scholarly journals Development and Optimization of Chromosomally-Integrated Fluorescent Mycobacterium tuberculosis Reporter Constructs

2020 ◽  
Vol 11 ◽  
Author(s):  
Katharina Kolbe ◽  
Alice C. Bell ◽  
Gareth A. Prosser ◽  
Maike Assmann ◽  
Hee-Jeong Yang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Recombinant Dna ◽  
Optimization Techniques ◽  
Fluorescent Reporter ◽  
Stimulus Response ◽  
Response Characteristics ◽  
Treatment Regimens ◽  
Reporter Strains ◽  
Drug Efficiency

Mycobacterium tuberculosis resides in the lungs in various lesion types with unique microenvironmental conditions. This diversity is in line with heterogeneous disease progression and divergent drug efficiency. Fluorescent reporter strains can be used to decipher the micromilieu and to guide future treatment regimens. Current reporters using replicating plasmids, however, are not suitable for long-term mouse infections or studies in non-human primates. Using a combination of recombinant DNA and protein optimization techniques, we have developed reporter strains based on integrative plasmids, which exhibit stimulus-response characteristics and fluorescence intensities comparable to those based on replicating plasmids. We successfully applied the concepts by constructing a multi-color reporter strain able to detect simultaneous changes in environmental pH, Mg2+ concentrations, and protein expression levels.

scholarly journals Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thanuja D. Sudasinghe ◽  
Michael T. Banco ◽  
Donald R. Ronning
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Binding Sites ◽  
Enzyme Inhibitor ◽  
Structural Information ◽  
Alkylating Agents ◽  
Enzyme Active Site ◽  
Treatment Regimens ◽  
Domains Of Life ◽  
Substrate Binding Sites

AbstractErgothioneine (EGT) is a low molecular weight histidine betaine essential in all domains of life but only synthesized by selected few organisms. Synthesis of EGT by Mycobacterium tuberculosis (M. tb) is critical for maintaining bioenergetic homeostasis and protecting the bacterium from alkylating agents, oxidative stress, and anti-tubercular drugs. EgtD, an S-adenosylmethionine-dependent methyltransferase (AdoMet), catalyzes the trimethylation of L-Histidine to initiate EGT biosynthesis and this reaction has been shown to be essential for EGT production in mycobacteria and for long-term infection of murine macrophages by M. tb. In this work, library screening and structure-guided strategies identified multiple classes of M. tb EgtD inhibitors that bind in various regions of the enzyme active site. X-ray crystal structures of EgtD-inhibitor complexes confirm that L-Histidine analogs bind solely to the L-Histidine binding site while drug-like inhibitors, such as TGX-221, and S-Glycyl-H-1152 span both the L-Histidine and AdoMet binding sites. These enzyme-inhibitor complexes provide detailed structural information of compound scaffolds useful for developing more potent inhibitors that could shorten Tuberculosis treatment regimens by weakening important bacterial defenses.

Considering a Potential Role of Linalool as a Mood Stabilizer for Bipolar Disorder

2020 ◽  
Vol 26 (40) ◽  
pp. 5128-5133
Author(s):  
Kate Levenberg ◽  
Wade Edris ◽  
Martha Levine ◽  
Daniel R. George
Keyword(s):  
Bipolar Disorder ◽  
Treatment Options ◽  
Mood Stabilizer ◽  
Well Being ◽  
Epidemiologic Studies ◽  
Treatment Regimens ◽  
Bipolar Spectrum Disorders ◽  
Short And Long Term

Epidemiologic studies suggest that the lifetime prevalence of bipolar spectrum disorders ranges from 2.8 to 6.5 percent of the population. To decrease morbidity and mortality associated with disease progression, pharmacologic intervention is indicated for the majority of these patients. While a number of effective treatment regimens exist, many conventional medications have significant side effect profiles that adversely impact patients’ short and long-term well-being. It is thus important to continue advancing and improving therapeutic options available to patients. This paper reviews the limitations of current treatments and examines the chemical compound Linalool, an alcohol found in many plant species, that may serve as an effective mood stabilizer. While relatively little is known about Linalool and bipolar disorder, the compound has been shown to have antiepileptic, anti-inflammatory, anxiolytic, anti-depressive, and neurotrophic effects, with mechanisms that are comparable to current bipolar disorder treatment options.

scholarly journals Optimal Fractional PID Controller for Buck Converter Using Cohort Intelligent Algorithm

2021 ◽  
Vol 4 (3) ◽  
pp. 50
Author(s):  
Preeti Warrier ◽  
Pritesh Shah
Keyword(s):  
Fractional Order ◽  
Pid Controller ◽  
Power Converters ◽  
Buck Converter ◽  
Optimization Techniques ◽  
Superior Performance ◽  
Computational Time ◽  
Optimization Approach ◽  
Response Characteristics ◽  
Fractional Order Controller

The control of power converters is difficult due to their non-linear nature and, hence, the quest for smart and efficient controllers is continuous and ongoing. Fractional-order controllers have demonstrated superior performance in power electronic systems in recent years. However, it is a challenge to attain optimal parameters of the fractional-order controller for such types of systems. This article describes the optimal design of a fractional order PID (FOPID) controller for a buck converter using the cohort intelligence (CI) optimization approach. The CI is an artificial intelligence-based socio-inspired meta-heuristic algorithm, which has been inspired by the behavior of a group of candidates called a cohort. The FOPID controller parameters are designed for the minimization of various performance indices, with more emphasis on the integral squared error (ISE) performance index. The FOPID controller shows faster transient and dynamic response characteristics in comparison to the conventional PID controller. Comparison of the proposed method with different optimization techniques like the GA, PSO, ABC, and SA shows good results in lesser computational time. Hence the CI method can be effectively used for the optimal tuning of FOPID controllers, as it gives comparable results to other optimization algorithms at a much faster rate. Such controllers can be optimized for multiple objectives and used in the control of various power converters giving rise to more efficient systems catering to the Industry 4.0 standards.

Tubercular Abscess of the Spleen in a Child: Conservative Management and Long-Term Follow-Up

2017 ◽  
Vol 13 (04) ◽  
pp. 316-318
Author(s):  
Vijai Williams ◽  
Sarvanan Chandrasekaran ◽  
Keerthivasan Seetharaman ◽  
Kushaljit Sodhi ◽  
Devi Dayal
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Splenic Abscess ◽  
Complete Healing ◽  
Rare Occurrence ◽  
Line Probe Assay ◽  
Rare Manifestation ◽  
Long Term Follow Up ◽  
Probe Assay

AbstractIsolated involvement of the spleen is a rare manifestation of childhood tuberculosis. The rare occurrence and presence of nonspecific clinical features often pose diagnostic challenges even in countries where tuberculosis is endemic. Splenectomy is often performed for establishing the diagnosis or achieving a cure in combination with antitubercular therapy (ATT). In this report, we describe a boy who presented with nonspecific symptoms and was detected to have a well-defined lesion in the spleen on ultrasonography. The diagnosis of tubercular splenic abscess was made after line probe assay for the detection of Mycobacterium tuberculosis and cytomorphology of the aspirated material. The tubercular abscess showed complete healing after 9 months of four-drug ATT.

scholarly journals Knockdown of MicroRNA-1 in the Hippocampus Ameliorates Myocardial Infarction Induced Impairment of Long-Term Potentiation

2018 ◽  
Vol 50 (4) ◽  
pp. 1601-1616 ◽  
Author(s):  
Ji-Chao Ma ◽  
Ming-Jing Duan ◽  
Ke-Xin Li ◽  
Das Biddyut ◽  
Shuai Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Sham Group ◽  
Long Term Potentiation ◽  
Stimulus Response ◽  
Protein Levels ◽  
Term Potentiation ◽  
Passive And Active Avoidance ◽  
Related Proteins

Backgrounds/Aims: It has been reported that myocardial infarction (MI) is a risk factor for vascular dementia. However, the molecular mechanism remains largely unknown. Methods: MI mice were generated by ligation of the left coronary artery (LCA) for 4 weeks. Passive and active avoidance tests were performed to evaluate the cognitive ability of MI mice. A theta-burst stimulation (TBS) protocol was applied to elicit long-term potentiation (LTP) of the perforant pathway-dentate gyrus synapse (PP-DG). Western blot analysis was employed to assess protein levels. Results: In this study, we demonstrated that after 4 weeks of MI, C57BL/6 mice had significantly impaired memory. Compared with the sham group, in vivo physiological recording in the MI group revealed significantly decreased amplitude of population spikes (PS) with no effect on the latency and duration of the stimulus-response curve. The amplitude of LTP was markedly decreased in the MI group compared with the sham group. Further examination showed that the expression of the TBS-LTP-related proteins BDNF, GluA1 and phosphorylated GluA1 were all decreased in the MI group compared with those in the sham group. Strikingly, all these changes were prevented by hippocampal stereotaxic injection of an anti-miR-1 oligonucleotide fragment carried by a lentivirus vector (lenti-pre-AMO-1). Conclusion: MI induced cognitive decline and TBS-LTP impairment, and decreased BDNF and GluA1 phosphorylation levels from overexpression of miR-1ated were involved in this process.

Complications of therapy for ANCA-associated vasculitis

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_3) ◽  
pp. iii74-iii78 ◽  
Author(s):  
Rona Smith
Keyword(s):  
Cardiovascular Disease ◽  
Clinical Course ◽  
Disease Process ◽  
Organ Damage ◽  
Therapeutic Strategies ◽  
Early Mortality ◽  
Treatment Regimens ◽  
Anca Associated Vasculitis ◽  
Monitoring Strategies

Abstract The introduction of immunosuppressive therapies has transformed ANCA-associated vasculitis (AAV) from a largely fatal condition to a chronic relapsing disorder. However, progressive organ damage and disability, both from the disease process itself and from therapies used for treatment, eventually affect the majority of patients. Infection, rather than uncontrolled vasculitis, is the greatest cause of early mortality and remains a major problem thereafter. Increased rates of malignancy and cardiovascular disease are additional important long term sequelae. This review focuses on the complications associated with the immunosuppressive therapies most commonly used to treat ANCA-associated vasculitis, and considers prophylactic and monitoring strategies to minimize these risks. Achieving a balance between immunosuppression to reduce relapse risk and minimizing the adverse effects associated with therapy has become key. The contribution of glucocorticoids to treatment toxicity is increasingly being recognized, and future therapeutic strategies must concentrate on glucocorticoid minimization or sparing strategies. Development of robust predictors of an individual’s future clinical course is needed in order to individually tailor treatment regimens.

scholarly journals The effect of the main active substances of antihypertensive eye drops on condition of the eyes of glaucoma patients

2020 ◽  
pp. 5-10
Author(s):  
O. N. Onufriichuk ◽  
I. R. Gazizova ◽  
A. V. Kuroyedov ◽  
A. V. Seleznev
Keyword(s):  
Quality Of Life ◽  
Adverse Reactions ◽  
Hypotensive Effect ◽  
Eye Drops ◽  
Common Cause ◽  
Treatment Regimens ◽  
Active Substances ◽  
Lifetime Treatment

Today, glaucoma is considered to be the most common cause of irreversible blindness. The treatment of this disease is aimed at reducing intraocular tension in order to slow down the deterioration of visual functions and to maintain accept‑ able quality of life. Most ophthalmologists prefer local medicamentous therapy. Despite a significant expansion of the range of antihypertensive medicines, a significant increase in the hypotensive effect is not always achieved in each certain case, at the same time, at long-term (sometimes lifetime) treatment local and systemic adverse reactions arise and intensify. The findings of recent clinical trials presented in this overview demonstrate an adverse effect of active compounds, preservatives and ad‑ ditives of ophthalmic medicines not only on the eye surface but also on the structure of anterior and posterior eye segments. Taking into account possible side effects of each component of medicines used in glaucoma therapy, ophthalmologists will be able to reasonably approach the choice of optimal treatment regimens with the lowest risk for patients.

scholarly journals Local adaptation of Mycobacterium tuberculosis on the Tibetan Plateau

2021 ◽  
Vol 118 (17) ◽  
pp. e2017831118
Author(s):  
Qingyun Liu ◽  
Haican Liu ◽  
Li Shi ◽  
Mingyu Gan ◽  
Xiuqin Zhao ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Local Adaptation ◽  
Population Genomics ◽  
Genetic Evidence ◽  
The Tibetan Plateau ◽  
Lower Altitude ◽  
Local Environments ◽  
Plausible Model ◽  
Genes Encoding

During its global dispersal, Mycobacterium tuberculosis (Mtb) has encountered varied geographic environments and host populations. Although local adaptation seems to be a plausible model for describing long-term host–pathogen interactions, genetic evidence for this model is lacking. Here, we analyzed 576 whole-genome sequences of Mtb strains sampled from different regions of high-altitude Tibet. Our results show that, after sequential introduction of a few ancestral strains, the Tibetan Mtb population diversified locally while maintaining strict separation from the Mtb populations on the lower altitude plain regions of China. The current population structure and estimated past population dynamics suggest that the modern Beijing sublineage strains, which expanded over most of China and other global regions, did not show an expansion advantage in Tibet. The mutations in the Tibetan strains showed a higher proportion of A > G/T > C transitions than strains from the plain regions, and genes encoding DNA repair enzymes showed evidence of positive selection. Moreover, the long-term Tibetan exclusive selection for truncating mutations in the thiol-oxidoreductase encoding sseA gene suggests that Mtb was subjected to local selective pressures associated with oxidative stress. Collectively, the population genomics of Mtb strains in the relatively isolated population of Tibet provides genetic evidence that Mtb has adapted to local environments.

scholarly journals Pre-stimulus phase and amplitude regulation of phase-locked responses are maximized in the critical state

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Arthur-Ervin Avramiea ◽  
Richard Hardstone ◽  
Jan-Matthis Lueckmann ◽  
Jan Bím ◽  
Huibert D Mansvelder ◽  
...  
Keyword(s):  
Computational Model ◽  
Critical State ◽  
Global Dynamics ◽  
Critical Dynamics ◽  
Neuronal Responses ◽  
Scale Free ◽  
Stimulus Response ◽  
Functional States ◽  
The Brain

Understanding why identical stimuli give differing neuronal responses and percepts is a central challenge in research on attention and consciousness. Ongoing oscillations reflect functional states that bias processing of incoming signals through amplitude and phase. It is not known, however, whether the effect of phase or amplitude on stimulus processing depends on the long-term global dynamics of the networks generating the oscillations. Here, we show, using a computational model, that the ability of networks to regulate stimulus response based on pre-stimulus activity requires near-critical dynamics—a dynamical state that emerges from networks with balanced excitation and inhibition, and that is characterized by scale-free fluctuations. We also find that networks exhibiting critical oscillations produce differing responses to the largest range of stimulus intensities. Thus, the brain may bring its dynamics close to the critical state whenever such network versatility is required.

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