ЗАСАДИ УПРАВЛІННЯ У СФЕРІ ЗАБЕЗПЕЧЕННЯ РОЗВИТКУ СІЛЬСЬКИХ ПРИКОРДОННИХ ТЕРИТОРІЙ

The article deals with the principles of management of the process of ensuring the balanced development of territorial economic systems, in particular, the border areas of the countryside. The prerequisites of the use of competitive advantages of rural border areas in the conditions of integration and convergence have been substantiated. In order to reflect the diversity of aspects of the development of the territorial economic system, in particular the rural border areas, and the generalization of existing experience, the classification species characteristics of the development of the studied systems have been systematized. The necessity of combining the interests of the state, bodies of state administration, local self-government and the territorial community has been noted, in the direction of providing effective management in the process of functioning of economic structures within the boundaries of rural border territories and balanced development of territorial economic systems in general.В статье рассмотрены основы управления процессом обеспечения сбалансированного развития территориальных экономических систем, в частности приграничных территорий сельской местности. Обоснованны предпосылки использования конкурентных преимуществ сельских приграничных территорий в условиях интеграции и конвергенции. С целью отображения многообразия аспектов развития территориальной экономической системы, в том числе сельских приграничных территорий, и обобщения существующего опыта, систематизированы классификационные видовые признаки развития исследуемых систем. Отмечено необходимость сочетания интересов государства, органов государственного управления, местного самоуправления и территориальной общины в направлении обеспечения эффективного управления в процессе функционирования хозяйствующих структур в пределах сельских приграничных территорий и сбалансированного развития территориальных экономических систем в целом.У статті розглянуто засади управління процесом забезпечення збалансованого розвитку територіальних економічних систем, зокрема прикордонних територій сільської місцевості. Обґрунтовано передумови використання конкурентних переваг сільських прикордонних територій в умовах інтеграції й конвергенції. З метою відображення багатоманітності аспектів розвитку територіальної економічної системи, зокрема й сільських прикордонних територій, та узагальнення існуючого досвіду, систематизовано класифікаційні видові ознаки розвитку досліджуваних систем. Відмічено необхідність поєднання інтересів держави, органів державного управління, місцевого самоврядування та територіальної громади, у напрямі забезпечення дієвого управління у процесі функціонування господарюючих структур в межах сільських прикордонних територій та збалансованого розвитку територіальних економічних систем в цілому

Latency reversal and viral clearance to cure HIV-1

Research toward a cure for human immunodeficiency virus type 1 (HIV-1) infection has joined prevention and treatment efforts in the global public health agenda. A major approach to HIV eradication envisions antiretroviral suppression, paired with targeted therapies to enforce the expression of viral antigen from quiescent HIV-1 genomes, and immunotherapies to clear latent infection. These strategies are targeted to lead to viral eradication—a cure for AIDS. Paired testing of latency reversal and clearance strategies has begun, but additional obstacles to HIV eradication may emerge. Nevertheless, there is reason for optimism that advances in long-acting antiretroviral therapy and HIV prevention strategies will contribute to efforts in HIV cure research and that the implementation of these efforts will synergize to markedly blunt the effect of the HIV pandemic on society

Combined approaches for HIV cure

A serious effort has begun to develop therapies that may be capable of eradicating established HIV infection in man. Because of the biological complexity of HIV infection that persists despite potent antiretroviral therapy, it is widely believed that if such therapies can be developed they will involve complex, multimodality approaches. We highlight some of the recent studies in this effort

A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges

Pre-exposure prophylaxis (PrEP) using antiretroviral drugs (ARVs) has been shown to reduce HIV transmission in people at high risk of HIV infection. Adherence to PrEP strongly correlates with the level of HIV protection. Long-acting injectable ARVs provide sustained systemic drug exposures over many weeks and can improve adherence due to infrequent parenteral administration. Here, we evaluated a new long-acting formulation of raltegravir for prevention of vaginal HIV transmission

siRNA Screening of a Targeted Library of DNA Repair Factors in HIV Infection Reveals a Role for Base Excision Repair in HIV Integration

Host DNA repair enzymes have long been assumed to play a role in HIV replication, and many different DNA repair factors have been associated with HIV. In order to identify DNA repair pathways required for HIV infection, we conducted a targeted siRNA screen using 232 siRNA pools for genes associated with DNA repair. Mapping the genes targeted by effective siRNA pools to well-defined DNA repair pathways revealed that many of the siRNAs targeting enzymes associated with the short patch base excision repair (BER) pathway reduced HIV infection. For six siRNA pools targeting BER enzymes, the negative effect of mRNA knockdown was rescued by expression of the corresponding cDNA, validating the importance of the gene in HIV replication. Additionally, mouse embryo fibroblasts (MEFs) lacking expression of specific BER enzymes had decreased transduction by HIV-based retroviral vectors. Examining the role BER enzymes play in HIV infection suggests a role for the BER pathway in HIV integration

CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells

The persistence of HIV reservoirs, including latently infected, resting CD4+ T cells, is the major obstacle to cure HIV infection. CD32a expression was recently reported to mark CD4+ T cells harboring a replication-competent HIV reservoir during antiretroviral therapy (ART) suppression. We aimed to determine whether CD32 expression marks HIV latently or transcriptionally active infected CD4+ T cells. Using peripheral blood and lymphoid tissue of ART-treated HIV+ or SIV+ subjects, we found that most of the circulating memory CD32+ CD4+ T cells expressed markers of activation, including CD69, HLA-DR, CD25, CD38, and Ki67, and bore a TH2 phenotype as defined by CXCR3, CCR4, and CCR6. CD32 expression did not selectively enrich for HIV- or SIV-infected CD4+ T cells in peripheral blood or lymphoid tissue; isolated CD32+ resting CD4+ T cells accounted for less than 3% of the total HIV DNA in CD4+ T cells. Cell-associated HIV DNA and RNA loads in CD4+ T cells positively correlated with the frequency of CD32+ CD69+ CD4+ T cells but not with CD32 expression on resting CD4+ T cells. Using RNA fluorescence in situ hybridization, CD32 coexpression with HIV RNA or p24 was detected after in vitro HIV infection (peripheral blood mononuclear cell and tissue) and in vivo within lymph node tissue from HIV-infected individuals. Together, these results indicate that CD32 is not a marker of resting CD4+ T cells or of enriched HIV DNA–positive cells after ART; rather, CD32 is predominately expressed on a subset of activated CD4+ T cells enriched for transcriptionally active HIV after long-term ART

Non-classical ProIL-1beta activation during mammary gland infection is pathogen-dependent but caspase-1 independent

Infection of the mammary gland with live bacteria elicits a pathogen-specific host inflammatory response. To study these host-pathogen interactions wild type mice, NF-kappaB reporter mice as well as caspase-1 and IL-1beta knockout mice were intramammarily challenged with Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The murine mastitis model allowed to compare the kinetics of the induced cytokine protein profiles and their underlying pathways. In vivo and ex vivo imaging showed that E. coli rapidly induced NF-kappaB inflammatory signaling concomitant with high mammary levels of TNF-alpha, IL-1 alpha and MCP-1 as determined by multiplex analysis. In contrast, an equal number of S. aureus bacteria induced a low NF-kappaB activity concomitant with high mammary levels of the classical IL-1beta fragment. These quantitative and qualitative differences in local inflammatory mediators resulted in an earlier neutrophil influx and in a more extensive alveolar damage post-infection with E. coli compared to S. aureus. Western blot analysis revealed that the inactive proIL-1beta precursor was processed into pathogen-specific IL-1beta fragmentation patterns as confirmed with IL-1beta knockout animals. Additionally, caspase-1 knockout animals allowed to investigate whether IL-1beta maturation depended on the conventional inflammasome pathway. The lack of caspase-1 did not prevent extensive proIL-1beta fragmentation by either of S. aureus or E. coli. These non-classical IL-1beta patterns were likely caused by different proteases and suggest a sentinel function of IL-1beta during mammary gland infection. Thus, a key signaling nodule can be defined in the differential host innate immune defense upon E. coli versus S. aureus mammary gland infection, which is independent of caspase-1

Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors

A family of histone deacetylases (HDACs) mediates chromatin remodeling, and repression of gene expression. Deacetylation of histones within the HIV-1 long terminal repeat (LTR) by HDACs plays a key role in the maintenance of latency, whereas acetylation of histones about the LTR is linked to proviral expression and escape of HIV from latency. Global HDAC inhibition may adversely affect host gene expression, leading to cellular toxicities. Potent inhibitors selective for HDACs that maintain LTR repression could be ideal antilatency therapeutics