bluuebunny/crossref_metadata_2025_split huggingface dataset:
ARHGEF18 is a flow-responding exchange factor controlling endothelial tight junctions and vascular leakage
Authors: Batta Surya Prakash Rao , Rio Marc , Lebot Corentin , Baron-Menguy Céline , Moutaoukil Reda , Le Ruz Robin , Loirand Gervaise , Vion Anne-Clémence 
Published: September 2022

AbstractThe shear stress resulting from blood flow is a major regulator of endothelial cell (EC) biology and morphology. Rho protein-mediated cytoskeleton remodeling is an early and essential step of EC responses to flow. However, how Rho protein signaling is controlled by shear stress remains unclear. Here we demonstrate that phosphorylation, activity and expression of the Rho nucleotide exchange factor (RhoGEF) ARHGEF18 in ECs are modulated by the magnitude of shear stress. ARHGEF18 interacts with tight junctions, participates in ECs elongation and alignment and allows the maintenance of the endothelial barrier under physiological flow conditions. ARHGEF18 also promotes EC adhesion and migration by controlling focal adhesion formation.In vivo, ARHGEF18 is involved in flow response of ECs and in the control of vascular permeability in mice. Together, our results identified ARHGEF18 as the first flow-sensitive RhoGEF in ECs, whose activity is essential for the maintenance of intercellular junctions and the control of vascular permeabilityin vivo.
Mapping the glial transcriptome in Huntington’s disease using snRNAseq: Selective disruption of glial signatures across brain regions
Authors: Bøstrand Sunniva M. K. , Seeker Luise A. , Kazakou Nina-Lydia , Bestard-Cuche Nadine , Jäkel Sarah , Kenkhuis Boyd , Henderson Neil C. , de Bot Susanne T. , van Roon-Mom Willeke , Priller Josef , Williams Anna 
Published: September 2022

ABSTRACTHuntington’s disease (HD) is a severely debilitating, autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from people with HD, and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight two possible mechanisms that characterise the glial contribution to disease pathology. Firstly, we show that upregulation of molecular chaperones represents a cross-glial signature in HD, which likely reflects an adaptive response to the accumulation of mutant Huntingtin (mHTT). Secondly, we show an oligodendrocyte-specific upregulation of the calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1A (PDE1A) in HD brain compared to controls, which may cause dysfunction of key cellular functions due to the downregulation of the important second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease. As glia are more tractable to treat than neurons, our findings may be of therapeutic relevance.
Postsynaptic receptors regulate presynaptic transmitter stability through trans-synaptic bridges
Authors: Godavarthi Swetha K. , Hiramoto Masaki , Ignatyev Yuri , Levin Jacqueline B. , Li Hui-quan , Pratelli Marta , Borchardt Jennifer , Czajkowski Cynthia , Borodinsky Laura N. , Sweeney Lora , Cline Hollis T. , Spitzer Nicholas C. 
Published: September 2022

AbstractStable matching of neurotransmitters with their receptors is fundamental to synapse function, to achieve reliable and robust communication in neural circuits. Presynaptic neurotransmitters regulate selection of postsynaptic transmitter receptors. However, whether postsynaptic receptors regulate selection of presynaptic transmitters is unknown. Here we show that blockade of postsynaptic acetylcholine receptors at the neuromuscular junction leads to loss of the cholinergic phenotype in motor neurons and stabilization of an earlier, developmentally transient glutamatergic phenotype. Exogenous postsynaptic expression of GABAAreceptors leads to the stabilization of an earlier, developmentally transient GABAergic motor neuron phenotype. Both acetylcholine receptors and GABA receptors are linked to presynaptic neurons through trans-synaptic bridges. Knock-down of different components of these trans-synaptic bridges prevents stabilization of the cholinergic and GABAergic phenotypes. We conclude that this bidirectional communication enforces a match between transmitter and receptor and ensures the fidelity of synaptic transmission. Our findings suggest a role of dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter.
The mobility of the cap domain is essential for the substrate promiscuity of a family IV esterase from sorghum rhizosphere microbiome
Authors: Distaso Marco , Cea-Rama Isabel , Coscolín Cristina , Chernikova Tatyana N. , Tran Hai , Ferrer Manuel , Sanz-Aparicio Julia , Golyshin Peter N. 
Published: September 2022

ABSTRACTMetagenomics offers the possibility to screen for versatile biocatalysts. In this study, the microbial community of theSorghum bicolorrhizosphere was spiked with technical cashew nut shell liquid, and after incubation, the eDNA was extracted and subsequently used to build a metagenomic library. We report the biochemical features and crystal structure of a novel esterase from the family IV, EH0, retrieved from an uncultured sphingomonad after a functional screen in tributyrin agar plates. EH0(Topt, 50 °C; Tm, 55.7 °C; pHopt, 9.5) was stable in the presence of 10-20% v/v organic solvents and exhibited hydrolytic activity againstp-nitrophenyl esters from acetate to palmitate, preferably butyrate (496 U mg−1), and a large battery of 69 structurally different esters (up to 30.2 U mg−1), including bis(2-hydroxyethyl)-terephthalate (0.16 ± 0.06 U mg−1). This broad substrate specificity contrasts with the fact that EH0showed a long and narrow catalytic tunnel, whose access appears to be hindered by a thigth folding of its cap domain. We propose that this cap domain is a highly flexible structure whose opening is mediated by unique structural elements, one of which is the presence of two contiguous proline residues likely acting as possible hinges, that altogether allow for the entrance of the substrates. Therefore, this work provides a new role for the cap domain, which until now was thought to be immobile elements that contain hydrophobic patches involved in substrate pre-recognition and in turn substrate specificity within family IV esterases.IMPORTANCEA better understanding of structure–function relationships of enzymes allows revealing key structural motifs or elements. Here, we studied the structural basis of the substrate promiscuity of EH0, a family IV esterase, isolated from a sample of theSorghum bicolorrhizosphere microbiome exposed to technical cashew nut shell liquid. The analysis of EH0revealed the potential of the sorghum rhizosphere microbiome as a source of enzymes with interesting properties, such as pH and solvent tolerance and remarkably broad substrate promiscuity. Its structure resembled those of homologous proteins from mesophilicParvibaculumandErythrobacterspp. and hyperthermophilicPyrobaculumandSulfolobusspp. and had a very narrow, single-entry access tunnel to the active site, access which is controlled by a capping domain that includes a number of not conserved proline residues. These structural markers, distinct from those of other substrate promiscuous esterases, can help tuning substrate profiles beyond tunnel and active site engineering.
SETD2 deficiency promotes renal fibrosis through the TGF-β/Smad signaling pathway in the absence of VHL
Authors: Liu Changwei , Li Xiaoxue , Zhu Yiwen , Feng Wenxin , Zhang Wei , Ma Chunxiao , Xu Yue , Gui Liming , Aji Rebiguli , Gao Wei-Qiang , Li Li 
Published: September 2022

AbstractRenal fibrosis is the final development pathway and the most common pathological manifestation of chronic kidney disease. An important intrinsic cause of renal fibrosis is epigenetic alterations. SET domain–containing 2 (SETD2) is the sole histone H3K36 trimethyltransferase, catalyzing H3K36 dimethylation to trimethylation. There is evidence that SETD2-mediated epigenetic alterations are implicated in many diseases. However, it is unclear what role SETD2 plays in the development of renal fibrosis. Clinical data indicate that SETD2 is lowly expressed in patients with renal fibrosis. Here, we established genetically engineered mice with SETD2 and VHL deficiency. SETD2 deficiency leads to severe renal fibrosis in VHL-deficient mice. Mechanically, SETD2 maintains the transcriptional level of Smad7, a negative feedback factor of the TGF-β/Smad signaling pathway, thereby preventing the activation of the TGF-β/Smad signaling pathway. Deletion of SETD2 leads to reduced smad7 expression, which results in activation of the TGF-β/Smad signaling pathway and ultimately fibrosis in the absence of VHL. Our findings reveal the role of SETD2-mediated H3K36me3 of Smad7 in regulating the TGF-β/Smad signaling pathway in renal fibrogenesis. Thus, our study provides innovative insights into SETD2 as a potential therapeutic target for the treatment of renal fibrosis.
Germplasm Collections and Morphological Studies of Andropogon gayanus-Andropogon tectorum Complex in Southwestern Nigeria
Authors: Ojo Funmilola Mabel , Nwokeocha Chinyere Constance , Faluyi Julius Olaoye 
Published: September 2022

ABSTRACTMorphological studies were carried out on collections of Andropogon gayanus-Andropogon tectorum complex from Southwestern Nigeria. This is with the view to providing full characterization of the accession of the two species of Andropogon and elucidating their population dynamics.Morphological data from selected accessions of A. gayanus and A. tectorum from different parts of Southwestern Nigeria were collected and characterized using an adaptation of the Descriptors for Wild and Cultivated Rice (Oryza spp), Biodiversity International. Preliminary morphological description of the accessions were carried out at the point of collection. Garden populations were raised from the vegetative parts of some accessions and maintained in Botanical Garden of the Obafemi Awolowo University, Ile-Ife. The data obtained were subjected to inferential tests and Duncan’s multiple range test.The results revealed a distinct distribution pattern of the two species of Andropogon in the area of study which suggests a south-ward migration of Andropogon gayanus, that is from the northern vegetational zones of Nigeria to the southern ecological zones. The migration of A. gayanus around Igbeti with occasional occurrence of A. tectorum along the roadsides without any distinct phenotypic hybrid, and Budo-Ode in Oyo State is established as the southern limit of the spread of A. gayanus. This migration of A. gayanus to the South is not an invasion but a slow process. There was no A. gayanus encountered in Osun, Ondo, Ekiti and Ogun States. Andropogon gayanus and Andropogon tectorum do not only emerge from the rootstocks rapidly but can also produce independent propagules by rooting at some nodes. The plants can spread by means of these propagules even if it does not produce sexual or apomictic seeds. This potential for vegetative propagation in addition to the perennial habit confer considerable advantage for colonization by the Andropogon gayanus-Andropogon tectorum complex.
A small dynamic leaf-level model predicting photosynthesis in greenhouse tomatoes
Authors: Joubert D , Zhang N , Berman S.R. , Kaiser E , Molenaar J , Stigter J.D. 
Published: September 2022

AbstractThe conversion of supplemental greenhouse light energy into biomass is not always optimal. Recent trends in global energy prices and discussions on climate change highlight the need to reduce our energy footprint associated with the use of supplemental light in greenhouse crop production. This can be achieved by implementing “smart” lighting regimens which in turn rely on a good understanding of how fluctuating light influences photosynthetic physiology.Here, a simple fit-for-purpose dynamic model is presented. It accurately predicts net leaf photosynthesis under natural fluctuating light. It comprises two ordinary differential equations predicting: 1) the total stomatal conductance to CO2 diffusion and 2) the CO2 concentration inside a leaf. It contains elements of the Farquhar-von Caemmerer-Berry model and the successful incorporation of this model suggests that for tomato (Solanum lycopersicum L.), it is sufficient to assume that Rubisco remains activated despite rapid fluctuations in irradiance. Furthermore, predictions of the net photosynthetic rate under both 400ppm and enriched 800ppm ambient CO2 concentrations indicate a strong correlation between the dynamic rate of photosynthesis and the rate of electron transport. Finally, we are able to indicate whether dynamic photosynthesis is Rubisco or electron transport rate limited.Author summaryThe cultivation of greenhouse crops under optimised conditions will become increasingly important, with supplemental lighting playing a vital role. However, converting light energy into plant photosynthesis is not always optimal. A potential venue that may lead to the efficient conversion of light energy involves a model-based implementation of “smart” lighting control strategy. This approach does however necessitate a good understanding of how plants harness light energy under natural fluctuating irradiance. Accordingly, as a first step, we have developed a small leaf-level model that predicts dynamic photosynthesis in natural fluctuating light. It may potentially be used in future supplemental light control applications.
FGF signaling regulates salivary gland branching morphogenesis by modulating cell adhesion
Authors: Ray Ayan T. , Soriano Philippe 
Published: September 2022

ABSTRACTLoss of FGF signaling leads to defects in salivary gland branching, but the mechanisms underlying this phenotype remain largely unknown. We disrupted expression of Fgfr1 and Fgfr2 in salivary gland epithelial cells and find that both receptors function coordinately in regulating branching. Strikingly, branching morphogenesis in double knockouts is restored by Fgfr1/2 knockin alleles incapable of engaging canonical RTK signaling, suggesting that additional FGF dependent mechanisms play a role during salivary gland branching. Fgfr1/2 conditional null mutants showed defective cell-cell and cell-matrix adhesion, both of which have been shown to play instructive roles in salivary gland branching. Loss of FGF signaling led to disordered cellbasement membrane interactions in vivo as well as in organ culture. This was partially restored upon introducing Fgfr1/2 wild type or signaling alleles incapable of eliciting canonical intracellular signaling. Together, our results identify non-canonical FGF signaling mechanisms that regulate branching morphogenesis through cell adhesion processes.
The effects of acute Methylene Blue administration on cerebral blood flow and metabolism in humans and rats
Authors: Singh Nisha , MacNicol Eilidh , DiPasquale Ottavia , Randall Karen , Lythgoe David , Mazibuko Ndabezinhle , Simmons Camilla , Selvaggi Pierluigi , Stephenson Stephanie , Turkheimer Federico E , Cash Diana , Zelaya Fernando , Colasanti Alessandro 
Published: September 2022

AbstractMethylene Blue (MB) is a brain-penetrating drug with putative neuroprotective, antioxidant and metabolic enhancing effects. In vitro studies suggest that MB enhances mitochondrial complexes activity. However, no study has directly assessed the haemodynamic and metabolic effects of MB in the human brain.We used in vivo neuroimaging to measure the effect of MB on cerebral blood flow (CBF) and brain metabolism in humans and in rats. Two doses of MB (0.5 and 1 mg/kg in humans; 2 and 4 mg/kg in rats; iv) induced reductions in global cerebral blood flow (CBF) in humans (F(1.74, 12.17)5.82, p=0.02) and rats (F(1,5)26.04, p=0.0038). Human cerebral metabolic rate of oxygen (CMRO2) was also significantly reduced (F(1.26, 8.84)8.01, p=0.016), as was the rat cerebral metabolic rate of glucose (CMRglu) (t=2.6(16) p=0.018).This was contrary to our hypothesis that MB will increase CBF and energy metrics. Nevertheless, our results were reproducible across species and dose dependent. One possible explanation is that the concentrations used, although clinically relevant, reflect MB’s hormetic effects, i.e., higher concentrations produce inhibitory rather than augmentation effects on metabolism. Additionally, here we used healthy volunteers and healthy rats with normal cerebral metabolism where MB’s ability to enhance cerebral metabolism might be limited.
Rear cortex contraction aids in nuclear transit during confined migration by increasing pressure in the cell posterior
Authors: Keys Jeremy , Cheung Brian C.H. , Elpers Margaret A. , Wu Mingming , Lammerding Jan 
Published: September 2022

AbstractAs cells migrate through biological tissues, they must frequently squeeze through micron-sized constrictions in the form of interstitial pores between extracellular matrix fibers and/or other cells. Although it is now well recognized that such confined migration is limited by the nucleus, which is the largest and stiffest organelle, it remains incompletely understood how cells apply sufficient force to move their nucleus through small constrictions. Here, we report a mechanism by which contraction of the cell rear cortex pushes the nucleus forward to mediate nuclear transit through constrictions. Laser ablation of the rear cortex reveals that pushing forces behind the nucleus are the result of increased intracellular pressure in the rear compartment of the cell. The pushing forces behind the nucleus depend on accumulation of actomyosin in the rear cortex and require Rho-kinase (ROCK) activity. Collectively, our results suggest a mechanism by which cells generate elevated, intracellular pressure in the posterior compartment to facilitate nuclear transit through 3D constrictions. This mechanism may supplement or even substitute for other mechanisms supporting nuclear transit, ensuring robust cell migrations in confined 3D environments.
The baseless mutant links protein phosphatase 2A with basal cell identity in the brown alga Ectocarpus
Authors: Godfroy Olivier , Zheng Min , Yao Haiqin , Henschen Agnes , Peters Akira F. , Scornet Delphine , Colin Sebastien , Ronchi Paolo , Hipp Katharina , Nagasato Chikako , Motomura Taizo , Cock J. Mark , Coelho Susana M. 
Published: September 2022

SummaryThe first mitotic division of the initial cell is a key event in all multicellular organisms and is usually concomitant with the establishment of major developmental axes and cell fates. The brown alga Ectocarpus has a haploid-diploid life cycle that involves the development of two multicellular and independent generations, the sporophyte and the gametophyte. Each generation deploys a distinct developmental program autonomously from an initial cell, whose first cell division sets up the future body pattern. Here, we show that mutations in the BASELESS (BAS) gene result in multiple cellular defects during the first division of the initial cell and subsequently failure to produce basal structures (rhizoids and prostrate filaments) during both generations of the life cycle. Cloning-by-sequencing revealed that BAS encodes a type B” regulatory subunit of protein phosphatase 2A, and transcriptomic analysis of early developmental stages uncovered potential effector genes involved in setting up basal cell fate in this organism. The bas mutant phenotype is very similar to that observed in the distag (dis) mutants, which lack a functional TBCCd1 protein, at both the cellular and morphological levels. The high level of similarity of the dis and bas mutant phenotypes indicate that TBCCd1 and PP2A are two critical components of the cellular machinery that regulates the division of the initial cell and mediates the establishment of basal cell fate in the developing thallus.
An ImageJ-based tool for three-dimensional registration between different types of microscopic images
Authors: Koyama Hiroshi , Kishi Kanae , Fujimori Toshihiko 
Published: September 2022

AbstractThree-dimensional (3D) registration (i.e. alignment) between two microscopic images is substantially helpful to study tissues not adhere to substrates such as mouse embryos and organoids which are often three-dimensionally rotated during imaging. However, there is no 3D registration tool easily accessible for experimental biologists. Here we developed an ImageJ-based tool which achieves 3D registration accompanying both quantitative evaluation of the accuracy and reconstruction of 3D rotated images. In this tool, several landmarks are manually provided in two images to be aligned, and 3D rotation is computed so that the distances between the paired landmarks from the two images are minimized. By simultaneously providing multiple points (e.g. all nuclei in the regions of interest) other than the landmarks in the two images, the correspondence of each point between the two images is quantitatively explored: a certain nucleus in one image corresponds to which nucleus in another image. Furthermore, the 3D rotation is applied to one of the two images, resulting in reconstruction of 3D rotated images. We demonstrated that this tool successfully achieved 3D registration and reconstruction of images in mouse pre-implantation embryos, where one image was obtained during live imaging and another image from fixed embryos after live imaging. This approach provides a versatile tool applicable for various tissues and species.
Mutational Landscape of Cancer-Driver Genes Across Human Cancers
Authors: Sinkala Musalula 
Published: September 2022

AbstractThe cancer driver genes are involved in transforming healthy cells into cancerous cells. The molecular aberrations which lead to cancer involve gain and loss of function mutations in various cancer driver genes. Here, we examine the genome sequences of 20,066 primary tumours representing 43 distinct human cancers to identify and catalogue driver mutations in 729 known cancer genes. We show that the frequency of driver mutations in these genes varies significantly between cancer types. We find that the class of cancer driver genes most frequently mutated are the tumour suppressor genes (94%), followed by oncogenes (93%), transcription factors (72%), kinases (64%), cell surface receptors (63%), and phosphatases (22%). Furthermore, we identify the subset of these genes within which mutations exhibit a co-occurrence or mutually exclusive pattern. Interestingly, we find that patients with tumours with different combinations of driver gene mutation patterns tend to exhibit variable survival outcomes. Here, among the well-studied cancer genes, we showed that patients with tumours with KRAS and TP53 mutations are associated with the worst disease outcomes, and those with PI3KCA and BRAF mutations are associated with favourable survival outcomes. Besides providing new insights into cancer driver mutations, we unearth mutation patterns associated with disease outcomes and various hallmarks of cancer that bring us closer to fully understanding various forms of cancer.