Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.
- MeSH
- Chlorocebus aethiops MeSH
- COS Cells MeSH
- Zebrafish genetics MeSH
- Child MeSH
- HEK293 Cells MeSH
- Humans MeSH
- Intellectual Disability * genetics MeSH
- Microcephaly * genetics pathology MeSH
- Mice MeSH
- Neurons metabolism pathology MeSH
- Child, Preschool MeSH
- Microtubule-Associated Proteins genetics metabolism MeSH
- Nerve Tissue Proteins genetics metabolism MeSH
- Developmental Disabilities * genetics MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Male MeSH
- Mice MeSH
- Child, Preschool MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
OBJECTIVE: Although genetic causes of drug-resistant focal epilepsy and selected focal malformations of cortical development (MCD) have been described, a limited number of studies comprehensively analysed genetic diagnoses in patients undergoing pre-surgical evaluation, their outcomes and the effect of genetic diagnosis on surgical strategy. METHODS: We analysed a prospective cohort of children enrolled in epilepsy surgery program over January 2018-July 2022. The majority of patients underwent germline and/or somatic genetic testing. We searched for predictors of surgical outcome and positive result of germline genetic testing. RESULTS: Ninety-five patients were enrolled in epilepsy surgery program and 64 underwent resective epilepsy surgery. We ascertained germline genetic diagnosis in 13/74 patients having underwent germline gene testing (pathogenic or likely pathogenic variants in CHRNA4, NPRL3, DEPDC5, FGF12, GRIA2, SZT2, STXBP1) and identified three copy number variants. Thirty-five patients underwent somatic gene testing; we detected 10 pathogenic or likely pathogenic variants in genes SLC35A2, PTEN, MTOR, DEPDC5, NPRL3. Germline genetic diagnosis was significantly associated with the diagnosis of focal epilepsy with unknown seizure onset. SIGNIFICANCE: Germline and somatic gene testing can ascertain a definite genetic diagnosis in a significant subgroup of patients in epilepsy surgery programs. Diagnosis of focal genetic epilepsy may tip the scales against the decision to proceed with invasive EEG study or surgical resection; however, selected patients with genetic focal epilepsies associated with MCD may benefit from resective epilepsy surgery and therefore, a genetic diagnosis does not disqualify patients from presurgical evaluation and epilepsy surgery.
- MeSH
- Child MeSH
- Epilepsies, Partial * complications MeSH
- Epilepsy * genetics surgery complications MeSH
- Fibroblast Growth Factors genetics MeSH
- Genetic Testing MeSH
- Humans MeSH
- Malformations of Cortical Development * genetics MeSH
- Prospective Studies MeSH
- GTPase-Activating Proteins genetics MeSH
- Nerve Tissue Proteins genetics MeSH
- Drug Resistant Epilepsy * diagnosis genetics surgery MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
PURPOSE OF THE STUDY This paper aims to detect, through a retrospective study, the migration of the tips of used metal implants (K-wires or a screw) in the direction out from the proximal femoral epiphysis as a part of studied basic radiometric characteristics of the cohort, with no intention of the authors to evaluate the therapy outcomes. MATERIAL AND METHODS It was a retrospective multicentre study including patients of two orthopaedic clinics and one department of orthopaedics treated in the period 2005-2018. The same treatment procedure was used in all three centres. The "in situ" fixation was indicated in patients, in whom the Southwick angle in anteroposterior and Lauenstein views was not much greater than 30°, whether primarily due to a mild slip or thanks to careful reduction either in acute or acute-on-chronic forms. All X-rays were measured by a single author (M.S.). In AP and Lauenstein view, overlap of the implant tip (K-wire or a screw) above the subcapital growth plate, the height of epiphysis and Southwick angle are measured at the beginning and at the end of treatment. In a smaller group of patients, also the inter-observer error (M.S. and J.P.) was identified. RESULTS K-wire transfixation was used in 43 patients (50 joints), with the mean age of 11.7 years and the mean duration of transfixation of 18.2 months. The slip of the implant tip out of the head, assessed separately for each introduced K-wire and then averaged, was in both views considered statistically significant (in AP view the level of significance was 5% (p-value = 1.393 x 10^(-6) < 0.05) , in Lauenstein view the level of significance was also 5% (p-value = 0.0001652 < 0.05)). The Wilcoxon signed rank test with continuity correction was used. Transfixation by screw alternatively with one K-wire was used in 23 patients (28 joints), with the mean age of 12.4 years and the mean duration of transfixation of 14.4 months. The slip of the screw tip outside the head was assessed as significant (in AP view at the level of significance of 5% (p-value = 9.41 x 10^(-5) < 0.05), in Lauenstein view at the level of significance of 5% (p-value = 0.003557 < 0.05)). The Wilcoxon signed rank test with continuity correction was used. DISCUSSION This paper aims to detect, through a retrospective study, the so-called migration of the tips of used metal implants (K-wires or a screw) outside the femoral head. Smooth and thin implants such as Kirschner wires should not compromise the continuing growth from subcapital growth plate contrary to the AO screw with threads in the femoral head, the screw head rested against the lateral cortical bone and the screw inserted as a compression one. Nonetheless, with some exceptions, the literature confirms the continued growth of the femoral neck even in the case of screws. In general, implants that do not compromise femoral neck growth provide an opportunity to remodel the anterolateral prominence of the femoral metaphysis, especially in younger patients. In agreement with other authors, the data from our study confirmed, even after a short period of time, a certain degree of proximal femoral remodelling expressed by changes in the Southwick angle. CONCLUSIONS Our study confirmed that in the case of "smooth" K-wires as well as cannulated screws the tips of both implants migrate outside the head. The differences were statistically significant. Therefore, the introduction of a conventional cannulated screw cannot be claimed to immediately produce the effect of epiphyseodesis. Yet, smooth implants less compromise the growth of the femoral neck, which is why they have recently been preferred. Key words: coxa vara adolescentium, metal implants, migration.
- MeSH
- Coxa Vara * MeSH
- Child MeSH
- Femur Head surgery MeSH
- Femur Neck surgery MeSH
- Humans MeSH
- Retrospective Studies MeSH
- Slipped Capital Femoral Epiphyses * surgery MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
BACKGROUND: MAPK/ERK signaling is a well-known mediator of extracellular stimuli controlling intracellular responses to growth factors and mechanical cues. The critical requirement of MAPK/ERK signaling for embryonic stem cell maintenance is demonstrated, but specific functions in progenitor regulation during embryonic development, and in particular kidney development remain largely unexplored. We previously demonstrated MAPK/ERK signaling as a key regulator of kidney growth through branching morphogenesis and normal nephrogenesis where it also regulates progenitor expansion. Here, we performed RNA sequencing-based whole-genome expression analysis to identify transcriptional MAPK/ERK targets in two distinct renal populations: the ureteric bud epithelium and the nephron progenitors. RESULTS: Our analysis revealed a large number (5053) of differentially expressed genes (DEGs) in nephron progenitors and significantly less (1004) in ureteric bud epithelium, reflecting likely heterogenicity of cell types. The data analysis identified high tissue-specificity, as only a fraction (362) of MAPK/ERK targets are shared between the two tissues. Tissue-specific MAPK/ERK targets participate in the regulation of mitochondrial energy metabolism in nephron progenitors, which fail to maintain normal mitochondria numbers in the MAPK/ERK-deficient tissue. In the ureteric bud epithelium, a dramatic decline in progenitor-specific gene expression was detected with a simultaneous increase in differentiation-associated genes, which was not observed in nephron progenitors. Our experiments in the genetic model of MAPK/ERK deficiency provide evidence that MAPK/ERK signaling in the ureteric bud maintains epithelial cells in an undifferentiated state. Interestingly, the transcriptional targets shared between the two tissues studied are over-represented by histone genes, suggesting that MAPK/ERK signaling regulates cell cycle progression and stem cell maintenance through chromosome condensation and nucleosome assembly. CONCLUSIONS: Using tissue-specific MAPK/ERK inactivation and RNA sequencing in combination with experimentation in embryonic kidneys, we demonstrate here that MAPK/ERK signaling maintains ureteric bud tip cells, suggesting a regulatory role in collecting duct progenitors. We additionally deliver new mechanistic information on how MAPK/ERK signaling regulates progenitor maintenance through its effects on chromatin accessibility and energy metabolism.
- MeSH
- Epithelial Cells MeSH
- Kidney * metabolism MeSH
- Humans MeSH
- Nephrons * metabolism MeSH
- Organ Specificity MeSH
- Gene Expression Profiling MeSH
- Pregnancy MeSH
- Check Tag
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Angiosperm mature pollen represents a quiescent stage with a desiccated cytoplasm surrounded by a tough cell wall, which is resistant to the suboptimal environmental conditions and carries the genetic information in an intact stage to the female gametophyte. Post pollination, pollen grains are rehydrated, activated, and a rapid pollen tube growth starts, which is accompanied by a notable metabolic activity, synthesis of novel proteins, and a mutual communication with female reproductive tissues. Several angiosperm species (Arabidopsis thaliana, tobacco, maize, and kiwifruit) were subjected to phosphoproteomic studies of their male gametophyte developmental stages, mostly mature pollen grains. The aim of this review is to compare the available phosphoproteomic studies and to highlight the common phosphoproteins and regulatory trends in the studied species. Moreover, the pollen phosphoproteome was compared with root hair phosphoproteome to pinpoint the common proteins taking part in their tip growth, which share the same cellular mechanisms.
Soil biota contribute to diverse soil ecosystem services such as greenhouse gas mitigation, carbon sequestration, pollutant degradation, plant disease suppression and nutrient acquisition for plant growth. Here, we provide detailed insight into different perturbation approaches to disentangle soil microbiome functions and to reveal the underlying mechanisms. By applying perturbation, one can generate compositional and functional shifts of complex microbial communities in a controlled way. Perturbations can reduce microbial diversity, diminish the abundance of specific microbial taxa and thereby disturb the interactions within the microbial consortia and with their eukaryotic hosts. Four different microbiome perturbation approaches, namely selective heat, specific biocides, dilution-to-extinction and genome editing are the focus of this mini-review. We also discuss the potential of perturbation approaches to reveal the tipping point at which specific soil functions are lost and to link this change to key microbial taxa involved in specific microbiome-associated phenotypes.
Single-point mutation in the ACTIN2 gene of the der1-3 mutant revealed that ACTIN2 is an essential actin isovariant required for root hair tip growth, and leads to shorter, thinner and more randomly oriented actin filaments in comparison to the wild-type C24 genotype. The actin cytoskeleton has been linked to plant defense against oxidative stress, but it is not clear how altered structural organization and dynamics of actin filaments may help plants to cope with oxidative stress. In this study, we characterized root growth, plant biomass, actin organization and antioxidant activity of the der1-3 mutant under oxidative stress induced by paraquat and H2O2. Under these conditions, plant growth was better in the der1-3 mutant, while the actin cytoskeleton in the der1-3 carrying pro35S::GFP:FABD2 construct showed a lower bundling rate and higher dynamicity. Biochemical analyses documented a lower degree of lipid peroxidation, and an elevated capacity to decompose superoxide and hydrogen peroxide. These results support the view that the der1-3 mutant is more resistant to oxidative stress. We propose that alterations in the actin cytoskeleton, increased sensitivity of ACTIN to reducing agent dithiothreitol (DTT), along with the increased capacity to decompose reactive oxygen species encourage the enhanced tolerance of this mutant against oxidative stress.
... Excess fetal risks associated with obesity 62 -- 47 Ultrasound assessment in obesity 63 -- Fetal growth ... ... assessment 65 -- 47 Technical tips for ultrasound in obese women 65 -- Financial issues 65 -- 47 Medicolegal ... ... 153 -- Glucose metabolism and fetal growth 154 -- Maternal lipid supply and fetal growth 154 -- Amino ... ... Obesity, insulin resistance, and placental dysfunction—fetal growth 191 -- Mariam Al Beloushi, Anjum ... ... surgery 311 -- Nutrition 311 -- Anemia 311 -- Gastrointestinal symptoms 311 -- Monitoring of fetal growth ...
Second edition xxi, 349 stran : ilustrace, tabulky ; 28 cm
- Conspectus
- Gynekologie. Porodnictví
- NML Fields
- gynekologie a porodnictví
- obezitologie
- NML Publication type
- kolektivní monografie
Alterations of hydrogen peroxide (H2O2) levels have a profound impact on numerous signaling cascades orchestrating plant growth, development, and stress signaling, including programmed cell death. To expand the repertoire of known molecular mechanisms implicated in H2O2 signaling, we performed a forward chemical screen to identify small molecules that could alleviate the photorespiratory-induced cell death phenotype of Arabidopsisthaliana mutants lacking H2O2-scavenging capacity by peroxisomal catalase2. Here, we report the characterization of pakerine, an m-sulfamoyl benzamide from the sulfonamide family. Pakerine alleviates the cell death phenotype of cat2 mutants exposed to photorespiration-promoting conditions and delays dark-induced senescence in wild-type Arabidopsis leaves. By using a combination of transcriptomics, metabolomics, and affinity purification, we identified abnormal inflorescence meristem 1 (AIM1) as a putative protein target of pakerine. AIM1 is a 3-hydroxyacyl-CoA dehydrogenase involved in fatty acid β-oxidation that contributes to jasmonic acid (JA) and salicylic acid (SA) biosynthesis. Whereas intact JA biosynthesis was not required for pakerine bioactivity, our results point toward a role for β-oxidation-dependent SA production in the execution of H2O2-mediated cell death.
- MeSH
- Arabidopsis cytology drug effects genetics metabolism MeSH
- Cell Death drug effects MeSH
- Cell Respiration drug effects genetics MeSH
- Cyclopentanes metabolism MeSH
- Photosynthesis drug effects genetics MeSH
- Stress, Physiological MeSH
- Hydroponics methods MeSH
- Salicylic Acid metabolism MeSH
- Plant Leaves cytology drug effects metabolism MeSH
- Meristem cytology drug effects metabolism MeSH
- Multienzyme Complexes genetics metabolism MeSH
- Oxylipins metabolism MeSH
- Hydrogen Peroxide antagonists & inhibitors pharmacology MeSH
- Arabidopsis Proteins genetics metabolism MeSH
- Gene Expression Regulation, Plant * MeSH
- Plant Cells drug effects metabolism MeSH
- Seeds drug effects MeSH
- Signal Transduction MeSH
- Gene Expression Profiling MeSH
- Sulfonamides chemical synthesis pharmacology MeSH
- Transcriptome MeSH
- Computational Biology methods MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Axon regeneration in the CNS is inhibited by many extrinsic and intrinsic factors. Because these act in parallel, no single intervention has been sufficient to enable full regeneration of damaged axons in the adult mammalian CNS. In the external environment, NogoA and CSPGs are strongly inhibitory to the regeneration of adult axons. CNS neurons lose intrinsic regenerative ability as they mature: embryonic but not mature neurons can grow axons for long distances when transplanted into the adult CNS, and regeneration fails with maturity in in vitro axotomy models. The causes of this loss of regeneration include partitioning of neurons into axonal and dendritic fields with many growth-related molecules directed specifically to dendrites and excluded from axons, changes in axonal signalling due to changes in expression and localization of receptors and their ligands, changes in local translation of proteins in axons, and changes in cytoskeletal dynamics after injury. Also with neuronal maturation come epigenetic changes in neurons, with many of the transcription factor binding sites that drive axon growth-related genes becoming inaccessible. The overall aim for successful regeneration is to ensure that the right molecules are expressed after axotomy and to arrange for them to be transported to the right place in the neuron, including the damaged axon tip.
- MeSH
- Axonal Transport physiology MeSH
- Axons physiology MeSH
- Central Nervous System cytology physiology MeSH
- Humans MeSH
- Neural Inhibition physiology MeSH
- Neurogenesis physiology MeSH
- Protein Biosynthesis physiology MeSH
- Nerve Regeneration physiology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
