bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis of receptor-binding adaptation of human-infecting H3N8 influenza A virus
Authors: Hao Tianjiao , Xie Yufeng , Chai Yan , Zhang Wei , Zhang Di , Qi Jianxun , Shi Yi , Song Hao , Gao George F. 
Published: February 2025

ABSTRACT

Recent avian-origin H3N8 influenza A virus (IAV) that have infected humans pose a potential public health concern. Alterations in the viral surface glycoprotein, hemagglutinin (HA), are typically required for IAVs to cross the species barrier for adaptation to a new host, but whether H3N8 has adapted to infect humans remains elusive. The observation of a degenerative codon in position 228 of HA in human H3N8 A/Henan/4-10/2022 protein sequence, which could be residue G or S, suggests a dynamic viral adaptation for human infection. Previously, we found this human-isolated virus has shown the ability to transmit between ferrets via respiratory droplets, with the HA-G228S substitution mutation emerging as a critical determinant for the airborne transmission of the virus in ferrets. Here, we investigated the receptor-binding properties of these two H3N8 HAs. Our results showed H3N8 HAs have dual receptor-binding properties with a preference for avian receptor binding, and G228S slightly increased binding to human receptors. Cryo-electron microscopy structures of the two H3N8 HAs with avian and human receptor analogs revealed the basis for dual receptor binding. Mutagenesis studies reveal that the Q226L mutation shifts H3N8 HA’s receptor preference from avian to human, while the G228S substitution enhances binding to both receptor types. H3N8 exhibits distinct antigenic sites compared to H3N2, prompting concerns regarding vaccine efficacy. These findings suggest that the current H3N8 human isolates are yet to adapt for efficient human-to-human transmission and further continuous surveillance should be implemented.

IMPORTANCE
Influenza virus transmission remains a public health concern currently. H3N8 subtype influenza A viruses infect humans and their HAs acquire the ability to bind to both human and avian receptors, posing a threat to human health. We have solved and analyzed the structural basis of dual receptor binding of recently human-infecting H3N8 HA, and we demonstrate that the G228S enhances human receptor binding and adaptation. We also found that HN/4-10 H3N8 HA has distinct antigenic sites, which challenges vaccine efficacy. Taken together, our work is critical to the prevention and control of human H3 influenza virus infection.
(p)ppGpp and DksA play a crucial role in reducing the efficacy of β-lactam antibiotics by modulating bacterial membrane permeability
Authors: Chawla Meenal , Verma Jyoti , Kumari Shashi , Matta Tushar , Senapati Tarosi , Babele Prabhakar , Kumar Yashwant , Bhadra Rupak K. , Das Bhabatosh 
Published: February 2025

ABSTRACT

The key signaling molecules in the bacterial stress-sensing pathway, the alarmone (p)ppGpp and the transcription factor DksA, play a crucial role in bacterial survival during nutritional deprivation and exposure to xenobiotics by modulating cellular metabolic pathways. In
Vibrio cholerae
, (p)ppGpp metabolism is solely linked with the functions of three proteins: RelA, SpoT, and RelV. The effects of threshold or elevated concentrations of (p)ppGpp on cellular metabolites and proteins, both in the presence and absence of DksA, have not yet been comprehensively studied in
V. cholerae
or other bacteria. We engineered the genome of
V. cholerae
to develop DksA null mutants in the presence and absence of (p)ppGpp biosynthetic enzymes. We observed that the N16:Δ
relA
Δ
relV
Δ
spoT
Δ
dksA V. cholerae
mutant, which lacks both (p)ppGpp and DksA, exhibits higher sensitivity to different ꞵ-lactam antibiotics compared with the wild-type (WT) strain. Our whole-cell metabolomic and proteome analysis revealed that the cell membrane and peptidoglycan biosynthesis pathways are significantly altered in the N16:Δ
relA
Δ
relV
Δ
spoT
, N16:Δ
dksA
, and N16:Δ
relA
Δ
relV
Δ
spoT
Δ
dksA V. cholerae
strains. Furthermore, the mutant strains displayed enhanced inner and outer membrane permeabilities in comparison to the WT strains. These results correlate with
V. cholerae’s
tolerance and survival against β-lactam antibiotics and may inform the development of adjuvants that inhibit stringent response modulators.

IMPORTANCE

The (p)ppGpp biosynthetic pathway is widely conserved in bacteria. Intracellular levels of (p)ppGpp and the transcription factor DksA play crucial roles in bacterial multiplication and viability in the presence of antibiotics and/or other xenobiotics. The present findings have shown that (p)ppGpp and DksA significantly reduce the efficacy of ꞵ-lactam and other antibiotics by modulating the availability of peptidoglycan and cell membrane-associated metabolites by reducing membrane permeability. Nevertheless, the whole-cell proteome analysis of N16:Δ
relA
Δ
relV
Δ
spoT
, N16:Δ
dksA
, and N16:Δ
relA
Δ
relV
Δ
spoT
Δ
dksA
strains identified the biosynthetic pathways and associated enzymes that are directly modulated by the stringent response effector molecules. Thus, the (p)ppGpp metabolic pathways and DksA could be a potential target for increasing the efficacy of antibiotics and developing antibiotic adjuvants.
Conservation translocation of Atlantic wolffish (Anarhichas lupus) to a depleted Arctic fjord ecosystem
Authors: Olsen Esben Moland , Strand Hans Kristian 
Published: February 2025

Predators have important functional roles in coastal ecosystems. In cases where such species are locally depleted or extirpated, a proactive restoration strategy may include conservation translocation. This study reports on such translocations of Atlantic wolffish ( Anarhichas lupus) to fjord habitats in northern Norway where the species is currently severely depleted. A total of 20 pioneer individuals measuring 42–80 cm in length were captured in outer coastal habitats and subsequently tagged, released, and tracked within a fjord using acoustic telemetry. A first group of seven individuals were monitored for 14 months during 2017 and 2018, while a second group of 13 individuals were monitored for 4 months during 2019. Up to 40% of translocated wolffish remained inside their new fjord environment until the study was terminated, while the remaining 60% likely dispersed. Weekly home range size decreased substantially with time for larger fish, while this trend was weaker for smaller fish. Our study implies that there is reason for cautious optimism regarding the implementation of conservation translocation of wolffish in coastal ecosystems, while acknowledging the challenge of accounting for animal dispersal in aquatic systems.
Circulating Tumor Microenvironment in Metastasis
Authors: Tang Rui , Luo Shujuan , Liu Hui , Sun Yan , Liu Manran , Li Lu , Ren Haoyu , Angele Martin K. , Börner Nikolaus , Yu Keda , Guo Zufeng , Yin Guobing , Luo Haojun 
Published: February 2025

Abstract
Activation of invasion and metastasis is a central hallmark of cancer, contributing to the primary cause of death for cancer patients. In the multistep metastatic process, cancer cells must infiltrate the circulation, survive, arrest at capillary beds, extravasate, and form metastatic clones in distant organs. However, only a small proportion of circulating tumor cells (CTCs) successfully form metastases, with transit of CTCs in the circulation being the rate-limiting step. The fate of CTCs is influenced by the circulating tumor microenvironment (cTME), which encompasses factors affecting their biological behaviors in the circulation. This liquid and flowing microenvironment differs significantly from the primary tumor microenvironment or the pre-metastatic niche. This review summarizes the latest advancements in identifying the biophysical cues, key components, and biological roles of the cTME, highlighting the network among biophysical attributes, blood cells, and non-blood factors in cancer metastasis. In addition to the potential of the cTME as a therapeutic target for inhibiting metastasis, the cTME could also represent as a biomarker for predicting patient outcomes and developing strategies for treating cancer.
Arginine Deprivation Induces Quiescence and Confers Vulnerability to Ferroptosis in Colorectal Cancer
Authors: Lin Yanyun , Zhang Yanhong , Huang Tianze , Chen Junguo , Li Guanman , Zhang Bin , Xu Liang , Wang Kai , He Hui , Chen Hao , Liu Danling , Guo Shuang , He Xiaosheng , Lan Ping 
Published: February 2025

Abstract
Metabolic reprogramming is a hallmark of cancer. Rewiring of amino acid metabolic processes provides the basis for amino acid deprivation therapies. In this study, we found that arginine biosynthesis is limited in colorectal cancer (CRC) due to the deficiency of ornithine transcarbamylase (OTC). Accordingly, CRC cells met the demand for arginine by increasing external uptake. The addiction to environmental arginine resulted in the susceptibility of CRC to arginine deprivation, which dramatically decreased proliferation in CRC cells and promoted these cells to enter a reversible quiescence state. Arginine deprivation induced quiescence by activating the AMPK-p53-p21 pathway. RNA sequencing data indicated that CRC cells may be vulnerable to ferroptosis during arginine deprivation, and the combination of ferroptosis inducers and arginine deprivation strongly impeded tumor growth in vivo. These findings suggest that dietary modification combined with ferroptosis induction could be a potential therapeutic strategy for CRC.
Longitudinal Profiling of Circulating Tumor DNA Reveals the Evolutionary Dynamics of Metastatic Prostate Cancer During Serial Therapy
Authors: Zhao Yuehui , Ramesh Naveen , Xu Ping , Sei Emi , Hu Min , Bai Shanshan , Troncoso Patricia , Aparicio Ana M. , Logothetis Christopher J. , Corn Paul G. , Navin Nicholas E. , Zurita Amado J. 
Published: February 2025

Abstract
Treatment decisions in metastatic castration-resistant prostate cancer (mCRPC) are mostly guided by clinical variables, but efforts to molecularly monitor the disease remain hampered by challenges in acquiring tumor tissue repeatedly. Here, we simultaneously profiled the genome copy number and exome in longitudinal plasma circulating tumor DNA (ctDNA) acquired before, during, and upon progression to serial treatments with androgen signaling inhibitors (ASI) and taxane chemotherapy from 60 mCRPC patients (2-10 samples per patient). The genomic data was used to delineate the clonal substructure and evolutionary dynamics of each patient, and an evolutionary dynamic index (EDI) was developed to measure the longitudinal changes of the tumor subclones. Treatment with ASI resulted in greater subclonal selection and population structure changes than taxane treatment. The subclones that emerged in association with serial therapy resistance harbored recurrent aberrations in previously identified and new candidate genes, with particular enrichment in genes related to PI3K-AKT signaling. These findings indicate that the integration of detailed clinical and genomics data can provide a framework for future unbiased genomic applications for ctDNA in the clinic to enable precision medicine.
Palmitic Acid Accumulation Activates Fibroblasts and Promotes Matrix Stiffness in Colorectal Cancer
Authors: Deng Shenghe , Wang Jun , Zou Falong , Cheng Denglong , Chen Mian , Gu Junnan , Shi Jianguo , Yang Jia , Xue Yifan , Jiang Zhengxin , Qin Le , Mao Fuwei , Chang Xiaona , Nie Xiu , Liu Li , Cao Yinghao , Cai Kailin 
Published: February 2025

Abstract
Obstructions can occur during any stage of colorectal cancer (CRC) and correspond with poor prognosis. Obstructive colorectal cancer (OCRC) is harder and exhibits increased tumor budding and proliferation of myofibroblasts compared to non-obstructive CRC, suggesting that the occurrence of obstruction may be related to extracellular matrix (ECM) remodeling. Here, we found that CRC and OCRC samples differed substantially in ECM composition, specifically in collagen (newly formed and mature) and proteoglycans (including glycosaminoglycan, hyaluronic acid, and chondroitin sulfate). OCRC also exhibited considerable changes in ECM biomechanics and collagen arrangement. Interestingly, OCRC samples presented a notable increase in matrix cancer-associated fibroblasts (mCAFs). The abundance of mCAFs correlated with the accumulation of palmitic acid (PA), and high concentrations of PA increased the secretion of ECM-related proteins by mCAFs. Additionally, PA did not directly affect normal fibroblasts (NFs) but rather activated the NF-κB pathway in tumor cells to stimulate secretion of CSF-1, TGF-β1 and CXCL8, which promoted the activation of NFs into mCAFs and exacerbated ECM stiffening. Drug screening with a natural compound library identified vanillylacetone as a potential inhibitor of PA-induced cytokine secretion and ECM stiffening. These findings highlight intratumoral PA accumulation as a key mechanism driving ECM alterations and OCRC progression and suggest that targeting this axis may be useful for treating CRC patients with risk of obstruction.
Biomarkers of toxicant exposure among youth in Canada, England and the United States who vape and/or smoke tobacco or do neither
Authors: Hammond David , Reid Jessica L. , Goniewicz Maciej L. , McNeill Ann , O'Connor Richard J. , Corsetti Danielle , Brose Leonie S. , Schurr Bradley , Robson Deborah 
Published: February 2025

Abstract
Background: Few studies examine biomarkers of exposure to vaping and tobacco products among youth. We compared biomarkers for toxicants between youth who vape, smoke, ‘dual-use’, or neither. Methods: Participants aged 16-19 in Canada, England, and the United States (US) completed surveys and self-collected urine samples between September 2019 and January 2022 (N=364). Urine was tested for metabolites of tobacco-specific nitrosamine NNK and six volatile organic compounds (VOCs). Regression models examined differences in biomarker concentrations by past-week tobacco smoking and vaping, adjusting for creatinine, age, sex, country, and cannabis use. Results: Compared to no vaping/smoking, exclusive vaping was associated with similar exposure to acrolein and acrylonitrile, but higher exposure to toluene (p=.04) and acrylamide (p=.034, only in sensitivity analysis using past-24-hour measure). Compared to dual-use or exclusive smoking, exclusive vaping was associated with lower exposure to NNK, acrolein, acrylamide, and acrylonitrile (p≤.01), but higher toluene exposure than dual use (p=0.012). Exposure was similar for dual-use and exclusive smoking. Benzene and xylene biomarkers were detected in &lt;5% and not compared. Among those smoking, NNK exposure was higher in the US (geometric mean=25.4pg/mg creatinine) versus Canada (16.1pg/mg; p=0.006) and England (14.1pg/mg; p=0.018). Conclusions: Youth exclusively vaping had similar exposure as no vaping/smoking except for two VOCs, and lower exposure than smoking or dual use except toluene. Higher NNK levels among US youth who smoke likely reflect differences in tobacco blend. Impact: Findings are generally consistent with literature indicating lower toxicant exposure from vaping versus smoking, but elevated exposure versus no use for some.
Pembrolizumab with chemotherapy for patients with recurrent or metastatic nasal cavity and paranasal sinus squamous cell carcinoma: A prospective phase ll study
Authors: Qian Yuquan , Tang Le , Yao Jiarui , Zhu Yiming , Zhang Ye , Lu Haizhen , Li Weihua , An Changming , Gui Lin 
Published: February 2025

Abstract
Purpose: Patients with recurrent or metastatic sinonasal squamous cell carcinoma (R/M SNSCC) lack standardized systemic treatment and prospective studies. We evaluated the anti-tumor response and safety of pembrolizumab with nab-paclitaxel and platinum in R/M SNSCC. Patients and Methods: R/M SNSCC patients received pembrolizumab 200mg, nab-paclitaxel 260mg/m2 plus cisplatin 75 mg/m2 or carboplatin at an area under the curve 5 on day 1 every 21 days for up to six cycles, followed by pembrolizumab maintenance until progression or unacceptable toxicity or 35 cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Immunohistochemistry and high-resolution sequencing of the tumor samples were performed. Results: The ORR in 20 patients was 60.0% (95% CI: 36.1%-80.9%) and two patients (2/20, 10%) achieved CR. The DCR was 100%. Median follow-up was 18.1 months (range:5.2-31.7), the median PFS was 12.2 months (95% CI: 9.0 months-not estimated) and the median OS was not reached. Patients with PD-L1 CPS ≥20 exhibited better ORR (80.0% vs 28.6%, p=0.144), median PFS (not reached vs 7.0 months, p=0.0137), and median OS (not reached vs 17.8 months, p=0.0401) compared to those with PD-L1 CPS &lt; 20. Grade 3/4 treatment-related adverse events (AE) accounted for 30.0% (6/20), and all come from hematologic toxicity. Hypothyroidism was the most common immune-related AE (12/20, 60.0%). Conclusions: Pembrolizumab plus nab-paclitaxel and platinum shows promising antitumor activity and manageable safety in first-line R/M SNSCC patients.
Identification of Causal Plasma Proteins in Hepatocellular Carcinoma via Two-sample Mendelian Randomization and Integrative Transcriptomic‒Proteomic Analysis
Authors: Tang Weihao , Ma Xiaoke 
Published: February 2025

Abstract
Hepatocellular carcinoma (HCC) poses a serious threat to human health. Identifying diagnostic and therapeutic targets from plasma proteins is essential for early HCC detection and treatment. Large-scale plasma proteomics data and Mendelian randomization (MR) offer opportunities for this type of research. Proteomic data from protein quantitative trait loci (pQTLs) were obtained from the UKB-PPP. Two-sample MR was used to evaluate the causal association between plasma protein levels and HCC. Sensitivity, directionality, and colocalization analyses were conducted to validate the causal associations identified by MR. Robustness was further tested through colocalization analysis. The single-cell dataset GSE166635 was used to assess the expression of genes corresponding to proteins identified via MR. Potential drugs targeting these proteins were evaluated using the DSigDB/DrugBank databases and molecular docking. Seven proteins with potential causal associations with HCC were identified: ASS1, B2M, FUOM, GABARAPL1, ST8SIA1, STOML2, and KRT8. Among these genes, ASS1, KRT8, and STOML2 presented the strongest effects in the colocalization analyses. In a single-cell liver cancer dataset, ASS1, KRT8, and STOML2 were expressed mainly in hepatic progenitor cells (HPCs) and malignant cells, with KRT8 predominantly found in HPCs and playing a role in the oncogenesis of malignant liver cells. Potential drugs included ASS1 with arginine, aspartic acid, and citrulline; KRT8 with ambroxol, diltiazem, and amikacin; and STOML2 with chlortetracycline, chlorzoxazone, and dirithromycin. This study identified several novel causal plasma proteins, providing new insights into the early diagnosis and treatment of HCC.
Effects of lateralization of language on cognition among left-handers
Authors: Cano-Melle Cristina , Villar-Rodríguez Esteban , Baena-Pérez María , Parcet María-Antonia , Avila César 
Published: February 2025

Abstract
Atypical language lateralization is associated with a different organization of the entire brain. However, it remains unknown whether this cerebral organization is linked to differences in cognitive task performance. In this study, several neuropsychological tests requiring fast processing speed were administered to left-handed participants, classified based on their language lateralization: left language dominance (N = 48), bilateral (N = 15), and right language dominance (N = 23). A factor analysis was conducted to derive three cognitive function dimensions: reading, articulation and verbal reasoning, spatial processing, and interference/inhibition. The results showed that right language dominance was associated with poorer overall performance, particularly on tasks related to spatial processing, reading, articulation and verbal reasoning. We conclude that the atypical development of language lateralization is accompanied by lower cognitive skills in tasks requiring speed of processing and interhemispheric connectivity.
The Double Standard of Ownership
Authors: Washington Zofia , Friedman Ori 
Published: February 2025

Abstract
Owners are often blamed when their property causes harm but might not receive corresponding praise when their property does good. This suggests a double standard of ownership, wherein owning property poses risks for moral blame that are not balanced with equal opportunities for credit. We investigated this possibility in three preregistered experiments on 746 US residents. Participants read vignettes where agentic property (e.g., animals, robots) produced bad or good outcomes, and judged whether owners and the property were morally responsible. With bad outcomes, participants assigned owners more blame than property (Experiments 1 and 2) or similar blame (Experiment 3). But with good outcomes, participants consistently assigned owners much less praise relative to their property. The first two experiments also examined if the double standard arises in two other relationships between authorities and subordinates; participants showed the double standard when assessing moral responsibility for parents and children, but not for employers and employees. Together, these findings point to a novel asymmetry in how owners are assigned responsibility.