bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep Learning in Magnetic Resonance Enterography for Crohn’s Disease Assessment: A Systematic Review
Authors: Brem Ofir , Elisha David , Konen Eli , Amitai Michal , Klang Eyal
Published: December 2023

Crohn’s disease (CD) poses significant morbidity, underscoring the need for effective, non-invasive inflammatory assessment using magnetic resonance enterography (MRE).

This literature review evaluates recent publications on deep learning’s role in enhancing MRE segmentation, image quality, and visualization of inflammatory activity related to CD.

We searched MEDLINE/PUBMED for studies that reported the use of deep learning algorithms for assessment of CD activity. The study was conducted according to the PRISMA guidelines. The risk of bias was evaluated using the QUADAS_J2 tool.

Five eligible studies, encompassing 468 subjects, were identified.

Our study suggests that diverse deep learning applications, including image quality enhancement, bowel segmentation, and motility measurement are useful and promising for CD assessment. However, most of the studies are preliminary, retrospective studies, and have a high risk of bias in at least one category.

Future research is needed to assess how automated deep learning can impact patient care, especially when considering the increasing integration of these models into hospital systems.
Using the illness-death model to estimate age- and sex-standardized incidence rates of diabetes in Mexico from 2003 to 2015
Authors: Silverman-Retana Omar , Brinks Ralph , Hoyer Annika , Witte Daniel R. , Tönnies Thaddäus
Published: December 2023

Objectives

To estimate the age-specific and age-standardized incidence rate of diabetes for men and women in Mexico between 2003 and 2015, and to assess the relative change in incidence of diabetes between 2003 and 2015.

Methods

We use a partial differential equation describing the illness-death model to estimate the incidence rate (IR) of diabetes for the years 2003, 2009 and 2015 based on prevalence data from National Health Surveys conducted in Mexico, the mortality rate of the Mexican general population and plausible input values for age-specific mortality rate ratios associated with diabetes.

Results

The age-standardized IR of diabetes per 1000 person years (pryr) was similar among men (IRm) and women (IRw) in the year 2003 (IRm 6.1 vs. IRw 6.5 1000/pryr), 2009 (IRm: 7.0 vs. IRw: 8.4 1000/pryr), and in 2015 (IRm 8.0 vs. IRw 10.6 1000/pryr).

Conclusions

The incidence rate of diabetes in Mexico between the years 2003 and 2015 remained stable. However, rates were markedly higher among women in the age group 40-49 and 50-59 in the year 2015 compared with rates in 2003.
Evaluation of a training course for general practitioners within the Melanoma Multimedia Education Programme of the Italian Melanoma Intergroup: study protocol
Authors: Stanganelli Ignazio , Magi Serena , Bucchi Lauro , Crocetti Emanuele , Mancini Silvia , Vattiato Rosa , Falcinelli Stefano , Re Patrizia , Melandri Davide , Brusasco Marco , Gandini Sara , Falcini Fabio , Zamagni Federica ,   the FAD MelaMEd Working Group
Published: December 2023

The text discusses the role of general practitioners (GPs) in the prevention and early diagnosis of melanoma, a type of skin cancer. It highlights the need for GPs to be able to recognize suspicious skin lesions and refer patients to specialist dermatology centers. However, many GPs lack comprehensive training in diagnosing melanoma. The text mentions that various training courses have been conducted for GPs, but their impact on clinical practice has been limited.

The “MelaMEd Programme” is an e-learning course developed by the Italian Melanoma Intergroup (IMI). The program aims to provide GPs with comprehensive knowledge of melanoma prevention, diagnosis, and treatment. It includes an e-learning section and a dedicated platform called MelaMEd platform, which offers a multimedia atlas of melanoma.

The objective of the study is to evaluate the impact of the MelaMEd programme on GPs’ diagnostic accuracy, knowledge of melanoma, and management of suspicious lesions. The methodology involves administering pre-training and post-training questionnaires to participants, assessing their diagnostic skills and evaluating the training course’s effectiveness.

The study aims to demonstrate the effectiveness of the MelaMEd programme in improving GPs’ ability to recognize and manage melanoma. It also seeks to identify areas for improvement and recommend interventions to enhance diagnostic accuracy. The results will be analyzed statistically using descriptive, univariate, and multivariate analysis methods.
Investigating the spatial accessibility and coverage of the pediatric COVID-19 vaccine: an ecologic study of regional health data
Authors: Bemanian Amin , Mosser Jonathan F
Published: December 2023

Background

The COVID-19 pandemic presented healthcare workers and public health agency a unique challenge of having to rapidly deliver a novel set of vaccines during a public health crisis. For pediatric patients, there was an additional layer of complexity given the delayed timeline to deliver these vaccines and the differences in dosing and available products depending on the age of those receiving the vaccine. This paper investigates the spatial accessibility and uptake of the COVID-19 vaccine in King County, WA, USA.

Methods

Public data for COVID-19 vaccine sites to calculate spatial accessibility using an enhanced two step floating catchment area (E2SFCA) technique. Spatial regression analyses were done looking at the relationship between spatial accessibility and ZIP code level vaccination rates. Relationships with other socioeconomic and demographic variables were calculated as well.

Findings

Higher rates of vaccine accessibility and vaccine coverage were found in adolescent (12 to 17-year-old) individuals relative to school age (5 to 11-year-old) individuals. Vaccine accessibility was positively associated with coverage in both age groups in the univariable analysis. This relationship was affected by neighborhood educational attainment.

Interpretation

This paper successfully demonstrates how spatial accessibility measures such as E2SFCA can be used to assess the availability of the COVID-19 vaccine in a region such as a metropolitan area or county. It also provides insight into some of the ecological factors that affect COVID-19 vaccination rates. Implementation of these technique could help public health authorities and healthcare organization plan future vaccination efforts.
Resistance to cortical amyloid-beta associates with cognitive health in centenarians
Authors: Rohde Susan K. , Fierro-Hernández Patricia , Rozemuller Annemieke J.M. ,   Netherlands Brain Bank, Lorenz Linda M.C. , Zhang Meng , Graat Marieke , van der Hoorn Myke , Daatselaar Dominique , Hulsman Marc , Scheltens Philip , Sikkes Sietske A.M. , Hoozemans Jeroen J.M. , Holstege Henne
Published: December 2023

BACKGROUND

Amyloid-beta(Aβ)-plaques accumulate in non-demented individuals, particularly at advanced ages. The unclear association between Aβ-pathology and cognition in elderly raises the question whether Aβ-pathology should be considered a benign consequence of aging.

METHODS

Post-mortem brains of 95 centenarians and 27 Alzheimer’s disease(AD) patients were evaluated for Aβ-plaque distribution according to the Thal phase and quantitative Aβ-load in the neocortex. For centenarians, Aβ-pathology was correlated toAPOE-genotype and performance on 12 cognitive tests administered shortly before death.

FINDINGS

While 35% of centenarians exhibited Aβ-loads similar to AD patients, cortical Aβ-load was limited in 65% of centenarians, some of which had the highest Thal phase. Cortical Aβ-load, as opposed to Thal phase, associated withAPOE-genotype and cognitive performance in centenarians.

DISCUSSION

Despite increasing Aβ-accumulation in various brain regions with age, actual Aβ-loads remain low in cognitively healthy centenarians. Therefore, Aβ-pathology in the oldest-old may not be considered a benign consequence of aging.
Exposure to Wood dust and its Respiratory Health Effects Among Wood Workers in Yaoundé (Cameroon)
Authors: Takougang Innocent , Bukam Guemnyen Gilles Wilfried , Edzamba Michel Franck , Lekeumo Cheuyem Fabrice Zobel , Assomo Ndemba Peguy Brice , Pefura Walter Yone
Published: December 2023

Background

Occupational respiratory diseases are responsible of one-third of all documented work-related deaths. Exposure to wood dust leads to multiple respiratory manifestations including cough, chest pain, asthma and altered lung function. The aim of this study was to assess the level of exposure to wood dust and its respiratory health correlates among woodworkers in Yaoundé.

Methodology

The present descriptive cross-sectional study was conducted in 37 carpentry workshops in the city of Yaoundé. From October 2021 to February 2022. The geographical site selection was purposeful, taking into account areas with large numbers of workers and woodworker shop. Woodworker shops were enumerated and randomly selected. Respiratory manifestations were assessed upon a clinical respiratory examination involving cough, expectoration, wheezing and dyspnea. The force expiratory volume was determined using a dry spirometer. Statistical analyses were performed using IBM SPSS version 23.0 software; tables and graphs were generated using Excel 2013 software. The significance level was set at 0.05.

Results

The study population was exclusively male, with a mean age of 34.04 ± 11.69 years. With 15.02 ± 12 years of woodwork experience. The respiratory symptoms reported were cough that was productive (41.8%) or dry (33.6%), chest pain (34.4%), dyspnea (41%) and wheezing (15.6%). The lung function decreased among the duration of woodwork experience.

Conclusion

Respiratory manifestation among woodworkers were reported. And there is a urgent need to implement woodwork safety measures including education on exposure and adherence to protective measure.
Discovery and Optimization of Narrow Spectrum Inhibitors of Tousled Like Kinase 2 (TLK2) Using Quantitative Structure Activity Relationships
Authors: Asquith Christopher R. M. , East Michael P. , Laitinen Tuomo , Alamillo-Ferrer Carla , Hartikainen Erkka , Wells Carrow I , Axtman Alison D. , Drewry David H. , Tizzard Graham J. , Poso Antti , Willson Timothy M. , Johnson Gary L.
Published: December 2023

The oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was a potent off-target kinase. The oxindole has long been considered a promiscuous inhibitor template, but across these 4 specific literature oxindoles TLK2 activity was consistent, while the kinome profile was radically different from narrow to broad spectrum coverage. We synthesized a large series of analogues and through quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites, small-molecule x-ray structural analysis and kinome profiling, narrow spectrum, sub-family selective, chemical tool compounds were identified to enable elucidation of TLK2 biology.
Tying the Knot: Unraveling the Intricacies of the Coronavirus Frameshift Pseudoknot
Authors: Trinity Luke , Stege Ulrike , Jabbari Hosna
Published: December 2023

Understanding and targeting functional RNA structures towards treatment of coronavirus infection can help us to prepare for novel variants of SARS-CoV-2 (the virus causing COVID-19), and any other coronaviruses that could emerge via human-to-human transmission or potential zoonotic (inter-species) events. Leveraging the fact that all coronaviruses use a mechanism known as -1 programmed ribosomal frameshifting (-1 PRF) to replicate, we apply algorithms to predict the most energetically favourable secondary structures (each nucleotide involved in at most one pairing) that may be involved in regulating the -1 PRF event in coronaviruses, especially SARS-CoV-2. We compute previously unknown most stable structure predictions for the frameshift site of coronaviruses via hierarchical folding, a biologically motivated framework where initial non-crossing structure folds first, followed by subsequent, possibly crossing (pseudoknotted), structures. Using mutual information from 181 coronavirus sequences, in conjunction with the algorithm KnotAli, we compute secondary structure predictions for the frameshift site of different coronaviruses. We then utilize the Shapify algorithm to obtain most stable SARS-CoV-2 secondary structure predictions guided by frameshift sequence-specific and genome-wide experimental data. We build on our previous secondary structure investigation of the singular SARS-CoV-2 68 nt frameshift element sequence, by using Shapify to obtain predictions for 132 extended sequences and including covariation information. Previous investigations have not applied hierarchical folding to extended length SARS-CoV-2 frameshift sequences. By doing so, we simulate the effects of ribosome interaction with the frameshift site, providing insight to biological function. We contribute in-depth discussion to contextualize secondary structure dual-graph motifs for SARS-CoV-2, highlighting the energetic stability of the previously identified 3_8 motif alongside the known dominant 3_3 and 3_6 (native-type) -1 PRF structures. Integrating experimental data within minimum free energy (MFE) hierarchical folding algorithms provides novel structure predictions to distill the relationship between RNA structure and function. In particular, fully categorizing most stable secondary structure predictions via hierarchical folding supports our identification of motif transitions and critical site targets for future therapeutic research.
Replication-driven HBV cccDNA loss in chimeric mice with humanized livers
Authors: Zhang Bai-Hua , Zhou Yuanping , Tempel Ben , Pan Honggang , Horrigan Stephen , Luckenbaugh Laura , Zoulim Fabien , Hu Jianming , Zhang Yong-Yuan
Published: December 2023

Hepatitis B virus (HBV) infection is largely noncytopathic and requires the establishment of covalently closed circular DNA (cccDNA), which is considered stable in the nuclei of infected cells. Although challenging, approaches to directly target cccDNA molecules or kill infected cells are recommended to eliminate cccDNA. Herein, cccDNA levels were investigated in HBV-infected chimeric mice with humanized livers. HBV-infected cells support robust replication, progressively retain viral products, and head for cytopathic destruction and cccDNA loss. It is difficult for infected cells to retain cccDNA and remain noncytopathic. Replication-driven cccDNA loss is observed at both phases of spread of and persistent infection. The cccDNA replenishment is required to compensate for cccDNA loss. Blocking cccDNA replenishment pathways reduces cccDNA levels by >100-fold. These results prove an unconventional cccDNA elimination strategy that does not directly target cccDNA but aims to transform spontaneous cccDNA loss into progressive cccDNA elimination by blocking cccDNA replenishment.
Preliminary Insights into the Effects of Spinal Manipulation Therapy of Different Force Magnitudes on Blood Biomarkers of Oxidative Stress and Pro-Resolution of Inflammation Mediators
Authors: Duarte Felipe C. K. , Funabashi Martha , Starmer David , Partata Wania A.
Published: December 2023

Introduction

Evidence has reported that spinal manipulation therapy (SMT) leads to spine segmental hypoalgesia through neurophysiological and peripheral mechanisms related to regulating inflammatory biomarker function. However, these studies also showed substantial inter-individual variability in the biomarker responses. Such variability may be due to the incomplete understanding of the fundamental effects of force-based manipulations (e.g., patient-specific force-time characteristics) on a person’s physiology in health and disease. This study investigated the short-term effects of distinct SMT force-time characteristics on blood oxidative stress and pro-resolution of inflammation biomarkers.

Methods

Nineteen healthy adults were clustered into three groups: control (preload only), target total peak force of 400N, and 800N. A validated force-sensing table technology (FSTT®) determined the SMT force-time characteristics. Blood samples were collected at pre-intervention, immediately after SMT, and 20 minutes post-intervention. Parameters of the oxidant system (total oxidant status, lipid peroxidation and lipid hydroperoxide), the antioxidant system (total antioxidant capacity and bilirubin), and lipid-derived resolvin D1 were evaluated in plasma and erythrocytes through enzyme-linked immunosorbent assay and colorimetric assays.

Results

Overall, 400N seemed to decrease blood oxidants, and 800N generally increased blood oxidants, decreased antioxidants and resolvin D1 mediator

Conclusion

Our findings indicate that different single SMT force-time characteristics presented contrasting effects on the systemic redox signalling biomarkers and pro-resolution of inflammation mediators in healthy participants, providing baseline information and direction for future studies in a clinical population.
Modeling the simultaneous dynamics of proteins in blood plasma and the cerebrospinal fluid in humanin vivo
Authors: Giroux Pierre , Vialaret Jérôme , Kindermans Jana , Gabelle Audrey , Bauchet Luc , Hirtz Christophe , Lehmann Sylvain , Colinge Jacques
Published: December 2023

The analysis of protein dynamics or turnover in patients has the potential to reveal altered protein recycling such as in Alzheimer disease, and to provide informative data regarding drug efficacy, or certain biological processes. The observed protein dynamics in a solid tissue or a fluid is the net result of protein synthesis and degradation, but also transport across biological compartments. We report an accurate 3-biological compartment model able simultaneously account for the protein dynamics observed in blood plasma and the cerebrospinal fluid (CSF) including a hidden central nervous system (CNS) compartment. We successfully applied this model to 69 proteins of a single individual displaying similar or very different dynamics in plasma and CSF. This study put a strong emphasis on the methods and tools needed develop this type of model. We believe it will be useful to any researcher dealing with protein dynamics data modeling.
Cross-Species Variability in Lobular Geometry and Cytochrome P450 Hepatic Zonation: Insights into CYP1A2, CYP2E1, CYP2D6 and CYP3A4
Authors: Albadry Mohamed , Küttner Jonas , Grzegorzewski Jan , Dirsch Olaf , Kindler Eva , Klopfleisch Robert , Liska Vaclav , Moulisova Vladimira , Nickel Sandra , Palek Richard , Rosendorf Jachym , Saalfeld Sylvia , Settmacher Utz , Tautenhahn Hans-Michael , König Matthias , Dahmen Uta
Published: December 2023

This study explores the critical interplay between lobular geometry and the zonated distribution of cytochrome P450 (CYP) enzymes across species. We present an innovative approach to assess lobular geometry and zonation patterns using whole slide imaging (WSI). This method allows a detailed, systematic comparison of lobular structures and spatial distribution of key CYP450 enzymes and glutamine synthetase in four different species (mouse, rat, pig, and human). Our results shed light on species differences in lobular geometry and enzymatic zonation, providing critical insights for drug metabolism research. Based on our approach we could determine the minimum number of lobules required for a statistically representative analysis, an important piece of information when evaluating liver biopsies and deriving information from WSI.
A single-cell transposable element atlas of human cell identity
Authors: Reyes-Gopar Helena , Marston Jez L , Singh Bhavya , Greenig Matthew , Lin Jonah , Ostrowski Mario A , Randall Kipchoge N , Sandoval-Motta Santiago , Dopkins Nicholas , Lawrence Elsa , O'Mara Morgan M , Fei Tongyi , Duarte Rodrigo R. R. , Powell Timothy R , Hernandez-Lemus Enrique , Iniguez Luis P , Nixon Douglas F , Bendall Matthew L
Published: December 2023

Single cell RNA sequencing (scRNA-seq) is revolutionizing the study of complex biological systems. However, most sequencing studies overlook the contribution of transposable element (TE) expression to the transcriptome. In both scRNA-seq and bulk tissue RNA sequencing (RNA-seq), quantification of TE expression is challenging due to repetitive sequence content and poorly characterized TE gene models. Here, we developed a tool and analysis pipeline for Single cell Transposable Element Locus Level Analysis of scRNA Sequencing (Stellarscope) that reassigns multi-mapped reads to specific genomic loci using an expectation-maximization algorithm. Using Stellarscope, we built an atlas of TE expression in human PBMCs. We found that locus-specific TEs delineate cell types and define new cell subsets not identified by standard mRNA expression profiles. Altogether, this study provides comprehensive insights into the influence of transposable elements in human biology.
Eukfinder: a pipeline to retrieve microbial eukaryote genomes from metagenomic sequencing data
Authors: Zhao Dandan , Salas-Leiva Dayana E. , Williams Shelby K. , Dunn Katherine A. , Roger Andrew J.
Published: December 2023

Whole-genome shotgun (WGS) metagenomic sequencing of microbial communities allows us to discover the functions, physiologies, and evolutionary histories of microbial prokaryote and eukaryote members of diverse ecosystems. Despite their importance, metagenomic studies of microbial eukaryotes lag behind those of prokaryotes, due to the difficulty in identifying and assembling high-quality eukaryotic genomes from WGS data. To address this problem, we have developed Eukfinder, a bioinformatics pipeline that recovers and assembles nuclear and mitochondrial genomes of eukaryotic microbes from WGS metagenomics data. As part of its workflow, it utilizes two specialized databases to classify reads based on taxonomy which can be customized to the dataset or environment of interest. We applied Eukfinder to human gut microbiome WGS metagenomic sequencing data to recover genomes from the protistan parasiteBlastocystissp., a highly prevalent colonizer of the gastrointestinal tract of humans and animals. We tested Eukfinder using both a series of simulated gut microbiome datasets, which included varying numbers ofBlastocystisreads combined with bacterial reads and by using real metagenomic gut samples containingBlastocystis.We compared the results of Eukfinder with other published workflows. With sufficient reads, Eukfinder efficiently assembles high-quality near-complete nuclear and mitochondrial genomes from diverseBlastocystissubtypes from metagenomic data without the aid of a reference genome. Furthermore, with sufficient depth of sequence sampling, Eukfinder outperforms similar tools used to recover eukaryotic genomes from metagenomic data. Eukfinder will be a useful tool for reference-independent and cultivation-free study of eukaryotic microbial genomes from environmental metagenomic sequencing samples.

IMPORTANCE

Rapid advancements in next-generation sequencing technologies have made whole-genome shotgun (WGS) metagenomic sequencing an efficient method forde novoreconstruction of microbial genomes from samples taken from different environments. So far, thousands of new prokaryotic genomes have been characterized from strains or species that were unknown to science. However, the relatively large size and complexity of protistan genomes has, until recently, precluded the use of the WGS metagenomic approach to sample microbial eukaryotic diversity. The bioinformatics pipeline we developed, Eukfinder, can recover eukaryotic microbial genomes from environmental WGS metagenomic samples. By retrieving high-quality protistan genomes from diverse metagenomic samples, we can increase numbers of reference genomes available to aid future metagenomic investigations into the functions, physiologies, and evolutionary histories of eukaryotic microbes in the gut microbiome and a variety of other ecosystems.
Novel inhibitors of TTLL12’s oncogenic potential that overcome suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin
Authors: Deshpande Amit , Brants Jan , Wasylyk Christine , van Hooij Onno , Verhaegh Gerald W , Maas Peter , Schalken Jack A , Wasylyk Bohdan
Published: December 2023

Tubulin tyrosine ligase 12 (TTLL) is a promising target for therapeutic intervention since it has been implicated in tumour progression, the innate immune response to viral infection, ciliogenesis and abnormal cell division. It is the most mysterious of a fourteen-member TTL/TTLL family, since, although it is the topmost conserved in evolution, it does not have predicted enzymatic activities. TTLL12 seems to act as a pseudo-enzyme that modulates various processes indirectly. Given the need to target its functions, we initially set out to identify a property of TTLL12 that could be used to develop a reliable high-throughput screening assay. We discovered that TTLL12 suppresses the cell toxicity of nitrotyrosine (3-nitrotyrosine) and its ligation to the C-terminus of detyrosinated α-tubulin (abbreviated to ligated-nitrotyrosine). Nitrotyrosine is produced by oxidative stress and is associated with cancer progression. Ligation of nitrotyrosine has been postulated to be a check-point induced by excessive cell stress. We found that the cytotoxicities of nitrotyrosine and tubulin poisons are independent of one another, suggesting that drugs that increase nitrotyrosination could be complementary to current tubulin-directed therapeutics. TTLL12 suppression of nitrotyrosination of α-tubulin was used to develop a robust cell-based ELISA assay that detects increased nitrotyrosination in cells that overexpress TTLL12 We adapted it to a high throughput format and used it to screen a 10,000 molecule World Biological Diversity SETTMcollection of low-molecular weight molecules. Two molecules were identified that robustly activate nitrotyrosine ligation at 1 μM concentration. This is the pioneer screen for molecules that modulate nitrotyrosination of α-tubulin. The molecules from the screen will be useful for the study of TTLL12, as well as leads for the development of drugs to treat cancer and other pathologies that involve nitrotyrosination.
Moonlight Polarisation Pattern Guides Nocturnal Bull Ants Home
Authors: Freas Cody A , Narendra Ajay , Murray Trevor , Cheng Ken
Published: December 2023

For the first time in any animal, we show that nocturnal bull ants use the exceedingly dim polarisation pattern produced by the moon for overnight navigation. The sun or moon can provide directional information via their position; however, they can often be obstructed by clouds, canopy or the horizon. Despite being hidden, these bodies can still provide compass information through the polarised light pattern they produce/reflect. Sunlight produces polarised light patterns across the overhead sky as it enters the atmosphere, and solar polarised light is a well-known compass cue for navigating animals. Moonlight produces an analogous pattern, albeit a million times dimmer than sunlight. Here we show the first evidence that polarised moonlight forms part of the celestial compass of navigating nocturnal ants. Nocturnal bull ants leave their nest at twilight and rely heavily on the overhead solar polarisation pattern to navigate. Yet many foragers return home overnight when the sun cannot guide them. We demonstrate that these bull ants use polarised moonlight to navigate home during the night, by rotating the ambient polarisation pattern above homing ants, who alter their headings in response. Furthermore, these ants can detect this cue throughout the lunar month, even under crescent moons, when polarised light levels are at their lowest. Finally, we show long-term incorporation of this moonlight pattern into the ants path integration system throughout the night for homing, as polarised sunlight is incorporated throughout the day.
Structural insights into rice KAI2 receptor provide functional implications for perception and signal transduction
Authors: Guercio Angelica M. , Gilio Amelia K. , Pawlak Jacob , Shabek Nitzan
Published: December 2023

KAI2 proteins, classified as plant α/β hydrolase receptors, are capable of perceiving smoke-derived butenolide signals and endogenous, yet unidentified KAI2-ligands (KLs). While the number of functional KAI2 receptors varies among land plant species, rice possesses only one KAI2 gene. Rice, a significant crop and representative of grasses, relies on KAI2-mediated Arbuscular mycorrhiza (AM) symbioses to flourish in traditionally arid and nutrient-poor environments. This study presents the first crystal structure of an active rice KAI2 hydrolase receptor. Our structural and biochemical analyses uncover grass-unique pocket residues influencing ligand sensitivity and hydrolytic activity. Through structure-guided analysis, we identify a specific residue whose mutation enables the increase or decrease of ligand perception, catalytic activity, and signal transduction. Furthermore, we investigate rice KAI2-mediated signaling by examining its ability to form a complex with its binding partner, the F-box protein DWARF3 (D3) ubiquitin ligase, demonstrating the significant role of hydrophobic interactions in the KAI2-D3 interface. This study provides new insights into the diverse and pivotal roles of the KAI2 signaling pathway in the plant kingdom, particularly in grasses.
A targeted CRISPR-Cas9 mediated F0 screen identifies genes involved in establishment of the enteric nervous system
Authors: Moreno-Campos Rodrigo , Singleton Eileen W. , Uribe Rosa A.
Published: December 2023

The vertebrate enteric nervous system (ENS) is a crucial network of enteric neurons and glia resident within the entire gastrointestinal tract (GI). Overseeing essential GI functions such as gut motility and water balance, the ENS serves as a pivotal bidirectional link in the gut-brain axis. During early development, the ENS is primarily derived from enteric neural crest cells (ENCCs). Disruptions to ENCC development, as seen in conditions like Hirschsprung disease (HSCR), lead to absence of ENS in the GI, particularly in the colon. In this study, using zebrafish, we devised anin vivoF0 CRISPR-based screen employing a robust, rapid pipeline integrating single-cell RNA sequencing, CRISPR reverse genetics, and high-content imaging. Our findings unveil various genes, including those encoding for opioid receptors, as possible regulators of ENS establishment. In addition, we present evidence that suggests opioid receptor involvement in neurochemical coding of the larval ENS. In summary, our work presents a novel, efficient CRISPR screen targeting ENS development, facilitating the discovery of previously unknown genes, and increasing knowledge of nervous system construction.
Obesity modifies cell fate plasticity ofPdgfrα-expressing adipocyte progenitors to promote an aberrant mammary microenvironment
Authors: Kwende Sharon A. , Nuthalapati Prashant , Sunder Singh Jacqulene P. , Maity Subhajit , Ning Dun , Shryock Douglas G. , Xuan Zhenyu , Joshi Purna A.
Published: December 2023

Excess fat gain culminating in obesity is a mounting global pandemic associated with a myriad of diseases including a higher risk of developing multiple cancers such as breast cancer. The underlying biological basis for obesity-linked breast cancer is attributed to alterations in adipose tissue-derived endocrine, metabolic and inflammatory factors. However, the precise cell types responsible for generating a cancer-susceptible mammary gland in obesity are not well understood. Using diet-induced obesity in conjunction with genetic reporter mouse models, we reveal elevated mammary adipocyte progenitors (MAPs) expressing Platelet-Derived Growth Factor Receptor alpha (PDGFRα) in the mammary tissue microenvironment during obesity. Single-cell RNA sequencing analysis demonstrate intensified obesity-driven trajectories of MAPs to immune and epithelial progenitor cells. Further, lineage tracing indicates an invasive cellular state of MAPs that confers greater access of MAP descendants into the mammary epithelium concomitant with their transition into immune and epithelial cell fates. MAPs in obesity exhibit heightened activation of cancer-associated and inflammatory pathways whereEgfris identified as a common target upregulated in MAPs. Mechanistic studies on purified MAPs with a major obesity diet component and EGFR stimulation corroborate dynamic EGFR-mediated MAP responses. Our findings uncover MAPs as key contributors to forging an aberrant mammary gland in obesity, providing insight into the potential utility of targeting this cell lineage for eradicating cancer risk related to augmented adiposity.
Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape
Authors: Cook Ashley L , Sur Surojit , Dobbyn Laura , Watson Evangeline , Cohen Joshua D , Ptak Blair , Lee Bum Seok , Paul Suman , Hsiue Emily , Popoli Maria , Vogelstein Bert , Papadopoulos Nickolas , Bettegowda Chetan , Gabrielson Kathy , Zhou Shibin , Kinzler Kenneth W , Wyhs Nicolas
Published: December 2023

Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD. This screen implicated disruption of kinase SMG1’s phosphorylation of UPF1 as a potential disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from truncating mutationsin vivoandin vitro. Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable HLA class I-associated peptides from NMD-downregulated proteins on the surface of cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases.

One Sentence Summary

Disruption of the nonsense-mediated decay pathway with a newly developed SMG1 inhibitor within-vivoactivity increases the expression of T-cell targetable cancer neoantigens resulting from truncating mutations.
Single tissue proteomics inCaenorhabditis elegansreveals proteins resident in intestinal lysosome-related organelles
Authors: Tan Chieh-Hsiang , Wang Ting-Yu , Park Heenam , Lomenick Brett , Chou Tsui-Fen , Sternberg Paul W.
Published: December 2023

The nematode intestine is the primary site for nutrient uptake and storage as well as the synthesis of biomolecules; lysosome-related organelles known as gut granules are important for many of these functions. Aspects of intestine biology are not well understood, including the export of the nutrients it imports and the molecules it synthesizes, as well as the complete functions and protein content of the gut granules. Here, we report a mass spectrometry-based proteomic analysis of the intestine of theCaenorhabditis elegansand of its gut granules. Overall, we identified approximately 5,000 proteins each in the intestine and the gonad and showed that most of these proteins can be detected in samples extracted from a single worm, suggesting the feasibility of individual-level genetic analysis using proteomes. Comparing proteomes and published transcriptomes of the intestine and the gonad, we identified proteins that appear to be synthesized in the intestine and then transferred to the gonad. To identify gut granule proteins, we compared the proteome of individual intestines deficient in gut granules to the wild-type. The identified gut granule proteome includes proteins known to be exclusively localized to the granules and additional putative novel gut granule proteins. We selected two of these putative gut granule proteins for validation via immunohistochemistry, and our successful confirmation of both suggests that our strategy was effective in identifying the gut granule proteome. Our results demonstrate the practicability of single tissue mass-spectrometry- based proteomic analysis in small organisms and in its utility for making discoveries.

Significance statement

We show that tissue-specific proteomic analysis is achievable and can be done efficiently at an individual level in a small nematode, with resolution sufficient for genetic analysis on a single animal basis. With data collected from single animals, we produced high-quality sets of proteins that described the proteomes of the gonad and the intestine. Comparison of these proteomes with the organs’ transcriptomes improved our understanding of interorgan protein transport. We applied single-tissue proteomic to describe the proteome of the gut granules in the nematode intestine, a specialized lysosome-related organelle with important functions but which is not well characterized, identifying proteins not previously known to be associated with LROs and verifying two by subcellular localization.
A conceptual framework for the ICU of the future evaluated by the MIMIC-III digital archive
Authors: Markopoulos Dimitrios , Tsolakidis Anastasios , Triantafyllou Ioannis , Giannakopoulos Georgios A. , Skourlas Christos
Published: December 2023

Purpose

This study aims to analyze a conspicuous corpus of literature related to the field of technology-based intensive care research and to develop an architecture model of the future smart intensive care unit (ICU).

Design/methodology/approach

Papers related to the topics of electronic health record (EHR), big data, data flow and clinical decision support in ICUs were investigated. These concepts have been analyzed in combination with secondary use of data, prediction models, data standardization and interoperability challenges. Based on the findings, an architecture model evaluated using MIMIC III is proposed.

Findings

Research identified issues regarding implementation of systems, data sources, interoperability, management of big data and free text produced in ICUs and lack of accuracy of prediction models. ICU should be treated as part of a greater system, able to intercommunicate with other entities.

Research limitations/implications

The research examines the current needs of ICUs in interoperability and data management. As environment changes dynamically, continuous assessment and evaluation of the model with other ICU databases is required.

Originality/value

The proposed model improves ICUs interoperability in national health system, ICU staff intercommunication, remote access and decision support. Its modular approach ensures that ICUs can have their own particularities and specialisms while ICU functions provide ongoing expertise and training to upgrade its staff.
Exploring the influence of content marketing strategies on the expansion of the fashion second-hand market: a theoretical prediction study
Authors: wei Lingwen , Hong Yan , Zeng Xianyi
Published: December 2023

Purpose

The purpose of this research is to conduct a theoretical prediction study exploring the effectiveness of different content marketing strategies in expanding the second-hand market for fashion brands, comparing the costs and risks involved in these strategies in practice.

Design/methodology/approach

First, the expert interview method is employed to extract the content marketing strategies of the fashion second-hand market. Then, a descriptive space that is able to identify various fashion brand images is established. Then, experts' perceptions of the relationships between content marketing strategies and fashion brand image dimensions are obtained through a subjective evaluation procedure. Data of semantic evaluation were quantified and analyzed using the fuzzy logic method.

Findings

When fashion brands expand to the second-hand market, they not only need to focus on improving the individual differentiation of products but also give priority to the quality of products and services and the overall customer experience. Exploring the “social impact strategy” will become an important direction for the development of fashion brands in the future.

Originality/value

The research methodology employed herein exhibits a noteworthy degree of novelty. This study introduces a pioneering theoretical prediction approach utilizing fuzzy logic, marking the inaugural exploration of this emerging and captivating dimension within the context of the study. Simultaneously, the study provides comparative results among content marketing strategies for expanding the fashion second-hand market, offering guidance for market expansion.
Real versus virtual celebrity endorsement: presentation of online product information and consumer attitudes toward digital products
Authors: Li Baoku , Nan Yafeng
Published: December 2023

Purpose

This paper aims to reveal the influence of the presentation of online product information (POPI) on consumer attitudes in the context of online buying digital products.

Design/methodology/approach

Two main experimental designs are used to collect data. The ANOVA, t-test and Bootstrap methods are applied to check hypotheses.

Findings

Findings of Study 1 indicate that if the POPI is combined with different types of celebrity endorsement (CE) (real vs virtual), the self-brand connection will be changed and further influence consumer attitudes toward digital products. Study 2 verifies the diverse moderating effects of the type of virtual CE. The CRP (central-route presentation) online product information with SVCE (super-realistic-digital virtual CE) can decrease consumer attitudes, while the PRP (peripheral-route presentation) online product information with AVCE (anthropomorphic virtual CE) can enhance consumer attitudes.

Practical implications

E-commerce enterprises should optimize the current layout of POPI by considering diverse matchings between POPI and CE to increase consumer attitudes. Moreover, marketers could make various schemes of POPI considering (virtual) CE and self-brand connection.

Originality/value

Findings contribute to understanding the relationship between POPI and consumer attitudes considering the mediation of self-brand connection and the mediations of virtual/real CE. Additionally, this study bridges the gap between research on virtual CE and business practices.
A VUCA-ready workforce: exploring employee competencies and learning and development implications
Authors: Shet Sateesh V.
Published: December 2023

Purpose

The author aims to develop an employee competency framework for a volatility, uncertainty, complexity and ambiguity (VUCA) environment and propose learning and development (L&D) interventions for organisations and employees to develop competencies for thriving in a VUCA environment.

Design/methodology/approach

The framework synthesis method was used to determine employee competencies that are essential in a VUCA world.

Findings

The author identified 10 competencies that are essential for employee development in a VUCA world. The author categorised these employee competencies as cognitive (cognitive flexibility, agility mindset and personal ambidexterity), cross-cultural (cross-cultural intelligence and cross-cultural collaboration), analytical (creativity and complex problem solving) and personal effectiveness competencies (personal resilience, continuous learning and adaptive mindset).

Practical implications

The proposed competencies could be used for the personal development of employees and organisations. The VUCA competency framework developed in this study includes behavioural dimensions for each competency, which could be used in self-assessment, recruitment and selection and talent and performance management. Furthermore, the author proposes L&D interventions required for developing these competencies. Overall, this study contributes to human resources (HR) development in the VUCA era by proposing the development of specific individual competencies as necessary conditions for survival and growth.

Originality/value

VUCA competencies empower employees to not only survive but also thrive in an unpredictable and rapidly changing world. By incorporating these competencies in L&D interventions, organisations can help employees develop the necessary competencies to thrive in a VUCA environment, thus contributing to their personal and organisational success.
Lung and blood perioperative metalloproteinases in patients undergoing oncologic lung surgery: Prognostic implications
Authors: Alonso Angel , de la Gala Francisco , Vara Elena , Hortal Javier , Piñeiro Patricia , Reyes Almudena , Simón Carlos , Garutti Ignacio
Published: December 2023

Background

Metalloproteinases (MMPs) have been reported to be related to oncologic outcomes. The main goal of the study was to study the relationship between these proteins and the long‐term prognosis of patients undergoing oncologic lung resection surgery.

Methods

This was a substudy of the phase IV randomized control trial (NCT 02168751). We analyzed MMP‐2, ‐3, ‐7, and ‐9 in blood samples and bronchoalveolar lavage (LBA) and the relationship between MMPs and long postoperative outcomes (survival and disease‐free time of oncologic recurrence).

Results

Survival was longer in patients who had lower MMP‐2 levels than those with higher MMP‐2 in blood samples taken 6 h after surgery (6.8 vs. 5.22 years; p = 0.012) and MMP‐3 (6.82 vs. 5.35 years; p = 0.03). In contrast, survival was longer when MMP‐3 levels were higher in LBA from oncologic lung patients than those with lower MMP‐3 (7.96 vs. 6.02 years; p = 0.005). Recurrence‐free time was longer in patients who had lower MMP‐3 levels in blood samples versus higher (5.97 vs. 4.23 years; p = 0.034) as well as lower MMP‐7 (5.96 vs. 4.5 years; p = 0.041) or lower MMP‐9 in LBA samples (6.21 vs. 4.18 years; p = 0.012).

Conclusion

MMPs were monitored during the perioperative period of oncologic lung resection surgery. These biomarkers were associated with mortality and recurrence‐free time. The role of the different MMPs analyzed during the study do not have the same prognostic implications after this kind of surgery.
EAACI/ENDA position paper on drug provocation testing
Authors: Barbaud Annick , Garvey Lene Heise , Torres Maria , Laguna Jose Julio , Arcolaci Alessandra , Bonadonna Patrizia , Scherer Hofmeier Kathrin , Chiriac Anca Mirela , Cernadas Josefina , Caubet Jean Christoph , Brockow Knut
Published: December 2023

In drug hypersensitivity, drug provocation testing (DPT), also called drug challenge, is the gold standard for investigation. In recent years, risk stratification has become an important tool for adjusting the diagnostic strategy to the perceived risk, whilst still maintaining a high level of safety for the patient. Skin tests are recommended before DPT but may be omitted in low‐risk patients. The task force suggests a strict definition of such low‐risk patients in children and adults. Based on experience and evidence from studies of allergy to beta‐lactam antibiotics, an algorithm on how to adjust DPT to the risk, and when to omit skin tests before DPT, is presented. For other antibiotics, non‐steroidal anti‐inflammatory drugs and other drugs, skin tests are poorly validated and DPT is frequently necessary. We recommend performing DPT with chemotherapeutics and biologicals to avoid unnecessary desensitization procedures and DPT with skin tests negative contrast media. We suggest DPT with anesthetics only in highly specialized centers. Specifics of DPT to proton pump inhibitors, anticonvulsants and corticosteroids are discussed. This position paper provides general recommendations and guidance on optimizing use of DPT, whilst balancing benefits with patient safety and optimizing the use of the limited available resources.