Botryoidal and spherulitic hematite as experimental evidence of highly acidic conditions in burning coal-waste dumps and potentially on Mars.

In the extreme setting of burning coal-waste dumps in the Upper Silesian Coal Basin in Poland, botryoidal and spherulitic hematite occurs in association with sulphates and chlorides. A series of simple experiments aimed at replicating the conditions leading to the formation of hematite spherules on the burning dumps are described. Goethite synthesised in the laboratory, mixed with various combinations of other reactants, was heated in a heating chamber or a tubular furnace. Temperature, duration of heating, water and oxygen access, and pH were experimental variables. The results show that hematite may form spherules from goethite where access to oxygen is limited and where conditions are strongly acidic. The spherulitic shape of hematite produced due to dynamically changing physicochemical conditions in the burning dumps can be an indicator of an extremely acidic environment during the closing stages of coal-waste self-heating. The conditions of hematitic-spherule formation on burning coal-waste dumps may apply in a variety of other unrelated settings, e.g., waning volcanism, sulphuric acid speleologenesis and even the formation of blueberries on Mars.

Research on the Pathogenesis of Cognitive and Neurofunctional Impairments in Patients with Noonan Syndrome: The Role of Rat Sarcoma-Mitogen Activated Protein Kinase Signaling Pathway Gene Disturbances.

Noonan syndrome (NS) is one of the most common genetic conditions inherited mostly in an autosomal dominant manner with vast heterogeneity in clinical and genetic features. Patients with NS might have speech disturbances, memory and attention deficits, limitations in daily functioning, and decreased overall intelligence. Here, 34 patients with Noonan syndrome and 23 healthy controls were enrolled in a study involving gray and white matter volume evaluation using voxel-based morphometry (VBM), white matter connectivity measurements using diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI). Fractional anisotropy (FA) and mean diffusivity (MD) probability distributions were calculated. Cognitive abilities were assessed using the Stanford Binet Intelligence Scales. Reductions in white matter connectivity were detected using DTI in NS patients. The rs-fMRI revealed hyper-connectivity in NS patients between the sensorimotor network and language network and between the sensorimotor network and salience network in comparison to healthy controls. NS patients exhibited decreased verbal and nonverbal IQ compared to healthy controls. The assessment of the microstructural alterations of white matter as well as the resting-state functional connectivity (rsFC) analysis in patients with NS may shed light on the mechanisms responsible for cognitive and neurofunctional impairments.

Heavy metal- and organic-matter pollution due to self-heating coal-waste dumps in the Upper Silesian Coal Basin (Poland).

This study provides potential insight between self-heating coal-waste dumps and related environmental pollution in southern Poland. Samples collected from dumps in the Upper Silesian Coal Basin were used to quantify released contents of organic- and inorganic pollutants, i.e., polycyclic aromatic hydrocarbons (PAHs) and trace elements (Pb, Cd, Cr, Cu, Zn, Ni, Hg, As). Elevated Hg concentrations (~100-1078 mg/kg) and Pb (~600-2000 mg/kg) attest to the evaporation of these metals from deeper parts of the dumps. The acidic pH levels (3.0-4.5) may help to mobilize these elements. Pearson's correlation coefficients for samples analyzed by AAS and ICP-MS indicate a similar origin for Cd, Zn, and As. Mostly 2- and 3-ring PAHs, especially anthracene in burnt soil, dominate in the samples. Chlorinated PAHs, thiophenol, pyridines, quinolines (and derivatives) in thermally-altered samples, and waste containing pyrolytic bitumen indicate coking conditions. The high levels of Hg, Pb, and Cd, and chlorinated PAHs and nitrogen heterocycles formed or enriched during self-heating in these dumps should be deemed a significant environmental hazard. Calculating the lifetime cancer risks due to PAHs and heavy metals accumulations in the dumps are substantial, and access to these dumps should be prohibited.

Correction to: Splicing mutations in human genetic disorders: examples, detection, and confirmation.

The original version on this paper contained an error. The first names and last names of Anna Abramowicz and Monika Gos are inadvertently interchanged and are incorrectly displayed in indexing sites. The correct names are presented above.

MAP2K2 mutation as a cause of cardio-facio-cutaneous syndrome in an infant with a severe and fatal course of the disease.

Cardio-facio-cutaneous syndrome (CFCS), a rare congenital disorder of RASopathies, displays high phenotypic variability. Complications during pregnancy and in the perinatal period are commonly reported. Polyhydramnios is observed in over half of pregnancies and might occur with fetal macrocephaly, macrosomia, and/or heart defects. Premature birth is not uncommon and any complications like respiratory insufficiency, edema, and feeding difficulties are present and might delay accurate clinical diagnosis. Besides neonatal complications, CFCS newborns and later infants have distinctive dysmorphic features usually accompanied by neurological (hypotonia with motor delay, neurocognitive delay) findings. Also, heart defects usually present at birth. Herein, we present the case of a female baby born prematurely from a pregnancy complicated with polyhydramnios, presenting at birth with craniofacial features typical for RASopathies, heart defects, neurological abnormalities, and hyperkeratosis unusual for a neonatal period. Due to the presence of a heart defect and other complications related to premature birth, the course of the disease was severe with a fatal outcome at the age of 9 months. The RASopathy, particularly CFCS, clinical diagnosis was confirmed and de novo p.Phe57Ile mutation in MAP2K2 was identified.

Towards a Better Molecular Diagnosis of FMR1-Related Disorders-A Multiyear Experience from a Reference Lab.

The article summarizes over 20 years of experience of a reference lab in fragile X mental retardation 1 gene (FMR1) molecular analysis in the molecular diagnosis of fragile X spectrum disorders. This includes fragile X syndrome (FXS), fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS), which are three different clinical conditions with the same molecular background. They are all associated with an expansion of CGG repeats in the 5'UTR of FMR1 gene. Until 2016, the FMR1 gene was tested in 9185 individuals with the pre-screening PCR, supplemented with Southern blot analysis and/or Triplet Repeat Primed PCR based method. This approach allowed us to confirm the diagnosis of FXS, FXPOI FXTAS in 636/9131 (6.96%), 4/43 (9.3%) and 3/11 (27.3%) of the studied cases, respectively. Moreover, the FXS carrier status was established in 389 individuals. The technical aspect of the molecular analysis is very important in diagnosis of FXS-related disorders. The new methods were subsequently implemented in our laboratory. This allowed the significance of the Southern blot technique to be decreased until its complete withdrawal. Our experience points out the necessity of implementation of the GeneScan based methods to simplify the testing procedure as well as to obtain more information for the patient, especially if TP-PCR based methods are used.

[Neurofibromin - protein structure and cellular functions in the context of neurofibromatosis type I pathogenesis]. / Neurofibromina ­ budowa i funkcje bialka w kontekscie patogenezy nerwiakowlókniakowatosci typu I.

Neurofibromatosis type I (NF1) is multisystemic disease characterized by pigmentary skin changes, increased susceptibility to tumor formation, neurological deficits and skeletal defects. The disease is a monogenic, autosomal dominant disorder, caused by the presence of mutations in the NF1 gene encoding neurofibromin - a multifunctional regulatory protein. The basic function of neurofibromin protein is modulation of the RAS protein activity necessary for regulation of cell proliferation and differentiation by the RAS/MAPK and RAS/PI3K/AKT signal transduction pathways. In addition, neurofibromin is a regulator of adenylate cyclase activity and therefore may interfere with signaling by the cAMP/protein kinase A pathway that regulates cell cycle progression or learning and memory formation processes. Neurofibromin also interacts with many other proteins that are engaged in intracellular transport (tubulin, kinesin), actin cytoskeleton rearrangements (LIMK2, Rho and Rac) or morphogenesis of neural cells (syndecans, CRMP proteins). The activity of neurofibromin is strictly regulated by the expression of different NF1 mRNA isoforms depending on tissue type or period in organism development, the protein localization, posttranslational modifications (phosphorylation, ubiquitination) or interactions with other proteins (e.g. 14-3-3). The fact that neurofibromin is engaged in many cellular processes has significant consequences when the proper protein functioning is impaired due to decreased protein level or activity. It affects the normal cell function and results in disturbances of organism development that lead to the occurrence of clinical signs specific for NF1. In the article, the basic neurofibromin functions are presented in the context of the molecular pathogenesis of NF1.

Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.

BACKGROUND: Noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. The identification of novel genes associated with Noonan syndrome has become increasingly challenging, since they might be responsible for very small fractions of the cases. METHODS: A cohort of 50 Brazilian probands negative for pathogenic variants in the known genes associated with Noonan syndrome was tested through whole-exome sequencing along with the relatives in the familial cases. Families from the USA and Poland with mutations in the newly identified genes were included subsequently. RESULTS: We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands. SOS2 and LZTR1 variants were also found to segregate in one American and one Polish family. Notably, SOS2 variants were identified in patients with marked ectodermal involvement, similar to patients with SOS1 mutations. CONCLUSIONS: We identified two novel genes, SOS2 and LZTR1, associated with Noonan syndrome, thereby expanding the molecular spectrum of RASopathies. Mutations in these genes are responsible for approximately 3% of all patients with Noonan syndrome. While SOS2 is a natural candidate, because of its homology with SOS1, the functional role of LZTR1 in the RAS/MAPK pathway is not known, and it could not have been identified without the large pedigrees. Additional functional studies are needed to elucidate the role of LZTR1 in RAS/MAPK signalling and in the pathogenesis of Noonan syndrome.

Neurofibromin in neurofibromatosis type 1 - mutations in NF1gene as a cause of disease.

Neurofibromatosis type I (NF1) is a disease associated with the presence of benign neurofibromas and malignant tumours of the central and peripheral nervous system, that are accompanied by characteristic changes in the skin, such as café-au-lait spots or axillary freckling. In 50% of NF1 patients, the clinical symptoms become apparent below 1st year and in 97%, before the age of 8 years. The disease is mainly caused by the presence of mutation in the NF1 gene that encodes neurofibromin - a protein involved in the regulation of several cellular signaling pathways responsible for cell proliferation and differentiation. Neurofibromin is necessary for embryonic development and involved mainly in the differentiation of neural crest derived cells, mesenchymal cells, neural cells, melanocytes and bone cells. Type I neurofibromatosis is inherited in autosomal dominant manner, nevertheless about 50% of detected mutations are de novo ones. The mutations have full penetrance, although they also have significant pleiotropic effect. Over 1485 different mutations have been identified in the NF1 gene so far, most of which lead to a synthesis of truncated, non-functional protein. It is estimated that the point mutations are responsible for approximately 90% of cases of NF1. The remaining 5-7% of NF1 cases are associated with the presence of a single exon or whole NF1 gene deletion (17q11.2 microdeletion syndrome). The article discusses the role of neurofibromin in cell signaling with the special attention to RAS/MAPK pathway regulation as well as in organism development. Also the basic methods of molecular analysis of NF1 gene are presented in the context of their application in the diagnosis and clinical differentiation of the disease.

[RAS/MAPK signal transduction pathway and its role in the pathogenesis of Noonan syndrome]. / Sciezka sygnalowa RAS/MAPK i jej rola w etiopatogenezie zespolu Noonan.

Noonan syndrome (NS) is one of the most frequent dysmorphic syndromes in children with a frequency of 1/1000-1/2500 of newborns. Noonan syndrome is a multi-organ disease with a broad spectrum of clinical symptoms. The most characteristic features of NS are: craniofacial dysmorphy, short stature, cardiovascular defects, bone and skeletal defects and delayed puberty (cryptorchidism in males). Noonan syndrome has a genetic background and is inherited in autosomal dominant manner. The recent studies have shown that it is due to the presence of mutation in one of the genes encoding proteins of RAS/MAPK signalling pathway responsible for cell proliferation and differentiation. Till now, NS causing mutations were identified in PTPN11, SOS1, RAF1, KRAS, BRAF, SHOC2 and NRAS genes, and this may partially explain the broad phenotypic spectrum observed in patients. Noonan syndrome is one of the RAS-opathies, therefore the molecular analysis of RAS/ MAPK genes might be a very useful tool in clinical differentiation of the disease.