Цифровые системы в публичной политике и городском планировании: лоббирование, примеры и рекомендации к дальнейшему применению

The use of digital systems in the face of growing global competition is one of the most important trends in the development of both corporate and public governance worldwide. Hence, the key task of the article is to analyze the specifics of the implementation and optimization of digital management systems in terms of minimizing political and economic risks. A comparative analysis of various cases clearly demonstrates that even lobbying for the introduction of digital planning and management systems can have both a positive and negative impact on government policy, depending on the specific situation. However, the demand for their use in state institutions at the federal and regional levels is only increasing every year, which opens up opportunities not only for potential customers, but also for performers and developers of digital systems. The authors prove that the deployment of innovative management technologies plays a crucial role in shaping the competitiveness and profitability of a company in both the public and private sectors. As an example, the authors consider options for implementing an enterprise resource planning system (ERP systems or Enterprise Resource Planning, i.e. a software solution that integrates the various business processes and functions of an organization into a single system), which led to failures due to a number of factors. On the other hand, examples of successful implementation of digital transformation projects in Russia are presented and a list of factors worth paying attention to when implementing urban planning projects in order to avoid financial losses in the future is given. The introduction of digital management systems in the practice of functioning of the unified system of public authority of the Russian Federation is an important step towards improving the management of public resources and improving the efficiency of government structures in general.Применение цифровых систем в условиях растущей глобальной конкуренции является одним из важнейших трендов развития как корпоративного, так и публичного управления во всем мире. Отсюда ключевая задача статьи проанализировать специфику внедрения и совершенствования цифровых систем управления в аспекте минимизации политико-экономических рисков. Сравнительный анализ различных кейсов наглядно демонстрирует, что даже лоббирование внедрения цифровых систем планирования и управления может оказать как положительное, так и отрицательное влияние на политику правительства в зависимости от конкретной ситуации. Однако запрос на их использование в государственных институтах федерального и регионального уровней с каждым годом неизменно возрастает, что открывает возможности не только для потенциальных заказчиков, но и для исполнителей, а также разработчиков цифровых систем. Авторы доказывают, что развертывание инновационных технологий управления играет решающую роль в формировании конкурентоспособности и рентабельности компании как государственного, так и частного секторов. В качестве примера авторы рассматривают варианты имплементации системы планирования ресурсов предприятия (ERP-систем или Enterprise Resource Planning, т.е. программное решение, которое объединяет различные бизнес-процессы и функции организации в единую систему). В частности, в исследовании представлены примеры успешной реализации проектов по цифровой трансформации в России и составлен перечень потенциальных рисков, на которые стоит обратить внимание при реализации проектов по городскому планированию, дабы в дальнейшем избежать финансовых потерь. Внедрение цифровых систем управления в практику функционирования единой системы публичной власти РФ является важным шагом на пути к совершенствованию управления государственными ресурсами и повышению эффективности работы государственных структур в целом

Inhibiting α-Synuclein Oligomerization by Stable Cell-Penetrating β-Synuclein Fragments Recovers Phenotype of Parkinson's Disease Model Flies

The intracellular oligomerization of α-synuclein is associated with Parkinson's disease and appears to be an important target for disease-modifying treatment. Yet, to date, there is no specific inhibitor for this aggregation process. Using unbiased systematic peptide array analysis, we indentified molecular interaction domains within the β-synuclein polypeptide that specifically binds α-synuclein. Adding such peptide fragments to α-synuclein significantly reduced both amyloid fibrils and soluble oligomer formation in vitro. A retro-inverso analogue of the best peptide inhibitor was designed to develop the identified molecular recognition module into a drug candidate. While this peptide shows indistinguishable activity as compared to the native peptide, it is stable in mouse serum and penetrates α-synuclein over-expressing cells. The interaction interface between the D-amino acid peptide and α-synuclein was mapped by Nuclear Magnetic Resonance spectroscopy. Finally, administering the retro-inverso peptide to a Drosophila model expressing mutant A53T α-synuclein in the nervous system, resulted in a significant recovery of the behavioral abnormalities of the treated flies and in a significant reduction in α-synuclein accumulation in the brains of the flies. The engineered retro-inverso peptide can serve as a lead for developing a novel class of therapeutic agents to treat Parkinson's disease

Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma

Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. / Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. / Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. / Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic–atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants

Systemic traumatic stress: The couple adaptation to traumatic stress model

Research traditionally has focused on the development of symptoms in those who experienced trauma directly but overlooked the impact of trauma on the families of victims. In recent years, researchers and clinicians have begun to examine how individual exposure to traumatic stress affects the spouses/partners, children, and professional helpers of trauma survivors. However, empirically supported, theory-based literature that identifies the mechanisms by which interpersonal or "secondary trauma" occurs in response to traumatic events is limited. Here, we present the Couple Adaptation to Traumatic Stress Model, a systemic model of the development of interpersonal symptoms in the couple dyad based on empirical literature. Potential mechanisms and clinical vignettes are included to describe the systemic processes that occur with trauma couples. Areas for future research and clinical implications also are identified

Widespread establishment and regulatory impact of Alu exons in human genes

The Alu element has been a major source of new exons during primate evolution. Thousands of human genes contain spliced exons derived from Alu elements. However, identifying Alu exons that have acquired genuine biological functions remains a major challenge. We investigated the creation and establishment of Alu exons in human genes, using transcriptome profiles of human tissues generated by high-throughput RNA sequencing (RNA-Seq) combined with extensive RT-PCR analysis. More than 25% of Alu exons analyzed by RNA-Seq have estimated transcript inclusion levels of at least 50% in the human cerebellum, indicating widespread establishment of Alu exons in human genes. Genes encoding zinc finger transcription factors have significantly higher levels of Alu exonization. Importantly, Alu exons with high splicing activities are strongly enriched in the 5′-UTR, and two-thirds (10/15) of 5′-UTR Alu exons tested by luciferase reporter assays significantly alter mRNA translational efficiency. Mutational analysis reveals the specific molecular mechanisms by which newly created 5′-UTR Alu exons modulate translational efficiency, such as the creation or elongation of upstream ORFs that repress the translation of the primary ORFs. This study presents genomic evidence that a major functional consequence of Alu exonization is the lineage-specific evolution of translational regulation. Moreover, the preferential creation and establishment of Alu exons in zinc finger genes suggest that Alu exonization may have globally affected the evolution of primate and human transcriptomes by regulating the protein production of master transcriptional regulators in specific lineages

A targeted population carrier screening program for severe and frequent genetic diseases in Israel

A national carrier screening program targeted at communities in which severe genetic diseases are present with a frequency higher than 1/1000 live births, has been in existence in Israel since 2002. Within the communities at risk, carrier screening is voluntary whereas genetic counseling and testing is provided free of charge. During the first 5 years of the program more than 13 000 tests were performed, and at the end of 2007 it was offered in 35 different localities/communities for a total of 36 diseases. Many of the couples identified to be at risk opted for prenatal diagnosis and in two cases an affected pregnancy was terminated. In some cases the couples declined prenatal diagnosis and two of those families gave birth to an affected child. Based on the experience learnt from this targeted screening program it appears that a knowledge-based, voluntary screening program operated within the community is an effective way to provide genetic services and test referrals. The community program directed toward couples in their reproductive period does not seem to have led to stigmatization at either the individual or the community level

Molecular basis of the interaction between the antiapoptotic Bcl-2 family proteins and the proapoptotic protein ASPP2

We have characterized the molecular basis of the interaction between ASPP2 and Bcl-2, which are key proteins in the apoptotic pathway. The C-terminal ankyrin repeats and SH3 domain of ASPP2 (ASPP2Ank-SH3) mediate its interactions with the antiapoptotic protein Bcl-2. We used biophysical and computational methods to identify the interaction sites of Bcl-2 and its homologues with ASPP2. Using peptide array screening, we found that ASPP2Ank-SH3 binds two homologous sites in all three Bcl proteins tested: (i) the conserved BH4 motif, and (ii) a binding site for proapoptotic regulators. Quantitative binding studies revealed that binding of ASPP2Ank-SH3 to the Bcl-2 family members is selective at two levels: (i) interaction with Bcl-2-derived peptides is the tightest compared to peptides from the other family members, and (ii) within Bcl-2, binding of ASPP2Ank-SH3 to the BH4 domain is tightest. Sequence alignment of the ASPP2-binding peptides combined with binding studies of mutated peptides revealed that two nonconserved positions where only Bcl-2 contains positively charged residues account for its tighter binding. The experimental binding results served as a basis for docking analysis, by which we modeled the complexes of ASPP2Ank-SH3 with the full-length Bcl proteins. Using peptide arrays and quantitative binding studies, we found that Bcl-2 binds three loops in ASPP2Ank-SH3 with similar affinity, in agreement with our predicted model. Based on our results, we propose a mechanism in which ASPP2 induces apoptosis by inhibiting functional sites of the antiapoptotic Bcl-2 proteins