bluuebunny/crossref_metadata_2025_split huggingface dataset:
Signal Transduction Pathway Mediating Carotid Body Dependent Sympathetic Activation and Hypertension by Chronic Intermittent Hypoxia
Authors: Peng Ying-Jie , Nanduri Jayasri , Wang Ning , Su Xiaoyu , Hildreth Matthew , Prabhakar Nanduri R 
Published: January 2025

Abstract
Patients with obstructive sleep apnea (OSA) experience chronic intermittent hypoxia (CIH). OSA patients and CIH-treated rodents exhibit overactive sympathetic nervous system and hypertension, mediated through hyperactive carotid body (CB) chemoreflex. Activation of olfactory receptor 78 (Olfr78) by hydrogen sulfide (H2S) is implicated in CB activation and sympathetic nerve responses to CIH, but the downstream signaling pathways remain unknown. Given that odorant receptor signaling is coupled to adenylyl cyclase 3 (Adcy3), we hypothesized that Adcy3-dependent cyclic adenosine monophosphate (cAMP) contributes to CB and sympathetic responses to CIH. Our findings show that CIH increases cAMP levels in the CB, a response absent in Adcy3, Cth (encoding CSE), and Olfr78 null mice. CBs from Cth and Olfr78 mutant mice lacked a persulfidation response to CIH, indicating that Adcy3 activation requires Olfr78 activation by H2S in CIH. CIH also enhanced glomus cell Ca2+ influx, an effect absent in Cnga2 (encoding cyclic nucleotide–gated channel alpha2 subunit) and Adcy3 mutants, suggesting that CIH-induced cAMP mediates enhanced Ca2+ responses through cyclic nucleotide–gated channels. Furthermore, Adcy3 null mice did not exhibit either CB activation or sympathetic activation by CIH. These results demonstrate that Adcy3-dependent cAMP is a downstream signaling pathway to H2S/Olfr78, mediating CIH-induced CB activation, sympathetic activity and hypertension.
Tandem Repeats Provide Evidence for Convergent Evolution to Similar Protein Structures
Authors: Wright Erik S 
Published: January 2025

Abstract
Homology is a key concept underpinning the comparison of sequences across organisms. Sequence-level homology is based on a statistical framework optimized over decades of work. Recently, computational protein structure prediction has enabled large-scale homology inference beyond the limits of accurate sequence alignment. In this regime, it is possible to observe nearly identical protein structures lacking detectable sequence similarity. In the absence of a robust statistical framework for structure comparison, it is largely assumed similar structures are homologous. However, it is conceivable that matching structures could arise through convergent evolution, resulting in analogous proteins without shared ancestry. Large databases of predicted structures offer a means of determining whether analogs are present among structure matches. Here, I find that a small subset (∼2.6%) of Foldseek clusters lack sequence-level support for homology, including ∼1% of strong structure matches with template modeling score ≥ 0.5. This result by itself does not imply these structure pairs are nonhomologous, since their sequences could have diverged beyond the limits of recognition. Yet, strong matches without sequence-level support for homology are enriched in structures with predicted repeats that could induce spurious matches. Some of these structural repeats are underpinned by sequence-level tandem repeats in both matching structures. I show that many of these tandem repeat units have genealogies inconsistent with their corresponding structures sharing a common ancestor, implying these highly similar structure pairs are analogous rather than homologous. This result suggests caution is warranted when inferring homology from structural resemblance alone in the absence of sequence-level support for homology.
A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator
Authors: Lee Matthew A , Hatcher Charlie A , Hazelwood Emma , Goudswaard Lucy J , Tsilidis Konstantinos K , Vincent Emma E , Martin Richard M , Smith-Byrne Karl , Brenner Hermann , Cheng Iona , Kweon Sun-Seog , Le Marchand Loic , Newcomb Polly A , Schoen Robert E , Peters Ulrike , Gunter Marc J , Van Guelpen Bethany , Murphy Neil 
Published: January 2025

Abstract

Background
Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, are unclear.

Methods
Utilizing two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable associations between: (i) body mass index (BMI) and waist–hip ratio (WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (ii) BMI and WHR and circulating proteins, and (iii) adiposity-associated circulating proteins and CRC risk. We used MVMR to investigate the potential mediating role of adiposity- and CRC-related circulating proteins in the adiposity–CRC association.

Results
BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumor site. In total, 6591 adiposity–protein (2628 unique circulating proteins) and 33 protein–CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. One circulating protein, GREM1, was associated with BMI (only) and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI–CRC association for GREM1, effect estimates were attenuated—suggestive of a potential mediating role—most strongly for the BMI–overall CRC association in women.

Conclusion
Results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from UVMR and colocalization analyses using cis-single-nucleotide polymorphisms, GREM1 was identified as a potential mediator of the BMI–CRC association, particularly in women.
P24 In vitro activity of cefepime/enmetazobactam, and comparators, against OXA carbapenemase-positive Acinetobacter baumannii
Authors: Ward Jon , Dunkel Nathalie , Quevedo Juan , Morrisey Ian , Santerre Henriksen Anne 
Published: January 2025

Abstract

Background
Cefepime/enmetazobactam (FEP/META) is a new β-lactam/β-lactamase inhibitor combination with broad-spectrum activity against MDR Enterobacterales (including OXA-48-producing isolates) which has demonstrated superiority to piperacillin/tazobactam for the treatment of complicated urinary tract infections. This study was conducted to evaluate the activity of cefepime/enmetazobactam against a collection of Acinetobacter baumannii isolates positive for characterized OXA carbapenemases.

Methods
The MICs of cefepime, FEP/META (META tested at a fixed concentration of 8 mg/L) and other relevant agents were determined by broth microdilution according to EUCAST guidelines against a panel of 120 OXA-positive A. baumannii collected globally (30 isolates each positive for OXA-23, OXA-24, OXA-51 and OXA-58 carbapenemases).

Results
The A. baumannii isolates producing class D carbapenemases were 0.8% susceptible to ciprofloxacin or meropenem, and 22.5% susceptible to gentamicin. At the proposed FEP/META breakpoint of 8 mg/L, the susceptibility of OXA-positive A. baumannii isolates was 31.7% showing synergy compared with FEP alone. FEP/META had a limited in vitro activity against the most common carbapenem resistant A. baumannii (OXA-23 or OXA-24 producers), but it showed promising activity against OXA-58 and OXA-51 producers.

Conclusions
Enmetazobactam displayed a capacity to restore cefepime activity against clinical isolates of OXA-51 and OXA-58 carbapenemase producing A. baumannii, rendering many of the isolates that were resistant to commercial comparators susceptible to FEP/META.
Exoskeleton Robot Training in Two Patients with an Electrical Burn and Septic Arthritis: A Case Report
Authors: Lee Seung Yeol , Seo Cheong Hoon , Ch Yoon Soo , Kim Youngmin , Yoon Youngsuh , Joo So Young 
Published: January 2025

Abstract
Septic arthritis (SA) is rare in patients with burns, but delayed treatment can result in irreversible joint destruction. Early diagnosis and immediate treatment are necessary to prevent joint destruction. Robot training in patients with musculoskeletal diseases and burns can improve joint range of motion (ROM), muscle strength, and lower extremity function. The aim of this report is to present robot training utility in patients with lower extremity electrical burns and associated SA. Rebless (H-Robotics, Korea) for ROM and strength training can operate in passive or active modes in knee or ankle flexion and extension. Rebless works by providing visual feedback on angles during flexion and extension training. Two participants, diagnosed with SA after burns and unable to walk before training because of joint pain, limited ROM, and muscle weakness, underwent 30 min of robot training using Rebless with 30-min conventional therapy, 5 days a week for 8 weeks. After training, the gait function, muscle strength, and pain scores of the participants improved without adverse effects on joint ROM. This report is the first to demonstrate that robot training has a positive effect on gait function, pain, muscle strength with no soft tissue contractures, or other complications in a patient with burn injury and SA.
On-farm evaluation of swede midge (Diptera: Cecidomyiidae) susceptibility among popular kale varieties
Authors: Izzo Victor M , Lewins Scott A , Nouri-Aiin Maryam 
Published: January 2025

Abstract
The swede midge, Contarinia nasturtii Kieffer (Diptera:Cecidomyiidae), is a gall-forming insect pest that targets cruciferous plants. Since its introduction to North America in the early 2000s, the midge has expanded its range to include farming regions in Quebec and the Northeastern USA. In this study, we evaluated the susceptibility of 4 popular kale varieties—Green Curly—(Vates), Red Russian, Red Curly (RedBor), and Lacinato/Tuscan—to swede midge infestation in on-farm trials conducted over consecutive years. Our results indicate substantial variability in susceptibility among varieties, with Red Russian kale consistently exhibiting the highest damage incidence across both years. These findings provide valuable insights for developing effective integrated pest management (IPM) strategies tailored to organic and small-scale vegetable farming contexts, emphasizing the role of crop genetic resources in pest mitigation and sustainable agriculture. In addition, this study highlights the potential of non-chemical approaches for managing swede midge, leading to a more diverse and adaptable IPM toolbox for growers.
Teleost IgM+ plasma-like cells: beyond antibody secretion
Authors: Wu Liting , Morel Esther , Simón Rocío , Perdiguero Pedro , Zhang Yong-An , Ye Jianmin , Tafalla Carolina 
Published: January 2025

Abstract
Upon antigen encounter, B cells start a differentiation process toward antibody-secreting cells (ASCs), initially plasmablasts, and eventually long-lived plasma cells. All these ASCs specialize in secreting important amounts of antibodies and usually lose other functionalities of naïve B cells. This differentiation process is scarcely characterized in teleost fish, in which B cells have been shown to share many functional and phenotypic characteristics of mammalian B1 innate subsets. In this context, we were prompted to investigate further the functionalities of ASCs in teleosts, using rainbow trout (Oncorhynchus mykiss) as a model. Our results demonstrate that IgM+ plasma-like cells in the rainbow trout head kidney exhibit a strong IgM secreting capacity along with phagocytic and antigen-presenting capacities, even higher than those of naïve B cells. These IgM+ plasma-like cells were capable of surviving in vitro for 2 wk secreting IgM. Interestingly, they retained a functional B cell receptor that responded to TNP conjugated to lipopolysaccharide, a thymus-independent model antigen, which also rendered these cells more reactive to B cell receptor crosslinking. These findings shed light on the differentiation process of teleost B cells, demonstrating that teleost plasma-like cells conserve other phenotypical attributes beyond immunoglobulin secretion, being capable of directly responding to antigens. These findings point to an exclusive differentiation process of teleost B cells, which might provide mechanistic insights on how mammalian innate subsets such as B1 cells or IgM-expressing plasma cells differentiate.
PVR exposure influences the activation, adhesion, and protein expression of human CD8+ T cells, including the CD96-mediated transfer of PVR
Authors: Huang Xueting , Pawge Girija , Snicer Christina E , Hsiao Chia-Hung Christine , Wiemer Andrew J 
Published: January 2025

Abstract
Poliovirus receptor (PVR) ligands have gained attention as immunotherapy targets, yet their regulation remains unclear. Here, we examine the impact of PVR exposure on primary human CD8+ T cells. We used flow cytometry and Western blot analysis to quantify expression of PVR and its ligands in naïve and effector T cells and used adhesion assays and enzyme-linked immunosorbent assay (ELISA) to assess the impact of PVR on T cell adhesion and cytokine production. Stimulation with phytohemagglutinin P strongly increased DNAM-1 expression and caused a less robust and more variable increase in TIGIT expression. Exposure to PVR-Fc enhanced the CD8+ T cell adhesion to ICAM-1–coated plates in a dose-dependent manner, while exposure to PVR-expressing K32 cells mildly decreased CD8+ T cell interferon γ release. However, PVR exposure strongly decreased the expression of DNAM-1, TIGIT, and CD96. The reduction of DNAM-1, TIGIT, and CD96 induced by PVR was dominant to the increase caused by T cell receptor signaling. The impact of PVR on their expression was completely abolished by the Q63R and F128R point mutations of PVR, while DNAM-1 was partially rescued by inhibitors of Src and protein kinase C. Additionally, PVR exposure along with T cell receptor signaling promoted the transfer of surface proteins including PVR from K32 cells to CD8+ T cells. This PVR transfer was mediated by the IgV domain of PVR and CD96 on CD8+ T cells and required cellular contact. Our findings collectively demonstrate that PVR engagement has a mild antagonistic effect on interferon γ production but strongly impacts CD8+ T cell adhesion and protein expression.
Topoisomerase 1 is required for the development and function of thymus
Authors: Kumar Amit , Choubey Pallawi , Kaur Harshdeep , Muralidhara Prerana , Bansal Kushagra 
Published: January 2025

Abstract
Thymus organogenesis is critical for proper maturation of developing T cells. In this study, we identified Top1 as a novel gene involved in thymus development and function. We created a mouse line with deletion of Top1 in thymic epithelial cells (TECs), and our results demonstrate that biallelic loss of Top1 in TECs causes congenital thymic aplasia, precipitating T cell immunodeficiency. Transcriptomic analysis provides insights into the molecular mechanism of Top1 in thymus development as we identify key genes involved in thymus organogenesis as the transcriptional targets of Top1 in TECs. Analysis of peripheral immunological compartments revealed severe loss of αβ T cells complemented with a disproportionate accumulation of γδ T cells and myeloid cells upon deletion of Top1 in TECs. The residual αβ T cells in Top1 knockout mice were effector and oligoclonal in nature highlighting their self-reactivity. These results reveal a previously unknown role of Top1 in thymus development and T cell homeostasis. We propose Top1 as a genetic target for altered thymic development and T cell lymphopenia.
Suppression of NF-κB and downstream XBP1 by DcR3 contributes to a decrease in antibody secretion
Authors: Liu Po-Chun , Huang Szu-Ying , Lin Kuo-I , Hsieh Shie-Liang , Leu Chuen-Miin 
Published: January 2025

Abstract
Decoy receptor 3 (DcR3), a soluble receptor in the tumor necrosis factor receptor superfamily, regulates the functions of monocytes, macrophages, dendritic cells, and T cells. Previous studies have demonstrated that DcR3 suppresses B cell proliferation in vitro and ameliorates autoimmune diseases in animal models; however, whether and how DcR3 regulates antibody production is unclear. Using a DcR3 transgenic mouse model, we found that DcR3 impaired the T cell–dependent antigen-stimulated antibody response. The number of Ag-specific antibody-secreting cells was transiently reduced, but the concentration of specific antibodies continued to decrease in the DcR3 transgenic mice, implying a direct suppression of antibody production by DcR3. In vitro assays showed that the DcR3-Fc fusion protein attenuated T cell–dependent induced antibody production and reduced the expression of secretory Igh and Xbp1. We found that nuclear factor κB (NF-κB) activity was essential for the expression of Xbp1 in activated B cells. DcR3-Fc attenuated anti-CD40-induced NF-κB activity and Xbp1 promoter activity. Furthermore, DcR3-Fc decreased the expression of Xbp1 in Blimp1+ antibody-secreting cells. Restoration of spliced XBP1 (X-box binding protein 1) in DcR3-treated B cells increased the secretory Ighg1 transcript levels, suggesting that reducing XBP1 is one of the mechanisms by which DcR3 regulates antibody production both in vitro and in vivo. Collectively, these results indicate that in addition to blocking proliferation, DcR3 impairs NF-κB activation, subsequently decreasing the expression of Xbp1, eventually leading to a reduction in antibody secretion.
Immune suppression sustained allograft acceptance requires PD1 inhibition of CD8+ T cells
Authors: Miller-Handley Hilary , Harper Gavin , Pham Giang , Turner Lucien H , Shao Tzu-Yu , Russi Abigail E , Erickson John J , Ford Mandy L , Araki Koichi , Way Sing Sing 
Published: January 2025

Abstract
Organ transplant recipients require continual immune-suppressive therapies to sustain allograft acceptance. Although medication nonadherence is a major cause of rejection, the mechanisms responsible for graft loss in this clinically relevant context among individuals with preceding graft acceptance remain uncertain. Here, we demonstrate that skin allograft acceptance in mice maintained with clinically relevant immune-suppressive therapies, tacrolimus and mycophenolate, sensitizes hypofunctional PD1hi graft-specific CD8+ T cells. Uninterrupted immune-suppressive therapy is required because drug discontinuation triggers allograft rejection, replicating the requirement for immune-suppressive therapy adherence in transplant recipients. Graft-specific CD8+ T cells in allograft-accepted mice show diminished effector differentiation and cytokine production, with reciprocally increased PD1 expression. Allograft acceptance–induced PD1 expression is essential, as PDL1 blockade reinvigorates graft-specific CD8+ T cell activation with ensuing allograft rejection despite continual immune-suppressive therapy. Thus, PD1 sustained CD8+ T cell inhibition is essential for allograft acceptance maintained by tacrolimus plus mycophenolate. This necessity for PD1 in sustaining allograft acceptance explains the high rates of rejection in transplant recipients with cancer administered immune checkpoint inhibitors targeting PD1/PDL1, highlighting shared immune suppression pathways exploited by tumor cells and current therapies for averting allograft rejection.
Noise reduction of low-dose electron holograms using the wavelet hidden Markov model
Authors: Tomita Yuto , Midoh Yoshihiro , Tamaoka Takehiro , Murakami Yasukazu 
Published: January 2025

Abstract
The precision in electron holography studies on electrostatic and magnetic fields depends on the image quality of an electron hologram. Enhancing the image quality of electron holograms is essential for the comprehensive analysis of weak electromagnetic fields; however, extended electron beam irradiation can lead to undesirable radiation damage and contamination. Recent studies have demonstrated that noise reduction using the wavelet hidden Markov model (WHMM) can improve the precision of phase analysis for limited thin-foiled crystals. In this study, we examine the effects of WHMM-based denoising on the electron holography data of weakly charged nanoparticles collected under low-electron-dose conditions. The results indicate that effective noise reduction with the WHMM allows for a reduction in the magnitude of the electron dose by approximately half relative to data collection without WHMM denoising, while maintaining the same level of charge determination precision: less than one elementary charge. Notably, at a low electron dose of 0.40 e−/pixel, WHMM denoising enables the clear visualization of a weak stray electric field outside a charged latex sphere. This method offers significant advantages for electron holography studies of electron-beam-sensitive materials requiring minimal time for electron exposure.
Abdominal visceral and subcutaneous adipose tissue associations with postmenopausal breast cancer incidence
Authors: Bea Jennifer W , Ochs-Balcom Heather M , Valencia Celina I , Chen Zhao , Blew Robert M , Lind Kimberly E , Caan Bette J , Roe Denise J , Rohan Thomas E , Reeves Katherine W , Manson JoAnn E , Ballinger Tarah , Reding Kerryn W , Follis Shawna , Ziller Shelby G , Odegaard Andrew O 
Published: January 2025

Abstract

Background
Obesity, classified by body mass index (BMI), is associated with higher postmenopausal breast cancer (BCa) risk. Yet, the associations between abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) with BCa are unclear.

Methods
We assessed BCa associations with abdominal VAT and SAT in a prospective cohort of postmenopausal women without a history of cancer and with 27 years follow-up (N = 9950), during which all new cancers were adjudicated. Dual-energy X-ray absorptiometry scans assessed adiposity at baseline, year 3, and year 6. Competing risks multivariable sub-hazard ratios (SHR), with adjustments for sociodemographic, behavioral, reproductive, and anthropometric characteristics, were estimated for baseline and time-dependent associations between VAT, SAT, and incident BCa.

Results
Participants averaged 63.3 ± 7.4 years of age and a BMI of 28.20 ± 5.72 kg/m2 at baseline. The models included 738 incident BCa cases (N = 593 invasive; N = 145 in situ). Baseline VAT and SAT area were associated with significantly increased BCa risk, by 36% and 19% respectively. Increasing VAT/SAT ratio was associated with an 8% increase in incident BCa. Time-dependent models produced similar results. VAT and VAT/SAT associated BCa risk was highest for African American/Black women, though not significantly different from other groups. Quartiles (Q) of VAT/SAT were also explored; the SHR for Q4 compared to Q1 was 1.49 (95% CI: 1.18, 1.87).

Conclusion
Higher abdominal VAT and SAT are associated with an increased risk of postmenopausal BCa, and VAT/SAT may provide a distinctive risk estimate. Potential racial and ethnic differences require replication in a larger sample.(NCT00000611)