Drug Repurposing for Alzheimer’s Disease Based on Protein-Protein Interaction Network

Alzheimer’s disease (AD) is known as a critical neurodegenerative disorder. It worsens as symptoms concerning dementia grow severe over the years. Due to the globalization of Alzheimer’s disease, its prevention and treatment are vital. This study proposes a method to extract substantial gene complexes and then introduces potential drugs in Alzheimer’s disease. To this end, a protein-protein interaction (PPI) network was utilized to extract five meaningful gene complexes functionally interconnected. An enrichment analysis to introduce the most important biological processes and pathways was accomplished on the obtained genes. The next step is extracting the drugs related to AD and introducing some new drugs which may be helpful for this disease. Finally, a complete network including all the genes associated with each gene complex group and genes’ target drug was illustrated. For validating the proposed potential drugs, Connectivity Map (CMAP) analysis was accomplished to determine target genes that are up- or downregulated by proposed drugs. Medical studies and publications were analyzed thoroughly to introduce AD-related drugs. This analysis proves the accuracy of the proposed method in this study. Then, new drugs were introduced that can be experimentally examined as future work. Raloxifene and gentian violet are two new drugs, which have not been introduced as AD-related drugs in previous scientific and medical studies, recommended by the method of this study. Besides the primary goal, five bipartite networks representing the genes of each group and their target miRNAs were constructed to introduce target miRNAs.

Cell-Permeable Oct4 Gene Delivery Enhances Stem Cell-like Properties of Mouse Embryonic Fibroblasts

Direct conversion of one cell type into another is a trans-differentiation process. Recent advances in fibroblast research revealed that epithelial cells can give rise to fibroblasts by epithelial-mesenchymal transition. Conversely, fibroblasts can also give rise to epithelia by undergoing a mesenchymal to epithelial transition. To elicit stem cell-like properties in fibroblasts, the Oct4 transcription factor acts as a master transcriptional regulator for reprogramming somatic cells. Notably, the production of gene complexes with cell-permeable peptides, such as low-molecular-weight protamine (LMWP), was proposed to induce reprogramming without cytotoxicity and genomic mutation. We designed a complex with non-cytotoxic LMWP to prevent the degradation of Oct4 and revealed that the positively charged cell-permeable LMWP helped condense the size of the Oct4-LMWP complexes (1:5 N:P ratio). When the Oct4-LMWP complex was delivered into mouse embryonic fibroblasts (MEFs), stemness-related gene expression increased while fibroblast intrinsic properties decreased. We believe that the Oct4-LMWP complex developed in this study can be used to reprogram terminally differentiated somatic cells or convert them into stem cell-like cells without risk of cell death, improving the stemness level and stability of existing direct conversion techniques.

Tumor Microenvironment-Specific Chemical Internalization for Enhanced Gene Therapy of Metastatic Breast Cancer

Benefiting from treating diseases at the genetic level, gene therapy has been considered a new revolution in the biomedical field. However, the extracellular and intracellular barriers during gene transport such as enzymatic degradation and endo-/lysosomal sequestration significantly compromise the therapeutic efficacy. Though photochemical internalization (PCI) has emerged as a promising approach for causing endo-/lysosomal leakage with translocation of the internalized molecules into the cytosol, its effect is still unsatisfactory due to the insufficient light penetration depth. Here, we develop tumor microenvironment-specific enhanced gene delivery by means of ROS generated from the in situ cascaded catalytic reactions in tumors involving GOx-mediated redox reaction and Mn2+-mediated Fenton-like reaction. The efficient enzymatic protection and successful endo-/lysosomal escape of cargo gene complexes have been demonstrated. Moreover, anti-Twist siRNA-loaded G@MMSNs-P exhibit tumor-specific biodegradation, excellent T1-weighted MR imaging, and significant inhibitory effects against breast cancer growth and pulmonary metastasis.

Drug Repurposing for Alzheimer’s Disease based on Protein-Protein Interaction Network

Background: Alzheimer's disease (AD) is known as a critical neurodegenerative disorder. It worsens as symptoms concerning dementia grow severe over the years. Due to the globalization of Alzheimer’s disease, its prevention and treatment is vital. This study proposes a method to extract substantial gene complexes and accomplish an enrichment analysis to introduce the most significant biological procedures. The next step is extracting the drugs related to AD and introduce some new drugs which may be useful for this disease. Results: To this end, protein-protein interactions (PPI) network was utilized to extract five meaningful gene complexes functionally interconnected. The next step was to construct a five bipartite network representing the genes of each group and their target miRNAs. Finally, a complete network including all the genes related to each gene complex group and genes’ target drug was illustrated. medical studies and publications were analyzed thoroughly to introduce AD-related drugs. Conclusions: This analysis proves the accuracy of the proposed method in this study. Then, new drugs were introduced that can be experimentally examined as future work. RALOXIFENE, GENTIAN VIOLET are two new drugs, which have not been introduced as AD-related drugs in previous scientific and medical studies, recommended by the method of this study. These two drugs.

Current and Forthcoming Approaches for Benchmarking Genetic and Genomic Diversity

The current attrition of biodiversity extends beyond loss of species and unique populations to steady loss of a vast genomic diversity that remains largely undescribed. Yet the accelerating development of new techniques allows us to survey entire genomes ever faster and cheaper, to obtain robust samples from a diversity of sources including degraded DNA and residual DNA in the environment, and to address conservation efforts in new and innovative ways. Here we review recent studies that highlight the importance of carefully considering where to prioritize collection of genetic samples (e.g., organisms in rapidly changing landscapes or along edges of geographic ranges) and what samples to collect and archive (e.g., from individuals of little-known subspecies or populations, even of species not currently considered endangered). Those decisions will provide the sample infrastructure to detect the disappearance of certain genotypes or gene complexes, increases in inbreeding levels, and loss of genomic diversity as environmental conditions change. Obtaining samples from currently endangered, protected, and rare species can be particularly difficult, thus we also focus on studies that use new, non-invasive ways of obtaining genomic samples and analyzing them in these cases where other sampling options are highly constrained. Finally, biological collections archiving such samples face an inherent contradiction: their main goal is to preserve biological material in good shape so it can be used for scientific research for centuries to come, yet the technologies that can make use of such materials are advancing faster than collections can change their standardized practices. Thus, we also discuss current and potential new practices in biological collections that might bolster their usefulness for future biodiversity conservation research.

Engineering the Composition and Fate of Wild Populations with Gene Drive

Insects play important roles as predators, prey, pollinators, recyclers, hosts, parasitoids, and sources of economically important products. They can also destroy crops; wound animals; and serve as vectors for plant, animal, and human diseases. Gene drive—a process by which genes, gene complexes, or chromosomes encoding specific traits are made to spread through wild populations, even if these traits result in a fitness cost to carriers—provides new opportunities for altering populations to benefit humanity and the environment in ways that are species specific and sustainable. Gene drive can be used to alter the genetic composition of an existing population, referred to as population modification or replacement, or to bring about population suppression or elimination. We describe technologies under consideration, progress that has been made, and remaining technological hurdles, particularly with respect to evolutionary stability and our ability to control the spread and ultimate fate of genes introduced into populations.

Staphylococcal cassette chromosome mec elements from Staphylococcus intermedius group (SIG) isolates from dogs in a center for veterinary diagnostics in Brazil

ABSTRACT: Methicillin resistance in the Staphylococcus intermedius group (SIG) has emerged in small animal practice. Methicillin-resistant SIG (MRSIG) members have been implicated as causes of infections in both companion animals and humans. Staphylococcal cassette chromosome mec (SCCmec) elements carry the mecA/C genes, which encode for the transpeptidase PBP2a (PBP2’) responsible for β-lactam antibiotic resistance in staphylococci. This study examined the SCCmec types of MRSIG isolates from different clinical specimens of dogs that exhibited methicillin MIC ≥ 0.5 μg/mL by an automated identification and susceptibility system in a Center for Veterinary Diagnostics in São Paulo, Brazil. Susceptibility to methicillin was determined by broth microdilution testing, and Oxoid® M.I.C.Evaluator® strips. PBP2a production was detected using a latex agglutination assay. SCCmec typing was performed according to the International Working Group on the Classification of Staphylococcal Cassette Chromosome Elements (IWG-SCC) guidelines. SCCmec type II (2A), SCCmec type III (3A), composite SCC structures consisting of a class A mec gene complex in addition to multiple ccr gene complexes, and non-typable SCCmec elements were reported in these MRSIG isolates. SCCmec type variants differing from those so far acknowledged by IWG-SCC were found, indicating new rearrangements in the genetic context of mecA in these canine MRSIG isolates.

Expression, Interaction, and Role of Pseudogene Adh6-ps1 in Cancer Phenotypes

Pseudogenes have been classified as functionless and their annotation is an ongoing problem. The Adh6-ps1—a mouse pseudogene belonging to the alcohol dehydrogenase gene complex (Adh) was analyzed to review the conservation, homology, expression, and interactions and identify any role it plays in disease phenotypes using bioinformatics databases. Results showed that Adh6-ps1 have 2 transcripts (processed and unprocessed) which may have emerged from a transposition and duplication event, respectively, and that induced inversions (Uox gene, In(3)11Rk) involving gene complexes associated with Adh6-ps1 have been implicated in a diverse range of diseases. Adh6-ps1 is highly conserved in vertebrates particularly rodents and expressed in the liver. The top 5 MirRNA targets were Mir455, Mir511, Mir1903, Mir361, and Mir669o markers. While much is unknown about Mir1903 and Mir669o, the silencing of Mir455 and Mir511 is linked with hepatocellular carcinoma (HCC), and Mir361 is implicated in endometrial cancers. Given the identified MirRNA interactions with Adh6-ps1 and its expression in HCC and reproductive systems, it may well have a role in tumorigenesis and disease phenotypes. Nonetheless, further studies are required to establish these facts to add to the growing efforts to understand pseudogenes and their potential involvement in disease conditions.

Disentangling the effects of sex, life history and genetic background in Atlantic salmon: growth, heart and liver under common garden conditions

Livestock domestication has long been a part of agriculture, estimated to have first occurred approximately 10 000 years ago. Despite the plethora of traits studied, there is little understanding of the possible impacts domestication has had on internal organs, which are key determinants of survival. Moreover, the genetic basis of observed associated changes in artificial environments is still puzzling. Here we examine impacts of captivity on two organs in Atlantic salmon ( Salar salar ) that have been domesticated for approximately 50 years: heart and liver, in addition to growth. We studied multiple families of wild, domesticated, F 1 and F 2 hybrid, and backcrossed strains of S. salar in replicated common garden tanks during the freshwater and marine stages of development. Heart and liver weight were investigated, along with heart morphology metrics examined in just the wild, domesticated and F 1 hybrid strains (heart height and width). Growth was positively linked with the proportion of the domesticated strain, and recombination in F 2 hybrids (and the potential disruption of co-adapted gene complexes) did not influence growth. Despite the influence of domestication on growth, we found no evidence for domestication-driven divergence in heart or liver morphology. However, sexual dimorphism was detected in heart morphology, and after controlling for body size, females exhibited significantly larger heart weight and heart width when compared with males. Wild females also had an increased heart height when compared with wild males, and this was not observed in any other strain. Females sampled in saltwater showed significantly larger heart height with rounder hearts, than saltwater males. Collectively, these results demonstrate an additive basis of growth and, despite a strong influence of domestication on growth, no clear evidence of changes in heart or liver morphology associated with domestication was identified.

GENETIC DIVERSITY OF SIMMENTAL CATTLE LINES BY POLYMORPHIC BLOOD GROUP SYSTEMS

Marking the cattle populations by individual genes and gene complexes createsnew opportunities for the development of selection when genetic methods aim to prevent the decrease of the populations’ gene variability. The article reveals the studies of the genetic structure of the Simmental cattle population, PAT breeding facility "Chervoniy Veleten" for erythrocyte antigens of 9 genetic systems (A, B, C, F, J, L, M, S, Z); linear affiliation of animals was taken into account. Animal erythrocyte antigens were determined by hemolysis reaction using monospecific sera - reagents. It is established that the spectrum of certain antigens is specific for Simmental cattle. The high frequency of antigenic factors G2, T2, E3/, G/, I/, O/, Q/, B// (q = 0,364 - 0,636) let us identify allele markers inherent in Simmental cattle: BGKE/G/O/Q/, BGKE/O/, BGO/, G2O2Y2, as well as OQ/, OI/Q/, TV /P/. The analysis of the of the most numerous factory lines (Neolit, Lavra, Zorkiy, Biser, Lascar) was carried out. It was shown that the markers of the Neolit line can be considered as the alleles: BOI'Q'(q = 0.2931) and BOTG`K` (q = 0.2392), Lavra - BBIA`K` (q = 0.1863) and BO` (q = 0.2500), Zorkiy - ВBGO` (q = 0.1325) and Вb, Biser - ВOI`Q` (q = 0.2246) and BG/ (q = 0.1920), Lascara - ВBGKE`GÒ `Q` (q = 0.1405) and BO` (q = 0.2735). It was found, that alleles EAB, which are more common for Laurel and Lascar lines (Kv=32.04%) are marked by the most similarities in the alleles of the EAB - blood group system, the highest values of the difference coefficient are characteristic of the Neolit - Lascar and Neolit - Laurel lines (55.66% and 54.86% respectively), the most differentiated was the Neolit line (Kv ser. = 49.48%, dser. = 0.332). Detection of interlinear differences in related groups of Simmental cattle allows preliminary prediction, correction and plan the animal selection for factory mating.