bluuebunny/crossref_metadata_2025_split huggingface dataset:
The drug disposition in the Spleen: A novel study of CYP and UGT-mediated drug metabolism
Authors: Inuwa Patience , Paine Stuart , Best Stuart , Mosinska-Kodzik Karolina , Rauch Cyril 
Published: April 2024

AbstractUnderstanding the fate of a drug, its disposition and pharmacokinetics as it reaches the site of action is key to any pharmaceutical research and development. The emerging role of the spleen in its involvement in regulating the immune system has garnered interest in new immunotherapeutic strategies. Using novel precision immunotherapeutic drugs that will potentially engage with the host immune system to specifically target and eliminate diseased cells, makes this approach a better alternative to conventional therapies. The spleen poses as a potential immunotherapeutic target and confirmation of drugs reaching its site of action requires monitoring enzymes that engages with xenobiotics like drugs. The pig was selected as the model for human based on the close homology conveyed between pig and human using a phylogenetic construction of Cytochrome P450s (CYP450) and UDP-glucuronosyltransferases (UGT) in both species. Moreover, an RNAseq transcriptome analysis between the human spleen, pig liver and spleen tissues were obtained from a next generation sequencing (NGS) to identify genes associated with drug metabolism. Immunofluorescence and Western Blot analysis was carried out to determine the protein expression of metabolizing CYP450s and UGTs in pig spleen. Therefore, drug substrates and their metabolites known in human liver were investigated in pig spleen to determine the functional expression of CYP450s and UGTs. Promisingin-vitroresults has demonstrated the expression of these metabolic enzymes at a functional level from observations showing elimination of drug substrates and the apparent metabolites formed. Monitoring the enzyme activities would also indicate uptake of these substrates in splenocytes, confirm that the spleen can metabolize drugs, and provide further insight into therapeutic or toxic related implications from drug interactions.
Molecular and functional profiling unravels targetable vulnerabilities in colorectal cancer
Authors: Vlachavas Efstathios-Iason , Voutetakis Konstantinos , Kosmidou Vivian , Tsikalakis Spyridon , Roditis Spyridon , Pateas Konstantinos , Kim Ryangguk , Pagel Kymberleigh , Wolf Stephan , Warsow Gregor , Dimitrakopoulou-Strauss Antonia , Zografos Georgios N , Pintzas Alexander , Betge Johannes , Papadodima Olga , Wiemann Stefan 
Published: April 2024

AbstractWhile colorectal cancer (CRC) patients with microsatellite instability (MSI) respond well to immunotherapy those with microsatellite stable (MSS) tumors rely on conventional chemotherapy, often with poor outcomes. Both types frequently carry mutations inKRASorBRAFproto-oncogenes, rendering them more resistant to treatment. New therapeutic biomarkers and treatments remain a clinical need, especially for MSS tumors. We performed whole exome and RNA-Sequencing from 28 tumors of the Athens Comprehensive Cancer Center CRC cohort, and molecularly characterized colorectal cancer patients based on their MSI status, SNVs/CNAs, and pathway/transcription factor activities at the individual patient level. Variants were classified using a new computational score for integrative cancer variant annotation and prioritization. Complementing this molecular data with public multi-omics datasets, we identified activation of transforming growth factor beta (TGFβ) signaling to be stronger activated in the MSS patients whereas JAK-STAT and MAPK molecular cascades were activated specifically in MSI. We unraveled mechanisms consistently perturbed in the transcriptional and mutational circuits and identified RUNX transcription factors as putative novel targets. Assessing the immunogenicity of CRC tumors in the context of RAS/RAF mutations and MSI/MSS status revealed a critical impactKRASmutations have on immunogenicity particularly in the MSS patient subgroup, with implications for diagnosis and treatment.
DOES EXPERIENCE MODULATE AUTOMATIC IMITATION? A NEW LOOK
Authors: Genovese Francesca , Fanghella Martina , Sinigaglia Corrado , Barchiesi Guido 
Published: April 2024

AbstractAutomatic imitation is a stimulus-response compatibility effect wherein observing an action automatically influences motor performance. However, the mechanism underlying this effect remains controversial. Associative Sequence Learning suggests that automatic imitation arises from contingent visual and motor activity associations. Prior studies have shown that exposure to counter-imitative training can alter these visuomotor associations, suggesting that automatic imitation can be modulated by experience. Here, we aim to bring new insight into how this modulation occurs by exploring the time course of automatic imitation before and after counter-imitative training. If automatic imitation is merely a result of contingent associations, as previously suggested, the effect should consistently be modulated following such training. However, if this is not the case, automatic imitation is not, or not only, a matter of contingent association, at least not as currently understood.
Circulating tumor cells shed large extracellular vesicles in capillary bifurcations that activate endothelial and immune cells
Authors: Vrynas Angelos , Bazban-Shotorbani Salime , Arfan Sara , Satia Karishma , Ashna Mymuna , Zhang Aoyu , Visan Diana , Chen Aisher , Carter Mathew , Blackhall Fiona , Simpson Kathryn L. , Dive Caroline , Huang Paul , Au Sam H. 
Published: April 2024

AbstractCirculating tumor cells (CTCs) and their clusters are the drivers of metastasis, but we have an incomplete understanding of how they interact with capillary beds. Using microfluidic models mimicking human capillary bifurcations, we observed cell size- and bifurcation-dependent shedding of nuclei-free fragments by patient CTCs, CTC-derived explant cells and numerous cancer cell lines. Shedding reduced cell sizes up to 61%, facilitating their transit through bifurcations. We demonstrated that shed fragments were a novel subclass of large extracellular vesicles (LEVs), “shearosomes”, that require shear stress for their biogenesis and whose proteome was associated with immune-related pathways. Shearosomes exhibited functions characteristic of previously identified EVs including cell-directed internalization by endothelial and immune cells, and intercellular communication abilities such as disruption of endothelial barrier integrity, polarization of monocytes into M2 tumor-promoting macrophages and interactions between endothelial and immune cells. Cumulatively, these findings suggest that CTCs shed shearosomes in capillary beds that drive key processes involved in the formation of pre-metastatic niches.
Methods in cancer research: Assessing therapy response of spheroid cultures by life cell imaging using a Cost-Effective Live-Dead Staining Protocol
Authors: Phour Jaison , Vassella Erik 
Published: April 2024

AbstractSpheroid cultures of cancer cell lines or primary cells represent a more clinically relevant model for predicting therapy response compared to two-dimensional cell culture. However, current live-dead staining protocols used for treatment response in spheroid cultures are often expensive, toxic to the cells, or limited in their ability to monitor therapy response over an extended period due to reduced stability. In our study, we have developed a cost-effective method utilizing calcein-AM and Helix NP™ Blue for live-dead staining, enabling the monitoring of therapy response of spheroid cultures for up to 10 days. Using the example of glioblastoma cell lines and primary glioblastoma cells we show that spheroid cultures typically exhibit a green outer layer of viable cells, a turquoise mantle of hypoxic quiescent cells, and a blue core of necrotic cells when visualized using confocal microscopy. Upon treatment of spheroids with the alkylating agent temozolomide, we observed a reduction in the viability of glioblastoma cells after an incubation period of six to seven days. This method can also be adapted for monitoring therapy response in different cancer systems, offering a versatile and cost-effective approach for assessing therapy efficacy in three-dimensional culture models.
Non-canonical nuclear function of glutaminase cooperates with Wnt signaling to drive EMT during neural crest development
Authors: Nekooie Marnany Nioosha , Dady Alwyn , Relaix Frédéric , Motterlini Roberto , Foresti Roberta , Dufour Sylvie , Duband Jean-Loup 
Published: April 2024

ABSTRACTMetabolic reprograming has been linked to epithelial-to-mesenchymal transition (EMT) in cancer cells, but how it influences EMT in normal cells remains largely unknown. Here we explored how metabolism impacts delamination and migration of avian trunk neural crest cells, an important stem cell population of the vertebrate embryo. We report that delamination exhibits a quiescent metabolic phenotype whereas migration is characterized by OXPHOS-driven metabolism coupled to distinct expression of metabolic, EMT and developmental genes. While glucose and glutamine are required for delamination and migration, we uncover a novel role for glutamine and its catabolizing enzyme glutaminase in delamination. Specifically, glutamine is required for nuclear translocation of glutaminase, which interacts and cooperates with Wnt signaling to regulate EMT gene expression and cell cycle during delamination. Our data indicate that similarly to cancer cells, embryonic cells engage metabolic enzymes for non-canonical signaling functions to connect metabolism with EMT.
First endangered black-footed ferrets,Mustela nigripes, cloned for genetic rescue
Authors: Novak Ben J. , Gober Pete , Bortner Robyn , Garelle Della , Wright Mary , Chuven Justin , Houck Marlys L. , Ryder Oliver A. , Milutinovich Dennis , Benavidez Jill , Ryan Kerry , Walker Shawn , Arenivas Sanaz Sadeghieh , Aston Lauren , Russell Blake , Marinari Paul , Crosier Adrienne , Helmick Kelly , Gibson Mary R. , Carlsen Daniel P. , Swanson Bradley J. , Wisely Samantha M. , White Zoe S. , Lynch Colleen , Phelan Ryan 
Published: April 2024

AbstractAn endangered black-footed ferret female that died in 1988 with no living descendants in the current population was successfully cloned from cryopreserved cells using cross-species somatic cell nuclear transfer, producing three healthy kits. Incorporating progeny from these clones would provide an 8th founder to the breeding program and increase genetic variation to the species’ limited gene-pool. This marks the first time a native U.S. endangered species has been cloned.
Whatandwherein electromagnetic brain imaging
Authors: de Cheveigné Alain 
Published: April 2024

AbstractTo understand the brain, we need to observe the nature and dynamics of the activity (the “what”), and the location or distribution of its sources (the “where”). This paper proposes a new approach in which these two elements are derived in parallel from separate columns of a data-driven analysis matrix. A subset of columns enhances the activity of interest, and its complement defines spatial filters that suppress that activity (null filters). Each null filter is combined with an anatomy-dependent source model to estimate a set of locations within the sources space in which the source might reside (the “zero set” of that filter) and the final estimate is derived from the intersection of zero sets. There is no theoretical limit to the accuracy with which the location of a source can be estimated in this way, but practical limits may arise from noise in the data, imperfect calibration, or an incomplete or inaccurate source model. The method is illustrated with simulated and real data from EEG, MEG and SEEG.
Nutribloods: novel synthetic lepidopteran haemolymphs for understanding insect-microbe interactionsin vitro
Authors: Holdbrook Robert , Randall Joanna L. , Reavey Catherine E. , Andongma Awawing A. , Rice Annabel , Smith Judith A. , Simpson Stephen J. , Cotter Sheena C. , Wilson Kenneth 
Published: April 2024

ABSTRACTUnderstanding the role of nutrients in microbial population dynamics relies on a sound appreciation of their nutritional environment and how this may vary in different habitats. For microbial pathogens and commensals, this can be especially challenging because the microbe may share nutritional resources with its host. Here we design a series of 20 synthetic haemolymphs (nutribloods) that mimic haemolymph nutrient profiles of caterpillars fed on one of 20 chemically-defined diets, that vary in their protein:carbohydrate (P:C) ratio and caloric density. Using these, we are able to simulate the range of nutritional conditions that insect blood pathogens might face, providing a model system for understanding the role of nutrition in microbial growth. We tested this using the entomopathogen,Xenorhabdus nematophila, a gram-positive extracellular bacterium of insect hosts. This revealed that whilst bacterial fitness peaked innutribloodnutrient space that was high in carbohydrates and low in proteins, levels of amino acids in the nutribloods also appear to be an important driving force for bacterial growth. Using synthetic haemolymphs that had average levels of all nutrients other than carbohydrate, protein or amino acids, we also established that bacterial growth is generally enhanced by carbohydrate and amino acids but reduced by proteins. Here, we have established a tractable model system for examining the role that nutrition plays in the growth of an entomopathogenic bacterium. In future work, this model host-pathogen system can be used to test a range of nutritionally-driven processes, including competition during co-infection and interactions with the host microbiome, as well as comparative studies of other entomopathogens.
Comparative study on the accuracy of speech recognition using a contact microphone attached to the surface of the head and neck
Authors: Asakura Takumi , Konuma Yuki 
Published: April 2024

AbstractThe accuracy of speech recognition through an air-conducted microphone can be less accurate under a highly noisy environment or when the volume of the user’s voice is relatively low. One solution to this problem is the use of contact microphones. However, neither the microphone locations that provide optimal speech recognition accuracy for each user nor the mechanisms underlying these contact forces have been clarified. In this study, we experimentally investigated the effects of placement, contact force, user gender, and speech recognition platform on the accuracy of speech recognition with contact microphones placed on the surface of the head and neck. The experimental results indicated that the mechanism underlying the influence of each factor on speech recognition accuracy differs for speech acquired at the neck and head locations. In particular, the effect of the user’s gender was significant for the neck-acquired sound, but not the head-acquired sound. The results also revealed that the microphone contact force did not affect the recognition accuracy or user discomfort for the head-acquired sound. Moreover, the results of speech recognition experiments in a simulated noisy environment showed that bone-conducted sounds acquired on the head and neck surfaces were more robust than air-conducted sounds.
5’-S-(3-aminophenyl)-5’-thioadenosine, a novel chemoprotective agent for reducing toxic side effects of fluorouracil in treatment of MTAP-deficient cancers
Authors: Zhang Si , Xue Hui , Wong Nelson K.Y. , Doerksen Thomas , Ban Fuqiang , Aderson Shawn , Volik Stanislav , Lin Yen-Yi , Dai Zhongye , Bratanovic Ivica , Cheng Hongwei , Collins Colin C. , Cherkasov Artem , Wulff Jeremy , Wang Yuzhuo 
Published: April 2024

AbstractBackgroundNucleobase analogue (NBA) drugs are effective chemotherapeutics, but their clinical use is limited by severe side effects. Compelling evidence suggests the use ofS-methyl-5’-thioadenosine (MTA) can selectively reduce NBA toxicity on normal tissues while maintaining the efficacy of NBAs on methylthioadenosine phosphorylase (MTAP)-deficient cancers. However, we found that MTA induced hypothermia at its effective dose, limiting its translational potential. We intended to find an MTA analogue that can exert MTA function while minimize the undesired side effects of MTA. Thus, such an analogue can be used in combination with NBAs in selectively targeting MTAP-deficient cancers.MethodsWe screened a library of MTA analogues for the following criteria: 1) being substrates of MTAP; 2) selectively protection on MTAP-expressing cells from NBA toxicity usingMTAP-isogenic cell lines; 3) ability to protect the host from NBA toxicity without hypothermic effect; and 4) lack of interference on the tumor-suppressive effect of NBA in mice bearing MTAP-deficient tumors.ResultsWe identified 5’-S-(3-aminophenyl)-5’-thioadenosine (m-APTA) that did not induce hypothermia at the effective doses. We demonstrated that m-APTA could be converted to adenine by MTAP. Consequently, m-APTA selectively protected mouse hosts from 5-FU-induced toxicity (i.e. anemia); yet it did not interfere with the drug efficacy on MTAP-deficient bladder cancers.In silicodocking studies revealed that, unlike MTA, m-APTA interact inefficiently with adenosine A1receptor, providing a plausible explanation of the superior safety profile of m-APTA.Conclusionm-APTA can significantly improve the translational potential of the NBA toxicity reduction strategy in selectively targeting MTAP-deficient cancers.
Dirichlet distribution parameter estimation with applications in microbiome analyses
Authors: Fuller Daniel T. , Mondal Sumona , Sur Shantanu , Pal Nabendu 
Published: April 2024

AbstractMicrobiomes are of vital importance for understanding human and environmental health. However, quantifying microbial composition remains challenging and relies on statistical modeling of either the raw taxonomic counts or the relative abundances. Relative abundance measures are commonly preferred over the absolute counts to analyze and interpret microbiome (as the sampling fraction are unknown in sequence data) but currently there is no ideal distribution for carrying out this modeling . In this work, the Dirichlet distribution is proposed to model the relative abundances of taxa directly without the use of any further transformation. In a comprehensive simulation study, we compared biases and standard errors of two Methods of Moments Estimators (MMEs) and Maximum Likelihood Estimator (MLE) of the Dirichlet distribution. Comparison of each estimator is done over three different cases of differing sample size and dimension: (i) small dimension and small sample size; (ii) small dimension and large sample size; (iii) large dimension with both large and small sample size. We demonstrate the Dirichlet modeling methodology with four real world microbiome datasets and show how the results of the Dirichlet model differ from those obtained by a commonly used method, namely Bayesian Dirichlet-Multinomial estimation (BDME). We find that the results of parameter estimation can be dependent upon the sequencing depth and sequencing technique used to produce a given microbiome dataset. However, for all datasets, the Dirichlet MLE (DMLE) results are comparable to the BDME results while requiring less computational time in each case.
Impact of Pathogenic Variants of the Ras-MAPK Pathway on Major White Matter Tracts in the Human Brain
Authors: Siqueiros-Sanchez Monica , Dai Erpeng , McGhee Chloe A. , McNab Jennifer A. , Raman Mira M. , Green Tamar 
Published: April 2024

AbstractNoonan syndrome (NS) and Neurofibromatosis type-1 (NF1) are genetic conditions linked to pathogenic variants in genes of the Ras-MAPK signaling pathway. Both conditions hyperactivate signaling of the Ras pathway and exhibit a high prevalence of neuropsychiatric disorders. Further, animal models of NS and NF1 and human imaging studies show white-matter abnormalities in both conditions. While these findings suggest Ras pathway hyper-activation effects on white-matter, it is unknown whether these effects are syndrome-specific or pathway-specific. To characterize the effect of NS and NF1 on human white-matter microstructural integrity and discern potential syndrome-specific influences on microstructural integrity of individual tracts, we collected diffusion-weighted imaging data from children with NS (n=24), NF1 (n=28), and age and sex-matched controls (n=31). We contrasted the clinical groups (NS or NF1) and controls using voxel-wise, tract-based, and along-tract analyses. Outcomes included voxel-wise, tract-based and along-tract fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD). NS and NF1 showed similar patterns of reduced FA and increased AD, RD, and MD on white-matter relative to controls and different spatial patterns. NS presented a more extensive spatial effect than NF1 on white-matter integrity as measured by FA. Tract-based analysis also demonstrated differences in effect magnitude with overall lower FA in NS compared to NF1 (d=0.4). At the tract-level, NS specific-effects on FA were detected in association tracts (superior longitudinal, uncinate and arcuate fasciculi; p’s <0.012) and NF1 specific-effects were detected in the corpus callosum (p’s<0.037) compared to controls. Results from along-tract analyses aligned with results from tract-based analyses and indicated that effects are pervasive along the affected tracts. In conclusion, we find that pathogenic variants in the Ras-MAPK pathway are associated with white-matter abnormalities as measured by diffusion in the developing brain. Overall NS and NF1 show common effects on FA and diffusion scalars, as well as specific unique effects, namely on temporoparietal-frontal tracts (intra-hemispheric) in NS and on the corpus callosum (inter-hemispheric) in NF1. The observed specific effects not only confirm prior observations from independent cohorts of NS and NF1 but also inform on syndrome-specific susceptibility of individual tracts. Thus, these findings suggest potential targets for precise, brain-focused outcome measures for existing medications, such as MEK inhibitors, that act on the Ras pathway.
Circular DNA vcDNA-S7 derived from segmented-dsRNA virus BmCPV attenuated viral infection through RNase H1
Authors: Pan Jun , Tong Xinyu , Ding Yuming , Lei Chao , Wei Shulin , Xu An , Han Yaxuan , Qiu Qunnan , Pang Huilin , Hu Xiaolong , Gong Chengliang , Zhu Min 
Published: April 2024

AbstractViral circDNA derived from insect positive-sense single-stranded RNA viruses plays a crucial role in regulating viral infections depending on the RNAi pathway. Our previous research has revealed thatBombyx moricypovirus (BmCPV), a segmented-dsRNA virus, can generate viral circDNA vcDNA-S7, which can be transcribed to form RNA and further processed into small RNAs to defend against the virus through RNAi. However, whether vcDNA-S7 employs other mechanisms to resist the viruses. Presently, vcDNA-S7 has been found to resist BmCPV infection via a novel mechanism that depends on ribonuclease RNase H1 activity. It was found that the expression level of RNase H1 increased upon BmCPV infection (RNA virus) but not uponB. morinucleopolyhedrovirus (BmNPV) (DNA virus) infection. RNase H1 has been shown to negatively regulate BmCPV infections. In addition, vcDNA-S7 was found to form a heteroduplex with the viral RNA and subsequently recruit RNase H1 to degrade the viral RNA within the heteroduplex, ultimately leading to the suppression of viral replication. Furthermore, the resistance of vcDNA-S7 to viruses was significantly reduced when cellular RNase H1 gene was silenced. These findings not only reveal a new antiviral mechanism involving circular DNA formed by reovirus but also offer intriguing insights into the antiviral function of RNase H1 in cells.