bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic fluctuations in ascending heart–to–brain communication under mental stress
Authors: Candia-Rivera Diego , Norouzi Kian , Ramsøy Thomas Zoëga , Valenza Gaetano 
Published: September 2022

AbstractDynamical information exchange between central and autonomic nervous systems, as referred to functional brain–heart interplay, occurs during emotional and physical arousal. It is well documented that physical and mental stress lead to sympathetic activation. Nevertheless, the role of autonomic inputs in nervous-system-wise communication under mental stress is yet unknown. In this study, we estimated the causal and bidirectional neural modulations between EEG oscillations and peripheral sympathetic and parasympathetic activities using a recently proposed computational framework for a functional brain–heart interplay assessment, namely the sympathovagal synthetic data generation model. Mental stress was elicited in 37 healthy volunteers by increasing their cognitive demands throughout three tasks associated with increased stress levels. Stress elicitation induced an increased variability in sympathovagal markers, as well as increased variability in the directional brain–heart interplay. The observed heart–to–brain interplay was primarily from sympathetic activity targeting a wide range of EEG oscillations, whereas variability in the efferent direction seemed mainly related to EEG oscillations in the gamma band. These findings extend current knowledge on stress physiology, which mainly referred to top-down neural dynamics. Our results suggest that mental stress may not cause an increase in sympathetic activity exclusively as it initiates a dynamic fluctuation within brain-body networks including bidirectional interactions at a brain–heart level. We conclude that directional brain–heart interplay measurements may provide suitable biomarkers for a quantitative stress assessment and bodily feedback may modulate the perceived stress caused by increased cognitive demand.
Motor and cognitive deficits limit the ability to flexibly modulate spatiotemporal gait features in older adults with mild cognitive impairment
Authors: Rosenberg Michael C. , Slusarenko Alexandra , Cao Ke , McKay J. Lucas , Emmery Laura , Kesar Trisha M. , Hackney Madeleine E. 
Published: September 2022

AbstractIntroductionDance-based therapies are an emerging form of movement therapy aiming to improve motor and cognitive function in older adults with mild cognitive impairments (MCIs). Despite promising effects of dance-based therapies on function, it remains unclear how age-related declines in motor and cognitive function affect movement capacity and influence which movements and rhythms maximize dance therapy efficacy. Here, we evaluated the effects of age and MCI on the ability to accurately modulate spatial (i.e., joint kinematics), temporal (i.e., step timing), and spatiotemporal features of gait to achieve spatial and temporal targets during walking.MethodsWe developed novel rhythmic movement sequences - nine spatial, nine temporal, and four spatiotemporal - that deviated from typical spatial and temporal features of walking. Healthy young adults (HYA), healthy older adults (HOA), and adults with MCI were trained on each gait modification before performing the modification overground, with kinematic data recorded using wearable sensors.ResultsHOA performed spatial (p = 0.010) and spatiotemporal (p = 0.048) gait modifications less accurately than HYA. Individuals with MCI performed spatiotemporal gait modifications less accurately than HOA (p = 0.017). Spatial modifications to the swing phase of gait (p = 0.006, Cohen’sd= -1.3), and four- and six-stepDuplerhythms during temporal modifications (p<0.030, Cohen’sd>0.9) elicited the largest differences in gait performance in HYA vs. HOA and HOA vs. MCI, respectively.DiscussionThese findings suggest that age-related declines in strength and balance reduce the ability to accurately modulate spatial gait features, while declines in working memory in individuals with MCI may reduce the ability to perform longer temporal gait modification sequences.Differences in rhythmic movement sequence performance highlight motor and cognitive factors potentially underlying deficits in gait modulation capacity, which may guide therapy personalization and provide more sensitive indices to track intervention efficacy.
Heterogeneous migration of neuronal progenitors to the insula shapes the human brain
Authors: Mallela Arka N. , Deng Hansen , Gholipour Ali , Warfield Simon K , Goldschmidt Ezequiel 
Published: September 2022

ABSTRACTThe human cerebrum consists of a precise and stereotyped arrangement of lobes, gyri, and connectivity that underlies human cognition. The development of this arrangement is less clear. Current models of radial glial cell migration explain individual gyral formation but fail to explain the global configuration of the cerebral lobes. Moreover, the insula, buried in the depths of the Sylvian fissure, belies conventional models. Here, we show that the insula has unique morphology in adults, that insular morphology and slow volumetric growth emerge during fetal development, and that a novel theory of curved migration is required to explain these findings. We calculated morphologic data in the insula and other lobes in adults (N=107) and in anin uterofetal brain atlas (N=81 healthy fetuses).In utero, the insula grows an order of magnitude slower than the other lobes and demonstrates shallower sulci, less curvature, and less surface complexity both in adults and progressively throughout fetal development. Novel spherical projection analysis demonstrates that the lenticular nuclei obstruct 60-70% of radial pathways from the ventricular zone (VZ) to the insula, forcing a curved migration path to the insula in contrast to a direct radial pathway. Using fetal diffusion tractography, we identify streams of putative progenitor cells that originate from the VZ and migrate tangentiallyaroundthe lenticular nuclei to form the insula. These results challenge existing models of radial migration to the cortex, provide an alternative model for insular and cerebral development, and lay the groundwork to understand cerebral malformations, insular functional connectivity, and insular pathologies.
SPECC1L binds MYPT1/PP1β and can regulate its distribution between microtubules and filamentous actin
Authors: Mehta V , Decan N , Gaudreau-Lapierre A , Copeland JW , Trinkle-Mulcahy L 
Published: September 2022

ABSTRACTThe subcellular localization, activity and substrate specificity of the serine/threonine protein phosphatase 1 catalytic subunit (PP1 cat) is mediated through its dynamic association with regulatory subunits in holoenzyme complexes. While some functional overlap is observed for the three human PP1cat isoforms, they also show distinct targeting based on relative preferences for specific regulatory subunits. A well-known example is the preferential association of MYPT1 with PP1β in the myosin phosphatase complex. In smooth muscle, MYPT1/ PP1β counteracts the muscle contraction induced by phosphorylation of the light chains of myosin by the myosin light chain kinase. This phosphatase complex is also found in non-muscle cells, where it is targeted to both myosin and non-myosin substrates and contributes to regulation of the balance of cytoskeletal structure and motility during cell migration and division. Although it remains unclear how MYPT1/PP1β traffics between microtubule- and actin-associated substrates, our identification of the microtubule- and actin-binding protein SPECC1L in both the PP1β and MYPT1 interactomes suggested that it may be the missing link. Validation of their association, together with the strong overlap that we observed for the SPECC1L and MYPT1 interactomes, suggested that they exist in a stable complex in the cell. We further showed that SPECC1L binds MYPT1 directly, and that it can impact the balance of the distribution of the MYPT1/ PP1β complex between the microtubule and filamentous actin networks.
Intrinsic catalytic properties of histone H3 lysine-9 methyltransferases preserve monomethylation levels under lowS-adenosylmethionine
Authors: Haws Spencer A. , Miller Lillian J. , Rojas La Luz Diego , Kuznetsov Vyacheslav I. , Trievel Raymond C. , Craciun Gheorghe , Denu John M. 
Published: September 2022

AbstractS-adenosylmethionine (SAM) is the methyl donor for site-specific methylation reactions on histone proteins, imparting key epigenetic information. During SAM-depleted conditions that can arise from dietary methionine restriction, lysine di- and tri-methylation are reduced while sites such as Histone-3 lysine-9 (H3K9) are actively maintained, allowing cells to restore higher-state methylation upon metabolic recovery. Here, we investigated if the intrinsic catalytic properties of H3K9 histone methyltransferases (HMTs) contribute to this epigenetic persistence. We employed systematic kinetic analyses and substrate binding assays using four recombinant H3K9 HMTs (i.e., EHMT1, EHMT2, SUV39H1, and SUV39H2). At both high and low (sub-saturating) [SAM], all HMTs displayed the highest catalytic efficiency (kcat/KM) for monomethylation compared to di- and trimethylation on H3 peptide substrates. The favored monomethylation reaction was also reflected inkcatvalues, apart from SUV39H2 which displayed a similarkcatregardless of substrate methylation state. Using differentially-methylated nucleosomes as substrates, kinetic analyses of EHMT1 and EHMT2 revealed similar catalytic preferences. Orthogonal binding assays revealed only small differences in substrate affinity across methylation states, suggesting that catalytic steps dictate the monomethylation preferences of EHMT1, EHMT2, and SUV39H1. To linkin vitrocatalytic rates with nuclear methylation dynamics, we built a mathematical model incorporating measured kinetic parameters and a time course of mass spectrometry-based H3K9 methylation measurements following cellular SAM depletion. The model revealed that the intrinsic kinetic constants of the catalytic domains could recapitulatein vivoobservations. Together, these results suggest catalytic discrimination by H3K9 HMTs maintain nuclear H3K9me1, ensuring epigenetic persistence after metabolic stress.
Transcription and DNA methylation signatures of paternal behavior in hippocampal dentate gyrus of prairie voles
Authors: Waddell Nicholas J. , Liu Yan , Chitaman Javed M. , Kaplan Graham J. , Wang Zuoxin , Feng Jian 
Published: September 2022

ABSTRACTIn socially monogamous prairie voles (Microtus ochrogaster), parental behaviors not only occur in mothers and fathers, but also exist in some virgin males. In contrast, the other virgin males display aggressive behaviors towards conspecific pups. However, little is known about the molecular underpinnings of this behavioral dichotomy, such as gene expression changes and their regulatory mechanisms. To address this, we profiled the transcriptome and DNA methylome of hippocampal dentate gyrus of four prairie vole groups, namely attacker virgin males, parental virgin males, fathers, and mothers. While we found a concordant gene expression pattern between parental virgin males and fathers, the attacker virgin males have a more deviated transcriptome. Moreover, numerous DNA methylation changes were found in pair-wise comparisons among the four groups. We found some of these DNA methylation changes correlate with transcription differences, particularly at genes with extreme expression changes. Furthermore, the gene expression changes and methylome alterations are selectively enriched in certain biological pathways, such as Wnt signaling, which suggest a canonical transcription regulatory role of DNA methylation in paternal behavior. Therefore, our study presents an integrated view of prairie vole dentate gyrus transcriptome and epigenome that provides a DNA epigenetic based molecular insight of paternal behavior.
PI 4-kinases promote cell surface expansion and facilitate tissue morphogenesis during Drosophila cellularization and gastrulation
Authors: Chen Wei , Bergstein Victoria , He Bing 
Published: September 2022

AbstractDuring epithelial morphogenesis, dynamic cell shape change driven by intrinsic or extrinsic forces requires prompt regulation of cell surface area. Using Drosophila ventral furrow formation as a model, we identified the PI 4-kinase Fwd as an important regulator for apical constriction-mediated cell shape changes. These morphological changes involve prompt lateral surface expansion in the constricting cells and apical surface expansion in the non-constricting cells adjacent to the constriction domain, both of which are impeded upon depletion of Fwd. Computer modeling demonstrates that restricting apical and lateral cell surface expansion will result in specific tissue-level morphological abnormalities during furrow formation, which well predicts the phenotypes observed in the fwd deficient embryos. Fwd also promotes cell surface expansion during cellularization, but this function is largely redundant with another PI 4-kinase, PI4KIIα. Together, our findings uncover an important role of Fwd in facilitating cell surface expansion in support of dynamic epithelial remodeling.
Structural insights into the organization and channel properties of human Pannexin isoforms 1 and 3
Authors: Hussain Nazia , Apotikar Ashish , Pidathala Shabareesh , Mukherjee Sourajit , Burada Ananth Prasad , Sikdar Sujit Kumar , Kutti Vinothkumar R. , Penmatsa Aravind 
Published: September 2022

AbstractPannexins are single-membrane large-pore ion channels that release ATP upon activation. Three isoforms of pannexins, 1, 2, and 3, perform diverse cellular roles, including inflammation, differentiation, neuropathic pain, and ATP release. In this study, we report the cryoEM structure of pannexin 3 at 3.9 Å and characterize the structural differences with pannexin isoforms 1 and 2. We observe the organization of the Pannexin 3 vestibule into two distinct chambers with a wider pore radius in comparison to both PANX1 and 2 isoforms. We further report the structure of pannexin1 congenital mutant R217H in the resolution range of 3.9 Å. The congenital mutant R217H in transmembrane helix3 (TM3), R217H induce structural changes that leads to a partially closed pore and altered ATP interaction propensities. The channel conductance of the congenital mutant displays weakened voltage sensitivity. The results showcase a complete comparison of the three pannexin isoform structures that along with the structure of Pannexin 1 congenital mutant highlight distinct structural features of pannexin isoforms and the allosteric role of distant substitutions in dictating channel behavior in Pannexin 1.
Insights into the activation of Kinesin1 from the molecular characterisation of JIP3/4 binding to Kif5b
Authors: Vilela Fernando , Chenon Mélanie , Velours Christophe , Andreani Jessica , Llinas Paola , Ménétrey Julie 
Published: September 2022

AbstractWhereas our understanding of kinesin auto-inhibition mechanisms is improving faster, important insights into kinesin activation mechanisms such as those controlled by cargo-motor adaptors are still missing. JIP3 and JIP4 are versatile motor-cargo adaptors for kinesin1 and dynein-dynactin motors enabling bi-directional transport on microtubules. JIP3 activates kinesin1 heavy chains, independently of kinesin1 light chains. In this report, we characterize the molecular details of the binding of the kinesin1 heavy chain, Kif5b to the motor-cargo adaptors, JIP3 and JIP4, using biophysical approaches. The definition of the exact binding site of Kif5b, as well as the specificity of interaction between JIP3 and JIP4 provide new insights into kinesin1 activation.
Remodelling of carbon metabolism during sulfoglycolysis inEscherichia coli
Authors: Mui Janice W.-Y. , De Souza David P. , Saunders Eleanor C. , McConville Malcolm J. , Williams Spencer J. 
Published: September 2022

AbstractSulfoquinovose (SQ) is a major metabolite in the global sulfur cycle produced by nearly all photosynthetic organisms. One of the major pathways involved in the catabolism of SQ in bacteria, such asEscherichia coli, is a variant of the glycolytic Embden-Meyerhof-Parnas (EMP) pathway termed the sulfoglycolytic EMP (sulfo-EMP) pathway, which leads to consumption of three of the six carbons of SQ and excretion of 2,3-dihydroxypropanesulfonate (DHPS). Comparative metabolite profiling of aerobically Glc-grown and SQ-grownE. coliwas undertaken to identify the metabolic consequences of switching from glycolysis to sulfoglycolysis. Sulfoglycolysis was associated with the diversion of triose-phosphates to synthesize sugar phosphates (gluconeogenesis), and an unexpected accumulation of trehalose and glycogen storage carbohydrates. Sulfoglycolysis was also associated with global changes in central carbon metabolism, as indicated by changes in levels of intermediates in the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway (PPP), polyamine metabolism, pyrimidine metabolism and many amino acid metabolic pathways. Upon entry into stationary phase and depletion of SQ,E. coliutilize their glycogen, indicating a reversal of metabolic fluxes to allow glycolytic metabolism.ImportanceThe sulfosugar sulfoquinovose is estimated to be produced on a scale of 10 billion tonnes per annum, making it a major organosulfur species in the biosulfur cycle. Microbial degradation of sulfoquinovose through sulfoglycolysis allows utilization of its carbon content and contributes to biomineralization of its sulfur. However, the metabolic consequences of microbial growth on sulfoquinovose are unclear. We use metabolomics to identify the metabolic adaptations thatEscherichia coliundergoes when grown on sulfoquinovose versus glucose. This revealed increased flux into storage carbohydrates through gluconeogenesis, and reduced flux of carbon into the TCA cycle and downstream metabolism. These changes are relieved upon return to stationary phase growth and reversion to glycolytic metabolism. This work provides s new insights into the metabolic consequences of microbial growth on an abundant sulfosugar.
High-resolution volumetric imaging constrains compartmental models to explore synaptic integration and temporal processing by cochlear nucleus globular bushy cells
Authors: Spirou George A. , Kersating Matthew G. , Carr Sean , Razzaq Bayan , Alves-Pinto Carolyna Y. , Dawson Mariah , Ellisman Mark H. , Manis Paul B. 
Published: September 2022

AbstractGlobular bushy cells (GBCs) of the cochlear nucleus play central roles in the temporal processing of sound. Despite investigation over many decades, fundamental questions remain about their dendrite structure, afferent innervation, and integration of synaptic inputs. Here, we use volume electron microscopy (EM) to construct synaptic maps that precisely specify convergence ratios and synaptic weights for auditory- nerve innervation and accurate surface areas of all postsynaptic compartments. Detailed biophysically-based compartmental models can help develop hypotheses regarding how GBCs integrate inputs to yield their recorded responses to sound. We established a pipeline to export a precise reconstruction of auditory nerve axons and their endbulb terminals together with high-resolution dendrite, soma, and axon reconstructions into biophysically-detailed compartmental models that could be activated by a standard cochlear transduction model. With these constraints, the models predict auditory nerve input profiles whereby all endbulbs onto a GBC are subthreshold (coincidence detection mode), or one or two inputs are suprathreshold (mixed mode). The models also predict the relative importance of dendrite geometry, soma size, and axon initial segment length in setting action potential threshold and generating heterogeneity in sound-evoked responses, and thereby propose mechanisms by which GBCs may homeostatically adjust their excitability. Volume EM also reveals new dendritic structures and dendrites that lack innervation. This framework defines a pathway from subcellular morphology to synaptic connectivity, and facilitates investigation into the roles of specific cellular features in sound encoding. We also clarify the need for new experimental measurements to provide missing cellular parameters, and predict responses to sound for furtherin vivostudies, thereby serving as a template for investigation of other neuron classes.
Evolutionary and cellular analysis of the dark pseudokinase PSKH2
Authors: Byrne Dominic P , Shrestha Safal , Daly Leonard A , Marensi Vanessa , Ramakrishnan Krithika , Eyers Claire E , Kannan Natarajan , Eyers Patrick A 
Published: September 2022

AbstractPseudokinases, so named because they lack one or more conserved canonical amino acids that define their catalytically-active relatives, have evolved a variety of biological functions in both prokaryotic and eukaryotic organisms. Human PSKH2 is closely related to the canonical kinase PSKH1, which maps to the CAMK family of protein kinases. Primates encode PSKH2 in the form of a pseudokinase, which is predicted to be catalytically inactive due to loss of the invariant catalytic Asp residue. Although the biological role(s) of vertebrate PSKH2’s remains unclear, we previously identified species-level adaptions in PSKH2 that have led to the appearance of kinase or pseudokinase variants in vertebrate genomes alongside a canonical PSKH1 paralog. In this paper we confirm that, as predicted, PSKH2 lacks detectable protein phosphotransferase activity, and exploit structural informatics, biochemistry and cellular proteomics to begin to characterise vertebrate PSKH2 orthologues. AlphaFold 2-based structural analysis predicts functional roles for both the PSKH2 N- and C-regions that flank the pseudokinase domain core, and cellular truncation analysis confirms that the N-terminal domain, which contains a conserved myristoylation site, is required for both stable human PSKH2 expression and localisation to a membrane-rich subcellular fraction containing mitochondrial proteins. Using mass spectrometry-based proteomics, we confirm that human PSKH2 is part of a cellular mitochondrial protein network, and that its expression is regulated through client-status within the HSP90/Cdc37 molecular chaperone system. HSP90 interactions are mediated through binding to the PSKH2 C-terminal tail, leading us to predict that this region might act as both a cis and trans regulatory element, driving outputs linked to the PSKH2 pseudokinase domain that are important for functional signalling.
Sialidases and Fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria
Authors: Shuoker Bashar , Pichler Michael J. , Jin Chunsheng , Hiroka Sakanaka , Wu Haiyang , Martínez Gascueña Ana , Liu Jining , Nielsen Tine Sofie , Holgersson Jan , Nordberg Karlsson Eva , Juge Nathalie , Meier Sebastian , Morth Jens Preben , Karlsson Niclas G. , Abou Hachem Maher 
Published: September 2022

AbstractThe gut mucolytic specialist Akkermansia muciniphila is strongly associated with the integrity of the mucus layer. Mucin glycan utilization requires the removal of diverse protective caps, notably, fucose and sialic acid, but the enzymatic details of this process remain largely unknown. Here, we describe the specificities of ten A. muciniphila glycoside hydrolases, which collectively remove all known sialyl and fucosyl mucin caps including those with double sulphated epitopes. Structural analyses revealed an unprecedented fucosidase modular arrangement and explained the exclusive sialyl T-antigen specificity of a sialidase of a previously unknown family and catalytic apparatus. Key cell attached sialidases and fucosidases conferred mucin-binding and their inhibition abolished growth of A. muciniphila on mucin. Remarkably, the sialic acid fucose did not contribute to A. muciniphila growth, but instead promoted butyrate production by co-cultured Clostridia. This study brings unique mechanistic insight into the initiation of mucin O-glycan degradation by A. muciniphila and the nutrient sharing between key mucus-associated bacteria.