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Automated phenotyping of rodent behavior in the Cylinder Exploration Test using machine learning
No full textRodent models are essential in neuroscience research for investigating brain function, CNS disease mechanisms, and therapeutic interventions. Beyond molecular and physiological analyses, precise behavioral characterization provides crucial functional readouts of neural circuit changes. Accurate behavioral phenotyping is critical for detecting genotype-phenotype relationships, enabling cross-model comparisons, and supporting translational research. Here we developed a machine learning framework for automated rodent behavior analysis in the Cylinder Exploration Test (CET) using pose estimation and explainable machine learning. The framework quantifies freezing, rearing, exploratory movement, and general locomotion activity while identifying key behavioral features that differentiate between experimental conditions. To validate this approach, we phenotyped two rat strains with dopaminergic and serotonergic dysfunction: dopamine transporter knockout (DAT-KO), tryptophan hydroxylase 2 knockout (Tph2-KO), and their wild-type controls. The analysis successfully identified distinct strain-specific behavioral phenotypes and characterized the discriminative features between genotypes, achieving high classification accuracy (AUC = 0.84 for DAT-KO versus DAT-WT and AUC = 0.98 for Tph2-KO versus Tph2-WT). These findings demonstrate that automated Cylinder Exploration Test can detect genotype-specific signatures and establish a scalable method for standardized phenotyping in neuroscience and preclinical research
**Response to ACC-D_25-00707: on the cardiac tamponade scoring system in the 2025 ESC guidelines*
No full textEndogenous retroviral elements LTR8B and MER65 regulate the PSG9 locus that promotes trophoblast syncytialization: insights into placental evolution and pre-eclampsia pathology
Full text linkBACKGROUND: Understanding the causes of the exceptional rate of evolution of the mammalian placenta is likely to aid the understanding of placental development and the aetiology of the human-specific pregnancy disorder pre-eclampsia (PE). As retroelements (REs) are often lineage-specific and known to be co-opted for placental functioning, here we consider the RE binding of GATA3 and DLX5, these transcription factors being dysregulated in PE, and their downstream consequences. METHODS: Multiomics analyses identified the retroviral regulatory sequence LTR8B in the PSG gene array, as a contributor to expression diversification in the placenta. To characterize this genomic domain, we performed copy number variation analysis and whole-genome sequencing. Multiomics data was employed to identify loci that might act as an active chromatin loop boundary around the PSG region. CRISPR-Cas9 knockouts with aligned RNAseq and epigenetic mark data tested for trophoblast-specific cis-regulatory elements (CREs-enhancer and/or promoter sequences) of resulting loci. Functional assays were employed to characterize the phenotypic effects of a candidate locus. Structural analysis of PSG family members also identified an additional RE, MER65-int. RNA-seq and antibody staining was employed to consider polyadenylation and functional diversification. RESULTS: The LTR8B CRE facilitates the binding of transcription factors (e.g., GATA3, DLX5, TFAP2A/C), resulting in a diversified PSG gene expression pattern within a primate-specific genomic region that exhibits high intraspecies variability. The LTR8B/PSG9 regulatory element influences other PSG family members. PSG9, unique among PSGs, produces both secreted and membrane-anchored isoforms, MER65-int providing alternative polyA signals, enabling the evolution of secreted PSG variants through the truncation of the ancestral CEACAM protein’s transmembrane domain. The LTR8B/PSG9 locus regulates the differentiation of multinucleated trophoblasts (syncytialization) and, like chorionic gonadotropin and syncytin1, determines the identity of syncytiotrophoblasts. Notably, PSG9 is the most upregulated PSG in PE, with levels correlated with GATA3 and DLX5 levels. CONCLUSIONS: REs contribute to the structural and expression evolution of PSG genes, facilitating lineage-specific placental evolution. The LTR8B/PSG9 regulatory network plays a central role in syncytiotrophoblast differentiation. Given the association between DLX5/GATA3 dysregulation and elevated PSG9 levels, along with PSG9’s expression in the first trimester, PSG9 shows potential as a predictive biomarker for PE
Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming
Full text linkSpatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to upregulation of the cysteine-generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naive to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature ageing, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Notably, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases
Current treatment strategies for first relapse of high-risk neuroblastoma
Full text linkMore than 50 % of patients with high-risk neuroblastoma (HRNB) will relapse despite intensive multimodal therapy. Most relapses occur within 2 years of diagnosis. Overall survival at relapse is 20 % at 4 years, but long-term survival can be achieved in a patient subset. A biopsy at relapse with in-depth molecular characterization should now become accepted as standard of care to confirm active neuroblastoma and identify potential targets for biomarker-based targeted therapy or immunotherapy. No clear consensus currently exists about optimal therapy because the field lacks umbrella trials covering all phases of relapse treatment (re-induction, consolidation, maintenance) in a homogenous strategy. Recruitment into clinical trials (e.g. BEACON2) should be prioritized. Current evidence supports starting re-induction therapy with a camptothecin-based chemotherapy regimen combined with monoclonal antibody therapy targeting GD2 or VEGF (or ALK inhibitors if ALK-aberrant) as the first choice. The RIST regimen is a promising first choice for MYCN-amplified disease. After an objective response to re-induction therapy, GD2-directed immunotherapy or cellular therapies harnessing the immune system (haploidentical stem cell transplantation, CAR T cells) are of high interest as a consolidation strategy. Long-term maintenance therapy must be feasible as outpatient treatment, have a low toxicity profile and be well-tolerable to suit patients with relapsed HRNB. For optimal care, new options must be tested as maintenance therapy in randomized trials. The most promising salvage options for patients responding insufficiently to treatment are the chemotherapy combinations, topotecan/vincristine/doxorubicin (TVD), topotecan/cyclophosphamide/etoposide (TCE), ifosfamide/carboplatin/etoposide (ICE) or topotecan/cyclophosphamide (TopoCy), or [I]-mIBG therapy. Early-phase clinical trials are also a possible option in this setting
Temporomandibuläre Störungen: Prävalenz und assoziierte biopsychosoziale Faktoren. Eine Analyse von Daten der NAKO Gesundheitsstudie
No full textHINTERGRUND: Der Ausdruck „temporomandibuläre Störungen“ (TMD) bezeichnet als Überbegriff Beschwerden im Bereich der Kiefergelenke und Kaumuskulatur. TMD gehören zu den häufigsten Ausprägungen muskuloskelettaler Schmerzen. Bisherige Prävalenzschätzungen sind jedoch methodisch limitiert. Die NAKO Gesundheitsstudie ermöglicht erstmals eine untersuchungsbasierte Schätzung der Prävalenz schmerzhafter TMD in einer großen Bevölkerungsstichprobe. METHODE: Die Basiserhebung (2014–2019) umfasste eine Teilstichprobe mit standardisierten Untersuchungen zur Kiefermobilität und Palpation der Kaumuskulatur. Schmerzhafte TMD wurden erfasst, wenn eine positive Schmerzanamnese mit lokalisierbarem und provozierbarem Schmerz kombiniert war. Rohe und adjustierte Prävalenzen wurden berechnet und der Zusammenhang mit potenziellen ätiologischen und assoziierten Faktoren mittels logistischer Regression analysiert. ERGEBNISSE: Von 20 603 Teilnehmenden berichteten 10,9 % von Kiefer- oder Gesichtsschmerzen innerhalb des letzten Monats. Die Punktprävalenz schmerzhafter TMD betrug 3,7 %, in der Altersgruppe 20–29 Jahre 6 %. Frauen hatten eine 2,72-fache Odds Ratio; 95-%-Konfidenzintervall: [2,28; 3,25]. Ein ebenfalls erhöhtes Risiko hatten Raucherinnen und Raucher (1,42 [1,16; 1,74]), Personen mit Schlafproblemen (1,96 [1,6; 2,4]), mit Kindheitstraumata (1,11 [1,08; 1,14] pro Skalenpunkt), Ängstlichkeit (1,12 [1,09; 1,14] pro Skalenpunkt) oder Depressivität (1,11 [1,09; 1,13] pro Skalenpunkt). Bei kieferorthopädischer Behandlung vor dem 19. Lebensjahr war die Chance auf schmerzhafte TMD weder vergrößert noch verringert. Von der Norm abweichende Zahn- und Kieferstellungen waren mit geringerer Prävalenz assoziiert. SCHLUSSFOLGERUNG: Schmerzhafte TMD sind ein häufiges Gesundheitsproblem, das nicht mit dental-morphologischen, sondern diversen biopsychosozialen Faktoren assoziiert ist. Die Ergebnisse unterstreichen die Notwendigkeit interdisziplinärer Diagnostik und Therapie
Alpha-actinin-3 deficiency links genetic susceptibility to renal fibrosis: evidence from hemodialysis patients and murine models
Full text linkThe X allele of ACTN3 R577X polymorphism results in α-actinin-3 deficiency and has been associated with muscle damage and impaired recovery. While its role has been explored in musculoskeletal and cardiac contexts, no studies have evaluated its impact on chronic kidney disease (CKD). To investigate the prevalence of the ACTN3 R577X polymorphism in patients with end-stage renal disease undergoing hemodialysis (HD) and explore its potential involvement in renal fibrosis through experimental models. A total of 217 HD patients and 413 healthy controls were genotyped for the ACTN3 R577X polymorphism. Associations with clinical variables were analyzed using multivariate regression. Renal Actn3 expression was evaluated in mice subjected to folic acid-induced acute and chronic kidney injury. In vitro, fibroblasts were exposed to TGF-β or LPS to assess gene expression responses. The X allele was significantly more frequent in HD patients (83.7% vs. 64.4%, p < 0.0001), and XX individuals began HD up to 11 years earlier than RR homozygotes. Experimental models showed persistent upregulation of Actn3 in fibrotic kidneys and in TGF-β-treated fibroblasts, but not in inflammatory conditions. Actn3 expression paralleled that of fibrosis markers such as Col1a1 and Acta2. The ACTN3 X allele is associated with earlier onset of renal failure and increased susceptibility to tubulointerstitial disease. Experimental data support its involvement in renal fibrosis. ACTN3 genotyping may help identify patients at greater risk for CKD progression
The functional role of glial cells in the pathologic brain as reviewed by Alois Alzheimer in 1910
Full text linkAlois Alzheimer is known for the clinical diagnosis and neuropathological analysis of the neurodegenerative disease named after him. Yet, a less celebrated but equally fundamental contribution lies in his monograph, “Contributions to the knowledge of the pathologic neuroglia and their relationship to degenerative processes in the nervous tissue.” This work, now translated, meticulously details the dynamic role of glial cells in brain pathology, a paradigm-shifting concept for its time. Alzheimer applied then-novel staining techniques -including adaptations of Scharlach red and Mallory hematoxylin- to visualize lipids and protoplasmic degradation in post-mortem human brains. These approaches revealed striking changes in the glial network across disorders ranging from stroke and trauma to multiple sclerosis, syphilis-related dementia, various forms of neurodegeneration, and schizophrenia. He documented the appearance of two novel glial forms, which he termed “ameboid glia” and “glial granule cells”, involved in the phagocytosis of “fatty matter” and “lipoid substances” from degenerating nervous tissue. He also documented “neuronophagia,” where glial cells appeared to directly interact with and “dissolve” damaged neurons. This work laid the conceptual groundwork for modern neuroscience. We now recognize Alzheimer’s “ameboid glia” as the earliest documented observations of activated microglia and astrocytes, and his descriptions of glia’s engagement with cellular damage provided the first evidence for what we now call neuroinflammation. His methodical approach and detailed observations proved that glial cells are not passive bystanders but central, active players that sense, respond to, and shape the course of brain diseases. The English translation and the original German text can be found in the attachment
Quantitative confounder analysis of electrocardiogram signals in cardiac magnetic resonance at 1.5, 3 and 7 T-assessing standardized electrode positions and sequence types-towards quality assurance
Full text linkBACKGROUND: The electrocardiogram (ECG) used for gating in cardiac MRI may be compromised by multiple confounders inside the scanner bore. PURPOSE: To quantify the influence of magnetic field strengths (1.5 T/3 T/7 T), standardized electrode positions, and imaging sequences on ECG signals used for gating. STUDY TYPE: Prospective. POPULATION: Sixteen healthy volunteers (eight male; mean age 26.25 ± 7.67 years). FIELD STRENGTH/SEQUENCE: Balanced steady-state free precession cine (1.5 T/3 T), fast low-angle shot cine (7 T), and 4D flow (1.5 T/3 T/7 T) sequences. ASSESSMENT: ECG-signals were recorded during breath-hold and non-breath-hold short axis cine (sax-bh and sax-nbh, respectively) and 4D flow scans at 1.5 T/3 T/7 T. All scans were repeated with 4 standardized electrode positionings (pos1-4) at each field strength. Pos1/2 were vendor-recommended positionings for 1.5 T/3 T/7 T scans, respectively, whereas pos3/4 were alternative positionings recommended in previous studies. Similarity between confounded ECG-signals and unconfounded baseline ECG-signals was assessed by QRS-feature correlation. Cine image quality (IQ) was assessed by 3 readers (with 6, 10, and 22 years experience) on a four-point Likert scale. STATISTICAL TESTS: Linear mixed models with type III tests of fixed effects (overall) and t tests with adjusted degrees of freedom (pairwise subgroup-comparisons) at significance level p < 0.05. RESULTS: Increasing field strength resulted in significantly decreasing similarity to baseline measurements, with r values (provided with 95% confidence interval) of 1.5 T: 97% (92.6-101.3); 3 T: 91.4% (87.1-95.8); 7 T: 50.4% (46-54.9) and lower IQ: 1.5 T: 2.33 (2.12-2.55); 3 T: 1.96 (1.75-2.17); 7 T: 0.91 (0.7-1.12). Vendor-specified electrode positions pos1: 91.8% (87.2-96.5), pos2: 88.3% (83.7-92.9) showed significantly higher correlation with baseline measurements than alternative positions pos3: 67.5% (62.9-72.1) and pos4: 70.8% (66.2-75.4). The evaluated standardized sequences showed similar amounts of electrocardiogram distortion, with r values of: sax-bh: 77.3% (73-81.7); 4D: 79.3% (75-83.7), p = 0.54; sax-nbh: 82.1% (77.8-86.5), p = 0.31, but the difference between sax-bh and sax-nbh: 4.8% (2.88-6.72) was significant. DATA CONCLUSION: Increasing field strength leads to significant ECG signal distortions. Vendor-specified positions 1/2 resulted in less distorted ECG signals than alternative positions 3/4 recommended in previous publications. TECHNICAL EFFICACY: Stage 5
Cystine import and oxidative catabolism fuel vascular growth and repair via nutrient-responsive histone acetylation
Full text linkEndothelial metabolism underpins tissue regeneration, health, and longevity. We uncover a nuclear oxidative catabolic pathway linking cystine to gene regulation. Cells preparing to proliferate upregulate the SLC7A11 transporter to import cystine, which is oxidatively catabolized by cystathionine-γ-lyase (CSE) in the nucleus. This generates acetyl units via pyruvate dehydrogenase, driving site-specific histone H3 acetylation and chromatin remodeling that sustain endothelial transcription and proliferation. Combined loss of SLC7A11 and CSE abolishes cystine oxidative and reductive metabolism and causes embryonic lethality, whereas single deletions reveal distinct effects. SLC7A11 deficiency triggers compensatory cysteine de novo biosynthesis, partially maintaining angiogenesis, while CSE deletion disrupts nuclear cystine oxidative catabolism, transcription, and vessel formation. Therapeutically, cystine supplementation promotes vascular repair in retinopathy of prematurity, myocardial infarction, and injury in aging. These findings establish the role of cystine nuclear oxidative catabolism as a fundamental metabolic axis coupling nutrient utilization to gene regulation, with implications for vascular regeneration