bluuebunny/crossref_metadata_2025_split huggingface dataset:
MAT2a and AHCY inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival
Authors: Rowland Emma C. , D’Antuono Matthew , Jermakowicz Anna , Ayad Nagi G. 
Published: November 2024

AbstractGlioblastoma (GBM) is a highly aggressive primary malignant adult brain tumor that inevitably recurs with a fatal prognosis. This is due in part to metabolic reprogramming that allows tumors to evade treatment. We therefore must uncover the pathways mediating these adaptations to develop novel and effective treatments. We searched for genes that are essential in GBM cells as measured by a whole-genome pan-cancer CRISPR screen available from DepMap and identified the methionine metabolism genesMAT2AandAHCY. We conducted genetic knockdown, evaluated mitochondrial respiration, and performed targeted metabolomics to study the function of these genes in GBM. We demonstrate thatMAT2AorAHCYknockdown induces oxidative stress, hinders cellular respiration, and reduces the survival of GBM cells. Furthermore, selective MAT2a or AHCY inhibition reduces GBM cell viability, impairs oxidative metabolism, and changes the metabolic profile of these cells towards oxidative stress and cell death. Mechanistically, MAT2a or AHCY regulates spare respiratory capacity, the redox buffer cystathionine, lipid and amino acid metabolism, and prevents DNA damage in GBM cells. Our results point to the methionine metabolic pathway as a novel vulnerability point in GBM.SignificanceWe demonstrated that methionine metabolism maintains antioxidant production to facilitate pro-tumorigenic ROS signaling and GBM tumor cell survival. Importantly, targeting this pathway in GBM can potentially reduce tumor growth and improve survival in patients.
Modeling Primer-Template Interactions using BERT Tokenizer to Predict PCR Amplification with Attention-BiLSTM
Authors: Latifian Niloofar , Nazer Naghme , Jafarpisheh Amir Masoud , Hossein Khalaj Babak 
Published: November 2024

AbstractPolymerase Chain Reaction (PCR) is a widely used molecular biology technique to amplify DNA sequences. PCR amplification is affected by factors such as binding dynamics and primer-template interactions. This study aims to reduce the time and cost of the experiment by predicting PCR outcomes based on these factors. To achieve this, we first identify the most stable binding sites for each primer-template pair by calculating the Gibbs free energy. Then, we propose a unique labelling strategy that captures primer-template interactions in the binding sites by analyzing match and mismatch positions. We categorize a set of English words into two semantically distinct groups: one for match positions and another for mismatch positions. Words within each group have a higher cosine similarity to one another than to words in the opposing group. We assign the corresponding word to each base pair based on whether it is a match or a mismatch. The labelled sequence is then tokenized with BERT, serving as input to an attention Bi-LSTM model. Achieving 96.3% accuracy, this approach significantly outperforms prior methods and pioneers BERT-based analysis in primer-template bindings.
The Alzheimer’s Disease Risk Genes MS4A4A And MS4A6A Cooperate to Negatively Regulate Trem2 and Microglia states
Authors: Rosner Dalya , Sun Jessica , Yee Angie , Wagh Chaitanya , Rychkova Anna , Cacace Rita , Buonfiglioli Alice , Alwahagri Muhammed , Kong Phil , Roell Marina , Ho Wei-Hsien , Gong Belvin , Denton Heidi , Muscarnera Giacomo , Meese Tim , El-Khatib Malak , Bermingham Daniel , Ibrahim Adiljan , Kuhn Julia , Wang Xiaoting , Gulbranson Daniel , Rhinn Herve , Khan Zia , Mitra Ananya , Schwabe Tina , Srinivisan Karpagam , Tassi Ilaria , DeWitte Lotje , Mancuso Renzo , Long Hua , Heutink Peter , Kenkare-Mitra Sara , Rosenthal Arnon 
Published: November 2024

AbstractGenetic variations inMS4A4AandMS4A6Aare linked to the regulation of cerebrospinal fluid soluble TREM2 (sTREM2) levels and are associated with Alzheimer’s disease (AD) risk and progression. Using CRISPR knockout and MS4A4A-degrading antibodies in primary human microglia, non-human primates (NHP), and a xenotransplantation model of amyloid pathology, we provide evidence thatMS4A4AandMS4A6Aare negative regulators of both the transmembrane and soluble TREM2 proteins. They also negatively regulate microglia proliferation, survival, metabolism, lysosomal function, energetics, phagocytosis, and disease-fighting states. Mechanistically, we find that MS4A4A exerts negative regulation by interacting with MS4A6A and protecting it from degradation. MS4A6A in turn forms a complex with and blocks the co-receptor DAP12, which is required for the stability, cell surface localization, and signaling of TREM2 and other receptors. Taken together, the data indicate thatMS4A4AandMS4A6Aare cooperating, post-transcriptional negative regulators of TREM2 and microglial function, and potential drug targets for AD.
Heat stress impacts the gut microbiome of Atlantic salmon by promoting growth of Vibrionaceae and is associated with extensive cast production
Authors: Bowman John P. 
Published: November 2024

AbstractAtlantic salmon (Salmo salar) when exposed to heat stress have reduced voluntary feeding and exhibit changes in digesta consistency. This study was performed to determine what bacterial species occur and the overall bacterial abundance in the gut microbiome in heat stressed Atlantic salmon. For this Atlantic salmon in seawater tanks at 15°C were fed for 2 to 4 weeks. Tank temperatures were increased to 19°C until voluntary feeding abated at which point tank temperatures were cooled to 15°C for 4 weeks. At the end of each temperature phase the fish were stripped of feces and microbiome profiles were determined using 16S rRNA V1-V3 metabarcoding. The tank experiment was repeated three times in successive years. Vibrionaceae comprised most reads after the warm phase completed. The prominent levels of Vibrionaceae were accompanied by a large predominance of cast (sloughed intestinal mucosa) containing fecal samples. qPCR estimated Vibrionaceae cell populations increased 1.9-3.4 log units/g after the warm phase but and slightly decreased by 0.3-1.1 log units/g after the 15°C recovery phase. The results indicated heat stress induced inappetence corresponds to increased cast production accompanied by predominance of Vibrionaceae. Vibrionaceae colonizing the Atlantic salmon gut should be the focus of studies on the microbiology of thermally induced inappetence and dysbiosis in Atlantic salmon.Key ContributionThe experiments confirm that thermal stress increased cast production in Atlantic salmon. The increase in cast production coincides with increased predominance of Vibrionaceae. Though the growth of Vibrionaceae in the gut of salmon is not associated with acute disease it may represent a dysbiosis effect. The results suggest extended summers in regions where sea surface temperatures are at the tolerance limits require increased husbandry management of farmed fish. In addition, more studies are needed to determine if novel approaches can limit overgrowth of Vibrionaceae.
Blood draw site and blood matrix influence mineral assessment
Authors: Alejandro Mikail G. , Schultz Kathleen , Killilea David W. 
Published: November 2024

AbstractCirculating mineral concentrations are used to assess nutritional status or as markers for clinical conditions, but the quality of these measurements depends on the methods used for blood processing. Since the procedures for measuring mineral levels in blood are not standardized, discrepancies in sampling may influence the analytical results. We previously reported that zinc content in blood samples showed significant variation depending on several pre-analytical variables selected during blood collection and processing. In this study, we extend our analysis to determine how other mineral levels might be affected by different blood draw sites (capillary or venous) or sample matrices (plasma or serum). Sequential capillary and venous blood samples were collected from a diverse cohort of sixty healthy adults and analyzed for multiple minerals using inductively coupled plasma– optical emission spectrometry. Calcium, copper, iron, and magnesium were the only minerals that were detected in all samples and were free from contamination in the blood collection tubes used for the study. When assessing different blood draw sites, the concentrations of calcium, copper, iron, and magnesium were 2-11% higher from capillary compared to the venous plasma. When assessing different blood sample matrices, the concentrations of calcium, copper, and magnesium were 2-5% higher in serum compared to plasma samples, whereas the concentration of iron was 7% higher in plasma compared to serum samples. The differences observed in these four essential minerals from discrepant draw sites and blood matrices demonstrate the importance of controlling key pre-analytic variables when assessing mineral levels in blood.
Mdxmice dosed with antisense to CD49d and dystrophin exon skip morpholino; reduced force loss and affected gene expression pathways support ATL1102 combination therapy in DMD patients
Authors: Padhye A. S. , Kiriaev L. , Tiong C. , Gearing L.J , Wilson T , Houweling P. J. , Tachas G. 
Published: November 2024

AbstractBackgroundVLA-4 is a disease progression biomarker in patients with Duchenne Muscular Dystrophy (DMD) including those treated with corticosteroids. ATL1102 an antisense oligonucleotide (ASO) inhibitor of human CD49d chain of adhesion molecule VLA-4 shows promising phase-2 results in non-ambulant DMD stabilizing upper limb function (PUL2.0), grip strength, and MRI muscle fat fraction, compared to worsening with corticosteroids.MethodsASO to mouse CD49d (ISIS348574) was used in combination with a known mdx dystrophin morpholino exon-23 skipping restoration drug (PMO), dose-time chosen for low dystrophin restoration.Mdxmice were treated once weekly for 8 weeks with ASO, control mismatch oligonucleotide, saline, or PMO alone for 4 weeks, and PMO in combination with ASO or mismatch.ResultsASO+PMO demonstrated increased specific maximum force and eccentric muscle force retention in the exterior digitorum longus (EDL) muscle after 1-7 muscle eccentric contractions relative to saline. Area-under-curve force remaining after 8-10 contractions was higher for ASO+PMO versus PMO monotherapy and ASO monotherapy, PMO monotherapy versus saline, and the ASO monotherapy versus saline and mismatch.RNA-sequencing of quadriceps muscle evaluated gene expression changes, with false discovery rate (FDR) adjusted p-values up to <0.1. ASO monotherapy at FDR<0.05 showed 2 unique genes,Gm2ain immune neutrophil function andTrdnwithRyr2muscle calcium channel function, versusmdxsaline and none with MM. The lowest FDR PMO gene was another calcium channelCacna1s, with PMO+MM FDR<0.05. ASO+PMO treatment at FDR<0.05 modulated 55 genes, 53 unique to the combination and 2* also in ASO FDR<0.06. Affected genes were involved in immune response (Btla*,Ppml1,Tnfsm13), lipolysis (Fabp4*,G0s2), fibrosis (Igfbp-7, Calu), muscle cell (Asb15) and muscle stem cell function (Adam10, Mt-Tp, Myom1).ConclusionASO+PMO EDL muscle function protection inmdxmice, and gene expression pathways affected, support the development of ATL1102 in combination therapy with conditionally approved morpholino dystrophin restoration drugs in DMD patients.
The resilience ofSalmonellato bile stress is impaired due to the reduced efflux pump activity mediated by the antioxidant enzyme YqhD
Authors: Parmar Kirti , Kumari Yogyta , Rajmani Raju S , Chakravortty Dipshikha 
Published: November 2024

AbstractBile salts play a critical role in modulating the host gut. They have antimicrobial properties wherein they disrupt the bacterial membrane and produce reactive oxygen species, causing DNA damage. Bile-resistant pathogen likeSalmonellaregulates their metabolic activity to counteract the effects of bile. This study explores the role of YqhD, a putative alcohol dehydrogenase, inSalmonella’s bile salt susceptibility. We observed increased survival ofyqhDmutant in the in vitro studies in LB media with bile, liver cell line HepG2 and C57BL/6 mice on treatment with 8% sodium cholate in the intestine. Bile salts are produced for the digestion of fat. Replacing the chow diet with a high-fat diet (HFD) in mice increased organ burden in C57BL/6 mice of theyqhDmutant.Mutation ofyqhDon bile salt exposure leads to increased reactive oxygen species and modulation of antioxidant genes in the bacteria. The oxidative stress of theyqhDmutant is indispensable for improved survival when exposed to bile salt. The addition of antioxidant glutathionein vitroreduced the enhanced growth of theyqhDmutant. Similarly, in the gp91−/−phox mice, there was a reduced organ burden ofyqhDmutant on exposure to HFD compared to chow-fed mice. Furthermore, theyqhDmutant increases AcrAB efflux pump activity regulated by RamA/R regulon.TeaserRedox geneyqhDregulates bile salt susceptibility by modulatingSalmonella’sROS and efflux pump activity.Graphical abstractA.STM ΔyqhDhas less organ burden in the C57BL/6 mice than STM WT, and there was a similar organ burden ingp91phox−/−. On HFD exposure, the organ burden of STM ΔyqhDbecame similar to STM WT in C57BL/6 mice, and there was reduced organ of STM ΔyqhDburden whengp91phox−/−were exposed to HFD.B.On bile salt exposure, YqhD inSalmonellareduces ROS in bacteria and expression of RamA, decreasing the AcrAB efflux pump activity and reducing survival.
Dopamine alters motor learning performance in the presence and absence of feedback
Authors: Leow Li-Ann , Tan Ashley Huey-Ryu , Carroll Timothy J , Adam Rob , Dux Paul E , Filmer Hannah L 
Published: November 2024

AbstractSkilled motor performance is essential for survival. Indeed, we often not only choose to learn motor skills because of some external reward, but also because skilled movement, in and of itself, is satisfying. While dopamine is known to drive reward-based motor learning, it remains unclear whether dopamine is implicated in motor learning under conditions ostensibly driven by intrinsic rewards/motivation (i.e., in the absence of extrinsic feedback or reward). Here, we investigated the role of dopamine in motor skill learning guided by internally determined signals of performance success, using a task where learning occurred either in the absence or presence of feedback. We found that dopamine altered performance both in the presence and in the absence of information on task success. This provides direct causal evidence for a role of dopamine in motor learning driven by internal task goals.
GRNIX: A Graph Neural Network Framework for Explainable Gene Regulatory Network Inference in Autoimmune Diseases Using XAI
Authors: Mortadha Manai Mohamed 
Published: November 2024

AbstractAutoimmune diseases result from dysregulated immune mechanisms influenced by complex gene regulatory net-works (GRNs). Deciphering these networks has significant implications for understanding disease mechanisms, predicting disease progression, and identifying novel therapeutic targets.Traditional GRN inference techniques rely on statistical correlations or deterministic models, which are limited in capturing nonlinear interactions and often fail to provide interpretable outputs. Machine learning (ML)-based approaches, while more powerful, typically function as black-box systems, impeding their adoption in clinical settings.To bridge this gap, we introduce GRNIX, a GRN inference framework designed to balance predictive accuracy with explainability. The framework integrates multi-omics data, incorporates biological and structural priors, and applies explainable artificial intelligence (XAI) techniques to enhance interpretability..
Brain Feature Maps Reveal Progressive Animal-Feature Representations in the Ventral Stream
Authors: Zhang Z. , Hartmann T.S. , Born R.T. , Livingstone M.S. , Ponce C.R. 
Published: November 2024

AbstractWhat are the fundamental units of representation in the primate visual brain? Whileobjectshave become an intuitive framework for studying neurons in many parts of cortex, it is possible that neurons follow a more expressive organizational principle, such as encoding generic features present across textures, places, and objects. In this study, we used multi-electrode arrays to record from neurons in early (V1/V2), middle (V4), and late (posterior inferotemporal cortex (PIT)) areas across the visual hierarchy, estimating the local operation of each neuron over the entire visual scene. These estimates, called “heatmaps,” approximate theweight sharingoperation of convolutional neural networks. We found that while populations of neurons across V1, V4, and PIT responded over the full scene, they focused on salient sub-regions within object outlines. The best captured object feature class belonged toanimals, not general objects, as a trend that increased over the visual hierarchy. These results show that the monkey ventral stream is partially organized to encode local animal features over objects, even as early as primary visual cortex.
mTOR inhibition alleviated tau phosphorylation-induced mitochondrial impairment, oxidative stress, and cognitive impairment
Authors: Tang Zhi , Guo Min , Ding Yuanting , Wang Li , Chen Huilin , Li Bo , Xiao Yan , Ni Ruiqing , Qi Xiaolan , Guan Zhizhong 
Published: November 2024

AbstractAimHyperphosphorylated tau plays a crucial role in the pathogenesis of Alzheimer’s disease (AD). Whether mammalian target of rapamycin (mTOR) directly interacts with the Tau protein at Ser214, Ser356 and Thr231 is not clear. This study aimed to investigate whether mTOR-regulated tau phosphorylation disrupts mitochondrial dynamics and function and whether rapamycin, an mTOR inhibitor, can modulate tau phosphorylation levels and attenuate AD-related alterations.MethodsAdeno-associated virus (AAV) vectors were used to intracranially deliver the TauS214E/T231E/S356E (Tau3E) variant into 2-month-old C57BL/6 mice. The mice were intraperitoneally administered the mTOR inhibitor rapamycin for one week, followed by assessment via the Morris water maze test. Western blot analysis, immunofluorescence staining, and flow cytometry were employed to measure the expression levels of mTOR, p70S6K, and tau; mitochondrial dynamics; and reactive oxygen species (ROS) in HT22 cells and a mouse model overexpressing Tau3E, as well as in postmortem brain tissues from AD patients.Resultsp-mTORS2448 colocalized with p-TauSer214, p-TauSer356, and p-TauThr231 in the hippocampal CA3 region of AD patients. HT22 cells and C57BL/6 mice overexpressing Tau3Epresented elevated levels of p-mTOR, downstream target p-p70S6K, and ROS production; mitochondrial fragmentation; and p-TauSer214, p-TauSer356, and p-TauThr231. Rapamycin treatment partially mitigated the cognitive and molecular alterations in Tau3Emice.ConclusionThis study revealed a causal link between Tau phosphorylation at Ser214, Ser356, and p-Thr231 and mTOR upregulation and downstream impairments in ROS, mitochondrial dysfunction and cognitive function. Treatment using mTOR inhibitor rapamycin (i.p.) can alleviate impairment, reduce p-Tau and restore mitochondrial homeostasis, neuronal loss and cognitive impairment in mice.
Streamlined and efficient genome editing inCupriavidus necatorH16 using an optimised SIBR-Cas system
Authors: Della Valle Simona , Orsi Enrico , Creutzburg Sjoerd C. A. , Jansen Luc F. M. , Pentari Evangelia-Niki , Beisel Chase L. , Steel Harrison , Nikel Pablo I. , Staals Raymond H. J. , Claassens Nico J. , van der Oost John , Huang Wei E. , Patinios Constantinos 
Published: November 2024

AbstractCupriavidus necatorH16 is a promising microbial platform strain for CO2valorisation. WhileC. necatoris amenable to genome editing, existing tools are often inefficient or rely on lengthy protocols, hindering its rapid transition to industrial applications. In this study, we simplified and accelerated the genome editing pipeline forC. necatorby harnessing the Self-splicing Intron-Based Riboswitch (SIBR) system. We used SIBR to tightly control and delay Cas9-based counterselection, achieving >80% editing efficiency at two genomic loci within 48 hours after electroporation. To further increase the versatility of the genome editing toolbox, we upgraded SIBR to SIBR2.0 and used it to regulate the expression of Cas12a. SIBR2.0-Cas12a could mediate gene deletion inC. necatorwith ∼70% editing efficiency. Overall, we streamlined the genome editing pipeline forC. necator, facilitating its potential role in the transition to a bio-based economy.
Tomographic constraints on the production rate of gravitational waves from astrophysical sources
Authors: Alonso David , Nikjoo Mehraveh , Renzini Arianna I. , Bellini Emilio , Ferreira Pedro G. 
Published: November 2024

Using an optimal quadratic estimator, we measure the large-scale cross-correlation between maps of the stochastic gravitational-wave intensity, constructed from the first three LIGO-Virgo observing runs, and a suite of tomographic samples of galaxies covering the redshift range z≲2. We do not detect any statistically significant cross-correlation, but the tomographic nature of the data allows us to place constraints on the (bias-weighted) production rate density of gravitational waves by astrophysical sources as a function of cosmic time. Our constraints range from ⟨bΩ˙GW⟩<3.0×10−9  Gyr−1 at z∼0.06 to ⟨bΩ˙GW⟩<2.7×10−7  Gyr−1 at z∼1.5 (95% confidence level), assuming a frequency spectrum of the form f2/3 (corresponding to an astrophysical background of binary mergers), and a reference frequency fref=25  Hz. Although these constraints are ∼2 orders of magnitude higher than the expected signal, we show that a detection may be possible with future experiments.

Published by the American Physical Society
2024
Optimists, moderates and sceptics – identifying consumer groups and their willingness to consume cultured proteins in Finland
Authors: Heiskanen Aino , Ryynänen Toni 
Published: November 2024

PurposeIt is suggested that the detrimental externalities of intensive livestock production can be reduced by manufacturing animal proteins with cellular agriculture technologies. This study explores consumer attitudes towards cultured proteins based on representative Finnish survey data (n = 1,452).Design/methodology/approachSum variables from the principal component analysis were utilized in the cluster analysis to identify potential consumer groups of cultured proteins in Finland. A regression analysis was used to find out the explanatory factors of positive first reaction, willingness to taste, willingness to use and support for the establishment of a national cultured meat sector.FindingsMost of the respondents (72%) would taste cultured products, but attitudes of optimists (n = 516), moderates (n = 479) and sceptics (n = 457) differ in terms of the environment, livestock farming and cultured proteins. Most optimists (77%), almost quarter (23%) of moderates and less than a fifth (18%) of sceptics support cultured proteins. The environmental concerns are shared by optimists and moderates, whereas moderates and sceptics tend to be more suspicious. Positive attitudes are significantly influenced by social norms and respondents' beliefs regarding their global and national benefits. Major concerns pertain to anticipated dictation force of big companies, negative effects on Finnish agriculture, product attributes, use of genetically modified organisms and experienced (un)naturalness of cultured foods.Originality/valueThis study contributes to the understanding of Finnish consumers' attitudes towards cultured proteins. The identification of potential consumer segments and the elucidation of their attitudes are relevant, given the anticipated acceleration in the development of cultured foods.