bluuebunny/crossref_metadata_2025 huggingface dataset:
Elastic-plastic behavior of nickel-based single crystal superalloys with γ-γ′ phases based on molecular dynamics simulations
Authors: Cao Jing-Zhao , Zhang Yun-Guang , Zhang Zhong-Kui , Fan Jiang-Peng , Dong Qi , Fang Ying-Ying
Published: February 2025

In this paper, the effects of temperature and Re content on the mechanical properties, dislocation morphology, and deformation mechanism of γ-γ′ phases nickel-based single crystal superalloys are investigated by using the molecular dynamics method through the model of γ-γ′ phases containing hole defect. The addition of Re makes the dislocation distribution tend towards the γ phase. The higher the Re content, the earlier the γ phase yields, while the γ' phase yields later. Dislocation bends under the combined action of the applied force and the resistance of the Re atoms to form a bend point. The Re atoms are located at the bend points and strengthen the alloy by fixing the dislocation and preventing it from cutting the γ′ phase. Dislocations nucleate first in the γ phase, causing the γ phase to deform plastically before the γ′ phase. As the strain increases, the dislocation length first remains unchanged, then increases rapidly, and finally fluctuates and changes. The dislocation lengths in the γ phase are larger than those in the γ′ phase at different temperatures. The dislocation length shows a decreasing tendency with the increase of the temperature. Temperature can affect movement of the dislocation, and superalloys have different plastic deformation mechanisms at low, medium and high temperatures.
ViTax: adaptive hierarchical viral taxonomy classification with a taxonomy belief tree on a foundation model
Authors: He YuShuang , Zhou Feng , Bai JiaXing , Gao YiChun , Huang Xiaobing , Wang Ying
Published: February 2025

Viruses exert a profound influence on both human health and the global ecosystem, yet they remain largely unexplored. Precise taxonomic classification of viral sequences is essential for discovering novel viruses, elucidating their functions, and assessing their implications for public health and environmental monitoring. Traditional taxonomy methods based on genome references are limited by the vast number of unexplored viruses, rapid mutation rates, and high genetic diversity. Additionally, highly imbalanced species distribution and significant variances in inter-species genomic distances across taxonomic units pose challenges to classifier training. Conceptualizing genomic sequences as sentences in a natural language, large language models provide novel approaches for extracting intrinsic viral genome characteristics. In this study, we introduce ViTax, a virus taxonomy classification tool powered by HyenaDNA, a large language foundation model for long-range genomic sequences at single nucleotide resolution. ViTax integrates supervised prototypical contrastive learning to address the highly imbalanced distributions across various taxonomic clades and demonstrates superior performance to current leading methods in virus taxonomy, particularly significant for long sequences. Moreover, ViTax designs a belief mapping tree using the Lowest Common Ancestor algorithm to adaptively assign a sequence to the lowest taxonomy clade with confidence. For the open-set problem, where sequences belong to novel and unexplored genera, ViTax can adaptively assign them to a higher level of known taxonomy with outstanding performance. These capabilities make ViTax a robust tool for advancing the accuracy and reliability of viral taxonomy classification. The code is available at https://github.com/Ying-Lab/ViTax.
APNet, an explainable sparse deep learning model to discover differentially active drivers of severe COVID-19
Authors: Gavriilidis George I , Vasileiou Vasileios , Dimitsaki Stella , Karakatsoulis Georgios , Giannakakis Antonis , Pavlopoulos Georgios A , Psomopoulos Fotis
Published: February 2025

Motivation

Computational analyses of bulk and single-cell omics provide translational insights into complex diseases, such as COVID-19, by revealing molecules, cellular phenotypes, and signalling patterns that contribute to unfavourable clinical outcomes. Current in silico approaches dovetail differential abundance, biostatistics, and machine learning, but often overlook non-linear proteomic dynamics, like post-translational modifications, and provide limited biological interpretability beyond feature ranking.

Results

We introduce APNet, a novel computational pipeline that combines differential activity analysis based on SJARACNe co-expression networks with PASNet, a biologically-informed sparse deep learning model, to perform explainable predictions for COVID-19 severity. The APNet driver-pathway network ingests SJARACNe co-regulation and classification weights to aid result interpretation and hypothesis generation. APNet outperforms alternative models in patient classification across three COVID-19 proteomic datasets, identifying predictive drivers and pathways, including some confirmed in single-cell omics and highlighting under-explored biomarker circuitries in COVID-19.

Availability and Implementation

APNet’s R, Python scripts and Cytoscape methodologies are available at https://github.com/BiodataAnalysisGroup/APNet.

Supplementary Information

Supplementary information can be accessed in Zenodo (10.5281/zenodo.14680520).
Pulsed Dye Laser-Activated Photodynamic Therapy for Extramammary Paget Disease: A Case Report
Authors: Stretch Sophie , Hitchens Emma , Alexander Ruth , Keith Daniel , Carson Naomi
Published: February 2025

Extramammary Paget’s Disease of the Skin (EMPD) is a rare malignant dermatological condition with metastatic potential, characteristically affecting the axillae, genitalia or perineum. Standard treatment is staged surgical excision, however this can prove challenging - particularly in cases of extensive disease - and recurrence rates are high. Patient factors may also mean that a case is not suitable for surgery. We describe the first reported case of successful PDL-activated PDT for EMPD. Whilst further study is essential, we present this case report as a contribution to the body of evidence of treatments which may be effective in managing this condition.
T1 mapping magnetic resonance imaging predicts decline of kidney function
Authors: Huber Aurélie , Aslam Ibtisam , Crowe Lindsey , Pruijm Menno , de Perrot Thomas , de Seigneux Sophie , Vallée Jean-Paul , Berchtold Lena
Published: February 2025

Background

Renal cortical interstitial fibrosis, typically assessed by biopsy, is crucial for kidney function prognosis. MRI is a promising method to assess fibrosis non-invasively. Diffusion-Weighted (DW) MRI correlates with renal fibrosis and predicts kidney function decline in chronic kidney disease (CKD) and kidney allograft patients. This study evaluates whether T1 and T2 mapping predict kidney function decline and if their simultaneous use enhances the predictive power of a DW-MRI-based model.

Methods

We prospectively included 197 patients (42 CKD, 155 allograft kidneys). Each underwent a biopsy followed by multiparametric MRI without contrast within a week. Over a median follow-up of 2.2 years, laboratory parameters were recorded. Primary endpoint was a rapid decline in kidney function (GFR reduction > 30%) or replacement therapy initiation. T1 and T2 mapping sequences’ ability to predict poor renal outcome was examined using multivariable Cox regression models, incorporating MRI-derived parameters, eGFR, and proteinuria.

Results

Renal outcome occurred in 54 patients after a median of 1.1 years (IQR 0.9–2.1). Univariable survival analysis showed cortical T1 was associated with poor renal outcome (HR: 3.02 [1.44–6.33]), while T2 sequences had no significant predictive value. Adding cortical T1 to the established model (ΔADC, eGFR, proteinuria) did not improve the hazard ratio (from 4.62 [1.56–13.67] to 4.36 [1.46–13.02]) and marginally increased Harrell's C-index (0.77 to 0.79). Adjusting the regression model for ΔT2 yielded no enhancement in predictive power.

Conclusions

Cortical T1 is strongly associated with poor renal outcome but did not enhance prognostic power of the DW-MRI-based model.
T-helper cell phenotypes are repeatable, positively correlated, and associated with helminth infection in wild Soay sheep
Authors: Corripio-Miyar Yolanda , Hayward Adam D , Lemon Hannah , Bal Xavier , Cunnea Cameron , Kenyon Fiona , Pilkington Jill G , Pemberton Josephine M , Nussey Daniel H , McNeilly Tom N
Published: February 2025

Background

T-helper (Th) cells co-ordinate immune responses to ensure that infections with diverse parasites are controlled effectively. Helminth parasites such as gastrointestinal nematodes (GIN) are generally associated with T-helper type 2 (Th2) responses, while intracellular parasites are associated with Th1 responses. Although laboratory models have reported that Th1 and Th2 can be antagonistic, this has been challenged by studies of natural infections.

Methods

Between 2019 and 2022 we completed 759 captures of 538 wild Soay sheep (1–4 captures per animal) and monitored body weight, parasite egg counts, Th phenotypes, cytokines, and GIN-specific antibodies.

Results

While different Th cell counts, cytokines and antibody isotypes were generally positively correlated with each other, no strong positive associations were observed between these measurements. Cell counts had low repeatability (among-individual variation) across 4 years, while antibody levels were highly repeatable. The Th1 and Th2 cytokines Interferon-gamma (IFN-γ) and Interleukin-4 (IL-4) were moderately repeatable and were positively correlated at both the between- and within-individual levels independent of body condition or parasite exposure. IL-4 was negatively associated with GIN faecal egg count, while IFN-γ was negatively associated with coccidian faecal oocyst count, suggesting that these cytokines reflect resistance to these parasites. None of our immune markers were strongly associated with lamb survival.

Conclusions

Our results provide insights into how different aspects of immune function interact to produce effective responses to complex infections but suggest longer-term data collection is required to address the causes of these interactions and to detect fitness consequences of variation in T cell phenotypes under natural conditions.
Informal social interactions, academic achievement and behavior: Evidence from peers on the school bus
Authors: Lenard Matthew A , Silliman Mikko
Published: February 2025

We study the effects of informal social interactions on academic achievement and behavior using idiosyncratic variation in peer groups stemming from changes in bus routes across elementary, middle, and high school. Our results suggest that student interactions outside the classroom—especially in adolescence—may be an important factor in the education production function for both academic and, particularly, behavioral skills. The effects of interactions on the bus are also related to neighborhood measures—suggesting that one way that interactions on the bus may matter is by amplifying interactions in the neighborhood.
Descriptive analysis and outcomes of PitNETs treated surgically during pregnancy and postpartum
Authors: Odot Cindy , Brière Mathilde , Villa Chiara , Henry Théophraste , Gaillard Stephan , Caron Philippe , Groussin Lionel , Reznik Yves , Rod Anne , Ghorra Camille , Raffin-Sanson Marie-Laure , Baussart Bertrand , Hage Mirella
Published: February 2025

Objective

Data on pituitary neuroendocrine tumors (PitNETs) surgically treated during pregnancy is limited, and no studies have compared these cases to those treated in non-pregnant women. This study aimed to describe the clinical, radiological, and histological profiles of patients treated surgically for PitNETs during pregnancy and evaluate long-term prognosis.

Design

This study was multicentric, observational and retrospective.

Methods

We included 10 patients from 5 university hospitals who underwent surgical treatment for PitNETs during pregnancy or within 12 months postpartum, along with 30 matched non-pregnant controls treated surgically for PitNETs. Clinical and histological data, as well as progression-free survival without additional treatment, were compared between pregnant and non-pregnant patients.

Results and Conclusions

Among the 10 PitNETs, 4 were corticotropic, 2 gonadotropic, 2 lactotropic, and 2 somatotropic. The primary surgical indication (tumour syndrome with or without failure of medical treatment) was similar between the two groups: 7/10 vs 19/30 (p = 1.00). There was no statistically significant difference in volume (p = 0.072) or radiological invasion markers (optic chiasm compression, p = 0.059, and cavernous sinus invasion, p = 0.274). However, PitNETs in pregnant women showed higher mitotic activity (p = 0.038) and were more frequently classified as grade 2b (Trouillas clinicopathological classification; p=0.049). The need for second-line treatment was also more frequent (p = 0.005). PitNETs requiring surgical treatment during pregnancy are characterized by increased proliferative activity and progression after surgery. Despite this, the long-term prognosis remains favorable. These results need confirmation in a larger study.
Biochemical characterization of diaminopimelate decarboxylase from the hyperthermophile Thermotoga maritima
Authors: Miyamoto Tetsuya , Yazawa Akari , Mishima Rio , Sakai-Kato Kumiko
Published: February 2025

The peptidoglycan stem peptides of the hyperthermophile Thermotoga maritima contain an unusual D-lysine (D-Lys) alongside the usual D-alanine and D-glutamate. We identified a Lys racemase that catalyzes racemization between L-Lys and D-Lys, and a diaminopimelate (Dpm) epimerase that catalyzes epimerization between LL-Dpm and meso-Dpm. Herein, we characterized a Dpm decarboxylase (TM1517) that catalyzes the conversion of meso-Dpm to L-Lys. TM1517 displayed high decarboxylase activity toward meso-Dpm but no activity toward LL-Dpm. D-Lys was not detected in the decarboxylation of meso-Dpm. The pH and temperature dependencies and kinetic parameters of decarboxylase activity were determined. Although other amino acid metabolizing activities of TM1517 were investigated, TM1517 did not exhibit any activities. Therefore, TM1517 is a Dpm decarboxylase associated with L- and D-Lys biosynthesis in T. maritima.
Challenges in elucidating ethylene glycol metabolism in Saccharomyces cerevisiae
Authors: Senatore Vittorio Giorgio , Masotti Fiorella , Milanesi Riccardo , Ceccarossi Sofia , Maestroni Letizia , Serra Immacolata , Branduardi Paola
Published: February 2025

Polyethylene terephthalate (PET) is one of the most used polymers in the packaging industry; enzymatic recycling is emerging as a sustainable strategy to deal with waste PET, producing the virgin monomers terephthalic acid and ethylene glycol (EG). These monomers can be feedstocks for further microbial transformations. While EG metabolism has been uncovered in bacteria, in yeast the pathway for the oxidation to glycolic acid (GA) has only been proposed, but never experimentally elucidated.

In this work, we investigated in Saccharomyces cerevisiae the potential contribution to this metabolism of two endogenous genes, YLL056C (a putative alcohol dehydrogenase) and GOR1 (glyoxylate reductase). Secondly, the possible role of alcohol dehydrogenases (ADHs) was considered, too. Finally, two heterologous genes (gox0313 from Gluconobacter oxydans and AOX1 from Komagataella phaffii) were expressed with the intent to push EG oxidation towards GA. Our main findings revealed that i) Gor1, Yll056c and ADHs are not involved in EG oxidation, ii) the bottleneck of the catabolism is the first step in the pathway, due to the endogenous mechanisms for aldehyde detoxification. Multiomics studies are required to completely elucidate the pathway for EG catabolism, while further engineering directed towards relieving the bottleneck is needed to fully unleash the potential of yeasts for the upcycling of EG to GA.
Genome-wide association studies dissect the genetic architecture of seed and yield component traits in cowpea (Vigna unguiculata L. Walp)
Authors: Akinmade Habib , Ferreira Rebecca Caroline Ulbricht , Leite Andrade Mario Henrique Murad , Fernandes Claudio , Sipowicz Pablo , Muñoz-Amatriaín María , Rios Esteban
Published: February 2025

The identification of loci related to seed and yield component traits in cowpea constitutes a key step for improvement through marker-assisted selection (MAS). Furthermore, seed morphology has an impact on industrial processing and influences consumer and farmer preferences. In this study, we performed genome-wide association studies (GWAS) on a mini-core collection of cowpea to dissect the genetic architecture and detect genomic regions associated with seed morphological traits and yield components. Phenotypic data were measured both manually and by high-throughput image-based approaches to test associations with 41,533 single-nucleotide polymorphism markers using the FarmCPU model. From genome-associated regions, we also investigated putative candidate genes involved in the variation of the phenotypic traits. We detected 42 marker-trait associations for pod length and hundred seed weight, length, width, perimeter, and area of the seed. Candidate genes encoding leucine-rich repeat-containing (LRR) and F-box proteins, known to be associated with seed size, were identified; in addition, we identified candidate genes encoding PPR (Pentatricopeptide repeat) proteins, recognized to have an important role in seed development in several crops. Our findings provide insights into natural variation in cowpea for yield-related traits and valuable information for MAS breeding strategies in this and other closely related crops.
Employment Status and Life Satisfaction Among Older Adults: Disentangling the Gendered Effects of Entering and Exiting Employment
Authors: Park Sujeong , Kim Jinho
Published: February 2025

Background and Objectives

This study examines the relationship between employment transitions and life satisfaction among Korean adults aged 65 and older, with a focus on the distinct effects of entering and exiting employment. Moreover, the study explores whether these associations vary by gender.

Research Design and Methods

Utilizing data from the Korean Longitudinal Study of Ageing, the study employed innovative asymmetric fixed effects models to separately assess the impacts of entering and exiting employment. Gender-stratified analyses were also conducted to explore potential differences in these effects between men and women.

Results

Conventional fixed effects models suggested that employment status is not significantly related to life satisfaction in older adults. However, the asymmetric fixed effects models revealed a more nuanced picture: entering employment is associated with an increase in life satisfaction while exiting employment shows no significant association. The gender-stratified analysis further indicated that for men, entering employment improved life satisfaction, while exiting had no effect. In contrast, for older women, entering employment did not enhance life satisfaction, but exiting employment had a positive impact.

Discussion and Implications

These findings highlight the need for gender-sensitive employment policies for older adults, aimed at enhancing their well-being based on their unique experiences of employment transitions.
Cold atmospheric plasma pretreatment on the extraction of bioactive compounds from Scutellaria baicalensis Georgi
Authors: Zhang Jiaming , Chu Jiangnan , Wu Zhengwei
Published: February 2025

Scutellaria baicalensis Georgi (SBG) is a traditional medicinal plant for its anti-inflammatory, antibacterial and antiviral properties. Nevertheless, the current conventional means of extracting the bioactive compounds of SBG are less efficient, and this study aimed to improve the extraction efficiency of flavonoids from SBG by pretreatment with cold atmospheric pressure plasma (CAP) technique. The results showed that CAP pretreatment could facilitate an increase in the specific surface area, a reduction in particle size, thus increasing the area in contact to the extraction solvent. The reactive oxygen of CAP can also degrade cell wall components. Ultimately, the extraction efficiency of flavonoids was improved by 8.25%–59.77%. In conclusion, this study demonstrated that CAP is an effective method to enhance the extraction efficiency of SBG bioactive compounds, indicating the potential to improve the nutritional and functional properties of plants in the food industry.
Inhibition of PDE4B ameliorates cognitive defects in the model of alcoholic dementia in 3×Tg-AD mice via PDE4B/cAMP/PKA signaling
Authors: Sun Rongzhen , Han Mei , Lin Yuanyuan , Ma Shengyao , Tu Huan , Yang Xueliang , Zhang Fang , Zhang Han-Ting
Published: February 2025

Background

Chronic, heavy alcohol use may lead to permanent brain damage, cognitive impairment, and dementia. One of the most serious consequences is alcoholic dementia (AlD). Phosphodiesterase-4 (PDE4) inhibitors have been shown to exhibit beneficial effects on cognition deficits and alcoholism. However, it is not known whether PDE4 inhibitors can be used to treat AlD. A33, a relatively selective PDE4B inhibitor, is absent of the emetic effect associated with PDE4D. The effect of A33 on memory and cognition in AlD remains unclear.

Methods

We investigated the effects of A33 and the PDE4 inhibitor rolipram on memory and cognition using an AlD animal model, i.e., APP/PS1/Tau mice drinking alcohol in the two-bottle choice test, with or without A33 or rolipram treatment for 3 wk. The animal groups were compared in behavioral tests related to learning and memory. Neurochemical measures were conducted to explore the underlying mechanism of A33.

Results

Compared to WT controls, AlD mice showed impairments of learning ability and memory in the behavior tests; this was attenuated by treatment of rolipram or A33. In addition, administration of rolipram or A33 in AlD mice further alleviated neuropathological alterations in the hippocampus, including Aβ expression and deposition; rolipram or A33 also decreased the levels of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, as well as NF-κB. Further, rolipram or A33 decreased the activation of microglia while increased cAMP levels in the hippocampus of AlD mice.

Conclusions

These results revealed that the alleviation of the cognitive impairment of AlD in APP/PS1/Tau triple transgenic mice by rolipram or A33 was linked to the action of the PDE4B/cAMP/PKA signaling pathway. A33 can be a promising therapeutic agent for AlD-related cognitive dysfunction.
Human Challenge Models for Vaccine Development – Strengths, Limitations and Expansion into Endemic Settings: a HIC-Vac Meeting Report
Authors: Wagstaffe Helen R , Ascough Stephanie , Openshaw Peter J M ,   HIC-Vac meeting contributors
Published: February 2025

The HIC-Vac network is a unique association of researchers focused on the development and use of Human Infection Challenge (HIC, otherwise known as Controlled Human Infection Models or CHIM) studies for vaccine and therapeutic development, particularly for pathogens of high global impact. The 5th annual meeting of the HIC-Vac network was held on 1st-3rd November 2023. The theme of the meeting was capacity-building in endemic settings particularly in Low- and Middle-Income Countries (LMIC), where pathogens cause the greatest morbidity and mortality. In this report we highlight the strengths and limitations of HIC and expansion of such studies into endemic settings, noting that immune responses and vaccine efficacy differ across diverse settings and populations. The consensus was that HIC studies must not be restricted to high income settings if they are to be relevant to LMIC populations. This report summarises the work presented at the HIC-Vac annual meeting, highlighting current and future challenge models, challenge agent manufacture, public engagement, ethics, and industry perspectives.
Factors Associated With the Transmission of the Delta Severe Acute Respiratory Syndrome Coronavirus 2 Variant in Households: The Israeli COVID-19 Family Study (ICoFS)
Authors: Cortier Thomas , Gilboa Mayan , Layan Maylis , Joseph Gili , Meltzer Lilac , Amit Sharon , Rubin Carmit , Lustig Yaniv , Alroy-Preis Sharon , Kreiss Yitshak , Cauchemez Simon , Regev-Yochay Gili
Published: February 2025

Understanding how interpersonal interactions and immunological factors shape severe acute respiratory syndrome coronavirus 2 transmission in households is crucial for designing control measures. We developed a Bayesian data augmentation transmission model to evaluate the effects of isolation, parental care, and vaccine-induced immunity on Delta variant transmission from the follow-up of 1093 Israeli households (July–August 2021). Among the 2883 household contacts, 1096 (38%) were infected. Children were 38% (95% Credibleconfidence interval [CrI], 7%–81%) more likely to be infected than adults. Isolation measures reduced transmission by 52% (95% CrI, 46%–57%). Transmission was 39% (95% CrI, 11%–76%) higher between children and female adults than between children and male adults. Vaccine effectiveness was 78% (95% CrI, 54%–90%), 85% (95% CrI, 70%–94%), and 73% (95% CrI, 49%–88%), respectively, for 1, 2, and 3 recent vaccine doses (within ≤90 days) but dropped to 18% (95% 95% CrI, −6% to 36%) for 2 doses administered >90 days earlier. Household member interactions significantly shaped transmission, and isolation measures effectively reduced transmission.
The TET-TDG axis in T cells and biological processes
Authors: Suzuki Kazumasa , Rao Anjana , Onodera Atsushi
Published: February 2025

Ten-eleven translocation (TET) proteins are dioxygenases that sequentially oxidize the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). All three epigenetic modifications are intermediates in DNA demethylation. In the “passive” (replication-dependent) DNA demethylation pathway, sequential oxidation reactions by TETs are essential and modified cytosines (C) are diluted at each cycle of DNA replication. In the “active” (replication-independent) DNA demethylation pathway, both thymine DNA glycosylase (TDG) and TETs play important roles. TDG removes 5fC and 5caC from 5fC:G and 5caC:G base pairs and these modified bases are replaced by unmodified C via base excision repair. Through epigenetic regulation of DNA demethylation, TETs and TDG are involved in cell development, differentiation, and homeostasis. The interplay between TDG and TETs is involved in embryo development, stem cell differentiation, neural development, immune responses, and tumorigenesis. Loss-of-function mutations of TET proteins in immune cells are associated with a variety of abnormalities, including inflammation, cancer, and clonal hematopoiesis, a condition related to aging. Loss of TETs also has a significant impact on the plasticity and differentiation of T cells, which contributes to inflammation and cancer. In this review, we describe recent findings in function of TETs in T cell plasticity and differentiation and the TET-TDG axis in selected biological processes.
Correlation of Interferons and Autoimmune Aspects in Long COVID-19 Patients
Authors: Hattori Fumiyuki , Nishiyama Junji , Hasuo Hideaki
Published: February 2025

Long COVID, or post-acute sequelae of COVID-19 (PASC), represents a major global health challenge, with its underlying mechanisms remaining poorly understood despite substantial research and clinical trials. This study investigates the role of the interferon (IFN) axis in the pathogenesis of PASC, drawing parallels to systemic lupus erythematosus (SLE). The potential pathogenic role of IFNs was detected by meta-analyses of mRNA sequencing data comparing PASC patients to healthy controls. We analyzed serum samples from 39 PASC patients and found significant correlations among multiple IFN subtypes, including IFN alpha-2, beta, gamma, lambda-1, and lambda-2/3. The biological activity of IFNs in the serum was positively correlated with levels of both total and type III IFNs. Notably, we detected the widespread presence of anti-double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies in these patients, with anti-dsDNA levels showing a strong correlation with IFN activity. Based on these findings, we propose a hypothetical autoimmune pathogenesis for PASC highlighting the crucial role of IFN signaling.
Obesity may extend the time required to reach a steady-state 25-hydroxyvitamin D level after initiating vitamin D supplementation
Authors: Dawson-Hughes Bess , Konieczynski Elsa M , Ceglia Lisa
Published: February 2025

Obesity is known to influence the circulating 25-hydroxyvitamin D [25(OH)D] level but less is known about whether it influences the time required to reach a stable 25(OH)D level after initiating vitamin D supplementation.

This observational study was done to investigate whether body mass index (BMI) modified the time required to reach a steady-state 25(OH)D level in response to vitamin D supplementation. Participants in the Boston STOP IT study who were treated for 12 months with 700 IU of vitamin D3 and 500 mg of calcium daily and had 25(OH)D measures at 0, 6, and 12 months, were included. We assessed the trajectory of 25(OH)D levels by baseline BMI category (normal weight, BMI 18.5-24.9 kg/m2, n = 62; overweight and obese, BMI ≥ 25 kg/m2, n = 105). Baseline 25(OH)D levels were 78 ± 31.3 nmol/L (normal weight) and 74.7 ± 36.5 nmol/L (overweight and obese). In a linear mixed model examining the influence of time and baseline BMI category on change in the mean 25(OH)D level, there was a significant time x BMI group interaction (p=.024. The normal weight participants had reached steady-state 25(OH)D levels by 6 months whereas 25(OH)D levels continued to rise between 6 and 12 months in the overweight and obese participants.

This analysis suggests that the time required to reach a steady-state 25(OH)D level after initiating vitamin D supplementation in overweight and obese adults is greater than the usual 3-month time point commonly used in clinical practice. A more refined definition of the time course of circulating 25(OH)D response to supplementation is needed in overweight and obese individuals in order to optimize clinical monitoring of vitamin D status.
Predictable ecological dynamics over incredibly small spatial scales influence early-life phenotypes in a species with temperature-dependent sex determination
Authors: Terebiznik Mariel , Leivesley Jessica A , Edge Christopher B , Nancekivell E Graham , Brooks Ronald J , Rollinson Njal
Published: February 2025

Phenotype-environment associations in neonatal animals may arise in wild environments by virtue of ecological dynamics within the nest. Such dynamics may be of special importance to the evolution of temperature-dependent sex determination (TSD), an enigmatic trait which can be adaptive when the incubation temperatures that affect sexual differentiation also have differential effects on fitness of the sexes. To infer causal effects of the nest environment on fitness-relevant phenotypes, we apply structural equation modeling (SEM) to a 14-year dataset of 3085 individual embryos whose position in 179 wild snapping turtle nests could be estimated. We find that temperature has a positive effect on hatchling size, and that the same temperatures that predict hatchling size also predict sex of hatchlings. Further, the probability that embryos develop as males is correlated with hatchling size in the wild, where across all environments, males are slightly and significantly larger than females at hatching. Our SEM reveals that the covariance between size and sex arises because of temperature effects on size, and because of a predictable covariance between egg placement within the nest coupled with maternal effects on egg size. Finally, embryos deep in the nest have a high probability of becoming male even in the hottest years. Our study suggests ecological dynamics occurring within the nest are an interesting and underappreciated source of phenotypic variation. Our study also supports the view that TSD is an adaptive trait, rather than a neutral trait, by showing consistent associations between phenotype and temperature in wild nests of a TSD reptile.
Ethylene signaling is essential for mycorrhiza-induced resistance against chewing herbivores in tomato
Authors: Lidoy Javier , Rivero Javier , Ramšak Živa , Petek Marko , Križnik Maja , Flors Victor , Lopez-Raez Juan A , Martinez-Medina Ainhoa , Gruden Kristina , Pozo Maria J
Published: February 2025

Arbuscular mycorrhizal (AM) symbiosis can prime plant defenses, leading to mycorrhiza-induced resistance (MIR) against different attackers, including insect herbivores. Still, our knowledge of the complex molecular regulation leading to MIR is very limited. Here, we show that the AM fungus Funneliformis mosseae protects tomato plants against two different chewing herbivores, Spodoptera exigua and Manduca sexta. We explore the underlying molecular mechanism through genome-wide transcriptional profiling, bioinformatics network analyses, and functional bioassays. Herbivore-triggered JA-regulated defenses were primed in leaves of mycorrhizal plants, while ET biosynthesis and signaling were also higher both before and after herbivory. We hypothesized that fine-tuned ET signaling is required for the primed defensive response leading to MIR. ET is a complex regulator of plant responses to stress and is generally considered a negative regulator of plant defenses against herbivory. However, ET-deficient or insensitive lines did not show AM-primed JA biosynthesis or defense response, and were unable to develop MIR against any of the herbivores. Thus, we demonstrate that hormone crosstalk is central to the priming of plant immunity by beneficial microbes, with ET fine-tuning being essential for the primed JA biosynthesis and boosted defenses leading to MIR in tomato.
The Periodical Olam Katan (1901–1904) and Its Readers: A Study in Modern Jewish Childhood in Eastern Europe
Authors: Jagodzińska Agnieszka
Published: February 2025

Olam Katan [Small World] was the first illustrated Hebrew periodical for children, edited by Avraham Leib Shalkovich (aka Ben-Avigdor) and Shmuel Leib Gordon (aka Shalag). It was published first in Vienna (1901–1902) and then in Cracow (1902–1904). This article reconstructs the readership of this periodical through the analysis of a unique source: a collection of children’s letters sent to Olam Katan and printed in its pages. Children’s Zionist culture is studied as reflected in the readers’ correspondence. Applying quantitative and qualitative methods, and methods of digital humanities and spatial analysis, this article reconstructs the geography, age, and gender of the readers of Olam Katan, setting them in the broader context of modern Jewish childhood in Eastern Europe.
Timing and noise analysis of five millisecond pulsars observed with MeerKAT
Authors: Chisabi M , Andrianomena S , Enwelum U , Gasennelwe E G , Idris A , Idogbe E A , Shilunga S , Geyer M , Reardon D J , Okany C F , Shamohammadi M , Shannon R M , Krishnan V Venkatraman , Abbate F , Kramer M
Published: February 2025

Millisecond pulsars (MSPs) in binary systems are precise laboratories for tests of gravity and the physics of dense matter. Their orbits can show relativistic effects that provide a measurement of the neutron star mass and the pulsars are included in timing array experiments that search for gravitational waves. Neutron star mass measurements are key to eventually solving the neutron star equation of state and these can be obtained by a measure of the Shapiro delay if the orbit is viewed near edge-on. Here, we report on the timing and noise analysis of five MSPs observed with the MeerKAT radio telescope: PSRs J0900–3144, J0921–5202, J1216–6410, J1327–0755, and J1543–5149. We searched for the Shapiro delay in all of the pulsars and obtain weak detections for PSRs J0900–3144, J1216–6410, and J1327–0755. We report a higher significance detection of the Shapiro delay for PSR J1543–5149, giving a precise pulsar mass of $M_{\rm p} = 1.349^{+0.043}_{-0.061}\,$M$_\odot$ and companion white-dwarf mass $M_{\rm c} = 0.223^{+0.005}_{-0.007}$ M$_\odot$. This is an atypically low-mass measurement for a recycled MSP. In addition to these Shapiro delays, we also obtain timing model parameters including proper motions and parallax constraints for most of the pulsars.
Characterization of H2O:N2 ice under bombardment by cosmic rays – I. Reaction rates and chemical equilibrium
Authors: Queiroz L M S V , Silva J R C , Ferrão L F A , Pilling S
Published: February 2025

In space, nitrogen-rich ice is constantly exposed to ionizing radiation, which triggers chemical reactions and desorption processes allowing a chemical enhancement of interstellar medium (ISM). Here, we present the first part of a series of studies on the effect of cosmic ray bombardment (40 MeV Ni$^{11+}$ ions) on H$_2$O:N$_2$ (1:5) ice at 15 K, employing the PROCODA code as the modelling tool including 28 chemical species and 930 chemical coupled equations (also including desorption). This first part focuses on the reaction rates and chemical equilibrium stage due to radiation processing. Among the results, we characterize the molecular abundances at chemical equilibrium, including experimentally observed and non-observed species (predicted) suggesting some candidates as a target for astronomical observation. The best-fitting models provided the effective rate coefficients, which can be employed in astrochemical models to understand the chemistry of cold space environments. The findings also help to clarify the chemical processes of N-bearing species in the ISM and frozen surfaces of the Solar system, including the moon of giant planets, outer solar system objects, and ices in the interstellar and protostellar medium.
Selection increases mitonuclear DNA discordance but reconciles incompatibility in African cattle
Authors: Shi Xian , Ma Cheng , Chen Ningbo , Xu Ming-Min , Kambal Sumaya , Cai Zheng-Fei , Yang Qiwen , Adeola Adeniyi C , Liu Li-Sheng , Wang Jun , Lu Wen-Fa , Li Yan , Msalya George M , Lei Chuzhao , Mwacharo Joram M , Han Jian-Lin , Hanotte Olivier , Zhang Ya-Ping , Peng Min-Sheng
Published: February 2025

Mitochondrial function relies on the coordinated interactions between genes in the mitochondrial (mtDNA) and nuclear genomes. Imperfect interactions following mitonuclear incompatibility may lead to reduced fitness. MtDNA introgressions across species and populations are common and well documented. Various strategies may be expected to reconcile mitonuclear incompatibility in hybrids or admixed individuals. African admixed cattle (Bos taurus × B. indicus) show sex-biased admixture, with taurine (B. taurus) mtDNA and a nuclear genome predominantly of humped zebu (B. indicus). Here, we leveraged local ancestry inference approaches to identify the ancestry and distribution patterns of nuclear functional genes associated with the mitochondrial oxidative phosphorylation process in the genomes of African admixed cattle. We show that most of the nuclear genes involved in mitonuclear interactions are under selection and of humped zebu ancestry. Variation in mtDNA copy number (mtDNA-CN) may have contributed to the recovery of optimal mitochondrial function following admixture with the regulation of gene expression, alleviating or nullifying mitochondrial dysfunction. Interestingly, some nuclear mitochondrial genes with enrichment in taurine ancestry may have originated from ancient African aurochs (B. primigenius africanus) introgression. They may have contributed to the local adaptation of African cattle to pathogen burdens. Our study provides further support and new evidence showing that the successful settlement of cattle across the continent was a complex mechanism involving adaptive introgression, mtDNA-CN variation, regulation of gene expression, and selection of ancestral mitochondria-related genes.
T cell costimulatory blockade ameliorates induction of experimental membranous nephropathy potentially through T-helper 17 cell suppression in the kidney
Authors: Chung Edmund Y M , Wang Yuan Min , Shaw Karli , Ronning Emily , Wang Ya , Yu Zhang Geoff , Hu Min , Keung Karen , McCarthy Hugh J , Harris David C H , Alexander Stephen I
Published: February 2025

Background and hypothesis

Recent advances in membranous nephropathy treatment have focused on B cell depletion, which is incompletely effective, potentially due to persistent autoantibody-producing plasma cells or alternative pathways of injury. T cell costimulatory blockade (cytotoxic-T-lymphocyte-associated antigen 4 (CTLA4)-Ig) to prevent T cell-dependent B cell activation and short-course proteasome inhibition (bortezomib) to deplete plasma cells may represent a complementary form of treatment.

Methods

Lewis rats were immunized with Fx1A and complete Freund's adjuvant (CFA) to induce experimental membranous nephropathy (Heymann nephritis or HN) and treated with CTLA4-Ig alone or CTLA4-Ig plus a short-course of bortezomib. Serum creatinine, proteinuria, kidney histology, serum anti-Fx1A levels, kidney and spleen messenger RNA expression, and flow cytometry on splenocytes were evaluated at 12 weeks.

Results

CTLA4-Ig-treated and CTLA4-Ig plus bortezomib-treated rats had significant and similar reductions in serum creatinine and proteinuria, with less histological kidney injury compared to untreated HN rats. Glomerular IgG deposition was reduced in CTLA4-Ig-treated and CTLA4-Ig plus bortezomib-treated rats compared to untreated HN rats but there were no significant differences in serum anti-Fx1A levels. CTLA4-Ig-treated and CTLA4-Ig plus bortezomib-treated rats exhibited significantly reduced T helper (Th)-17 cell cytokines (interleukin (IL)-6, IL-17, IL-21) and regulatory T cell (Foxp3, TGF-β) expression in the kidney but not the spleen. Immunohistochemical staining of CD4+ and intracellular STAT3+ cells were reduced in CTLA4-Ig plus bortezomib-treated and CTLA4-Ig-treated compared to untreated HN rats. On flow cytometry, CTLA4-Ig reduced B cells and plasma cells but not T cell subsets.

Conclusion

CTLA4-Ig ameliorated induction of experimental membranous nephropathy, potentially through suppression of Th17 cells in the kidney and may represent an effective adjunct treatment in membranous nephropathy.
Phase 1 Trial of Hypofractionated Stereotactic Re-irradiation in Combination with Nivolumab, Ipilimumab, and Bevacizumab for Recurrent High-Grade Gliomas
Authors: Sahebjam Solmaz , Raval Raju R , Forsyth Peter A , Enderling Heiko , Tran Nam D , Arrington John A , Macaulay Robert , Perlow Haley K , Palmer Joshua D , Ghose Jayeeta , Rajappa Prajwal , Giglio Pierre , Li Zihai , Etame Arnold B , Mokhtari Sepideh , Cruz-Chamorro Ruben J , Bhandari Menal , Thapa Ram , Robinson Timothy J , Chen Dung-Tsa , Yu Hsiang-Hsuan Michael
Published: February 2025

Background

Our previous clinical investigation suggested that hypofractionated stereotactic re-irradiation (HFSRT) and PD-1 blockade may act synergistically to enhance the immune response against glioma. This subsequent trial investigated the dual blockade of CTLA4 and PD-1 in combination with HFSRT and bevacizumab.

Methods

This phase I study enrolled eligible patients with bevacizumab-naïve recurrent glioblastoma or anaplastic astrocytoma. Participants received nivolumab, ipilimumab and bevacizumab concurrently with HFSRT (3000 cGy in 5 fractions). Subsequently, nivolumab, ipilimumab and bevacizumab were administered for a total of 4 cycles followed by nivolumab and bevacizumab until progression. The primary end point of this study was safety and tolerability of HFSRT in combination with nivolumab, ipilimumab, and bevacizumab in patients with recurrent HGGs. Secondary end points included 6-months survival and 9-months survival.

Results

Twenty-six patients were treated. Treatment-related adverse events (TRAEs) of grade 3 or 4 were observed in 12 (48%) of evaluable patients with no unexpected TRAEs. Six-months and 9-months survival were 92% (95% CI, 82 to 100%) and 75% (95% CI, 60 to 95%), respectively. The median progression-free survival and overall survival were 7.1 months (95% CI, 5.2–12.2) and 15.6 months (95% CI, 11.3–27.0), respectively.

Conclusions

The combination of HFSRT with ipilimumab, nivolumab and bevacizumab is safe. Our results underscore the potential synergies between stereotactic re-irradiation and checkpoint immunotherapy in patients with recurrent high-grade gliomas.
Characterizing long- and short survival glioblastoma patients with FLT-PET/MRI and metabolomics
Authors: Axelsson Jan , Björkblom Benny , Asklund Thomas , Brandel Jens , Larhed Svante , Ringmar Gabriela M , Hedman Karolina , Riklund Katrine , Sjöberg Rickard L , Sandström Maria
Published: February 2025

Background

Glioblastoma is the most aggressive and malignant brain tumour, characterized by a high degree of heterogeneity, invasiveness, and resistance to treatment. Patients with glioblastoma have a very poor prognosis despite multimodal interventions. In this study, we investigated how 18F-flourothymidine (18F-FLT) PET combined with contrast-enhanced MRI and blood metabolomics can contribute to evaluate prognosis and treatment response for patients with glioblastoma.

Methods

Patients, scheduled for surgery due to suspected high-grade glioma were included in this clinical study and underwent four 18F-FLT-PET/MRI examinations prior to surgery and during standard treatment. Blood samples were collected and analyzed by metabolomics. Patients were grouped according to survival as long-time survivors (>3 years) and short-time survivors (<500 days).

Results

Both 2 and 6 weeks into treatment, short-time survivors displayed a significantly larger tumour volume than long-time survivors. When comparing MRI findings during treatment, long-time survivors displayed a substantial tumour decrease, whereas the short-time survivors showed minor or no effect. Regarding 18F-FLT-PET the results were not as unambiguous. Furthermore, there was a clear and significant separation in the metabolomic pattern in blood between the survival groups and across treatment time points.

Conclusions

MRI measures of tumour volume and growth during treatment appear to be prognostic clinical factors that affect outcome. Metabolomic patterns in blood differ significantly between the defined survival groups and may serve as support for an early forecast of prognosis. We also observe a clear separation in metabolite levels between different time points during treatment, which likely reflects treatment effects.
Chronic tobacco smoking and emotional processing abilities: a systematic review
Authors: Martini Elisa , Gautier Mado , Lannoy Séverine , Maurage Pierre
Published: February 2025

Introduction

Tobacco use disorder (TUD) remains highly prevalent and is associated with widespread cognitive impairments, particularly in attentional functions. Conversely, the understanding of emotional deficits related to TUD remains limited, despite its potential impact on mood regulation.

Methods

We conducted the first systematic review on emotional processing in TUD, based on a well-established model of emotion distinguishing three processes (emotional identification, emotional response and emotional regulation), to which we added emotional attention as a fourth component. Capitalizing on a pre-registered approach and following PRISMA guidelines, we synthesized existing literature on emotional processing impairments in TUD, identifying 14 relevant studies.

Results

Findings indicate large-scale impairments encompassing all emotional components in TUD, demonstrating that emotional processing constitutes a crucial dimension of TUD.

Conclusion

Emotional processing emerges as a key aspect of TUD but, in view of the currently limited quantity and quality of research in this area, we offer guidelines for more comprehensive and theory-grounded investigations, to advance theoretical knowledge and pave the way for efficient interventions.

Implications

This systematic review shows that tobacco use disorder (TUD) is associated, beyond the already documented cognitive deficits, with emotional impairments encompassing emotional identification, response, regulation and attention. Such widespread modifications of emotional processing might be involved in the emergence and persistence of TUD, and hence constitute new targets for researchers and clinical practitioners.