bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced phenotypes for identifying opioid overdose in emergency department visit electronic health record data
Authors: Ward Ralph , Obeid Jihad S , Jennings Lindsey , Szwast Elizabeth , Hayes William Garrett , Pipaliya Royal , Bailey Cameron , Faul Skylar , Polyak Brianna , Baker George Hamilton , McCauley Jenna L , Lenert Leslie A
Published: September 2023

Background

Accurate identification of opioid overdose (OOD) cases in electronic healthcare record (EHR) data is an important element in surveillance, empirical research, and clinical intervention. We sought to improve existing OOD electronic phenotypes by incorporating new data types beyond diagnostic codes and by applying several statistical and machine learning methods.

Materials and Methods

We developed an EHR dataset of emergency department visits involving OOD cases or patients considered at risk for an OOD and ascertained true OOD status through manual chart reviews. We developed and validated prediction models using Random Forest, Extreme Gradient Boost, and Elastic Net models that incorporated 717 features involving primary and second diagnoses, chief complaints, medications prescribed, vital signs, laboratory results, and procedural codes. We also developed models limited to single data types.

Results

A total of 1718 records involving 1485 patients were manually reviewed; 541 (36.4%) patients had one or more OOD. Prediction performance was similar for all models; sensitivity varied from 94% to 97%; and area under the receiver operating characteristic curve (AUC) was 98% for all methods. The primary diagnosis and chief complaint were the most important contributors to AUC performance; primary diagnoses and medication class contributed most to sensitivity; chief complaint, primary diagnosis, and vital signs were most important for specificity. Models limited to decision support data types available in real time demonstrated robust prediction performance.

Conclusions

Substantial prediction performance improvements were demonstrated for identifying OODs in EHR data. Our e-phenotypes could be applied in surveillance, retrospective empirical applications, or clinical decision support systems.
Development of the Preschool Life Impact Burn Recovery Evaluation (PS-LIBRE1-5) Profile
Authors: Patel Khushbu F , Ni Pengsheng , Surette Kate E , Rencken Camerin A , Rodríguez-Mercedes Silvanys L , McGwin Madeleine B , Fabia Renata , Tully Carrie , Warner Petra , Romanowski Kathleen S , Palmieri Tina , Stoddard Frederick J , Schneider Jeffrey C , Kazis Lewis E , Ryan Colleen M
Published: September 2023

Physical, social, and psychological outcomes have been identified as relevant to the rehabilitation process of children with burn injuries. Existing legacy measures are limited in item content and only cover a few constructs. Condition-specific outcomes are highly relevant to gauge early growth and development. Computerized adaptive tests (CATs) leveraging advanced psychometric technologies minimize respondent burden. This project developed PS-LIBRE1–5 Profile CAT (Preschool Life Impact Burn Recovery Evaluation) to measure relevant postburn outcomes in children aged one to five. Responses to the field-tested PS-LIBRE1–5 Profile (188 items) were measured on a scale of frequency or ability. Scores were coded from 0 to 4 where higher scores reflected better functioning. Factor analysis identified the items retained in the final item bank of each scale. CAT simulations were conducted to estimate the mean score of each scale. The simulated CAT score and full item bank scores were compared based upon the score range, ceiling and floor effects, and marginal reliabilities. The child mean age was 3.0 ± 1.5 years (n = 500). Average burn size and time since burn injury were 4.2% TBSA and 1.1 years, respectively. Psychometric analysis resulted in eight scales: Physical, Communication and Language, Emotional Wellbeing, Mood, Anxiety, Peer Acceptance, Play, and Peer Relations. Ceiling effects were acceptable at <13% for all scales. Marginal reliabilities of the CATs were credible. The PS-LIBRE1–5 Profile CAT contains 111 items, and is a comprehensive measure that captures physical, communication and language, psychological, and social functioning of preschool burn survivors.
CJEU grapples with the intertwined nature of private copies and retransmission of online television broadcasts
Authors: Priora Giulia , Costa Novaes Amanda
Published: September 2023

In Ocilion, the Court of Justice of the European Union ruled on two intricated aspects of the relationship between copyright law and Internet TV services, clarifying that de-duplication systems of copying of TV broadcasts do not fall within the scope of the private copying exception and that facilitating online retransmission does not amount to a communication to the public.
Semiparametric M-quantile regression with measurement error in spatial covariates: an application to housing price modelling
Authors: Borgoni Riccardo , Schirripa Spagnolo Francesco , Michelangeli Alessandra , Salvati Nicola , Carcagnì Antonella
Published: September 2023

Spatial data are becoming increasingly accessible to urban scientists, but these data are often prone to measurement error. Motivated by the analysis of the Milan (Italy) apartment market heterogeneity, we propose a semiparametric approach to adjust for the presence of measurement error in the covariates when estimating M-quantile regression. The M-quantile approach helps explain the heterogeneity across individual units, preserving robustness and efficiency in the estimates. The model’s parameters are estimated within a penalised likelihood framework and an analytical expression is proposed to estimate standard errors. Asymptotic properties of estimates are also provided.
Interplay between MYZUS PERSICAE-INDUCED LIPASE 1 and OPDA signaling in limiting green peach aphid infestation on Arabidopsis thaliana
Authors: Archer Lani , Mondal Hossain A , Behera Sumita , Twayana Moon , Patel Monika , Louis Joe , Nalam Vamsi J , Keereetaweep Jantana , Chowdhury Zulkarnain , Shah Jyoti
Published: September 2023

MYZUS PERSICAE-INDUCED LIPASE1 (MPL1) encodes a lipase in Arabidopsis thaliana that is required for limiting infestation by the green peach aphid (GPA; Myzus persicae), an important phloem sap-consuming insect pest. Previously, we demonstrated that MPL1 expression was up-regulated in response to GPA infestation, and GPA fecundity was higher on the mpl1 mutant, compared with the wild-type (WT), and lower on 35S:MPL1 plants that constitutively expressed MPL1 from the 35S promoter. Here, we show that the MPL1 promoter is active in the phloem and expression of the MPL1 coding sequence from the phloem-specific SUC2 promoter in mpl1 is sufficient to restore resistance to GPA. The GPA infestation-associated up-regulation of MPL1 requires CYCLOPHILIN 20-3 (CYP20-3), which encodes a 12-oxo-phytodienoic acid (OPDA)-binding protein that is involved in OPDA signaling, and is required for limiting GPA infestation. OPDA promotes MPL1 expression to limit GPA fecundity, a process that requires CYP20-3 function. These results along with our observation that constitutive expression of MPL1 from the 35S promoter restores resistance to GPA in the cyp20-3 mutant, and MPL1 acts in a feedback loop to limit OPDA levels in GPA-infested plants, suggest that an interplay between MPL1, OPDA, and CYP20-3 contributes to resistance to GPA.
Sixty years of conjecture over a urinary biomarker: a step closer to understanding the proposed link between anxiety and urinary pyrroles
Authors: Sherwin Angela , Shaw Ian C
Published: September 2023

Objective

For over 60 years there has been conjecture about the identity of an Ehrlich’s test positive pyrrole (Mauve Factor) reputed to be a biomarker for psychological disorders, including anxiety. We reviewed studies that attempt to identify Mauve Factor and subjected authentic standards of the 2 main candidates, kryptopyrrole and hydroxypyrrole, to the Ehrlich’s reaction.

Methods

Modified Ehrlich’s test for kryptopyrrole and hydroxypyrrole were applied to urine samples from 10 volunteers, anxious and nonanxious.

Results

Based on the mechanistic chemistry of Ehrlich’s reaction and reactions of the 2 compounds, Mauve Factor cannot be hydroxypyrrole. Analyses of urine samples from volunteers, identified by the Generalized Anxiety Disorder - 7 item scale (GAD-7 ≥10; n = 5) and control urine samples (GAD-7 <10; n = 5) using a kryptopyrrole calibration graph, show that concentrations are similar in both groups.

Conclusion

Kryptopyrrole may be the elusive Mauve Factor. Its possible origin from stercobilin via gut microbiome–mediated metabolism, its link to gut-mediated neurological effects via γ-aminobutyric acid (GABA) receptors, and its predicted interaction with Zn2+ and consequent impact on zinc homeostasis are discussed. The GAD-7 scale does not differentiate between state and trait anxiety and as such, the minimal difference in pyrrole levels between volunteer groups requires further study.
The source of electrons at comet 67P
Authors: Stephenson P , Beth A , Deca J , Galand M , Goetz C , Henri P , Heritier K , Lewis Z , Moeslinger A , Nilsson H , Rubin M
Published: September 2023

We examine the origin of electrons in a weakly outgassing comet, using Rosetta mission data and a 3D collisional model of electrons at a comet. We have calculated a new data set of electron-impact ionization (EII) frequency throughout the Rosetta escort phase, with measurements of the Rosetta Plasma Consortium’s Ion and Electron Sensor (RPC/IES). The EII frequency is evaluated in 15-min intervals and compared to other Rosetta data sets. EII is the dominant source of electrons at 67P away from perihelion and is highly variable (by up to three orders of magnitude). Around perihelion, EII is much less variable and less efficient than photoionization at Rosetta. Several drivers of the EII frequency are identified, including magnetic field strength and the outgassing rate. Energetic electrons are correlated to the Rosetta-upstream solar wind potential difference, confirming that the ionizing electrons are solar wind electrons accelerated by an ambipolar field. The collisional test particle model incorporates a spherically symmetric, pure water coma and all the relevant electron-neutral collision processes. Electric and magnetic fields are stationary model inputs, and are computed using a fully kinetic, collision-less Particle-in-Cell simulation. Collisional electrons are modelled at outgassing rates of Q = 1026 s−1 and Q = 1.5 × 1027 s−1. Secondary electrons are the dominant population within a weakly outgassing comet. These are produced by collisions of solar wind electrons with the neutral coma. The implications of large ion flow speed estimates at Rosetta, away from perihelion, are discussed in relation to multi-instrument studies and the new results of the EII frequency obtained in this study.
The spectra of IceCube Neutrino (SIN) candidate sources – IV. Spectral energy distributions and multiwavelength variability
Authors: Karl Martina , Padovani Paolo , Giommi Paolo
Published: September 2023

We present hybrid spectral energy distributions, combining photon, and neutrino fluxes, for a sample of blazars, which are candidate IceCube neutrino sources. We furthermore check for differences in our sources’ variability in the near-infrared, optical, X-ray, and γ-ray bands compared to a sample of non-neutrino source candidate blazars, and investigate the state of each blazar at the arrival time of high-energy neutrinos. We find no significant differences when comparing our sample with control sources, also in terms of their spectral energy distributions, and no correlation between flaring states and neutrino arrival times. Looking for signatures of hadronic production, we check for similar strengths of the γ-ray and neutrino fluxes and find a $2.2\, \sigma$ signal for our source candidates. The hybrid spectral energy distributions assembled here will form the basis of the next step of our project, namely lepto-hadronic modelling of these blazars to assess the physical likelihood of a neutrino connection.
Unraveling the role of ZNF506 as a human PBS-pro-targeting protein for ERVP repression
Authors: Wu Qian , Fang Lu , Wang Yixuan , Yang Peng
Published: September 2023

Krüppel-associated box zinc finger proteins (KZFPs) function as a defense mechanism to maintain the genome stability of higher vertebrates by regulating the transcriptional activities of transposable elements (TEs). While previous studies have characterized ZFP809 as responsible for binding and repressing ERVs containing a proline tRNA primer-binding site (PBS-Pro) in mice, comparable KZFPs have not been identified in humans yet. Here, we identified ZNF506 as a PBS-Pro-binding protein in humans, which functions as a transcriptional repressor of PBS-Pro-utilizing retroviruses by recruiting heterochromatic modifications. Although they have similar functions, the low protein similarities between ZNF506, ZFP809 and KZFPs of other species suggest their independent evolution against the invasion of PBS-Pro-utilizing retroviruses into their respective ancestor genomes after species divergence. We also explored the link between ZNF506 and leukemia. Our findings suggest that ZNF506 is a unique human KZFP that can bind to PBS-Pro, highlighting the diverse evolution of KZFPs in defending against retroviral invasions. Additionally, our study provides insights into the potential role of ZNF506 in leukemia, contributing to the expanding knowledge of KZFPs' crucial function in disease and genome stability.
Large-scale phenogenomic analysis of human cancers uncovers frequent alterations affecting SMC5/6 complex components in breast cancer
Authors: Roy Shamayita , Zaker Arvin , Mer Arvind , D’Amours Damien
Published: September 2023

Cancer cells often experience large-scale alterations in genome architecture because of DNA damage and replication stress. Whether mutations in core regulators of chromosome structure can also lead to cancer-promoting loss in genome stability is not fully understood. To address this question, we conducted a systematic analysis of mutations affecting a global regulator of chromosome biology –the SMC5/6 complex– in cancer genomics cohorts. Analysis of 64 959 cancer samples spanning 144 tissue types and 199 different cancer genome studies revealed that the SMC5/6 complex is frequently altered in breast cancer patients. Patient-derived mutations targeting this complex associate with strong phenotypic outcomes such as loss of ploidy control and reduced overall survival. Remarkably, the phenotypic impact of several patient mutations can be observed in a heterozygous context, hence providing an explanation for a prominent role of SMC5/6 mutations in breast cancer pathogenesis. Overall, our findings suggest that genes encoding global effectors of chromosome architecture can act as key contributors to cancer development in humans.
Identification of experimentally-supported poly(A) sites in single-cell RNA-seq data with SCINPAS
Authors: Moon Youngbin , Burri Dominik , Zavolan Mihaela
Published: September 2023

Alternative polyadenylation is a main driver of transcriptome diversity in mammals, generating transcript isoforms with different 3’ ends via cleavage and polyadenylation at distinct polyadenylation (poly(A)) sites. The regulation of cell type-specific poly(A) site choice is not completely resolved, and requires quantitative poly(A) site usage data across cell types. 3’ end-based single-cell RNA-seq can now be broadly used to obtain such data, enabling the identification and quantification of poly(A) sites with direct experimental support. We propose SCINPAS, a computational method to identify poly(A) sites from scRNA-seq datasets. SCINPAS modifies the read deduplication step to favor the selection of distal reads and extract those with non-templated poly(A) tails. This approach improves the resolution of poly(A) site recovery relative to standard software. SCINPAS identifies poly(A) sites in genic and non-genic regions, providing complementary information relative to other tools. The workflow is modular, and the key read deduplication step is general, enabling the use of SCINPAS in other typical analyses of single cell gene expression. Taken together, we show that SCINPAS is able to identify experimentally-supported, known and novel poly(A) sites from 3’ end-based single-cell RNA sequencing data.
Urinary peptidomic liquid biopsy for non-invasive differential diagnosis of chronic kidney disease
Authors: Mavrogeorgis Emmanouil , He Tianlin , Mischak Harald , Latosinska Agnieszka , Vlahou Antonia , Schanstra Joost P , Catanese Lorenzo , Amann Kerstin , Huber Tobias B , Beige Joachim , Rupprecht Harald D , Siwy Justyna
Published: September 2023

Background and hypothesis

Specific urinary peptides hold information on disease pathophysiology, which, in combination with artificial intelligence, could enable non-invasive assessment of chronic kidney disease (CKD) aetiology. Existing approaches are generally specific for the diagnosis of single aetiologies. We present the development of models able to simultaneously distinguish and spatially visualize multiple CKD aetiologies.

Methods

The urinary peptide data of 1850 healthy control (HC) and CKD [diabetic kidney disease (DKD), immunoglobulin A nephropathy (IgAN) and vasculitis] participants were extracted from the Human Urinary Proteome Database. Uniform manifold approximation and projection (UMAP) coupled to a support vector machine algorithm was used to generate multi-peptide models to perform binary (DKD, HC) and multiclass (DKD, HC, IgAN, vasculitis) classifications. This pipeline was compared with the current state-of-the-art single-aetiology CKD urinary peptide models.

Results

In an independent test set, the developed models achieved 90.35% and 70.13% overall predictive accuracies, respectively, for the binary and the multiclass classifications. Omitting the UMAP step led to improved predictive accuracies (96.14% and 85.06%, respectively). As expected, the HC class was distinguished with the highest accuracy. The different classes displayed a tendency to form distinct clusters in the 3D space based on their disease state.

Conclusion

Urinary peptide data present an effective basis for CKD aetiology differentiation using machine learning models. Although adding the UMAP step to the models did not improve prediction accuracy, it may provide a unique visualization advantage. Additional studies are warranted to further validate the pipeline's clinical potential as well as to expand it to other CKD aetiologies and also other diseases.
Antifungal Therapeutic Drug Monitoring Practices: Results of an Emerging Infections Network Survey
Authors: Benedict Kaitlin , Gold Jeremy A W , Beekmann Susan E , Polgreen Philip M , Toda Mitsuru , Smith Dallas J
Published: September 2023

In a survey of 523 infectious disease specialists, a moderate to high percentage reported using any antifungal therapeutic drug monitoring (TDM) during itraconazole (72%), posaconazole (72%), and voriconazole (90%) treatment, and a low to moderate percentage reported using any antifungal TDM during prophylaxis (32%, 55%, and 65%, respectively). Long turnaround times for send-out TDM testing and logistical difficulties were frequent barriers.
Inductive sensing of magnetic microrobots under actuation by rotating magnetic fields
Authors: Christiansen Michael G , Stöcklin Lucien R , Forbrigger Cameron , Venkatesh Shashaank Abhinav , Schuerle Simone
Published: September 2023

The engineering space for magnetically manipulated biomedical microrobots is rapidly expanding. This includes synthetic, bioinspired, and biohybrid designs, some of which may eventually assume clinical roles aiding drug delivery or performing other therapeutic functions. Actuating these microrobots with rotating magnetic fields (RMFs) and the magnetic torques they exert offers the advantages of efficient mechanical energy transfer and scalable instrumentation. Nevertheless, closed-loop control still requires a complementary noninvasive imaging modality to reveal position and trajectory, such as ultrasound or X-rays, increasing complexity and posing a barrier to use. Here, we investigate the possibility of combining actuation and sensing via inductive detection of model microrobots under field magnitudes ranging from 100 s of microtesla to 10 s of millitesla rotating at 1 to 100 Hz. A prototype apparatus accomplishes this using adjustment mechanisms for both phase and amplitude to finely balance sense and compensation coils, suppressing the background signal of the driving RMF by 90 dB. Rather than relying on frequency decomposition to analyze signals, we show that, for rotational actuation, phase decomposition is more appropriate. We demonstrate inductive detection of a micromagnet placed in two distinct viscous environments using RMFs with fixed and time-varying frequencies. Finally, we show how magnetostatic selection fields can spatially isolate inductive signals from a micromagnet actuated by an RMF, with the resolution set by the relative magnitude of the selection field and the RMF. The concepts developed here lay a foundation for future closed-loop control schemes for magnetic microrobots based on simultaneous inductive sensing and actuation.
The frontline of alternatives to animal testing: novel in vitro skin model application in drug development and evaluation
Authors: Zhao He , Chen Zhaozeng , Kang Xingchen , Yang Bo , Luo Peihua , Li Hui , He Qiaojun
Published: September 2023

The FDA Modernization Act 2.0 has brought nonclinical drug evaluation into a new era. In vitro models are widely used and play an important role in modern drug development and evaluation, including early candidate drug screening and preclinical drug efficacy and toxicity assessment. Driven by regulatory steering and facilitated by well-defined physiology, novel in vitro skin models are emerging rapidly, becoming the most advanced area in alternative testing research. The revolutionary technologies bring us many in vitro skin models, either laboratory-developed or commercially available, which were all built to emulate the structure of the natural skin to recapitulate the skin’s physiological function and particular skin pathology. During the model development, how to achieve balance among complexity, accessibility, capability, and cost-effectiveness remains the core challenge for researchers. This review attempts to introduce the existing in vitro skin models, align them on different dimensions, such as structural complexity, functional maturity, and screening throughput, and provide an update on their current application in various scenarios within the scope of chemical testing and drug development, including testing in genotoxicity, phototoxicity, skin sensitization, corrosion/irritation. Overall, the review will summarize a general strategy for in vitro skin model to enhance future model invention, application, and translation in drug development and evaluation.
A Dual Transcriptomic Approach Reveals Contrasting Patterns of Differential Gene Expression During Drought in Arbuscular Mycorrhizal Fungus and Carrot
Authors: Keller-Pearson Michelle , Bortolazzo Anthony , Willems Luke , Smith Brendan , Peterson Annika , Ané Jean-Michel , Silva Erin M.
Published: September 2023

While arbuscular mycorrhizal (AM) fungi are known for providing host plants with improved drought tolerance, we know very little about the fungal response to drought in the context of the fungal–plant relationship. In this study, we evaluated the drought responses of the host and symbiont, using the fungus Rhizophagus irregularis with carrot ( Daucus carota) as a plant model. Carrots inoculated with spores of R. irregularis DAOM 197198 were grown in a greenhouse. During taproot development, carrots were exposed to a 10-day water restriction. Compared with well-watered conditions, drought caused diminished photosynthetic activity and reduced plant growth in carrot with and without AM fungi. Droughted carrots had lower root colonization. For R. irregularis, 93% of 826 differentially expressed genes (DEGs) were upregulated during drought, including phosphate transporters, several predicted transport proteins of potassium, and the aquaporin RiAQPF2. In contrast, 78% of 2,486 DEGs in AM carrot were downregulated during drought, including the symbiosis-specific genes FatM, RAM2, and STR, which are implicated in lipid transfer from the host to the fungus and were upregulated exclusively in AM carrot during well-watered conditions. Overall, this study provides insight into the drought response of an AM fungus in relation to its host; the expression of genes related to symbiosis and nutrient exchange were downregulated in carrot but upregulated in the fungus. This study reveals that carrot and R. irregularis exhibit contrast in their regulation of gene expression during drought, with carrot reducing its apparent investment in symbiosis and the fungus increasing its apparent symbiotic efforts.

[Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
New Biochemical Principles for NLR Immunity in Plants
Authors: Chai Jijie , Song Wen , Parker Jane E.
Published: September 2023

While working for the United States Department of Agriculture on the North Dakota Agricultural College campus in Fargo, North Dakota, in the 1940s and 1950s, Harold H. Flor formulated the genetic principles for coevolving plant host-pathogen interactions that govern disease resistance or susceptibility. His ‘gene-for-gene’ legacy runs deep in modern plant pathology and continues to inform molecular models of plant immune recognition and signaling. In this review, we discuss recent biochemical insights to plant immunity conferred by nucleotide-binding domain/leucine-rich-repeat (NLR) receptors, which are major gene-for-gene resistance determinants in nature and cultivated crops. Structural and biochemical analyses of pathogen-activated NLR oligomers (resistosomes) reveal how different NLR subtypes converge in various ways on calcium (Ca2+) signaling to promote pathogen immunity and host cell death. Especially striking is the identification of nucleotide-based signals generated enzymatically by plant toll-interleukin 1 receptor (TIR) domain NLRs. These small molecules are part of an emerging family of TIR-produced cyclic and noncyclic nucleotide signals that steer immune and cell-death responses in bacteria, mammals, and plants. A combined genetic, molecular, and biochemical understanding of plant NLR activation and signaling provides exciting new opportunities for combatting diseases in crops.

[Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Biocontrol Efficacy and Induced Resistance of Paenibacillus polymyxa J2-4 Against Meloidogyne incognita Infection in Cucumber
Authors: Shi Qianqian , Zhang Jie , Fu Qi , Hao Guangyang , Liang Chen , Duan Fangmeng , Zhao Honghai , Song Wenwen
Published: September 2023

Meloidogyne incognita is one of the most destructive agricultural pathogens around the world, resulting in severe damage to yield and quality in agricultural production. Biological control promises to be a great potential alternative to chemical agents against M. incognita. Paenibacillus polymyxa J2-4, isolated from ginger plants injured by M. incognita, has shown excellent biocontrol efficacy against M. incognita in cucumber. In vitro experiments with the strain J2-4 resulted in a correct mortality rate of 88.79% (24 h) and 98.57% (48 h) for second-stage juveniles (J2s) of M. incognita. Strain J2-4 significantly suppressed nematode infection on potted plants, with a 65.94% reduction in galls and a 51.64% reduction in eggs compared with the control. The split-root assay demonstrated that strain J2-4 not only reduced J2s’ invasion but also inhibited nematode development through the dependence on salicylic acid and jasmonic acid signaling of strain J2-4 induction of plant resistance in local and systemic roots of cucumbers. Genomic analysis of strain J2-4 indicated biosynthetic gene clusters encoding polymyxin, fusaricidin B, paenilan, and tridecaptin. In addition, genetic analysis showed that none of the genes encoding virulence factors were detected in the genome of J2-4 compared with the pathogenic Bacillus species. Taking all the data together, we conclude that P. polymyxa J2-4 has potential as a biological control agent against M. incognita on cucumbers and can be considered biologically safe when used in agriculture.
Unveiling the Role of Diffusible Signal Factor-Family Quorum Sensing Signals in Regulating Behavior of Xanthomonas and Lysobacter
Authors: Li Kaihuai , Ma Chaoyun , Xiong Chunlan , Zhou Xue , Mao Yahui , Wang Yong , Liu Fengquan
Published: September 2023

Diffusible signal factor (DSF) family signals represent a unique group of quorum sensing (QS) chemicals that modulate a wide range of behaviors for bacteria to adapt to different environments. However, whether DSF-mediated QS signaling acts as a public language to regulate the behavior of biocontrol and pathogenic bacteria remains unknown. In this study, we present groundbreaking evidence demonstrating that RpfFXc1 or RpfFOH11 could be a conserved DSF-family signal synthase in Xanthomonas campestris or Lysobacter enzymogenes. Interestingly, we found that both RpfFOH11 and RpfFXc1 have the ability to synthesize DSF and BDSF signaling molecules. DSF and BDSF positively regulate the biosynthesis of an antifungal factor (heat-stable antifungal factor, HSAF) in L. enzymogenes. Finally, we show that RpfFXc1 and RpfFOH11 have similar functions in regulating HSAF production in L. enzymogenes, as well as the virulence, synthesis of virulence factors, biofilm formation, and extracellular polysaccharide production in X. campestris. These findings reveal a previously uncharacterized mechanism of DSF-mediated regulation in both biocontrol and pathogenic bacteria.
Adrenomedullin/FOXO3 enhances sunitinib resistance in clear cell renal cell carcinoma by inhibiting FDX1 expression and cuproptosis
Authors: Wang Xin , Jia Jiang‐Hua , Zhang Ming , Meng Qing‐Song , Yan Bo‐Wen , Ma Zi‐Yue , Wang Dong‐Bin
Published: September 2023

Cuproptosis, a new type of copper‐induced cell death, is involved in the antitumor activity and resistance of multiple chemotherapeutic drugs. Our previous study revealed that adrenomedullin (ADM) was engaged in sunitinib resistance in clear cell renal cell carcinoma (ccRCC). However, it has yet to be investigated whether and how ADM regulates sunitinib resistance by cuproptosis. This study found that the ADM expression was elevated in sunitinib‐resistant ccRCC tissues and cells. Furthermore, the upregulation of ADM significantly enhanced the chemoresistance of sunitinib compared with their respective control. Moreover, cuproptosis was involved in ADM‐regulated sunitinib resistance by inhibiting mammalian ferredoxin 1 (FDX1) expression. Mechanically, the upregulated ADM activates the p38/MAPK signaling pathway to promote Forkhead box O3 (FOXO3) phosphorylation and its entry into the nucleus. Consequently, the increased FOXO3 in the nucleus inhibited FDX1 transcription and cell cuproptosis, promoting chemoresistance. Collectively, cuproptosis has a critical effector role in ccRCC progress and chemoresistance and thus is a relevant target to eradicate the cell population of sunitinib resistance.
Quizartinib inhibits necroptosis by targeting receptor‐interacting serine/threonine protein kinase 1
Authors: Li Min , Wei Jun , Zhu Guofeng , Fu Shufang , He Xiaoyan , Hu Xinqian , Yu Yajie , Mou Yan , Wang Jia , You Xiaoling , Xiao Xin , Gu Tanrong , Ye Zhi , Zha Yunhong
Published: September 2023

Systemic inflammatory response syndrome (SIRS), at least in part driven by necroptosis, is characterized by life‐threatening multiple organ failure. Blocking the progression of SIRS and consequent multiple organ dysfunction is challenging. Receptor‐interacting serine/threonine protein kinase 1 (RIPK1) is an important cell death and inflammatory mediator, making it a potential treatment target in several diseases. Here, using a drug repurposing approach, we show that inhibiting RIPK1 is also an effective treatment for SIRS. We performed cell‐based high‐throughput drug screening of an US Food and Drug Administration (FDA)‐approved drug library that contains 1953 drugs to identify effective inhibitors of necroptotic cell death by SYTOX green staining. Dose–response validation of the top candidate, quizartinib, was conducted in two cell lines of HT‐22 and MEFs. The effect of quizartinib on necroptosis‐related proteins was evaluated using western blotting, immunoprecipitation, and an in vitro RIPK1 kinase assay. The in vivo effects of quizartinib were assessed in a murine tumor necrosis factor α (TNFα)‐induced SIRS model. High‐throughput screening identified quizartinib as the top “hit” in the compound library that rescued cells from necroptosis in vitro. Quizartinib inhibited necroptosis by directly inhibiting RIPK1 kinase activity and blocking downstream complex IIb formation. Furthermore, quizartinib protected mice against TNFα‐induced SIRS. Quizartinib, as an FDA‐approved drug with proven safety and efficacy, was repurposed for targeted inhibition of RIPK1. This work provides essential preclinical data for transferring quizartinib to the treatment of RIPK1‐dependent necroptosis‐induced inflammatory diseases, including SIRS.
Prevalence and correlates of frailty in older hypertensive outpatients according to different tools: the HYPER-FRAIL pilot study
Authors: Rivasi Giulia , Ceolin Ludovica , Turrin Giada , Tortu’ Virginia , D’Andria Maria Flora , Testa Giuseppe Dario , Montali Sara , Tonarelli Francesco , Brunetti Enrico , Bo Mario , Romero-Ortuno Roman , Mossello Enrico , Ungar Andrea
Published: September 2023

Objectives:

To date, few studies have investigated frailty in hypertensive individuals. This study aimed at identifying the prevalence of frailty in a sample of hypertensive older outpatients using six different identification tools. Clinical correlates of frailty and agreement between different frailty definitions were also investigated.

Methods:

The HYPER-FRAIL pilot study recruited hypertensive patients aged at least 75 years from two geriatric outpatient clinics of Careggi Hospital, Florence, Italy. Four frailty scales [Fried Frailty Phenotype, Frailty Index, Clinical Frailty Scale (CFS), Frailty Postal Score] and two physical performance tests [Short Physical Performance Battery (SPPB) and usual gait speed] were applied. The Cohen's kappa coefficient was calculated to assess agreement between measures. Multiple logistic regression was used to identify clinical features independently associated with frailty.

Results:

Among 121 participants (mean age 81, 60% women), frailty prevalence varied between 33 and 50% according to the tool used. Moderate agreement was observed between Fried Frailty Phenotype, Frailty Index and SPPB, and between Frailty Index and CFS. Agreement was minimal or weak between the remaining measures (K < 0.60). Use of walking aids and depressive symptoms were independently associated with frailty, regardless of the definition used. Frailty correlates also included dementia, disability and comorbidity burden, but not office and 24-h blood pressure values.

Conclusion:

Frailty is highly prevalent among older hypertensive outpatients, but agreement between different frailty tools was moderate-to-weak. Longitudinal studies are needed to assess the prognostic role of different frailty tools and their clinical utility in the choice of antihypertensive treatment.
Measuring the longitudinal impact of a transgender and gender diverse curriculum on nurse practitioner students' and nurse practitioners' cultural competence, knowledge, skills, and attitudes
Authors: Mueller Rebecca C.
Published: September 2023

Nurse practitioners (NPs) are well positioned to provide inclusive, person-centered care to patients who are transgender and gender diverse (TGD); however, few NPs have been trained on how to do so. This study demonstrates the longitudinal effect of an educational intervention that used readings, lecture, a patient panel, and a standardized patient encounter on NPs' and nurse practitioner students' cultural competency, knowledge, skills, and attitudes toward patients who are TGD. The study followed participants for 3 months and used the Sexual Orientation Counselor Competency Scale version 3 tool to measure changes across three data points. Significant improvements were demonstrated in cultural competency and clinical skills, with knowledge and attitude increases that did not reach significances. The findings from this study have implications for the inclusion of TGD content in graduate nursing curriculum and continuing education activities and provide educators with best practices to integrate this content into learning activities.
Cystic partially differentiated nephroblastoma in an 18-month-old girl: a case report
Authors: Alhassoun Alia , Bara Albaraa H. , Ibrahim Mohammad N. , Berro Selman M. , Khalil Mays G.
Published: September 2023

Introduction and importance:

Cystic partially differentiated nephroblastoma (CPDN) is a rare cystic tumor that affects the kidney. It has a low potential for malignancy. It usually presents as an abdominal mass. It may be difficult to confirm the diagnosis of CPDN without a histopathological study.

Case presentation:

The authors report a case of an 18-month-old girl with abdominal distention, which was noticed by her parents. An abdominal computed tomography scan showed a large multilocular cystic mass arising from the lower pole of the left kidney. A left total nephrectomy was performed. Immature blastemal elements without evidence of malignant cells were observed on histological analysis.

Conclusion:

The authors report a case of an 18-month-old girl with CPDN managed by total nephrectomy. CPDN should be considered in the differential diagnosis of patients with cystic renal lesions. The authors would also like to affirm that partial or total nephrectomy should be done in all cases of CPDN and other cystic renal tumors.
Systemic sclerosis sine scleroderma with atypical clinical course: a rare case report
Authors: Samha Raghad , Ghaddar Sawsane A. , Raya Maria , Abdalhadi Safaa
Published: September 2023

Introduction and importance:

Systemic sclerosis (SSc) is divided into three subtypes: limited cutaneous SSc (lcSSc), diffuse cutaneous SSc (dcSSc), and systemic sclerosis sine scleroderma (ssSSc). ssSSc is a rare subtype of SSc that presents with internal organ manifestations but no cutaneous findings.

Case presentation:

We report the case of a 58-year-old patient with a history of pulmonary hypertension who presented with symptoms of fatigue, inflammatory polyarthritis, and joint swelling. Following a comprehensive clinical examination and laboratory tests, the patient was diagnosed with ssSSc.

Clinical discussion:

Due to its atypical clinical course, we present this case report, which commenced with idiopathic pulmonary hypertension. Subsequently, after 7 months, the patient presented complaints of polyarthritis with positive antinuclear antibodies. Raynaud’s phenomenon was identified 2 months later during the rheumatology clinic examination. Typically, the clinical course encompasses all three features simultaneously, without any gap between them.

Conclusion:

Diagnosis of ssSSc remains challenging, and it is essential to consider this disease form in all cases involving unexplained fibrotic involvement of the internal organs.
Primary Sarcoidosis of the Temporal Bone a Clinical Pathologic Correlation
Authors: Fallon Keelin , Akalin Ali , Wu Peggy , Remenschneider Aaron K.
Published: September 2023

Objective:

This report describes a case of sarcoidosis that presented as a lytic bone lesion in the squamous part of the temporal bone.

Patients:

A 64-year-old woman presented with right-sided aural fullness, pulsatile tinnitus, and intermittent otalgia.

Interventions:

CT and MRI were performed without contrast and suggested an osseodestructive, lytic bone lesion. An excisional biopsy was performed, showing granulomatous infiltration suggestive of osseous sarcoidosis.

Main Outcome Measures:

Removal of mass and resolution of symptoms.

Results:

Initial findings from patient imaging suggested a lytic bone lesion. An excisional biopsy was required for diagnosis and was performed with little patient morbidity. Biopsy findings showed granulomatous infiltration suggestive of osseous sarcoidosis. Osseous involvement of sarcoidosis is a rare manifestation and typically occurs secondary to other disease manifestations. After the removal of the mass and a short unrelated course of steroids, the patient’s symptoms resolved.

Conclusions:

Sarcoidosis should be added to the differential diagnosis of lytic bone lesions in the temporal bone.
Effect of Neurotoxin Exposure on Blood Biomarkers of Neurodegeneration and Alzheimer Disease
Authors: Schubert Carla R. , Paulsen Adam J. , Pinto A. Alex , Chappell Richard J. , Chen Yanjun , Ferrucci Luigi , Hancock Laura M. , Cruickshanks Karen J. , Merten Natascha
Published: September 2023

Aim:

To determine whether exposure to neurotoxins in midlife is associated with changes in blood-based biomarkers of neurodegeneration and Alzheimer disease pathology.

Methods:

Blood cadmium, lead, neurofilament light (NfL) chain, total tau (TTau), and amyloid beta (Aβ) 40 and Aβ42 concentrations were measured in 1516 participants in the Beaver Dam Offspring Study. Linear mixed-effect models were used to determine associations between baseline cadmium and lead levels and baseline NfL, TTau, and Aβ42/Aβ40, and 10-year change in concentrations using repeated measures of these biomarkers as the outcome.

Results:

In women, higher cadmium and lead levels were associated with higher baseline TTau concentrations. A higher baseline cadmium level was associated with lower baseline Aβ42/Aβ40 in both men and women. In age-sex-adjusted models, a doubling in baseline cadmium level was associated with a 0.2% (95% CI: 0.0, 0.3) higher increase per year in NfL concentrations. In men, a doubling of baseline lead level was associated with a 0.9% (95% CI: 0.1, 1.7) higher increase per year in TTau concentration.

Conclusions:

Participants with relatively higher levels of cadmium and lead had blood biomarker concentrations consistent with more neuronal damage and Alzheimer disease pathology. Environmental exposure to neurotoxins may contribute to neurodegeneration.
Harvesting Underground: (re)generative theories and vegetal analogies in the early modern debate on mineral ores (I)
Authors: Luzzini Francesco
Published: September 2023

The early modern use of vegetal terms to explain the origin and growth of ores was widespread in mining industry, alchemy, and natural philosophy. In the writings of authors from many different backgrounds, mineral veins were often described as ‘trees’ which moved upwards, bore fruits, and underwent a life cycle. Accordingly, the existence in ores of ‘seeds’ (and, therefore, of a (re)generative power) was frequently invoked to explain the apparent similarities between minerals and plants. This method of describing mineral processes—called here the
botanical model
—also had a lasting terminological influence, as is attested by various expressions that are still common among miners and scientists. The notions underlying these terms are part of a larger body of ‘organic interpretations’ of mineral resources that endured into the eighteenth century and contributed to the development of the Earth sciences, mining industry, and the human–environment relationship. In focusing mainly on the rise of the
botanical model
in Renaissance Europe, this essay is the first part of a more extensive study (to be completed in a forthcoming paper) on the evolution of this important concept and its interaction with the
new science
throughout the early modern period.
ICTV Virus Taxonomy Profile: Arenaviridae 2023
Authors: Radoshitzky Sheli R. , Buchmeier Michael J. , Charrel Rémi N. , Gonzalez Jean-Paul J. , Günther Stephan , Hepojoki Jussi , Kuhn Jens H. , Lukashevich Igor S. , Romanowski Víctor , Salvato Maria S. , Sironi Manuela , Stenglein Mark D. , Torre Juan Carlos de la
Published: September 2023

Arenaviridae is a family for ambisense RNA viruses with genomes of about 10.5 kb that infect mammals, snakes, and fish. The arenavirid genome consists of two or three single-stranded RNA segments and encodes a nucleoprotein (NP), a glycoprotein (GP) and a large (L) protein containing RNA-directed RNA polymerase (RdRP) domains; some arenavirids encode a zinc-binding protein (Z). This is a summary of the International Committee on Taxonomy of Viruses (ICTV) report on the family Arenaviridae, which is available at www.ictv.global/report/arenaviridae.
The linear and non-linear effects of CYP2C19 metaboliser status on DNA methylation: a methylome-wide association study
Authors: Shen Chen , Adams Mark James , Davyson Eleanor , Iveson Matthew , McIntosh Andrew M , Shen Xueyi
Published: September 2023

CYP2C19 metabolises many medications e.g., antidepressants, proton pump inhibitors and its enzymatic activity can be inferred from genetic variants within its encoding gene, linking to the efficacy of drug treatments and their side effects. It is however unclear if enzymatic activity is associated with local or widespread differences in DNA methylation. DNA methylation differences associated with CYP2C19 metabolising status may also have the potential to reveal interacting genes and pathways that underly CYP2C19 effects on drug response and health consequences. A methylome-wide association study was conducted in the Generation Scotland cohort (n=18,396) to investigate the linear and non-linear effects of CYP2C19 metaboliser status on genome-wide DNA methylation. Pathway enrichment analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with CYP2C19 metaboliser status. We examined whether the associations between CYP2C19 metaboliser status and DNA methylation were independent of the use of drugs that are inducers, inhibitors, or substrates of the CYP2C19 enzyme by interaction analysis. Forty-eight CpG probes were significantly associated with both linear and quadratic terms of CYP2C19 metaboliser status (PBonferroni < 0.05). These CpG are annotated to genes involving drug metabolism, inflammation, lipid level, and Type 2 diabetes. Pathway enrichment analysis showed enrichment in biological processes involving metabolic activities and the Cytochrome P450 pathway. However, DNA methylation signals associated with CYP2C19 metaboliser status did not vary by CYP2C19-related medication use. This research suggests that genetically-determined CYP2C19 metaboliser status is associated with both local and distal DNA methylation. These associations are independent of whether individuals were receiving drugs that are related to this enzyme.