scholarly journals Computational Identification of Master Regulators Influencing Trypanotolerance in Cattle

2021 ◽  
Vol 22 (2) ◽  
pp. 562
Author(s):  
Abirami Rajavel ◽  
Armin Otto Schmitt ◽  
Mehmet Gültas
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Clinical Signs ◽  
Cattle Breed ◽  
Tsetse Fly ◽  
Therapeutic Interventions ◽  
Master Regulators ◽  
Cattle Breeds ◽  
Regulatory Cascades ◽  
Animal Trypanosomiasis

African Animal Trypanosomiasis (AAT) is transmitted by the tsetse fly which carries pathogenic trypanosomes in its saliva, thus causing debilitating infection to livestock health. As the disease advances, a multistage progression process is observed based on the progressive clinical signs displayed in the host’s body. Investigation of genes expressed with regular monotonic patterns (known as Monotonically Expressed Genes (MEGs)) and of their master regulators can provide important clue for the understanding of the molecular mechanisms underlying the AAT disease. For this purpose, we analysed MEGs for three tissues (liver, spleen and lymph node) of two cattle breeds, namely trypanosusceptible Boran and trypanotolerant N’Dama. Our analysis revealed cattle breed-specific master regulators which are highly related to distinguish the genetic programs in both cattle breeds. Especially the master regulators MYC and DBP found in this study, seem to influence the immune responses strongly, thereby susceptibility and trypanotolerance of Boran and N’Dama respectively. Furthermore, our pathway analysis also bolsters the crucial roles of these master regulators. Taken together, our findings provide novel insights into breed-specific master regulators which orchestrate the regulatory cascades influencing the level of trypanotolerance in cattle breeds and thus could be promising drug targets for future therapeutic interventions.

scholarly journals Identifying Cattle Breed-Specific Partner Choice of Transcription Factors during the African Trypanosomiasis Disease Progression Using Bioinformatics Analysis

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 246 ◽  
Author(s):  
Abirami Rajavel ◽  
Felix Heinrich ◽  
Armin Otto Schmitt ◽  
Mehmet Gültas
Keyword(s):  
Disease Progression ◽  
Neuronal Degeneration ◽  
Cattle Breed ◽  
Tsetse Fly ◽  
Partner Choice ◽  
Sub Saharan Africa ◽  
Economic Losses ◽  
Intermittent Fever ◽  
Cattle Breeds ◽  
Animal Trypanosomiasis

African Animal Trypanosomiasis (AAT) is a disease caused by pathogenic trypanosomes which affects millions of livestock every year causing huge economic losses in agricultural production especially in sub-Saharan Africa. The disease is spread by the tsetse fly which carries the parasite in its saliva. During the disease progression, the cattle are prominently subjected to anaemia, weight loss, intermittent fever, chills, neuronal degeneration, congestive heart failure, and finally death. According to their different genetic programs governing the level of tolerance to AAT, cattle breeds are classified as either resistant or susceptible. In this study, we focus on the cattle breeds N’Dama and Boran which are known to be resistant and susceptible to trypanosomiasis, respectively. Despite the rich literature on both breeds, the gene regulatory mechanisms of the underlying biological processes for their resistance and susceptibility have not been extensively studied. To address the limited knowledge about the tissue-specific transcription factor (TF) cooperations associated with trypanosomiasis, we investigated gene expression data from these cattle breeds computationally. Consequently, we identified significant cooperative TF pairs (especially D B P − P P A R A and D B P − T H A P 1 in N’Dama and D B P − P A X 8 in Boran liver tissue) which could help understand the underlying AAT tolerance/susceptibility mechanism in both cattle breeds.

scholarly journals Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective

2022 ◽  
Vol 23 (2) ◽  
pp. 954
Author(s):  
Ipek Akol ◽  
Fabian Gather ◽  
Tanja Vogel
Keyword(s):  
Molecular Mechanisms ◽  
Social Withdrawal ◽  
Neurodevelopmental Disorder ◽  
Therapeutic Interventions ◽  
Master Regulators ◽  
Forebrain Development ◽  
Forkhead Box ◽  
The Central Nervous System ◽  
Spatiotemporal Control ◽  
Foxg1 Syndrome

Development of the central nervous system (CNS) depends on accurate spatiotemporal control of signaling pathways and transcriptional programs. Forkhead Box G1 (FOXG1) is one of the master regulators that play fundamental roles in forebrain development; from the timing of neurogenesis, to the patterning of the cerebral cortex. Mutations in the FOXG1 gene cause a rare neurodevelopmental disorder called FOXG1 syndrome, also known as congenital form of Rett syndrome. Patients presenting with FOXG1 syndrome manifest a spectrum of phenotypes, ranging from severe cognitive dysfunction and microcephaly to social withdrawal and communication deficits, with varying severities. To develop and improve therapeutic interventions, there has been considerable progress towards unravelling the multi-faceted functions of FOXG1 in the neurodevelopment and pathogenesis of FOXG1 syndrome. Moreover, recent advances in genome editing and stem cell technologies, as well as the increased yield of information from high throughput omics, have opened promising and important new avenues in FOXG1 research. In this review, we provide a summary of the clinical features and emerging molecular mechanisms underlying FOXG1 syndrome, and explore disease-modelling approaches in animals and human-based systems, to highlight the prospects of research and possible clinical interventions.

scholarly journals Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Saba Sheikh ◽  
Safia ◽  
Ejazul Haque ◽  
Snober S. Mir
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Therapeutic Interventions ◽  
Conformational Diseases ◽  
Considerable Evidence ◽  
Recent Trends ◽  
Lateral Sclerosis

Neurodegenerative diseases are multifactorial debilitating disorders of the nervous system that affect approximately 30 millionindividuals worldwide. Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis diseases are the consequence of misfolding and dysfunctional trafficking of proteins. Beside that, mitochondrial dysfunction, oxidative stress, and/or environmental factors strongly associated with age have also been implicated in causing neurodegeneration. After years of intensive research, considerable evidence has accumulated that demonstrates an important role of these factors in the etiology of common neurodegenerative diseases. Despite the extensive efforts that have attempted to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. However, in order to explore the therapeutic interventions directed towards treatment of neurodegenerative diseases, neuroscientists are now fully exploiting the data obtained from studies of these basic mechanisms that have gone awry. The novelty of these mechanisms represents a challenge to the identification of viable drug targets and biomarkers for early diagnosis of the diseases. In this paper, we are reviewing various aspects associated with the disease and the recent trends that may have an application for the treatment of the neurodegenerative disorders.

Epidemiology and Economic Importance of African Animal Trypanosomiasis

2021 ◽  
pp. 24-52
Author(s):  
Esther Gwae Kimaro ◽  
Popoola Moshood Abiola
Keyword(s):  
Clinical Signs ◽  
Economic Importance ◽  
Tsetse Fly ◽  
Clinical Aspects ◽  
Special Focus ◽  
Parasite Life Cycle ◽  
Comprehensive Overview ◽  
African Animal Trypanosomiasis ◽  
Transmission Cycle ◽  
Animal Trypanosomiasis

African animal trypanosomiasis (AAT), also called Nagana, is a vector-borne parasitic disease caused by an extracellular protozoan belonging to the genus Trypanosoma. It has serious effects on the health status and welfare of domestic mammals which considerably results in a reduction in their productivity. In this review, a comprehensive overview of the epidemiology of AAT was provided with a special focus on its general clinical aspects (the clinical signs and pathogenesis as well as its transmission cycle), the parasite (Trypanosoma spp.), the parasite life cycle and transmission, its vector (Glossina spp.), tsetse fly lifecycle and reproduction, risk factors of AAT, and economic importance of AAT in the affected countries. The present work gave a detailed account of epidemiology in the context of infestation patterns, the parasite causing it, its vector, and the economic impacts of the disease on different livestock species.

scholarly journals Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective

2021 ◽  
Author(s):  
Ipek Akol ◽  
Fabian Gather ◽  
Tanja Vogel
Keyword(s):  
Molecular Mechanisms ◽  
Social Withdrawal ◽  
Neurodevelopmental Disorder ◽  
Therapeutic Interventions ◽  
Master Regulators ◽  
Forebrain Development ◽  
Forkhead Box ◽  
The Central Nervous System ◽  
Spatiotemporal Control ◽  
Foxg1 Syndrome

Development of the central nervous system (CNS) depends on accurate spatiotemporal control of signalling pathways and transcription programs. Forkhead Box G1 (FOXG1) is one of the master regulators that plays fundamental roles in forebrain development, from the timing of neurogenesis to the patterning of the cerebral cortex. Mutations in the FOXG1 gene cause a rare neurodevelopmental disorder called FOXG1 syndrome, also known as congenital form of Rett syndrome. Patients presenting with FOXG1 syndrome manifest a spectrum of phenotypes ranging from severe cognitive dysfunction and microcephaly to social withdrawal and communication deficits with varying severities. To develop and improve therapeutic interventions, there has been considerable progress towards unravelling the multi-faceted functions of FOXG1 in neurodevelopment and pathogenesis of FOXG1 syndrome. Moreover, recent advances in genome editing and stem cell technologies, as well as increased yield of information from high throughput omics opened promising and important new avenues in FOXG1 research. In this review, we provide a summary of clinical features and emerging molecular mechanisms underlying FOXG1 syndrome, and explore disease-modelling approaches in animals and human-based systems to highlight prospects of research and possible clinical interventions.

Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

2020 ◽  
Vol 134 (17) ◽  
pp. 2243-2262
Author(s):  
Danlin Liu ◽  
Gavin Richardson ◽  
Fehmi M. Benli ◽  
Catherine Park ◽  
João V. de Souza ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiovascular System ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Therapeutic Interventions ◽  
Low Grade ◽  
Cardiovascular Research ◽  
Inflammatory Processes ◽  
Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

REALIZATION OF PARENTAL INDICES OF COW PRODUCTIVITY IN DIFFERENT MILKING BREEDS AT BREEDING FARM "AGROFIRMA "PAKHMA"

2020 ◽  
Keyword(s):  
Milk Yield ◽  
Cattle Breed ◽  
Holstein Cattle ◽  
Milk Productivity ◽  
Cattle Breeds ◽  
Significant Difference ◽  
Production Indices ◽  
High Level ◽  
Beta Lactoglobulin ◽  
Percentage Protein

Combination of genotypes of main types’ genetic markers causes milk productivity in cattle. The article studies correlation between kappa casein genotypes (C3N3), beta-lactoglobulin (LGB), their complexes and milk production indices in cows bred under equal conditions at a breeding farm. The calculation of parental milk yield and fat indices between the three breeds showed a significant difference (P>0,999) of PCI of Ayrshire and Holstein cattle breed milk yield - 3395 kg, PCI of fat - 0,22%; between Holstein and Yaroslavl cattle breeds - 3200 kg, PCI offat - 0,16%. A significant difference of realization indices of protein between all three breeds was not stated. The highest realization ofparental milk yield index was stated - between Ayrshire and Yaroslavl cattle breeds- 113%, Holstein cattle breed - 88%. As for the fat and protein indices, all three cattle breeds showed a high realization of PCI from 98% to 109%. However, Holstein cattle breed showed the highest percentage: protein - 101%, fat - 109%. A significant difference of PCI realization of milk productivity in CSN3 and LGB genotypes was not stated. It was also stated that there is a tendency of high level parental indices realization when there is a higher number of B-allele variants in genotypes of cows.

Wnt/beta-catenin and PI3K/Akt/mTOR Signaling Pathways in Glioblastoma: Two Main Targets for Drug Design: A Review

2020 ◽  
Vol 26 (15) ◽  
pp. 1729-1741 ◽  
Author(s):  
Seyed H. Shahcheraghi ◽  
Venant Tchokonte-Nana ◽  
Marzieh Lotfi ◽  
Malihe Lotfi ◽  
Ahmad Ghorbani ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Chemotherapy Resistance ◽  
Wnt Signaling Pathway ◽  
Therapeutic Interventions ◽  
Beta Catenin ◽  
Clinical Prognosis ◽  
Invasion And Migration ◽  
And Migration

: Glioblastoma (GBM) is the most common and malignant astrocytic glioma, accounting for about 90% of all brain tumors with poor prognosis. Despite recent advances in understanding molecular mechanisms of oncogenesis and the improved neuroimaging technologies, surgery, and adjuvant treatments, the clinical prognosis of patients with GBM remains persistently unfavorable. The signaling pathways and the regulation of growth factors of glioblastoma cells are very abnormal. The various signaling pathways have been suggested to be involved in cellular proliferation, invasion, and glioma metastasis. The Wnt signaling pathway with its pleiotropic functions in neurogenesis and stem cell proliferation is implicated in various human cancers, including glioma. In addition, the PI3K/Akt/mTOR pathway is closely related to growth, metabolism, survival, angiogenesis, autophagy, and chemotherapy resistance of GBM. Understanding the mechanisms of GBM’s invasion, represented by invasion and migration, is an important tool in designing effective therapeutic interventions. This review will investigate two main signaling pathways in GBM: PI3K/Akt/mTOR and Wnt/beta-catenin signaling pathways.

Identifying Alzheimer’s Disease-related miRNA Based on Semi-clustering

2019 ◽  
Vol 19 (4) ◽  
pp. 216-223 ◽  
Author(s):  
Tianyi Zhao ◽  
Donghua Wang ◽  
Yang Hu ◽  
Ningyi Zhang ◽  
Tianyi Zang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Feature Vector ◽  
Mirna Gene ◽  
Interaction Network ◽  
Gene Interaction ◽  
Proteinprotein Interaction ◽  
Synaptic Structures

Background: More and more scholars are trying to use it as a specific biomarker for Alzheimer’s Disease (AD) and mild cognitive impairment (MCI). Multiple studies have indicated that miRNAs are associated with poor axonal growth and loss of synaptic structures, both of which are early events in AD. The overall loss of miRNA may be associated with aging, increasing the incidence of AD, and may also be involved in the disease through some specific molecular mechanisms. Objective: Identifying Alzheimer’s disease-related miRNA can help us find new drug targets, early diagnosis. Materials and Methods: We used genes as a bridge to connect AD and miRNAs. Firstly, proteinprotein interaction network is used to find more AD-related genes by known AD-related genes. Then, each miRNA’s correlation with these genes is obtained by miRNA-gene interaction. Finally, each miRNA could get a feature vector representing its correlation with AD. Unlike other studies, we do not generate negative samples randomly with using classification method to identify AD-related miRNAs. Here we use a semi-clustering method ‘one-class SVM’. AD-related miRNAs are considered as outliers and our aim is to identify the miRNAs that are similar to known AD-related miRNAs (outliers). Results and Conclusion: We identified 257 novel AD-related miRNAs and compare our method with SVM which is applied by generating negative samples. The AUC of our method is much higher than SVM and we did case studies to prove that our results are reliable.

scholarly journals Pathomechanisms in the Kidneys in Selected Protozoan Parasitic Infections

2021 ◽  
Vol 22 (8) ◽  
pp. 4209
Author(s):  
Karolina Kot ◽  
Natalia Łanocha-Arendarczyk ◽  
Michał Ptak ◽  
Aleksandra Łanocha ◽  
Elżbieta Kalisińska ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Molecular Mechanisms ◽  
Kidney Injury ◽  
Therapeutic Interventions ◽  
Parasitic Infections ◽  
Injury Mechanisms ◽  
Kidney Involvement ◽  
Leishmania Spp ◽  
Apoptosis Process ◽  
Insight Into

Leishmaniasis, malaria, toxoplasmosis, and acanthamoebiasis are protozoan parasitic infections. They remain important contributors to the development of kidney disease, which is associated with increased patients’ morbidity and mortality. Kidney injury mechanisms are not fully understood in protozoan parasitic diseases, bringing major difficulties to specific therapeutic interventions. The aim of this review is to present the biochemical and molecular mechanisms in kidneys infected with Leishmania spp., Plasmodium spp., Toxoplasma gondii, and Acanthamoeba spp. We present available mechanisms of an immune response, oxidative stress, apoptosis process, hypoxia, biomarkers of renal injury in the serum or urine, and the histopathological changes of kidneys infected with the selected parasites. Pathomechanisms of Leishmania spp. and Plasmodium spp. infections have been deeply investigated, while Toxoplasma gondii and Acanthamoeba spp. infections in the kidneys are not well known yet. Deeper knowledge of kidney involvement in leishmaniasis and malaria by presenting their mechanisms provides insight into how to create novel and effective treatments. Additionally, the presented work shows gaps in the pathophysiology of renal toxoplasmosis and acanthamoebiasis, which need further research.

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