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Purpose To characterize a novel neurodevelopmental syndrome due to loss-of-function (LoF) variants in Ankyrin 2 (ANK2), and to explore the effects on neuronal network dynamics and homeostatic plasticity in human-induced pluripotent stem cell-derived neurons. Methods We collected clinical and molecular data of 12 individuals with heterozygous de novo LoF variants in ANK2. We generated a heterozygous LoF allele of ANK2 using CRISPR/Cas9 in human-induced pluripotent stem cells (hiPSCs). HiPSCs were differentiated into excitatory neurons, and we measured their spontaneous electrophysiological responses using micro-electrode arrays (MEAs). We also characterized their somatodendritic morphology and axon initial segment (AIS) structure and plasticity. Results We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy. Using MEAs, we found that hiPSC-derived neurons with heterozygous LoF of ANK2 show a hyperactive and desynchronized neuronal network. ANK2-deficient neurons also showed increased somatodendritic structures and altered AIS structure of which its plasticity is impaired upon activity-dependent modulation. Conclusions Phenotypic characterization of patients with de novo ANK2 LoF variants defines a novel NDD with early onset epilepsy. Our functional in vitro data of ANK2-deficient human neurons show a specific neuronal phenotype in which reduced ANKB expression leads to hyperactive and desynchronized neuronal network activity, increased somatodendritic complexity and AIS structure and impaired activity-dependent plasticity of the AIS.

Purpose To investigate the association between oocyte area and fertilization rate, embryo usage, and preimplantation embryo development in order to establish if oocyte area can be a marker for optimal early embryo development. Methods From 2017 to 2020, 378 couples with an indication for IVF (n = 124) or ICSI (n = 254) were included preconceptionally in the Rotterdam Periconception Cohort. Resulting oocytes (n = 2810) were fertilized and submitted to time-lapse embryo culture. Oocyte area was measured at the moment of fertilization (t0), pronuclear appearance (tPNa), and fading (tPNf). Fertilization rate, embryo usage and quality, and embryo morphokinetics from 2-cell stage to expanded blastocyst stage (t2-tEB) were used as outcome measures in association with oocyte area. Oocytes were termed “used” if they were fertilized and embryo development resulted in transfer or cryopreservation, and otherwise termed “discarded”. Analyses were adjusted for relevant confounders. Results Oocyte area decreased from t0 to tPNf after IVF and ICSI, and oocytes with larger area shrank faster (β − 12.6 µm2/h, 95%CI − 14.6; − 10.5, p 2 versus discarded 9679 ± 673 µm2, p p used 1.669, 95%CI 1.336; 2.085, p p = 0.016) and higher ICM quality. Conclusion Oocyte area is an informative marker for the preimplantation development of the embryo, as a larger oocyte area is associated with higher quality, faster developing embryos, and higher chance of being used. Identifying determinants associated with oocyte and embryo viability and quality could contribute to improved preconception care and subsequently healthy pregnancies.

A prenatal second-hit genetic change that occurs on the wild-type allele in an embryo with a congenital pathogenic variant allele results in mosaicism of monoallelic and biallelic defect of the gene, which is called superimposed mosaicism. Superimposed mosaicism of Hailey-Hailey disease (HHD) has been demonstrated in one familial case. Here, we report two unrelated HHD cases with superimposed mosaicism: a congenital monoallelic pathogenic variant of ATP2C1, followed by a postzygotic copy-neutral loss of heterozygosity. Uniquely, neither patient had a family history of HHD at the time of presentation. In the first case, the congenital pathogenic variant had occurred de novo. In the second case, the father had the pathogenic variant but had not yet developed skin symptoms. Our cases showed that superimposed mosaicism in HHD can lack a family history and that genetic analysis is crucial to classify the type of mosaicism and evaluate the risk of familial occurrence.

The sodium channel and clathrin linker 1 gene (SCLT1) has been involved in the pathogenesis of various ciliopathy disorders such as Bardet-Biedl syndrome, orofaciodigital syndrome type IX, and Senior-Løken syndrome. Detailed exams are warranted to outline all clinical features. Here, we present a family with a milder phenotype of SCLT1-related disease. Comprehensive eye examination including fundus images, OCT, color vision, visual fields and electroretinography were performed. Affected individuals were assessed by a pediatrician and a medical geneticist for systemic features of ciliopathy. Investigations included echocardiography, abdominal ultrasonography, blood work-up for diabetes, liver and kidney function. Genetic testing included NGS retinal dystrophy panel, segregation analysis and transcriptome sequencing. Two male children, age 10 and 8 years, were affected with attention deficit hyperactivity disorder (ADHD), obesity and mild photophobia. The ophthalmic exam revealed reduced best-corrected visual acuity (BCVA), strabismus, hyperopia, astigmatism and moderate red-green defects. Milder changes suggesting photoreceptors disease were found on retinal imaging. Electroretinogram confirmed cone photoreceptors dysfunction. Genetic testing revealed a homozygous likely pathogenic, splice-site variant in SCLT1 gene NM_144643.3: c.1439 + 1del in the proband and in the affected brother. The unaffected parents were heterozygous for the SCLT1 variant. Transcriptome sequencing showed retention of intron 16 in the proband. In this report, we highlight the importance of further extensive diagnostics in patients with unexplained reduced vision, strabismus, refractive errors and ADHD spectrum disorders. SCLT1-related retinal degeneration is very rare and isolated reduced function of cone photoreceptors has not previously been observed.

This Position Statement provides guidelines to assist all health professionals who receive requests for carrier testing and laboratory staff conducting the tests. In this Statement, the term ‘carrier testing’ refers to genetic testing in an individual to determine whether they have inherited a pathogenic variant associated with an autosomal or X-linked recessive condition previously identified in a blood relative. Carrier testing recommendations: (1) Carrier testing should only be performed with the individual’s knowledge and consent; (2) An individual considering (for themselves, or on behalf of another) whether to have a carrier test should be supported to make an informed decision; (3) The mode of inheritance, the individual’s personal experience with the condition, and the healthcare setting in which the test is being performed should be considered when determining whether carrier testing should be offered by a genetic health professional. Regarding children and young people: Unless there is direct medical benefit in the immediate future, the default position should be to postpone carrier testing until the child or young person can be supported to make an informed decision. There may be some specific situations where it is appropriate to facilitate carrier testing in children and young people (see section in this article). In such cases, testing should only be offered with pre- and post-test genetic counseling in which genetic health professionals and parents/guardians should explore the rationale for testing and the interests of the child and the family.

In the postgenomic era, variant interpretation is crucial for diagnosing monogenic diseases, which is the premise of precision medicine. The bottleneck and difficulty of genetic disease diagnosis have switched from the inaccessibility of detection technology to the interpretation of sequencing results. Multiple studies have suggested that the inconsistency rate of interlaboratory variant interpretation is approximately 10~40%. However, many clinicians have not paid enough attention to this area at present. In this review, we summarized the reasons for inconsistency, including classification methodology, information obtained by the interpreter, evidence application, and expert judgement. For clinicians, genetic counsellors, and molecular pathologists, it is necessary to reevaluate genetic reports, especially those supported by old literature and databases in clinical practice. For unresolvable cases, pedigree analysis, collaboration with research labs for functional experiments, and long-term follow-up to combine advanced clinical presentations with updated data and literature are needed.

This population-based cohort study investigated the prevalence, potential risk factors, and consequences of birth weight discordance (BWD) among same-sex twins. We retrieved data from the automated system of healthcare utilization databases of Lombardy Region, Northern Italy (2007–2021). BWD was defined as 30% or more disparity in birth weights between the larger and the smaller twin. Multivariate logistic regression was used to analyze the risk factors of BWD in deliveries with same-sex twins. In addition, the distribution of several neonatal outcomes was assessed overall and according to BWD level (i.e., ≤20%, 21–29, and ≥30%). Finally, a stratified analysis by BWD was performed to assess the relationship between assisted reproductive technologies (ART) and neonatal outcomes. We identified 11,096 same-sex twin deliveries; 556 (5.0%) pairs of twins were affected by BWD. Multivariate logistic regression analysis showed that maternal age ≥35 years (OR 1.26, 95% CI [1.05,5.51]), low level of education (OR 1.34, 95% CI [1.05, 1.70]), and ART (OR 1.16, 95% CI [0.94, 1.44], almost significant due to the low power) were independent risk factors for BWD in same-sex twins. Conversely, parity (OR 0.73, 95% CI [0.60, 0.89]) was inversely related. All the adverse outcomes observed were more common among BWD pairs than non-BWD ones. Instead, a protective effect of ART was observed for most neonatal outcomes considered among BWD twins. Our results suggest that conception after ART increases the risk of developing a high disparity between the weights of the two twins. However, the presence of BWD may complicate twin pregnancies, compromising neonatal outcomes, regardless of the modality of conception.

Studying the role of inositol phosphates in the regulation of signal exchange between leguminous plants and nodule bacteria is of great interest since it affects the regulation of calcium level in the root cells in response to bacterial signals during symbiosis development. The regulation of intracellular calcium content is one of the key events in the control of symbiosis development, but remains very poorly understood. In present work, we revealed a significant increase in the content of inositol hexasphosphate (IP6), which occurs in response to the recognition of Nod factors and indicates that in plants, unlike animals, this form (along with the inositol triphosphate (IP3)) may be important for signal transduction. This is consistent with the data that receptor for IP3 in plants has not yet been found, despite numerous efforts. Expression analysis of the genes encoding enzymes of two biosynthetic pathways for inositol phosphates showed stimulation of the PsITPK1 gene (Psat6g210960), which can control the phospholipid-independent pathway for synthesis of these compounds. Despite the fact that PsPIP5K (Psat5g134320) important for another pathway did not show increased expression in our experiments upon inoculation, the activation of the phospholipid-dependent pathway of inositol phosphate biosynthesis can be evidenced by stimulation of a number of genes encoding pospholipases C (PLCs) which were previously found in pea Pisum sativum as well as during analysis of transcriptome of Medicago truncatula root treated with Nod factors. Therefore, in plants, in contrast to animals, the pathways for the synthesis of inositol phosphates can be more diverse, which indicates the plasticity of signal pathways.

The dynamics of the composition of the populations of Adalia bipunctata L. in St. Petersburg and Yalta (Crimean Peninsula) for 4732 years has been studied. The proportion of black individuals in them decreased by almost 2 times. Comparison of the composition of populations with climatic features of habitats (average annual temperature) showed that the proportion of black individuals in the population negatively correlates with the average annual temperature of the previous year. The observed change in the composition of geographically remote populations is probably the effect of global warming.

Variability of terry flowers in buttercup Ranunculus acris from different populations demonstrates the anthropogenic impact on the environment. Schoolchildren carried out training works analyzing the frequency of occurrence of the trait double of a buttercup flower in the populations of the North-West Region of Russia. The data obtained made it possible to discuss questions about the mechanisms of action of environmental pollution by surfactants and unsaturated hydrocarbons. The article emphasizes the importance: of the direct joint participation of schoolchildren and university professional teachers in environmental research; of the visibility, evidence and significance of their results; of competent comprehensive discussion for the formation of a bio- and ecocentric worldview. The latter is especially important for the tuition of qualified scientific staff in the field of ecological genetics.

Demographic history reconstruction is based on the estimation of effective population size (Ne), which is inferred and interpreted in various fields of evolutionary and conservation biology. Interest in Ne estimation is growing, as the key evolutionary forces and their are linked to Ne, and genetic data become increasingly accessible. However, what is effective population size, and how can we obtain an estimate of effective population size? In this review, we describe the history of the term Ne and explore existing methods for obtaining historical and contemporary estimates of changes in effective population size. We provide a detailed overview of methods based on sequential Markovian coalescence (SMC), generalized phylogenetic coalescence (G-PhoCS), identity by descent (IBD) and identity by state (IBS) similarity, as well as methods using allele frequency spectrum (AFS). For each method, we briefly summarize the underlying theory and note its advantages and disadvantages. In the final section of the review, we present examples of the use of these methods for various non-model species with conservation status.

BACKGROUND: The causal relationship between mutagenesis and carcinogenesis is well known. Hence the wide interest in the study of the mutagen-modifying effects of natural and synthetic compounds. Particular attention is drawn to widespread compounds. One of them, metformin, is widely used as a hypoglycemic drug. AIM: evaluation of the influence of metformin on the cytogenetic effects of doxorubicin and cyclophosphamide in mouse bone marrow cells. MATERIALS AND METHODS: Male F1 CBAxC57Bl/6 hybrid mice were used. Cyclophosphamide (20 mg/kg) or doxorubicin (10 mg/kg) was administered intraperitoneally, metformin was given orally once or for 4 consecutive days. The latter administration of metformin was combined with mutagen administration. Cytogenetic preparations of bone marrow cells were prepared 18 hours after metformin administration and 24 hours after its combined administration with mutagens. Chromosomal aberrations were analyzed according to accepted protocols. RESULTS: Metformin per se showed no cytogenetic activity at doses of 500, 1000, and 2000 mg/kg. At a dose of 500 mg/kg, but not 100 or 250 mg/kg, metformin reduced the cytogenetic effects of doxorubicin. Metformin administered once and for 4 days at doses of 100, 250, and 500 mg/kg or once at doses of 10 and 20 mg/kg increased the number of metaphases with chromosome aberrations induced by cyclophosphamide by a factor of 2 to 3. At doses of 2.5 and 5 mg/kg, metformin had no modifying effect on the mutagen effect. CONCLUSION: Metformin attenuates the cytogenetic effects of doxorubicin and enhances the cytogenetic activity of cyclophosphamide in mouse bone marrow cells. This allows us to conclude that metformin has mutagen-modifying properties.

BACKGROUND: The study of the VIR corn collection in order to search for economically valuable sources and donors is topical. MATERIALS AND METHODS: Studies of the biochemical components of grain during its deep processing were carried out on 27 hybrids from Germany, presented in the VIR collection. Valuable results have been obtained using the method of IR spectrometry and deep processing of grain in laboratory conditions, which make it possible to identify samples of interest for the production of native starch and its by-products. RESULTS: The starch yield of more than 65% solids (% DM) grain dry matter is established for the following hybrids: KHV 7262, KHV 6431, KHV 6331, KHV 5440, Karpatis, DS 21209C, DS 21215B, DS 21212A, DS 21205B, DS 22188D. The maximum starch yield, more than 70% grain DM, is set for DS 21205B hybrids. The maximum yield of the embryo was set for the hybrid KHV 4126 up to 10% DM of the grain, the yield of starch during the processing of the grain of this hybrid was 61.2% DM. The highest yield of gluten, 18% or more, was established during the processing of hybrids DS 23190B and DS 21203B. The pulp yield of more than 15% CB was obtained by processing grain DS 22182C. Based on the results obtained, the following hybrids are proposed as the starting material for corn breeding for deep grain processing: KHV 7262, KHV 5440, DS 21209C, DS 21215B, DS 21212A, DS 21205B, DS 22188D. CONCLUSIONS: Of greatest interest as a starting material is hybrid DS 21205B, during the processing of which starch was extracted in an amount of more than 70% grain DM.

Background. The epigenome of gametes is formed under the control of the developmental programme and the influence of environmental factors. How cytosine oxidation patterns are formed and altered in human spermatogenesis remains obscure so far. The aim of the study was to assess 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) patterns in human spermatogenic cells and spermatozoa. Materials and Methods. The study was performed on testicular biopsy samples of 10 azoospermic patients and ejaculate samples of 5 sperm donors and 8 patients from infertile couples. The microscope slides were prepared for further indirect immunofluorescence to detect 5fC and 5caC and FISH to determine spermatogenic cell ploidy. Results. 5fC and 5caC were undetectable in mitotic and meiotic chromosomes of spermatogenic cells, and was present exclusively in some spermatogonia and spermatid interphase nuclei as well as in some ejaculated spermatozoa. The frequency of spermatozoa with 5fC and 5caC varied in a wide range and was higher in patients than in sperm donors (p=0,007, p=0,028). The increase in frequency of spermatozoa with 5fC and 5caC was accompanied with the decrease in frequency of morphologically normal and progressively motile spermatozoa. Conclusions. 5fC and 5caC are differentially distributed in human spermatogenic cells and spermatozoa. The immunocytochemically detected increase of 5fC and 5caC in individual spermatozoa is most likely induced by oxidative stress caused by effects of internal and external factors rather than developmental programme. The evaluation of 5fC and 5caC in spermatozoa can be potentially used as an additional criterion of ejaculate quality.

The expansion of the spectrum of use of food additives and, in particular, food dyes (FD), increases the risk of increasing human exposure to genotoxicants. Since in real life, not pure substances with proven genetic safety are in contact with a person, but complex mixtures of unknown composition, even minor impurities in which can become an additional source or modifier of genome instability effects. Of particular concern in this aspect are synthetic FD azo and diazo compounds which can be transformed by human intestinal microflora to some forms of genotoxicants. The purpose of the work is to evaluate the genotoxic effects of 02 mg/mL of Tartrazine FD (E102) purchased in a retail network in a micronucleus test on human blood cells cultured under cytokinetic block conditions in parallel in presence and without rat S9 hepatocyte metabolic activation system. Genotoxic effects were found in cultures without metabolic activation at 0.00002560,00064 mg/mL and 0.4 mg/mL of tartrazine, and in the presence of S9 at 0.0000256 mg/mL, 0,000128 mg/mL and 0.16 mg/mL of tartrazine. For the first time, a dose-dependent suppression of mitotic and proliferative activity of lymphocytes induced by the tested tartrazine sample was revealed, as well as a dose-dependent U-shaped curve in the frequency of apoptosis. The data obtained indicate the presence of genotoxic activity of the studied sample. We discuss the necessity to create the system for evaluation the genotoxic safety of FD real mixtures from a retail network.

Mutations in the SCAPER gene have previously been reported to be a rare cause of syndromic and non-syndromic autosomal recessive retinitis pigmentosa (RP). We report a case of syndromic RP caused by a frameshift heterozygous mutation in SCAPER. Our case has a relatively mild ocular phenotype with the presence of cone involvement noted on full field electroretinogram (ffERG) without impacting central or color vision. A 17-year-old male presented with progressive nyctalopia in both eyes. He underwent ophthalmic examination and multimodal imaging. A complete retinal degeneration panel consisting of 322 genes was used to screen for molecular causes of retinal dystrophy in this patient along with family segregation analysis. Fundus examination of the proband revealed mild RP phenotype with waxy pallor of optic discs, attenuated retinal arterioles, and single bone spicule like pigmentary change in the mid-periphery bilaterally. Multimodal imaging and ffERG demonstrated a picture of RP with cone dysfunction without impacting central or color vision bilaterally. Examined family members were found to be normal. The proband was found to be heterozygous for two novel frameshift pathogenic variants in SCAPER c.3781del, p. (Val1261Serfs*26), c.868_869del, p. (Glu290Serfs*7) both leading to predicted premature termination. The family members tested were found to be heterozygous for SCAPER c.868_869del, p. (Glu290Serfs*7) pathogenic variant confirming their carrier status. We report a case of a syndromic RP of previously unreported ocular phenotype associated with SCAPER pathogenic variant, which will add to the phenotypic spectrum of retinopathy and systemic features associated with pathogenic variants in SCAPER.

Male circumcision is the most frequently performed surgical procedure among Muslim and Jewish communities, mainly for medical, religious, and traditional reasons (1-4). In the USA, circumcision is frequently performed for cosmetic purposes. Although it is seen as a simple procedure, it is quite prone to complications like other surgical procedures. The early and long-term complications of circumcision are well known and the overall complication rate has been reported between 0.2% and 3.9%. Common complications associated with circumcision are acute bleeding, pain, edema, wound infection, and unnecessary foreskin. Rare complications include meatal stenosis, urethral fistula, partial and total glandular amputations, glandular necrosis, penile curvature, and penile rotation. In addition, keloid formation and scar hypertrophy are some rare complications that cause poor cosmetic appearance.The aim of paper: Our aim in this study was to investigate the effect of the number of sutures placed during circumcision on postoperative pain, infection, bleeding amount, and analgesic need in children.Materials and methods: A total of 715 patients who applied to our hospital for circumcision requests between November 2019 and January 2022 were retrospectively analyzed. The patients were randomly divided into three groups according to the number of knots used during the surgical procedure: Group 1 (8 sutures), group 2 (6 sutures), and group 3 (4 sutures). The patients were evaluated in terms of whether they needed analgesics in the postoperative period (1-hour), bleeding status, and whether this bleeding needed re-intervention.Results: The average age of the participants in the study was 4.06±2.51 years, and the average weight was 18.66±7.07 kg. The operation was completed using 8 sutures (group 1) in 47.5%, 6 sutures (group 2) in 27.7%, and 4 sutures (group 3) in 24.9% of the patients. Postoperative infection developed in 2.8% of the participants, and bleeding was observed in 25.1%. The number of participants who needed analgesia for the first hour after the operation was 66.8%. The median value of the postoperative pain scale was 5 (range: 1-9), and those with a pain scale of 5-9 were 65.5%. There was no significant difference between the groups in terms of age, weight, development of infection, and bleeding (p>0.05). Analgesia was needed in 88.7% of those in group 1, 69.9% of those in group 2, and 21.6% of those in group 3 (p

Whether the decline of birth weight (BW) reported in developed countries in the early 2000s is ongoing remains unknown. Furthermore, despite recent sharp increases in twin births, comparing secular trends of BW between singletons and twins is difficult, as studies have rarely examined secular trends of BW in twins and singletons simultaneously. Therefore, this study aimed to investigate the most recent 20-year trends (2000–2020) of BW in twins and singletons in South Korea. Annual natality files from 2000 to 2020 obtained from the Korean Statistical Information Service were analyzed. A yearly decrease of BW was 3 g among singletons and 5 to 6 g in twins from 2000 to 2020, indicating a widening gap of BW between twins and singletons with increasing years. Gestational age (GA) also decreased in twins and singletons with yearly decreases of 0.28 days in singletons and 0.41 days in twins. Whereas BW decreased in term (GA ≥ 37 weeks), and very preterm groups (28 weeks ≤ GA < 32 weeks) from 2000 to 2020 in twins and singletons, it increased in moderate to late preterm (32 weeks ≤ GA < 37 weeks) groups, indicating a non-linear relationship between BW and GA. The prevalence of macrosomia (BW > 4000 g) in singletons decreased from 2000 to 2020, whereas low birth weight (LBW; BW < 2500 g) increased in twins and singletons. LBW is associated with adverse health outcomes. Effective public health strategies aiming at reduction in the incidence of LBW in the population should be developed.