bluuebunny/crossref_metadata_2025 huggingface dataset:
On the role of arkypallidal and prototypical neurons for phase transitions in the external pallidum
Authors: Gast Richard , Gong Ruxue , Schmidt Helmut , Meijer Hil G.E. , Knösche Thomas R.
Published: January 2021

The external pallidum (GPe) plays a central role for basal ganglia functions and dynamics and, consequently, has been included in most computational studies of the basal ganglia. These studies considered the GPe as a homogeneous neural population. However, experimental studies have shown that the GPe contains at least two distinct cell types (prototypical and arkypallidal cells). In this work, we provide in silico insight into how pallidal heterogeneity modulates dynamic regimes inside the GPe and how they affect the GPe response to oscillatory input.

We derive a mean-field model of the GPe system from a microscopic spiking neural network of recurrently coupled prototypical and arkypallidal neurons. Using bifurcation analysis, we examine the influence of the intra-pallidal connectivity on the GPe dynamics. We find that under healthy conditions, the inhibitory coupling determines whether the GPe is close to either a bi-stable or an oscillatory regime. Furthermore, we show that oscillatory input to the GPe, arriving from subthalamic nucleus or striatum, leads to characteristic patterns of cross-frequency coupling observed at the GPe. Based on these findings, we propose two different hypotheses of how dopamine depletion at the GPe may lead to phase-amplitude coupling between the parkinsonian beta rhythm and a GPe-intrinsic gamma rhythm. Finally, we show that these findings generalize to realistic spiking neural networks of sparsely coupled type-I excitable GPe neurons.

Significant Statement

Our work provides (a) insight into the theoretical implications of a dichotomous GPe organization for its macroscopic dynamic regimes, and (b) an exact mean-field model that allows for future investigations of the relationship between GPe spiking activity and local field potential fluctuations. We identify the major phase transitions that the GPe can undergo when subject to static or periodic input and link these phase transitions to the emergence of synchronized oscillations and cross-frequency coupling in the basal ganglia. Due to the close links between our model and experimental findings on the structure and dynamics of prototypical and arkypallidal cells, our results can be used to guide both experimental and computational studies on the role of the GPe for basal ganglia dynamics in health and disease.
A syntenin-deficient microenvironment educates AML for aggressiveness
Authors: Leblanc R , Fares J , Goubard A , Castellano R , Camoin L , Balzano M , Ghossoub R , Bou-Tayeh B , Fauriat C , Vey N , Borg JP , Collette Y , Aurrand-Lions M , David G , Zimmermann P
Published: January 2021

In acute myeloid leukemia (AML), the stromal microenvironment plays a prominent role in promoting tumor cell survival and progression. Although widely explored, the crosstalk between leukemic and stromal cells remains poorly understood. Syntenin, a multi-domain PDZ protein, controls both the trafficking and signaling of key molecules involved in intercellular communication. Therefore, we aimed to clarify the role of environmental syntenin in the progression of AML. Byin vivoapproaches in syngeneic mice, we demonstrate that a syntenin-deficient environment reprograms AML blasts to survive independently of the stroma. Up-regulation of EEF1A2 in the blasts controls this gain of cell survival. Furthermore, usingex vivoco-culture systems, we show that syntenin-deficient bone marrow stromal cells (BMSC) enhance the survival of different types of AML cells, including patient samples, and suffice to educate syngeneic AML, recapitulating micro-environmental effects observedin vivo.We establish that syntenin-deficiency causes an increase of eIF5A and autophagy-related factors in BMSC, and provide evidence that the inhibition of autophagy prevents syntenin-deficient BMSC to stimulate AML survival. Altogether, these findings indicate that host-syntenin in the BM microenvironment acts as a repressor of AML aggressiveness.

Key points

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A syntenin-deficient host reprograms AML blasts, enhancing total protein synthesis and cell survival pathways

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Autophagy in the syntenin-deficient microenvironment is responsible for the gain of AML cell survival
BMP pathway antagonism byGrem1regulates epithelial cell fate in intestinal regeneration
Authors: Koppens Martijn AJ , Davis Hayley , Valbuena Gabriel N , Mulholland Eoghan J , Nasreddin Nadia , Colombe Mathilde , Antanaviciute Agne , Biswas Sujata , Friedrich Matthias , Lee Lennard ,   Oxford IBD cohort investigators, Wang Lai Mun , Koelzer Viktor H , East James E , Simmons Alison , Winton Douglas J , Leedham Simon J
Published: January 2021

In the intestine, the homeostatic effect of Bone Morphogenetic Protein (BMP) on cell fate has predominantly been inferred through pathway inactivation. Here, we assessed the impact of autocrineBmp4expression on secretory cell fate. Ligand exposure reduced proliferation, expedited terminal differentiation, abrogated long-term secretory cell survival and prevented dedifferentiation. As stem cell plasticity is required for regenerative adaptive reprogramming, we spatiotemporally mapped and functionally explored BMP’s role in epithelial restitution. Following ulceration, physiological attenuation of BMP signalling arose through upregulation of the secreted antagonist,Grem1,from topographically distinct populations of stromal cells. Concomitant expression supported functional compensation, followingGrem1deletion from tissue-resident fibroblasts. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory, but functionally sub-maximal, as regeneration was impaired or enhanced by epithelial overexpression ofBmp4orGrem1respectively. Mechanistically,Bmp4abrogated regenerative stem cell reprogramming, despite a convergent impact of YAP/TAZ on cell fate in remodelled wounds.
Functionnectome: a framework to analyse the contribution of brain circuits to fMRI
Authors: Nozais Victor , Forkel Stephanie J. , Foulon Chris , Petit Laurent , Thiebaut de Schotten Michel
Published: January 2021

In recent years, the field of functional neuroimaging has moved away from a pure localisationist approach of isolated functional brain regions to a more integrated view of these regions within functional networks. However, the methods used to investigate functional networks rely on local signals in grey matter and are limited in identifying anatomical circuitries supporting the interaction between brain regions. Mapping the brain circuits mediating the functional signal between brain regions would propel our understanding of the brain’s functional signatures and dysfunctions. We developed a novel method to unravel the relationship between brain circuits and functions: The Functionnectome. The Functionectome combines the functional signal fromfMRI with white matter circuits’ anatomy to unlock and chart the first maps of functional white matter. To showcase this new method’s versatility, we provide the first functional white matter maps revealing the joint contribution of connected areas to motor, working memory, and language functions. The Functionnectome comes with an open-source companion software and opens new avenues into studying functional networks by applying the method to already existing dataset and beyond taskfMRI.
Extracellular Matrix Dysfunction in Sorsby Patient-Derived Retinal Pigment Epithelium
Authors: Engel Abbi L. , Wang YeKai , Khuu Thomas H. , Worrall Emily , Manson Megan A. , Lim Rayne R. , Knight Kaitlen , Yanagida Aya , Qi Jian Hua , Ramakrishnan Aravind , Weleber Richard G , Klein Michael L. , Wilson David J. , Anand-Apte Bela , Hurley James B. , Du Jianhai , Chao Jennifer R.
Published: January 2021

Sorsby Fundus Dystrophy (SFD) is a rare form of macular degeneration that is clinically similar to age-related macular degeneration (AMD), and a histologic hallmark of SFD is a thick layer of extracellular deposits beneath the retinal pigment epithelium (RPE). Previous studies of SFD patient-induced pluripotent stem cell (iPSC) derived RPE differ as to whether these cultures recapitulate this key clinical feature by forming increased drusenoid deposits. The primary purpose of this study is to examine whether SFD patient-derived iPSC-RPE form basal deposits similar to what is found in affected family member SFD globes and to determine whether SFD iPSC RPE may be more oxidatively stressed. We performed a careful comparison of iPSC RPE from three control individuals, multiple iPSC clones from two SFD patients’ iPSC RPE, and post-mortem eyes of affected SFD family members. We also examined the effect of CRISPR-Cas9 gene correction of the S204CTIMP3mutation on RPE phenotype. Finally, targeted metabolomics analysis with liquid chromatography and mass spectrometry analysis and stable isotope-labeled metabolite analysis was performed to determine whether SFD RPE are more oxidatively stressed. We found that SFD iPSC-RPE formed significantly more sub-RPE deposits (∼6-90 μm in height) compared to control RPE at 8 weeks. These deposits were similar in composition to the basal laminar drusen found in SFD family member globes by immunofluorescence staining and TEM imaging. S204CTIMP3correction by CRISPR-Cas9 gene editing in SFD iPSC RPE cells resulted in significantly reduced basal laminar and sub-RPE calcium deposits. We detected a ∼18-fold increase in TIMP3 accumulation in the extracellular matrix (ECM) of SFD RPE, and targeted metabolomics showed that intracellular 4-hydroxyproline, a major breakdown product of collagen, is significantly elevated in SFD RPE, suggesting increased ECM turnover. Finally, SFD RPE cells have decreased intracellular reduced glutathione and were found to be more vulnerable to oxidative stress. Our findings suggest that elements of SFD pathology can be demonstrated in culture which may lead to insights into disease mechanisms.
Easymap: a user-friendly software package for rapid mapping by sequencing of point mutations and large insertions
Authors: Lup Samuel Daniel , Wilson-Sánchez David , Andreu-Sánchez Sergio , Micol José Luis
Published: January 2021

Mapping-by-sequencing strategies combine next-generation sequencing (NGS) with classical linkage analysis, allowing rapid identification of the causal mutations of the phenotypes exhibited by mutants isolated in a genetic screen. Computer programs that analyze NGS data obtained from a mapping population of individuals derived from a mutant of interest in order to identify a causal mutation are available; however, the installation and usage of such programs requires bioinformatic skills, modifying or combining pieces of existing software, or purchasing licenses. To ease this process, we developed Easymap, an open-source program that simplifies the data analysis workflows from raw NGS reads to candidate mutations. Easymap can perform bulked segregant mapping of point mutations induced by ethyl methanesulfonate (EMS) with DNA-seq or RNA-seq datasets, as well as tagged-sequence mapping for large insertions, such as transposons or T-DNAs. The mapping analyses implemented in Easymap have been validated with experimental and simulated datasets from different plant and animal model species. Easymap was designed to be accessible to all users regardless of their bioinformatics skills by implementing a user-friendly graphical interface, a simple universal installation script, and detailed mapping reports, including informative images and complementary data for assessment of the mapping results.

One sentence summary

Easymap is a versatile user-friendly software tool that facilitates mapping-by-sequencing of large insertions and point mutations in plant and animal genomes
Enhanced Solid Tumor Recognition and T cell Stemness with SynNotch CAR Circuits
Authors: Hyrenius-Wittsten Axel , Su Yang , Park Minhee , Garcia Julie M. , Perry Nathaniel , Montgomery Garrett , Liu Bin , Roybal Kole T.
Published: January 2021

The lack of highly tumor-specific antigens limits the development of engineered T cell therapeutics because of life-threatening “on-target/off-tumor” toxicities. Here we identify ALPPL2 as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma. ALPPL2 can act as a sole target for chimeric antigen receptor (CAR) therapy or be combined with tumor-associated antigens such as MCAM or mesothelin in synthetic Notch (synNotch) CAR combinatorial antigen circuits. SynNotch CAR T cells display superior tumor control when compared to CAR T cells to the same antigens by prevention of CAR-mediated tonic signaling allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable target for multiple solid tumors and demonstrate the multi-faceted therapeutic benefits of synNotch CAR T cells.

ONE SENTENCE SUMMARY

SynNotch CAR circuits targeting novel solid tumor antigens enhance specificity and improve therapeutic efficacy by regulating T cell exhaustion.
The dysregulated Pink1-Drosophila mitochondrial proteome is partially corrected with exercise
Authors: Ebanks Brad , Ingram Thomas L , Katyal Gunjan , Ingram John R , Moisoi Nicoleta , Chakrabarti Lisa
Published: January 2021

One of the genes which has been linked to the onset of juvenile/early onset Parkinson’s disease (PD) is PINK1. There is evidence that supports the therapeutic potential of exercise in the alleviation of PD symptoms. It is possible that exercise may enhance synaptic plasticity, protect against neuro-inflammation and modulate L-Dopa regulated signalling pathways. We explored the effects of exercise onPink1deficientDrosophila melanogasterwhich undergo neurodegeneration and muscle degeneration. We used a ‘power-tower’ type exercise platform to deliver exercise activity toPink1-and age matched wild-type flies. Mitochondrial proteomic profiles responding to exercise were obtained. Of the 516 proteins identified, 105 proteins had different levels betweenPink1-and wild-type (WT) non-exercisedD. melanogaster. Gene ontology enrichment analysis and STRING network analysis highlighted proteins and pathways with altered expression within the mitochondrial proteome. Comparison of thePink1-exercised proteome to WT proteomes showed that exercising thePink1-flies caused their proteomic profile to return towards wild-type levels.
Cellular drivers of injury response and regeneration in the adult zebrafish heart
Authors: Hu Bo , Lelek Sara , Spanjaard Bastiaan , Simões Mariana Guedes , Aliee Hananeh , Schäfer Ronny , Theis Fabian , Panáková Daniela , Junker Jan Philipp
Published: January 2021

Myocardial infarction is a leading cause of death worldwide, as the adult human heart does not have the ability to regenerate efficiently after insults. In contrast, the adult zebrafish heart has a high capacity for regeneration, and understanding the mechanisms of regenerative processes in fish allows identification of novel therapeutic strategies. While several pro-regenerative factors have been described, the cell types orchestrating heart regeneration remain largely elusive. To overcome this conceptual limitation, we dissected cell type diversity in the regenerating zebrafish heart based on single cell transcriptomics and spatiotemporal analysis. We discovered a dramatic induction of several pro-regenerative cell types with fibroblast characteristics. To understand the cascade of events leading to heart regeneration, we determined the origin of these cell types by high-throughput lineage tracing. We found that pro-regenerative fibroblasts are derived from two separate sources, the epicardium and the endocardium. Mechanistically, we identified Wnt signaling as a key regulator of the endocardial regenerative response. In summary, our results uncover specialized fibroblast cell types as major drivers of heart regeneration, thereby opening up new possibilities to interfere with the regenerative capacity of the vertebrate heart.
Global transcriptional response ofMethylorubrum extorquensto formaldehyde stress expands the role of EfgA and is distinct from antibiotic translational inhibition
Authors: Bazurto Jannell V. , Riazi Siavash , D’Alton Simon , Deatherage Daniel E. , Bruger Eric L. , Barrick Jeffrey E. , Marx Christopher J.
Published: January 2021

The potency and indiscriminate nature of formaldehyde reactivity upon biological molecules make it a universal stressor. However, some organisms such asMethylorubrum extorquenspossess means to rapidly and effectively mitigate formaldehyde-induced damage. EfgA is a recently identified formaldehyde sensor predicted to halt translation in response to elevated formaldehyde as a means to protect cells. Herein, we investigate growth and changes in gene expression to understand howM. extorquensresponds to formaldehyde with and without the EfgA-formaldehyde-mediated translational response, and how this mechanism compares to antibiotic-mediated translation inhibition. These distinct mechanisms of translation inhibition have notable differences: they each involve different specific players and in addition, formaldehyde also acts as a general, multi-target stressor and a potential carbon source. We present findings demonstrating that in addition to its characterized impact on translation, functional EfgA allows for a rapid and robust transcriptional response to formaldehyde and that removal of EfgA leads to heightened proteotoxic and genotoxic stress in the presence of increased formaldehyde levels. We also found that many downstream consequences of translation inhibition were shared by EfgA-formaldehyde- and kanamycin-mediated translation inhibition. Our work uncovered additional layers of regulatory control enacted by functional EfgA upon experiencing formaldehyde stress, and further demonstrated the importance this protein plays at both transcriptional and translational levels in this model methylotroph.
SLTRiP induces long lasting and protective T-cell memory response
Authors: Quadiri Afshana , Kashif Mohammad , Kalia Inderjeet , Singh Agam Prasad
Published: January 2021

Major developments have been made in the past many years to characterize and explore potential vaccine candidates that can induce host immune responses against parasite. These advances were based on the fact that the induction of host immune responses could effectively target parasite at different stages of its life cycle and thus, abrogatePlasmodiuminfections. The role of T-cells against malaria comes from initial studies on rodents showing these cells could inhibit parasite development during pre-erythrocytic stages. Since then, the importance of the cellular immune responses against malaria has been increasingly emphasized, especially for vaccine development against pre-erythrocytic stages. Previous work in our laboratory has confirmed that SLTRiP confers protection against the pre-erythrocytic stage ofPlasmodiumgrowth in rodents. Here we report that the protection is mainly due to cell mediated immune responses andPbSLTRiP specific cellular memory responses could be efficiently recalled in mice challenged withP. bergheiparasites even after a year following immunization. Our results thereby, highlight the role of the T cell response involved in protection. Characterization of T-cells by intracellular cytokine staining (ICS) revealed that the induced T cells were polyfunctional and involved in secretion of pro-inflammatory cytokines which mediate anti-parasitic activity. The findings contribute to our understanding of the immunological mechanisms underlying the protective vaccines.
Strain variation inBacillus cereusbiofilms and their susceptibility to extracellular matrix-degrading enzymes
Authors: Lim Eun Seob , Baek Seung-Youb , Oh Taeyoung , Koo Minseon , Lee Joo Young , Kim Hyun Jung , Kim Joo-Sung
Published: January 2021

Bacillus cereusis a foodborne pathogen and can form biofilms on food contact surfaces, which causes food hygiene problems. While it is necessary to understand strain-dependent variation to effectively control these biofilms, strain-to-strain variation in the structure ofB cereusbiofilms is poorly understood. In this study,B. cereusstrains from tatsoi and the ATCC 10987 reference strain were incubated at 30°C to form biofilms in the presence of the extracellular matrix-degrading enzymes DNase I, proteinase K, dispase II, cellulase, amyloglucosidase, and α-amylase to assess the susceptibility to these enzymes. The four strains exhibited four different patterns in terms of biofilm susceptibility to the enzymes as well as morphology of surface-attached biofilms or suspended cell aggregates. DNase I inhibited the biofilm formation of strains ATCC 10987 and BC4 but not of strains BC10 and BC72. This result suggests that some strains may not have extracellular DNA, or their extracellular DNA may be protected in their biofilms. In addition, the strains exhibited different patterns of susceptibility to protein- and carbohydrate-degrading enzymes. While other strains were resistant, strains ATCC 10987 and BC4 were susceptible to cellulase, suggesting that cellulose or its similar polysaccharides may exist and play an essential role in their biofilm formation. Our compositional analysis of strains ATCC 10987 and BC4 suggested that the physicochemical properties of their biofilms are distinct, as calculated by the carbohydrate to protein ratio. Taken together, our study suggests that the extracellular matrix ofB. cereusbiofilms may be highly diverse and provides insight into the diverse mechanisms of biofilm formation amongB. cereusstrains.
The peripheral T cell population is associated with pneumonia severity in cynomolgus monkeys experimentally infected with severe acute respiratory syndrome coronavirus 2
Authors: Nagata Noriyo , Iwata-Yoshikawa Naoko , Sano Kaori , Ainai Akira , Shiwa Nozomi , Shirakura Masayuki , Kishida Noriko , Arita Tomoko , Suzuki Yasushi , Harada Toshihiko , Kawai Yasuhiro , Ami Yasushi , Iida Shun , Katano Harutaka , Fujisaki Seiichiro , Sekizuka Tsuyoshi , Shimizu Hiroyuki , Suzuki Tadaki , Hasegawa Hideki
Published: January 2021

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that began in December 2019. Lymphopenia is a common feature in severe cases of COVID-19; however, the role of T cell responses during infection is unclear. Here, we inoculated six cynomolgus monkeys, divided into two groups according to the CD3+ T cell population in peripheral blood, with two clinical isolates of SARS-CoV-2: one of East Asian lineage and one of European lineage. After initial infection with the isolate of East Asian lineage, all three monkeys in the CD3+ low group showed clinical symptoms, including loss of appetite, lethargy, and transient severe anemia with/without short-term fever, within 14 days post-infection (p.i.). By contrast, all three monkeys in the CD3+ high group showed mild clinical symptoms such as mild fever and loss of appetite within 4 days p.i. and then recovered. After a second inoculation with the isolate of European lineage, three of four animals in both groups showed mild clinical symptoms but recovered quickly. Hematological, immunological, and serological tests suggested that the CD3+ high and low groups mounted different immune responses during the initial and second infection stages. In both groups, anti-viral and innate immune responses were activated during the early phase of infection and re-infection. However, in the CD3+ low group, inflammatory responses, such as increased production of monocytes and neutrophils, were stronger than those in the CD3+ high group, leading to more severe immunopathology and failure to eliminate the virus. Taken together, the data suggest that the peripheral T lymphocyte population is associated with pneumonia severity in cynomolgus monkeys experimentally infected with SARS-CoV-2.

Author summary

SARS-CoV-2 infection causes an illness with clinical manifestations that vary from asymptomatic or mild to severe; examples include severe pneumonia and acute respiratory distress syndrome. Lymphopenia, which is common in severe COVID-19 cases, is characterized by markedly reduced numbers of CD4+ T cells, CD8+ T cells, B cells, and natural killer cells. Here, we showed that cynomolgus monkeys selected according to the T cell populations in peripheral blood have different outcomes after experimental infection with SARS-CoV-2. These findings will increase our understanding of disease pathogenesis and may facilitate the development of animal models for vaccine evaluation.
Comprehensive comparison of transcriptomes in SARS-CoV-2 infection: alternative entry routes and innate immune responses
Authors: Cao Yingying , Xu Xintian , Kitanovski Simo , Song Lina , Wang Jun , Hao Pei , Hoffmann Daniel
Published: January 2021

The pathogenesis of COVID-19 emerges as complex, with multiple factors leading to injury of different organs. Several studies on underlying cellular processes have produced contradictory claims, e.g. on SARS-CoV-2 cell entry or innate immune responses. However, clarity in these matters is imperative for therapy development. We therefore performed a meta-study with a diverse set of transcriptomes under infections with SARS-CoV-2, SARS-CoV and MERS-CoV, including data from different cells and COVID-19 patients. Using these data, we investigated viral entry routes and innate immune responses. First, our analyses support the existence of cell entry mechanisms for SARS and SARS-CoV-2 other than the ACE2 route with evidence of inefficient infection of cells without expression of ACE2; expression of TMPRSS2/TPMRSS4 is unnecessary for efficient SARS-CoV-2 infection with evidence of efficient infection of A549 cells transduced with a vector expressing human ACE2. Second, we find that innate immune responses in terms of interferons and interferon simulated genes are strong in relevant cells, for example Calu3 cells, but vary markedly with cell type, virus dose, and virus type.
Engineering the thermotolerant industrial yeastKluyveromyces marxianusfor anaerobic growth
Authors: Dekker Wijbrand J. C. , Ortiz-Merino Raúl A. , Kaljouw Astrid , Battjes Julius , Wiering Frank W. , Mooiman Christiaan , de la Torre Pilar , Pronk Jack T.
Published: January 2021

Current large-scale, anaerobic industrial processes for ethanol production from renewable carbohydrates predominantly rely on the mesophilic yeastSaccharomyces cerevisiae. Use of thermotolerant, facultatively fermentative yeasts such asKluyveromyces marxianuscould confer significant economic benefits. However, in contrast toS. cerevisiae, these yeasts cannot grow in the absence of oxygen. Response ofK. marxianusandS. cerevisiaeto different oxygen-limitation regimes were analyzed in chemostats. Genome and transcriptome analysis, physiological responses to sterol supplementation and sterol-uptake measurements identified absence of a functional sterol-uptake mechanism as a key factor underlying the oxygen requirement ofK. marxianus. Heterologous expression of a squalene-tetrahymanol cyclase enabled oxygen-independent synthesis of the sterol surrogate tetrahymanol inK. marxianus. After a brief adaptation under oxygen-limited conditions, tetrahymanol-expressingK. marxianusstrains grew anaerobically on glucose at temperatures of up to 45 °C. These results open up new directions in the development of thermotolerant yeast strains for anaerobic industrial applications.
Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera
Authors: Xie Xuping , Zou Jing , Fontes-Garfias Camila R. , Xia Hongjie , Swanson Kena A. , Cutler Mark , Cooper David , Menachery Vineet D. , Weaver Scott , Dormitzer Philip R. , Shi Pei-Yong
Published: January 2021

Rapidly spreading variants of SARS-CoV-2 that have arisen in the United Kingdom and South Africa share the spike N501Y substitution, which is of particular concern because it is located in the viral receptor binding site for cell entry and increases binding to the receptor (angiotensin converting enzyme 2). We generated isogenic N501 and Y501 SARS-CoV-2. Sera of 20 participants in a previously reported trial of the mRNA-based COVID-19 vaccine BNT162b2 had equivalent neutralizing titers to the N501 and Y501 viruses.
GC-1 spg cells are most similar to Leydig cells, a testis somatic cell-type, and not germ cells
Authors: Norman Andrew R. , Byrnes Lauren , Reiter Jeremy F.
Published: January 2021

GC-1 spg is an immortalized cell line derived from an adult mouse testis and reported to be most similar to spermatocytes, a male germ cell-type. However, immunofluorescence indicates that GC-1 spg cells express WT1, a marker of testis somatic cells, and do not express markers of germ cells. Transcriptomic profiling indicate GC-1 cells are most similar to Leydig cells. Therefore, we conclude that GC-1 spg cells are most similar to testis somatic cells.
Synthetic gene networks recapitulate dynamic signal decoding and differential gene expression
Authors: Benzinger Dirk , Ovinnikov Serguei , Khammash Mustafa
Published: January 2021

Cells live in constantly changing environments and employ dynamic signaling pathways to transduce information about the signals they encounter. However, the mechanisms by which dynamic signals are decoded into appropriate gene expression patterns remain poorly understood. Here, we devise networked optogenetic pathways that achieve novel dynamic signal processing functions that recapitulate cellular information processing. Exploiting light-responsive transcriptional regulators with differing response kinetics, we build a falling-edge pulse-detector and show that this circuit can be employed to demultiplex dynamically encoded signals. We combine this demultiplexer with dCas9-based gene networks to construct pulsatile-signal filters and decoders. Applying information theory, we show that dynamic multiplexing significantly increases the information transmission capacity from signal to gene expression state. Finally, we use dynamic multiplexing for precise multidimensional regulation of a heterologous metabolic pathway. Our results elucidate design principles of dynamic information processing and provide original synthetic systems capable of decoding complex signals for biotechnological applications.
Intracellular softening and fluidification reveals a mechanical switch of cytoskeletal material contributions during division
Authors: Hurst Sebastian , Vos Bart E. , Betz Timo
Published: January 2021

The life and death of an organism depends largely on correct cell division. While the overall biochemical signaling and morphological processes during mitosis are well understood, the importance of mechanical forces and material properties is only just starting to be discovered. Recent studies of global cell stiffening during cell division may imply an understanding of the cytosol mechanics that is mistaken. Here we show that in contrast to the stiffening process in the cell cortex, the interior of the cell undergoes a softening and fluidification that is accompanied by a decrease of active forces driving particle mobility. Using optical tweezers-based microrheology we capture the complex active and passive material state of the cytoplasm using only six relevant parameters. We demonstrate that the softening occurs because of a surprising role switch between microtubules and actin, where the intracellular, actin-based mechanics is largely controlled by a formin-mediated network.
Effects of Emodin, a Plant-Derived Anthraquinone, on TGF-β1-Induced Cardiac Fibroblast Activation and Function
Authors: Carver Wayne , Fix Ethan , Fix Charity , Fan Daping , Chakrabarti Mrinmay , Azhar Mohamad
Published: January 2021

Cardiac fibrosis accompanies a number of pathological conditions and results in altered myocardial structure, biomechanical properties and function. The signaling networks leading to fibrosis are complex, contributing to the general lack of progress in identifying effective therapeutic approaches to prevent or reverse this condition. Several studies have shown protective effects of emodin, a plant-derived anthraquinone, in animal models of fibrosis. A number of questions remain regarding the mechanisms whereby emodin impacts fibrosis. TGF-β1 is a potent stimulus of fibrosis and fibroblast activation. In the present study, experiments were performed to evaluate the effects of emodin on activation and function of cardiac fibroblasts following treatment with TGF-β1. We demonstrate that emodin attenuates TGF-β1-induced fibroblast activation and collagen accumulation in vitro. Emodin also inhibits activation of several canonical (SMAD2/3) and non-canonical (Erk1/2) TGF-β signaling pathways, while activating the p38 pathway. These results suggest that emodin may provide an effective therapeutic agent for fibrosis that functions via specific TGF-β signaling pathways.
Atomistic Dynamics of a Viral Infection Process: Release of Membrane Lytic Peptides from a Non-Enveloped Virus
Authors: Jana Asis K. , May Eric R.
Published: January 2021

Molecular simulations have played an instrumental role in uncovering the structural dynamics and physical properties of virus capsids. In this work we move beyond equilibrium physicochemical characterization of a virus system to study a stage of the infection process which is required for viral proliferation. Despite many biochemical and functional studies, the molecular mechanism of host cell entry by non-enveloped viruses remains largely unresolved. Flock House Virus (FHV) is model system for non-enveloped viruses and is the subject of the current study. FHV infects through the acid-dependent endocytic pathway, where low pH triggers externalization of membrane disrupting (γ) peptides from the capsid interior. Employing all-atom equilibrium and enhanced sampling simulations, the mechanism and energetics of γ peptide liberation and the effect of pH on this process is investigated. Our computations agree with experimental findings and reveal nanoscopic details regarding the pH control mechanism which are not readily accessible in experiments.
Gradual differentiation uncoupled from cell cycle exit generates heterogeneity in the epidermal stem cell layer
Authors: Cockburn Katie , Annusver Karl , Ganesan Smirthy , Mesa Kailin R. , Kawaguchi Kyogo , Kasper Maria , Greco Valentina
Published: January 2021

High turnover tissues continually lose specialized cells that are replaced by stem cell activity. In the adult mammalian epidermis, it is unclear how molecularly heterogenous stem/progenitor cell populations fit into the complete trajectory of epidermal differentiation. We show that differentiation, from commitment to exit from the stem cell layer, is a multi-day process wherein cells transit through a continuum of transcriptional changes. Differentiation-committed cells remain capable of dividing to produce daughter cells fated to further differentiate, demonstrating that differentiation is uncoupled from cell cycle exit. These cell divisions are not required as part of an obligate transit amplifying program but instead protect density in the stem cell layer. Thus, instead of distinct contributions from multiple progenitors, a continuous gradual differentiation process fuels homeostatic epidermal turnover.

One sentence summary

Heterogeneity in the epidermal stem cell layer reflects a gradual differentiation program that is uncoupled from the loss of proliferative capacity.
Ischemic tolerance and cardiac repair in the African spiny mouse
Authors: Koopmans Tim , van Beijnum Henriette , Roovers Elke F. , Malhotra Divyanshu , Tomasso Antonio , Boeter Jochem , Versteeg Danielle , van Rooij Eva , Bartscherer Kerstin
Published: January 2021

Ischemic heart disease and by extension myocardial infarction is the primary cause of death worldwide, necessitating regenerative therapies to restore heart function. Current models of heart regeneration are restricted in that they are not of adult mammalian origin, precluding the study of class-specific traits that have emerged throughout evolution, and reducing translatability of research findings to humans. Here, we overcome those restrictions by introducing the African spiny mouse (Acomys spp.), a murid rodent that has recently been found to exhibitbona fideregeneration of the back skin and ear pinna. We show that spiny mice exhibit tolerance to myocardial infarction through superior survivability, improved ventricular conduction, smaller scar size, and near-absence of cardiac remodeling. Critically, spiny mice display increased vascularization and cardiomyocyte expansion, with an associated improvement in heart function. These findings present new avenues for mammalian heart research by leveraging unique tissue properties of the spiny mouse.
Microglial Neuropilin-1 trans-regulates oligodendrocyte expansion during development and remyelination
Authors: Sherafat Amin , Pfeiffer Friederike , Reiss Alexander M. , Wood William M. , Nishiyama Akiko
Published: January 2021

NG2 glia or oligodendrocyte precursor cells (OPCs) are distributed throughout the gray and white matter and generate myelinating cells. OPCs in white matter proliferate more than those in gray matter in response to platelet-derived growth factor AA (PDGF AA), despite similar levels of its alpha receptor (PDGFRα) on their surface. Here we show that the type 1 integral membrane protein Neuropilin-1 (Nrp1) is expressed not on OPCs but on amoeboid and activated microglia in white but not gray matter in an age- and activity-dependent manner. Microglia-specific deletion of Nrp1 compromised developmental OPC proliferation in white matter as well as OPC expansion and subsequent myelin repair after acute demyelination. Exogenous Nrp1 increased PDGF AA-induced OPC proliferation and PDGFRα phosphorylation on dissociated OPCs, most prominently in the presence of suboptimum concentrations of PDGF AA. These findings uncover a novel mechanism of regulating oligodendrocyte lineage cell density that involves trans-activation of PDGFRα on OPCs via Nrp1 expressed by adjacent microglia.
A high throughput lipidomics method usingscheduledmultiple reaction monitoring
Authors: Bhaskar Akash Kumar , Naushin Salwa , Ray Arjun , Pradhan Shalini , Adlakha Khushboo , Siddiqua Towfida Jahan , Malakar Dipankar , Sengupta Shantanu
Published: January 2021

Lipid compositions of cells, tissues and bio-fluids are complex, with varying concentrations and structural diversity, which makes their identification challenging. Newer methods for comprehensive analysis of lipids are thus necessary. Herein, we propose a targeted-mass spectrometry based method for large-scale lipidomics using a combination of variable retention time window and relative dwell time weightage. Using this, we detected more than 1000 lipid species, including structural isomers. The limit of detection varied from femtomolar to nanomolar range and the coefficient of variance <30% for 849 lipid species. We used this method to identify lipids altered due to Vitamin B12deficiency and found that the levels of lipids with ω-3 fatty acid chains decreased while those with ω-6 increased. This method enables identification of by far the largest number of lipid species with structural isomers in a single experiment and would significantly advance our understanding of the role of lipids in biological processes.
Call to Action: Recommendations to Improve the Methodological Reporting of Games-Based Drills in Basketball Research
Authors: O’Grady Cody J. , Fox Jordan L. , Conte Daniele , Ferioli Davide , Scanlan Aaron T. , Dalbo Vincent J.
Published: January 2021

Purpose: Games-based drills are the predominant form of training adopted during basketball practice. As such, researchers have begun to quantify the physical, physiological, and perceptual demands of different games-based drill formats. However, study methodology has not been systematically reported across studies, limiting the ability to form conclusions from existing research. The authors developed this call to action to draw attention to the current standard of methodological reporting in basketball games-based drill research and establish a systematic reporting standard the authors hope will be utilized in future research. The Basketball Games-Based Drill Methodical Reporting Checklist (BGBDMRC) was developed to encourage the systematic reporting of games-based drill methodology. The authors used the BGBDMRC to evaluate the current methodological reporting standard of studies included in their review published in the International Journal of Sports Physiology and Performance, “A Systematic Review of the External and Internal Workloads Experienced During Games-Based Drills in Basketball Players” (2020), which highlighted this issue. Of the 17 studies included in their review, only 38% (±18%) of applicable checklist items were addressed across included studies, which is problematic as checklist items are essential for study replication. Conclusions: The current standard of methodological reporting in basketball games-based drill research is insufficient to allow for replication of examined drills in future research or the application of research outcomes to practice. The authors implore researchers to adopt the BGBDMRC to improve the quality and reproducibility of games-based drill research and increase the translation of research findings to practice.
The Interaction Between Long-Term Memory and Postural Control: Different Effects of Episodic and Semantic Tasks
Authors: Tixier Maëlle , Cian Corinne , Barraud Pierre-Alain , Laboissiere Rafael , Rousset Stéphane
Published: January 2021

The aim of this experiment was to investigate the postural response to specific types of long-term memory (episodic vs. semantic) in young adults performing an unperturbed upright stance. Although a similar level of steadiness (mean distance) was observed, dual tasking induced a higher velocity, more energy in the higher frequency range (power spectral density), and less regularity (sample entropy) compared with a simple postural task. Moreover, mean velocity was always greater in the semantic than in the episodic task. The differences in postural control during dual tasking may result from the types of processes involved in the memory task. Findings suggest a spatial process sharing between posture and episodic memory.
What is the risk of missing orbital cellulitis in children?
Authors: Ibrahim Laila F , Babl Franz E , Hopper Sandy M , Bryant Penelope A
Published: January 2021

Background

Preseptal cellulitis can be difficult to distinguish from orbital cellulitis in children. The majority of patients with periorbital infections are admitted for intravenous antibiotics. This study aimed to investigate the risk of missing orbital cellulitis and the outcomes of missed patients.

Methods

A prospective cohort study of children aged 3 months to 18 years diagnosed with preseptal cellulitis over 5 years. Data were collected prospectively, including demographics, clinical features and outcomes.

Results

There were 216 children diagnosed with preseptal cellulitis. 75 (35%) were treated with oral antibiotics and 141 (65%) with intravenous antibiotics. 5 (2%) children who were hospitalised were subsequently determined to have orbital cellulitis. All 5 children were either a young infant with difficult eye examination, or had headache or vomiting.

Conclusion

The risk of missing orbital cellulitis is low. Young infants with difficult eye examination or the presence of headache or vomiting should increase suspicion of orbital cellulitis.
Group-led creative writing and behavioural health in cancer: a randomised clinical trial
Authors: Nesterova Darya , Zhu Junjia , Kramer Courtney , Vasekar Monali , Truica Cristina , Joshi Aditya , Hayes Michael , Kessler Jolene , Saunders Erika F H , Drabick Joseph J , Joshi Monika
Published: January 2021

Background

Cancer diagnosis can adversely affect mental well-being and overall clinical outcome. We evaluated the efficacy of a group-led creative writing workshop (CWW) on mood in patients with cancer prospectively.

Methods

We conducted a single-institution phase II study. Sixty adult patients with cancer (any type or stage) were randomised 2:1 to CWW (4×CWW sessions, bimonthly over 8 weeks) versus active control (AC) (independent writing at home with the help of a book, four sessions, bimonthly over 8 weeks). The total study duration was 6 months with a follow-up of up to 3 months. Primary objective: changes in overall mood, depression and anxiety symptoms before and after intervention in both arms. Emotional Thermometer Scale (ETS) was used to assess changes in patients’ mood. Additionally, the Patient Health Questionnaire (PHQ)-9 and General Anxiety Disorder Scale (GAD)-7 were used to evaluate depression and anxiety symptoms.

Results

Of 50 evaluable patients (CWW 34, AC 17), 26 patients in the CWW arm attended at least one class and 19 attended at least four classes. Patients in CWW had significant immediate improvement in the overall ETS (post vs preclass scores; p<0.0001, 95% CI −4.31 to −2.47). Four of the five subscale ETS scores were significantly lower for the CWW arm: distress (p=0.0346, 95% CI −2.6 to −0.1), anxiety (p=0.0366, 95% CI −4.1 to −0.2), depression (p=0.0441, 95% CI −3.9 to −0.1) and anger (p=0.0494, 95% CI −3.3 to 0). No significant differences were seen in the AC arm. No significant differences were observed in the PHQ-9 or the GAD-7 scores.

Conclusion

CWW had a positive effect on mood based on ETS scores, suggesting a potential therapeutic benefit among patients with cancer.
Survival and risk of recurrence of takotsubo syndrome
Authors: Lau Christopher , Chiu Sarah , Nayak Rohith , Lin Bryan , Lee Ming-Sum
Published: January 2021

Objective

The goal of this study is to evaluate the long-term outcomes of patients with takotsubo syndrome and assess factors associated with death or recurrence.

Methods

This is a retrospective population-based cohort study of consecutive patients who presented to an integrated health system in Southern California with takotsubo syndrome between 2006 and 2016. Medical records were manually reviewed to confirm diagnosis and to identify predisposing factors, medication treatment and long-term outcomes. Factors associated with death or recurrent takotsubo syndrome were tested using Cox regression models.

Results

Between 2006 and 2016, there were 519 patients with a confirmed diagnosis of takotsubo syndrome. Patients were followed for 5.2 years (IQR 3.0–7.2). During the follow-up period, 39 (7.5%) had recurrent takotsubo syndrome and 84 (16.2%) died. In multivariate modelling, factors associated with higher risk of recurrence or death were age (HR 1.56 per 10-year increase, 95% CI 1.29 to 1.87), male sex (HR 2.52, 95% CI 1.38 to 4.60), diabetes (HR 1.6, 95% CI 1.06 to 2.43), pulmonary disease (HR 2.0, 95% CI 1.37 to 2.91) and chronic kidney disease (HR 1.58, 95% CI 1.01 to 2.47). Treatment with beta-blockers were associated with lower risk of recurrence or death (HR 0.46, 95% CI 0.29 to 0.72). No association was observed between treatment with ACE inhibitors or angiotensin-receptor blockers and recurrence or death (HR 0.92, 95% CI 0.59 to 1.42).

Conclusions

Recurrent takotsubo syndrome occurred in a minor subset of patients. Treatment with beta-blocker was associated with higher event-free survival.
Cultivating not gatekeeping: a key leadership role in the creative process
Authors: Katz Joshua H , Herman Geoffrey L , Johnson Mark A , Loewenstein Jeffrey
Published: January 2021

BackgroundCreativity and innovation are frequent features in healthcare discussions and proposals. A burgeoning area of research shows that evaluating proposals is a crucial juncture in the creative process. Leadership can make a substantial difference in how well the evaluation process does.

ResultOrganisational leaders want creativity, yet often inadvertently act as gatekeepers and disproportionately reject creative proposals. We review research to provide guidance for leaders on how to cultivate creativity through improvements in the process of evaluating proposals.