bluuebunny/crossref_metadata_2025 huggingface dataset:
Approaching fast ion transport via anion-dipole interaction in weakly-solvated electrolytes enables stable Li platting chemistry
Authors: Niu Min , Dong Liwei , Chen Xingyu , Feng Rong-Juan , Li Qian , Qi Hang , Xin Sen , Liang Jia-Yan , Yang Chunhui , Guo Yu-Guo
Published: February 2025

The graphite/Li-metal hybrid anode demonstrates great potential in cycling stability and energy density with designed weakly-solvated electrolytes, considering the common issue of solvent co-intercalation and vulnerable interface chemistry with graphite anode and Li anode, respectively. The weakly-solvated electrolytes show weak ion-dipole interaction and promote rapid desolvation but face with sluggish ion transport kinetics, thus inducing high overpotential and Li dendrite formation. Herein, by applying methyl propionate as a weakly-coordinated cosolvent, a loose solvation shell regulated by anion-solvent interaction enables weakened Li+-anion interaction while maintaining adequate anion participation, featuring a facilitated bulk ion transport route via anion dissociation, originally endowing a high ionic conductivity of 17.74 mS cm−1 in weakly-solvated electrolytes at 25 °C. Consequently, this advanced electrolyte design markedly mitigates concentration polarization and regulates uniform Li deposition, and thus the hybrid anode achieves 99.8% average Coulombic efficiency within 1500 cycles at 4C and improved cycling stability at a low N/P ratio of 0.5, making a breakthrough in alkali-metal-ion batteries.
Realization of highly asymmetric hydrogenated graphene in the van der Waals confined space
Authors: Huang Xianlei , Zheng Hang , Liu Weilin , Zhu Li , Yuan Guowen , Xu Jie , Wang Kaiyuan , Wang Lei , Li Shao-Chun , Gao Libo
Published: February 2025

Van der Waals (vdW) confined space provides distinct environment from free space, enabling the production of two-dimensional Janus materials, like highly asymmetric hydrogenated graphene (AH-Gr). Here, we develop a vdW confined space assisted hydrogenation method to produce AH-Gr. The confined space between graphene and the substrate aggregates hydrogen radicals, making the bottom-side of graphene more prone to hydrogenation. The dense and homogeneous confined spaces between adjacent vdW crystals promote rapid and uniform distribution of carbon-hydrogen (C-H) bonds. The hydrogen-to-carbon atomic (H/C) ratios can be quantitatively controlled by adjusting the permeated proton dose. All AH-Gr, regardless of H/C ratios, remain vacancy-free. The spatial distributions of C-H bonds significantly influence the electrical and magnetic properties of AH-Gr. Asymmetric hydrogenation transforms graphene from a semi-metal to a semiconductor, suppresses the quantum Hall effect, and reduces the phase coherence length. This study provides new insights into the preparation and characteristics of hydrogenated graphene, broadening the applications of vdW confined space.
Non-coordinating charge transfer enables ultrafast desolvation of hydrated zinc ions in the outer Helmholtz layer for stable aqueous Zn metal batteries
Authors: Guo Xiuli , Peng Qiaoling , Yang Rui , Cao Gengyou , Wen Jianfeng , Shin Kyungsoo , Zheng Ye , Tunmee Sarayut , Zou Caineng , Zheng Yongping , Zhou Xiaolong , Tang Yongbing
Published: February 2025

The formation of a strong coordination structure, [Zn(H2O)6]2+ often increases direct contact between the solvated H2O and Zn anodes on the inner Helmholtz layer, which exacerbates undesirable side reactions and dendrite growth, hindering the practical application of aqueous Zn metal batteries. Here, we identify that the solvated H2O can be effectively minimized by an artificial solid electrolyte interphase (SEI) consisting of highly nitrogen-doped amorphous carbon (NC) and perfluorosulfonic acid polymer (Nafion). Theoretical and experimental analyses reveal that NC raises the Fermi level of the composite SEI and activates the non-coordinating charge transfer from the SEI to [Zn(H2O)6]2+, which leads to ultrafast desolvation of hydrated Zn-ions in the outer Helmholtz layer; while the Nafion framework ensures selective transport channels for Zn ions. Remarkably, the derived NC-Nafion@Zn symmetric cell exhibits a long lifespan (3400 h, 1 mA cm–2; 2000 h, 5 mA cm–2); moreover, the NC-Nafion@Zn//Mn4O3-carbon nanotubes full battery delivers ultralong cycling stability of 9300 cycles at 2 A g–1 with a high retention of 91.3%.
Massive aortic root dilation in a Young male with previously undiagnosed acromegaly: a case report and review
Authors: Gomaa Mahmoud , El-Shirbiny Hassan , Elshaer Osama
Published: February 2025

Background

Acromegaly is an endocrine disorder characterized by excessive growth hormone (GH) production, causing abnormal bone and tissue enlargement. Typically, it presents with distinct physical changes, but some cases may lack noticeable features and still have internal abnormalities like aortic root dilation. Though rare, a family history can raise suspicion.

Case presentation

This report presents a case of a 23-year-old male with no significant medical history, who presented with severe dyspnea after a chest infection. He lacked distinct physical features of genetic or endocrinal disorders, but his uncle had acromegaly. Echocardiography revealed left ventricular hypertrophy and massive aortic root dilation. Elevated insulin-like growth factor 1 (IGF-1) confirmed the diagnosis of acromegaly. The patient underwent a Bentall procedure, and his acromegaly was managed with octreotide and regular follow-ups.

Conclusions

The report emphasizes the potential genetic link, and the possibility of massive aortic root dilation associated with acromegaly.
Statin-induced immune mediated necrotising myopathy presenting with a markedly elevated cardiac troponin T in the absence of myocardial injury
Authors: Hall David , Mbonu Goodness , Nadeem Zulakha
Published: February 2025

Cardiac troponin (cTn) is a sensitive test to assess for myocardial injury. However certain clinical situations can result in a raised cTn in the absence of cardiac involvement. Here we present a case of a 65-year-old woman on long term atorvastatin who presented with generalised weakness, non-specific chest pain, and a persistently elevated high sensitivity cardiac troponin T. Upon further investigation acute myocardial injury was excluded and a diagnosis of statin-induced immune mediated necrotising myopathy (IMNM) was made. The patient improved with cessation of atorvastatin and initiation of immunosuppressive therapy with mycophenolate, intravenous immunoglobulin, and steroids. The mechanism for cTn elevation in skeletal myopathies without cardiac damage and the presentation and treatment of statin-induced IMNM are reviewed. We highlight the importance that in these cases the true cause of the raised cTn is recognised to allow prompt diagnosis and treatment of the underlying myopathy.
Did Trump’s Indictments Rally His Base? Evidence from the Counterfactual Format
Authors: Barari Soubhik , Coppock Alexander , Graham Matthew H , Padgett Zoe
Published: February 2025

In the task of assessing how sudden, significant events causally affect public opinion, political pollsters often ask respondents how the event affected their attitudes and beliefs. We study the case of former President Donald Trump’s federal indictment for allegedly mishandling classified documents using two methods of retrospective causal inference. The commonly used change format asks respondents to state directly how the event affected their attitudes: Republicans say the event increased their support of Trump, while Democrats say the opposite. Like previous work, we argue that the change format exhibits a form of bias known as response substitution. The alternative counterfactual format is plausibly free of this source of error and asks respondents to imagine what their attitudes and beliefs would have been if the event had not happened. Using this method, Republican primary voters report that the indictment increased their belief that Trump mishandled documents (+2.5 pp) and decreased their intention to vote for him in the primaries (−1.6 pp). We argue that the counterfactual format is particularly valuable for studying the effects of highly salient news events like the Trump indictment on public opinion.
CARA: Convolutional Autoencoders for the detection of Radio Anomalies
Authors: Brand Kevin , Grobler Trienko L , Kleynhans Waldo
Published: February 2025

With the advent of modern radio interferometers, a significant influx in data is expected. This influx will render the manual inspection of samples infeasible and thus necessitates the development of automated approaches to find radio sources with anomalous morphologies. In this paper, we investigate the use of autoencoders for anomalous source detection, based on the assumption that autoencoders will reconstruct anomalies poorly. Specifically, we compare an autoencoder architecture from the literature to two other autoencoder architectures, as well as to four conventional machine learning models. Our results showed that the reconstruction errors of these autoencoders were generally more informative with respect to identifying anomalies than machine learning models were when trained on PCA components. Furthermore, we found that the use of a memory unit in our autoencoders resulted in the best performance, as it further restricted the ability of autoencoders to generalise to anomalous sources.

Whilst investigating the use of different reconstruction error metrics as anomaly scores, we determined that they were more informative when combined than they were in isolation. Thus, applying the machine learning models to the combined anomaly scores from the autoencoders resulted in the best overall performance. Particularly, random forests and XGBoost models were the most effective, with isolation forests also being competitive when using a small number of labelled anomalies to tune their hyperparameters. Such isolation forests are also more likely to generalise to unseen classes of anomalies than supervised models such as random forests and XGBoost.
Interrelationships of disease activity, central sensitization, psychosocial and lifestyle factors in axial spondyloarthritis
Authors: Kieskamp Stan C , van der Kraan Yvonne , Arends Suzanne , Wink Fréke , Bos Reinhard , Stewart Roy , Paap Davy , Spoorenberg Anneke
Published: February 2025

Objectives

In a substantial portion of patients with axial spondyloarthritis (axSpA), disease activity scores remain high despite anti-inflammatory treatment. This is possibly due to factors beyond active inflammation including different pain mechanisms and psychosocial factors. Therefore, our aim was to build a biopsychosocial model to explore the interrelationships of Axial Spondyloarthritis Disease Activity Score (ASDAS) with central sensitization (CS), psychological and lifestyle factors in patients with axSpA.

Methods

Consecutive patients from the prospective Groningen Leeuwarden axSpA (GLAS) cohort were included in this cross-sectional study. Assessments included in the model were educational level, body mass index (BMI), questionnaires on CS, illness perception, pain catastrophizing, coping, anxiety and depression, physical activity (mSQUASH) and ASDAS. Structural equation modelling (SEM), a multivariate analysis testing hypothesized interrelationships between variables, was applied to investigate the effects of CS, psychosocial and lifestyle factors on ASDAS.

Results

332 consecutive axSpA patients were eligible for analyses of which 59% were male, median symptom duration was 21 years, and mean ASDAS was 2.2 ± 0.9. The final SEM model had a satisfactory fit (RMSEA = 0.057 (95% CI 0.45–0.70), CFI = 0.936). Illness perception, CS and BMI had direct, significant, effects on ASDAS. Psychological well-being and educational level were significantly indirectly associated with ASDAS through illness perception.

Conclusion

Our analyses exploring the interrelationships of biopsychosocial factors related to ASDAS showed that factors beyond inflammation, especially illness perception and CS, seem to contribute significantly to ASDAS in patients treated for axSpA in our standard-of-care cohort, confirming the need for a biopsychosocial approach.
Treat-to-target in SLE: is serology important? Results from an integrated analysis of five randomised clinical trials of belimumab
Authors: Gomez Alvaro , Lindblom Julius , Parodis Ioannis , Bertsias George
Published: February 2025

Objectives

DORIS remission, based on clinical activity, and Lupus Low Disease Activity State (LLDAS), which includes serological markers, are protective targets in SLE. However, it remains unclear whether their prognostic impact is influenced by serum anti-dsDNA and complement levels

Methods

We analysed data from five phase III trials (BLISS-52, BLISS-76, BLISS-SC, BLISS-NEA, EMBRACE) totalling 45 254 monthly visits. Generalized linear models evaluated the effects of DORIS/LLDAS -with or without active serology- on the risk for severe (BILAG ≥1A/2B) and renal (BILAG A/B) flares. Organ damage was also assessed.

Results

Normal serology occurred in 544/1871 (29.1%) DORIS and 1879/4760 (39.5%) LLDAS visits. Using no-DORIS as reference, DORIS with anti-dsDNA(-) or normal/high C3/C4 demonstrated stronger protection against severe flares (odds ratios[ORs] 0.042; 95% CI 0.005–0.331 and 0.216; 95% CI 0.094–0.494, respectively) compared with DORIS with anti-dsDNA(+) or low C3/C4 (ORs 0.511; 95% CI 0.284–0.919 and 0.528; 95% CI 0.261–1.067). Similarly, LLDAS with normal serology showed greater risk-reduction in severe flares compared with LLDAS with active serology, especially low C3/C4. For renal flares, DORIS with serological activity carried ∼6-fold higher risk compared with combined clinical/serological remission (OR 5.94; 95% CI 1.26–28.04). Damage accrual was lowest in patients with sustained DORIS and ≥1 visit showing anti-dsDNA(-) (0.8%) or normal C3/C4 (1.8%).

Conclusion

Normal serology enhances the protection of DORIS and LLDAS against severe and renal SLE flares, possible reflecting deeper states of disease control. Patients with recently active disease who meet clinical targets but have persistently abnormal serology may require close monitoring to minimize flare-risk.
Avenciguat: a novel soluble guanylate cyclase activator that affects multiple cell types to inhibit IFN-1 signalling and fibrosis
Authors: Kaufman Julia , Nabozny Gerald , Tran-Manh Cuong , Liebel Christoph , Zhou Xiang , Daley Lee-Anne , Wang Chao-Ting , Ebenezer David L , Delic Denis , Wohnhaas Christian T , Trinh-Minh Thuong , Distler Jörg H W
Published: February 2025

Objectives

The soluble guanylate cyclase (sGC) stimulator riociguat is approved for the treatment of pulmonary arterial hypertension and may have antifibrotic effects. However, in fibrotic tissues, oxidative stress and hypoxia can render sGC insensitive to sGC stimulators. sGC activators overcome this limitation. Here, we characterize the novel sGC activator, avenciguat, in preclinical models of SSc.

Methods

Human microvascular endothelial cells-dermal (HMVEC-d) cultured in hypoxic conditions and activated human platelet-rich plasma were incubated with varying doses of avenciguat, and the levels of TGF-β2 and human CXC chemokine family ligand 4 (CXCL4) were measured, respectively. Treatment with avenciguat was analysed in mice with bleomycin-induced dermal and pulmonary fibrosis.

Results

Avenciguat reduced hypoxia-induced synthesis of TGF-β2 by HMVEC-d and inhibited CXCL4 release by platelets. Moreover, avenciguat demonstrated antifibrotic effects on bleomycin-induced dermal and pulmonary fibrosis. RNA sequencing of affected skin uncovered a unique profile distinguishing avenciguat from riociguat. Avenciguat treatment resulted in deeper regulation of IFN-1 signalling and genes associated with immune response vs riociguat treatment.

Conclusion

In preclinical studies, avenciguat shows the potential to influence vascular, fibrotic and immune-related processes in murine models of SSc. These studies suggest that it may offer therapeutic benefit across multiple aspects of SSc pathophysiology and support the rationale for further investigation in a Phase II clinical trial (VITALISScE™; NCT05559580) of avenciguat in SSc.
Mind the Empathy Gap: An Analysis of Agency and Emotional Encounters in the Asylum Appeals of Former Unaccompanied Asylum-Seeking Minors
Authors: Allsopp Jennifer
Published: February 2025

The role of emotion in asylum processes is one that has gained attention in recent years. This article situates itself as a response to this emerging body of literature by shedding new light on how emotions shaped the asylum appeals of a group of former unaccompanied minors in England through the application of the new concept of “empathy gap.” Five socio-legal themes are used to structure the analysis: (i) age disputes, (ii) credibility, (iii) affective ties, (iv) right to voice, and (v) precarious legal status. It is the first article to explore in depth what happens during the asylum appeals process for former unaccompanied minors in Britain and the first to consider how questions of emotion affect their lived experiences of, and the process of, legal proceedings. The article has wider implications for how social processes and relations and informal processes, in particular emotions, influence formal legal proceedings leading to potential for unfair outcomes. The article finds that, to avoid empathy-enhanced reasoning becoming yet another variable leading to inconsistency in the judicial process, systematic training and monitoring are required. These findings carry implications far beyond the immediate context of UK asylum tribunals by offering empirically informed insights for theory and practice regarding the role of emotion in judicial proceedings, and therefore have enduring relevance.
Structure-specific variation in per- and polyfluoroalkyl substances toxicity among genetically diverse Caenorhabditis elegans strains
Authors: Leuthner Tess C , Zhang Sharon , Kohrn Brendan F , Stapleton Heather M , Baugh L Ryan
Published: February 2025

Per- and polyfluoroalkyl substances (PFAS) are in 99% of humans and are associated with a range of adverse health outcomes. It is impossible to test the >14,500 structurally diverse “forever chemicals” for safety, therefore improved assays to quantify structure–activity relationships are needed. Here, we determined the toxicity of a structurally distinct set of PFAS in 12 genetically diverse strains of the genetic model system Caenorhabditis elegans. Dose–response curves for perfluoroalkyl carboxylic acids (PFNA, PFOA, PFPeA, and PFBA), perfluoroalkyl sulfonic acids (PFOS and PFBS), perfluoroalkyl sulfonamides (PFOSA and PFBSA), fluoroether carboxylic acids (GenX and PFMOAA), fluoroether sulfonic acid (PFEESA), and fluorotelomers (6:2 FTCA and 6:2 FTS) were determined in the C. elegans laboratory reference strain, N2, and 11 genetically diverse wild strains. Body length was quantified after 48 h of developmental exposure of L1 arrest-synchronized larvae to estimate effective concentration values (EC50). PFAS toxicity ranged by 3 orders of magnitude. Long-chain PFAS had greater toxicity than short-chain. Fluorosulfonamides were more toxic than carboxylic and sulfonic acids. Genetic variation resulted in variation in susceptibility among 12 strains to almost all chemicals. Different C. elegans strains varied in susceptibility to different PFAS, which suggests distinct molecular responses to specific structural attributes. Harnessing the natural genetic diversity of C. elegans and the structural complexity of PFAS is a powerful approach that can be used to investigate mechanisms of toxicity which may identify potentially susceptible individuals or populations and predict toxicity of untested PFAS to inform regulatory policies and improve human and environmental health.
MLKL deficiency exacerbates early injury in a mouse model of acetaminophen hepatotoxicity
Authors: Sanchez-Guerrero Giselle , Umbaugh David S , Smith Sawyer H , Akakpo Jephte Y , Jaeschke Hartmut , Ramachandran Anup
Published: February 2025

An overdose of acetaminophen (APAP) is the leading cause of drug-induced hepatotoxicity and acute liver failure (ALF) in the United States. It is established that the predominant mode of hepatocyte cell death after an APAP overdose is through necrosis, and it is now recognized that this occurs through regulated pathways involving RIP kinases. These kinases, along with the pseudo-kinase MLKL are central players in classical necroptotic cell death. Despite the skepticism regarding the role of necroptosis in APAP-induced liver injury, recent research demonstrating necroptosis-independent roles for MLKL led us to re-examine the role of this pseudo-kinase in APAP pathophysiology. Treatment of Mlkl-/-mice with a moderate (300 mg/kg) overdose of APAP resulted in an exacerbation of liver injury at 6- and 12-hours post-APAP as evidenced by elevated plasma alanine aminotransferase activities, and extensive necrosis accompanied by diminished glutathione levels. Interestingly, these differences between Mlkl-/- and wild type mice were negated at the 24-hour mark, previously scrutinized by others. At 6 and 12 hours post APAP, Mlkl-/- mice exhibited augmented translocation of AIF and Endonuclease G without affecting JNK activation, suggesting enhanced mitochondrial permeability transition in the absence of MLKL. Lack of MLKL also impacted autophagy, the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, with decreased levels of p62 and LC3B and increased expression of CHOP and GRP78 at 6 hours post APAP. In essence, our findings illuminate a noncanonical role for MLKL in the early phases of APAP-induced liver injury, warranting further exploration of its influence on APAP pathophysiology.
Congenital syphilis: epidemiological profile of Brazilian regions in the last decade
Authors: Casagrande Maria Eugênia Costa , da Silva Anderson Soares , Nunes Altacílio Aparecido
Published: February 2025

Congenital syphilis (CS) is transmitted to the fetus through the transplacental route at any stage of gestation when the pregnant women are either untreated or inadequately treated. In this study, we aimed to analyze trends in epidemiological indicators of CS in Brazil. This is a cross-sectional study utilizing data on CS across Brazilian regions from 1 January 2012 to 31 December 2021. Epidemiological indicators such as incidence, prevalence, and case-fatality rates were calculated. During the evaluated period, 192 055 CS cases were recorded in Brazil. Among pregnant women who underwent prenatal care, 58.5% were diagnosed during pregnancy, 33.9% at the time of birth, and 7.5% after birth. In 77.5% of the notifications, the partners were not treated. The average number of cases diagnosed during prenatal care was 5.6 times higher than those not reported. The Southeast region presented the highest incidence rate per 1000 live births, whereas the Midwest region had the lowest incidence. Despite an increase in rates across all regions and Brazil overall, there was no significant difference (P-value > .05) between the means for the two evaluated periods. However, there was a significant decrease (P-value < .05) in the case-fatality rate in the Northeast (1.9%–1.25%) and South (2.15%–0.92%) regions, as well as throughout Brazil (from 1.77% to 1.24%). The findings indicate that the incidence rates of CS continue to rise, suggesting that the disease remains a significant public health issue in Brazil. Effective preventive measures are urgently required.
Fluid restriction for term infants with hypoxic-ischemic encephalopathy following perinatal asphyxia—a randomized controlled trial
Authors: Ananthan Anitha , Balasubramanian Haribalakrishna , Nanavati Ruchi , Raghavendra Prashanth
Published: February 2025

Fluid management in the first postnatal week among infants with perinatal asphyxia and hypoxic-ischemic encephalopathy (HIE) is an important knowledge gap. We aimed to evaluate the effects of fluid restriction on short- and long-term outcomes in infants with HIE. Term infants with moderate or severe HIE on therapeutic hypothermia were randomized within 6 hours of age to receive either restricted intravenous maintenance fluids (45 ml/kg/day on day 1 to a maximum of 120 ml/kg/day on day 6) vs conventional fluid (60 ml/kg/day on day 1 to a maximum of 150 ml/kg/day on day 6). The primary outcome was a composite of mortality or neurological abnormality at hospital discharge. We studied neurodevelopmental disability at 18–24 months using Bayley Scales of Infant Development, third edition. A total of 210 infants were randomized. Three infants died during the hospital stay. The primary outcome of mortality or neurological abnormality at discharge was not significantly different between the restricted and the conventional fluid group [57% vs 53%, RR: 1.07 (95% CI: 0.83, 1.37), P-value .58]. The incidence of cranial magnetic resonance imaging abnormalities was similar in the groups (65% vs 71%, P-value .30). There were no differences in the rates of severe neurodevelopmental disability at 18–24 months in the two groups [27% vs 28%, RR: 0.96 (95% CI: 0.62, 1.50), P-value .88]. Adverse outcomes were similar in both groups. Fluid restriction in the first postnatal week of life did not improve short- and long-term neurodevelopmental outcomes in term infants with moderate or severe HIE.
Notch signaling pathway in osteogenesis, bone development, metabolism, and diseases
Authors: Dilawar Muhammad , Yu Xuan , Jin Yuanyuan , Yang Jing , Lin Sisi , Liao Junguang , Dai Qi , Zhang Xingen , Nisar Muhammad Farrukh , Chen Guiqian
Published: February 2025

The skeletal system provides vital importance to support organ development and functions. The Notch signaling pathway possesses well‐established functions in organ development and cellular homeostasis. The Notch signaling pathway comprises five typical ligands (JAG1, JAG2, DLL1, DLL3, and DLL4), four receptors (Notch1‐4), and four intracellular domains (NICD1‐4). Each component of the Notch signaling pathway has been demonstrated to be fundamental in osteoblast differentiation and bone formation. The dysregulation in the Notch signaling pathway is highly linked with skeletal disorders or diseases at the developmental and postnatal stages. Recent studies have highlighted the importance of the elements of the Notch signaling pathway in the skeletal system, as well as its interaction with signaling, such as Wnt/β‐catenin, BMP, TGF‐β, FGF, autophagy, and hedgehog (Hh) to construct a potential gene regulatory network to orchestrate osteogenesis and ossification. Our review has provided a comprehensive summary of the Notch signaling pathway in the skeletal system, as well as the insights targeting Notch signaling for innovative potential drug discovery targets or therapeutic interventions to treat bone disorders, such as osteoporosis and osteoarthritis. An in‐depth molecular mechanistic strategy to modulate the Notch signaling pathway and its associated signaling pathway will be encouraged for consideration to trigger enhanced therapeutic approaches for bone disorders by defining Notch‐regulating drugs for clinical use.
The aryl hydrocarbon receptor affects the inflammatory response of bone marrow mesenchymal stem cell via the hippo–YAP pathway to exacerbate systemic lupus erythematosus
Authors: Yang Xingzhi , Si Mingjun , Liu Ting , Yang Jingyu , Jiang Lili , Sun Ximeng , Yu Haitao
Published: February 2025

The impaired immune regulation of bone marrow mesenchymal stem cells (BM‐MSCs) disrupts T‐cell homeostasis and alters the immunological environment in individuals with systemic lupus erythematosus (SLE). However, the specific molecular mechanisms underlying the defective immune functions of BM‐MSCs in patients with SLE remain unclear. Here, we report that BM‐MSCs derived from MRL/lpr mice exhibit a diminished proliferative capacity, elevated levels of aryl hydrocarbon receptor (AhR) and increased levels of secreted proinflammatory cytokines, including IL‐1β, IL‐6, and TNF‐α. These BM‐MSCs can increase splenocyte proliferation and upregulate the expression of retinoic acid receptor‐related orphan receptor gamma t (RORγt) in EL4 cells, which constitute a murine T‐cell lymphoblastic leukemia cell line. Furthermore, MRL/lpr mice treated with FICZ (an AhR agonist) displayed splenomegaly and exacerbated renal pathology, alongside increased levels of AhR, and inflammatory cytokines. Notably, BM‐MSCs isolated from FICZ‐treated mice also facilitated splenocyte proliferation and increased the RORγt level in EL4 cells during coculture. Similar effects were observed when BM‐MSCs were exposed to FICZ in vitro, but these effects were reversed by the administration of CH223191 (an AhR antagonist). Additionally, the expression of Yes‐associated protein (YAP) was significantly increased in both MRL/lpr mice and FICZ‐treated BM‐MSCs. Importantly, verteporfin (a Hippo–YAP inhibitor) attenuated the elevated RORγt levels in EL4 cells and the increased splenocyte proliferation. This study advances our understanding of SLE pathogenesis by pinpointing AhR as a pivotal modulator of the inflammatory response of BM‐MSCs through the Hippo–YAP pathway in individuals with SLE. This novel insight not only enriches the current knowledge of SLE mechanisms but also highlights new potential therapeutic targets for SLE.
ralphi: a deep reinforcement learning framework for haplotype assembly
Authors: Battistella Enzo , Maheshwari Anant , Ekim Barış , Berger Bonnie , Popic Victoria
Published: February 2025

Haplotype assembly is the problem of reconstructing the combination of alleles on the maternally and paternally inherited chromosome copies. Individual haplotypes are essential to our understanding of how combinations of different variants impact phenotype. In this work, we focus on read-based haplotype assembly of individual diploid genomes, which reconstructs the two haplotypes directly from read alignments at variant loci. We introduceralphi, a novel deep reinforcement learning framework for haplotype assembly, which integrates the representational power of deep learning with reinforcement learning to accurately partition read fragments into their respective haplotype sets. To set the reward objective for reinforcement learning, our approach uses the classic reduction of the problem to themaximum fragment cutformulation on fragment graphs, where nodes correspond to reads and edge weights capture the conflict or agreement of the reads at shared variant sites. We trainedralphion a diverse dataset of fragment graph topologies derived from genomes in the 1000 Genomes Project. We show thatralphiconsistently achieves lower error rates at comparable or longer haplotype block lengths over the state of the art for short and long ONT reads at varying coverage in standard human genome benchmarks.ralphiis available athttps://github.com/PopicLab/ralphi.
Using The Cancer Genome Atlas from cBioPortal to Develop Genomic Datasets for Machine Learning Assisted Cancer Treatment
Authors: Asaduzzaman Abu , Thompson Christian C. , Sibai Fadi N. , Uddin Md J.
Published: February 2025

Predicting the impact of genetic mutations is crucial for understanding diseases like cancer. Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant From Tolerant (SIFT) are key tools for assessing how amino acid substitutions affect protein function and mutation pathogenicity. To our knowledge, no ready-to-use genomic dataset exists for prediction models to identify potentially harmful mutations, which could support research and clinical decisions. This study develops genomic and non-genomic datasets using The Cancer Genome Atlas (TCGA) from cBioPortal and applies machine learning models to predict PolyPhen and SIFT scores. We explore three classification models: Random Forest (RF), Extreme Gradient Boosting (XGBoost), and an ensemble RF-XGBoost model. Experimental results show that genomic data yields more accurate predictions than non-genomic data. The ensemble RF-XGBoost model performs best on genomic data, achieving average accuracies of 88.43% for PolyPhen and 95.13% for SIFT, highlighting the potential of artificial intelligence in genetic mutation analysis for disease treatment.
DAF-18/PTEN protects LIN-35/Rb from CLP-1/CAPN-mediated cleavage to promote starvation resistance
Authors: Chen Jingxian , Chitrakar Rojin , Baugh L. Ryan
Published: February 2025

Starvation resistance is a fundamental trait with profound influence on fitness and disease risk. DAF-18, theC. elegansortholog of the tumor suppressor PTEN, promotes starvation resistance. PTEN is a dual phosphatase, and DAF-18 promotes starvation resistance as a lipid phosphatase by antagonizing insulin/IGF and PI3K signaling, activating the tumor suppressor DAF-16/FoxO. However, if or how DAF-18/PTEN protein-phosphatase activity promotes starvation resistance is unknown. Using genetic, genomic, bioinformatic, and biochemical approaches, we identified theC. elegansretinoblastoma/RB protein homolog, LIN-35/Rb, as a critical mediator of the effect of DAF-18/PTEN on starvation resistance. We show that DAF-18/PTEN protects LIN-35/Rb from cleavage by the μ-Calpain homolog CLP-1/CAPN, and that LIN-35/Rb together with the repressive DREAM complex promote starvation resistance. We conclude that the tumor suppressors DAF-18/PTEN and LIN-35/Rb function in a linear pathway, with LIN-35/Rb and the rest of the DREAM complex functioning as a transcriptional effector of DAF-18/PTEN protein-phosphatase activity resulting in repression of germline gene expression. This work is significant for revealing a network of tumor suppressors that promote survival during cellular and developmental quiescence.
Human ADME/PK is lost in translation and prediction fromin silicotoin vitrotoin vivo
Authors: Fagerholm Urban , Hellberg Sven
Published: February 2025

Background

Measurements and predictions of aqueous solubility (S), apparent cell permeability (Papp), unbound microsomal intrinsic clearance (CLint,u), unbound fraction in plasma (fu), log D, Lipinski’s Rule of 5 (Ro5) and BBB+/BBB- (blood-brain-barrier) are commonly used in early drug discovery to evaluate whether compounds are likely to have adequate ADME/PK in humans. The main objective was to evaluate the validity and proposed thresholds for commonly usedin silicotoin vitro(with particular interest in the ADMET Predictor software) andin vitrotoin vivohuman ADME/PK prediction methods, and physicochemical estimates and rules of thumb. A secondary aim was to compare validity and thresholds to that for the prediction software ANDROMEDA.

Methods

Data were collected from literature and own studies. Main measures of validity were Q2(true predictive accuracy;in silicomodels), R2(correlation coefficient;in vitromodels), Q2• R2(for translation fromin silicotoin vivoviain vitro), skewness, range, % correct predicted class and clinical relevance.

Results and Discussion

Poor accuracies (Q2• R2=0.05, 0.05, 0.36 and 0.45; ∼0 at low to moderate, decision-critical levels) and class predictions, limited ranges (not covering low to moderate estimates), systematic errors (often considerable overprediction at low values), poor clinical relevance and inadequate thresholds were found. Predictive accuracy was mainly lost in the translation fromin vitrotoin vivo. Log D and Ro5 are poor predictors of oral bioavailability and half-life. Ro5 produced 63 % false negatives for prediction of poor/good oral absorption. The overall mean Q2for ANDROMEDA was 3 times higher (0.57vs0.2). Advantages with ANDROMEDA compared toin vitrodata-basedin silicomodels include wider application domain (high resolution at low values), extrahepatic elimination models, minimal skewness, clinical relevance, balanced thresholds, and compound- and parameter-unique confidence intervals. ANDROMEDA successfully predicted the human clinical ADME/PK for all small drugs marketed in 2021, while thein silicotoin vitrotoin vivoapproach was out of reach for all.

Conclusion

The validity of investigated methodologies (including ADMET Predictor) and thresholds were overall very low. Unless both predicted S, permeability and fuare high and CLintis moderate (an overall criterium not met for investigated modern small drugs) one is more or less lost in the translation, and will jeopardize compound selection and optimization. This clearly shows the need for better and thoroughly validated prediction models and software. Marked improvements in accuracy, range, balance and clinical relevance were achieved with ANDROMEDA, which predicts human clinical ADME/PK directly from chemical structures and has undergone extensive validation.
Single-cell transcriptomics identifies a dampened neutrophil function and accentuated T-cell cytotoxicity in tobacco flavored e-cigarette exposed mouse lungs
Authors: Kaur G , Lamb T , Tjitropranoto A , Rahman Irfan
Published: February 2025

E-cigarettes (e-cigs) are a public health concern for young adults due to their popularity and evidence for increased oxidative stress and immunotoxicity. Yet an extensive study defining the cell-specific immune changes upon exposure to flavored e-cigs remains elusive. To understand the immunological lung landscape upon acute nose-only exposure of C57BL/6J to flavored e-cig aerosols we performed single-cell RNA sequencing (scRNA seq). scRNA profiles of 71,725 cells were generated from control and treatment groups (n=2/sex/group). A distinct phenotype of Ly6G-neutrophils was identified in lungs exposed to tobacco flavored e-cig aerosol which demonstrated dampened IL-1 mediated and pattern recognition signaling as compared to air controls. Differential gene expression analyses identified dysregulation of T-cell mediated pro-inflammation (Cct7,Cct8) and stress-response signals (Neurl3,Stap1,CirbpandHtr2c)in the lungs of mice exposed to e-cig aerosols, with pronounced effects for tobacco flavor. Flow cytometry analyses and cytokine/chemokine assessments within the lungs corroborated the scRNA seq data, demonstrating a significant increase in T-cell percentages and levels of T-cell associated cytokine/chemokines in the lungs of tobacco-flavored aerosol exposed mice. Increased levels ofKlra4andKlra8expression also suggest an enhanced natural killer (NK) cell activity in this mouse group. Overall, this is a pilot study identifying increase in the percentages of Ly6G-neutrophils that may be responsible for dampened innate immune responses and heightened T-cell cytotoxicity in lungs of tobacco-flavored e-cig aerosol exposed mice. In addition, we provide preliminary evidence for sex-specific changes in the transcriptional landscape of mouse lungs upon exposure to e-cig aerosol, an area that warrants further study.
Indigenous gut microbes modulate neural cell state and neurodegenerative disease susceptibility
Authors: Blackmer-Raynolds Lisa , Sampson Maureen M. , Kozlov Anna , Yang Aimee , Lipson Lyndsey , Hamilton Adam M. , Kelly Sean D. , Chopra Pankaj , Chang Jianjun , Sloan Steven A. , Sampson Timothy R.
Published: February 2025

The native microbiome influences a plethora of host processes, including neurological function. However, its impacts on diverse brain cell types remains poorly understood. Here, we performed single nucleus RNA sequencing on hippocampi from wildtype, germ-free mice and reveal the microbiome-dependent transcriptional landscape across all major neural cell types. We found conserved impacts on key adaptive immune and neurodegenerative transcriptional pathways, underscoring the microbiome’s contributions to disease-relevant processes. Mono-colonization with select indigenous microbes identified species-specific effects on the transcriptional state of brain myeloid cells. Colonization byEscherichia coliinduced a distinct adaptive immune and neurogenerative disease-associated cell state, suggesting increased disease susceptibility. Indeed,E. coliexposure in the 5xFAD mouse model resulted in exacerbated cognitive decline and amyloid pathology, demonstrating its sufficiency to worsen Alzheimer’s disease-relevant outcomes. Together, these results emphasize the broad, species-specific, microbiome-dependent consequences on neurological transcriptional state and highlight the capacity of specific microbes to modulate disease susceptibility.

Highlights

The microbiome impacts the transcriptional landscape of all major brain cell types.

Discrete microbes specifically modulate resident myeloid cell status.

GutE. colitriggers dynamic transcriptional responses across neural cell types.

Exposure toE. coliexacerbates behavioral and cellular pathologies in 5xFAD mice.
Paired primary-metastasis patient-derived organoids and mouse models identify phenotypic evolution and druggable dependencies of peritoneal metastasis from appendiceal cancer
Authors: Mahmoud Ahmed , Choi Philip H. , Sukhwa Christine , Pintar Jura , Walch Henry , Zhao Nan , Bermeo Jonathan , Chung Sebastian , Raghavan Manisha , Bapat Samhita , Jiang Qingwen , Karagkounis Georgios , Meredith Julia , Giarrizzo Michael , Firat Canan , Cercek Andrea , Foote Michael B. , Schultz Nikolaus , Chatila Walid K. , Nash Garrett M. , Shia Jinru , Sanchez-Vega Francisco , Larson Steven , Dar Arvin C. , Rosen Neal , Ganesh Karuna
Published: February 2025

Peritoneal carcinomatosis is a common yet deadly manifestation of gastrointestinal cancers, with few effective treatments. To identify targetable determinants of peritoneal metastasis, we focused on appendiceal adenocarcinoma (AC), a gastrointestinal cancer that metastasizes almost exclusively to the peritoneum. Current treatments are extrapolated from colorectal cancer (CRC), yet AC has distinct genomic alterations, mucinous morphology and peritoneum restricted metastatic pattern. Further, no stable preclinical models of AC exist, limiting drug discovery and representing an unmet clinical need. We establish a first-in-class stable biobank of 16 long-term cultured AC patient-derived organoids (PDOs), including 3 matched, simultaneously resected primary AC-peritoneal carcinomatosis (AC-PC) pairs. By enriching for cancer cells, AC PDOs enable accurate genomic characterization relative to paucicellular AC tissue. We establish an organoid orthotopic intraperitoneal xenograft model that recapitulates diffuse peritoneal carcinomatosis and show that PC-organoids retain increased metastatic capacity, decreased growth factor dependency and sensitivity to standard of care chemotherapy relative to matched primary AC organoids. Single cell profiling of AC-PC pairs reveals dedifferentiation from mucinous differentiated states in primary AC into intestinal stem cell and fetal progenitor states in AC-PC, with upregulation of oncogenic signaling pathways. Through hypothesis-driven drug testing, we identify KRASMULTI-ON inhibitor RMC-7977 and Wnt-targeting tyrosine kinase inhibitor WNTinib as novel, clinically actionable strategies to target AC-PC more effectively.
Reduced plasma hexosylceramides in frontotemporal dementia are a biomarker of white matter integrity
Authors: Marian Oana C. , Matis Sophie , Dobson-Stone Carol , Kim Woojin S. , Kwok John B. , Piguet Olivier , Halliday Glenda M. , Landin-Romero Ramon , Don Anthony S.
Published: February 2025

INTRODUCTION

Blood biomarkers are needed to facilitate new therapeutic trials and improve management of behavioural variant frontotemporal dementia (bvFTD). Since altered white matter integrity is characteristic of bvFTD, this study aimed to determine if plasma levels of myelin-enriched glycolipids are altered in bvFTD and correlate with white matter integrity.

METHODS

Nineteen glycolipids were quantified in bvFTD (n=31) and control (n=26) plasma samples. White matter integrity was assessed using MRI-derived fibre tract density and cross-section (FDC).

RESULTS

Eleven lipids were significantly lower in bvFTD compared to control subjects, seven were inversely correlated with disease duration, and twelve were positively correlated with cognitive performance, with C22:0 hexosylceramide most strongly correlated. FDC was lower in frontotemporal white matter tracts of bvFTD compared to control subjects, and plasma C22:0 hexosylceramide was significantly correlated with FDC in these tracts.

DISCUSSION

Circulating glycolipids may be a valuable biomarker of myelin integrity and disease progression in FTD.
Generation of appropriate protein structures for virtual screening using AlphaFold3 predicted protein–ligand complexes
Authors: Yasumitsu Yuki , Ohue Masahito
Published: February 2025

In early drug discovery, virtual screening—a computational method for selecting candidate compounds—helps reduce development costs. Traditionally, structure-based virtual screening required experimental protein structures, but advances like AlphaFold2 have begun to overcome this limitation. However, AlphaFold2 does not capture ligand-induced conformational changes (transition from apo to holo forms), limiting its utility for protein–ligand docking. In this study, we evaluate AlphaFold3, which predicts protein–ligand complex structures when both protein and ligand inputs are provided. Using the DUD-E dataset and Uni-Dock, we show that holo structures predicted with ligand inclusion yield higher screening performance than apo structures generated without ligand input. Notably, incorporating active ligands enhances screening performance, whereas inactive (decoy) ligands produce results similar to apo predictions. The use of template structures further improves outcomes. We also analyze the impact of ligand molecular weight, binding pocket location, and AlphaFold3 ranking scores on screening performance. Our findings indicate that lower molecular weight ligands tend to generate predicted structures that more closely resemble experimental holo structures, thus improving screening efficacy. Conversely, larger ligands (700–800) can induce open binding pockets that favor screening for some targets. These results suggest that employing AlphaFold3 with appropriate ligand inputs is a promising strategy for virtual screening, particularly for proteins lacking experimental structural data.
Dissecting Force Transmission across SUN Proteins Using Nuclear Tension Sensors
Authors: Wang Jinfeng , Qiu Juhui , Lu Shaoying , Ding Saiyang , Xu Fangning , Luo Yanfeng , Zhou Jing , Peng Qin
Published: February 2025

Forces on the linker of the nucleoskeleton and cytoskeleton (LINC) complex control nuclear mechano-sensing and mechano-adaptation. However, the force transmission dynamics across the LINC complex are not fully understood, mainly because of the lack of imaging tools. We developed a set of genetically-encoded fluorescence resonance energy transfer (FRET)-based nuclear tension sensors (NuTS) that measure tension forces across SUN1/2 proteins in living cells with high sensitivity. SUN2-based NuTS (NuTS2) responded rapidly to mechanical changes in cell contractility and matrix stiffness. Notably, NuTS2 dynamically showed force transmission with high spatiotemporal resolution during cell adhesion, migration and squeeze. We also used NuTS2 to monitor tension force changes as the notochord matures in zebrafish development. NuTS2 detected a gradient tension force that increased from the posterior tail buds to the anterior as vacuoles expanded in notochord cells. Force reduction affected notochord maturation and zebrafish embryo development. Our results provide a biophysical cue for dissecting how force transmission on SUN2 protein regulates embryo development.

Teaser

Nuclear tension sensor (NuTS) was developed for direct force measurement across SUN proteins in living cells and zebrafish.