bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment options to break the cycle of recurrent pericarditis
Authors: Raisinghani Ajit B. , Luis Sushil Allen
Published: January 2025

Purpose of review

This review provides a contemporary, evidence-based update on the pathophysiological mechanisms and rapidly evolving therapeutic options for recurrent pericarditis.

Recent findings

Recent studies have elucidated the pathogenesis of recurrent pericarditis, identifying autoinflammation as a key mechanism and interleukin-1 (IL-1) as a central modulator of the inflammatory cascade. Multiple clinical trials have investigated novel therapeutic approaches, particularly focusing on IL-1 inhibition. The recent FDA approval of IL-1 pathway blockade for recurrent pericarditis has revolutionized treatment, offering patients significantly improved quality of life and symptom management.

The enhanced understanding of the autoinflammatory nature of recurrent pericarditis, coupled with groundbreaking advances in targeted therapies, has transformed the treatment landscape for affected patients. The emergence of IL-1 inhibitors as an effective therapeutic option promises substantial improvements in clinical outcomes and patient well being. Clinicians must familiarize themselves with these new treatments, their efficacy, and potential limitations to optimize patient care and guide therapeutic decision-making in this challenging condition.
Prevalence of Anti-HIV Antibodies at 12 Months of Age in Infants Exposed to HIV
Authors: Magdaleno Amanda Milman , Friedrich Luciana , Ramos Maithe Antonello , Corso Andréa Lúcia
Published: January 2025

This study determined the prevalence of reactive HIV serology at 12 months of age in infants exposed to HIV in utero. Of the 80 patients analyzed, 50 (63.3%) were anti-HIV reactive. This study suggests that it is probably not helpful to perform HIV antibody testing in HIV-exposed non-breastfed infants who have met virologic criteria to exclude HIV infection in the first year of life.
Use of Narrow Band Imaging to Guide Endobronchial Biopsy for Suspected Sarcoidosis
Authors: Vis Daniel , Dumoulin Elaine , Vakil Erik , MacEachern Paul , Samy Laila , Hergott Chris , Tremblay Alain
Published: January 2025

Background:

Diagnosis of sarcoidosis often involves endobronchial biopsy (EBB), but studies have shown varying yields for EBB in suspected sarcoidosis, partly due to differences in identifying abnormal mucosa under white light (WL). Narrow band imaging (NBI) may assist in the visualization of abnormal mucosa, but its role in sarcoidosis remains to be characterized.

Methods:

Individuals referred for suspected sarcoidosis were considered for enrollment. Bronchoscopy with both WL and NBI was conducted, followed by EBB. The main objectives were to characterize NBI abnormalities in this patient population and determine the incremental yield of NBI-directed EBB.

Results:

In our cohort of 100 suspected sarcoidosis patients (66% male, median age 42), 88 were diagnosed with sarcoidosis, through cytopathology (n=78) or clinical evaluation (n=10). NBI high-grade lesions were more common than WL high-grade lesions (58% vs. 27%, difference 31%, 95% CI 18.3-42.5% P<0.001). High-grade WL EBB were more likely to be positive than low-grade WL biopsies [20/31 (65%) vs. 20/91 (22%), odds ratio (OR) 6.5, 95% CI 2.7-15.6, P<0.01]). Conversely, high-grade NBI lesions were no more likely to be positive than low-grade NBI lesions [23/63 (37%) vs. 17/59, (29%), OR 1.42, 95% CI 0.66-3.0, P=0.366]. EBB positivity and false-negative EBUS-TBNA were more common in patients with Scadding stage 2 or greater, suggesting that the chest radiography stage may help select patients more likely to benefit from adjunctive EBB.

Conclusion:

NBI abnormalities are common in patients with sarcoidosis, but unlike WL abnormalities, do not predict the finding of granulomatous inflammation on EBB. The chest radiography stage may be useful to identify patients more likely to benefit from EBB in addition to EBUS-TBNA.
Specialized pro-resolving lipid mediators in gut immunophysiology: from dietary precursors to inflammation resolution
Authors: Albuquerque-Souza Emmanuel , Dalli Jesmond
Published: January 2025

Purpose of review

This review aims to examine recent research on the role of specialized pro-resolving mediators (SPMs) in the regulation of gut immunophysiology.

Recent findings

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract, driven by disruptions in the intestinal barrier and an imbalance between the host immune system and gut microbiota. Dietary polyunsaturated fatty acids (PUFAs), especially ω-3 and ω-6, are key regulators of immune responses and help maintain the integrity of the intestinal barrier. These PUFAs serve as precursors to SPMs, lipid mediators that play a critical role in resolving inflammation. SPMs actively reprogram immune cells, promoting the clearance of cellular debris, reducing cytokine production, and restoring tissue homeostasis without suppressing the immune response. Emerging evidence indicates that in the gut, SPMs strengthen intestinal barrier function, modulate immune responses in colitis and colon cancer, and influence gut microbiota composition.

The recent evidence strongly supports the central role of SPMs in maintaining gut health and restoring organ function following inflammatory challenges. This evidence highlights the potential of therapeutic approaches that target these pathways for both the prevention and treatment of gut-related inflammatory conditions.
Trends in Obesity Care Among US Adults, 2010–2021
Authors: Podolsky Meghan I. , Raquib Rafeya , Hempstead Katherine , Stokes Andrew C.
Published: January 2025

Background:

Obesity is a major contributor to mortality in the United States. Clinical guidelines emphasize the need for multimodal treatment, but novel treatments may be changing care-seeking behavior.

Objective:

To characterize obesity treatment access patterns and factors associated with obesity care from 2010 to 2021 in the United States.

Research Design:

This multiyear cross-sectional study was conducted using Medical Expenditure Panel Survey data, covering respondents from 2010 to 2021.

Subjects:

We defined individuals with a body mass index ≥30 or those with any health care event linked to a diagnosis of obesity as being clinically eligible for obesity treatment.

Measure(s):

The primary outcome was the proportion of individuals assumed eligible for obesity treatment who accessed obesity treatment or were prescribed medication to treat obesity in each calendar year from 2010 to 2021.

Results:

The population of individuals eligible for obesity treatment was 82,729. In total, 1311 (1.6%) reported receiving treatment for obesity. The proportion of participants receiving a prescription for obesity increased from 0.3% (0.2%, 0.6%) in 2010 to 1.8% (1.3%, 2.5%) in 2021. Multivariable l﻿ogistic regression found that female individuals, older individuals, and those with higher levels of education had higher odds of ﻿accessing obesity medication or any obesity treatment.

Conclusions:

Utilization of pharmaceutical and nonpharmaceutical obesity treatment has increased from 2010 to 2021 but remains low. The likelihood of receiving treatment was lower for groups with lower socioeconomic status. As more effective obesity therapies become available, efforts should be made to ensure equitable access.
Is there a role for neoadjuvant therapies followed by radical cystectomy in oligometastatic bladder cancer?
Authors: Cadenar Anna , Mancon Stefano , Shariat Shahrokh F. , D’Andrea David
Published: January 2025

Purpose of review

This review explores the potential role of neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) for oligometastatic bladder cancer (OMBC) treatment. We focused on extrapolating evidence from studies including lymph node-positive only and metastatic bladder cancer to address the key challenges and therapeutic strategies for OMBC.

Recent findings

Current evidence for NAC and RC in OMBC is limited, with most data derived from studies in locally advanced bladder cancer. NAC has shown efficacy in downstaging and improving survival in patients with locally advanced disease, but its benefits in OMBC remain speculative. Additionally, diagnostic uncertainties, particularly regarding the inclusion of pelvic lymph nodes and the role of FDG-PET/CT, pose significant challenges to accurate staging and treatment decisions. Recent studies highlight the potential of metastasis-directed therapy, but uncertainties remain on patient selection and treatment protocols for OMBC.

There is need for prospective studies to evaluate neoadjuvant systemic treatments and RC specifically in OMBC. Moreover, resolving current diagnostic challenges is crucial to avoid undertreatment due to inaccurate staging. Until more concrete evidence emerges, changes to standard treatment protocols should be approached with caution and offered only within trials.
Intestinal stem cell marker MEX3A regulates PPARγ expression with functional impact in colorectal carcinogenesis
Authors: Silva Ana R. , Coelho Alexandre , Machado Vanessa , Russel Morgana , Mexieiro Dalila , Amaral Ana L. , Cavadas Bruno , Carvalho-Maia Carina , Gigliano Davide , Jerónimo Carmen , Almeida Raquel , Pereira Bruno
Published: January 2025

RNA-binding proteins (RBPs) are major effectors of post-transcriptional regulation. Recently, we described the role of MEX3A in maintaining intestinal stem cell identity and epithelial renewal by repressing the PPARγ pathway. This work aimed to study MEX3A functional impact in colorectal cancer (CRC). MEX3A and PPARγ expression profiles were characterized in murine and human models. CRISPR/Cas9-mediated MEX3A knockout was performed in patient-derived CRC tumoroids (PDCTs) and MEX3A RNA targets identified through the HyperTRIBE technique.Apc+/fl;Mex3a+/−mice presented a significant reduction in tumor burden.Apc+/fl;Kras+/G12D;Mex3a+/−mice presented a reduced tumor area, while corresponding tumoroids exhibited reduced growth and enhanced differentiation potential mediated by PPARγ signalling. MEX3A overexpression (85% of human CRC cases) was inversely correlated with PPARγ downregulation (72% of cases). Accordingly, MEX3A-depleted PDCTs showed decreasedLGR5expression, accompanied by increased PPARγ expression and higher sensitivity to 5-Fluorouracil/Oxaliplatin (FOLFOX)-based chemotherapy. The HyperTRIBE results revealed a direct interaction between MEX3A andPPARGtranscripts.

STATEMENT OF SIGNIFICANCE

These results emphasize that MEX3A plays a crucial role in colorectal carcinogenesis, partially through regulation of the PPARG pathway, mediating tumour development and response to therapy, thus constituting a potential therapeutic target.
Phototriggered proton-selective carrier currents through photoswitchable membranes
Authors: Pfeffermann Juergen , Yadav Rohit , Glasnov Toma , Thorn-Seshold Oliver , Pohl Peter
Published: January 2025

The regulation of ion transport across biological membranes using light is a powerful research tool with potential therapeutic applications. Microbial channelrhodopsins, widely used in optoge-netics, enable passive photocurrents that facilitate advanced studies of synaptic plasticity and neuronal connectivity. However, their applicability is limited by the need for genetic transfection to introduce channelrhodopsins into target cells. Here, we present a synthetic alternative combining small-molecule carriers with azobenzene-containing photolipids (OptoDArG) to achieve rapid and reversible ion-selective permeability modulation by light. Incorporating a novel lipidated nile blue derivative (NB-lipid) into photoswitchable bilayers enabled fully reversible ≈200-fold on–off modulation of H+currents under UV and blue light illumination. The transport kinetics classify NB-lipids as cationic protonophores, demonstrating high sensitivity to OptoDArG-mediated changes in lipid packing and bilayer thickness. Another protonophore, carbonyl cyanidem-chlorophenylhydrazone (CCCP), exhibited similar sensitivity, though to a lesser extent. This concept extends beyond protonophores: valinomycin-mediated K+currents showed several-fold increases under UV light, rapidly reversed by blue light-induced generation of OptoDArG’s trans photoisomer. Our approach demonstrates that rapid, non-invasive, spatially precise, and reversible light-triggered currents can be achieved without genetic modifications. This strategy, exemplified by H+-selective currents, may be extended to other ions through tailored carrier design.
Label-free Detection and Characterization of Metabolism in Fresh and Cryopreserved Macrophages
Authors: Canales Daniela De Hoyos , Hu Linghao , Walsh Alex J.
Published: January 2025

Cryopreservation is a widely used technique to preserve biological samples for extended periods of time at low temperatures. Even though it is known to have significant effects on cell viability, its effect on their metabolism remains unexplored. Studying how cryopreservation influences the metabolism of cells is important to guarantee the reliability of samples transported between sites for analysis. Optical metabolic imaging allows for the study of cellular metabolism in a label-free manner by using the autofluorescence properties of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD), two metabolic coenzymes. The goal of this research is to study the metabolic changes in macrophages after cryopreservation and compare these results with freshly isolated macrophage samples to evaluate if the metabolic data is retained after cryopreservation. The metabolism of macrophages was analyzed with fluorescence lifetime imaging microscopy (FLIM) using a multiphoton microscope. Monocytes were isolated from human whole blood and separated into two groups. In Group 1, freshly isolated monocytes were differentiated into macrophages using macrophage-colony stimulating factor (M-CSF) over 8 days. In Group 2, isolated monocytes were cryopreserved after separation from whole blood and then thawed and stimulated with M-CSF for 8 days. Single-cell analysis showed there are significant changes in FLIM parameters between the groups suggesting that the metabolic data of macrophages is altered after a cryopreservation and cell thawing cycle. Our research bridges the current gap by studying the metabolic changes of cells after cryopreservation using a non-invasive and label-free imaging technique.
spEMO: Exploring the Capacity of Foundation Models for Analyzing Spatial Multi-Omic Data
Authors: Liu Tianyu , Huang Tinglin , Ying Rex , Zhao Hongyu
Published: January 2025

Several pathology foundation models have been designed by pre-training a model with pathology information for disease-centered downstream applications. These models have been treated as a breakthrough for pathology research. Along with pathology images, we can also measure spatial multi-omic expression levels for each spot, which provide additional information for understanding the spatial context. However, we still lack an effective tool to leverage the contributions of these technologies. Here, we present a novel artificial intelligence system, named as spEMO, to incorporate the embeddings from pathology foundation models and large language models to analyze spatial multi-omic data. Overall, spEMO outperforms foundation models trained only with single-modality data through introducing better representations. Our method also explores different approaches to combining information from various sources and shows the contributions of integrating external embedding information to handle different novel downstream applications, including spatial domain identification, spot-type prediction, whole-slide disease-state prediction and interpretation, multi-cellular interaction inference, and medical report generation. Furthermore, we define a new task of multi-modal alignment to assess the information retrieval ability of pathology foundation models. This task offers a new direction to evaluate the quality of foundation models and gain insights for model development.
Binding Kinetics, Bias, Receptor Internalization and Effects on Insulin Secretionin vitroandin vivoof a Novel GLP-1R/GIPR Dual Agonist, HISHS-2001
Authors: Manchanda Yusman , Jones Ben , Carrat Gaelle , Ramchunder Zenouska , Marchetti Piero , Leclerc Isabelle , Thennati Rajamannar , Burade Vinod , Natarajan Muthukumaran , Shahi Pradeep , Tomas Alejandra , Rutter Guy A.
Published: January 2025

The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss in type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off target effects, including nausea and diarrhoea, remain a complication of using these agents, and modified versions with optimized pharmacological profiles and/or biased signaling at the cognate receptors are increasingly sought. Here, we describe the synthesis and properties of a molecule which binds to both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors (GLP-1R and GIPR) to enhance insulin secretion. HISHS-2001 shows increased affinity at the GLP-1R, as well as a tendency towards reduced internalization and recycling at this receptorversusFDA-approved dual GLP-1R/GIPR agonist tirzepatide. HISHS-2001 also displayed significantly greater bias towards cAMP generationversusβ-arrestin 2 recruitment compared to tirzepatide. In contrast, Gαsrecruitment was lowerversustirzepatide at the GLP-1R, but higher at the GIPR. Administered to obese hyperglycaemicdb/dbmice, HISHS-2001 increased circulating insulin whilst lowering body weight and HbA1c with similar efficacy to tirzepatide at substantially lower doses. Thus, HISHS-2001 represents a novel dual receptor agonist with an improved pharmacological profile.
ntSynt-viz: Visualizing synteny patterns across multiple genomes
Authors: Coombe Lauren , Warren René L. , Birol Inanc
Published: January 2025

With the explosion of chromosome-scale genome assemblies being generated in recent years, there is vast potential for comparative genomics analyses through detecting multi-genome synteny. While existing tools can detect synteny blocks between multiple genomes, their text-based outputs make it challenging to intuitively explore large-scale synteny patterns. Interpretable, information-rich and easy-to-use synteny visualization tools are imperative to enable important biological insights from the synteny block data output by the aforementioned utilities. Here, we present ntSynt-viz, a command-line tool for automated sorting, normalization and plotting of multi-genome synteny blocks. We show how ntSynt-viz provides clearer and more easily interpretable chromosome-painting ribbon plots compared to the state-of-the-art tool NGenomeSyn when evaluating synteny between 14 human genomes and 9 hoverfly genomes. We expect that ntSynt-viz will provide crucial insights into large-scale synteny patterns between divergent genomes, thereby advancing research into key evolutionary questions. ntSynt-viz is freely available on GitHub (https://github.com/bcgsc/ntsynt-viz).
Sense of coherence and self-care in people with diabetes: systematic review
Authors: Vega-Martínez María del Carmen , López-Martínez Catalina , del-Pino-Casado Rafael
Published: January 2025

Introduction

Diabetes mellitus is one of the diseases with the greatest social and health impact. Self-care in people with diabetes requires constant physical and emotional effort, which is one of the barriers to adherence to the care plan. Sense of coherence can play an important role in self-care.

Aims

To examine the relationship between sense of coherence and self-care in individuals with diabetes mellitus.

Method

A systematic review with narrative synthesis for all included studies and with meta-analysis in those with adequate statistical data. We searched PubMed, CINAHL, PsychInfo and Scopus up to July 2024. We included original studies that reported effect sizes on the association between sense of coherence and self-management of care plans in individuals with diabetes. Methodological quality of the studies was independently assessed by two researchers by evaluating the risk of selection bias, classification bias and confounding bias. Meta-analysis was performed using a random-effects model and various sensitivity and subgroup analyses were performed to assess the robustness of the meta-analysis result.

Results

Thirteen articles were included in the review (six were included in the meta-analysis), whose participants (9,800) were people with type 1 or 2 diabetes. In the studies analyzing the relationship between sense of coherence and adherence to self-care (diet, exercise, and medication), a positive association was observed between these variables. In addition, sense of coherence may have a protective effect against negative perceptions of self-care. In the meta-analysis, a positive and moderate association between sense of coherence and adherence to self-care was found, with no heterogeneity and possible publication bias that does not affect the results of the meta-analysis.

Limitations

Small number of studies; all were cross-sectional.

Conclusions

Sense of coherence may play a relevant role in improving adherence to the self-care plan in people with type 1 or 2 diabetes.

PROSPERO id

CRD42023390705
Cortical Manifolds in Cognitive Recovery following Supratentorial Neurosurgery
Authors: Poologaindran A , Romero-Garcia R , Luppi AI , Hart MG , Santarius T , Price S , Sughrue ME , Bethlehem RAI , Sonkusare S , Erez Y , Suckling J
Published: January 2025

The cerebral cortex is topographically organized to integrate and segregate unimodal (e.g. sensorimotor) and transmodal brain networks to scaffold cognition. Cortical gradient mapping provides a framework to examine the relationship between connectivity patterns of macroscale functional brain networks within a low-dimensional (manifold) space. Using this technique, we longitudinally examine how diffuse gliomas, their neurosurgical resection, and subsequent cognitive rehabilitation impact the topographic organization of brain networks. First, using UKBioBank data (n=4000), we validate the general assembly of cortical gradients in healthy individuals. Next, using CamCan data (n=620), we found that gradient dispersion relates to executive functions (EFs) across the lifespan. Finally, in diffuse glioma patients undergoing neurosurgery (n=17), we observed that gliomas integrate into the cortical manifold by reducing gradient dispersion compared to healthy controls. This finding was replicated in an independent cohort and contrasted with meningioma patients. Finally, long-term cognitive improvement after surgery was linked to increases in gradient dispersion, while long-term deficits were associated with decreases in gradient dispersion. Overall, diffuse gliomas minimally disrupt the assembly of cortical manifolds, but the ability to reorganize the cortical manifold post-surgery is predictive of long-term cognitive outcomes. By investigating neurosurgical patients with atypical neuroanatomy, this study contributes to the expanding literature on how aging, disease, and pharmacological interventions impact cortical gradients. Future studies are warranted to further assess the utility of mapping cortical manifolds in neurosurgical patients.
Depression and incidence of inflammation-related physical health conditions: a cohort study in UK Biobank
Authors: Saha Shuvajit , Prigge Regina , Jackson Caroline A , Guthrie Bruce , Fleetwood Kelly J
Published: January 2025

Background

Depression is associated with multiple physical health conditions, and inflammation is a mechanism commonly proposed to explain this association. We aimed to investigate the association between depression and the incidence of physical health conditions thought to have an inflammatory etiological component, including coronary heart disease, peripheral arterial disease, type 2 diabetes, inflammatory bowel disease, inflammatory arthritis and Parkinson’s Disease.

Methods

We conducted a cohort study using UK Biobank (UKB) data linked to primary care, hospital admission and death data. We ascertained depression at baseline using primary care and hospital records, and self-report at the UKB baseline assessment. We identified incident physical health conditions during follow-up using primary care, hospital admission and death data. We used Cox proportional hazards models to determine hazard ratios of each incident inflammation-related condition in those with versus without depression at baseline, serially adjusting for sociodemographic factors, lifestyle factors and baseline count of morbidities.

Result

We included 172,556 UKB participants who had continuous primary care records. Of these, 30,770 (17.8%) had a history of depression at baseline. After excluding participants with missing data, 168,641 (98%) were included in analysis. Median follow-up was 7.1 years (IQR: 6.3, 8.0). In the model adjusted for age and sex, depression was significantly associated with a higher hazard of all inflammation-related conditions. After additionally accounting for differences in country, ethnicity and deprivation, the association between depression and each condition generally attenuated but remained statistically significant, with effect estimates ranging from a 30% increased hazard of inflammatory bowel disease (HR 1.30, 95% CI 1.06 to 1.58) to a 53% increased hazard of Parkinson’s Disease (HR 1.53, 95% CI 1.25 to 1.87). After further adjusting for lifestyle factors and comorbidity count, the association persisted only for Parkinson’s Disease (HR 1.45, 95% CI 1.18 to 1.79).

Conclusions

Our study found that depression is consistently associated with multiple inflammation-related physical health conditions, although associations did not persist after adjustment for lifestyle factors and baseline physical condition count. Further research is needed to explore underlying mechanisms, including inflammatory biomarkers and modifiable lifestyle factors on the causal pathway.
Invasive lobular carcinoma integrated multi-omics analysis reveals silencing of Arginosuccinate synthase and upregulation of nucleotide biosynthesis in tamoxifen resistance
Authors: Gupta Annapurna , Choueiry Fouad , Reardon Jesse , Pramod Nikhil , Kulkarni Anagh , Shankar Eswar , Sizemore Steven T. , Stover Daniel G. , Zhu Jiangjiang , Ramaswamy Bhuvaneswari , Majumder Sarmila
Published: January 2025

Invasive Lobular Carcinoma (ILC), a distinct subtype of breast cancer is hallmarked by E-Cadherin loss, slow proliferation, and strong hormone receptor positivity. ILC faces significant challenges in clinical management due to advanced stage at diagnosis, late recurrence, and development of resistance to endocrine therapy - a cornerstone of ILC treatment. To elucidate the mechanisms underlying endocrine resistance in ILC, ILC cell lines (MDA-MB-134-VI, SUM44PE) were generated to be resistant to tamoxifen, a selective estrogen receptor modulator. The tamoxifen-resistant (TAMR) cells exhibit a 2-fold increase tamoxifen IC50relative to parental cells. Metabolomics and RNA-sequencing revealed deregulation of alanine, aspartate, and glutamate metabolism, purine metabolism, and arginine and proline metabolism in TAMR cells. Among the fifteen commonly dysregulated genes in these pathways, lowASS1expression was identified in the TAMR cells and was significantly correlated with poor outcome in ILC patients, specifically in the context of endocrine therapy. Our study reveals methylation mediated silencing ofASS1in TAMR cells as a likely mechanism of downregulation. Demethylation restoredASS1expression and correspondingly reduced tamoxifen IC50toward parental levels. Nucleic acid biosynthesis is augmented in TAMR cells, evidenced by increase in nucleotide intermediates. Both TAMR cell lines demonstrated increased expression of several nucleic acid biosynthesis enzymes, includingPAICS, PRPS1, ADSS2, CAD, and DHODH. Furthermore, CAD, the key multifunctional protein ofde novopyrimidine biosynthesis pathway is differentially activated in TAMR cells. Treating TAMR cell with Decitabine, a demethylating agent, or Farudodstat, a pyrimidine biosynthesis inhibitor, markedly augmented efficacy of tamoxifen. Collectively, our study unveilsASS1downregulation as a novel mechanism underlying acquired tamoxifen resistance in ILC and establishes a metabolic link between ASS1 and nucleic acid biosynthesis. RestoringASS1expression or inhibiting pyrimidine biosynthesis restored tamoxifen sensitivity.ASS1could be a potential biomarker and therapeutic target in tamoxifen resistant ILC patients, warranting further investigation.
Role of X chromosome and dosage compensation mechanisms in complex trait genetics
Authors: Fu Yu , Kenttämies Aino , Ruotsalainen Sanni , Pirinen Matti , Tukiainen Taru
Published: January 2025

The X chromosome (chrX) is often excluded from genome-wide association studies due to its unique biology complicating the analysis and interpretation of genetic data. Consequently, the influence of chrX to human complex traits remains debated. Here, we systematically assessed the relevance of chrX and the effect of its biology on complex traits by analyzing 48 quantitative traits in 343,695 individuals in UK Biobank with replication in 412,181 individuals from FinnGen. We show that, in the general population, chrX contributes to complex trait heritability at a rate of 3% of the autosomal heritability, consistent with the amount of genetic variation observed in chrX. We find that a pronounced male-bias in chrX heritability supports the presence of near-complete dosage compensation between sexes through X chromosome inactivation (XCI). However, we also find subtle yet plausible evidence of escape from XCI contributing to human height. Assuming full XCI, the observed chrX contribution to complex trait heritability in both sexes is greater than expected given presence of only a single active copy of chrX, mirroring potential dosage compensation between chrX and the autosomes. We find this enhanced contribution attributable to systematically larger active allele effects from chrX compared to autosomes in both sexes, independent of allele frequency and variant deleteriousness. Together these findings support a model where the two dosage compensation mechanisms work in concert to balance the influence of the chrX across the population while preserving sex-specific differences at a manageable level. Overall, our study advocates for more comprehensive locus discovery efforts in chrX.
Terminal complement complexes with or without C9 potentiate antimicrobial activity againstNeisseria gonorrhoeae
Authors: Lamb Evan R. , Criss Alison K.
Published: January 2025

The complement cascade is a front-line defense against pathogens. Complement activation generates the membrane attack complex (MAC), a 10-11 nm diameter pore formed by complement proteins C5b through C8 and polymerized C9. The MAC embeds within the outer membrane of Gram-negative bacteria and displays bactericidal activity. In the absence of C9, C5b-C8 complexes can form 2-4 nm pores on membranes, but their relevance to microbial control is poorly understood. Deficiencies in terminal complement components uniquely predispose individuals to infections by pathogenicNeisseria,includingN. gonorrhoeae(Gc). Increasing antibiotic resistance in Gc makes new therapeutic strategies a priority. Here, we demonstrate that MAC formed by complement activity in human serum disrupts the Gc outer and inner membranes, potentiating the activity of antimicrobials against Gc and re-sensitizing multidrug resistant Gc to antibiotics. C9-depleted serum also disrupts Gc membranes and exerts antigonococcal activity, effects that are not reported in other Gram-negative bacteria. C5b-C8 complex formation potentiates Gc sensitivity to azithromycin but not lysozyme. These findings expand our mechanistic understanding of complement lytic activity, suggest a size limitation for terminal complement-mediated enhancement of antimicrobials against Gc, and suggest complement manipulation can be used to combat drug-resistant gonorrhea.

Importance

The complement cascade is a front-line arm of the innate immune system against pathogens. Complement activation results in membrane attack complex (MAC) pores forming on the outer membrane of Gram-negative bacteria, resulting in bacterial death. Individuals who cannot generate MAC are specifically susceptible to infection by pathogenicNeisseriaspecies includingN. gonorrhoeae(Gc). High rates of gonorrhea and its complications like infertility, and high-frequency resistance to multiple antibiotics, make it important to identify new approaches to combat Gc. Beyond direct anti-Gc activity, we found the MAC increases the ability of antibiotics and antimicrobial proteins to kill Gc and re-sensitizes multidrug-resistant bacteria to antibiotics. The most terminal component, C9, is needed to potentiate the anti-Gc activity of lysozyme, but azithromycin activity is potentiated regardless of C9. These findings highlight the unique effects of MAC on Gc and suggest novel translational avenues to combat drug-resistant gonorrhea.
A preparatory cranial potential for saccadic eye movements in macaque monkeys
Authors: Errington Steven P. , Schall Jeffrey D.
Published: January 2025

Response preparation is accomplished by gradual accumulation in neural activity until a threshold is reached. In humans, such a preparatory signal, referred to as the lateralized readiness potential, can be observed in the EEG over sensorimotor cortical areas before execution of a voluntary movement. Although well-described for manual movements, less is known about preparatory EEG potentials for saccadic eye movements in humans and nonhuman primates. Hence, we describe a lateralized readiness potential over the frontolateral cortex in macaque monkeys. Homologous to humans, we observed lateralized electrical potentials ramping before the execution of both rewarded and non-rewarded contralateral saccades. This potential parallels the neural spiking of saccadic movement neurons in the frontal eye field, suggesting that it may offer a non-invasive correlate of intracortical spiking activity. However, unlike neural spiking in the frontal eye field, polarization in frontolateral channels did not distinguish between saccade generation and inhibition. These findings provide new insights into non-invasive electrophysiological signatures of saccadic preparation in nonhuman primates, highlighting the potential of EEG measures to bridge invasive neural recordings and non-invasive studies of eye movement control in humans.
Preclinical Evaluation of [18F]P4B-2412 as Phosphodiesterase 4B Radioligand for Positron Emission Tomography Imaging
Authors: Song Zhendong , Li Yinlong , Feng Siyan , Chen Jiahui , Zhou Xin , Zhang Zachary , Sun Zhenkun , Rong Jian , Zhao Chunyu , Chaudhary Ahmad , Patel Jimmy S. , Gao Yabiao , Collier Thomas L. , Ran Chongzhao , Haider Achi , Yuan Hongjie , Liang Steven H.
Published: January 2025

Phosphodiesterase 4B (PDE4B) plays a critical role in cAMP hydrolysis and is highly expressed in brain regions associated with neuroinflammation and central nervous system (CNS) disorders. Selective PDE4B radioligands hold significant potential for elucidating disease mechanisms, such as those in Parkinson’s disease and schizophrenia, and enabling target occupancy measurements. In this study, we developed [18F]P4B-2412, a novel PDE4B-selective radioligand, and evaluated its utility for positron emission tomography imaging (PET). [18F]P4B-2412 was synthesized in high radiochemical yield (27.2%), excellent radiochemical purity (99%), and favorable molar activity (66.2 ± 2.5 GBq/μmol.In vitroautoradiography and dynamic PET imaging demonstrated high specificity for PDE4B in rodent brain regions, with blocking studies confirming negligible interaction with PDE4D. [18F]P4B-2412 also exhibited robustin vitroandin vivometabolic stability. These results establish [18F]P4B-2412 as a promising PET imaging agent for visualizing PDE4B activity, offering a valuable tool for investigating neuroinflammation and advancing CNS drug development.
Electronic Health Record-Based Prediction Models to Inform Decisions about HIV Pre-exposure Prophylaxis: A Systematic Review
Authors: Agovi Afiba Manza-A. , Thompson Caitlin T. , Meadows Rachel J. , Lu Yan , Ojha Rohit P.
Published: January 2025

Background

Several clinical prediction models have been developed using electronic health records data to help inform decisions about HIV pre-exposure prophylaxis (PrEP) prescribing, but the characteristics and quality of these models have not been systematically assessed. We identified and critically appraised the characteristics and quality of studies reporting the development of electronic health records (EHR)-based models predicting HIV risk to inform decisions about PrEP prescribing.

Methods

We searched PubMed and the CINAHL databases between January 1, 2013 and June 19, 2023, with keywords related to EHR, HIV, and clinical prediction. We extracted data using the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) checklist and assessed risk of bias using the Prediction model Risk Of Bias Assessment Tool (PROBAST) short form. We used narrative synthesis to describe characteristics and quality of eligible models.

Results

We identified 324 studies, of which 7 studies (resulting in 7 models) were eligible for our review. Several studies inadequately reported key components of the corresponding model. Most models were developed in the United States and used machine learning methods. The area under the receiver operating characteristic curve was reported for six models, which ranged between 0.77 and 0.89. All models had high risk of bias, primarily because of low events per variable and risk of overfitting.

Conclusions

We observed inadequate reporting of key components and high risk of bias across all EHR-based models. Future studies would benefit from following standard reporting guidelines and best practices for developing prediction models, which may strengthen the validity and applicability of EHR-based prediction models for informing decisions about HIV PrEP prescribing.

Trial registration

The review protocol was registered and published in PROSPERO (CRD42023428057)
Chinese consumers’ dish value: a best–worst scaling approach
Authors: Wang Erpeng , Nian Yefan , Gao Zhifeng
Published: January 2025

Purpose

This paper aims to identify Chinese consumers’ dish value systems and investigate whether and to what extent their dish values vary by type of consumers.

Design/methodology/approach

We used a best–worst scaling (BWS) developed based on previous literature on food values and attributes of Chinese dishes to elicit Chinese consumers’ dish value structure. Then, we estimated each participant’s share of preferences for dish values and applied Ward’s linkage cluster analysis to identify the heterogeneity of their dish values.

Findings

Our results indicate that food safety values, including the safety of agricultural products, additives and food processing, are valued most by Chinese consumers. They rate health-nutrition values as the second most important dish values. There is significant heterogeneity in Chinese consumers' dish values. Their dish values tend to drive their dish consumption patterns.

Originality/value

The dish is the mainstay of the Chinese meal. This study is among a few studies that examine Chinese consumers’ dish values that underlie consumer dish preferences and choices. The results provide essential information to promote a healthy and sustainable diet among Chinese consumers by understanding their values and motivations for making dish choices.
Three‐dimensional gravity forward modelling based on rectilinear grid and Block–Toeplitz Toeplitz–Block methods
Authors: Wan Ling , Li Shihe , Ye Rui , Wang Yifan , Ma Zenghan , Lin Tingting
Published: January 2025

The main method for calculating the gravity field involves discretizing the density sources into a stack of rectangular prisms with a regular grid distribution. The analytical formulation of the gravity anomaly for a right‐angled rectangular prism is affected by depth, with the kernel function decaying as depth increases. In addition, the efficiency of the computation and the storage requirements often pose challenges. We present a fast computational method for three‐dimensional gravity forward modelling of subsurface space using rectilinear grid and apply the Block–Toeplitz Toeplitz–Block method to the rectilinear grid. The size of the upright rectangles increases with depth to offset the effect of depth. We assume that the observation points are distributed on a homogeneous grid, and the kernel sensitivity matrices exhibit a Block–Toeplitz Toeplitz–Block structure, which is symmetric. For rectilinear dissections of subsurface space in MATLAB, the logarithmic interval size is used. The rectilinear mesh can offset the effect of depth to some degree allowing gravity anomalies to decrease more quickly. For the test of a single model, the gravity anomalies decrease faster and more rapidly in the case of the rectilinear grid compared to the uniform grid. In addition to this, we performed simulations on more complex models and demonstrated that using the Block–Toeplitz Toeplitz–Block method on this basis greatly improves the computational efficiency.
Bioacoustic Assessment of Mangrove Health: Influence of Habitat Characteristics on Bird Richness
Authors: Rahim Al‐Kautsar Hidayanto Abdul , Puan Chong Leong , Mah Amera Natasha Mah Muhammad Adam , Zakaria Mohamed , Jamaludin Nurhaidah , Wahaf Nurul Syafiqa Abdul
Published: January 2025

Mangroves play a vital role in coastal ecosystems, providing numerous ecosystem functions and services as well as supporting high levels of biodiversity. Using a bioacoustic approach, we assessed the influence of mangrove habitat variables on birds in four sites in Peninsular Malaysia. We set up 20 bioacoustic audio recorders across Telok Gong, Kapar Tambahan, Banjar Utara Forest Reserves, and Kuala Selangor Nature Park. The recorders operated for 30 min every hour over a period of 24 h for seven consecutive days. We assessed the habitat characteristics at each site by establishing one 20 m × 20 m quadrat at each of the recording points. Generalized linear mixed models indicated that the percentage of canopy cover, average tree height, forest age, number of saplings, forest size, and ground cover positively influenced bird richness. Our findings highlight the importance of maintaining these habitat features to support higher bird species richness in mangroves. This study demonstrated the possible use of bioacoustics to assess mangrove restoration recovery progress via birds as bioindicators.

Abstract in Malay is available with online material.
Investigating the Role of Quercetin, an Active Ingredient in Bazhen Decoction, in Targeting CXCL8 to Inhibit Macrophage M2 Polarization and Reshape the Immunological Microenvironment of Colorectal Cancer
Authors: Wang Wenwu , Lin Fangfeng , Shi Shuping , Yu Yunqiu , Lin Mengyan , Lian Wenliang , Chen Biyin , Qi Xiaoyan
Published: January 2025

Bazhen Decoction (Eight Treasures Decoction) has demonstrated efficacy in the treatment of colorectal cancer (CRC), yet the active ingredients in it and the mechanisms underlying their anti‐cancer properties are not well understood. Through network pharmacology, the effective components of Bazhen Decoction against CRC and their corresponding key genes were delineated. Molecular docking was executed to identify the active component targeting the key gene CXCL8, which led to the discovery of Quercetin. The cellular thermal shift assay method was then used to verify the binding interaction. CRC cells were treated with incremental concentrations of Quercetin, cell viability was evaluated by the Cell Counting Kit‐8 assay to calculate the IC50, and apoptosis rates were determined by flow cytometry. Expression of the apoptosis‐related proteins Bcl‐2 and Cleaved caspase‐3 was measured using western blot. The impact of Quercetin on macrophage polarization was studied by co‐culturing the treated CRC cells with macrophages, assessing M1 and M2 macrophage distribution via flow cytometry, and quantifying cytokine levels (IL‐6, IL‐10, IL‐12, and CXCL8) with enzyme‐linked immunosorbent assay (ELISA). The active ingredient Quercetin from Bazhen Decoction exhibited a targeted binding affinity with the key gene CXCL8, which enabled it to inhibit the proliferation of CRC cells and induce cell apoptosis. The overexpression of CXCL8 was associated with the promotion of CRC malignancy, yet the presence of Quercetin could lessen the impact of CXCL8 overexpression on CRC cells. Moreover, the treatment with Quercetin leads to a diminished abundance of M2 macrophages and an increase in the levels of cytokines IL‐6 and IL‐12, while reducing the levels of IL‐10 and CXCL8, which indicates that Quercetin has an inhibitory effect on macrophage M2 polarization. Quercetin, the active component in Bazhen Decoction that is known for anti‐CRC effects, targets and inhibits CXCL8 to impede the malignant behaviors and the M2 polarization of macrophages. Thus, Quercetin may be utilized as an immunomodulatory agent in CRC treatment.
Wild boar hunting and trapping as a threat for wildlife conservation on Sumatra, Indonesia
Authors: Kartika Erlinda C. , Andono Ardi , Heitkönig Ignas M. A.
Published: January 2025

Wild pig has one of the widest geographic distributions of terrestrial mammals. Dog‐assisted wild pig hunting may reduce crop raiding but also elevates the potential disease transmission from dogs to wildlife and vice versa. On Sumatra, game hunting tends to focus on wild pig, where hunters either actively use dogs or firearms, or passively use snares. Our objectives are to understand: (1) the extent of active and passive wild pig hunting in Sumatra; (2) dog‐assisted hunting practices; (3) potential disease transmission by hunting dogs to game. We conducted three types of data collection to cover the wide range of hunting techniques: (1) information from social media (i.e., Facebook) about dog‐assisted wild pig hunting events in West Sumatra; (2) a questionnaire‐guided survey among hunters around the Batanghari Protected Forest, West Sumatra; (3) expert interviews from provincial conservation offices about wild pig hunting practices in Sumatra. Active and passive wild pig hunting occurred in Sumatra. Firearm and snare hunting occurred in all eight provinces while dog‐assisted hunting occurred only in six provinces. We documented at least 1331 dog‐assisted wild pig hunting events which occurred in 2019 across the province of West Sumatra. The number of hunting parties and dog‐assisted hunting group members on Facebook showed a dramatic increase between 2020 and 2022. Many dogs used for hunting are reportedly not vaccinated (35%), risking transmission of diseases like Rabies and Canine Distemper Virus to game and wild predators. Hunting is inadequately regulated, rendering enforcement of these regulations impossible. The extent of wild pig hunting has yet been unquantified but likely will have strong effects on the remaining wildlife populations. We call for proper quantification of hunting bags, and regulation, including the use and health status of dogs, to prevent disease transmission from dogs to wild animals and to protect remaining wildlife populations.