Chorismate mutase (CM), an essential enzyme at the branch-point of the shikimate pathway, is required for the biosynthesis of phenylalanine and tyrosine in bacteria, archaea, plants, and fungi. MtCM, the CM from Mycobacterium tuberculosis, has less than 1% of the catalytic efficiency of a typical natural CM and requires complex formation with 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase for high activity. To explore the full potential of MtCM for catalyzing its native reaction, we applied diverse iterative cycles of mutagenesis and selection, thereby raising kcat/Km 270-fold to 5 × 105 m−1s−1, which is even higher than for the complex. Moreover, the evolutionarily optimized autonomous MtCM, which had 11 of its 90 amino acids exchanged, was stabilized compared with its progenitor, as indicated by a 9 °C increase in melting temperature. The 1.5 Å crystal structure of the top-evolved MtCM variant reveals the molecular underpinnings of this activity boost. Some acquired residues (e.g. Pro52 and Asp55) are conserved in naturally efficient CMs, but most of them lie beyond the active site. Our evolutionary trajectories reached a plateau at the level of the best natural enzymes, suggesting that we have exhausted the potential of MtCM. Taken together, these findings show that the scaffold of MtCM, which naturally evolved for mediocrity to enable inter-enzyme allosteric regulation of the shikimate pathway, is inherently capable of high activity.

Tuberculosis (TB), caused by the infection of Mycobacterium tuberculosis (MTB), is one of the leading causes of death worldwide, especially in children. However, the mechanisms by which MTB infects its cellular host, activates an immune response, and triggers inflammation remain unknown. Mitochondria play important roles in the initiation and activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, where mitochondria-associated endoplasmic reticulum membranes (MAMs) may serve as the platform for inflammasome assembly and activation. Additionally, mitofusin 2 (MFN2) is implicated in the formation of MAMs, but, the roles of mitochondria and MFN2 in MTB infection have not been elucidated. Using mircroarry profiling of TB patients and in vitro MTB stimulation of macrophages, we observed an up-regulation of MFN2 in the peripheral blood mononuclear cells of active TB patients. Furthermore, we found that MTB stimulation by MTB-specific antigen ESAT-6 or lysate of MTB promoted MFN2 interaction with NLRP3 inflammasomes, resulting in the assembly and activation of the inflammasome and, subsequently, IL-1β secretion. These findings suggest that MFN2 and mitochondria play important role in the pathogen-host interaction during MTB infection.

Natalie Bruiners
Dec 1, 2020; 61:1617-1628
Research Articles

The rise of drug-resistant tuberculosis poses a major risk to public health. Statins, which inhibit both cholesterol biosynthesis and protein prenylation branches of the mevalonate pathway, increase anti-tubercular antibiotic efficacy in animal models. However, the underlying molecular mechanisms are unknown. In this study, we used an in vitro macrophage infection model to investigate simvastatin’s anti-tubercular activity by systematically inhibiting each branch of the mevalonate pathway and evaluating the effects of the branch-specific inhibitors on mycobacterial growth. The anti-tubercular activity of simvastatin used at clinically relevant doses specifically targeted the cholesterol biosynthetic branch rather than the prenylation branches of the mevalonate pathway. Using Western blot analysis and AMP/ATP measurements, we found that simvastatin treatment blocked activation of mechanistic target of rapamycin complex 1 (mTORC1), activated AMP-activated protein kinase (AMPK) through increased intracellular AMP:ATP ratios, and favored nuclear translocation of transcription factor EB (TFEB). These mechanisms all induce autophagy, which is anti-mycobacterial. The biological effects of simvastatin on the AMPK-mTORC1-TFEB-autophagy axis were reversed by adding exogenous cholesterol to the cells. Our data demonstrate that the anti-tubercular activity of simvastatin requires inhibiting cholesterol biosynthesis, reveal novel links between cholesterol homeostasis, the AMPK-mTORC1-TFEB axis, and Mycobacterium tuberculosis infection control, and uncover new anti-tubercular therapy targets.

The Delaware Division of Public Health (DPH) will join health organizations and advocates around the globe to recognize World Tuberculosis (TB) Day on Sunday, March 24. This day commemorates Dr. Robert Koch’s groundbreaking discovery of Mycobacterium tuberculosis and is used to raise awareness and increase education about the threat of TB. DPH’s Tuberculosis Elimination and […]

YouTube might be testing a swipe-up gesture in its horizontal video player, but users aren't thrilled.

to youtube videos manually

Underground tunnels created by lava flows provided humans with shelter for thousands of years beneath the hot desert landscape of Saudi Arabia

Title: 'Alarming' Rise Seen in Drug-Resistant Tuberculosis
Category: Health News
Created: 8/30/2012 2:05:00 PM
Last Editorial Review: 8/31/2012 12:00:00 AM

Title: Newer Breathing Tube Might Save More Cardiac Arrest Patients
Category: Health News
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Category: Health News
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Extract

With a disproportionate burden of tuberculosis (TB) amongst migrants in Europe [1], Burman et al. [2] have highlighted the pressing need for alternative approaches to make TB infection (TBI) screening comprehensive and accessible. Across high-income Organisation for Economic Co-operation and development countries, a median of 52% of TB cases occur in foreign-born individuals, who are at their highest risk of developing TB disease within the first 5 years of migration [3]. Molecular epidemiological studies indicate that the majority of these cases occur as a result of TBI reactivation, often acquired overseas [4]. Within the UK, overseas-born migrants have a 14-fold higher TB incidence than UK-born individuals [5]. The World Health Organization therefore recommends that migrants from countries with a high TB burden may be prioritised for TBI screening [6, 7].

Background

Computer-aided detection (CAD) systems hold promise for improving tuberculosis (TB) detection on digital chest radiographs. However, data on their performance in exclusively paediatric populations are scarce.

Background

Control of latent tuberculosis infection (LTBI) is a priority in the World Health Organization strategy to eliminate TB. Many high-income, low TB incidence countries have prioritised LTBI screening and treatment in recent migrants. We tested whether a novel model of care, based entirely within primary care, was effective and safe compared to secondary care.

Exclusive sneak-peek of how Andrea gets her #BrilliantSmile holiday ready in Episode 7 of The Smile Show.

GOVERNMENT OF INDIA MINISTRY OF FINANCE (DEPARTMENT OF REVENUE)

Toshiyuki Morikawa stars as titular dog in 12 episodes now streaming

Алексей Леонидович Траньков зашёл с козырей при описании Rutube и сравнении его с YouTube, озвучив тезис, что хорошие проекты не рождаются по указке, а на любой хороший проект тут же собираются желающие побить себя в грудь с воплями «мы, мы, мы!», а вот в Америке не так, там всё по уму, и всех закидывают баблом. В тексте было несколько кажущихся мне спорными моментов, в частности, расцвет Rutube увязывается с президентством Медведева (Rutube был запущен в 2006-м), и то, что Rutube был обречён на успех. Проще всего спросить об этом у Михаила Паулкина, основателя Rutube.

Argentine side Deportivo Riestra are accused of a "lack of respect" after picking a YouTube star as a striker in a top-flight match.

For the first time, scientists have devised an innovative method to deliver tuberculosis (TB) (!--ref1--) medication directly to the brain through the nasal route.

Lecturers at the Faculty of Social and Communication Sciences of the University of the Basque Country/Euskal Herriko University (UPV/EHU) analyzed a playlist

The Uttar Pradesh health department has adopted YouTube as a platform for ongoing medical education and professional development of government doctors stationed in remote areas (!--ref1--).

IWMI's Amjad Jamal discusses the implications of Pakistan's shift to solar-powered tube wells, specifically unchecked groundwater depletion.

The post Solarization of tube wells: A ‘double-edged sword’ in Pakistan first appeared on International Water Management Institute (IWMI).

medlinkHIV/medlink patients with pulmonary tuberculosis had broader and more potent HIV antibodies compared to those without suspected or documented

A promising new therapy for medlinktuberculosis/medlink (TB) has been shown to be compatible with combined antiretroviral therapy (cART), stated research

It may have come a bit too late, but a very deserving Robert Edwards has finally been awarded the Nobel Prize in Medi

Home lighting decoration becoming a part of modern living environment has drawn increasing attention. Home lighting can render a good home environment and outstanding design features for our lives to create a warm ambience. It is easy when...

Software major Adobe on Friday announced it has acquired video advertising platform TubeMogul for nearly $540 million.

YouTube has announced a major update for content creators, bringing a host of new AI-powered tools that are set to reshape video production on the platform. The announcement came at the Made on YouTube event in New York City, where the

YouTube has announced an update to YouTube Shorts, making it easier and more fun for creators. YouTube has confirmed it is extending the ability to create longer vertical videos. This has come after many creators asked YouTube to allow them to

In recent weeks, some YouTube users have voiced concerns that the platform is making it more difficult to skip ads, with reports circulating about black rectangles obscuring the skip button. These claims surfaced on Reddit, and users reported a lack of

YouTube is introducing several updates, seemingly inspired by user suggestions. One of the notable changes is the ability to adjust playback speed in smaller increments of 0.05, compared to the previous 0.25 steps. However, the maximum speed remains capped at 2x.

Bollywood Latest News in Hindi Today: मनोरंजन की दुनिया में आए दिन कुछ ना कुछ लगा ही रहता है। अगर आप भी सितारों के बारे में जानना चाहते हैं तो फटाफट जुड़ें फिल्मी बीट की लाइव न्यूज से। जहां

Social media giant X (formerly Twitter) is making a bold move into the video streaming landscape with the announcement of a brand new TV app. This app signifies a strategic shift for X, placing video content at the forefront and aiming

Jimmy Donaldson, known to many as MrBeast, has reached a new milestone. His YouTube channel now has over 269 million subscribers, surpassing T-Series, which has about 266 million. This marks a significant achievement in the online world. Donaldson made the announcement

YouTube has officially launched YouTube Shopping in India, a feature designed to expand revenue opportunities for video creators by integrating e-commerce directly into their content.   Building on the success of similar launches in markets like South Korea and the U.S.,

München ; Wien : De Gruyter Oldenbourg, [2023]

Salman Khan had fun with the kids on the show.