bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid and accurate SNP genotyping of clonal bacterial pathogens with BioHansel
Authors: Labbé Geneviève , Kruczkiewicz Peter , Robertson James , Mabon Philip , Schonfeld Justin , Kein Daniel , Rankin Marisa A. , Gopez Matthew , Hole Darian , Son David , Knox Natalie , Laing Chad R. , Bessonov Kyrylo , Taboada Eduardo N. , Yoshida Catherine , Ziebell Kim , Nichani Anil , Johnson Roger P. , Van Domselaar Gary , Nash John H. E.
Published: September 2021

Hierarchical genotyping approaches can provide insights into the source, geography and temporal distribution of bacterial pathogens. Multiple hierarchical SNP genotyping schemes have previously been developed so that new isolates can rapidly be placed within pre-computed population structures, without the need to rebuild phylogenetic trees for the entire dataset. This classification approach has, however, seen limited uptake in routine public health settings due to analytical complexity and the lack of standardized tools that provide clear and easy ways to interpret results. The BioHansel tool was developed to provide an organism-agnostic tool for hierarchical SNP-based genotyping. The tool identifies split k-mers that distinguish predefined lineages in whole genome sequencing (WGS) data using SNP-based genotyping schemes. BioHansel uses the Aho-Corasick algorithm to type isolates from assembled genomes or raw read sequence data in a matter of seconds, with limited computational resources. This makes BioHansel ideal for use by public health agencies that rely on WGS methods for surveillance of bacterial pathogens. Genotyping results are evaluated using a quality assurance module which identifies problematic samples, such as low-quality or contaminated datasets. Using existing hierarchical SNP schemes for

Mycobacterium tuberculosis

and

Salmonella

Typhi, we compare the genotyping results obtained with the k-mer-based tools BioHansel and SKA, with those of the organism-specific tools TBProfiler and genotyphi, which use gold-standard reference-mapping approaches. We show that the genotyping results are fully concordant across these different methods, and that the k-mer-based tools are significantly faster. We also test the ability of the BioHansel quality assurance module to detect intra-lineage contamination and demonstrate that it is effective, even in populations with low genetic diversity. We demonstrate the scalability of the tool using a dataset of ~8100 S. Typhi public genomes and provide the aggregated results of geographical distributions as part of the tool’s output. BioHansel is an open source Python 3 application available on PyPI and Conda repositories and as a Galaxy tool from the public Galaxy Toolshed. In a public health context, BioHansel enables rapid and high-resolution classification of bacterial pathogens with low genetic diversity.
Financial and Non-financial Conflicts of Interest Among the Japanese Government Advisory Board Members Concerning Coronavirus Disease 2019
Authors: Mamada Hanano , Murayama Anju , Ozaki Akihiko , Hashimoto Takanao , Saito Hiroaki , Sawano Toyoaki , Bhandari Divya , Shrestha Sunil , Tanimoto Tetsuya
Published: September 2021

Objectives

This study aimed to assess the extent of conflicts of interest among the Japanese government COVID-19 advisory board members and elucidate the accuracy of conflicts of interest (COI) disclosure and management strategies.

Methods

Using the payment data from all 79 pharmaceutical companies in Japan between 2017 and 2018 and direct research grants from the Japanese government between 2019 and 2020, we evaluated the extent of financial and non-financial COI among all 20 Japanese government COVID-19 advisory board members.

Results

Japanese government COVID-19 advisory board members were predominantly male (75.0%) and physicians (50.0%). Between 2019 and 2020, two members (10.0%) received a total of $819,244 in government research funding. Another five members (25.0%) received $419,725 in payments, including $223,183 in personal fees, from 28 pharmaceutical companies between 2017 and 2018. The average value of the pharmaceutical payments was $20,986 (standard deviation: $81,762). Further, neither the Ministry of Health, Labor, and Welfare nor the Japanese Cabinet Secretariat disclosed financial or non-financial COI with industry. Further, the government and had no policies for managing COI among advisory board members.

Conclusions

This study found that the Japanese government COVID-19 advisory board had financial and non-financial COI with pharmaceutical companies and the government. Further, there were no rigorous COI management strategies for the COVID-19 advisory board members. Any government must ensure the independence of scientific advisory boards by implementing more rigorous and transparent management strategies that require the declaration and public disclosure of all COI.
Butyrate and related epigenetic changes link Parkinson’s disease to inflammatory bowel disease and depressive symptoms
Authors: Xie Aoji , Ensink Elizabeth , Li Peipei , Gordevičius Juozas , Marshall Lee L. , George Sonia , Pospisilik J. Andrew , Aho Velma T. E. , Houser Madelyn C. , Pereira Pedro A. B. , Rudi Knut , Paulin Lars , Tansey Malú G. , Auvinen Petri , Brundin Patrik , Brundin Lena , Labrie Viviane , Scheperjans Filip
Published: September 2021

Background

The gut microbiome and its metabolites can impact brain health and are altered in Parkinson’s disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Here, we investigate whether the changes in the gut microbiome and associated metabolites are linked to PD symptoms and epigenetic markers in leucocytes and neurons.

Methods

Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified the genome-wide DNA methylation by targeted bisulfite sequencing.

Results

We show that lower fecal butyrate and reduced Roseburia, Romboutsia, and Prevotella counts are linked to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA (mDNA) regions in PD overlap with those altered in gastrointestinal, autoimmune, and psychiatric diseases.

Conclusions

Decreased levels of bacterially produced butyrate are linked to epigenetic changes in leucocytes and neurons from PD patients, and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain gastrointestinal and psychiatric disorders, which could be relevant for their epidemiological linkage.
Profiles of US Hispanics Unvaccinated for COVID-19
Authors: Piper Brian J. , Sanchez Bianca V. , Madera Joshua D. , Sulzinski Michael A.
Published: September 2021

Background

The COVID-19 pandemic has disproportionately impacted Hispanics in the US with increased rates of SARS-Cov2 infections, hospitalizations, and deaths. The objective of this report was to characterize the demographics and beliefs of unvaccinated Hispanics to help address their concerns that lead to vaccine hesitancy.

Methods

Of 1,011 potential participants from a national online panel, 22.3% (N=225, 51.6% female, age = 40.5) met inclusion criteria of Hispanic adults and not receiving at least one dose of the COVID-19 vaccine. The 30-item survey included items about demographics, political affiliations, sources of news (e.g., Fox vs. CNN), reasons for being unvaccinated, and ratings (0 = strongly disagree, 100 = strongly agree) of 10 controversial statements regarding COVID-19.

Results

Over three-fifths (62.6%) identified side effects and safety concerns while almost one-third (30.5%) a lack of efficacy as their top reasons for being unvaccinated. Agreement to “The developers of the COVID-19 vaccine rushed the development and cut-corners” was rated highest (63.22) which was significantly (p < .001) higher than the other nine statements (e.g., “The COVID-19 vaccine does not work”). Many vaccine attitudes differed significantly by political party affiliation and some by gender and news source. Republicans (59.9 ± 4.2) scored higher than Democrats (38.5 ± 4.2, p ≤ .001) to “If I’ve already had COVID-19, I don’t need the vaccine.”

Conclusions

This study identified heterogeneity in COVID-19 vaccine attitudes among Hispanics. Further research is needed to determine if the subgroups identified are differentially receptive to interventions to facilitate reconsideration of prior vaccination decisions.
Murine Fetal Tracheal Occlusion Increases Lung Basal Cells via Increased Yap Signaling
Authors: Serapiglia Vincent , Stephens Chad , Joshi Rashika , Aydin Emrah , Oria Marc , Marotta Mario , Peiro Jose L. , Varisco Brian M.
Published: September 2021

Fetal endoscopic tracheal occlusion (FETO) is an emerging surgical therapy for congenital diaphragmatic hernia (CDH). Ovine and rabbit data suggested altered lung epithelial cell populations after TO with transcriptomic signatures implicating basal cells. To test this hypothesis, we deconvolved mRNA-seq data and used quantitative image analysis in fetal rabbit lungs to showed increased basal cells and reduced ciliated cells after TO. In a fetal mouse TO model, flow cytometry showed increased basal cells, and immunohistochemistry demonstrated basal cell extension to the subpleura. Nuclear yap, a known regulator of basal cell fate, was increased in TO lung, and Yap ablation on the lung epithelium abrogated TO-mediated basal cell expansion. mRNA-seq of TO lung showed increased activity of downstream Yap genes. Human lung specimens with congenital and fetal endoscopic tracheal occlusion had clusters of subpleural basal cell that were not present in control. TO increases lung epithelial cell nuclear Yap leading to basal cell expansion.
Separating Clinical and Subclinical Depression by Big Data Informed Structural Vulnerability Index and Its impact on Cognition: ENIGMA Dot Product
Authors: Kochunov Peter , Ma Yizhou , Hatch Kathryn S. , Schmaal Lianne , Jahanshad Neda , Thompson Paul M. , Adhikari Bhim M. , Bruce Heather , Chiappelli Joshua , Van der vaart Andrew , Goldwaser Eric L. , Sotiras Aris , Ma Tianzhou , Chen Shuo , Nichols Thomas E. , Hong L. Elliot
Published: September 2021

Big Data neuroimaging collaborations including Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) integrated worldwide data to identify regional brain deficits in major depressive disorder (MDD). We evaluated the sensitivity of translating ENIGMA-defined MDD deficit patterns to the individual level. We treated ENIGMA MDD deficit patterns as a vector to gauge the similarity between individual and MDD patterns by calculating ENIGMA dot product (EDP). We analyzed the sensitivity and specificity of EDP in separating subjects with (1) subclinical depressive symptoms without a diagnosis of MDD, (2) single episode MDD, (3) recurrent MDD, and (4) controls free of neuropsychiatric disorders. We compared EDP to the Quantile Regression Index (QRI; a linear alternative to the brain age metric) and the global gray matter thickness and subcortical volumes and fractional anisotropy (FA) of water diffusion. We performed this analysis in a large epidemiological sample of UK Biobank (UKBB) participants (N=17,053/19,265 M/F). Group-average increases in depressive symptoms from controls to recurrent MDD was mirrored by EDP (r2=0.85), followed by FA (r2=0.81) and QRI (r2=0.56). Subjects with MDD showed worse performance on cognitive tests than controls with deficits observed for 3 out of 9 cognitive tests administered by the UKBB. We calculated correlations of EDP and other brain indices with measures of cognitive performance in controls. The correlation pattern between EDP and cognition in controls was similar (r2=0.75) to the pattern of cognitive differences in MDD. This suggests that the elevation in EDP, even in controls, is associated with cognitive performance - specifically in the MDD-affected domains. That specificity was missing for QRI, FA or other brain imaging indices. In summary, translating anatomically informed meta-analytic indices of similarity using a linear vector approach led to better sensitivity to depressive symptoms and cognitive patterns than whole-brain imaging measurements or an index of accelerated aging.
Fluency Changes due to Sports-Related Concussion
Authors: Patel Sona , Grabowski Caryn , Dayalu Vikram , Cunningham Mercedes , Testa Anthony J.
Published: September 2021

Background

Alterations in speech have long been identified as indicators of various neurologic conditions including traumatic brain injury (TBI), neurodegenerative diseases, and stroke. TBIs that can be assessed using the Glasgow Coma Scale often result in speech symptoms such as dysarthria and occasionally neurogenic stuttering. The manifestation of symptoms including the specific changes in speech occurring in mild TBIs (or concussions) may differ from more severe head injuries. This work aims to compare speech fluency in sport-related concussion to baseline performance as well as non-athlete controls.

Methods

A total of 230 Division I student athletes participated in pre-season speech testing. Of these, 12 students (18-22 years) who sustained a concussion also participated in speech testing in the days following diagnosis of concussion. Samples of picture descriptions were independently coded by three trained raters as 17 error types within the three traditional categories of errors defined in fluency analysis (Stuttering-Like Disfluency, Articulation Error, Other Disfluency).

Results

Within-subjects analysis comparing the difference in percent error scores at baseline and post-concussion revealed significant differences for interjections (t(11)=-2.678, p< .05). The Other Disfluency category was also significantly different (t(11)= -2.735, p< .05), with more errors occurring after a concussion. No change in the Stuttering-Like Disfluency (t(11)= -0.799, p>.05) or Articulation Error category (t(11)=-0.045, p>.05) was found.

Conclusions

These results demonstrate that speech changes occur following mild sports-related concussions. Specifically, the rate of interjections increased in a limited sample of college athletes who sustain a concussion. Changes in additional error types (fillers, pauses) were trending, but were not significant potentially due to the low sample size. Future studies should consider speech as a diagnostic tool for concussion.
Odorant receptor copy number change, co-expression, and positive selection establish peripheral coding differences between fly species
Authors: Auer Thomas O. , Álvarez-Ocaña Raquel , Cruchet Steeve , Benton Richard , Arguello J. Roman
Published: September 2021

1.

Despite numerous examples of chemoreceptor gene family expansions and contractions, how these changes relate to modifications in the neural circuitry in which they are expressed remains unclear. Drosophila’s Odorant receptor (Or) family is ideal for addressing this question because a large majority of Ors are uniquely expressed in single olfactory sensory neuron (OSN) types. Between-species changes in Or copy number, therefore, may indicate diversification/reduction of OSN populations. To test this, we investigated a rapidly duplicated/deleted subfamily (named Or67a) in Drosophila melanogaster and its sister species (D. simulans, D. sechellia, and D. mauritiana). We found that the common ancestor had three Or67a paralogs that had already diverged adaptively in their odor-evoked responses. Following their speciation, two Or67a paralogs were lost independently in D. melanogaster and D. sechellia, with ongoing positive selection acting on the intact genes. Instead of the expected singular expression of each diverged Ors, the three D. simulans Or67a paralogs are co-expressed. Thus, while neuroanatomy is conserved between these species, independent selection on co-expressed receptors has contributed to species-specific peripheral coding of olfactory information. This work reveals a model of adaptive change previously not considered for olfactory evolution and raises the possibility that similar processes may be operating among the largely uninvestigated cases of Or co-expression.
Ultrasensitive detection of Bacillus anthracis by real time PCR targeting a polymorphism in multi-copy 16S rRNA genes and their transcripts
Authors: Braun Peter , Nguyen Martin Duy-Thanh , Walter Mathias C. , Grass Gregor
Published: September 2021

The anthrax pathogen Bacillus anthracis poses a significant threat to human health. Identification of B. anthracis is challenging because of the bacterium’s close genetic relationship to other Bacillus cereus group species. Thus, molecular detection is founded on species-specific PCR targeting single-copy genes. Here, we validated a previously recognized multi-copy target, a species-specific SNP present in 2-5 copies in every B. anthracis genome analyzed. For this, a hydrolysis probe-based real time PCR assay was developed and rigorously tested. The assay was specific as only B. anthracis DNA yielded positive results, was linear over 9 log10 units and was sensitive with a limit of detection (LoD) of 2.9 copies/reaction. Though not exhibiting a lower LoD than established single copy PCR targets (dhp61 or PL3), the higher copy number of the B. anthracis–specific 16S rRNA gene allele afforded ≤2 unit lower threshold (Ct) values. To push the detection limit even further, the assay was adapted for reverse transcription PCR on 16S rRNA transcripts. This RT-PCR assay was also linear over 9 log10 units and was sensitive with a LoD of 6.3 copies/reaction.In a dilution-series of experiments, the 16S RT-PCR assay achieved a thousand-fold higher sensitivity than the DNA-targeting assays. For molecular diagnostics, we recommend a real time RT-PCR assay variant in which both DNA and RNA serve as templates (thus, no requirement for DNase treatment). This will at least provide results equaling the DNA-based implementation if no RNA is present but will be superior even at the lowest residual rRNA concentrations.
Effects of testing and vaccination levels on the dynamics of the COVID-19 pandemic and the prospects for its termination
Authors: Nesteruk Igor , Rodionov Oleksii
Published: September 2021

A simple statistical analysis of the accumulated and daily numbers of new COVID-19 cases and deaths per capita was performed with the use of recent datasets for European and some other countries and regions. It was shown that vaccination can significantly reduce the likelihood of deaths. However, existing vaccines do not prevent new infections, and vaccinated individuals can spread the infection as intensely as unvaccinated ones. Therefore, it is too early to lift quarantine restrictions in Europe and most other countries. The constant appearance of new cases due to re-infection increases the likelihood of new coronavirus strains, including very dangerous. As existing vaccines are not able to prevent this, it remains to increase the number of tests per registered case. If the critical value of 520 is exceeded, one can hope to stop the occurrence of new cases.
Fractional-order Approach to Modeling and Characterizing the Complex and Frequency-dependent Apparent Arterial Compliance: In Human and Animal Validation
Authors: Bahloul Mohamed A. , Aboelkassem Yasser , Laleg-Kirati Taous-Meriem
Published: September 2021

Recently, experimental and theoretical studies have revealed the potential of fractional calculus to represent viscoelastic blood vessel and arterial biomechanical properties. This paper presents five fractional-order models to describe the dynamic relationship between aortic blood pressure and volume, representing the apparent vascular compliance. The proposed model employs fractional-order capacitor element (FOC) to lump the complex and frequency dependence characteristics of arterial compliance. FOC combines both resistive and capacitive properties, which the fractional differentiation order, α, can control. The proposed representations have been compared with generalized integer-order models of arterial compliance. All structures have been validated using different aortic pressure and flow rate waveforms collected from various human and animal species such as pigs and dogs. The results demonstrate that the fractional-order scheme can reconstruct the overall dynamic of the complex and frequency-dependent apparent compliance dynamic and reduce the complexity. The physiological relevance of the proposed models’ parameters was assessed by evaluating the variance-based global sensitivity analysis. Moreover, the simplest fractional-order representation has been embed in a global arterial lumped parameter representation to develop a novel fractional-order modified arterial Windkessel. The introduced arterial model has been validated by applying real human and animal hemodynamic data and shows an accurate reconstruction of the proximal blood pressure. The novel proposed paradigm confers a potential to be adopted in clinical practice and basic cardiovascular mechanics research.
Learning about threat from friends and strangers is equally effective: an fMRI study on observational fear conditioning
Authors: Kaźmierowska Anna M. , Szczepanik Michał , Wypych Marek , Droździel Dawid , Marchewka Artur , Michałowski Jarosław M. , Olsson Andreas , Knapska Ewelina
Published: September 2021

Humans often benefit from social cues when learning about the world. For instance, learning about threats from others can save the individual from dangerous first-hand experiences. Familiarity is believed to increase the effectiveness of social learning, but it is not clear whether it plays a role in learning about threats. Using functional magnetic resonance imaging, we undertook a naturalistic approach and investigated whether there was a difference between observational fear learning from friends and strangers. Participants (observers) witnessed either their friends or strangers (demonstrators) receiving aversive (shock) stimuli paired with colored squares (observational learning stage). Subsequently, participants watched the same squares, but without receiving any shocks (direct-expression stage). We observed a similar pattern of brain activity in both groups of observers. Regions related to threat responses (amygdala, anterior insula, anterior cingulate cortex) and social perception (fusiform gyrus, posterior superior temporal sulcus) were activated during the observational phase, reflecting the fear contagion process. The anterior insula and anterior cingulate cortex were also activated during the subsequent stage, indicating the expression of learned threat. Because there were no differences between participants observing friends and strangers, we argue that social threat learning is independent of the level of familiarity with the demonstrator.

Highlights

We compared observational learning of fear from friends and strangers

Familiarity does not enhance social learning of fear in humans

Bayesian statistics confirm absence of differences between friends and strangers

Observational fear learning activates social and fear networks including amygdala

Amygdala activations are absent when learned fear is recalled
Assessing the optimal frequency of early parasitoid releases in an apple orchard to control Dysaphis plantaginea: a proof of concept study
Authors: Ferrais L. , Tougeron K. , Gardin P. , Hance T.
Published: September 2021

Alternative measures to pesticides to control the rosy apple aphid Dysaphis plantaginea are being developed. Naturally occurring predators and parasitoids often fail to reduce aphid abundance below the economic threshold in orchards, because they are active too late after the aphid first infestation. We tested the efficiency of mass release of two parasitoid species, Aphidius matricariae and Ephedrus cerasicola, early in the season to match the presence of aphid fundatrix (sensitive stages). In this trial focusing on an organic apple orchard, three releases were done either every week or every two weeks to test the effect of the release frequency, during two consecutive years. The number of aphid colonies and aphid number per tree were monitored from late March to late May. Degree-days necessary for parasitoid emergence in the field after release were calculated. We show that a sufficient level of aphid control by parasitoids is reached during the first month of the survey, but control mostly fails during the second part of the monitoring session, for both release treatments, and compared to the neem oil control treatment. The relative effects of release frequencies were different between years probably because of interannual differences in aphid population dynamics and initial infestation in orchards. The field survey and the degree-day model suggest that parasitoid releases, at either frequency, are promising candidates for biological control of the rosy aphid, although the method still needs proper calibration. This conclusion needs to be reinforced by repeating the study in more orchards, but our case study lays the first empirical basis that will help to develop future control methods of aphids by parasitoid releases in apple orchards. We argue that releases should be done one to two weeks before first aphid detection to account for long development times of parasitoids at relatively low temperatures.
Algebraic theorem of selection by spatial sorting
Authors: Goel Nikunj
Published: September 2021

Heritable variation in traits that enhance dispersal rates can accumulate at population margins by spatial sorting. This mechanism of selection differs from natural selection as evolutionary change can ensue even in the absence of differential lifetime reproductive success. Although evidence suggests that populations are rapidly evolving at margins due to global change pressures, such as invasions and range shifts, we lack a mathematical theory of spatial sorting to understand these evolutionary patterns. To this end, we present an algebraic theorem, or the sorting theorem, to elucidate the nature of selection at margins, which can, in turn, facilitate axiomatic development of spatial sorting theory. The role of the sorting theorem in guiding research in this context is analogous to that of Price's theorem in natural selection theory.
WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma
Authors: Mitchell Kelly , Shakya Sajina , Arora Sonali , Sprowls Samuel A. , Silver Daniel J. , Goins Christopher M. , Wallace Lisa , Roversi Gustavo , Schafer Rachel , Kay Kristen , Miller Tyler E. , Lauko Adam , Bassett John , Kashyap Anjali , D’Amato Kass J. , Mulkearns-Hubert Erin E. , Johnson Sadie , Alvarado Joseph , Rich Jeremy N. , Paddison Patrick J. , Patel Anoop P. , Stauffer Shaun R. , Hubert Christopher G. , Lathia Justin D.
Published: September 2021

Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1-family-mediated Lys4 methylation of histone H3, associated with positive regulation of transcription. In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment diminished reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSCin vitrogrowth and self-renewal as well asin vivotumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.

Significance

In this study, we perform an epigenetic-focused functional genomics screen in glioblastoma organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche.

Graphical Abstract
Interferon induction and not replication interference mainly determines anti-influenza virus activity of defective interfering particles
Authors: Arora Prerna , Bdeir Najat , Gärtner Sabine , Reiter Stefanie , Pelz Lars , Felgenhauer Ulrike , Reichl Udo , Ludwig Stephan , Weber Friedemann , Hoffmann Markus , Winkler Michael , Pöhlmann Stefan
Published: September 2021

Defective interfering (DI) RNAs arise during influenza virus replication, can be packaged into particles (DIPs) and suppress spread of wildtype (WT) virus. However, the molecular signatures of DI RNAs and the mechanism underlying antiviral activity are incompletely understood. Here, we show that any central deletion is sufficient to convert a viral RNA into a DI RNA and that antiviral activity of DIPs is inversely correlated with DI RNA length when induction of the interferon (IFN) system is disfavored. When induction of the IFN system was allowed, it was found to be the major contributor to DIP antiviral activity. Finally, while both DIPs and influenza virus triggered expression of IFN-stimulated genes (ISG) only virus stimulated robust expression of IFN. These results suggest a key role of innate immune activation in DIP antiviral activity and point towards previously unappreciated differences in DIP- and influenza virus-mediated activation of the effector functions of the IFN system.

Importance

Defective interfering (DI) RNAs naturally arise during RNA virus infection. They can be packaged into defective interfering particles (DIPs) and exert antiviral activity by suppressing viral genome replication and inducing the interferon (IFN) system. However, inhibition of influenza virus infection by DI RNAs has been incompletely understood. Here, we show that induction of the IFN system and not suppression of genome replication is the major determinant of DIP antiviral activity. Moreover, we demonstrate that DIPs induce IFN-stimulated genes (ISG) but not IFN with high efficiency. Our results reveal unexpected major differences in influenza virus and DIP activation of the IFN system, a key barrier against viral infection, and provide insights into how to design DIPs for antiviral therapy.
Successive pandemic waves with more virulent strains, and the effects of vaccination for SARS-CoV-2
Authors: Castro-e-Silva Alcides , Bernardes Américo T , Gonçalves Barbosa Eduardo Augusto , Dáttilo Wesley , Ribeiro Sérvio P.
Published: September 2021

Hundred years after the flu pandemic of 1918, the world faces an outbreak of a new severe acute respiratory syndrome, caused by a novel coronavirus. With a high transmissibility, the pandemic spreads worldwide, creating a scenario of devastation in many countries. By the middle of 2021, about 3% of the world population has been infected and more than 4 million people have died. Different from the H1N1 pandemic, which had a deadly wave and cessed, the new disease is maintained by successive waves, mainly produced by new virus variants, and the small number of vaccinated people. In the present work, we create a version of the SIR model with spatial localization of persons, their movements, and taking into account social isolation probabilities. We discuss the effects of virus variants, and the role of vaccination rate in the pandemic dynamics. We show that, unless a global vaccination is implemented, we will have continuous waves of infections.

Highlights

The COVID-19 has infected more than 200 millions and has killed more than 4 million persons.

WHO has not been successful in defining a global vaccination policy.

Many epidemic scenarios arise when different countries apply different vaccination strategies.

Present model can show some insights on how vaccination programs can be managed.
Protective Transfer: Maternal passive immunization with a rotavirus-neutralizing dimeric IgA protects against rotavirus disease in suckling neonates
Authors: Langel SN , Steppe JT , Chang J , Travieso T , Webster H , Otero CE , Williamson LE , Crowe JE , Greenberg HB , Wu H , Hornik C , Mansouri K , Edwards RJ , Stalls V , Acharya P , Blasi M , Permar SR
Published: September 2021

Breast milk secretory IgA antibodies provide a first line of defense against enteric infections. Despite this and an effective vaccine, human rotaviruses (RVs) remain the leading cause of severe infectious diarrhea in children in low- and middle-income countries (LMIC) where vaccine efficacy is lower than that of developed nations. Therapeutic strategies that deliver potently neutralizing antibodies into milk could provide protection against enteric pathogens such as RVs. We developed a murine model of maternal protective-transfer using systemic administration of a dimeric IgA (dIgA) monoclonal antibody. We confirmed that systemically-administered dIgA passively transferred into milk and stomach of suckling pups in a dose-dependent manner. We then demonstrated that systemic administration of an engineered potent RV-neutralizing dIgA (mAb41) in lactating dams protected suckling pups from RV-induced diarrhea. This maternal protective-transfer immunization platform could be an effective strategy to improve infant mortality against enteric infections, particularly in LMIC with high rates of breastfeeding.

GRAPHICAL ABSTRACT
Multi-modal profiling of the extracellular matrix of human fallopian tubes and serous tubal Intraepithelial carcinomas
Authors: Renner Carine , Gomez Clarissa , Visetsouk Mike R , Taha Isra , Khan Aisha , McGregor Stephanie , Weisman Paul , Naba Alexandra , Masters Kristyn S , Kreeger Pamela K
Published: September 2021

Recent evidence supports the fimbriae of the fallopian tube as a potential origin site for high-grade serous ovarian cancer (HGSOC). The progression of many solid tumors is accompanied by changes in the microenvironment, including alterations of the extracellular matrix (ECM). The ECM of fallopian tube and HGSOC has not been well characterized. Therefore, we sought to determine the ECM composition of the benign fallopian tube and how it changes with the onset of serous intraepithelial carcinomas (STICs), precursor of HGSOC. The ECM composition of benign human fallopian tube was first defined from a meta-analysis of published proteomic datasets and identified 190 ECM proteins. We then conducted de novo proteomics using ECM enrichment and identified 88 proteins, 7 of which were not identified in prior studies. We further investigated the levels and localization of seven of these ECM proteins (type I, III, and IV collagens, fibronectin, laminin, versican, perlecan) and hyaluronic acid using multi-spectral immunohistochemical staining of fimbriae from patients with benign conditions or STICs. Quantification revealed an increase in stromal fibronectin and a decrease in epithelial versican in STICs. Our results provide an in-depth picture of the ECM in the benign fallopian tube and identified ECM changes that accompany STIC formation.
Functional Analysis of the Expanded Phosphodiesterase Gene Family in Toxoplasma gondii Tachyzoites
Authors: Moss William J. , Patterson Caitlyn E. , Jochmans Alexander K. , Brown Kevin M.
Published: September 2021

Toxoplasma motility is both activated and suppressed by 3’-5’ cyclic nucleotide signaling. Cyclic GMP (cGMP) signaling through TgPKG activates motility, whereas cyclic AMP (cAMP) signaling through TgPKAc1 inhibits motility. Despite their importance, it remains unclear how cGMP and cAMP levels are maintained in Toxoplasma. Phosphodiesterases (PDEs) are known to inactivate cyclic nucleotides and are highly expanded in the Toxoplasma genome. Here we analyzed the expression and function of the 18-member TgPDE family in tachyzoites, the virulent life-stage of Toxoplasma. We detected the expression of 11 of 18 TgPDEs, confirming prior expression studies. A knockdown screen of the TgPDE family revealed four TgPDEs that contribute to lytic Toxoplasma growth (TgPDE1, TgPDE2, TgPDE5, and TgPDE9). Depletion of TgPDE1 or TgPDE2 caused severe growth defects, prompting further investigation. While TgPDE1 was important for extracellular motility, TgPDE2 was important for host cell invasion, parasite replication, host cell egress, and extracellular motility. TgPDE1 displayed a plasma membrane/cytomembranous distribution, whereas TgPDE2 displayed an endoplasmic reticulum/cytomembranous distribution. Biochemical analysis of TgPDE1 and TgPDE2 purified from Toxoplasma lysates revealed that TgPDE1 hydrolyzes both cGMP and cAMP, whereas TgPDE2 was cAMP-specific. Interactome studies of TgPDE1 and TgPDE2 indicated that they do not physically interact with each other or other TgPDEs but may be regulated by kinases and proteases. Our studies have identified TgPDE1 and TgPDE2 as central regulators of tachyzoite cyclic nucleotide levels and enable future studies aimed at determining how these enzymes are regulated and cooperate to control Toxoplasma motility and growth.

Importance

Apicomplexan parasites require motility to actively infect host cells and cause disease. Cyclic nucleotide signaling governs apicomplexan motility, but it is unclear how cyclic nucleotide levels are maintained in these parasites. In search of novel regulators of cyclic nucleotides in the model apicomplexan Toxoplasma, we identified and characterized two catalytically active phosphodiesterases, TgPDE1 and TgPDE2, that are important for Toxoplasma’s virulent tachyzoite lifecycle. Enzymes that generate, sense, or degrade cyclic nucleotides make attractive targets for therapies aimed at paralyzing and killing apicomplexan parasites.
Carbapenem-Resistant Acinetobacter baumannii in US hospitals: diversification of circulating lineages and antimicrobial resistance
Authors: Iovleva Alina , Mustapha Mustapha M. , Griffith Marissa P. , Komarow Lauren , Luterbach Courtney , Evans Daniel R , Cober Eric , Richter Sandra S. , Rydell Kirsten , Arias Cesar A. , Jacob Jesse T. , Salata Robert A. , Satlin Michael J. , Wong Darren , Bonomo Robert A. , van Duin David , Cooper Vaughn S. , Van Tyne Daria , Doi Yohei
Published: September 2021

Carbapenem-resistant Acinetobacter baumannii (CRAb) are a major cause of healthcare-associated infections. CRAb are typically multidrug-resistant and infection is difficult to treat. Despite the urgent threat that CRAb pose, few systematic studies of CRAb clinical and molecular epidemiology have been conducted. The Study Network of Acinetobacter as a Carbapenem-Resistant Pathogen (SNAP) is designed to investigate the clinical characteristics and contemporary population structure of CRAb circulating in US hospital systems using whole genome sequencing (WGS). Analysis of the initial 120 SNAP patients from four US centers revealed that CRAb remain a significant threat to hospitalized patients, affecting the most vulnerable patients and resulting in 24% all-cause 30-day mortality. The majority of currently circulating isolates belonged to ST2Pas, a part of Clonal Complex 2 (CC2), which is the dominant drug-resistant lineage in the United States and Europe. We identified three distinct sub-lineages within CC2, which differed in their antibiotic resistance phenotypes and geographic distribution. Most concerning, colistin resistance (38%) and cefiderocol (10%) resistance were common within CC2 sub-lineage C (CC2C), where the majority of isolates belonged to ST2Pas/ST281Ox. Additionally, we identified a newly emergent lineage, ST499Pas that was the most common non-CC2 lineage in our study and had a more favorable drug susceptibility profile compared to CC2. Our findings suggest a shift within the CRAb population in the US during the past 10 years, and emphasize the importance of real-time surveillance and molecular epidemiology in studying CRAb dissemination and clinical impact.

Importance

Carbapenem-resistant Acinetobacter baumannii (CRAb) constitute a major threat to public health. To elucidate the molecular and clinical epidemiology of CRAb in the US, clinical CRAb isolates were collected along with data on patient characteristics and outcomes and bacterial isolates underwent whole genome sequencing and antibiotic susceptibility phenotyping. Key findings included emergence of new sub-lineages within the globally predominant clonal complex (CC) 2, increased colistin and cefiderocol resistance within one of the CC2 sub-lineages, and the emergence of ST499Pas as a previously unrecognized CRAb lineage in US hospitals.
Nationally Representative Social Contact Patterns among U.S. adults, August 2020-April 2021
Authors: Nelson Kristin N. , Siegler Aaron J , Sullivan Patrick S , Bradley Heather , Hall Eric , Luisi Nicole , Hipp-Ramsey Palmer , Sanchez Travis , Shioda Kayoko , Lopman Benjamin A
Published: September 2021

The response to the COVID-19 pandemic in the U.S prompted abrupt and dramatic changes to social contact patterns. Monitoring changing social behavior is essential to provide reliable input data for mechanistic models of infectious disease, which have been increasingly used to support public health policy to mitigate the impacts of the pandemic. While some studies have reported on changing contact patterns throughout the pandemic., few have reported on differences in contact patterns among key demographic groups and none have reported nationally representative estimates. We conducted a national probability survey of US households and collected information on social contact patterns during two time periods: August-December 2020 (before widespread vaccine availability) and March-April 2021 (during national vaccine rollout). Overall, contact rates in Spring 2021 were similar to those in Fall 2020, with most contacts reported at work. Persons identifying as non-White, non-Black, non-Asian, and non-Hispanic reported high numbers of contacts relative to other racial and ethnic groups. Contact rates were highest in those reporting occupations in retail, hospitality and food service, and transportation. Those testing positive for SARS-CoV-2 antibodies reported a higher number of daily contacts than those who were seronegative. Our findings provide evidence for differences in social behavior among demographic groups, highlighting the profound disparities that have become the hallmark of the COVID-19 pandemic.
Experimental reproducibility limits the correlation between mRNA and protein abundances in tumour proteomic profiles
Authors: Upadhya Swathi Ramachandra , Ryan Colm J.
Published: September 2021

Large-scale studies of human proteomes have revealed only a moderate correlation between mRNA and protein abundances. It is unclear to what extent this moderate correlation reflects post-transcriptional regulation and to what extent it reflects measurement error. Here, by analysing replicate profiles of tumours and cell lines, we show that there is considerable variation in the reproducibility of measurements of transcripts and proteins from individual genes. Proteins with more reproducible measurements tend to have higher mRNA-protein correlation, suggesting that measurement reproducibility accounts for a substantial fraction of the unexplained variation between mRNA and protein abundances. The reproducibility of individual proteins is somewhat consistent across studies and we exploit this to develop an aggregate reproducibility score that explains a substantial amount of the variation in mRNA-protein correlation across multiple studies. Finally, we show that pathways previously reported to have higher-than-average mRNA-protein correlation may simply contain members that can be more reproducibly quantified.
A science friction story – Molecular interactions in semiflexible polymer networks
Authors: Mollenkopf Paul , Prascevic Dusan , Glaser Martin , Smith David M. , Schnauß Jörg
Published: September 2021

Established model theories, developed to capture the mechanical behavior of soft complex materials composed of semiflexible polymers assume entropic interactions between filaments to determine the mechanical response. In recent studies, the general accepted tube model has been challenged in terms of its basic assumption about filament-filament interactions, but also because of its predictions regarding the frequency dependence of the elastic modulus in the intermediate frequency regime. A central question is how molecular interactions and friction between network constituents influence the rheological response of isotropic entangled networks of semiflexible polymers. It was shown that friction forces between aligned pairs of actin filaments are not negligible. Here, we systematically investigate the influence of friction forces and attractive interactions on network rheology by means of a targeted surface modification. We show that these forces have a qualitative and quantitative influence on the viscoelastic properties of semiflexible polymer networks and contribute to the response to nonlinear deformations. By comparing two polymer model systems with respect to their surface compositions we give a possible explanation about the origin of acting forces on a molecular level.
Hsp40 Affinity to Identify Proteins Destabilized by Cellular Toxicant Exposure
Authors: Quanrud Guy M. , Montoya Maureen R. , Mei Liangyong , Awad Mohammad R. , Genereux Joseph C.
Published: September 2021

Environmental toxins and toxicants can damage proteins and threaten cellular proteostasis. Most current methodologies to identify misfolded proteins in cells survey the entire proteome for sites of changed reactivity. We describe and apply a quantitative proteomics methodology to identify destabilized proteins based on their binding to the human Hsp40 chaperone DNAJB8. These protein targets are validated by an orthogonal limited proteolysis assay using parallel reaction monitoring. We find that brief exposure of HEK293T cells to meta-arsenite increases the affinity of two dozen proteins to DNAJB8, including known arsenite-sensitive proteins. In particular, arsenite treatment destabilizes both the pyruvate dehydrogenase complex E1 subunit and several RNA-binding proteins. This platform can be used to explore how environmental toxins impact cellular proteostasis, and to identify the susceptible proteome.