bluuebunny/crossref_metadata_2025 huggingface dataset:
Human innate lymphoid cell activation by adenoviruses is modified by host defence proteins and neutralizing antibodies
Authors: Paris Océane , Mennechet Franck JD , Kremer EJ
Published: June 2022

Innate lymphoid cells (ILCs), the complements of diverse CD4 T helper cells, help maintain tissue homeostasis by providing a link between innate and adaptive immune responses. While pioneering studies over the last decade have advanced our understanding how ILCs influence adaptive immune responses to pathogens, far less is known about whether the adaptive immune response feeds back into an ILC response. In this study, we isolated ILCs from blood of healthy donors, fine-tuned culture conditions, and then directly challenged them with human adenoviruses (HAdVs), with HAdVs and host defence proteins (HDPs) or neutralizing antibodies (NAbs), to mimic interactions in a host with pre-existing immunity. Additionally, we developed anex vivoapproach to identify how bystander ILCs respond to the uptake of HAdVs ± neutralizing antibodies by monocyte-derived dendritic cells. We show that ILCs take up HAdVs, which induces phenotypic maturation and cytokine secretion. Moreover, NAbs and HDPs complexes modified the cytokine profile generated by ILCs, consistent with a feedback loop for host antiviral responses and potential to impact adenovirus-based vaccine efficacy.

Author Summary

Several studies have shown the importance of innate lymphoid cells (ILCs) both from an immune and physiological point of view, in particular for their role in the maintenance of tissue integrity, pathogens clearance, or in the establishment of immune tolerance. Our study focuses on the role of ILCs during direct challenge with prototype vaccines based on human adenoviruses (HAdVs) ± host defence proteins (HDPs) or neutralizing antibodies (NAbs) to mimic interactions in a host with pre-existing immunity. In parallel, through an ex vivo approach we observe how bystander ILCs respond to the uptake of HAdVs ± NAbs by monocyte-derived dendritic cells. We show that ILCs take up HAdVs, which induces pro- inflammatory and antiviral responses through phenotypic maturation and cytokine secretion. Moreover, HAdV-NAb and HAdV-HDP complexes modified the cytokine profile generated by ILCs, consistent with a feedback loop for host antiviral responses and potential to impact HAdV vaccine efficacy.
Characterizing the polarization continuum of macrophage subtypes M1, M2a and M2c
Authors: Oates TCL , Moura PL , Cross SJ , Roberts K , Baum HE , Haydn-Smith KL , Wilson MC , Heesom KJ , Severn CE , Toye AM
Published: June 2022

Macrophages are vital components of the inflammatory response and exhibit phenotypical plasticity through active conversion between pro- and anti-inflammatory cell subtypes, a feature which can be reproduced inex vivoculture. We employed a multifaceted approach utilizing proteomics, flow cytometry, activity assays and livecell microscopy imaging to characterize four cultured macrophage subtypes: unstimulated MØ, classically activated M1, alternatively activated M2a, and deactivated M2c macrophages. Whole cell proteomics identified a total of 5435 proteins, with >50% of these proteins exhibiting significant alterations in abundance between the different subtypes. This confirms that four distinct macrophage subtypes are induced from the same originating donor material through stimulation with specific cytokines. Additional surfaceome analysis revealed that M2c macrophages significantly upregulate pro-inflammatory markers compared to the MØ baseline and thus appear to be activated or primed to activate, similar to M1. Surface protein expression provided further subtype characterization, in particular distinguishing between the M2a and M2c macrophages.

We next explored the re-polarization capabilities of macrophages using dexamethasone, an anti-inflammatory glucocorticoid known to induce macrophage polarization towards the M2c de-activated phenotype. We show that activated M1 macrophages treated with dexamethasone for 48-hours upregulate the levels of CD163 and CD206, markers synonymous with a phenotypical shift from M1 to M2c yet retain key surface markers and display the functional phenotype of M1 macrophages. The observed repolarization of M1 pro-inflammatory macrophages provides a potential mechanism through which dexamethasone treatment improves COVID-19 prognosis and constitutes evidence of partial repolarization along the macrophage continuum. These proteomic and functionalex vivomacrophage datasets provide a valuable resource for studying macrophage polarity and the impact of dexamethasone on macrophage phenotype and function.
Automated non-lethal moth traps can be used for robust estimates of moth abundance
Authors: Möglich Jonas Mielke , Lampe Patrick , Fickus Mario , Gottwald Jannis , Nauss Thomas , Brandl Roland , Brändle Martin , Friess Nicolas , Freisleben Bernd , Heidrich Lea
Published: June 2022

Recent reports of insect decline highlight the need for extensive large-scale insect monitoring. However, obtaining abundance or species richness data at high spatial and temporal resolution is difficult due to personnel, maintenance, and post-processing costs as well as ethical considerations. Non-invasive automated insect monitoring systems could provide a solution to address these constraints. However, every new insect monitoring design needs to be evaluated with respect to reliability and bias based on comparisons with conventional methods.

In this study, we evaluate the effectiveness of an automated moth trap (AMT), built from off-the-shelf-hardware, in capturing variations in moth abundance, by comparing it to a conventional, lethal trap. Both trap types were operated five times on 16 plots from the beginning of July 2021 to the end of August 2021.

Moth abundance scaled isometrically between the two trap types. Consequently, the respective seasonal patterns in abundance determined over the monitoring period were similar.

The AMT samples phenological patterns using a robust and non-lethal method. However, an initial quantitative in-field test revealed that its long-term applicability must be preceded by several adjustments to the power supply and to data transfer. Depending on the software implementation, the AMT can be used to address a broad range of research questions while also reducing both energy expenditure and the disturbance of non-target animals.
Distinct sequencing success at non-B-DNA motifs
Authors: Weissensteiner Matthias H. , Cremona Marzia A. , Guiblet Wilfried , Stoler Nicholas , Harris Robert S. , Cechova Monika , Eckert Kristin A. , Chiaromonte Francesca , Huang Yi-Fei , Makova Kateryna D.
Published: June 2022

Modern sequencing technologies are not error-free, and might have elevated error rates at some locations of the genome. A potential cause for such elevated error rates is the formation of alternative DNA structures (non-B DNA), such as G-quadruplexes (G4s), Z-DNA, or cruciform structures, during sequencing. Approximately 13% of the human genome has the potential to form such structures, which have been previously shown to affect the activity of DNA polymerases and helicases. Here we tested whether motifs with the potential to form non-B DNA (non-B motifs) influence the sequencing success of three major sequencing technologies—Illumina, Pacific Biosciences (PacBio) HiFi, and Oxford Nanopore Technologies (ONT). We estimated sequencing success by computing the rates of single-nucleotide, insertion, and deletion errors, as well as by evaluating mean read depth and mean base quality. Overall, all technologies exhibited altered sequencing success for most non-B motif types. Single-nucleotide error rates were generally increased for G-quadruplexes (G4s) and Z-DNA motifs in all three technologies. Illumina and PacBio HiFi deletion error rates were also increased for all non-B types except for Z-DNA motifs, while in ONT they were increased substantially only for G4 motifs. Insertion error rates for non-B motifs were highly elevated in Illumina, moderately elevated in PacBio HiFi, and only slightly elevated in ONT. Using Poisson regression modeling, we evaluated how non-B DNA motifs and other factors influence sequencing error profiles. Using the error rates at non-B motifs, we developed a probabilistic approach to determine the number of false-positive single-nucleotide variants (SNVs) in different sample size and variant frequency cutoff scenarios, as well as in previously generated sequencing data sets (1000Genomes, Simons Genome Diversity Project, and gnomAD). Overall, the effect of non-B DNA on sequencing should be considered in downstream analyses, particularly in studies with limited read depth—e.g., single-cell and ancient DNA sequencing, as well as sequencing of pooled population samples—and when scoring variants with low frequency (e.g., singletons). Because each sequencing technology analyzed has a unique error profile at non-B motifs, a combination of different technologies should be considered in future sequencing studies of such motifs, to maximize accuracy.
MicroRNA-27a is essential for bone remodeling by modulating p62-mediated osteoclast signaling
Authors: Wang Shumin , Maruyama Eri O , Martinez John , Lopes Justin , Hsu Trunee , Wu Wencheng , Hsu Wei , Maruyama Takamitsu
Published: June 2022

The ability to simultaneously modulate a set of genes for lineage-specific development has made microRNA an ideal master regulator for organogenesis. However, most microRNA deletions do not exhibit obvious phenotypic defects possibly due to functional redundancy. MicroRNAs are known to regulate skeletal lineages as the loss of their maturation enzyme Dicer impairs bone remodeling processes. Therefore, it is important to identify specific microRNA essential for bone homeostasis. We report the loss of miR-27a causing severe osteoporosis in mice. MiR-27a affects osteoclast-mediated bone resorption but not osteoblast-mediated bone formation during skeletal remodeling. Gene profiling and bioinformatics further identify the specific targets of miR-27a in osteoclast cells. MiR-27a exerts its effects on osteoclast differentiation through modulation of Squstm1/p62 whose mutations have been linked to Paget’s disease of bone. Our findings reveal a new miR-27a-p62 axis necessary and sufficient to mediate osteoclast differentiation and highlight a therapeutic implication for osteoporosis.
Disentanglement of Resting State Brain Networks for Localizing Epileptogenic Zone in Focal Epilepsy
Authors: Ye Shuai , Bagić Anto , He Bin
Published: June 2022

Resting state electromagnetic recordings have been analyzed in epilepsy patients aiding presurgical evaluation. However, it has been rarely explored how pathological networks can be separated and thus used for epileptogenic focus localization purpose. We proposed here a resting state EEG/MEG analysis framework, to disentangle brain functional networks represented by electrophysiological oscillations. Firstly, by using an Embedded Hidden Markov Model (EHMM), we constructed a state space for resting state recordings consisting of brain states with different spatiotemporal patterns. After that, functional connectivity analysis along with graph theory were applied on the extracted brain states to quantify the network features of the extracted brain states, and we determine the source location of pathological states based on these features. The EHMM model was rigorously evaluated using computer simulations. Our simulation results revealed the proposed framework can extract brain states with high accuracy regarding both spatial and temporal profiles. We than validated the entire framework as compared with clinical ground truth in 10 patients with drug-resistant focal epilepsy who underwent MEG recordings. We segmented the resting state MEG recordings into a few brain states with diverse connectivity patterns and extracted pathological brain states by applying graph theory on the constructed functional networks. We showed reasonable localization results using the extracted pathological brain states in 6/10 patients, as compared to the invasive clinical findings. The framework can serve as an objective tool in extracting brain functional networks from noninvasive resting state electromagnetic recordings. It promises to aid presurgical evaluation guiding intracranial EEG electrodes implantation.
Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release
Authors: Liu Xiaojie , Vickstrom Casey R. , Yu Hao , Liu Shuai , Snarrenberg Shana Terai , Friedman Vladislav , Mu Lianwei , Chen Bixuan , Kelly Thomas J. , Baker David A. , Liu Qing-song
Published: June 2022

Repeated exposure to drugs of abuse results in an upregulation of cAMP signaling in the mesolimbic dopamine system, a molecular adaptation thought to be critically involved in the development of drug dependence. Exchange protein directly activated by cAMP (Epac2) is a major cAMP effector abundantly expressed in the brain. However, it remains unknown whether Epac2 contributes to cocaine reinforcement. Here, we report that Epac2 in the mesolimbic dopamine system promotes cocaine reinforcement via enhancement of dopamine release. Conditional knockout of Epac2 from midbrain dopamine neurons (Epac2-cKO) and the selective Epac2 inhibitor ESI-05 decreased cocaine self-administration in mice under both fixed-ratio and progressive-ratio reinforcement schedules and across a broad range of cocaine doses. In addition, Epac2-cKO led to reduced evoked dopamine release, whereas Epac2 agonism robustly enhanced dopamine release in the nucleus accumbens in vitro. This mechanism is central to the behavioral effects of Epac2 disruption, as chemogenetic activation of ventral tegmental area (VTA) dopamine neurons increased dopamine release and reversed the impairment of cocaine self-administration in Epac2-cKO mice. Conversely, chemogenetic inhibition of VTA dopamine neurons reduced dopamine release and cocaine self-administration in wild-type mice. Epac2-mediated enhancement of dopamine release may therefore represent a novel and powerful mechanism that contributes to cocaine reinforcement.
Prenatal arsenic exposure stymies gut butyrate production and enhances gut permeability in post natal life even in absence of arsenic deftly through miR122-Occludin pathway
Authors: Chakraborty Mainak , Gautam Anupam , Das Oishika , Masid Aaheli , Bhaumik Moumita
Published: June 2022

This discourse attempts to capture a few important dimensions of gut physiology like microbial homeostasis, short chain fatty acid (SCFA) production, occludin expression and gut permeability in post-natal life of mice those received arsenic only during pre-natal life (pAs-mice). The pAs-mice showed a striking reduction in Firmicutes to Bacteroidetes (F/B) ratio coupled with decrease in tight junction protein, occludin resulting in increase in gut permeability, increased infiltration of inflammatory cells in the colon and decrease in common SCFAs in which butyrate reduction was quite prominent in fecal samples as compared to normal control. The above phenotypes of pAs-mice were mostly reversed by supplementing butyrate with food. The talismanic ability of butyrate in enhancing occludin expression, in particular, was dissected further. As miR122 causes degradation of Occludin mRNA, we transiently overexpressed miR122 by injecting appropriate plasmids and showed reversal of butyrate effects in pAs-mice. Thus, pre-natal arsenic exposure orchestrates variety of effects by decreasing in butyrate in pAs-mice leading to increased permeability due to reduced occludin expression. Our research adds a new dimension to our understanding that pre-natal arsenic exposure imprints in post-natal life while there was no further arsenic exposure.

Highlights

Prenatal Arsenic exposure decreases prevalence of butyrate producing bacteria and butyrate production in gut.

Lack of butyrate production in the gut is responsible for increased permeability and decreased occludin expression.

Oral supplementation with butyrate reverses the prenatal arsenic induced changes in the gut.

Butyrate increases Occludin gene expression by downregulating miR122 in the gut.
Collective Decision-making in Response to Visual Looming Stimuli in Medaka Fish
Authors: Nakahata Ryohei , Takeuchi Hideaki
Published: June 2022

Various social animals synchronously make behavioral choices among alternatives (i.e., collective decision-making) to efficiently migrate, forage, or escape from predators. Here, we demonstrated that medaka fish, Oryzias latipes, make collective decisions in response to visual looming stimuli (LS), a simulated predator attack. The group-level response to the LS could be classified into 2 patterns: freezing synchronously or not freezing, indicating that medaka selected their response to the LS from 2 alternative choices. Furthermore, the behavioral response to the LS persisted over multiple behavioral trials for 3 days, indicating that each group made a consistent decision to freeze or not to freeze. Finally, we showed that the group response could be predicted by the maximum swimming speed among individuals during the LS presentation. If a group included at least 1 individual that responded to the LS with high-speed movement (>7.4 cm/s), the group tended to freeze synchronously in response to the LS. If no member of the group was moving at high-speed during the LS presentation, the group tended to continue moving after the LS presentation. Our findings suggest that the presence of 1 or more individual medaka with a strong fear response in a group determines the group-level decision of how to respond to a threatening stimulus.
Distinct trajectories in low-dimensional neural oscillation state space track dynamic decision-making in humans
Authors: Thiery Thomas , Rainville Pierre , Cisek Paul , Jerbi Karim
Published: June 2022

The brain evolved to govern behavior in a dynamic world, in which pertinent information about choices is often in flux. Thus, the commitment to an action choice must reflect a balance between monitoring that information and the necessity to act before opportunities are lost. Here, we investigate the mechanisms of dynamic decision-making in humans using low dimensional space representation of brain wide magnetoencephalography recordings. We show that the principal components (PCs) of alpha (9-13 Hz) and beta power (16-24 Hz) are involved in tracking sensory information evolving over time in the sensorimotor and visual cortex. We also found that alpha PCs reflect the commitment to a particular choice, while beta PCs reflect motor execution. Finally, higher frequency components in subcortical areas reflect the adjustment of speed- accuracy tradeoff policies. These results provide a new detailed characterization of the distributed oscillatory brain processes underlying dynamic decision-making in humans.
Optimized intramuscular immunization with VSV-vectored spike protein triggers a superior protective humoral immune response to SARS-CoV-2
Authors: Taddeo Adriano , Veiga Inês Berenguer , Devisme Christelle , Boss Renate , Plattet Philippe , Weigang Sebastian , Kochs Georg , Thiel Volker , Benarafa Charaf , Zimmer Gert
Published: June 2022

Immunization with vesicular stomatitis virus (VSV)-vectored COVID-19 vaccine candidates expressing the SARS-CoV-2 spike protein in place of the VSV glycoprotein relies implicitly on expression of the ACE2 receptor at the muscular injection site. Here, we report that such a viral vector vaccine did not induce protective immunity following intramuscular immunization of K18-hACE2 transgenic mice. However, when the viral vector was trans-complemented with the VSV glycoprotein, intramuscular immunization resulted in high titers of spike-specific neutralizing antibodies. The vaccinated animals were fully protected following infection with a lethal dose of SARS-CoV-2-SD614G via the nasal route, and partially protected if challenged with the SARS-CoV-2Delta variant. While dissemination of the challenge virus to the brain was completely inhibited, replication in the lung with consequent lung pathology was not entirely controlled. Thus, intramuscular immunization was clearly enhanced by trans-complementation of the VSV-vectored vaccines by the VSV glycoprotein and led to protection from COVID-19, although not achieving sterilizing immunity.
Chromosome-level genome and the identification of sex chromosomes in Uloborus diversus
Authors: Miller Jeremiah , Zimin Aleksey V , Gordus Andrew
Published: June 2022

The orb-web is a remarkable example of animal architecture that is observed in families of spiders that diverged over 200 million years ago. While several genomes exist for Araneid orb-weavers, none exist for other orb-weaving families, hampering efforts to investigate the genetic basis of this complex behavior. Here we present a chromosome-level genome assembly for the cribellate orb-weaving spider Uloborus diversus. The assembly reinforces evidence of an ancient arachnid genome duplication and identifies complete open reading frames for every class of spidroin gene, which encode the proteins that are the key structural components of spider silks. We identified the two X chromosomes for U. diversus and identify candidate sex-determining genes. This chromosome-level assembly will be a valuable resource for evolutionary research into the origins of orb-weaving, spidroin evolution, chromosomal rearrangement, and chromosomal sex-determination in spiders.
Subventricular zone cytogenesis provides trophic support for neural repair
Authors: Williamson Michael R. , Le Stephanie P. , Franzen Ronald L. , Donlan Nicole A. , Rosow Jill L. , Dunn Andrew K. , Jones Theresa A. , Drew Michael R.
Published: June 2022

Stroke enhances proliferation of neural precursor cells within the subventricular zone (SVZ) and induces ectopic migration of newborn cells towards the site of injury. Here we characterize the identity of cells arising from the SVZ after stroke and provide insight into their function by uncovering a mechanism through which they facilitate neural repair and functional recovery. Using genetic lineage tracing, we show that SVZ-derived cells that migrate towards stroke- induced cortical lesions in mice are predominantly undifferentiated precursors, suggesting that the main function of post-injury cytogenesis is not cell replacement. We find that SVZ-derived cells are a unique cellular source of trophic factors that instruct neural repair. Chemogenetic ablation of neural precursor cells or conditional knockout of VEGF in the adult neural stem cell lineage impairs neuronal and vascular reparative responses and worsens functional recovery after stroke. In addition, normal aging markedly diminishes the cytogenic response to stroke, resulting in worse functional recovery. Therapeutic replacement of VEGF in peri-infarct cortex is sufficient to induce neural repair and functional recovery in mice with arrested cytogenesis. These findings indicate that the SVZ cytogenic response following brain injury is a source of trophic support that drives neural repair and recovery.
A novel method to selectively elicit cold sensations without touch
Authors: Ezquerra-Romano Ivan , Chowdhury Maansib , Leone Caterina Maria , Iannetti Gian Domenico , Haggard Patrick
Published: June 2022

Background

Thermal and tactile stimuli are transduced by different receptor classes. However, mechano- and thermo-sensitive afferents interact at spinal and supraspinal levels. Yet, most studies on responses to cooling stimuli are confounded by mechanical contact, making these interactions difficult to isolate. Methods for precise control of non-mechanical thermal stimulations remain challenging, particularly in the cold range.

New Method

We developed a non-tactile, focal, temperature-controlled, multi-purpose cooling stimulator. This method controls the exposure of a target skin region to a dry-ice source. Using a thermal camera to monitor skin temperature, and adjusting the source-skin distance accordingly, we could deliver non-tactile cooling stimuli with customisable profiles, for studying different aspects of cold sensation.

Results

To validate our method, we measured absolute and relative thresholds for cold sensation without mechanical contact in 13 human volunteer participants, using the method of limits. We found that the absolute cold detection threshold was 32.71°C ± 0.88 °C. This corresponded to a threshold relative to each participant’s baseline skin temperature of -1.08 °C ± 0.37 °C.

Comparisons with Existing Method

Our method allows cooling stimulation without the confound of mechanical contact, in a controllable and focal manner.

Conclusions

We report a non-contact cooling stimulator and accompanying control system. We used this to measure cold thresholds in the absence of confounding touch. Our method enables more targeted studies of both cold sensory pathways, and of cold-touch interactions.

Highlights

Most studies on cold sensation fail to control for concomitant tactile input.

A method to deliver non-tactile cooling stimuli was developed.

The method combines dry ice, a thermal camera, and motorised stages.

The method delivers rapid ramps and feedback-controlled pulses.

Thresholds for contactless cold perception were estimated in humans.
MGTdb: A web service and database for studying the global and local genomic epidemiology of bacterial pathogens
Authors: Kaur Sandeep , Payne Michael , Luo Lijuan , Octavia Sophie , Tanaka Mark M. , Sintchenko Vitali , Lan Ruiting
Published: June 2022

Multilevel genome typing (MGT) enables the genomic characterization of bacterial isolates and the relationships among them. The MGT system describes an isolate using multiple multilocus sequence typing (MLST) schemes, referred to as levels. Thus, for a new isolate, sequence types (STs) assigned at multiple precisely defined levels can be used to type isolates at multiple resolutions. The MGT designation for isolates is stable, and assignment is faster than existing approaches. MGT’s utility has been demonstrated in multiple species.

This paper presents a publicly accessible web service called MGTdb, which enables the assignment of MGT sequence types to isolates, along with their storage, retrieval and analysis. The MGTdb web service enables upload of genome data as sequence reads or alleles, which are processed and assigned MGT identifiers. Additionally, any newly sequenced isolates deposited in NCBI Sequence Read Archive are also regularly retrieved (currently daily), processed, assigned MGT and made publicly available in MGTdb. Interactive visualisation tools are presented to assist analysis, along with capabilities to download publicly available isolates and assignments for use with external software.

MGTdb is currently available for Salmonella enterica serovars Typhimurium and Enteritidis, and Vibrio cholerae. We demonstrate the usability of MGTdb through three case studies to study the long-term national surveillance of S. Typhimurium, and the local epidemiology and outbreaks of S. Typhimurium, and the global epidemiology of V. cholerae. Thus, MGTdb enables epidemiological and microbiological investigations at multiple levels of resolution for all publicly available isolates of these pathogens.

Database URL

https://mgtdb.unsw.edu.au
Isolation-by-distance and population-size history inferences from the coho salmon (Oncorhynchus kisutch) genome
Authors: Rondeau Eric B. , Christensen Kris A. , Minkley David R. , Leong Jong S. , Chan Michelle T.T. , Despins Cody A. , Mueller Anita , Sakhrani Dionne , Biagi Carlo A. , Rougemont Quentin , Normandeau Eric , Jones Steven J.M. , Devlin Robert H. , Withler Ruth E. , Beacham Terry D. , Naish Kerry A. , Yáñez José M. , Neira Roberto , Bernatchez Louis , Davidson William S. , Koop Ben F.
Published: June 2022

Coho salmon (Oncorhynchus kisutch) are a culturally and economically important species that return from multiyear ocean migrations to spawn in rivers that flow to the Northern Pacific Ocean. Southern stocks of coho salmon have significantly declined over the past quarter century, and unfortunately, conservation efforts have not reversed this trend. To assist in stock management and conservation efforts, we generated two chromosome-level genome assemblies and sequenced 24 RNA-seq libraries to better annotate the coho salmon genome assemblies. We also resequenced the genomes of 83 coho salmon across their North American range to identify nucleotide variants, characterize the broad effects of isolation-by-distance using a genome-wide association analysis approach, and understand the demographic histories of these salmon by modeling population size from genome-wide data. We observed that more than 13% of all SNPs were associated with latitude (before multiple test correction), likely an affect of isolation-by-distance. From demographic history modeling, we estimated that the SNP latitudinal gradient likely developed as recently as 8,000 years ago. In addition, we identified four genes each harboring multiple SNPs associated with latitude; all of these SNPs were also predicted to modify the function of the gene. Three of these genes have roles in cell junction maintenance and may be involved in osmoregulation. This signifies that ocean salinity may have been a factor influencing coho salmon recolonization after the last glaciation period – generating the current pattern of variation in these three genes.
Inhibition of Fas Receptor Endocytosis Sensitizes Cancer Cells to Fas-induced Apoptosis
Authors: Kural Mehmet H. , Djakbarova Umidahan , Cakir Bilal , Tanaka Yoshiaki , Madraki Yasaman , Qian Hong , Park Jinkyu , Sewanan Lorenzo R. , Kural Comert , Niklason Laura E.
Published: June 2022

Fas (CD95/APO-1) is a transmembrane death receptor that transduces apoptotic signals upon binding to its ligand and assembling into a death-inducing signaling complex (DISC) (1, 2). Intracellular trafficking of Fas receptors, including recycling from endosomes to the plasma membrane, plays a vital role in ligand-induced assembly of DISC (3, 4). Although Fas is highly expressed in tumor cells (5, 6), insufficient expression of these receptors on the cell surface makes cancer cells insensitive to the Fas-induced apoptosis (4, 7–9). Here we show that inhibition of endocytosis increases the formation of Fas microaggregates on the plasma membrane and sensitizes cancer cells to Fas-induced apoptosis. We have identified a clinically used vasodilator, Fasudil, that slows down endocytosis by increasing plasma membrane tension. Fasudil enhanced apoptosis in cancerous cells when combined with exogenous soluble Fas ligand (FasL), whereas the synergistic effect was substantially weaker in nonmalignant cells. Additionally, the FasL and Fasudil combination prevented glioblastoma cell growth in embryonic stem cell-derived brain organoids and induced tumor regression in a xenograft U87 tumor model in nude mice. Our results demonstrate that FasL treatment has strong potential as an apoptosis-directed cancer therapy when the formation of Fas microaggregates is augmented by slowing down endocytosis dynamics.
In colon cancer cells, fascin1 functions as a mechanosensor that transforms adherens junction mechanotransduction
Authors: Esmaeilniakooshkghazi Amin , Pham Eric , George Sudeep P. , Ahrorov Afzal , Villagomez Fabian R. , Byington Michael , Mukhopadhyay Srijita , Patnaik Srinivas , Conrad Jacinta C. , Naik Monali , Ravi Saathvika , Tebbuttt Niall , Mooi Jennifer , Reehorst Camilla M , Mariadason John M. , Khurana Seema
Published: June 2022

Fascin1 expression in colorectal carcinomas (CRCs) is linked to a clinically aggressive disease with poor prognosis. Despite that fascin1’s role in the etiology of CRCs has not been directly investigated. We show fascin1 expression in one-third of all CRCs underscoring the critical need to identify fascin1’s function in colorectal carcinogenesis. Here, we identify for the first time, fascin1’s role as a mechanosensor that modulates CRC cell adherens junction (AJ) plasticity to induce tumor growth and metastasis. We show that fascin1 expression drives protein sorting to transform AJ mechanotransduction and we reveal how these force-sensitive pathways activate oncogenic signaling in CRC cells. We made the novel finding that AJ remodeling by fascin1 also controls “collective plasticity” and bidirectional cell migration. Few studies have examined AJ plasticity in cancer cells, which remains poorly understood and has not been therapeutically targeted. Our findings could have widespread implications for understanding and treating metastatic carcinomas.
Influencing Factors for the Persistence of SARS-Cov-2 (Covid-19) exposed in Environmental Matrices and Disinfection Methods: Systematic Review
Authors: Yu Chaw Chaw , Hlaing Thein , Tun Kyaw Myo
Published: June 2022

Background

Since the COVID-19 pandemic has been pestilential over a considerable duration, global deployment and financial crisis could not be reversed as before. It brought up essentials to allow the nations back to work with effective preventive measures. This review intended to evaluate the persistence of SARS-CoV-2(COVID-19) exposed in the environmental matrices, influencing factors on the virus persistence and disinfection methods.

Methods

Applying the PRISMA 2020 tool, MEDLINE/PubMed, HINARI, and Google Scholar were primarily explored. Data were extracted, entered into the modified data extraction forms and analysed narratively. Quality appraisal was done by the Mixed-Methods Appraisal Tool. The findings were presented descriptively.

Results

Persistence of SARS-CoV-2 was revealed <4 hours on aluminium, 4 hours on copper, 24 hours on cardboard, 44 hours on glass, 48 hours on stainless steel, 72 hours on plastic, 92 hours on polystyrene plastic, 1.1-1.2 hours in the air, 7 days (higher titer) to 3 days(lower titer) in wastewater. Virus decaying was noted 5-10 times faster at 27°C than at 10°C and 2-5 times faster with 65% relative humidity (RH) than with 40% and 100% RH. Virus infectivity was reduced by far-UVC-(222 nm) light for 90%-(8 minutes), 95%-(11 minutes), 99%-(16 minutes) and 99.99%-(25 minutes). Sodium hypochlorite (800 g/m3) and ammonium-based detergents were remarkably effective for preliminary disinfection.

Conclusions

This review identified the duration of SARS-CoV-2 survival in environmental matrices for both healthcare and non-healthcare settings. The study explored the impacts of environmental factors on the virus and effective disinfection methods to be considered accordingly to the findings.
How acceptable is rapid whole genome sequencing for infectious disease management in hospitals? Perspectives of those involved in managing nosocomial SARS-CoV-2
Authors: Flowers Paul , McLeod Julie , Mapp Fiona , Stirrup Oliver , Blackstone James , Snell Luke B , Peters Christine , Thomson Emma , Holmes Alison , Price James , Partridge Dave , Shallcross Laura , de Silva Thushan I , Breuer Judith
Published: June 2022

Structured summary

Background

Whole genome sequencing (WGS) for managing healthcare associated infections (HCAIs) has developed considerably through experiences with SARS-CoV-2. We interviewed various healthcare professionals (HCPs) with direct experience of using WGS in hospitals (within the COG-UK Hospital Onset COVID-19 Infection (HOCI) study) to explore its acceptability and future use.

Method

An exploratory, cross-sectional, qualitative design employed semi-structured interviews with 39 diverse HCPs between December 2020 and June 2021. Participants were recruited from five sites within the larger clinical study of a novel genome sequencing reporting tool for SARS-CoV-2 (the HOCI study). All had experience, in their diverse roles, of using sequencing data to manage nosocomial SARS-CoV-2 infection. Deductive and inductive thematic analysis identified themes exploring aspects of the acceptability of sequencing.

Findings

The analysis highlighted the overall acceptability of rapid WGS for infectious disease using SARS-CoV-2 as a case study. Diverse professionals were largely very positive about its future use and believed that it could become a valuable and routine tool for managing HCAIs. We identified three key themes ‘1) ‘Proof of concept achieved’; 2) ‘Novel insights and implications’; and 3) ‘Challenges and demands’.

Conclusion

Our qualitative analysis, drawn from five diverse hospitals, shows the broad acceptability of rapid sequencing and its potential. Participants believed it could and should become an everyday technology capable of being embedded within typical hospital processes and systems. However, its future integration into existing healthcare systems will not be without challenges (e.g., resource, multi-level change) warranting further mixed methods research.
The influence of place on COVID-19 vaccine coverage in Alberta: A multilevel analysis
Authors: Paudel Yuba Raj , Du Crystal , MacDonald Shannon E.
Published: June 2022

Background

While there is evidence of urban/rural disparities in COVID-19 vaccination coverage, there is limited data on the influence of other place-based variables.

Methods

In this cross-sectional study, we analyzed population-based linked administrative health data to examine vaccination coverage for 3,945,103 residents in Alberta, Canada. We used multilevel logistic regression to examine the association of vaccination coverage with various place-based variables.

Results

After 4 months of widely available COVID-19 vaccine, coverage varied widely between rural and urban areas (58% to 73%) and between geographic health authority zones (55.8% to 72.8%). Residents living in neighborhoods with lower COVID-19 disease incidence had the lowest vaccination coverage (63.2%), while coverage in higher incidence neighborhoods ranged from 68.3% to 71.9%. The multilevel logistic regression model indicated that residence in metro (adjusted odds ratio [aOR] 1.37; 95% CI: 1.31-1.42) and urban areas (aOR 1.11; 95% CI: 1.08-1.14) was associated with higher vaccine coverage than residence in rural areas. Similarly, residence in Edmonton, Calgary, and South health zones was associated with higher vaccine coverage compared to residence in Central zone. Higher income neighborhoods reported higher vaccine coverage than the lowest-income neighborhoods, and the highest COVID-19 risk neighborhoods reported higher vaccine coverage than the lowest risk neighborhoods (aOR 1.52; 95% CI: 1.12-2.05).

Conclusion

In the first four months of wider vaccine availability in Alberta, COVID-19 vaccine coverage varied according to various place-based characteristics. Vaccine distribution strategies need to consider place-based variables for program prioritization and delivery.
A network of DZF proteins controls alternative splicing regulation and fidelity
Authors: Haque Nazmul , Will Alexander , Cook Atlanta G. , Hogg J. Robert
Published: June 2022

Proteins containing DZF (domain associated withzinc fingers) modules play important roles throughout gene expression, from transcription to translation. Derived from nucleotidyltransferases but lacking catalytic residues, DZF domains serve as heterodimerization surfaces between DZF protein pairs. Three DZF proteins are widely expressed in mammalian tissues, ILF2, ILF3, and ZFR, which form mutually exclusive ILF2-ILF3 and ILF2-ZFR heterodimers. Using eCLIP-Seq, we find that ZFR binds across broad intronic regions to regulate the alternative splicing of cassette and mutually exclusive exons. ZFR preferentially binds dsRNAin vitroand is enriched on introns containing conserved dsRNA elements in cells. Many splicing events are similarly altered upon depletion of any of the three DZF proteins; however, we also identify independent and opposing roles for ZFR and ILF3 in alternative splicing regulation. Along with widespread involvement in cassette exon splicing, the DZF proteins control the fidelity and regulation of over a dozen highly validated mutually exclusive splicing events. Our findings indicate that the DZF proteins form a complex regulatory network that leverages dsRNA binding by ILF3 and ZFR to modulate splicing regulation and fidelity.
AKT1-FOXO4 AXIS RECIPROACLLY REGULATES HEMOCHORIAL PLACENTATION
Authors: Kozai Keisuke , Moreno-Irusta Ayelen , Iqbal Khursheed , Winchester Mae-Lan , Scott Regan L. , Simon Mikaela E. , Muto Masanaga , Parrish Marc R. , Soares Michael J.
Published: June 2022

Hemochorial placentation involves the differentiation of specialized cells called invasive trophoblast cells possessing the capacity to exit the placenta and invade into the uterus where they restructure the vasculature. Invasive trophoblast cells arise from a well-defined compartment within the placenta, referred to as the junctional zone in the rat and the extravillous trophoblast cell column in the human. In this study, we investigated roles for AKT1, a serine/threonine kinase, in placental development using a genome-edited/loss-of-function rat model. Disruption of AKT1 resulted in placental, fetal, and postnatal growth restriction. Forkhead box O4 (Foxo4), which encodes a transcription factor and known AKT substrate, was abundantly expressed in the junctional zone and invasive trophoblast cells of the rat placentation site.Foxo4gene disruption using genome-editing resulted in placentomegaly, including an enlarged junctional zone. AKT1 and FOXO4 regulate the expression of many of the same transcripts expressed by trophoblast cells; however, in opposite directions. In summary, we have identified AKT1 and FOXO4 as part of a regulatory network that reciprocally controls critical indices of hemochorial placenta development.

SUMMARY STATEMENT

Genome-edited rat models were utilized to investigate roles for AKT1 and FOXO4 in hemochorial placentation. AKT1 and FOXO4 possess reciprocal actions in regulating development of the hemochorial placenta.
Uncertainty quantification of reference based cellular deconvolution algorithms
Authors: Seiler Vellame Dorothea , Shireby Gemma , MacCalman Ailsa , Dempster Emma L , Burrage Joe , Gorrie-Stone Tyler , Schalkwyk Leonard S , Mill Jonathan , Hannon Eilis
Published: June 2022

The majority of epigenetic epidemiology studies to date have generated genome-wide profiles from bulk tissues (e.g. whole blood) however these are vulnerable to confounding from variation in cellular composition. Proxies for cellular composition can be mathematically derived from the bulk tissue profiles using a deconvolution algorithm however, there is no method to assess the validity of these estimates for a dataset where the true cellular proportions are unknown. In this study, we describe, validate and characterise a sample level accuracy metric for derived cellular heterogeneity variables. The CETYGO score captures the deviation between a sample’s DNAm profile and its expected profile given the estimated cellular proportions and cell type reference profiles.We demonstrate that the CETYGO score consistently distinguishes inaccurate and incomplete deconvolutions when applied to reconstructed whole blood profiles. By applying our novel metric to > 6,300 empirical whole blood profiles, we find that estimating accurate cellular composition is influenced by both technical and biological variation. In particular, we show that when using the standard reference panel for whole blood, less accurate estimates are generated for females, neonates, older individuals and smokers. Our results highlight the utility of a metric to assess the accuracy of cellular deconvolution, and describe how it can enhance studies of DNA methylation that are reliant on statistical proxies for cellular heterogeneity. To facilitate incorporating our methodology into existing pipelines, we have made it freely available as an R package (https://github.com/ds420/CETYGO).
Phase-Restoring Subpixel Image Registration: Enhancing Motion Detection Performance in Fourier-domain Optical Coherence Tomography
Authors: Li Huakun , Tan Bingyao , Pandiyan Vimal Prabhu , Barathi Veluchamy Amutha , Sabesan Ramkumar , Schmetterer Leopold , Ling Tong
Published: June 2022

Phase-sensitive Fourier-domain optical coherence tomography (FD-OCT) enables in-vivo, label- free imaging of cellular movements with detection sensitivity down to the nanometer scale, and it is widely employed in emerging functional imaging modalities, such as optoretinography (ORG), Doppler OCT, and optical coherence elastography. However, when imaging tissue dynamics in vivo, tissue movement or bulk motion introduces decorrelation noise that compromises motion detection performance, particularly in terms of sensitivity and accuracy. Here, we demonstrate that the motion-related decorrelation noise in FD-OCT can be accurately corrected by restoring the initial sampling points using our proposed Phase-Restoring Subpixel Image Registration (PRESIR) method. Derived from a general FD-OCT model, the PRESIR method enables translational shifting of complex-valued OCT images over arbitrary displacements with subpixel precision, while accurately restoring phase components. Unlike conventional approaches that shift OCT images either in the spatial domain at the pixel level or in the spatial frequency domain for subpixel correction, our method reconstructs OCT images by correcting axial displacement in the spectral domain (k domain) and lateral displacement in the spatial frequency domain. We validated the PRESIR method through simulations, phantom experiments, and in-vivo optoretinography in both rodents and human subjects. Our approach significantly reduced decorrelation noise during the imaging of moving samples, achieving phase sensitivity close to the fundamental limit determined by the signal-to-noise ratio (SNR).
Single locus phosphoproteomics reveals phosphorylation of RPA-1 is required for generation of single-strand DNA following a break at a subtelomeric locus
Authors: McLaughlin Emilia , Dujeancourt-Henry Annick , Chaze Thibault , Gianetto Quentin Giai , Matondo Mariette , Urbaniak Michael D , Glover Lucy
Published: June 2022

Damage to the genetic material of the cell poses a universal threat to all forms of life. Central to the DNA damage response (DDR) is a phosphorylation signalling cascade that leads to the co-ordination of the cellular response to a DNA break. Identifying the proteins that are phosphorylated is crucial to understanding the mechanisms underlying this DDR. We have used SILAC-based quantitative phosphoproteomics to profile changes in phosphorylation site abundance following a single double strand break (DSB) at a chromosome internal locus and the subtelomeric bloodstream form expression site in Trypanosoma brucei. We report >6500 phosphorylation sites, including a core set of 211 DSB responsive phosphorylation sites. Along with phosphorylation of canonical DNA damage factors, we find that there is a striking distinction between the proteins phosphorylated in response to a chromosome internal DSB and one at the active BES and describe a single phosphorylation event on Replication factor A (RPA) 1 that is required for efficient resection at a bloodstream form expression site.