bluuebunny/crossref_metadata_2025_split huggingface dataset:
Danicamtiv increases myosin recruitment and alters the chemomechanical cross bridge cycle in cardiac muscle
Authors: Kooiker Kristina B. , Mohran Saffie , Turner Kyrah L. , Ma Weikang , Flint Galina , Qi Lin , Gao Chengqian , Zheng Yahan , McMillen Timothy S , Mandrycky Christian , Martinson Amy , Mahoney-Schaefer Max , Freeman Jeremy C. , Costales Arenas Elijah Gabriela , Tu An-Yu , Irving Thomas C. , Geeves Michael A. , Tanner Bertrand C.W. , Regnier Michael , Davis Jennifer , Moussavi-Harami Farid 
Published: February 2023

AbstractModulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Detailed mechanism of action of these agents can help predict potential unwanted affects and identify patient populations that can benefit most from them. Danicamtiv is a novel myosin activator with promising preclinical data that is currently in clinical trials. While it is known danicamtiv increases force and cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies regarding its mode of action are lacking. Using porcine cardiac tissue and myofibrils we demonstrate that Danicamtiv increases force and calcium sensitivity via increasing the number of myosin in the “on” state and slowing cross bridge turnover. Our detailed analysis shows that inhibition of ADP release results in decreased cross bridge turnover with cross bridges staying on longer and prolonging myofibril relaxation. Using a mouse model of genetic dilated cardiomyopathy, we demonstrated that Danicamtiv corrected calcium sensitivity in demembranated and abnormal twitch magnitude and kinetics in intact cardiac tissue.Significance StatementDirectly augmenting sarcomere function has potential to overcome limitations of currently used inotropic agents to improve cardiac contractility. Myosin modulation is a novel mechanism for increased contraction in cardiomyopathies. Danicamtiv is a myosin activator that is currently under investigation for use in cardiomyopathy patients. Our study is the first detailed mechanism of how Danicamtiv increases force and alters kinetics of cardiac activation and relaxation. This new understanding of the mechanism of action of Danicamtiv can be used to help identify patients that could benefit most from this treatment.
A statistical approach to identify regulatory DNA variations
Authors: Baumgarten Nina , Rumpf Laura , Kessler Thorsten , Schulz Marcel H. 
Published: February 2023

AbstractNon-coding variations located within regulatory elements may alter gene expression by modifying Transcription Factor (TF) binding sites and thereby lead to functional consequences like various traits or diseases. To understand these molecular mechanisms, different TF models are being used to assess the effect of DNA sequence variations, such as Single Nucleotide Polymorphisms (SNPs). However, few statistical approaches exist to compute statistical significance of results but they often are slow for large sets of SNPs, such as data obtained from a genome-wide association study (GWAS) or allele-specific analysis of chromatin data.ResultsWe investigate the distribution of maximal differential TF binding scores for general computational models that assess TF binding. We find that a modified Laplace distribution can adequately approximate the empirical distributions. A benchmark onin vitroandin vivodata sets showed that our new approach improves on an existing method in terms of performance and speed. In applications on large sets of eQTL and GWAS SNPs we could illustrate the usefulness of the novel statistic to highlight cell type specific regulators and TF target genes.ConclusionsOur approach allows the evaluation of DNA changes that induce differential TF binding in a fast and accurate manner, permitting computations on large mutation data sets. An implementation of the novel approach is freely available athttps://github.com/SchulzLab/SNEEP.Contactmarcel.schulz@em.uni-frankfurt.de
Depletion-assisted multiplexed cell-free RNA sequencing reveals distinct human and microbial signatures in plasma versus extracellular vesicles
Authors: Wang Hongke , Zhan Qing , Ning Meng , Guo Hongjie , Wang Qian , Zhao Jiuliang , Bao Pengfei , Xing Shaozhen , Chen Shanwen , Zuo Shuai , Li Mengtao , Wang Pengyuan , Lu Zhi John 
Published: February 2023

AbstractCell-free long RNAs in human plasma and extracellular vesicles (EVs) have shown promise as biomarkers in liquid biopsy, despite their fragmented nature. To investigate these fragmented cell-free RNAs (cfRNAs), we developed a cost-effective cfRNA sequencing method called DETECTOR-seq (depletion-assisted multiplexedcell-freetotalRNAsequencing). DETECTOR-seq utilized a meticulously tailored set of customized guide RNAs to remove large amounts of unwanted RNAs (i.e., fragmented ribosomal and mitochondrial RNAs) in human plasma. Early barcoding strategy was implemented to reduce costs and minimize plasma requirements. Using DETECTOR-seq, we conducted a comprehensive analysis of cell-free transcriptomes in both whole human plasma and EVs. Our analysis revealed discernible distributions of RNA types in plasma and EVs. Plasma exhibited pronounced enrichment in structured circular RNAs, tRNAs, Y RNAs, and viral RNAs, while EVs showed enrichment in mRNAs and srpRNAs. Functional pathway analysis highlighted RNA splicing-related ribonucleoproteins (RNPs) and antimicrobial humoral response genes in plasma, while EVs demonstrated enrichment in transcriptional activity, cell migration, and antigen receptor-mediated immune signals. Our study indicates the comparable potential of cfRNAs from whole plasma and EVs in distinguishing cancer patients (i.e., colorectal and lung cancer) from healthy donors. And microbial cfRNAs in plasma showed potential in classifying specific cancer types. Our comprehensive analysis of total and EV cfRNAs in paired plasma samples provides valuable insights for determining the need for EV purification in cfRNA-based studies. We envision the cost-effectiveness and efficiency of DETECTOR-seq will empower transcriptome-wide investigations in the fields of extracellular vesicles and liquid biopsy.
Killing them softly with EPO: a new role for erythropoietin in the homeostasis of red blood cells
Authors: Arias Clemente F. , Valente-Leal Nuno , Bertocchini Federica , Marques Sofia , Acosta Francisco J. , Fernandez-Arias Cristina 
Published: February 2023

ABSTRACTThe regulation of red blood cell (RBC) homeostasis is widely assumed to rely on the control of cell production by erythropoietin (EPO) and the destruction of cells at a fixed, species-specific age. In this work, we show that such a regulatory mechanism is a poor homeostatic solution to satisfy the changing needs of the body. Effective homeostatic control requires RBC lifespan to be variable and tightly regulated. We show that EPO controls RBC lifespan by determining CD47 expression in newly formed RBCs and SIRP-αexpression in sinusoidal macrophages. EPO also controls the initiation and intensity of anti-RBC autoimmune responses that curtail RBC lifespan in some circumstances. These mechanisms continuously modulate the rate of RBC destruction depending on oxygen availability. The finding of new homeostatic roles for EPO and autoimmunity critically challenges the current paradigm of RBC homeostasis and sets the grounds for a new approach to this field.
Aberrant circuitry underlying olfaction in the face of severe olfactory bulb degeneration
Authors: Licht Tamar , Yunerman Michael , Maor Ido , Lawabny Naheel , Oz Rokach Renana , Mizrahi Adi , Rokni Dan 
Published: February 2023

AbstractThe olfactory bulb (OB) is a critical component of mammalian olfactory neuroanatomy. Beyond being the first and sole relay station for olfactory information to the rest of the brain, it also contains elaborate stereotypical circuitry that is considered essential for olfaction. Indeed, substantial lesions of the OB in rodents lead to anosmia. Here, we examined the circuitry that underlies olfaction in a mouse model with severe developmental degeneration of the OB. These mice could perform odor-guided tasks and even responded normally to innate olfactory cues. Despite the near total loss of the OB, piriform cortex in these mice responded to odors normally and its neural activity sufficed to decode odor identity. We analyzed the circuitry that supports olfactory function in these mice. We found that sensory neurons express the full repertoire of olfactory receptors and their axons project primarily to the rudimentary OB, but also ectopically, to olfactory cortical regions. Within the OB, the number of principal neurons was greatly reduced and the morphology of their dendrites was abnormal, extending over larger regions within the OB. Glomerular organization was lost. This study shows that olfactory functionality can be preserved despite reduced and aberrant circuitry that is missing many of the elements that are believed to be essential for olfaction, and may explain the retention of olfaction in humans with degenerated OBs.
Self-supervised learning on millions of pre-mRNA sequences improves sequence-based RNA splicing prediction
Authors: Chen Ken , Zhou Yue , Ding Maolin , Wang Yu , Ren Zhixiang , Yang Yuedong 
Published: February 2023

ABSTRACTRNA splicing is an important post-transcriptional process of gene expression in eukaryotic cells. Predicting RNA splicing from primary sequences can facilitate the interpretation of genomic variants. In this study, we developed a novel self-supervised pre-trained language model, SpliceBERT, to improve sequence-based RNA splicing prediction. Pre-training on pre-mRNA sequences from vertebrates enables SpliceBERT to capture evolutionary conservation information and characterize the unique property of splice sites. SpliceBERT also improves zero-shot prediction of variant effects on splicing by considering sequence context information, and achieves superior performance for predicting branchpoint in the human genome and splice sites across species. Our study highlighted the importance of pre-training genomic language models on a diverse range of species and suggested that pre-trained language models were promising for deciphering the sequence logic of RNA splicing.
Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer
Authors: Ghobashi Ahmed H. , Vuong Truc T. , Kimani Jane W. , O’Hagan Heather M. 
Published: February 2023

AbstractColorectal cancer (CRC) develops in part through the deregulation of different signaling pathways, including activation of the WNT/β-catenin and PI3K/AKT pathways. Enhancer of zeste homolog 2 (EZH2) is a lysine methyltransferase that is involved in regulating stem cell development and differentiation and is overexpressed in CRC. However, depending on the study EZH2 has been found to be both positively and negatively correlated with the survival of CRC patients suggesting that EZH2’s role in CRC may be context specific. In this study, we explored how PI3K/AKT activation alters EZH2’s role in CRC. We found that activation of AKT by PTEN knockdown or by hydrogen peroxide treatment induced EZH2 phosphorylation at serine 21. Phosphorylation of EZH2 resulted in EZH2-mediated methylation of β-catenin and an associated increased interaction between β-catenin, TCF1, and RNA polymerase II. AKT activation increased β-catenin’s enrichment across the genome and EZH2 inhibition reduced this enrichment by reducing the methylation of β-catenin. Furthermore, PTEN knockdown increased the expression of epithelial-mesenchymal transition (EMT)-related genes, and somewhat unexpectedly EZH2 inhibition further increased the expression of these genes. Consistent with these findings, EZH2 inhibition enhanced the migratory phenotype of PTEN knockdown cells. Overall, we demonstrated that EZH2 modulates AKT-induced changes in gene expression through the AKT/EZH2/ β-catenin axis in CRC with active PI3K/AKT signaling. Therefore, it is important to consider the use of EZH2 inhibitors in CRC with caution as these inhibitors will inhibit EZH2-mediated methylation of histone and non-histone targets such as β-catenin, which can have tumor-promoting effects.
Modelling idiopathic intracranial hypertension in rats: contributions of high fat diet and testosterone to intracranial pressure and cerebrospinal fluid production
Authors: Wardman Jonathan H. , Jensen Mette Nyholm , Andreassen Søren Norge , Styrishave Bjarne , Wilhjelm Jens E. , Sinclair Alexandra J. , MacAulay Nanna 
Published: February 2023

ABSTRACTBackgroundIdiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure (ICP), impaired vision, and headache. Most cases of IIH occur in obese women of childbearing age, though age, BMI, and female sex do not encompass all aspects of IIH pathophysiology. Systemic metabolic dysregulation has been identified in IIH with a profile of androgen excess. However, the mechanistic coupling between obesity/hormonal perturbations and cerebrospinal fluid dynamics remains unresolved.MethodsFemale Wistar rats were either fed a high fat diet (HFD) or exposed to adjuvant testosterone treatment to recapitulate IIH causal drivers. Cerebrospinal fluid (CSF) and blood testosterone levels were determined with mass spectrometry, ICP and CSF dynamics within vivoexperimentation, and the choroid plexus function revealed with transcriptomics and exvivoisotopebased flux assays.ResultsHFD-fed rats presented with increased ICP, which was not accompanied by altered CSF dynamics or modified choroid plexus function. Chronic adjuvant testosterone treatment of lean rats caused elevated CSF secretion rate, in association with increased activity of the choroid plexus Na+,K+,2Cl-cotransporter, NKCC1.ConclusionsHFD-induced ICP elevation in experimental rats did not originate from an increased rate of CSF secretion. Such modulation of CSF dynamics only came about with adjuvant testosterone treatment, mimicking the androgen excess observed in female IIH patients. Obesity-induced androgen dysregulation may thus play a crucial role in the disease mechanism of IIH.
Modeling the radiative, thermal and chemical microenvironment of 3D scanned corals
Authors: Murthy Swathi , Picioreanu Cristian , Kühl Michael 
Published: February 2023

AbstractReef building corals are efficient biological collectors of solar radiation and consist of a thin stratified tissue layer spread over a light scattering calcium carbonate skeleton surface that together construct complex three dimensional (3D) colony structures forming the foundation of coral reefs. They exhibit a vast diversity of structural forms to maximize photosynthesis of their dinoflagellate endosymbionts (Symbiodiniaceae), while simultaneously minimizing photodamage. The symbiosis takes place in the presence of dynamic gradients of light, temperature and chemical species that are affected by the interaction of incident irradiance and water flow with the coral colony.We developed a multiphysics modelling approach to simulate microscale spatial distribution of light, temperature and O2in coral fragments with accurate morphology determined by 3D scanning techniques.Model results compared well with spatial measurements of light, O2and temperature under similar flow and light conditions. The model enabled us to infer the effect of coral morphology and light scattering in tissue and skeleton on the internal light environment experienced by the endosymbionts, as well as the combined contribution of light, water flow and ciliary movement on O2and temperature distributions in the coral.The multiphysics modeling approach is general enough to enable simulation of external and internal light, O2and temperature microenvironments in 3D scanned coral species with varying degrees of branching and morphology under different environmental conditions. This approach is also relevant for simulating structure-function relationships in other benthic systems such as photosynthetic biofilms and aquatic plant tissue, and can also be adapted to other sessile organisms such as symbiont-bearing giant clams, ascidians, jellyfish or foraminifera. The model could also be useful in more applied research such as optimization of 3D bioprinted constructs where different designs can be evaluated and optimized.
Thermal Stimulus Task fMRI in the Cervical Spinal Cord at 7 Tesla
Authors: Seifert Alan C. , Xu Junqian , Kong Yazhuo , Eippert Falk , Miller Karla L. , Tracey Irene , Vannesjo S. Johanna 
Published: February 2023

AbstractPurposeAlthough functional MRI is widely applied in the brain, fMRI of the spinal cord is more technically demanding. Proximity to the vertebral column and lungs results in strong spatial inhomogeneity and temporal fluctuations in B0. Increasing field strength enables higher spatial resolution and improved sensitivity to BOLD signal, but amplifies the effects of B0inhomogeneity. In this work, we present the first task fMRI in the spinal cord at 7 T. Further, we compare the performance of single-shot and multi-shot 2D EPI protocols, which differ in sensitivity to spatial and temporal B0inhomogeneity.MethodsThe cervical spinal cords of 11 healthy volunteers were scanned at 7 T using single-shot 2D EPI at 0.75 mm in-plane resolution and multi-shot 2D EPI at 0.75 and 0.6 mm in-plane resolutions. All protocols used 3 mm slice thickness. For each protocol, the BOLD response to thirteen 10-second noxious thermal stimuli applied to the right thumb was acquired in a 10-minute fMRI run. Image quality, temporal SNR, and BOLD activation (percent signal change and z-stat) at both individual-and group-level were evaluated between the protocols.ResultsTemporal SNR was highest in single-shot and multi-shot 0.75 mm protocols. In group-level analyses, activation clusters appeared in all protocols in the ipsilateral dorsal quadrant at the expected C6 neurological level. In individual-level analyses, activation clusters at the expected level were detected in some, but not all subjects and protocols. Single-shot 0.75 mm generally produced the highest mean z-statistic, while multi-shot 0.60 mm produced the best-localized activation clusters and the least geometric distortion. Larger than expected within-subject segmental variation of BOLD activation along the cord was observed.ConclusionGroup-level sensory task fMRI of the cervical spinal cord is feasible at 7 T with single-shot or multi-shot EPI. The best choice of protocol will likely depend on the relative importance of sensitivity to activation versus spatial localization of activation for a given experiment.HighlightsFirst stimulus task fMRI results in the spinal cord at 7 TSingle-shot 0.75 mm 2D EPI produced the highest mean z-statisticMulti-shot 0.60 mm 2D EPI provided the best-localized activation and least distortion
Path integration selectively predicts midlife risk of Alzheimer’s disease
Authors: Newton Coco , Pope Marianna , Rua Catarina , Henson Richard , Ji Zilong , Burgess Neil , Rodgers Christopher T. , Stangl Matthias , Dounavi Maria-Eleni , Castegnaro Andrea , Koychev Ivan , Malhotra Paresh , Wolbers Thomas , Ritchie Karen , Ritchie Craig W. , O’Brien John , Su Li , Chan Dennis ,   PREVENT Dementia Research Programme
Published: February 2023

AbstractThe entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer’s disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours.Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.
A thin-film optogenetic visual prosthesis
Authors: Knudsen Eric B , Zappitelli Kara , Brown Jennifer , Reeder Jonathan , Smith Kevin Sean , Rostov Marat , Choi Jaebin , Rochford Amy , Slager Nate , Miura Satoru K , Rodgers Kyle , Reed Ansel , Lewis Israeli Yonatan R , Shiraga Seton , Seo Kyung Jin , Wolin Corey , Dawson Paul , Eltaeb Mohamed , Dasgupta Arvind , Rothman Max , Yoon Eugene , Chong Paul , Charles Seleipiri , Stewart Jay M. , Silva Ruwan A , Kim Tyson , Kong Yifan , Mardinly Alan R , Hodak Max 
Published: February 2023

AbstractRetinitis pigmentosa and macular degeneration lead to photoreceptor death and loss of visual perception. Despite recent progress, restorative technologies for photoreceptor degeneration remain largely unavailable. Here, we describe a novel optogenetic visual prosthesis (FlexLED) based on a combination of a thin-film retinal display and optogenetic activation of retinal ganglion cells (RGCs). The FlexLED implant is a 30 µm thin, flexible, wireless µLED display with 8,192 pixels, each with an emission area of 66 µm2. The display is affixed to the retinal surface, and the electronics package is mounted under the conjunctiva in the form factor of a conventional glaucoma drainage implant. In a rabbit model of photoreceptor degeneration, optical stimulation of the retina using the FlexLED elicits activity in visual cortex. This technology is readily scalable to hundreds of thousands of pixels, providing a route towards an implantable optogenetic visual prosthesis capable of generating vision by stimulating RGCs at near-cellular resolution.
Hybridization Mediated Range Expansion and Climate Change Resilience in Two Keystone Tree Species of Boreal Forests
Authors: Karunarathne Piyal , Zhou Qiujie , Lascoux Martin , Milesi Pascal 
Published: February 2023

AbstractCurrent global climate change is expected to affect biodiversity negatively at all scales leading to mass biodiversity loss. Many studies have shown that the distribution of allele frequencies across a species’ range is often influenced by specific genetic loci associated with local environmental variables. This association reflects local adaptation and allele changes at those loci could thereby contribute to the evolutionary response to climate change. However, predicting how species will adapt to climate change from this type of data alone remains challenging. In the present study, we combined exome capture sequences and environmental niche reconstruction, to test multiple methods for assessing local adaptation and climate resilience in two widely distributed conifers, Norway spruce and Siberian spruce. Both species are keystone species of the boreal forest and share a vast hybrid zone. We show that local adaptation in conifers can be detected through allele frequency variation, population-level ecological preferences, and historical niche movement. Moreover, we integrated genetic and ecological information into genetic offset predictive models to show that hybridization plays a central role in expanding the niche breadth of the two conifer species and may help both species to cope better with future changing climates. This joint genetic and ecological analysis also identified genetically isolated populations that are at risk under current climate change.