bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translatome proteomics identifies autophagy as a resistance mechanism to on-target FLT3 inhibitors in acute myeloid leukemia
Authors: Koschade Sebastian E. , Klann Kevin , Shaid Shabnam , Vick Binje , Stratmann Jan A. , Thölken Marlyn , Meyer Laura M. , Nguyen The Duy , Campe Julia , Moser Laura M. , Hock Susanna , Baker Fatima , Meyer Christian T. , Wempe Frank , Serve Hubert , Ullrich Evelyn , Jeremias Irmela , Münch Christian , Brandts Christian H. 
Published: August 2022

AbstractInternal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in 25 % of acute myeloid leukemia (AML) patients, drive leukemia progression and confer a poor prognosis. Primary resistance to FLT3 kinase inhibitors (FLT3i) quizartinib, crenolanib and gilteritinib is a frequent clinical challenge and occurs in the absence of identifiable genetic causes. This suggests that adaptive cellular mechanisms mediate primary resistance to on-target FLT3i therapy. Here, we systematically investigated acute cellular responses to on-target therapy with multiple FLT3i in FLT3-ITD + AML using recently developed functional translatome proteomics (measuring changes in the nascent proteome) with phosphoproteomics. This pinpointed AKT-mTORC1-ULK1-dependent autophagy as a dominant resistance mechanism to on-target FLT3i therapy. FLT3i induced autophagy in a concentration- and time-dependent manner specifically in FLT3-ITD + cells in vitro and in primary human AML cells ex vivo. Pharmacological or genetic inhibition of autophagy increased the sensitivity to FLT3-targeted therapy in cell lines, patient-derived xenografts and primary AML cells ex vivo. In mice xenografted with FLT3-ITD + AML cells, co-treatment with oral FLT3 and autophagy inhibitors synergistically impaired leukemia progression and extended overall survival. Our findings identify a molecular mechanism responsible for primary FLT3i treatment resistance and demonstrate the pre-clinical efficacy of a rational combination treatment strategy targeting both FLT3 and autophagy induction.
Association between antidepressant use and ED or hospital visits in outpatients with SARS-CoV-2
Authors: Fritz Bradley A. , Hoertel Nicolas , Lenze Eric J. , Jalali Farid , Reiersen Angela M. 
Published: August 2022

AbstractAntidepressants have previously been associated with better outcomes in patients hospitalized with COVID-19, but their effect on clinical deterioration among ambulatory patients has not been fully explored. The objective of this study was to assess whether antidepressant exposure was associated with reduced emergency department (ED) or hospital visits among ambulatory patients with SARS-CoV-2 infection. This retrospective cohort study included adult patients (N = 25 034) with a positive SARS-CoV-2 test performed in a non-hospital setting. Logistic regression analyses tested associations between home use of antidepressant medications and a composite outcome of ED visitation or hospital admission within 30 days. Secondary exposures included individual antidepressants and antidepressants with functional inhibition of acid sphingomyelinase (FIASMA) activity. Patients with antidepressant exposure were less likely to experience the primary composite outcome compared to patients without antidepressant exposure (adjusted odds ratio [aOR] 0.89, 95% CI 0.79–0.99, p = 0.04). This association was only observed with daily doses of at least 20 mg fluoxetine-equivalent (aOR 0.87, 95% CI 0.77–0.99, p = 0.04), but not with daily doses lower than 20 mg fluoxetine-equivalent (aOR 0.94, 95% CI 0.80–1.11, p = 0.48). In exploratory secondary analyses, the outcome incidence was also reduced with exposure to selective serotonin reuptake inhibitors (aOR 0.87, 95% CI 0.75–0.99, p = 0.04), bupropion (aOR 0.70, 95% CI 0.55–0.90, p = 0.005), and FIASMA antidepressant drugs (aOR 0.87, 95% CI 0.77–0.99, p = 0.03). Antidepressant exposure was associated with a reduced incidence of emergency department visitation or hospital admission among SARS-CoV-2 positive patients, in a dose-dependent manner. These data support the FIASMA model of antidepressants’ effects against COVID-19.
CDK5RAP3 acts as a tumour suppressor in gastric cancer through the infiltration and polarization of tumour-associated macrophages
Authors: Wang Jia-Bin , Gao You-Xin , Ye Yin-Hua , Lin Tong-Xing , Li Ping , Lin Jian-Xian , Chen Qi-Yue , Cao Long-Long , Lin Mi , Tu Ru-Hong , Lin Ju-Li , Huang Ze-Ning , Zheng Hua-Long , Xie Jian-Wei , Zheng Chao-Hui , Huang Chang-Ming 
Published: August 2022

AbstractWe have demonstrated that CDK5RAP3 exerts a tumour suppressor effect in gastric cancer, but its role in regulating tumour-associated macrophages (TAMs) has not yet been reported. Here, we show that CDK5RAP3 is related to the infiltration and polarization of macrophages. It inhibits the polarization of TAMs to M2 macrophages and promotes the polarization of the M1 phenotype. CDK5RAP3 reduces the recruitment of circulating monocytes to infiltrate tumour tissue by inhibiting the CCL2/CCR2 axis in gastric cancer. Blocking CCR2 reduces the growth of xenograft tumours and the infiltration of monocytes. CDK5RAP3 inhibits the nuclear transcription of NF-κB, thereby reducing the secretion of the cytokines IL4 and IL10 and blocking the polarization of M2 macrophages. In addition, the absence of CDK5RAP3 in gastric cancer cells allows macrophages to secrete more MMP2 to promote the epithelial-mesenchymal transition (EMT) process of gastric cancer cells, thereby enhancing the invasion and migration ability. Our results imply that CDK5RAP3 may be involved in the regulation of immune activity in the tumour microenvironment and is expected to become a potential immunotherapy target for gastric cancer.
Estimating effects of parents’ cognitive and non-cognitive skills on offspring education using polygenic scores
Authors: Demange Perline A. , Hottenga Jouke Jan , Abdellaoui Abdel , Eilertsen Espen Moen , Malanchini Margherita , Domingue Benjamin W. , Armstrong-Carter Emma , de Zeeuw Eveline L. , Rimfeld Kaili , Boomsma Dorret I. , van Bergen Elsje , Breen Gerome , Nivard Michel G. , Cheesman Rosa 
Published: August 2022

AbstractUnderstanding how parents’ cognitive and non-cognitive skills influence offspring education is essential for educational, family and economic policy. We use genetics (GWAS-by-subtraction) to assess a latent, broad non-cognitive skills dimension. To index parental effects controlling for genetic transmission, we estimate indirect parental genetic effects of polygenic scores on childhood and adulthood educational outcomes, using siblings (N = 47,459), adoptees (N = 6407), and parent-offspring trios (N = 2534) in three UK and Dutch cohorts. We find that parental cognitive and non-cognitive skills affect offspring education through their environment: on average across cohorts and designs, indirect genetic effects explain 36–40% of population polygenic score associations. However, indirect genetic effects are lower for achievement in the Dutch cohort, and for the adoption design. We identify potential causes of higher sibling- and trio-based estimates: prenatal indirect genetic effects, population stratification, and assortative mating. Our phenotype-agnostic, genetically sensitive approach has established overall environmental effects of parents’ skills, facilitating future mechanistic work.
Linear and nonlinear correlation estimators unveil undescribed taxa interactions in microbiome data
Authors: Lin Huang , Eggesbø Merete , Peddada Shyamal Das 
Published: August 2022

AbstractIt is well-known that human gut microbiota form an ecosystem where microbes interact with each other. Due to complex underlying interactions, some microbes may correlate nonlinearly. There are no measures in the microbiome literature we know of that quantify these nonlinear relationships. Here, we develop a methodology called Sparse Estimation of Correlations among Microbiomes (SECOM) for estimating linear and nonlinear relationships among microbes while maintaining the sparsity. SECOM accounts for both sample and taxon-specific biases in its model. Its statistical properties are evaluated analytically and by comprehensive simulation studies. We test SECOM in two real data sets, namely, forehead and palm microbiome data from college-age adults, and Norwegian infant gut microbiome data. Given that forehead and palm are related to skin, as desired, SECOM discovers each genus to be highly correlated between the two sites, but that is not the case with any of the competing methods. It is well-known that infant gut evolves as the child grows. Using SECOM, for the first time in the literature, we characterize temporal changes in correlations among bacterial families during a baby’s first year after birth.
Evolution of longitudinal division in multicellular bacteria of the Neisseriaceae family
Authors: Nyongesa Sammy , Weber Philipp M. , Bernet Ève , Pulido Francisco , Nieves Cecilia , Nieckarz Marta , Delaby Marie , Viehboeck Tobias , Krause Nicole , Rivera-Millot Alex , Nakamura Arnaldo , Vischer Norbert O. E. , vanNieuwenhze Michael , Brun Yves V. , Cava Felipe , Bulgheresi Silvia , Veyrier Frédéric J. 
Published: August 2022

AbstractRod-shaped bacteria typically elongate and divide by transverse fission. However, several bacterial species can form rod-shaped cells that divide longitudinally. Here, we study the evolution of cell shape and division mode within the familyNeisseriaceae, which includes Gram-negative coccoid and rod-shaped species. In particular, bacteria of the generaAlysiella,SimonsiellaandConchiformibius, which can be found in the oral cavity of mammals, are multicellular and divide longitudinally. We use comparative genomics and ultrastructural microscopy to infer that longitudinal division withinNeisseriaceaeevolved from a rod-shaped ancestor. In multicellular longitudinally-dividing species, neighbouring cells within multicellular filaments are attached by their lateral peptidoglycan. In these bacteria, peptidoglycan insertion does not appear concentric, i.e. from the cell periphery to its centre, but as a medial sheet guillotining each cell. Finally, we identify genes and alleles associated with multicellularity and longitudinal division, including the acquisition of amidase-encoding geneamiC2, and amino acid changes in proteins including MreB and FtsA. Introduction ofamiC2and allelic substitution ofmreBin a rod-shaped species that divides by transverse fission results in shorter cells with longer septa. Our work sheds light on the evolution of multicellularity and longitudinal division in bacteria, and suggests that members of theNeisseriaceaefamily may be good models to study these processes due to their morphological plasticity and genetic tractability.
Raptors avoid the confusion effect by targeting fixed points in dense aerial prey aggregations
Authors: Brighton Caroline H. , Kloepper Laura N. , Harding Christian D. , Larkman Lucy , McGowan Kathryn , Zusi Lillias , Taylor Graham K. 
Published: August 2022

AbstractCollective behaviours are widely assumed to confuse predators, but empirical support for a confusion effect is often lacking, and its importance must depend on the predator’s targeting mechanism. Here we show that Swainson’s Hawks Buteo swainsoni and other raptors attacking swarming Mexican Free-tailed Bats Tadarida brasiliensis steer by turning towards a fixed point in space within the swarm, rather than by using closed-loop pursuit of any one individual. Any prey with which the predator is on a collision course will appear to remain on a constant bearing, so target selection emerges naturally from the geometry of a collision. Our results show how predators can simplify the demands on their sensory system by decoupling steering from target acquisition when capturing prey from a dense swarm. We anticipate that the same tactic will be used against flocks and schools across a wide range of taxa, in which case a confusion effect is paradoxically more likely to occur in attacks on sparse groups, for which steering and target acquisition cannot be decoupled.
Derivation and utility of schizophrenia polygenic risk associated multimodal MRI frontotemporal network
Authors: Qi Shile , Sui Jing , Pearlson Godfrey , Bustillo Juan , Perrone-Bizzozero Nora I. , Kochunov Peter , Turner Jessica A. , Fu Zening , Shao Wei , Jiang Rongtao , Yang Xiao , Liu Jingyu , Du Yuhui , Chen Jiayu , Zhang Daoqiang , Calhoun Vince D. 
Published: August 2022

AbstractSchizophrenia is a highly heritable psychiatric disorder characterized by widespread functional and structural brain abnormalities. However, previous association studies between MRI and polygenic risk were mostly ROI-based single modality analyses, rather than identifying brain-based multimodal predictive biomarkers. Based on schizophrenia polygenic risk scores (PRS) from healthy white people within the UK Biobank dataset (N = 22,459), we discovered a robust PRS-associated brain pattern with smaller gray matter volume and decreased functional activation in frontotemporal cortex, which distinguished schizophrenia from controls with >83% accuracy, and predicted cognition and symptoms across 4 independent schizophrenia cohorts. Further multi-disease comparisons demonstrated that these identified frontotemporal alterations were most severe in schizophrenia and schizo-affective patients, milder in bipolar disorder, and indistinguishable from controls in autism, depression and attention-deficit hyperactivity disorder. These findings indicate the potential of the identified PRS-associated multimodal frontotemporal network to serve as a trans-diagnostic gene intermediated brain biomarker specific to schizophrenia.
Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models
Authors: Xie Ying Xue , Naseri Nima N. , Fels Jasmine , Kharel Parinati , Na Yoonmi , Lane Diane , Burré Jacqueline , Sharma Manu 
Published: August 2022

AbstractConsiderable evidence supports the release of pathogenic aggregates of the neuronal protein α-Synuclein (αSyn) into the extracellular space. While this release is proposed to instigate the neuron-to-neuron transmission and spread of αSyn pathology in synucleinopathies including Parkinson’s disease, the molecular-cellular mechanism(s) remain unclear. To study this, we generated a new mouse model to specifically immunoisolate neuronal lysosomes, and established a long-term culture model where αSyn aggregates are produced within neurons without the addition of exogenous fibrils. We show that neuronally generated pathogenic species of αSyn accumulate within neuronal lysosomes in mouse brains and primary neurons. We then find that neurons release these pathogenic αSyn species via SNARE-dependent lysosomal exocytosis. The released aggregates are non-membrane enveloped and seeding-competent. Additionally, we find that this release is dependent on neuronal activity and cytosolic Ca2+. These results propose lysosomal exocytosis as a central mechanism for the release of aggregated and degradation-resistant proteins from neurons.
Covalent TCR-peptide-MHC interactions induce T cell activation and redirect T cell fate in the thymus
Authors: Szeto Christopher , Zareie Pirooz , Wirasinha Rushika C. , Zhang Justin B. , Nguyen Andrea T. , Riboldi-Tunnicliffe Alan , La Gruta Nicole L. , Gras Stephanie , Daley Stephen R. 
Published: August 2022

AbstractInteractions between a T cell receptor (TCR) and a peptide-major histocompatibility complex (pMHC) ligand are typically mediated by noncovalent bonds. By studying T cells expressing natural or engineered TCRs, here we describe covalent TCR-pMHC interactions that involve a cysteine-cysteine disulfide bond between the TCR and the peptide. By introducing cysteines into a known TCR-pMHC combination, we demonstrate that disulfide bond formation does not require structural rearrangement of the TCR or the peptide. We further show these disulfide bonds still form even when the initial affinity of the TCR-pMHC interaction is low. Accordingly, TCR-peptide disulfide bonds facilitate T cell activation by pMHC ligands with a wide spectrum of affinities for the TCR. Physiologically, this mechanism induces strong Zap70-dependent TCR signaling, which triggers T cell deletion or agonist selection in the thymus cortex. Covalent TCR-pMHC interactions may thus underlie a physiological T cell activation mechanism that has applications in basic immunology and potentially in immunotherapy.
Unveiling Trail Making Test: visual and manual trajectories indexing multiple executive processes
Authors: Linari Ignacio , Juantorena Gustavo E. , Ibáñez Agustín , Petroni Agustín , Kamienkowski Juan E. 
Published: August 2022

AbstractThe Trail Making Test (TMT) is one of the most popular neuropsychological tests for executive functions (EFs) assessment. It presents several strengths: it is sensitive to executive dysfunction, it is easy to understand, and has a short administration. However, it has important limitations. First, the underlying EFs articulated during the task are not well discriminated, which makes it a test with low specificity. Second, the pen-and-paper version presents one trial per condition which introduces high variability. Third, only the total time is quantified, which does not allow for a detailed analysis. Fourth, it has a fixed spatial configuration per condition. We designed a computerised version of the TMT to overcome its main limitations and evaluated it in a group of neurotypical adults. Eye and hand positions are measured with high resolution over several trials, and spatial configuration is controlled. Our results showed a very similar performance profile compared to the traditional TMT. Moreover, it revealed differences in eye movements between parts A and B. Most importantly, based on hand and eye movements, we found an internal working memory measure that showed an association to a validated working memory task. Additionally, we proposed another internal measure as a potential marker of inhibitory control. Our results showed that EFs can be studied in more detail using traditional tests combined with powerful digital setups. The cTMT showed potential use in older adult populations and patients with EFs disorders.
Comparison of the modified Singapore myocardial infarction registry risk score with GRACE 2.0 in predicting 1-year acute myocardial infarction outcomes
Authors: Sia Ching-Hui , Zheng Huili , Ko Junsuk , Ho Andrew Fu-Wah , Foo David , Foo Ling-Li , Lim Patrick Zhan-Yun , Liew Boon Wah , Chai Ping , Yeo Tiong-Cheng , Tan Huay-Cheem , Chua Terrance , Chan Mark Yan-Yee , Tan Jack Wei Chieh , Fox Keith A. A. , Bulluck Heerajnarain , Hausenloy Derek J. 
Published: August 2022

AbstractRisk stratification plays a key role in identifying acute myocardial infarction (AMI) patients at higher risk of mortality. However, current AMI risk scores such as the Global Registry of Acute Coronary Events (GRACE) score were derived from predominantly Caucasian populations and may not be applicable to Asian populations. We previously developed an AMI risk score from the national-level Singapore Myocardial Infarction Registry (SMIR) confined to ST-segment elevation myocardial infarction (STEMI) patients and did not include non-STEMI (NSTEMI) patients. Here, we derived a modified SMIR risk score for both STEMI and NSTEMI patients and compared its performance to the GRACE 2.0 score for predicting 1-year all-cause mortality in our multi-ethnic population. The most significant predictor of 1-year all-cause mortality in our population using the GRACE 2.0 score was cardiopulmonary resuscitation on admission (adjusted hazards ratio [HR] 6.50), while the most significant predictor using the SMIR score was age 80–89 years (adjusted HR 7.78). Although the variables used in the GRACE 2.0 score and SMIR score were not exactly the same, the c-statistics for 1-year all-cause mortality were similar between the two scores (GRACE 2.0 0.841 and SMIR 0.865). In conclusion, we have shown that in a multi-ethnic Asian AMI population undergoing PCI, the SMIR score performed as well as the GRACE 2.0 score.
Roundup and glyphosate’s impact on GABA to elicit extended proconvulsant behavior in Caenorhabditis elegans
Authors: Naraine Akshay S. , Aker Rebecca , Sweeney Isis , Kalvey Meghan , Surtel Alexis , Shanbhag Venkatesh , Dawson-Scully Ken 
Published: August 2022

AbstractAs 3 billion pounds of herbicides are sprayed over farmlands every year, it is essential to advance our understanding how pesticides may influence neurological health and physiology of both humans and other animals. Studies are often one-dimensional as the majority examine glyphosate by itself. Farmers and the public use commercial products, like Roundup, containing a myriad of chemicals in addition to glyphosate. Currently, there are no neurological targets proposed for glyphosate and little comparison to Roundup. To investigate this, we compared how glyphosate and Roundup affect convulsant behavior in C.elegans and found that glyphosate and Roundup increased seizure-like behavior. Key to our initial hypothesis, we found that treatment with an antiepileptic drug rescued the prolonged convulsions. We also discovered over a third of nematodes exposed to Roundup did not recover from their convulsions, but drug treatment resulted in full recovery. Notably, these effects were found at concentrations that are 1,000-fold dilutions of previous findings of neurotoxicity, using over 300-fold less herbicide than the lowest concentration recommended for consumer use. Exploring mechanisms behind our observations, we found significant evidence that glyphosate targets GABA-A receptors. Pharmacological experiments which paired subeffective dosages of glyphosate and a GABA-A antagonist yielded a 24% increase in non-recovery compared to the antagonist alone. GABA mutant strain experiments showed no effect in a GABA-A depleted strain, but a significant, increased effect in a glutamic acid decarboxylase depleted strain. Our findings characterize glyphosate’s exacerbation of convulsions and propose the GABA-A receptor as a neurological target for the observed physiological changes. It also highlights glyphosate’s potential to dysregulate inhibitory neurological circuits.
Spatial and temporal variation in New Hampshire bat diets
Authors: O’Rourke Devon , Rouillard Nicholas P. , Parise Katy L. , Foster Jeffrey T. 
Published: August 2022

AbstractInsectivorous bats consume a diverse array of arthropod prey, with diets varying by bat species, sampling location, and season. North American bat diets remain incompletely described, which is concerning at a time when many bat and insect populations appear to be declining. Understanding the variability in foraging is thus an essential component for effective bat conservation. To comprehensively evaluate local foraging, we assessed the spatial and temporal variability in prey consumed by the little brown bat,Myotis lucifugus, in New Hampshire, USA. We collected bat guano samples from 20 sites over 2 years and analyzed sequence data for 899 of these samples using a molecular metabarcoding approach targeting the cytochrome oxidase I subunit (COI) gene. Some prey items were broadly shared across locations and sampling dates, with the most frequently detected arthropod orders broadly similar to previous morphological and molecular analyses; at least one representative sequence variant was assigned to Coleoptera in 92% of samples, with other frequently detected orders including Diptera (73%), Lepidoptera (65%), Trichoptera (38%), and Ephemeroptera (32%). More specifically, two turf and forest pests were routinely detected: white grubs in the genusPhyllophaga(50%), and the Asiatic Garden beetle,Maladera castanea(36%). Despite the prevalence of a few taxa shared among many samples and distinct seasonal peaks in consumption of specific arthropods, diet composition varied both temporally and spatially. However, species richness did not strongly vary indicating consumption of a broad diversity of taxa throughout the summer. These data characterize little brown bats as flexible foragers adept at consuming a broad array of locally available prey resources.