bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alcohol dependence activates ventral tegmental area projections to central amygdala in male mice and rats
Authors: Avegno Elizabeth M , Kasten Chelsea R , Snyder William B , Kelley Leslie K , Lobell Thomas D , Templeton Taylor J , Constans Michael , Wills Tiffany A , Middleton Jason W , Gilpin Nicholas W 
Published: November 2020

AbstractThe neural adaptations that occur during the transition to alcohol dependence are not entirely understood, but may include a gradual recruitment of brain stress circuitry by mesolimbic reward circuitry that is activated during early stages of alcohol use. Here, we focused on dopaminergic and non-dopaminergic projections from the ventral tegmental area (VTA), important for mediating acute alcohol reinforcement, to the central nucleus of the amygdala (CeA), important for alcohol dependence-related negative affect and escalated alcohol drinking. The VTA projects directly to the CeA, but the functional relevance of this circuit is not fully established. Therefore, we combined retrograde and anterograde tracing, anatomical, and electrophysiological experiments in mice and rats to demonstrate that the CeA receives input from both dopaminergic and non-dopaminergic projection neurons primarily from the lateral VTA. We then used slice electrophysiology and fos immunohistochemistry to test the effects of alcohol dependence on activity and activation profiles of CeA-projecting neurons in the VTA. Our data indicate that alcohol dependence activates midbrain projections to the central amygdala, suggesting that VTA projections may trigger plasticity in the CeA during the transition to alcohol dependence and that this circuit may be involved in mediating behavioral dysregulation associated with alcohol dependence.
Assessing uncertainty in connective field estimations from resting state fMRI activity
Authors: Invernizzi Azzurra , Gravel Nicolas , Haak Koen V. , Renken Remco J. , Cornelissen Frans W. 
Published: November 2020

AbstractConnective Field (CF) modeling estimates the local spatial integration between signals in distinct cortical visual field areas. As we have shown previously using 7T data, CF can reveal the visuotopic organization of visual cortical areas even when applied to BOLD activity recorded in the absence of external stimulation. This indicates that CF modeling can be used to evaluate cortical processing in participants in which the visual input may be compromised. Furthermore, by using Bayesian CF modelling it is possible to estimate the co-variability of the parameter estimates and therefore, apply CF modeling to single cases. However, no previous studies evaluated the (Bayesian) CF model using 3T resting-state fMRI data, although this is important since 3T scanners are much more abundant and more often used in clinical research than 7T ones. In this study, we investigate whether it is possible to obtain meaningful CF estimates from 3T resting state (RS) fMRI data. To do so, we applied the standard and Bayesian CF modeling approaches on two RS scans interleaved by the acquisition of visual stimulation in 12 healthy participants.Our results show that both approaches reveal good agreement between RS- and visual field (VF)-based maps. Moreover, the 3T observations were similar to those previously reported at 7T. In addition, to quantify the uncertainty associated with each estimate in both RS and VF data, we applied our Bayesian CF framework to provide the underlying marginal distribution of the CF parameters. Finally, we show how an additional CF parameter,beta, can be used as a data-driven threshold on the RS data to further improve CF estimates. We conclude that Bayesian CF modeling can characterize local functional connectivity between visual cortical areas from RS data at 3T. In particular, we expect the ability to assess parameter uncertainty in individual participants will be important for future clinical studies.HighlightsLocal functional connectivity between visual cortical areas can be estimated from RS-fMRI data at 3T using both standard CF and Bayesian CF modelling.Bayesian CF modelling quantifies the model uncertainty associated with each CF parameter on RS and VF data, important in particular for future studies on clinical populations.3T observations were qualitatively similar to those previously reported at 7T.
The Hsc70 Disaggregation Machinery Removes Monomer Units Directly from α-Synuclein Fibril Ends
Authors: Schneider Matthias M. , Gautam Saurabh , Herling Therese W. , Andrzejewska Ewa , Krainer Georg , Miller Alyssa M. , Peter Quentin A. E. , Ruggeri Francesco Simone , Vendruscolo Michele , Bracher Andreas , Dobson Christopher M. , Hartl F. Ulrich , Knowles Tuomas P. J. 
Published: November 2020

AbstractMolecular chaperones contribute to the maintenance of cellular protein homeostasis through a wide range of mechanisms, including the assistance ofde novoprotein folding, the rescue of misfolded proteins, and the prevention of amyloid formation. Chaperones of the Hsp70 family have a striking capability of disaggregating otherwise irreversible aggregate structures such as amyloid fibrils that accumulate during the development of neurodegenerative diseases. However, the mechanisms of this key emerging functionality remain largely unknown. Here, we bring together microfluidic measurements with kinetic analysis and show that that the Hsp70 protein heat chock complement Hsc70 together with its two co-chaperones DnaJB1 and the nucleotide exchange factor Apg2 is able to completely reverse the aggregation process of alpha-synuclein, associated with Parkinson’s disease, back to its soluble monomeric state. Moreover, we show that this reaction proceeds with first order kinetics in a process where monomer units are taken off directly from the fibril ends. Our results demonstrate that all components of the chaperone triad are essential for fibril disaggregation. Lastly, we quantify the interactions between the three chaperones as well as between the chaperones and the fibrils in solution, yielding both binding stoichiometries and dissociation constants. Crucially, we find that the stoichiometry of Hsc70 binding to fibrils suggests Hsc70 clustering at the fibril ends. Taken together, our results show that the mechanism of action of the Hsc70–DnaJB1–Apg2 chaperone system in disaggregating α-synuclein fibrils involves the removal of monomer units without any intermediate fragmentation steps. These findings are fundamental to our understanding of the suppression of amyloid proliferation early in life and the natural clearance mechanisms of fibrillar deposits in Parkinson’s disease, and inform on the possibilities and limitations of this strategy in the development of therapeutics against synucleinopathies and related neurodegenerative diseases.
Zinc-embedded fabrics inactivate SARS-CoV-2 and influenza A virus
Authors: Gopal Vikram , Nilsson-Payant Benjamin E. , French Hollie , Siegers Jurre Y. , Yung Wai-shing , Hardwick Matthew , te Velthuis Aartjan J.W. 
Published: November 2020

AbstractInfections with respiratory viruses can spread via liquid droplets and aerosols, and cause diseases such as influenza and COVID-19. Face masks and other personal protective equipment (PPE) can act as barriers that prevent the spread of respiratory droplets containing these viruses. However, influenza A viruses and coronaviruses are stable for hours on various materials, which makes frequent and correct disposal of these PPE important. Metal ions embedded into PPE may inactivate respiratory viruses, but confounding factors such as absorption of viruses make measuring and optimizing the inactivation characteristics difficult. Here we used polyamide 6.6 (PA66) fibers that had zinc ions embedded during the polymerisation process and systematically investigated if these fibers can absorb and inactivate pandemic SARS-CoV-2 and influenza A virus H1N1. We find that these viruses are readily absorbed by PA66 fabrics and inactivated by zinc ions embedded into this fabric. The inactivation rate (pfu·gram−1·min−1) exceeds the number of active virus particles expelled by a cough and supports a wide range of viral loads. Moreover, we found that the zinc content and the virus inactivating property of the fabric remain stable over 50 standardized washes. Overall, these results provide new insight into the development of “pathogen-free” PPE and better protection against RNA virus spread.
Elemental Mapping of Labeled Biological Specimens at Intermediate Energy Loss in an Energy-Filtered TEM acquired using a Direct Detection Device
Authors: Ramachandra Ranjan , Mackey Mason R. , Hu Junru , Peltier Steven T. , Xuong Nguyen-Huu , Ellisman Mark H. , Adams Stephen R. 
Published: November 2020

ABSTRACTThe multi-color or single-color EM that was developed previously, by the pseudo-colored overlay of the core-loss or high-loss EFTEM elemental map/s of the lanthanide onto the conventional image, the lanthanide chelates conjugated to diaminobenzidine being sequentially deposited as a result of selective oxidization by orthogonal photosensitizers / peroxidases. The synthesis of the new second generation lanthanide DABs, which contains 4 times more lanthanide per DAB, gives significant signal amplification and enabling collection of elemental maps at much lower energy-loss regions more favorable. Under the same experimental conditions, acquiring EFTEM elemental maps for the lanthanides at the lower energy-loss of N4,5edge instead of the core-loss M4,5edge, provides ~4x increase in signal-to-noise and ~2x increase in resolution. The higher signal at the N4,5edge, also allows for more sophisticated technique of EFTEM spectrum Image for the acquisition of elemental maps with very high signal fidelity.
Cervical cancer stem-like cell transcriptome profiles predict response to chemoradiotherapy
Authors: Zuccherato Luciana W. , Machado Christina M. T. , Magalhães Wagner C. S. , Martins Patrícia R. , Campos Larissa S. , Braga Letícia C. , Teixeira-Carvalho Andrea , Martins-Filho Olindo A. , Franco Telma M. R. F. , Paula Sálua O. C. , de Silva Israel Tojal , Drummond Rodrigo , Gollob Kenneth J. , Salles Paulo Guilherme O. 
Published: November 2020

ABSTRACTCervical cancer (CC) represents a major global health issue, particularly impacting women from resource constrained regions worldwide. Treatment refractoriness to standard chemo-radiotherapy has identified cancer stem cells as critical coordinators behind the biological mechanisms of resistance, contributing to CC recurrence. In this work, we evaluated differential gene expression in cervical cancer stem-like cells (CCSC) as biomarkers related to intrinsic chemoradioresistance in CC. A total of 31 patients with locally advanced CC and referred to Mario Penna Institute (Belo Horizonte, Brazil) from August 2017 to May 2018 were recruited for the study. Fluorescence-activated cell sorting (FACS) was used to enrich CD34+/CD45-CCSC from tumor biopsies. Transcriptome was performed using ultra-low input RNA sequencing and differentially expressed genes (DEGs) using Log2 fold differences and adjusted p value < 0.05 were determined. A panel of biomarkers was selected using the rank-based AUC (Area Under the ROC Curve) and pAUC (partial AUC) measurements for diagnostic sensitivity and specificity. The analysis showed 1062 DEGs comparing between the Non-Responder (n=10) and Responder (n=21) groups to chemoradiotherapy. Overlapping of the 20 highest AUC and pAUC values revealed five transcripts potentially implicated in innate chemoresistance (ILF2, SNX2, COPZ1, AC016722.1 and AL360175.1). This study identifies DEG signatures that serve as potential biomarkers in CC prognosis and treatment outcome, as well as identifies potential alternative targets for cancer therapy.
Community interventions for people with complex emotional needs that meet the criteria for ‘personality disorder’ diagnoses: a systematic review of economic evaluations
Authors: Botham Joe , Clark Amy , Steare Thomas , Stuart Ruth , Oram Sian , Lloyd-Evans Brynmor , Jeynes Tamar , Broeckelmann Eva , Crawford Mike , Johnson Sonia , Simpson Alan , McCrone Paul 
Published: November 2020

AbstractBackgroundDiagnoses of “personality disorder” are prevalent among people using community secondary mental health services. Whilst the effectiveness of a range of community-based treatments have been considered, as the NHS budget is finite, it is also important to consider the cost-effectiveness of those interventions.AimsTo assess the cost-effectiveness of primary or secondary care community-based interventions for people with complex emotional needs that meet criteria for a diagnosis of “personality disorder” to inform healthcare policy making.MethodSystematic review (PRESPORO #: CRD42020134068) of five databases, supplemented by reference list screening and citation tracking of included papers. We included economic evaluations of interventions for adults with complex emotional needs associated with a diagnosis of ‘personality disorder’ in community mental health settings published between before 18 September 2019. Study quality was assessed using the CHEERS statement. Narrative synthesis was used to summarise study findings.ResultsEighteen studies were included. The studies mainly evaluated psychotherapeutic interventions. Studies were also identified which evaluated altering the setting in which care was delivered and joint crisis plans. No strong economic evidence to support a single intervention or model of community-based care was identified.ConclusionThere is no robust economic evidence to support a single intervention or model of community-based care for people with complex emotional needs. The review identified the strongest evidence for Dialectical Behavioural Therapy with all three identified studies indicating the intervention is likely to be cost-effective in community settings compared to treatment as usual. Further research is needed to provide robust evidence on the cost-effectiveness of community-based interventions upon which decision makers can confidently base guidelines or allocate resources.
T2 heterogeneity as anin vivomarker of microstructural integrity in medial temporal lobe subfields in ageing and mild cognitive impairment
Authors: Wearn Alfie R. , Nurdal Volkan , Saunders-Jennings Esther , Knight Michael J. , Madan Christopher R. , Fallon Sean-James , Isotalus Hanna K. , Kauppinen Risto A. , Coulthard Elizabeth J. 
Published: November 2020

ABSTRACTA better understanding of early brain changes that precede loss of independence in diseases like Alzheimer’s disease (AD) is critical for development of disease-modifying therapies. Quantitative MRI, such as T2 relaxometry, can identify microstructural changes relevant to early stages of pathology. Recent evidence suggests heterogeneity of T2 may be a more informative measure of early pathology than absolute T2. Here we test whether T2 markers of brain integrity precede the volume changes we know are present in established AD and whether such changes are most marked in medial temporal lobe (MTL) subfields known to be most affected early in AD. We show that T2 heterogeneity was greater in people with mild cognitive impairment (MCI; n=49) compared to healthy older controls (n=99) in all MTL subfields, but this increase was greatest in MTL cortices, and smallest in dentate gyrus. This reflects the spatio-temporal progression of neurodegeneration in AD. T2 heterogeneity in the entorhinal cortex also predicted cognitive decline over a year in people with MCI, where measures of volume or T2 in any other subfield or whole hippocampus could not. Increases in T2 heterogeneity in MTL cortices may reflect localised pathological change and may present as one of the earliest detectible brain changes prior to atrophy. Finally, we describe a mechanism by which memory, as measured by accuracy and reaction time on a paired associate learning task, deteriorates with age. Age-related memory deficits were explained in part by lower subfield volumes, which in turn were directly associated with greater T2 heterogeneity. We propose that tissue with high T2 heterogeneity represents extant tissue at risk of permanent damage but with the potential for therapeutic rescue. This has implications for early detection of neurodegenerative disease.
Test-adjusted results of mortality for Covid-19 in Germany, USA, UK
Authors: Mimkes Jürgen , Janssen Rainer 
Published: November 2020

AbstractIn a disease, where all infected persons show symptoms, it is reasonable to calculate mortality by case to fatality rate CFR. Deaths follow infections by a certain time lag. However, in the Covid-19 pandemic many infectious patients show no or hardly any symptoms. The reported infections and deaths do not run parallel, but diverge with the volume of tests.Our investigations for Germany, USA and UK indicate that deaths do not follow the number of infections, but the positive rate of tests, multiplied by a constant factor F and shifted by about two weeks. These test adjusted results of mortality allow for the estimation of the number of deaths of Covid-19 about two weeks ahead, even in a sharply rising state of the pandemic. This gives medical authorities two weeks of time to plan for resources.
Intraspecific variation in symbiont density in an insect-microbe symbiosis
Authors: Parker Benjamin J. , Hrček Jan , McLean Ailsa H.C. , Brisson Jennifer A. , Godfray H. Charles J. 
Published: November 2020

AbstractMany insects host vertically-transmitted microbes, which can confer benefits to their hosts but are costly to maintain and regulate. A key feature of these symbioses is variation: for example, symbiont density can vary among host and symbiont genotypes. However, the evolutionary forces maintaining this variation remain unclear. We studied variation in symbiont density using the pea aphid (Acyrthosiphon pisum) and the bacteriumRegiella insecticola, a symbiont that can protect its host against fungal pathogens. We found that relative symbiont density varies both between twoRegiellaphylogenetic clades and among aphid ‘biotypes’. Higher-density symbiont infections are correlated with stronger survival costs, but variation in density has little effect on the protectionRegiellaprovides against fungus. Instead, we found that in some aphid genotypes, a dramatic decline in symbiont density precedes the loss of a symbiont infection. Together, our data suggest that the optimal density of a symbiont infection is likely different from the perspective of aphid and microbial fitness.Regiellamight prevent loss by maintaining high within-host densities, but hosts do not appear to benefit from higher symbiont numbers and may be advantaged by losing costly symbionts in certain environments. The standing variation in symbiont density observed in natural populations could therefore be maintained by antagonistic coevolutionary interactions between hosts and their symbiotic microbes.
RESTORING CONNEXIN-36 FUNCTION IN DIABETOGENIC ENVIRONMENTS PRECLUDES MOUSE AND HUMAN ISLET DYSFUNCTION
Authors: St. Clair Joshua R , Westacott Matthew J , Miranda Jose , Farnsworth Nikki L , Kravets Vira , Schleicher Wolfgang E , Dwulet JaeAnn M , Levitt Claire H , Heintz Audrey , Ludin Nurin WF , Benninger Richard KP 
Published: November 2020

ABSTRACTThe secretion of insulin from β-cells in the islet of Langerhans is governed by a series of metabolic and electrical events, which can fail during the progression of type2 diabetes (T2D). β-cells are electrically coupled via Cx36 gap junction channels, which coordinates the pulsatile dynamics of [Ca2+] and insulin release across the islet. Factors such as pro-inflammatory cytokines and free fatty acids disrupt gap junction coupling under invitro conditions. Here we test whether gap junction coupling and coordinated [Ca2+] dynamics are disrupted in T2D, and whether recovery of gap junction coupling can recover islet function. We examine islets from donors with T2D, from db/db mice, and islets treated with proinflammatory cytokines (TNF-α, IL-1β, IFN-ɣ) or free fatty acids (palmitate). We modulate gap junction coupling using Cx36 over-expression or pharmacological activation via modafinil. We also develop a peptide mimetic (S293) of the c-terminal regulatory site of Cx36 designed to compete against its phosphorylation. Cx36 gap junction permeability and [Ca2+] dynamics were disrupted in islets from both human donors with T2D and db/db mice, and in islets treated with proinflammatory cytokines or palmitate. Cx36 over-expression, modafinil treatment and S293 peptide all enhanced Cx36 gap junction coupling and protected against declines in coordinated [Ca2+] dynamics. Cx36 over-expression and S293 peptide also reduced apoptosis induced by proinflammatory cytokines. Critically S293 peptide rescued gap junction coupling and [Ca2+] dynamics in islets from both db/db mice and a sub-set of T2D donors. Thus, recovering or enhancing Cx36 gap junction coupling can improve islet function in diabetes.KEY POINTS- Cx36 gap junction permeability and associated coordination of [Ca2+] dynamics is diminished in human type 2 diabetes (T2D) and mouse models of T2D.- Enhancing Cx36 gap junction permeability protects against disruptions to the coordination of [Ca2+] dynamics.- A novel peptide mimetic of the Cx36 c-terminal regulatory region protects against declines in Cx36 gap junction permeability.- Pharmacological elevation in Cx36 or Cx36 peptide mimetic recovers [Ca2+] dynamics and GSIS in human T2D and mouse models of T2D.
Integrating real-time data analysis into automatic tracking of social insect behavior
Authors: Sclocco Alessio , Ong Shirlyn Jia Yun , Aung Sai Yan Pyay , Teseo Serafino 
Published: November 2020

AbstractAutomatic video tracking has become a standard tool for investigating the social behavior of insects. The recent integration of computer vision in tracking technologies will likely lead to fully automated behavioral pattern classification within the next few years. However, most current systems rely on offline data analysis and use computationally expensive techniques to track pre-recorded videos. To address this gap, we developed BACH (Behavior Analysis maCHine), a software that performs video tracking of insect groups in real time. BACH uses object recognition via convolutional neural networks and identifies individually tagged insects via an existing matrix code recognition algorithm. We compared the tracking performances of BACH and a human observer across a series of short videos of ants moving in a 2D arena. We found that, concerning computer vision-based ant detection only, BACH performed only slightly worse than the human observer. Contrarily, individual identification only attained human-comparable levels when ants moved relatively slow, and fell when ants walked relatively fast. This happened because BACH had a relatively low efficiency in detecting matrix codes in blurry images of ants walking at high speeds. BACH needs to undergo hardware and software adjustments to overcome its present limits. Nevertheless, our study emphasizes the possibility of, and the need for, integrating real time data analysis into the study of animal behavior. This will accelerate data generation, visualization and sharing, opening possibilities for conducting fully remote collaborative experiments.