bluuebunny/crossref_metadata_2025 huggingface dataset:
Transient Clozapine-induced Myocarditis Without Discontinuation of Medication: A Series of 2 Patients
Authors: Klein Nadav , Barnett Laura , Guirgis Hossam , Stearns Walter H.
Published: March 2022

Background:

Clozapine, an antipsychotic medication used to treat treatment-refractory schizophrenia, has been associated with various dangerous side effects, including myocarditis. However, there have been few published cases reporting on patients with clozapine-induced myocarditis confirmed by cardiac magnetic resonance imaging or the management, treatment, and follow-up of these patients.

Methods:

This report describes 2 cases of patients with treatment-refractory schizophrenia evidencing transient clozapine-induced myocarditis. Detailed information including laboratory values, imaging results, and clinical notes were gathered.

Findings:

The 2 cases demonstrated differing manifestations of clozapine-induced myocarditis. Both cases showed that such myocarditis can be transient and can be treated clinically with close observation without discontinuation of clozapine.

Implications:

These cases show that clozapine-induced myocarditis is transient at times and can self-resolve without discontinuation of clozapine. These observations may suggest a change in clinical practice so that, with close observation, we can avoid risking psychiatric decompensation in select patients with a history of treatment-resistant schizophrenia.
Anosognosia and Memory Encoding in Huntington Disease
Authors: Considine Ciaran Michael , Hughes Shelby , Sellers Gibson Jessie , Isaacs David , McDonell Katherine , Darby R. Ryan , Claassen Daniel
Published: March 2022

Background:

Anosognosia can manifest as an unawareness of neurobehavioral symptoms in individuals with Huntington disease (HD). Measurement of anosognosia is challenging, but the Anosognosia Scale (AS) represents a brief option with promising findings in small samples.

Objective:

To replicate application of the AS in a larger HD sample than previous studies in order to assess psychometrics and demographic correlates and to investigate the genetic, motor, and neuropsychological correlates of the AS in individuals with HD.

Method:

We retrospectively reviewed the AS ratings of 74 genetically confirmed Huntington gene carriers, nearly all early motor manifest, who had been referred for clinical neuropsychological assessment. Concurrent clinical neurologic examination and neuropsychometric assessment data were compiled, where available (ns = 35–74). The severity of the anosognosia per AS ratings was characterized for the HD sample.

Results:

The AS ratings did not correlate with demographic variables, genetic markers, or motor dysfunction severity. Correlation analyses revealed that higher AS ratings correlated with worse recognition–discrimination memory performance (r = 0.38, P < 0.05) but not cognitive control on executive functioning performance or on collateral-reported frontal–behavioral symptoms. Higher AS ratings also correlated with fewer patient-reported depressive symptoms (r = –0.38, P < 0.01) and diurnal hypersomnia symptoms (r = –0.44, P < 0.01).

Conclusion:

Anosognosia (per AS) is associated with recognition–discrimination deficits and fewer self-reported neuropsychiatric symptoms in individuals with pre-to-early manifest HD, though not with HD severity per genetic or motor markers, nor to executive dysfunction or collateral-reported frontal–behavioral symptoms.
Developing a Standardized Approach to Grading the Level of Brain Dysfunction on EEG
Authors: Dhakar Monica B. , Sheikh Zubeda B. , Desai Masoom , Desai Raj A. , Sternberg Eliezer J. , Popescu Cristina , Baron-Lee Jacqueline , Rampal Nishi , Hirsch Lawrence J. , Gilmore Emily J. , Maciel Carolina B.
Published: March 2022

Purpose:

To assess variability in interpretation of electroencephalogram (EEG) background activity and qualitative grading of cerebral dysfunction based on EEG findings, including which EEG features are deemed most important in this determination.

Methods:

A web-based survey (Qualtrics) was disseminated to electroencephalographers practicing in institutions participating in the Critical Care EEG Monitoring Research Consortium between May 2017 and August 2018. Respondents answered 12 questions pertaining to their training and EEG interpretation practices and graded 40 EEG segments (15-second epochs depicting patients' most stimulated state) using a 6-grade scale. Fleiss' Kappa statistic evaluated interrater agreement.

Results:

Of 110 respondents, 78.2% were attending electroencephalographers with a mean of 8.3 years of experience beyond training. Despite 83% supporting the need for a standardized approach to interpreting the degree of dysfunction on EEG, only 13.6% used a previously published or an institutional grading scale. The overall interrater agreement was fair (k = 0.35). Having Critical Care EEG Monitoring Research Consortium nomenclature certification (40.9%) or EEG board certification (70%) did not improve interrater agreement (k = 0.26). Predominant awake frequencies and posterior dominant rhythm were ranked as the most important variables in grading background dysfunction, followed by continuity and reactivity.

Conclusions:

Despite the preference for a standardized grading scale for background EEG interpretation, the lack of interrater agreement on levels of dysfunction even among experienced academic electroencephalographers unveils a barrier to the widespread use of EEG as a clinical and research neuromonitoring tool. There was reasonable agreement on the features that are most important in this determination. A standardized approach to grading cerebral dysfunction, currently used by the authors, and based on this work, is proposed.
Variation in hospital cost trajectories at the end of life by age, multimorbidity and cancer type
Authors: Diernberger Katharina , Luta Xhyljeta , Bowden Joanna , Droney Joanne , Lemmon Elizabeth , Tramonti Giovanni , Shinkins Bethany , Gray Ewan , Marti Joachim , Hall Peter S
Published: March 2022

Background

Approximately thirty thousand people in Scotland are diagnosed with cancer annually, of whom a third live less than one year. The timing, nature and value of hospital-based healthcare for patients with advanced cancer are not well understood. The aim of this study was to describe patterns of hospital-based healthcare use and associated costs in the last year of life for patients with a cancer diagnosis.

Methods

We undertook a Scottish population-wide administrative data linkage study of hospital-based healthcare use for individuals with a cancer diagnosis aged 60 years and over on their date of death, who died between 2012 and 2017. Hospital admissions, length of stay (LOS), number and nature of outpatient and day case appointments were analysed for all cancer types. Generalised linear models were used to adjust costs for age, gender, socioeconomic deprivation status, rural-urban (RU) status and comorbidity.

Results

The study included 85,732 decedents with a cancer diagnosis, for whom 64,553 (75.3%) cancer was the primary cause of death. Mean age at death was 80.01 (SD 8.15) years. The mean number of inpatient stays in the last year of life was 5.88 (SD 5.68), with a mean LOS of 7 days. Mean total inpatient, outpatient and daycase costs per patient were £10261, £1275 and £977 respectively. Admission rates rose sharply in the last month of life. One year adjusted and unadjusted costs decreased with increasing age. A higher comorbidity burden was associated with higher costs and major cost differences between cancer types were also observed.

Conclusions

People in Scotland in their last year of life with cancer are high users of secondary care. Hospitalisation accounts for a high proportion of costs, particularly in the last month of life. Further research is needed to examine triggers for unplanned hospitalisation and to identify modifiable reasons for variation in hospital use among different cancer cohorts.
Using Twitter Data for Cohort Studies of Drug Safety in Pregnancy: A Proof-of-Concept with Beta-Blockers
Authors: Klein Ari Z. , O’Connor Karen , Levine Lisa D. , Gonzalez-Hernandez Graciela
Published: March 2022

Background

Despite that medication is taken during more than 90% of pregnancies, the fetal risk for most medications is unknown, and the majority of medications have no data regarding safety in pregnancy.

Objective

Using beta-blockers as a proof-of-concept, the primary objective of this study was to assess the utility of Twitter data for a cohort study design—in particular, whether we could identify (1) Twitter users who have posted tweets reporting that they took a beta-blocker during pregnancy and (2) their associated pregnancy outcomes.

Methods

We searched for mentions of beta-blockers in 2.75 billion tweets posted by 415,690 users who announced their pregnancy on Twitter. We manually reviewed the matching tweets to first determine if the user actually took the beta-blocker mentioned in the tweet. Then, to help determine if the beta-blocker was taken during pregnancy, we used the timestamp of the tweet reporting intake and drew upon an automated natural language processing (NLP) tool that estimates the date of the user’s prenatal time period. For users who posted tweets indicating that they took or may have taken the beta-blocker during pregnancy, we drew upon additional NLP tools to help identify tweets that report their adverse pregnancy outcomes, including miscarriage, stillbirth, preterm birth, low birth weight, birth defects, and neonatal intensive care unit admission.

Results

We retrieved 5114 tweets, posted by 2339 users, that mention a beta-blocker, and manually identified 2332 (45.6%) tweets, posted by 1195 (51.1%) of the users, that self-report taking the beta-blocker. We were able to estimate the date of the prenatal time period for 356 pregnancies among 334 (27.9%) of these 1195 users. Among these 356 pregnancies, we identified 257 (72.2%) during which the beta-blocker was or may have been taken. We manually verified an adverse pregnancy outcome—preterm birth, neonatal intensive care unit admission, low birth weight, birth defects, or miscarriage—for 38 (14.8%) of these 257 pregnancies.

Conclusions

Our ability to detect pregnancy outcomes for Twitter users who posted tweets reporting that they took or may have taken a beta-blocker during pregnancy suggests that Twitter can be a complementary resource for cohort studies of drug safety in pregnancy.
Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19
Authors: Carmona-Rivera Carmelo , Zhang Yu , Dobbs Kerry , Markowitz Tovah E. , Dalgard Clifton L. , Oler Andrew J. , Claybaugh Dillon R. , Draper Deborah , Truong Meng , Delmonte Ottavia M. , Licciardi Francesco , Ramenghi Ugo , Crescenzio Nicoletta , Imberti Luisa , Sottini Alessandra , Quaresima Virginia , Fiorini Chiara , Discepolo Valentina , Vecchio Andrea Lo , Guarino Alfredo , Pierri Luca , Catzola Andrea , Biondi Andrea , Bonfanti Paolo , Harlowe Maria Cecilia Poli , Espinosa Yasmin , Astudillo Camila , Rey-Jurado Emma , Vial Cecilia , de la Cruz Javiera , Gonzalez Ricardo , Pinera Cecilia , Mays Jacqueline W. , Ng Ashley , Platt Andrew ,   NIH COVID Autopsy Consortium,   COVID STORM Clinicians, Drolet Beth , Moon John , Cowen Edward W. , Kenney Heather , Weber Sarah E. , Castagnoli Riccardo , Magliocco Mary , Stack Michael A. , Montealegre Gina , Barron Karyl , Hewitt Stephen M. , Arkin Lisa M. , Chertow Daniel S. , Su Helen C. , Notarangelo Luigi D. , Kaplan Mariana J.
Published: March 2022

Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease including MIS-C and chilblain-like lesions (CLL), otherwise known as “COVID toes”, remains unclear. Studying multinational cohorts, we found that, in CLL, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs post-disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased levels of NETs when compared to other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.

NET formation and degradation are dysregulated in pediatric and symptomatic adult patients with various complications of COVID-19, in association with disease severity. NET degradation impairments are multifactorial and associated with natural inhibitors of DNase 1, G-actin and anti-DNase1L3 and anti-NET antibodies. Infection with the Omicron variant is associated with decreased levels of NETs when compared to other SARS-CoV-2 strains.
EpiBERTope: a sequence-based pre-trained BERT model improves linear and structural epitope prediction by learning long-distance protein interactions effectively
Authors: Park Minjun , Seo Seung-woo , Park Eunyoung , Kim Jinhan
Published: March 2022

Motivation

Epitopes are the immunogenic regions of antigen that are recognized by antibodies in a highly specific manner to trigger an immune response. Predicting such regions is extremely difficult yet contains profound implications for complex mechanisms of humoral immunogenicity.

Results

Here, we present a BERT-based epitope prediction model called EpiBERTope, a pre-trained model on the Swiss-Prot protein database, which can predict both linear and structural epitopes using protein sequences only. The model achieves an AUC of 0.922 and 0.667 for linear and structural epitope datasets respectively, outperforming all benchmark classification models including random forest, gradient boosting, naive Bayesian, and support vector machine models. In conclusion, EpiBERTope is a sequence-based model that captures content-based global interactions of antigen sequences, which will be transformative in epitope discovery with high specificity.

Contact

minjun.park@standigm.com
Dynamic molecular evolution of a supergene with suppressed recombination in white-throated sparrows
Authors: Jeong Hyeonsoo , Baran Nicole M. , Sun Dan , Chatterjee Paramita , Layman Thomas S. , Balakrishnan Christopher N. , Maney Donna L. , Yi Soojin V.
Published: March 2022

In white throated sparrows, two alternative morphs differing in plumage and behavior segregate with a large chromosomal rearrangement. As with sex chromosomes such as the mammalian Y, the rearranged version of chromosome two (ZAL2m) is in a near-constant state of heterozygosity, offering opportunities to investigate both degenerative and selective processes during the early evolutionary stages of ‘supergenes.’ Here, we generated, synthesized, and analyzed extensive genome-scale data to better understand the forces shaping the evolution of the ZAL2m chromosome in this species. We found that features of ZAL2m are consistent with substantially reduced recombination and low levels of degeneration. We also found evidence that selective sweeps took place both on ZAL2m and its standard counterpart, ZAL2, after the rearrangement event. Signatures of positive selection were associated with allelic bias in gene expression, suggesting that antagonistic selection has operated on gene regulation. Finally, we discovered a region exhibiting two long-range haplotypes inside the rearrangement on ZAL2m. These two haplotypes appear to have been maintained by balancing selection, retaining genetic diversity within the supergene. Together, our analyses illuminate mechanisms contributing to the evolution of a young chromosomal polymorphism, revealing complex selective processes acting concurrently with genetic degeneration to drive the evolution of supergenes.
Triple Negative Breast Cancer-derived Small Extracellular Vesicles as Modulator of Biomechanics in target cells
Authors: Senigagliesi Beatrice , Samperi Giuseppe , Cefarin Nicola , Gneo Luciana , Petrosino Sara , Apollonio Mattia , Caponnetto Federica , Sgarra Riccardo , Collavin Licio , Cesselli Daniela , Casalis Loredana , Parisse Pietro
Published: March 2022

Extracellular vesicle (EV) mediated communication has recently been proposed as one of the pivotal routes in the development of cancer metastasis. EVs are nano-sized vesicles swapped between cells, carrying a biologically active content that can promote tumor–induced immune suppression, metastasis and angiogenesis. Thus, EVs constitute a potential target in cancer therapy. However, their role in triggering the premetastatic niche and in tumor spreading is still unclear. Here, we focused on the EV ability to modulate the biomechanical properties of target cells, known to play a crucial role in metastatic spreading. To this purpose, we isolated and thoroughly characterized triple-negative breast cancer (TNBC)-derived small EVs. We then evaluated variations in the mechanical properties (cell stiffness, cytoskeleton/nuclear/morphology and Yap activity rearrangements) of non-metastatic breast cancer MCF7 cells upon EV treatment. Our results suggest that TNBC-derived small EVs are able to directly modify MCF7 cells by inducing a decrease in cell stiffness, rearrangements in cytoskeleton, focal adhesions and nuclear/cellular morphology, and an increase in Yap downstream gene expression. Testing the biomechanical response of cells after EV addition might represent a new functional assay in metastatic cancer framework that can be exploited for future application both in diagnosis and in therapy.
Transcriptome and DNA methylome dynamics reveal differential characteristics of inflorescence development between two ecotypes in Panicum hallii
Authors: Weng Xiaoyu , Song Haili , Sreedasyam Avinash , Haque Taslima , Zhang Li , Chen Cindy , Yoshinaga Yuko , Williams Melissa , O’Malley Ronan C. , Grimwood Jane , Schmutz Jeremy , Juenger Thomas E.
Published: March 2022

The morphological diversity of the inflorescence determines flower and seed production, which is critical for plant adaptation and fitness. Cytosine methylation is an epigenetic mark that contributes to gene expression regulation during inflorescence development. Panicum hallii is a wild perennial grass in the subfamily Panicoideae that has been developed as a model to study perennial grass biology and adaptive evolution. Highly divergent inflorescences have evolved between the two major ecotypes in P. hallii, the upland ecotype with compact inflorescence and large seed and the lowland ecotype with an open inflorescence and small seed. Here we performed a comparative transcriptome and DNA methylome analysis across different stages of inflorescence between these two divergent ecotypes of P. hallii. Global transcriptome analysis identified differentially expressed genes (DEGs) involved in panicle divergence, stage-specific expression, and co-expression modules underlying inflorescence development. Comparing DNA methylome profiles revealed a remarkable level of differential DNA methylation associated with the evolution of the P. hallii inflorescence. We found that most differentially methylated regions (DMRs) occurred within the flanking regulatory regions of genes, especially the promoter. Integrative analysis of DEGs and DMRs characterized the global features of DMR-associated DEGs in the divergence of P. hallii inflorescence, which includes homologs of important inflorescence and seed developmental genes that have been previously identified in domesticated crops. Evolutionary analysis measured by Ka/Ks ratio suggested that most DMR-associated DEGs are under relatively strong purifying selection. This study provides insights into the transcriptome and epigenetic landscape of inflorescence divergence in P. hallii and a novel genomic resource for perennial grass biology.

One sentence summary:

A comparative transcriptome and DNA methylome analysis of inflorescence between upland and lowland ecotypes reveal gene expression and DNA methylation variation underlying inflorescence divergence in Panicum hallii.
Magnetoencephalography can reveal deep brain network activities linked to memory processes
Authors: López-Madrona Víctor J. , Villalon Samuel Medina , Badier Jean-Michel , Trébuchon Agnès , Jayabal Velmurugan , Bartolomei Fabrice , Carron Romain , Barborica Andrei , Vulliémoz Serge , Alario F. Xavier , Bénar Christian G.
Published: March 2022

Recording from deep neural structures such as hippocampus non-invasively and yet with high temporal resolution remains a major challenge for human neuroscience. Although it has been proposed that deep neuronal activity might be recordable during cognitive tasks using magnetoencephalography (MEG), this remains to be demonstrated as the contribution of deep structures to MEG recordings may be too small to be detected or might be eclipsed by the activity of large-scale neocortical networks. In the present study, we disentangled mesial activity and large-scale networks from the MEG signals thanks to blind source separation (BSS). We then validated the MEG BSS components using intracerebral EEG signals recorded simultaneously in patients during their presurgical evaluation of epilepsy. In the MEG signals obtained during a memory task involving the recognition of old and new images, we identified with BSS a putative mesial component, which was present in all patients and all control subjects. The time course of the component selectively correlated with SEEG signals recorded from hippocampus and rhinal cortex, thus confirming its mesial origin. This finding complements previous studies with epileptic activity and opens new possibilities for using MEG to study deep brain structures in cognition and in brain disorders.
The endoplasmic reticulum in perisynaptic astrocytic processes: shape, distribution and effect on calcium activity
Authors: Denizot Audrey , Veloz Castillo María Fernanda , Puchenkov Pavel , Calì Corrado , De Schutter Erik
Published: March 2022

Astrocytes recently emerged as key regulators of information processing in the brain. Ca2+ signals in perisynaptic astrocytic processes (PAPs) notably allow astrocytes to fine-tune neurotransmission at so-called tripartite synapses. As most PAPs are below the diffraction limit, their content in Ca2+ stores and the contribution of the latter to astrocytic Ca2+ activity is unclear. Here, we reconstruct tripartite synapses in 3D from electron microscopy and find that 75% of PAPs contain some endoplasmic reticulum (ER), a major astrocytic Ca2+ store, displaying strikingly diverse geometrical properties. To investigate the role of such spatial properties, we implemented an algorithm that creates 3D PAP meshes of various ER distributions and constant shape. Reaction-diffusion simulations in those meshes reveal that astrocyte activity is shaped by a complex interplay between the location of Ca2+ channels, Ca2+ buffering, ER shape and distribution. Overall, this study sheds new light into mechanisms regulating signal transmission in the brain.
Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation
Authors: Yshii Lidia , Pasciuto Emanuela , Bielefeld Pascal , Mascali Loriana , Lemaitre Pierre , Marino Marika , Dooley James , Kouser Lubna , Verschoren Stijn , Lagou Vasiliki , Kemps Hannelore , Gervois Pascal , de Boer Antina , Burton Oliver T. , Wahis Jérôme , Verhaert Jens , Tareen Samar , Roca Carlos P. , Singh Kailash , Whyte Carly E. , Kerstens Axelle , Callaerts-Vegh Zsuzsanna , Poovathingal Suresh , Prezzemolo Teresa , Wierda Keimpe , Dashwood Amy , Xie Junhua , Van Wonterghem Elien , Creemers Eline , Aloulou Meryem , Gsell Willy , Abiega Oihane , Munck Sebastian , Vandenbroucke Roosmarijn E. , Bronckaers Annelies , Lemmens Robin , De Strooper Bart , Van Den Bosch Ludo , Himmelreich Uwe , Fitzsimons Carlos P. , Holt Matthew G. , Liston Adrian
Published: March 2022

The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune-modulation and a delivery system capable of crossing the blood-brain-barrier. The recent identification and characterization of a small population of regulatory T cells (Tregs) resident in the brain presents one such potential therapeutic target. Here we identified brain IL2 levels as a limiting factor for brain-resident Tregs. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially-direct delivery to inflammatory sites. Mice with brain-specific IL2 delivery were protected from traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL2 gene-delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.
Human hippocampal responses to network intracranial stimulation vary with theta phase
Authors: Lurie Sarah M. , Kragel James E. , Schuele Stephan U. , Voss Joel L.
Published: March 2022

Hippocampal-dependent memory is thought to be supported by distinct connectivity states, with strong input to the hippocampus benefitting encoding and weak input benefitting retrieval. Previous research in rodents suggests that the hippocampal theta oscillation orchestrates the transition between these states, with opposite phase angles predicting minimal versus maximal input. We investigated whether this phase dependence exists in humans using network-targeted intracranial stimulation. Intracranial local field potentials were recorded from individuals with epilepsy undergoing medically necessary stereotactic electroencephalographic recording. In each subject, biphasic bipolar direct electrical stimulation was delivered to lateral temporal sites with demonstrated connectivity to hippocampus. Lateral temporal stimulation evoked ipsilateral hippocampal potentials with distinct early and late components. Using evoked component amplitude to measure functional connectivity, we assessed whether the phase of hippocampal theta predicted relatively high versus low connectivity. We observed an increase in the continuous phase-amplitude relationship selective to the early and late components of the response evoked by lateral temporal stimulation. The maximal difference in these evoked component amplitudes occurred across 180 degrees of separation in the hippocampal theta rhythm; i.e., the greatest difference in component amplitude was observed when stimulation was delivered at theta peak versus trough. The pattern of theta phase dependence observed for hippocampus was not identified for control locations. These findings demonstrate that hippocampal receptivity to input varies with theta phase, suggesting that theta phase reflects connectivity states of human hippocampal networks. These findings confirm a putative mechanism by which neural oscillations modulate human hippocampal function.
New Insights on the Evolutionary Relationships Between the Major Lineages of Amoebozoa
Authors: Tekle Yonas I. , Wang Fang , Wood Fiona C. , Anderson O. Roger , Smirnov Alexey
Published: March 2022

The supergroup Amoebozoa unites a wide diversity of amoeboid organisms and encompasses enigmatic lineages recalcitrant to modern phylogenetics. Deep divergences, taxonomic placement of some key taxa and character evolution in the group largely remain poorly elucidated or controversial. We surveyed available Amoebozoa genomes and transcriptomes to mine conserved putative single copy genes, which were used to enrich gene sampling and generate the largest supermatrix (824 genes) in the group to date. We recovered a well-resolved and supported tree of Amoebozoa, revealing novel deep level relationships and resolving placement of enigmatic lineages congruent with morphological data. In our analysis the deepest branching group is Tubulinea. A recent proposed major clade Tevosa, uniting Evosea and Tubulinea, is not supported. Based on the new phylogenetic tree, paleoecological and paleontological data as well as data on the biology of presently living amoebozoans, we hypothesize that the evolution of Amoebozoa probably was driven with the need to disrupt and graze on microbial mats - a dominant ecosystem of the mid-Proterozoic period of the Earth history.
A feature-specific prediction error model explains dopaminergic heterogeneity
Authors: Lee Rachel S. , Sagiv Yotam , Engelhard Ben , Witten Ilana B. , Daw Nathaniel D.
Published: March 2022

The hypothesis that midbrain dopamine (DA) neurons broadcast an error for the prediction of reward (reward prediction error, RPE) is among the great successes of computational neuroscience1–3. However, recent results contradict a core aspect of this theory: that the neurons uniformly convey a scalar, global signal. For instance, when animals are placed in a high-dimensional environment, DA neurons in the ventral tegmental area (VTA) display substantial heterogeneity in the features to which they respond, while also having more consistent RPE-like responses at the time of reward4. We argue that the previously predominant family of extensions to the RPE model, which replicate the classic model in multiple parallel circuits, are ill-suited to explaining these and other results concerning DA heterogeneity within the VTA. Instead, we introduce a complementary “feature-specific RPE” model positing that DA neurons within VTA report individual RPEs for different elements of a population vector code for an animal’s state (moment-to-moment situation). To investigate this claim, we train a deep reinforcement learning model on a navigation and decision-making task and compare the feature-specific RPE derived from the network to population recordings from DA neurons during the same task. The model recapitulates key aspects of VTA DA neuron heterogeneity. Further, we show how our framework can be extended to explain patterns of heterogeneity in action responses reported among SNc DA neurons5. Thus, our work provides a path to reconcile new observations of DA neuron heterogeneity with classic ideas about RPE coding, while also providing a new perspective on how the brain performs reinforcement learning in high dimensional environments.
Chronic obstructive pulmonary disease and cigarette smoke exposure lead to dysregulated MAIT cell activation by bronchial epithelial cells
Authors: Huber Megan E. , Larson Emily , Lust Taylor N. , Heisler Chelsea M. , Harriff Melanie J.
Published: March 2022

Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation, increased infiltration by CD8+ T lymphocytes, and infection-driven exacerbations. COPD is most commonly caused by cigarette smoke (CS), however the mechanisms driving development of COPD in some smokers but not others are incompletely understood. Lung-resident mucosal-associated invariant T (MAIT) cells play a role in both microbial infections and inflammatory diseases. MAIT cell frequency is reduced in the peripheral blood of individuals with COPD, however the role of MAIT cells in COPD pathology is unknown. Here, we examined MAIT cell activation in response to CS-exposed primary human bronchial epithelial cells (BEC) from healthy, COPD, or smoker donors. We observed significantly higher MAIT cell responses to COPD BEC than healthy BEC. However, COPD BEC stimulated a smaller fold-increase in MAIT cell response despite increased microbial infection. For all donor groups, CS-exposed BEC elicited reduced MAIT cell responses; conversely, CS exposure increased ligand-mediated MR1 surface translocation in healthy and COPD BEC. Our data demonstrate MAIT cell activation is dysregulated in the context of CS and COPD. MAIT cells could contribute to CS- and COPD-associated inflammation through both inappropriate activation and reduced early recognition of bacterial infection, contributing to microbial persistence and COPD exacerbations.
Mutations in Parkinsonism-linked endocytic proteins synaptojanin1 and auxilin have synergistic effects on dopaminergic axonal pathology
Authors: Ng Xin Yi , Wu Yumei , Lin Youneng , Yaqoob Sidra Mohamed , Greene Lois E. , Camilli Pietro De , Cao Mian
Published: March 2022

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by defective dopaminergic (DAergic) input to the striatum. Mutations in two genes encoding synaptically enriched clathrin-uncoating factors, synaptojanin 1 (SJ1) and auxilin, have been implicated in atypical Parkinsonism. SJ1 knock-in (SJ1-KIRQ) mice carrying a disease-linked mutation display neurological manifestations reminiscent of Parkinsonism. Here we report that auxilin knockout (Aux-KO) mice display dystrophic changes of a subset of nigrostriatal DAergic terminals similar to those of SJ1-KIRQmice. Furthermore, Aux-KO/SJ1-KIRQdouble mutant mice have shorter lifespan and more severe synaptic defects than single mutant mice. These include increase in dystrophic striatal nerve terminals positive for DAergic markers and for the PD risk protein SV2C, as well as adaptive changes in striatal interneurons. The synergistic effect of the two mutations demonstrates a special lability of DAergic neurons to defects in clathrin uncoating, with implications for PD pathogenesis in at least some forms of this condition.
Protein-protein interaction map in pre-eclampsia through the interaction of hub genes, transcription factors and microRNAs
Authors: Guttula Praveen Kumar , Agrawal Kirti , Gupta Mukesh Kumar
Published: March 2022

Pre-eclampsia causes complications in pregnancy and characterized by uremia, proteinuria and hypertension in unattended cases. Blood biomarkers for pre-eclampsia are lacking. In this study, microarray gene expression data from peripheral blood of pre-eclampsia women was analyzed. In our study we developed a combined network approach for hub node prediction regulated by transcription factors and microRNAs corresponding to pre-eclampsia. Differentially expressed genes (DEGs) interaction map was constructed using STRING database. JUN, RPL35, NDUFB2, ATP5I, UQCRQ, COX7C, and FN1 were predicted as potential novel hub genes. Pathway analysis showed metabolic pathways, cytokine signaling in the immune system, Wnt, and MAPK signaling pathways involvement in pre-eclampsia. Regulatory network analysis showed that transcription factors JUN and STAT1 were connected with hub nodes, and microRNAs (miRNAs) like hsa-miR-26b-5p and hsa-miR-155-5p. In conclusion, the expression pattern of hub genes, analyzed deciphers a molecular signature for understanding the pathophysiology of pre-eclampsia and prediction of biomarkers for diagnosis.
Cellular and Circuit Organization of the Locus Coeruleus of Adult Mice
Authors: McKinney Andrew , Hu Ming , Hoskins Amber , Mohammadyar Arian , Naeem Nabeeha , Jing Junzhan , Patel Saumil S. , Sheth Bhavin R. , Jiang Xiaolong
Published: March 2022

The locus coeruleus (LC) houses the vast majority of noradrenergic neurons in the brain and regulates many fundamental functions including fight and flight response, attention control, and sleep/wake cycles. While efferent projections of the LC have been extensively investigated, little is known about its local circuit organization. Here, we performed large-scale multi-patch recordings of noradrenergic neurons in adult mouse LC to profile their morpho-electric properties while simultaneously examining their interactions. LC noradrenergic neurons are diverse and could be classified into two major morpho-electric types. While fast excitatory synaptic transmission among LC noradrenergic neurons was not observed in our preparation, these mature LC neurons connected via gap junction at a rate similar to their early developmental stage and comparable to other brain regions. Most electrical connections form between dendrites and are restricted to narrowly spaced pairs or small clusters of neurons of the same type. In addition, more than two electrically coupled cell pairs were often identified across a cohort of neurons from individual multi-cell recording sets that followed a chain-like organizational pattern. The assembly of LC noradrenergic neurons thus follows a spatial and cell type-specific wiring principle that may be imposed by a unique chain-like rule.
Genome-Wide DNA Methylation Profiling of the Failing Human Heart with Mechanical Unloading IdentifiesLINC00881as an Essential Regulator of Calcium Handling in the Cardiomyocyte
Authors: Liao Xianghai , Kennel Peter J. , Liu Bohao , Nash Trevor R. , Zhuang Richard , Godier-Furnemont Amandine F. , Xue Chenyi , Lu Rong , Colombo Paolo C. , Uriel Nir , Reilly Muredach P. , Marx Steven O. , Vunjak-Novakovic Gordana , Topkara Veli K.
Published: March 2022

Background

Human heart failure is characterized by global alterations in the myocardial DNA methylation profile, yet little is known about epigenetic regulation of non-coding transcripts and potential reversibility of DNA methylation with left ventricular assist device (LVAD) support.

Method

Genome-wide mapping of myocardial DNA methylation was performed in 36 patients with end-stage heart failure at the time of LVAD implant, 8 patients at the time of LVAD explant, and 7 non-failing controls using high-density bead array platform. Transcriptomic and functional studies were performed in human induced pluripotent stem cell derived cardiomyocytes (iPSCs).

Results

Etiology-specific analysis revealed 2079 differentially methylated positions (DMPs) in ischemic cardiomyopathy (ICM) and 261 DMPs in non-ischemic cardiomyopathy (NICM). 192 DMPs were common to ICM and NICM. Analysis of paired samples before and after LVAD support demonstrated reverse methylation of only 3.2% of HF-specific DMPs. Methylation-expression correlation analysis yielded several protein-coding genes that are hypomethylated and upregulated (HTRA1, FAM65A, FBXO16, EFCAB13, AKAP13, RPTOR) or hypermethylated and downregulated (TBX3) in ICM and NICM patients. A novel cardiac-specific super-enhancer lncRNA (LINC00881) is hypermethylated and downregulated in the failing human heart.LINC00881is an upstream regulator of sarcomere and calcium channel gene expression includingMYH6, CACNA1C, andRYR2. LINC00881knockdown significantly reduced peak calcium amplitude in the beating human iPSCs.

Conclusions

Failing human heart exhibits etiology-specific changes in DNA methylation including coding and non-coding regions, which are minimally reversible with mechanical unloading. Epigenetic reprogramming may be necessary to achieve transcriptional normalization and sustained clinical recovery from heart failure.
FunHoP analysis reveals upregulation of mitochondrial genes in prostate cancer
Authors: Rise Kjersti , Tessem May-Britt , Drabløs Finn , Rye Morten B.
Published: March 2022

Mitochondrial activity in cancer cells has been central to cancer research since Otto Warburg first published his thesis on the topic in 1956. Although Warburg proposed that oxidative phosphorylation in the tricarboxylic acid (TCA) cycle was perturbed in cancer, later research has shown that oxidative phosphorylation is activated in most cancers, including prostate cancer (PCa). However, more detailed knowledge on mitochondrial metabolism and metabolic pathways in cancers is still lacking. In this study we expand our previously developed method for analyzing functional homologous proteins (FunHoP), which can provide a more detailed view of metabolic pathways. FunHoP uses results from differential expression analysis of RNA-Seq data to improve pathway analysis. By adding information on subcellular localization based on experimental data and computational predictions we can use FunHoP to differentiate between mitochondrial and non-mitochondrial processes in cancerous and normal prostate cell lines. Our results show that mitochondrial pathways are upregulated in PCa and that splitting metabolic pathways into mitochondrial and non-mitochondrial counterparts using FunHoP adds to the interpretation of the metabolic properties of PCa cells.
EEG evidence that morally relevant autobiographical memories can be suppressed
Authors: Satish Akul , Hellerstedt Robin , Anderson Michael C. , Bergström Zara M.
Published: March 2022

Remembering unpleasant events can trigger negative feelings. Fortunately, research indicates that unwanted memories can be suppressed to prevent them from intruding into awareness, improving our mental state. The current scientific understanding of memory suppression is, however, based mostly on simpler memories such as associations between words or pictures, which may not reflect how people control unpleasant memory intrusions in everyday life. Here, we investigated the neural and behavioural dynamics of suppressing personal and emotional autobiographical memories using a modified version of the Think/No-Think task. We asked participants to suppress memories of their own past immoral actions, which were hypothesised to be both highly intrusive and motivating to suppress. We report novel evidence from behavioural, ERP and EEG oscillation measures that autobiographical memory retrieval can be suppressed and suggest that autobiographical suppression recruits similar neurocognitive mechanisms as suppression of simple laboratory associations. Suppression did fail sometimes, and EEG oscillations indicated that such memory intrusions occurred from lapses in sustained control. Importantly however, participants improved at limiting intrusions with repeated practice. Furthermore, both behavioural and EEG evidence indicated that intentional suppression may be more difficult for memories of our morally wrong actions than memories of our morally right actions. The findings elucidate the neurocognitive correlates of autobiographical retrieval suppression and have implications for theories of morally motivated memory control.
PRL1 and CK2 collaborate to time morning and evening phase in short photoperiods
Authors: Lear Bridget C. , Kula-Eversole Ela , Allada Ravi
Published: March 2022

The TIMELESS (TIM) phosphatase, Phosphatase of Regenerating Liver-1 (PRL-1), is required for setting behavioral phase especially under short photoperiod conditions. Yet the circadian clock neurons and underlying mechanisms important for these effects are unknown. Here we demonstrate that PRL-1 function in PDF neurons is necessary and sufficient for timing morning and evening phase under short photoperiod (6:18) conditions. In standard (12:12) photoperiod, we find that PRL-1 rescue or blocking PRL-1 knockdown in PDF neurons restores wild-type morning phase. Expression of the TIM kinase shaggy (sgg) in PDF neurons suppresses in an additive manner PRL-1 period lengthening and delayed morning phase further underscoring the role of PDF neurons. In contrast to knockdown in all clock neurons, knockdown of PRL-1 selectively in PDF clock neurons does not alter the timing of morning or evening phase under standard photoperiod conditions, suggesting PRL-1 function in non-PDF neurons may also be important. In contrast to SGG effects, we find that phase delay of evening onset due to expression of a dominant negative version of the TIM kinase CK2 (CK2alphaTik) requires PRL-1. Given that TIM is a substrate of both the PRL-1 phosphatase and CK2 kinase, we hypothesize that PRL-1 dephosphorylation at specific sites may be necessary for subsequent CK2 phosphorylation to time behavior.
The GEF-GAP pair Solo and DLC3 balances Rho activity during endocytic transport
Authors: Lungu Cristiana , Meyer Florian , Hörning Marcel , Steudle Jasmin , Braun Anja , Noll Bettina , Benz David , Fränkle Felix , Schmid Simone , Eisler Stephan A. , Olayioye Monilola A.
Published: March 2022

The control of intracellular membrane trafficking by Rho GTPases is central to cellular homeostasis. How defined pairs of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) come together to locally balance GTPase activation cycles in this process is nevertheless largely unclear. By performing a microscopy-based RNAi screen we here identify the RhoGEF protein Solo as a counterpart of DLC3, a RhoGAP protein with established roles in membrane trafficking. Biochemical, imaging and optogenetics assays further uncover Solo as a novel regulator of endosomal RhoB. Remarkably, we find that the interplay between Solo and DLC3 controls not only the activity but also total protein levels of RhoB. Together, the results of our study uncover the first functionally connected RhoGAP-RhoGEF pair at endomembranes and place the Solo-DLC3 axis at the core of endocytic trafficking.
FtsZ is essential until the late stage of constriction
Authors: Goodman Lauren C. Corbin , Erickson Harold P.
Published: March 2022

1

There has been recent debate as to the source of constriction force during cell division. FtsZ can generate a constriction force on tubular membranes in vitro, suggesting it may generate the constriction force in vivo. However, another study showed that mutants of FtsZ did not affect the rate of constriction, whereas mutants of the PG assembly did, suggesting that PG assembly may push the constriction from the outside. Supporting this model, two groups found that cells that have initiated constriction can complete septation while the Z ring is poisoned with PC190723. PC19 arrests treadmilling but leaves FtsZ in place. We sought to determine if a fully assembled Z ring is necessary during constriction. To do this, we used a temperature sensitive FtsZ mutant, FtsZ84. FtsZ84 behaves as wild type at 30° C, but it disassembles from the Z ring within one min upon a temperature jump to 42° C. Following the temperature jump we found that cells in early constriction stop constricting. Cells that had progressed to the later stage of division finished constriction without a Z ring. These results show that in Escherichia coli, an assembled Z ring is essential for constriction except in the final stage, contradicting the simplest interpretation of previous studies using PC19.
Selective endocytosis controls slit diaphragm maintenance and dynamics
Authors: Lang Konrad , Milosavljevic Julian , Heinkele Helena , Chen Mengmeng , Gerstner Lea , Spitz Dominik , Kayser Séverine , Helmstädter Martin , Walz Gerd , Köttgen Michael , Spracklen Andrew , Poulton John , Hermle Tobias
Published: March 2022

The kidneys generate about 180 liters of primary urine per day by filtration of plasma. An essential part of the filtration barrier is the slit diaphragm, a multiprotein complex containing nephrin as major component. Filter dysfunction typically manifests with proteinuria and mutations in endocytosis regulating genes were discovered as causes of proteinuria. However, it is unclear how endocytosis regulates the slit diaphragm and how the filtration barrier is maintained without either protein leakage or filter clogging. Here we study nephrin dynamics in podocyte-like nephrocytes of Drosophila and show that selective endocytosis either by dynamin- or flotillin-mediated pathways regulates a stable yet highly dynamic architecture. Short-term manipulation of endocytic functions indicates that dynamin-mediated endocytosis of ectopic nephrin restricts slit diaphragm formation spatially while flotillin-mediated turnover of nephrin within the slit diaphragm is needed to maintain filter permeability by shedding of molecules bound to nephrin in endosomes. Since slit diaphragms cannot be studied in vitro and are poorly accessible in mouse models, this is the first analysis of their dynamics within the slit diaphragm multiprotein complex. Identification of the mechanisms of slit diaphragm maintenance will help to develop novel therapies for proteinuric renal diseases that are frequently limited to symptomatic treatment.