bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dilated cardiomyopathy mutation E525K in human beta-cardiac myosin stabilizes the interacting heads motif and super-relaxed state of myosin
Authors: Rasicci D.V. , Tiwari P. , Desetty R. , Sadler F.W. , Sivaramakrishnan S. , Craig R. , Yengo C.M. 
Published: February 2022

AbstractThe auto-inhibited, super-relaxed (SRX) state of cardiac myosin is thought to be crucial for regulating contraction, relaxation, and energy conservation in the heart. We used single ATP turnover experiments to demonstrate that a dilated cardiomyopathy (DCM) mutation (E525K) in human beta-cardiac myosin increases the fraction of myosin heads in the SRX state (with slow ATP turnover), especially in physiological ionic strength conditions. We also utilized FRET between a C-terminal GFP tag on the myosin tail and Cy3ATP bound to the active site of the motor domain to estimate the fraction of heads in the closed, interacting-heads motif (IHM); we found a strong correlation between the IHM and SRX state. Negative stain EM and 2D class averaging of the construct demonstrated that the E525K mutation increased the fraction of molecules adopting the IHM. Overall, our results demonstrate that the E525K DCM mutation may reduce muscle force and power by stabilizing the auto-inhibited SRX state. Our studies also provide direct evidence for a correlation between the SRX biochemical state and the IHM structural state in cardiac muscle myosin. Furthermore, the E525 residue may be implicated in crucial electrostatic interactions that modulate this conserved, auto-inhibited conformation of myosin.Significance StatementDilated cardiomyopathy can be caused by single point mutations in cardiac muscle myosin, the motor protein that powers contraction of the myocardium. We found that the E525K DCM mutation in the cardiac myosin heavy chain stabilizes the auto-inhibited, super-relaxed state, suggesting a mechanism by which this mutation reduces muscle force and power. The E525K mutation also highlights critical electrostatic interactions important for forming the conserved, auto-inhibited conformational state of striated muscle myosins.
The Influence of Leaf Anatomical Traits on Photosynthetic in Coffee Leaves
Authors: Xiao Ziwei , Ma Guanrun , Bai Xuehui , Li Jinhong , Zhao Mingzhu , Su Linlin , Zhou Hua 
Published: February 2022

AbstractLeaf photosynthesis is largely determined by anatomical features. This study aimed to reveal the quantitative effects of the anatomical structure ofCoffea arabicaleaves on photosynthesis. Pearson’s correlation and path analysis were used to explore the correlation between leaf structure and photosynthesis. To calculate the comprehensive evaluation value of the correlation between leaf anatomical traits and photosynthetic parameters, the Criteria Importance Through Intercriteria Correlation (CRITIC) method was used to obtain the objective weight of each photosynthetic parameter. Most of the anatomical traits of the leaf significantly (P<0.05) to highly significantly (P<0.01) correlated with photosynthetic parameters, suggesting that anatomical traits greatly affected the photosynthetic capacity inCoffea arabicaleaf. Likewise, path coefficient analysis revealed that the photosynthetic capacity of Arabic coffee leaves is strongly correlated, both directly and indirectly, with the stomatal characteristics of the leaves. The results of the comprehensive evaluation also indicated that leaf thickness (LT) and stomatal density (d) were the anatomical characteristics most closely related to photosynthesis. In these results, understanding the effects of the anatomical structure of coffee leaves on photosynthesis, may provide useful information for coffee breeding programs and the management of coffee plantations to increase photosynthesis.
Partial illustration of human sperm DNA via microscopy and quantitative analysis of nucleotides
Authors: Barzideh Jaleh 
Published: February 2022

AbstractBackgroundgeneral structure of human sperm has not been profiled yet. Human sperm DNA characterization should progress the medical diagnostic and therapeutic methods rather than developing biological sciences. The aim of the present study was to provide biological insights into the common structure of human sperm. The value of this investigation is establishing an initial basic map of sperm head structure that leads to further advanced standardization of normality in this creature. For this purpose, analytical and microscopic methods were applied.MethodsHigh-performance Liquid Chromatography (HPLC) and flow cytometry were hired to quantify the DNA compositions. As well fluorescent, confocal and advanced light microscopy was applied to identify the stained sperm DNA by chromomycinA3 (CMA3) and 5-methylcytosine antibody (5-mc)ResultsHPLC demonstrated the mean values of nucleotide bases’ percentage in the structure of the sperm DNA regardless of the fraction that sperm was collected from gradient wash, sequenced from 27.6%, 8.92%, 27.05% and 35.36%. Also, quantitative flow cytometry of global 5-methylcytosine showed not a regular fluctuation in individuals with normal sperm while, there is a permanent increase in 50% fraction collected from percoll gradients.CMA3-positivity levels as well, were negatively correlated with sperm quality harvest by percoll gradients (p<0.0001), and positively correlated (P<0.05) with global methylation as determined by flow cytometry. Interestingly, in this text microscopy of immunocytochemistry of sperm cells stained by CMA3, demonstrated a different view from cells’ heads.Conclusionsobviously these explorations suggest some new possibilities in assessment of rough chemical level of nucleotides and cytochemistry of sperm head structure. The chromatin brightness presented with CMA3 by microscopy shows a direct relation with more extensive DNA methylation in sperms collected from low gradients of percoll wash. While, fluctuated 5-methylcytosine levels show personal presentation and even exclusive to individual sperm expression. This study induces further research on new assumptions in nuclear equilibrium in the axiom of DNA ladder in related to 5-mcytosine level in human sperm.
Prolonged β-Adrenergic Stimulation Disperses Ryanodine Receptor Clusters in Cardiomyocytes: Implications for Heart Failure
Authors: Shen Xin , van den Brink Jonas , Bergan-Dahl Anna , Kolstad Terje R. , Norden Einar S. , Hou Yufeng , Laasmaa Martin , Quick Ann P. , Espe Emil K.S. , Sjaastad Ivar , Wehrens Xander H.T. , Edwards Andrew G. , Soeller Christian , Louch William E. 
Published: February 2022

AbstractRyanodine Receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that “dispersion” of RyR clusters disrupts Ca2+ homeostasis during heart failure (HF) (Kolstad et al., eLife, 2018). Here, we investigated whether prolonged β-adrenergic stimulation, a hallmark of HF, promotes RyR cluster dispersion, and examined the underlying mechanisms. We observed that treatment of healthy rat cardiomyocytes with isoproterenol for 1 hour triggered progressive fragmentation of RyR clusters. Pharmacological inhibition of CaMKII reversed these effects, while cluster dispersion was reproduced by specific activation of CaMKII, and in mice with constitutively active Ser2814-RyR. A similar role of protein kinase A (PKA) in promoting RyR cluster fragmentation was established by employing PKA activation or inhibition. Progressive cluster dispersion was linked to declining Ca2+ spark fidelity and magnitude, and slowed release kinetics from Ca2+ propagation between more numerous RyR clusters. In healthy cells, this served to dampen the stimulatory actions of β-adrenergic stimulation over the longer term, and protect against pro-arrhythmic Ca2+ waves. However, during HF, RyR dispersion was linked to impaired Ca2+ release. Thus, RyR localization and function are intimately linked via channel phosphorylation by both CaMKII and PKA which, while finely tuned in healthy cardiomyocytes, underlies impaired cardiac function during pathology.Significance statementThe heartbeat is triggered by the release of Ca2+ from Ryanodine Receptors (RyRs) within cardiomyocytes. Recent data indicate RyR arrangement is highly malleable. However, mechanisms controlling RyR reorganisation and the subsequent impact on Ca2+ homeostasis remain unclear. Here, we show that prolonged β-adrenergic stimulation causes RyR clusters to disperse, drastically altering the frequency and kinetics of Ca2+ release events called “Ca2+ sparks” in a process that is dependent on CaMKII and PKA. In healthy cells, these compensatory effects protect against arrhythmogenic Ca2+ over-activity. However, during heart failure, RyR hyper-phosphorylation and dispersion impairs Ca2+ release and cardiac performance. Thus, RyR localization and function are intimately linked via channel phosphorylation which, while finely tuned in health, underlies impaired cardiac function during pathology.
Silencing KCC2 in mouse dorsal hippocampus compromises spatial and contextual memory
Authors: Simonnet Clémence , Sinha Manisha , Goutierre Marie , Moutkine Imane , Daumas Stéphanie , Poncer Jean Christophe 
Published: February 2022

AbstractDelayed upregulation of the neuronal chloride extruder KCC2 underlies the progressive shift in GABA signaling polarity during development. Conversely, KCC2 downregulation is observed in a variety of neurological and psychiatric disorders often associated with cognitive impairment. Reduced KCC2 expression and function in mature networks may disrupt GABA signaling and promote anomalous network activities underlying these disorders. However, the causal link between KCC2 downregulation, altered brain rhythmogenesis and cognitive function remains elusive. Here, by combining behavioral exploration with in vivo electrophysiology we assessed the impact of chronic KCC2 silencing in mouse dorsal hippocampus and showed it compromises both spatial and contextual memory. This was associated with altered hippocampal rhythmogenesis and neuronal hyperexcitability, with increased CA1 pyramidal cell burst firing during non-REM sleep. Reducing neuronal excitability with terbinafine, a specific Task-3 leak potassium channel activator, occluded the impairment of contextual memory upon KCC2 silencing. Our results establish a causal relationship between KCC2 expression and cognitive performance and suggest that impaired rhythmopathies and neuronal hyperexcitability are central to the deficits caused by KCC2 silencing in the adult mouse brain.
Multi-eGO: anin-silicolens to look into protein aggregation kinetics at atomic resolution
Authors: Scalone Emanuele , Broggini Luca , Visentin Cristina , Erba Davide , Toplek Fran Bačić , Peqini Kaliroi , Pellegrino Sara , Ricagno Stefano , Paissoni Cristina , Camilloni Carlo 
Published: February 2022

AbstractProtein aggregation into amyloid fibrils is the archetype of aberrant biomolecular self-assembly processes, with more than 50 diseases associated that are mostly uncurable. Understanding aggregation mechanisms is thus of fundamental importance and goes in parallel with the characterization of the structures of the transient oligomers formed in the process. Oligomers have been proven elusive to high-resolution structural techniques, while the large sizes and long-time scales typical of aggregation processes have limited, so far, the use of computational methods. To surmount these limitations, we introduce here multi-eGO, an atomistic, hybrid structure-based model, which leveraging on the knowledge of monomers conformational dynamics and of fibril structures, can efficiently capture the essential structural and kinetics aspects of protein aggregation. Multi-eGO molecular dynamics simulations can describe the aggregation kinetics of thousands of monomers. The concentration dependence of the simulated kinetics, as well as the structural features of the resulting fibrils, are in qualitative agreement within vitroexperiments on an amyloidogenic peptide of Transthyretin, a protein responsible for one of the most common cardiac amyloidosis. Multi-eGO simulations allow to observe in time and at atomic resolution the formation of primary nuclei in a sea of transient lower order oligomers, to follow their growth and the subsequent secondary nucleation events, till the maturation of multiple fibrils. Multi-eGO, combined with the many experimental techniques deployed to study protein aggregation, can provide the structural basis needed to advance the design of molecules targeting amyloidogenic diseases.Significance StatementAlzheimer’s and Parkinson’s diseases are uncurable pathologies associated to the aberrant aggregation of specific proteins into amyloid fibrils. Understanding the mechanism leading to protein aggregation, by characterizing the structures of the oligomeric species populated in the process, would have a tremendous impact on the design of therapeutic molecules. We propose that a structure-based approach to molecular dynamics simulations can allow following at high resolution the aggregation kinetics of thousands of monomers. Having shown that simulations can describe the aggregation of a Transthyretin amyloidogenic peptide, we demonstrate how their efficiency allows acquiring a wealth of structural information. We foresee that integrating the latter with the many techniques developed to study protein aggregation will support the design of molecules to modulate amyloidogenesis.
Dyslexia linked to profound impairment in the magnocellular medial geniculate nucleus
Authors: Meng Qianli , Schneider Keith 
Published: February 2022

AbstractThe neurological basis of dyslexia, a common reading disorder, remains unclear but is hypothesized to be caused by either dysfunction of the magnocellular system in the brain, abnormal temporal processing, and/or deficient phonological skills. Using functional magnetic resonance imaging, we measured activity in the magnocellular portion of the medial geniculate nucleus, the auditory relay in the thalamus, and observed profoundly attenuated responses to non-linguistic transient but not sustained sounds in every subject with dyslexia we tested, compared to normal readers. Our finding unifies these three hypotheses and identifies a core deficit causing dyslexia.
D2 dopamine receptor expression, sensitivity to rewards, and reinforcement learning in a complex value-based decision-making task
Authors: Banuelos Cristina , Creswell Kasey , Walsh Catherine , Manuck Stephen B. , Gianaros Peter J. , Verstynen Timothy 
Published: February 2022

AbstractIn the basal ganglia, different dopamine subtypes have opposing dynamics at post-synaptic receptors, with the ratio of D1 to D2 receptors determining the relative sensitivity to gains and losses, respectively, during value-based learning. This effective sensitivity to reward feedback interacts with phasic dopamine levels to determine the effectiveness of learning, particularly in dynamic feedback situations where frequency and magnitude of rewards need to be integrated over time to make optimal decisions. Using both simulations and behavioral data in humans, we evaluated how reduced sensitivity to losses, relative to gains, leads to suboptimal learning in the Iowa Gambling Task (IGT), a complex value-learning task. In the behavioral data, we tested individuals with a variant of the human dopamine receptor D2 (DRD2; -141C Ins/Del and Del/Del) gene that associates with lower levels of D2 receptor expression (N=119) and compared their performance to non-carrier controls (N=319). The magnitude of the reward response was measured by looking at ventral striatal (VS) reactivity to rewards in the Cards task using fMRI. DRD2 variant carriers had generally lower performance in the IGT than non-carriers, consistent with reduced sensitivity to losses. There was also a positive association between VS reactivity and performance in the IGT, however, we found no statistically significant difference in this effect between DRD2 carriers and non-carriers. Thus, while reduced D2 receptor expression was associated with less efficient learning in the IGT, we did not find evidence for the moderation of this effect by the magnitude of the reward response.
Generating an in vitro gut model with physiologically relevant biophysical mucus properties
Authors: McCright Jacob , Sinha Arnav , Maisel Katharina 
Published: February 2022

AbstractIntroductionGastrointestinal (GI) in vitro models have received lasting attention as an effective tool to model drug and nutrient absorption, study GI diseases, and design new drug delivery vehicles. A complete model of the GI epithelium should at a minimum include the two key functional components of the GI tract: mucus and the underlying epithelium. Mucus plays a key role in protecting and lubricating the GI tract, poses a barrier to orally administered therapies and pathogens, and serves as the microenvironment for the GI microbiome. These functions are reliant on the biophysical material properties of the mucus produced, including viscosity and pore size.MethodsIn this study, we generated in vitro models containing Caco-2 enterocyte-like cells and HT29-MTX goblet-like cells and determined the effects of coculture and mucus layer on epithelial permeability and biophysical properties of mucus using multiple particle tracking (MPT).ResultsWe found that mucus height increased as the amount of HT29-MTX goblet-like cells increased. Additionally, we found that increasing the amount of HT29-MTX goblet-like cells within culture corresponded to an increase in mucus pore size and mucus microviscosity, measured using MPT. When compared to ex vivo mucus samples from mice and pigs, we found that a 90:10 ratio of Caco-2:HT29-MTX coculture displayed similar mucus pore size to porcine jejunum and that the mucus produced from 90:10 and 80:20 ratios of cells shared mechanical properties to porcine jejunum and ileum mucus.ConclusionsGI coculture models are valuable tools in simulating the mucus barrier and can be utilized for a variety of applications including the study of GI diseases, food absorption, or therapeutic development.BiographyDr. Maisel joined the University of Maryland in January 2019 having done interdisciplinary training in nanotechnology, mucosal immunology, lymphatic immunology, and immunoengineering. She completed her PhD in Biomedical Engineering at the Johns Hopkins University in 2014 after which she was an NIH postdoctoral fellow at the University of Chicago in Molecular Engineering and Immunology. The Maisel Lab uses in vitro modeling, nanotechnology, and immunoengineering approaches to study and develop treatments for diseases at mucosal surfaces. They are interested in designing nanoparticles to take advantage of and study the interface between biological barriers, particularly the lymphatics, interstitial tissue, and mucosal surfaces, and nanoparticles. Dr. Maisel has won a number of awards, including NSF GRFP and NIH F32 fellowships as a trainee, the American Lung Association Dalsemer Award, LAM Foundation Career Development Award, an NSF CAREER Award, and an NIH NIGMS Maximizing Investigator Research Award. Her work has led to numerous high-impact publications, particularly in the field of drug delivery and mucosal immunoengineering, and several patents.
Using Mathematical Modeling to Distinguish Intrinsic and Acquired Targeted Therapeutic Resistance in Head and Neck Cancer
Authors: Cardenas Santiago D. , Reznik Constance J. , Ranaweera Ruchira , Song Feifei , Chung Christine H. , Fertig Elana J. , Gevertz Jana L. 
Published: February 2022

AbstractThe promise of precision medicine has been limited by the pervasive therapeutic resistance to many targeted therapies for cancer. Inferring the timing (i.e., pre-existing or acquired) and mechanism (i.e., drug-induced) of such resistance is crucial for designing effective new therapeutics. This paper studies the mechanism and timing of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) using tumor volume data obtained from patient-derived tumor xenografts. We propose a family of mathematical models, with each member of the family assuming a different timing and mechanism of resistance. We present a method for fitting these models to individual volumetric data, and utilize model selection and parameter sensitivity analyses to ask: which member of the family of models best describes HNSCC response to cetuximab, and what does that tell us about the timing and mechanisms driving resistance? We find that along with time-course volumetric data to a single dose of cetuximab, the initial resistance fraction and, in some instances, dose escalation volumetric data are required to distinguish among the family of models and thereby infer the mechanisms of resistance. These findings can inform future experimental design so that we can best leverage the synergy of wet laboratory experimentation and mathematical modeling in the study of novel targeted cancer therapeutics.
Reduced variability of bursting activity during working memory
Authors: Lundqvist Mikael , Rose Jonas , Warden Melissa , Buschman Tim , Herman Pawel , Miller Earl 
Published: February 2022

AbstractWorking memories have long been thought to be maintained by persistent spiking. However, mounting evidence from multiple-electrode recording (and single-trial analyses) shows that the underlying spiking is better characterized by intermittent bursts of activity. A counterargument suggested this intermittent activity is at odds with observations that spike-time variability reduces during task performance. However, this counterargument rests on assumptions, such as randomness in the timing of the bursts, that may not be correct. Thus, we analyzed spiking and LFPs from the prefrontal cortex (PFC) of monkeys to determine if task-related reductions in variability can co-exist with intermittent spiking. We found that it does because both spiking and associated gamma bursts were task-modulated, not random. In fact, the task-related reduction in spike variability could be explained by a related reduction in gamma burst variability. Our results provide further support for the intermittent activity models of working memory as well as novel mechanistic insights into how spike variability is reduced during cognitive tasks.
Rapamycin treatment during development extends lifespan and healthspan
Authors: Shindyapina Anastasia V. , Cho Yongmin , Kaya Alaattin , Tyshkovskiy Alexander , Castro José P. , Gordevicius Juozas , Poganik Jesse R. , Horvath Steve , Peshkin Leonid , Gladyshev Vadim N. 
Published: February 2022

AbstractThe possibility that pace of development is tightly connected to aging is supported by the fact that the onset of reproduction is associated with lifespan and that many longevity interventions target growth and development. However, it has been unknown whether targeting development with pharmacological intervention can lead to a longer lifespan. To test this possibility, we subjected genetically diverse UMHET3 mice to the mTOR inhibitor rapamycin for the first 45 days of life and followed them up until death. Treated mice grew slower, with most of the deceleration occurring in the first week, and remained smaller for their entire lives. Their reproductive age was delayed but without affecting offspring numbers. The treatment was sufficient to extend the median lifespan by 10%, with the most effect in males, and to preserve better health as measured by frailty index, gait speed, and glucose and insulin tolerance tests. Mechanistically, the liver transcriptome of treated mice was younger at the completion of treatment and stayed younger into the old ages in males. Rapamycin initially reduced DNA methylation age of livers, however, that effect was lost with aging. Analogous to mice, rapamycin exposure only during development robustly extended the lifespan of Daphnia magna as well as reduced their body size, suggesting evolutionary conserved mechanisms of this early life effect. Overall, the results demonstrate that short-term rapamycin treatment during early life is a novel longevity intervention that establishes causality between pace of development and longevity in evolutionary distant organisms.