bluuebunny/crossref_metadata_2025 huggingface dataset:
Serological reconstruction of COVID-19 epidemics through analysis of antibody kinetics to SARS-CoV-2 proteins
Authors: Pelleau Stéphane , Woudenberg Tom , Rosado Jason , Donnadieu Françoise , Garcia Laura , Obadia Thomas , Gardais Soazic , Elgharbawy Yasmine , Velay Aurelie , Gonzalez Maria , Nizou Jacques Yves , Khelil Nizar , Zannis Konstantinos , Cockram Charlotte , Hélène Merkling Sarah , Meola Annalisa , Kerneis Solen , Terrier Benjamin , de Seze Jerome , Planas Delphine , Schwartz Olivier , Dejardin François , Petres Stéphane , von Platen Cassandre , Arowas Laurence , de Facci Louise Perrin , Duffy Darragh , Cheallaigh Clíona Ní , Conlon Niall , Townsend Liam , Auerswald Heidi , Backovic Marija , Hoen Bruno , Fontanet Arnaud , Mueller Ivo , Fafi-Kremer Samira , Bruel Timothée , White Michael
Published: March 2021

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a complex antibody response that varies by orders of magnitude between individuals and over time. Waning antibody levels lead to reduced sensitivity of serological diagnostic tests over time. This undermines the utility of serological surveillance as the SARS-CoV-2 pandemic progresses into its second year. Here we develop a multiplex serological test for measuring antibodies of three isotypes (IgG, IgM, IgA) to five SARS-CoV-2 antigens (Spike (S), receptor binding domain (RBD), Nucleocapsid (N), Spike subunit 2, Membrane-Envelope fusion) and the Spike proteins of four seasonal coronaviruses. We measure antibody responses in several cohorts of French and Irish hospitalized patients and healthcare workers followed for up to eleven months after symptom onset. The data are analysed with a mathematical model of antibody kinetics to quantify the duration of antibody responses accounting for inter-individual variation. One year after symptoms, we estimate that 36% (95% range: 11%, 94%) of anti-S IgG remains, 31% (9%, 89%) anti-RBD IgG remains, and 7% (1%, 31%) anti-N IgG remains. Antibodies of the IgM isotype waned more rapidly, with 9% (2%, 32%) anti-RBD IgM remaining after one year. Antibodies of the IgA isotype also waned rapidly, with 10% (3%, 38%) anti-RBD IgA remaining after one year. Quantitative measurements of antibody responses were used to train machine learning algorithms for classification of previous infection and estimation of time since infection. The resulting diagnostic test classified previous infections with 99% specificity and 98% (95% confidence interval: 94%, 99%) sensitivity, with no evidence for declining sensitivity over the time scale considered. The diagnostic test also provided accurate classification of time since infection into intervals of 0 – 3 months, 3 – 6 months, and 6 – 12 months. Finally, we present a computational method for serological reconstruction of past SARS-CoV-2 transmission using the data from this test when applied to samples from a single cross-sectional sero-prevalence survey.
A common TMPRSS2 variant protects against severe COVID-19
Authors: David Alessia , Parkinson Nicholas , Peacock Thomas P , Pairo-Castineira Erola , Khanna Tarun , Cobat Aurelie , Tenesa Albert , Sancho-Shimizu Vanessa ,   GenOMICC Investigators,   ISARIC4C Investigators, Casanova Jean-Laurent , Abel Laurent , Barclay Wendy S. , Baillie J. Kenneth , Sternberg Michael JE
Published: March 2021

Infection with SARS-CoV-2 has a wide range of clinical presentations, from asymptomatic to life-threatening. Old age is the strongest factor associated with increased COVID19-related mortality, followed by sex and pre-existing conditions. The importance of genetic and immunological factors on COVID19 outcome is also starting to emerge, as demonstrated by population studies and the discovery of damaging variants in genes controlling type I IFN immunity and of autoantibodies that neutralize type I IFNs. The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus’ spike protein, facilitating entry into target cells. We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760), which has a minor allele frequency of ∼25% in the population. In a large population of SARS-CoV-2 positive patients, we show that this variant is associated with a reduced likelihood of developing severe COVID19 (OR 0.87, 95%CI:0.79-0.97, p=0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p=1.3×10−3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, impacts the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells.

TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID19. Further studies are needed to assess the expression of the TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID19. Clinical trials are needed to confirm this.
A study of sociodemographic and clinical profiles of HIV-1 infected North Indian patients
Authors: Barik Sushanta Kumar , Tripathy Srikanth Prasad , Karunaianantham Ramesh , Pattabiraman Sathyamurthi , Yadav Virendra Singh , Singh Tej Pal , Tandon Rekha , Tomar Sheetal , Jena Srikanta , Patil Shripad A , Mohanty Keshar Kunja
Published: March 2021

The aim of this study was to analyze the sociodemographic, clinical, immunologic, and risk factors of drug-resistant (>1000 copies/ml) and virologically suppressed (<1000 to <40 copies /ml to target not detected levels) patients at the ART center, Sarojini Naidu Medical College, Agra, North India. A total of 193 patients on first-line antiretroviral therapy were included those were recruited from December 2009 to November 2016. The patients included in this study had a CD4 cell count of ≤ 350 cubic/mm. The details of Demographic, clinical, and social factors were collected in a patient information leaflet and statistically analyzed. After viral load, two groups of patients were observed. The drug-resistant group (N=58) had a viral load ≥1000 copies/ml and virologically suppressed group (N=135) had a viral load <1000 copies/ml to target not detected level. A comparison statement result was presented in both groups of drug-resistant and virologically suppressed patients. Males were observed in the highest frequency (42, 72.41%). The heterosexual mode of transmission was predominant (40, 68.96%, and 98,72.59%). The highest number of married couples and illiterates in the two groups. Tuberculosis was observed in the highest numbers in the two groups. The analysis of socioeconomic factors of North Indian patients will be a concern issue in the demographic profiles of HIV-1 patients. The clinical features, analysis would help clinicians in further therapy implementation, monitoring CD4 and Viral load counts of North Indian patients.
Development and application of an evidence-based directed acyclic graph to evaluate the associations between metal mixtures and cardiometabolic outcomes
Authors: Riseberg Emily , Melamed Rachel D. , James Katherine A. , Alderete Tanya L. , Corlin Laura
Published: March 2021

Objectives

Specifying analytic models to assess relationships among metal mixtures and cardiometabolic outcomes requires evidence-based models of the causal structures; however, such models have not been previously published. The objective of this study was to develop and evaluate a directed acyclic graph diagraming metal mixture exposure and cardiometabolic outcomes.

Methods

We conducted a systematic literature search to develop the directed acyclic graph (DAG) of metal mixtures and cardiometabolic outcomes. To evaluate consistency of the DAG, we tested the suggested conditional independence statements using linear and logistic regression analyses with data from the San Luis Valley Diabetes Study (SLVDS; n=1795). We compared the proportion of statements supported by the data to the proportion of conditional independence statements supported by 100 DAGs with the same structure but randomly permuted nodes. Next, we used our DAG to identify minimally sufficient adjustment sets needed to estimate the association between metal mixtures and cardiometabolic outcomes in the SLVDS and applied them using Bayesian kernel machine regression models.

Results

From the 42 articles included in the review, we developed an evidence-based DAG with 163 testable conditional independence statements (64% supported by SLVDS data). Only 5% of DAGs with randomly permuted nodes indicated more agreement with the data than our evidence-based DAG. We did not observe evidence for an association between metal mixtures and cardiometabolic outcomes in the pilot analysis.

Conclusions

We developed, tested, and applied an evidence-based approach to analyze associations between metal mixtures and cardiometabolic health.
Investigating the first stage of the COVID-19 pandemic in Ukraine using epidemiological and genomic data
Authors: Gankin Yuriy , Nemira Alina , Koniukhovskii Vladimir , Chowell Gerardo , Weppelmann Thomas A. , Skums Pavel , Kirpich Alexander
Published: March 2021

The novel coronavirus SARS-CoV-2 was first detected in China in December 2019 and has rapidly spread around the globe. The World Health Organization declared COVID-19 a pandemic in March 2020 just three months after the introduction of the virus. Individual nations have implemented and enforced a variety of social distancing interventions to slow the virus spread, that had different degrees of success. Understanding the role of non-pharmaceutical interventions (NPIs) on COVID-19 transmission in different settings is highly important. While most such studies have focused on China, neighboring Asian counties, Western Europe, and North America, there is a scarcity of studies for Eastern Europe. The aim of this study is to contribute to filling this gap by analyzing the characteristics of thefirst months of the epidemicin Ukraine using agent-based modelling and phylodynamics. Specifically, first we studied the dynamics of COVID-19 incidence and mortality and explored the impact of epidemic NPIs. Our stochastic model suggests, that even a small delay of weeks could have increased the number of cases by up to 50%, with the potential to overwhelm hospital systems. Second, the genomic data analysis suggests that there have been multiple introductions of SARS-CoV-2 into Ukraine during the early stages of the epidemic. Our findings support the conclusion that the implemented travel restrictions may have had limited impact on the epidemic spread. Third, the basic reproduction number for the epidemic that has been estimated independently from case counts data and from genomic data suggest sustained intra-country transmissions.
A Patient-Specific Model of Transcatheter Valve Replacement in a Bicuspid Heart Valve
Authors: McGee Orla M. , McNamara Adrian , McNamara Laoise M.
Published: March 2021

Bicuspid Aortic Valves (BAVs) are a common congenital heart disease where two cusps of the aortic heart valve become fused together, this leads to two unequally sized leaflets compared to the normal trileaflet valve. Transcatheter Aortic Valves are currently used in off-label treatmet of stenosed BAVs, however, due to the abnormal valve anatomy, debate surrounds the sizing of transcatheter valves. In this study, finite element models were developed to simulate the deployment of two different valves sizes (a 25 mm and a 27 mm) of the Lotus valve into the patient-specific aortic root geometry of a clinical stenosed BAV case. These models were used to investigate and compare the eccentricity, stress and mal-apposition of the two valve sizes. The results demonstrated that the 25 mm valve was the most suitable in terms of eccentricity and stress reduction. It was also shown that the smaller 25 mm valve size did not increase the likelihood of mal-apposition. As the 25 mm valve was deemed suitable based on current sizing algorithms, on the basis of these results traditional annulus measurement and device sizing may be suitable in the case of the Lotus valve.
Intra-epithelial non-canonical Activin A signalling safeguards prostate progenitor quiescence
Authors: Cambuli Francesco , Foletto Veronica , Alaimo Alessandro , De Felice Dario , Gandolfi Francesco , Palumbieri Maria Dilia , Zaffagni Michela , Genovesi Sacha , Lorenzoni Marco , Celotti Martina , Bertossio Emiliana , Mazzero Giosuè , Bertossi Arianna , Bisio Alessandra , Berardinelli Francesco , Antoccia Antonio , Gaspari Marco , Barbareschi Mattia , Fiorentino Michelangelo , Shen Michael M. , Loda Massimo , Romanel Alessandro , Lunardi Andrea
Published: March 2021

The healthy prostate is a relatively quiescent tissue. Yet, prostate epithelium overgrowth is a common condition during ageing, associated with urinary dysfunction and tumorigenesis. For over thirty years, TGF-β ligands have been known to induce cytostasis in a large variety of epithelia, but the intracellular pathway mediating this signal in the prostate, as well as its relevance for quiescence, have remained elusive.

Here, using mouse prostate organoids to model epithelial progenitors, we found that intra-epithelial non-canonical Activin A signalling inhibited cell proliferation in a Smad-independent manner. Mechanistically, Activin A triggered Tak1 and p38 MAPK activity, leading to p16 and p21 nuclear import. Spontaneous evasion from this quiescent state occurred upon prolonged culture, due to reduced Activin A secretion, a condition associated with DNA replication stress and aneuploidy. Organoids capable to escape quiescencein vitrowere also able to implant with increased frequency into immunocompetent mice.

Our study demonstrates that non-canonical Activin A signalling safeguards epithelial quiescence in the healthy prostate, with potential implications for the understanding of cancer initiation, and the development of therapies targeting quiescent tumour progenitors.
Reduction of genotyping marker density for genomic selection is not an affordable approach to long-term breeding in cross-pollinated crops
Authors: DoVale Júlio César , Carvalho Humberto Fanelli , Sabadin Felipe , Fritsche-Neto Roberto
Published: March 2021

The selection of informative markers has been studied massively as an alternative to reduce genotyping costs for the genomic selection (GS) application. Low-density marker panels are attractive for GS because they decrease computational time-consuming and multicollinearity beyond more individuals can be genotyped with the same cost. Nevertheless, these inferences are usually made empirically using “static” training sets and populations, which are adequate only to predict a breeding program’s initial cycles but might not for long-term cycles. Moreover, to the best of our knowledge, none of these inferences considered the inclusion of dominance into the GS models, which is particularly important to predict cross-pollinated crops. Therefore, that reveals an important and unexplored topic for allogamous long-term breeding. To achieve this goal, we employed two approaches: the former used empirical maize datasets, and the latter simulations of long-term breeding cycles of phenotypic and genomic recurrent selection (intrapopulation and reciprocal). Then, we observed the reducing marker density effect on populations (mean, the best genotypes performance, accuracy, additive variance) over cycles and models (additive, additive-dominance, specific combining ability (SCA)). Our results indicate that the markers reduction based on different linkage disequili brium (LD) levels is viable only within a cycle and brings a significant decrease in predictive ability over generations. Furthermore, in the long-term, regardless of the selection scheme adopted, the more makers, the better because they buffer LD losses caused by recombination over breeding cycles. Finally, regarding the accuracy, the additive-dominant models tend to outperform the additive ones and perform similar to the SCA.
Neural responses to natural visual motion are spatially selective across the visual field, with selectivity differing across brain areas and task
Authors: Ki Jason J , Dmochowski Jacek P , Touryan Jonathan , Parra Lucas C
Published: March 2021

It is well established that neural responses to visual stimuli are enhanced at select locations in the visual field. While spatial selectivity and the effects of spatial attention are well-understood for discrete tasks (e.g., visual cueing paradigms), little is known about neural response during a naturalistic visual experience that involves complex dynamic visual stimuli, for instance, driving. In this study, we assess the strength of neural responses across the visual space during a kart race video game. Specifically, we measure the correlation strength of scalp evoked potentials with optical flow magnitude at individual locations on the screen. We find the strongest neural responses for task-relevant locations in visual space, selectively extending to areas beyond the focus of overt attention: while the driver’s gaze is directed upon the heading direction at the center of the screen, we observe robust neural evoked responses also to peripheral areas such as the road and surrounding buildings. Importantly, this spatial selectivity of neural responses differs across scalp locations. Moreover, during active gameplay, the strength of the spatially-selective neural responses are enhanced compared to passive viewing. Spatially selective neural gains have previously been interpreted as an attentional gain mechanism. In this view, the present data suggest that different brain areas focus attention on different task-relevant portions of the visual field, reaching beyond the focus of overt attention.
Pathogenic tau disrupts the cellular program that maintains neuronal identity
Authors: Beckmann Adrian , Ramirez Paulino , Gamez Maria , Ray William J. , Frost Bess
Published: March 2021

Neurons in human Alzheimer’s disease acquire phenotypes that are also present in various cancers, including over-stabilization of the cytoskeleton, nuclear pleomorphism, decondensation of constitutive heterochromatin, and aberrant activation of the cell cycle. Unlike in cancer, in which cell cycle activation drives tumor formation, activation of the cell cycle in post-mitotic neurons is sufficient to induce neuronal death. Multiple lines of evidence suggest that abortive cell cycle activation is a consequence of pathogenic forms of tau, a protein that drives neurodegeneration in Alzheimer’s disease and related “tauopathies.” We have combined network analysis of human Alzheimer’s disease and mouse tauopathy with mechanistic studies inDrosophilato discover that pathogenic forms of tau drive abortive cell cycle activation by disrupting the cellular program that maintains neuronal identity. Mechanistically, we identify Moesin, a prognostic biomarker for cancer and mediator of the epithelial-mesenchymal transition (EMT), as a major effector of tau-induced neurotoxicity. We find that aberrant activation of Moesin in neurons acts through the actin cytoskeleton to dysregulate the cellular program that maintains neuronal identity. Our study identifies mechanistic parallels between tauopathy and cancer and sets the stage for novel therapeutic approaches.
Evaluate effects of multiple users in collaborative Brain-Computer Interfaces: A SSVEP study
Authors: Do Tien-Thong Nguyen , Huynh Thanh Tung
Published: March 2021

This study investigates the effects of collaboration on task performance in brain-computer interface (BCI) based on steady-state visually evoked potential (SSVEP). Navigation tasks were performed in a virtual environment under two conditions, e.g., individual performance and team performance. The results showed that average task completion time in the collaborative condition is decreased by 6 percent compared with that of individual performance, which is inline with other studies in collaborative BCI (cBCI) and joint decision-making. Our work is a step forward for the progress in BCI studies that include multi-user interactions.
Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays
Authors: Mulvey Bernard , Dougherty Joseph D.
Published: March 2021

Family and population studies indicate clear heritability of major depressive disorder (MDD), though its underlying biology remains unclear. The majority of single-nucleotide polymorphism (SNP) linkage blocks associated with MDD by genome-wide association studies (GWASes) are believed to alter transcriptional regulators (e.g., enhancers, promoters), based on enrichment of marks correlated with these functions. A key to understanding MDD pathophysiology will be elucidation of which SNPs are functional and how such functional variants biologically converge to elicit the disease. Furthermore, retinoids can elicit MDD in patients, and promote depressive behaviors in rodent models, acting via a regulatory system of retinoid receptor transcription factors (TFs). We therefore sought to simultaneously identify functional genetic variants and assess retinoid pathway regulation of MDD risk loci. Using Massively Parallel Reporter Assays (MPRAs), we functionally screened over 1 000 SNPs prioritized from 39 neuropsychiatric trait/disease GWAS loci, with SNPs selected based on overlap with predicted regulatory features—including expression quantitative trait loci (eQTL) and histone marks—from human brains and cell cultures. We identified >100 SNPs with allelic effects on expression in a retinoid-responsive model system. Further, functional SNPs were enriched for binding sequences of retinoic acid-receptive transcription factors (TFs); with additional allelic differences unmasked by treatment with all-transretinoic acid (ATRA). Finally, motifs overrepresented across functional SNPs corresponded to TFs highly specific to serotonergic neurons, suggesting anin vivosite of action. Our application of MPRAs to screen MDD-associated SNPs suggests a shared transcriptional regulatory program across loci, a subset of which are unmasked by retinoids.
Accounting for dispersal improves the understanding of species abundance patterns
Authors: Feng Xiao , Qiao Huijie
Published: March 2021

A long-standing question in ecology is how are species’ population distributed across space. The highest abundance has been hypothesized to be in the spatial or niche center, though mixed patterns from empirical studies has triggered a recent debate. Here we propose a conceptual framework based on environmental suitability and dispersal to interpret the mixed evidence. We demonstrate that the highest abundance could occur in the spatial center, in the niche center, or somewhere in-between the two centers, depending on the environmental setup and dispersal ability. We found that spatial and niche centers rarely overlap, suggesting the counteracting effect between the two factors, rather than reinforcement, is the norm in determining abundance patterns. The varied locations of highest abundance mirror the mixed evidence in literature, suggesting the “abundant-centre” and “abundant-niche centre” hypotheses are not mutually exclusive. This highlights the importance in understanding the biogeographic patterns through the lens of underlying mechanisms.
A STUDY OF ETIOLOGICAL AND CLINICAL PROFILE OF PATIENTS WITH LMN CRANIAL NERVE PALSY IN A TERTIARY CARE CENTER AT THANJAVUR MEDICAL COLLEGE AND HOSPITAL
Authors: Priyanka B. Nandini , Gunasekaran A. , Thangaraj M.
Published: March 2021

Background

Neurological presentation with isolated/multiple cranial nerve palsy is normal and its different causes incorporate infection, autoimmune, neoplastic, and inflammatory pathologies. The etiological range may rely on geological areas. We attempted this study to investigate the clinical range and etiological profile of numerous cranial nerve palsy.

Materials and methods

This planned observational study was led from January 2020 to January 2021. All the patients with cranial nerve palsy coming to the neurology OPD were taken for examinations. Essential targets were to characterize anatomical disorder/cranial nerve combinations and to set up etiology. The primary goals were to examine related components. Patients with neuromuscular junction disorder, anterior horn cell disease, myopathies, first and second cranial nerve dysfunction were excluded from the study. All patients went through an organized convention of clinical assessment, examinations, and few particular examinations as per clinical protocol for analysis.

Results

Cavernous sinus was the commonest anatomical condition of different cranial nerve paralyses and tuberculous disease was the commonest cause in this investigation.7thcranial nerve was the common isolated nerve involved with idiopathic ethology, diabetes was the most common cause overall found with third nerve involvement.
Multiplexed Ion Beam Imaging Readout of Single-Cell Immunoblotting
Authors: Lomeli Gabriela , Bosse Marc , Bendall Sean C. , Angelo Michael , Herr Amy E.
Published: March 2021

Improvements in single-cell protein analysis are required to study the cell-to-cell variation inherent to diseases, including cancer. Single-cell immunoblotting (scIB) offers proteoform detection specificity, but often relies on fluorescence-based readout and is therefore limited in multiplexing capability. Among rising multiplexed imaging methods is multiplexed ion beam imaging by time of flight (MIBI-TOF), a mass spectrometry imaging technology. MIBI-TOF employs metal-tagged antibodies that do not suffer from spectra overlap to the same degree as fluorophore-tagged antibodies. We report for the first-time MIBI-TOF of single-cell immunoblotting (scIB-MIBI-TOF). The scIB assay subjects single-cell lysate to protein immunoblotting on a microscale device consisting of a 50- to 75-μm thick hydrated polyacrylamide (PA) gel matrix for protein immobilization prior to in-gel immunoprobing. We confirm antibody-protein binding in the PA gel with indirect fluorescence readout of metal-tagged antibodies. Since MIBI-TOF is a layer-by-layer imaging technique, and our protein target is immobilized within a 3D PA gel layer, we characterize the protein distribution throughout the PA gel depth by fluorescence confocal microscopy and find that the highest signal-to-noise ratio is achieved by imaging the entirety of the PA gel depth. Accordingly, we report the required MIBI-TOF ion dose strength needed to image varying PA gel depths. Lastly, by imaging ~42% of PA gel depth with MIBI-TOF, we detect two isoelectrically separated TurboGFP (tGFP) proteoforms from individual glioblastoma cells, demonstrating that highly multiplexed mass spectrometry-based readout is compatible with scIB.
Context dependency of time-based event-related expectations for different modalities
Authors: Ball Felix , Andreca Julia , Noesselt Toemme
Published: March 2021

Expectations about the temporal occurrence of events (when) are often tied with the expectations about certain event-related properties (what and where) happening at these time points. For instance, slowly waking up in the morning we expect our alarm clock to go off; however, the longer we do not hear it the more likely we already missed it. However, most current evidence for complex time-based event-related expectations (TBEEs) is based on the visual modality. Here we tested whether TBEEs can also act cross-modally. To this end, visual and auditory stimulus streams were presented which contained early and late targets embedded among distractors (to maximise temporal target uncertainty). Foreperiod-modality-contingencies were manipulated run-wise so that visual targets either occurred early in 80% of trials and auditory targets occurred late in 80 % of trials or vice versa. Participants showed increased sensitivity for expected auditory early/visual late targets which increased over time while the opposite pattern was observed for visual early/auditory late targets. A benefit in reaction times was only found for auditory early trials. Together, this pattern of results suggests that context-dependent TBEEs for auditory targets after short foreperiods (be they correct or not) dominated and determined which modality became more expected at the late position irrespective of the veridical statistical regularity. Hence, TBEEs in cross-modal and uncertain environments are context-dependent, shaped by the dominant modality in temporal tasks (i.e. auditory) and only boost performance cross-modally when expectations about the event after the short foreperiod match with the run-wise context (i.e. auditory early/visual late).
Aberrant Temporal-spatial Patterns to Sad expressions in Major Depressive Disorders via Hidden Markov Model
Authors: Dai Zhongpeng , Zhang Siqi , Zhou Hongliang , Wang Xinyi , Wang Huan , Yao Zhjjian , Lu Qing
Published: March 2021

Background

The pathological mechanisms of Major depressive disorders (MDD) is associated with over-expressing of negative emotions, and the overall temporal-spatial patterns underlying over-representation in depression still remained to be revealed to date. We hypothesized that the aberrant spatio-temporal attributes of the process of sad expressions relate to MDD and help to detect depression severity.

Methods

We enrolled a total of 96 subjects including 47 MDDs and 49 healthy controls (HCs), and recorded their Magnetoencephalography data under a sad expressions recognition task. A hidden Markov model (HMM) was applied to separate the whole neural activity into several brain states, then to characterize the dynamics. To find the disrupted spatial-temporal features, power estimations and fractional occupancy of each state were contrasted between MDDs and HCs.

Results

Three states were found over the period of emotional stimuli processing procedure. The visual state was mainly distributed in early stage (0 - 270ms) and the limbic state in middle and later stage (270ms - 600ms) of the task, while the fronto-parietal state remained a steady proportion across the whole period. MDDs activated statistically more in limbic system during limbic state (p= 0.0045) and less in frontoparietal control network during fronto-parietal state (p =5.38*10−5) relative to HCs. Hamilton-Depression-Rating Scale scores was significantly correlated with the predicted severity value using the state descriptors (p= 0.0062,r= 0.3933).

Discussion

As human brain exhibited varied activation patterns under the negative stimuli, MDDs expressed disrupted temporal-spatial activated patterns across varied stages involving the primary visual perception and emotional contents processing compared to HCs, indicting disordered regulation of brain functions. Furthermore, descriptors built by HMM could be potential biomarkers for identifying the severity of depression disorders.
Rapid and automated quantification of TDP-43 and FUS mislocalisation for screening of frontotemporal dementia and amyotrophic lateral sclerosis gene variants
Authors: Oyston Lisa J. , Ubiparipovic Stephanie , Fitzpatrick Lauren , Hallupp Marianne , Boccanfuso Lauren M. , Kwok John B. , Dobson-Stone Carol
Published: March 2021

Background

Identified genetic mutations cause 20% of frontotemporal dementia (FTD) and 5-10% of amyotrophic lateral sclerosis (ALS) cases: however, for the remainder of patients the origin of the disease is uncertain. The overlap in genetic, clinical and pathological presentation of FTD and ALS suggests these two diseases are related. Post-mortem, 97% of ALS and ∼50% of FTD patients show redistribution of the nuclear proteins TDP-43 or FUS to the cytoplasm within affected neurons. We exploited this predominant neuropathological feature to develop an automated method for the quantification of cytoplasmic TDP-43 and FUS in human cell lines.

Results

Utilising fluorescently-tagged cDNA constructs to identify cells of interest, the fluorescence intensity of TDP-43 or FUS was measured in the nucleus and cytoplasm of HEK293 and SH-SY5Y cells. Confocal microscope images were input into the freely available software CellProfiler, which was used to isolate and measure the two cellular compartments. Significant increases in the amount of cytoplasmic TDP-43 and FUS were detectable in cells expressing known ALS-causativeTARDBPandFUSgene mutations. Pharmacological intervention with the apoptosis inducer staurosporine also induced measurable cytoplasmic mislocalisation of endogenous FUS. Additionally, this technique was able to detect the subtler effect of mutation in a secondary gene (CYLD) on endogenous TDP-43 localisation.

Conclusions

These findings validate this methodology as a novelin vitrotechnique for the quantification of TDP-43 or FUS mislocalisation that can be used to assess the pathogenicity of predicted FTD- or ALS-causative mutations.
The DMT and Psilocin Treatment Changes CD11b+ Activated Microglia Immunological Phenotype
Authors: Kozłowska Urszula , Klimczak Aleksandra , Wiatr Kalina , Figiel Maciej
Published: March 2021

Psychedelics are new, promising candidate molecules for clinical use in psychiatric disorders such as Treatment-Resistant Depression (TRD) and Post Traumatic Stress Disorder (PTSD). They were recently also proposed as molecules supporting neural tissue repair by anti-inflammatory properties. Here we reported that two classic psychedelics, DMT and psilocin, can influence microglial functions by reducing the level of TLR4, p65, CD80 proteins, which are markers of the immune response, and upregulat TREM2 neuroprotective receptor. Psilocin also secured neuronal survival in the neuron-microglia co-culture model by attenuating the phagocytic function of microglia. We conclude that DMT and psilocin regulate the immunomodulatory potential of microglia. Of note, psychedelics were previously reported as a relatively safe treatment approach. The demonstrated regulation of inflammatory molecules and microglia phagocytosis suggests that psychedelics or their analogs are candidates in the therapy of neurological disorders where microglia and inflammation significantly contribute to pathogenic disease mechanisms.
An Investigation into Patient-Specific 3D Printed Titanium Stents and the use of Etching to Overcome Selective Laser Melting Design Constraints
Authors: McGee Orla M. , Geraghty Sam , Hughes Celia , Jamshidi Parastoo , Kenny Damien P. , Attallah Moataz M. , Lally Caitríona
Published: March 2021

There is currently a clear clinical need in the area of stenting for paediatric patients, whereby currently commercially available adult stents are often required to be used off-label for paediatric patients resulting in less than optimal outcomes. The increasingly widespread use of CT and/or MR imaging for pre-surgical assessment, and the emergence of additive manufacturing processes such as 3D printing, could enable bespoke devices to be produced efficiently and cost-effectively. However, 3D printed metallic stents need to be self-supporting leading to limitations in the design of stents available through additive manufacturing. In this study we investigate the use of etching to overcome these design constraints and improve stent surface finish. Furthermore, using a combination of experimental bench testing and finite element methods we investigate how etching influences stent performance and using an inverse finite element approach the material properties of the printed and etched stents were calibrated and compared. Finally, using patient-specific finite element models the stent performance was tested to assess patient outcomes. Within this study, etching is confirmed as a means to create open-cell stent designs whilst conforming to additive manufacturing ‘rules’ and concomitantly improving stent surface finish. Additionally, the feasibility of using an in-vivo imaging to product development pipeline is demonstrated that enables patient-specific stents to be produced for varying anatomies to achieve optimum device performance.

Figure 1.

Graphical abstract.
Combined MEK and STAT3 inhibition reprograms stromal inflammation to overcome immunotherapy resistance in pancreatic cancer
Authors: Datta Jashodeep , Dai Xizi , Bianchi Anna , De Castro Silva Iago , Mehra Siddharth , Garrido Vanessa , Lamichhane Purushottam , Singh Samara , Zhou Zhiqun , Dosch Austin R. , Messaggio Fanuel , Ban Yuguang , Umland Oliver , Hosein Peter J. , Nagathihalli Nagaraj S. , Merchant Nipun B.
Published: March 2021

Pancreatic ductal adenocarcinoma (PDAC) is characterized by immune exclusion, pro-inflammatory polarization of cancer-associated fibroblasts (CAF), and resistance to immune checkpoint inhibition (ICI). We have previously demonstrated that reciprocally activated RAS/MEK/ERK and JAK/STAT3 pathways mediate therapeutic resistance, while combined MEK and STAT3 inhibition (MEKi+STAT3i) overcomes such resistance in preclinical models. We now show that combined MEKi+STAT3i not only alters stromal architecture but also uncovers stromal plasticity by revealing a substantial attenuation ofIl6/Cxcl1-expressing secretory andLrrc15-expressing myofibroblastic CAF phenotypes with a concomitant enrichment ofLy6a/Cd34-expressing CAF phenotypes exhibiting mesenchymal progenitor-like properties via single-cell RNA sequencing inPtf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox(PKT) mice. This remodeling of CAF heterogeneity is associated with reprogramming of immunosuppressive myeloid populations and enhanced trafficking of CD8+T-cells which exhibit a distinct effector transcriptional program. These MEKi+STAT3i-mediated repercussions are in part CAF-dependent, since CRISPR/Cas9 genetic silencing of CAF-restrictedMek1/Stat3mitigates inflammatory CAF polarization and myeloid infiltrationin vivo. Addition of MEKi+STAT3i to PD-1 blockade overcomes ICI resistance by significantly augmenting anti-tumor responses and dramatically improving survival in PKT mice compared with anti-PD-1 monotherapy. The addition of MEKi+STAT3i to PD-1 blockade not only augments the recruitment of activated and memory T-cell populations, but also improves their degranulating capacity and functional cytotoxicity compared to PD-1 blockade alone. Importantly, treatment of a patient with chemotherapy-refractory metastatic PDAC with MEKi (Trametinib), STAT3i (Ruxolitinib), and PD-1 inhibitor (Nivolumab) was well-tolerated and yielded clinical benefit. These data uncover a novel paradigm in which combined MEKi+STAT3i reprograms stromal inflammation and immune tolerance to overcome immunotherapy resistance in PDAC.
Neuronal cultures show bidirectional axonal conduction with antidromic action potentials depolarizing the soma
Authors: Mateus JC , Lopes CDF , Aroso M , Costa AR , Gerós A , Meneses J , Faria P , Neto E , Lamghari M , Sousa MM , Aguiar P
Published: March 2021

Recent technological advances are revealing the complex physiology of the axon and challenging long-standing assumptions. Namely, while most action potential (AP) initiation occurs at the axon initial segment in central nervous system neurons, initiation in distal parts of the axon has been shown to occur in both physiological and pathological conditions. However, such ectopic action potential (EAP) activity has not been reported yet in studies using neuronal cultures and its functional role, if exists, is still not clear. Here, we show the spontaneous occurrence of EAPs and effective antidromic conduction in hippocampal neuronal cultures. We also observe a significant fraction of bidirectional axonal conduction in dorsal root ganglia neuronal cultures. We investigate and characterize this antidromic propagation via a combination of microfluidics, microelectrode arrays, advanced data analysis andin silicostudies. We show that EAPs and antidromic conduction can occur spontaneously, and after distal axotomy or physiological changes in the axon biochemical environment. Conduction velocity is asymmetrical, with antidromic conduction being slower than orthodromic. Importantly, EAPs may carry information and can have a functional impact on the neuron, as they consistently depolarize the soma. Thus, plasticity or gene transduction mechanisms triggered by soma depolarization can also be affected by these antidromic APs. Altogether these findings have important implications for the study of neuronal functionin vitro, reshaping our understanding on how information flows in neuronal cultures.
Hypothalamic perineuronal nets are regulated by sex and dietary interventions
Authors: Zhang Nan , Yan Zili , Liu Hailan , Yu Meng , He Yang , Liu Hesong , Liang Chen , Tu Longlong , Wang Lina , Yin Na , Han Junying , Scarcelli Nikolas , Yang Yongjie , Wang Chunmei , Zeng Tianshu , Chen Lu-Lu , Xu Yong
Published: March 2021

Perineuronal nets (PNNs) are widely present in the hypothalamus, and are thought to provide physical protection and ion buffering for neurons, and regulate their synaptic plasticity and intracellular signaling. Recent evidence indicates that PNNs in the mediobasal hypothalamus plays an important role in the regulation of glucose homeostasis. However, whether and how hypothalamic PNNs are regulated are not fully understood. In the present study, we examined whether PNNs in various hypothalamic regions in mice can be regulated by sex, gonadal hormones, dietary interventions, or their interactions. We demonstrated that gonadal hormones are required to maintain normal PNNs in the arcuate nucleus of hypothalamus in both male and female mice. In addition, PNNs in the terete hypothalamic nucleus display a sexual dimorphism with females higher than males, and high-fat diet feeding increases terete PNNs only in female mice but not in male mice. On the other hand, PNNs in other hypothalamic regions are not influenced by sex, gonadal hormones or dietary interventions. In summary, we demonstrated that hypothalamic PNNs are regulated in a region-specific manner and these results provide a framework to further investigate the potential functions of PNNs in regulating energy/glucose homeostasis at the interplay of sex, gonadal hormones and diets.
Impaired Cx43 gap junction endocytosis causes cardiovascular defects in zebrafish
Authors: Hyland Caitlin , Mfarej Michael , Hiotis Giorgos , Lancaster Sabrina , Novak Noelle , Kathryn Iovine M. , Falk Matthias M.
Published: March 2021

Gap junction proteins, termed connexins (Cx), mediate direct cell-to-cell communication by forming channels that physically couple cells, thereby linking their cytoplasm, permitting exchange of molecules, ions, and electrical impulses. The most ubiquitously expressed gap junction protein, connexin43 (Cx43) has been implicated in cardiovascular diseases including arrhythmias, cardiomyopathies, hypertension and diabetes. The Cx43 C-terminal (CT) domain serves as the regulatory hub of the protein affecting all aspects of gap junction function. Here, deletion within the Cx43 CT (amino acids 256-289), a region known to encode key residues regulating gap junction turnover is employed to examine the effects of dysregulated Cx43 gap junction endocytosis using cultured cells (Cx43Δ256-289) and zebrafish model (cx43lh10). We report that this CT deletion causes defective gap junction endocytosis as well as increased gap junction intercellular communication (GJIC). Increased Cx43 protein content in cx43lh10zebrafish, specifically in the cardiac tissue, larger gap junction plaques and longer Cx43 protein half-lives coincide with severely impaired cardiovascular development. These findings suggest that normal, unimpaired Cx43 gap junction endocytosis and turnover is an essential aspect of gap junction function as demonstrated here for cardiovascular development that when impaired can give rise to arrhythmias, heart malformations and aberrant vasculature structure and function.
Habitual Coffee Consumption Increases Risks for Metabolic Diseases: Genome-wide Association Studies and a Phenotype-wide Two Sample Mendelian Randomization Analysis
Authors: Li Jiuling , Choudhury Tasnim , Zhang Miaoran , Chen Lanlan , Wen Jianping , Liu Wanqing , Chen Peng
Published: March 2021

Background and aims

Coffee is one of the most widely consumed beverages in the world and has received considerable concerns regarding its impact on human health. Mendelian randomization (MR) could be valuable to explore the potential health effects of coffee via instrumental variables. In this study, we aim to identify novel genetic loci associated with habitual coffee consumption using genome-wide meta-analysis (GWMA) and to evaluate the broad impact of coffee consumption on human health and disease risk via a large-scale, phenotype-wide, two sample Mendelian randomization (TSMR) analysis.

Methods

We conducted a genome-wide association study (GWAS) among 283,926 coffee consumers of European ancestry in the UK Biobank (UKBB) to identify single nucleotide polymorphisms (SNPs) associated with the amount of coffee consumption (cups/day, GWAS 1), caffeine intake (GWAS 2) as well as the intake of non-caffeine substance in coffee (GWAS 3). The GWAS 1 results were further combined with the published results from the Coffee and Caffeine Genetics Consortium (CCGC) for a GWMA. TSMR were performed to evaluate the causal-relationship between coffee/caffeine/non-caffeine substance consumption and 1,101 diseases and health traits.

Results

The GWMA identified 50 lead SNPs among 19 genomic regions for habitual coffee consumption. Nine out of the 19 loci were novel, including ADAMTSL4-AS1, CACNA2D2, LINC02123-ADCY2, UBD-SNORD32B, SEMA4D-GADD45G, LOC101929457-LINGO1, RAI1, HCN2,and BRWD1. The GWAS 2 and 3 identified 2 (SORCS2 and SLC39A8) and 5 (LINC02060-LINC00461, AGR3-AHR, PRR4-TAS2R14, CYP1A1-CYP1A2, and FTO) genomic regions, respectively. TSMR analysis indicated that coffee consumption increased the risk of high blood lipids, obesity, and diabetes. Meanwhile, intake of caffeine and non-caffeine coffee components decreased and increased some of the blood lipids levels, respectively.

Conclusions

Our study provided evidence that habitual coffee consumption could increase the risk of metabolic perturbations. The bioactive components in coffee, other than caffeine, may be more harmful to human health. Our findings have significant implications for global public health given the increasing burden of metabolic diseases.