bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep learning identifies erroneous microarray-based, gene-level conclusions in literature
Authors: Qin Yanan , Yi Daiyao , Chen Xianghao , Guan Yuanfang
Published: October 2021

More than 110 000 publications have used microarrays to decipher phenotype-associated genes, clinical biomarkers and gene functions. Microarrays rely on digital assaying the fluorescence signals of arrays. In this study, we retrospectively constructed raw images for 37 724 published microarray data, and developed deep learning algorithms to automatically detect systematic defects. We report that an alarming amount of 26.73% of the microarray-based studies are affected by serious imaging defects. By literature mining, we found that publications associated with these affected microarrays have reported disproportionately more biological discoveries on the genes in the contaminated areas compared to other genes. 28.82% of the gene-level conclusions reported in these publications were based on measurements falling into the contaminated area, indicating severe, systematic problems caused by such contaminations. We provided the identified published, problematic datasets, affected genes and the imputed arrays as well as software tools for scanning such contamination that will become essential to future studies to scrutinize and critically analyze microarray data.
Acceptability, Usability, and Performance of Lateral Flow Immunoassay Tests for Severe Acute Respiratory Syndrome Coronavirus 2 Antibodies: REACT-2 Study of Self-Testing in Nonhealthcare Key Workers
Authors: Davies Bethan , Araghi Marzieh , Moshe Maya , Gao He , Bennet Kimberly , Jenkins Jordan , Atchison Christina , Darzi Ara , Ashby Deborah , Riley Steven , Barclay Wendy , Elliott Paul , Ward Helen , Cooke Graham
Published: October 2021

Background

Seroprevalence studies are essential to understand the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Various technologies, including laboratory assays and point-of-care self-tests, are available for antibody testing. The interpretation of seroprevalence studies requires comparative data on the performance of antibody tests.

Methods

In June 2020, current and former members of the United Kingdom police forces and fire service performed a self-test lateral flow immunoassay (LFIA), had a nurse-performed LFIA, and provided a venous blood sample for enzyme-linked immunosorbent assay (ELISA). We present the prevalence of antibodies to SARS-CoV-2 and the acceptability and usability of self-test LFIAs, and we determine the sensitivity and specificity of LFIAs compared with laboratory ELISA.

Results

In this cohort of 5189 current and former members of the police service and 263 members of the fire service, 7.4% (396 of 5348; 95% confidence interval [CI], 6.7–8.1) were antibody positive. Seroprevalence was 8.9% (95% CI, 6.9–11.4) in those under 40 years, 11.5% (95% CI, 8.8–15.0) in those of nonwhite ethnicity, and 7.8% (95% CI, 7.1–8.7) in those currently working. Self-test LFIA had an acceptability of 97.7% and a usability of 90.0%. There was substantial agreement between within-participant LFIA results (kappa 0.80; 95% CI, 0.77–0.83). The LFIAs had a similar performance: compared with ELISA, sensitivity was 82.1% (95% CI, 77.7–86.0) self-test and 76.4% (95% CI, 71.9–80.5) nurse-performed with specificity of 97.8% (95% CI, 97.3–98.2) and 98.5% (95% CI, 98.1–98.8), respectively.

Conclusions

A greater proportion of this nonhealthcare key worker cohort showed evidence of previous infection with SARS-CoV-2 than the general population at 6.0% (95% CI, 5.8–6.1) after the first wave in England. The high acceptability and usability reported by participants and similar performance of self-test and nurse-performed LFIAs indicate that the self-test LFIA is fit for purpose for home testing in occupational and community prevalence studies.
Evaluation of the anti-biofilm activities of bacterial cellulose-tannic acid-magnesium chloride composites using an in vitro multispecies biofilm model
Authors: He Wei , Zhang Zhaoyu , Chen Jing , Zheng Yudong , Xie Yajie , Liu Wenbo , Wu Jian , Mosselhy Dina A
Published: October 2021

Chronic wounds are a serious worldwide problem, which are often accompanied by wound infections. In this study, bacterial cellulose (BC)-based composites introduced with tannic acid (TA) and magnesium chloride (BC-TA-Mg) were fabricated for anti-biofilm activities. The prepared composites’ surface properties, mechanical capacity, thermal stability, water absorption and retention property, releasing behavior, anti-biofilm activities and potential cytotoxicity were tested. Results showed that TA and MgCl2 particles closely adhered to the nanofibers of BC membranes, thus increasing surface roughness and hydrophobicity of the membranes. While the introduction of TA and MgCl2 did not influence the transparency of the membranes, making it beneficial for wound inspection. BC-TA and BC-TA-Mg composites displayed increased tensile strength and elongation at break compared to pure BC. Moreover, BC-TA-Mg exhibited higher water absorption and retention capacity than BC and BC-TA, suitable for the absorption of wound exudates. BC-TA-Mg demonstrated controlled release of TA and good inhibitory effect on both singly cultured Staphylococcus aureus and Pseudomonas aeruginosa biofilm and co-cultured biofilm of S. aureus and P. aeruginosa. Furthermore, the cytotoxicity grade of BC-TA-6Mg membrane was eligible based on standard toxicity classifications. These indicated that BC-TA-Mg is potential to be used as wound dressings combating biofilms in chronic wounds.
‘Everyone seems to be agreeing at the minute that face-to-face is the way forward’: practitioners’ perspectives on post-pandemic mathematics and statistics support
Authors: Gilbert Holly , Hodds Mark , Lawson Duncan
Published: October 2021

Mathematics and statistics support (MSS) is now firmly embedded in the learning and teaching infra-structure of most UK universities and in many universities worldwide. In common with other higher education activities, in response to restrictions put in place to reduce the spread of Covid-19, MSS transitioned rapidly to online delivery in spring 2020. This paper reports on thinking within the practitioner community about good practice in the delivery of online MSS. A two-phase approach was used to collect this shared wisdom: an initial questionnaire in May 2020 (just after provision had moved online) and interviews with practitioners in January/February 2021 after colleagues had some experience in online provision and had had the opportunity to reflect on and modify the measures hastily put in place in spring 2020. The focus of the study is not only on what is currently being provided but also on what MSS will look like once all pandemic related restrictions have been ended. The overall feeling of the participants is that face-to-face MSS will return as the dominant form of delivery but that the benefits of online provision are such that a significant minority of provision will remain in this form.
Modelling
gambiense
human African trypanosomiasis infection in villages of the Democratic Republic of Congo using Kolmogorov forward equations
Authors: Davis Christopher N. , Keeling Matt J. , Rock Kat S.
Published: October 2021

Stochastic methods for modelling disease dynamics enable the direct computation of the probability of elimination of transmission. For the low-prevalence disease of human African trypanosomiasis (gHAT), we develop a new mechanistic model for gHAT infection that determines the full probability distribution of the gHAT infection using Kolmogorov forward equations. The methodology allows the analytical investigation of the probabilities of gHAT elimination in the spatially connected villages of different prevalence health zones of the Democratic Republic of Congo, and captures the uncertainty using exact methods. Our method provides a more realistic approach to scaling the probability of elimination of infection between single villages and much larger regions, and provides results comparable to established models without the requirement of detailed infection structure. The novel flexibility allows the interventions in the model to be implemented specific to each village, and this introduces the framework to consider the possible future strategies of test-and-treat or direct treatment of individuals living in villages where cases have been found, using a new drug.
Genomic surveillance of invasive Streptococcus pneumoniae isolates in the period pre-PCV10 and post-PCV10 introduction in Brazil
Authors: Almeida Samanta C. G. , Lo Stephanie W. , Hawkins Paulina A. , Gladstone Rebecca A. , Cassiolato Ana Paula , Klugman Keith P. , Breiman Robert F. , Bentley Stephen D. , McGee Lesley , Brandileone Maria-Cristina de C.
Published: October 2021

In 2010, Brazil introduced the 10-valent pneumococcal conjugate vaccine (PCV10) into the national children’s immunization programme. This study describes the genetic characteristics of invasive

Streptococcus pneumoniae

isolates before and after PCV10 introduction. A subset of 466 [pre-PCV10 (2008–2009): n=232, post-PCV10 (2012–2013): n=234;<5 years old: n=310, ≥5 years old: n=156] pneumococcal isolates, collected through national laboratory surveillance, were whole-genome sequenced (WGS) to determine serotype, pilus locus, antimicrobial resistance and genetic lineages. Following PCV10 introduction, in the <5 years age group, non-vaccine serotypes (NVT) serotype 3 and serotype 19A were the most frequent, and serotypes 12F, 8 and 9 N in the ≥5 years old group. The study identified 65 Global Pneumococcal Sequence Clusters (GPSCs): 49 (88 %) were GPSCs previously described and 16 (12 %) were Brazilian clusters. In total, 36 GPSCs (55 %) were NVT lineages, 18 (28 %) vaccine serotypes (VT) and 11 (17 %) were both VT and NVT lineages. In both sampling periods, the most frequent lineage was GPSC6 (CC156, serotypes 14/9V). In the <5 years old group, a decrease in penicillin (P=0.0123) and cotrimoxazole (P<0.0001) resistance and an increase in tetracycline (P=0.019) were observed. Penicillin nonsusceptibility was predicted in 40 % of the isolates; 127 PBP combinations were identified (51 predicted MIC≥0.125 mg l−1); cotrimoxazole (folA and/or folP alterations), macrolide (mef and/or ermB) and tetracycline (tetM, tetO or tetS/M) resistance were predicted in 63, 13 and 21.6 % of pneumococci studied, respectively. The main lineages associated with multidrug resistance in the post-PCV10 period were composed of NVT, GPSC1 (CC320, serotype 19A), and GPSC47 (ST386, serotype 6C). The study provides a baseline for future comparisons and identified important NVT lineages in the post-PCV10 period in Brazil.
Circadian regulation of the transcriptome in a complex polyploid crop
Authors: Rees Hannah , Rusholme-Pilcher Rachel , Bailey Paul , Colmer Joshua , White Benjamen , Reynolds Connor , Ward Sabrina Jaye , Graham Calum A. , Dantas Luíza Lane de Barros , Dodd Antony N. , Hall Anthony
Published: October 2021

The circadian clock is a finely balanced time-keeping mechanism that coordinates programmes of gene expression. It is currently unknown how the clock regulates expression of homoeologous genes in polyploids. Here, we generate a high-resolution time-course dataset to investigate the circadian balance between sets of three homoeologous genes (triads) from hexaploid bread wheat. We find a large proportion of circadian triads exhibit imbalanced rhythmic expression patterns, with no specific sub-genome favoured. In wheat, period lengths of rhythmic transcripts are found to be longer and have a higher level of variance than in other plant species. Expression of transcripts associated with circadian controlled biological processes are largely conserved between wheat and Arabidopsis, however striking differences are seen in agriculturally critical processes such as starch metabolism. Together, this work highlights the ongoing selection for balance versus diversification in circadian homoeologs, and identifies clock-controlled pathways that might provide important targets for future wheat breeding.
An exploratory analysis of 4844 withdrawn articles and their retraction notes
Authors: Toma Catalin , Padureanu Liliana
Published: October 2021

The objective of our study was to obtain an updated image of the dynamic of retractions and retraction notes, retraction reasons for questionable research and publication practices, countries producing retracted articles, and the scientific impact of retractions by studying 4844 PubMed indexed retracted articles published between 2009 and 2020 and their retraction notes.

RESULTS

Mistakes/inconsistent data account for 32% of total retractions, followed by images(22,5%), plagiarism(13,7%) and overlap(11,5%).

Thirty countries account for 94,79% of 4844 retractions. Top five are: China(32,78%), United States(18,84%), India(7,25%), Japan(4,37%) and Italy(3,75%).

The total citations number for all articles is 140810(Google Scholar), 96000(Dimensions).

Average exposure time(ET) is 28,89 months. Largest ET is for image retractions(49,3 months), lowest ET is for editorial errors(11,2 months).

The impact of retracted research is higher for Spain, Sweden, United Kingdom, United States, and other nine countries and lower for Pakistan, Turkey, Malaysia, and other six countries, including China.

CONCLUSIONS

Mistakes and data inconsistencies represent the main retraction reason; images and ethical issues show a growing trend, while plagiarism and overlap still represent a significant problem. There is a steady increase in QRP and QPP article withdrawals. Retraction of articles seems to be a technology-dependent process.

The number of citations of retracted articles shows a high impact of papers published by authors from certain countries. The number of retracted articles per country does not always accurately reflect the scientific impact of QRP/QPP articles.

The country distribution of retraction reasons shows structural problems in the organization and quality control of scientific research, which have different images depending on geographical location, economic development, and cultural model.
Frequency of surveillance testing necessary to reduce transmission of the Delta variant of SARS-CoV-2
Authors: Elbanna Ahmed , Goldenfeld Nigel
Published: October 2021

We estimate the reduction in transmission of SARS-CoV-2 achievable by surveillance testing of a susceptible population at different frequencies, comparing the cases of both the original Wuhan strain and the Delta variant. We estimate the viral dynamics using viral copy number at first detection combined with considerations arising from aerosol transmission. We take into account the recent findings that infected vaccinated adults may have live viral loads at the same level as infected unvaccinated adults. Our estimates suggest that twice weekly testing, which was adequate for the original strains of SARS-CoV-2 will be insufficient on its own to contain the spread of the Delta variant of concern. We exclude consideration of contact tracing since the rapidity of the onset of viral titre in the case of the Delta variant suggests that unless contact tracing and quarantine are performed very rapidly (ie. much less than a day), these mitigations will be of minimal impact in reducing transmission. These crude estimates do not take into account heterogeneity of susceptibility, social activity, and compliance, nor do they include the additional reduction in transmission that could be achieved by masking and social distancing. In the setting of a large public university, these considerations suggest that risk-targeted testing of vaccinated students, staff and faculty combined with surveillance testing of all unvaccinated individuals is the most efficient way to reduce transmission of COVID-19.
COVID-19 data reporting systems in Africa reveal insights for pandemic preparedness
Authors: Judson Seth D , Torimiro Judith , Pigott David M , Maima Apollo , Mostafa Ahmed , Samy Ahmed , Rabinowitz Peter , Njabo Kevin
Published: October 2021

Background: Throughout the coronavirus disease 2019 (COVID-19) pandemic, there have been a variety of practices for international reporting of COVID-19 data. African countries have used different national reporting systems to publicly share data. Analyzing the content, format, and frequency of these systems could elucidate lessons for future pandemics.
Methods: We examined national COVID-19 reporting practices across 54 African countries through 2020. Reporting systems were compared by type of report, frequency, and data content. We also compared reporting of metrics such as a patient demographics and co-morbidities, healthcare capacity, and diagnostic testing. We further evaluated regional and country-specific reporting practices in Cameroon, Egypt, Kenya, Senegal, and South Africa as examples from different sub-regions.
Results: National COVID-19 reporting systems were identified in 53/54 (98.1%) countries in 2020. Reporting systems were diverse and could be categorized into social media postings, websites, press releases, situation reports, and online dashboards. Of countries with reporting systems, 36/53 (67.9%) had recurrent situation reports and/or online dashboards which provided the highest quality of data.
Conclusions: African countries created diverse reporting systems to share COVID-19 data. Many countries used routinely updated situation reports or online dashboards. However, few countries reported patient demographics, co-morbidities, diagnostic testing practices, and healthcare capacity. Including these metrics as well as improving standardization and accessibility of data reporting systems could augment research and decision-making, as well as increase public awareness and transparency for national governments.
ALBUMIN CREATININE RATIO AS AN INDICATOR OF NON-HEALING FOOT WOUND FORMATION IN DIABETES
Authors: Greenidge André , Quimby Kim R , Speede Amy P , Hambleton Ian R , Anderson Simon G , Landis Robert Clive
Published: October 2021

Aims: To investigate whether kidney injury, determined by albumin creatinine ratio, was associated with current non-healing foot wounds in type 2 diabetes.
Materials and Methods: Eighty–nine Barbadians with diabetes were recruited. Cases had a current foot wound and controls had no current foot wound and no history of a non-healing foot wound. Cases were matched to controls using sex, age and duration of diabetes. Participants were from wound dressing and diabetes clinics at the Queen Elizabeth Hospital and Polyclinics, and from private healthcare practitioners. The relationship between albumin creatinine ratio and foot ulceration, adjusting for selected potential risk factors, was analyzed using logistic regression and presented as odds ratios.
Results: Forty–four cases and 45 controls were matched, with no statistically significant difference in matching criteria. There were statistically important differences in measures of neuropathy, blood glucose, HbA1c and Albumin:creatinine ratio between cases and controls. Cases were 3 times more likely than controls to have microalbuminuria (95% CI 0.9 – 10.2; p=0.08). Cases were 7.4 times more likely than controls to have macroalbuminuria (95% CI 1.2 – 47.5; p=0.04).
Conclusions: The possible association of albumin:creatinine ratio with diabetic foot wounds raises the possibility of its use in earlier identification of persons on the pathway to developing diabetic foot.
In vitro Anti-Cancer Activity of Oliveria decumbens Vent. Extract, an Endemic Persian Medicinal Plant, on HT-29 Colorectal Cancer Cell Line
Authors: Khodavirdipour Amir , Haddadi Fatemeh , nejad Hamideh Rouhani , Shiri Yasoub , Tilak Veronica Preetha
Published: October 2021

Introduction

The top 3 causes of death worldwide include heart disease, injury, and cancer; and cancer records the 2nd place as the leading cause of death in the United States of America after cardiovascular diseases and injuries. Cancer can begin and progress in a very highly twisted and complex pattern and follow the multifactorial route. There is only very few research on medicinal properties Oliveria decumbens rare and valuable plant specially on cancer. So, in this study we tried to cover all needs for future in vivo research.

Methods

MTT assay has been performed to estimate the cytotoxicity of the ethanolic extract of the plant. Its free radical capacity evaluation was done by DPPH assay. Furthermore, real-time PCR, the wound-healing assay along with a DNA damage test to study DNA fragmentation characteristics. The plant’s transcriptomic study was performed by NGS de Novo assembly.

Result

Oliveria decumbens ethanolic extract showed an Ic50 of 14.39 μg/ml. The real-time PCR showed that Oliveria decumbens ethanolic extract significantly induced apoptosis by upregulating the bax gene and slight downregulation of bcl2 an anti-apoptosis gene. The NGS de Novo transcriptome analysis discovered 38 genes responsible for secondary metabolite synthesis so far. The remaining genes and reconstruction of the co-expression network of the transcriptome are underway.

Conclusion

The outcome of the Scratch-test and DNA fragmentation confirmed the anti-metastatic and DNA damage properties respectively. Based on these findings; Oliveria decumbens ethanolic extract shall be considered as potential anticancer and chemotherapeutic agents which may elucidate in upcoming studies.
CHD8 regulates gut epithelial cell function and affects autism-related behaviours through the gut-brain axis
Authors: Chatterjee Ipsita , Getselter Dimitry , Ghaneem Nasreen , Bel Shai , Elliott Evan
Published: October 2021

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by early onset deficits in social behavior and repetitive behavior. Chromodomain helicase DNA binding protein (CHD8) is one of the genes with the strongest association to autism. Alongside with the core symptoms of ASD, individuals with ASD are reported to have gastrointestinal (GI) problems, and a majority of individuals with CHD8 mutations display GI problems. However, the relationship between autism related genes, such as CHD8, gastrointestinal function, and autism related behaviours are yet very unclear. In the current study, we found that mice haploinsufficient for CHD8 have leaky gut, a dysregulated transcriptome in gut epithelial cells, decreased gut tuft cells and goblet cells, and an increase in microbial load. Specific deletion of CHD8 in gut epithelial cells induced an increase in anxiety-related behaviours in, a phenotype that is often observed in autism and full body knockdown of CHD8, in addition to decreased tuft cells. In addition, antibiotic treatment of CHD8 haploinsufficient mice attenuates sociability deficits. Therefore, the current study determines a pathway for autism-related GI deficits, and how these deficits may play a direct role in the development of autism-related behaviours.
Neural language processing across time, space, frequency and age: MEG-MVPA classification of intertrial phase coherence
Authors: Jensen Mads , Hyder Rasha , Westner Britta U. , Højlund Andreas , Shtyrov Yury
Published: October 2021

Language is a key part of human cognition. Whereas many neurocognitive abilities decline with age, for language the picture is much less clear and how exactly language processing changes with aging is still unknown. To investigate this, we employed magnetoencephalography (MEG) and recorded neuromagnetic brain responses to auditory linguistic stimuli in healthy participants of younger and older age using a passive task-free paradigm and a range of different linguistic stimulus contrasts, which enabled us to assess neural language processes at multiple levels (lexical, semantic, morphosyntactic). By using machine learning-based classification algorithms to scrutinise intertrial phase coherence of MEG responses in source space, we found significant differences between younger and older participants across several frequency bands and for all tested processing types, which shows multiple changes in the brain’s neurolinguistic circuits which may be due to both healthy aging in general and compensatory processes in particular.
Le Petit Prince: A multilingual fMRI corpus using ecological stimuli
Authors: Li Jixing , Bhattasali Shohini , Zhang Shulin , Franzluebbers Berta , Luh Wen-Ming , Spreng R. Nathan , Brennan Jonathan R. , Yang Yiming , Pallier Christophe , Hale John
Published: October 2021

Neuroimaging using more ecologically valid stimuli such as audiobooks has advanced our understanding of natural language comprehension in the brain. However, prior naturalistic stimuli have typically been restricted to a single language, which limited generalizability beyond small typological domains. Here we present theLe Petit PrincefMRI Corpus (LPPC–fMRI), a multilingual resource for research in the cognitive neuroscience of speech and language during naturalistic listening (Open-Neuro: ds003643). 49 English speakers, 35 Chinese speakers and 28 French speakers listened to the same audiobookThe Little Princein their native language while multi-echo functional magnetic resonance imaging was acquired. We also provide time-aligned speech annotation and word-by-word predictors obtained using natural language processing tools. The resulting timeseries data are shown to be of high quality with good temporal signal-to-noise ratio and high inter-subject correlation. Data-driven functional analyses provide further evidence of data quality. This annotated, multilingual fMRI dataset facilitates future re-analysis that addresses cross-linguistic commonalities and differences in the neural substrate of language processing on multiple perceptual and linguistic levels.
Why a Globally Fair COVID-19 Vaccination? An Analysis based on Agent-Based Simulation
Authors: Zia Kashif
Published: October 2021

In this paper, an Agent-Based Model (ABM) is proposed to evaluate the impact of COVID-19 vaccination drive in different settings. The main focus is to evaluate the counter-effectiveness of disparity in vaccination drive among different regions/countries. The model proposed is simple yet novel in the sense that it captures the spatial transmission-induced activity into consideration, through which we are able to relate the transmission model to the mutated variations of the virus. Some important what-if questions are asked in terms of the number of deaths, and time required and the percentage of the population needed to be vaccinated before the pandemic is eradicated. The simulation results have revealed that it is necessary to maintain a global (rather than regional or country-oriented) vaccination drive in case of a new pandemic or continual efforts against COVID-19.
Systematic discovery of mutation-directed neo-protein-protein interactions in cancer
Authors: Mo Xiulei , Niu Qiankun , Ivanov Andrey A. , Tsang Yiu Huen , Tang Cong , Shu Changfa , Wahafu Alafate , Doyle Sean P. , Cicka Danielle , Yang Xuan , Fan Dacheng , Reyna Matthew A. , Cooper Lee A.D. , Moreno Carlos S. , Zhou Wei , Owonikoko Taofeek , Lonial Sagar , Khuri Fadlo R. , Du Yuhong , Ramalingam Suresh S. , Mills Gordon B. , Fu Haian
Published: October 2021

Comprehensive sequencing of patient tumors reveals numerous genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative High Throughput differential Screening (qHT-dS) platform. Coupling of highly sensitive BRET biosensors with miniaturized co-expression in an ultra-HTS format allows large-scale monitoring of interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. Screening of 13,392 interactions with 1,474,560 data points revealed a landscape of gain-of-interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAFV600E-KEAP1 signaling axis and creating collateral vulnerability to NQO1 substrates, offering a combination therapeutic strategy. Thus, cancer genomic alterations can create neo-interactions, informing variant-directed therapeutic approaches for precision medicine.
AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE
Authors: Barclay William E. , Deerhake M. Elizabeth , Inoue Makoto , Nonaka Toshiaki , Nozaki Kengo , Luzum Nathan A. , Aggarwal Nupur , Miao Edward A. , Shinohara Mari L.
Published: October 2021

Inflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are such autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here we use multiple genetically modified mouse models to monitor activated inflammasomesin situbased on ASC oligomerization in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation was dependent on AIM2, but low IL-1β expression and no significant signs of cell death were found in astrocytes during EAE. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.

SIGNIFICANCE STATEMENT

Inflammasome activation in the peripheral immune system is pathogenic in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, inflammasome activity in the central nervous system (CNS) is largely unexplored. Here, we used genetically modified mice to determine inflammasome activation in the CNS during EAE. Our data indicated heightened AIM2 inflammasome activation in astrocytes after the disease peak. Unexpectedly, neither CNS-infiltrated myeloid cells nor microglia were the primary cells with activated inflammasomes in SC during EAE. Despite AIM2 inflammasome activation, astrocytes did not undergo apparent cell death and produced little of the proinflammatory cytokine, IL-1β, during EAE. This study showed that CNS inflammasome activation occurs during EAE without associating with IL-1β-mediated inflammation.
Immunometabolic hijacking of immune cells by a Pseudomonas aeruginosa quorum-sensing signal
Authors: Bandyopadhaya Arunava , Singh Vijay K , Chakraborty Arijit , Tzika A. Aria , Rahme Laurence G
Published: October 2021

Macrophages utilize metabolic pathways to generate energy and metabolites that may be vulnerable to pathogen hijacking to favor pathogen survival and persistence. It is unclear how bacterial pathogens alter metabolic pathways in immune cells for their benefit and persistence in the infected host. We have shown that the Pseudomonas aeruginosa quorum sensing (QS) signal molecule 2-aminoacetophenone (2-AA) allows pathogen persistence in host tissues by triggering host tolerization via histone deacetylase (HDAC)1-mediated epigenetic reprogramming. Here, we provide strong evidence that 2-AA-meditated persistence is linked to specific metabolic pathway alterations that reduce energy availability and biosynthetic macromolecules involved in host immune responses. 2-AA promotes a Warburg-like metabolic reprogramming effect, thereby increasing levels of lactate, which repressed inflammatory signaling in macrophages. Moreover, it interferes with pyruvate translocation to mitochondria, reducing mitochondrial (mt)-oxidative phosphorylation (OXPHOS) due to down-regulation of estrogen-regulated receptor (ERR)α and mitochondrial pyruvate carrier (MPC)-1. This metabolic reprogramming dampened energy production, reduced the acetyl-CoA pool, and generated an anti-inflammatory milieu that favors P. aeruginosa persistence. These findings provide evidence of first-in-class metabolic reprogramming in immune cells mediated by a QS signaling molecule. The specific metabolic programs affected provide insights that may guide the design and development of therapeutics and protective interventions against pathogen-induced immunometabolic alterations and persistence factors.
Polyvinyl Chloride Degradation by Intestinal Klebsiella of Pest larvae
Authors: Zhe Zhang , Peng Haoran , Yang Dongchen , Zhang Guoqing , Zhang Jinlin , Ju Feng
Published: October 2021

Microbial degradation of polyvinyl chloride (PVC) is eco-friendly and economically attractive but extremely challenging due to the lack of a molecular understanding of the degrading strains and enzymes. Motivated by the serendipitous discovery that the larva of an agricultural invasive insect pest, Spodoptera frugiperda, effectively survived PVC film alone, we profiled the intestinal microbiota of S. frugiperda larva and screened for PVC-degrading strains. Feeding on PVC film significantly changed the larval intestinal microbiota through selective enrichment of Enterococcus, Ochrobactrum, Falsochrobactrum, Microbaterium, Sphingobacterium and Klebsiella. From the larval intestine, we isolated the biofilm-forming Klebsiella sp. EMBL-1 and experimentally verified it as the first Klebsiella bacterium known to actively degrade and utilize PVC by various classic physicochemical and morphological analyses. We further used multiomic analyses, complementarily integrating genomic, transcriptomic, proteomic, and metabolomic insights, to identify enzyme-coding genes responsible for PVC degradation and proposed a biodegradation pathway for the bacterial strain. Overall, both S. frugiperda and strain EMBL-1 are first found to survive effectively on PVC film by using the polymer as the sole energy source. Moreover, this work exemplifying PVC biodegradation provides a reference for discovering more microbes and enzymatic resources for degrading other recalcitrant plastics.
Optimization of anastomotic technique and gastric conduit perfusion with hyperspectral imaging in an experimental model for minimally invasive esophagectomy
Authors: Nickel F. , Studier-Fischer A. , Özdemir B. , Odenthal J. , Müller L.R. , Knödler S. , Kowalewski K.F. , Camplisson I. , Allers M.M. , Dietrich M. , Schmidt K. , Salg G.A. , Kenngott H.G. , Billeter A.T. , Gockel I. , Sagiv C. , Hadar O.E. , Gildenblat J. , Ayala L. , Seidlitz S. , Maier-Hein L. , Müller-Stich B.P.
Published: October 2021

Objective

To optimize anastomotic technique and gastric conduit perfusion with hyperspectral imaging (HSI) for total minimally invasive esophagectomy (MIE) with linear stapled anastomosis.

Summary Background Data

Esophagectomy is the mainstay of esophageal cancer treatment but anastomotic insufficiency related morbidity and mortality remain challenging for patient outcome.

Methods

A live porcine model (n=50) for MIE was used with gastric conduit formation and linear stapled side-to-side esophagogastrostomy. Four main experimental groups differed in stapling length (3 vs. 6 cm) and anastomotic position on the conduit (cranial vs. caudal). Tissue oxygenation around the anastomotic site was evaluated using HSI and was validated with histopathology.

Results

The tissue oxygenation (ΔStO2) after the anastomosis remained constant only for the short stapler in caudal position (−0.4± 4.4%, n.s.) while it dropped markedly in the other groups (short-cranial: -15.6± 11.5%, p=0.0002; long-cranial: -20.4± 7.6%, p=0.0126; long-caudal: -16.1± 9.4%, p<0.0001) Tissue samples from deoxygenated stomach as measured by HSI showed correspondent eosinophilic pre-necrotic changes in 35.7± 9.7% of the surface area.

Conclusions

Tissue oxygenation at the anastomotic site of the gastric conduit during MIE is influenced by stapling technique. Optimal oxygenation was achieved with a short stapler (3 cm) and sufficient distance of the anastomosis to the cranial end of the gastric conduit. HSI tissue deoxygenation corresponded to histopathologic necrotic tissue changes. These findings allow for optimization of gastric conduit perfusion and anastomotic technique in MIE.

Level of Evidence

Not applicable. Translational animal science. Original article.
Proteome biology of primary colorectal carcinoma and corresponding liver metastases
Authors: Fahrner Matthias , Bronsert Peter , Fichtner-Feigl Stefan , Jud Andreas , Schilling Oliver
Published: October 2021

Colorectal adenocarcinomas (CRC) are one of the most commonly diagnosed tumors worldwide. Colorectal adenocarcinomas primarily metastasize into the liver and (less often) into the peritoneum. Patients suffering from CRC-liver metastasis (CRC-LM) typically present with a dismal overall survival compared to non-metastasized CRC patients. The metastasis process and metastasis-promoting factors in patients with CRC are under intensive debate. However, CRC studies investigating the proteome biology are lacking. Formalin-fixed paraffin-embedded (FFPE) tissue specimens provide a valuable resource for comprehensive proteomic studies of a broad variety of clinical malignancies. The presented pilot study compares the proteome of primary CRC and patient-matched CRC-LM. The applied protocol allows a reproducible and straightforward identification and quantification of over 2,600 proteins within the dissected tumorous tissue. Subsequent unsupervised clustering reveals distinct proteome biologies of the primary CRC and the corresponding CRC-LM. Statistical analysis yields multiple differentially abundant proteins in either primary CRC or their corresponding liver metastases. A more detailed analysis of dysregulated biological processes suggests an active immune response in the liver metastases, including several proteins of the complement system. Proteins with structural roles, e.g. cytoskeleton organization or cell junction assembly appear to be less prominent in liver metastases as compared to primary CRC. Immunohistochemistry corroborates proteomic high expression levels of metabolic proteins in CRC-LM. We further assessed how thein vitroinhibition of two in CRC-LM enriched metabolic proteins affected cell proliferation and chemosensitivity. The presented proteomic investigation in a small clinical cohort promotes a more comprehensive understanding of the distinct proteome biology of primary CRC and their corresponding liver metastases.
Signatures of vibration frequency tuning in human neocortex
Authors: Wang Lingyan , Yau Jeffrey M.
Published: October 2021

The spectral content of vibrations produced in the skin conveys essential information about textures and underlies sensing through hand-held tools. Humans can perceive and discriminate vibration frequency, yet the central representation of this fundamental feature is unknown. Using fMRI, we discovered that cortical responses are tuned for vibration frequency. Voxel tuning was biased in a manner that reflects perceptual sensitivity and the response profile of the Pacinian afferent system. These results imply the existence of tuned populations that may encode naturalistic vibrations according to their constituent spectra.
Lamina cribrosa vessel and collagen beam networks are distinct
Authors: Waxman Susannah , Brazile Bryn L. , Yang Bin , Gogola Alexandra L. , Hua Yi , Lam Po , Lee Po-Yi , Voorhees Andrew P. , Rizzo Joseph F. , Jakobs Tatjana C. , Sigal Ian A.
Published: October 2021

Our goal was to analyze the spatial interrelation between vascular and collagen networks in the lamina cribrosa (LC). Specifically, we quantified the percentages of collagen beams with/without vessels and of vessels inside/outside of collagen beams. To do this, the vasculature of six normal monkey eyes was labelled by perfusion post-mortem. After enucleation, coronal cryosections through the LC were imaged using fluorescence and polarized light microscopy to visualize the blood vessels and collagen beams, respectively. The images were registered to form 3D volumes. Beams and vessels were segmented, and their spatial interrelationship was quantified in 3D. We found that 22% of the beams contained a vessel (range 14% to 32%), and 21% of vessels were outside beams (13% to 36%). Stated differently, 78% of beams did not contain a vessel (68% to 86%), and 79% of vessels were inside a beam (64% to 87%). Individual monkeys differed significantly in the fraction of vessels outside beams (p<0.01 by linear mixed effect analysis), but not in the fraction of beams with vessels (p>0.05). There were no significant differences between contralateral eyes in the percent of beams with vessels and of vessels outside beams (p>0.05). Our results show that the vascular and collagenous networks of the LC in monkey are clearly distinct, and the historical notions that each LC beam contains a vessel and all vessels are within beams are inaccurate. We postulate that vessels outside beams may be relatively more vulnerable to mechanical compression by elevated IOP than are vessels shielded inside of beams.

Research highlights

- We combined fluorescence and polarized light microscopy to map in 3D the lamina cribrosa vessels and collagen beams of three pairs of monkey eyes

- Collagen beam and vessel networks of the lamina cribrosa have distinct topologies

- Over half of lamina cribrosa collagen beams did not contain a blood vessel

- One fifth of blood vessels in the lamina cribrosa were outside collagen beams

- Beams with/without vessels and vessels inside/outside beams may respond differently to IOP
Th2 single-cell heterogeneity and clonal interorgan distribution in helminth-infected mice
Authors: Radtke Daniel , Thuma Natalie , Kirchner Philipp , Ekici Arif B , Voehringer David
Published: October 2021

Th2 cells provide effector functions in type 2 immune responses to helminths and allergens. Despite knowledge about molecular mechanisms of Th2 cell differentiation, there is little information on Th2 cell heterogeneity and clonal distribution between organs. To address this, we performed combined single-cell transcriptome and TCR clonotype analysis on murine Th2 cells in mesenteric lymph nodes (MLN) and lung after infection withNippostrongylus brasiliensis(Nb) as a human hookworm infection model. We find organ-specific expression profiles, but also populations with conserved migration or effector/resident memory signatures that unexpectedly cluster with potentially regulatoryIl10posFoxp3negcells. A substantial MLN subpopulation with an interferon response signature suggests a role for interferon-signaling in Th2 differentiation or diversification. Further RNA-inferred developmental directions indicate proliferation as a hub for differentiation decisions. We also link long notedCxcr3expression in the Th2 compartment to a population ofIl4posNKT cells. Although the TCR repertoire is highly heterogeneous, we identified expanded clones and CDR3 motifs. Clonal relatedness between distant organs confirmed effective exchange of Th2 effector cells, although locally expanded clones dominated the response. These results provide new insights in Th2 cell subset diversity and clonal relatedness in distant organs.
F-Actin Bending Facilitates Net Actomyosin Contraction By Inhibiting Expansion With Plus-End-Located Myosin Motors
Authors: Tam Alexander K. Y. , Mogilner Alex , Oelz Dietmar B.
Published: October 2021

Contraction of actomyosin networks underpins important cellular processes including motility and division. The mechanical origin of actomyosin contraction is not fully-understood. We investigate whether contraction arises on the scale of individual filaments, without needing to invoke network-scale interactions. We derive discrete force-balance and continuum partial differential equations for two symmetric, semi-flexible actin filaments with an attached myosin motor. Assuming the system exists within a homogeneous background material, our method enables computation of the stress tensor, providing a measure of contractility. After deriving the model, we use a combination of asymptotic analysis and numerical solutions to show how F-actin bending facilitates contraction on the scale of two filaments. Rigid filaments exhibit polarity-reversal symmetry as the motor travels from the minus to plus-ends, such that contractile and expansive components cancel. Filament bending induces a geometric asymmetry that brings the filaments closer to parallel as a myosin motor approaches their plus-ends, decreasing the effective spring force opposing motor motion. The reduced spring force enables the motor to move faster close to filament plus-ends, which reduces expansive stress and gives rise to net contraction. Bending-induced geometric asymmetry provides both new understanding of actomyosin contraction mechanics, and a hypothesis that can be tested in experiments.
Stepwise progression of β-selection during T cell development as revealed by histone deacetylation inhibition
Authors: Chann Anchi S , Charnley Mirren , Newton Lucas M. , Newbold Andrea , Wiede Florian , Tiganis Tony , Humbert Patrick O , Johnstone Ricky W , Russell Sarah M
Published: October 2021

During T cell development, the first step in creating a unique T Cell Receptor (TCR) is the genetic recombination of the TCRβ chain. The quality of the newly recombined TCRβ is assessed at the β-selection checkpoint. Most cells fail this checkpoint and die, but the coordination of the complex events that control fate at the β-selection checkpoint is not yet understood. We shed new light on fate determination during β-selection using a selective inhibitor of histone deacetylase 6, ACY1215. ACY1215 disrupted the β-selection checkpoint. Characterising the basis for this disruption revealed a new, pivotal stage in β-selection, bookended by upregulation of the TCR co-receptors, CD28 and CD2 respectively. Within this ‘DN3bPre’stage, CD5 and Lef1 are upregulated to reflect pre-TCR signalling and their expression correlates with proliferation. During this phase, ACY1215-mediated disruption of the organisation of the β-selection immunological synapse is associated with a breakdown in connectivity of expression of pre-TCR, CD5 and Lef1. Subsequent deregulation of pre-TCR-induced proliferation leads to bypass of the β-selection checkpoint and subsequent failure to progress. We propose that the progressive expression of CD28, CD5 and Lef1, then CD2 reports and modulates the pre-TCR signal to orchestrate passage through the β-selection checkpoint. These findings suggest a refined model of β-selection in which a coordinated increase in expression of pre-TCR, CD28, CD5 and Lef1 allows for modulating TCR signalling strength, and culminates in the expression of CD2 to enable exit from the β-selection checkpoint.