bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of high intensity interval exercise on cerebrovascular function: A systematic review
Authors: Whitaker Alicen A , Alwatban Mohammed , Freemyer Andrea , Perales-Puchalt Jaime , Billinger Sandra A
Published: May 2020

High intensity interval exercise (HIIE) improves aerobic fitness with decreased exercise time compared to moderate continuous exercise. A gap in knowledge exists regarding the effects of HIIE on cerebrovascular function such as cerebral blood velocity and autoregulation. The objective of this systematic review was to ascertain the effect of HIIE on cerebrovascular function in healthy individuals. We searched PubMed and the Cumulative Index to Nursing and Allied Health Literature databases with apriori key words. We followed the Preferred Reporting Items for Systematic Reviews. Twenty articles were screened and thirteen articles were excluded due to not meeting the apriori inclusion criteria. Seven articles were reviewed via the modified Sackett’s quality evaluation. Outcomes included middle cerebral artery blood velocity (MCAv) (n=4), dynamic cerebral autoregulation (dCA) (n=2), cerebral de/oxygenated hemoglobin (n=2), cerebrovascular reactivity to carbon dioxide (CO2) (n=2) and cerebrovascular conductance/resistance index (n=1). Quality review was moderate with 3/7 to 5/7 quality criteria met. HIIE acutely lowered exercise MCAv compared to moderate intensity. HIIE decreased dCA phase following acute and chronic exercise compared to rest. HIIE acutely increased de/oxygenated hemoglobin compared to rest. HIIE acutely decreased cerebrovascular reactivity to higher CO2 compared to rest and moderate intensity. The acute and chronic effects of HIIE on cerebrovascular function vary depending on the outcomes measured. Therefore, future research is needed to confirm the effects of HIIE on cerebrovascular function in healthy individuals and better understand the effects in individuals with chronic conditions. In order to conduct rigorous systematic reviews in the future, we recommend assessing MCAv, dCA and CO2 reactivity during and post HIIE.
How and when to end the COVID-19 lockdown: an optimisation approach
Authors: Rawson Thomas , Brewer Tom , Veltcheva Dessislava , Huntingford Chris , Bonsall Michael B.
Published: May 2020

Countries around the world are in a state of lockdown to help limit the spread of SARS-CoV-2. However, as the number of new daily confirmed cases begins to decrease, governments must decide how to release their populations from quarantine as efficiently as possible without overwhelming their health services. We applied an optimal control framework to an adapted Susceptible-Exposure-Infection-Recovery (SEIR) model framework to investigate the efficacy of two potential lockdown release strategies, focusing on the UK population as a test case. To limit recurrent spread, we find that ending quarantine for the entire population simultaneously is a high-risk strategy, and that a gradual re-integration approach would be more reliable. Furthermore, to increase the number of people that can be first released, lockdown should not be ended until the number of new daily confirmed cases reaches a sufficiently low threshold.

We model a gradual release strategy by allowing different fractions of those in lockdown to re-enter the working non-quarantined population. Mathematical optimisation methods, combined with our adapted SEIR model, determine how to maximise those working while preventing the health service from being overwhelmed. The optimal strategy is broadly found to be to release approximately half the population two-to-four weeks from the end of an initial infection peak, then wait another three-to-four months to allow for a second peak before releasing everyone else. We also modelled an ''on-off'' strategy, of releasing everyone, but re-establishing lockdown if infections become too high. We conclude that the worst-case scenario of a gradual release is more manageable than the worst-case scenario of an on-off strategy, and caution against lockdown-release strategies based on a threshold-dependent on-off mechanism.

The two quantities most critical in determining the optimal solution are transmission rate and the recovery rate, where the latter is defined as the fraction of infected people in any given day that then become classed as recovered. We suggest that the accurate identification of these values is of particular importance to the ongoing monitoring of the pandemic.
The impact of social distancing on COVID19 spread: State of Georgia case study
Authors: Keskinocak Pinar , Oruc Buse Eylul , Baxter Arden , Asplund John , Serban Nicoleta
Published: May 2020

As the spread of COVID19 in the US continues to grow, local and state officials face difficult decisions about when and how to transition to a “new normal.” The goal of this study is to project the number of COVID19 infections and resulting severe outcomes, and the need for hospital capacity under social distancing, particularly, shelter-in-place and voluntary quarantine for the State of Georgia. We developed an agent-based simulation model to project the infection spread. The model utilizes COVID19-specific parameters and data from Georgia on population interactions and demographics. The simulation study covered a seven and a half-month period, testing different social distancing scenarios, including baselines (no-intervention or school closure only) and combinations of shelter-in-place and voluntary quarantine with different timelines and compliance levels. The following outcomes are compared at the state and community levels: the number and percentage of cumulative and daily new symptomatic and asymptomatic infections, hospitalizations, and deaths; COVID19-related demand for hospital beds, ICU beds, and ventilators. The results suggest that shelter-in-place followed by voluntary quarantine reduced peak infections from approximately 180K under no intervention and 113K under school closure, respectively, to below 53K, and delayed the peak from April to July or later. Increasing shelter-in-place duration from four to five weeks yielded 2-9% and 3-11% decrease in cumulative infection and deaths, respectively. Regardless of the shelter-in-place duration, increasing voluntary quarantine compliance decreased daily new infections from almost 53K to 25K, and decreased cumulative infections by about 50%. The cumulative number of deaths ranged from 6,660 to 19,430 under different scenarios. Peak infection date varied across scenarios and counties; on average, increasing shelter-in-place duration delayed the peak day by 6 days. Overall, shelter-in-place followed by voluntary quarantine substantially reduced COVID19 infections, healthcare resource needs, and severe outcomes.
Suppress, and not just flatten:Strategies for Rapid Suppression of COVID19 transmission in Small World Communities
Authors: Bhattacharyya Chiranjib , Vinay V.
Published: May 2020

Many countries have introduced Lockdowns to contain the
COVID19 epidemic. Lockdowns, though an effective policy for
containment, imposes a heavy cost on the economy as it enforces
extreme social distancing measures on the whole population. The
objective of this note is to study alternatives to Lockdown which are
either more targeted or allows partial opening of the economy.
Cities are often spatially organized into wards. We introduce
Multi-lattice small world (MLSW) network as a model of a city where
each ward is represented by a 2D lattice and each vertex in the latex represents an
agent endowed with SEIR dynamics. Through simulation studies on MLSW
we examine a variety of candidate suppression policies and find that
restricting lockdowns to infected wards can indeed out-perform global
Lockdowns in both reducing the attack rate and also shortening the
duration of the epidemic. Even policies such as partial opening of the economy, such as
Two Day Work Week, can be competitive if augmented with extensive Contact Tracing.
Elevated D-Dimer Levels are Associated with Increased Risk of Mortality in COVID-19: A Systematic Review and Meta-Analysis
Authors: Shah Siddharth , Shah Kuldeep , Patel Siddharth B , Patel Forum S , Osman Mohammed , Velagapudi Poonam , Turagam Mohit K. , Lakkireddy Dhanunjaya , Garg Jalaj
Published: May 2020

Introduction

The 2019 novel Coronavirus (2019-nCoV), now declared a pandemic has an overall case fatality of 2–3% but it is as high as 50% in critically ill patients. D-dimer is an important prognostic tool, often elevated in patients with severe COVID-19 infection and in those who suffered death. In this systematic review, we aimed to investigate the prognostic role of D-dimer in COVID-19 infected patients.

Methods

We searched PubMed, Medline, Embase, Ovid, and Cochrane for studies reporting admission D-dimer levels in COVID-19 patients and its effect on mortality.

Results

18 studies (16 retrospective and 2 prospective) with a total of 3,682 patients met the inclusion criteria. The pooled mean difference (MD) suggested significantly elevated D-dimer levels in patients who died versus those survived (MD 6.13 mg/L, 95% CI 4.16 − 8.11, p <0.001). Similarly, the pooled mean D-dimer levels were significantly elevated in patients with severe COVID-19 infection (MD 0.54 mg/L, 95% CI 0.28 − 0.8, p< 0.001). In addition, the risk of mortality was four-fold higher in patients with positive D-dimer vs negative D-dimer (RR 4.11, 95% CI 2.48 − 6.84, p< 0.001) and the risk of developing the severe disease was two-fold higher in patients with positive D-dimer levels vs negative D-dimer (RR 2.04, 95% CI 1.34 − 3.11, p < 0.001).

Conclusion

Our meta-analysis demonstrates that patients with COVID-19 presenting with elevated D-dimer levels have an increased risk of severe disease and mortality.
Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: An Exploratory Randomized, Controlled Trial
Authors: Lou Yan , Liu Lin , Yao Hangping , Hu Xingjiang , Su Junwei , Xu Kaijin , Luo Rui , Yang Xi , He Lingjuan , Lu Xiaoyang , Zhao Qingwei , Liang Tingbo , Qiu Yunqing
Published: May 2020

Background

Effective antiviral drugs for COVID-19 are still lacking. This study aims to evaluate the clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients.

Methods

Favipiravir and baloxavir acid were evaluated for their antiviral activity against SARS-CoV-2 in vitro before the trial initiation. We conducted an exploratory trial with 3 arms involving hospitalized adult patients with COVID-19. Patients were randomized assigned in a 1:1:1 ratio into baloxavir marboxil group, favipiravir group, and control group. The primary outcome was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement. Virus load reduction, blood drug concentration and clinical presentation were also observed. The trial was registered with Chinese Clinical Trial Registry (ChiCTR 2000029544).

Results

Baloxavir showed antiviral activity in vitro with the half-maximal effective concentration (EC50) of 5.48 µM comparable to arbidol and lopinavir, but favipiravir didn’t demonstrate significant antiviral activity up to 100 µM. Thirty patients were enrolled. The percentage of patients who turned viral negative after 14-day treatment was 70%, 77%, and 100% in the baloxavir, favipiravir, and control group respectively, with the medians of time from randomization to clinical improvement was 14, 14 and 15 days, respectively. One reason for the lack of virological effect and clinical benefits may be due to insufficient concentrations of these drugs relative to their antiviral activities.

Conclusions

Our findings do not support that adding either baloxavir or favipiravir under the trial dosages to the existing standard treatment.
Comparison of surgical quality and long-term outcome between hybrid trans-anal total meso-rectal excision and laparoscopic total meso-rectal excision: a systematic review and meta-analysis
Authors: Yang Yingchi , Wang Huihui , Zhao Kaixin , Chu Xiangyu , Pang Kai , Yang Yun , Li Jun , Yao Hongwei , Jin Lan , Zhang Zhongtao
Published: May 2020

BACKGROUND Laparoscopy-assisted trans-anal TME (ta-TME), or hybrid ta-TME, inherited the advantages of both trans-anal surgery and trans-abdominal surgery, and is gaining increasing acceptance from colorectal surgeons worldwide. This research aims to make a comprehensive comparison between hybrid ta-TME surgery and traditional laparoscopic TME (la-TME) surgery regarding surgical quality and long-term survival.
METHODS Cochrane Library, EMbase, Web of Science and PubMed were searched for studies comparing hybrid ta-TME with traditional la-TME. Indicators for surgical quality and long-term prognosis were extracted and pooled. Heterogeneity was assessed with I2 index and was significant when p<0.1 and I2>50%. Publication bias was estimated by Egger test, where p<0.1 was considered statistically significant.
RESULTS 13 studies with 992 patients were included in meta-analysis, of which 467 were in hybrid ta-TME cohorts, and 525 were in traditional la-TME cohorts. Compared with traditional la-TME, hybrid ta-TME has lower rate of positive circumferential margin (RR=0.454, 95%CI 0.240~0.862, p=0.016) and lower conversion rate (RR=0.336, 95%CI 0.134~0.844, p=0.020). On rate of positive distal resection margin, completeness/near-completeness of meso-rectum, overall complications, anal leakage, ileus, urinary dysfunction, 2-year DFS and 2-year OS, there were no significant difference between the two techniques.
CONCLUSIONS Hybrid ta-TME is significantly superior to traditional la-TME in ensuring CRM safety and lowering intra-operative conversion rate, and is meanwhile not inferior on other major outcome indicators concerning surgical quality and long-term survival. To further understand this new surgical technique, we need high-quality RCTs, as well as previous researchers updates with results of prolonged follow-up.
Viable circulating endothelial cells and their progenitors are increased in Covid-19 patients
Authors: Mancuso Patrizia , Gidaro Antonio , Gregato Giuliana , Raveane Alessandro , Cremonesi Paola , Quarna Jessica , Caccia Sonia , Gusso Luca , Cogliati Chiara , Bertolini Francesco
Published: May 2020

During the course of Covid-19, the disease caused by the new Coronavirus SARS-CoV-2, thrombotic phenomena and/or diffuse vascular damage are frequent, and viral elements have been observed within endothelial cells. Circulating endothelial cells (CECs) and their progenitors (CEPs) are increased in cardiovascular, thrombotic, infectious and cancer diseases. Using a validated flow cytometry procedure, we found that viable CEPs/mL were significantly increased in Covid-19 patients compared to healthy controls. This increase was observed in patients with mild symptoms and not further augmented in patients with severe symptoms. In patients who recovered, CEPs decreased, but were in a range still significantly higher than normal controls. Regarding mature CECs, in Covid-19 patients their absolute number was similar to those observed in healthy controls, but the viable/apoptotic CEC ratio was significantly different. Both mild and severe Covid-19 patients had significantly more viable CECs compared to healthy controls. Patients who recovered had significantly less CECs/mL when compared to controls as well as to mild and severe Covid-19 patients. A positive correlation was found between the copies of SARS-CoV-2 RNA in the cellular fraction and apoptotic CEPs/mL in severe Covid-19 patients. These findings suggest that CECs and CEPs might be investigated as candidate biomarkers of endothelial damage in Covid-19 patients.
Radiation of nitrogen-metabolizing enzymes across the tree of life tracks environmental transitions in Earth history
Authors: Parsons Chris , Stüeken Eva , Rosen Caleb , Mateos Katherine , Anderson Rika
Published: May 2020

Nitrogen is an essential element to life and exerts a strong control on global biological productivity. The rise and spread of nitrogen-utilizing microbial metabolisms profoundly shaped the biosphere on the early Earth. Here we reconciled gene and species trees to identify birth and horizontal gene transfer events for key nitrogen-cycling genes, dated with a time-calibrated tree of life, in order to examine the timing of the proliferation of these metabolisms across the tree of life. Our results provide new insights into the evolution of the early nitrogen cycle that expand on geochemical reconstructions. We observed widespread horizontal gene transfer of molybdenum-based nitrogenase back to the Archean, minor horizontal transfer of genes for nitrate reduction in the Archean, and an increase in the proliferation of genes metabolizing nitrite around the time of the Mesoproterozoic (∼1.5 Ga). The latter coincides with recent geochemical evidence for a mid-Proterozoic rise in oxygen levels. Geochemical evidence of biological nitrate utilization in the Archean and early Proterozoic may reflect at least some contribution of dissimilatory nitrate reduction to ammonium (DNRA) rather than pure denitrification to N2. Our results thus help unravel the relative dominance of two metabolic pathways that are not distinguishable with current geochemical tools. Overall, our findings thus provide novel constraints for understanding the evolution of the nitrogen cycle over time and provide insights into the bioavailability of various nitrogen sources in the early Earth with possible implications for the emergence of eukaryotic life.
Epithelial Cell Regulation of Type 2 Cytokine Release by Peripheral Blood Mononuclear Cells
Authors: Southern Amy , Gondrand Aurelia , Layzell Scott , Cane Jennifer L , Pavord Ian D , Powell Timothy J
Published: May 2020

Background

Type 2 cytokines such as IL-13 and IL-5 are important drivers of pathophysiology and exacerbation in asthma. Defining how these type 2 cytokine responses are regulated is a research priority. Epithelial cells promote type 2 responses by releasing alarmins including IL-25, IL-33 and TSLP, but much less is known about inhibitory factors.

Methods

IL-13 release was measured from peripheral blood mononuclear cells (PBMC) cultured with Interleukin (IL)-2 for five days. Epithelial cell lines or human bronchial epithelial cells (HBEC) isolated from healthy or asthma donors were added to these PBMC cultured with IL-2 and release of IL-13 or IL-5 measured. To characterise the mechanisms, we assessed the effect of mechanical disruption of epithelial cells, addition of the COX inhibitor indomethacin and the G-protein inhibitor pertussis toxin.

Results

PBMC cultured with IL-2 secreted type 2 cytokines in a cell number and time dependent manner. Epithelial cell lines inhibited IL-13 and IL-5 release after co-culture with PBMC in the presence of IL-2, directly, across a transwell and using epithelial cell supernatant. Cells or supernatant from HBEC from healthy or asthma donors also inhibited the cytokine release. Trypsin treatment of conditioned media indicated that inhibitory factor(s) are trypsin insensitive. Mechanical disruption of epithelial cells or indomethacin treatment had no effect, but pertussis toxin reduced epithelial cell inhibition of IL-2 driven type 2 cytokine release.

Conclusion

Epithelial cells regulate cytokine release by soluble factor(s) and this could be an important immunoregulatory function of the airway epithelium.
The most efficient metazoan swimmer creates a ‘virtual wall’ to enhance performance
Authors: Gemmell Brad J. , Du Clos Kevin T. , Colin Sean P. , Sutherland Kelly R. , Costello John H.
Published: May 2020

It has been well documented that animals (and machines) swimming or flying near a solid boundary get a boost in performance1-6. This ground effect is often modeled as an interaction between a mirrored pair of vortices represented by a true vortex and an opposite sign ‘virtual vortex’ on the other side of the wall7. However, most animals do not swim near solid surfaces and thus near body vortex-vortex interactions in open-water swimmers have been poorly investigated. In this study we examine the most energetically efficient metazoan swimmer known to date, the jellyfishAurelia aurita, to elucidate the role that vortex interactions can play in animals that swim away from solid boundaries. We used high speed video tracking, laser-based digital particle image velocimetry (dPIV) and an algorithm for extracting pressure fields from flow velocity vectors to quantify swimming performance and the effect of near body vortex-vortex interactions. Here we show that a vortex ring (stopping vortex), created underneath the animal during the previous swim cycle, is critical for increasing propulsive performance. This well positioned stopping vortex acts in the same way as a virtual vortex during wall-effect performance enhancement, by helping converge fluid at the underside of the propulsive surface and generating significantly higher pressures which result in greater thrust. These findings advocate that jellyfish can generate a wall-effect boost in open water by creating what amounts to a ‘virtual wall’ between two real, opposite sign vortex rings. This explains the significant propulsive advantage jellyfish possess over other metazoans and represents important implications for bio-engineered propulsion systems.
Lectins-glycoconjugates interactions: Experimental and computational docking studies of the binding and agglutination of eight different lectins in a comparative manner
Authors: Kumar Amit , Hinge Vijaya Kumar , Venugopal Ashapogu , Nadimpalli Siva Kumar , Rao Chebrolu Pulla
Published: May 2020

Altering the lectin properties by chemically synthesized glycoconjugates is important in glycobiology. A series of eight plant lectins with varying carbohydrate specificity were chosen as model systems to study the binding by synthetic glycoconjugates. One of our earlier paper1deals with the binding of glycoconjugates by jacalin. Further to this, we have now extended the studies to several other lectins having specificities towards glucose/mannose, galactose and lactose, and the results are reported in this paper on a comparative manner. The binding aspects were established by hemagglutination and fluorescence spectroscopy, and the conformational changes by CD spectroscopy. Out of the fourteen glycoconjugates used in the present study, a galactosyl-naphthyl derivative,1cturns out to be most effective towards galactose-specific lectin in agglutination inhibition, fluorescence quenching by inducing considerable conformational changes. Similarly, mannosyl-naphthyl derivative,3cturns out to be most effective in inhibiting the agglutination of Glc/Man specific lectins. Present study demonstrates differential recognition of conjugates towards lectins. The results also supported the existence of a correlation between the glycoconjugate and lectin specificity at the carbohydrate recognition domain (CRD). The glycoconjugate that inhibits the agglutination binds in the CRD via polar interactions as well as by nonpolar/hydrophobic interactions arising from the aromatic moiety of the conjugate, whereas, the non-inhibiting conjugates bind primarilyviahydrophobic interactions. The specific and selective binding of the glycoconjugates by these lectins were proven by the docking studies. Thus, the present study has contributed immensely towards understanding the molecular interactions present between the lectins and small molecules that will eventually help better drug design where the presence of hydrophoibic moieties would play important role.
Knock-down of hippocampal DISC1 in immune-challenged mice impairs the prefrontal-hippocampal coupling and the cognitive performance throughout development
Authors: Xu Xiaxia , Song Lingzhen , Hanganu-Opatz Ileana L.
Published: May 2020

Disrupted-in-Schizophrenia 1 (DISC1) gene represents an intracellular hub of developmental processes and has been related to cognitive dysfunction in psychiatric disorders. Mice with whole-brain DISC1 knock-down show memory and executive deficits as result of impaired prefrontal-hippocampal communication throughout development, especially when combined with early environmental stressors, such as maternal immune activation (MIA). While synaptic dysfunction of layer 2/3 pyramidal neurons in neonatal prefrontal cortex (PFC) has been recently identified as one source of abnormal long-range coupling in these mice, it is still unclear whether the hippocampus (HP) is also compromised during development. Here we aim to fill this knowledge gap by combiningin vivoelectrophysiology and optogenetics with morphological and behavioral assessment of immune-challenged mice with DISC1 knock-down either in the whole brain (GE) or restricted to pyramidal neurons in CA1 area of intermediate/ventral HP (i/vHP) (GHPE). Both groups of mice show abnormal network activity, sharp-waves (SPWs) and neuronal firing in CA1 area. Moreover, optogenetic stimulation of CA1 pyramidal neurons fails to activate the local circuits in the neonatal PFC. These deficits that persist until pre-juvenile development are due to dendrite sparsification and loss of spines of CA1 pyramidal neurons. As a long-term consequence, DISC1 knock-down in immune-challenged mice leads to poorer recognition memory at pre-juvenile age. Thus, besides PFC, hippocampal CA1 area has a critical role for the developmental miswiring and long-lasting cognitive impairment related to mental illness.

Significance Statement

Developmental miswiring within prefrontal-hippocampal networks has been proposed to account for cognitive impairment in mental disorders. Indeed, during development, long before the emergence of cognitive deficits, the functional coupling within these networks is reduced in mouse models of disease. However, the cellular mechanisms of dysfunction are largely unknown. Here we combine in vivo electrophysiology and optogenetics with behavioral assessment in immune-challenged mice with hippocampus-confined DISC1 knock-down and show that pyramidal neurons in CA1 area are critical for the developmental dysfunction of prefrontal-hippocampal communication and cognitive impairment.
A New Framework for MR Diffusion Tensor Distribution
Authors: Magdoom Kulam Najmudeen , Pajevic Sinisa , Dario Gasbarra , Basser Peter J.
Published: May 2020

The ability to characterize heterogeneous and anisotropic water diffusion processes within macro-scopic MRI voxels non-invasively andin vivois adesideratumin biology, neuroscience, and medicine. While an MRI voxel may contain approximately a microliter of tissue, our goal is to examine intravoxel diffusion processes on the order of picoliters. Here we propose a new theoretical framework and experimental design to describe and measure such intravoxel structural heterogeneity and anisotropy. We assume that a constrained normal tensor-variate distribution (CNTVD) describes the variability of positive definite diffusion tensors within a voxel which extends its applicability to a wide range of b-values unlike existing models. We use a Monte Carlo scheme to synthesize realistic numerical diffusion tensor distribution (DTD) phantoms and invert the MR signal. We show that the signal inversion is well-posed and estimate the CNTVD parameters parsimoniously by exploiting the different symmetries of the mean and covariance tensors of CNTVD. The robustness of the estimation pipeline is assessed by adding noise to calculated MR signals and compared with the ground truth. A family of invariant parameters which characterize microscopic shape, size and orientation heterogeneity within a voxel are also presented.
Metabolic and haemodynamic resting-state connectivity of the human brain: a high-temporal resolution simultaneous BOLD-fMRI and FDG-fPET multimodality study
Authors: Jamadar Sharna D , Ward Phillip GD , Liang Emma Xingwen , Orchard Edwina R , Chen Zhaolin , Egan Gary F
Published: May 2020

Simultaneous FDG-PET/fMRI ([18F]-fluorodeoxyglucose positron emission tomography functional magnetic resonance imaging) provides the capacity to image two sources of energetic dynamics in the brain – glucose metabolism and haemodynamic response. Functional fMRI connectivity has been enormously useful for characterising interactions between distributed brain networks in humans. Metabolic connectivity based on static FDG-PET has been proposed as a biomarker for neurological disease; but static FDG-PET cannot be used to estimate subjectlevel measures ofconnectivity, only across-subjectcovariance. Here, we applied high-temporal resolution constant infusion fPET to measure subject-level metabolic connectivity simultaneously with fMRI connectivity. fPET metabolic connectivity was characterised by fronto-parietal connectivity within and between hemispheres. fPET metabolic connectivity showed moderate similarity with fMRI primarily in superior cortex and frontoparietal regions. Significantly, fPET metabolic connectivity showed little similarity with static FDG-PET metabolic covariance, indicating that metabolic brain connectivity is a non-ergodic process whereby individual brain connectivity cannot be inferred from group level metabolic covariance. Our results highlight the complementary strengths of fPET and fMRI in measuring the intrinsic connectivity of the brain, and open up the opportunity for novel fundamental studies of human brain connectivity as well as multi-modality biomarkers of neurological diseases.
Actin reorganization at the centrosomal area and the immune synapse regulates polarized secretory traffic of multivesicular bodies in T lymphocytes
Authors: Bello-Gamboa Ana , Velasco Marta , Moreno Solange , Herranz Gonzalo , Ilie Roxana , Huetos Silvia , Dávila Sergio , Sánchez Alicia , de la Serna Jorge Bernardino , Calvo Víctor , Izquierdo Manuel
Published: May 2020

T-cell receptor stimulation induces the convergence of multivesicular bodies towards the microtubule-organizing center (MTOC) and the polarization of the MTOC to the immune synapse (IS). These events lead to exosome secretion at the IS. We describe here that upon IS formation centrosomal area F-actin decreased concomitantly with MTOC polarization to the IS. PKCδ-interfered T cell clones showed a sustained level of centrosomal area F-actin associated with defective MTOC polarization. We analysed the contribution of two actin cytoskeleton-regulatory proteins, FMNL1 and paxillin, to the regulation of cortical and centrosomal F-actin networks. FMNL1β phosphorylation and F-actin reorganization at the IS were inhibited in PKCδ-interfered clones. F-actin depletion at the central region of the IS, a requirement for MTOC polarization, was associated with FMNL1β phosphorylation at its C-terminal, autoregulatory region. Interfering all FMNL1 isoforms prevented MTOC polarization; nonetheless, FMNL1β re-expression restored MTOC polarization in a centrosomal area F-actin reorganization-independent manner. Moreover, PKCδ-interfered clones exhibited decreased paxillin phosphorylation at the MTOC, which suggests an alternative actin cytoskeleton regulatory pathway. Our results infer that PKCδ regulates MTOC polarization and secretory traffic leading to exosome secretion in a coordinated manner by means of two distinct pathways, one involving FMNL1β regulation and controlling F-actin reorganization at the IS, and the other, comprising paxillin phosphorylation potentially controlling centrosomal area F-actin reorganization.
Uclacyanin proteins are required for lignified nanodomain formation within Casparian strips
Authors: Reyt Guilhem , Chao Zhenfei , Flis Paulina , Castrillo Gabriel , Chao Dai-Yin , Salt David E.
Published: May 2020

Casparian strips (CS) are cell wall modifications of vascular plants restricting extracellular free diffusion into and out the vascular system. This barrier plays a critical role in controlling the acquisition of nutrients and water necessary for normal plant development. CS are formed by the precise deposition of a band of lignin approximately 2 μm wide and 150 nm thick spanning the apoplastic space between adjacent endodermal cells. Here, we identified a copper-containing protein, Uclacyanin1 (UCC1) that is sub-compartmentalised within the CS. UCC1 forms a central CS nanodomain in comparison with other CS-located proteins that are found to be mainly accumulated at the periphery of the CS. We found that loss-of-function of two uclacyanins (UCC1andUCC2) reduces lignification specifically in this central CS nanodomain, revealing a nano-compartmentalised machinery for lignin polymerisation. This lack of lignification leads to increased endodermal permeability, and consequently to a loss of mineral nutrient homeostasis.
Versatile live-cell activity analysis platform for characterization of neuronal dynamics at single-cell and network level
Authors: Yuan Xinyue , Schröter Manuel , Obien Marie Engelene J. , Fiscella Michele , Gong Wei , Kikuchi Tetsuhiro , Odawara Aoi , Noji Shuhei , Suzuki Ikuro , Takahashi Jun , Hierlemann Andreas , Frey Urs
Published: May 2020

Chronic imaging of neuronal networksin vitrohas provided fundamental insights into mechanisms underlying neuronal function. Existing labeling and optical imaging methods, however, cannot be used for continuous and long-term recordings of the dynamics and evolution of neuronal networks, as fluorescence indicators can cause phototoxicity. Here, we introduce a versatile platform for label-free, comprehensive and detailed electrophysiological live-cell imaging of various neurogenic cells and tissues over extended times. We report on a novel dual-mode high-density microelectrode array, which can simultaneously record in i) full-frame mode with 19,584 recording sites and ii) high-signal-to-noise mode with 246 channels. We set out to demonstrate the capabilities of this platform with recordings from primary and iPSC-derived neuronal cultures and tissue preparations over several weeks, providing detailed morpho-electrical phenotypic parameters at subcellular, cellular and network level. Moreover, we developed reliable analysis tools with drastically increased throughput for extracting axonal morphology and conduction parameters.
Examining the neural antecedents of tics in Tourette syndrome using electroencephalography
Authors: Maiquez Barbara Morera , Jackson Georgina M. , Jackson Stephen R.
Published: May 2020

Tourette syndrome (TS) is a neurological disorder of childhood onset that is characterised by the occurrence of motor and vocal tics. TS is associated with cortical-striatal-thalamic-cortical circuit [CSTC] dysfunction and hyper-excitability of cortical limbic and motor regions that are thought to lead to the occurrence of tics. Importantly, individuals with TS often report that their tics are preceded by ‘premonitory sensory/urge phenomena’ (PU) that are described as uncomfortable bodily sensations that precede the execution of a tic and are experienced as a strong urge for motor discharge. While tics are most often referred to as involuntary movements, it has been argued that tics should be viewed as voluntary movements that are executed in response to the presence of PU and bring temporary relief from the uncomfortable bodily sensations that are associated with PU. This issue remains unresolved but has very important implications for the design of clinical interventions for TS. To investigate this issue further, we conducted a study using electroencephalography (EEG). Specifically, we recorded movement-related EEG (mu and beta band oscillations) during (a) the immediate period leading up to the execution of voluntary movements by a group of individuals with TS and a group of matched healthy control participants, and (b) the immediate period leading up to the execution of a tic in a group of individuals with TS. We demonstrate that movement-related mu and beta band oscillations arenotobserved prior to tics in individuals with TS. We interpret this effect as reflecting the greater involvement of a network of brain areas, including the insular and cingulate cortices, basal ganglia nuclei, and the cerebellum, in the generation of tics in TS. We also show that beta-band desynchronization does occur when individuals with TS initiate voluntary movements, but, in contrast to healthy controls, desynchronization of mu-band oscillations is not observed during the execution of voluntary movements for individuals with TS. We interpret this finding as reflecting a dysfunction of physiological inhibition in TS, thereby contributing to an impaired ability to suppress neuronal populations that may compete with movement preparation processes.
A new species ofMesopolobusWestwood (Hymenoptera, Pteromalidae) from black locust crops
Authors: László Zoltán , Lakatos K. Tímea , Dénes Avar-Lehel
Published: May 2020

A new species of the genusMesopolobusWestwood,Mesopolobus robiniaesp. n., is described and illustrated from east-central Europe (Romania and Hungary). The species was reared from black locust (Robinia pseudoacacia) seedpod samples, where it most likely parasitizes the black locust’s seed predatorBruchophagus robiniaeZerova, 1970. Here we present the new species and report on its ecological relationships within the European seed predator community of black locust. We also give details regarding type material and type locality, a detailed description with images, a differential diagnosis of the new species, and a modification to the identification key published by Graham (1969), that distinguishes this new species from closely related species. In addition, we provide information on the distribution, biology and results of barcoding analysis. We also provide the DNA sequence data to complement the morphological taxonomy.
Adult-born granule cells support pathological microcircuits in the chronically epileptic dentate gyrus
Authors: Sparks FT , Liao Z , Li W , Soltesz I , Losonczy A
Published: May 2020

Temporal lobe epilepsy (TLE) is characterized by recurrent seizures driven by synchronous neuronal activity. The dentate gyrus (DG) region of the hippocampal formation is highly reorganized in chronic TLE; in particular, pathological remodeling of the “dentate gate” is thought to open up pathological conduction pathways for synchronous discharges and seizures in the mesial temporal lobe. However, this pathophysiological framework lacks a mechanistic explanation of how macroscale synchronous dynamics emerge from alterations of the DG at the microcircuit level. In particular, the relative contribution of developmentally defined subpopulations of adult-born (abGCs) and mature (mGCs) granule cells to epileptiform network events remains unknown. To address this question, we optically recorded activity dynamics of identified populations of abGCs and mGCs during interictal epileptiform discharges (IEDs) in mice with chronic TLE. We find that disjoint subsets of IEDs differentially recruit abGC and mGC populations. We used these observations to develop a neural topic modeling framework, under which we find that the epileptic DG network organizes into disjoint, cell-type specific pathological ensembles, a subset of which are recruited by each IED. We found that statistics of this ensemble structure are highly conserved across animals, with abGCs disproportionately driving network activity in the epileptic DG during IEDs. Our results provide the firstin vivocharacterization of activity dynamics of identified GC subpopulations in the epileptic DG, the first microcircuit-level correlates of IEDsin vivo, and reveal a specific contribution of abGCs to interictal epileptic events.

Highlights

We relate electrographic signatures of epilepsy to microcircuit dynamics at single-cell resolution

The chronically epileptic dentate gyrus granule cell network is organized in lineage-specific pathological ensembles

A novel generative model framework for ensemble recruitment relates local field potential signatures to microcircuit activation during interictal epileptiform discharges

Adult-born granule cell-dominated ensembles are disproportionately represented among the inferred ensembles

The most active ensemble during an interictal epileptiform discharge can be decoded directly from the local field potential spectrum

This Latent Ensemble Recruitment model of cell recruitment by interictal events is the first application of Bayesian topic modeling toin vivotwo-photon calcium imaging data
Pre-target oculomotor inhibition reflects temporal orienting rather than certainty
Authors: Tal-Perry Noam , Yuval-Greenberg Shlomit
Published: May 2020

Recent studies suggested that eye movements are linked to temporal predictability. These studies manipulated predictability by setting the cue-target interval (foreperiod) to be fixed or random throughout block. Findings showed that pre-target oculomotor behavior was reduced in the fixed relative to the random condition. This effect was interpreted as reflecting the formation of temporal expectation. However, it is unknown whether the effect is driven by target-specific temporal orienting, or rather a result of a more context-dependent state of certainty that participants may experience during blocks with a high predictability rate.

In thus study we dissociated certainty and orienting in a tilt-discrimination task. In each trial, a temporal cue (fixation color change) was followed by a tilted grating-patch. The foreperiod distribution was varied between blocks to be either fully fixed (same foreperiod in 100% of trials), mostly fixed (80% of trials with one foreperiod and 20% with another) or random (five foreperiods in equal probabilities). The two hypotheses led to different prediction models which were tested against the experimental data.

Results were consistent with the orienting hypothesis and inconsistent with the certainty hypothesis, supporting the link between oculomotor inhibition and temporal orienting and its validity as a temporal expectations marker.
Integrator terminates promoter-proximal Pol II to generateC. eleganspiRNA precursors
Authors: Beltran Toni , Pahita Elena , Ghosh Subhanita , Lenhard Boris , Sarkies Peter
Published: May 2020

Piwi-interacting RNAs (piRNAs) play key roles in germline development and genome defence in metazoans. InC. elegans, piRNAs are transcribed from >15000 discrete genomic loci by RNA polymerase II, resulting in 28 nt short-capped piRNA precursors. Here we investigate transcription termination at piRNA loci. We show that the Integrator complex, which terminates snRNA transcription, is recruited to piRNA loci. We show that the catalytic activity of Integrator cleaves nascent capped piRNA precursors associated with promoter-proximal Pol II, resulting in termination of transcription. Loss of Integrator activity, however, does not result in transcriptional readthrough at the majority of piRNA loci. Our results draw new parallels between snRNA and piRNA biogenesis in nematodes, and provide evidence of a role for the Integrator complex as a terminator of promoter-proximal RNA polymerase II.

Highlights

- Integrator localises to sites of piRNA biogenesis in nematodes

- Integrator cleaves nascent RNAs associated with promoter-proximal Pol II at piRNA loci to release short capped piRNA precursors from chromatin

- Repression of Pol II elongation at the majority of piRNA loci is independent of Integrator
Shared genetic etiology of age of menarche and socioeconomic variables: No evidence for genetic overlap with psychiatric traits
Authors: Steppan Martin
Published: May 2020

Earlier research has shown observational associations of early pubertal timing and poor mental health. Mendelian randomization (MR) studies demonstrated a transient effect of pubertal timing on mental health during adolescence, but not later in life. MR studies also showed that there is a likely causal association of pubertal timing with life history traits. However, the strongest causal effects and genetic correlations with age of menarche have been found for Body Mass Index (BMI). As high BMI is associated with lower socioeconomic status and with poor mental health, the shared genetic etiology of socioeconomic status, BMI and poor mental health is not yet fully understood. BMI correlates negatively with socioeconomic status and several mental health outcomes. Despite their substantial genetic overlap, the underlying genetic etiology of these phenotypes remains unclear. In this study we applied Linkage Disequi-librium score regression to test genetic correlations of age of menarche with 33 socioeconomic, life history, social interaction, personality and psychiatric traits, and BMI. We further applied spectral decomposition and hierarchical clustering to the genetic correlation matrix. After controlling for multiple testing, we could only identify significant genetic correlations with BMI and three socioeconomic traits (household income, deprivation and parental longevity). The results suggest that genome-wide association studies on age of menarche also contain socioeconomic information. Future MR studies aiming to test the unconfounded effect of pubertal timing should make sure that genetic instruments have no pleiotropic effect on socioeconomic variables, or (if possible) also control for socioeconomic status on the observational level.
Constitutive activation of cellular immunity underlies the evolution of resistance to infection
Authors: Leitão Alexandre B. , Arunkumar Ramesh , Day Jonathan P. , Geldman Emma M. , Jiggins Francis M.
Published: May 2020

Organisms rely on inducible and constitutive immune defences to combat infection. Constitutive immunity enables a rapid response to infection but may carry a cost for uninfected individuals, leading to the prediction that it will be favoured when infection rates are high. When we exposed populations ofDrosophila melanogasterto intense parasitism by the parasitoid waspLeptopilina boulardi, they evolved resistance by developing a more reactive cellular immune response. Using single-cell RNA sequencing, we found that immune-inducible genes had become constitutively upregulated. This was the result of resistant larvae differentiating precursors of specialized immune cells called lamellocytes that were previously only produced after infection. Therefore, populations evolved resistance by genetically hard-wiring an induced immune response to become constitutive.
Early-life Temperature Exposure Affects Thyroid Hormone Receptor Signaling and Epigenetic Regulation of the Paraventricular Nucleus in Female Rat Pups
Authors: Lauby Samantha C. , McGowan Patrick O.
Published: May 2020

Early-life maternal care received has a profound effect on later-life behaviour in adult offspring and previous studies have suggested epigenetic mechanisms (e.g., DNA methylation) are involved. Changes in thyroid hormone receptor signaling might be related to differences in maternal care received and DNA methylation modifications. We investigated the effects of two factors in the maternal environment, temperature exposure (a proxy of maternal contact) and licking-like tactile stimulation, on these processes in week-old female rat pups. We assessed thyroid hormone receptor signaling by measuring circulating triiodothyronine and transcript abundance of thyroid hormone receptors and the thyroid hormone-responsive genes DNA methyltransferase 3a and oxytocin in the paraventricular nucleus of the hypothalamus. DNA methylation of the oxytocin promoter was assessed in relation to changes in thyroid hormone receptor binding. Repeated room temperature exposure was associated with a decrease in thyroid hormone receptor signaling measures relative to nest temperature exposure, while acute room temperature exposure was associated with an increase. Repeated room temperature exposure also increased thyroid hormone receptor binding and DNA methylation at the oxytocin promoter. These findings suggest that repeated room temperature exposure may affect DNA methylation levels as a consequence of alterations in thyroid hormone receptor signaling.