bluuebunny/crossref_metadata_2025 huggingface dataset:
Climate change has affected the spillover risk of bat-borne pathogens
Authors: Van de Vuurst P , Qiao H , Soler-Tovar D , Escobar LE
Published: September 2022

Bat-borne viruses are a threat to global health and have in recent history had major impacts to human morbidity and mortality. Examples include diseases such as rabies, Ebola, SARS-Cov-1, and SARS-Cov-2 (COVID-19). Climate change could exacerbate the emergence of bat-borne pathogens by affecting the distribution and abundance of bats in tropical ecosystems. Here we report an assessment of historical climate and vampire bat occurrence data for the last century, which revealed a relationship between climatic variation and risk of disease spillover triggered by changes in bat distributions. This report represents one of the first examples of empirical evidence of global change effects on continental patterns of bat-borne pathogen transmission risk. We therefore recommend that more research is necessary on the impacts of climate change on bat-borne pathogen spillover risk, and that climate change impacts on bat-borne disease should be considered in global security initiatives.

Highlights

Bat-borne viruses are a threat to global health and include diseases such as rabies, Ebola, SARS-Cov-1, and SARS-Cov-2 (COVID-19).

Climate change could exacerbate the emergence of bat-borne pathogens by affecting the distribution and abundance of bats.

Here we report an assessment of historical climate and vampire-bat occurrence data for the last century, which reveals a relationship between climatic variation and risk of disease spillover triggered by changes in bat distributions.
Deregulations of miR-1 and its target Multiplexin promote dilated cardiomyopathy associated with myotonic dystrophy type 1
Authors: Souidi Anissa , Nakamori Masayuki , Zmojdzian Monika , Jagla Teresa , Renaud Yoan , Jagla Krzysztof
Published: September 2022

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy. It is caused by the excessive expansion of non-coding CTG repeat, which when transcribed affect functions of RNA-binding factors. Specifically, MBNL1 is sequestered in nuclear foci while CELF1 is stabilised, with adverse effects on alternative splicing, processing and stability of a large set of muscular and cardiac transcripts. Among these effects, inefficient processing and down-regulation of muscle- and heart-specific miRNA, miR-1, has been reported in DM1 patients, but the impact of reduced miR-1 on DM1 pathogenesis was unknown. Here, we used Drosophila DM1 models to explore miR-1 involvement in cardiac dysfunction in DM1. We found that miR-1 down-regulation in the heart led to dilated cardiomyopathy (DCM), a DM1-associated phenotype. We then combined in silico screening for miR-1 targets with transcriptional profiling of DM1 cardiac cells to identify miR-1 target genes with potential roles in DCM. We identified Multiplexin (Mp) as a new cardiac miR-1 target involved in DM1. Mp and its human ortholog Col15A1 were both highly enriched in cardiac cells of DCM-developing DM1 flies and in heart samples from DM1 patients with DCM, respectively. Importantly, when overexpressed in the heart, Mp induced DCM, whereas its attenuation ameliorated the DCM phenotype in aged DM1 flies. Reduced levels of miR-1 and consecutive up-regulation of its target Mp/Col15A1 are thus critical in DM1-associated DCM.
Development and application of a computable genotype model in the GA4GH Variation Representation Specification
Authors: Goar Wesley , Babb Lawrence , Chamala Srikar , Cline Melissa , Freimuth Robert R. , Hart Reece K. , Kuzma Kori , Lee Jennifer , Nelson Tristan , Prlić Andreas , Riehle Kevin , Smith Anastasia , Stahl Kathryn , Yates Andrew D. , Rehm Heidi L. , Wagner Alex H.
Published: September 2022

As the diversity of genomic variation data increases with our growing understanding of the role of variation in health and disease, it is critical to develop standards for precise inter-system exchange of these data for research and clinical applications. The Global Alliance for Genomics and Health (GA4GH) Variation Representation Specification (VRS) meets this need through a technical terminology and information model for disambiguating and concisely representing variation concepts. Here we discuss the recent Genotype model in VRS, which may be used to represent the allelic composition of a genetic locus. We demonstrate the use of the Genotype model and the constituent Haplotype model for the precise and interoperable representation of pharmacogenomic diplotypes, HGVS variants, and VCF records using VRS and discuss how this can be leveraged to enable interoperable exchange and search operations between assayed variation and genomic knowledgebases.
One-step generation of a conditional allele in mice using a short artificial intron
Authors: Cassidy Annelise M , Thomas Destinée B , Kuliyev Emin , Chen Hanying , Pelletier Stephane
Published: September 2022

Despite tremendous advances in genome editing technologies, generation of conditional alleles in mice has remained challenging. Recent studies in cells have successfully made use of short artificial introns to engineer conditional alleles. The approach consists of inserting intronic sequences flanked by two loxP sites within an exon of a gene using CRISPR-Cas9 technology. Under normal conditions, the artificial intron is removed by the splicing machinery, allowing for expression of the gene product. Following Cre-mediated recombination of the two loxP sites, the intron is disabled, and splicing can no longer occur. The remaining intronic sequences create a frameshift and early translational termination. Here we describe the application of this technology to engineer conditional alleles in mice using Scyl1 as a model gene. Insertion of the cassette occurred in 17% of edited mice obtained from pronuclear stage zygote microinjection. Mice homozygous for the insertion expressed SCYL1 at levels comparable to wild-type mice and showed no overt abnormalities associated with the loss of Scyl1 function, indicating the proper removal of the artificial intron. Deletion of the cassette via Cre-mediated recombination in vivo occurred at high frequency, abrogated SCYL1 protein expression, and resulted in loss-of-function phenotypes. Our results broaden the applicability of this approach to engineering conditional alleles in mice.
Genetic depletion of de novo coenzyme A biosynthesis exacerbates puromycin toxicity
Authors: Khadka Sunada , Chatoff Adam , Snyder Nathaniel W. , DePinho Ronald , Muller Florian
Published: September 2022

Puromycin is an amino nucleoside that inhibits protein synthesis by interrupting elongation of nascent peptide chains. It is a commonly used selection antibiotic in molecular biology research via engineered expression of a puromycin resistance transgene. The enzyme puromycin acetyl transferase (pac) or PuroR inactivates puromycin by N-acetylating its reactive amino group. Puromycin acetylation by pac requires the central metabolite and acetyl group donor acetyl-CoA as a substrate. We found that puromycin treatment exacerbates sensitivity of cancer cells to knockdown of pantothenate kinases, the proteins that catalyze the rate-limiting step of de novo coenzyme A production in cells. Mechanistically, we found that ablation of PANKs together with puromycin depletes acetyl-CoA levels, in a manner modulated by the dose of puromycin. Our findings provide a note of caution and context in the use of puromycin for metabolism research in that interference with the major acyl donor used for inactivating biotransformation may exacerbate toxicity under selection. Broadly, our findings also invite studies to explore how targeting CoA and acetyl-CoA synthesis may be exploited to enhance cytotoxic effects of cancer drugs that undergo acetylation.
CRISPR screens in 3D assembloids reveal disease genes associated with human interneuron development
Authors: Meng Xiangling , Yao David , Kelley Kevin W , Reis Noah , Thete Mayuri V , Kulkarni Shravanti , Bassik Michael C , Pasca Sergiu P
Published: September 2022

The assembly of cortical circuits involves the generation and migration of cortical interneurons from the ventral to the dorsal forebrain, which has been challenging to study in humans as these processes take place at inaccessible stages of late gestation and early postnatal development. Autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs) have been associated with abnormal cortical interneuron development, but which of the hundreds of NDD genes impact interneuron generation and migration into circuits and how they mediate these effects remain unknown. We previously developed a stem cell-based platform to study human cortical interneurons in self-organizing organoids resembling the ventral forebrain and their migration using forebrain assembloids. Here, we integrate assembloid technology with CRISPR screening to systematically investigate the involvement of 425 NDD genes in human interneuron development. The first screen aimed at interneuron generation revealed 13 candidate genes, including the RNA-binding protein CSDE1 and the canonical TGFβ signaling activator SMAD4. Then, we ran an interneuron migration screen in ~1,000 forebrain assembloids that identified 33 candidate genes, including cytoskeleton-related genes and, notably, the endoplasmic reticulum (ER)-related gene LNPK. Interestingly, we discovered that, during interneuron migration, the ER is displaced along the leading neuronal branch prior to nuclear translocation. Deletion of LNPK interfered with this ER displacement and resulted in reduced interneuron saltation length, indicating a critical role for the ER in this migratory process. Taken together, these results highlight how this versatile CRISPR-assembloid platform can be used to systematically map disease genes onto early stages of human neural development and to reveal novel mechanisms regulating interneuron development.
Discovery of another mechanism for the inhibition of particulate guanylyl cyclases by the natriuretic peptide clearance receptor
Authors: Liu Dianxin , Ceddia Ryan P. , Zhang Wei , Shi Fubiao , Fang Huafeng , Collins Sheila
Published: September 2022

The cardiac natriuretic peptides (NPs) control pivotal physiological actions such as fluid and electrolyte balance, cardiovascular homeostasis, and adipose tissue metabolism by activating their receptor enzymes (NPRA and NPRB). These receptors are homodimers that generate intracellular cyclic guanosine monophosphate (cGMP). The NP receptor NPRC, nicknamed the clearance receptor, lacks a guanylyl cyclase domain; instead, it can bind the NPs to internalize and degrade them. The conventional paradigm is that by competing for and internalizing NPs, NPRC blunts the ability of NPs to signal through NPRA and NPRB. Here we show another previously unknown mechanism by which NPRC can interfere with the cGMP signaling function of the NP receptors. By forming a heterodimer with monomeric NPRA or NPRB, NPRC can prevent the formation of a functional guanylyl cyclase domain and thereby suppress cGMP production in a cell-autonomous manner.

Significance Statement

Natriuretic peptides (NP) are hormones that are established regulators of vascular and cardiac function, in part through their regulation of fluid and electrolyte balance. NPs signal through particulate guanylyl cyclases (NPRA and NPRB), which are homodimeric membrane-bound receptor enzymes that generate cGMP upon NP binding. Additionally, a ‘silent’ NP receptor (NPRC) lacks the guanylyl cyclase domain and is a negative regulator of NP signaling. It has been demonstrated that NPRC undergoes internalization and recycling and thus removes NPs, thereby blunting activation of the guanylyl cyclase-containing receptors. Here we show an additional mechanism by which NPRC inhibits NP signaling. Our results show that NPRC can directly interact with NPRA and NPRB, forming non-functional receptor heterodimers with NPRA and NPRB, thereby abrogating NP-evoked cGMP production. This finding establishes another novel mechanistic role for NPRC.
Generation of floxed alleles for cell-specific knockout in zebrafish
Authors: Shin Masahiro , Nozaki Takayuki , Toles Benjamin , Kolb Amy , Luk Kevin , Isogai Sumio , Ishida Kinji , Hanasaka Tomohito , Parsons Michael J. , Wolfe Scot A. , Lawson Nathan D.
Published: September 2022

A benefit of the zebrafish as a model is its amenability to genetic approaches. However, a lack of conditional deletion alleles makes it a challenge to perform stage- or cell-specific knockout. Here, we initially applied an existing protocol to establish a floxed allele for gata2a and encountered several issues, including off-target integration and incomplete knock-in. To address these problems, we developed a protocol incorporating simultaneous co-targeting with Cas12a to insert loxP sites in cis, together with transgenic counter-screening to identify off-target insertions. We applied this protocol to establish a floxed allele of foxc1a in a single generation. We demonstrate the utility of our floxed alleles by verifying Cre-dependent deletion, which yielded expected phenotypes in each case. Finally, we used the floxed gata2a allele to demonstrate an endothelial autonomous requirement in lymphatic valve development. Together, our results provide a framework for straightforward generation and application of floxed alleles in zebrafish.
Enterococcal linear plasmids adapt to Enterococcus faecium and spread within multidrug-resistant clades
Authors: Hashimoto Yusuke , Suzuki Masato , Kobayashi Sae , Hirahara Yuki , Nomura Takahiro , Kurushima Jun , Hirakawa Hidetada , Tanimoto Koichi , Tomita Haruyoshi
Published: September 2022

Antimicrobial resistance (AMR) of bacterial pathogens, including enterococci, is a global concern, and plasmids are crucial for spreading and maintaining AMR genes. Plasmids with linear topology were recently identified in clinical multidrug-resistant enterococci. The enterococcal linear-form plasmids, such as pELF1, confer resistance to clinically important antimicrobials, including vancomycin; however, little information exists about their epidemiological and physiological effects. In this study, we identified several lineages of enterococcal linear plasmids that are structurally conserved and occur globally. pELF1-like linear plasmids show plasticity in acquiring and maintaining AMR genes, often via transposition with the mobile genetic element IS1216E. This linear plasmid family has several characteristics enabling long-term persistence in the bacterial population, including high horizontal self-transmissibility, low-level transcription of plasmid-encoded genes, and a moderate effect on the Enterococcus faecium genome alleviating fitness cost and promoting vertical inheritance. Combined with its broad host range, the linear plasmid is an important factor in the spread and maintenance of AMR genes among enterococci.
Calcium binding and permeation in TRPV channels: insights from molecular dynamics simulations
Authors: Liu Chunhong , Song Chen
Published: September 2022

Some calcium channels selectively permeate Ca2+, despite the high concentration of monovalent ions in the surrounding environment, which is essential for many physiological processes. Without atomistic and dynamical ion permeation details, the underlying mechanism of Ca2+ selectivity has long been an intensively studied, yet controversial, topic. This study takes advantage of the homologous Ca2+-selective TRPV6 and non-selective TRPV1 and utilizes the recently solved open-state structures and a newly developed multi-site calcium model to investigate the ion binding and permeation features in TRPV channels by molecular dynamics simulations. Our results revealed that the open-state TRPV6 and TRPV1 show distinct ion-binding patterns in the selectivity filter, which lead to different ion permeation features. Two Ca2+ ions simultaneously bind to the selectivity filter of TRPV6 compared with only one Ca2+ in case of TRPV1. Multiple Ca2+ binding at the selectivity filter of TRPV6 permeated in a concerted manner, which could efficiently block the permeation of Na+. Cations of various valences differentiate between the binding sites at the entrance of the selectivity filter in TRPV6. Ca2+ preferentially binds to the central site with a higher probability of permeation, repelling Na+ to a peripheral site. Therefore, we believe that ion binding competition at the selectivity filter of calcium channels, including the binding strength and number of binding sites, determines Ca2+ selectivity under physiological conditions. Additionally, our results showed that pore helix flexibility and the cytosolic domain of TRPV channels regulate ion permeability.
Synteny identifies reliable orthologs for phylogenomics and comparative genomics of the Brassicaceae
Authors: Walden Nora , Schranz M. Eric
Published: September 2022

Large genomic datasets are becoming the new normal for any facet of phylogenetic research, but identification of true orthologous genes and exclusion of problematic paralogs is still challenging when applying commonly used sequencing methods such as target enrichment. Here, we compared conventional ortholog detection using OrthoFinder with ortholog detection through genomic synteny in a dataset of eleven representative diploid Brassicaceae whole genome sequences spanning the entire phylogenetic space. We then evaluated the resulting gene sets regarding gene number, functional annotation, gene and species tree resolution. Finally, we used the syntenic gene sets for comparative genomics and ancestral genome analysis. The use of synteny resulted in considerably more orthologs and also allowed us to reliably identify paralogs. Surprisingly, we did not detect notable differences between species trees reconstructed from syntenic orthologs compared other gene sets, including the Angiosperm353 set and a Brassicaceae specific target enrichment gene set. However, the synteny dataset comprised a multitude of gene functions, strongly suggesting that this method of marker selection for phylogenomics is suitable for studies that value downstream gene function analysis, gene interaction and network studies. Finally, we present the first ancestral genome reconstruction for the Core Brassicaceae predating the Brassicaceae lineage diversification ∼25 million years ago.
Nano-scale solution of the Poisson-Nernst-Planck (PNP) equations in a fraction of two neighboring cells reveals the magnitude of intercellular electrochemical waves
Authors: Jæger Karoline Horgmo , Ivanovic Ena , Kucera Jan P. , Tveito Aslak
Published: September 2022

The basic building blocks of the electrophysiology of cardiomyocytes are ion channels integrated in the cell membranes. Close to the ion channels there are very strong electrical and chemical gradients. However, these gradients extend for only a few nano-meters and are therefore commonly ignored in mathematical models. The full complexity of the dynamics is modelled by the Poisson-Nernst-Planck (PNP) equations but these equations must be solved using temporal and spatial scales of nano-seconds and nano-meters. Here we report solutions of the PNP equations in a fraction of two abuttal cells separated by a tiny extracellular space. We show that when only the potassium channels of the two cells are open, a stationary solution is reached with the well-known Debye layer close to the membranes. When the sodium channels of the left cell are opened, a very strong and brief electrochemical wave emanates from the channels. If the extracellular space is sufficiently small and the number of sodium channels is sufficiently high, the wave extends all the way over to the neighboring cell and may therefore explain cardiac conduction even at very low levels of gap junctional coupling.
Online detection of bus bar plane stress based on electromagnetic loading
Authors: Guo Yufeng , Zhang Chuang , Qi Lei , Yu Haixu , Liu Suzhen , Jin Liang
Published: September 2022

Purpose

The purpose of this study is to develop an electromagnetic loading method for online measurement of the acoustoelastic coefficients and bus bar plane stress.

Design/methodology/approach

A method based on the combination of electromagnetic loading and the acoustoelastic effect is proposed to realize online measurement of acoustoelastic coefficients and plane stress. Electromagnetic loading is performed on the bus bar specimen, and the acoustoelastic coefficients and the bus bar plane stress are obtained by the ultrasonic method. An electromagnetic loading experimental platform is designed to provide electromagnetic force to the metal plate, including an electromagnetic loading module, an ultrasonic testing module and a stress simulation module.

Findings

The feasibility of the proposed electromagnetic loading method is proved by verification experiments. The acoustoelastic coefficients and plane stress measured using the electromagnetic loading method are more accurate than those measured using the traditional method.

Originality/value

The proposed electromagnetic loading method provides a new study perspective and enables more accurate measurement of the acoustoelastic coefficients and plane stress. The study provides an important basis for evaluating the operation status of electrical equipment.
Evaluating and optimizing performance of public–private partnership projects using copula Bayesian network
Authors: Ghorbany Siavash , Yousefi Saied , Noorzai Esmatullah
Published: September 2022

Purpose

Being an efficient mechanism for the value of money, public–private partnership (PPP) is one of the most prominent approaches for infrastructure construction. Hence, many controversies about the performance effectiveness of these delivery systems have been debated. This research aims to develop a novel performance management perspective by revealing the causal effect of key performance indicators (KPIs) on PPP infrastructures.

Design/methodology/approach

The literature review was used in this study to extract the PPPs KPIs. Experts’ judgment and interviews, as well as questionnaires, were designed to obtain data. Copula Bayesian network (CBN) has been selected to achieve the research purpose. CBN is one of the most potent tools in statistics for analyzing the causal relationship of different elements and considering their quantitive impact on each other. By utilizing this technique and using Python as one of the best programming languages, this research used machine learning methods, SHAP and XGBoost, to optimize the network.

Findings

The sensitivity analysis of the KPIs verified the causation importance in PPPs performance management. This study determined the causal structure of KPIs in PPP projects, assessed each indicator’s priority to performance, and found 7 of them as a critical cluster to optimize the network. These KPIs include innovation for financing, feasibility study, macro-environment impact, appropriate financing option, risk identification, allocation, sharing, and transfer, finance infrastructure, and compliance with the legal and regulatory framework.

Practical implications

Identifying the most scenic indicators helps the private sector to allocate the limited resources more rationally and concentrate on the most influential parts of the project. It also provides the KPIs’ critical cluster that should be controlled and monitored closely by PPP project managers. Additionally, the public sector can evaluate the performance of the private sector more accurately. Finally, this research provides a comprehensive causal insight into the PPPs’ performance management that can be used to develop management systems in future research.

Originality/value

For the first time, this research proposes a model to determine the causal structure of KPIs in PPPs and indicate the importance of this insight. The developed innovative model identifies the KPIs’ behavior and takes a non-linear approach based on CBN and machine learning methods while providing valuable information for construction and performance managers to allocate resources more efficiently.
Economic policy uncertainty, entrepreneurial risk appetite, and corporation innovation in innovative cities – empirical evidence from the Shenzhen Special Economic Zone
Authors: Zhu Mengfei , Tao Yitao
Published: September 2022

Purpose

This study investigates the impact of economic policy uncertainty on corporation innovation in innovative cities. The study sheds light on different results from the previous literature by testing the moderator effects of entrepreneurial risk appetite on such impact.

Design/methodology/approach

A static panel estimator is applied to a Chinese sample of 416 firm-year observations from 2010 to 2019. This paper uses regression model to test the impact of uncertainty on enterprise innovation in innovative cities, and to test the regulatory role of entrepreneurial risk appetite. For a series of robustness analysis conducted by the author to deal with endogeneity, the results are robust.

Findings

The author finds reliable evidence that the economic policy uncertainty can promote corporations to invest more in R&D in innovative cities. In addition, the role of the entrepreneurial initiative is significant, and there is a positive moderating effect of entrepreneurial risk appetite between policy uncertainty and corporation innovation.

Research limitations/implications

From a practical point of view, this study examines the impact of economic policy uncertainty on corporation innovation in innovative cities for the first time. It emphasizes the role of entrepreneurial risk-taking in the development of corporation innovation in Shenzhen, an innovative city. This research is of great significance to the formulation of government policies and the innovative choice of entrepreneurs. In addition, the research shows that the entrepreneurial risk appetite in innovative cities can have a positive impact on enterprise innovation. Therefore, when formulating policies, the government should take the subjective factors of entrepreneurs into account and support enterprises with innovation potential. The evidence of this study also helps entrepreneurs make innovative decisions and enhance their confidence in enterprise development.

Originality/value

By studying the impact of economic policy uncertainty on enterprise innovation under the regulation of enterprise risk appetite, this study shows the subjective and positive role of entrepreneurs in risk grasp in innovative cities for the first time. In addition, it fills the gap of the impact of policy uncertainty on innovative urban enterprises. In fact, although it is traditionally believed that economic policy uncertainty has a negative impact on enterprise innovation, the sensitive findings of this study reveal completely different results from previous studies.
The costs of care: An ethnography of care work in residential homes for older people
Authors: Johnson Eleanor K.
Published: September 2022

The cost of social care, the work conditions experienced by care workers and the quality of care provided by residential homes for older people are all linked, yet we know very little about how this relationship works in practice. Drawing upon an ethnography of two differently priced residential care homes for older people in Southern England, I examine the implications of different financial regimes for care‐giving practices. I show how the scheduling and allocation of resources—conveyed, for example, in formal routines and staffing levels—structure the care workers’ time, tasks and activities in each setting. This acts to symbolically demarcate what, or who, is valued. I argue that the availability of resources facilitates and impedes the symbolic culture of care work, shapes care workers’ ability to afford dignity to the individuals in their care and affects how care workers experience, and relate to, their labour. I conclude by discussing how current practices of funding and pricing social care have effects seeping beyond the practical and measurable, and into the realm of the symbolic.
Biosynthesis of L‐5‐methyltetrahydrofolate by genetically engineered Escherichia coli
Authors: Wang Yubo , Zhang Meng , Li Lexin , Yi Jihong , Liang Jiyu , Wang Shuning , Xu Ping
Published: September 2022

L‐5‐Methyltetrahydrofolate (L‐5‐MTHF) is the only biologically active form of folate in the human body. Production of L‐5‐MTHF by using microbes is an emerging consideration for green synthesis. However, microbes naturally produce only a small amount of L‐5‐MTHF. Here, Escherichia coli BL21(DE3) was engineered to increase the production of L‐5‐MTHF by overexpressing the intrinsic genes of dihydrofolate reductase and methylenetetrahydrofolate (methylene‐THF) reductase, introducing the genes encoding formate‐THF ligase, formyl‐THF cyclohydrolase and methylene‐THF dehydrogenase from the one‐carbon metabolic pathway of Methylobacterium extorquens or Clostridium autoethanogenum and disrupting the gene of methionine synthase involved in the consumption and synthesis inhibition of the target product. Thus, upon its native pathway, an additional pathway for L‐5‐MTHF synthesis was developed in E. coli, which was further analysed and confirmed by qRT‐PCR, enzyme assays and metabolite determination. After optimizing the conditions of induction time, temperature, cell density and concentration of IPTG and supplementing exogenous substances (folic acid, sodium formate and glucose) to the culture, the highest yield of 527.84 μg g−1 of dry cell weight for L‐5‐MTHF was obtained, which was about 11.8 folds of that of the original strain. This study paves the way for further metabolic engineering to improve the biosynthesis of L‐5‐MTHF in E. coli.
Optimal diagnostic criteria for lateral lymph node dissection using magnetic resonance imaging: a multicenter prospective study
Authors: Kawai Kazushige , Shiomi Akio , Miura Takuya , Uehara Kay , Watanabe Jun , Kazama Shinsuke , Ueno Hideki , Sakamoto Kazuhiro , Kinugasa Yusuke , Takahashi Keiichi , Hida Koya , Hamada Madoka , Ishihara Soichiro , Sugihara Kenichi
Published: September 2022

Background

LLND in cases with suspected lateral lymph node (LLN) metastasis has been focused on as a novel treatment strategy in recent years. However, the optimal indication for LLND in rectal cancer patients has not been determined. This study aimed to establish the optimal indication for lateral lymph node dissection (LLND) in patients with rectal cancer using magnetic resonance imaging (MRI).

Methods

A total of 209 patients with rectal adenocarcinoma who underwent total mesorectal excision and LLND in 13 hospitals were prospectively registered. By matching the sizes of the harvested LNs and those in magnetic resonance imaging (MRI), the pathological outcome of each LN was confirmed one‐by‐one. Using parameters of the LLNs in MRI, the optimal diagnostic criteria for LLND were established.

Results

Of 3241 harvested LLNs, including 83 metastatic nodes, 1010 (31.1%) were visualized on MRI. Although all parameters assessed showed strong correlations with the presence of metastasis, none of these parameters could discriminate metastatic LLNs from non‐metastatic nodes with sufficient sensitivity. However, by using the combination of long axis and short/long ratio in pretreatment MRI, we could establish optimal criteria for LLND. The sensitivity and specificity of the criteria for LLN metastasis were 94.3% and 40.2%, respectively.

Conclusions

In conclusion, we established novel criteria for LLND in rectal cancer patients using MRI. Our criteria will be of great clinical use in determining indications for LLND.
Risk of gestational diabetes mellitus in relation to early pregnancy and gestational weight gain before diagnosis: A population‐based cohort study
Authors: Xu Huiling , Hutcheon Jennifer A. , Liu Xingrong , Stephansson Olof , Cnattingius Sven , Arkema Elizabeth V. , Johansson Kari
Published: September 2022

Introduction

Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with adverse consequences for the mother and offspring in both short and long term. The aim of this study was to investigate associations between risk of GDM and gestational weight gain in early pregnancy and before diagnosis.

Material and methods

Our population‐based cohort study included 131 164 singleton pregnancies in the Stockholm‐Gotland region in Sweden from 2008 through 2013. The exposures were weight gain in early pregnancy (<22 weeks) and weight gain before diagnosis, standardized into gestational age‐specific z scores. The outcome was GDM. We used logistic regression models with a generalized estimating equations method to estimate odds ratios with 95% confidence intervals for GDM, stratified by early‐pregnancy body mass index (BMI) category.

Results

Above average weight gain before diagnosis (z score >0) was associated with increased risk of GDM among all BMI groups except for obese III. Early gestational weight gain above average was associated with increased risk for GDM in overweight women. Below average weight gain before diagnosis (z score <0) was only associated with decreased risk of GDM in obese III. Early gestational weight gain below average was associated with reduced risks of GDM in obese class I, II, and III women.

Conclusions

The risk of GDM increased with higher weight gain before diagnosis in all BMI groups except obese class III, whereas the risk was reduced with lower weight gain before diagnosis in obese III women only. The risk of GDM increased with higher early gestational weight gain in overweight women, while the risk was reduced with lower early gestational weight gain among obese women. Obese women may benefit from lower weight gain, especially in early pregnancy.
Ethical implications of text generation in the age of artificial intelligence
Authors: Illia Laura , Colleoni Elanor , Zyglidopoulos Stelios
Published: September 2022

We are at a turning point in the debate on the ethics of Artificial Intelligence (AI) because we are witnessing the rise of general‐purpose AI text agents such as GPT‐3 that can generate large‐scale highly refined content that appears to have been written by a human. Yet, a discussion on the ethical issues related to the blurring of the roles between humans and machines in the production of content in the business arena is lacking. In this conceptual paper, drawing on agenda setting theory and stakeholder theory, we challenge the current debate on the ethics of AI and aim to stimulate studies that develop research around three new challenges of AI text agents: automated mass manipulation and disinformation (i.e., fake agenda problem), massive low‐quality content production (i.e., lowest denominator problem) and the creation of a growing buffer in the communication between stakeholders (i.e., the mediation problem).
Self‐enhancement and physical health: A meta‐analysis
Authors: Zell Ethan , Stockus Christopher A. , Lesick Tara L. , Sedikides Constantine
Published: September 2022

A prior meta‐analysis yielded a positive relation between self‐enhancement and psychological health. We present the first meta‐analysis of the association between self‐enhancement and physical health (k = 87; N = 22,415). We relied predominantly on social desirability as an operationalization of self‐enhancement and secondarily on comparative judgement and narcissism. Further, we operationalized physical health in terms of self‐rated health, symptoms and biomarkers. Overall, self‐enhancement yielded a near‐zero association with physical health, r = .01. However, this association was more pronounced for comparative judgement (r = .18, k = 6) than social desirability (r = .03, k = 41) or narcissism (r = −.0001, k = 8), and for self‐rated health (r = .09, k = 9) than symptoms (r = .01, k = 29) or biomarkers (r = −.13, k = 17). The association between self‐enhancement and physical health fluctuates across measures of both constructs calling for more focussed and nuanced investigations.
Combined chemoradiotherapy and programmed cell death‐ligand 1 blockade leads to changes in the circulating T‐cell receptor repertoire of patients with non‐small‐cell lung cancer
Authors: Someya Masanori , Tokita Serina , Kanaseki Takayuki , Kitagawa Mio , Hasegawa Tomokazu , Tsuchiya Takaaki , Fukushima Yuki , Gocho Toshio , Kozuka Yoh , Mafune Shoh , Ikeuchi Yutaro , Takahashi Mamoru , Moniwa Keigo , Matsuo Kazuhiko , Hasegawa Tadashi , Torigoe Toshihiko , Sakata Koh‐ichi
Published: September 2022

Combined chemoradiotherapy (CRT) and programmed cell death‐ligand 1 (PD‐L1) blockade is a new care standard for unresectable stage III non‐small‐cell lung cancer (NSCLC). Although this consolidation therapy has improved the overall survival of patients with NSCLC, the synergistic action mechanisms of CRT and immunotherapy on T cells remain unclear. In addition, there is a paucity of reliable biomarkers to predict clinical responses to therapy. In this study, we analyzed T‐cell receptor (TCR) sequences in the peripheral blood of five patients with NSCLC. T‐cell receptor analysis was undertaken before treatment, after CRT, and after PD‐L1 blockade. Notably, we observed the expansion and alteration of the dominant T‐cell clonotypes in all cases with a complete response. In contrast, neither expansion nor alteration of the TCR repertoire was observed in cases with progressive disease. T cell expansion was initiated after CRT and was further enhanced after PD‐L1 blockade. Our findings suggest the systemic effect of CRT on circulating T cells in addition to the curative effect on limited tumor sites. Dynamic changes in circulating T‐cell clonotypes could have a prognostic significance for combined CRT and PD‐L1 blockade.
Glioma stem cell signature predicts the prognosis and the response to tumor treating fields treatment
Authors: Chen Bo , Zhou Xiaoxi , Yang Liting , Zhou Hongshu , Meng Ming , Wu Hao , Liu Zhixiong , Zhang Liyang , Li Chuntao
Published: September 2022

Introduction

Glioma stem cells (GSCs) play an important role in glioma recurrence and chemo‐radiotherapy (CRT) resistance. Currently, there is a lack of efficient treatment approaches targeting GSCs. This study aimed to explore the potential personalized treatment of patients with GSC‐enriched gliomas.

Methods

Single‐cell RNA sequencing (scRNA‐seq) was used to identify the GSC‐related genes. Then, machine learning methods were applied for clustering and validation. The least absolute shrinkage and selection operator (LASSO) and COX regression were used to construct the risk scores. Survival analysis was performed. Additionally, the incidence of chemo‐radiotherapy resistance, immunotherapy status, and tumor treating field (TTF) therapy response were evaluated in high‐ and low‐risk scores groups.

Results

Two GSC clusters exhibited significantly different stemness indices, immune microenvironments, and genomic alterations. Based on GSC clusters, 11‐gene GSC risk scores were constructed, which exhibited a high predictive value for prognosis. In terms of therapy, patients with high GSC risk scores had a higher risk of resistance to chemotherapy. TTF therapy can comprehensively inhibit the malignant biological characteristics of the high GSC‐risk‐score gliomas.

Conclusion

Our study constructed a GSC signature consisting of 11 GSC‐specific genes and identified its prognostic value in gliomas. TTF is a promising therapeutic approach for patients with GSC‐enriched glioma.
Advantages and challenges of metagenomic sequencing for the diagnosis of pulmonary infectious diseases
Authors: Chen Yan , Fan Li‐Chao , Chai Yan‐Hua , Xu Jin‐Fu
Published: September 2022

Objective

We aim to familiarize the application status of metagenomic sequencing in diagnosing pulmonary infections, to compare metagenomic sequencing with traditional diagnostic methods, to conclude the advantages and limitations of metagenomic sequencing, and to provide some advice for clinical practice and some inspiration for associated researches.

Data Sources

The data were obtained from peer‐reviewed literature, white papers, and meeting reports.

Results

This review focused on the applications of untargeted metagenomic sequencing in lungs infected by bacteria, viruses, fungi, chlamydia pneumoniae, Mycoplasma pneumoniae, parasites, and other pathogens. Compared with conventional diagnostic methods, metagenomic sequencing is better in detecting novel, rare, and unexpected pathogens and being applied in co‐infections. Meanwhile, it can also provide more comprehensive information about pathogens. However, metagenomic sequencing still has limitations. Also, the situations that should be applied in and how the results should be interpreted are discussed in this review.

Conclusion

Metagenomic sequencing improves efficiency to identify pathogens compared with traditional diagnostic methods and can be applied in clinical diagnosis. However, the technology of metagenomic sequencing still needs to be improved. Also, clinicians should learn more about when to use metagenomic sequencing and how to interpret its results.
Fusobacterium nucleatum promotes proliferation in oesophageal squamous cell carcinoma via AHR/CYP1A1 signalling
Authors: Yin Haisen , Zhang Jianwei , Zhang Hanping , Li Qing , Qiu Hu , Hong Kunqiao , Wang Wei , Xiao Yong , Yu Baoping
Published: September 2022

Fusobacterium nucleatum (Fn) is reportedly involved in poor prognosis of oesophageal squamous cell carcinoma (ESCC), but the responsible mechanisms remain unclear. The present study aimed to explore the function of Fn in ESCC progression, and to identify the key genes or signals involved. Fluorescence in situ hybridization and quantitative PCR assays were applied to measure the abundance of Fn in ESCC tissues, finding that ESCC tissues displayed a higher abundance of Fn compared to adjacent tissues. Furthermore, Fn abundance in advanced ESCC tissues was found to be higher than that in early stage ESCC. The proliferation assays and wound healing assays indicated that Fn infection promoted ESCC cell proliferation and migration. Based on high‐throughput sequencing, cytochrome P450 1A1 (CYP1A1) was the most significantly upregulated (eightfold increase) gene, and AKT signalling was activated in KYSE‐450 cells treated with Fn. Knocking down CYP1A1 or inactivating AKT signalling with LY294002 downregulated p‐AKTS473, inhibited cell proliferation, and compromised the proliferation effect induced by Fn in both in vitro and in vivo experiments. Inactivating the aryl hydrocarbon receptor (AHR) by CH‐223191 reversed CYP1A1 expression induced by Fn and inhibited the proliferation of ESCC cells. Taken together, our findings indicate that Fn may promote ESCC cell proliferation via AHR/CYP1A1/AKT signalling. Targeting Fn or AHR/CYP1A1 signalling could yield approaches relevant to the treatment of ESCC.
Usefulness of neutrophil‐to‐lymphocyte ratio in predicting progression and survival outcomes after atezolizumab–bevacizumab treatment for hepatocellular carcinoma
Authors: Ochi Hironori , Kurosaki Masayuki , Joko Kouji , Mashiba Toshie , Tamaki Nobuharu , Tsuchiya Kaoru , Marusawa Hiroyuki , Tada Toshifumi , Nakamura Shinichiro , Narita Ryoichi , Uchida Yasushi , Akahane Takehiro , Kondo Masahiko , Mori Nami , Takaki Shintaro , Tsuji Keiji , Kusakabe Atsunori , Furuta Koichiro , Kobashi Haruhiko , Arai Hirotaka , Nonogi Michiko , Tamada Takashi , Hasebe Chitomi , Izumi Namiki
Published: September 2022

Aim

We investigated pretreatment neutrophil‐to‐lymphocyte ratio (NLR) for predicting survival outcomes of atezolizumab plus bevacizumab therapy for hepatocellular carcinoma (HCC) and determined the predictive ability of combined liver reserve–NLR.

Methods

This retrospective, multicenter study enrolled 242 patients receiving atezolizumab plus bevacizumab for unresectable HCC. Pretreatment NLR <2.56 was designated as the “low group” and NLR ≥2.56 as the “high group” (120 and 122 patients, respectively). Propensity score‐matched analysis was undertaken between the low and high groups.

Results

In this cohort, the objective response and disease control rates were 20% and 72.5%, respectively, in the low group and 19.6% and 72.9%, respectively, in the high group. After matching, median progression‐free survival (PFS) time was 283 and 167 days in the low and high groups, respectively (p = 0.022). Neutrophil‐to‐lymphocyte ratio ≥2.56 (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.05–2.28; p = 0.028), modified albumin–bilirubin index (mALBI) grade 2b or 3 (HR 1.55; 95% CI, 1.05–2.29; p = 0.025), and protein induced by vitamin K absence or antagonist‐II ≥ 400 (HR 2.03; 95% CI, 1.36–3.02; p = 0.001) were significantly associated with PFS in univariate analysis using the Cox proportional hazards model. In cases involving mALBI grade 1 or 2a (n = 131), the median PFS time was not reached in the low group, whereas it was 210 days in the high group (p = 0.037).

Conclusions

Pretreatment NLR is a simple tool for routine measurement in clinical practice. It can predict PFS in patients with unresectable HCC treated with atezolizumab plus bevacizumab, especially mALBI grade 1 or 2a.
Predictive factors for the effectiveness of novel androgen receptor axis‐targeted agents in patients with metastatic prostate cancer
Authors: Koshiro Nishimoto , Nakajima Kenichi , Oyama Masafumi , Kaneko Go , Takahashi Satoru , Matsuyama Hideyasu , Shiina Hiroaki , Ichikawa Tomohiko , Horikoshi Hiroyuki , Hashine Katsuyoshi , Sugiyama Yutaka , Miyao Takeshi , Kamiyama Manabu , Harada Kenichi , Ito Akito , Mizokami Atsushi ,   PROSTAT‐BSI Investigators
Published: September 2022

Objective

Novel androgen receptor axis‐targeted agents (ARATAs) have been developed for mCRPC and improved overall survival (OS). Here, we aimed to find predictors who will receive the greatest benefits from ARATAs.

Methods

We previously performed a multicenter study to identify prognostic factors for metastatic hormone‐sensitive prostate cancer (mHSPC, n = 148) and mCRPC (n = 99), and showed that the bone scan index (BSI) was one of the significant prognostic factors for 3‐year OS (PROSTAT‐BSI study). mHSPC progressed to mCRPC (n = 101), for which 69 patients were treated with (n = 39) or without ARATAs (n = 30, prior to the approval of ARATAs). The 69 patients were divided into two groups according to patient factors, and these cohorts were further divided into two subgroups by usage of ARATAs. OS was compared between subgroups in each group.

Results

The predictors were age (<71.4 years), serum levels of C‐reactive protein (≥0.16 ng/ml) and alkaline phosphatase (≥548 U/L), time to PSA progression after ADT (<8.9 months), the lowest PSA level (≥1 ng/ml) after ADT, and the rate of PSA decline 3 months after ADT (<0.987), whereas hemoglobin levels, PSA before ADT, Gleason scores, existence of visceral metastases, and BSI were not.

Conclusions

The present study identified predictors for the effectiveness of ARATAs. The number of bone metastases (≒BSI), existence of visceral metastases, and Gleason scores, which were identified as high‐risk factors in the LATITUDE study and disease volume in CHAARTED criteria, did not appear to be useful for predicting effectiveness from ARATAs.