bluuebunny/crossref_metadata_2025_split huggingface dataset:
Click-to-Release: Cleavable Radioimmunoimaging with89Zr-DFO-Trans-Cyclooctene-Trastuzumab Increases Tumor-to-Blood Ratio
Authors: Vlastara Maria , Rossin Raffaella , Hoeben Freek J.M. , de Roode Kim E. , Boswinkel Milou , Kleijn Laurens H.J. , Nagarajah James , Rijpkema Mark , Robillard Marc S. 
Published: March 2023

AbstractOne of the main challenges of PET imaging with89Zr-labeled monoclonal antibodies (mAbs) remains the long blood circulation of the radiolabeled mAbs, leading to high background signals, decreasing image quality. To overcome this limitation, here we report the use of a bioorthogonal linker cleavage approach (click-to-release chemistry) to selectively liberate [89Zr]Zr-DFO fromtrans-cyclooctene-functionalized trastuzumab (TCO-Tmab) in blood, following the administration of a tetrazine compound (trigger) in BT-474 tumor-bearing mice.MethodsWe created a series of TCO-DFO constructs and evaluated their performance in [89Zr]Zr-DFO release from Tmab in vitro using different trigger compounds. The in vivo behavior of the best performing [89Zr]Zr-TCO-Tmab was studied in healthy mice first, to determine the optimal dose of the trigger. To find the optimal time for the trigger administration, the rate of [89Zr]Zr-TCO-Tmab internalization was studied in BT-474 cancer cells. Finally, the trigger was administered 6 h or 24 h after [89Zr]Zr-TCO-Tmab-administration in tumor-bearing mice to liberate the [89Zr]Zr-DFO fragment. PET scans were obtained of tumor-bearing mice that received the trigger 6 h post-[89Zr]Zr-TCO-Tmab administration.ResultsThe [89Zr]Zr-TCO-Tmab and trigger pair with the best in vivo properties exhibited 83% release in 50 % mouse plasma. In tumor-bearing mice the tumor-blood ratios were markedly increased from 1.0 ± 0.4 to 2.3 ± 0.6 (p=0.0057) and from 2.5 ± 0.7 to 6.6 ± 0.9 (p<0.0001) when the trigger was administered at 6 h and 24 h post-mAb, respectively. Same day PET imaging clearly showed uptake in the tumor combined with a strongly reduced background due to the fast clearance of the released [89Zr]Zr-DFO-containing fragment from the circulation through the kidneys.ConclusionsThis is the first demonstration of the use oftrans-cyclooctene-tetrazine click-to-release chemistry to release a radioactive chelator from a mAb in mice to increase tumor-blood ratios. Our results suggest that click-cleavable radioimmunoimaging may allow for substantially shorter intervals in PET imaging with full mAbs, reducing radiation doses and potentially even enabling same day imaging.
Mutation nsp6 L232F associated with MERS-CoV zoonotic transmission confers higher viral replication in human respiratory tract cultures ex-vivo
Authors: So Ray TY , Chu Daniel KW , Hui Kenrie PY , Mok Chris KP , Sanyal Sumana , Nicholls John M , Ho John C. W. , Cheung Man-chun , Ng Ka-chun , Yeung Hin-Wo , Chan Michael CW , Poon Leo LM , Zhao Jincun , Peiris Malik 
Published: March 2023

AbstractMiddle East respiratory syndrome coronavirus (MERS-CoV) causes zoonotic disease. Dromedary camels are the source of zoonotic infection. We identified a mutation of amino acid leucine to phenylalanine in the codon 232 position of the non-structural protein 6 (nsp6) (nsp6 L232F) that is repeatedly associated with zoonotic transmission. We generated a pair of isogenic recombinant MERS-CoV with nsp6 232L and 232F residues, respectively, and showed that the nsp6 L232F mutation confers higher replication competence in ex-vivo culture of human nasal and bronchial tissues and in lungs of mice experimentally infected in-vivo. Mechanistically, the nsp6 L232F mutation appeared to modulate autophagy and was associated with higher exocytic virus egress, while innate immune responses and zippering activity of the endoplasmic reticulum remained unaffected. Our study suggests that MERS-CoV nsp6 may contribute to viral adaptation to humans. This highlights the importance of continued surveillance of MERS-CoV in both camels and humans.ImportanceViral host adaptation plays an important role in zoonotic transmission of coronaviruses. For MERS-CoV that widely circulates in dromedary camels from Arabian Peninsula, camel-to human transmissions are ongoing, raising the possibility of human adaptive evolution for MERS-CoV. Here, we analysed MERS-CoV sequences and identified an amino acid mutation L232F in nsp6 to occur repeatedly in human MERS-CoV over the years since the first outbreak in 2012. We found the nsp6 L232F confers increase viral replication in-vitro, in ex-vivo upper human respiratory tract cultures and in mice, using a reverse genetics approach. Our results showed the nsp6 L232F may be advantageous for MERS-CoV to replicate in humans. This study highlighted a human adaptation of MERS-CoV and a need for continued surveillance of MERS-CoV to identify any further adaptations in humans, which may be relevant to the pandemic potential of MERS-CoV.
IDoser: Improving individualized dosing policies with clinical practice and machine learning
Authors: Correa Nuria , Cerquides Jesus , Vassena Rita , Popovic Mina , Arcos Josep Lluis 
Published: March 2023

AbstractBackgroundFinding the correct drug dose for a specific condition is a key step in many treatments, and failing to do so can lead to deleterious consequences to patient health. Clinical protocols are derived from drug development phase prospective trials. While carefully designed, these often do not include all potential patients, comorbidities or clinical outcomes, ultimately leading to sub-optimal dosing policies. Observational datasets provide real-world information that cannot be substituted with data collected in a controlled environment. Several published methodologies have applied observational datasets for the development of clinical protocols, however these are only applicable whenever these datasets are varied and complete. Often, clinical observational datasets do not comply with these requirements. Computational methods can and should exploit field knowledge to address weaknesses associated with clinical observational data.MethodsThis paper proposes IDoser, a core dosing model that links drug dose to relevant covariates via a set of coefficients, and includes a loss function to codify needed assumptions and requirements. Coordinate descent is used to obtain a fitted model with minimal loss. The loss function is also used to measure performance when validating the model with unseen data. Our proposal is validated using the case of follicle stimulating hormone (FSH) dosing for controlled ovarian stimulation (COS).ResultsThe proposed Individualized Doser (IDoser) achieved significant improvements when loss values were compared to observed clinical practice and a selected literature benchmark and during the validation phase.ConclusionsThis methodology constitutes a simple but effective method to bridge the gap between current clinical dosing policies and gold policies based on the true underlying and often unknown dose-response functions.
Association of 24-hour activity patterns with risk of Alzheimer’s disease, Parkinson’s disease, and cognitive decline
Authors: Winer Joseph R. , Lok Renske , Weed Lara , He Zihuai , Poston Kathleen L. , Mormino Elizabeth C. , Zeitzer Jamie M. 
Published: March 2023

ABSTRACTSleep-wake regulating circuits are affected during prodromal stages in the pathological progression of both Alzheimer’s disease (AD) and Parkinson’s disease (PD). Assessment of 24-hour rhythm impairment may serve as an early indicator of disease and cognitive decline. Our objective was to determine whether objective markers of 24-hour activity are associated with subsequent development of AD, PD, and cognitive decline. This longitudinal study obtained UK Biobank data from 82,829 individuals with valid accelerometer data (collected from June 2013 to January 2016) out of 103,671 eligible adults aged 40 to 79 years with a mean (±SD) follow-up of 6.8 (±0.9) years. AD and PD diagnoses were ascertained through September 2021, with data analysis conducted March to November 2022. The outcomes were accelerometer-derived measures of 24-hour activity (derived by cosinor, nonparametric, and functional principal component methods), incident AD and PD diagnosis (obtained through hospitalization or primary care records), longitudinal tests of cognitive function, and demographic characteristics. 82,829 participants consisted of 46,683 women (56%) and 36,146 men (44%) with a mean (±SD) age of 62.0 (±7.8) years at the time of actigraphy data collection. During the follow-up period, 191 individuals converted to AD (0.2%) and 266 to PD (0.3%). After adjusting for covariates, interdaily stability, a measure of regularity, (hazard ratio [HR] per SD increase 1.24, 95% confidence interval [CI] 1.04-1.47), diurnal amplitude (HR 0.77, CI 0.64-0.93), mesor (mean activity; HR 0.73, CI 0.56-0.95), and activity during most active 10 hours (HR 0.73, CI 0.59-0.91), were each associated with an increased risk of AD. Diurnal amplitude (HR 0.28, CI 0.23-0.34), mesor (HR 0.12, CI 0.10-0.16), activity during least active 5 hours (HR 0.24, CI 0.08-0.68), and activity during most active 10 hours (HR 0.20, CI 0.16-0.25), were associated with an increased risk of PD. Several measures were additionally predictive of longitudinal cognitive test performance. In this community-based longitudinal study, objective measures of 24-hour activity were associated with elevated risk of AD, PD, and accelerated cognitive decline, suggesting actigraphy-estimated 24-hour rhythm integrity may serve as a scalable early marker of neurodegenerative disease.
Targeting wild-type IDH1 enhances chemosensitivity in pancreatic cancer
Authors: Zarei Mehrdad , Hajihassani Omid , Hue Jonathan J. , Graor Hallie J. , Rothermel Luke D. , Winter Jordan M. 
Published: March 2023

AbstractPancreatic cancer (PC) is one of the most aggressive types of cancer, with a five-year overall survival rate of 11% among all-comers. Current systemic therapeutic options are limited to cytotoxic chemotherapies which have limited clinical efficacy and are often associated with development of drug resistance. Analysis of The Cancer Genome Atlas showed that wild-type isocitrate dehydrogenase (wtIDH1) is overexpressed in pancreatic tumors. In this study, we focus on the potential roles of wtIDH1 in pancreatic cancer chemoresistance. We found that treatment of pancreatic cancer cells with chemotherapy induced expression of wtIDH1, and this serves as a key resistance factor. The enzyme is protective to cancer cells under chemotherapy-induced oxidative stress by producing NADPH and alpha-ketoglutarate to maintain redox balance and mitochondrial function. An FDA-approved mutant IDH1 inhibitor, ivosidenib (AG-120), is actually a potent wtDH1 inhibitor under a nutrient-deprived microenvironment, reflective of the pancreatic cancer microenvironment. Suppression of wtIDH1 impairs redox balance, results in increased ROS levels, and enhances chemotherapy induced apoptosis in pancreatic cancer vis ROS damagein vitro.In vivoexperiments further revealed that inhibiting wtIDH1 enhances chemotherapy anti-tumor effects in patient-derived xenografts and murine models of pancreatic cancer. Pharmacologic wtIDH1 inhibition with ivosidenib represents an attractive option for combination therapies with cytotoxic chemotherapy for patients with pancreatic cancer. Based on these data, we have initiated phase Ib trial combining ivosidenib and multi-agent chemotherapy in patients with pancreatic cancer (NCT05209074).
Recent reactivation of a pathogenicity-associated transposable element triggers major chromosomal rearrangements in a fungal wheat pathogen
Authors: Badet Thomas , Feurtey Alice , Croll Daniel 
Published: March 2023

SummaryTransposable elements (TEs) are key drivers of genomic variation contributing to recent adaptation in most species. Yet, the evolutionary origins and insertion dynamics within species remain poorly understood. We recapitulate the spread of the pathogenicity-associatedStyxelement across five species that last diverged ∼11,000 years ago. We show that the element likely originated in theZymoseptoriafungal pathogen genus and underwent multiple independent reactivation events. Using a global 900-genome panel of the wheat pathogenZ. tritici,we assessStyxcopy number variation and identify renewed transposition activity in Oceania and South America. We show that the element can mobilize to create additionalStyxcopies in a four-generation pedigree. Importantly, we find that new copies of the element are not affected by genomic defenses revealing a recent loss of control against the element.Styxcopies are preferentially located in recombination breakpoints and likely triggered multiple types of large chromosomal rearrangements. Taken together, we establish the origin, diversification, and reactivation of a highly active TE with major consequences for chromosomal integrity and the expression of disease.
Specific ABA-independent tomato transcriptome reprogramming under abiotic stress combination
Authors: Pardo-Hernández Miriam , Martínez-Lorente Sara E. , Martí-Guillén José M , Arbona Vicent , Simón Inmaculada , Rivero Rosa M 
Published: March 2023

SUMMARYCrops often have to face several abiotic stresses simultaneously, and under these conditions, the plant’s response significantly differs from that observed under a single stress. Nevertheless, most of the molecular markers identified for increasing plant stress tolerance have been characterized under single abiotic stresses, explaining their unexpected results when they are tested under real field conditions. One important regulator of the plant’s responses to abiotic stresses is ABA. The ABA signaling system engages many stress-responsive genes, however, many others do not respond to ABA treatments. Thus, the ABA-independent pathway, which is still largely unknown, involve multiple signaling pathways and important molecular components necessary for the plant’s adaptation to climate change.In the present study, tomato ABA-deficient mutants (flacca, flc) were subjected to salinity, heat, or their combination. A deep RNA-seq analysis revealed that the combination of salinity and heat induced an important reprogramming of the tomato transcriptome, and from the 685 genes that were specifically regulated under this combination in our flc mutants, 463 genes were regulated by ABA-independent systems. Among these genes, we identified 6 transcription factors (TFs) belonging to the R2R3MYB family that were significantly upregulated. A protein-protein interaction network showed that the TFs SlMYB50 and SlMYB86 were directly involved in the upregulation of the flavonol biosynthetic pathway-related genes. This is the first time that some important ABA-independent TFs involved in the specific plant response to abiotic stress combination have been identified. Considering that ABA levels dramatically change in response to environmental factors, the study of ABA-independent genes that are specifically regulated under stress combination may provide a marvelous tool for increasing plant resilience to climate change.SIGNIFICANCE STATEMENTThis study in tomato Wt and ABA-deficient mutant plants reveals a specific and unique ABA-independent transcriptome reprogramming under abiotic stress combination, with the identification of some key TFs that were induced under these specific conditions. Taking into account that ABA levels dramatically change in all crops in response to environmental factors, the study of ABA-independent genes that are specifically regulated under stress combination may provide a marvelous tool for increasing plant resilience to climate change.
Research and optimization design of two-stage isolated inverter power supply based on series quasi-resonance
Authors: Wang Dangshu , Yi Jiaan , Song Luwen , Deng Xuan , Wang Xinxia , Dong Zhen 
Published: March 2023

Purpose
This paper aims to solve the problems of large hard switching loss and unclear resonant parameter design in the existing inverter power supply topology.

Design/methodology/approach
This paper proposes a simple and reliable two-stage isolated inverter composed of series quasi-resonant push-pull and external freewheeling diode full-bridge inverter. The power supply topology is analyzed, the topology mode is analyzed, the mathematical model of the converter is established and the DC gain of the converter is deduced. The relationship between the load and the output gain of the resonant tank is presented, a new resonant parameter design method is proposed, and the parameter design of the resonant element of the converter is clarified.

Findings
The resonant components of the converter are designed according to the proposed resonant parameter design method, and the correctness of the method is verified by simulation and the development and testing of a 500 W experimental prototype. After experimental tests, the peak efficiency of the experimental prototype can reach 94%. Because the experimental prototype achieves soft switching, the heat generation of the switch is greatly reduced, so the heavy heat sink is removed, and the volume is reduced by about 30% compared with the traditional power supply, and the total harmonic distortion of the output voltage is about 2%.

Originality/value
The feasibility of the scheme is verified by experiments, which is of great significance for improving the efficiency of the inverter power supply and parameter optimization.
Efficient scale and scope of business models used in municipal solid waste management
Authors: Beccarello Massimo , Di Foggia Giacomo 
Published: March 2023

PurposeThe paper aims to compare the efficiency of alternative municipal solid waste (MSW) management business models: a single provider against multiple providers.Design/methodology/approachIn this paper the drivers of MSW management costs are analysed to test the impact of the scale and scope of MSW management services on the average cost. While the business-as-usual scenario foresees a single provider, the alternative scenario foresees multiple providers.FindingsBased on the empirical data on municipal waste management costs, on average, the size and the average cost of the service are inversely related. This trend is supported using sub-sets defined by the quantity of waste managed. Multiple factors aid in explaining this result, and among others, due to scale and scope, factors such as transition costs increase with the number of players running different services.Practical implicationsThe provision of public services of economic interest should favour the participation of more companies wherever possible to the extent that social surplus is produced. However, pursuing this principle to the detriment of efficient service delivery is not ideal. This paper demonstrated that a single-provider waste management business model is efficient under specific conditions, as in this article.Originality/valueThis paper presents an original research methodology for comparatively analysing waste management service efficiency in urban areas and provides adequate evidence using alternative measures of costs according to the phase of the waste management chain, the scale and ultimately the scope of MSW management services.
Impacts of supply chain integration on product- and service-oriented mass customisation capability: the role of customer need
Authors: Yang Qian , Geng Ruoqi , Feng Taiwen , Li Tianxiong 
Published: March 2023

PurposeThis study aimed to investigate how different supply chain integrations (SCIs) (i.e. information integration and organisational integration) would impact product- and service-oriented mass customisation capability (MCC) differently and the moderating role of characteristics of customer needs (i.e. customer need tacitness and diversity).Design/methodology/approachFrom the perspective of information processing theory (IPT), the authors tested the hypotheses using survey data from 277 Chinese manufacturers.FindingsThe findings indicate that both information and operational integration contribute to product- and service-oriented MCCs. Operational integration promotes product-oriented MCC more, whereas information integration has a greater impact on service-oriented MCC. In addition, customer need tacitness negatively moderates the impact of operational integration on both product- and service-oriented MCC. Customer need diversity negatively moderates only the impact of operational integration on service-oriented MCC.Practical implicationsManagers should focus on not only the position (internal or external) but also the function of SCI when making decisions towards enhancing MCC. Diverse abilities to integrate with different functions are associated with different MCCs.Originality/valueThis study distinguishes between product- and service-oriented MCCs and provides novel insights for understanding how to enhance MCC from a SCI perspective.
Digitization policy design and implementation in the logistics and supply chain sector during the time of Covid-19
Authors: Mishrif Ashraf , Khan Asharul 
Published: March 2023

PurposeThe border closure and lockdowns due to Covid-19 pandemic resulted in partial closure of many industrial and commercial complexes, halted the performance of key strategic sectors such as logistics and supply chains, and thus disrupted the global value chains and the economy. The authors argue, however, that the pursuit of survival has driven companies to innovate and use digitization to overcome the negative consequences of the pandemic. More specifically, in this paper the authors aim to assess the success and challenges faced by companies in digitization policy design, adoption and implementation and their effects on firms’ operation, outputs and customer base during Covid-19.Design/methodology/approachSixty-one samples of the companies surveyed between 10 January and 30 April 2021 were analyzed, using the Krushkal–Wallis test and Independent-Samples Mann–Whitney U test to identify the relationships between variables including operation, overall output, customer base, digitization policy, technology use and implementation costs of new technologies.FindingsResults revealed a positive impact of digitization on the operation and overall outputs, while no effect was observed on the customer base. Analysis also showed that only 1.8% of companies were able to fully implement digitization, and that the cost of technology prevented most companies from using emerging technology or implementing their digitization policy.Research limitations/implicationsWhile the research has practical implications, it is not without flaws. For instance, the outcome of technology varies as per geographic area and people. The study was conducted in the Sultanate of Oman, a developing country in the Middle East region; therefore, it is difficult to generalize the outcomes suited to developed countries. The developed countries usually have a population quite used to the advanced technologies so some of the issues raised in the study might not work in the logistics and supply chain sectors of the developed countries. Such countries need separate studies.Practical implicationsThe findings will have implications for both supply chain companies as well as the technology providers. The supply chain companies will invest in technology infrastructure and add technology as an important component in their business models. The technology providers will consider the costs of implementation and adoption issues of technology in the supply chain companies.Originality/valueTo the best of authors' knowledge, no work has been produced on logistics and supply chain companies considering the technological sustainability during the time of Covid-19. The study will improve understanding of the digitization policy design, adoption and implementation and their effects on logistics and supply chain companies’ performance.