bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytomegalovirus Restricts the Innate Immune Response by Nuclear Export of Host Restriction Factor DDX41
Authors: Baruah Vargab , O’Connor Christine M. 
Published: October 2024

AbstractThe innate immune response is the first line of defense against invading pathogens, including the betaherpesvirus, human cytomegalovirus (CMV). The host’s innate response acts as the first line of defense, and CMV, like other viruses, has consequently evolved multiple mechanisms to manipulate host interferon (IFN) responses. DEAD-box Helicase 41 (DDX41) is an intracellular dsDNA sensor that, upon activation by Bruton’s tyrosine kinase (BTK), triggers type I IFN production through the Stimulator of Interferon Genes (STING) signaling pathway. Here, we show the activation of this signaling pathway during lytic CMV infection, wherein BTK, DDX41, and STING are activated through tyrosine phosphorylation, and both DDX41 and BTK interact with STING. Further, CMV infection re-localizes DDX41 from the nucleus to the cytoplasm, where it localizes to the perinuclear virus assembly compartment (vAC). Here, DDX41 phosphorylation is attenuated, suggesting cytoplasmic redistribution leads to a less active or inactive form. Additionally, DDX41 co-localizes in the vAC with the CMV tegument proteins, pp65 and pp71, each of which interact with DDX41 in immunoprecipitation assays. We further demonstrate the protective role of this signaling pathway, as treatment with the BTK inhibitor, orelabrutinib, attenuates DDX41 phosphorylation/activation and supports increased expression of viral proteins and virus replication. In sum, our work highlights the important role of BTK-DDX41-STING signaling in the innate immune response against CMV, which the virus subverts by attenuating its cytoplasmic activity, thereby diverting it from its typically protective function.ImportanceHuman cytomegalovirus (CMV) is a ubiquitous pathogen that poses a significant threat to immunocompromised individuals, highlighting the critical role of innate immunity in controlling this viral infection. Despite extensive research, the complex mechanisms underlying innate immunity against CMV and the virus’s strategies for evading immune detection remain only partially understood. This study identifies the activation of the cellular BTK-DDX41-STING innate signaling axis during lytic CMV infection, which ultimately results in protective interferon responses. Our findings show that CMV infection triggers the cytoplasmic redistribution of the cellular protein, DDX41, leading to reduced phosphorylation and activity, thereby undermining its protective function. Additionally, pharmacological inhibition of BTK enhances viral protein expression and replication, highlighting the importance of this pathway in immune defense. Our work identifies BTK- and DDX41-dependent STING signaling as important for innate immune responses against CMV and further advances our understanding of CMV’s manipulation of these responses.
Secreted spermidine synthase reveals a paracrine role for PGC1α-induced growth suppression in prostate cancer
Authors: Schaub-Clerigué Ariane , Hermanova Ivana , Pintor-Rial Ainara , Macchia Alice , Valcarcel-Jimenez Lorea , Lectez Benoit , Garcia-Longarte Saioa , Fagoaga-Eugui Maider , Zabala-Letona Amaia , Pujana-Vaquerizo Mikel , Royo Félix , Azkargorta Mikel , Berra Edurne , Sutherland James D. , Peinado Héctor , Falcón-Perez Juan Manuel , Elortza Félix , Carracedo Arkaitz , Torrano Verónica 
Published: October 2024

ABSTRACTProstate cancer is the fifth cause of death by cancer worldwide, second in incidence in the male population. The definition of the molecular basis of its development and the oncogenic signals driving lethality continue to be important objectives in prostate cancer research. Prior work from others and us has demonstrated that loss of PGC1α expression results in a metabolic, signaling and transcriptional reprogramming that supports the development of metastatic disease. However, we do not fully understand the spectrum of tumor suppressive effects regulated by this co-regulator. Here we show that PGC1α governs non-cell autonomous paracrine tumor suppression in prostate cancer. A systematic analysis of the transcriptional landscapes associated to PGC1α loss of expression revealed that PGC1α alters the expression of genes encoding for secreted proteins. Cell secretome studies corroborated that PGC1α-dependent ERRα regulation in prostate cancer cells suppresses the growth of tumor cells exposed to their conditioned media. The integration ofin vitroandin vivosecretomics data and genetic perturbation assays revealed spermidine synthase as a transcriptional target of PGC1α and mediator of a paracrine metabolic growth suppressive effect. Moreover, the activity of the regulatory axis PGC1α-ERRα-SRM was reflected in patients and had prognostic value. Altogether, this work provides unprecedented evidence of the non-cell autonomous tumor suppression role of PGC1α, which broadens the view of this co-regulator as a multifactorial tumor suppressor in prostate cancer.
Aphis craccivora (Hemiptera: Aphididae) synthesizes juvenile hormone III via a pathway involving epoxidation followed by esterification, potentially providing an epoxidation active site for the synthesis of juvenile hormone SB3
Authors: Li Haolin , Kong Xue , Fang Yan , Hou Jiangan , Zhang Wenjie , Zhang Yongheng , Wei Jiguang , Li Xuesheng 
Published: October 2024

AbstractJuvenile hormones (JHs) play a crucial role in regulating development and reproduction in insects. Most insects predominantly synthesize JH III, which typically involves esterification followed by epoxidation, lepidopteran insects use a pathway of epoxidation followed by esterification. Although hemipteran insects have JH III and JH skipped bisepoxide III (JH SB3), the synthesis pathway and key epoxidases remain unclear. This study was conducted on Aphis craccivora, and demonstrated that corpora allata, microsomes, Ac‐CYP15C1, and Ac‐JHAMT catalyze JH III production in vitro, establishing the pathway of epoxidation followed by esterification. These findings were further confirmed through RNA interference and molecular docking. The presence of JH III and JH SB3 in A. craccivora was identified, and their synthesis pathway was elucidated as follows: Ac‐CYP15C1 oxidizes farnesic acid to JH A, followed by methylation to JH III by Ac‐JHAMT, possibly providing an epoxidation site on the second carbon for JH SB3. This alteration may significantly contribute to the differentiation and functional diversification of JH types in insects.
Glucagon‐like peptide‐1 receptor agonists and kidney outcomes
Authors: MacIsaac Richard J. , Trevella Philippa , Ekinci Elif I. 
Published: October 2024

AbstractGlucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have gained increasing attention for their potential benefits in people with type 2 diabetes mellitus (T2DM) with chronic kidney disease (CKD). Most supportive evidence of a kidney‐protective effect of the GLP‐1RA class of medications has been derived from kidney‐related outcomes reported from cardiovascular outcome trials (CVOTs). GLP‐1RAs have been shown to reduce albuminuria, mitigate cardiovascular risk, and possibly attenuate estimated glomerular filtration rate (eGFR) decline. The kidney‐protective effects of GLP‐1RAs are thought to be attributed to their anti‐inflammatory, antioxidant, and vasodilatory properties. Despite these promising findings, the use of GLP‐RAs has yet to be definitively shown to slow progression to chronic kidney failure in people with T2DM. The Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW trial) is the first major trial assessing the potential of a GLP‐1RA to slow progression of kidney disease in people with established CKD to clinically important kidney end points. On March 5, 2024, the top line result from FLOW was announced with semaglutide 1.0 mg being reported to reduce the primary end point of the trial by a significant 24% compared with placebo. Here, we summarize the kidney outcomes reported from CVOTs for the GLP‐1RA class of medication and briefly describe kidney outcomes from other major GLP‐1RAs trials. We also discuss a potential role of the dual GLP‐1/glucose‐dependent insulinotropic polypeptide (GIP) receptor agonist, tirzepatide, as a kidney‐protective agent.image
Managing climate change impacts on crops: The influence of soil tillage on a triticale crop under water stress conditions
Authors: Madejón Paula , Fernández‐Boy Elena , Madejón Engracia , Morales‐Salmerón Laura , Domínguez María Teresa 
Published: October 2024

AbstractWater limitations for agriculture will likely become crucial in the next decades in some regions such as the Mediterranean basin with the current climate change projections. In this context, recent evidence suggests that the application of conservation agriculture, which reduces the frequency and intensity of soil tillage, could confer a higher stability of agricultural systems against climate variability. However, not many experiments have addressed the interaction between tillage type and the resistance to drought in rainfed crops. In this work, we evaluated the resistance to drought of triticale (Triticale hexaploide L.) crops managed with different tillage systems: traditional tillage (TT), reduced tillage (RT) and no tillage (NT). A rainfall exclusion experiment was carried out in a typical wheat/legume Mediterranean rotation in SW Spain, in a long‐term experiment established in 2008 comparing the three tillage systems. Grain yield and different variables related to plant ecophysiology, root development, biomass allocation and colonisation by arbuscular mycorrhizal fungi (AMF) were evaluated over one crop cycle. Tillage type had a significant influence on soil water storage (SWS), such that soils under NT had, on average, a 16% greater SWS than soils under RT or TT. Grain yield was significantly reduced by rainfall exclusion, in particular in the TT, where drought reduced grain yield by 31%. Gas exchange data also showed that plants in the TT system were more sensitive to drought, such that maximum photosynthesis rates were reduced by 25% because of rainfall exclusion in this tillage system. Drought had a negative impact on root biomass across the three tillage systems, especially in the RT, where a reduction in the root:shoot ratio was observed. The effect of tillage on mycorrhizal colonisation was more evident than the effect of drought; in general, conservation tillage systems (RT and NT) tended to have higher values for all AMF traits compared to the TT. In summary, the NT system tended to exhibit more favourable performance in terms of soil water retention, grain yield stability under drought conditions and mycorrhizal symbiosis, which suggests enhanced resource use efficiency in this system.
The current attitudes and practices of dentists in Australia towards composite repair: A cross‐sectional survey study
Authors: Khanna R , Han J , Liang E , Lee CY , Manakil J 
Published: October 2024

AbstractBackgroundWhether to replace or repair a composite restoration is controversial and varies among clinicians. This study was designed to collect information on the attitudes and practices of Australian dentists towards composite repair.MethodsAn electronic 16‐item questionnaire was distributed online on Australian clinicians’ dental forum with a URL address and instructions on completing the survey. The questionnaire remained accessible for 2 months. The data collected were analysed statistically using descriptive, average rank, Pearson chi‐square and Kruskal–Wallis tests at α = 0.05.ResultsRepair of composite restorations was a widely accepted treatment modality among surveyed dentists. Despite this, approximately half of clinicians reported the prognosis of repaired restorations to be worse when compared to replacement. The most cited indications for repair were partial loss or fracture of the restoration, while the most common reason for repair was because this treatment modality was more conservative in terms of tooth structure removal. Most important patient factor influencing decision to repair composite restoration was caries risk of the patient (n = 50). Most significant situational factor to consider in decision whether to repair was previous (failed) attempts to repair (n = 74). The most important tooth level factor was the proximity of restoration to pulp (mean statistic rank 2.22). The most common composite surface treatment employed by participants bonding to old composite was acid etching (n = 87), and the main reason participants employed their chosen surface treatment was based on personal experience (n = 72).ConclusionThe repair of composite restorations was a commonly performed procedure that is well accepted but may still be viewed as an inferior treatment to replacement by many Australian dentists. Most dentists agreed on indications for repair restorations and surface conditioning techniques, but there was wide variation in opinions overall. Due to the lack of high‐quality evidence regarding composite repair techniques, dentists tend to rely on personal experience to guide their clinical decisions.
hACE2 upregulation and participation of macrophages and clear cells in the immune response of epididymis to SARS‐CoV‐2 in K18‐hACE2 mice
Authors: da Silva André Acácio Souza , de Oliveira Salmo Azambuja , Battistone Maria Agustina , Hinton Barry Thomas , Cerri Paulo Sérgio , Sasso‐Cerri Estela 
Published: October 2024

AbstractBackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus caused the coronavirus disease 2019 pandemic, and the prevalence of deaths among men is higher than among women. The epididymis, divided into caput, corpus, and cauda, shows a region‐specific immunity. The K18‐hACE2 mouse expresses human angiotensin‐converting enzyme 2 (hACE2), the receptor that allows SARS‐CoV‐2 infection. However, studies using this transgenic mouse to evaluate the impact of this viral infection in epididymis have not yet been performed.ObjectivesWe evaluated the expression of hACE2 in the epididymis of SARS‐CoV‐2‐infected K18‐hACE2 mice, and assessed the epididymal immune response, focusing on F4/80+ mononuclear phagocytes and tumor necrosis factor‐alpha expression.Materials and methodsThe following analyses were performed in the epididymal sections of infected mice: epithelial height and duct diameter, birefringent collagen, Terminal deoxynucleotidyl Transferase‐mediated dUTP Nick End Labelling, immunoreactions for detection of hACE2, spike, FGF, V‐ATPase, F4/80, tumor necrosis factor‐alpha, and iNOS. Viral particles were identified under electron microscopy. hACE2, Rigi, Tgfb1 and Tnfa expression were also evaluated by real‐time quantitative polymerase chain reaction.ResultsAll epididymal regions expressed hACE2, which increased in all epididymal regions in the infected mice. However, the caput appeared to be the most infected region. Despite this, the caput region showed minimal changes while the cauda showed significant epithelial changes associated with increased iNOS immunoexpression. The F4/80+ mononuclear phagocyte area increased significantly in both stroma and epithelium. In addition to the epithelial and stromal mononuclear phagocytes, tumor necrosis factor‐alpha was also detected in clear cells, whose cytoplasm showed a significant increase of this cytokine in the infected animals.Discussion and conclusionThe K18‐hACE2 mouse is a useful model for evaluating the impact of SARS‐CoV‐2 infection in the epididymis. The infection induced hACE2 upregulation, favoring the virulence in the epididymis. The epididymal regions responded differentially to infection, and the activation of F4/80+ mononuclear phagocytes associated with the increased tumor necrosis factor‐alpha immunolabeling in clear cells indicates a role of clear cells/mononuclear phagocytes immunoregulatory mechanisms in the epididymal immune response to SARS‐CoV‐2 infection.
Reproductive outcomes after antenatal corticosteroids: Secondary analysis of 50‐year follow‐up of the Auckland steroid randomized trial
Authors: St Clair Sophie L. , Walters Anthony G. B. , Crowther Caroline A. , Dalziel Stuart R. , Eagleton Carl , Gamble Gregory D. , McKinlay Christopher J. D. , Milne Barry J. , Harding Jane E. ,   for the ANCHOR Study Group
Published: October 2024

AbstractIntroductionAntenatal corticosteroids are widely used to prevent morbidity and mortality after preterm birth, but there are ongoing concerns about the possible risk of long‐term adverse effects, including perturbation of endocrine systems, with potential implications for reproduction. A small number of animal studies have suggested possible adverse effects on reproduction after antenatal exposure to corticosteroids, but there is a paucity of human data.Material and MethodsThis is a secondary cohort analysis of the 50‐year follow‐up of the Auckland Steroid Trial (1969–1974) comparing antenatal exposure to corticosteroids or placebo. Participants whose mothers took part in the placebo‐controlled randomized trial of antenatal corticosteroids completed a questionnaire reporting reproductive outcomes at 50 years of age. The main outcome was at least one pregnancy ≥20 weeks or fathered at least one pregnancy ≥20 weeks. Additional outcomes included a number of pregnancies or fathered pregnancies ≥20 weeks, outcomes relating to female reproductive lifespan (including age at menarche and menopause), and outcomes relating to their offspring (including birthweight and gestation).ResultsOf 917 eligible participants, 415 (45% of eligible) completed the questionnaire at a mean (SD) age of 49.3 (1.0) years. The proportion of participants who had experienced at least one pregnancy ≥20 weeks or fathered at least one pregnancy ≥20 weeks was similar in betamethasone and placebo‐exposed groups (163/217 [75%] vs. 136/190 [72%]; RR 1.08, (95% CI 0.95 to 1.22); p = 0.23). Participants exposed to betamethasone had a slightly higher number of pregnancies or fathered pregnancies ≥20 weeks compared to those exposed to placebo (mean 1.89 vs. 1.60; marginal mean difference 0.20, (95% CI 0.03–0.37); p = 0.03). Other outcomes, including female reproductive lifespan and offspring‐related outcomes, were similar in both randomized groups. There were also no differences in any outcomes between those born preterm and those born at term.ConclusionsAntenatal exposure to corticosteroids appears to have no clinically important effect on reproductive outcomes to 50 years.
Metastasis‐free survival of uveal melanoma by tumour size category based on The Cancer Genome Atlas (TCGA) classification in 1001 cases
Authors: Bansal Rolika , Sener Hidayet , Ganguly Arupa , Shields Jerry A. , Shields Carol L. 
Published: October 2024

AbstractBackgroundUveal melanoma (UM) can be classified by tumour size category and by The Cancer Genome Atlas (TCGA) groups (cytogenetic‐based, 4‐category prognostic classification into Groups A‐D). This study was conducted to assess impact on metastasis‐free survival (MFS) in UM by tumour size category based on correlation with TCGA classification.MethodsRetrospective analysis of 1001 cases categorised as small (0.0–3.0 mm), medium (3.1–8.0 mm) and large (≥8.1 mm), grouped by TCGA classification.ResultsOf 1001 cases, TCGA Groups (A/B/C/D) included small (n = 270, 75%/11%/13%/1%), medium (n = 503, 46%/14%/27%/13%) and large (n = 228, 23%/19%/38%/20%) UM. The 5‐and 10‐year Kaplan–Meier MFS for small UM revealed Group A (98%, 98%), Group B (100%, 100%), Group C (86%, NA) and Group D (100%, NA). For medium UM, the values dropped with Group A (95%, 93%), Group B (90%, 90%), Group C (68%, 38%), and Group D (44%, NA). For large UM, the values dropped further with Group A (94%, 86%), Group B (85%, NA), Group C (40%, 28%), and Group D (23%, NA). Additionally, a comparison (small vs. medium vs. large tumour size category) revealed TCGA low‐risk grouping (Groups A or B) in 86% vs. 60% vs. 58% cases with UM.ConclusionBy tumour size category, favourable cytogenetics (Groups A or B) is found in 86% of small tumours, 60% of medium tumours, and 58% of large tumours. The MFS at 10 years for favourable cytogenetics was 98% for small tumours, 92% for medium tumours, and 54% for large tumours. Tumour size category can serve as a surrogate for TCGA.
The L‐type calcium channel CaV1.3: A potential target for cancer therapy
Authors: Liu Xuerun , Shen Boqiang , Zhou Jingyi , Hao Juan , Wang Jianliu 
Published: October 2024

AbstractCancer remains a prominent cause to life expectancy, and targeted cancer therapy stands as a pivotal approach in contemporary therapy. Calcium (Ca2+) signalling plays a multifaceted role in cancer progression, such as proliferation, invasion and distant metastasis. Otherwise, it also exerts an important influence on the efficacy of clinical treatment, including cancer therapy resistance. In this review we discuss the role of the L‐type calcium channel CaV1.3 (calcium voltage‐gated channel subunit alpha1 D) in different types of cancers, highlighting its potential as a therapeutic target for certain cancer types. The development of selective blockers of the CaV1.3 channel has been of great interest and is expected to be a new option for the treatment of cancers such as prostate cancer and endometrial cancer. We present the pharmacological properties of CaV1.3 and the current status of selective blocker development, and analyse the challenges and possible directions for breakthroughs in the development of tailored medicines.
KDELR2 is necessary for chronic obstructive pulmonary disease airway Mucin5AC hypersecretion via an IRE1α/XBP‐1s‐dependent mechanism
Authors: Wu Xiaojuan , Du Fawang , Zhang Aijie , Zhang Guoyue , Xu Rui , Du Xianzhi 
Published: October 2024

AbstractAirway mucus hypersecretion, a crucial pathological feature of chronic obstructive pulmonary disease (COPD), contributes to the initiation, progression, and exacerbation of this disease. As a macromolecular mucin, the secretory behaviour of Mucin5AC (MUC5AC) is highly dependent on a series of modifying and folding processes that occur in the endoplasmic reticulum (ER). In this study, we focused on the ER quality control protein KDEL receptor (KDELR) and demonstrated that KDELR2 and MUC5AC were colocalized in the airway epithelium of COPD patients and COPD model rats. In addition, knockdown of KDELR2 markedly reduced the expression of MUC5AC both in vivo and in vitro and knockdown of ATF6 further decreased the levels of KDELR2. Furthermore, pretreatment with 4μ8C, an IRE1α inhibitor, led to a partial reduction in the expression of KDELR2 and MUC5AC both in vivo and in vitro, which indicated the involvement of IRE1α/XBP‐1s in the upstream signalling cascade. Our study revealed that KDELR2 plays a crucial role in airway MUC5AC hypersecretion in COPD, which might be dependent on ATF6 and IRE1α/XBP‐1s upstream signalling.