bluuebunny/crossref_metadata_2025 huggingface dataset:
Drugst.One — a plug-and-play solution for online systems medicine and network-based drug repurposing
Authors: Maier Andreas , Hartung Michael , Abovsky Mark , Adamowicz Klaudia , Bader Gary D , Baier Sylvie , Blumenthal David B , Chen Jing , Elkjaer Maria L , Garcia-Hernandez Carlos , Helmy Mohamed , Hoffmann Markus , Jurisica Igor , Kotlyar Max , Lazareva Olga , Levi Hagai , List Markus , Lobentanzer Sebastian , Loscalzo Joseph , Malod-Dognin Noel , Manz Quirin , Matschinske Julian , Mee Miles , Oubounyt Mhaned , Pastrello Chiara , Pico Alexander R , Pillich Rudolf T , Poschenrieder Julian M , Pratt Dexter , Pržulj Nataša , Sadegh Sepideh , Saez-Rodriguez Julio , Sarkar Suryadipto , Shaked Gideon , Shamir Ron , Trummer Nico , Turhan Ugur , Wang Rui-Sheng , Zolotareva Olga , Baumbach Jan
Published: May 2024

In recent decades, the development of new drugs has become increasingly expensive and inefficient, and the molecular mechanisms of most pharmaceuticals remain poorly understood. In response, computational systems and network medicine tools have emerged to identify potential drug repurposing candidates. However, these tools often require complex installation and lack intuitive visual network mining capabilities. To tackle these challenges, we introduce Drugst.One, a platform that assists specialized computational medicine tools in becoming user-friendly, web-based utilities for drug repurposing. With just three lines of code, Drugst.One turns any systems biology software into an interactive web tool for modeling and analyzing complex protein-drug-disease networks. Demonstrating its broad adaptability, Drugst.One has been successfully integrated with 21 computational systems medicine tools. Available at https://drugst.one, Drugst.One has significant potential for streamlining the drug discovery process, allowing researchers to focus on essential aspects of pharmaceutical treatment research.
Kinetics of programmed and spontaneous ribosome sliding along the mRNA
Authors: Senyushkina Tamara , Samatova Ekaterina , Klimova Maria , Rodnina Marina V
Published: May 2024

The ribosome can slide along mRNA without establishing codon-anticodon interactions. This movement can be regulated (programmed) by the elements encoded in the mRNA, as observed in bypassing of non-coding gap in gene 60 of bacteriophage T4, or occur spontaneously, such as during traversal by the 70S ribosome of the 3′UTRs or upon re-initiation on bacterial polycistronic genes. In this study, we investigate the kinetic mechanism underlying the programmed and spontaneous ribosome sliding. We show that the translation rate of gene 60 mRNA decreases as the ribosome approaches the take-off site, especially when the KKYK regulatory sequence in the nascent peptide reaches the constriction site in the ribosome exit tunnel. However, efficiency of bypassing increases when the ribosome traverses the gap quickly. With the non-coding gap exceeding the natural 50 nt, the processivity of sliding remains high up to 56 nt, but drops sharply beyond that due to the loss of mRNA elements support. Sliding efficiency is temperature-dependent; while temperature regulates the number of ribosomes initiating programmed bypassing, traversing the long gaps becomes increasingly unfavorable at lower temperatures. This data offers novel insights into the kinetic determinants of programmed and spontaneous ribosome sliding along the mRNA.
SLiMAn 2.0: meaningful navigation through peptide-protein interaction networks
Authors: Reys Victor , Pons Jean-Luc , Labesse Gilles
Published: May 2024

Among the myriad of protein–protein interactions occurring in living organisms, a substantial amount involves small linear motifs (SLiMs) recognized by structured domains. However, predictions of SLiM-based networks are tedious, due to the abundance of such motifs and a high portion of false positive hits. For this reason, a webserver SLiMAn (Short Linear Motif Analysis) was developed to focus the search on the most relevant SLiMs. Using SLiMAn, one can navigate into a given (meta-)interactome and tune a variety of parameters associated to each type of SLiMs in attempt to identify functional ELM motifs and their recognition domains. The IntAct and BioGRID databases bring experimental information, while IUPred and AlphaFold provide boundaries of folded and disordered regions. Post-translational modifications listed in PhosphoSite+ are highlighted. Links to PubMed accelerate scrutiny into the literature, to support (or not) putative pairings. Dedicated visualization features are also incorporated, such as Cytoscape for macromolecular networks and BINANA for intermolecular contacts within structural models generated by SCWRL 3.0. The use of SLiMAn 2.0 is illustrated on a simple example. It is freely available at https://sliman2.cbs.cnrs.fr.
MolModa: accessible and secure molecular docking in a web browser
Authors: Kochnev Yuri , Ahmed Mayar , Maldonado Alex M , Durrant Jacob D
Published: May 2024

Molecular docking advances early-stage drug discovery by predicting the geometries and affinities of small-molecule compounds bound to drug-target receptors, predictions that researchers can leverage in prioritizing drug candidates for experimental testing. Unfortunately, existing docking tools often suffer from poor usability, data security, and maintainability, limiting broader adoption. Additionally, the complexity of the docking process, which requires users to execute a series of specialized steps, often poses a substantial barrier for non-expert users. Here, we introduce MolModa, a secure, accessible environment where users can perform molecular docking entirely in their web browsers. We provide two case studies that illustrate how MolModa provides valuable biological insights. We further compare MolModa to other docking tools to highlight its strengths and limitations. MolModa is available free of charge for academic and commercial use, without login or registration, at https://durrantlab.com/molmoda.
Next-generation IEDB tools: a platform for epitope prediction and analysis
Authors: Yan Zhen , Kim Kevin , Kim Haeuk , Ha Brendan , Gambiez Anaïs , Bennett Jason , de Almeida Mendes Marcus Fabiano , Trevizani Raphael , Mahita Jarjapu , Richardson Eve , Marrama Daniel , Blazeska Nina , Koşaloğlu-Yalçın Zeynep , Nielsen Morten , Sette Alessandro , Peters Bjoern , Greenbaum Jason A
Published: May 2024

The Next-Generation (NG) IEDB Tools website (https://nextgen-tools.iedb.org) provides users with a redesigned interface to many of the algorithms for epitope prediction and analysis that were originally released on the legacy IEDB Tools website. The initial release focuses on consolidation of all tools related to HLA class I epitopes (MHC binding, elution, immunogenicity, and processing), making all of these predictions accessible from a single application and allowing for their simultaneous execution with minimal user inputs. Additionally, the PEPMatch tool for identifying highly similar epitopes in a set of curated proteomes, as well as a tool for epitope clustering, are available on the site. The NG Tools site allows users to build data pipelines by sending the output of one tool as input for the next. Over the next several years, all pre-existing IEDB Tools, and any newly developed tools, will be integrated into this new site. Here we describe the philosophy behind the redesign and demonstrate the utility and productivity enhancements that are enabled by the new interface.
DDMut-PPI: predicting effects of mutations on protein–protein interactions using graph-based deep learning
Authors: Zhou Yunzhuo , Myung YooChan , Rodrigues Carlos H M , Ascher David B
Published: May 2024

Protein–protein interactions (PPIs) play a vital role in cellular functions and are essential for therapeutic development and understanding diseases. However, current predictive tools often struggle to balance efficiency and precision in predicting the effects of mutations on these complex interactions. To address this, we present DDMut-PPI, a deep learning model that efficiently and accurately predicts changes in PPI binding free energy upon single and multiple point mutations. Building on the robust Siamese network architecture with graph-based signatures from our prior work, DDMut, the DDMut-PPI model was enhanced with a graph convolutional network operated on the protein interaction interface. We used residue-specific embeddings from ProtT5 protein language model as node features, and a variety of molecular interactions as edge features. By integrating evolutionary context with spatial information, this framework enables DDMut-PPI to achieve a robust Pearson correlation of up to 0.75 (root mean squared error: 1.33 kcal/mol) in our evaluations, outperforming most existing methods. Importantly, the model demonstrated consistent performance across mutations that increase or decrease binding affinity. DDMut-PPI offers a significant advancement in the field and will serve as a valuable tool for researchers probing the complexities of protein interactions. DDMut-PPI is freely available as a web server and an application programming interface at https://biosig.lab.uq.edu.au/ddmut_ppi.
CASTpFold: Computed Atlas of Surface Topography of the universe of protein Folds
Authors: Ye Bowei , Tian Wei , Wang Boshen , Liang Jie
Published: May 2024

Geometric and topological properties of protein structures, including surface pockets, interior cavities and cross channels, are of fundamental importance for proteins to carry out their functions. Computed Atlas of Surface Topography of proteins (CASTp) is a widely used web server for locating, delineating, and measuring these geometric and topological properties of protein structures. Recent developments in AI-based protein structure prediction such as AlphaFold2 (AF2) have significantly expanded our knowledge on protein structures. Here we present CASTpFold, a continuation of CASTp that provides accurate and comprehensive identifications and quantifications of protein topography. It now provides (i) results on an expanded database of proteins, including the Protein Data Bank (PDB) and non-singleton representative structures of AlphaFold2 structures, covering 183 million AF2 structures; (ii) functional pockets prediction with corresponding Gene Ontology (GO) terms or Enzyme Commission (EC) numbers for AF2-predicted structures and (iii) pocket similarity search function for surface and protein–protein interface pockets. The CASTpFold web server is freely accessible at https://cfold.bme.uic.edu/castpfold/.
A high-resolution map of functional miR-181 response elements in the thymus reveals the role of coding sequence targeting and an alternative seed match
Authors: Verheyden Nikita A , Klostermann Melina , Brüggemann Mirko , Steede Hanna M , Scholz Anica , Amr Shady , Lichtenthaeler Chiara , Münch Christian , Schmid Tobias , Zarnack Kathi , Krueger Andreas
Published: May 2024

MicroRNAs (miRNAs) are critical post-transcriptional regulators in many biological processes. They act by guiding RNA-induced silencing complexes to miRNA response elements (MREs) in target mRNAs, inducing translational inhibition and/or mRNA degradation. Functional MREs are expected to predominantly occur in the 3′ untranslated region and involve perfect base-pairing of the miRNA seed. Here, we generate a high-resolution map of miR-181a/b-1 (miR-181) MREs to define the targeting rules of miR-181 in developing murine T cells. By combining a multi-omics approach with computational high-resolution analyses, we uncover novel miR-181 targets and demonstrate that miR-181 acts predominantly through RNA destabilization. Importantly, we discover an alternative seed match and identify a distinct set of targets with repeat elements in the coding sequence which are targeted by miR-181 and mediate translational inhibition. In conclusion, deep profiling of MREs in primary cells is critical to expand physiologically relevant targetomes and establish context-dependent miRNA targeting rules.
The activity of CobB1 protein deacetylase contributes to nucleoid compaction in Streptomyces venezuelae spores by increasing HupS affinity for DNA
Authors: Duława-Kobeluszczyk Julia , Strzałka Agnieszka , Tracz Michał , Bartyńska Magdalena , Pawlikiewicz Katarzyna , Łebkowski Tomasz , Wróbel Sara , Szymczak Justyna , Zarek Anna , Małecki Tomasz , Jakimowicz Dagmara , Szafran Marcin J
Published: May 2024

Streptomyces are soil bacteria with complex life cycle. During sporulation Streptomyces linear chromosomes become highly compacted so that the genetic material fits within limited spore volume. The key players in this process are nucleoid-associated proteins (NAPs). Among them, HU (heat unstable) proteins are the most abundant NAPs in the cell and the most conserved in bacteria. HupS, one of the two HU homologues encoded by the Streptomyces genome, is the best-studied spore-associated NAP. In contrast to other HU homologues, HupS contains a long, C-terminal domain that is extremely rich in lysine repeats (LR domain) similar to eukaryotic histone H2B and mycobacterial HupB protein. Here, we have investigated, whether lysine residues in HupS are posttranslationally modified by reversible lysine acetylation. We have confirmed that Streptomyces venezuelae HupS is acetylated in vivo. We showed that HupS binding to DNA in vitro is controlled by the acetylation. Moreover, we identified that CobB1, one of two Sir2 homologues in Streptomyces, controls HupS acetylation levels in vivo. We demonstrate that the elimination of CobB1 increases HupS mobility, reduces chromosome compaction in spores, and affects spores maturation. Thus, our studies indicate that HupS acetylation affects its function by diminishing DNA binding and disturbing chromosome organization.
MinActionPath2: path generation between different conformations of large macromolecular assemblies by action minimization
Authors: Koehl Patrice , Navaza Rafael , Tekpinar Mustafa , Delarue Marc
Published: May 2024

Recent progress in solving macromolecular structures and assemblies by cryogenic electron microscopy techniques enables sampling of their conformations in different states that are relevant to their biological function. Knowing the transition path between these conformations would provide new avenues for drug discovery. While the experimental study of transition paths is intrinsically difficult, in-silico methods can be used to generate an initial guess for those paths. The Elastic Network Model (ENM), along with a coarse-grained representation (CG) of the structures are among the most popular models to explore such possible paths. Here we propose an update to our software platform MinActionPath that generates non-linear transition paths based on ENM and CG models, using action minimization to solve the equations of motion. The new website enables the study of large structures such as ribosomes or entire virus envelopes. It provides direct visualization of the trajectories along with quantitative analyses of their behaviors at http://dynstr.pasteur.fr/servers/minactionpath/minactionpath2_submission.
Transposon DNA sequences facilitate the tissue-specific gene transfer of circulating tumor DNA between human cells
Authors: Cinar Munevver , Martinez-Medina Lourdes , Puvvula Pavan K , Arakelyan Arsen , Vardarajan Badri N , Anthony Neil , Nagaraju Ganji P , Park Dongkyoo , Feng Lei , Sheff Faith , Mosunjac Marina , Saxe Debra , Flygare Steven , Alese Olatunji B , Kaufman Jonathan L , Lonial Sagar , Sarmiento Juan M , Lossos Izidore S , Vertino Paula M , Lopez Jose A , El-Rayes Bassel , Bernal-Mizrachi Leon
Published: May 2024

The exchange of genes between cells is known to play an important physiological and pathological role in many organisms. We show that circulating tumor DNA (ctDNA) facilitates cell-specific gene transfer between human cancer cells and explain part of the mechanisms behind this phenomenon. As ctDNA migrates into the nucleus, genetic information is transferred. Cell targeting and ctDNA integration require ERVL, SINE or LINE DNA sequences. Chemically manufactured AluSp and MER11C sequences replicated multiple myeloma (MM) ctDNA cell targeting and integration. Additionally, we found that ctDNA may alter the treatment response of MM and pancreatic cancer models. This study shows that retrotransposon DNA sequences promote cancer gene transfer. However, because cell-free DNA has been detected in physiological and other pathological conditions, our findings have a broader impact than just cancer. Furthermore, the discovery that transposon DNA sequences mediate tissue-specific targeting will open up a new avenue for the delivery of genes and therapies.
Comparing the Fagerström Test and Heaviness of Smoking Index in Predicting Smoking Abstinence in Cancer Patients
Authors: Rodríguez-Cano Rubén , Kypriotakis George , Robinson Jason D , Karam-Hage Maher , Blalock Janice A , Minnix Jennifer A , Beneventi Diane , Cinciripini Paul M
Published: May 2024

Introduction

People with cancer who smoke exhibit greater cigarette dependence than people without cancer who smoke, a crucial factor in smoking cessation. Research is limited on the predictive potential of the Fagerström Test for Cigarette Dependence (FTCD) and the Heaviness of Smoking Index (HSI) on smoking abstinence in cancer patients undergoing smoking cessation treatment.

Aims and Methods

We analyzed data from 5934 cancer patients seeking smoking cessation treatment at The University of Texas MD Anderson Cancer Center (female 52.08%; Mean age = 55.52, SD = 11.17). We evaluated the predictive accuracy of FTCD and HSI on abstinence at 3, 6, and 9 months from the first consultation, and assessed the concordance between these tools in measuring cigarette dependence using Cohen’s kappa test and different correlation and regression models. We also analyzed variations across sex at birth and race/ethnicity.

Results

Both the FTCD and the HSI demonstrated comparable predictive accuracy for smoking cessation at all follow-ups, with neither showing high accuracy (Areas Under the Curve scores around 0.6). Concordance analysis revealed substantial agreement between FTCD and HSI scores (Cohen’s kappa ~ 0.7), particularly at lower levels of dependence. However, this agreement varied by race, with reduced concordance observed in non-Hispanic Blacks.

Conclusions

Our results indicate that both the FTCD and HSI are effective tools for predicting smoking cessation in cancer patients, with the HSI offering a less burdensome assessment option. Nevertheless, the findings suggest the need for tailored approaches in assessing cigarette dependence that could predict smoking cessation more accurately, considering racial differences.

Implications

The burden of assessing cigarette dependence in cancer care settings can be reduced by using the HSI instead of the FTCD. In addition, both instruments could be substantially interchanged and used for meta-analytic studies examining dependence and abstinence, but race/ethnicity should be considered.
A Review of the Toxicity of Ingredients in e-Cigarettes, Including Those Ingredients Having the FDA’s “Generally Recognized as Safe (GRAS)” Regulatory Status for Use in Food
Authors: Kassem Nada O F , Strongin Robert M , Stroup Andrea M , Brinkman Marielle C , El-Hellani Ahmad , Erythropel Hanno C , Etemadi Arash , Exil Vernat , Goniewicz Maciej L , Kassem Noura O , Klupinski Theodore P , Liles Sandy , Muthumalage Thivanka , Noël Alexandra , Peyton David H , Wang Qixin , Rahman Irfan , Valerio Luis G
Published: May 2024

Some firms and marketers of electronic cigarettes (e-cigarettes; a type of electronic nicotine delivery system (ENDS)) and refill liquids (e-liquids) have made claims about the safety of ingredients used in their products based on the term “GRAS or Generally Recognized As Safe” (GRAS). However, GRAS is a provision within the definition of a food additive under section 201(s) (21 U.S.C. 321(s)) of the U.S. Federal Food Drug and Cosmetic Act (FD&C Act). Food additives and GRAS substances are by the FD&C Act definition intended for use in food, thus safety is based on oral consumption; the term GRAS cannot serve as an indicator of the toxicity of e-cigarette ingredients when aerosolized and inhaled (ie, vaped). There is no legal or scientific support for labeling e-cigarette product ingredients as “GRAS.” This review discusses our concerns with the GRAS provision being applied to e-cigarette products and provides examples of chemical compounds that have been used as food ingredients but have been shown to lead to adverse health effects when inhaled. The review provides scientific insight into the toxicological evaluation of e-liquid ingredients and their aerosols to help determine the potential respiratory risks associated with their use in e-cigarettes.
Mechanistic Insights into the Function of 14-3-3 Proteins as Negative Regulators of Brassinosteroid Signaling in Arabidopsis
Authors: Obergfell Elsa , Hohmann Ulrich , Moretti Andrea , Chen Houming , Hothorn Michael
Published: May 2024

Brassinosteroids (BRs) are vital plant steroid hormones sensed at the cell surface by a membrane signaling complex comprising the receptor kinase BRI1 and a SERK family co-receptor kinase. Activation of this complex lead to dissociation of the inhibitor protein BKI1 from the receptor and to differential phosphorylation of BZR1/BES1 transcription factors by the glycogen synthase kinase 3 protein BIN2. Many phosphoproteins of the BR signaling pathway, including BRI1, SERKs, BKI1 and BZR1/BES1 can associate with 14-3-3 proteins. In this study, we use quantitative ligand binding assays to define the minimal 14-3-3 binding sites in the N-terminal lobe of the BRI1 kinase domain, in BKI1, and in BZR1 from Arabidopsis thaliana. All three motifs require to be phosphorylated to specifically bind 14-3-3s with mid- to low-micromolar affinity. BR signaling components display minimal isoform preference within the 14-3-3 non-ε subgroup. 14-3-3λ and 14-3-3 ω isoform complex crystal structures reveal that BKI1 and BZR1 bind as canonical type II 14-3-3 linear motifs. Disruption of key amino acids in the phosphopeptide binding site through mutation impairs the interaction of 14-3-3λ with all three linear motifs. Notably, quadruple loss-of-function mutants from the non-ε group exhibit gain-of-function BR signaling phenotypes, suggesting a role for 14-3-3 proteins as overall negative regulators of the BR pathway. Collectively, our work provides further mechanistic and genetic evidence for the regulatory role of 14-3-3 proteins at various stages of the BR signaling cascade.
An insertion in the promoter of a malate dehydrogenase gene regulates malic acid content in apple fruit
Authors: Gao Meng , Yang Nanxiang , Shao Yingli , Shen Tian , Li Wenxin , Ma Baiquan , Wei Xiaoyu , Ruan Yong-Ling , Ma Fengwang , Li Mingjun
Published: May 2024

Malic acid is an important flavor determinant in apple (Malus × domestica Borkh.) fruit. One known variation controlling malic acid is the A/G single nucleotide polymorphism in an aluminum-activated malate transporter gene (MdMa1). Nevertheless, there are still differences in malic acid content in apple varieties with the same Ma1 genotype (Ma1/Ma1 homozygous), such as ‘Honeycrisp’ (high malic acid content) and ‘Qinguan’ (low malic acid content), indicating that other loci may influence malic acid and fruit acidity. Here, the F1 (Filial 1) hybrid generation of ‘Honeycrisp’ × ‘Qinguan’ was used to analyze quantitative trait loci for malic acid content. A major locus (Ma7) was identified on chromosome 13. Within this locus, a malate dehydrogenase gene, MDH1 (MdMa7), was the best candidate for further study. Subcellular localization suggested that MdMa7 encodes a cytosolic protein. Overexpression and RNA interference of MdMa7 in apple fruit increased and decreased malic acid content, respectively. An insertion/deletion (indel) in the MdMa7 promoter was found to affect MdMa7 expression and malic acid content in both hybrids and other cultivated varieties. The insertion and deletion genotypes were designated as MA7 and ma7, respectively. The transcription factor MdbHLH74 was found to stimulate MdMa7 expression in the MA7 genotype but not in the ma7 genotype. Transient transformation of fruit showed that MdbHLH74 affected MdMa7 expression and malic acid content in ‘Gala’ (MA7/MA7) but not in ‘Fuji’ (ma7/ma7). Our results indicated that genetic variation in the MdMa7 (MDH1) promoter alters the binding ability of the transcription factor MdbHLH74, which alters MdMa7 (MDH1) transcription and the malic acid content in apple fruit, especially in Ma1/Ma1 homozygous accessions.
Cyclicity and Exponent of Elliptic Curves Modulo p in Arithmetic Progressions
Authors: Wong Peng-Jie
Published: May 2024

In this article, we study the cyclicity problem of elliptic curves $E/\mathbb{Q}$ modulo primes in a given arithmetic progression. We extend the recent work of Akbal and Güloğlu by proving an unconditional asymptotic for such a cyclicity problem over arithmetic progressions for elliptic curves E, which also presents a generalization of the previous works of Akbary, Cojocaru, M.R. Murty, V.K. Murty and Serre. In addition, we refine the conditional estimates of Akbal and Güloğlu, which gives log-power savings (for small moduli) and consequently improves the work of Cojocaru and M.R. Murty. Moreover, we study the average exponent of E modulo primes in a given arithmetic progression and obtain several conditional and unconditional estimates, extending the previous works of Freiberg, Kim, Kurlberg and Wu.
Islam and the Transmission of Cultural Identity in Four European Countries
Authors: Karim Sakeef M
Published: May 2024

Studies exploring the integration of European immigrants tend to find cultural gaps between Muslim children and their peers. While some scholars argue that parent-to-child transmission is a key mechanism underlying this pattern, others privilege extrafamilial explanations by pointing to differences in cultural values within Muslim households. In the present study, I argue that these mixed results stem from a tendency in the literature to analyze distinct components of personal culture in isolation from cognate dimensions. To address this shortcoming, I use multigroup latent class models to explore how a wide range of attitudes (tapping ethnocultural identity, gender norms, sexual liberalism, and perspectives on integration) are clustered together in disparate regions of the belief space, marking distinct cultural identities. Then, I fit a series of logistic regressions to map how these cultural identities are distributed among immigrant-origin samples in four European countries and transmitted across generational lines. Ultimately, I arrive at the following conclusion: while Muslim youth stand out from their peers vis-à-vis their cultural identity profiles, there is little evidence to suggest that this pattern is decisively shaped by parent-to-child transmission.
Moderate chronic sleep perturbation impairs glucose and lipid homeostasis in rats
Authors: Tonet Natália Stinghen , da Silva Marçal Danilo Francisco , da Silva Flavia Natividade , Brunetta Henver Simionato , Mori Marcelo Alves da Silva , dos Santos Gustavo Jorge , Moreira Eduardo Luiz Gasnhar , Rafacho Alex
Published: May 2024

Study Objectives

Sleep deprivation is a potential risk factor for metabolic diseases, including obesity and type 2 diabetes. We evaluated the impacts of moderate chronic sleep deprivation on glucose and lipid homeostasis in adult rats.

Methods

Wistar rats (both sexes) were sleep-perturbed daily for 2 hours at the early (06:00–08:00) and the late light cycle (16:00–18:00) five days a week (except weekends) for 4 weeks.

Results

Sleep perturbation (SP) resulted in reduced body weight gain in both sexes, associated with altered food intake and reduced adiposity. SP did not alter the short- or long-term memories or cause anxiogenic behavior. No major changes were observed in the plasma insulin, leptin, triacylglycerol, non-esterified fatty acids, and blood glucose upon SP. After SP, females exhibited a transitory glucose intolerance, while males became glucose intolerant at the end of the experimental period. Male rats also developed higher insulin sensitivity at the end of the SP protocol. Morphometric analyses revealed no changes in hepatic glycogen deposition, pancreatic islet mass, islet-cell distribution, or adrenal cortex thickness in SP rats from both sexes, except for lower adipocyte size compared with controls. We did not find homogeneous changes in the relative expression of circadian and metabolic genes in muscle or hepatic tissues from the SP rats.

Conclusions

Moderate chronic SP reduces visceral adiposity and causes glucose intolerance with a more pronounced impact on male rats, reinforcing the metabolic risks of exposure to sleep disturbances.
Evaluating the impact of anatomical and physiological variability on human equivalent doses using PBPK models
Authors: Schacht Celia M , Meade Annabel E , Bernstein Amanda S , Prasad Bidya , Schlosser Paul M , Tran Hien T , Kapraun Dustin F
Published: May 2024

Addressing human anatomical and physiological variability is a crucial component of human health risk assessment of chemicals. Experts have recommended probabilistic chemical risk assessment paradigms in which distributional adjustment factors are used to account for various sources of uncertainty and variability, including variability in the pharmacokinetic behavior of a given substance in different humans. In practice, convenient assumptions about the distribution forms of adjustment factors and human equivalent doses (HEDs) are often used. Parameters such as tissue volumes and blood flows are likewise often assumed to be lognormally or normally distributed without evaluating empirical data for consistency with these forms. In this work, we performed dosimetric extrapolations using physiologically based pharmacokinetic (PBPK) models for dichloromethane (DCM) and chloroform that incorporate uncertainty and variability to determine if the HEDs associated with such extrapolations are approximately lognormal and how they depend on the underlying distribution shapes chosen to represent model parameters. We accounted for uncertainty and variability in PBPK model parameters by randomly drawing their values from a variety of distribution types. We then performed reverse dosimetry to calculate HEDs based on animal points of departure for each set of sampled parameters. Corresponding samples of HEDs were tested to determine the impact of input parameter distributions on their central tendencies, extreme percentiles, and degree of conformance to lognormality. This work demonstrates that the measurable attributes of human variability should be considered more carefully and that generalized assumptions about parameter distribution shapes may lead to inaccurate estimates of extreme percentiles of HEDs.
Effects of combustible cigarettes and heated tobacco products on immune cell-driven inflammation in chronic obstructive respiratory diseases
Authors: Kastratovic Nikolina , Cekerevac Ivan , Sekerus Vanesa , Markovic Vladimir , Arsenijevic Aleksandar , Volarevic Ana , Harrell Carl Randall , Jakovljevic Vladimir , Djonov Valentin , Volarevic Vladislav
Published: May 2024

Since long-term effects of heated tobacco products (HTP) on the progression of chronic obstructive pulmonary disease (COPD) are unknown, we used COPD mice model to compare immune cell-dependent pathological changes in the lungs of animals which were exposed to HTP or combustible cigarettes (CCs). We also performed intracellular staining and flow cytometry analysis of immune cells which were present in the blood of CCs and HTP users who suffered from immune cell-driven chronic obstructive respiratory diseases. CCs enhanced NLRP3 inflammasome-dependent production of inflammatory cytokines in lung-infiltrated neutrophils and macrophages and increased influx of cytotoxic Th1, Th2, and Th17 lymphocytes in the lungs of COPD mice. Similarly, CCs promoted generation of inflammatory phenotype in circulating leukocytes of COPD patients. Opposite to CCs, HTP favored expansion of immunosuppressive, IL-10-producing, FoxP3-expressing T, NK, and NKT cells in inflamed lungs of COPD mice. Compared with CCs, HTP had weaker capacity to promote synthesis of inflammatory cytokines in lung-infiltrated immune cells. Significantly lower number of inflammatory neutrophils, monocytes, Th1, Th2, and Th17 lymphocytes were observed in the blood of patients who consumed HTP than in the blood of CCs users, indicating different effects of CCs and HTP on immune cells’ phenotype and function.
Divergent patterns of cranial suture fusion in marsupial and placental mammals
Authors: White Heather E , Tucker Abigail S , Goswami Anjali
Published: May 2024

Cranial sutures, both open and closed, support a myriad of skull functions, including redistributing strain, accommodating brain expansion, supporting cranial bone growth, and protecting the brain. Thus, variation in the degree, timing, and pattern of suture fusion has functional implications. Using a comparative ontogenetic framework across Mammalia, we quantified degree and pattern of suture fusion through ontogeny for 22 mammalian species (N = 165). Suture closure was scored on a discrete scale for 31 cranial sutures and used to calculate closure scores for individual sutures and specimens. Ancestral state estimations found the degree of ancestral marsupial fusion to be more derived, differing from both the ancestral placental and ancestral therian. The average placental pattern followed the Krogman pattern of suture fusion (cranial vault, cranial base, circum-meatal, palatal, facial, and cranio-facial), whereas marsupials showed a distinct pattern. We propose a new pattern of suture fusion for marsupials: vault, cranio-facial, facial, circum-meatal, palate, cranial base. Delayed fusion of the marsupial cranial base is hypothesized here to support prolonged postnatal growth of the marsupial brain. Collectively, our study has identified a clear marsupial-placental dichotomy in the degree, timing, and pattern of suture fusion, with implications for understanding skull function and ontogeny.
Current updates for hyperuricemia and gout in age‐related macular degeneration
Authors: Pai Hung‐Liang , Lin David Pei‐Cheng , Chang Han‐Hsin
Published: May 2024

The escalating prevalence of metabolic syndrome poses a significant public health challenge, particularly among aging populations, with metabolic dysfunctions contributing to pro‐inflammatory states. In this review, we delved into the less recognized association between hyperuricemia (HUA), a manifestation of metabolic syndrome and a primary risk factor for gout, and age‐related macular degeneration (AMD), a sight‐threatening ailment predominantly affecting the elderly. In recent years, inflammation, particularly its involvement in complement pathway dysregulation, has gained prominence in AMD pathophysiology. The contradictory role of uric acid (UA) in intercellular and intracellular environments was discussed, highlighting its antioxidant properties in plasma and its pro‐oxidant effects intracellularly. Emerging evidence suggests a potential link between elevated serum uric acid levels and choroid neovascularization in AMD, providing insights into the role of HUA in retinal pathologies. Various pathways, including crystal‐induced and non‐crystal‐induced mechanisms, were proposed to indicate the need for further research into the precise molecular interactions. The implication of HUA in AMD underscores its potential involvement in retinal pathologies, which entails interdisciplinary collaboration for a comprehensive understanding of its impact on retina and related clinical manifestations.
MIF as a potential diagnostic and prognostic biomarker for triple‐negative breast cancer that correlates with the polarization of M2 macrophages
Authors: Chen Mengting , Liu Hongsen , Hong Bo , Xiao Yufei , Qian Yun
Published: May 2024

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a crucial role in antitumor immunity. However, the role of MIF in influencing the tumor microenvironment (TME) and prognosis of triple‐negative breast cancer (TNBC) remains to be elucidated. Using R, we analyzed single‐cell RNA sequencing (scRNA‐seq) data of 41 567 cells from 10 TNBC tumor samples and spatial transcriptomic data from two patients. Relationships between MIF expression and immune cell infiltration, clinicopathological stage, and survival prognosis were determined using samples from The Cancer Genome Atlas (TCGA) and validated in a clinical cohort using immunohistochemistry. Analysis of scRNA‐seq data revealed that MIF secreted by epithelial cells in TNBC patients could regulate the polarization of macrophages into the M2 phenotype, which plays a key role in modulating the TME. Spatial transcriptomic data also showed that epithelial cells (tumor cells) and MIF were proximally located. Analysis of TCGA samples confirmed that tumor tissues of patients with high MIF expression were enriched with M2 macrophages and showed a higher T stage. High MIF expression was significantly associated with poor patient prognosis. Immunohistochemical staining showed high MIF expression was associated with younger patients and worse clinicopathological staging. MIF secreted by epithelial cells may represent a potential biomarker for the diagnosis and prognosis of TNBC and may promote TNBC invasion by remodeling the tumor immune microenvironment.
Beyond the Baker's Cyst: Pathology and Variant Anatomy in the Popliteal Fossa on Routine Knee MRI
Authors: Baker Adam N. , Dayan Etan , Koo Clara , Sun Sean , Zhou Rebecca
Published: May 2024

Primary evaluation of the knee focuses on evaluation of cartilaginous degeneration, meniscal injury, ligamentous or tendinous abnormality, and bony lesions, rather than the posterior and extracapsular popliteal fossa. A succinct review of normal popliteal fossa anatomy and normal fat planes is key to recognizing clinically significant pathology and variant anatomy. Abnormal insertion of the medial head of the gastrocnemius, or an accessory head of the gastrocnemius, can increase the risk of popliteal artery entrapment, an underrecognized cause of posterior calf and knee pain. Abnormal branching and course of the popliteal artery can increase risk of surgical vulnerability during multiple knee procedures, including arthroscopy and high tibial osteotomy. Finally, not all masses in the popliteal fossa are Baker's cysts; synovial sarcomas, vascular malformations, and other tumors can present in this anatomic space and can mimic popliteal cysts.
Assessment of the Educational and Training Modalities in Point-of-Care Ultrasound (POCUS) for Anesthesiologists
Authors: Mozingo Cy , Neely Grant
Published: May 2024

Point-of-care ultrasound (POCUS) has been developed as a critical tool for diagnostic patient evaluation and clinical management. Its transcendence into anesthesiology necessitates appropriate and effective educational strategies to assist in the development of anesthesia POCUS learners. Several professional societies, including the American Society of Anesthesiologists (ASA), American Society of Regional Anesthesia (ASRA), and Accreditation Council for Graduate Medical Education (ACGME) for anesthesiology have established minimum training standards for POCUS education for anesthesiologists, residents, and fellows.1,4 The article at hand aims to summarize and provide insight into the various educational modalities utilized in POCUS training, incorporate these strategies in the established “Indication, Acquisition, Interpretation, and Medical decision-making” (I-AIM) framework, and include recommendations on the minimum number of POCUS exams to aid in achieving competency.
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Assessment of postoperative pain in children following sclerotherapy of vascular malformations: a retrospective single centre cohort study
Authors: Klein Tank Cees , Himantono Nadia , Verhoeven Bas H. , Malagon Ignacio
Published: May 2024

BACKGROUND

Inadequately controlled postprocedural pain following sclerotherapy in patients with vascular malformations is a well recognised problem. Reliable epidemiological data and risk factors associated with postprocedural pain in children are lacking.

OBJECTIVES

To evaluate and quantify postprocedural pain in children and identify possible risk factors based on characteristics of the patient, treatment, and medication.

DESIGN

A retrospective single centre cohort study.

SETTING

A tertiary single centre study in the Netherlands.

PATIENTS

Two hundred and nine chiuldren with ‘simple’ subtypes of congenital vascular malformation who had undergone sclerotherapy.

PRIMARY OUTCOME MEASURE

Quantifying inadequately controlled postprocedural pain.

SECONDARY OUTCOME MEASURES

Identifying potential patient and treatment characteristics associated with inadequately controlled postprocedural pain.

RESULTS

A total of 209 patients who underwent 679 procedures were included in this study. The mean age at first intervention was 11.8 ± 4.5 years. Inadequately controlled postprocedural pain was found in 34.8% of the 679 procedures. Venous malformations (VM) were the most prevalent subtype of vascular malformation (80%), followed by arteriovenous malformations (AVM) (14.6%) and lymphatic malformations (LM) (5.4%). The odds ratio (OR) (95% confidence intervals), and P values obtained from multivariable mixed effect logistic regression analysis for patient and treatment characteristics found to be associated with inadequately controlled postprocedural pain were: chronic use of analgesics (OR 2.74 (1.40 to 5.34), P = 0.003), treatment with ethanol (OR 2.39 (1.01 to 5.65, P = 0.05) or esketamine (OR 7.43 (1.32 to 41.81), P = 0.02). Patients treated with lauromacrogol (OR 0.42 (0.22 to 0.82, P = 0.01) and patients receiving intra-operative NSAIDs (OR 0.32, (0.12 to 0.85), P = 0.02) were less likely to experience inadequately controlled postprocedural pain.

CONCLUSIONS

Despite aiming to achieve best practice, the 34.8% incidence of unsatisfactory postoperative pain management in the children studied confirms that postprocedural pain after sclerotherapy is a common problem that requires further attention.
Longitudinal profiles of the vaginal microbiota of pre-, peri-, and postmenopausal women: preliminary insights from a secondary data analysis
Authors: Stennett Christina A. , France Michael , Shardell Michelle , Robbins Sarah J. , Brown Sarah E. , Johnston Elizabeth D. , Mark Katrina , Ravel Jacques , Brotman Rebecca M.
Published: May 2024

Objective

Menopause is often accompanied by lowered Lactobacillus spp. relative abundance and increased abundance of diverse anaerobic/aerobic bacteria in the vaginal microbiota due in part to declines in estrogen. These microbiota are associated with urogenital symptoms and infections. In premenopause, vaginal microbiota can fluctuate rapidly, particularly with menstrual cycles and sexual activity; however, the longitudinal dynamics of vaginal microbiota are understudied in peri- and postmenopause. We described vaginal community stability across reproductive stages.

Methods

Pre- (n = 83), peri- (n = 8), and postmenopausal (n = 11) participants provided twice-weekly mid-vaginal samples (total, 1,556; average, 15 per participant) over 8 weeks in an observational study. Composition of the vaginal microbiota was characterized by 16S rRNA gene amplicon sequencing, and a community state type (CST) was assigned to each sample. Clustering of longitudinal CST profiles, CST transition rates, duration of low-Lactobacillus/high bacterial diversity CSTs, and other metrics of bacterial community dynamics were assessed across reproductive stages.

Results

The proportion of participants with longitudinal CST profiles characterized by low-Lactobacillus CSTs was similar among pre- (38.6%), peri- (37.5%), and postmenopausal (36.4%) participants (P = 0.69). CST transition rates between consecutive samples were 21.1%, 16.7%, and 14.6% for pre-, peri-, and postmenopausal participants, respectively (P = 0.49). Low-Lactobacillus CST tended to persist for at least 4 weeks, irrespective of reproductive stage.

Conclusions

Findings from this small yet frequently sampled cohort revealed vaginal bacterial fluctuations over 8 weeks that were similar across reproductive stages. Larger and longer-term studies based on these preliminary data could provide insights into the influence of microbiota dynamics on urogenital outcomes during menopause.
Idiopathic Calcinosis Cutis of the Hand
Authors: Shahriari Shawhin R.K. , Murali Tharani , Clarke Tegan N. , Kuhn Joseph F. , Stepenaskie Shelly A. , Borah Gregory L.
Published: May 2024

Calcinosis cutis is a disease process characterized by calcified lesions in the skin. Although there are five subtypes of calcinosis, idiopathic calcinosis cutis is a rare disease process with no clear etiology. It has been described in many parts of the body; however, there are only five reported cases specifically involving the hands. We describe the presentation and successful treatment of a case of idiopathic calcinosis cutis in a 65-year-old man with lesions on his bilateral hands. We believe that surgical excision of symptomatic lesions is a safe and effective treatment for idiopathic calcinosis cutis of the hands.
Research progress on the toxicity of Asari Radix et Rhizoma
Authors: Li Xin , Chen Ranyun , Duan Shuni , Li Yijie , Zhou Huiping , Liu Runping , Sun Rong
Published: May 2024

Asari Radix et Rhizoma (ARR), also known as Xixin, has been broadly used as a traditional herbal medicine in East Asia and is an important component of classic prescriptions, including Mahuang Fuzi Xixin decoction. It was initially classified as a “top grade” herb in ancient Chinese Pharmacopeia, Shennong’s Materia Medica. Volatile oils, lignans, fatty acids, flavonoids, and nitrogen-containing compounds are the main ARR components. Previous pharmacological studies have shown that ARR exerts beneficial effects in humans for treating headaches, toothaches, and several inflammatory diseases by dispelling wind and cold, alleviating pain, and eliminating phlegm. However, “the dosage of ARR should not exceed one coin (approximately 3.75 grams),” as stated in Shizhen Li’s Compendium of Materia, which emphasized the considerable ARR toxicity and significantly constrained its clinical application. This review aimed to consolidate recent advancements in the understanding of the toxic ARR components. Additionally, we provide an overview of the hepatotoxicity, genotoxicity, neurotoxicity, and pulmonary toxicity of ARR and discuss the underlying molecular mechanisms. This study reviews the limitations of current studies and enhances our understanding of the toxic effects of ARR from the perspective of its toxic components and mechanisms, thereby providing a theoretical basis for the rational clinical practice of ARR-based medications.
Safety evaluation of traditional Chinese medicine: new era, new strategy
Authors: Zhao Xu , Bai Zhaofang , Zhan Xiaoyan , Wang Jiabo , Cheng Yungchi , Xiao Xiaohe
Published: May 2024

Today, as the use of traditional Chinese medicine (TCM) becomes widespread globally, TCM is confronted with numerous new safety issues and challenges. In particular, the frequent emergence of safety issues/events such as liver and kidney injury associated with traditionally “non-toxic” TCM has overturned the conventional understanding of the toxicity and safety of TCM. This has also posed significant challenges to the development and internationalization of TCM. So, how should we understand the situation and problems of TCM safety? How can we scientifically solve the problems in evaluation and risk control of TCM? Our team proposes the following: First, we must keep pace with the times and view the issues of TCM safety in a dialectical manner, without exaggeration or underestimation. Second, we must break through the traditional perception that toxicity only came from the medicine itself, and innovate the theories of TCM toxicity. Third, we must establish precise prevention and control strategies for TCM with different types of toxicity, promoting a shift in the management of TCM safety risks from passive response to scientific and proactive control. On this basis, we have put forward the concept and methodological system of the “New Outlook on TCM safety”, hoping to provide new theories, strategies, methods, and successful examples for systematically solving the problems in the evaluation and risk control of TCM.