bluuebunny/crossref_metadata_2025 huggingface dataset:
What are the latest clinical findings regarding the association of neurotoxic brain antibodies found in the cerebrospinal fluid in patients with autoimmune disorders?
Authors: Arinuma Yoshiyuki
Published: April 2020

Purpose of review

Recently, experiments show that the autoantibodies with direct access to neurons following blood brain barrier (BBB) disruption destroy neurons and lead to remodeling in damaged neurons. These are critical steps in autoantibody-mediated central nervous system disorder called neuropsychiatric syndromes in systemic lupus erythematosus (NPSLE). The purpose of this review is to examine therapeutic opportunities to repress neuronal remodeling by microglia after acute neuronal injury by autoantibodies.

Recent findings

Recent studies have demonstrated that BBB disruption is a critical step for developing NPSLE, and serum anti-Sm antibodies have been significantly associated with BBB breakdown. In addition, it has been reported that antiglucose regulated protein-78 in patients with SLE also disrupt the BBB. Experiments with anti-N-methyl-d-aspartate antibodies show that HMGB1 and C1q were essential to activate microglia which, in turn, remodel damaged neurons in vivo. Interestingly treatment with angiotensin-converting enzyme inhibitor inactivated microglia and blunted neuronal remodeling as well as positively affected behavioral abnormalities.

BBB disruption, acute neuronal damage and neuronal remodeling by activated microglia are all critical steps for NPSLE development, and each step will afford novel therapeutic targets.
Introducing the National Drug Early Warning System
Authors: Artigiani Eleanor Erin , Wish Eric D.
Published: April 2020

Purpose of review

In 2013, NIH NIDA released a special funding opportunity to update and expand their longstanding Community Epidemiology Workgroup (CEWG) by creating a coordinating center for a new type of monitoring system that became the National Drug Early Warning System (NDEWS). This article provides an overview of four primary NDEWS components: core staff; an approach to detecting and monitoring emerging drug trends including community-based epidemiologists and national databases; small rapid follow-up studies; and innovative multimedia approaches for disseminating information.

Recent findings

The cornerstones for detecting and monitoring are the 1700+ member NDEWS Network and a coalition of local epidemiologists. Follow-up studies are designed with local researchers, practitioners, and policymakers to focus on local trends. Among NDEWS accomplishments are developing protocols for expanded urinalyses in high-risk populations and conducting follow-up studies with local collaborators in New Hampshire, New York, Ohio, Oregon, and a tribal nation in Minnesota.

During its first 6 years, NDEWS has advanced its mission to develop multidisciplinary collaborations and innovative technologies for identifying, monitoring, and following up on emerging drug trends and has contributed to the translation of science into practice.

Video abstract

http://links.lww.com/YCO/A55.
A Covid-19 case mortality rate without time delay systematics
Authors: Lieu Richard , Quenby Siobhan , Jiang Ally Bi-Zhu
Published: April 2020

Concerning the two approaches to the Covid-19 case mortality rate published in the literature, namely computing the ratio of (a) the daily number of deaths to a time delayed daily number of confirmed infections; and (b) the cumulative number of deaths to confirmed infections up to a certain time, both numbers having been acquired in the middle of an outbreak, it is shown that each suffers from systematic error of a different source. We further show that in the absence of detailed knowledge of the time delay distribution of (a), the true case mortality rate is obtained by pursuing method (b) at the end of the outbreak when the fate of every case has decisively been rendered. The approach is then employed to calculate the mean case mortality rate of 13 regions of China where every case has already been resolved. This leads to a mean rate of 0.527 ± 0.001 %.
A snapshot of SARS-CoV-2 genome availability up to 30thMarch, 2020 and its implications
Authors: Mavian Carla , Marini Simone , Prosperi Mattia , Salemi Marco
Published: April 2020

The SARS-CoV-2 pandemic has been growing exponentially, affecting nearly 900 thousand people and causing enormous distress to economies and societies worldwide. A plethora of analyses based on viral sequences has already been published, in scientific journals as well as through non-peer reviewed channels, to investigate SARS-CoV-2 genetic heterogeneity and spatiotemporal dissemination. We examined full genome sequences currently available to assess the presence of sufficient information for reliable phylogenetic and phylogeographic studies in countries with the highest toll of confirmed cases. Although number of-available full-genomes is growing daily, and the full dataset contains sufficient phylogenetic information that would allow reliable inference of phylogenetic relationships, country-specific SARS-CoV-2 datasets still present severe limitations. Studies assessing within country spread or transmission clusters should be considered preliminary at best, or hypothesis generating. Hence the need for continuing concerted efforts to increase number and quality of the sequences required for robust tracing of the epidemic.

Significance Statement

Although genome sequences of SARS-CoV-2 are growing daily and contain sufficient phylogenetic information, country-specific data still present severe limitations and should be interpreted with caution.
Long-term development of white matter fibre density and morphology up to 13 years after preterm birth
Authors: Kelly Claire E , Thompson Deanne K , Genc Sila , Chen Jian , Yang Joseph YM , Adamson Chris , Beare Richard , Seal Marc L , Doyle Lex W , Cheong Jeanie LY , Anderson Peter J
Published: April 2020

Background

It is well documented that infants born very preterm (VP) are at risk of brain injury and altered brain development in the neonatal period, however there is a lack of long-term, longitudinal studies on the effects of VP birth on white matter development over childhood. Most previous studies were based on voxel-averaged, non-fibre-specific diffusion magnetic resonance imaging (MRI) measures, such as fractional anisotropy. In contrast, the novel diffusion MRI analysis framework, fixel-based analysis (FBA), enables whole-brain analysis of microstructural and macrostructural properties of individual fibre populations at a sub-voxel level. We applied FBA to investigate the long-term implications of VP birth and associated perinatal risk factors on fibre development in childhood and adolescence.

Methods

Diffusion images were acquired for a cohort of VP (born <30 weeks’ gestation) and full-term (FT, ≥37 weeks’ gestation) children at two ages: mean (SD) 7.6 (0.2) years (n=138 VP and 32 FT children) and 13.3 (0.4) years (n=130 VP and 45 FT children). 103 VP and 21 FT children had images at both ages for longitudinal analysis. At every fixel (individual fibre population within an image voxel) across the white matter, we compared FBA metrics (fibre density (FD), cross-section (FC) and a combination of these properties (FDC)) between VP and FT groups cross-sectionally at each age, and longitudinally between ages. We also examined associations between perinatal risk factors and FBA metrics in the VP group.

Results

Compared with FT children, VP children had lower FD, FC and FDC throughout the white matter, particularly in the corpus callosum, tapetum, inferior fronto-occipital fasciculus, fornix and cingulum at ages 7 and 13 years, as well as the motor pathways at age 13 years. VP children also had slower FDC development in the corpus callosum and corticospinal tract between ages 7 and 13 years compared with FT children. Within VP children, earlier gestational age at birth, lower birth weight z-score, and neonatal brain abnormalities were associated with lower FD, FC and FDC throughout the white matter at both ages.

Conclusions

VP birth and concomitant perinatal risk factors are associated with fibre tract-specific alterations to axonal development in childhood and adolescence.
Viral Induced Genetics Revealed by Multi-Dimensional Precision Medicine Transcriptional Workflow
Authors: Prokop Jeremy W , Gupta Ruchir , Leimanis Mara L. , Nedveck Derek , Shankar Rama , Uhl Katie , Chen Bin , Hartog Nicholas L. , Van Veen Jason , Sisco Joshua S. , Sirpilla Olivia , Lydic Todd , Boville Brian , Hernandez Angel , Braunreiter Chi , Kuk ChiuYing Cynthia , Singh Varinder , Mills Joshua , Wegener Marc , Adams Marie , Rhodes Mary , Bachmann Andre S , Pan Wenjing , Byrne-Steele Miranda L. , Smith D. Casey , Depinet Mollye , Brown Brittany E. , Eisenhower Mary , Han Jian , Haw Marcus , Madura Casey , Sanfilippo Dominic J , Seaver Laurie H. , Bupp Caleb , Rajasekaran Surender
Published: April 2020

Precision medicine requires the translation of basic biological understanding to medical insights, mainly applied to characterization of each unique patient. In many clinical settings, this requires tools that can be broadly used to identify pathology and risks. Patients often present to the intensive care unit with broad phenotypes, including multiple organ dysfunction syndrome (MODS) resulting from infection, trauma, or other disease processes. Etiology and outcomes are unique to individuals, making it difficult to cohort patients with MODS, but presenting a prime target for testing/developing tools for precision medicine. Using multi-time point whole blood (cellular/acellular) total transcriptomics in 27 patients, we highlight the promise of simultaneously mapping viral/bacterial load, cell composition, tissue damage biomarkers, balance between syndromic biology vs. environmental response, and unique biological insights in each patient using a single platform measurement. Integration of a transcriptome workflow yielded unexpected insights into the complex interplay between host genetics and viral/bacterial specific mechanisms, highlighted by a unique case of virally induced genetics (VIG) within one of these 27 patients. The power of RNAseq to study unique patient biology while investigating environmental contributions can be a critical tool moving forward for translational sciences applied to precision medicine.

One Sentence Summary

RNAseq shows the potential of a multidimensional workflow to define molecular signatures for precision/individualized medicine within the pediatric intensive care unit, identifying mechanisms such as viral-induced dominant genetics and infection signatures.
Confronting COVID-19: Surging critical care capacity in Italy
Authors: Rodriguez-Llanes Jose M , Delgado Rafael Castro , Pedersen Morten Gram , González Pedro Arcos , Meneghini Matteo
Published: April 2020

The current spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Europe threats Italian’s capacity and that of other national health systems to effectively respond to the needs of patients who require intensive care, mostly due to pneumonia and derived complications from concomitant disease and age. Predicting the surge in capacity has proved difficult due to the requirement of a subtle combination of diverse expertise and difficult choices to be made on selecting robust measures of critical care utilization, and parsimonious epidemic modelling which account for changing government measures. We modelled the required surge capacity of ICU beds in Italy exclusively for COVID-19 patients at epidemic peak. Because new measures were imposed by the Italian government, suspending nearly all non-essential sectors of the economy, we included the potential impacts of these new measures. The modelling considered those hospitalized and home isolated as quarantined, mimicking conditions on the ground. The percentage of patients in intensive care (out of the daily active confirmed cases) required for our calculations were chosen based on clinical relevance and robustness, and this number was consistently on average 9·9% from February 24 to March 6, 2020. Five different scenarios were produced (two positive and three negative). Under most positive scenarios, in which R0 is reduced below 1 (i.e., 0 ·71), the number of daily active confirmed cases will peak at nearly 89 000 by the early days of April and the total number of intensive care beds exclusively dedicated to COVID-19 patients required in Italy estimated at 8791. Worst scenarios produce unmanageable numbers. Our results suggest that the decisive moment for Italy has come. Jointly reinforcement by the government of the measures approved so far, including home confinement, but even more important the full commitment of the civil society in respecting home confinement, social distancing and hygiene will be key in the next days. Yet, even under the best circumstances, intensive care capacity will need to get closer to 9000 units in the country to avoid preventable mortality. So far, only strong measures were effective in Italy, as shown by our modelling, and this may offer an opportunity to European countries to accelerate their interventions.
Disability-Adjusted Life-Years (DALYs) for Breast Cancer and Risk Factors in 195 countries: Findings from Global Burden of Disease Study 2017
Authors: Liu Jieyu , Wang Jiaxiang
Published: April 2020

Background

Breast cancer is a leading cancer burden for females. In order to picture the patterns and time trends of the breast cancer burden across different regions, the disability-adjusted life years (DALYs) were used to estimate breast cancer burden in 1990–2017.

Methods

Data from Global Burden of Disease Study 2017 (GBD 2017) was used to estimate the disability-adjusted life-years (DALYs) for the burden of breast cancer by locations, regions, years (with corresponding 95% uncertainty intervals [UI]). Besides, the associated potentially modifiable risk factors were estimated to provide targeted means for controlling the burden of breast cancer.

Results

All-age numbers of DALYs reached over 17.42 million years in 2017 globally, despite the decreasing trends in all-age and age-standardized rate. The rates for DALYs was the highest in Western Sub-Saharan Africa [694.23 (534.43 to 906.05)] in 2017. High fasting plasma glucose [1.07 million (0.20 to 2.43) DALYs] and high body-mass index (BMI) [0.81 million (0.27 to 1.53) DALYs] have become great attributors to DALYs of breast cancer in 2017.

Conclusions

The levels and trends in causes of DALYs of breast cancer, generally show similiarities between 2007 and 2017, although differences exist. The differences observed countries can be attributed high fasting plasma glucose and high body-mass index across the world. Concerned efforts at national and regional levels are required to tackle the emerging burden of breast cancer in the world.
Topological Analysis of SARS CoV-2 Main Protease
Authors: Estrada Ernesto
Published: April 2020

There is an urgent necessity of effective medication against SARS CoV-2, which is producing the COVID-19 pandemic across the world. Its main protease (Mpro) represents an attractive pharmacological target due to its involvement in essential viral functions. The crystal structure of free Mproshows a large structural resemblance with the main protease of SARS CoV (nowadays known as SARS CoV-1). Here we report that as average SARS CoV-2 Mprois 1900% more sensitive than SARS CoV-1 Mproin transmitting tiny structural changes across the whole protein through long-range interactions. The largest sensitivity of Mproto structural perturbations is located exactly around the catalytic site Cys-145, and coincides with the binding site of strong inhibitors. These findings, based on a simplified representation of the protein as a residue network, may help in designing potent inhibitors of SARS CoV-2 Mpro.

The main protease of the new coronavirus SARS CoV-2 represents one of the most important targets for the antiviral pharmacological actions againsts COVID-19. This enzyme is essential for the virus due to its proteolytic processing of polyproteins. Here we discover that the main protease of SARS CoV-2 is topologically very similar to that of the SARS CoV-1. This is not surprising taking into account that both proteases differ only in 12 amino acids. However, we remarkable found a topological property of SARS CoV-2 that has increased in more than 1900% repect to its SARS CoV-1 analogue. This property reflects the capacity of the new protease of transmitting perturbations across its domains using long-range interactions. Also remarkable is the fact that the amino acids displaying such increased sensitivity to perturbations are around the binding site of the new protease, and close to its catalytic site. We also show that this sensititivy to perturbations is related to the effects of powerful protease inhibitors. In fact, the strongest inhibitors of the SARS CoV-2 main protease are those that produce the least change of this capacity of transmitting perturbations across the protein. We think that these findings may help in the design of new potent anti-SARS CoV-2 inhibitors.
Bacterial lipoproteins induce distinct IL-8 inductions relying on their lipid moieties in pulmonary epithelial cells
Authors: Woo Sang Su
Published: April 2020

Pulmonary epithelial cells play a crucial role in host defense against bacterial insult. However, the innate immunity in pulmonary epithelium is relatively less characterized than that of professional immune cells. In the current study, we investigated IL-8 induction by bacterial cell wall components in human lung epithelial A549 cells and primary human bronchial epithelial cells. We found that lipoproteins are the most potent IL-8 inducers among bacterial cell wall components. Using synthetic lipopeptides that mimic bacterial lipoprotein pam2CSK4 and pam3CSK4, we further investigated signal transduction mechanism. Interestingly, IL-8 secretion appeared higher upon diacylated pam2CSK4 treatment than triacylated pam3CSK4. A role of TLR2 in lipopeptide-induced IL-8 secretion was monitored by siRNA transfection and functional blocking antibodies. We found that TLR2 in A549 cell localizes to intracellular compartment. Activation mechanism for the intracellular TLR2 differed between pam2CSK4 and pam3CSK4. Pam2CSK4 utilized a lipid-raft dependent mechanism while pam3CSK4 utilizes clathrin-dependnet endocytosis. Using CHO/CD14/TLR2 cell line, we found the distinct IL-8 induction level initiates at the receptor activation level. Subsequent pharmacological inhibitor studies showed that pam2CSK4 and pam3CSK4 utilizes different MAPK pathways. Downstream transcription factor activation was determined by electro-mobility shift assay (EMSA) and luciferase reporter assays. The results showed distinct pattern of activation for NF-κB, NF-IL6 and AP-1 from human IL-8 promoter. These results suggest that bacterial lipoproteins from cell walls are an important determinant in initiating tissue inflammation in pulmonary epithelium upon bacterial insult.
Food intake dependent and independent effects of heat stress on lactation and mammary gland development
Authors: Xiao Yao , Kronenfeld Jason M. , Renquist Benjamin J.
Published: April 2020

With a growing population, a reliable food supply is increasingly important. Heat stress reduces livestock meat and milk production. Genetic selection of high producing animals increases endogenous heat production, while climate change increases exogenous heat exposure. Both sources of heat exacerbate the risk of heat-induced depression of production. Rodents are valuable models to understand mechanisms conserved across species. Heat exposure suppresses feed intake across homeothermic species including rodents and production animal species. We assessed the response to early-mid lactation or late gestation heat exposure on milk production and mammary gland development/function, respectively. Using pair-fed controls we experimentally isolated the food intake dependent and independent effects of heat stress on mammary function and mass. Heat exposure (35°C, relative humidity 50%) decreased daily food intake. When heat exposure occurred during lactation, hypophagia accounted for approximately 50% of the heat stress induced hypogalactia. Heat exposure during middle to late gestation suppressed food intake, which was fully responsible for the lowered mammary gland weight of dams at parturition. However, the impaired mammary gland function in heat exposed dams measured by metabolic rate and lactogenesis could not be explained by depressed food consumption. In conclusion, mice recapitulate the depressed milk production and mammary gland development observed in dairy species while providing insight regarding the role of food intake. This opens the potential to apply genetic, experimental and pharmacological models unique to mice to identify the mechanism by which heat is limiting animal production.

Summary Statements

This study demonstrates that heat stress decreases lactation and mammary development through food intake dependent and independent mechanisms.
Virologic and clinical characteristics for prognosis of severe COVID-19: a retrospective observational study in Wuhan, China
Authors: Fu Sha , Fu Xiao-yu , Song Yang , Li Min , Pan Pin-hua , Tang Tao , Zhang Chun-hu , Jiang Tie-jian , Tan De-ming , Fan Xue-gong , Sha Xin-ping , Ma Jing-dong , Huang Yan , Li Sha-ling , Zheng Yi-xiang , Qian Zhao-xin , Xiong Zeng , Xiao Li-zhi , Long Hui-bao , Chen Jiang-hai , Ouyang Yi
Published: April 2020

Background

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has progressed to a pandemic associated with substantial morbidity and mortality. The WHO and the United States Center for Disease Control and Prevention (CDC) have issued interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19), but there is limited data on the virologic and clinical characteristics for prognosis of severe COVID-19.

Methods

A total of 50 patients with severe COVID-19 were divided into good and poor recovery groups. The dynamic viral shedding and serological characteristics of SARS-CoV-2 were explored. The risk factors associated with poor recovery and lung lesion resolutions were identified. In addition, the potential relationships among the viral shedding, the pro-inflammatory response, and lung lesion evolutions were characterized.

Results

A total of 58% of the patients had poor recovery and were more likely to have a prolonged interval of viral shedding. The longest viral shedding was 57 days after symptom onset. Older age, hyperlipemia, hypoproteinemia, corticosteroid therapy, consolidation on chest computed-tomography (CT), and prolonged SARS-CoV-2 IgM positive were all associated with poor recovery. Additionally, the odds of impaired lung lesion resolutions were higher in patients with hypoproteinemia, hyperlipemia, and elevated levels of IL-4 and ferritin. Finally, viral shedding and proinflammatory responses were closely correlated with lung lesion evolutions on chest CT.

Conclusions

Patients with severe COVID-19 have prolonged SARS-CoV-2 infection and delayed intermittent viral shedding. Older age, hyperlipemia, hypoproteinemia, corticosteroid usage, and prolonged SARS-CoV-2 IgM positive might be utilized as predicative factors for the patients with poor recovery.
A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease
Authors: Hendrickx Diana M , Garcia Pierre , Ashrafi Amer , Sciortino Alessia , Schmit Kristopher J , Kollmus Heike , Nicot Nathalie , Kaoma Tony , Vallar Laurent , Buttini Manuel , Glaab Enrico
Published: April 2020

Understanding Parkinson’s disease (PD) in particular in its earliest phases is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful to investigate PD progression. Here, we compare ventral midbrain transcriptomics profiles fromα-synuclein transgenic mice with a progressive, early PD-like striatum neurodegeneration across different ages using pathway, gene set and network analysis methods. Our study uncovers statistically significant altered genes across ages and between genotypes with known, suspected or unknown function in PD pathogenesis and key pathways associated with disease progression. Among those are genotype-dependent alterations associated with synaptic plasticity, neurotransmission, as well as mitochondria-related genes and dysregulation of lipid metabolism. Age-dependent changes were among others observed in neuronal and synaptic activity, calcium homeostasis, and membrane receptor signaling pathways, many of which linked to G-protein coupled receptors. Most importantly, most changes occurred before neurodegeneration was detected in this model, which points to a sequence of gene expression events that may be relevant for disease initiation and progression. It is tempting to speculate that molecular changes similar to those changes observed in our model happen in midbrain dopaminergic neurons before they start to degenerate. In other words, we believe we have uncovered molecular changes that accompany the progression from preclinical to early PD.
Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression
Authors: Wall Mark J. , Hill Emily , Huckstepp Robert , Barkan Kerry , Deganutti Giuseppe , Leuenberger Michele , Preti Barbara , Winfield Ian , Carvalho Sabrina , Suchankova Anna , Wei Haifeng , Safitri Dewi , Huang Xianglin , Imlach Wendy , La Mache Circe , Dean Eve , Hume Cherise , Hayward Stephanie , Oliver Jess , Zhao Fei-Yue , Spanswick David , Reynolds Christopher A. , Lochner Martin , Ladds Graham , Frenguelli Bruno G.
Published: April 2020

The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A1 receptors (A1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A1R-selective agonist, BnOCPA, is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A1Rs arises from BnOCPA’s unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A1R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism.

Short summary

We describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective Gα agonism.
Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation
Authors: Grieve Adam G , Yeh Yi-Chun , Zarcone Lucrezia , Breuning Johannes , Johnson Nicholas , Stříšovský Kvido , Brown Marion H , Parekh Anant B , Freeman Matthew
Published: April 2020

Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease, RHBDL2. We show that RHBDL2 prevents stochastic signalling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved, disease-linked proline residue is responsible for RHBDL2 recognising only the active conformation of Orai1, and cleavage by RHBDL2 is required to sharpen switch-like signalling triggered by store-operated calcium entry. Loss of RHBDL2 control of Orai1 causes severe dysregulation of CRAC channel effectors including transcription factor activation, inflammatory cytokine expression and T cell activation. We propose that this seek-and-destroy function may represent an ancient activity of rhomboid proteases in degrading unwanted signalling proteins.
Topological Analysis of Differential Effects of Ketamine and Propofol Anesthesia on Brain Dynamics
Authors: Varley Thomas F. , Denny Vanessa , Sporns Olaf , Patania Alice
Published: April 2020

Research has found that the vividness of conscious experience is related to brain dynamics. Despite both being anesthetics, propofol and ketamine produce different subjective states: we explore the different effects of these two anaesthetics on the structure of dynamic attractors reconstructed from electrophysiological activity recorded from cerebral cortex of two macaques. We used two methods: the first embeds the recordings in a continuous high-dimensional manifold on which we use topological data analysis to infer the presence of higher-order dynamics. The second reconstruction, an ordinal partition network embedding, allows us to create a discrete state-transition network, which is amenable to information-theoretic analysis and contains rich information about state-transition dynamics. We find that the awake condition generally had the “richest” structure, visiting the most states, the presence of pronounced higher-order structures, and the least deterministic dynamics. In contrast, the propofol condition had the most dissimilar dynamics, transitioning to a more impoverished, constrained, low-structure regime. The ketamine condition, interestingly, seemed to combine aspects of both: while it was generally less complex than the awake condition, it remained well above propofol in almost all measures. These results provide provides deeper and more comprehensive insights than what is typically gained by using point-measures of complexity.
Automatic subtyping of individuals with Primary Progressive Aphasia
Authors: Themistocleous Charalambos , Ficek Bronte , Webster Kimberly , den Ouden Dirk-Bart , Hillis Argye E. , Tsapkini Kyrana
Published: April 2020

Background

The classification of patients with Primary Progressive Aphasia (PPA) into variants is time-consuming, costly, and requires combined expertise by clinical neurologists, neuropsychologists, speech pathologists, and radiologists.

Objective

The aim of the present study is to determine whether acoustic and linguistic variables provide accurate classification of PPA patients into one of three variants: nonfluent PPA, semantic PPA, and logopenic PPA.

Methods

In this paper, we present a machine learning model based on Deep Neural Networks (DNN) for the subtyping of patients with PPA into three main variants, using combined acoustic and linguistic information elicited automatically via acoustic and linguistic analysis. The performance of the DNN was compared to the classification accuracy of Random Forests, Support Vector Machines, and Decision Trees, as well as expert clinicians’ classifications.

Results

The DNN model outperformed the other machine learning models with 80% classification accuracy, providing reliable subtyping of patients with PPA into variants and it even outperformed auditory classification of patients into variants by clinicians.

Conclusions

We show that the combined speech and language markers from connected speech productions provide information about symptoms and variant subtyping in PPA. The end-to-end automated machine learning approach we present can enable clinicians and researchers to provide an easy, quick and inexpensive classification of patients with PPA.
Neural dynamics of phoneme sequences: Position-invariant code for content and order
Authors: Gwilliams Laura , King Jean-Remi , Marantz Alec , Poeppel David
Published: April 2020

Speech consists of a continuously-varying acoustic signal. Yet human listeners experience it as a sequence of discrete units (phonemes and words). To identify how the brain continuously represents and updates speech units, we recorded two-hour magnetoencephalograms from 21 subjects listening to short narratives. Our encoding and decoding analyses show that the human brain uses a dynamic coding scheme to represent approximately three successive phonetic features at each time sample. These dynamic phonetic representations, not directly accessible from the acoustic signal, are active earlier when phonemes are more predictable, and are sustained when lexical identity is uncertain. The results reveal how phoneme sequences in natural speech are neurally represented and shed new light on how the human brain combines them to probe the mental lexicon.

One sentence summary

The human brain keeps track of the relative order of speech sound sequences by jointly encoding content and elapsed processing time
Microbial dark matter driven degradation of carbon fiber polymer composites
Authors: Breister Adam M. , Imam Muhammad A. , Zhou Zhichao , Anantharaman Karthik , Prabhakar Pavana
Published: April 2020

Polymer composites have become attractive for structural applications in the built environment due to their lightweight and high strength properties but can suffer from degradation due to environmental factors. While impacts of abiotic factors like temperature and moisture are well studied, little is known about the influence of naturally occurring microbial communities on their structural integrity. Here we apply complementary time-series multi-omics of biofilms growing on polymer composites and materials characterization to elucidate, for the first time, the processes driving their degradation. We measured a reduction in mechanical properties due to molecular chain breakage and reconstructed 121 microbial genomes to describe microbial diversity and pathways associated with their degradation. The composite microbiome is dominated by four bacterial groups including the Candidate Phyla Radiation that possess pathways for breakdown of acrylate, esters, and bisphenol, abundant in composites. Overall, we provide a foundation for understanding interactions of next-generation structural materials with their natural environment that can predict their durability and drive future designs.
Neural mechanisms underlying distractor inhibition on the basis of feature and/or spatial expectations
Authors: van Moorselaar Dirk , Daneshtalab Nasim , Slagter Heleen A.
Published: April 2020

A rapidly growing body of research indicates that inhibition of distracting information may not be under flexible, top-down control, but instead heavily relies on expectations derived from past experience about the likelihood of events. Yet, how expectations about distracting information influence distractor inhibition at the neural level remains unclear. To determine how expectations induced by distractor features and/or location regularities modulate distractor processing, we measured EEG while participants performed two variants of the additional singleton paradigm. Critically, in these different variants, target and distractor features either randomly swapped across trials, or were fixed, allowing for the development of distractor feature-based expectations. Moreover, the task was initially performed without any spatial regularities, after which a high probability distractor location was introduced. Our results show that both distractor feature- and location regularities contributed to distractor inhibition, as indicated by corresponding reductions in distractor costs during visual search and an earlier distractor-evoked Pd component. Yet, control analyses showed that while observers were sensitive to regularities across longer time scales, the observed effects to a large extent reflected intertrial repetition. Large individual differences further suggest a functional dissociation between early and late Pd components, with the former reflecting early sensory suppression related to intertrial priming and the latter reflecting suppression sensitive to expectations derived over a longer time scale. Also, counter to some previous findings, no increase in anticipatory alpha-band activity was observed over visual regions representing the expected distractor location, although this effect should be interpreted with caution as the effect of spatial statistical learning was also less pronounced than in other studies. Together, these findings suggest that intertrial priming and statistical learning may both contribute to distractor suppression and reveal the underlying neural mechanisms.
CovProfile: profiling the viral genome and gene expressions of SARS-COV-2
Authors: Yu Yonghan , Li Zhengtu , Li Yinhu , Yu Le , Jia Wenlong , Jiang Yiqi , Ye Feng , Li Shuai Cheng
Published: April 2020

The SARS-CoV-2 virus has infected more than one million people worldwide to date. Knowing its genome and gene expressions is essential to understand the virus’ mechanism. Here, we propose a computational tool CovProfile to detect the viral genomic variations as well as viral gene expressions from the sequences obtained from Nanopore devices. We applied CovProfile to 11 samples, each from a terminally ill patient, and discovered that all the patients are infected by multiple viral strains, which might affect the reliability of phylogenetic analysis. Moreover, the expression of viral genes ORF1ab gene, S gene, M gene, and N gene are high among most of the samples. While performing the tests, we noticed a consistent abundance of transcript segments of MUC5B, presumably from the host, across all the samples.
Natural gene drives offer potential pathogen control strategies in plants
Authors: Gardiner Donald M. , Rusu Anca , Barrett Luke , Hunter Gavin C. , Kazan Kemal
Published: April 2020

Globally, fungal pathogens cause enormous crop losses and current control practices are not always effective, economical or environmentally sustainable. Tools enabling genetic management of wild pathogen populations could potentially solve many problems associated with plant diseases.

A natural gene drive from a heterologous species can be used in the globally important cereal pathogen,Fusarium graminearum, to remove pathogenic traits from contained populations of the fungus. The gene drive element became fixed in a freely crossing populations in only three generations.

Repeat induce point mutation, a natural genome defence mechanism in fungi, may be useful to recall the gene drive following release, should a failsafe mechanism be required.

We propose that gene drive technology is a potential tool to control plant pathogens.
Contact lenses can cause the reverse Pulfrich effect and anti-Pulfrich monovision corrections can eliminate it
Authors: Rodriguez-Lopez Victor , Dorronsoro Carlos , Burge Johannes
Published: April 2020

Interocular differences in image blur can cause dramatic misperceptions of the distance and three-dimensional direction of moving objects. This new illusion—the reverse Pulfrich effect—is caused by the optical conditions induced by monovision, a common correction for presbyopia. Fortunately, anti-Pulfrich monovision corrections, in which the blurring lens is slightly darkened, can eliminate the illusion for a wide range of viewing conditions. However, the reverse Pulfrich effect and the efficacy of anti-Pulfrich corrections have previously been demonstrated only with trial lenses. This situation should be addressed, for both clinical and scientific reasons. First, monovision is most commonly prescribed with contact lenses. It is important to replicate these effects in the most common monovision delivery system. Second, trial lenses of different powers, unlike contacts, cause large magnification differences between the eyes. To confidently attribute the reverse Pulfrich effect to differences in optical blur between the eyes, and to ensure that the reported effect sizes are reliable, one must control for magnification. Here, in a within observer study with five separate experiments, we demonstrate i) that contact lenses induce reverse Pulfrich effects that are indistinguishable from those induced by trial lenses, ii) that overall magnification differences do not cause or impact the Pulfrich effect, and iii) that anti-Pulfrich corrections (i.e. darkening the blurring lens) are equally effective when induced by contact lenses and by trial lenses.
Investigating TRSV Phytoalexin Infusions as a Novel Treatment for Alzheimer’s Disease Using ApoE4 Plasmid Transfections in Neuro2a Cell Complexes
Authors: Gandhi Om
Published: April 2020

Because the accumulation of amyloid plaques plays a central role in the pathogenesis of Alzheimer’s disease (AD) and is responsible for many of its neurodegenerative effects, this project aims to evaluate the effectiveness of TRSV phytoalexin infusions as a novel treatment for the disease by comparing three separate agents and determining its impact on the accumulation of amyloid plaques in mouse Neuro2a cells. The experimental model is as follows: Neuro2a cells were first thawed using incubation and centrifugation techniques. The subculturing protocol was then performed to maximize cellular viability using DPBS and TrypLE dissociation reagents. The cells were transfected with pCMV4-ApoE4 bacterial plasmid using Opti-MEM medium and Lipofectamine LTX while also being treated with phytoalexin agents. Bradford’s assay was performed on the samples using CBB G-250 reagent, and they were run through a spectrophotometer and a Python low-pass filter to generate readings. The experimental data showed that natural grape seed phytoalexin extract was the most effective treating agent, followed by curcumin extract and synthetic RDS phytoalexin. All treating agents lessened the accumulation of the amyloid plaques significantly, supporting the novel infusion protocol as a treatment for AD.
Natural image statistics at depth edges modulate perceptual stability
Authors: Başgöze Zeynep , White David N. , Burge Johannes , Cooper Emily A.
Published: April 2020

Binocular fusion relies on matching points in the two eyes that correspond to the same physical feature in the world. However, not all world features are binocularly visible. In particular, at depth edges parts of a scene are often visible to only one eye (so-calledhalf occlusions). Accurate detection of these monocularly visible regions is likely to be important for stable visual perception. If monocular regions are not detected as such, the visual system may attempt to binocularly fuse non-corresponding points, which can result in unstable percepts. We investigated the hypothesis that the visual system capitalizes upon statistical regularities associated with depth edges in natural scenes to aid binocular fusion and facilitate perceptual stability. By sampling from a large set of stereoscopic natural image patches, we found evidence that monocularly visible regions near depth edges in natural scenes tend to have features more visually similar to the adjacent binocularly visible background region than to the adjacent binocularly visible foreground. The generality of these results was supported by a parametric study of three-dimensional (3D) viewing geometry in simulated environments. In two perceptual experiments, we examined if this statistical regularity may be leveraged by the visual system. The results show that perception tended to be more stable when the visual properties of the depth edge were statistically more likely. Exploiting regularities in natural environments may allow the visual system to facilitate fusion and perceptual stability of natural scenes when both binocular and monocular regions are visible.

Precis

We report an analysis of natural scenes and two perceptual studies aimed at understanding how the visual statistics of depth edges impact perceptual stability. Our results suggest that the visual system exploits natural scene regularities to aid binocular fusion and facilitate perceptual stability.
Actin bundles play different role in shaping scale as compare to bristle in mosquitoAedes aegypti
Authors: Djokic Sanja , Anna Bakhrat , Zurim Ido , Urakova Nadya , Rasgon Jason L. , Abdu Uri
Published: April 2020

Insect epithelial cells contain cellular extensions such as bristles, hairs and scales. It has been suggested that these cellular extensions are homologous structures that differ in morphology and function. These cellular extensions contain actin bundles that dictate their cellular morphology; bristle and hair are cylindrical in shape, while scales are wider and flattened. While the organization, function and identity of the major actin bundling protein in bristles and hairs is known, this information in scales is unknown. In this study, we characterized the development of scales and the role of actin bundles in the mosquito,Aedes aegypti. We show that scales undergo drastic morphological changes during development, from cylindrical shape to flat shape with longer membrane invagination. Scale actin bundle distribution changes during development, from symmetrical organization of actin bundles located throughout the bristle membrane, to asymmetrical organization of the actin bundles. By chemically inhibiting actin polymerization and by knocking-out theforkedgene in the mosquito (Ae-Forked;a known actin bundling protein), by CRISPR-Cas9 gene editing, we showed that actin bundles are required for shaping bristle, hair and scale morphology. We demonstrated that actin bundles andAe-Forkedare required for bristle elongation, but not that of scales. In scales, actin bundles are required for width formation. Our results reveal a differential requirement of actin bundles in shaping mosquito scales compared to bristles.
Comparative analyses of two primate species diverged by more than 60 million years show different rates but similar distribution of genome-wide UV repair events
Authors: Akkose Umit , Kaya Veysel Ogulcan , Lindsey-Boltz Laura , Karagoz Zeynep , Brown Adam D. , Larsen Peter A. , Yoder Anne D. , Sancar Aziz , Adebali Ogun
Published: April 2020

Nucleotide excision repair is the primary DNA repair mechanism that removes bulky DNA adducts such as UV-induced pyrimidine dimers. Correspondingly, genome-wide mapping of nucleotide excision repair with eXcision Repair sequencing (XR-seq), provides comprehensive profiling of DNA damage repair. A number of XR-seq experiments at a variety of conditions for different damage types revealed heterogenous repair in the human genome. Although human repair profiles were extensively studied, how repair maps vary between primates is yet to be investigated. Here, we characterized the genome-wide UV-induced damage repair in gray mouse lemur,Microcebus murinus, in comparison to human. Mouse lemurs are strictly nocturnal, are the world’s smallest living primates, and last shared a common ancestor with humans at least 60 million years ago. We derived fibroblast cell lines from mouse lemur, exposed them to UV irradiation. The following repair events were captured genome-wide through the XR-seq protocol. Mouse lemur repair profiles were analyzed in comparison to the equivalent human fibroblast datasets. We found that overall UV sensitivity, repair efficiency, and transcription-coupled repair levels differ between the two primates. Despite this, comparative analysis of human and mouse lemur fibroblasts revealed that genome-wide repair profiles of the homologous regions are highly correlated. This correlation is stronger for the highly expressed genes. With the inclusion of an additional XR-seq sample derived from another human cell line in the analysis, we found that fibroblasts of the two primates repair UV-induced DNA lesions in a more similar pattern than two distinct human cell lines do. Our results suggest that mouse lemurs and humans, and possibly primates in general, share a homologous repair mechanism as well as genomic variance distribution, albeit with their variable repair efficiency. This result also emphasizes the deep homologies of individual tissue types across the eukaryotic phylogeny.