bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient and Visit Characteristics of Pediatric Patients With High-frequency Low-acuity Emergency Department Visits
Authors: Cohen Joanna S. , Berkowitz Deena , Nosker Lois , Shaukat Haroon , Kim Dana , Koutroulis Ioannis , Breslin Kristen A.
Published: December 2020

Introduction

Pediatric patients account for a disproportionate number of low-acuity emergency department (ED) visits. The aim of this study is to describe pediatric patient and visit characteristics for high-frequency users for low-acuity visits.

Methods

This was a retrospective cohort study of children presenting to a tertiary care pediatric ED and an affiliated community ED, over a 2-year period, with at least 10 low-acuity visits. Twenty patients with the highest number of visits were classified as “superusers.” We analyzed patient data from the larger sample of high-frequency users and visit specific data from superuser visits. IBM SPSS Statistics 25 (SPSS Inc., Chicago, IL) was used to perform descriptive statistics and to summarize demographic and visit specific variables.

Results

We identified 181 high-frequency users with a mean number of visits of 14.3 ± 4.3 and a subpopulation of 20 superusers accounting for 434 visits. The majority of high-frequency users (89%) identified as African American and had public insurance (96.1%). Many patients received primary care affiliated with the home institution. In the first year of the study, 50.3% of high-frequency users were infants younger than 1 year at the index visit and 47.4% of superusers were infants at the index visit.

Superuser visits were evenly distributed among seasons and the majority of visits occurred during the weekdays (70.7%). The majority of visits were for medical complaints (86.6%) and almost half (47.6%) resulted in some testing (24.9%) or treatment (30.6%); however, only 1.4% resulted in hospital admission.

Conclusions

In our sample, most high-frequency low-acuity ED patients were infants, African American and have public insurance. Many are seen during clinic hours and are paneled at affiliated clinics. Among superusers, the majority of the visits did not require any testing, intervention, or treatment.
Paraflavitalea devenefica sp. nov., isolated from urban soil
Authors: Hou Xiaoxiao , Liu Hongliang , Shang Yumang , Mao Sidi , Li Shucheng , Sang Feng , Deng Hongkuan , Wang Lijuan , Kong Ling , Zhang ChunYang , Ding Zhongfeng , Gao Yan , Wei Shuzhen , Chen Zhiwei
Published: December 2020

A Gram-stain-negative, rod-shaped, mesophilic, milky white-pigmented, aerobic, non-spore-forming and non-flagellated bacterium, designated strain X16T, was isolated from urban soil of Zibo, Shandong, China. According to 16S rRNA gene sequence analysis, the isolate showed highest similarities with

Paraflavitalea soli

5GH32-13T (97.6 %),

Pseudoflavitalea soli

KIS20-3T (96.2 %),

Pseudobacter ginsenosidimutans

Gsoil 221T (96.0 %) and

Pseudoflavitalea rhizosphaerae

T16R-265T (95.8 %). The neighbour-joining tree based on 16S rRNA gene sequences showed that strain X16T formed a subcluster with

Paraflavitalea soli

5GH32-13T, and the subcluster was closely related to

Pseudoflavitalea soli

KIS20-3T,

Pseudobacter ginsenosidimutans

Gsoil 221T and

Pseudoflavitalea rhizosphaerae

T16R-265T. Strain X16T also formed a subcluster with

Paraflavitalea soli

5GH32-13T in phylogenetic tree based on genomic sequences. The polar lipids are phosphatidylethanolamine, two unknown aminolipids, two unknown aminophospholipids, two unknown lipids and two unknown phospholipids. The major quinone of strain X16T is menaquinone-7 and the main fatty acids (>10 % of total fatty acids) of strain X16T are iso-C15 : 0, iso-C17 : 0 3-OH and iso-C15 : 1 G. The genome length of strain X16T is 8.7 Mb with a DNA G+C content of 47.4 %. ANI values among strain X16T and strain

Paraflavitalea soli

5GH32-13T,

Pseudobacter ginsenosidimutans

Gsoil 221T, and

Pseudoflavitalea rhizosphaerae

T16R-265T are 78.1, 70.7, 70.6 %, respectively. On the basis of the results of the polyphasic characterization presented in this study, it is concluded that strain X16T represents a novel species. Besides, strain X16T can detoxify high toxicity selenite [Se(IV)] to low toxicity elemental selenium [Se(0)], for which the name Paraflavitale devenefica sp. nov. is proposed. The type strain is X16T (=KACC 21698T=GDMCC1.1757T).
Spatiotemporal changes in biodiversity by ecosystem engineers: how beavers structure the richness of large mammals
Authors: Gauvin Lindsay Y. , Gallant Daniel , Tremblay Eric , Berteaux Dominique , Lecomte Nicolas
Published: December 2020

High levels of biodiversity may be needed to maintain ecosystem functioning. By creating niches for other species, ecosystem engineers have the potential to promote biodiversity, but it is unclear how this translates across spatiotemporal scales. We evaluated the long-term impact of ecosystem engineering by beavers (Castor canadensis) on the diversity of mobile species. We tested the hypothesis that the spatial distribution of engineered habitats in different states resulting from ecosystem engineering by beavers increases the biodiversity of large mammals across spatial scales. We tested a second hypothesis that engineered habitat in different states resulting from ecosystem engineering by beavers drive the diversity of large mammals. We compared the richness and composition of boreal mammals using camera traps between habitats with and without history of occurrence by beavers within a protected area, where trapping, hunting, and forest exploitation are prohibited. We found that unique species were mostly found in specific engineered habitats, with ponds and wet meadows showing more species than dry meadows. In addition to the increased diversity of dispersal-limited species, our results show that beavers promote the diversity of mobile species at both local and landscape scales, signaling the importance of niche creation in structuring animal communities across scales.
Pharmacologic inhibition of Protein Kinase C α and Protein Kinase C β halts renal function decline indirectly, by blunting hyperphagia, and directly reduces adiposity in the ZSF1 rat model of type 2 diabetes
Authors: Wang Ju , Casimiro-Garcia Agustin , Johnson Bryce G. , Duffen Jennifer , Cain Michael , Savary Leigh , Wang Stephen , Nambiar Prashant , Lech Matthew , Zhao Shanrong , Xi Li , Zhan Yutian , Olson Jennifer , Stejskal James A. , Lin Hank , Zhang Baohong , Martinez Robert V. , Masek-Hammerman Katherine , Schlerman Franklin J. , Dower Ken
Published: December 2020

Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences. Despite advances that address some of the metabolic aspects of T2D, for many patients these approaches do not sufficiently control the disease. As a result, an emerging therapeutic strategy is to target the pathobiological mechanisms downstream of T2D metabolic derangement that can result in organ damage, morbidity, and mortality in afflicted individuals. One such proposed mechanism involves the Protein Kinase C (PKC) family members PKCα and PKCβ, which have been linked to diabetes-induced tissue damage to organs including the kidneys. To evaluate the therapeutic potential of dual inhibition of PKCα and PKCβ in the context of T2D, we have evaluated a potent and orally bioavailable inhibitor, herein referred to as Cmpd 1, in the ZSF1 rat model of leptin-receptor deficiency, obesity-driven T2D. Therapeutic dosing of Cmpd 1 virtually halted renal function decline but did so indirectly by blunting the hyperphagia response of these animals. Beyond this clear but indirect effect, Cmpd 1 had direct and prominent effects on body weight and in liver and inguinal white adipose tissue (iWAT) when administered to ZSF1 obese rats.
Altered biomechanical strategies of the paretic hip and knee joints during a step-up task: a pilot study
Authors: Goyal Vatsala , Dragunas Andrew , Askew Robert L. , Sukal-Moulton Theresa , López-Rosado Roberto
Published: December 2020

Stroke often leads to chronic motor impairments in the paretic lower limb that can constrain lower extremity movement and negatively impact the ability to navigate stairs or curbs. This exploratory study investigated the differences in hip and knee biomechanical strategies during a step-up task between 5 adults with hemiparetic stroke and 5 age-matched adults without stroke. Participants were instructed to step up onto a 4-inch platform, where joint biomechanics were quantified for the hip in the frontal plane and the hip and knee in the sagittal plane. Peak joint kinematics were identified during the leading limb swing phase and peak joint moments and power were identified during the leading limb pull-up phase of stance. Mixed effects regression models estimated fixed effects of limb (3 levels: control dominant, stroke non-paretic, and stroke paretic) on biomechanical outcomes, while a random effect of participant controlled for within-participant correlations. Repeated assessments within participants (approximately 60 trials per lower limb) increased the effective sample size from 10 to between 12.0 to 19.6. Altered biomechanical strategies of the paretic lower limb included reduced flexion angles and increased pelvic obliquity angles during swing, decreased power generation in the hip frontal plane during stance, and decreased moment and power generation in the knee sagittal plane during stance. A strategy of substantial interest was the elevated hip sagittal plane moment and power generation in both stroke limbs. Overall, our findings suggest that chronic motor impairments from stroke can lead to inefficient biomechanical strategies when stepping up.
Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery
Authors: Herrera Marco , Kim Jeonghwan , Eygeris Yulia , Jozic Antony , Sahay Gaurav
Published: December 2020

Lipid-based nanoparticles (LNPs) for the delivery of mRNA have jumped to the forefront of non-viral gene delivery. Despite this exciting development, poor endosomal escape after LNP cell entry remains an unsolved, rate-limiting bottleneck. Here we report the use of galectin 8-GFP (Gal8-GFP) cell reporter system to visualize the endosomal escaping capabilities of LNPs encapsulating mRNA. LNPs substituted with phytosterols in place of cholesterol exhibited various levels of Gal8 recruitment in the Gal8-GFP reporter system. In live-cell imaging, the results of the LNPs containing β-sitosterol (LNP-Sito) showed a 10-fold increase in detectable endosomal perturbation events when compared to the standard cholesterol LNPs (LNP-Chol), suggesting the superior capability of LNP-Sito to escape from endosomal entrapment. Trafficking studies of these LNPs showed strong localization with late endosomes. This highly sensitive and robust Gal8-GFP reporter system can be a valuable tool to elucidate intricacies of LNP trafficking and ephemeral endosomal escape events, enabling the advancement in gene delivery.
Broken, silent, and in hiding: Tamed endogenous pararetroviruses escape elimination from the genome of sugar beet (Beta vulgaris)
Authors: Schmidt Nicola , Seibt Kathrin M. , Weber Beatrice , Schwarzacher Trude , Schmidt Thomas , Heitkam Tony
Published: December 2020

Background and Aims

Endogenous pararetroviruses (EPRVs) are widespread components of plant genomes that originated from episomal DNA viruses of theCaulimoviridaefamily. Due to fragmentation and rearrangements, most EPRVs have lost their ability to replicate through reverse transcription and to initiate viral infection. Similar to the closely related retrotransposons, extant EPRVs were retained and often amplified in plant genomes for several million years. Here, we characterize the complete genomic EPRV fraction of the crop sugar beet (Beta vulgaris, Amaranthaceae) to understand how they shaped the beet genome and to suggest explanations for their absent virulence.

Methods

Using next- and third-generation sequencing data and the genome assembly, we reconstructed full-lengthin silicorepresentatives for the three host-specific EPRV families (beetEPRVs) in theB. vulgarisgenome. Focusing on the canonical family beetEPRV3, we investigated its chromosomal localization, abundance, and distribution by fluorescentin situand Southern hybridization.

Key Results

BeetEPRVs range between 7.5 and 10.7 kb (0.3 % of theB. vulgarisgenome) and are heterogeneous in structure and sequence. Although all three beetEPRV families were assigned to the florendoviruses, they showed variably arranged protein-coding domains, different degrees of fragmentation, and preferences for diverse sequence contexts. We observed small RNAs that target beetEPRVs in a family-specific manner, indicating stringent epigenetic suppression. We localized beetEPRV3 on all 18 sugar beet chromosomes, occurring preferentially in clusters and associated with heterochromatic, centromeric and intercalary satellite DNAs. BeetEPRV3 variants also exist in the genomes of related wild species, indicating an initial beetEPRV3 integration 13.4 to 7.2 million years ago.

Conclusions

Our study in beet illustrates the variability of EPRV structure and sequence in a single host genome. Evidence of sequence fragmentation and epigenetic silencing imply possible plant strategies to cope with long-term persistence of EPRVs, including amplification, fixation in the heterochromatin, and containment of EPRV virulence.
Tissue heterogeneity is prevalent in gene expression studies
Authors: Sturm Gregor , List Markus , Zhang Jitao David
Published: December 2020

Background

Lack of reproducibility in gene expression studies has recently attracted much attention in and beyond the biomedical research community. Previous efforts have identified many underlying factors, such as batch effects and incorrect sample annotations. Recently,tissue heterogeneity, a consequence of unintended profiling of cells of other origins than the tissue of interest, was proposed as a source of variance that exacerbates irreproducibility and is commonly ignored.

Results

Here, we systematically analyzed 2,692 publicly available gene expression datasets including 78,332 samples for tissue heterogeneity. We found a prevalence of tissue heterogeneity in gene expression data that affects on average 5-15% of the samples, depending on the tissue type. We distinguish cases of severe heterogeneity, which may be caused by mistakes in annotation or sample handling, from cases of moderate heterogeneity, which are more likely caused by tissue infiltration or sample contamination.

Conclusions

Tissue heterogeneity is a widespread issue in publicly available gene expression datasets and thus an important source of variance that should not be ignored. We advocate the application of quality control methods such asBioQCto detect tissue heterogeneity prior to mining or analysing gene expression data.
Independent parental contributions initiate zygote polarization inArabidopsis thaliana
Authors: Wang Kai , Chen Houming , Miao Yingjing , Ma Yanfei , Henschen Agnes , Lohmann Jan U. , Laubinger Sascha , Bayer Martin
Published: December 2020

Embryogenesis of flowering plants is initiated by polarization of the zygote, a prerequisite for correct axis formation in the embryo. Zygote polarity and the decision between embryonic and non-embryonic development in the daughter cells is controlled by a MITOGEN-ACTIVATING PROTEIN (MAP) kinase signaling pathway including the MAPKK kinase YODA (YDA). Upstream of YDA act two members of the BRASINOSTEROID SIGNALING KINASE (BSK) family, BSK1 and BSK2. These membrane-associated proteins serve as signaling relay linking receptor kinase complexes with intracellular signaling cascades. The receptor kinases acting upstream of BSK1 and BSK2 in the zygote, however, have so far not been identified. Instead, YDA can in part be activated by the non-canonical BSK family member SHORT SUSPENSOR (SSP) that is contributed by the sperm cell during fertilization. Here, we show that the receptor kinase ERECTA plays a crucial role in zygote polarization as maternally contributed part of the embryonic YDA pathway. SSP on the other hand provides an independent, paternal input to YDA activation, outlining a Y-shaped pathway. We conclude that two independent parental contributions initiate zygote polarization and control suspensor formation and embryonic development.
Self-beneficial belief updating as a coping mechanism for stress-induced negative affect
Authors: Czekalla Nora , Baumann Janine , Stolz David S. , Mayer Annalina V. , Voges Johanna F. , Rademacher Lena , Paulus Frieder M. , Krach Sören , Müller-Pinzler Laura
Published: December 2020

Being confronted with social-evaluative stress elicits a physiological and a psychological stress response. This calls for regulatory processes to manage negative affect and maintain self-related optimistic beliefs. The aim of the current study was to investigate the affect-regulating potential of self-related belief updating after exposure to social-evaluative stress, in comparison to non-social physical stress or no stress. We assessed self-related belief updating using trial-by-trial performance feedback and described the updating behavior in a mechanistic way using computational modeling. We found that social-evaluative stress was accompanied by an increase in cortisol and negative affect which was related to a shift in self-related belief updating towards the positive direction. This self-beneficial belief updating, which was absent after physical stress or control, was associated with a better recovery from stress-induced negative affect. This indicates that enhanced integration of positive self-related feedback can act as a coping strategy to deal with social-evaluative stress.
Threat induces changes in cardiac activity and metabolism negatively impacting survival in flies
Authors: Barrios Natalia , Farias Matheus , Moita Marta A
Published: December 2020

Adjusting to a dynamic environment involves fast changes in the body’s internal state, characterized by coordinated alterations in brain activity, physiological and motor responses. Threat-induced defensive states are a classic example of coordinated adjustment of bodily responses, being cardiac regulation one of the best characterized in vertebrates. A great deal is known regarding the neural basis of invertebrate defensive behaviours, mainly inDrosophila melanogaster. However, whether physiological changes accompany these remains unknown. Here, we set out to describe the internal bodily state of fruit flies upon an inescapable threat and found cardiac acceleration during running and deceleration during freezing. In addition, we found that freezing leads to increased cardiac pumping from the abdomen towards the head-thorax, suggesting mobilization of energy resources. Concordantly, threat-triggered freezing reduces sugar levels in the hemolymph and renders flies less resistant to starvation. The cardiac responses observed during freezing were absent during spontaneous immobility, underscoring the active nature of freezing response. Finally, we show that baseline cardiac activity predicts the amount of freezing upon threat. This work reveals a remarkable similarity with the cardiac responses of vertebrates, suggesting an evolutionarily convergent defensive state in flies. Our findings are at odds with the widespread view that cardiac deceleration while freezing has first evolved in vertebrates and that it is energy sparing. Investigating the physiological changes coupled to defensive behaviours in the fruit fly has revealed that freezing is costly, yet accompanied by cardiac deceleration, and points to heart activity as a key modulator of defensive behaviours.
Effect of human synovial fluid from osteoarthritis patients and healthy individuals on lymphatic contractility
Authors: Michalaki Eleftheria , Nepiyushchikh Zhanna , Bernard Fabrice C. , Rudd Josephine M. , Mukherjee Anish , McKinney Jay M. , Doan Thanh N. , Willett Nick J. , Dixon J. Brandon
Published: December 2020

The lymphatic system has been proposed to play a crucial role in the development and progression of osteoarthritis (OA). The synovial fluid (SF) of arthritic joints contains mediators of the inflammatory response and products of the injury to articular tissues, while lymphatic system plays a critical role in resolving inflammation and overall joint homeostasis. Despite the importance of both the lymphatic system and SF in OA disease, their relationship is still poorly understood. Here, we utilized SF derived from osteoarthritis patients (OASF) and healthy individuals (HSF) to investigate potential effects of SF on migration of lymphatic endothelial cells (LECs)in vitro, and lymphatic contractility of femoral lymphatic vessels (LVs)ex vivo. Both OASF and HSF treatments led to an increased migratory responsein vitrocompared to LECs treatment with media without serum.Ex vivo, both OASF and HSF treatments to the lumen of isolated LVs led to significant differences in the tonic and phasic contractions and these observations were dependent on the SF treatment time. Specifically, OASF treatment transiently enhanced the RFLVs tonic contractions. Regarding the phasic contractions, OASF generated either an abrupt reduction after 1 hr of treatment or a complete cease of contractions after an overnight treatment, while HSF treatment displayed a gradual decrease in lymphatic contractility. The observed variations after SF treatments suggest that the pump function of lymphatic vessel draining the joint could be directly compromised in OA and thus might present a new therapeutic target.
The local and global geometry of trabecular bone
Authors: Callens Sebastien J.P. , Tourolle né Betts Duncan C. , Müller Ralph , Zadpoor Amir A.
Published: December 2020

Abstract

The organization and shape of the microstructural elements of trabecular bone govern its physical properties, are implicated in bone disease, and can serve as blueprints for biomaterial design. To devise fundamental structure-property relationships, it is essential to characterize trabecular bone from the perspective of geometry, the mathematical study of shape. Here, we used the micro-computed tomography images of 70 donors at five different sites to characterize the local and global geometry of human trabecular bone, respectively quantified by surface curvatures and Minkowski functionals. We find that curvature density maps provide sensitive shape fingerprints for bone from different sites. Contrary to a common assumption, these curvature maps also show that bone morphology does not approximate a minimal surface but exhibits a much more intricate curvature landscape. At the global (or integral) perspective, our Minkowski analysis illustrates that trabecular bone exhibits other types of anisotropy/ellipticity beyond interfacial orientation, and that anisotropy varies substantially within the trabecular structure. Moreover, we show that the Minkowski functionals unify several traditional morphometric indices. Our geometric approach to trabecular morphometry provides a fundamental language of shape that could be useful for bone failure prediction, understanding geometry-driven tissue growth, and the design of complex tissue engineering scaffolds.
Reduced activity of Adenylyl Cyclase 1 Attenuates Morphine Induced Hyperalgesia and Inflammatory Pain in Mice
Authors: Johnson Kayla , Doucette Alexis , Edwards Alexis , Watts Val J. , Klein Amanda H.
Published: December 2020

Opioid tolerance and opioid-induced hyperalgesia during repeated opioid administration and chronic pain are associated with upregulation of adenylyl cyclase activity. The objective of this study was to test the hypothesis that a reduction in adenylyl cyclase 1 (AC1) activity or expression would attenuate morphine tolerance and hypersensitivity, and inflammatory pain using murine models. To investigate opioid tolerance and opioid-induced hyperalgesia, mice were subjected to twice daily treatments of saline or morphine using either a static (15 mg/kg, 5 days) or an escalating tolerance paradigm (10-40 mg/kg, 4 days). Systemic treatment with an AC1 inhibitor, ST03437 (5 mg/kg, ip), reduced morphine tolerance and morphine hyperalgesia in mice. Lumbar intrathecal administration of a vector incorporating adeno-associated virus and short-hairpin RNA againstAdcy1reduced morphine induced hypersensitivity compared to control vector treated mice. In contrast, morphine antinociception, along with baseline thermal paw withdrawal latencies, motor performance, exploration in an open field test, and burrowing behaviors were not affected by intrathecalAdcy1knockdown. Knockdown ofAdcy1by intrathecal injection also attenuated inflammatory mechanical hyperalgesia after intraplantar administration of Complete Freund’s Adjuvant (CFA) after one week post injection. ThisAdcy1knockdown strategy also increased burrowing and nesting activity after CFA injection when compared to controls. Together, these data indicate targeting AC1 to mitigate opioid-induced adverse effects, or as a method to treat chronic pain, are appropriate as a clinical approach and further development into generating pharmaceuticals targeting these genes/proteins may prove beneficial in the future.
Multi-omic analysis of lung tumors defines pathways activated in neuroendocrine transformation
Authors: Quintanal-Villalonga Alvaro , Taniguchi Hirozaku , Zhan Yingqian A. , Hasan Maysun M. , Meng Fanli , Uddin Fathema , Donoghue Mark , Won Helen H. , Chavan Shweta S. , Chan Joseph M. , Ciampricotti Metamia , Chow Andrew , Offin Michael , Chang Jason C. , Ray-Kirton Jordana , Egger Jacklynn , Bhanot Umesh K. , Silber Joachim , Iacobuzio-Donahue Christine A. , Roehrl Michael H. , Hollmann Travis J. , Yu Helena A. , Rekhtman Natasha , Poirier John T. , Houck-Loomis Brian , Koche Richard P. , Rudin Charles M. , Sen Triparna
Published: December 2020

Lineage plasticity, a capacity to reprogram cell phenotypic identity under evolutionary pressure, is implicated in treatment resistance and metastasis in multiple cancers. In lung adenocarcinomas (LUADs) amenable to treatment with targeted inhibitors, transformation to an aggressive neuroendocrine (NE) carcinoma resembling small cell lung cancer (SCLC) is a recognized mechanism of acquired resistance. Defining molecular mechanisms of NE transformation in lung cancer has been limited by a paucity of well annotated pre- and post-transformation clinical samples. We hypothesized that mixed histology LUAD/SCLC tumors may capture cancer cells proximal to, and on either side of, histologic transformation. We performed detailed genomic, epigenomic, transcriptomic and proteomic characterization of combined LUAD/SCLC tumors as well as pre- and post-transformation clinical samples. Our data support that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm in pre-transformation LUADs. Consistent shifts in gene expression programs in NE transformation include induction of several stem/progenitor cell regulatory pathways, including upregulation of PRC2 and WNT signaling, and suppression of Notch pathway activity. We observe induction of PI3K/AKT and an immunosuppressive phenotype in NE transformation. Taken together our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer.
Normalizing the brain connectome for communication through synchronization
Authors: Petkoski S. , Jirsa V.K.
Published: December 2020

Networks in neuroscience determine how brain function unfolds, and their perturbations lead to psychiatric disorders and brain disease. Brain networks are characterized by their connectomes, which comprise the totality of all connections, and are commonly described by graph theory. This approach is deeply rooted in a particle view of information processing, based on the quantification of informational bits such as firing rates. Oscillations and brain rhythms demand, however, a wave perspective of information processing based on synchronization. We extend traditional graph theory to a dual particle-wave-perspective, integrate time delays due to finite transmission speeds and derive a normalization of the connectome. When applied to the data base of the Human Connectome project, we explain the emergence of frequency-specific network cores including the visual and default mode networks. These findings are robust across human subjects (N=100) and are a fundamental network property within the wave picture. The normalized connectome comprises the particle view in the limit of infinite transmission speeds and opens the applicability of graph theory to a wide range of novel network phenomena, including physiological and pathological brain rhythms. These two perspectives are orthogonal, but not incommensurable, when understood within the novel here proposed generalized framework of structural connectivity.

AUTHOR SUMMARY

All networks are composed of nodes and links, forming the structural frame, in which communication occurs. We demonstrate that graph theoretical tools make the implicit assumption of information transmission via exchange of bits, suggesting that the stronger connected nodes are more impactful upon the remainder of the network. This corollary does not extend to communication through oscillations, which is the prominent information carrier in brain networks. We extend traditional network analysis to the oscillatory domain and derive a novel network normalization including descriptive metrics. Along the prototypical example of the brain as a network, we illustrate the consequences of this novel approach and demonstrate that the normalization robustly explains the emergence of the prominent frequency-specific network cores, which cannot be understood within the traditional framework.
THE CIRCADIAN CLOCK IN THE RETINAL PIGMENT EPITHELIUM CONTROLS THE DIURNAL RHYTHM OF PHAGOCYTIC ACTIVITY
Authors: DeVera Christopher , Dixon Jendayi , Chrenek Micah A. , Baba Kenkichi , Iuvone P. Michael , Tosini Gianluca
Published: December 2020

The diurnal peak of phagocytosis by the retinal pigment epithelium (RPE) of photoreceptor outer segments (POS) is under circadian control, and it is believed that this process involves interactions from both the retina and RPE. Previous studies have demonstrated that a functional circadian clock exists within multiple retinal cell types and RPE cells. Thereby, the aim of the current study was to determine whether the circadian clock in the retina and or RPE controls the diurnal phagocytic peak of photoreceptor outer segments and whether selective disruption of the circadian clock in the RPE would affect RPE cells function and the viability during aging. To that aim, we first generated and validated an RPE tissue-specific KO of the essential clock gene, Bmal1, and then we determined the daily rhythm in phagocytic activity by the RPE in mice lacking a functional circadian clock in the retina or RPE. Then using electroretinography, spectral domain-optical coherence tomography, and optomotor response measurements of visual function we determined the effect ofBmal1removal in young (6-month old) and old (18-month old) mice. RPE morphology and lipofuscin accumulation was also determined in young and old mice. Our data show that the circadian clock in the RPE controls the daily diurnal phagocytic peak of POS. Surprisingly, the lack of a functional RPE circadian clock or the diurnal phagocytic peak does not result in any detectable age-related degenerative phenotype in the retina or RPE. Thus, our results demonstrate that the loss of the circadian clock in the RPE or the lack of the daily peak in phagocytosis of POS does not result in deterioration of photoreceptors or the RPE during aging.
Early cis-regulatory events in the formation of retinal horizontal cells
Authors: Schick Estie , Gonzalez Kevin C. , Dutta Pooja , Hossain Kazi , Ghinia Tegla Miruna G. , Emerson Mark M.
Published: December 2020

During retinal development, multipotent and restricted progenitor cells generate all of the neuronal cells of the retina. Among these are horizontal cells, which are interneurons that modulate the light-induced signal from photoreceptors. This study utilizes the identification of novel cis-regulatory elements as a method to examine the gene regulatory networks that direct the development of horizontal cells. Here we describe a screen for cis-regulatory elements, or enhancers, for the horizontal cell-associated genes PTF1A, ONECUT1 (OC1), TFAP2A (AP2A), and LHX1. The OC1ECR22 and Tfap2aACR5 elements were shown to be potential enhancers for OC1 and TFAP2A, respectively, and to be specifically active in developing horizontal cells. The OC1ECR22 element is activated by PTF1A and RBPJ, which translates to regulation of OC1 expression and suggests that PTF1A is a direct activator of OC1 expression in developing horizontal cells. The region within the Tfap2aACR5 element that is responsible for its activation was determined to be a 100 bp sequence named Motif 4. Both OC1ECR22 and Tfap2aACR5 are negatively regulated by the nuclear receptors THRB and RXRG, as is the expression of OC1 and AP2A, suggesting that nuclear receptors may have a role in the negative regulation of horizontal cell development.
LOCAL REGULATION AND FUNCTION OF IMPORTIN-β1 IN HIPPOCAMPAL NEURONS DURING TRANSCRIPTION-DEPENDENT PLASTICITY
Authors: Lee Yan Jun , Navakkode Sheeja , Tan Chee Fan , Sze Siu Kwan , Sajikumar Sreedharan , Ch’ng Toh Hean
Published: December 2020

Activity-dependent transcription is critical for the encoding of long-term memories. Regulated nuclear entry of soluble proteins is one method to relay synaptic signals to the nucleus to couple neuronal excitation with transcription. To date, the role of importin-β1 in nuclear shuttling of proteins during activity-dependent transcription has always been inferred but not directly investigated. In this study, we demonstrate activity-dependent nuclear accumulation of importin-β1 from the soma and the synapto-dendritic compartments. Importantly, inhibition of importin-β1 mediated nuclear import during synaptic stimulation impairs long-term plasticity. We show evidence that importin-β1 mRNA-ribosome complex is distributed throughout the synapto-dendritic compartment and synaptic stimulation induces importin-β1 local protein synthesis. Finally, we identified candidate proteins that associate with importin-β1 at the synapse and characterize NDRG1 as an importin-β1 interactor that undergoes activity-dependent translocation into the nucleus. Collectively, our results highlight the crucial role of importin-β1 in the nuclear import of soluble proteins during long-term plasticity.
Mapping genetic effects on cell type-specific chromatin accessibility and annotating complex trait variants using single nucleus ATAC-seq
Authors: Benaglio Paola , Newsome Jacklyn , Han Jee Yun , Chiou Joshua , Aylward Anthony , Corban Sierra , Okino Mei-Lin , Kaur Jaspreet , Gorkin David U , Gaulton Kyle J
Published: December 2020

Gene regulation is highly cell type-specific and understanding the function of non-coding genetic variants associated with complex traits requires molecular phenotyping at cell type resolution. In this study we performed single nucleus ATAC-seq (snATAC-seq) and genotyping in peripheral blood mononuclear cells from 10 individuals. Clustering chromatin accessibility profiles of 66,843 total nuclei identified 14 immune cell types and sub-types. We mapped chromatin accessibility QTLs (caQTLs) in each immune cell type and sub-type which identified 6,248 total caQTLs, including those obscured from assays of bulk tissue such as with divergent effects on different cell types. For 3,379 caQTLs we further annotated putative target genes of variant activity using single cell co-accessibility, and caQTL variants were significantly correlated with the accessibility level of linked gene promoters. We fine-mapped loci associated with 16 complex immune traits and identified immune cell caQTLs at 517 candidate causal variants, including those with cell type-specific effects. At the 6q15 locus associated with type 1 diabetes, in line with previous reports, variant rs72928038 was a naïve CD4+ T cell caQTL linked toBACH2and we validated the allelic effects of this variant on regulatory activity in Jurkat T cells. These results highlight the utility of snATAC-seq for mapping genetic effects on accessible chromatin in specific cell types and provide a resource for annotating complex immune trait loci.
Evolutionary Emergence of First Animal Organisms Triggered by Environmental Mechano-Biochemical Marine Stimulation
Authors: Nguyen Ngoc Minh , Merle Tatiana , Broders Florence , Brunet Anne-Christine , Sarron Florian , Jha Aditya , Genisson Jean-Luc , Rottinger Eric , Farge Emmanuel
Published: December 2020

The evolutionary emergence of the first animals is thought to have been intimately associated to the formation of a primitive endomesodermal gut (i.egastrulation) from ancestral multi-cellular spheres, blastulae, more than 700 million years ago. However, the biochemical cues having been at the origin of endomesoderm formation remain a mystery.

Here we find that hydrodynamic mechanical strains developed by sea wavelets on pre-bilaterianNematostella vectensisand pre-metazoanChoanoeca flexarepresentatives, which common ancestor dates back to more than 700 million years ago, can trigger gastrulation in a Myo-II dependent mechanotransductive process. Gastrulation in turn induces endomesoderm first biochemical specification through the mechanical activation of the βcat pathway in pre-bilaterianNematostella vectensis, like in Drosophila and zebrafish embryos, which common ancestor dates back to 600-700 million years ago.

These observations converge to animal emergence that has been mechanotransductively triggered by wavelet mechanical strains on the sea-shore in multicellular choanoflagellates through Myo-II more than 700 million years ago, a process achieved in first metazoan through mechanosensitive Y654-containing βcat evolutionary emergence found as conserved in all metazoan.

One sentence summary

Marine hydrodynamic strains have activated first gastric organ formation from ancestral pre-animal cell colonies.
Dietary restriction in the long-chain acyl-CoA dehydrogenase knockout mouse
Authors: F. Diekman Eugène , van Weeghel Michel , Suárez-Fariñas Mayte , Argmann Carmen , Ranea-Robles Pablo , Wanders Ronald J.A. , Visser Gepke , van der Made Ingeborg , Creemers Esther E. , Houten Sander M.
Published: December 2020

Patients with a disorder of mitochondrial long-chain fatty acid β-oxidation (FAO) have reduced fasting tolerance and may present with hypoketotic hypoglycemia, hepatomegaly, (cardio)myopathy and rhabdomyolysis. Patients should avoid a catabolic state because it increases reliance on FAO as energy source. It is currently unclear whether weight loss through a reduction of caloric intake is safe in patients with a FAO disorder. We used the long-chain acyl-CoA dehydrogenase knockout (LCAD KO) mouse model to study the impact of dietary restriction (DR) on the plasma metabolite profile and cardiac function. For this, LCAD KO and wild type (WT) mice were subjected to DR (70% of ad libitum chow intake) for 4 weeks and compared to ad libitum chow fed mice. We found that DR had a relatively small impact on the plasma metabolite profile of WT and LCAD KO mice. Echocardiography revealed a small decrease in left ventricular systolic function of LCAD KO mice, which was most noticeable after DR, but there was no evidence of DR-induced cardiac remodeling. Our results suggest that weight loss through DR does not have acute and detrimental consequences in a mouse model for FAO disorders.
Pharmacologic IRE1/XBP1s Activation Promotes Systemic Adaptive Remodeling in Obesity
Authors: Madhavan Aparajita , Kok Bernard P. , Grandjean Julia M.D. , Albert Verena , Sukiasyan Ara , Rius Bibiana , Powers Evan T. , Galmozzi Andrea , Saez Enrique , Wiseman R. Luke
Published: December 2020

In obesity, overexpression of the IRE1-regulated transcription factor XBP1s protects against metabolic dysfunction by stimulating adaptive remodeling of multiple tissues, most notably the liver.1–5This observation suggests that pharmacologically increasing IRE1/XBP1s signaling might be an attractive approach to mitigate pathologies in obesity and its associated complications.6–8Here, we tested this notion by treating diet-induced obese (DIO) mice with the pharmacologic IRE1/XBP1s activator IXA4.9We show that IXA4 treatment selectively activated protective IRE1/XBP1s signaling in livers of DIO mice without inducing obesity-linked pathologies associated with IRE1 hyperactivity, such as liver inflammation and fibrosis.10,11Chronic IXA4 treatment improved systemic glucose metabolism and feeding-induced insulin action in the liver of DIO mice. These improvements were linked to IRE1/XBP1s-induced remodeling of the liver transcriptome, which dampened glucose production and reduced hepatic steatosis. Further, we show that IXA4 treatment enhanced pancreatic β cell function and insulin homeostasis, indicating that systemic activation of IRE1/XBP1s signaling engendered multi-tissue benefits that integrated to mitigate systemic metabolic dysfunction in DIO mice. Our findings show that selective pharmacological activation of protective IRE1/XBP1s signaling reprograms multiple metabolic tissues, such as liver and pancreas, and represents a potential strategy to correct metabolic alterations in obesity.
A Complex Containing HNRNPA2B1 and N6-methyladenosine Modified Transcripts Mediates Actions of Toxic Tau Oligomers
Authors: Jiang Lulu , Lin Weiwei , Zhang Cheng , Verma Mamta , Kwan Julian , van Vliet Emily , Ash Peter E. A. , Cruz Anna Lourdes , Boudeau Samantha , Maziuk Brandon F. , Lei Shuwen , Song Jaehyup , Alvarez Victor E. , Kayed Rakez , Kanaan Nicholas , Murray Melissa E. , Crary Johnathan F. , Petrucelli Leonard , Li Hu , Emili Andrew , Wolozin Benjamin
Published: December 2020

The microtubule associated protein tau oligomerizes in response to stress and disease, but the function of oligomeric tau (oTau) and the ultimate mechanisms of toxicity are unknown. To gain insights, we have now used Cry2-based optogenetics to induce tau oligomers (oTau-c) in neuronal cultures. oTau-c can seed tau aggregation and biochemical fractionates in a manner similar to oTau. Optical induction of oTau elicits a translational stress response that includes cytoplasmic translocation of the TIA1, abundant stress granules (SGs) and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau. Imaging and immunoprecipitation verify the HNRNPA2B1 association with endogenous oTau in neurons, animal models and human Alzheimer brain tissue. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine modified transcripts (m6A). Knockdown of HNRNPA2B1 prevents oTau from associating with m6A, prevents oTau-induced reductions in protein synthesis and reduces oTau-induced toxicity. Finally, we show striking increases in m6A-oTau and -HNRNPA2B1 complexes in brains of Alzheimer subjects and P301S tau mice. These results reveal a novel complex containing oTau, HNRNPA2B1 and m6A that contributes to the integrated stress response of oTau.

Highlights

Development of a powerful method combining optical induction of tau oligomerization with precision mass spectrometry to obtain time resolved evolution of protein interaction networks.

Demonstration of a tripartite complex that links tau oligomers with HNRNPA2B1 and N6-methyladenosine modified RNA in cytoplasmic stress granules.

Knockdown of HNRNPA2B 1 abrogates the interactions of oTau with N6-methyladenosine modified RNA, as well as inhibits oTau-mediated neurodegeneration.

Discovery that N6-methyladenosine modified RNA is significantly increased in the brains of P301S tau transgenic mice and in patients with Alzheimer’s disease.
Redox Imbalance and Biochemical Changes in Cancer by probing redox-sensitive mitochondrial cytochromes in label-free visible resonance Raman imaging
Authors: Abramczyk H. , Brozek-Pluska B. , Kopec M. , Błaszczyk M. , Radek M.
Published: December 2020

Background

To monitoring redox state changes and biological mechanisms occurring in mitochondrial cytochromes in cancers improving novel methods are required.

Methods

We used Raman spectroscopy and Raman imaging to monitor changes in the redox state of the mitochondrial cytochromes in ex vivo human brain and breast tissues at 532 nm, 633 nm, 785 nm.

Results

We identified the oncogenic processes that characterize human infiltrating ductal carcinoma (IDC) and human brain tumors: gliomas; astrocytoma and medulloblastoma based on the quantification of cytochrome redox status by exploiting the resonance-enhancement effect of Raman scattering. We visualized localization of cytochromes by Raman imaging in the breast and brain tissues and analyzed cytochrome c vibrations at 750, 1126, 1337 and 1584 cm-1as a function of malignancy grade. We found that the concentration of reduced cytochrome c becomes abnormally high in human brain tumors and breast cancers and correlates with the grade of cancer aggressiveness.

Conclusions

We showed that Raman imaging provides additional insight into the biology of astrocytomas and breast ductal invasive cancer, which can be used for noninvasive grading, differential diagnosis, delineation of tumor extent, planning of surgery, and radiotherapy and post-treatment monitoring.

Simple Summary

Gliomas comprise around 30% of human brain tumors, while invasive ductal carcinoma (IDC) comprises around 80% of human breast cancers. The aim of our study was to show that cancerogenesis affects the redox status of mitochondrial cytochromes, which can be tracked by using Raman spectroscopy and imaging. We have shown the correlation between the intensity of cytochromes Raman bands at 750, 1126, 1337 and 1584 cm-1and malignancy grade for brain and breast cancers.

Graphical Abstract
TENT4A non-canonical poly(A) polymerase regulates DNA-damage tolerance via multiple pathways which are mutated in endometrial cancer
Authors: Swain Umakanta , Friedlander Gilgi , Sehrawat Urmila , Sarusi-Portuguez Avital , Rotkopf Ron , Ebert Charlotte , Paz-Elizur Tamar , Dikstein Rivka , Carell Thomas , Geacintov Nicholas , Livneh Zvi
Published: December 2020

TENT4A (PAPD7) is a non-canonical poly(A) polymerase, of which little is known. Here we show that TENT4A regulates multiple biological pathways, and focus on its multilayer regulation of translesion DNA synthesis (TLS), in which unrepaired DNA lesions are bypassed by error-prone DNA polymerases. We show that TENT4A regulates mRNA stability and/or translation of DNA polymerase η and RAD18 E3 ligase, which guides the polymerase to replication stalling sites, and monoubiquitinates PCNA, thereby enabling recruitment of error-prone DNA polymerases to damaged DNA sites. Remarkably, in addition to the effect on RAD18 mRNA stability via controlling its poly(A) tail, TENT4A indirectly regulates RAD18 via the tumor suppressor CYLD, and via the long non-coding antisense RNAPAXIP1-AS2, which had no known function. Knocking down the expression ofTENT4AorCYLD, or overexpression ofPAXIP1-AS2led each to reduced amounts of the RAD18 protein and DNA polymerase η, leading to reduced TLS, highlightingPAXIP1-AS2as a new TLS regulator. Bioinformatics analysis revealed that TLS error-prone DNA polymerase genes and theirTENT4A-related regulators are frequently mutated in endometrial cancer genomes, suggesting that TLS is dysregulated in this cancer.