Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with fronto-temporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement.

Relevance. The absence of a registered vaccine against G145R escape mutant determines the need to develop a drug for the prophylaxis of infectious hepatitis caused by the hepatitis B virus.The aim of the study was to evaluate the safety and reactogenicity of a new hepatitis B recombinant Bubo®-Unigep yeast vaccine in healthy volunteers.Materials & Methods. To confirm the safety of the new trivalent Bubo®-Unigep vaccine, an open, single- center, nonrandomized clinical trial was conducted in healthy male volunteers at the clinical base of «Uromed» (Smolensk) according to the protocol developed by the contract research organization R&D Pharma.Results and discussions. Safety and reactogenicity assessment was carried out throughout the study period. In the safety assessment, one adverse event was reported that was not related to the use of Bubo®-Unigep vaccine. No serious adverse events have been reported. There were no local reactions at the injection site throughout the observation period. The results indicate a high safety and areactogenicity of Bubo®-Unigep vaccine.Conclusions: The confirmed safety and areactogenicity of a new Bubo®-Unigep vaccine in a phase I clinical trial allows to proceed to the next stage and to conduct a registration study in which immunogenicity, safety and reactogenicity will be studied during the full course of vaccination. The introduction of such a vaccine on the market will contribute to a more effective vaccination against those serotypes of the hepatitis B virus that are endemic and prevail in the Russian Federation. Due to the created complete immunity, the infection threshold rises and the number of cases of hepatitis B among the already vaccinated population decreases.

Background. To optimize the process of bread wheat breeding for earliness and environmental adaptability, searching for new source material is a crucial task. The ultra-early line Rico (k-65588) – Triticum aestivum var. erythrospermum Koern. – stands out among the bread wheat accessions from the VIR collection for its important adaptive features.Materials and methods. Spring wheat accessions with different speed of development were selected from the VIR collection for this study, along with the ultra-early lines Rifor 1 ... 10 (F6-7 Rico × Forlani Roberto k-42641) and Fori 1 ... 8 (k-65589 ... k-65596) (F4 Foton k-55696 × Rico). Their responses to a short 12-hour day were assessed. Vernalization conditions were 30 days at 3°C. The genetics of plant sensitivity to vernalization and photoperiods was studied using allele-specific primers for the genes Vrn-A1, Vrn-B1, Vrn-D1 and Ppd-D1.Results and conclusions. In the Northwest of Russia, the period from seeding to heading for Rico plants was 39.9 ± 1.49 days, or 14.8 ± 1.22 days less than for the released commercial wheat cultivars. Among the 8400 wheat accessions, studied by the Wheat Genetic Resources Department of VIR in this area from 1948 to 2018, the shortest period from germination to heading was observed in the line Rico: 29 (28–30) days. The absence of response to vernalization in Rico, Fori and Rifor lines was determined by the dominant alleles Vrn-A1, Vrn-B1 and Vrn-D1. Photoperiodism in Rico and partially in Rifor was controlled by at least two genes: Ppd-D1 and Ppd-B1. In the F2 population of Rico hybrids with 8 wheat accessions no transgression was observed beyond the limits of Rico‘s variation. The difference in the development rate between Rico and other wheat accessions is controlled by two or three non-allelic genes. Rifor lines can compete in productivity with commercialized wheat cultivars.

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Hereditary spastic paraplegia (HSP) is an extremely heterogeneous group of neurodegenerative disorders affecting the longest axons in the central nervous system. The most common genetic form accounting for about 40% of the autosomal-dominant HSP (ADHSP) cases is spastin gene, SPG4. We performed mutation screening of the spastin gene on 36 unrelated HSP patients from three different ethnic groups (Bulgarian, Turks and Gypsies) and found four new mutations and one already reported. The phenotype-genotype correlations in Bulgarian SPG4 patients showed a great difference in the age at disease onset between patients with missense mutations and those harboring deletions and splice-site mutations. Our study is the first to present corroborative clinical data in favor of the general hypothesis that the clinical course of the disease is related to the type of the spastin mutation. The clinical and genealogical findings in Bulgarian SPG4 patients suggest that a positive family history for inheritance as an autosomal-dominant trait is a strong indication for spastin mutation screening.

Replenishment of the collection of durum wheat (Triticum durum Desf.), like any other crop collection held by VIR, is a permanent process aimed at expanding the geographic, morphological and agrobiological diversity of the crop’s gene pool. A special status in this process is given to the achievements of domestic breeders, whose cultivars and lines over time remain only in the ex situ collection and constitute the national heritage of Russia. Replenishment, along with conservation, studying and sharing with the users, is a mandatory task when managing a plant germplasm collection. It can be fulfilled by sending requests for seeds to other genebanks, through the exchange with the collections of foreign research centers, contacts with individual breeders or breeding centers in Russia, or when crop cultivars are submitted to VIR from the State Register of Breeding Achievements Approved for Utilization in Russia. Besides, new accessions are added to the genebank by collecting missions.Descriptions have been made for 570 accessions included in the main catalogue of VIR’s durum wheat collection from 2000 to 2019. They originated from 28 countries of Europe, Asia, the Near East, Africa and North America, and from 16 regions of Russia.The durum wheat collection of VIR was replenished with accessions interesting both from the geographic and agrobiological viewpoints. Cultivars developed by domestic breeders are included in the global genetic resources collection primarily with the purpose of their conservation and comprehensive utilization, both now and in the future.

Background. Development of early-ripening spring bread wheat (Triticum aestivum L.) cultivars is an important task for Russian breeders. Knowledge of the genetics of ultraearly varieties – sources of valuable genes that determine an earlier-maturing type of plant development –will be used to work out methods for obtaining source material for breeding.Materials and methods. The ultra-early lines Rico (k65588, var. erythrospermum Koern.) and Rimax (k-67257, var. lutescens (Alef.) Mansf.), and cvs. ‘Max’ (k-57181, var. lutescens) and ‘Leningradskaya 6’ (k-64900, var. lutescens) were studied. Alleles of the Vrn and Ppd genes were identified by PCR according to known publications, and genomic DNA was isolated from 3-day-old seedlings by the CTAB method.Results. In the environments of Northwest Russia, the Rimax and Rico lines are characterized by the highest rate of development before heading among the spring wheat accessions from the VIR collection. In the Rimax and Rico genotypes, the Vrn-A1, Vrn-B1, Vrn-D1 and Ppd-D1 genes were found. Genotypes with different alleles of Ppd-D1 and Vrn-B1 were identified in the Rimax line. Under conditions of a long day (18 hours), in the population of F2  (F3 ) Rico × Rimax hybrids, the ratio of phenotypes with a high development rate to all others was observed as 1 : 15 (χ2 1: 15 = 0.64). Under a short day (12 hours), 5 clearly tested groups were identified in F2 with the ratio 1 : 4 : 6 : 4 : 1 (χ2  = 3.03; χ2 0.05 = 9.48), which indicates the manifestation of cumulative polymerization.Conclusion. Each of the Rimax and Rico lines has two pairs of independent duplicated genes that determine a high development rate. Under short-day conditions, these genes can interact like cumulative polymers. The Rimax and Rico lines, due to their high development rate, are valuable source material to be used in breeding for earliness.

Background. The knowledge of genetic control of vernalization response in the ultra-early accessions can facilitate bread wheat breeding for a high adaptive capacity. Materials and methods. The study involved the ultra-early lines Rico (k-65588) and Rimax (k-67257) as the earliest maturing lines in the VIR bread wheat collection, as well as 10 Rifor lines (k-67120, k-67121, k-67250-67256) with a high rate of development before heading. A late ripening accession ‘Forlani Roberto’ (k-42641) and ‘Leningradskaya 6’ variety (k-64900), regionally adapted to Northwestern Russia, were also studied. The alleles of the Vrn and Ppd genes were identified by the PCR analysis using the allele-specific primers published in literature sources. The response to vernalization (30 days at 3°C) and a short 12-hour day were determined using a methodology accepted at VIR. Results. The ultra-early lines respond to a short 12-hour day and 30-day vernalization very poorly. The genotype of ultra-early wheat lines is mainly represented by three genes, Vrn-A1, Vrn-B1a, and Vrn-D1, which ensure insensitivity to vernalization alongside with the expression of Ppd-D1a, which controls the response to photoperiod. The ultra-early lines Rifor 4 and Rifor 5 have a recessive allele vrn-A1a, like the original ‘Forlani Roberto’ accession. The lines Rifor 4 and Rifor 5 are vernalization-insensitive under the long day and have a very weak response under the short day (3.5±0.42 days and 4.0±0.61 days, respectively). However, ‘Forlani Roberto’ with the vrn-A1a gene responds to vernalization in the same way under any photoperiod (12.3±1.58 days and 12.2±0.74 days). Conclusion The ultra-early lines of bread wheat Rifor 4 and Rifor 5 with the vrn-A1a gene can have no response to vernalization or have a low level response. This effect can be a reason for the formation of a complex of modifier genes along with the dominant gene Vrn-D1, which forms during the hybridization of F7-8 Rico × Forlani Roberto. The ultra-early lines of bread wheat Rico, Rimax and Rifor (k-67120, k-67121, k-67250-67256) can serve as effective sources of genes for earliness in common wheat breeding.