bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and Pharmacokinetics of a Novel Non-Steroidal Mineralocorticoid Receptor Antagonist, KBP-5074, in Hemodialysis and Non-Hemodialysis Patients with Severe Chronic Kidney Disease
Authors: Connaire Jeffrey , Bush Mark , Ruckle Jon , Yang Fred , Liu Jinrong , Tan Xiaojuan , Wang Ping , Zhou Tian , Zhang Min , Benn Vincent
Published: May 2020

Objective

KBP-5074 is a novel non-steroidal mineralocorticoid receptor antagonist for the potential treatment of hypertension. The purpose of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single dose of 0.5 mg KBP-5074 in subjects with end stage renal disease on and not on hemodialysis.

Results

Single doses of 0.5 mg KBP-5074 were generally well tolerated in both hemodialysis (N=6) and non-hemodialysis (N=5) subjects with severe renal impairment. Of the 11 subjects in the study, there was a single report of hyperkalemia in a hemodialysis subject on Day 14 that was not considered drug-related and was resolved in 2 days. Mean plasma KBP-5074 concentrations peaked at 6 and 4 hours in non-dialysis and dialysis subjects, respectively, and slowly declined through 312 hours postdose. Overall, the KBP-5074 exposures were significantly lower and had a shorter half-life in hemodialysis subjects compared with the non-hemodialysis subjects. However, hemodialysis had minimal direct impact on drug concentrations with negligible drug levels in the dialysate samples. Plasma aldosterone and serum potassium concentrations were generally comparable between non-hemodialysis and hemodialysis subjects, most likely to due to high variability in the hemodialysis subjects.

Conclusion

The overall plasma exposure of KBP-5074 was statistically significantly lower in hemodialysis subjects compared to subjects with renal impairment not on hemodialysis.
A Systems Approach Identifies Key Regulators of HPV-Positive Cervical Cancer
Authors: Sinkala Musalula , Zulu Mildred , Nkhoma Panji , Kafita Doris , Zulu Ephraim , Tembo Rabecca , Ngwira Zifa , Daka Victor , Munsaka Sody
Published: May 2020

Cervical cancer has remained the most prevalent and lethal malignancy among women worldwide and accounted for over 250,000 deaths in 2019. Nearly ninety-five per cent of cervical cancer cases are associated with persistent infection with high-risk Human Papillomavirus (HPV), and seventy per cent of these are associated with viral integration in the host genome. HPV-infection imparts specific changes in the regulatory network of infected cancer cells that are of diagnostic, prognostic and importance. Here, we conducted a systems-level analysis of the regulatory network changes, and the associated regulatory proteins thereof, in HPV-positive cervical cancer. We applied functional pathway analysis to show that HPV-positive cancers are characterised by perturbations of numerous cellular processes, predominantly in those linked to the cell cycle, mitosis, cytokine and immune cell signalling. Using computational predictions, we revealed that HPV-positive cervical cancers are regulated by transcription factors including, SOX2, E2F, NANOG, OCT4, and MYC, which control various processes such as the renewal of cancer stem cells, and the proliferation and differentiation of tumour cells. Through the analysis of upstream regulatory kinases, we identified the mitogen-activated protein kinases; among others, MAPK1, MAPK3 and MAPK8, and the cyclin-dependent kinases; among others, CDK1, CDK2 and CDK4, as the key kinases that control the biological processes in HPV-positive cervical cancers. Taken together, we uncover a landscape of the key regulatory pathways and proteins in HPV-positive cervical cancers, all of which may provide attractive drug targets for future therapeutics.
Hypoxia-Sensing CAR T-Cells Provide Safety and Efficacy in Treating Solid Tumors
Authors: Kosti Paris , Opzoomer James W. , Larios-Martinez Karen I. , Henley-Smith Rhonda , Scudamore Cheryl L. , Okesola Mary , Taher Mustafa Y.M. , Davies David M. , Muliaditan Tamara , Larcombe-Young Daniel , Woodman Natalie , Gillett Cheryl E. , Thavaraj Selvam , Maher John , Arnold James N.
Published: May 2020

There has been significant interest in the prospects of chimeric antigen receptor (CAR) T-cell therapy in the treatment of solid malignancies, and multiple clinical trials are in progress1. However, the scope of these trials has been restricted by the lack of availability of tumorspecific targets to direct CAR binding. Tumor specificity is crucial as on-target off-tumor activation of CAR T-cells in healthy tissues can result in potentially lethal toxicities due to uncontrolled cytokine release syndrome2. Here we engineer a stringent hypoxia-sensing CAR T-cell system which achieves selective expression of a pan-ErbB-targeted CAR within a solid tumor, a microenvironment characterized by an inadequate oxygen supply. Using murine xenograft models, we demonstrate that despite widespread expression of ErbB receptors in healthy organs, the approach provides anti-tumor efficacy without off-tumor toxicity. This dynamic on/off oxygen-sensing safety switch has the potential to facilitate the unlimited expansion of the CAR T-cell target repertoire for treating solid malignancies.
An adaptive pre-DNA-damage-response protects genome integrity
Authors: Ragu Sandrine , Matos-Rodrigues Gabriel , Droin Nathalie , Barascu Aurélia , Caillat Sylvain , Zarkovic Gabriella , Siberchicot Capucine , Dardillac Elodie , Gelot Camille , Radicella Juan Pablo , Ishchenko Alexander A. , Ravanat Jean-Luc , Solary Eric , Lopez Bernard S.
Published: May 2020

The DNA damage response (DDR) interrupts cell cycle progression to restore genome integrity. However, unchallenged proliferating cells are continually exposed to endogenous stress, raising the question of a stress-threshold for DDR activation. Here, we identified a stress threshold below which primary human fibroblasts, activate a cell-autonomous response that not activates full DDR and not arrests cell cycle progression,. We characterized this “pre-DDR” response showing that it triggers the production of reactive oxygen species (ROS) by the NADPH oxidases DUOX1 and DUOX2, under the control of NF-κB and PARP1. Then, replication stress-induced ROS (RIR) activates the FOXO1 detoxifying pathway, preventing the nuclear accumulation of the pre-mutagenic 8-oxoGuanine lesion, upon endogenous as well as exogenous pro-oxidant stress. Increasing the replication stress severity above the threshold triggers the canonical DDR, leading to cell cycle progression arrest, but also to RIR suppression. These data reveal that cells adapt their response to stress severity, unveiling a tightly regulated ”pre-DDR” adaptive response that protects genome integrity without arresting cell cycle progression.
PIDDosome-induced p53-activation for ploidy restriction facilitates hepatocarcinogenesis
Authors: Sladky Valentina , Knapp Katja , Szabo Tamas G. , Bongiovanni Laura , van den Bos Hilda , Spierings Diana C.J. , Westendorp Bart , Stojakovic Tatjana , Scharnagl Hubert , Timelthaler Gerald , Tsuchia Kaoru , Pinter Matthias , Foijer Floris , de Bruin Alain , Reiberger Thomas , Rohr-Udilova Nataliya , Villunger Andreas
Published: May 2020

Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. The PIDDosome multi-protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome-deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome-induced p53-activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome-deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro-tumorigenic effect of PIDDosome-mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome-deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts of survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and tumor cell density serves as a novel prognostic marker for recurrence free survival in HCC patients.
Network Analysis and Transcriptome Profiling Identify Autophagic and Mitochondrial Dysfunctions in SARS-CoV-2 Infection
Authors: Singh Komudi , Chen Yun-Ching , Judy Jennifer T , Seifuddin Fayaz , Tunc Ilker , Pirooznia Mehdi
Published: May 2020

Analyzing host transcriptional changes in response to SARS-CoV-2 infection will help delineate biological processes underlying viral pathogenesis. Comparison of expression profiles of lung cell lines A549 (infected with either SARS-CoV-2 (with ACE2 expression)) or Influenza A virus (IAV)) and Calu3 (infected with SARS-CoV-2 or MERS-CoV) revealed upregulation of the antiviral interferon signaling in all three viral infections. However, perturbations in inflammatory, mitochondrial, and autophagy processes were specifically observed in SARS-CoV-2 infected cells. Validation of findings from cell line data revealed perturbations in autophagy and mitochondrial processes in the infected human nasopharyngeal samples. Specifically, downregulation of mTOR expression, mitochondrial ribosomal, mitochondrial complex I, and lysosome acidification genes were concurrently observed in both infected cell lines and human datasets. Furthermore, SARS-CoV-2 infection impedes autophagic flux by upregulating GSK3B in lung cell lines, or by downregulating autophagy genes, SNAP29 and lysosome acidification genes in human samples, contributing to increased viral replication. Therefore, drugs targeting lysosome acidification or autophagic flux could be tested as intervention strategies. Additionally, downregulation of MTFP1 (in cell lines) or SOCS6 (in human samples) results in hyperfused mitochondria and impede proper interferon response. Coexpression networks analysis identifies correlated clusters of genes annotated to inflammation and mitochondrial processes that are misregulated in SARS-CoV-2 infected cells. Finally, comparison of age stratified human gene expression data revealed impaired upregulation of chemokines, interferon stimulated and tripartite motif genes that are critical for antiviral signaling. Together, this analysis has revealed specific aspects of autophagic and mitochondrial function that are uniquely perturbed in SARS-CoV-2 infection.
The two-component system CopRS maintains femtomolar levels of free copper in the periplasm ofPseudomonas aeruginosausing a phosphatase-based mechanism
Authors: Novoa-Aponte Lorena , Soncini Fernando C. , Argüello José M.
Published: May 2020

Two component systems control periplasmic Cu+homeostasis in Gram-negative bacteria. In characterized systems such asEscherichia coliCusRS, upon Cu+binding to the periplasmic sensing domain of CusS, a cytoplasmic phosphotransfer domain phosphorylates the response regulator CusR. This drives the expression of efflux transporters, chaperones, and redox enzymes to ameliorate metal toxic effects. Here, we show that thePseudomonas aeruginosatwo component sensor histidine kinase CopS exhibits a Cu-dependent phosphatase activity that maintains a non-phosphorylated CopR when the periplasmic Cu levels are below its activation threshold. Upon Cu+binding to the sensor, the phosphatase activity is blocked and the phosphorylated CopR activates transcription of the CopRS regulon. Supporting the model, mutagenesis experiments revealed that the ΔcopSstrain showed constitutive high expression of the CopRS regulon, lower intracellular Cu+levels, and larger Cu tolerance when compared to wild type cells. The invariant phospho-acceptor residue His235of CopS was not required for the phosphatase activity itself, but necessary for its Cu-dependency. To sense the metal, the periplasmic domain of CopS binds two Cu+ions at its dimeric interface. Homology modeling of CopS based on CusS structure (four Ag+binding sites) clearly explains the different binding stoichiometries in both systems. Interestingly, CopS binds Cu+/2+with 30 × 10−15M affinities, pointing to the absence of free (hydrated) Cu+/2+in the periplasm.

IMPORTANCE

Copper is a micronutrient required as cofactor in redox enzymes. When free, copper is toxic, mismetallating proteins, and generating damaging free radicals. Consequently, copper overload is a strategy that eukaryotic cells use to combat pathogens. Bacteria have developed copper sensing transcription factors to control copper homeostasis. The cell envelope is the first compartment that has to cope with copper stress. Dedicated two component systems control the periplasmic response to metal overload. This manuscript shows that the copper sensing two component system present in Pseudomonadales exhibits a signal-dependent phosphatase activity controlling the activation of the response regulator, distinct from previously described periplasmic Cu sensors. Importantly, the data show that the sensor is activated by copper levels compatible with the absence of free copper in the cell periplasm. This emphasizes the diversity of molecular mechanisms that have evolved in various bacteria to manage the copper cellular distribution.
Single Cell Transcriptomics-guided Antisense Treatment Improves Endoderm Differentiation of iPSCs
Authors: Hor P. , Punj V. , Borok Z. , Ryan (Firth) A.L. , Ichida J.K.
Published: May 2020

Directed differentiation of induced pluripotent stem cells (iPSCs) enables the production of relevant cell types for studies of human biology, disease-modeling, and efforts towards cellular therapy and transplantation. However, the low yield and purity of desired cell types can limit the utility of this approach. Enhancing differentiation purity can require extensive optimization of morphogen treatments, and this can still be ineffective for iPSC lines with biased or aberrant differentiation propensities. To address these limitations, we have developed a new approach for increasing the purity of iPSC directed differentiation cultures calledRNA sequencing andAntisense-assistedDifferentiation (RAD). We performed trajectory analysis of single cell RNA sequencing during iPSC differentiation into endoderm to identify transcription factors responsible for committing cells to undesired, non-endodermal fates. Specific suppression of these transcription factors using antisense oligonucleotides (ASOs) increased the percentage of endodermal cells by up to 20-fold in 3 different iPSC lines that exhibited poor endoderm differentiation. Moreover, this approach required minimal culture manipulation. Thus, RAD improves the utility of iPSCs for basic and translational studies.
Reprogramming of larval locomotory pattern during baculovirus-induced host manipulation
Authors: Hikida Hiroyuki , Katsuma Susumu
Published: May 2020

Many parasites manipulate host behaviour to enhance their transmission. Baculovirus induces enhanced locomotory activity (ELA) combined with subsequent climbing behaviour in lepidopteran larvae, which facilitates viral dispersal. Previously, larval locomotion during ELA was summarized as the distance travelled for a few minutes at several time points. However, as ELA continues for several hours, these methods are unlikely to evaluate larval locomotion precisely during ELA. We developed a novel method to continuously trace the locomotion ofBombyx morilarvae using time-lapse imaging. This method successfully quantified the locomotory activities of larvae infected withBombyx mori nucleopolyhedrovirus(BmNPV) for 24 h. We found that both mock- and BmNPV-infected larvae periodically repeated moving and pausing with a similar frequency. In contrast, BmNPV-infected larvae showed fast and long-lasting locomotion compared with mock-infected larvae, which resulted in longer locomotory distances in infected larvae. Moreover, BmNPV-infected larvae exhibited biphasic behaviour. Initially, BmNPV-infected larvae showed longer locomotory distances, but the locomotory pattern was similar to mock-infected larvae. However, during the second phase, the locomotory pattern was drastically altered, with an extremely larger locomotory area. These results indicate that BmNPV reprograms host locomotory pattern, which is a turning point for the process of BmNPV-induced host manipulation.
Regularity extraction under stress: boosted statistical learning but unaffected sequence learning
Authors: Tóth-Fáber Eszter , Janacsek Karolina , Szőllősi Ágnes , Kéri Szabolcs , Németh Dezső
Published: May 2020

Acute stress can crucially influence learning and memory processes. One of the key processes underlying human learning and memory is the ability of our brain to rapidly detect and extract regularities from sensory input across time and space leading to effective predictive processing. Here, we aimed to get an in-depth look into the effect of stress on the acquisition of two aspects of regularity extraction. We examined whether and how stress affects (1) processes and learning of probability-based, statistical regularities and (2) serial order-based, sequential regularities in the same experimental design, and (3) explicit access to the acquired information. Considering that the acquisition of statistical regularities is a rapid process, we primarily focused on the early phases of the task. We induced stress with the Socially Evaluated Cold Pressor Test in 27 young adults, while 26 participants were enrolled in the control group. Salivary cortisol levels and subjective ratings of affective states showed successful stress induction. After the stress induction, we measured regularity extraction with the cued Alternating Serial Reaction Time task. We found that stress promoted the acquisition of statistical regularities and did not alter the learning of sequential regularities. Post-block reports showed weaker explicit access to the sequential regularities in the stress group. Our results give a process-level understanding on how stress alters learning and memory functions related to predictive processes.
Automatic Wake-Sleep Stages Classification using Electroencephalogram Instantaneous Frequency and Envelope Tracking
Authors: Rahbar Alam Mahdi , Sameni Reza
Published: May 2020

Background

The study of cerebral activity during sleep using the electroencephalograph (EEG) is a major research field in neuroscience. Despite the rich literature in this field, the automatic and accurate categorization of wake-sleep stages remains an open problem.

New Method

A robust model-based Kalman filtering scheme is proposed for tracking the poles of a second order time-varying autoregressive model fitted over the EEG acquired during different wake/sleep stages. The pole angle/phase is regarded as the dominant frequency of the EEG spectrum (known as the instantaneous frequency in literature). The frequency resolution is improved by splitting the wide frequency band to subbands corresponding to well-known brain rhythms. Using recent findings in field of EEG phase/frequency tracking, the instantaneous envelope of the narrow-band signal’s analytic form is also tracked as a complementary feature.

Results

The minimal set of instantaneous frequency and envelope features is employed in three classification schemes, using training labels from R&k and AASM sleep scoring standards. The LDA classifier resulted in the highest performance using the proposed feature set.

Comparison with Existing Methods

The proposed method resulted in a higher mean decoding accuracy and a lower standard deviation on the entire dataset, as compared with state-of-the-art techniques.

Conclusions

The accurate tracking of the instantaneous frequency and envelope are highly informative for sleep stage scoring. The proposed method is shown to have additional applications, including the prediction of wake-sleep transition, which can be used for drowsiness detection from the EEG.
Energy dynamics for systemic configurations of virus-host co-evolution
Authors: Romano Alessandra , Casazza Marco , Gonella Francesco
Published: May 2020

Abstract (no-technical summary)

Virus cause multiple outbreaks, for which comprehensive tailored therapeutic strategies are still missing. Virus and host cell dynamics are strictly connected, and convey in virion assembly to ensure virus spread in the body. Study of the systemic behavior of virus-host interaction at the single-cell level is a scientific challenge, considering the difficulties of using experimental approaches and the limited knowledge of the behavior of emerging novel virus as a collectivity. This work focuses on positive-sense, single-stranded RNA viruses, like human coronaviruses, in their virus-individual host interaction, studying the changes induced in the host cell bioenergetics. A systems-thinking representation, based on stock-flow diagramming of virus-host interaction at the cellular level, is used here for the first time to simulate the system energy dynamics. We found that reducing the energy flow which fuels virion assembly is the most affordable strategy to limit the virus spread, but its efficacy is mitigated by the contemporary inhibition of other flows relevant for the system.

Positive-single-strand ribonucleic acid ((+)ssRNA) viruses can cause multiple outbreaks, for which comprehensive tailored therapeutic strategies are still missing. Virus and host cell dynamics are strictly connected, generating a complex dynamics that conveys in virion assembly to ensure virus spread in the body.

This work focuses on (+)ssRNA viruses in their virus-individual host interaction, studying the changes induced in the host cell bioenergetics. A systems-thinking representation, based on stock-flow diagramming of virus-host interaction at the cellular level, is used here for the first time to simulate the energy dynamics of the system.

By means of a computational simulator based on the systemic diagramming, we identifid host protein recycling and folded-protein synthesis as possible new leverage points. These also address different strategies depending on time setting of the therapeutic procedures. Reducing the energy flow which fuels virion assembly is addressed as the most affordable strategy to limit the virus spread, but its efficacy is mitigated by the contemporary inhibition of other flows relevant for the system. Counterintuitively, targeting RNA replication or virion budding does not give rise to relevant systemic effects, and can possibly contribute to further virus spread. The tested combinations of multiple systemic targets are less efficient in minimizing the stock of virions than targeting only the virion assembly process, due to the systemic configuration and its evolution overtime. Viral load and early addressing (in the first two days from infection) of leverage points are the most effective strategies on stock dynamics to minimize virion assembly and preserve host-cell bioenergetics.

As a whole, our work points out the need for a systemic approach to design effective therapeutic strategies that should take in account the dynamic evolution of the system.
On the correlation between material-induced cell shape and phenotypical response of human mesenchymal stem cells
Authors: Vasilevich Aliaksei S , Vermeulen Steven S , Kamphuis Marloes , Roumans Nadia , Eroume Said , Hebels Dennie G.A.J. , Peppel Jeroen van de , Reihs Rika , Beijer Nick R.M. , Carlier Aurelie , Carpenter Anne E. , Singh Shantanu , de Boer Jan
Published: May 2020

Learning rules by which cell shape impacts cell function would enable control of cell physiology and fate in medical applications, particularly, on the interface of cells and material of the implants. We defined the phenotypic response of human bone marrow-derived mesenchymal stem cells (hMSCs) to 2176 randomly generated surface topographies by probing basic functions such as migration, proliferation, protein synthesis, apoptosis, and differentiation using quantitative image analysis. Clustering the surfaces into 28 archetypical cell shapes, we found a very strict correlation between cell shape and physiological response and selected seven cell shapes to describe the molecular mechanism leading to phenotypic diversity. Transcriptomics analysis revealed a tight link between cell shape, molecular signatures, and phenotype. For instance, proliferation is strongly reduced in cells with limited spreading, resulting in down-regulation of genes involved in the G2/M cycle and subsequent quiescence, whereas cells with large filopodia are related to activation of early response genes and inhibition of the osteogenic process. Thus, we have started to unravel the open question of how cell function follows cell shape. This will allow designing implants that can actively regulate cellular, molecular signalling through cell shape. Here we are proposing an approach to tackle this question.
In Vitro Inhibition of SARS-CoV-2 Infection by Bovine Lactoferrin
Authors: de Carvalho Carlos Alberto Marques , da Rocha Matos Aline , Caetano Braulia Costa , de Sousa Junior Ivanildo Pedro , da Costa Campos Samir Pereira , Geraldino Barbara Rodrigues , Barros Caroline Augusto , de Almeida Matheus Augusto Patricio , Rocha Vanessa Pimenta , da Silva Andréa Marques Vieira , Melgaço Juliana Gil , da Costa Neves Patrícia Cristina , da Costa Barros Tamiris Azamor , Ano Bom Ana Paula Dinis , Siqueira Marilda Mendonça , Missailidis Sotiris , Gonçalves Rafael Braga
Published: May 2020

Since its emergence in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been posing a serious threat to public health worldwide as the causative agent of coronavirus disease 2019 (COVID-19). Now distributed in a pandemic pattern, this disease still lacks an effective drug treatment with low toxicity, leading pharmaceutical companies and research labs to work against time to find a candidate molecule to efficiently treat the affected patients. Due to the well-known broad-spectrum antimicrobial activity of the lactoferrin protein, we sought to verify whether its bovine form (bLf) would also be effective in vitro against SARS-CoV-2. Using an antiviral assay based on quantitative reverse transcription-polymerase chain reaction (qRT-PCR), we found that bLf reduced progeny virus yield by up to ∼84,6% in African green monkey kidney epithelial cells (Vero E6) and ∼68,6% in adenocarcinomic human alveolar basal epithelial cells (A549) at 1 mg/mL, a concentration previously shown to have low cytotoxicity. Therefore, our preliminary data suggest that bLf has the potential to constitute a biochemical approach to fight the new coronavirus pandemic.
Cerebellar Golgi cell models predict dendritic processing and mechanisms of synaptic plasticity
Authors: Masoli Stefano , Ottaviani Alessandra , D’Angelo Egidio
Published: May 2020

The Golgi cells are the main inhibitory interneurons of the cerebellar granular layer. Although recent works have highlighted the complexity of their dendritic organization and synaptic inputs, the mechanisms through which these neurons integrate complex input patterns remained unknown. Here we have used 8 detailed morphological reconstructions to develop multicompartmental models of Golgi cells, in which Na, Ca, and K channels were distributed along dendrites, soma, axonal initial segment and axon. The models faithfully reproduced a rich pattern of electrophysiological and pharmacological properties and predicted the operating mechanisms of these neurons. Basal dendrites turned out to be more tightly electrically coupled to the axon initial segment than apical dendrites. During synaptic transmission, parallel fibers caused slow Ca-dependent depolarizations in apical dendrites that boosted the axon initial segment encoder and Na-spike backpropagation into basal dendrites, while inhibitory synapses effectively shunted backpropagating currents. This oriented dendritic processing set up a coincidence detector controlling voltage-dependent NMDA receptor unblock in basal dendrites, which, by regulating local calcium influx, may provide the basis for spike-timing dependent plasticity anticipated by theory.

Author Summary

The Golgi cells are the main inhibitory interneurons of the cerebellum granular layer and play a fundamental role in controlling cerebellar processing. However, it was unclear how spikes are processed in the dendrites by specific sets of ionic channels and how they might contribute to integrate synaptic inputs and plasticity. Here we have developed detailed multicompartmental models of Golgi cells that faithfully reproduced a large set of experimental findings and revealed the nature of signal interchange between dendrites and axo-somatic compartments. A main prediction of the models is that synaptic activation of apical dendrites can effectively trigger spike generation in the axonal initial segment followed by rapid spike backpropagation into basal dendrites. Here, incoming mossy fiber inputs and backpropagating spikes regulate the voltage-dependent unblock of NMDA channels and the induction of spike timing-dependent plasticity (STDP). STDP, which was predicted by theory, may therefore be controlled by contextual information provided by parallel fibers and integrated in apical dendrites, supporting the view that spike timing is fundamental to control synaptic plasticity at the cerebellar input stage.
The effect of respiratory gases and incubation temperature on early stage embryonic development in sea turtles
Authors: Booth David Terrington , Archibald-Binge Alexander , Limpus Colin James
Published: May 2020

Sea turtle embryos at high density nesting beaches experience relative high rates of early stage embryo death. One hypothesis to explain this high dead rate is that there is an increased probability that newly constructed nests are located close to maturing clutches whose metabolising embryos cause low oxygen levels, high carbon dioxide levels, and high temperatures. Although these altered environmental conditions are well tolerated by mature embryos, early stage embryos may not be as tolerant leading to an increase in their mortality. To test this hypothesis, we incubated newly laid sea turtle eggs for a week over a range of temperatures in different combinations of oxygen and carbon dioxide concentrations and assessed embryo development and death rates. We found that gas mixtures of decreased oxygen and increased carbon dioxide, similar to those found in natural sea turtle nest containing mature embryos, slowed embryonic development but did not influence embryo mortality of early stage embryos. In contrast, high incubation temperature not only decreased embryo development rate, but prolonged incubation at 34°C was fatal.
Insights into molecular evolution recombination of pandemic SARS-CoV-2 using Saudi Arabian sequences
Authors: Nour Islam , Alanazi Ibrahim O. , Hanif Atif , Kohl Alain , Eifan Saleh
Published: May 2020

The recently emerged SARS-CoV-2 (Coronaviridae; Betacoronavirus) is the underlying cause of COVID-19 disease. Here we assessed SARS-CoV2 from the Kingdom of Saudi Arabia alongside sequences of SARS-CoV, bat SARS-like CoVs and MERS-CoV, the latter currently detected in this region. Phylogenetic analysis, natural selection investigation and genome recombination analysis were performed. Our analysis showed that all Saudi SARS-CoV-2 sequences are of the same origin and closer proximity to bat SARS-like CoVs, followed by SARS-CoVs, however quite distant to MERS-CoV. Moreover, genome recombination analysis revealed two recombination events between SARS-CoV-2 and bat SARS-like CoVs. This was further assessed by S gene recombination analysis. These recombination events may be relevant to the emergence of this novel virus. Moreover, positive selection pressure was detected between SARS-CoV-2, bat SL-CoV isolates and human SARS-CoV isolates. However, the highest positive selection occurred between SARS-CoV-2 isolates and 2 bat-SL-CoV isolates (Bat-SL-RsSHC014 and Bat-SL-CoVZC45). This further indicates that SARS-CoV-2 isolates were adaptively evolved from bat SARS-like isolates, and that a virus with originating from bats triggered this pandemic. This study thuds sheds further light on the origin of this virus.

AUTHOR SUMMARY

The emergence and subsequent pandemic of SARS-CoV-2 is a unique challenge to countries all over the world, including Saudi Arabia where cases of the related MERS are still being reported. Saudi SARS-CoV-2 sequences were found to be likely of the same or similar origin. In our analysis, SARS-CoV-2 were more closely related to bat SARS-like CoVs rather than to MERS-CoV (which originated in Saudi Arabia) or SARS-CoV, confirming other phylogenetic efforts on this pathogen. Recombination and positive selection analysis further suggest that bat coronaviruses may be at the origin of SARS-CoV-2 sequences. The data shown here give hints on the origin of this virus and may inform efforts on transmissibility, host adaptation and other biological aspects of this virus.
Mitochondrial nicotinic acetylcholine receptors form complexes with Bax upon apoptosis induction
Authors: Kalashnyk Olena , Lykhmus Olena , Uspenska Kateryna , Izmailov Mykhailo , Komisarenko Sergiy , Skok Maryna
Published: May 2020

Nicotinic acetylcholine receptors (nAChRs) mediate fast synaptic transmission in muscles and autonomic ganglia and regulate cytokine and neurotransmitter release in the brain and nonexcitable cells. The nAChRs expressed in the outer membrane of mitochondria control the early events of mitochondria-driven apoptosis like cytochrome c release by affecting intramitochondrial kinase pathways. However, the mechanisms through which nAChRs influence mitochondrial permeability remain obscure. Previously we demonstrated that mitochondrial nAChRs interact with voltage-dependent anion channels (VDAC) involved in forming the pore in mitochondria membrane. Here we put an aim to explore the connection of nAChRs to pro-apoptotic protein Bax and its changes in the course of apoptosis induction. By using molecular modeling in silico, it was shown that both Bax and VDAC bind within the 4thtransmembrane portion of nAChR subunits. Experimentally, α7 nAChR-Bax and α7 nAChR-VDAC complexes were identified by sandwich ELISA in mitochondria isolated from astrocytoma U373 cells. Stimulating apoptosis of U373 cells by 1μM H2O2disrupted α7-VDAC complexes and favored formation of α7-Bax complexes. α7-selective agonist PNU282987 and type 2 positive allosteric modulator PNU120596 disrupted α7-Bax and returned α7 nAChR to complex with VDAC. It is concluded that mitochondrial nAChRs regulate apoptosis-induced mitochondrial channel formation by modulating the interplay of apoptosis-related proteins in mitochondria outer membrane.
Nicotinamide restricts neural precursor proliferation to enhance catecholaminergic neuronal subtype differentiation from mouse embryonic stem cells
Authors: Griffin Síle M. , Pickard Mark R. , Hawkins Clive P. , Williams Adrian C. , Fricker Rosemary A.
Published: May 2020

Emerging evidence indicates that a strong relationship exists between brain regenerative therapies and nutrition. Early life nutrition plays an important role during embryonic brain development, and there are clear consequences to an imbalance in nutritional factors on both the production and survival of mature neuronal populations and the infant’s risk of diseases in later life. Our research and that of others suggest that vitamins play a fundamental role in the formation of neurons and their survival. There is a growing body of evidence that nicotinamide, the water-soluble amide form of vitamin B3, is implicated in the conversion of pluripotent stem cells to clinically relevant cells for regenerative therapies. This study investigated the ability of nicotinamide to promote the development of mature catecholaminergic neuronal populations (associated with Parkinson’s disease) from mouse embryonic stem cells, as well as investigating the underlying mechanisms of nicotinamide’s action.

Nicotinamide selectively enhanced the production of tyrosine hydroxylase-expressing neurons and serotonergic neurons from mouse embryonic stem cell cultures (Sox1GFP knock-in 46C cell line). A 5-Ethynyl-2’-deoxyuridine (EdU) assay ascertained that nicotinamide, when added in the initial phase, reduced cell proliferation. Nicotinamide drove tyrosine hydroxylase-expressing neuron differentiation as effectively as an established cocktail of signalling factors, reducing the proliferation of neural progenitors and accelerating neuronal maturation, neurite outgrowth and neurotransmitter expression.

These novel findings show that nicotinamide enhanced and enriched catecholaminergic differentiation and inhibited cell proliferation by directing cell cycle arrest in mouse embryonic stem cell cultures, thus driving a critical neural proliferation-to-differentiation switch from neural progenitors to neurons. Further research into the role of vitamin metabolites in embryogenesis will significantly advance cell-based regenerative medicine, and help realize their role as crucial developmental signalling molecules in brain development.
Rethinking GPS Navigation: Creating Cognitive Maps Through Auditory Clues
Authors: Clemenson Gregory D. , Maselli Antonella , Fiannaca Alex , Miller Amos , Gonzalez-Franco Mar
Published: May 2020

GPS navigation is commonplace in everyday life. While it has the capacity to make our lives easier, it is often used to automate functions that were once exclusively performed by our brain. Staying mentally active is key to healthy brain aging. Therefore, is GPS navigation causing more harm than good? Here we demonstrate that traditional turn-by-turn navigation promotes passive spatial navigation and ultimately, poor spatial learning of the surrounding environment. We propose an alternative form of GPS navigation based on sensory augmentation, that has the potential to fundamentally alter the way we navigate with GPS. By implementing a 3D spatial audio system similar to an auditory compass, users are directed towards their destination without explicit directions. Rather than being led passively through verbal directions, users are encouraged to take an active role in their own spatial navigation, leading to more accurate cognitive maps of space. Technology will always play a significant role in everyday life; however, it is important that we actively engage with the world around us. By simply rethinking the way we interact with GPS navigation, we can engage users in their own spatial navigation, leading to a better spatial understanding of the explored environment.
Pattern Separation Contributes to Categorical Face Perception
Authors: Baker Stevenson , Youm Ariana , Levy Yarden , Moscovitch Morris , Rosenbaum R. Shayna
Published: May 2020

Traditionally considered a memory structure, the hippocampus has been shown to contribute to non-memory functions, from perception to language. Recent evidence suggests that the ability to differentiate highly confusable faces could involve pattern separation, a mnemonic process mediated by the hippocampal dentate gyrus (DG). Hippocampal involvement, however, may depend on existing face memories. To investigate these possibilities, we tested BL, a rare individual with bilateral lesions selective to the DG, and healthy controls. Both were administered morphed images of famous and nonfamous faces in a categorical perception (CP) identification and discrimination experiment. All participants exhibited nonlinear identification of famous faces with a midpoint category boundary. Controls identified newly learned nonfamous faces with lesser fidelity, while BL showed a notable shift in category boundary. When discriminating face pairs, controls showed typical CP effects of better between-category than within-category discrimination — but only for famous faces. BL showed extreme within-category “compression,” reflecting his tendency to pattern complete following suboptimal pattern separation. We provide the first evidence that pattern separation contributes to CP of faces.
Cell fate coordinates mechano-osmotic forces in intestinal crypt morphogenesis
Authors: Yang Qiutan , Xue Shi-Lei , Chan Chii Jou , Rempfler Markus , Vischi Dario , Gutierrez Francisca Mauer , Hiiragi Takashi , Hannezo Edouard , Liberali Prisca
Published: May 2020

Intestinal organoids derived from single cells undergo complex crypt-villus patterning and morphogenesis. However, the nature and coordination of the underlying forces remains poorly characterized. Through light-sheet microscopy and mechanical perturbations, we demonstrate that organoid crypt formation coincides with stark lumen volume reduction, which works synergistically with actomyosin-generated crypt apical and villus basal tension to drive morphogenesis. We analyse these mechanical features in a quantitative 3D biophysical model and detect a critical point in actomyosin tensions, above which crypt becomes robust to volume changes. Finally, via single-cell RNA sequencing and pharmacological perturbations, we show that enterocyte-specific expressed sodium/glucose cotransporter modulates lumen volume reduction via promoting cell swelling. Altogether, our study reveals how cell fate-specific changes in osmotic and actomyosin forces coordinate robust organoid morphogenesis.

One Sentence Summary

Emergence of region-specific cell fates drive actomyosin patterns and luminal osmotic changes in organoid development
The role of synergy and antagonism in designing multidrug adaptive chemotherapy schedules
Authors: Newton P.K. , Ma Y.
Published: May 2020

Chemotherapeutic resistance via the mechanism of competitive release of resistant tumor cell subpopulations is a major problem associated with cancer treatments and one of the main causes of tumor recurrence. Often, chemoresistance is mitigated by using multidrug schedules (two or more combination therapies) that can act synergistically, additively, or antagonistically on the heterogeneous population of cells as they evolve. In this paper, we develop a three-component evolutionary game theory model to design two-drug adaptive schedules (timing and dose levels associated withC1(t) andC2(t)) that mitigate chemoresistance and delay tumor recurrence in an evolving collection of tumor cells with two resistant subpopulations:R1(sensitive to drug 1, resistant to drug 2), andR2(sensitive to drug 2, resistant to drug 1). A key parameter,e, takes us from synergistic (e >0), to additive (e= 0), to antagonistic (e <0) drug interactions. In addition to the two resistant populations, the model includes a population of chemosensitive cells,Sthat have higher baseline fitness but are not resistant to either drug. Using the nonlinear replicator dynamical system with a payoff matrix of Prisoner’s Dilemma (PD) type (enforcing a cost to resistance), we investigate the nonlinear dynamics of the three-component system (S, R1, R2), along with an additional tumor growth model whose growth rate is a function of the fitness landscape of the tumor cell populations. We show thatantagonisticdrug interactions generally result in slower rates of adaptation of the resistant cells thansynergisticones, making them more effective in combating the evolution of resistance. We then design closed loops in the three-component phase space by shaping the fitness landscape of the cell populations (i.e. altering the evolutionary stable states of the game) using appropriately designed time-dependent schedules (adaptive therapy), altering the dosages and timing of the two drugs using information gleaned from constant dosing schedules. We show that the bifurcations associated with the evolutionary stable states are transcritical, and we detail a typical antagonistic bifurcation that takes place between the sensitive cell populationSand theR1population, and a synergistic bifurcation that takes place between the sensitive cell populationSand theR2population for fixed values ofC1andC2. These bifurcations help us further understand why antagonistic interactions are more effective at controlling competitive release of the resistant population than synergistic interactions in the context of an evolving tumor.
Epigraph Hemagglutinin Vaccine Induces Broad Cross-reactive Immunity Against Swine H3 Influenza Virus
Authors: Bullard Brianna L. , Corder Brigette N. , Korber Bette , Weaver Eric A.
Published: May 2020

Swine influenza virus (SIV) is a significant burden on the pork industry and threat to human health due to its zoonotic potential. Here, we utilized epigraph, a computational algorithm, to design a universal swine H3 (swH3) influenza vaccine. The epigraph hemagglutinin proteins were delivered using an Adenovirus type 5 vector and compared to a wild type hemagglutinin and the commercial inactivated vaccine, FluSure. In mice, epigraph vaccination led to significant cross-reactive antibody and T-cell responses against a diverse panel of swH3 isolates. Epigraph vaccination also reduced weight loss and lung viral titers in mice after challenge with three divergent swH3 viruses. Vaccination studies in swine, the target species for this vaccine, showed stronger levels of cross-reactive antibodies and T-cell responses after immunization with epigraph vaccine compared to the wild type and FluSure vaccines. In both murine and swine models, epigraph vaccination showed superior cross-reactive immunity that should be further investigated as a universal swH3 vaccine.