bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurophysiological correlates of ketamine-induced dissociative state in bipolar disorder: insights from real-world clinical settings
Authors: Agnorelli Claudio , Cinti Alessandra , Barillà Giovanni , Lomi Francesco , Scoccia Adriano , Benelli Alberto , Neri Francesco , Smeralda Carmelo Luca , Cuomo Alessandro , Santarnecchi Emiliano , Tatti Elisa , Godfrey Kate , Tarantino Francesca , Fagiolini Andrea , Rossi Simone 
Published: January 2025

Abstract
Ketamine, a dissociative compound, shows promise in treating mood disorders, including treatment-resistant depression (TRD) and bipolar disorder (BD). Despite its therapeutic potential, the neurophysiological mechanisms underlying ketamine’s effects are not fully understood. This study explored acute neurophysiological changes induced by subanesthetic doses of ketamine in BD patients with depression using electroencephalography (EEG) biomarkers. A cohort of 30 BD (F = 12) inpatients with TRD undergoing ketamine treatment was included in the study. EEG recordings were performed during one of the ketamine infusions with doses ranging from 0.5 to 1 mg/kg, and subjective effects were evaluated using the Clinician-Administered Dissociative States Scale (CADSS). Both rhythmic and arrhythmic features were extrapolated from the EEG signal. Patients who exhibited a clinical response to ketamine treatment within one week were classified as early responders (ER), whereas those who responded later were categorized as late responders (LR). Ketamine reduced low-frequency spectral power density while increasing gamma oscillatory power. Additionally, ketamine flattened the slope of the power spectra, indicating altered scale-free dynamics. Ketamine also increased brain signal entropy, particularly in high-frequency bands. Notably, LR exhibited greater EEG changes compared to ER, suggesting endophenotypic differences in treatment sensitivity. These findings provide valuable insights into the neurophysiological effects of ketamine in BD depression, highlighting the utility of EEG biomarkers for assessing ketamine’s therapeutic mechanisms in real-world clinical settings. Understanding the neural correlates of ketamine response may contribute to personalized treatment approaches and improved management of mood disorders.
Chimeric antigen receptor with novel intracellular modules improves antitumor performance of T cells
Authors: Wang Pengju , Wang Yiyi , Zhao Xiaojuan , Zheng Rui , Zhang Yiting , Meng Ruotong , Dong Hao , Liang Sixin , He Xinyi , Song Yang , Su Haichuan , Yan Bo , Yang An-Gang , Jia Lintao 
Published: January 2025

Abstract
The excessive cytokine release and limited persistence represent major challenges for chimeric antigen receptor T (CAR-T) cell therapy in diverse tumors. Conventional CARs employ an intracellular domain (ICD) from the ζ subunit of CD3 as a signaling module, and it is largely unknown how alternative CD3 chains potentially contribute to CAR design. Here, we obtained a series of CAR-T cells against HER2 and mesothelin using a domain comprising a single immunoreceptor tyrosine-based activation motif from different CD3 subunits as the ICD of CARs. While these reconstituted CARs conferred sufficient antigen-specific cytolytic activity on equipped T cells, they elicited low tonic signal, ameliorated the exhaustion and promoted memory differentiation of these cells. Intriguingly, the CD3ε-derived ICD outperformed others in generation of CAR-T cells that produced minimized cytokines. Mechanistically, CD3ε-based CARs displayed a restrained cytomembrane expression on engineered T cells, which was ascribed to endoplasmic reticulum retention mediated by the carboxyl terminal basic residues. The present study demonstrated the applicability of CAR reconstitution using signaling modules from different CD3 subunits, and depicted a novel pattern of CAR expression that reduces cytokine release, thus paving a way for preparation of CAR-T cells displaying improved safety and persistence against diverse tumor antigens.
Safety and efficacy of the ROCK-2-inhibitor Belumosudil in cGvHD treatment - a retrospective, German-Swiss multicenter real-world data analysis
Authors: Heidenreich Silke , Egger-Heidrich Katharina , Halter Jörg P. , Jost Lasse , Stölzel Friedrich , Perl Markus , Denk Alexander , Edinger Matthias , Herr Wolfgang , Kröger Nicolaus , Wolff Daniel , Ayuk Francis , Fante Matthias A. 
Published: January 2025

Abstract
Belumosudil is a first in class ROCK2-inhibitor approved by the FDA for the 3rd line treatment of chronic graft-versus-host disease (cGvHD). In this retrospective real-world analysis, we report safety and efficacy data of belumosudil treatment from 5 German/Swiss transplant centers. A total of 33 adult patients (median age 59 years) with moderate (n = 2) or severe (n = 31) cGvHD were treated on individual request due to lack of EMA approval. The patient cohort had a long history of cGvHD (median 44 months) and was heavily pretreated (median 4 prior lines). The overall response rate was 42% (95%CI, 25–60%) including organ responses in all organs except the liver (n = 2). The median time to response was 3 months (range, 1–9 months) and 8 of 14 patients (57%) had a durable response at last follow-up. One-third of patients had at least a 50% reduction in concomitant corticosteroid dosage. Median failure-free survival and median overall survival were 16.5 and 23.1 months, respectively. Adverse events ≥CTCAE grade 3 were reported in 27% of patients, with a predominance of infectious events, including one fatal course. The results are consistent with previous prospective trials including a favorable safety profile, while acknowledging the challenges of a heavily pretreated patient cohort.
The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer’s disease
Authors: Sha Xudong , Lin Jiayuan , Wu Kexin , Lu Jia , Yu Zhihua 
Published: January 2025

Abstract
Microglia are progressively activated by inflammation and exhibit phagocytic dysfunction in the pathogenesis of neurodegenerative diseases. Lipid-droplet-accumulating microglia were identified in the aging mouse and human brain; however, little is known about the formation and role of lipid droplets in microglial neuroinflammation of Alzheimer’s disease (AD). Here, we report a striking buildup of lipid droplets accumulation in microglia in the 3xTg mouse brain. Moreover, we observed significant upregulation of PKM2 and sterol regulatory element binding protein 1 (SREBP1) levels, which were predominantly localized in microglia of 3xTg mice. PKM2 dimerization was necessary for SREBP1 activation and lipogenesis of lipid droplet-accumulating microglia. RNA sequencing analysis of microglia isolated from 3xTg mice exhibited transcriptomic changes in lipid metabolism, innate inflammation, and phagocytosis dysfunction; these changes were improved with capsaicin-mediated pharmacological activation of TRPV1 via inhibition of PKM2 dimerization and reduction of SREBP1 activation. Lipid droplet-accumulating microglia exhibited increased mitochondrial injury accompanied by impaired mitophagy, which was abrogated upon of TRPV1 activation. Capsaicin also rescued neuronal loss, tau pathology, and memory impairment in 3xTg mice. Our study suggests that TRPV1-PKM2-SREBP1 axis regulation of microglia lipid metabolism could be a therapeutic approach to alleviate the consequences of AD.
Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53
Authors: Wang Yidan , Kroll Todd G. , Hao Linhui , Wen Zhi 
Published: January 2025

Abstract
The orphan nuclear receptor NR2E3 has emerged as a potential tumor suppressor, yet its precise mechanisms in tumorigenesis require further investigation. Here, we demonstrate that the full-length protein isoform of NR2E3 instead of its short isoform activates wild-type p53 and is capable of rescuing certain p53 mutations in various cancer cell lines. Importantly, we observe a higher frequency of NR2E3 mutations in three solid tumors compared to the reference population, highlighting its potential significance in tumorigenesis. Specifically, we identify a cancer-associated NR2E3R97H mutation, which not only fails to activate p53 but also impedes NR2E3WT-mediated p53 acetylation. Moreover, we show that the small-molecule agonist of NR2E3, 11a, penetrates tumor mass of uterine cancer patients and increases p53 activation. Additionally, both NR2E3 and 11a exhibit similar multifaceted anti-cancer properties, underscoring NR2E3 as a novel molecular vulnerability in cancer cells. We further explore drug repurposing screens of FDA-approved anti-cancer drugs to develop NR2E3-targeted combinatorial treatments, such as the 11a-Romidepsin combination in HeLa cells. The underlying molecular mechanisms of these drug synergies include the activation of p53 pathway and inhibition of oncogenic pathway like MYC. Overall, our findings suggest that NR2E3 holds promise as a therapeutic target for cancer treatment, offering new avenues for effective anti-cancer strategies.
Gap junction intercellular communications regulates activation of SARM1 and protects against axonal degeneration
Authors: Zhu Wen Jie , Liu Jun , Li Wan Hua , Zhao Zhi Ying , Huang Chongquan , Yang Jian Yuan , Lee Hon Cheung , Zhao Yong Juan 
Published: January 2025

Abstract
Sterile alpha and Toll/interleukin-1 receptor motif containing 1 (SARM1), a nicotinamide adenine dinucleotide (NAD)-utilizing enzyme, mediates axon degeneration (AxD) in various neurodegenerative diseases. It is activated by nicotinamide mononucleotide (NMN) to produce a calcium messenger, cyclic ADP-ribose (cADPR). This activity is blocked by elevated NAD level. Here, we verified this metabolic regulation in somatic HEK-293T cells by overexpressing NMN-adenyltransferase to elevate cellular NAD, which resulted not only in inhibition of their own SARM1 from producing cADPR but, surprisingly, also in the 5–10 neighboring wildtype cells in mixed cultures via connexin (Cx)-43. Direct visualization of gap junction intercellular communication (GJIC) was achieved by incubating cells with a permeant probe, PC11, which is converted by SARM1 into PAD11, a fluorescent NAD analog capable of traversing GJs. Extending the findings to dorsal root ganglion neurons, we further showed that CZ-48, a permeant NMN analog, or axotomy, activated SARM1 and the produced PAD11 was transferred to contacting axons via GJIC. The gap junction involved was identified as Cx36 instead. This neuronal GJIC was demonstrated to be functional, enabling healthy neurons to protect adjacent axotomized axons from degeneration. Inhibition of GJIC in mice by AAV-PHP.eB-mediated knockdown of Cx36 in brain induced neuroinflammation, which in turn activated SARM1 and resulted in axon degeneration as well as behavioral deficits. Our results demonstrate a novel intercellular regulation mechanism of SARM1 and reveal a protective role of healthy tissue against AxD induced by injury or neuroinflammation.
A patient with TPCN2-related hypopigmentation and ocular phenotype
Authors: Courdier Cécile , Michaud Vincent , Diallo Modibo , Plaisant Claudio , Lasseaux Eulalie , Helot Isabelle , Philippe Elodie , Vrielynck Els , Willems Marjolaine , Arveiler Benoit 
Published: January 2025

Abstract
Pigmentation is orchestrated by hundreds of genes involved in cellular functions going from early developmental fate of pigment cells to melanin synthesis. The Two Pore Channel 2 (TPC2) a Ca2+ and Na+ channel acidifies melanosomal pH and thus inhibits pigmentation. A young patient was recently reported with generalized hypopigmentation but uneventful ocular examination, caused by the de novo heterozygous TPCN2 variant c.628C>T;p.Arg210Cys that constitutively activates TPC2. Here we report a young patient with the same de novo variant presenting with generalized hypopigmentation, and ophthalmologic features including low grade retinal hypopigmentation and foveal hypoplasia, photophobia, mild hypermetropia, and astigmatism, which are features of albinism. Skin fragility and episodes of fever with diarrhea and fatigue were also observed. This extends the phenotype of patients with TPCN2 variants, warranting further investigations in patients with alterations of this gene, and raises the question whether TPCN2 might be considered as an albinism gene.
Clade 2.3.4.4b but not historical clade 1 HA replicating RNA vaccine protects against bovine H5N1 challenge in mice
Authors: Hawman David W. , Tipih Thomas , Hodge Eddie , Stone E. Taylor , Warner Nikole , McCarthy Natalie , Granger Brian , Meade-White Kimberly , Leventhal Shanna , Hatzakis Kiara , Park Stephanie , Gaffney Karen , Rosenke Kyle , Erasmus Jesse H. , Feldmann Heinz 
Published: January 2025

Abstract
The ongoing circulation of influenza A H5N1 in the United States has raised concerns of a pandemic caused by highly pathogenic avian influenza. Although the United States has stockpiled and is prepared to produce millions of vaccine doses to address an H5N1 pandemic, currently circulating H5N1 viruses contain multiple mutations within the immunodominant head domain of hemagglutinin (HA) compared to the antigens used in stockpiled vaccines. It is unclear if these stockpiled vaccines will need to be updated to match the contemporary H5N1 strains. Here we show that a replicating RNA vaccine expressing the HA of an H5N1 isolated from a US dairy cow confers complete protection against homologous lethal challenge in mice. A repRNA encoding the HA of a clade 1 H5 from 2004 (A/Vietnam/1203/2004) as utilized by some stockpiled vaccines, confers only partial protection. Our data highlight the utility of nucleic acid vaccines to be rapidly updated to match emergent viruses of concern while demonstrating that contemporary bovine H5N1 viruses can evade immunity elicited by historical HA antigens.
Intelligent in-cell electrophysiology: Reconstructing intracellular action potentials using a physics-informed deep learning model trained on nanoelectrode array recordings
Authors: Rahmani Keivan , Yang Yang , Foster Ethan Paul , Tsai Ching-Ting , Meganathan Dhivya Pushpa , Alvarez Diego D. , Gupta Aayush , Cui Bianxiao , Santoro Francesca , Bloodgood Brenda L. , Yu Rose , Forro Csaba , Jahed Zeinab 
Published: January 2025

Abstract
Intracellular electrophysiology is essential in neuroscience, cardiology, and pharmacology for studying cells’ electrical properties. Traditional methods like patch-clamp are precise but low-throughput and invasive. Nanoelectrode Arrays (NEAs) offer a promising alternative by enabling simultaneous intracellular and extracellular action potential (iAP and eAP) recordings with high throughput. However, accessing intracellular potentials with NEAs remains challenging. This study presents an AI-supported technique that leverages thousands of synchronous eAP and iAP pairs from stem-cell-derived cardiomyocytes on NEAs. Our analysis revealed strong correlations between specific eAP and iAP features, such as amplitude and spiking velocity, indicating that extracellular signals could be reliable indicators of intracellular activity. We developed a physics-informed deep learning model to reconstruct iAP waveforms from extracellular recordings recorded from NEAs and Microelectrode arrays (MEAs), demonstrating its potential for non-invasive, long-term, high-throughput drug cardiotoxicity assessments. This AI-based model paves the way for future electrophysiology research across various cell types and drug interactions.
Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling
Authors: Kentistou Katherine A. , Lim Brandon E. M. , Kaisinger Lena R. , Steinthorsdottir Valgerdur , Sharp Luke N. , Patel Kashyap A. , Tragante Vinicius , Hawkes Gareth , Gardner Eugene J. , Olafsdottir Thorhildur , Wood Andrew R. , Zhao Yajie , Thorleifsson Gudmar , Day Felix R. , Ozanne Susan E. , Hattersley Andrew T. , O’Rahilly Stephen , Stefansson Kari , Ong Ken K. , Beaumont Robin N. , Perry John R. B. , Freathy Rachel M. 
Published: January 2025

Abstract
Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 participants. Rare protein-truncating and deleterious missense variants are collapsed to perform gene burden tests. We identify 9 genes; 5 with fetal-only effects on birth weight, 1 with maternal-only effects, 3 with both, and observe directionally concordant associations in an independent sample. Four of the genes were previously implicated by GWAS of birth weight. IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (fetal-acting) are involved in adipose tissue regulation, and the latter two also show associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG (fetal-acting) in adipocyte differentiation and placental angiogenesis. NOS3 (fetal and maternal-acting), NRK (fetal), and ADAMTS8 (maternal-acting) have been implicated in placental function and hypertension. To conclude, our analysis of rare coding variants identifies regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, and further evidence for the role of insulin-like growth factors.
Systems immunology integrates the complex endotypes of recessive dystrophic epidermolysis bullosa
Authors: Hirt Nell , Manchon Enzo , Chen Qian , Delaroque Clara , Corneau Aurelien , Hemon Patrice , Saker-Delye Safaa , Bataille Pauline , Bouaziz Jean-David , Bourrat Emmanuelle , Hovnanian Alain , Le Buanec Helene , Aoudjit Fawzi , El Costa Hicham , Jabrane-Ferrat Nabila , Al-Daccak Reem 
Published: January 2025

Abstract
Endotypes are characterized by the immunological, inflammatory, metabolic, and remodelling pathways that explain the mechanisms underlying the clinical presentation (phenotype) of a disease. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering disease caused by COL7A1 pathogenic variants. Although underscored by animal studies, the endotypes of human RDEB are poorly understood. To fill this gap, we apply systems immunology approaches using single-cell high-dimensional techniques to capture the signature of peripheral immune cells and the diversity of metabolic profiles in RDEB adults, sampled outside of any opportunistic infection and active cancer. Our study, demonstrates the particular inflammation and immunity characteristics of RDEB adults, with activated / effector T and dysfunctional natural killer cell signatures, concomitant with an overall pro-inflammatory lipid signature. Artificial intelligence prediction models and principal component analysis stress that RDEB is not solely confined to cutaneous issues but has complex systemic endotypes marked by immune dysregulation and hyperinflammation. By characterising the phenotype-endotype association in RDEB adults, our study lays the groundwork for translational interventions that could by lessening inflammation, alleviate the everlasting suffering of RDEB patients, while awaiting curative genetic therapies.
Vialess heterogeneous skin patch for multimodal monitoring and stimulation
Authors: Lee Hyeokjun , Song Soojeong , Yea Junwoo , Ha Jeongdae , Oh Saehyuck , Jekal Janghwan , Hong Myung Seok , Won Chihyeong , Jung Han Hee , Keum Hohyun , Han Sangyoon , Cho Jeong Ho , Lee Taeyoon , Jang Kyung-In 
Published: January 2025

Abstract
System-level wearable electronics require to be flexible to ensure conformal contact with the skin, but they also need to integrate rigid and bulky functional components to achieve system-level functionality. As one of integration methods, folding integration offers simplified processing and enhanced functionality through rigid-soft region separation, but so far, it has mainly been applied to modality of electrical sensing and stimulation. This paper introduces a vialess heterogeneous skin patch with multi modalities that separates the soft region and strain-robust region through folded structure. Our system includes electrical and optical modalities for hemodynamic and cardiovascular monitoring, and a force-electrically driven micropump for drug delivery. Each modality is demonstrated through on-demand drug delivery, flexible waveguide-based PPG monitoring, and ECG and body movement monitoring. Wireless data transmission and real-time measurement validate the feedback operation for multi-modalities. This engineered closed-loop platform offers the possibility for broad applications, including cardiovascular monitoring and chronic disease management.
White light-emitting electrochemical cells based on metal-free TADF emitters
Authors: Tang Shi , Tsuchiya Youichi , Wang Jia , Adachi Chihaya , Edman Ludvig 
Published: January 2025

Abstract
The attainment of white emission from a light-emitting electrochemical cell (LEC) is important, since it enables illumination and facile color conversion from devices that can be cost-efficient and sustainable. However, a drawback with current white LECs is that they either employ non-sustainable metals as an emitter constituent or are intrinsically efficiency limited by that the emitter only converts singlet excitons to photons. Organic compounds that emit by thermally activated delayed fluorescence (TADF) can address these issues since they can harvest all excitons for light emission while being metal free. Here, we report on the first white LEC based on solely metal-free TADF emitters, as accomplished through careful tuning of the energy-transfer processes and the electrochemically formed doping structure in the single-layer active material. The designed TADF-LEC emits angle-invariant white light (color rendering index = 88) with an external quantum efficiency of 2.1 % at a luminance of 350 cd/m2.
Expression of some circulating microRNAs as predictive biomarkers for prognosis and treatment response in glioblastoma
Authors: Ali Elham , Ahmed Marwa Adel , Shawki May A. , El Arab Lobna R. Ezz , Khalifa Mohamed K. , Swellam Menha 
Published: January 2025

Abstract
Glioblastoma multiforme (GBM) is the most prevalent, treatment-resistant, and fatal form of brain malignancy. It is characterized by genetic heterogeneity, and an infiltrative nature, and GBM treatment is highly challenging. Despite multimodal therapies, clinicians lack efficient prognostic and predictive markers. Therefore, new insights into GBM management are urgently needed to increase the chance of therapeutic success. Circulating miRNAs (miRs) are important regulators of cancer progression and are potentially useful for GBM diagnosis and treatment. This study investigated how miR-29a, miR-106a, and miR-200a affect the prognosis of GBM patients. This study was conducted on 25 GBM patients and 20 healthy volunteers as a control group. The expression levels of target miRs were analyzed pre- and post-treatment using qRT-PCR and evaluated in relation to both clinical GBM criteria and the patient’s survival modes. The diagnostic efficacy of target miRs was assessed using the receiver operating characteristic (ROC) curve. MiRs levels showed significant differences among the enrolled participants. All investigated miRs were significantly elevated in GBM patients with non-frontal lesions. Only miR-200a showed a significant difference in GBM patients older than 60 years with a tumor size ≥ 5 mm. Regarding miR-106a, a significant difference was detected based on the surgical strategy and use of an Eastern Cooperative Oncology Group (ECOG) performance status equal to 2. For miR-29a, a significant upregulation was detected according to the surgical strategy. All post-treatment miRs levels in GBM patients were significantly downregulated. In conclusion, circulating miRs revealed a significant role in predicting GBM patient treatment outcomes providing valuable insights for personalized therapeutic strategies.