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Cornified envelopes (CEs) of human epidermis ordinarily consist of transglutaminase-mediated cross-linked proteins and are essential for skin barrier function. However, in addition to enzyme-mediated isopeptide bonding, protein cross-linking could also arise from oxidative damage. Our group recently demonstrated abnormal incorporation of cellular proteins into CEs by pro-oxidants in woodsmoke. In this study, we focused on 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), mesquite liquid smoke (MLS), and 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), to further understand the mechanisms through which environmental pro-oxidants induce CE formation and alter the CE proteome. CEs induced by the ionophore X537A were used for comparison. Similar to X537A, DMNQ- and MLS-induced CE formation was associated with membrane permeabilization. However, since DMNQ is non-adduct forming, its CEs were similar in protein profile to those from X537A. By contrast, MLS, rich in reactive carbonyls that can form protein adducts, caused a dramatic change in the CE proteome. TCDD-CEs were found to contain many CE precursors, such as small proline-rich proteins and late cornified envelope proteins, encoded by the epidermal differentiation complex. Since expression of these proteins is mediated by the aryl hydrocarbon receptor (AhR), and its well-known downstream protein, CYP1A1, was exclusively present in the TCDD group, we suggest that TCDD alters the CE proteome through persistent AhR activation. This study demonstrates the potential of environmental pro-oxidants to alter the epidermal CE proteome and indicates that the cellular redox state has an important role in CE formation. [ABSTRACT FROM AUTHOR]

Background: Newborn screening (NBS) aims to detect congenital anomalies, and next‐generation sequencing (NGS) has shown promise in this aspect. However, the NBS strategy for monogenic inherited diseases in China remains insufficient. Methods: We developed a NeoEXOME panel comprising 601 genes that are relevant to the Chinese population found through extensive research on available databases. An interpretation system to grade the results into positive (high‐risk, moderate‐risk, and low‐risk genotypes), negative, and carrier according to the American College of Medical Genetics (ACMG) guidelines was also developed. We validated the panel to evaluate its efficacy by using data from the "1000 Genomes Project" and conducted a pilot multicenter study involving 3423 neonates. Results: The NGS positive rate in the 1000 Genomes Project was 7.6% (23/301), whereas the rate was 12.0% in the multicenter study, including 3249 recruited neonates. Notably, in 200 neonates, positive per conventional NBS, 58.5% (69/118) showed results consistent with NGS. In the remaining 3049 neonates showing negative results in conventional NBS, 271 (8.9%) were positive per NGS, and nine of them were clinically diagnosed with diseases in the follow‐up. Conclusion: We successfully designed a NeoEXOME panel for targeted sequencing of monogenic inherited diseases in NBS. The panel demonstrated high performance in the Chinese population, particularly for the early detection of diseases with no biochemical markers. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited the proliferation of epithelial cells and attenuated the activation of fibroblasts. In addition, deficiency of Trio Rho Guanine Nucleotide Exchange Factor (TRIO) in epithelial cells and fibroblasts decreases susceptibility to lung fibrosis. TRIOBP interacting with TRIO promoted abnormal epithelial–mesenchymal crosstalk and modulated the nucleocytoplasmic translocation of β-catenin. We concluded that the miR-29b‒TRIOBP–TRIO–β-catenin axis might be a key anti-fibrotic axis in IPF to regulate lung regeneration and fibrosis, which may provide a promising treatment strategy for lung fibrosis. [ABSTRACT FROM AUTHOR]

The small volume, Mesozoic alkali gabbro intrusions of the Budgell Harbour and Dildo Pond stocks and associated alkaline lamprophyre dykes in Notre Dame Bay in Newfoundland are an example of onshore magmatism that may be associated with North Atlantic Ocean opening. Chemical abrasion isotope dilution thermal ionization mass spectrometry U–Pb dating of zircon from Budgell Harbour Stock drill core samples yielded a weighted average 206Pb/238U age of 147.9 ± 0.5 Ma (95% confidence interval, mean square weighted deviation = 0.10). Five 40Ar/39Ar laser step-heating, single phlogopite grain analyses from the Budgell Harbour and Dildo Pond stocks, plus a lamprophyre dyke, yielded ages ranging from 146.3 ± 0.2 to 149.5 ± 0.5 Ma. The data demonstrate a ca. 148 Ma (Jurassic and Tithonian) alkaline magmatic event in Newfoundland, contemporaneous with rifting and offshore basin formation. These new age data and published determinations from magmatic rocks on conjugate margins and adjacent regions reveal long-lived episodic magmatism in the embryonic North Atlantic rift environment. We propose a new model whereby magmatism occurred in Notre Dame Bay at the convergence of older crustal-scale faults and localized Moho depth variations that may have triggered lithospheric mantle melting through isothermal, distal, and edge-driven upwelling related to regional extension. [ABSTRACT FROM AUTHOR]

The Elm Decline (ED), is a marked reduction in Ulmus recognised in pollen diagrams from across north/northwest Europe c. 5-6000 cal BP, the causes of which have been much discussed for over half a century, partly because of its broad chronological correspondence with the Mesolithic-Neolithic transition. We present a formal statistical analysis of the ED chronology in Ireland, analysing its association with early Neolithic anthropogenic activity as indicated indirectly by palynological evidence and directly through radiocarbon dated cereal macrofossils. The results derived from pollen records regarded as sufficiently robust for Bayesian modelling indicate the date for the ED ranges from the later Mesolithic to middle Neolithic. Different palynological 'expressions' of the ED are identified, and comparison of the ED date range and increases in Plantago lanceolata indicate that although correlation between anthropogenic activity and the onset of the 'Elm Decline' can be identified at several sites, this is not consistent. Comparison with the cereal macrofossil record demonstrates that generally the ED occurred prior to the onset of Neolithic cereal cultivation as defined by these data. We discuss implications for understanding the patterns and processes that may underlie the ED and question whether the 'Elm Decline' continues to merit the definite article. [ABSTRACT FROM AUTHOR]

Background: DM1 is a multisystem disorder caused by expansion of a CTG triplet repeat in the 3' non-coding region of DMPK. Neuropsychological consequences and sleep abnormalities are important associations in DM1. Objective: To describe the clinical phenotype, disease progression and characterize the sleep alterations and cognitive abnormalities in a sub-set of patients. Materials and Methods: A retrospective study on 120 genetically confirmed DM1 cases. Findings in neuropsychological assessment and multiple sleep questionnaires were compared with 14 age and sex matched healthy individuals. All 120 patients were contacted through letters/telephonic consultation/hospital visits to record their latest physical and functional disabilities. Results: The mean age at symptom onset was 23.1 ± 11.4 years, M: F = 3.8:1, mean duration of illness = 14.3 ± 9.5 years. Clinically 54.2% had adult onset form, juvenile = 27.5%, infantile = 10.8%, late adult onset = 7.5%. Paternal transmission occurred more frequently. The predominant initial symptoms were myotonia (37.5%), hand weakness (21.7%), lower limb weakness (23.3%) and bulbar (10%). Twenty patients completed sleep questionnaires (SQ). Abnormal scores were noted in Epworth sleepiness scale (55%); Pittsburgh sleep quality index (45%); Berlin SQ (30%); Rapid eye movement sleep Behaviour Disorder SQ (15%); Restless leg syndrome rating scale (10%). Neuropsychological assessment of 20 patients revealed frontal executive dysfunction, attention impairment and visuospatial dysfunction. Frontal lobe was most affected (72%) followed by parietal (16%) and temporal lobe (12%). Conclusions: The current study provides a comprehensive account of the clinical characteristics in Indian patients with DM1. Hypersomnolence was most commonly seen. Excessive daytime sleepiness and Sleep disordered breathing were the most common sleep related abnormality. Cognitive impairment comprised predominantly of frontal lobe dysfunction. [ABSTRACT FROM AUTHOR]

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Introduction: The American continent populations have a wide genetic diversity, as a product of the admixture of three ethnic groups: Amerindian, European, and African Sub-Saharan. Spinocerebellar ataxia type 10 (SCA10) and Huntington disease-like 2 (HDL2) have very ancient ancestral origins but are restricted to two populations: Amerindian and African Sub-Saharan, respectively. This study aimed to investigate the genetic epidemiological features of these diseases in Venezuela., Methods: In-phase haplotypes with the expanded alleles were established in seven unrelated index cases diagnosed with SCA10 and in 11 unrelated index cases diagnosed with HDL2. The origins of remote ancestors were recorded., Results: The geographic origin of the ancestors showed grouping in clusters. SCA10 had a minimal general prevalence of 1:256,174 families in the country, but within the identified geographic clusters, the prevalence ranged from 5 per 100,000 to 43 per 100,000 families. HDL2 had a general prevalence of 1:163,016 families, however, within the clusters, the prevalence ranged from 31 per 100,000 to 60 per 100,000 families. The locus-specific haplotype shared by all families worldwide, including the Venezuelans, supports a single old ancestral origin in each case., Conclusion: Knowing the genetic ancestry and geographic origins of patients in Ibero-American mixed populations could have significant diagnostic implications; thus, both diseases in Venezuela should always be first explored in patients with a suggestive phenotype and ancestors coming from the same known geographic clusters., (© 2024 University College London (UCL) and John Wiley & Sons Ltd.)

Background: The NKX2‐1‐related disorders (NKX2‐1‐RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2‐1‐RD, aiming to provide clinical recommendations for its management. Methods: A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2‐1‐RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. Results: Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. Conclusions: The management of chorea in individuals with NKX2‐1‐RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations. [ABSTRACT FROM AUTHOR]

Objective: The clinical and genetic characteristics of a child with inherited bone marrow failure syndrome as prominent clinical manifestations and special facial features were analyzed, and the etiology and mechanism were explored in, combination with clinical practice. Methods: Blood samples and clinical information were collected separately from the proband and their biological parents. The pathogenic variant was verified using next-generation sequencing technology screening, and the candidate variable sites were confirmed by using Sanger sequencing among all members of the family. Results: A heterozygous nonsense mutation in exon 17 of KAT6A (NM_006766), c.4177G > T (p.E1393*) predicted to cause truncation within the acidic domain of the protein was identified. Pedigree analysis did not reveal any variation in this locus between the proband's father and mother. No report of this pathogenic variant was found in a literature search of domestic and foreign databases, indicating that it is a newly discovered mutation. According to the guidelines of the American College of Medical Genetics, the variation was preliminarily determined to be a pathogenic. The newly discovered heterozygous mutation in KAT6A may be the cause of the disease in this child. Additionally, inherited bone marrow failure syndrome is a prominent manifestation. Conclusion: This study not only provides us with an in-depth understanding of this rare syndrome but also deepens our understanding of the function of KAT6A. [ABSTRACT FROM AUTHOR]

Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo mutations in Lysine(K) acetyltransferase 6A (KAT6A). ARTHS is clinically heterogeneous and characterized by several common features, including intellectual disability, developmental and speech delay, and hypotonia, and affects multiple organ systems. KAT6A is the enzymatic core of a histone–acetylation protein complex; however, the direct histone targets and gene regulatory effects remain unknown. In this study, we use ARTHS patient (n = 8) and control (n = 14) dermal fibroblasts and perform comprehensive profiling of the epigenome and transcriptome caused by KAT6A mutations. We identified differential chromatin accessibility within the promoter or gene body of 23% (14/60) of genes that were differentially expressed between ARTHS and controls. Within fibroblasts, we show a distinct set of genes from the posterior HOXC gene cluster (HOXC10, HOXC11, HOXC-AS3, HOXC-AS2, and HOTAIR) that are overexpressed in ARTHS and are transcription factors critical for early development body segment patterning. The genomic loci harboring HOXC genes are epigenetically regulated with increased chromatin accessibility, high levels of H3K23ac, and increased gene–body DNA methylation compared to controls, all of which are consistent with transcriptomic overexpression. Finally, we used unbiased proteomic mass spectrometry and identified two new histone post-translational modifications (PTMs) that are disrupted in ARTHS: H2A and H3K56 acetylation. Our multi-omics assays have identified novel histone and gene regulatory roles of KAT6A in a large group of ARTHS patients harboring diverse pathogenic mutations. This work provides insight into the role of KAT6A on the epigenomic regulation in somatic cell types. [ABSTRACT FROM AUTHOR]

Seizure liability remains a significant cause of attrition throughout drug development. Advances in stem cell biology coupled with an increased understanding of the role of ion channels in seizure offer an opportunity for a new paradigm in screening. We assessed the activity of 15 pro-seizurogenic compounds (7 CNS active therapies, 4 GABA receptor antagonists, and 4 other reported seizurogenic compounds) using automated electrophysiology against a panel of 14 ion channels (Nav1.1, Nav1.2, Nav1.6, Kv7.2/7.3, Kv7.3/7.5, Kv1.1, Kv4.2, KCa4.1, Kv2.1, Kv3.1, KCa1.1, GABA α1β2γ2, nicotinic α4β2, NMDA 1/2A). These were selected based on linkage to seizure in genetic/pharmacological studies. Fourteen compounds demonstrated at least one "hit" against the seizure panel and 11 compounds inhibited 2 or more ion channels. Next, we assessed the impact of the 15 compounds on electrical signaling using human-induced pluripotent stem cell neurons in microelectrode array (MEA). The CNS active therapies (amoxapine, bupropion, chlorpromazine, clozapine, diphenhydramine, paroxetine, quetiapine) all caused characteristic changes to electrical activity in key parameters indicative of seizure such as network burst frequency and duration. The GABA antagonist picrotoxin increased all parameters, but the antibiotics amoxicillin and enoxacin only showed minimal changes. Acetaminophen, included as a negative control, caused no changes in any of the parameters assessed. Overall, pro-seizurogenic compounds showed a distinct fingerprint in the ion channel/MEA panel. These studies highlight the potential utility of an integrated in vitro approach for early seizure prediction to provide mechanistic information and to support optimal drug design in early development, saving time and resources. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a gaseous molecule that has a central role in signaling pathways involved in numerous physiological processes (e.g., vasodilation, neurotransmission, inflammation, apoptosis, and tumor growth). Due to its gaseous form, NO has a short half‐life, and its physiology role is concentration dependent, often restricting its function to a target site. Providing NO from an external source is beneficial in promoting cellular functions and treatment of different pathological conditions. Hence, the multifaceted role of NO in physiology and pathology has garnered massive interest in developing strategies to deliver exogenous NO for the treatment of various regenerative and biomedical complexities. NO‐releasing platforms or donors capable of delivering NO in a controlled and sustained manner to target tissues or organs have advanced in the past few decades. This review article discusses in detail the generation of NO via the enzymatic functions of NO synthase as well as from NO donors and the multiple biological and pathological processes that NO modulates. The methods for incorporating of NO donors into diverse biomaterials including physical, chemical, or supramolecular techniques are summarized. Then, these NO‐releasing platforms are highlighted in terms of advancing treatment strategies for various medical problems. [ABSTRACT FROM AUTHOR]

Hand pose estimation is a challenging task in hand-object interaction scenarios due to the uncertainty caused by object occlusions. Inspired by human reasoning from a hand-object interaction video sequence, we propose a hand pose estimation model. It uses three cascaded modules to imitate human's estimation and observation process. The first module predicts an initial pose based on the visible information and the prior hand knowledge. The second module updates the hand shape memory based on the new information coming from the subsequent frames. The bone's length updating is initiated by the predicted joint's reliability. The third module refines the coarse pose according to the hand-object contact state represented by the object's Signed Distance Function field. Our model gets the mean joints estimation error of 21.3 mm, the Procrustes error of 9.9 mm, and the Trans &Scale error of 22.3 mm on HO3Dv2, and Root-Relative error of 12.3 mm on DexYCB which are superior to other state-of-the-art models. [ABSTRACT FROM AUTHOR]

DNA methylation is a crucial topic in bioinformatics research. Traditional wet experiments are usually time-consuming and expensive. In contrast, machine learning offers an efficient and novel approach. In this study, we propose DeepMethylation, a novel methylation predictor with deep learning. Specifically, the DNA sequence is encoded with word embedding and GloVe in the first step. After that, dilated convolution and Transformer encoder are utilized to extract the features. Finally, full connection and softmax operators are applied to predict the methylation sites. The proposed model achieves an accuracy of 97.8% on the 5mC dataset, which outperforms state-of-the-art methods. Furthermore, our predictor exhibits good generalization ability as it achieves an accuracy of 95.8% on the m1A dataset. [ABSTRACT FROM AUTHOR]

Constitutional deletions of chromosome 1q42 region are rare. The phenotype spectrum associated with this copy number change is variable, including developmental delay, intellectual disability, seizures, and dysmorphology. This study describes a patient with developmental delays and brain abnormalities. G-banded karyotype, FISH, SNP oligonucleotide microarray analysis (SOMA), and whole exome sequencing analysis were performed. Postnatal reanalysis of prenatal SOMA and follow-up parental testing revealed a paternally inherited 63 kb deletion at 1q42.11 in the patient. We characterized the clinical features of this patient, providing insight into the clinical phenotype associated with deletions of the 1q42.11 sub-band. Our study provides new evidence supporting the potential functional importance of the FBXO28 3′ UTR region and the hypothesis that FBXO28 is a critical gene in the pathogenesis of chromosome 1q41q42 microdeletion syndrome. It also highlights the different goals and reporting criteria between prenatal and postnatal microarray tests. [ABSTRACT FROM AUTHOR]

Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development. [ABSTRACT FROM AUTHOR]

Culturally modified trees (CMTs) are a unique form of archaeology and cultural heritage. There are several factors affecting the survival of culturally modified trees in Australia, and these will all likely be exacerbated by climate change. Boab trees (Adansonia gregorii), which are endemic to northwest Australia, have been subject to modification by Indigenous people both prior to and following the settlement of the Kimberley region by European and Anglo-Australians. Many of the potential impacts of climate change on boab tree survival are yet to be determined, but a range of new threats are emerging as potential endangerment. Through the insights of Indigenous knowledge, this paper discusses one particularly significant boab tree in Nyikina Country and how its demise may be linked to erroneous human actions in the recent past. This provides a unique perspective on how the complexities of climate change may be conceptualised through living knowledge and experience. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common skin disease worldwide. The major causes of AD are skin barrier defects, immune dysfunction, and oxidative stress. In this study, we investigated the anti-oxidation and anti-inflammation effects of Coffea arabica extract (CAE) and its regulation of the skin barrier and immune functions in AD. In vitro experiments revealed that CAE decreased the reactive oxygen species levels and inhibited the translocation of nuclear factor-κB (NF-κB), further reducing the secretion of interleukin (IL)-1β and IL-6 induced by interferon-γ (IFN-γ)/tumor necrosis factor-α (TNF-α). Moreover, CAE decreased IFN-γ/TNF-α-induced NLR family pyrin domain-containing 3 (NLRP3), caspase-1, high-mobility group box 1 (HMGB1), and receptor for advanced glycation end products (RAGE) expression levels. It also restored the protein levels of skin barrier function-related markers including filaggrin and claudin-1. In vivo experiments revealed that CAE not only reduced the redness of the backs of mice caused by 2,4-dinitrochlorobenzene (DNCB) but also reduced the levels of pro-inflammatory factors in their skin. CAE also reduced transepidermal water loss (TEWL) and immune cell infiltration in DNCB-treated mice. Overall, CAE exerted anti-oxidation and anti-inflammation effects and ameliorated skin barrier dysfunction, suggesting its potential as an active ingredient for AD treatment. [ABSTRACT FROM AUTHOR]

Mutations in the SLC12A2 gene, which encodes the Na-K-2Cl cotransporter-1 (NKCC1), are linked to various conditions such as neurodevelopmental deficits, deafness, and fluid secretion in different epithelia. Cases of complete NKCC1 deficiency in young patients are straightforward, leading to clinical presentations that overlap with the phenotypes observed in NKCC1 knockout mouse models. However, cases involving deleterious variants in one allele are more difficult, as the clinical presentation is variable, and the cause-effect relationship is not always clear. For instance, we worked on a single patient's case from multiple angles and published six related papers to convince ourselves of the cause-and-effect relationship between her NKCC1 mutation and her clinical presentations. The cluster of mutations in a small portion of the carboxyl terminus and its association with deafness point to a cause-and-effect relationship, even if the molecular mechanism is unknown. Overall, the preponderance of evidence suggests that the SLC12A2 gene is a human disease-causing and likely haploinsufficient gene that requires further investigation. [ABSTRACT FROM AUTHOR]

Benign hereditary chorea (BHC) is an inherited neurological disorder consisting of childhood-onset, nonprogressive chorea, generally without any other manifestations. In most reported cases, the inheritance of BHC is autosomal dominant but both incomplete penetrance and variable expressivity are observed and can be caused by NKX2-1 mutations. The spectrum contains choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome. The neurological symptoms can be misdiagnosed as Huntington's disease (HD). The two Polish families were diagnosed with NKX2-1 gene mutations and a literature review concerning the NKX2-1-related disorders was conducted. All family members were examined by experienced movement disorders specialists. PubMed database was searched to obtain previously described NKX2-1 cases. Whole exome sequencing (WES) was performed in one proband (Family A) and direct NKX2-1 sequencing in the second (Family B). Two Polish families were diagnosed with NKX2-1 gene mutations (p.Trp208Leu and p.Cys117Alafs*8). In one family, the co-occurrence of HD was reported. Forty-nine publications were included in the literature review and symptoms of 195 patients with confirmed NKX2-1 mutation were analyzed. The most common symptoms were chorea and choreiform movements, and delayed motor milestones. The NKX2-1 mutation should always be considered as a potential diagnosis in families with chorea, even with a family history of HD. Lack of chorea does not exclude the NKX2-1-related disorders., (© 2024. The Author(s).)

KAT6B and KAT6A belong to the MYST family of lysine acetyltransferases, and regulate gene expression via histone modification. Although both proteins share similar structure and epigenetic regulatory functions, it remains unclear if KAT6A/6B mutation disorders, both very rare conditions, yield the same neurocognitive presentation and thus benefit from similar treatment approaches. This study provides a preliminary overview of neuropsychological functioning of 13 individuals with KAT6B disorder (Mean age = 9.01 years, SD = 5.46), which was compared to that of a recently published sample of 15 individuals with KAT6A syndrome (Mean age = 10.32 years, SD = 4.12). Participants completed a neuropsychological test battery to assess non-verbal cognition, and caregivers completed a series of standardized rating inventories to assess daily behavioral functioning. Results reveal those with KAT6B disorders present with severe adaptive deficits (92.3%) and autism-related behaviors (83.3%), juxtaposed with relatively low concerns with externalizing behaviors (7.6%), a pattern shared by the KAT6A group. Those with KAT6B disorders present with high levels of autistic features, including reduced affiliative interest, whereas social motivation is less affected within the KAT6A group. Overall, the levels of impairment in nonverbal cognition and receptive language were comparable among those with KAT6B disorders, a trend also seen in the KAT6A group. In brief, KAT6B and KAT6A disorders yield analogous neuropsychological profiles. Findings implicate common molecular pathophysiological mechanisms for these epigenetic disorders, such that similar therapies may have shared effect across diseases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pathogenic variants in TRIO, encoding the guanine nucleotide exchange factor, are associated with two distinct neurodevelopmental delay phenotypes: gain-of-function missense mutations within the spectrin repeats are causative for a severe developmental delay with macrocephaly (MIM: 618825), whereas loss-of-function missense variants in the GEF1 domain and truncating variants throughout the gene lead to a milder developmental delay and microcephaly (MIM: 617061). In three affected family members with mild intellectual disability/NDD and microcephaly, we detected a novel heterozygous TRIO variant at the last coding base of exon 31 (NM_007118.4:c.4716G>A). RNA analysis from patient-derived lymphoblastoid cells confirmed aberrant splicing resulting in the skipping of exon 31 (r.4615_4716del), leading to an in-frame deletion in the first Pleckstrin homology subdomain of the GEF1 domain: p.(Thr1539_Lys1572del). To test for a distinct gestalt, facial characteristics of the family members and 41 previously published TRIO cases were systematically evaluated via GestaltMatcher. Computational analysis of the facial gestalt suggests a distinguishable facial TRIO-phenotype not outlined in the existing literature., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

The application of genomics has greatly increased the diagnosis of specific monogenic causes of intellectual disability and improved our understanding of the neuronal processes that result in cognitive impairment. Meanwhile, families are building rare disease communities and seeking disease-specific treatments to change the trajectory of health and developmental outcomes for their children. To date, treatments for intellectual disability have focussed on metabolic disorders, where early treatment has improved cognition and neurodevelopmental outcomes. In this article, we discuss the treatment strategies that may be possible to change the neurodevelopmental outcome in a broader range of genetic forms of intellectual disability. These strategies include substrate modification, enzyme replacement therapy, gene therapy and molecular therapies. We argue that intellectual disability should now be considered a potentially treatable condition and a strong candidate for precision medicine., (© 2024 The Author(s). Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Since the SCA 1 gene was cloned in 1993 over 500 patients have been referred to the Edinburgh Molecular Genetics Service for mutation testing. Currently all referred patient DNAs are tested for SCA 1, SCA 2, SCA 3, SCA 6, SCA 7, SCA 8, DRPLA and Friedreich's Ataxia. For the period from 1993-1995 the majority of referrals were made by clinical geneticists from the four Scottish centres. Most referrals were for affected individuals with some evidence of a family history of dominant cerebellar ataxia. For this period mutations were detected in 30% of patients (10 / 33). Subsequent to 1995 the majority of referrals have been made by consultant neurologists. For this period mutations were detected in only 8.5% of cases. We present a breakdown of mutations identified by referring centre. We have found affected patients for all genes tested apart from SCA 7. The most common ADCA in our population is SCA 6 Information received with typical specimens for testing is inadequate to allow the selection of appropriate gene tests. Analysis of our data highlight the need for a set of clinical criteria to be fulfilled before molecular testing is undertaken. This test series is labour intensive and expensive and should be better targeted. More information on ADCA types would obviate the need for some tests. [ABSTRACT FROM AUTHOR]

Regulation of the volume and electrolyte composition of the cerebrospinal fluid (CSF) is vital for brain development and function. The Na-K-Cl co-transporter NKCC1 in the choroid plexus (ChP) plays key roles in regulating CSF volume by co-transporting ions and mediating same-direction water movements. Our previous study showed ChP NKCC1 is highly phosphorylated in neonatal mice as the CSF K+ level drastically decreases and that overexpression of NKCC1 in the ChP accelerates CSF K+ clearance and reduces ventricle size [1]. These data suggest that NKCC1 mediates CSF K+ clearance following birth in mice. In this current study, we used CRISPR technology to create a conditional NKCC1 knockout mouse line and evaluated CSF K+ by Inductively Coupled Plasma Optical Emission spectroscopy (ICP-OES). We demonstrated ChP-specific reduction of total and phosphorylated NKCC1 in neonatal mice following embryonic intraventricular delivery of Cre recombinase using AAV2/5. ChP-NKCC1 knockdown was accompanied by a delayed perinatal clearance of CSF K+. No gross morphological disruptions were observed in the cerebral cortex. We extended our previous results by showing embryonic and perinatal rats shared key characteristics with mice, including decreased ChP NKCC1 expression level, increased ChP NKCC1 phosphorylation state, and increased CSF K+ levels compared to adult. Collectively, these follow up data support ChP NKCC1's role in age-appropriate CSF K+ clearance during neonatal development. [ABSTRACT FROM AUTHOR]

Filaggrin (FLG) protein is indispensable for multiple aspects of the epidermal barrier function but its accumulation in a monomeric filaggrin form may initiate premature keratinocytes death; it is unclear how filaggrin levels are controlled before the formation of storing keratohyalin granules. Here we show that keratinocyte‐secreted small extracellular vesicles (sEVs) may contain filaggrin‐related cargo providing a route of eliminating excess filaggrin from keratinocytes; blocking of sEV release has cytotoxic effects on those cells. Filaggrin‐containing sEVs are found in plasma in both healthy individuals and atopic dermatitis patients. Staphylococcus aureus (S. aureus) enhances packaging and secretion of filaggrin‐relevant products within the sEVs for enhanced export via a TLR2‐mediated mechanism which is also linked to the ubiquitination process. This filaggrin removal system, preventing premature keratinocyte death and epidermal barrier dysfunction, is exploited by S. aureus which promotes filaggrin elimination from the skin that could help safeguard bacterial growth. [ABSTRACT FROM AUTHOR]

Overgrowth‐intellectual disability (OGID) syndromes are clinically and genetically heterogeneous group of disorders. The aim of this study was to examine the molecular etiology and long‐term follow‐up findings of Turkish OGID cohort. Thirty‐five children with OGID were included in the study. Single gene sequencing, clinical exome analysis, chromosomal microarray analysis and whole exome sequencing were performed. Five pathogenic copy number variants were detected in the patients; three of them located on chromosome 5q35.2 (encompassing NSD1), others on 9q22.3 and 22q13.31. In 19 of 35 patients; we identified pathogenic variants in OGID genes associated with epigenetic regulation, NSD1 (n = 15), HIST1H1E (n = 1), SETD1B (n = 1), and SUZ12 (n = 2). The pathogenic variants in PIK3CA (n = 2), ABCC9 (n = 1), GPC4 (n = 2), FIBP (n = 1), and TMEM94 (n = 1) which had a role in other growth pathways were detected in seven patients. The diagnostic yield was 31/35(88%). Twelve pathogenic variants were novel. The common facial feature of the patients was prominent forehead. The patients with Sotos syndrome were observed to have milder intellectual disability than patients with other OGID syndromes. In conclusion, this study showed, for the first time, that biallelic variants of SUZ12 caused Imagawa‐Matsumoto syndrome, monoallelic variants in SETDIB resulted in OGID. Besides expanded the phenotypes of very rare OGID syndromes caused by FIBP and TMEM94. [ABSTRACT FROM AUTHOR]

New detrital zircon age results from the Lusitanian Basin are integrated with published data for the Mesozoic of west Iberia and eastern Canada (4959 concordant ages). Zircons in new samples are either mainly Devonian‐Permian, Cryogenian‐Ediacaran or reveal a combination of these two age populations, showing secondary to minor Mesoproterozoic‐Archean ages. Statistical tools applied to the compiled age data allow grouping the samples according to age signatures and explain main features of the age spectra. Age signatures are determined by the abundance of zircon: (1) recycled from terranes involved in Pangea amalgamation; (2) associated with Acadian‐Variscan crystalline rocks (~420–310 Ma), which becomes younger from the Laurentian to the Gondwanan sides of the orogen; (3) associated with post‐collisional events (~300–285 Ma) that affected different terranes and were exhumed in major structures controlling basin formation; and (4) resulting from Mesozoic magmatism (~145 Ma) with a stronger imprint in the west Atlantic margin. [ABSTRACT FROM AUTHOR]

The diagnosis and management of fragile X syndrome (FXS) have significantly improved in the last three decades, although the current diagnostic techniques are not yet able to precisely identify the number of repeats, methylation status, level of mosaicism, and/or the presence of AGG interruptions. A high number of repeats (>200) in the fragile X messenger ribonucleoprotein 1 gene (FMR1) results in hypermethylation of promoter and gene silencing. The actual molecular diagnosis is performed using a Southern blot, TP-PCR (Triplet-Repeat PCR), MS-PCR (Methylation-Specific PCR), and MS-MLPA (Methylation-Specific MLPA) with some limitations, with multiple assays being necessary to completely characterise a patient with FXS. The actual gold standard diagnosis uses Southern blot; however, it cannot accurately characterise all cases. Optical genome mapping is a new technology that has also been developed to approach the diagnosis of fragile X syndrome. Long-range sequencing represented by PacBio and Oxford Nanopore has the potential to replace the actual diagnosis and offers a complete characterization of molecular profiles in a single test. The new technologies have improved the diagnosis of fragile X syndrome and revealed unknown aberrations, but they are a long way from being used routinely in clinical practice. [ABSTRACT FROM AUTHOR]

Epigenetics, one mechanism by which gene expression can change without any changes to the DNA sequence, was described nearly a century ago. However, the importance of epigenetic processes to neurodevelopment and higher order neurological functions like cognition and behavior is only now being realized. A group of disorders known as the Mendelian disorders of the epigenetic machinery are caused by the altered function of epigenetic machinery proteins, which consequently affects downstream expression of many genes. These disorders almost universally have cognitive dysfunction and behavioral issues as core features. Here, we review what is known about the neurodevelopmental phenotypes of some key examples of these disorders divided into categories based on the underlying function of the affected protein. Understanding these Mendelian disorders of the epigenetic machinery can illuminate the role of epigenetic regulation in typical brain function and can lead to future therapies and better management for a host of neurodevelopmental and neuropsychological disorders. [ABSTRACT FROM AUTHOR]

Background. Blocking agent for immune cytokine pathways is a novel treatment for atopic dermatitis (AD). Janus kinase (JAK) family is one of the cytoplasmic tyrosine kinases that mediate a variety of cytokines. Eight randomized controlled trials (RCTs) of JAK1 inhibitors (upadacitinib and abrocitinib) in AD have been published in the past three years. Objective. To evaluate the efficacy and safety of JAK1 inhibitors and compare upadacitinib with abrocitinib for the treatment of moderate-to-severe AD. Methods. Two independent reviewers searched Medline, Embase, Web of Science, and Cochrane databases updated on Apr 11th, 2023. We included data from phase two and three RCTs. Primary outcomes included the proportion of Investigator's Global Assessment (IGA) responders and Eczema Area and Severity Index-75 (EASI-75) responders. Results. In all, eight RCTs were included in our study with 4634 moderate-to-severe AD patients. Both JAK1 inhibitors showed apparent therapeutic effects, but the 200 mg abrocitinib group demonstrated less efficacy than the 30 mg upadacitinib group in IGA responders (end of treatment) and EASI-75 responders (after 2 weeks of treatment). However, both JAK1 inhibitor groups demonstrated significantly higher risks of acne (9.0%) and headache (6.3%). Besides, upadacitinib showed significantly higher risks of upper respiratory tract infection (7.6%) and nasopharyngitis (9.7%), and abrocitinib showed significantly higher risks of nausea (9.6%). Conclusion. JAK1 inhibitors demonstrate promising efficacy in AD with rapid response and dose-dependent response and significantly higher risks of acne and headache. Based on existing data, oral 30 mg upadacitinib QD has better outcome than oral 200 mg abrocitinib QD and is a recommended dosage regimen for moderate-to-severe AD patients. Oral 15 mg upadacitinib QD might be an alternative dosage regimen in case of treatment-emergent adverse events. [ABSTRACT FROM AUTHOR]

The vast majority of skin cancers can be classified into two main types: melanoma and keratinocyte carcinomas. The most common keratinocyte carcinomas include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Multiple familial syndromes have been identified that can increase the risk of developing SCC, BCC, and/or melanoma. The major syndromes include oculocutaneous albinism for SCC, basal cell nevus syndrome for BCC, familial atypical multiple mole-melanoma syndrome, and hereditary breast and ovarian cancer syndrome for melanoma. In addition, familial syndromes that can predispose individuals to all three major skin cancers include xeroderma pigmentosum and Li–Fraumeni syndrome. This review highlights the epidemiology, risk factors, pathogenesis, and etiology of the major and minor syndromes to better identify and manage these conditions. Current investigational trials in genomic medicine are making their way in revolutionizing the clinical diagnosis of these familial syndromes for earlier preventative measures and improvement of long-term prognosis in these patients. [ABSTRACT FROM AUTHOR]

Multi-proxy investigations at 2 Pier Road, North Woolwich, London, UK, have revealed deposits spanning the Middle-Late Holocene from the late Mesolithic (c. 4360 cal BC) onwards. Pollen data show an Elm Decline at c. 4210–3950 cal BC followed by landnám clearances at c. 4210–3910 cal BC and c. 3710–3030 cal BC and the first appearance of cereal at c. 3540–3030 cal BC. These events are potentially contemporary with the construction of nearby Neolithic trackways, providing indirect evidence for agriculture and settlement. REVEALS modelling shows the first significant reduction in woodland cover is coincident with the Neolithic Elm decline, but the main step-change to open conditions occurred in the Early Bronze Age, following a decline in lime at c. 2110–1630 cal BC. Palaeo-topographic modelling of the region shows that although the trend towards increasing openness coincides with gradual wetland expansion, the shift to open vegetation cover cannot be explained by this and is probably the result of human activity. This study highlights the value of combining deposit and vegetation cover modelling to contextualise wetland archaeology and shows that together these provide useful proxies for landscape-scale human activity that can identify ephemeral signals of prehistoric activity. [ABSTRACT FROM AUTHOR]

Gaseous fuels for heavy-duty internal combustion engines provide inherent advantages for reducing CO2, particulate matter (PM), and NOX emissions. Pilot-ignited direct-injected NG (PIDING) combustion uses a small pilot injection of diesel to ignite a late-cycle main direct injection of NG, resulting in significant reduction of unburned CH4 emissions relative to port-injected NG. Previous works have identified NG premixing as a critical parameter establishing indicated efficiency and emissions performance. To this end, a recent experimental investigation using a metal engine identified six general regimes of PIDING heat release and emissions behavior arising from variation of NG stratification through control of relative injection timing (RIT) of the NG with respect to the pilot diesel. The objective of the current work is to provide comprehensive description of in-cylinder fuel mixing of direct injected gaseous fuel and its impacts on combustion and pollutant formation processes for stratified PIDING combustion. In-cylinder imaging of OH*-chemiluminescence (OH*-CL) and PM (700 nm), and measurement of local concentration of fuel is considered for 11 different RIT , representing 5 regimes of stratified PIDING combustion (performed with P inj = 22. 0 MPa and ϕ = 0. 63). The magnitude and cyclic variability of premixed fuel concentration near the bowl wall provides direct experimental validation of thermodynamic metrics (RI T premix , SO I NG , trans , RI T * ) that describe the fuel-air mixture state of all 5 regimes of PIDING combustion. The local fuel concentration develops non-monotonically and is a function of RIT. High indicated efficiency and low CH4 emissions previously observed for stratified-premixed PIDING combustion in previous (non-optical) investigations are due to: (i) very rapid reaction zone growth (> 45 m/s) and (ii) more distributed early reaction zones when overlapping pilot and NG injections cause partial pilot quenching. These results connect and extend the findings of previous investigations and guide the future strategic implementation of NG stratification for improved combustion and emissions performance. [ABSTRACT FROM AUTHOR]

SRRM2 encodes a splicing factor recently implicated in developmental disorders due to a statistical enrichment of de novo mutations. Using data from the 100,000 Genomes Project, four unrelated individuals with intellectual disability (ID) were identified, each harbouring de novo whole gene deletions of SRRM2. Deletions ranged between 248 and 482 kb in size and all distal breakpoints clustered within a complex 144 kb palindrome situated 75 kb upstream of SRRM2. Strikingly, three of the deletions were complex, with inverted internal segments of 45-94 kb. In one proband-mother duo, de novo status was inferred by haplotype analysis. Together with two additional patients who harboured smaller predicted protein-truncating variants (p.Arg632 ∗ and p.Ala2223Leufs ∗ 13), we estimate the prevalence of this condition in cohorts of patients with unexplained ID to be ~1/1300. Phenotypic blending, present for two cases with additional pathogenic variants in CASR/PKD1 and SLC17A5, hampered the phenotypic delineation of this recently described condition. Our data highlights the benefits of genome sequencing for resolving structural complexity and inferring de novo status. The genomic architecture of 16p13.3 may give rise to relatively high rates of complex rearrangements, adding to the list of loci associated with recurrent genomic disorders. [ABSTRACT FROM AUTHOR]

Copyright of Geologia USP: Série Científica is the property of Geologia USP and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Prenatal genetic diagnosis of monogenic diseases is a process involving the use of a variety of molecular techniques for the molecular characterization of a potential monogenic disease in the fetus during pregnancy. Prenatal genetic diagnosis can be performed through invasive and non-invasive methods. A distinction must be made between "NIPD" (non-invasive prenatal diagnosis), which is considered to be diagnostic, from "NIPT" (non-invasive prenatal test), which is a screening test that requires subsequent confirmation by invasive methods. The different techniques currently available aim at detecting either, previously characterized pathogenic mutations in the family, the risk haplotype associated with the familial mutation, or potential pathogenic mutation(s) in a gene associated with a diagnostic suspicion. An overview is provided of relevant aspects of prenatal genetic diagnosis of monogenic diseases. The objective of this paper is to describe the main molecular techniques currently available and used in clinical practice. A description is provided of the indications, limitations and analytical recommendations regarding these techniques, and the standards governing genetic counseling. Continuous rapid advances in the clinical applications of genomics have provided increased access to comprehensive molecular characterization. Laboratories are struggling to keep in pace with technology developments. [ABSTRACT FROM AUTHOR]

Copyright of Advances in Laboratory Medicine / Avances en Medicina de Laboratorio is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Natural gas (NG) is an attractive fuel for heavy-duty internal combustion engines because of its potential for reduced CO2, particulate, and NOX emissions and lower cost of ownership. Pilot-ignited direct-injected NG (PIDING) combustion uses a small pilot injection of diesel to ignite a main direct injection of NG. Recent studies have demonstrated that increased NG premixing is a viable strategy to increase PIDING indicated efficiency and further reduce particulate and CO emissions while maintaining low CH4 emissions. However, it is unclear how the combustion strategies relate to one another, or where they fit within the continuum of NG stratification. The objective of this work is to present a systematic evaluation of pilot combustion, NG combustion, and emissions behavior of stratified-premixed PIDING combustion modes that span from fully-premixed to non-premixed conditions. A sweep of the relative injection timing, RIT , of NG and pilot diesel was performed in a heavy-duty PIDING engine with P inj = 140–220 bar, ϕ g = 0.47–0.71, and a constant NG energy fraction of 94%. Apparent heat release rate and emissions analyses identified interactions between the pilot fuel and NG, and qualitatively characterized the impact of NG stratification on combustion and emissions. Changes in the RIT resulted in six distinct PIDING combustion regimes, for all considered injection pressures and equivalence ratios: (i) RIT-insensitive premixed, (ii) stratified-premixed (early-cycle injection), (iii) NG jet impingement transition, (iv) stratified-premixed (late-cycle injection), (v) variable premixed fraction, and (vi) minimally-premixed. Parametric definitions for the bounds of each regime of combustion were valid for the wide range of P inj and ϕ g investigated, and are expected to be relevant for other PIDING engines, as previously identified regimes agree with those identified here. This conceptual framework encompasses and validates the findings of previous stratified PIDING investigations, including optimal ranges of operation that provide significantly increased efficiency and lower emissions of incomplete combustion products. [ABSTRACT FROM AUTHOR]

Varenicline (VAR) is a partial agonist of brain α4β2 nicotinic acetylcholine receptors recommended as a first line pharmacotherapy for smoking cessation. The aim of this study was to examine whether VAR affects the protective activity of four classic antiseizure medications, i.e., carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA) on maximal electroshock (MES)-induced seizures, which may serve as an experimental model of human-generalized tonic-clonic seizures in mice. VAR administered intraperitoneally (i.p.) at a subthreshold dose of 0.5 mg/kg decreased the protective activity of CBZ against MES-induced convulsions, increasing its median effective dose (ED50) from 10.92 ± 1.0 to 18.15 ± 1.73 mg/kg (p < 0.01). The effect of VAR was dose-dependent because a lower dose of VAR (0.25 mg/kg) failed to antagonize the protective activity of CBZ. VAR administered at the subthreshold dose of 0.5 mg/kg had no impact on the protective activity of PB, PHT, and VPA in the mouse MES model. The inhibitory effect of VAR on the protective activity of CBZ against tonic-clonic convulsions most likely resulted from the pharmacodynamic mechanism(s) and was not associated with the changes in total brain concentrations of CBZ. VAR-evoked alterations in the anticonvulsive activity of CBZ may be of serious concern for epileptic tobacco smokers. [ABSTRACT FROM AUTHOR]