bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host–virus interactions during infection with a wild-type ILTV strain or a glycoprotein G deletion mutant ILTV vaccine strain in an
ex vivo
system
Authors: Gopakumar Gayathri , Coppo Mauricio J.C. , Diaz-Méndez Andrés , Hartley Carol A. , Devlin Joanne M. 
Published: January 2025

ABSTRACT

Previous studies have demonstrated the safety and efficacy of a live-attenuated glycoprotein G (gG) deletion mutant vaccine strain of ILTV (∆gG-ILTV). In the current study, transcriptional profiles of chicken tracheal organ cultures (TOCs), 24 h post inoculation with ∆gG-ILTV or the gG-expressing parent wild-type strain, CSW-1 ILTV were explored and compared with the mock-infected TOCs using RNA-seq analysis. Transcriptomes of the vaccine and wild-type ILTV were also compared with each other. Although no viral genes (except for gG) were differentially regulated between the two ILTV-infected TOCs, pair-wise comparison of the transcriptomes of the ∆gG-ILTV or the CSW-1 ILTV-infected TOCs (each compared with mock-infected TOCs) identified the similarities and differences in host gene transcription between them. Several immune checkpoint inhibitors with likely roles in ILTV-mediated immune augmentation, and gene ontologies indicating cytokine response, and cytokine signaling were upregulated in both TOCs. Additionally, several other biological processes, molecular functions, and cellular components were enriched uniquely in the ∆gG-ILTV-infected TOCs, including those that indicated modifications to tracheal extracellular matrix (ECM) structural components, which may have a role in immune modulation
in vivo
. This study has revealed that the modifications of transcription of host genes during the early stages of ILTV infection are not limited to changes in cytokine or chemokine gene transcription, but several other immune-related genes and ECM components. Moreover, their differential regulation in the
ex vivo
system appears to be influenced by gG expression, potentially affecting the outcome of ILTV infection
in vivo
.

IMPORTANCE
Infectious laryngotracheitis virus (ILTV) remains a serious threat to poultry industries worldwide, causing significant economic losses. The glycoprotein G (gG) of ILTV is a virulence factor and a chemokine-binding protein with immunoregulatory functions. The influence of gG on the transcription of select host chemokine and cytokine genes has been demonstrated previously. This study extends our understanding of the early and localized host–ILTV interactions using genome-wide transcriptome analysis of ILTV-infected chicken tracheal organ cultures, and the role of gG during the process. Differential regulation of genes encoding immune checkpoint inhibitors observed in this study may have a role in ILTV-induced inhibition of type I interferon response, or negative regulation of T cell responses, bringing clarity to these ILTV immune-evasion mechanisms. Furthermore, differential regulation of genes encoding certain structural components and receptors with roles in cell migration, in the absence of gG, is consistent with the immunomodulatory role of ILTV gG.
Virulence profile of carbapenem-resistant
Klebsiella pneumoniae
strains by an
in vivo
model of
Galleria mellonella
Authors: Guembe María , Hafian Rama , Díaz-Navarro Marta , Visedo Andrés , De Maio Flavio , Pimpinelli Fulvia , Cavallo Ilaria , Truglio Mauro , Sivori Francesca , Di Domenico Enea Gino 
Published: January 2025

ABSTRACT

Klebsiella pneumoniae
is a significant healthcare-associated pathogen, notable for its diverse virulence and antibiotic resistance profiles. This study aimed to characterize the genotypic and phenotypic diversity of
K. pneumoniae
isolates and evaluate their virulence using the
Galleria mellonella
model. Biomass production, metabolic activity, capsule formation, and siderophore production were assessed in 27
K
.
pneumoniae
isolates from hospital-associated infections. Lethality curves were generated using the
G. mellonella
model, with survival monitored hourly from 16 to 48 hours. The most common sequence types (ST) identified were the high-risk clones ST307 (
N
= 10), ST512 (
N
= 8), ST101 (
N
= 7), and ST661 (
N
= 2). These STs were associated with distinct K-locus, including KL102, KL107, KL17, and KL39. Most isolates belonged to the O2afg locus (
N
= 18), with the
K. pneumoniae
carbapenemase genotype detected in 96.3% of strains. None of the isolates were classified as hypervirulent. Phenotypically, ST661 exhibited the highest biomass production despite showing similar metabolic activity to other STs. A positive correlation was observed between biomass and siderophore production, while capsule production was inversely correlated with biomass. In the
G. mellonella
model, ST661 demonstrated the highest virulence, resulting in 100% mortality by 48 hours, compared to survival rates of 21.4% for ST101, 38.0% for ST307, and 31.2% for ST512. These findings underscore the pathogenic potential of ST661 isolates with enhanced biofilm production. The
G. mellonella
model may serve as an effective
in vivo
system for evaluating the virulence of emerging
K. pneumoniae
lineages.

IMPORTANCE

We demonstrate that the
Galleria mellonella
model is a useful tool to analyze the virulence of carbapenem-resistant
Klebsiella pneumoniae
strains. Our findings highlight the pathogenicity of carbapenem-resistant
K pneumoniae
isolates, particularly the role of the ST661 that, despite being a rare lineage, harbors the blaVIM gene and is associated with high biofilm production and the highest mortality rates.
Gut colonization of
Bacteroides plebeius
suppresses colitis-associated colon cancer development
Authors: Chen Hung-Lin , Hu Po-Yuan , Chen Chang-Shan , Lin Wei-Han , Hsu Daniel K. , Liu Fu-Tong , Meng Tzu-Ching 
Published: January 2025

ABSTRACT

Colon cancer development may be initiated by multiple factors, including chronic inflammation, genetic disposition, and gut dysbiosis. The loss of beneficial bacteria and increased abundance of detrimental microbes exacerbates disease progression.
Bacteroides plebeius
(
B. plebeius
) is a human gut microbe, and its colon colonization is enhanced by a seaweed-supplemented diet. We found that mice orally administered with
B. plebeius
and fed a diet containing 1% seaweed developed a unique gut microbial composition. By linear discriminant analysis effect size analysis, we found that
B. plebeius
colonization increased the abundance of
Blautia coccoides
and reduced the abundance of
Akkermansia
sp. and
Dubosiella
sp. We also showed that colonization of
B. plebeius
suppressed the colon tumor development induced by azoxymethane/dextran sulfate sodium in specific-pathogen-free mice, coinciding with a reduced abundance of
Muribaculaceae
sp.,
Closteridale
sp., and
Bilophila
sp. Moreover,
B. plebeius
colonization in gnotobiotic mice resulted in enhanced production of selected metabolites, including propionic, taurocholic, cholic, alpha-, and beta-muricholic, as well as ursodeoxycholic acids. Importantly, some of these metabolites show anti-inflammatory and tumor-suppressive effects. We conclude that
B. plebeius
is able to restructure the gut microbial community and produce beneficial metabolites, leading to inhibition of colitis-associated colon cancer development.

IMPORTANCE

This work delves into the pivotal role of gut microbiota in suppressing the progression of colitis-associated colon cancer. By investigating the impact of
Bacteroides plebeius
that can be colonized in mouse gut by feeding the animal with seaweed diet, we unveil a novel mechanism through which this beneficial bacterium reshapes the gut microbial community and produces metabolites with anti-inflammatory and tumor-suppressive properties. Such findings underscore the potential of harnessing specific microbes, like
B. plebeius
shown in this study, to modulate the gut ecosystem and mitigate the risk of colitis-associated colon cancer.
Accuracy of a Superficial Landmark of the Recurrent Branch of the Median Nerve and Anatomical Features of Transverse Muscle Fibres Observed During Carpal Tunnel Release
Authors: KANAZUKA Aya , SUZUKI Takane , MATSUURA Yusuke , AKASAKA Tomoyo , KUNIYOSHI Kazuki , OHTORI Seiji 
Published: January 2025

Background: Surgeons use anatomical landmarks like the scaphoid tubercle, pisiform, trapezial tubercle and hook of hamate, along with Kaplan cardinal line (KCL) to avoid injury to the recurrent motor branch (RMB) of the median nerve during carpal tunnel release. The presence of transverse muscle fibres (TMF) overlying the transverse carpal ligament (TCL) may suggest proximity of the RMB, but their anatomical relationship is unclear. In this study, we evaluated the accuracy of anatomical landmarks to the RMB, TMF origin and insertion, and examined the relationship between TMF presence and RMB running patterns. Methods: We dissected 30 hands from 16 fresh-frozen cadavers. After marking the superficial landmarks, we made a skin incision to confirm the presence of TMF and examined their origins and insertions. We then opened the carpal tunnel, dissected the RMB and recorded each position on a coordinate system using a fluoroscopic imaging system. Results: TMF were observed in 18 hands (60%): 13 were continuous with the abductor pollicis brevis (APB), 2 were continuous with the superficial head of the flexor pollicis brevis (FPB) and 3 were continuous with both. The bifurcation point of the RMB was significantly located 4.5 mm ulnar and 7.5 mm proximal to the superficial landmark at the median. The RMB was classified according to Poisel classification: 24 (80%) were of the extraligamentous type, 4 (13%) of the transligamentous type, 1 (3%) of the preligamentous type and 1 (3%) of the subligamentous type. Amongst these, the transligamentous/preligamentous/subligamentous types are at high risk for RMB injury during TCL incision. No significant association existed between TMF presence and these high-risk RMB types.. Conclusions: The actual RMB may be located ulnar and proximal to the superficial landmark, indicating that surgeons should be cautious about RMB damage even in the absence of TMF.
Proactive Resilient Adaptive Sensor Node Management with Neuro-Symbolic Systems for Optimized Coverage Efficiency in the Mission-Critical Applications
Authors: P Dineshkumar , K Geetha , C Rajan 
Published: January 2025

Abstract
Wireless sensor networks (WSNs) play a critical role in applications such as wildlife monitoring, disaster recovery, and precision agriculture, where continuous coverage and longevity are paramount amidst dynamic environmental challenges. To address these demands, the cellular adaptive energy forecasting and coverage optimization (CAEFCO) framework integrates localized neuro-symbolic energy forecasting (LNS-EF), a novel concept that combines symbolic reasoning with neural network learning directly on sensor nodes. LNS-EF enables nodes to not only predict energy depletion based on past consumption patterns and environmental factors but also incorporate rule-based contextual reasoning for enhanced decision-making. Alongside this, CAEFCO employs an anomaly detection module that identifies disruptions, such as sensor damage or environmental interference, allowing real-time task redistribution. This dual approach ensures seamless task reallocation while extending network lifetime. CAEFCO’s proactive methodology demonstrates a 97% reduction in data loss and an 85% improvement in network longevity, offering a breakthrough in the resilience and sustainability of WSNs in mission-critical and harsh environments.
Effects of Tocotrienol on Cardiovascular Risk Markers in Patients With Chronic Kidney Disease: A Randomized Controlled Trial
Authors: Trugilho Liana , Alvarenga Lívia , Cardozo Ludmila , Paiva Bruna , Brito Jessyca , Barboza Isis , Almeida Jonatas , Anjos Juliana dos , Khosla Pramod , Ribeiro-Alves Marcelo , Mafra Denise 
Published: January 2025

Tocotrienols, isomers of vitamin E, may provide an effective nutritional strategy to mitigate common cardiovascular risks such as dyslipidemia, inflammation, and oxidative stress in patients with chronic kidney disease (CKD). This double‐blind, placebo‐controlled, randomized clinical trial aimed to evaluate the effects of a tocotrienol‐rich fraction (TRF) supplementation (300 mg/day) on oxidative stress and inflammatory markers, including transcription factors in nondialysis (ND) and hemodialysis (HD) CKD patients for three months. Interleukin‐6, tumor necrosis factor‐α (IL‐6 and TNF‐α), C‐reactive protein (CRP), lipid peroxidation, biochemical parameters, and transcription factors such as NRF2 and NF‐κB mRNA expression were evaluated. Seventeen HD patients (9 in the placebo group, 8 in the TRF group) and 16 ND CKD patients (8 in the placebo group and 8 in the TRF group) completed the study. In HD patients, significant reductions were observed in LDL cholesterol (p = 0.04) and total plasma cholesterol levels (p = 0.01) after TRF intervention. CRP serum levels decreased significantly in ND CKD patients (p = 0.05) after TRF supplementation. Transcription factors NRF2 and NF‐κB mRNA expressions remained unaltered in both groups. This study suggests that TRF supplementation may mitigate dyslipidemia and inflammation, factors involved with increased cardiovascular risk, in CKD patients, with variations in efficacy between HD and ND patients.Trial Registration: ClinicalTrials.gov identifier: NCT04900532
Myeloid Cells Induce Infiltration and Activation of B Cells and CD4+ T Follicular Helper Cells to Sensitize Brain Metastases to Combination Immunotherapy
Authors: Ninomiya Toshifumi , Kemmotsu Naoya , Mukohara Fumiaki , Magari Masaki , Miyamoto Ai , Ueda Youki , Ishino Takamasa , Nagasaki Joji , Fujiwara Tomohiro , Yamamoto Hidetaka , Hayashi Hidetoshi , Tachibana Kota , Ishida Joji , Otani Yoshihiro , Tanaka Shota , Toyooka Shinichi , Okamoto Isamu , Togashi Yosuke 
Published: January 2025

Abstract
Brain metastasis (BM) is a poor prognostic factor in cancer patients. Despite showing efficacy in many extracranial tumors, immunotherapy with anti-PD-1 monoclonal antibody (mAb) or anti-CTLA-4 mAb appears to be less effective against intracranial tumors. Promisingly, recent clinical studies have reported that combination therapy with anti-PD-1 and anti-CTLA-4 mAbs has a potent antitumor effect on BM, highlighting the need to elucidate the detailed mechanisms controlling the intracranial tumor microenvironment (TME) to develop effective immunotherapeutic strategies. Here, we analyzed the tumor-infiltrating lymphocytes in murine models of BM that responded to anti-CTLA-4 mAb to anti-PD-1 mAb. Activated CD4+ T follicular helper (TFH) cells with high CTLA-4 expression characteristically infiltrated the intracranial TME, which were activated by the combination anti-CTLA-4 and anti-PD-1 treatment. Loss of TFH cells suppressed the additive effect of CTLA-4 blockade on anti-PD-1 mAb. B cell-activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) produced by abundant myeloid cells, particularly CD80hiCD206lo pro-inflammatory M1-like macrophages, in the intracranial TME, induced B cell and TFH cell infiltration and activation. Furthermore, the intracranial TME of patients with non-small cell lung cancer featured TFH and B cell infiltration as tertiary lymphoid structures. Together, these findings provide insights into the immune cell crosstalk in the intracranial TME that facilitates an additive anti-tumor effect of CTLA-4 blockade with anti-PD-1 treatment, supporting the potential of a combination immunotherapeutic strategy for BM.
Impact of Co-mutations and Transcriptional Signatures in Non–Small Cell Lung Cancer Patients Treated with Adagrasib in the KRYSTAL-1 Trial
Authors: Negrao Marcelo V. , Paula Alvaro G. , Molkentine David , Hover Laura , Nilsson Monique , Vokes Natalie , Engstrom Lars , Calinisan Andrew , Briere David M. , Waters Laura , Hallin Jill , Diao Lixia , Altan Mehmet , Blumenschein George R. , Skoulidis Ferdinandos , Wang Jing , Kopetz Scott E. , Hong David S. , Gibbons Don L. , Olson Peter , Christensen James G. , Heymach John V. 
Published: January 2025

Abstract

Purpose:
KRAS inhibitors are revolutionizing the treatment of non–small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.

Experimental Design:
Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib [KRYSTAL-1 (NCT03785249)] were included in the analysis. Pretreatment next-generation sequencing data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free survival (PFS), and overall survival (OS). KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens.

Results:
KEAP1 MUT and STK11MUT were associated with shorter survival to adagrasib [KEAP1: PFS 4.1 vs. 9.9 months, HR 2.7, P &lt; 0.01; OS 5.4 vs. 19.0 months, HR 3.6, P &lt; 0.01; STK11: PFS 4.2 vs. 11.0 months, HR 2.2, P &lt; 0.01; OS 9.8 months vs. not reached (NR), HR 2.6, P &lt; 0.01]. KEAP1WT/STK11WT status identified adagrasib-treated patients with significantly longer PFS (16.9 months) and OS (NR). Preclinical analyses further validate the association between KEAP1 loss of function and adagrasib resistance. Adagrasib and mTOR inhibitor combinations produced higher treatment efficacy in NSCLC models harboring STK11 and KEAP1 co-mutations. NRF2HIGH signaling was associated with shorter survival to adagrasib (PFS: 4.2 vs. 8.4 months, HR 2.0, P = 0.02; OS: 6.5 vs. 19.0 months, HR 2.8, P &lt; 0.01) even in patients with KEAP1WT NSCLC. KEAP1WT/STK11WT/NRF2LOW status identified patients—32%—with longer survival to adagrasib (PFS 12.0 vs. 4.2 months, HR 0.2, P &lt; 0.01; OS NR vs. 8.0 months, HR 0.1, P &lt; 0.01).

Conclusions:
KEAP1, STK11, and NRF2 status define patients with KRASG12C-mutant NSCLC with markedly distinct outcomes to adagrasib. These results further support the use of genomic features—mutational and nonmutational—for the treatment selection of patients with KRASG12C-mutant NSCLC.
Intracellular Retention of Estradiol Is Mediated by GRAM Domain–Containing Protein ASTER-B in Breast Cancer Cells
Authors: Kim Hyung Bum , Kraus W. Lee 
Published: January 2025

Abstract
Elevated blood levels of estrogens have been associated with poor prognosis in estrogen receptor–positive (ER+) breast cancers, but the relationship between circulating hormone levels in the blood and intracellular hormone concentrations is not well characterized. We observed that MCF-7 cells treated acutely with 17β-estradiol (E2) retain a substantial amount of the hormone even upon the removal of the hormone from the culture medium. Moreover, global patterns of E2-dependent gene expression are sustained for hours after acute E2 treatment and hormone removal. Although circulating E2 is sequestered by sex hormone binding globulin, the potential mechanisms of intracellular E2 retention are poorly understood. We found that mislocalization of a steroid-binding GRAM domain–containing protein, ASTER-B, to the nucleus, which is observed in a subset of patients with breast cancer, is associated with higher cellular E2 retention. Accumulation and retention of E2 are related to the steroidal properties of E2 and require nuclear localization and steroid binding by ASTER-B, as shown using a panel of mutant ASTER-B proteins. Finally, we observed that nuclear ASTER-B–mediated E2 retention is required for sustained hormone-induced ERα chromatin occupancy at enhancers and gene expression, as well as subsequent cell growth responses. Our results add intracellular hormone retention as a mechanism controlling E2-dependent gene expression and downstream biological outcomes.
Implications: Mislocalized nuclear ASTER-B, which binds estradiol to support the functions of ER, can provide an alternate means of enhancing the biological effects of E2 in breast cancers and may be a potential therapeutic target that addresses multiple aspects of estrogen bioavailability.
Prognostic Value of LV Global Longitudinal Strain by 2D and 3D Speckle-Tracking Echocardiography in Patients With HFpEF
Authors: Lin Yixia , Xie Mingxing , Zhang Li , Zhang Yanting , Zhang Peige , Chen Xin , Ji Mengmeng , Gao Lang , He Qing , Wu Zhenni , Yang Yali , Li Yuman 
Published: January 2025

BACKGROUND:
In patients with heart failure with preserved ejection fraction (HFpEF), the impact of type 2 diabetes (T2D) on left ventricular global longitudinal strain (LV GLS) and its prognostic implications remains unclear. We aimed to evaluate LV function using two-dimensional (2D) and three-dimensional (3D) speckle-tracking echocardiography in patients with HFpEF with and without T2D, and to investigate its prognostic significance.

METHODS:
A total of 335 patients with HFpEF were prospectively enrolled for echocardiographic evaluation. LV GLS was obtained using 2D- and 3D-speckle-tracking echocardiography. Cox proportional hazards regression was used to determine predictors of adverse outcomes. The C-index, Akaike information criterion, integrated discrimination improvement, and net reclassification improvement were used to assess model performance and discriminative ability.

RESULTS:

LV 2D-GLS and 3D-GLS were impaired in patients with HFpEF and T2D compared with those without T2D. After a median follow-up of 17.6 months, 150 patients experienced adverse outcomes. Both 2D-GLS (hazard ratio, 1.323 [95% CI, 1.225–1.429];
P
<0.001) and 3D-GLS (hazard ratio, 1.412 [95% CI, 1.316–1.515];
P
<0.001) were independent predictors of adverse outcomes in patients with HFpEF after adjustment for confounders. The predictive accuracy of a model incorporating 3D-GLS (Akaike information criterion=−583.9, C-index=0.775 [95% CI, 0.742–0.808]) was superior to models using 2D-GLS (Akaike information criterion=−533.3, C-index=0.719 [95% CI, 0.678–0.760], ΔC-index=0.056;
P
=0.034) and LV ejection fraction (Akaike information criterion=−498.9, C-index=0.659 [95% CI, 0.610–0.708], ΔC-index=0.116;
P
<0.001). The addition of 2D-GLS and 3D-GLS to the base model significantly enhanced its discriminatory and predictive abilities (integrated discrimination improvement=0.225 and 0.280; net reclassification improvement=0.612 and 0.734, respectively,
P
<0.001 for all).

CONCLUSIONS:
LV 2D-GLS and 3D-GLS are impaired in patients with HFpEF and T2D, and are independent predictors of adverse outcomes. Moreover, 3D-GLS provides incremental prognostic value over 2D-GLS.

REGISTRATION:

URL:
https://www.chictr.org.cn/
; Unique identifier: ChiCTR2100047487.