Characterization of the Role of Transcriptional Regulator of AraC/XylS Family in Tularemia Pathogenesis

The Tier 1 Select Agent, Francisella tularensis causes an acute and fatal disease known as tularemia. Many studies have devoted enormous efforts to understand how F. tularensis avoids host defense mechanisms, replicates within an extremely secure immune system, and eventually causes the deadly disease tularemia. The extremely high virulence of Francisella depends on its ability to manipulate gene expression according to the surrounding environment. This process requires the involvement of unique transcriptional regulators. Francisella possesses very few transcriptional regulators, and a majority of them characterized to-date have been shown to regulate genes involved in virulence and cellular functions. The role of a transcriptional regulator of F. tularensis belonging to the AraC/XylS in gene regulation and virulence remains uncharacterized to-date. This study characterized the role of AraC in gene regulation, intramacrophage survival, and virulence of F. tularensis. In specific aim 1, we generated a deletion mutant (DaraC) of FTL_0689 gene encoding AraC of F. tularensis Live Vaccine Strain (LVS), and its transcomplemented strain (DaraC+paraC). Characterization of the DaraC mutant demonstrated that AraC does not regulate genes involved in arabinose utilization. Genomic organization of the araC gene suggested that it may have a role in the regulation of a unique multidrug efflux pump (MEP) located downstream of it. Our results revealed that the phenotype of the DaraC mutant mirrors that of the emrA1 and the silC mutants, the components of the MEP. However, these phenotypic similarities are not due to the direct regulation of MEP genes by AraC. Further characterization revealed that AraC is involved in providing resistance against oxidative stress. In specific aim 2, we investigated the role of AraC as a global transcriptional regulator in F. tularensis LVS strain. We studied gene expression profiles of the wild type F. tularensis LVS and the DaraC mutant under normal and oxidative stress conditions. The results revealed that AraC serves as a transcriptional regulator only when the bacteria are exposed to oxidative stress conditions. AraC is involved in the regulation of virulence genes encoded on Francisella Pathogenicity Island, stress response genes, energy production, genes encoding enzymes in the tricarboxylic acid (TCA) cycle, metabolism and regulatory proteins indicating its role as a global regulator. The differential expression of these genes also impaired the ability of the DaraC mutant to survive in macrophages and attenuated its virulence in mice. Collectively, this study identified and characterized a novel transcription factor, AraC, required for adaptation of Francisella to oxidative stress conditions encountered outside or within a host

The Effects of Autophagy on the Replication of Zika Virus

Zika virus is an enveloped virus with a single-stranded positive-sense RNA genome. The Zika virus is a member of the Flaviviridae family of viruses that was discovered to infect humans in 1952. The Flavivirus envelope is decorated by many copies of two membrane proteins that facilitate viral entry. The virus is primarily transmitted through mosquito bites. Another method by which Zika virus could be transmitted is through sexual contact with Zika infected partners or from an infected pregnant woman to fetus known as congenital transmission. Infected patients suffer from self-limiting febrile illness including headaches, skin rash myalgia, and conjunctivitis. Zika virus has a significant impact on pregnancies, causing developmental defects in fetal brain that leads to infants born with smaller head size, a disorder known as microcephaly. Zika virus has also been linked to the increase of the development of neurological disorder known as Guillain-Barre syndrome. Zika virus has been involved in multiple outbreaks around the world, beginning in 2007 where the Zika virus infected about 5,000 of the people of Yap Island in Micronesia. The following outbreak began between 2013-2014, affecting about 30,000 people in French Polynesia. In 2015-2016, Zika virus outbreak was reported to affect the Americas, where over 30,000 cases and about 4300 microcephaly cases. Upon entry into host cells, Zika virus begins to unpack and release the RNA genome to express the viral proteins as well as to replicate the RNA genome. Studies have revealed that autophagy, which is a cellular mechanism that protects host cells during starvation and pathogenic infections, is associated with Zika replication as it may facilitate the replication of the Zika virus. Here, we investigated the effects of autophagy in the replication of Zika virus using an autophagy inducer, rapamycin. For this study, we used a human trophoblast cell line which is physiologically relevant to congenital transmission of Zika virus. To better understand how autophagy is involved in Zika replication in trophoblast cells, a knockout was generated on one of the autophagy gene known as ATG12. The ATG12 autophagy protein forms a complex with another autophagy protein known as ATG5. PCR analysis revealed that the relative Zika viral load was increased in cells treated with rapamycin when compared to non-rapamycin treated cells. Consistent with the rapamycin treatment results, Zika replication was lower in ATG12-/- than wild type cells. Interestingly, the effect of rapamycin on Zika replication was abolished in ATG12-/- cells. These findings suggest that autophagy facilitates Zika replication. Understanding the effects that autophagy imposes on the replication of the Zika virus could provide therapeutic opportunities through designing drugs that control the autophagy by either entirely blocking the autophagy mechanism or partially in patients who have been infected with Zika virus. Another avenue that would benefit from controlling autophagy is by strategizing delivery of autophagy blockers to pregnant patients to control the severity of developmental disorders in fetuses such as microcephaly

Nanomedicine for SARS-CoV-2: Therapeutic and Prophylactic Approach in Immunocompromised Individuals

SARS-CoV-2 is a novel coronavirus that first appeared in Wuhan, China in December 2019 and then spread all over the world, causing a global respiratory epidemic COVID-19 illness. Certain health conditions can increase your exposure to COVID-19, such as chronic obstructive lung disease, high blood pressure, cardiovascular disease, and diabetes. The immune system of the host is severely compromised in the event of a respiratory viral infection. Immunocompromised patients have a more difficult time avoiding respiratory viral infections, making them more vulnerable to COVID-19 pneumonia and increasing the death rate to 19%. The ability of SARS-CoV-2 to damage the host cell by modifying its own DNA or RNA and proliferating inside the host cell, with antiviral treatments and prophylactic vaccinations being tested. In recent years, numerous innovative technologies have been examined to diagnose, prevent and treat viral infections. Nano technology opens the way to distinguish the living cell mechanisms and develop new technologies that make it possible to diagnose and cure various viral infections in the early stage. The therapeutic and preventative approaches of nanomedicine are essential factors for curing SARS-CoV-2. The delivery of antiviral drugs based on nanocarrier, changes in pharmacokinetic/pharmacodynamic properties, leading in dose reduction, reductions in toxicity, increased bioavailability, and the prevention of the virus. The overall efficiency and safety of vaccinated adjuvant vaccine nanoparticles (VANs) helps enhance the immune response of older, immunocompromised persons with the greatest death rate of SARS-CoV-2. The review focuses on recent advancements in nanomedicine treatments and prevention strategies for SARS-CoV-2

Politics and aspects of the development of Libya's air transport systems : A geographical analysis.

The aim of this thesis is to analyse the developments of Libya's air transport systems and infrastructures by analysing the evolution of these spatial organisations. Certain underlying factors are examined in order to explain these developments including the political element influencing the changing flows in, and structures of, the networks. The Study emphasises the need to examine similar systems in other developing countries in the light of internal political forces, and the impact of the policies of the major suppliers of air transport technology. The Preface defines the subject matter and methodology. The Introduction deals with the topic in order to introduce the ideas presented in the subsequent chapters of this thesis. The remainder of this thesis is divided into six chapters so that each covers a distinctive aspect of development. Chapter 1 investigates air transport in Libya in the pre-independence period before 1951, concentrating on the immediate pre-Independence years. Chapter 2 examines the impact of oil as an indigenous factor enabling the development of the Libyan air transport systems and infrastructure. The macro planning processes in Libyan air transport are considered in Chapter 3. Chapter 4 places the contemporary developments in Libya's international and domestic air networks in their wider geographical con-text with special reference to the four North African national airlines. Chapter 5 analyses the geographical and political aspects of the organisation of the Libyan air transport systems with emphasis on the predictions for changes in their organisation as a consequence of the removal of the administrative centre of the country from the historic location of Tripoli. This chapter also considers the revival of the strategic significance of the Libyan airport system. Chapter 6 considers the aircraft fleet aspect of Libyan air transport and throws light on the ability of the US Government to single handedly prevent its updating and to obstruct efforts towards an efficient system

Anaemia characteristic in end stage renal disease patients receiving haemodialysis at King Salman armed forced hospital in Tabuk, Saudi Arabia

BackgroundChronic kidney disease (CKD) is a disease associated with high rate of morbidity and mortality mainly due to cardiovascular disease. Anaemia is the most common haematological abnormality in end stage renal disease.AimsThe current Study aimed to determine the laboratory characteristic and management of anaemia among haemodialysis patients.Methods A cross sectional study conducted among 112 adult patients with the diagnosis of end stage renal disease (ESRD) on haemodialysis at King Salman Armed Forced Hospital in Tabuk, Saudi Arabia, data were collected by a pre-tested data collection sheet.Results There were 112 patients with a mean age of 43 years. The mean haemoglobin value was 10.5g/dL, which was lower than the target haemoglobin range recommended by Kidney Disease Outcomes Quality Initiative (KDOQI). Twenty- eight patients (25 per cent) had haemoglobin values between 11.0 and 12.0g/dL. Only seven patients (6.3 per cent) exceeded the recommended range (>12g/dL) and seventy- seven (68.7 per cent) had less than recommended range. The majority of patients had been receiving haemodialysis for two or more years. The most common primary cause of end stage renal failure was diabetic nephropathy. Hypertension was the most common co-morbidity, followed by diabetes, and ischemic heart disease.ConclusionPatients with end stage renal disease at a high risk for anaemia which should be investigated for correctable causes such as Iron-deficiency before initiating erythropoietin replacement therapy

Automated quantitative image analysis for the histological assessments of colorectal and pancreas cancer tissues

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