bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Microtubule Associated Protein Tau Regulates KIF1A Pausing Behavior and Motility
Authors: Lessard DV , Berger CL 
Published: August 2021

ABSTRACTMany neurodegenerative diseases result from dysfunction of axonal transport, a highly regulated cellular process responsible for site-specific neuronal cargo delivery. The kinesin-3 family member KIF1A is a key mediator of this process by facilitating long-distance cargo delivery in a spatiotemporally regulated manner. While misregulation of KIF1A cargo delivery is observed in many neurodegenerative diseases, the regulatory mechanisms responsible for KIF1A cargo transport are largely unexplored. Our lab has recently characterized a mechanism for a unique pausing behavior of KIF1A in between processive segments on the microtubule. This behavior, mediated through an interaction between the KIF1A K-loop and the polyglutamylated C-terminal tails of tubulin, helps us further understand how KIF1A conducts long-range cargo transport. However, how this pausing behavior is influenced by other regulatory factors on the microtubule is an unexplored concept. The microtubule associated protein Tau is one potential regulator, as altered Tau function is a pathological marker in many neurodegenerative diseases. However, while the effect of Tau on kinesin-1 and -2 has been extensively characterized, its role in regulating KIF1A transport is greatly unexplored at the behavioral level. Using single-molecule imaging, we have identified Tau-mediated regulation of KIF1A pausing behavior and motility. Specifically, our findings imply a competitive interaction between Tau and KIF1A for the C-terminal tails of tubulin. We introduce a new mechanism of Tau-mediated kinesin regulation by inhibiting the ability of KIF1A to use C-terminal tail reliant pauses to connect multiple processive segments into a longer run length. Moreover, we have correlated this regulatory mechanism to the behavioral dynamics of Tau, further elucidating the function of Tau diffusive and static behavioral state on the microtubule surface. In summary, we introduce a new mechanism of Tau-mediated motility regulation, providing insight on how disruptions in axonal transport can lead to disease state pathology.SIGNIFICANCEKIF1A mediated cargo transport is essential in many cellular processes such as axonal transport and neuronal development. Defects in KIF1A transport have been implicated in neurodegenerative diseases including Alzheimer’s disease and frontotemporal dementia. However, the mechanism of KIF1A’s pathological misregulation remains elusive, highlighting the importance of identifying regulators of KIF1A function. The microtubule associated protein Tau is an attractive potential regulator of KIF1A motility as Tau dysfunction is a hallmark of these neurodegenerative diseases. Here, we demonstrate a direct connection between Tau and KIF1A motility, revealing a unique form of Tau-mediated regulation of axonal transport. Our results provide a molecular foundation for understanding the role of motor protein misregulation in neurodegenerative disease progression.
Predicting epitopes Based on TCR sequence using an embedding deep neural network artificial intelligence approach
Authors: Kubick Norwin , Klimovich Pavel , Sacharczuk Mariusz , Mickael Michel-Edwar 
Published: August 2021

AbstractT cells receptors are fundamental in recognizing antigens and mediating an appropriate specific immune response against them. Today TCR sequencing has contributed to forming a large repertoire for different immune-associated pathologies. However, predicting epitopes based on TCR sequences has not been satisfactory achieved. We formed a deep neural network using a combination of an embedding autoencoder and selu and relu layers to predict epitopes based on TCR TCR β-chain CDR3. We trained our model using the VDJ database (VDJdb) and validated it using the manually curated catalog of pathology-associated T cell receptor sequences (McPAS-TCR). We used various metrics to measure the accuracy of our tool. We found that our tool can achieve an accuracy of 98 %. Overall our approach presents a step toward identifying microbes crosslinking epitopes that could be playing an important role in various immune diseases.
Soma and Neurite Density MRI (SANDI) of the in-vivo mouse brain
Authors: Ianuş Andrada , Carvalho Joana , Fernandes Francisca F. , Cruz Renata , Chavarrias Cristina , Palombo Marco , Shemesh Noam 
Published: August 2021

AbstractDiffusion MRI (dMRI) provides unique insights into the neural tissue milieu by probing interaction of diffusing molecules and tissue microstructure. Most dMRI techniques focus on white matter tissues (WM) due to the relatively simpler modelling of diffusion in the more organized tracts; however, interest is growing in gray matter characterisations. The Soma and Neurite Density MRI (SANDI) methodology harnesses a model incorporating water diffusion in spherical objects (assumed to be associated with cell bodies) and in impermeable “sticks” (representing neurites), which potentially enables the characterisation of cellular and neurite densities. Recognising the importance of rodents in animal models of development, aging, plasticity, and disease, we here sought to develop SANDI for preclinical imaging and provide a validation of the methodology by comparing its metrics with the Allen mouse brain atlas. SANDI was implemented on a 9.4T scanner equipped with a cryogenic coil, and experiments were carried out on N=6 mice. Pixelwise, ROI-based, and atlas comparisons were performed, and results were also compared to more standard Diffusion Kurtosis MRI (DKI) metrics. We further investigated effects of different pre-processing pipelines, specifically the comparison of magnitude and real-valued data, as well as different acceleration factors. Our findings reveal excellent reproducibility of the SANDI parameters, including the sphere and stick fraction as well as sphere size. More strikingly, we find a very good rank correlation between SANDI-driven soma fraction and Allen brain atlas contrast (which represents the cellular density in the mouse brain). Although some DKI parameters (FA, MD) correlated with some SANDI parameters in some ROIs, they did not correlate nearly as well as SANDI parameters with the Allen atlas, suggesting a much more specific nature of the SANDI parameters. We conclude that SANDI is a viable preclinical MRI technique that can greatly contribute to research on brain tissue microstructure.
Identification of the 216kbp gene cluster and structure elucidation of gargantulides B and C, new complex 52-membered macrolides fromAmycolatopsissp
Authors: Carretero-Molina Daniel , Ortiz-López Francisco Javier , Gren Tetiana , Oves-Costales Daniel , Martín Jesús , Román-Hurtado Fernando , Jørgensen Tue Sparholt , de la Cruz Mercedes , Díaz Caridad , Vicente Francisca , Blin Kai , Reyes Fernando , Weber Tilmann , Genilloud Olga 
Published: August 2021

AbstractGargantulides B and C, two new and highly complex 52-membered glycosylated macrolactones, were isolated fromAmycolatopsissp. strain CA-230715 during an antibacterial screening campaign. The structures of these giant macrolides were elucidated by 2D NMR spectroscopy and shown to be related to gargantulide A, although containing additionalβ-glucopyranose and/orα-arabinofuranose monosaccharides separately attached to their backbones. Genome sequencing allowed the identification of a strikingly large 216 kbp biosynthetic gene cluster, among the largest type I PKS clusters described so far, and the proposal of a biosynthetic pathway for gargantulides A-C. Additionally, genes putatively responsible for the biosynthesis of the amino sugarβ-3,6-deoxy-3-methylamino glucose, reported exclusively in gargantulide macrolides, were also found in the cluster and described in this work. The absolute configurations of gargantulides B and C were assigned based on a combination of NMR and bioinformatics analysis of ketoreductase and enoylreductase domains within the multimodular type I PKS. Furthermore, the absolute stereochemistry of the related macrolide gargantulide A has now been revised and completed. Gargantulides B and C display potent antibacterial activity against a set of drug-resistant Gram-positive bacteria and moderate activity against the clinically relevant Gram-negative pathogenAcinetobacter baumannii.
A novel SATB1 protein isoform with different biophysical properties
Authors: Zelenka Tomas , Papamatheakis Dionysios-Alexandros , Tzerpos Petros , Panagopoulos Giorgos , Tsolis Konstantinos C. , Papadakis Vassilis M. , Mariatos Metaxas Dimitris , Papadogkonas George , Mores Eleftherios , Kapsetaki Manouela , Papamatheakis Joseph , Stanek David , Spilianakis Charalampos 
Published: August 2021

AbstractIntra-thymic T cell development is coordinated by the regulatory actions of SATB1 genome organizer. In this report, we show that SATB1 is involved in the regulation of transcription and splicing, both of which displayed deregulation inSatb1knockout murine thymocytes. More importantly, we characterized a novel SATB1 protein isoform and described its distinct biophysical behavior, implicating potential functional differences compared to the commonly studied isoform. SATB1 utilized its prion-like domains to transition through liquid-like states to aggregated structures. This behavior was dependent on protein concentration as well as phosphorylation and interaction with nuclear RNA. Notably, the long SATB1 isoform was more prone to aggregate following phase separation. Thus, the tight regulation of SATB1 isoforms expression levels alongside with protein post-translational modifications, are imperative for SATB1’s mode of action in T cell development. Our data indicate that deregulation of these processes may also be linked to disorders such as cancer.
NSUN6, an RNA methyltransferase of 5-mC controls glioblastoma response to Temozolomide (TMZ) via NELFB and RPS6KB2 interaction
Authors: Awah Chidiebere U , Winter Jan , Mazdoom Claudiane M , Ogunwobi Olorunseun O. 
Published: August 2021

AbstractNop2/Sun RNA methyltransferase (NSUN6) is an RNA 5 - methyl cytosine (5mC) transferase with little information known of its function in cancer and response to cancer therapy. Here, we show that NSUN6 methylates both large and small RNA in glioblastoma and controls glioblastoma response to temozolomide with or without influence of the MGMT promoter status, with high NSUN6 expression conferring survival benefit to glioblastoma patients and in other cancers. Mechanistically, our results show that NSUN6 controls response to TMZ therapy via 5mC mediated regulation of NELFB and RPS6BK2. Taken together, we present evidence that show that NSUN6 mediated 5mC deposition regulates transcriptional pause (by accumulation of NELFB and the general transcription factor complexes (POLR2A, TBP, TFIIA, TFIIE) on the preinitiation complex at TATA binding site to control translation machinery in glioblastoma response to alkylating agents. Our findings open a new frontier into controlling of transcriptional regulation by RNA methyltransferase and 5mC.
Rab11 endosomes coordinate centrosome number and movement following mitotic exit
Authors: Krishnan Nikhila , Swoger Maxx , Bates Michael , Freshour Judy , Fioramonti Peter J. , Patteson Alison , Hehnly Heidi 
Published: August 2021

SUMMARYThe last stage of cell division involves two daughter cells remaining interconnected by a cytokinetic bridge that is cleaved in a process called abscission. During pre-abscission, we identified that the centrosome moves in a Rab11-dependent manner towards the cytokinetic bridge in human cells grown in culture and in an in vivo vertebrate model, Danio rerio (zebrafish). Rab11-endosomes are dynamically organized in a Rab11-GTP dependent manner at the centrosome during pre-abscission and this organization is required for the centrosome protein, pericentrin, to be enriched at the centrosome. Using zebrafish embryos, we found that reduction in pericentrin expression or optogenetically disrupting Rab11-endosome function inhibited centrosome movement towards the cytokinetic bridge and abscission resulting in daughter cells prone to being binucleated and/or having supernumerary centrosomes. These studies suggest that Rab11-endosomes contribute to centrosome function during pre-abscission by regulating pericentrin organization resulting in appropriate centrosome movement towards the cytokinetic bridge and subsequent abscission.
Forgetting Enhances Episodic Control with Structured Memories
Authors: Yalnizyan-Carson Annik , Richards Blake A. 
Published: August 2021

ABSTRACTForgetting is a normal process in healthy brains, and evidence suggests that the mammalian brain forgets more than is required based on limitations of mnemonic capacity. Episodic memories, in particular, are liable to be forgotten over time. Researchers have hypothesized that it may be beneficial for decision making to forget episodic memories over time. Reinforcement learning offers a normative framework in which to test such hypotheses. Here, we show that a reinforcement learning agent that uses an episodic memory cache to find rewards in maze environments can forget a large percentage of older memories without any performance impairments, if they utilize mnemonic representations that contain structural information about space. Moreover, we show that some forgetting can actually provide a benefit in performance compared to agents with unbounded memories. Our analyses of the agents show that forgetting reduces the influence of outdated information and states which are not frequently visited on the policies produced by the episodic control system. These results support the hypothesis that some degree of forgetting can be beneficial for decision making, which can help to explain why the brain forgets more than is required by capacity limitations.
Sulfonylureas target the neurovascular response to decrease Alzheimer’s pathology
Authors: Macauley Shannon L. , Stanley Molly S. , Caesar Emily E. , Moritz William R. , Bice Annie R. , Cruz-Diaz Nildris , Carroll Caitlin M. , Day Stephen M. , Grizzanti John , Mahan Thomas E. , Snipes James A. , Orr Timothy E. , Culver Joseph P. , Remedi Maria S. , Nichols Colin G. , Karch Celeste M. , Cox Laura A. , Diz Debra I. , Bauer Adam Q. , Holtzman David M. 
Published: August 2021

ABSTRACTHyperexcitability is a defining feature of Alzheimer’s disease (AD), where aberrant neuronal activity is both a cause and consequence of AD. Therefore, identifying novel targets that modulate cellular excitability is an important strategy for treating AD. ATP-sensitive potassium (KATP) channels are metabolic sensors that modulate cellular excitability. Sulfonylureas are KATPchannel antagonists traditionally used to combat hyperglycemia in diabetic patients by inhibiting pancreatic KATPchannels, thereby stimulating insulin release. However, KATPchannels are not limited to the pancreas and systemic modulation of KATPchannels has pleotropic physiological effects, including profound effects on vascular function. Here, we demonstrate that human AD patients have higher cortical expression of vascular KATPchannels, important modulators of vasoreactivity. We demonstrate that peripheral treatment with the sulfonylurea and KATPchannel inhibitor, glyburide, reduced the aggregation and activity-dependent production of amyloid-beta (Aβ), a hallmark of AD, in mice. Since glyburide does not readily cross the blood brain barrier, our data suggests that glyburide targets vascular KATPchannel activity to reduce arterial stiffness, improve vasoreactivity, and normalize pericyte-endothelial cell morphology, offering a novel therapeutic target for AD.Graphical abstractTargeting vascular KATPchannel activity for the treatment of Alzheimer’s disease pathology.
A temporally controlled sequence of X-chromosome inactivation and reactivation defines female mouse in vitro germ cells with meiotic potential
Authors: Severino Jacqueline , Bauer Moritz , Mattimoe Tom , Arecco Niccolò , Cozzuto Luca , Lorden Patricia , Hamada Norio , Nosaka Yoshiaki , Nagaoka So , Heyn Holger , Hayashi Katsuhiko , Saitou Mitinori , Payer Bernhard 
Published: August 2021

AbstractThe early mammalian germ cell lineage is characterized by extensive epigenetic reprogramming, which is required for the maturation into functional eggs and sperm. In particular, the epigenome needs to be reset before parental marks can be established and then transmitted to the next generation. In the female germ line, reactivation of the inactive X-chromosome is one of the most prominent epigenetic reprogramming events, and despite its scale involving an entire chromosome affecting hundreds of genes, very little is known about its kinetics and biological function.Here we investigate X-chromosome inactivation and reactivation dynamics by employing a tailor-made in vitro system to visualize the X-status during differentiation of primordial germ cell-like cells (PGCLCs) from female mouse embryonic stem cells (ESCs). We find that the degree of X-inactivation in PGCLCs is moderate when compared to somatic cells and characterized by a large number of genes escaping full inactivation. Nevertheless, PGCLCs that fail to undergo X-inactivation show an abnormal gene expression signature and deficiencies in meiotic entry. Subsequent to X-inactivation we observe gradual step-wise X-reactivation, which is mostly completed by the end of meiotic prophase I. Cells deviating from these progressive kinetics and undergoing X-reactivation too rapidly fail to enter a meiotic trajectory. Our data reveals that a fine-tuned X-inactivation and -reactivation cycle is a critical feature of female germ cell developmental competence towards meiosis and oogenesis
Nuclear SUN1 Stabilizes Endothelial Cell Junctions via Microtubules to Regulate Blood Vessel Formation
Authors: Buglak Danielle B , Kulikauskas Molly R , Liu Ziqing , Gold Ariel L , Marvin Allison P , Burciu Andrew , Tanke Natalie T , Ricketts Shea N , Kinghorn Karina , Oatley Morgan , Johnson Bryan N , Bougaran Pauline , Shiau Celia E , Rogers Stephen L , Bautch Victoria L 
Published: August 2021

ABSTRACTEndothelial cells line all blood vessels, where they coordinate blood vessel formation and the blood-tissue barrier via regulation of cell-cell junctions. The nucleus also regulates endothelial cell behaviors, but it is unclear how the nucleus contributes to endothelial cell activities at the cell periphery. Here we show that the nuclear-localized LINC complex protein SUN1 regulates vascular sprouting and barrier function via effects on endothelial cell-cell junction morphology and function. Loss of murine endothelial Sun1 impaired blood vessel formation and destabilized junctions, angiogenic sprouts formed but retracted in SUN1-depleted sprouts, and zebrafish vessels lacking Sun1b had aberrant junctions and defective cell-cell connections. At the cellular level, SUN1 stabilized endothelial cell-cell junctions, promoted barrier function, and regulated contractility. Mechanistically, SUN1 depletion altered cell behaviors via the cytoskeleton without changing transcriptional profiles. Reduced peripheral microtubule density, fewer junction contacts and increased catastrophes accompanied SUN1 loss, and microtubule depolymerization phenocopied effects on junctions. Depletion of GEF-H1, a microtubule-regulated Rho activator, or the LINC complex protein nesprin-1 rescued defective junctions of SUN1-depleted endothelial cells. Thus, endothelial SUN1 regulates peripheral cell-cell junctions from the nucleus via LINC complex-based microtubule interactions that affect peripheral microtubule dynamics and Rho-regulated contractility, and this long-range regulation is important for proper blood vessel sprouting and barrier function.SUMMARYThe nuclear membrane protein SUN1 promotes blood vessel formation and barrier function by stabilizing endothelial cell-cell junctions. Communication between SUN1 and endothelial cell junctions relies upon proper microtubule dynamics and Rho signaling far from the nucleus, revealing long-range cellular communication from the nucleus to the cell periphery that is important for vascular development and function.
Physiologically based modeling of the effect of physiological and anthropometric variability on indocyanine green based liver function tests
Authors: Köller Adrian , Grzegorzewski Jan , König Matthias 
Published: August 2021

ABSTRACTAccurate evaluation of liver function is a central task in hepatology. Dynamic liver function tests (DLFT) based on the time-dependent elimination of a test substance provide an important tool for such a functional assessment. These tests are used in the diagnosis and monitoring of liver disease as well as in the planning of hepatobiliary surgery. A key challenge in the evaluation of liver function with DLFTs is the large inter-individual variability. Indocyanine green (ICG) is a widely applied test compound used for the evaluation of liver function. After an intravenous administration, pharmacokinetic (PK) parameters are calculated from the plasma disappearance curve of ICG which provide an estimate of liver function. The hepatic elimination of ICG is affected by physiological factors such as hepatic blood flow or binding of ICG to plasma proteins, anthropometric factors such as body weight, age, and sex, or the protein amount of the organic anion-transporting polypeptide 1B3 (OATP1B3) mediating the hepatic uptake of ICG. Being able to account for and better understand these various sources of inter-individual variability would allow to improve the power of ICG based DLFTs and move towards an individualized evaluation of liver function. Within this work we systematically analyzed the effect of various factors on ICG elimination by the means of computational modeling. For the analysis, a recently developed and validated physiologically based pharmacokinetics (PBPK) model of ICG distribution and hepatic elimination was utilized. Key results are (i) a systematic analysis of the variability in ICG elimination due to hepatic blood flow, cardiac output, OATP1B3 abundance, liver volume, body weight and plasma bilirubin level; (ii) the evaluation of the inter-individual variability in ICG elimination via a largein silicocohort of n=100000 subjects based on the NHANES cohort with special focus on stratification by age, sex, and body weight; (iii) the evaluation of the effect of various degrees of cirrhosis on variability in ICG elimination. The presented results are an important step towards individualizing liver function tests by elucidating the effects of confounding physiological and anthropometric parameters in the evaluation of liver function via ICG.