bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of introducing somatic mitochondria into an early embryo on zygotic gene activation
Authors: Hayashi Yoshihiro , Bai Hanako , Takahashi Masashi , Mitani Tomohiro , Kawahara Manabu
Published: January 2025

Unlike differentiated somatic cells, which possess elongated mitochondria, undifferentiated cells, such as those of preimplantation embryos, possess round, immature mitochondria. Mitochondrial morphology changes dynamically during cell differentiation in a process called mitochondrial maturation. The significance of the alignment between cell differentiation and mitochondrial maturity in preimplantation development remains unclear. In this study, we analyzed mouse embryos into which liver-derived somatic mitochondria were introduced (SM-embryos). Most SM-embryos were arrested at the two-cell stage. Some of the introduced somatic mitochondria became round, while others remained elongated and large. RNA-sequencing revealed a disruption of both minor and major zygotic gene activation (ZGA) in SM-embryos. Minor ZGA did not terminate before major ZGA, and the onset of major ZGA was inhibited, as shown by histone modification analyses of histone H3 lysine 4 trimethylation and histone H3 lysine 27 acetylation. Further analysis of metabolites involved in histone modification regulation in SM-embryos showed a significantly lower NAD+/NADH ratio in SM-embryos than in control embryos. Additionally, the mitochondrial membrane potential, an indicator of mitochondrial function, was lower in SM-embryos than in control embryos. Our results demonstrated that introducing somatic mitochondria into an embryo induces mitochondrial dysfunction, thereby disrupting metabolite production, leading to a disruption in ZGA and inducing developmental arrest. Our findings reveal that the alignment between cell differentiation and mitochondrial maturity is essential for early embryonic development.
Intrinsic neuronal resilience as a tool for therapeutic discovery
Authors: Corti Stefania , Hedlund Eva
Published: January 2025

Corti and Hedlund argue that understanding the molecular underpinnings of neuronal resilience and vulnerability to neurodegenerative diseases such as ALS is key to identifying new therapeutic targets.
Improving UTI Diagnostics in Oncology: Reliability of Reflex Urine Culture in Immunosuppressed Neutropenic and Non-neutropenic Cancer Patients
Authors: Laracy Justin C , Chan June L , Kodama Rich , Yan Judy , Raible Kevin M , Sepkowitz Kent , McVoy Lauren , Babady N Esther , Kamboj Mini
Published: January 2025

Background

Urinary tract infections are prone to overdiagnosis, and reflex urine culture protocols offer a valuable opportunity for diagnostic stewardship in this arena. However, there is no recommended standard testing approach. Patients with cancer are often excluded from reflex urine culture protocols, especially if they are severely immunosuppressed or neutropenic. The aim of this study was to evaluate the performance characteristics of urine screening studies, including dipstick urinalysis for nitrite and leukocyte esterase and urine microscopy for white blood cell count, to detect significant pathogen growth.

Methods

A retrospective study of 58 098 urine cultures with a paired dipstick urinalysis with or without urine microscopy was performed at Memorial Sloan Kettering Cancer Center in New York City, evaluating data from 1 January 2018 to 31 December 2020. A dipstick urinalysis was considered negative only if leukocyte esterase and nitrite were undetected.

Results

A negative dipstick urinalysis had a negative predictive value of 98% for clinically significant bacteriuria in voided urine and 95% for catheterized urine. Notably, a negative urine dipstick test screen maintained a high negative predictive value among patients with neutropenia and in those with antibiotic exposure before testing. Finally, the presence of pyuria ≥10 white blood cells per high-power field on urine microscopy offered negligible incremental diagnostic benefit in samples with a negative dipstick urinalysis.

Conclusions

Reflex urine culture protocols contingent upon a screening dipstick urinalysis are a safe and effective platform for diagnostic stewardship in patients with cancer including those with neutropenia.
Left bundle branch area pacing in patients with transthyretin cardiac amyloidosis: a case series
Authors: Miyajima Keisuke , Kobayashi Wakaba , Hakamata Shogo , Takazawa Yasukazu , Kawaguchi Yoshitaka , Wakabayashi Yasushi , Maekawa Yuichiro
Published: January 2025

Background

Transthyretin cardiac amyloidosis is associated with various arrhythmias, including atrioventricular block. Despite this correlation, established treatments for transthyretin cardiac amyloidosis-associated arrhythmias are lacking. Left bundle branch area pacing is a promising physiological pacing technique.

Case summary

This case series describes three instances of successful left bundle branch area pacing in patients with transthyretin cardiac amyloidosis presenting with atrioventricular block. Despite significant ventricular septal hypertrophy across all cases, left bundle branch area pacing was implemented effectively without complications.

Discussion

Traditional pacing strategies in transthyretin cardiac amyloidosis, such as right ventricular pacing, have been associated with a reduced left ventricular ejection fraction and worsening heart failure. Although biventricular pacing has been explored, the supporting evidence remains limited and inconclusive. Recent studies have suggested that left bundle branch area pacing poses a lower risk of inducing heart failure than biventricular pacing. Our findings support the safety and efficacy of the left bundle branch area pacing in patients with transthyretin cardiac amyloidosis-related atrioventricular blocks and underscore its viability as a pacing strategy.
Echocardiography of the right heart in pulmonary arterial hypertension: insights from the ULTRA RIGHT VALUE study
Authors: Lo Giudice Francesco , Escribano-Subias Pilar , Tello Khodr , Kopec Grzegorz , Ghio Stefano , Giannakoulas George , D’Alto Michele , Filomena Domenico , Manzi Giovanna , Orlando Antonio , Greco Alessandra , Recchioni Tommaso , Yildiz Selin , López-Guarch Carmen Jiménez , Cruz-Utrilla Alejandro , Psochias Polykarpos , Patsiou Vasiliki , Stępniewski Jakub , Jonas Kamil , Scelsi Laura , Kremer Nils , Vergara Andrea , Vizza Carmine Dario , Naeije Robert , Badagliacca Roberto
Published: January 2025

Aims

Outcome in pulmonary arterial hypertension (PAH) is determined by right ventricular (RV) function adaptation to increased afterload. Echocardiography is easily available to assist bedside evaluation of the RV. However, no agreement exists about the feasibility and most relevant measurements. We therefore examined the feasibility, quality, and clinical correlations of standard echocardiographic variables in the evaluation of PAH.

Methods and results

The present multicentric study collected echocardiographic examinations with centralized reading in 401 patients with prevalent PAH. Clinical variables, as World Health Organization (WHO) functional class (FC), 6 min walk distance (6MWD), brain natriuretic peptide (BNP)/NT-proBNP, invasive haemodynamics, the European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines-derived four-strata score, and the United States Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) 2.0 score, were also collected. Echocardiographic measurements showed variable degrees of dilation of the right heart as assessed by right atrial and RV areas, altered indices of systolic function such as tricuspid annular plane systolic excursion (TAPSE), fractional area change, or 2D strain, and derived estimates of RV to pulmonary artery (PA) coupling by referring these measurements to systolic PA pressure (sPAP). All these measurements were feasible. All measurements of right heart dimensions and function, particularly TAPSE/sPAP, were correlated with WHO-FC, 6MWD, BNP/NT-proBNP, invasive haemodynamics, and ESC/ERS and REVEAL 2.0 scores.

Conclusion

The present quality-controlled data from a network of PAH referral centres offer the background needed for further evaluation of the added value of echocardiography to currently recommended risk assessments in PAH.
Cardiovascular diseases, prevention and management of complications in older adults and frail patients treated for elective or post-traumatic hip orthopaedic interventions
Authors: Guasti Luigina , Fumagalli Stefano , Afilalo Jonathan , Geisler Tobias , Abreu Ana , Ambrosetti Marco , Gevaert Sofie , Christodorescu Ruxandra , Richter Dimitri , Aboyans Victor , Chastaingt Lucie , Barisone Michela , Severgnini Paolo , Asteggiano Riccardo , Ferrini Marc
Published: January 2025

Due to the aging population, focusing on healthy aging has become a global priority.

Cardiovascular diseases (CVDs) and frailty, characterized by increased vulnerability to adverse stress and health events, interact synergistically in advanced age. In older adults, hip fractures are a frequent dramatic “life-transition” event. Conditions such as arrhythmias, orthostatic hypotension, heart failure, peripheral artery disease and adverse drug reactions may facilitate falls and thus bone fractures in older adults. Cardiovascular complications or the worsening of previous CVDs may increase the degree of frailty and disability following this surgery.

The close relationship between older age, CVDs, frailty and orthopaedic surgery leads to the need to focus on the various phases of interventions in a multidisciplinary approach.

This document aims to provide practical support to prevent cardiovascular complications in older and frail patients undergoing hip procedures by suggesting specific assessments and interventions.

In particular, in pre-operative care the focus should be on the assessment and management of concomitant CVD and frailty, while immediate peri- and post-operative care should highlight specific concerns for anesthesia, prevention and management of thrombotic complications, specific nursing needs, including the prevention of infections and delirium, and the establishment of an integrated rehabilitation program focusing on CVDs and the risk of new falls, with a positive role for care-givers.

Furthermore, by optimizing the “hip surgery pathway” the objective is to help avoid the deterioration of health and loss of independence that often result from this surgery through the correct management of cardiovascular patients in this peculiar context.
Air quality and the risk of acute atrial fibrillation (EP-PARTICLES study): a nationwide study in Poland
Authors: Kurasz Anna , Lip Gregory Y H , Święczkowski Michał , Tomaszuk-Kazberuk Anna , Dobrzycki Sławomir , Kuźma Łukasz
Published: January 2025

Aims

Air pollution remains the single largest environmental health risk factor, while atrial fibrillation (AF) is the most prevalent arrhythmia globally. The study aimed to investigate the relationship between short-term exposure to air pollution and acute AF admissions.

Methods and results

Individual data on AF hospitalization in the years 2011–20 were collected from the National Health Fund in Poland (ICD-10: I48.XX). To obtain high-resolution data on air pollution, we applied a modelling method using the GEM-AQ model. Associations between air pollution exposure and acute AF admissions were estimated using generalized additive models with Poisson regression. Over the analysed period, we recorded 252 566 acute admissions due to AF. Each 10 µg/m3 increment of particulate matter with diameters ≤2.5 (PM2.5) and nitrogen dioxide (NO2) concentration, 1 µg/m3 of sulfur dioxide and 10 ng/m3 of benzo(a)pyrene (BaP) concentration on the day of exposure resulted in 1.13% (0.70−1.55%), 1.65% (1.05−2.26%), 0.11% (0.01−0.21%), and 0.3% (0.04−0.55%) increases in acute AF admissions, respectively. The estimates are larger for women and older people. Stronger associations between PM2.5 and BaP concentrations and AF admissions in poorly urbanized areas were noted. Areas with high gross domestic product levels were more affected by the increase in NO2 concentrations, resulting in a 0.2% (1.001–1.003) increase in AF admissions. Exposure-response functions show steeper slopes of the pollutant-outcome associations in the lower ranges of exposures, far below World Health Organization (WHO) air quality guideline norms. For the zero-emission scenario, we estimate avoidable AF admissions—5873 for PM2.5 (95% confidence interval 3679 to 8047) and 3295 for NO2 (2108–4477).

Conclusion

Air pollution acts as a triggering factor and can be associated with acute AF hospitalizations. PM2.5 and NO2 have an impact on AF even at concentrations levels below WHO air quality guideline norms.
Paris in the Eyes of Argentine Women: Paula Wajsman’s Informe de París (1990) and María Moreno’s El Affair Skeffington (1992)
Authors: López Martínez Rodrigo
Published: January 2025

This article examines the fictional rendering of Paris in two Argentine novels published just two years apart but with strongly contrasting receptions: Paula Wajsman’s Informe de París (1990) and María Moreno’s El Affair Skeffington (1992). While Wajsman died in 1995, having published only one novel that went mostly unnoticed in literary and academic circles, Moreno has been a leading figure in the Argentine cultural scene for the past two decades. A comparative study of Wajsman and Moreno allows us to explore how they rewrote the paradigmatic significance of Paris for Argentine culture through a shared feminist lens. Ultimately, I argue that Informe de París and El Affair Skeffington situate their female characters in Paris as a means of turning the so-called ‘literary capital of Latin America’ into a ‘third space’ that enables renewed modes of literature and community beyond the limits of gender and the nation.
PhWRKY30 activates salicylic acid biosynthesis to positively regulate antiviral defense response in petunia
Authors: Wang Meiling , Yuan Yanping , Zhao Yike , Hu Zhuo , Zhang Shasha , Luo Jianrang , Jiang Cai-Zhong , Zhang Yanlong , Sun Daoyang
Published: January 2025

Petunia (Petunia hybrida) plants are highly threatened by a diversity of viruses, causing substantial damage to ornamental quality and seed yield. However, the regulatory mechanism of virus resistance in petunia is largely unknown. Here, we revealed that a member of petunia WRKY transcription factors, PhWRKY30, was dramatically up-regulated following Tobacco rattle virus (TRV) infection. Down-regulation of PhWRKY30 through TRV-based virus-induced gene silencing increased green fluorescent protein (GFP)-marked TRV RNA accumulation and exacerbated the symptomatic severity. In comparison to wild-type (WT) plants, PhWRKY30-RNAi transgenic petunia plants exhibited a compromised resistance to TRV infection, whereas an enhanced resistance was observed in PhWRKY30-overexpressing (OE) transgenic plants. PhWRKY30 affected salicylic acid (SA) production and expression of arogenate dehydratase 1 (PhADT1), phenylalanine ammonia-lyase 1 (PhPAL1), PhPAL2b, non-expressor of pathogenesis-related proteins 1 (PhNPR1), and PhPR1 in SA biosynthesis and signaling pathway. SA treatment restored the reduced TRV resistance to WT levels in PhWRKY30-RNAi plants, and application of SA biosynthesis inhibitor 2-aminoindan-2-phosphonic acid inhibited promoted resistance in PhWRKY30-OE plants. The protein-DNA binding assays showed that PhWRKY30 specifically bound to the promoter of PhPAL2b. RNAi silencing and overexpression of PhPAL2b led to decreased and increased TRV resistance, respectively. The transcription of a number of reactive oxygen species- and RNA silencing-associated genes was changed in PhWRKY30 and PhPAL2b transgenic lines. PhWRKY30 and PhPAL2b were further characterized to be involved in the resistance to Tobacco mosaic virus (TMV) invasion. Our findings demonstrate that PhWRKY30 positively regulates antiviral defense against TRV and TMV infections by modulating SA content.
PpERF17 alleviates peach fruit postharvest chilling injury under elevated CO2 by activating jasmonic acid and γ-aminobutyric acid biosynthesis
Authors: Ai Shaojie , Liang Ling , Liu Mengfei , Grierson Don , Chen Kunsong , Xu Changjie
Published: January 2025

Internal browning (IB) is a common chilling injury (CI) feature in peach fruit after prolonged cold storage. Our previous study demonstrated that low O2 and elevated CO2 (eCO2) condition of modified atmosphere (MA) storage alleviated CI by facilitating the accumulation of jasmonic acids (JAs) and γ-aminobutyric acid (GABA) in ‘Zhonghuashoutao’ (‘ZHST’) peach fruit. Here we show that 10 % CO2 alone can improve cold tolerance, with ethylene response factor 17 (PpERF17) identified as a pivotal transcription factor (TF) that promotes biosynthesis of JAs and GABA. Stable transformation of PpERF17 in tobacco resulted in reduced cold damage, attributed to decreased levels of hydrogen peroxide (H2O2) and malondialdehyde (MDA), as well as enhanced accumulation of JAs and GABA. Moreover, under eCO2, PpMYC2.1, the master regulator of JA signaling, was found to activate transcription of 13S-lipoxygenase (Pp13S-LOX), allene oxide synthase (PpAOS), 12-oxophytodienoate reductase 3 (PpOPR3) and glutamate decarboxylase (PpGAD), while also inducing the expression of the upstream TF PpERF17, thereby establishing positive feedback loops upregulating JA and GABA biosynthesis. Finally, application of methyl jasmonate (MeJA) to fruit before shelf transfer from cold storage alleviated chilling injury development, due to increased accumulation of JAs and GABA as a result of raised expression of related biosynthetic genes. Collectively, our results suggest that eCO2-induced PpERF17 enhances JAs and GABA accumulation while activating the JA signaling pathway. This contributes to a positive feedback loop mediated by PpMYC2.1, ultimately alleviating CI of peach fruit through the sustained accumulation of JAs and GABA.
Effectiveness and Safety of Adalimumab in Patients With Very Early-Onset Inflammatory Bowel Disease: A Retrospective Study on Behalf of the Porto Inflammatory Bowel Disease Working Group of European Society for Pediatric Gastroenterology Hepatology and Nutrition
Authors: Weintraub Yael , Collen Lauren V , Hussey Seamus , Mitrova Katarina , Machta Joseph S , Kang Ben , Granot Maya , D’Arcangelo Giulia , Spencer Elizabeth A , Kolho Kaija-Leena , Yeh Pai-Jui , Sladek Malgorzata , Scarallo Luca , Palomino Laura , Afzal Nadeem Ahmad , de Laffolie Jan , Miele Erasmo , Bramuzzo Matteo , Olén Ola , Russell Richard K , Rohani Pejman , Tzivinikos Christos , Urlep Darja , van Rheenen Patrick F , de Ridder Lissy , Yogev Dotan , Schneider Anna-Maria , Cohen Shlomi , Garcia-Romero Ruth , Dipasquale Valeria , Uhlig Holm H , Shouval Dror S
Published: January 2025

Background and aims

Patients with very early-onset inflammatory bowel disease (VEO-IBD), with an age of onset < 6 years, can present with severe manifestations and may require biologic therapy. Infliximab and adalimumab are approved for induction and maintenance in pediatric IBD patients but are licensed only above the age of 6 years. Effectiveness and safety data on adalimumab in this patient population are lacking. We assessed the therapeutic response to help close this gap.

Methods

This retrospective study involved 30 sites worldwide. Demographic, clinical, and laboratory data were collected from patients with VEO-IBD who commenced adalimumab therapy before the age of 6 years.

Results

Seventy-eight patients (37 Crohn’s disease, 26 ulcerative colitis, and 15 with IBD-unclassified) were included. Median age of IBD onset was 2.6 (1.3–4.1) years, with 30 (38.5%) patients diagnosed at age <2 years. Median age at adalimumab initiation was 4.2 (2.8-5.1) years. Adalimumab was used as second-line biologic therapy in 45 (57.7%) patients after infliximab. The median time to last follow-up was 63 (22-124) weeks. Significant improvement in clinical scores, CRP, fecal calprotectin, and weight Z-score were observed by Week 52. Adalimumab durability rates were 61.9%, 48.1%, and 35.6% after 1, 2, and 3 years, respectively. Drug discontinuation rates were not dependent on IBD type, age, prior anti-TNF exposure, or concomitant immunomodulatory treatment. Four (5.1%) patients developed serious infections, including 1 patient with TTC7A deficiency who died following adenovirus sepsis.

Conclusion

Adalimumab therapy is a viable therapeutic option in patients with VEO-IBD with an acceptable safety profile.
Reduction of Vancomycin-Associated Acute Kidney Injury With Montelukast
Authors: Teran Nicholas S , Hudson Cole S , Phe Kady , Wang Yunting , Zhang Yang , Chen Hua , Nigo Masayuki , Tam Vincent H
Published: January 2025

Background

Vancomycin ranks among the most utilized antimicrobial agents in the treatment of serious β-lactam–resistant gram-positive infections, but its use has been associated with nephrotoxicity. Reduction of acute kidney injury (AKI) has been reported in preclinical models with adjuvant montelukast. The purpose of the study was to ascertain if montelukast was associated with a reduction in the prevalence of vancomycin-associated AKI.

Methods

This retrospective cohort study examined adult patients who received intravenous vancomycin between January 2020 and January 2024. The RIFLE criteria (risk, injury, failure, loss, and end-stage kidney disease) were employed in identifying cases of AKI. Additionally, a preclinical vancomycin-associated nephrotoxicity model was established to provide insights into possible renal protective mechanisms.

Results

Patients receiving montelukast (n = 110) were compared with controls (n = 330), of which AKI was observed in 3 (2.7%) vs 35 (10.6%), respectively (P = .01). A multivariate logistic regression analysis revealed that weight (odds ratio [OR], 1.02; 95% CI, 1.006–1.03; P = .005) and intensive care unit admission (OR, 6.88; 95% CI, 2.96–18.8; P < .001) were independently associated with AKI, while montelukast (OR, 0.26; 95% CI, .06–.77; P = .03) and male gender were protective (OR, 0.41; 95% CI, .19–.85; P = .02). Our in vitro model also revealed that adjuvant montelukast can reduce injury to proximal tubule cells through activation of the p62/KEAP-1/HO-1 antioxidant pathway.

Conclusions

Our study suggests that montelukast during vancomycin therapy may be protective against AKI, which may reduce patient harm and hospitalization costs. Further studies are warranted to validate our findings prospectively.
Lack of Toll-Like Receptor 9 Exacerbates Ocular Impairment and Visual Loss During Systemic Cryptococcus gattii Infection
Authors: da Silva-Junior Elias Barbosa , Araújo Victor Guedes , Araujo-Silva Carlla Assis , Covre Luciana Polaco , Guimarães-de-Oliveira Joyce Cristina , Diniz-Lima Israel , Freire-de-Lima Leonardo , Morrot Alexandre , de Brito-Gitirana Lycia , Previato Jose Osvaldo , Mendonça-Previato Lucia , Vommaro Rossiane Claudia , Petrs-Silva Hilda , Decote-Ricardo Debora , de Matos Guedes Herbert Leonel , Freire-de-Lima Celio Geraldo
Published: January 2025

Cryptococcus gattii is a saprophytic basidiomycete that grows in the environment and can cause systemic cryptococcosis. Ocular cryptococcosis causes blindness and is commonly associated with central nervous system infection. Toll-like receptor 9 (TLR9) can control cryptococcosis and other mycoses. Here, using C57BL/6 TLR9 knockout mice (TLR9−/−), we evaluated the role of TLR9 signaling in ocular involvement during systemic C. gattii infection. We observed ocular impairment and found a high fungal burden in the retina, vitreous humor, and optic nerve of TLR9−/− mice 3 weeks after infection. Capsular polysaccharide glucuronoxylomannan deposition, astrogliosis, and morphological alterations in retina led to progressive blindness of TLR9−/− mice. The phenomenon observed in our work had not been explored previously in a murine model. These results contribute to the understanding of the role of TLR9 during ocular cryptococcosis. Therapies using TLR9 agonists may be important for the treatment of ocular cryptococcosis.
How not to defend aesthetic autonomism
Authors: Eker Bahadir
Published: January 2025

Aesthetic autonomism is standardly defined as the view that the aesthetic value of an artwork in no way depends on its moral value, and hence that considerations about the latter are irrelevant to aesthetic evaluation. However, it has recently been argued that definitions along these lines involve certain flaws and that autonomism should be characterized instead as the view that it is rationally permissible not to adjust one’s initial aesthetic judgment about a work in light of how one evaluates it morally. This paper argues that this proposal is seriously misguided in three central respects: its focus on evaluative adjustments is objectionably narrow and ignores other forms of evaluative conduct; its appeal to rationality misconstrues the core commitments of non-autonomists; and its permissivist character results in a distortion of what is at stake in the debate about the autonomy of the aesthetic.
High GRWD1 expression may predict clinically aggressive lower grade glioma, skin cutaneous melanoma, and kidney renal clear cell carcinoma carrying wild-type p53: a systematic study based on TCGA data analysis
Authors: Kayama Kota , Ooga Akihiro , Hasetsu Kouji , Kokubo Ryoma , Sugimoto Nozomi , Fujita Masatoshi
Published: January 2025

Glutamate-rich WD40 repeat-containing 1 (GRWD1) is a novel oncogene/oncoprotein that downregulates the p53 tumour suppressor protein through several mechanisms. One important mechanism involves binding of GRWD1 to RPL11, which competitively inhibits the RPL11–MDM2 interaction and releases RPL11-mediated suppression of MDM2 ubiquitin ligase activity towards p53. Here, we mined the TCGA (The Cancer Genome Atlas) database to gain in-depth insight into the clinical relevance of GRWD1. We found that high expression of GRWD1 is associated with a poor prognosis for lower grade glioma (LGG) of the brain, skin cutaneous melanoma (SKCM), and kidney renal clear cell carcinoma (KIRC) carrying wild-type p53. Further investigations revealed that copy number alterations in the GRWD1 gene are one determinant of GRWD1 expression level. By contrast, even in patients with a diploid GRWD1 gene, high GRWD1 expression was associated with a poor prognosis for LGG, SKCM, and KIRC carrying wild-type p53. Additional studies suggest that some transcriptional factors may be involved in regulation of GRWD1 in cancers with a diploid GRWD1 gene. Taken together, the data presented herein suggest that high expression of GRWD1 may contribute to malignant behaviour, and predict a clinically unfavourable prognosis for LGG, SKCM, and KIRC carrying wild-type p53.
Parathyroid hormone-related protein levels and treatment outcomes in hypercalcemia of malignancy: a retrospective cohort study
Authors: Kato Kazuhiko , Nakashima Akio , Kimura Ai , Maruyama Yukio , Ohkido Ichiro , Miyazaki Yoichi , Yokoo Takashi
Published: January 2025

The challenge of managing acute hypercalcemia in patients diagnosed with hypercalcemia of malignancy (HCM) merits further attention. Elevated levels of PTHrP may be a risk factor for treatment resistance in acute hypercalcemia; however, few studies have tested this hypothesis. This study aimed to investigate whether high PTHrP levels represent an independent risk factor that impedes the treatment of acute hypercalcemia. This retrospective cohort study recruited 159 patients aged 20-80 years with diagnosed malignancies who had been hospitalized for hypercalcemia with PTHrP levels above the reference value (1.1 pmol/L). The median (25%-75%) patient age was 69 (61-76) years, and the median PTHrP level was 6.3 (3.3-11.1) pmol/L. The corrected calcium levels decreased from 12.8 mg/dL (11.9-14.1 mg/dL) to 10.6 mg/dL (9.8-11.7 mg/dL) following treatments, such as bisphosphonates and saline solution. Multivariate linear regression analysis showed less significant decreases in the corrected calcium levels as natural logarithm-transformed PTHrP levels increased (β coefficient [95% CI]: 0.569 [0.225-0.914]; p = .001 for Model 3). Multivariate logistic regression analysis showed an association between high natural logarithm-transformed PTHrP levels and lack of treatment response, defined as a corrected calcium level of ≤10.4 mg/dL in the last blood test conducted within 2 wk of treatment initiation (odds ratio [95% CI]: 0.504 [0.312-0.814]; p = .005). Therefore, elevated PTHrP levels are a potential risk factor for treatment resistance in hypercalcemia in HCM patients, complicating management regardless of calcium levels.
Detection of new gamma-ray AGN candidates using SIMEFIC III and DBSCAN in Fermi-LAT data
Authors: Soor M , Akhondi F , Hedayati Kh H
Published: January 2025

We present the detection of new high-energy gamma-ray active galactic nucleus candidates using the Density-Based Spatial Clustering of Applications with Noise (DBSCAN) clustering algorithm on two-dimensional gamma-ray data from Fermi Large Area Telescope. Our approach involves iterative applications of the SIeving MEthod for FInding Core (SIMEFIC III) algorithm, designed to enhance point source detection. By integrating DBSCAN at each denoising step, we track and evaluate the significance of potential sources across iterations. Our findings indicate that source significance increases to a specific threshold, beyond which further denoising may remove genuine sources. At the optimal denoising stage, we identified 18 sources not listed in the Fermi catalogue, with several of these sources potentially matching entries in the the Candidate Gamma-Ray Blazar Survey (CRATES) and Roma-BZCAT (Roma-BZCAT Multi-Frequency Catalog of Blazars) catalogues.
Galaxy evolution in the Post-Merger Regime – I. Most merger-induced in situ stellar mass growth happens post-coalescence
Authors: Ferreira Leonardo , Ellison Sara L , Patton David R , Byrne-Mamahit Shoshannah , Wilkinson Scott , Bickley Robert , Conselice Christopher J , Bottrell Connor
Published: January 2025

Galaxy mergers can enhance star formation rates throughout the merger sequence, with this effect peaking around the time of coalescence. However, owing to a lack of information about their time of coalescence, post-mergers could only previously be studied as a single, time-averaged population. We use time-scale predictions of post-coalescence galaxies in the UNIONS survey, based on the Multi Model Merger Identifier deep learning framework (mummi) that predicts the time elapsed since the last merging event. For the first time, we capture a complete timeline of star formation enhancements due to galaxy mergers by combining these post-merger predictions with data from pre-coalescence galaxy pairs in SDSS. Using a sample of 564 galaxies with $M_* \ge 10^{10}\mathrm{ M}_\odot$ at $0.005 \lt z \lt 0.3$ we demonstrate that: (1) galaxy mergers enhance star formation by, on average, up to a factor of two; (2) this enhancement peaks within 500 Myr of coalescence; (3) enhancements continue for up to 1 Gyr after coalescence; and (4) merger-induced star formation significantly contributes to galaxy mass assembly, with galaxies increasing their final stellar masses by, 10 per cent to 20 per cent per merging event, producing on average $\log (M_*/\mathrm{ M}_\odot) = {9.56_{-0.19}^{+0.13}}$ more mass than non-interacting star-forming galaxies solely due to the excess star formation.
Persistent, Private, and Mobile Genes: A Model for Gene Dynamics in Evolving Pangenomes
Authors: Gamblin Jasmine , Lambert Amaury , Blanquart François
Published: January 2025

The pangenome of a species is the set of all genes carried by at least one member of the species. In bacteria, pangenomes can be much larger than the set of genes carried by a single organism. Many questions remain unanswered regarding the evolutionary forces shaping the patterns of the presence/absence of genes in pangenomes of a given species. We introduce a new model for bacterial pangenome evolution along a species phylogeny that explicitly describes the timing of appearance of each gene in the species and accounts for three generic types of gene evolutionary dynamics: persistent genes that are present in the ancestral genome, private genes that are specific to a given clade, and mobile genes that are imported once into the gene pool and then undergo frequent horizontal gene transfers. We call this model the Persistent-Private-Mobile (PPM) model. We develop an algorithm fitting the PPM model and apply it to a dataset of 902 Salmonella enterica genomes. We show that the best fitting model is able to reproduce the global pattern of some multivariate statistics like the gene frequency spectrum and the parsimony vs. frequency plot. Moreover, the gene classification induced by the PPM model allows us to study the position of accessory genes on the chromosome depending on their category, as well as the gene functions that are most present in each category. This work paves the way for a mechanistic understanding of pangenome evolution, and the PPM model developed here could be used for dynamics-aware gene classification.
Transcription factors induce differential splicing of duplicated ribosomal protein genes during meiosis
Authors: Petibon Cyrielle , Catala Mathieu , Morales Danna , Panchapakesan Shanker Shyam , Unrau Peter J , Abou Elela Sherif
Published: January 2025

In baker’s yeast, genes encoding ribosomal proteins often exist as duplicate pairs, typically with one ‘major’ paralog highly expressed and a ‘minor’ less expressed paralog that undergoes controlled expression through reduced splicing efficiency. In this study, we investigate the regulatory mechanisms controlling splicing of the minor paralog of the uS4 protein gene (RPS9A), demonstrating that its splicing is repressed during vegetative growth but upregulated during meiosis. This differential splicing of RPS9A is mediated by two transcription factors, Rim101 and Taf14. Deletion of either RIM101 or TAF14 not only induces the splicing and expression of RPS9A with little effect on the major paralog RPS9B, but also differentially alters the splicing of reporter constructs containing only the RPS9 introns. Both Rim101 and Taf14 co-immunoprecipitate with the chromatin and RNA of the RPS9 genes, indicating that these transcription factors may affect splicing co-transcriptionally. Deletion of the RPS9A intron, RIM101 or TAF14 dysregulates RPS9A expression, impairing the timely expression of RPS9 during meiosis. Complete deletion of RPS9A impairs the expression pattern of meiotic genes and inhibits sporulation in yeast. These findings suggest a regulatory strategy whereby transcription factors modulate the splicing of duplicated ribosomal protein genes to fine-tune their expression in different cellular states.
Control of cortical slow oscillations and epileptiform discharges with photoswitchable type 1 muscarinic ligands
Authors: Sanchez-Sanchez Jose M , Riefolo Fabio , Barbero-Castillo Almudena , Sortino Rosalba , Agnetta Luca , Manasanch Arnau , Matera Carlo , Bosch Miquel , Forcella Marta , Decker Michael , Gorostiza Pau , Sanchez-Vives Maria V
Published: January 2025

Acetylcholine and the cholinergic system are crucial to brain function, including functions such as consciousness and cognition. Dysregulation of this system is implicated in the pathophysiology of neurological conditions such as Alzheimer's disease. For this reason, cholinergic neuromodulation is relevant in both basic neuroscience and clinical neurology. In this study, we used photopharmacology to modulate neuronal activity using the novel selective type-1 muscarinic (M1) photoswitchable drugs: the agonist benzyl quinolone carboxylic acid-azo-iperoxo (BAI) and the antagonist cryptozepine-2. Our aim was to investigate the control over these cholinergic receptors using light and to investigate the effects of these drugs on physiological spontaneous slow waves and on epileptic activity in the cerebral cortex. First, we used transfected HEK cell cultures and demonstrated BAI’s preferential activation of M1 muscarinic acetylcholine receptors (mAChRs) compared with M2 mAChRs. Next, we found that white-light illumination of BAI increased the frequency of spontaneous slow-wave activity in brain cortical networks of both active slices and anesthetized mice, through M1-mAChRs activation. Illumination of cryptozepine-2 with UV light effectively suppressed not only the muscarinic-induced increase in slow-wave frequency, but also muscarinic-induced epileptiform discharges. These findings not only shed light on the role of M1 acetylcholine receptors in the cortical network dynamics but also lay the groundwork for developing advanced light-based pharmacological therapies. Photopharmacology offers the potential for high-precision spatiotemporal control of brain networks with high pharmacological specificity in both healthy and pathological conditions.
Senescence accelerated mouse-prone 8: a model of neuroinflammation and aging with features of sporadic Alzheimer’s disease
Authors: Ong Jun , Sasaki Kazunori , Ferdousi Farhana , Suresh Megalakshmi , Isoda Hiroko , Szele Francis G
Published: January 2025

The large majority of Alzheimer’s disease (AD) cases are sporadic with unknown genetic causes. In contrast, only a small percentage of AD cases are familial, with known genetic causes. Paradoxically, there are only few validated mouse models of sporadic AD but many of familial AD. Senescence accelerated mouse-prone 8 (SAMP8) mice are a model of accelerated aging with features of sporadic AD. They exhibit a more complete suite of human AD-relevant pathologies than most familial models. SAMP8 brains are characterized by inflammation, glial activation, b-amyloid deposits, and hyperphosphorylated Tau. The excess amyloid deposits congregate around blood vessels leading to vascular impairment and leaky BBBs in these mice. SAMP8 mice also exhibit neuronal cell death, a feature not typically seen in models of familial AD. Additionally, adult hippocampal neurogenesis is decreased in SAMP8 mice and correspondingly, they have reduced cognitive ability. In line with this, hippocampal LTP is significantly compromised in SAMP8 mice. No model is perfect and SAMP8 mice are limited by the lack of clarity about their genomic differences from control Senescence Accelerated Mouse-Resistant 1 (SAMR1) mice although their transcriptomics changes are being revealed. To further complicate matters, multiple substrains of SAMP8 mice have emerged over the years, sometimes making comparisons of studies difficult. Despite these challenges, we argue that SAMP8 mice can be useful for studying AD-relevant symptoms and propose important experiments to strengthen this already useful model.
Inhibitory and Curative Effects and Mode of Action of Hydroxychloroquine on Botrytis cinerea of Tomato
Authors: Xia Chengyan , Wang Xiansu , Qi Zeqi , Liu Fenghua , Li Dongxue , Zhang Xiaolin , Zhang Libo , Wang Delu , Chen Zhuo
Published: January 2025

Gray mold is an important disease of crops and is widespread, harmful, difficult to control, and prone to developing fungicide resistance. Screening new fungicides is an important step in controlling this disease. Hydroxychloroquine is an anti-inflammatory and anti-malarial agent, which has shown marked inhibitory activity against many fungi in medicine. This study evaluated the inhibitory activity of hydroxychloroquine against several phytopathogenic fungi, finding a half-maximal effective concentration of 113.82 μg/ml against the hyphal growth of Botrytis cinerea, with significant in-vivo curative effects of 92.37% or 78.37% for gray mold on detached tomato leaves or fruits at 10.0 or 200.0 mg/ml, respectively. Ultrastructural studies indicated that hydroxychloroquine induced collapse of hyphae, with a wrinkled surface, unclear organelle boundaries, and organelle disintegration. Transcriptomic assays revealed that hydroxychloroquine could affect the expression of metabolism-related genes. Molecular docking and molecular dynamics analyses indicated that hydroxychloroquine bound to glucose-methanol-choline oxidoreductase, with low free energy value of −11.4 kcal/mol. Cell membrane permeability assays and hyphal staining confirmed that hydroxychloroquine damaged the cell membrane, causing leakage of hyphal contents and disturbing cell function. Biochemical assays indicated that hydroxychloroquine reduced the concentration of soluble proteins and reducing sugars in the hyphae. In total, hydroxychloroquine disturbed amino acid metabolism, therefore inhibiting the production of biomacromolecules, damaging the cell membrane, and restraining the growth of hyphae, and hence inhibiting gray mold on tomato. This study will explore the use of medicine in the development of agricultural fungicides and their application in managing crop diseases, providing valuable background information.
A noncanonical‐GPRC5A signaling regulates keratinocyte adhesion and migration by nuclear translocation
Authors: Chanteloube Sarah , Ya Choua , Le Provost Gabrielle , Berthier Aurore , Dieryckx Cindy , Vadon‐Le Goff Sandrine , Nadal Florence , Fromy Bérengère , Debret Romain
Published: January 2025

G‐Protein Coupled Receptor, Class C, Group 5, Member A (GPRC5A) has been extensively studied in lung and various epithelial cancers. Nevertheless, its role in the skin remains to be elucidated. In this study, we sought to investigate the function of this receptor in skin biology. Our research demonstrated that its expression responds to mechanical substrate changes in human primary keratinocytes. Furthermore, we observed the reinduction of GPRC5A during wound healing at the leading edges in an ex vivo burn model, coinciding with the translocation of its C‐terminal region into the nucleus. We identified the cleavage site of GPRC5A by N‐TAILS analysis, and cathepsin G was characterized as the protease responsible for proteolysis in cultured cells. In order to gain a deeper understanding of the role of GPRC5A in keratinocytes, we performed a GPRC5A knockdown in N/TERT‐1 cells using short‐hairpin RNA. Our findings indicate a strong association between GPRC5A and adhesion regulation pathways. Additionally, our results demonstrate that GPRC5AKD enhances cell adhesion while reducing cell migration and differentiation. It is noteworthy that these effects were reversed by the addition of a recombinant polypeptide that mimics the C‐terminal region of GPRC5A. In conclusion, our study reveals that GPRC5A plays an unexpected role in regulating keratinocyte behavior, with implications for its C‐terminal region translocation into the nucleus. These results offer promising avenues for future research in the field of wound healing.
Bacterial components‐driven intrahepatic CXCR5hi B cells are important population for MASH progression through inducing inflammation
Authors: Kim Nam‐Hee , Kim Mi‐Yeon , Yang Yoon Mee , Jeong Won‐Il , Lee Hye Won , Kim Wooseob , Kang Seung Goo , Han Yong‐Hyun
Published: January 2025

Metabolic dysfunction‐associated steatohepatitis (MASH) is characterized by severe liver inflammation and fibrosis due to an imbalanced immune response caused by enhanced bacterial components. The progression of MASH is closely linked to increased permeability of intestinal mucosal barrier facilitating enter of bacterial components into hepatic portal venous system. B cells are important immune cells for adaptive responses and enhance hepatic inflammation through cytokine production and T cell activation. B cells are influenced by gut microbiota, but the specific B cell populations in MASH and their pathologic mechanism remain obscure. Here, we found that the numbers of B cells highly expressing CXCR5, the receptor of CXCL13 chemokine, were increased in the livers of MASH. CXCR5 high B cells are non‐proliferating naive B cells with inflammatory features mainly residing in hepatic parenchyma to affect liver pathology. Importantly, we revealed that CXCR5 high B cells were induced by bacterial components stimulating TLRs. These bacterial stimulator‐induced CXCR5hi B cells highly express TNFα, CD80, and MHC class II, leading to T cell activation. Consistently, we confirmed that intravenous injection of CXCR5 high B cells enhanced hepatic inflammation in MASH model. Ultimately, this study elucidates the role and mechanisms of CXCR5 high B cells in advancing MASH progression.
A Modified Procedure to Improve Pancreatic Drainage in Chronic Pancreatitis with Pancreatic Head Dominant Disease
Authors: Shaaban Mohamed A. , Beilman Greg J.
Published: January 2025

Objectives:

Chronic pancreatitis is a debilitating and progressive inflammatory disease with an altered quality of life due to severe abdominal pain. Pancreaticoduodenectomy is a surgical option for patients with bulky disease involving the head of the pancreas, especially when this disease has progressed to stricture of the bile duct, duodenum, or both. A long term issue associated with this procedure is stricture of the pancreatic anastomosis. Re-operative and endoscopic interventions are difficult related to difficulty in reaching the anastomosis endoscopically. We describe a variation of this procedure with potential to lead to longer term improvement in drainage of the residual pancreas.

Methods:

We reviewed electronic medical records of patients undergoing pancreaticoduodenectomy for chronic pancreatitis performed by one surgeon at the University of Minnesota Medical Center, Minneapolis, MN, between 2014 and 2023. Information gathered from the patients’ records included preoperative demographics, perioperative outcomes, and postoperative follow up information.

Results:

The described procedure was performed in eight patients between 2014 and 2023. Three patients have died since surgery at 1.5, 5.5, and 8 years postop, with no deaths related to pancreatitis or surgical complications. Of the remaining five patients, median time from surgery is 7.5 years.

Conclusions:

We describe a surgical technique which may reduce the risk of pancreaticojejunal stricture in patients undergoing pancreaticoduodenectomy for chronic pancreatitis. In a small series of patients, this procedure can be performed safely with acceptable results.
Factors associated with failure of humerus nonunion surgery in patients with initial nonoperative management
Authors: Hysong Alexander , Harrison Noah , Posey Samuel , Yu Ziqing , Chen Andrew T. , Pallitto Patrick , Hsu Joseph R. , Obremskey William ,   Evidence-Based Musculoskeletal Injury and Trauma Collaborative (EMIT)
Published: January 2025

Objectives:

To describe operative results after humerus nonunion surgery in patients whose initial humerus shaft fracture (OTA/AO code 12) was treated nonoperatively and to identify risk factors of nonunion surgery failure in the same population.

Design:

Case series.

Setting:

Nine academic level 1 trauma centers.

Patients/Participants:

One hundred twenty patients with humerus nonunion whose initial fracture was treated nonoperatively.

Intervention:

Operative treatment of humerus nonunions.

Main Outcome Measurements:

Rate of recalcitrant nonunion after humerus nonunion surgery.

Results:

Of 108 humerus nonunions, 26 (24.07%) failed to unite after nonunion surgery. Moreover, 34 patients (31.48%) experienced 1 or more postoperative complications. Multivariate analysis found that the use of bone graft or bone graft substitute was not associated with successful nonunion surgery (95% odds ratio confidence interval [CI] [0.67–5.3], P = 0.23). Tobacco use was associated with an increased risk of persistent nonunion (P = 0.0041). Postoperative complications (P = 0.0001) were also associated with an increased risk of persistent nonunion. Diabetes and open fracture were not associated with differences in the nonunion repair success rate.

Conclusions:

As the largest and most generalizable to date, this multicenter study found that nearly 1 in 4 patients with a humeral nonunion after initial nonoperative management failed their nonunion surgical treatment. While postoperative complications were associated with recalcitrant nonunion, surgical adjuncts such as bone grafting and type did not seem to influence the success rate of nonunion surgery. Smoking is a modifiable risk factor suggesting that smoking cessation should be part of the intervention. These findings can be used to give patients and surgeons a realistic expectation of results and complications after humerus nonunion surgery.

Level of Evidence:

Therapeutic level III.