bluuebunny/crossref_metadata_2025 huggingface dataset:
PTBGRP: predicting phage–bacteria interactions with graph representation learning on microbial heterogeneous information network
Authors: Pan Jie , You Zhuhong , You Wencai , Zhao Tian , Feng Chenlu , Zhang Xuexia , Ren Fengzhi , Ma Sanxing , Wu Fan , Wang Shiwei , Sun Yanmei
Published: September 2023

Identifying the potential bacteriophages (phage) candidate to treat bacterial infections plays an essential role in the research of human pathogens. Computational approaches are recognized as a valid way to predict bacteria and target phages. However, most of the current methods only utilize lower-order biological information without considering the higher-order connectivity patterns, which helps to improve the predictive accuracy. Therefore, we developed a novel microbial heterogeneous interaction network (MHIN)–based model called PTBGRP to predict new phages for bacterial hosts. Specifically, PTBGRP first constructs an MHIN by integrating phage–bacteria interaction (PBI) and six bacteria–bacteria interaction networks with their biological attributes. Then, different representation learning methods are deployed to extract higher-level biological features and lower-level topological features from MHIN. Finally, PTBGRP employs a deep neural network as the classifier to predict unknown PBI pairs based on the fused biological information. Experiment results demonstrated that PTBGRP achieves the best performance on the corresponding ESKAPE pathogens and PBI dataset when compared with state-of-art methods. In addition, case studies of Klebsiella pneumoniae and Staphylococcus aureus further indicate that the consideration of rich heterogeneous information enables PTBGRP to accurately predict PBI from a more comprehensive perspective. The webserver of the PTBGRP predictor is freely available at http://120.77.11.78/PTBGRP/.
EXPANSION: a webserver to explore the functional consequences of protein-coding alternative splice variants in cancer genomics
Authors: Arora Chakit , De Oliveira Rosa Natalia , Matic Marin , Cascone Mariastella , Miglionico Pasquale , Raimondi Francesco
Published: September 2023

EXPANSION (https://expansion.bioinfolab.sns.it/) is an integrated web-server to explore the functional consequences of protein-coding alternative splice variants. We combined information from Differentially Expressed (DE) protein-coding transcripts from cancer genomics, together with domain architecture, protein interaction network, and gene enrichment analysis to provide an easy-to-interpret view of the effects of protein-coding splice variants. We retrieved all the protein-coding Ensembl transcripts and mapped Interpro domains and post-translational modifications on canonical sequences to identify functionally relevant splicing events. We also retrieved isoform-specific protein–protein interactions and binding regions from IntAct to uncover isoform-specific functions via gene-set over-representation analysis. Through EXPANSION, users can analyze precalculated or user-inputted DE transcript datasets, to easily gain functional insights on any protein spliceform of interest.

Availability and Implementation

EXPANSION is freely available at http://expansion.bioinfolab.sns.it/. The code of the scripts used for EXPASION is available at: https://github.com/raimondilab/expansion. Datasets associated to this resource are available at the following URL: https://doi.org/10.5281/zenodo.8229120. The web-server was developed using Apache2 (https://https.apache.org/) and Flask (v2.0.2) (http://flask.pocoo.org/) for the web frontend and for the internal pipeline to handle back-end processes. We additionally used the following Python and JavaScript libraries at both back- and front-ends: D3 (v4), jQuery (v3.2.1), DataTables (v2.3.2), biopython (v1.79), gprofiler-officia l(v1.0.0), Mysql-connector-python (v8.0.31). To construct the API, Fast API library (v0.95.1) was used.
ScribbleDom: using scribble-annotated histology images to identify domains in spatial transcriptomics data
Authors: Rahman Mohammad Nuwaisir , Noman Abdullah Al , Turza Abir Mohammad , Abrar Mohammed Abid , Samee Md Abul Hassan , Rahman M Saifur
Published: September 2023

Motivation

Spatial domain identification is a very important problem in the field of spatial transcriptomics. The state-of-the-art solutions to this problem focus on unsupervised methods, as there is lack of data for a supervised learning formulation. The results obtained from these methods highlight significant opportunities for improvement.

Results

In this article, we propose a potential avenue for enhancement through the development of a semi-supervised convolutional neural network based approach. Named “ScribbleDom”, our method leverages human expert’s input as a form of semi-supervision, thereby seamlessly combines the cognitive abilities of human experts with the computational power of machines. ScribbleDom incorporates a loss function that integrates two crucial components: similarity in gene expression profiles and adherence to the valuable input of a human annotator through scribbles on histology images, providing prior knowledge about spot labels. The spatial continuity of the tissue domains is taken into account by extracting information on the spot microenvironment through convolution filters of varying sizes, in the form of “Inception” blocks. By leveraging this semi-supervised approach, ScribbleDom significantly improves the quality of spatial domains, yielding superior results both quantitatively and qualitatively. Our experiments on several benchmark datasets demonstrate the clear edge of ScribbleDom over state-of-the-art methods—between 1.82% to 169.38% improvements in adjusted Rand index for 9 of the 12 human dorsolateral prefrontal cortex samples, and 15.54% improvement in the melanoma cancer dataset. Notably, when the expert input is absent, ScribbleDom can still operate, in a fully unsupervised manner like the state-of-the-art methods, and produces results that remain competitive.

Availability and implementation

Source code is available at Github (https://github.com/1alnoman/ScribbleDom) and Zenodo (https://zenodo.org/badge/latestdoi/681572669).
Extending protein interaction networks using proteoforms and small molecules
Authors: Hernández Sánchez Luis Francisco , Burger Bram , Castro Campos Rodrigo Alexander , Johansson Stefan , Njølstad Pål Rasmus , Barsnes Harald , Vaudel Marc
Published: September 2023

Motivation

Biological network analysis for high-throughput biomedical data interpretation relies heavily on topological characteristics. Networks are commonly composed of nodes representing genes or proteins that are connected by edges when interacting. In this study, we use the rich information available in the Reactome pathway database to build biological networks accounting for small molecules and proteoforms modeled using protein isoforms and post-translational modifications to study the topological changes induced by this refinement of the network representation.

Results

We find that improving the interactome modeling increases the number of nodes and interactions, but that isoform and post-translational modification annotation is still limited compared to what can be expected biologically. We also note that small molecule information can distort the topology of the network due to the high connectedness of these molecules, which does not necessarily represent the reality of biology. However, by restricting the connections of small molecules to the context of biochemical reactions, we find that these improve the overall connectedness of the network and reduce the prevalence of isolated components and nodes. Overall, changing the representation of the network alters the prevalence of articulation points and bridges globally but also within and across pathways. Hence, some molecules can gain or lose in biological importance depending on the level of detail of the representation of the biological system, which might in turn impact network-based studies of diseases or druggability.

Availability and implementation

Networks are constructed based on data publicly available in the Reactome Pathway knowledgebase: reactome.org.
Risk factors for postoperative complications after adrenalectomy for phaeochromocytoma: multicentre cohort study
Authors: Parente Alessandro , Kamarajah Sivesh K , Thompson Joseph P , Crook Charlotte , Aspinall Sebastian , Melvin Ross , Stechman Michael J , Perry Helen , Balasubramanian Sabapathy P , Pannu Arslan , Palazzo Fausto F , Van Den Heede Klaas , Eatock Fiona , Anderson Hannah , Doran Helen , Wang Kelvin , Hubbard Johnathan , Aldrees Abdulaziz , Shore Susannah L , Fung Clare , Waghorn Alison , Ayuk John , Bennett Davinia , Sutcliffe Robert P
Published: September 2023

Background

To determine the incidence and risk factors for postoperative complications and prolonged hospital stay after adrenalectomy for phaeochromocytoma.

Methods

Demographics, perioperative outcomes and complications were evaluated for consecutive patients who underwent adrenalectomy for phaeochromocytoma from 2012 to 2020 in nine high-volume UK centres. Odds ratios were calculated using multivariable models. The primary outcome was postoperative complications according to the Clavien–­­Dindo classification and secondary outcome was duration of hospital stay.

Results

Data were available for 406 patients (female n = 221, 54.4 per cent). Two patients (0.5 per cent) had perioperative death, whilst 148 complications were recorded in 109 (26.8 per cent) patients. On adjusted analysis, the age-adjusted Charlson Co-morbidity Index ≥3 (OR 8.09, 95 per cent c.i. 2.31 to 29.63, P = 0.001), laparoscopic converted to open (OR 10.34, 95 per cent c.i. 3.24 to 36.23, P <0.001), and open surgery (OR 11.69, 95 per cent c.i. 4.52 to 32.55, P <0.001) were independently associated with postoperative complications. Overall, 97 of 430 (22.5 per cent) had a duration of stay ≥5 days and this was associated with an age-adjusted Charlson Co-morbidity Index ≥3 (OR 4.31, 95 per cent c.i. 1.08 to 18.26, P = 0.042), tumour size (OR 1.15, 95 per cent c.i. 1.05 to 1.28, P = 0.006), laparoscopic converted to open (OR 32.11, 95 per cent c.i. 9.2 to 137.77, P <0.001), and open surgery (OR 28.01, 95 per cent c.i. 10.52 to 83.97, P <0.001).

Conclusion

Adrenalectomy for phaeochromocytoma is associated with a very low mortality rate, whilst postoperative complications are common. Several risk factors, including co-morbidities and operative approach, are independently associated with postoperative complications and/or prolonged hospitalization, and should be considered when counselling patients.
B-301 In-vivo Continuous Therapeutic Drug Monitoring With Electrochemical Aptamer-based Sensors
Authors: Goncales V , Chamazketi A A , Harrison M , Leung K , Gerson J , Batchelor R H , Farnkopf A , Hodges A , Plaxco K
Published: September 2023

Therapeutic drug monitoring (TDM) is a clinical practice involving quantification of plasma drug concentrations to adjust treatment efficacy and minimize toxicity in patient care. TDM is relevant for drugs with a narrow therapeutic index, defined as the plasma concentration range over which a molecule is therapeutically effective without causing significant adverse effects. For narrow therapeutic index drugs, indirect predictors of a patient’s metabolism, such as age, body mass, or genotype, are insufficient to ensure effective dosing, and metabolic variability across different individuals needs to be considered. The importance of TDM is illustrated by the difficulty in treating a patient with vancomycin, an essential antibiotic used to combat gram-positive bacterial infections. The practice typically involves determining trough concentration, peak concentration, or exposure to the vancomycin area under the curve, necessitating blood sampling. After sampling, the current practices require patient blood to be sent to a laboratory, which can only provide an answer from hours after sample collection. Electrochemical aptamer-based (E-AB) sensors provide significant opportunities to make TDM a practice as frequent and convenient as the measurement of blood sugar has become for people with diabetes. This is because E-AB sensing is a molecular approach to continuously measuring concentrations of specific molecules. We present the selection of an aptamer against vancomycin and its adaptation into an E-AB sensor. Using this sensor, we then demonstrate the opportunities for rapid (seconds) measurement of plasma vancomycin and the real-time measurement of subject-specific vancomycin pharmacokinetics on rats (Fig. 1) [3]. Such capability provides a route toward improving TDM and the personalized delivery of pharmacological interventions.Fig. 1.Real-time continuous monitoring of subject-specific vancomycin pharmacokinetics with electrochemical aptamer-based sensors. Reprinted with permission from the American Chemical Society.
SLPs’ perceptions of language learning myths about children who are DHH
Authors: McDaniel Jena , Krimm Hannah , Schuele C Melanie
Published: September 2023

This article reports on speech-language pathologists’ (SLPs’) knowledge related to myths about spoken language learning of children who are deaf and hard of hearing (DHH). The broader study was designed as a step toward narrowing the research-practice gap and providing effective, evidence-based language services to children. In the broader study, SLPs (n = 106) reported their agreement/disagreement with myth statements and true statements (n = 52) about 7 clinical topics related to speech and language development. For the current report, participant responses to 7 statements within the DHH topic were analyzed. Participants exhibited a relative strength in bilingualism knowledge for spoken languages and a relative weakness in audiovisual integration knowledge. Much individual variation was observed. Participants’ responses were more likely to align with current evidence about bilingualism if the participants had less experience as an SLP. The findings provide guidance on prioritizing topics for speech-language pathology preservice and professional development.
Incidence and individual risk prediction of post-COVID-19 cardiovascular disease in the general population: a multivariable prediction model development and validation study
Authors: la Roi-Teeuw Hannah M , van Smeden Maarten , Geersing Geert-Jan , Klungel Olaf H , Rutten Frans H , Souverein Patrick C , van Doorn Sander
Published: September 2023

Aims

Previous studies suggest relatively increased cardiovascular risk after COVID-19 infection. This study assessed incidence and explored individual risk and timing of cardiovascular disease occurring post-COVID-19 in a large primary care database.

Methods and results

Data were extracted from the UK’s Clinical Practice Research Datalink. Incidence rates within 180 days post-infection were estimated for arterial or venous events, inflammatory heart disease, and new-onset atrial fibrillation or heart failure. Next, multivariable logistic regression models were developed on 220 751 adults with COVID-19 infection before 1 December 2020 using age, sex and traditional cardiovascular risk factors. All models were externally validated in (i) 138 034 vaccinated and (ii) 503 404 unvaccinated adults with a first COVID-19 infection after 1 December 2020. Discriminative performance and calibration were evaluated with internal and external validation. Increased incidence rates were observed up to 60 days after COVID-19 infection for venous and arterial cardiovascular events and new-onset atrial fibrillation, but not for inflammatory heart disease or heart failure, with the highest rate for venous events (13 per 1000 person-years). The best prediction models had c-statistics of 0.90 or higher. However, <5% of adults had a predicted 180-day outcome-specific risk larger than 1%. These rare outcomes complicated calibration.

Conclusion

Risks of arterial and venous cardiovascular events and new-onset atrial fibrillation are increased within the first 60 days after COVID-19 infection in the general population. Models’ c-statistics suggest high discrimination, but because of the very low absolute risks, they are insufficient to inform individual risk management.
A virus induces alterations in root morphology while exerting minimal effects on the rhizosphere and endosphere microorganisms in rice
Authors: Liu Xuewei , Wang Yirong , Han Lijuan , Xia Yuxian , Xie Jiaqin
Published: September 2023

The highly destructive southern rice black-streaked dwarf virus (SRBSDV) causes significant losses in rice production. To understand its impact on rice root, we studied fibrous root development and root microbiota variation (rhizosphere and endosphere) after SRBSDV infection. SRBSDV infection reduced the number and length of fibrous roots in rice. Interestingly, the rhizosphere had higher bacterial diversity and abundance at the initial (0 days) and 30-day postinfection stages, while 30-day-old roots showed increased diversity and abundance. However, there were no significant differences in microbiota diversity between infected and noninfected rice plants. The major rhizosphere microbiota included Proteobacteria, Bacteroidota, Acidobacteriota, and Planctomycetota, comprising about 80% of the community. The endosphere was dominated by Proteobacteria and Cyanobacteria, constituting over 90%, with Bacteroidota as the next most prominent group. Further, we identified differentially expressed genes related to plant–pathogen interactions, plant hormone signal, and ABC transporters, potentially affecting root morphology. Notably, specific bacteria (e.g. Inquilinus and Actinoplanes) showed correlations with these pathways. In conclusion, SRBSDV primarily influences root growth through host metabolism, rather than exerting direct effects on the root microbiota. These insights into the interactions among the pathogen, rice plant, and associated microbiota could have implications for managing SRBSDV’s detrimental effects on rice production.
‘Writing is an Act, the Poem a Weapon and Discussion an Assembly’: The Political Turn in Souffles during Morocco’s 1968
Authors: Stafford Andy
Published: September 2023

Using the recent publication in English translation of an anthology of texts from the Moroccan journal Souffles (Stanford University Press, 2016), this article is part of a wider project that links the journal’s moves to question Négritude with its postcolonial critique of folklorism. It considers the Moroccan journal as an archetypal May 1968 publication; first, by tracing the dramatic shift that Souffles makes between 1966 and 1969 from literary and cultural journal to revolutionary mouthpiece of Marxist anti-Zionism, and which takes place in a period of pan-Arabist crisis and during the social unrest of 1968–1971 in Morocco; and second, by looking closely at the theoretical and philosophical innovations of Abraham Serfaty, alongside the agitational poetry of Abdellatif Laâbi and the political theories emerging in sub-Saharan Africa and the Francophone Caribbean, that appear in Souffles in the wake of May 1968 in France. Finally, it locates an incipient Maoism in the radicalization of Souffles.
Dementia Prevention and Individual and Socioeconomic Barriers: Avoiding “Lifestyle” Stigma
Authors: Wilson Nikki-Anne , Anstey Kaarin J
Published: September 2023

Recent decades have seen exponential growth in research on modifiable risk factors for dementia across the lifespan, which has considerably advanced our understanding of brain health. Not all modifiable risk factors are equal, however, in the ease with which they can be addressed. Some individuals and populations face significant barriers to engaging in dementia risk-reduction behaviors. With the evolution of the dementia prevention field, there is a need to broaden our approach from identifying individual risk factors toward addressing inclusive and globally effective intervention strategies. Here, we argue for a greater awareness of individual and socioeconomic barriers to behavior change-oriented dementia risk reduction. We caution against inadvertently increasing health inequities through “lifestyle” stigma and call for an approach that both harnesses current dementia risk-reduction knowledge and effectively addresses barriers to change. A greater focus on more positive aspects of reducing dementia risk, such as enhancing mental well-being, may also be beneficial. Evidence for the negative ramifications of stigma in dementia is discussed as well as overly simplistic media representations of dementia as a disease, which one can “stave off” through lifestyle. Further, we explore potential negative implications for research funding and policy resulting from stigma. More research regarding the experience of stigma in dementia is needed, across diverse cultural and socioeconomic groups.
The Inner Lives of Cephalopods
Authors: Schnell Alexandra K , Farndale Wright Nathaniel R , Clayton Nicola S
Published: September 2023

Synopsis

The minds of cephalopods have captivated scientists for millennia, yet the extent that we can understand their subjective experiences remains contested. In this article, we consider the sum of our scientific progress towards understanding the inner lives of cephalopods. Here, we outline the behavioral responses to specific experimental paradigms that are helping us to reveal their subjective experiences. We consider evidence from three broad research categories, which help to illuminate whether soft-bodied cephalopods (octopus, cuttlefish, and squid) have an awareness of self, awareness of others, and an awareness of time. Where there are current gaps in the literature, we outline cephalopod behaviors that warrant experimental investigation. We argue that investigations, especially framed through the lens of comparative psychology, have the potential to extend our understanding of the inner lives of this extraordinary class of animals.
The Development and Expansion of in vivo Germline Editing Technologies in Arthropods: Receptor-Mediated Ovary Transduction of Cargo (ReMOT Control) and Beyond
Authors: Terradas Gerard , Macias Vanessa M , Peterson Hillary , McKeand Sage , Krawczyk Grzegorz , Rasgon Jason L
Published: September 2023

Synopsis

In the past 20 years, sequencing technologies have led to easy access to genomic data from nonmodel organisms in all biological realms. Insect genetic manipulation, however, continues to be a challenge due to various factors, including technical and cost-related issues. Traditional techniques such as microinjection of gene-editing vectors into early stage embryos have been used for arthropod transgenesis and the discovery of Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein (CRISPR–Cas) technologies allowed for targeted mutagenesis and the creation of knockouts or knock-ins in arthropods. Receptor-Mediated Ovary Transduction of Cargo (ReMOT Control) acts as an alternative to embryonic microinjections, which require expensive equipment and extensive hands-on training. ReMOT Control’s main advantage is its ease of use coupled with the ability to hypothetically target any vitellogenic species, as injections are administered to the egg-laying adult rather than embryos. After its initial application in the mosquito Aedes aegypti, ReMOT Control has successfully produced mutants not only for mosquitoes but for multiple arthropod species from diverse orders, such as ticks, mites, wasps, beetles, and true bugs, and is being extended to crustaceans, demonstrating the versatility of the technique. In this review, we discuss the current state of ReMOT Control from its proof-of-concept to the advances and challenges in the application across species after 5 years since its development, including novel extensions of the technique such as direct parental (DIPA)-CRISPR.
Systolic anterior motion due to morphology changes in constrictive pericarditis
Authors: Kumagai Yu , Nakajima Hiroyuki , Nakajima Tomomi , Yoshitake Akihiro
Published: September 2023

Systolic anterior motion (SAM) can be caused by multifactorial mechanisms, including structural, morphological and functional factors. We report an unusual case of a 76-year-old woman presenting with SAM associated with constrictive pericarditis. Echocardiography showed no septal hypertrophy but SAM and left ventricular outflow tract obstruction and moderate mitral regurgitation. The restoration of diastolic function after complete pericardiectomy successfully eliminated it.
Night shift work characteristics and risk of incident coronary heart disease among health care workers: national cohort study
Authors: Vestergaard Jesper Medom , Dalbøge Annett , Bonde Jens Peter Ellekilde , Garde Anne Helene , Hansen Johnni , Hansen Åse Marie , Larsen Ann Dyreborg , Härmä Mikko , Costello Sadie , Böttcher Morten , Kolstad Henrik Albert
Published: September 2023

Background

Night work has been associated with coronary heart disease. The present study examined exposure-response relations between quantitative night work characteristics and coronary heart disease (angina pectoris or myocardial infarction) with the aim to contribute to evidence-based recommendations for low-risk night work schedules.

Methods

We followed 100 149 night workers (80% women) and 153 882 day workers (78% women), all health care workers in Denmark with day by day payroll information on night shifts from 2007 to 2015. We analysed data with Poisson regression stratified by sex and adjusted for age, calendar year, diabetes, family history of cardiovascular disease, educational level, occupation, indicators for obesity, hypercholesterolaemia, and hypertension.

Results

Female and male night workers worked on average 1.7 and 1.8 night shifts per month for an average duration of less than 4 years. During follow-up, 1198 night and 2128 day workers were hospitalized with first-time coronary heart disease. When compared with day workers, the overall incidence rate ratios for female and male night workers were 1.06 [95% confidence interval (CI): 0.97, 1.17] and 1.22 (95% CI 1.07, 1.39). Highest risks were observed in top exposure categories for several night work characteristics. However, no consistent exposure-response relations by number of monthly night shifts, cumulative night shifts, years with rotating night shifts, years with any night shift and consecutive night shifts were observed among the night workers of either sex.

Conclusions

This study of a population with low exposure to night work does not indicate that reducing extent of monthly night shifts, cumulative night shifts, years with rotating night shifts, years with any night shift and consecutive night shifts would reduce the risk of coronary heart disease.
Spectral deconvolution of matrix models: the additive case
Authors: Tarrago Pierre
Published: September 2023

We implement a complex analytic method to build an estimator of the spectrum of a matrix perturbed by the addition of a random matrix noise in the free probabilistic regime. This method, which has been previously introduced by Arizmendi, Tarrago and Vargas, involves two steps: the first step consists in a fixed point method to compute the Stieltjes transform of the desired distribution in a certain domain, and the second step is a classical deconvolution by a Cauchy distribution, whose parameter depends on the intensity of the noise. This method thus reduces the spectral deconvolution problem to a classical one. We provide explicit bounds for the mean squared error of the first step under the assumption that the distribution of the noise is unitary invariant. In the case where the unknown measure is sparse or close to a distribution with a density with enough smoothness, we prove that the resulting estimator converges to the measure in the $1$-Wasserstein distance at speed $O(1/\sqrt{N})$, where $N$ is the dimension of the matrix.
Mechanisms that regulate the production of secondary siRNAs in plants
Authors: Fujimoto Yuji , Iwakawa Hiro-oki
Published: September 2023

Many organisms produce secondary small interfering RNAs (siRNAs) that are triggered by primary small RNAs to regulate various biological processes. Plants have evolved several types of secondary siRNA biogenesis pathways that play important roles in development, stress responses and defense against viruses and transposons. The critical step of these pathways is the production of double-stranded RNAs by RNA-dependent RNA polymerases. This step is normally tightly regulated, but when its control is released, secondary siRNA production is initiated. In this article, we will review the recent advances in secondary siRNA production triggered by microRNAs encoded in the genome and siRNAs derived from invasive nucleic acids. In particular, we will focus on the factors, events, and RNA/DNA elements that promote or inhibit the early steps of secondary siRNA biogenesis.
LncRNA H19 Inhibits Keratinocyte Cell Proliferation and Migration by Targeting miR-17-5p/RUNX1 Axis in Chronic Wounds
Authors: Ji Wei , Zhang Qian , Sun Zhibo , Cheng Yanyang
Published: September 2023

The migration and proliferation of keratinocytes are critical for re-epithelization during chronic wound healing. Runt-related transcription factor 1 (RUNX1) has been indicated to repress keratinocyte proliferation. Nonetheless, the potential molecular mechanism of RUNX1 in regulating keratinocyte proliferation and migration remains unclear. Cell counting kit-8 and wound-healing assays were implemented for examining keratinocyte viability and migration, respectively. Western blotting and real-time quantitative polymerase chain reaction were utilized for quantifying protein and RNA levels. Luciferase reporter assay was employed for verifying the interaction between RUNX1, miR-17-5p, and long noncoding RNA H19. The results showed that RUNX1 depletion promoted keratinocyte proliferation and migration and repressed extracellular matrix degradation. Mechanistically, H19 upregulated RUNX1 expression by competitively absorbing miR-17-5p. Rescue experiments revealed that overexpressing RUNX1 reversed H19 silencing-mediated effects on the phenotypes of keratinocytes. In conclusion, H19 knockdown promotes keratinocyte proliferation and migration and suppresses extracellular matrix degradation via the miR-17-5p/RUNX1 axis.
Close competitors? Bilateral bank competition and spatial variation in firms’ access to credit
Authors: De Haas Ralph , Lu Liping , Ongena Steven
Published: September 2023

We interviewed 379 bank CEOs in 20 emerging markets to identify their banks’ main competitors. We show that banks are more likely to identify another bank as a main competitor in small-business lending when both banks are foreign owned or relationship oriented; when there exists a large spatial overlap in their branch networks and when the potential competitor has fewer hierarchical layers. We then construct a novel bilateral competition measure at the locality level and assess how well it explains geographic variation in firms’ credit constraints. We show that intense bilateral bank competition tightens local credit constraints, especially for small firms, as competition may impede the formation of lending relationships.
Abolishing storage lipids induces protein misfolding and stress responses inYarrowia lipolytica
Authors: Zaghen Simone , Konzock Oliver , Fu Jing , Kerkhoven Eduard J
Published: September 2023

Yarrowia lipolytica naturally saves excess carbon as storage lipids. Engineering efforts allow redirecting the high precursor flux required for lipid synthesis toward added-value chemicals such as polyketides, flavonoids, and terpenoids. To redirect precursor flux from storage lipids to other products, four genes involved in triacylglycerol and sterol ester synthesis (DGA1, DGA2, LRO1, and ARE1) can be deleted. To elucidate the effect of the deletions on cell physiology and regulation, we performed chemostat cultivations under carbon and nitrogen limitations, followed by transcriptome analysis. We found that storage lipid-free cells show an enrichment of the unfolded protein response, and several biological processes related to protein refolding and degradation are enriched. Additionally, storage lipid-free cells show an altered lipid class distribution with an abundance of potentially cytotoxic free fatty acids under nitrogen limitation. Our findings not only highlight the importance of lipid metabolism on cell physiology and proteostasis, but can also aid the development of improved chassy strains of Y. lipolytica for commodity chemical production.
Single-cell transcriptomics reveal different maturation stages and sublineage commitment of human thymic invariant natural killer T cells
Authors: Maas-Bauer Kristina , Köhler Natalie , Stell Anna-Verena , Zwick Melissa , Acharya Swati , Rensing-Ehl Anne , König Christoph , Kroll Johannes , Baker Jeanette , Koßmann Stefanie , Pradier Amandine , Wang Sisi , Docquier Mylène , Lewis David B , Negrin Robert S , Simonetta Federico
Published: September 2023

Invariant natural killer T cells are a rare, heterogeneous T-cell subset with cytotoxic and immunomodulatory properties. During thymic development, murine invariant natural killer T cells go through different maturation stages differentiating into distinct sublineages, namely, invariant natural killer T1, 2, and 17 cells. Recent reports indicate that invariant natural killer T2 cells display immature properties and give rise to other subsets, whereas invariant natural killer T1 cells seem to be terminally differentiated. Whether human invariant natural killer T cells follow a similar differentiation model is still unknown. To define the maturation stages and assess the sublineage commitment of human invariant natural killer T cells during thymic development, in this study, we performed single-cell RNA sequencing analysis on human Vα24+Vβ11+ invariant natural killer T cells isolated from thymocytes. We show that these invariant natural killer T cells displayed heterogeneity, and our unsupervised analysis identified 5 clusters representing different maturation stages, from an immature profile with high expression of genes important for invariant natural killer T cell development and proliferation to a mature, fully differentiated profile with high levels of cytotoxic effector molecules. Evaluation of expression of sublineage-defining gene sets revealed mainly cells with an invariant natural killer T2 signature in the most immature cluster, whereas the more differentiated ones displayed an invariant natural killer T1 signature. Combined analysis with a publicly available single-cell RNA sequencing data set of human invariant natural killer T cells from peripheral blood suggested that the 2 main subsets exist both in thymus and in the periphery, while a third more immature one was restricted to the thymus. Our data point to the existence of different maturation stages of human thymic invariant natural killer T cells and provide evidence for sublineage commitment of invariant natural killer T cells in the human thymus.
Mitochondrial aldehyde dehydrogenase rescues against diabetic cardiomyopathy through GSK3β-mediated preservation of mitochondrial integrity and Parkin-mediated mitophagy
Authors: Zhang Yingmei , Zou Rongjun , Abudureyimu Miyesaier , Liu Qiong , Ma Jipeng , Xu Haixia , Yu Wei , Yang Jian , Jia Jianguo , Qian Sanli , Wang Haichang , Yang Yang , Wang Xin , Fan Xiaoping , Ren Jun
Published: September 2023

Mitochondrial aldehyde dehydrogenase (ALDH2) offers proven cardiovascular benefit, although its impact on diabetes remains elusive. This study examined the effects of ALDH2 overexpression and knockout on diabetic cardiomyopathy and the mechanism involved with a focus on mitochondrial integrity. Mice challenged with streptozotocin (STZ, 200 mg/kg, via intraperitoneal injection) exhibited pathological alterations, including reduced respiratory exchange ratio, dampened fractional shortening and ejection fraction, increased left ventricular end-systolic and diastolic diameters, cardiac remodeling, cardiomyocyte contractile anomalies, intracellular Ca2+ defects, myocardial ultrastructural injury, oxidative stress, apoptosis, and mitochondrial damage, which were overtly attenuated or accentuated by ALDH2 overexpression or knockout, respectively. Diabetic patients also exhibited reduced plasma ALDH2 activity, cardiac remodeling, and diastolic dysfunction. In addition, STZ challenge altered expression levels of mitochondrial proteins (PGC-1α and UCP2) and Ca2+ regulatory proteins (SERCA, Na+–Ca2+ exchanger, and phospholamban), dampened autophagy and mitophagy (LC3B ratio, TOM20, Parkin, FUNDC1, and BNIP3), disrupted phosphorylation of Akt, GSK3β, and Foxo3a, and elevated PTEN phosphorylation, most of which were reversed or worsened by ALDH2 overexpression or knockout, respectively. Furthermore, the novel ALDH2 activator torezolid, as well as the classical ALDH2 activator Alda-1, protected against STZ- or high glucose-induced in vivo or in vitro cardiac anomalies, which was nullified by inhibition of Akt, GSK3β, Parkin, or mitochondrial coupling. Our data discerned a vital role for ALDH2 in diabetic cardiomyopathy possibly through regulation of Akt and GSK3β activation, Parkin mitophagy, and mitochondrial function.
Different demographic responses of three species of container Aedes (Diptera: Culicidae) larvae to timing of extrinsic mortality
Authors: Juliano Steven A , McIntire Kristina M , Nichols Hannah O , Canizela Cecilia C , Frederick Kaitlyn M
Published: September 2023

Mortality imposed on a population can interact with negatively density-dependent mortality to produce overcompensation, wherein added mortality results in more survivors. Experimental mortality can cause overcompensation in mosquito larvae, which would be counterproductive if it resulted from mosquito control in nature. We tested for different demographic responses to mortality among 3 container Aedes species when impacted by density dependence. We imposed 48.2% mortality on cohorts of larvae 2, 6, or 8 days after hatching and compared adult production, development times, and female size to those variables for controls without mortality. Mortality significantly increased adult production compared to controls, but the 3 species varied in the details of that response. Aedes albopictus (Skuse) produced more adults with mortality on day 2 primarily because of greater production of males. Aedes triseriatus (Say) yielded more adults with mortality on day 2 primarily because of greater production of females. Aedes aegypti (L.) adult production was not significantly affected by mortality, but development times for both sexes were significantly shorter with mortality on day 8. There were no effects of mortality on female wing length. None of our mortality treatments yielded significant reductions of adults for any species. These species responses to mortality are not the same, despite their similar ecologies and life histories. Thus, we cannot assume that killing almost half the larvae present in a dense population will reduce adult production, nor can we assume that different Aedes species will respond to mortality in the same way.
NFYB increases chemosensitivity in glioblastoma by promoting HDAC5-mediated transcriptional inhibition of SHMT2
Authors: Zhang Yingfan , Huang Haoxuan , Liu Peikun , Xie Yuanyang
Published: September 2023

Temozolomide (TMZ) is a commonly used chemotherapeutic agent for glioblastoma (GBM), but acquired drug resistance prevents its therapeutic efficacy. We investigated potential mechanisms underlying TMZ resistance and glycolysis in GBM cells through regulation by nuclear transcription factor Y subunit β (NFYB) of the oncogene serine hydroxymethyltransferase 2 (SHMT2). GBM U251 cells were transfected with NFYB-, SHMT2-, and the potential NFYB target histone deacetylase 5 (HDAC5)-related vectors. Glucose uptake and lactate production were measured with detection kits. CCK-8/colony formation, scratch, Transwell, and flow cytometry assays were performed to detect cell proliferation, migration, invasion, and apoptosis, respectively. The binding of NFYB to the HDAC5 promoter and the regulation of NFYB on HDAC5 promoter activity were detected with chromatin immunoprecipitation and dual-luciferase reporter assays, respectively. NFYB and HDAC5 were poorly expressed and SHMT2 was expressed at high levels in GBM U251 cells. NFYB overexpression or SHMT2 knockdown decreased glucose uptake, lactate production, proliferation, migration, and invasion and increased apoptosis and TMZ sensitivity of the cells. NFYB activated HDAC5 to inhibit SHMT2 expression. SHMT2 overexpression nullified the inhibitory effects of NFYB overexpression on glycolysis and TMZ resistance. Thus, NFYB may reduce tumorigenicity and TMZ resistance of GBM through effects on the HDAC5/SHMT2 axis.
Attention-Deficit Hyperactivity Disorder Symptoms, Underperception of Respiratory Compromise, and Illness Representations in Black and Latino Children With Asthma
Authors: Fruchter Natalie , Arcoleo Kimberly , Rastogi Deepa , Serebrisky Denise , Warman Karen , Feldman Jonathan M
Published: September 2023

Objective

This study examined the associations between attention-deficit/hyperactivity disorder (ADHD) symptoms, underperception of respiratory compromise, and illness representations in Black and Latino children with asthma. We hypothesized that increased child-reported ADHD symptoms, as well as parent reports for their child, would be associated with underperception of respiratory compromise, and maladaptive asthma beliefs.

Methods

Two hundred ninety-six parent–child dyads were recruited from pediatric asthma and primary care clinics in the Bronx. Participants completed demographic questionnaires, the Conners-3 ADHD Index to measure ADHD symptoms, and the Asthma Illness Representation Scale to assess asthma beliefs. Perception of respiratory compromise was assessed by programmable electronic peak flow monitors that measured the child’s subjective estimates of peak expiratory flow (PEF) and actual PEF, with underperception as the primary measure.

Results

Child-reported ADHD symptoms were associated with greater underperception (β = .117, p = .049) of respiratory compromise. Parent-reported ADHD symptoms were associated with greater underperception (β = .129, p = .028) of respiratory compromise. Child-reported ADHD symptoms (β = −.188, p < .001) were associated with more maladaptive asthma beliefs, F(1, 341) = 13.135. Parent-reported ADHD symptoms (β = −.203, p ≤ .001) were associated with more maladaptive asthma beliefs, F(1, 341) = 15.644.

Conclusions

ADHD symptoms were associated with a greater underperception of respiratory compromise and more maladaptive asthma beliefs. Deficits of attentional processes and/or hyperactivity levels might be contributing factors. We emphasize the need for psychoeducation and interventions that improve perception and health beliefs in children with comorbid ADHD and asthma.
Adverse Childhood Events and Chronic Pain in Adolescents: The Role of Sleep Disturbance
Authors: Roman-Juan Josep , Solé Ester , Sánchez-Rodríguez Elisabet , Castarlenas Elena , Jensen Mark P , Miró Jordi
Published: September 2023

Objectives

This study aimed to (1) examine the extent to which the association between exposure to adverse childhood events (ACEs) and having chronic pain in adolescents is explained by the association between exposure to ACEs and sleep disturbance and (2) explore the role of sleep disturbance in the association between exposure to ACEs and anxiety and depressive symptoms in adolescents with chronic pain.

Methods

Cross-sectional data from 469 adolescents aged 13–18 years old were drawn from an epidemiological study on pediatric chronic pain conducted in Catalonia (Spain). Participants provided self-reports of demographic characteristics, exposure to ACEs, pain characteristics, sleep disturbance, anxiety, and depressive symptoms. Mediation and moderation models were conducted.

Results

Sleep disturbance explained a significant amount of the variance in the association between exposure to ACEs and the presence of chronic pain. Moreover, sleep disturbance explained a significant amount of the variance in the association between exposure to ACEs and depressive symptoms and moderated the association between exposure to ACEs and anxiety in adolescents with chronic pain.

Conclusion

The study findings suggest the possibility that addressing sleep disturbance in adolescents exposed to ACEs may help to prevent the development of chronic pain, anxiety, and depressive symptoms in those adolescents who already have chronic pain.
Trimethoprim–Sulfamethoxazole for Pediatric Osteoarticular Infections
Authors: McDaniel Lauren M , Fiawoo Suiyini , Tamma Pranita D , Same Rebecca G
Published: September 2023

Background

Trimethoprim–sulfamethoxazole (TMP–SMX) is active against most Staphylococcus aureus isolates but is not widely used for the treatment of pediatric osteoarticular infections.

Methods

This was a comparative effectiveness study of hospitalized patients ≤18 years treated with TMP–SMX vs. other antibiotic regimens for acute osteoarticular infections between 2016 and 2021 at 3 hospitals using inverse probability of treatment weighted propensity score analysis. The primary outcome was treatment failure, a composite of unanticipated emergency department (ED) or outpatient visits, hospital readmissions, extension, or change of antibiotic therapy due to inadequate clinical response, or death, all within 6 months after completing antibiotics. The secondary outcome was antibiotic-associated adverse events (AEs) within 6 months. The exposed group for the treatment failure analysis included children who received ≥7 days of TMP–SMX and did not experience treatment failure while on another antibiotic. Children receiving at least 1 dose of TMP–SMX were the exposed group for the AE analysis.

Results

One-hundred and sixteen patients met eligibility criteria; 26 (22.4%) patients were classified into the TMP–SMX cohort and 90 (77.6%) into the other antibiotics cohort (most commonly clindamycin, vancomycin, and cefazolin). There was no significant difference in treatment failure between TMP–SMX and other antibiotics (43% vs. 19%; 95% CI .9–10.4). More patients in the TMP–SMX cohort experienced an unplanned ED or outpatient visit (OR 4.8, 95% CI 1.3–17.8). There was no difference in hospital readmission, antibiotic change, or duration extension. Exposure to TMP–SMX was associated with more AEs (41% vs. 19%, P = .012).

Conclusions

Treatment with TMP–SMX was not associated with greater clinical failure but was associated with more AEs compared to alternative agents for the treatment of pediatric acute osteoarticular infections.
Novel peptide calcitonin gene-related peptide antagonists for migraine therapy
Authors: Killoran Patrick M , Capel Vicky , D’Aloisio Vera , Schofield Adam , Aczél Tímea , Bölcskei Kata , Helyes Zsuzsanna , von Mentzer Bengt , Kendall David A , Coxon Chris R , Hutcheon Gillian A
Published: September 2023

Objectives

It has previously been shown that the peptide (34Pro,35Phe)CGRP27–37 is a potent calcitonin gene-related peptide, CGRP receptor antagonist, and in this project we aimed to improve the antagonist potency through the structural modification of truncated C-terminal CGRP peptides.

Methods

Six peptide analogues were synthesized and the anti-CGRP activity confirmed using both in vitro and in vivo studies.

Key findings

A 10 amino acid-containing peptide VPTDVGPFAF-NH2 (P006) was identified as a key candidate to take forward for in vivo evaluation, where it was shown to be an effective antagonist after intraperitoneal injection into mice. P006 was formulated as a preparation suitable for nasal administration by spray drying with chitosan to form mucoadhesive microcarriers (9.55 ± 0.91 mm diameter) and a loading of 0.2 mg peptide per 20 mg dose.

Conclusions

The project has demonstrated the potential of these novel small peptide CGRP antagonists, to undergo future preclinical evaluation as anti-migraine therapeutics.