bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre-meiotic, 21-nucleotide Reproductive PhasiRNAs Emerged in Seed Plants and Diversified in Flowering Plants
Authors: Pokhrel Suresh , Huang Kun , Bélanger Sébastien , Caplan Jeffrey L. , Kramer Elena M. , Meyers Blake C. 
Published: October 2020

AbstractPlant small RNAs (sRNAs) are important regulatory elements that fine-tune gene expression and maintain genome integrity by silencing transposons. They have critical roles in most pathways involved in plant growth and reproductive development. Reproductive organs of monocots produce abundant phased, small interfering RNAs (phasiRNAs). The 21-nt reproductive phasiRNAs triggered by miR2118 are highly enriched in pre-meiotic anthers, and have not been described in eudicots. The 24-nt reproductive phasiRNAs are triggered by miR2275, and are highly enriched during meiosis in many angiosperms. Here, we describe additional variants of 21-nt reproductive phasiRNAs, including those triggered by miR11308 in wild strawberry, a eudicot, and we validate the presence of this pathway in rose. We report the widespread presence of the 21-nt reproductive phasiRNA pathway in eudicots, with novel biogenesis triggers in the basal eudicot columbine and the rosid flax. In eudicots, these 21-nt phasiRNAs are enriched in pre-meiotic stages, a spatiotemporal distribution consistent with that of monocots and suggesting a role in anther development. Although this pathway is apparently absent in well-studied eudicot families including the Brassicaceae, Solanaceae and Fabaceae, our work in eudicots supports a singular finding in spruce, indicating that the pathway of 21-nt reproductive phasiRNAs emerged in seed plants and was lost in some lineages.
Does somatosensory acuity influence the extent of internal model recalibration in young and older adults?
Authors: Vandevoorde Koenraad , de Xivry Jean-Jacques Orban 
Published: October 2020

AbstractThe ability to adjust movements to changes in the environment declines with aging. This age-related decline is caused by the decline of explicit adjustments. However, automatic adjustment of movement, or internal model recalibration, remains intact and might even be increased with aging. Since somatosensory information appears to be required for internal model recalibration, it might well be that an age-related decline in somatosensory acuity is linked to the increase of internal model recalibration. One possible explanation for an increased internal model recalibration is that age-related somatosensory deficits could lead to altered sensory integration with an increased weighting of the visual sensory-prediction error. Another possibility is that reduced somatosensory acuity results in an increased reliance on predicted sensory feedback. Both these explanations led to our preregistered hypothesis: we expect a relation between the decline of somatosensation and the increased internal model recalibration with aging. However, we failed to support this hypothesis. Our results question the existence of reliability-based integration of visual and somatosensory signals during motor adaptation.New & NoteworthyIs somatosensory acuity linked to implicit motor adaptation? The latter is larger in old compared to younger people? In light of reliability-based sensory integration, we hypothesized that this larger implicit adaptation was linked to an age-related lower reliability of somatosensation. Over two experiments and 130 participants, we failed to find any evidence for this. We discuss alternative explanations for the increase in implicit adaptation with age and the validity of our somatosensory assessment.
Relative demographic susceptibility does not explain the extinction chronology of Sahul’s megafauna
Authors: Bradshaw Corey J. A. , Johnson Christopher N. , Llewelyn John , Weisbecker Vera , Strona Giovanni , Saltré Frédérik 
Published: October 2020

AbstractThe causes of Sahul’s megafauna extinctions remain uncertain, although multiple, interacting factors were likely responsible. To test hypotheses regarding plausible ecological mechanisms underlying these extinctions, we constructed the first stochastic, age-structured models for 13 extinct megafauna species from five functional/taxonomic groups, as well as 8 extant species within these groups for comparison. Perturbing specific demographic rates individually, we tested which species were more demographically susceptible to extinction, and then compared these relative sensitivities to the fossil-derived extinction chronology. Here we show that the macropodiformes were the most resilient to extinction, followed by carnivores, monotremes, vombatiform herbivores, and large birds. Five of the eight extant species were as or more susceptible than were the extinct species. There was no clear relationship between extinction susceptibility and the extinction chronology for any perturbation scenario, but body mass and generation length explained much of the variation in relative risk. Our models reveal that the actual mechanisms leading to extinction were unlikely related to variation in demographic susceptibilityper se, but were driven instead by finer-scale variation in climate change and/or human prey choice and relative hunting success.
A Novel Class of Azoles with potent Anti-Leishmanial activity
Authors: Mathur Tarun , Kumar Manoj , Barman Tarani Kanta , Raj V. Samuel , Upadhyay Dilip J. , Verma Ashwani Kumar 
Published: October 2020

AbstractObjectivesTo investigate the anti-leishmanial activity of novel azole compounds againstLeishmania donovani, which causes deadly visceral leishmaniasis disease.MethodsA focused azole-based library was screened both against promastigotes and amastigotes forms ofL. donovanistrains in flat-bottomed 96-well tissue-culture plates and J774A.1 macrophages infected withL. donovani. The comprehensive screening azole-based library againstL. donovanistrains provided novel hits, which can serve as a good starting point to initiate hit to lead optimization campaign.ResultsHits identified from azole-based library exhibited potentin vitroactivity against promastigotes and amastigotes ofL. donovani.ConclusionsThese potent novel azole hits could be a good starting point to carry out for further medicinal chemistry exploration for anti-leishmania program.
The chromatin-binding domain of Ki-67 together with p53 protects human chromosomes from mitotic damage
Authors: Garwain Osama , Sun Xiaoming , Iyer Divya Ramalingam , Li Rui , Zhu Lihua Julie , Kaufman Paul D. 
Published: October 2020

AbstractVertebrate mammals express a protein called Ki-67 which is most widely known as a clinically useful marker of highly proliferative cells. Previous studies of human cells indicated that acute depletion of Ki-67 can elicit a delay at the G1/S boundary of the cell cycle, dependent on induction of the checkpoint protein p21. Consistent with those observations, we show here that acute Ki-67 depletion causes hallmarks of DNA damage, and the damage occurs even in the absence of checkpoint signaling. This damage is not observed in cells traversing S phase but is instead robustly detected in mitotic cells. The C-terminal chromatin binding domain of Ki-67 is necessary and sufficient to protect cells from this damage. We also observe synergistic effects when Ki-67 and p53 are simultaneously depleted, resulting in increased levels of chromosome bridges at anaphase, followed by the appearance of micronuclei. Therefore, these studies identify the C-terminus of Ki-67 as an important module for genome stability.
Binocular integration of retinal motion information underlies optic flow processing by the cortex
Authors: Rasmussen Rune N. , Matsumoto Akihiro , Arvin Simon , Yonehara Keisuke 
Published: October 2020

AbstractLocomotion creates various patterns of optic flow on the retina, which provide the observer with information about their movement relative to the environment. However, it is unclear how these optic flow patterns are encoded by the cortex. Here we use two-photon calcium imaging in awake mice to systematically map monocular and binocular responses to horizontal motion in four areas of the visual cortex. We find that neurons selective to translational or rotational optic flow are abundant in higher visual areas, whereas neurons suppressed by binocular motion are more common in the primary visual cortex. Disruption of retinal direction selectivity inFrmd7mutant mice reduces the number of translation-selective neurons in the primary visual cortex, and translation- and rotation-selective neurons as well as binocular direction-selective neurons in the rostrolateral and anterior visual cortex, blurring the functional distinction between primary and higher visual areas. Thus, optic flow representations in specific areas of the visual cortex rely on binocular integration of motion information from the retina.
Evidence for the role of cell reprogramming in naturally occurring cardiac repair
Authors: Shults Nataliia V. , Suzuki Yuichiro J. 
Published: October 2020

AbstractPulmonary arterial hypertension (PAH) is a fatal disease without a cure. If untreated, increased pulmonary vascular resistance kills patients within several years due to right heart failure. Even with the currently available therapies, survival durations remain short. By the time patients are diagnosed with this disease, the damage to the right ventricle (RV) has already developed. Therefore, agents that repair the damaged RV have therapeutic potential. We previously reported that cardiac fibrosis that occurs in the RV of adult Sprague-Dawley rats with PAH could naturally be reversed. We herein investigated the mechanism of this remarkable cardiac repair process. Counting of cardiomyocytes showed that the elimination of cardiac fibrosis is associated with the increased RV myocyte number, suggesting that new cardiomyocytes were generated. Immunohistochemistry showed the expression of α-smooth muscle actin and Sox-2 in RV myocytes of rats with PAH. Transmission electron microscopy detected the structure that resembles maturing cardiomyocytes in both the RV of PAH rats and cultured cardiomyocytes derived from induced pluripotent stem cells. We propose that the damaged RV in PAH can be repaired by activating the cell reprogramming mechanism that converts resident cardiac fibroblasts into induced cardiomyocytes.
Genetic insights into the causal relationship between physical activity and cognitive functioning
Authors: Cheval Boris , Darrous Liza , Choi Karmel W. , Klimentidis Yann C. , Raichlen David A. , Alexander Gene E. , Cullati Stéphane , Kutalik Zoltán , Boisgontier Matthieu P. 
Published: October 2020

AbstractPhysical activity and cognitive functioning are strongly intertwined. However, the causal relationships underlying this association are still unclear. Physical activity can enhance brain functions, but healthy cognition may also promote engagement in physical activity. Here, we assessed the bidirectional relationships between physical activity and general cognitive functioning using Latent Heritable Confounder Mendelian Randomization (LHC-MR). Association data were drawn from two large-scale genome-wide association studies (UK Biobank and COGENT) on accelerometer-measured moderate, vigorous, and average physical activity (N = 91,084) and cognitive functioning (N = 257,841). After Bonferroni correction, we observed significant LHC-MR associations suggesting that increased fraction of both moderate (b = 0.32, CI95%= [0.17,0.47], P = 2.89e-05) and vigorous physical activity (b = 0.22, CI95%= [0.06,0.37], P = 0.007) lead to increased cognitive functioning. In contrast, we found no evidence of a causal effect of average physical activity on cognitive functioning, and no evidence of a reverse causal effect (cognitive functioning on any physical activity measures). These findings provide new evidence supporting a beneficial role of moderate and vigorous physical activity (MVPA) on cognitive functioning.
Vasa vasorum lumen narrowing in brain vascular hyalinosis in systemic hypertension patients with ischemic stroke
Authors: Gychka Sergiy G. , Shults Nataliia V. , Nikolaienko Sofia I. , Marcocci Lucia , Sariipek Nurefsan E. , Rybka Vladyslava , Malysheva Tatiana A. , Dibrova Vyacheslav A. , Suzuki Yuichiro J. , Gavrish Alexander S. 
Published: October 2020

AbstractIschemic stroke is a major cause of death among patients with systemic hypertension. The narrowing of the lumen of the brain vasculature contributes to the increased incidence of stroke. While hyalinosis represents the major pathological lesions contributing to the vascular lumen narrowing and stroke, the pathogenic mechanism of brain vascular hyalinosis has not been well characterized. Thus, the present study examined the postmortem brain vasculature of human patients who died of ischemic stroke due to systemic hypertension. Hematoxylin and eosin staining and immunohistochemistry showed the occurrence of brain vascular hyalinosis with infiltrated plasma proteins along with the narrowing of vasa vasorum and oxidative stress. Transmission electron microscopy revealed the endothelial cell bulge protrusion into the vasa vasorum lumen and the occurrence of endocytosis in the vasa vasorum endothelium. The treatment of cultured microvascular endothelial cells with adrenaline also promoted the formation of the bulge as well as endocytic vesicles. siRNA knockdown of sortin nexin-9 (a mediator of clathrin-mediated endocytosis) inhibited the adrenaline-induced endothelial cell bulge formation. Adrenaline promoted protein-protein interactions between sortin nexin-9 and neural Wiskott–Aldrich Syndrome protein (a regulator of actin polymerization). We propose that endocytosis-depending endothelial cell bulge narrows the vasa vasorum, resulting in ischemic oxidative damage to the cerebral vessels, the formation of hyalinosis, the occurrence of ischemic stroke, and death in systemic hypertension patients.
Food restriction engages prefrontal corticostriatal cells and local microcircuitry to drive the decision to run vs conserve energy
Authors: Santiago Adrienne N. , Makowicz Emily A. , Du Muzi , Aoki Chiye 
Published: October 2020

ABSTRACTFood restriction (FR) evokes running, which may promote adaptive foraging in times of food scarcity, but can become lethal if energy expenditure exceeds caloric availability. Here, we demonstrate that chemogenetic activation of either the general medial prefrontal cortex (mPFC) pyramidal cell population, or the subpopulation projecting to dorsal striatum (DS) drives running specifically during hours preceding limited food availability, and not duringad libitumfood availability. Conversely, suppression of mPFC pyramidal cells generally, or targeting mPFC-to-DS cells, reduced wheel running specifically during FR and not duringad libitumfood access. Post-mortem c-Fos analysis and electron microscopy of mPFC layer 5 revealed distinguishing characteristics of mPFC-to-DS cells, when compared to neighboring non-DS projecting pyramidal cells: 1) greater recruitment of GABAergic activity and 2) less axo-somatic GABAergic innervation. Together, these attributes position the mPFC-to-DS subset of pyramidal cells to dominate mPFC excitatory outflow, particularly during FR, revealing a specific and causal role for mPFC-to-DS control of the decision to run during food scarcity. Individual differences in GABAergic activity correlate with running response to further support this interpretation. FR enhancement of PFC-to-DS activity may influence neural circuits both in studies using FR to motivate animal behavior and in human conditions hallmarked by FR.
Mitochondrial phenotypes in purified human immune cell subtypes and cell mixtures
Authors: Rausser Shannon , Trumpff Caroline , McGill Marlon A , Junker Alex , Wang Wei , Ho Siu-hong , Mitchell Anika , Karan Kalpita R , Monk Catherine , Segerstrom Suzanne C. , Reed Rebecca G. , Picard Martin 
Published: October 2020

AbstractUsing a high-throughput mitochondrial phenotyping platform to quantify multiple mitochondrial features among molecularly-defined immune cell subtypes, we quantify the natural variation in citrate synthase, mitochondrial DNA copy number (mtDNAcn), and respiratory chain enzymatic activities in human neutrophils, monocytes, B cells, and naïve and memory T lymphocyte subtypes. In mixed peripheral blood mononuclear cells (PBMCs) from the same individuals, we show to what extent mitochondrial measures are confounded by both cell type distributions and contaminating platelets. Cell subtype-specific measures among women and men spanning 4 decades of life indicate potential age- and sex-related differences, including an age-related elevation in mtDNAcn, which are masked or blunted in mixed PBMCs. Finally, a proof-of-concept, repeated-measures study in a single individual validates cell type differences and also reveals week-to-week changes in mitochondrial activities. Larger studies are required to validate and mechanistically extend these findings. These mitochondrial phenotyping data build upon established immunometabolic differences among leukocyte sub-populations, and provide foundational quantitative knowledge to develop interpretable blood-based assays of mitochondrial health.
AIBP-CAV1-VEGFR3 axis dictates lymphatic cell fate and controls lymphangiogenesis
Authors: Yang Xiaojie , Kim Jun-dae , Gu Qilin , Yan Qing , Astin Jonathan , Crosier Philip S , Yu Pengchun , Rockson Stanley G , Fang Longhou 
Published: October 2020

AbstractThe lymphatics are essential for the maintenance of tissue fluid homeostasis. Accordingly, lymphatic dysfunction contributes to lymphedema. In development, lymphangiogenesis often requires lymphatic endothelial cell (LEC) lineage specification from the venous ECs and subsequent LEC proliferation and migration, all of which are regulated by the VEGFC/VEGFR3 signaling. Cholesterol is essential for proper cell functions and organ development, yet the molecular mechanism by which cholesterol metabolism controls lymphangiogenesis is unknown. We show that the secreted protein, ApoA1 binding protein (AIBP), dictates lymphatic vessel formation by accelerating cholesterol efflux. Loss of Aibp2, the human paralog in zebrafish, impairs LEC progenitor specification and impedes lymphangiogenesis. Mechanistically, we found that caveolin-1 (CAV-1) suppresses VEGFR3 activation in LECs, and that AIBP-regulated cholesterol efflux disrupts lipid rafts/caveolae and reduces CAV-1 bioavailability, which abolishes the CAV-1 inhibition of VEGFR3 signaling, thereby augmenting VEGFR3 activation and increasing lymphangiogenesis. Enhancement of cholesterol efflux with ApoA1 overexpression or inhibition of cholesterol biosynthesis using atorvastatin restores proper lymphangiogenesis in Aibp2 mutant zebrafish. Loss of Cav-1 increases LEC progenitor specification in zebrafish, and rescues lymphangiogenesis in Aibp2-deficient animals. Recombinant AIBP supplement confers profound LEC fate commitment in the mouse embryonic stem cells (mESC) to LEC differentiation model. Furthermore, enhancement of AIBP-CAV-1-VEGFR3 signaling axis promotes VEGFC-engaged adult lymphangiogenesis in mice. Consistent with these data, AIBP expression is reduced in the epidermis of human lymphedematous skin. These studies identify that AIBP-mediated cholesterol efflux is a critical contributor for lymphangiogenesis. Our studies will provide a new therapeutic avenue for the treatment of lymphatic dysfunctions.One Sentence SummaryOur studies identify that AIBP-CAV-1-VEGFR3 axis enhances VEGFC-elicited lymphangiogenesis, which will guide a new therapeutic strategy for the treatment of lymphatic dysfunctions.
SKiM - A generalized literature-based discovery system for uncovering novel biomedical knowledge from PubMed
Authors: Raja Kalpana , Steill John , Ross Ian , Tsoi Lam C , Kuusisto Finn , Ni Zijian , Livny Miron , Thomson James , Stewart Ron 
Published: October 2020

AbstractLiterature-based discovery (LBD) uncovers undiscovered public knowledge by linking terms A to C via a B intermediate. Existing LBD systems are limited to process certain A, B, and C terms, and many are not maintained. We present SKiM (Serial KinderMiner), a generalized LBD system for processing any combination of A, Bs, and Cs. We evaluate SKiM via the rediscovery of discoveries by Don Swanson, who pioneered LBD. Using only literature from the 19th century up to a year before Swanson’s discoveries, SKiM uncovers all five discoveries. We apply SKiM to repurposing drugs for 26 conditions of high prevalence. Manual analysis confirmed 65 discoveries useful for four diseases from Swanson’s discoveries from one to 31 years prior to their first validation by clinical trials. SKiM predicts many new potential drug candidates representing prime targets for wet lab validation. SKiM can be applied to any biomedical inquiry sufficiently mentioned in the literature.
Predicting Brain Amyloid using Multivariate Morphometry Statistics, Sparse Coding, and Correntropy: Validation in 1,101 Individuals from the ADNI and OASIS Databases
Authors: Wu Jianfeng , Dong Qunxi , Gui Jie , Zhang Jie , Su Yi , Chen Kewei , Thompson Paul M. , Caselli Richard J. , Reiman Eric M. , Ye Jieping , Wang Yalin ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2020

ABSTRACTBiomarker-assisted preclinical/early detection and intervention in Alzheimer’s disease (AD) may be the key to therapeutic breakthroughs. One of the presymptomatic hallmarks of AD is the accumulation of beta-amyloid (Aβ) plaques in the human brain. However, current methods to detect Aβ pathology are either invasive (lumbar puncture) or quite costly and not widely available (amyloid PET). Our prior studies show that MRI-based hippocampal multivariate morphometry statistics (MMS) are an effective neurodegenerative biomarker for preclinical AD. Here we attempt to use MRI-MMS to make inferences regarding brain Aβ burden at the individual subject level. As MMS data has a larger dimension than the sample size, we propose a sparse coding algorithm, Patch Analysis-based Surface Correntropy-induced Sparse coding and max-pooling (PASCS-MP), to generate a low-dimensional representation of hippocampal morphometry for each subject. Then we apply these individual representations and a binary random forest classifier to predict brain Aβ positivity for each person. We test our method in two independent cohorts, 841 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and 260 subjects from the Open Access Series of Imaging Studies (OASIS). Experimental results suggest that our proposed PASCS-MP method and MMS can discriminate Aβ positivity in people with mild cognitive impairment (MCI) (Accuracy (ACC)=0.89 (ADNI)) and in cognitively unimpaired (CU) individuals (ACC=0.79 (ADNI) and ACC=0.81 (OASIS)). These results compare favorably relative to measures derived from traditional algorithms, including hippocampal volume and surface area, shape measures based on spherical harmonics (SPHARM), and our prior Patch Analysis-based Surface Sparse-coding and Max-Pooling (PASS-MP) methods.