboratories engaged in RNA biology and holds promise as a versatile platform for RNA-based applications.

A precise measurement of the Z-boson double-differential transverse momentum and rapidity distributions in the full phase space of the decay leptons with the ATLAS experiment at s=8\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\sqrt{s}=8$$\\end{document} TeV

This paper presents for the first time a precise measurement of the production properties of the Z boson in the full phase space of the decay leptons. This is in contrast to the many previous precise unfolded measurements performed in the fiducial phase space of the decay leptons. The measurement is obtained from proton–proton collision data collected by the ATLAS experiment in 2012 at s=8\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\sqrt{s} = 8$$\\end{document} TeV at the LHC and corresponding to an integrated luminosity of 20.2 fb-1\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{-1}$$\\end{document}. The results, based on a total of 15.3 million Z-boson decays to electron and muon pairs, extend and improve a previous measurement of the full set of angular coefficients describing Z-boson decay. The double-differential cross-section distributions in Z-boson transverse momentum pT\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$p_{\ ext {T}}$$\\end{document} and rapidity y\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$y$$\\end{document} are measured in the pole region, defined as 80<mℓℓ<100\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$80< m^{\\ell \\ell }< 100$$\\end{document} GeV, over the range |y|<3.6\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$|y| < 3.6$$\\end{document}. The total uncertainty of the normalised cross-section measurements in the peak region of the pT\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$p_{\ ext {T}}$$\\end{document}  distribution is dominated by statistical uncertainties over the full range and increases as a function of rapidity from 0.5–1.0% for |y|<2.0\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$|y| < 2.0$$\\end{document} to 2-7%\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$2-7\\%$$\\end{document} at higher rapidities. The results for the rapidity-dependent transverse momentum distributions are compared to state-of-the-art QCD predictions, which combine in the best cases approximate N4\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^4$$\\end{document}LL resummation with N3\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^3$$\\end{document}LO fixed-order perturbative calculations. The differential rapidity distributions integrated over pT\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$p_{\ ext {T}}$$\\end{document} are even more precise, with accuracies from 0.2–0.3% for |y|<2.0\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$|y| < 2.0$$\\end{document} to 0.4–0.9% at higher rapidities, and are compared to fixed-order QCD predictions using the most recent parton distribution functions. The agreement between data and predictions is quite good in most cases.

Abstract 7174: Pharmacokinetics and immunogenicity of anti-PD-1 antibody in humanized FcRn mouse models compared to immunocompetent mouse models

Abstract Introduction: The development and use of therapeutic antibodies in cancer therapy has increased significantly in recent years, led by the success of approved immune checkpoint blockade antibodies targeting PD-1 and PD-L1 axis. However, obtaining more clinically relevant pharmacokinetics (PK), safety and efficacy data for antibodies is still challenging in preclinical phase. Humanized FcRn (hFcRn) transgenic mouse model has a more faithful catabolism compared to WT mice, providing more accurate and predictable PK data of innovative antibody-based therapeutics at discovery stage[1]. In this study, we sought to investigate pharmacokinetics and immunogenicity characteristics of anti-PD-1 antibody in hFcRn transgenic mice and provide guidance for its differentiation of prediction value for drug PK and safety by comparing to WT mice. Methods: Non-tumor bearing hFcRn mice and wild type C57BL/6 mice were divided into 2 groups, 5 mice were enrolled into each group. Mice were administered anti-PD-1(Nivolumab) at 10 mg/kg single dose after grouping by intravenous (IV) injection. Blood samples at 12 timepoints (15min, 6h, 1, 2, 4, 7, 10, 14, 21, 28, 35, 42 days) post-dosing were collected for PK and Anti-Drug Antibody (ADA) analysis by MSD and ELISA. Results: Nivolumab clearance in hFcRn mice followed a typical linear profile with rapid distribution phase and slow elimination phase (t1/2 = 350 to 400 h). While the PK profile in C57BL/6 mice displayed non-linear clearance and very short elimination phase (t1/2 = 45 to 50 h). This data demonstrated that hFcRn mice have better correlated half-life with human (Nivolumab single dose by IV with 10mg/kg, t1/2 = 595 h) [2]. ADA analysis revealed that it was produced starting from Day 10 in wild type C57BL/6 mice and the frequency of ADA induced by Nivolumab in wild type mice (2/5) was higher than hFcRn mice (0/5). The variation of Nivolumab level was correlated with ADA production in wild type mice. This suggested hFcRn shows lower immunogenicity than wild type mice for human IgG drug and can potentially improve negative effect of ADA interference on PK evaluation. Conclusion: The result of this study demonstrated that the PK data in hFcRn mouse model was more predictive of human PK profile compared to wild type C57BL/6 mice. This advances innovation in antibody-based therapeutics and translational applications, with improved PK, safety and efficacy evaluation for preclinical human IgG drug development in cancer therapy.

Abstract 5807: Bicycle Toxin Conjugates®for the treatment of solid tumors

Abstract Bicycle Therapeutics is developing a unique class of chemically synthesized medicines. Based on its proprietary bicycle peptide (Bicycle®) phage display platform, Bicycles are a unique class of highly constrained peptides, which have demonstrated utility in the targeted delivery of different classes of payloads (for example cytotoxic agents, radioisotopes, immune modulators) into tumors. Bicycles are currently being explored in the clinic as Bicycle Toxin Conjugates® (BTCs) for targeted delivery of cytotoxic payloads into tumors. BTCs consist of a bicyclic peptide that is conjugated to a cytotoxic payload via a cleavable linker, which allows payload release in the tumor microenvironment or within the tumor cell. BTCs were developed to address the shortcomings of antibody drug conjugates (ADCs) in several ways. First, the small size of BTCs (∼4 kDa) compared to large biologic entities such as monoclonal antibody (mAb)-based conjugates (∼150 kDa) allows rapid distribution to tissues and extensive tumor penetration, which enables rapid delivery of payload into the tumor. Second, the peptidic nature of BTCs results in relatively short, yet tunable, duration of systemic exposure and liver-sparing renal elimination. These properties limit the body’s exposure to payload and should therefore minimize damage to normal tissue. In this body of work, we used in vitro cytotoxicity and cell uptake assays and mouse and rat cell line derived xenograft models for 1) cytotoxicity and anti-tumor activity evaluation, and 2) Bicycle and toxin uptake and biodistribution evaluation. Here, we show that BTCs targeting a number of different tumor antigens can deliver toxins to tumor tissue producing durable responses in a range of preclinical in vivo models, spanning several solid tumor indications. Citation Format: Stephen J. Walsh, Johanna Lahdenranta, Philip Huxley, Gemma Mudd, Gavin Bennett, Amy Brown, Katerine an Rietschoten, Liuhong Chen, Heather Scott, Gabriella Ivanova-Berndt, Katarzyna Dzionek, Mike Rigby, Olga Burenkova, Phil Jeffrey, Paul Beswick, Michael Skynner, Nicholas Keen. Bicycle Toxin Conjugates®for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5807.

Rapid pyrolysis mechanism and product distribution of coal model compounds containing typical C–O bonds

The structure and reactivity of coal is the core problem of coal chemistry, and solving it at the molecular level has been an international unsolved problem. The chemical similarity-based coal chemistry group elevates the study from the macroscopic to the molecular level. However, the previous free radical mechanism lacks experimental confirmation and theoretical computational support. Here, the pyrolysis products of model compounds are first utilized to predict pyrolysis. The hydrogen-donating solvent is then used as a radical trap to confirm the reaction. Subsequently, density functional theory calculations are utilized to aid in the validation. Finally, family components are utilized to demonstrate the universality of the free radical mechanism of coal pyrolysis. This work combines radical trapping with quantum chemical calculations to analyze the radical reaction mechanism of coal pyrolysis in depth at the molecular level. This will provide a theoretical basis for coal pyrolysis and clean and efficient utilization.

Extracting the hyperon-nucleon interaction via collective flows in heavy-ion collisions

The 2-body hyperon-nucleon interaction softens the equation of state of neutron star matter and leads to the maximum mass of neutron star to be 1.3-1.6M⊙, which deviates from the recent observation with the masses of PSR J0348+0432 (2.01±0.04M⊙) and J0740+6620 (2.14−0.09+0.10M⊙). One attempt is to introduce the more repulsive hyperon-nucleon interaction above the saturation density. A phenomenological Λ potential by fitting the 3-body ΛNN results of chiral effective field theory is implemented into the quantum molecular dynamics transport model to solve the ‘hyperon puzzle’ in neutron stars. It is found that the directed and elliptic flows are sensitive to the high-density hyperon-nucleon potentials in collisions of 197Au + 197Au and 124Sn + 124Sn. The influence of the phenomenological potential on the Λ yields, rapidity distributions and transverse momentum spectra is negligible in comparison with the ones calculated by the well-known relativistic mean-field model. The inclusion of the ΛN, ΣN and ΞN potentials leads to the reduction of hyperon production in the midrapidity region. The Λ directed flows and the slope in the midrapidity region are enhanced with the phenomenological potential and more consistent with the STAR data in collisions of 197Au + 197Au at sNN=3 GeV.

Pharmacokinetics, safety, and tolerability of the novel tetrameric gadolinium-based MRI contrast agent gadoquatrane in healthy Chinese and Japanese men: Two randomized dose-escalation studies including concentration–QTc modeling

PurposeTo investigate the pharmacokinetics, safety, and tolerability of the novel tetrameric high-relaxivity gadolinium-based contrast agent gadoquatrane in Japanese (Study 1) and Chinese men (Study 2). Participants and methodsIn two similarly designed single-center, randomized, single-blind, placebo-controlled, consecutive-cohort dose-escalation studies, healthy volunteers were randomly assigned to intravenous administration of gadoquatrane (0.01–0.1 mmol gadolinium/kg body weight) or placebo. Study procedures included blood sampling and collection of urine for pharmacokinetic analyses and safety assessments. ResultsTwenty-five healthy Japanese men (mean age ± standard deviation: 26±5.9 years) and 23 healthy Chinese men (31±7.6 years old) were evaluated. In both studies, the pharmacokinetic profile of gadoquatrane was characterized by rapid distribution of the drug into the extracellular space and fast renal elimination. Postdose gadolinium concentrations rapidly declined with a geometric mean effective half-life of 1.3–1.4 h. The exposure increased approximately dose-proportionally with dose. The body weight-normalized volume of distribution was constant across dose levels (0.21–0.24 L/kg). Total recovery of gadolinium in urine amounted to 82–95 % (Study 1) and 96–99 % (Study 2) of the dose administered.Only a few mild, transient adverse events were reported, none of which gave rise to any safety concerns. Exploratory drug concentration–QTc modeling indicated no risk of a clinically relevant QT/QTc prolongation at the anticipated diagnostic dose. ConclusionGadoquatrane was safe and well tolerated at all doses tested. The pharmacokinetic profile was essentially the same as that of other extracellular macrocyclic gadolinium-based contrast agents and was consequentially also similar for Japanese and Chinese participants.

Research on Multi-UAV Task Assignment Based on a Multi-Objective, Improved Brainstorming Optimization Algorithm

In response to the practice of rescue channel blocking and a shortage of emergency materials in the event of sudden significant disasters, a multi-UAV collaborative distribution scheme was designed based on the demand for rapid and accurate distribution of materials. This paper constructed a multi-UAV collaborative task assignment and routing problem with simultaneous delivery and pick-up and time windows (MVTARPSDPTW), considering the factors of UAV load, energy consumption, cargo quality, and volume to minimize the total cost of UAV distribution and the full penalty of the task, as well as optimizing the balance of UAV efficiency. This paper proposes a multi-objective, improved brainstorming optimization algorithm based on Pareto dominance (MIBSO) to solve the MVTARPSDPTW problem. With DTLZ4, DTLZ5, and DTLZ6 benchmarks, this work tests the algorithm performance according to the characteristic attributes of the model sought, selecting the four indicators of GD, the Spacing metric, HV, and IGD, concerning convergence, solution distribution, and comprehensive performance. Case validation is based on a COVID-19 scenario in Changchun, China, and the results show that the model algorithm designed in this paper has good performance and feasibility in convergence and distribution of reconciliation. Finally, the multi-UAV emergency material distribution solution provides practical, theoretical support for rescue tasks in sudden significant disasters.

Examining the influence of hadronic interactions on the directed flow of identified particles in RHIC Beam Energy Scan energies using UrQMD model

The directed flow of identified particles can serve as a sensitive tool for investigating the interactions during initial and final states in heavy ion collisions. This study examines the rapidity distribution ([Formula: see text]), rapidity-odd directed flow ([Formula: see text]) and its slope ([Formula: see text]) for [Formula: see text], [Formula: see text], p, and [Formula: see text] in Au+Au collisions at different collision centralities and beam energies ([Formula: see text], 11.5, 14.5, 19.6, 27, and 39[Formula: see text]GeV) using the UrQMD model. We investigate the impact of late-stage hadronic interactions on charge-dependent [Formula: see text] and its slope by modifying the duration of the hadronic cascade lifetime ([Formula: see text]). The energy dependence of [Formula: see text] for p ([Formula: see text]) exhibits distinct pattern compared to [Formula: see text] and [Formula: see text]. Notably, we observe a change in the sign reversal position of proton [Formula: see text] at different beam energies with varying [Formula: see text] in central and mid-central collisions. Moreover, the difference in [Formula: see text] between positively and negatively charged hadrons ([Formula: see text]) demonstrates a stark centrality dependence for different particle species. The deuteron displays a significant increase in [Formula: see text] with increasing [Formula: see text] compared to p and n. This investigation underscores the importance of considering the temporal evolution and duration of the hadronic phase when interpreting the sign reversal, charge splitting of [Formula: see text] and light nuclei formation at lower RHIC energies.

Insulin Delivery to the Brain via the Nasal Route: Unraveling the Potential for Alzheimer's Disease Therapy.

This comprehensive review delves into the potential of intranasal insulin delivery for managing Alzheimer's Disease (AD) while exploring the connection between AD and diabetes mellitus (DM). Both conditions share features of insulin signalling dysregulation and oxidative stress that accelerate inflammatory response. Given the physiological barriers to brain drug delivery, including the blood-brain barrier, intranasal administration emerges as a non-invasive alternative. Notably, intranasal insulin has shown neuroprotective effects, impacting Aβ clearance, tau phosphorylation, and synaptic plasticity. In preclinical studies and clinical trials, intranasally administered insulin achieved rapid and extensive distribution throughout the brain, with optimal formulations exhibiting minimal systemic circulation. The detailed mechanism of insulin transport through the nose-to-brain pathway is elucidated in the review, emphasizing the role of olfactory and trigeminal nerves. Despite promising prospects, challenges in delivering protein drugs from the nasal cavity to the brain remain, including enzymes, tight junctions, mucociliary clearance, and precise drug deposition, which hinder its translation to clinical settings. The review encompasses a discussion of the strategies to enhance the intranasal delivery of therapeutic proteins, such as tight junction modulators, cell-penetrating peptides, and nano-drug carrier systems. Moreover, successful translation of nose-to-brain drug delivery necessitates a holistic understanding of drug transport mechanisms, brain anatomy, and nasal formulation optimization. To date, no intranasal insulin formulation has received regulatory approval for AD treatment. Future research should address challenges related to drug absorption, nasal deposition, and the long-term effects of intranasal insulin. In this context, the evaluation of administration devices for nose-to-brain drug delivery becomes crucial in ensuring precise drug deposition patterns and enhancing bioavailability.