bluuebunny/crossref_metadata_2025 huggingface dataset:
Parents’ intention to vaccinate their child for COVID-19: a cross-sectional survey (CoVAccS – wave 3)
Authors: Smith Louise E. , Sherman Susan M. , Sim Julius , Amlôt Richard , Cutts Megan , Dasch Hannah , Sevdalis Nick , Rubin G James
Published: May 2022

Objectives

To investigate UK parents’ vaccination intention at a time when COVID-19 vaccination was available to some children.

Study design

Data reported are from the second wave of a prospective cohort study.

Methods

Online survey of 270 UK parents (conducted 4-15 October 2021). At this time, vaccination was available to 16- and 17-year-olds and had become available to 12- to 15- year-olds two weeks prior. We asked participants whose child had not yet been vaccinated how likely they were to vaccinate their child for COVID-19. Linear regression analyses were used to investigate factors associated with intention. Parents were also asked for their main reasons behind vaccination intention. Open-ended responses were analysed using content analysis.

Results

Parental vaccination intention was mixed (likely: 39.3%, 95% CI 32.8%, 45.7%; uncertain: 33.9%, 27.7%, 40.2%; unlikely: 26.8%, 20.9%, 32.6%). Intention was associated with: parental COVID-19 vaccination status; greater perceived necessity and social norms regarding COVID-19 vaccination; greater COVID-19 threat appraisal; and lower vaccine safety and novelty concerns. In those who intended to vaccinate their child, the main reasons for doing so were to protect the child and others. In those who did not intend to vaccinate their child, the main reason was safety concerns.

Conclusions

Parent COVID-19 vaccination and psychological factors explained a large percentage of the variance in vaccination intention for one’s child. How fluctuating infection rates, more children being vaccinated, and the UK’s reliance on vaccination as a strategy to live with COVID-19 may impact parents’ intention to vaccinate their child requires further study.
Leveraging social network topology could improve the efficiency of SARS-CoV-2 epidemic control strategies in resource-limited contexts
Authors: Evans MV , Ramiadantsoa T , Kauffman K , Moody J , Nunn C , Rabezara JY , Raharimalala P , Randriamoria TM , Soarimalala V , Titcomb G , Garchitorena A , Roche B
Published: May 2022

Targeted surveillance allows public health authorities to implement testing and isolation strategies when diagnostic resources are limited. When transmission patterns are determined by social contact rates, the consideration of social network topologies in testing schemes is one avenue for targeted surveillance, specifically by prioritizing those individuals likely to contribute disproportionately to onward transmission. Yet, it remains unclear how to implement such surveillance and control when network data is unavailable, as is often the case in resource-limited settings. We evaluated the efficiency of a testing strategy that targeted individuals based on their degree centrality on a social network compared to a random testing strategy in the context of low testing capacity. We simulated SARS-CoV-2 dynamics on two contact networks from rural Madagascar and measured the epidemic duration, infection burden, and tests needed to end the epidemics. In addition, we examined the robustness of this approach when individuals’ true degree centralities were unknown and were instead estimated via readily-available socio-demographic variables (age, gender, marital status, educational attainment, and household size). Targeted testing reduced the infection burden by between 5 - 50% at low testing capacities, while requiring up to 28% fewer tests than random testing. Further, targeted tested remained more efficient when the true network topology was unknown and prioritization was based on socio-demographic characteristics, demonstrating the feasibility of this approach under realistic conditions. Incorporating social network topology into epidemic control strategies is an effective public health strategy for health systems suffering from low testing capacity and can be implemented via socio-demographic proxies when social networks are unknown.

*French abstract available in Supplemental Materials
Comorbidities and sociodemographic factors on COVID-19 fatalities
Authors: Gerken Jacob , Zapata Demi , Kuivinen Daniel , Zapata Isain
Published: May 2022

Introduction

Previous studies have evaluated comorbidities and sociodemographic factors individually or by type but not comprehensively. This study aims to analyze the influence of a wide variety of factors in a single study to better understand the big picture of their effects on case-fatalities.

Methods

County-level comorbidities, social determinants of health such as income and race, measures of preventive healthcare, age, education level, average household size, population density, and political voting patterns were all evaluated on a national and regional basis. Analysis was performed through Generalized Additive Models and adjusted by CCVI.

Results

Factors associated with reducing COVID-19 case fatality rates were mostly sociodemographic factors such as age, education and income, and preventive health measures. Obesity, minimal leisurely activity, binge drinking, and higher rates of individuals taking high blood pressure medication were associated with increased case fatality rate in a county. Political leaning influences case case-fatality rates. Regional trends showed contrasting effects where larger household size was protective in the Midwest, yet harmful in Northeast. Notably, higher rates of respiratory comorbidities such as asthma and COPD diagnosis were associated with reduced case-fatality rates in the Northeast. Increased rates of CKD within counties were often the strongest predictor of increased case-fatality rates for several regions.

Conclusion

Our findings highlight the importance of considering the full context when evaluating contributing factors to case-fatality rates. The spectrum of factors identified in this study must be analyzed in the context of one another and not in isolation.
An apical protein, Pcr2, is required for persistent movement by the human parasiteToxoplasma gondii
Authors: Lopez Jonathan Munera , Tengganu Isadonna F. , Liu Jun , Murray John , Arias Padilla Luisa F. , Zhang Ying , Brown Peter T. , Florens Laurence , Hu Ke
Published: May 2022

The phylum Apicomplexa includes thousands of species of unicellular parasites that cause a wide range of human and animal diseases such as malaria and toxoplasmosis. To infect, the parasite must first initiate active movement to disseminate through tissue and invade into a host cell, and then cease moving once inside. The parasite moves by gliding on a surface, propelled by an internal cortical actomyosin-based motility apparatus. One of the most effective invaders in Apicomplexa isToxoplasma gondii, which can infect any nucleated cell and any warm-blooded animal. During invasion, the parasite first makes contact with the host cell “head-on” with the apical complex, which features an elaborate cytoskeletal apparatus and associated structures. Here we report the identification and characterization of a new component of the apical complex,Preconoidalregion protein2(Pcr2). Pcr2 knockout parasites replicate normally, but they are severely diminished in their capacity for host tissue destruction due to significantly impaired invasion and egress, two vital steps in the lytic cycle. When stimulated for calcium-induced egress, Pcr2 knockout parasites become active, and secrete effectors to lyse the host cell. Calcium-induced secretion of the major adhesin, MIC2, also appears to be normal. However, the movement of the Pcr2 knockout parasite is spasmodic, which drastically compromises egress. In addition to faulty motility, the ability of the Pcr2 knockout parasite to assemble the moving junction is impaired. Both defects likely contribute to the poor efficiency of invasion. Interestingly, actomyosin activity, as indicated by the motion of mEmerald tagged actin chromobody, appears to be largely unperturbed by the loss of Pcr2, raising the possibility that Pcr2 may act downstream of or in parallel with the actomyosin machinery.
Measuring single-virus fusion kinetics using an assay for nucleic acid exposure
Authors: Villamil Giraldo Ana M. , Mannsverk Steinar , Kasson Peter M.
Published: May 2022

The kinetics by which individual enveloped viruses fuse with membranes provide an important window into viral entry mechanisms. We have developed a real-time assay using fluorescent probes for single-virus genome exposure than can report on stages of viral entry including or subsequent to fusion pore formation and prior to viral genome trafficking. Encapsulating such fluorescence probes in the lumen of target membranes permits specific detection of fusion events and exclusion of leakage without fusion. Using this assay, we show that influenza virus fuses with liposomes of different sizes with indistinguishable kinetics, suggesting that the starting curvature of such liposomes does not control the rate-limiting steps in influenza entry.
Metabolic, Fibrotic, and Splicing Pathways Are All Altered in Emery-Dreifuss Muscular Dystrophy Spectrum Patients to Differing Degrees
Authors: de las Heras Jose I. , Todorow Vanessa , Krečinić-Balić Lejla , Hintze Stefan , Czapiewski Rafal , Webb Shaun , Schoser Benedikt , Meinke Peter , Schirmer Eric C.
Published: May 2022

Emery-Dreifuss muscular dystrophy (EDMD) is a genetically and clinically variable disorder. Previous attempts to use gene expression changes find its pathomechanism were unavailing, so we here engaged a functional pathway analysis. RNA-Seq was performed on cells from 10 patients diagnosed with an EDMD spectrum disease with different mutations in 7 genes. Upon comparing to controls, the pathway analysis revealed that multiple genes involved in fibrosis, metabolism, myogenic signaling, and splicing were affected in all patients. Splice variant analysis revealed alterations of muscle-specific variants for several important muscle genes. Deeper analysis of metabolic pathways revealed a reduction in glycolytic and oxidative metabolism and reduced numbers of mitochondria across a larger set of 14 EDMD patients and 7 controls. Intriguingly, the gene expression signatures segregated the patients into three subgroups whose distinctions could potentially relate to differences in clinical presentation. Finally, differential expression analysis of miRNAs changing in the patients similarly highlighted fibrosis, metabolism, and myogenic signaling pathways. This pathway approach revealed a clear EDMD signature that can both be used as the basis for establishing a biomarker panel specific to EDMD and direct further investigation into its pathomechanism. Furthermore, the segregation of specific gene changes into three distinct categories that appear to correlate with clinical presentation may be developed into prognostic biomarkers, though this will first require their testing in a wider set of patients with more clinical information.
Revealing druggable cryptic pockets in the Nsp-1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography
Authors: Borsatto Alberto , Akkad Obaeda , Galdadas Ioannis , Ma Shumeng , Damfo Shymaa , Haider Shozeb , Kozielski Frank , Estarellas Carolina , Gervasio Francesco Luigi
Published: May 2022

Non-structural protein 1 (Nsp1) is a main pathogenicity factor of α- and β-coronaviruses. Nsp1 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suppresses the host gene expression by sterically blocking 40S host ribosomal subunits and promoting host mRNA degradation. This mechanism leads to the downregulation of the translation-mediated innate immune response in host cells, ultimately mediating the observed immune evasion capabilities of SARS-CoV-2. Here, by combining extensive Molecular Dynamics simulations, fragment screening and crystallography, we reveal druggable pockets in Nsp1. Structural and computational solvent mapping analyses indicate the partial crypticity of these newly discovered and druggable binding sites. The results of fragment-based screening via X-ray crystallography confirm the druggability of the major pocket of Nsp1. Finally, we show how the targeting of this pocket could disrupt the Nsp1-mRNA complex and open a novel avenue to design new inhibitors for other Nsp1s present in homologous β-coronaviruses.
The rise of sparser single-cell RNAseq datasets; consequences and opportunities
Authors: Bouland Gerard A. , Mahfouz Ahmed , Reinders Marcel J.T.
Published: May 2022

There is an exponential increase in the number of cells measured in single-cell RNA sequencing (scRNAseq) datasets. Concurrently, scRNA-seq datasets become increasingly sparser as more zero counts are measured for many genes. We discuss that with increasing sparsity the binarized representation of gene expression becomes as informative as count-based expression. We show that downstream analyses based on binarized gene expressions give similar results to analyses based on count-based expressions. Moreover, a binarized representation scales to 17-fold more cells that can be analyzed using the same amount of computational resources. Based on these observations, we recommend the development of specialized tools for bit-aware implementations for downstream analyses tasks, creating opportunities to get a more fine-grained resolution of biological heterogeneity.
Mechanoreceptor signal convergence and transformation in the dorsal horn flexibly shape a diversity of outputs to the brain
Authors: Chirila Anda M. , Rankin Genelle , Tseng Shih-Yi , Emanuel Alan J. , Chavez-Martinez Carmine L. , Zhang Dawei , Harvey Christopher D. , Ginty David D.
Published: May 2022

The encoding of touch in the spinal cord dorsal horn (DH) and its influence on tactile representations in the brain are poorly understood. Using a range of mechanical stimuli applied to the skin, large scale in vivo electrophysiological recordings, and genetic manipulations, here we show that neurons in the mouse spinal cord DH receive convergent inputs from both low- and high-threshold mechanoreceptor subtypes and exhibit one of six functionally distinct mechanical response profiles. Genetic disruption of DH feedforward or feedback inhibitory motifs, comprised of interneurons with distinct mechanical response profiles, revealed an extensively interconnected DH network that enables dynamic, flexible tuning of postsynaptic dorsal column (PSDC) output neurons and dictates how neurons in primary somatosensory cortex respond to touch. Thus, mechanoreceptor subtype convergence and nonlinear transformations at the earliest stage of the somatosensory hierarchy shape how touch of the skin is represented in the brain.
Oncogenic KRAS alters splicing factor phosphorylation and alternative splicing in lung cancer
Authors: Lo April , McSharry Maria , Berger Alice
Published: May 2022

Background

Alternative RNA splicing is widely dysregulated in cancers including lung adenocarcinoma, where aberrant splicing events are frequently caused by somatic splice site mutations or somatic mutations of splicing factor genes. However, the majority of mis-splicing in cancers is unexplained by these known mechanisms. We hypothesize that the aberrant Ras signaling characteristic of lung cancers plays a role in promoting the alternative splicing observed in tumors.

Methods

We recently performed transcriptome and proteome profiling of human lung epithelial cells ectopically expressing oncogenic KRAS and another cancer-associated Ras GTPase, RIT1. Unbiased analysis of phosphoproteome data identified altered splicing factor phosphorylation in KRAS-mutant cells, so we performed differential alternative splicing analysis using rMATS to identify significantly altered isoforms in lung epithelial. To determine whether these isoforms were uniquely regulated by KRAS, we performed a large-scale splicing screen in which we generated over 300 unique RNA sequencing profiles of isogenic A549 lung adenocarcinoma cells ectopically expressing 75 different wild-type or variant alleles across 28 genes implicated in lung cancer.

Results

Mass spectrometry data showed widespread downregulation of splicing factor phosphorylation in lung epithelial cells expressing mutant KRAS compared to cells expressing wild-type KRAS. We observed alternative splicing in the same cells, with 2196 and 2416 skipped exon events in KRASG12V and KRASQ61H cells, respectively, 997 of which were shared (p < 0.001 by hypergeometric test). In the high-throughput splicing screen, mutant KRAS induced the greatest number of differential alternative splicing events, second only to the RNA binding protein RBM45 and its mutant allele RBM45M126I. We identified ten high confidence cassette exon events across multiple KRAS variants and cell lines. These included differential splicing of the Myc Associated Zinc Finger (MAZ). As MAZ regulates expression of KRAS, this splice variant may be a mechanism for the cell to modulate wild-type KRAS levels in the presence of oncogenic KRAS.

Conclusion

Proteomic and transcriptomic profiling of lung epithelial cells uncovered splicing factor phosphorylation and mRNA splicing events regulated by oncogenic KRAS. These data suggest that in addition to widespread transcriptional changes, Ras signaling pathways in cancer promote post-transcriptional splicing changes that may contribute to oncogenic processes.
Mutation in the matricellular gene fibulin-4 leads to endothelial dysfunction in resistance arteries
Authors: Lin Michelle , Jones Kara , Brengle Bridget M. , Mecham Robert P. , Halabi Carmen M.
Published: May 2022

Mutations in fibulin-4 (FBLN4), a matricellular gene required for extracellular matrix (ECM) assembly, result in autosomal recessive cutis laxa type 1B (ARCL1B), a syndrome characterized by loose skin, aortic aneurysms, pulmonary emphysema and skeletal abnormalities.

Fbln4E57K/E57K mice recapitulated the phenotypes observed in ARCL1B. In particular, they exhibited ascending aortic aneurysms, elastic fiber fragmentation and increased stiffness in large arteries, and systolic hypertension. Surprisingly however, internal elastic laminae of small resistance and muscular arteries were intact. Here, we show that the increased pulsatile flow resulting from the structural abnormalities and increased stiffness of conduit arteries in Fbln4E57K/E57K mice leads to increased shear stress, a highly oxidative environment, and endothelial dysfunction related to reduced nitric oxide bioavailability in resistance mesenteric arteries. These data have significant implications, not only for the basic biology of ECM assembly along the arterial tree, but also for the clinical consequences of large artery stiffness on the microcirculation.
High-throughput, real-time monitoring of engineered skeletal muscle function using magnetic sensing
Authors: Smith Alec S.T. , Luttrell Shawn M. , Dupont Jean-Baptiste , Gray Kevin , Lih Daniel , Fleming Jacob W. , Cunningham Nathan J. , Jepson Sofia , Hesson Jennifer , Mathieu Julie , Maves Lisa , Berry Bonnie J. , Fisher Elliot C. , Sniadecki Nathan J. , Geisse Nicholas A. , Mack David L.
Published: May 2022

Engineered muscle tissues represent powerful tools for examining tissue level contractile properties of skeletal muscle. However, limitations in the throughput associated with standard analysis methods limit their utility for longitudinal study, high throughput drug screens, and disease modeling. Here we present a method for integrating 3D engineered skeletal muscles with a magnetic sensing system to facilitate non-invasive, longitudinal analysis of developing contraction kinetics. Using this platform, we show that engineered skeletal muscle tissues derived from both induced pluripotent stem cell and primary sources undergo improvements in contractile output over time in culture. We demonstrate how magnetic sensing of contractility can be employed for simultaneous assessment of multiple tissues subjected to different doses of known skeletal muscle inotropes as well as the stratification of healthy versus diseased functional profiles in normal and dystrophic muscle cells. Based on these data, this combined culture system and magnet-based contractility platform greatly broadens the potential for 3D engineered skeletal muscle tissues to impact the translation of novel therapies from the lab to the clinic.
Lactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn mice
Authors: Weber André A. , Yang Xiaojing , Mennillo Elvira , Ding Jeffrey , Watrous Jeramie D. , Jain Mohit , Chen Shujuan , Karin Michael , Tukey Robert H.
Published: May 2022

Pediatric non-alcoholic fatty liver disease (NAFLD) is escalating in the United States, with a limited mechanistic understanding. Triclosan (TCS) is a high-volume antimicrobial additive that has been detected in human breastmilk and shown in adult mice to cause hepatosteatosis. To examine the effect of TCS presented to neonatal mice through lactation, we exposed pregnant females to TCS in their diet and evaluated its impact on nursing neonates. TCS is efficiently transferred by lactation to newborn mice, causing significant fatty liver (FL) during the suckling period. Lactational delivery stimulated hepatosteatosis, triglyceride accumulation, endoplasmic reticulum (ER) stress, inflammation, and liver fibrosis. These events were mirrored by inhibition of key metabolic regulators, FGF21 and AMPK. De novo lipogenesis (DNL) induced by lactational TCS exposure was blocked in mice deficient in hepatic ATF4 . In primary hepatocytes, siRNA specific inhibition of PERK, an ATF4 upstream activator and initiator of ER stress, blocked TCS induced DNL. Also, in the absence of PPARα, which targets regulation of ATF4, TCS induced triglyceride accumulation and the induction of DNL was blocked. The administration of obeticholic acid (OCA), a potent FXR agonist, as well as activation of intestinal mucosal-regenerative gp130 signaling, led to reduced liver ATF4 expression, PPARα signaling, and DNL when neonates were exposed to TCS. In summary, TCS exposure via lactation leads to early indicators of NAFLD development accompanied by hepatosteatosis that were mediated in a PERK-eIF2α-ATF4-PPARα cascade. These studies indicate that mother to child transmission of environmental toxicants such as TCS may underlie the recent increases in pediatric NAFLD.
Comparative genomic insights into the evolution of Halobacteria-associated “Candidatus Nanohaloarchaeota”
Authors: Zhao Dahe , Zhang Shengjie , Kumar Sumit , Zhou Heng , Xue Qiong , Sun Wurunze , Zhou Jian , Xiang Hua
Published: May 2022

The phylum “Candidatus Nanohaloarchaeota” is a representative halophilic lineage within DPANN superphylum. They are characterized by their nanosized cells and symbiotic lifestyle with Halobacteria. However, the development of the symbiosis remains unclear for the lack of genomes located at the transition stage. Here, we performed a comparative genomic analysis of “Ca. Nanohaloarchaeota”. We propose a novel family “Candidatus Nanoanaerosalinaceae” represented by five de-replicated metagenome-assembled genomes obtained from hypersaline sediments and the enrichment cultures of soda-saline lakes. Phylogeny analysis reveals that the novel family are placed at the root of the family “Candidatus Nanosalinaceae” including the well-researched taxa. Most members of “Ca. Nanoanaerosalinaceae” contain lower proportion of putative horizontal gene transfers from Halobacteria than “Ca. Nanosalinaceae”, while they maintain moderately acidic proteomes for hypersaline adaptation of “salt-in” strategy, suggesting that “Ca. Nanoanaerosalinaceae” have not established an intimate association with Halobacteria, and may descend from an intermediate stage. Functional prediction discloses that they exhibit divergent potentials in carbohydrate and organic acids metabolism, and environmental responses. Historical events reconstruction illustrates that the involved genes acquired at the putative ancestors possibly drive the evolutionary and symbiotic divergences. Globally, this research on the new family “Ca. Nanoanaerosalinaceae” enriches the taxonomic and functional diversity of “Ca. Nanohaloarchaeota”, and provides insights into the evolutionary process of “Ca. Nanohaloarchaeota” and their Halobacteria-associated symbiosis.

Importance

DPANN superphylum is a group of archaea widely distributing in various habitats. They generally have small cells, and perform a symbiotic lifestyle with other archaea. The archaeal symbiotic interaction is important to understand microbial community. However, the formation and evolution of the symbiosis between the DPANN lineages and other diverse archaea remain unclear. Based on phylogeny, hypersaline adaptation, functional potentials, and historical events of “Ca. Nanohaloarchaeota”, a representative phylum within the DPANN superphylum, we report a novel family descending from an intermediate stage, and we illustrate the evolutionary process of “Ca. Nanohaloarchaeota” and their Halobacteria-associated symbiosis. Furthermore, we find the acquired genes involved in carbohydrate and organic acids metabolism and environmental responses possibly drive the evolutionary and symbiotic divergences. Altogether, this research helps in understanding the evolution of the archaeal symbiosis, and provides a model for the evolution of the other DPANN lineages.
The efficacy of coenzyme Q10treatment in alleviating the symptoms of primary coenzyme Q10deficiency: a systematic review
Authors: Wang Ying , Hekimi Siegfried
Published: May 2022

Coenzyme Q10(CoQ10) is necessary for mitochondrial electron transport. Mutations in CoQ10biosynthetic genes cause primary CoQ10deficiency (PCoQD) and manifest as mitochondrial disorders. It is often stated that PCoQD patients can be treated by oral CoQ10supplementation. To test this, we compiled all studies describing PCoQD patients up to May 2022. We excluded studies with no data on CoQ10treatment, or with insufficient description of effectiveness. Out of 303 PCoQD patients identified, we retained 89 cases, of which 24 reported improvements after CoQ10treatment (27.0%). In five cases, the patient’s condition was reported to deteriorate after halting of CoQ10treatment. 12 cases reported improvement in the severity of ataxia, and 5 cases in the severity of proteinuria. Only a subjective description of improvement was reported for four patients described as responding. All reported responses were partial improvements of only some symptoms. For PCoQD patients, CoQ10supplementation is replacement therapy. Yet, there is only very weak evidence for the efficacy of the treatment. Our findings thus suggest a need for caution when seeking to justify the widespread use of CoQ10for the treatment of any disease or as dietary supplement.

Highlights

Only 27% of primary CoQ10deficiency patients benefited from CoQ10supplementation.

Studies of the effects of supplementation necessarily lacked controls and blinding.

All reported positive responses to treatment only partially improved few symptoms.

CoQ10supplementation for the treatment of any disease should be questioned.

Firm evidence of benefits requires randomize, controlled trials of CoQ10therapy.

Graphic Abstract
Nucleoli and the nucleoli-centromere association are dynamic during normal development and in cancer
Authors: Rodrigues Aaron , MacQuarrie Kyle L. , Freeman Emma , Leano Kurt , Willis Alexander B , Xu Zhaofa , Alvarez Angel A , Kosak Steven , Ma Yongchao , Perez White Bethany E , Foltz Daniel R , Huang Sui
Published: May 2022

Centromeres are known to cluster around nucleoli in drosophila and mammalian cells. However, the functional significance of nucleoli-centromere interaction remains underexplored. We hypothesize that if this conserved interaction is functionally important, it should be dynamic under different physiological and pathological conditions. We examined the nucleolar structure and centromeres at various differentiation stages using cell culture models. The results show dynamic changes of nucleolar number, area, and nucleoli-centromere interactions at differentiation stages and in cancer cells. Embryonic stem cells usually have a single large nucleolus, which associates with a high percentage of centromeres. As cells differentiate into intermediate states, the nucleolar number increases and the association with centromeres decreases. In terminally differentiated cells, including myotubes, neurons and keratinocytes, the number of nucleoli and their association with centromeres are at the lowest. Cancer cells demonstrate the pattern of nucleoli number and nucleoli-centromere association that is akin to proliferative less differentiated cell types, suggesting that nucleolar reorganization and changes in nucleoli-centromere interactions may help facilitate malignant transformation. This idea is supported in a case of pediatric rhabdomyosarcoma, in which induced differentiation inhibits cell proliferation and reduces nucleolar number and centromere association. These findings suggest active roles of nucleolar structure in centromere function and genome organization critical for cellular function in both normal development and cancer.
Time Lagged Multidimensional Pattern Connectivity (TL MDPC): An EEG/MEG Pattern Transformation Based Functional Connectivity Metric
Authors: Rahimi Setareh , Jackson Rebecca , Farahibozorg Seyedeh-Rezvan , Hauk Olaf
Published: May 2022

Functional and effective connectivity methods are essential to study the complex information flow in brain networks underlying human cognition. Only recently have connectivity methods begun to emerge that make use of the full multidimensional information contained in patterns of brain activation, rather than univariate summary measures of these patterns. To date, these methods have mostly been applied to fMRI data, and no method allows vertex-vertex transformation with the temporal specificity of EEG/MEG data. Here, we introduce time-lagged multidimensional pattern connectivity (TL-MDPC) as a novel bivariate functional connectivity metric for EEG/MEG research. TL-MDPC estimates the vertex-to-vertex transformations among multiple brain regions and across different latency ranges. It determines how well patterns in ROI X at time point tx can linearly predict patterns of ROI Y at time point ty. In the present study, we use simulations to demonstrate TL-MDPC’s increased sensitivity to multidimensional effects compared to a univariate approach across realistic choices of number of trials and signal-to-noise ratio. We applied TL-MDPC, as well as its univariate counterpart, to an existing dataset varying the depth of semantic processing of visually presented words by contrasting a semantic decision and a lexical decision task. TL-MDPC detected significant effects beginning very early on, and showed stronger task modulations than the univariate approach, suggesting that it is capable of capturing more information. With TL-MDPC only, we observed rich connectivity between core semantic representation (left and right anterior temporal lobes) and semantic control (inferior frontal gyrus and posterior temporal cortex) areas with greater semantic demands. TL-MDPC is a promising approach to identify multidimensional connectivity patterns, typically missed by univariate approaches.

Highlights

TL-MDPC is a multidimensional functional connectivity method for event-related EMEG

TL-MDPC captures both univariate and multidimensional connectivity

TL-MDPC yields both zero-lag and time-lagged dependencies

TL-MDPC produced richer connectivity than univariate approaches in a semantic task

TL-MDPC identified connectivity between the ATL hubs and semantic control regions
Development of fluoroquinolone resistance through antibiotic tolerance in Campylobacter jejuni
Authors: Park Myungseo , Kim Jinshil , Feinstein Jill , Lang Kevin S. , Ryu Sangryeol , Jeon Byeonghwa
Published: May 2022

Antibiotic tolerance not only enables bacteria to survive under acute antibiotic exposures but also provides bacteria with a window of time to develop antibiotic resistance. Campylobacter jejuni is increasingly resistant to clinically important antibiotics, particularly fluoroquinolones (FQs). Currently, little is known about antibiotic tolerance and its effects on resistance development in C. jejuni. Here, we show that exposure to ciprofloxacin and tetracycline at concentrations 10 and 100 times higher than the minimum inhibitory concentration (MIC) induce antibiotic tolerance in C. jejuni, whereas gentamicin and erythromycin treatment cause cell death. Interestingly, FQ resistance is rapidly developed in C. jejuni after tolerance induction by ciprofloxacin and tetracycline. Furthermore, alkyl hydroperoxide reductase plays a critical role in preventing FQ resistance development in C. jejuni during antibiotic tolerance by alleviating oxidative stress. Together, these results demonstrate that exposure of C. jejuni to antibiotics used to treat campylobacteriosis can induce antibiotic tolerance and that FQ-resistant (FQR) C. jejuni rapidly emerges through tolerance induction by FQs and non-FQ antibiotics. Work presented in this study shows mechanisms underlying the high prevalence of FQRC. jejuni and provides an insight into the effects of antibiotic tolerance on resistance development.

Importance

Antibiotic tolerance compromises the efficacy of antibiotic treatment by extending bacterial survival and developing mutations associated with antibiotic resistance. Despite growing public health concerns about antibiotic resistance in C. jejuni, antibiotic tolerance has not yet been investigated in this important zoonotic pathogen. Here, our results show that exposure of C. jejuni to ciprofloxacin and tetracycline, a common agricultural antibiotic, develops antibiotic tolerance, which subsequently facilitates the emergence of FQRC. jejuni. Since antibiotic-resistant C. jejuni is transmitted primarily from animals to humans, our study suggests that non-FQ drugs, such as tetracycline, used for animals can also promote FQ resistance development by inducing antibiotic tolerance in C. jejuni. Overall, the findings in this study help us understand mechanisms of resistance development through the induction of antibiotic tolerance.
Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation
Authors: Alexander Desi C , Corman Tanya , Mendoza Mariel , Glass Andrew , Belity Tal , Campbell Riane R , Han Joseph , Keiser Ashley A , Winkler Jeffrey , Wood Marcelo A , Kim Thomas , Garcia Benjamin A , Cohen Hagit , Mews Philipp , Egervari Gabor , Berger Shelley L
Published: May 2022

Histone acetylation is a key component in the consolidation of long-term fear memories. Epigenetic enzymes involved in histone acetylation, including histone acetyltransferases and deacetylases, have been put forward as potential pharmacological targets in the treatment of pathological fear memories, such as those that underlie post-traumatic stress disorder (PTSD). However, these enzymes typically play a ubiquitous role in gene regulation, which precludes the clinical use of systemic manipulations. Recently, we have found that a nuclear-localized metabolic enzyme, Acetyl-coA synthetase 2 (Acss2), modulates histone acetylation during learning and memory. Loss of Acss2 is well-tolerated in mice, with no impact on general health or baseline behavior. Here, we show that an Acss2 null mouse model shows reduced acquisition of long-term fear memories in assays of contextual and cued fear conditioning. We find that loss of Acss2 leads to consolidation-specific reductions in both histone acetylation and the expression of critical learning and memory-related genes in the dorsal hippocampus. Further, we show that systemic administration of blood-brain-barrier (BBB)-permeable Acss2 inhibitors during the consolidation window reduces fear memory formation in mice and rats, and also reduces anxiety in a predator-scent-stress (PSS) paradigm. Our findings suggest that Acss2 plays a critical role in the formation of fear memories, and represents a potential pharmacological target in the treatment of PTSD.
Pathogen dependence and inter-individual variability of post-infection reproductive fitness in Drosophila melanogaster
Authors: Basu Aabeer , Gupta Vandana , Prasad Nagaraj Guru
Published: May 2022

In the experiments reported in this manuscript, we explore the effect of bacterial infections on the reproductive output of Drosophila melanogaster females. Canonical view of host-pathogen interactions supposes two possible outcomes. Because of immune defence being an energy/resource intensive function, an infected female reallocates resources away from reproductive processes and towards immune defence, therefore compromising its reproductive output. Alternatively, faced with impending mortality, an infected female increases its reproductive output to compensate for lost opportunities of future reproduction. We tested if pathogen identity, infection outcome (survival vs. death), and/or time of death determines the reproductive output of females infected with three bacterial pathogens. Our results show that pathogen identity is a reliable predictor of population level response of infected females but does not reliably predict the behaviour of individual females. Additionally, females succumbing to infection exhibit greater variability in reproductive output, compared to both survivors and controls, but this variability is not explained by either the time of death or the identity of the infecting pathogen. Furthermore, survivors of infection have reproductive output similar to control females.
Differential excretory/secretory proteome of the adult female and male stages of the human blood fluke,Schistosoma mansoni
Authors: Kenney Eric T. , Mann Victoria H. , Ittiprasert Wannaporn , Rosa Bruce A. , Mitreva Makedonka , Bracken Bethany K. , Loukas Alex , Brindley Paul J. , Sotillo Javier
Published: May 2022

Intricate molecular communication between the schistosome (flatworms) and its mammalian host, as well as between paired male and female schistosomes has shaped the secreted proteome of these flatworms. Whereas the schistosome egg is responsible for the disease manifestations of chronic schistosomiasis, the long lived, adult female and male stages also release mediators that facilitate their long-lived intra-vascular existence in a hostile niche where they are bathed in immune cells and effector molecules. However, despite their importance, no studies have focused on analysing the excretory/secretory products (ESPs) from adult schistosomes.

Herein, ESPs from culturedSchistosoma mansonimale or female adult worms were identified, quantified, compared and contrasted using a label-free proteomic approach. Approximately 1,000 proteins were identified, from which almost 800 could be finally quantified. Considering the proteins uniquely identified and proteins with a significantly regulated expression pattern in male or female flukes, a total of 370 and 140 proteins were more abundantly secreted by males and females, respectively. Using functional analysis networks showing the gene ontology terms and KEGG pathways with the highest significance, we observed that male schistosomes secrete proteins related to carbohydrate metabolism, cytoskeletal organisation more abundantly than females, while female worms secreted more hydrolases and proteins involved in cellular homeostasis than males.

This analysis doubles the number of previously reported ESPs fromS. mansoni, contributing to a better understanding of the host-parasite dynamic interactions. Furthermore, these findings expand potential vaccine and diagnostic candidates for this neglected tropical disease pathogen, which will enable deeper understanding of the molecular communication critical to parasitism.
Patterns of lineage-specific genome evolution in the brood parasitic black-headed duck (Heteronetta atricapilla)
Authors: Wuitchik Sara JS , Hillier LaDeana W. , Balakrishnan Christopher N. , Sorenson Michael D. , Warren Wesley C. , Sackton Timothy B.
Published: May 2022

Occurring independently at seven separate origins across the avian tree of life, obligate brood parasitism is a unique suite of traits observed in only approximately 1% of all bird species. Obligate brood parasites exhibit varied physiological, morphological, and behavioural traits across lineages, but common among all obligate brood parasites is that the females lay their eggs in the nest of other species. Unique among these species is the black-headed duck (Heteronetta atricapilla), a generalist brood parasite that is the only obligate brood parasite among waterfowl. This provides an opportunity to assess evolutionary changes in traits associated with brood parasitism, notably the loss of parental care behaviours, with an unspecialized brood parasite. We generated new high-quality genome assemblies and genome annotations of the black-headed duck and three related non-parasitic species (freckled duck, African pygmy-goose, and ruddy duck). With these assemblies and existing public genome assemblies, we produced a whole genome alignment across Galloanserae to identify conserved non-coding regions with atypical accelerations in the black-headed duck and coding genes with evidence of positive selection, as well as to resolve uncertainties in the duck phylogeny. To complement these data, we sequenced a population sample of black-headed ducks, allowing us to conduct McDonald-Kreitman tests of lineage-specific selection. We resolve the existing polytomy between our focal taxa with concordance from coding and non-coding sequences, and we observe stronger signals of evolution in non-coding regions of the genome than in coding regions. Collectively, the new high-quality genomes, comparative genome alignment, and population genomics provide a detailed picture of genome evolution in the only brood parasitic duck.
A modular intramolecular triplex photo-switching motif that enables rapid and reversible control of aptamer binding activity
Authors: Trinh Tuan , Thompson Ian A. P. , Clark Finley , Remington Jacob M. , Eisenstein Michael , Li Jianing , Soh H. Tom
Published: May 2022

DNA switches that can change conformation in response to certain wavelengths of light could enable rapid and non-invasive control of chemical processes for a wide range of applications. However, most current photo-responsive DNA switches are limited either by irreversible switching or reversible switching with impractically slow kinetics. Here, we report the design of an intramolecular triplex photoswitch (TPS) design based on single-stranded DNA that undergoes rapid and reversible photoswitching between folded and unfolded states through isomerization of internal azobenzene modifications. After optimizing the performance of our photoswitch design, we used molecular dynamics (MD) simulations to reveal how individual azobenzenes contribute to the stabilization or destabilization of the triplex depending on their photoisomerization state. By coupling our TPS to an existing aptamer, we can reversibly modulate its binding affinity with less than 15 seconds of UV light exposure. We further demonstrate reproducible shifting in affinity over multiple cycles of UV and blue light irradiation without substantial photobleaching. Given that our TPS can introduce switching functionality to aptamers without manipulating the aptamer sequence itself, we believe our design methodology should offer a versatile means for integrating photo-responsive properties into DNA nanostructures.
CRISPR loss of function screening to identify genes involved in human primordial germ cell-like cells development
Authors: Hwang Young Sun , Blanco M. Andrés , Sasaki Kotaro
Published: May 2022

Despite our increasing knowledge of molecular mechanisms guiding various aspects of human reproduction, those underlying human primordial germ cell (PGC) development remain largely unknown. Here, we conducted custom CRISPR screening in an in vitro system of hPGC-like cells (hPGCLCs) to identify genes required for acquisition and maintenance of PGC fate in humans. Amongst our candidates, we identified TCL1A, an AKT coactivator. Functional assessment in our in vitro hPGCLCs system revealed that TCL1A played a critical role in later stages of hPGCLC development. Moreover, we found that TCL1A loss reduced AKT-mTOR signaling, downregulated expression of genes related to translational control, and subsequently led to a reduction in global protein synthesis and proliferation. Together, our study identifies novel regulators critical for hPGCLC development and demonstrates the importance of translational control in human reproduction.
Time-efficient relaxation measurements by 31P MR fingerprinting in human brain at 7T
Authors: Lim Song-I , Widmaier Mark Stephan , Wenz Daniel , Yun Jiang , Xin Lijing
Published: May 2022

Purpose

The goal of the study is to develop 31P spectroscopic MRF at 7T to measure T1 and T2 relaxation times simultaneously and to compare time efficiency and test-retest reproducibility of MRF with conventional inversion recovery and multi-TE methods.

Methods

A 31P MRF scheme was designed based on a balanced steady-state free precession type sequence. Dictionary was generated using the Bloch equations. B0 map was acquired experimentally and incorporated into the dictionary. 7 phantoms with different T1 and T2 relaxation times were prepared for MRF validation. Simulations were performed to evaluate estimation bias. 7 volunteers were scanned twice using both MRF and the conventional methods to evaluate the reproducibility.

Results

In phantom measurements, T1 and T2 values between MRF and conventional methods demonstrated a good agreement with Pearson’s correlation coefficients of 0.99 and 0.97, respectively. In in vivo experiments, estimated T1 by MRF were in good agreement with those measured by the inversion recovery and in the literature. On the other hand, estimated T2 values by MRF were shorter than those measured by the multi-TE method. 31P MRF method can reduce the acquisition time by 15 min providing less than 10% of mean CV for T1 estimations and less than 20% of mean CV for T2 estimations of metabolites.

Conclusion

Our results shows the feasibility of simultaneous T1 and T2 measurement of 31P metabolites in human brain using MRF at 7T. High reproducibility can be achieved especially for T1 measurement with 40% time reduction over conventional methods.
Audit committee composition and earnings management in a specific institutional environment: the case of Russia
Authors: Nikulin Egor D. , Smirnov Marat V. , Sviridov Andrei A. , Bandalyuk Olesya V.
Published: May 2022

Purpose

The purpose of this paper is to investigate the specifics of the relationship between audit committee characteristics and earnings management in Russian listed companies. This research is driven by the possibility of placing this relationship within the context of a specific institutional environment for company performance.

Design/methodology/approach

The authors apply a panel study of 184 Russian listed companies for the period 2014–2018. In addition to the standard fixed effects model, the authors test the results for potential endogeneity with two-stage least squares (2SLS) analysis.

Findings

The results show that audit committee representation on the board of directors results in some mitigation of earnings management. Results reveal that a higher level of audit committee independence and the presence of financial expertise on the committee are associated with lower earnings management. However, companies with relatively busy directors on audit committees are more inclined to practice earnings management. The study’s findings hold after testing for endogeneity of audit committee independence. The authors also reveal that some audit committee characteristics (for example, audit committee independence; its level of expertise) alleviate earnings management in listed state-owned companies (SOEs) more strongly than in listed non-SOEs.

Originality/value

The results add to the ongoing debate on the role of corporate governance mechanisms in mitigating earnings management in emerging markets by taking into account the type of ownership (state-owned vs private) as a moderating variable. This study reveals, in particular, that the effect of certain audit committee characteristics on earnings management is more prominent in listed SOEs than in listed non-SOEs.