Generation of two iPSC lines from healthy donor with a heterozygous mutation in the VPS13B gene.

The human induced pluripotent stem cell (iPSC) lines, iCS-MAF1-1 and iCS-MAF1-11, were generated from fibroblasts. The donor has a heterozygous mutation in the VPS13B gene, which manifests in her child as Cohen syndrome. It is a Golgi pathology, characterized by postnatal microcephaly and delayed growth and mental development. However, the process underlying pathological changes leading to the onset of the disease is still unknown. The use of iPSC will allow describing the early stages of neurogenesis, which is undoubtedly relevant for identifying key stages of development, at which phenotypic manifestations of mutations in the VPS13B gene are found.

Biallelic variants in PPP1R13L cause paediatric dilated cardiomyopathy.

Childhood dilated cardiomyopathy (DCM) is a leading cause of heart failure requiring cardiac transplantation and approximately 5% of cases result in sudden death. Knowledge of the underlying genetic cause can aid prognostication and clinical management and enables accurate recurrence risk counselling for the family. Here we used genomic sequencing to identify the causative genetic variant(s) in families with children affected by severe DCM. In an international collaborative effort facilitated by GeneMatcher, biallelic variants in PPP1R13L were identified in seven children with severe DCM from five unrelated families following exome or genome sequencing and inheritance-based variant filtering. PPP1R13L encodes inhibitor of apoptosis-stimulating protein of p53 protein (iASPP). In addition to roles in apoptosis, iASPP acts as a regulator of desmosomes and has been implicated in inflammatory pathways. DCM presented early (mean: 2 years 10 months; range: 3 months-9 years) and was progressive, resulting in death (n = 3) or transplant (n = 3), with one child currently awaiting transplant. Genomic sequencing technologies are valuable for the identification of novel and emerging candidate genes. Biallelic variants in PPP1R13L were previously reported in a single consanguineous family with paediatric DCM. The identification here of a further five families now provides sufficient evidence to support a robust gene-disease association between PPP1R13L and severe paediatric DCM. The PPP1R13L gene should be included in panel-based genetic testing for paediatric DCM.

Novel intronic variant in PALB2 gene and effective prevention of Fanconi anemia in family.

Despite the acceptance of NextGen sequencing as a diagnostic modality suitable for probands and carriers of Mendelian diseases, its efficiency in identifying causal mutations is limited by both technical aspects of variant call algorithms and by imperfect, consensus-based criteria for assessing the pathogenicity of the findings. Here we describe the medical history of the family with a child born with Fanconi anemia. In this case, typical diagnostic routines were complicated by unusual combination of mutations. PALB2 variant NM_024675.3:c.172_175delTTGT (p.Gln60Argfs) in maternal sample, previously classified as a definitely pathogenic frameshift mutation, was in compound heterozygous state with PALB2 NM_024675.3:c.3114-16_3114-11del (p.Asn1039Glyfs*7), which led to validated PALB2 exon 11 skipping event in paternal locus. Findings enabled the development of the PGТ and successful selection of two mutation-free embryos. We show that even in absence of definitive exome findings, clinician-guided research inquiries into the structure and function of the suspected loci allow definitive diagnosis. Described case provides an example of a crucial input of an investigational workflow in genetic prognosis and successful PGT.

Mapping the D.melanogaster En1A Enhancer Modules Responsible for Transcription Activation and Long-Distance Enhancer-Promoter Interactions.

The structure of the new enhancer En1A of the 1A region of the X chromosome of D. melanogaster was investigated. Two distinct regulatory elements were found. The first element is responsible for transcription activation, and the second element provides specific interaction with the promoter of the yellow gene. The findings support the hypothesis of a modular structure for enhancers, including certain sequences that bind transcription activators and special communication elements providing long-distance enhancer-promoter interaction.

First experience of hematopoietic stem cell transplantation treatment of Shwachman-Diamond syndrome using unaffected HLA-matched sibling donor produced through preimplantation HLA typing.

The only proven cure for Shwachman-Diamond syndrome (SDS) bone marrow failure is allogeneic hematopoietic stem cell transplantation (HSCT). However HSCT with donors other than HLA-identical siblings is associated with high mortality and unfavorable prognosis. This paper presents the first experience of HSCT treatment of SDS using an unaffected HLA-identical sibling produced through preimplantation genetic diagnosis (PGD). The patient was a 6-year-old blood transfusion-dependent SDS baby girl with secondary myelodysplastic syndrome, for whom no HLA-identical donor was available. As a result of PGD, two unaffected HLA matched embryos were identified; one of them was randomly selected for transfer, resulting in a clinical pregnancy and birth of an apparently healthy child. The patient underwent allogeneic transplantation of cord blood hematopoietic stem cells, together with bone marrow from this sibling, resulting in complete hemopoietic recovery. The patient was no longer transfusion-dependent and had normal blood values 160 days after transplantation.

Dependence of Young's modulus on the sodium content within the structural tunnels of a one-dimensional Na-ion battery cathode.

We report on the Young's modulus (YM) of single-crystalline Na4Mn9O18 (or Na0.44MnO2) nanowires (NWs), which have shown promise as reversible sodium-ion (Na(+)) intercalation cathodes with high capacity and excellent cyclability. In addition, acid treatment of this material yielded proton stabilized Na(0.44-y)MnO2 (y ∼ 0.23) NWs with a 74% increase in the YM. The tight correlation between YM and ionic content within the crystalline tunnels is particularly significant, since it points to the strong dependence of elastic properties on state-of-charge (SOC) within battery materials.

Single nanowire manipulation within dielectrophoretic force fields in the sub-crossover frequency regime.

This paper presents the quantitative relationship between the control parameters of a dielectrophoretic (DEP) force field and the resulting electrokinetic region of influence experienced by individual nanowires (NWs) in colloidal suspensions. Our results show that DEP operation at sub-crossover frequencies, which are defined as frequencies slightly below the transition from positive-to-negative DEP, offers a suitable but previously unexplored performance regime for single NW manipulation and assembly. The low-magnitude DEP forces at these frequencies, which are estimated to be 8 orders of magnitude smaller as compared to near-DC frequencies, provide an efficient avenue to controllably extend electrokinetic influence on suspension volumes that present isolated NWs. These results are demonstrated using α-phase manganese dioxide NWs as a model one-dimensional construct. Based on experimentally extracted values for the NW intrinsic conductivity and dielectric permittivity, we employ computational models to explain each of the performance regimes observed in this nanoassembly system. In addition, we use a new approach to estimate the concentration of a NW suspension from experimentally observed data for deposition yields.

[The characteristics of the wound-healing action of solubilized alpha-tocopherol acetate]. / Osobennosti ranozazhivliaiushchego deistviia soliubilizirovannogo al'fa-tokoferola atsetata.

The rat experiments were made to compare the wound-healing action of solubilized (aqueous) alpha-tocopherol acetate (SATA) prepared by the original techniques and its official oil-based preparation. A course intravenous SATA (2 mg four times at an interval of 4 days) administration was found to stimulate epithelial regeneration and suppress the formation of connective tissue of uncomplicated skin wounds. By healing the complicated wounds, SATA potentiated the occurrence of an inflammatory reaction and slowed down regeneration, whereas its oily solution failed to produce this effect.

[Use of a new M-cholinolytic drug KG-62 for correction of the course of experimental stomach ulcer]. / Primenenie novogo M-kholinoliticheskogo preparata KG-62 dlia korrektsiitecheniia éksperimental'noi iazvy zheludka.

The preparation KG-62 related to iodomethylates of hydroxyalkyl phosphinic acids with muscarinolytic effect has been studied. The study provides data on the development of experimental gastric ulcer among rats after injections of the preparation. On the basis of morphologic, morphometric and biochemical data it has been stated that the preparation KG-62 in a 5 mg/kg dose has a more strong effect leading to quick gastric ulcer healing. It was supposed that not only suppressing action on hydrochloric acid and pepsinogen secretion lies in the mechanism of the effect but also the activation of physiologic regulation in intact tissue.

[The role of endogenous regulators in the compensatory process after salivary gland resection]. / Rol' éndogennykh reguliatorov v kompensatornom protsesse pri rezektsii sliunnoi zhelezy.

The ways of penetration of submandibular salivary degeneration products into the blood after partial gland resection have been studied on 97 rats. Using isoenzyme LDH spectrum of the blood, as well as of gland and regional lymph node tissue, the acid-base balance values and morphological data, it has been shown that degeneration products of salivary glands penetrate into the general blood flow through regional lymph nodes, where they are partly modified. The true changes in LDH spectrum can be already registered half an hour after the injury of the gland. The influence of the degeneration products of gland tissue on the initiation of the compensation processes in cellular hyperplasia is discussed.

[Changes in the myocardial contractility of the left ventricle and in the central hemodynamic indices during the onset and termination of a paroxysmal tachycardia attack]. / Izmeneniia sokratimosti miokarda levogo zheludochka serdtsa i pokazatelei tsentral'noi gemodinamiki pri vozniknovenii i prekrashchenii pristupa paroksizmal'noi takhikardii.

Three types of myocardial contractility and central hemodynamic response were identified on the basis of myocardial function and heart rate during an attack of paroxysmal tachycardia. Heart rates of up to 180 beats per minute are not associated with any myocardial contractility disorders, and hemodynamic disturbances are controlled by elevated myocardial inotropism. Heart rates reaching 190 beats/min are associated with a suppression of myocardial relaxation, and the Frank-Starling mechanism is added to elevated inotropism to control the disturbance. Where the heart rate is above 200 beats per minute, both myocardial relaxation and contraction are suppressed; the Frank-Starling mechanism is responsible for the control here.

[Analysis of the blood serum after an injury to the rat submandibular gland]. / Analiz syvorotki krovi posle travmy podcheliustnoi sliunnoi zhelezy u krys.

Experiments on Wistar rats were carried out to examine the changes in protein, glycoprotein, enzymatic and antigenic blood content after sialotomy of the salivary gland with an object of detecting mitogens. It was demonstrated that injury is accompanied by a moderately pronounced dysproteinemia, an increase in the seromucoid fraction, 48 hours after injury, and by variation in the ratio of LDH isozyme fractions, characteristic of the anaerobic metabolic pattern. No antigens of the injured gland were seen in the blood. The evidence obtained does not confirm the participation of high-molecular proteins of the injured gland in the activation of distant proliferation in the corneal epithelium.