Heterozygous pathogenic variants in KDM6B have recently been associated to a rare neurodevelopmental disorder referred to as \"Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities\" and characterized by non-pathognomonic facial and body dysmorphisms, a wide range of neurodevelopmental and behavioral disorders and nonspecific neuroradiological findings. KDM6B encodes a histone demethylase, expressed in different tissues during development, which regulates gene expression through the modulation of chromatin accessibility by RNA polymerase. We herein describe a 11-year-old male patient carrying a novel de novo pathogenic variant in KDM6B exhibiting facial dysmorphisms, dysgraphia, behavioral traits relatable to oppositional defiant, autism spectrum, and attention deficit hyperactivity disorders, a single seizure episode, and a neuroimaging finding of a single cerebellar heterotopic nodule, never described to date in this genetic condition. These findings expand the phenotypic spectrum of this syndrome, highlighting the potential role for KDM6B in cerebellar development and providing valuable insights for genetic counseling.

Resistance training (RT) with blood flow restriction (BFR) or high intensity (HI) are effective to increase muscle mass. To understand this effect, techniques known as \"omics\" are used to identify possible biomarkers. This study analyzed the salivary proteomic profile of healthy individuals trained before and after two RT protocols both designed with eight exercises for upper- and lower-limbs, one performed at low percentage of one-maximum repetition (%1RM) with BFR technique, and other at high %1RM (HI) without BRF technique. Four healthy males between 18 and 28 years participated in the study. Stimulated saliva was collected before (BBFR/BHI) and immediately after (ABFR/AHI) the two RT protocols. All protein-related processing was performed using label-free proteomic. The difference in expression between groups was expressed as p < .05 for downregulated proteins and 1-p > .95 for upregulated proteins. There was difference in salivary flow between ABFR and BBFR (p = .005). For HI, 87 proteins were found after the practice and 119 before. Three hemoglobin isoforms were increased in AHI compared with BHI. In the BFR comparison, 105 proteins were identified after (ABFR) and 70 before (BBFR). Among those increased ABFR, we highlight five hemoglobin isoforms and Deleted in malignant brain tumors 1 protein. Between ABFR and AHI, 17 isoforms of histones, Transaldolase, Transketolase, Glyceraldehyde-3-phosphate dehydrogenase, and Antileukoproteinase were decreased ABFR. For HI, there was an increase in proteins related to oxidative stress and metabolism of the musculoskeletal system, compared with BFR. HI seems to induce higher anabolic signaling to muscle mass increase and antiatherosclerotic effects.

Genome sequencing has identified hundreds of histone post-translational modifications (PTMs) that define an open or compact chromatin nanostructure at the level of nucleosome proximity, and therefore serve as activators or repressors of gene expression. Direct observation of this epigenetic mode of transcriptional regulation in an intact single nucleus, is however, a complex task. This is because despite the development of fluorescent probes that enable observation of specific histone PTMs and chromatin density, the changes in nucleosome proximity regulating gene expression occur on a spatial scale well below the diffraction limit of optical microscopy. In recent work, to address this research gap, we demonstrated that the phasor approach to fluorescence lifetime imaging microscopy (FLIM) of Förster resonance energy transfer (FRET) between fluorescently labelled histones core to the nucleosome, is a readout of chromatin nanostructure that can be multiplexed with immunofluorescence (IF) against specific histone PTMs. Here from application of this methodology to gold standard gene activators (H3K4Me3 and H3K9Ac) versus repressors (e.g., H3K9Me3 and H3K27Me), we find that while on average these histone marks do impart an open versus compact chromatin nanostructure, at the level of single chromatin foci, there is significant spatial heterogeneity. Collectively this study illustrates the importance of studying the epigenetic landscape as a function of space within intact nuclear architecture and opens the door for the study of chromatin foci sub-populations defined by combinations of histone marks, as is seen in the context of bivalent chromatin.

MD simulations can provide uniquely detailed models of intrinsically disordered proteins (IDPs). However, these models need careful experimental validation. The coefficient of translational diffusion Dtr, measurable by pulsed field gradient NMR, offers a potentially useful piece of experimental information related to the compactness of the IDP\'s conformational ensemble. Here, we investigate, both experimentally and via the MD modeling, the translational diffusion of a 25-residue N-terminal fragment from histone H4 (N-H4). We found that the predicted values of Dtr, as obtained from mean-square displacement of the peptide in the MD simulations, are largely determined by the viscosity of the MD water (which has been reinvestigated as a part of our study). Beyond that, our analysis of the diffusion data indicates that MD simulations of N-H4 in the TIP4P-Ew water give rise to an overly compact conformational ensemble for this peptide. In contrast, TIP4P-D and OPC simulations produce the ensembles that are consistent with the experimental Dtr result. These observations are supported by the analyses of the 15N spin relaxation rates. We also tested a number of empirical methods to predict Dtr based on IDP\'s coordinates extracted from the MD snapshots. In particular, we show that the popular approach involving the program HYDROPRO can produce misleading results. This happens because HYDROPRO is not intended to predict the diffusion properties of highly flexible biopolymers such as IDPs. Likewise, recent empirical schemes that exploit the relationship between the small-angle x-ray scattering-informed conformational ensembles of IDPs and the respective experimental Dtr values also prove to be problematic. In this sense, the first-principle calculations of Dtr from the MD simulations, such as demonstrated in this work, should provide a useful benchmark for future efforts in this area.

BACKGROUND: HIST1H1E is a member of the H1 gene family. Excess de novo likely gene-disruptive variants involving the C-terminal tail of HIST1H1E have been reported in neurodevelopmental disorders. Although clinical phenotypes in some patients have been described in single studies, few studies have reviewed the genotype and phenotype relationships using a relatively large cohort of patients with HIST1H1E variants.
METHODS: Whole-exome sequencing (WES) was performed on the proband. The variant was validated using Sanger sequencing in both proband and parents. Published HIST1H1E variants in neuropsychiatric disorders were reviewed.
RESULTS: Herein, we reported a new de novo frameshift mutation in HIST1H1E (NM_005321.2, c.416_419dupAGAA, p.Ala141GlufsTer56) in an individual with Rahman syndrome. To explore the genotype-phenotype correlations for HIST1H1E variants in neurodevelopmental disorders, we comprehensively curated and summarized 23 variants and the clinical features from 52 patients. Our findings revealed that likely gene-disrupting variants in HIST1H1E contribute to a wide range of neurodevelopmental phenotypes. We observed the common phenotypes including craniofacial features, ID, hypotonia, and autism/behavior problem in patients with HIST1H1E variants. While the different genotypes corresponding to different phenotypes or the same phenotype were also observed.
CONCLUSIONS: These data provide scientific evidence for the genetic diagnosis and precision clinical management.

Giant cell tumor of the bone (GCTB) is a locally aggressive lesion, which characteristically arises from the epimetaphyseal region of long bones. They occur commonly in the third or fourth decade of life with a slight female preponderance. Various lesions such as chondroblastoma, aneurysmal bone cysts, and nonossifying fibromas can mimic the radiologic appearance of giant cell tumors. However, the greatest challenge is to differentiate between a conventional GCTB, a malignancy arising in a giant cell tumor, and osteoclast-rich osteosarcomas. The presence of a histone gene mutation, H3F3A, involving the substitution of glycine 34 has been reported in more than 95% of GCTB. Immunohistochemical (IHC) analysis of the biopsy specimens for H3.3pG34W expression is a surrogate for gene analysis and can be used to establish the presence of GCTB. Our report is the first in Indian literature to report the use of H3.3pG34W IHC in establishing the diagnosis of a primary malignant GCTB.

Central Nervous System (CNS) embryonal tumors represent a heterogeneous group of highly aggressive tumors occurring preferentially in children but also described in adolescents and adults. In 2021, the CNS World Health Organization (WHO) classification drastically changed the diagnosis of the other CNS embryonal tumors including new histo-molecular tumor types. Here, we report a pediatric case of a novel tumor type among the other CNS embryonal tumors classified within the methylation class \"CNS Embryonal Tumor with BRD4-LEUTX Fusion\". The patient was a 4-year girl with no previous history of disease. For a few weeks, she suffered from headaches, vomiting and mild fever associated with increasing asthenia and loss of weight leading to a global deterioration of health. MRI brain examination revealed a large, grossly well-circumscribed tumoral mass lesion located in the left parietal lobe, contralateral hydrocephalus and midline shift. Microscopic examination showed a highly cellular tumor with a polymorphic aspect. The majority of the tumor harbored neuroectodermal features composed of small cells with scant cytoplasm and hyperchromatic nuclei associated with small \"medulloblastoma-like\" cells characterized by syncytial arrangement and focally a streaming pattern. Tumor cells were diffusely positive for Synaptophysin, CD56, INI1 and SMARCA4 associated with negativity for GFAP, OLIG-2, EMA, BCOR, LIN28A and MIC-2. Additional IHC features included p53 protein expression in more than 10% of the tumor\'s cells and very interestingly, loss of H3K27me3 expression. The Heidelberg DNA-methylation classifier classified this case as \"CNS Embryonal Tumor with BRD4:LEUTX Fusion\". RNA-sequencing analyses confirmed the BRD4 (exon 13)-LEUTX (exon 2) fusion with no other molecular alterations found by DNA sequencing. Our case report confirmed that a new subgroup of CNS embryonal tumor with high aggressive potential, loss of H3K27me3 protein expression, BRDA4-LEUTX fusion, named \"Embryonal CNS tumor with BRD4-LEUTX fusion\", has to be considered into the new CNS WHO classification.

Diffuse hemispheric glioma, H3 G34-mutant, is a novel paediatric tumour type in the fifth edition of the WHO classification of CNS tumours associated with an invariably poor outcome. We present a comprehensive clinical, imaging and pathological review of this entity.
Patients with confirmed H3 G34R-mutant high-grade glioma were included in a single-centre retrospective cohort study and examined for clinical, radiological and histo-molecular data.
Twelve patients were enrolled in the study - 7 males/5 females; the mean age was 17.5 years (10-57 years). Most patients presented with signs of raised intracranial pressure (8/12). The frontal lobe (60%) was the prevalent location, with a mixed cystic-nodular appearance (10/12) and presence of vascular flow voids coursing through/being encased by the mass (8/12), and all tumours showed cortical invasion. Nine patients had subtotal resection limited by functional margins, two patients underwent supra-total resection, and one patient had biopsy only. 5-ALA was administered to 6 patients, all of whom showed positive fluorescence. Histologically, the tumours showed a marked heterogeneity and aggressive spread along pre-existing brain structures and leptomeninges. In addition to the diagnostic H3 G34R/V mutation, pathogenic variants in TP53 and ATRX genes were found in most cases. Potential targetable mutations in PDGFRA and PIK3CA genes were detected in five cases. The MGMT promoter was highly methylated in half of the samples. Methylation profiling was a useful diagnostic tool and highlighted recurrent structural chromosome abnormalities, such as PDGFRA amplification, CDKN2A/B deletion, PTEN loss and various copy number changes in the cyclin D-CDK4/Rb pathway. Radiochemotherapy was the most common adjuvant treatment (9/12), and the average survival was 19.3 months.
H3 G34R-mutant hemispheric glioma is a distinct entity with characteristic imaging and pathological features. Genomic landscaping of individual tumours can offer an opportunity to adapt individual therapies and improve patient management.

1) To quantify the association between anti-Porphyromonas gingivalis serum antibody concentrations and the risk of developing rheumatoid arthritis (RA), and 2) to quantify the associations among RA cases between anti-P. gingivalis serum antibody concentrations and RA-specific autoantibodies. Additional anti-bacterial antibodies evaluated included anti-Fusobacterium nucleatum and anti-Prevotella intermedia.
Serum samples were acquired pre- and post- RA diagnosis from the U.S. Department of Defense Serum Repository (n = 214 cases, 210 matched controls). Using separate mixed-models, the timing of elevations of anti-P. gingivalis, anti-P. intermedia, and anti-F. nucleatum antibody concentrations relative to RA diagnosis were compared in RA cases versus controls. Associations were determined between serum anti-CCP2, ACPA fine specificities (vimentin, histone, and alpha-enolase), and IgA, IgG, and IgM RF in pre-RA diagnosis samples and anti-bacterial antibodies using mixed-effects linear regression models.
No compelling evidence of case-control divergence in serum anti-P. gingivalis, anti-F. nucleatum, and anti-P. intermedia was observed. Among RA cases, including all pre-diagnosis serum samples, anti-P. intermedia was significantly positively associated with anti-CCP2, ACPA fine specificities targeting vimentin, histone, alpha-enolase, and IgA RF (p<0.001), IgG RF (p = 0.049), and IgM RF (p = 0.004), while anti-P. gingivalis and anti-F. nucleatum were not.
No longitudinal elevations of anti-bacterial serum antibody concentrations were observed in RA patients prior to RA diagnosis compared to controls. However, anti-P. intermedia displayed significant associations with RA autoantibody concentrations prior to RA diagnosis, suggesting a potential role of this organism in progression towards clinically-detectable RA.

BACKGROUND: Giant cell tumor of bone is a locally aggressive and rarely metastasizing neoplasm that typically affects the ends of long bones or the axial skeleton of young to middle-aged adults. As many as 69% to 100% of giant cell tumors harbor H3F3A gene mutations, while H3F3B gene mutations have rarely been reported.
METHODS: A 53-year-old male patient who underwent right distal femoral tumor resection.
METHODS: Preoperative CT plain scan indicated giant cell tumor of bone with pathological fracture. Laboratory findings were as follows: serum calcium was 2.23 mmol/L (reference range: 2.1-2.55 mmol/L) and serum phosphorus was 1.35 mmol/L (reference range: 0.81-1.45 mmol/L).
METHODS: The histological morphology showed the typical features of a conventional GCT. The immunoprecipitation analysis results were as follows: H3.3G34W(-), H3.3G34R(-), H3.3G34V(-), and H3K36M(-). Sanger sequencing showed that the H3F3A and H3F3B gene mutations were wild type. The high-throughput gene sequencing results revealed the H3F3B gene mutations H3.3p.Gly35Trp and H3.3p.Val36Leu.
RESULTS: The patient was stable with no recurrence in 12 months follow-up.
CONCLUSIONS: Giant cell tumor of bone with H3F3B gene mutations is extremely rare. In the pathological diagnosis of bone tumors, we need to analyze clinical presentation, imaging features, histology, immunophenotype, and cytogenetic/molecular alterations, in order to get a correct diagnosis.