bluuebunny/crossref_metadata_2025_split huggingface dataset:
Robust and accurate method for measuring tumor volume using optical 3D scanning for nonclinical in vivo efficacy study
Authors: Kobayashi Takuma , Katsumata Mayumi , Nakamura Yoshiki , Terado Yuri , Araki Hideo , Maeda Eiki 
Published: May 2024

ABSTRACTIn a nonclinicalin vivoefficacy test for anticancer drugs, immunodeficient mice subcutaneously transplanted with human cancer cells were quantified and evaluated with regard to the manner in which the skin bulges where locally proliferated cancer cells regress after drug administration. A caliper is conventionally used to measure the tumor bulge. However, its volume is an estimated value and results in high variability. Alternatively, cancer cell lines that express genetically encoded marker genes have been used in recent years for optical and nondestructive measurements. However, estimations using calipers exhibit large errors, and biological tissues have low light transparency. This hinders quantitative optical measurements. In addition, variations in measurements owing to subjective and human operations are likely.From the chemistry, manufacturing, and control (CMC) perspective, precise measurement is required to evaluate drug efficacy and quality. Therefore, we aimed to eliminate errors caused by the use of estimated values, subjectivity, and human manipulation by precisely quantifying the volume of the tumor bulge using a 3D scanner.This study demonstrated that optical 3D scanner measurements were accurate, had low variability, and was highly correlated with tumor weight. The tumor bulge was observed to vary to a flattened oval dome shape rather than a semicircle. This caused high variability in measurements of tumor volume. However, the proposed 3D scanner was more sensitive to volumetric regression than the caliper. Additionally, it exhibited drug efficacies with higher resolution than the caliper. Furthermore, the high linearity of the scanner provided more accurate measurements over a wider range of tumor sizes than luminescence imaging. The accurate and sensitive properties of such 3D scanners are also likely to make these exceptionally effective analytical tools for ensuring product equivalency when modifying raw materials or manufacturing processes in the development of cell therapy products.As described above, robust and accurate drug efficacy measurements using nondestructive and noninvasive 3D scanners that require no training and are convenient to operate provide many analytical improvements and advantages. This is likely to play an important role in 1) the efficacy evaluation of cell therapy products that have large variations originating from the raw materials and large differences between manufacturing lots and 2) the quality evaluation, property analysis of the characteristics of variations in the shape of tumor bulges over time, and comparability testing of the products in the CMC section of pharmaceutical companies.
Exploring the Limits of EPR-driven Tumor Accumulation with Non-opsonizing Nanomaterials
Authors: Serzants Rinalds , Svalbe Baiba , Cesnokova Irina , Stelfa Gundega , Sizovs Antons 
Published: May 2024

AbstractThe Enhanced Permeability and Retention (EPR) effect is a foundational concept used to rationalize nanomedicine development for cancer treatment and diagnostics. The attainable efficacy of passive tumor targeting due to EPR remains ambiguous owing to pervasive opsonization of nanoparticles. To address this, we developed nanomaterials with complete resistance to opsonization, exceptionally long systemic circulation, and used them to study the limits of the EPR in triple-negative breast cancer. Tumors exerted no impact on pharmacokinetic profiles, which were indistinguishable between healthy and tumor-bearing mice. Tumors were the primary accumulation sites and our data revealed that the maximum average achievable tumor accumulation via EPR is proximate to 60 %ID/g, tumor- to-liver selectivity is 4-to-1, and the optimal DHto fully exploit EPR lies between 18 and 54 nm. The significant heterogeneity observed in tumor accumulation, however, indicates that nanomedicines cannot achieve consistent efficacy across different patients by relying solely on EPR.
Targeting protein tyrosine phosphatase non-receptor type 2 with a novel inhibitor for AML therapy
Authors: Kuang Wenbin , Jiang Jinxin , Wang Xiao , Wang Dawei , Ji Minghui , Zhu Yasheng , Yuan Kai , Ding Jiayu , Wang Wenmu , Song Mingge , Min Wenjian , Huang Fei , Wang Liping , Gu Wanjian , Hao Haiping , Xiao Yibei , Yang Peng 
Published: May 2024

AbstractAcute myeloid leukemia (AML) is a fatal disease characterized by a bleak prognosis. For over four decades, treatment options for AML have been constrained to administering high-dose cytotoxic chemotherapy. However, the emergence of drug resistance and the resultant toxic side effects have created an urgent necessity for identifying novel therapeutic targets. In this study, non-receptor protein tyrosine phosphatase type 2 (PTPN2) is highly expressed in AML. Remarkably, knock down of PTPN2 expression markedly mitigated AML burden both in vitro and in vivo. Additionally, we unveiled the direct interaction between PTPN2 and C-MYC, establishing C-MYC as a direct acting substrate of PTPN2. Then, we performed a small-molecule compound screening to identify K73, a selective inhibitor of PTPN2. At the same time, K73 showed a good safety profile and exhibited strong activity against AML in vivo. In conclusion, we have pinpointed a considerable therapeutic potential in targeting PTPN2 for AML treatment and discovered a novel class of selective PTPN2 inhibitors suitable for AML therapy.
Inferring the composition of the blood plasma proteome by a human proteome distribution atlas
Authors: Malmström Erik , Hauri Simon , Mohanty Tirthankar , Scott Aaron , Karlsson Christofer , Gueto-Tettay Carlos , Åhrman Emma , Nozohoor Shahab , Tingstedt Bobby , Regner Sara , Elfving Peter , Bjermer Leif , Forsvall Andreas , Doyle Alexander , Magnusson Mattias , Hedenfalk Ingrid , Kannisto Päivi , Brandt Christian , Nilsson Emma , Dahlin Lars B , Malm Johan , Linder Adam , Malmström Lars , Nimeus Emma , Malmström Johan 
Published: May 2024

AbstractThe plasma proteome is maintained by the influx and efflux of proteins from surrounding organs and cells. To quantify the extent different organs and cells contribute to the plasma proteome composition, we developed a mass spectrometry-based proteomics strategy to infer the origin of proteins detected in human plasma in health and disease. First, we constructed an extensive human proteome atlas from 18 vascularized organs and the most abundant cell types in blood. Second, the atlas was interfaced with previous RNA/protein atlases to objectively define proteome wide protein-organ associations to enable both the inference of origin and the reproducible quantification of organ-specific proteins in plasma. We demonstrate that the resource can determine disease-specific quantitative changes of organ-enriched protein panels in three separate patient cohorts with infection, pancreatitis, and myocardial injury. The strategy can be extended to other diseases to advance our understanding of the processes contributing to plasma proteome dynamics.
MEK1/2 and ERK1/2 mediated lung endothelial injury and altered hemostasis promote diffuse alveolar hemorrhage in murine lupus
Authors: Zhuang Haoyang , Han Shuhong , Harris Neil S. , Reeves Westley H. 
Published: May 2024

AbstractObjectiveAbout 3% of lupus patients develop severe diffuse alveolar hemorrhage (DAH) with pulmonary vasculitis. B6 mice with pristane-induced lupus also develop DAH, but BALB/c mice are resistant. DAH is independent of TLR signaling and other inflammatory pathways. This study examined the role of the mitogen-activated protein kinase pathway (MEK1/2-ERK1/2, JNK, p38).MethodsB6 and BALB/c mice were treated with pristane ± inhibitors of MEK1/2 (trametinib/GSK1120212, “GSK”), ERK1/2 (SCH772984, “SCH”), JNK, or p38. Effects on lung hemorrhage and hemostasis were determined.ResultsGSK and SCH abolished DAH, whereas JNK and p38 inhibitors were ineffective. Apoptotic cells were present in lung from pristane-treated mice, but not mice receiving pristane+GSK and endothelial dysfunction was normalized. Expression of the ERK1/2-regulated transcription factorEgr1increased in pristane-treated B6, but not BALB/c, mice and was normalized by GSK. Pristane also increased expression of the anticoagulant genesTfpi(tissue factor pathway inhibitor) andThbd(thrombomodulin) in B6 mice. The ratio of tissue factor (F3) toTfpiincreased in B6 (but not BALB/c) mice and was normalized by GSK. Circulating Thbd protein increased in B6 mice and returned to normal after GSK treatment. Consistent with augmented endothelial anticoagulant activity, pristane treatment increased tail bleeding in B6 mice.ConclusionPristane treatment promotes lung endothelial injury and DAH in B6 mice by activating the MEK1/2-ERK1/2 pathway and impairing hemostasis. The hereditary factors determining susceptibility to lung injury and bleeding in pristane-induced lupus are relevant to the pathophysiology of life-threatening DAH in SLE and may help to optimize therapy.
Compartmental Differences in the Retinal Ganglion Cell Mitochondrial Proteome
Authors: Lewis Liam S.C. , Skiba Nikolai P. , Hao Ying , Bomze Howard M. , Arshavsky Vadim Y. , Cartoni Romain , Gospe Sidney M. 
Published: May 2024

AbstractAmong neurons, retinal ganglion cells (RGCs) are uniquely sensitive to mitochondrial dysfunction. The RGC is highly polarized, with a somatodendritic compartment in the inner retina and an axonal compartment projecting to targets in the brain. The drastically dissimilar functions of these compartments implies that mitochondria face different bioenergetic and other physiological demands. We hypothesized that compartmental differences in mitochondrial biology would be reflected by disparities in mitochondrial protein composition. Here, we describe a protocol to isolate intact mitochondria separately from mouse RGC somatodendritic and axonal compartments by immunoprecipitating labeled mitochondria from RGC MitoTag mice. Using mass spectrometry,471and357proteins were identified in RGC somatodendritic and axonal mitochondrial immunoprecipitates, respectively. We identified 10 mitochondrial proteins exclusively in the somatodendritic compartment and 19 enriched ≥2-fold there, while 3 proteins were exclusively identified and 18 enriched in the axonal compartment. Our observation of compartment-specific enrichment of mitochondrial proteins was validated through immunofluorescence analysis of the localization and relative abundance of superoxide dismutase (SOD2), sideroflexin-3 (SFXN3) and trifunctional enzyme subunit alpha (HADHA) in retina and optic nerve specimens. The identified compartmental differences in RGC mitochondrial composition may provide promising leads for uncovering physiologically relevant pathways amenable to therapeutic intervention for optic neuropathies.
The influence of calcific aortic stenosis on atrioventricular conduction: a prospective observational study and Mendelian randomization
Authors: Rao Karan , Ciofani Jonathan L , Han Daniel , Nazarzadeh Milad , Rahimi Kazem , Baer Alexandra , Saad Natasha , Litkouhi Princess Neila , Allahwala Usaid , Hansen Peter , Bhindi Ravinay 
Published: May 2024

AbstractBackgroundAortic stenosis (AS) may prolong atrioventricular (AV) conduction secondary to calcium infiltration of the atrioventricular-His-pathway, which is hypothesized to contribute to bradyarrhythmia and sudden cardiac death in this cohort. This study investigates the correlation between calcific AS and impaired AV conduction.MethodsWe performed an observational study and Mendelian randomization (MR). The observational study was a sub-analysis on AS patients undergoing transcatheter aortic valve implantation2021-2023). Regression analyses were used to assess the association between aortic valve calcium volumes with electrophysiology study derived markers of AV conduction. The primary MR analyses used European-ancestry genome-wide association studies for AS (653,867 participants,13,765 cases) and PR interval (271,570 participants). The exposure outcome was the genetic liability for AS, whilst the outcome was prolonged PR interval or AV block.ResultsThe mean age in the observational study (n=196) was 81.8 years, 64.8% were men, and 46(23.6%) had first-degree heart block. There was no significant association between total aortic valve complex calcium volume and first-degree heart block, or with PR, AH or HV intervals. On MR, no association was found between genetic liability for AS and PR interval (beta -0.41, 95%CI -1.33-0.51, p=0.38). Additional analyses evaluating genetic liability for AS and AV block suggested a significant association on IVW analysis (OR 1.15, 95%CI 1.02-1.30, p=0.02), but this was not supported by sensitivity analyses and thus interpreted with caution.ConclusionsThis study found no meaningful association between aortic valve calcification and PR, AH or HV interval, challenging the hypothesis that calcific AS impairs atrioventricular conduction.
Investigation and optimization the effect of electrical stimulation parameters on the differentiation of human adipose mesenchymal stem cells into neurons-like cells on carbon nanofibers
Authors: Nekounam Houra , Golmohammadi Hossein , Amini Seyed Mohammad , Shokrgozar Mohammad Ali , Faridi-Majid Reza 
Published: May 2024

AbstractBackgroundNeurodegenerative diseases are among the most challenging diseases because neuron cells are not able to regenerate spontaneously. Tissue engineering is one of the most promising stem cell-based therapies. Controlling stem cell differentiation is a very crucial aspect of tissue engineering.MethodsIn this study, carbon nanofibers with an average diameter of 181±45 nm were prepared as a conductive scaffold based on the electrospinning method and subsequent thermal processing. Scaffold structure characterization were performed with XRD, Raman and Electrical conductivity tests. A homemade device was prepared to transmit electrical current to cells seeded on the scaffold in a culture plate. Various current parameters such as current intensity, frequency, waveform, daily shock duration, and shock period on adipose mesenchymal stem cells were examined for differentiation into neuronal cells. SPSS software and the one-way analysis of variance (ANOVA) was used as statistical analysis.ResultsCharacterization tests confirmed the formation of the carbon and crystallite structure with the electrical conductivity . Current with 1500 uA intensity, 500Hz frequency, and square waveform were selected as the optimal current parameters. It was found that the daily and periodic increase in shock time leads to an increase in the expression of neural and glial genes. A comparison of groups with real-time PCR and immunofluorescence of nestin, Map2, TubB3, and GFAPgenes was evaluated.ConclusionsThere are a variety of chemical and physical methods to control cell behavior, one of which is electrical stimulation. Conductive scaffolding is required for direct electrical stimulation of cells. The results showed that the method based on electrical stimulation can well cause neural differentiation, and considering the problems in preparing and maintaining chemical differentiation agents, it can be used practically.Graphical abstract:stages of scaffold preparation and electrical stimulation of stem cells
Unveiling genetic anchors in Saccharomyces cerevisiae: QTL mapping identifies IRA2 as a key player in ethanol tolerance and beyond
Authors: Tristão Larissa Escalfi , de Sousa Lara Isensee Saboya , Vargas Beatriz de Oliveira , José Juliana , Carazzolle Marcelo Falsarella , Silva Eduardo Menoti , Galhardo Juliana Pimentel , Pereira Gonçalo Amarante Guimarães , de Mello Fellipe da Silveira Bezerra 
Published: May 2024

ABSTRACTEthanol stress inSaccharomyces cerevisiaeis a well-studied phenomenon, but pinpointing specific genes or polymorphisms governing ethanol tolerance remains a subject of ongoing debate. Naturally found in sugar-rich environments, this yeast has evolved to withstand high ethanol concentrations, primarily produced during fermentation in the presence of suitable oxygen or sugar levels. Originally a defense mechanism against competing microorganisms, yeast-produced ethanol is now a cornerstone of brewing and bioethanol industries, where customized yeasts require high ethanol resistance for economic viability. However, yeast strains exhibit varying degrees of ethanol tolerance, ranging from 8% to 20%, making the genetic architecture of this trait complex and challenging to decipher. In this study, we introduce a novel QTL mapping pipeline to investigate the genetic markers underlying ethanol tolerance in an industrial bioethanolS. cerevisiaestrain. By calculating missense mutation frequency in a prominent QTL region within a population of 1011S. cerevisiaestrains, we uncovered rare occurrences in geneIRA2. Following molecular validation, we confirmed the significant contribution of this gene to ethanol tolerance, particularly in concentrations exceeding 12% of ethanol.IRA2pivotal role in stress tolerance due to its participation in the Ras-cAMP pathway was further supported by its involvement in other tolerance responses, including thermotolerance, low pH tolerance, and resistance to acetic acid. Understanding the genetic basis of ethanol stress inS. cerevisiaeholds promise for developing robust yeast strains tailored for industrial applications.
Environment by environment interactions (ExE) differ across genetic backgrounds (ExExG)
Authors: Schmidlin Kara , Ogbunugafor C. Brandon , Sastokas Alexander , Geiler-Samerotte Kerry 
Published: May 2024

AbstractWhile the terms “gene-by-gene interaction” (GxG) and “gene-by-environment interaction” (GxE) are widely recognized in the fields of quantitative and evolutionary genetics, “environment-byenvironment interaction” (ExE) is a term used less often. In this study, we find that environmentby-environment interactions are a meaningful driver of phenotypes, and moreover, that they differ across different genotypes (suggestive of ExExG). To support this conclusion, we analyzed a large dataset of roughly 1,000 mutant yeast strains with varying degrees of resistance to different antifungal drugs. Our findings reveal that the effectiveness of a drug combination, relative to single drugs, often differs across drug resistant mutants. Remarkably, even mutants that differ by only a single nucleotide change can have dramatically different drug x drug (ExE) interactions. We also introduce a new framework that more accurately predicts the direction and magnitude of ExE interactions for some mutants. Understanding how ExE interactions change across genotypes (ExExG) is crucial not only for modeling the evolution of pathogenic microbes, but also for enhancing our knowledge of the underlying cell biology and the sources of phenotypic variance within populations. While the significance of ExExG interactions has been overlooked in evolutionary and population genetics, these fields and others stand to benefit from understanding how these interactions shape the complex behavior of living systems.
De novogenome assembly for an endangered lemur using portable nanopore sequencing in rural Madagascar
Authors: Hauff Lindsey , Rasoanaivo Noa Elosmie , Razafindrakoto Andriamahery , Ravelonjanahary Hajanirina , Wright Patricia C. , Rakotoarivony Rindra , Bergey Christina M. 
Published: May 2024

ABSTRACTAs one of the most threatened mammalian taxa, lemurs of Madagascar are facing unprecedented anthropogenic pressures. To address conservation imperatives such as this, researchers have increasingly relied on conservation genomics to identify populations of particular concern. However, many of these genomic approaches necessitate high-quality genomes. While the advent of next generation sequencing technologies and the resulting reduction of associated costs have led to the proliferation of genomic data and high-quality reference genomes, global discrepancies in genomic sequencing capabilities often result in biological samples from biodiverse host countries being exported to facilities in the Global North, creating inequalities in access and training within genomic research. Here, we present the first reference genome for the endangered red-fronted brown lemur (Eulemur rufifrons) from sequencing efforts conducted entirely within the host country using portable Oxford Nanopore sequencing. Using an archivedE. rufifronsspecimen, we conducted long-read, nanopore sequencing at the Centre ValBio Research Station near Ranomafana National Park, in rural Madagascar, generating over 750 Gb of sequencing data from 10 MinION flow cells. Exclusively using this long-read data, we assembled 2.21 gigabase, 20,330-contig nuclear assembly with an N50 of 98.9 Mb and a 17,108 bp mitogenome. The nuclear assembly had 31x average coverage and was comparable in completeness to other primate reference genomes, with a 95.47% BUSCO completeness score for primate-specific genes. As the first reference genome forE. rufifronsand the only annotated genome available for the specioseEulemurgenus, this resource will prove vital for conservation genomic studies while our efforts exhibit the potential of this protocol to address research inequalities and build genomic capacity.
In Utero Hematopoietic Stem Cell Transplant for Fanconi Anemia
Authors: Swartzrock Leah , Dib Carla , Denis Morgane , Willner Hana , Ho Katie , Haslett Ethan , Krampf Mark R. , Girsen Anna , Blumenfeld Yair J. , El-Sayed Yasser Y. , Roncarolo Maria G , MacKenzie Tippi C. , Czechowicz Agnieszka D. 
Published: May 2024

AbstractFanconi Anemia (FA) is an inherited DNA-repair deficiency caused by mutations in diverseFancgenes that leads to bone marrow failure and malignancies. FA disease begins at early embryonic stages, and while FA prenatal testing has long been available, no fetal therapies for FA currently exist. Postnatally, FA hematologic disease can be cured through allogeneic hematopoietic stem cell transplantation (HSCT); however, this requires chemotherapy and/or irradiation-based conditioning which amongst various side-effects also increases likelihood of malignancies later in life in these fragile patients. Given fetal immune tolerance and the competitive advantage of healthy hematopoietic stem and progenitor cells (HSPCs) over failing FA HSPCs, in utero HSCT without conditioning may be an alternative approach to stabilization of the hematopoietic system without conventional toxicities. We performed in utero HSCT using HSPCs from wildtype (WT) donors into two FA mouse models (Fancd2−/−,Fanca−/−) and observed robust multi-lineage hematopoietic donor engraftment in homozygous FA mice compared to both heterozygous FA and WT littermates. Upon serial assessments, we also observed increasing donor chimerism up to 94.1%, showcasing the competitive advantage of WT donor HSPCs over FA HSPCs. Given that 1% donor chimerism is predicted to stabilize FA BM, in utero HSCT may be a safe and curative prenatal treatment for all subtypes of FA.