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BET+ And Tyler Perry Studios Set Launch Date For 'BRUH'



Perry’s second original series for BET+




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Background Post and Media Uploading with WordPress for iOS 9.8

Upload images and media in the background with WordPress for iOS 9.8




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Existing and Emerging Highway Infrastructure Preservation, Maintenance, and Renewal Definitions, Practices, and Scenarios

The National Cooperative Highway Research Program's NCHRP Web-Only Document 272: Existing and Emerging Highway Infrastructure Preservation, Maintenance, and Renewal Definitions, Practices, and Scenarios provides appendices to NCHRP Report 750, Volume 7: Preservation, Maintenance, andRenewal of Highway Infrastructure .




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Amazon Studios Greenlights Season Two of "Upload" from the Emmy Award-Winning Creator Greg Daniels

Season two will exclusively stream on Amazon Prime Video in more than 200 countries and territories worldwide.




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If it feels like the software world is held together by string and a prayer, we don't blame you: Facebook SDK snafu breaks top iOS apps

Update used wrong data type, causing Tinder to Spotify to fall over

A change in the Facebook SDK backend managed to crash many popular iOS apps that integrated the code library, used for implementing various Facebook services.…




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Вышла iOS 13.5 beta 4 для разработчиков. Что нового

Время обновляться.




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It’s not all about muscle: fibroadipogenic progenitors contribute to facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) results from expression of the full-length double homeobox 4 (DUX4-FL) retrogene in skeletal muscle. However, even in cases of severe FSHD the presence of DUX4 is barely detectable. In this issue of the JCI, Bosnakovski et al. used an inducible, muscle-specific human DUX4 to reproduce the low-level, sporadic DUX4 expression of human FSHD muscle as well the myopathology seen in human FSHD disease. Notably, dysregulated fibroadipogenic progenitors accumulated in affected muscles, thus providing a mechanism for the replacement of muscle by fibrosis and fat.




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Пользователи жалуются на проблемы с iOS 13.2

Вскоре после выхода iOS 13.2 и iPasOS 13.2 пользователи стали замечать, что системы добавили устройствам от компании Apple автономности. Однако очень скоро выяснилось, на какие неприятные шаги пошел п...




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M-Industry Transforms Its Mobile Workforce with IBM MobileFirst for iOS

IBM today announced that M-Industry, one of the world’s largest private label consumer goods company and subsidiary of Switzerland’s largest retailer and supermarket chain, Migros Group, has launched a new IBM designed mobile offering to transform how product promoters work.



  • Services and solutions

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IBM lanza la primera plataforma cognitiva de servicios para transformar las operaciones de negocios

IBM anunció hoy la primera plataforma de servicios basada en IBM Watson y construida en IBM Cloud para aumentar la inteligencia humana y ayudar a mejorar las operaciones de los proveedores de servicios a través de tecnologías cognitivas.



  • Global Technology Services

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IBM presenta nuevo servicio de nube que da a los negocios la flexibilidad que requiere su transformación

IBM anuncia el lanzamiento de IBM Cloud Private, una plataforma de software creada para los clientes que requieren la flexibilidad y capacidad de una nube pública en un ambiente privado. IBM Cloud Private transforma los sistemas de TI (Tecnologías de la Información) en un ambiente de nube flexible para crear un puente hasta las nubes públicas y acelerar el desarrollo de aplicativos.




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Apple e IBM lanzan la primera ola de apps para iOS

Apple e IBM lanzaron hoy la primera ola de soluciones IBM MobileFirst para iOS, una nueva clase de apps creadas para los negocios y con soporte para servicios de Cloud, que llevan las capacidades Big Data y Analítica de IBM a los usuarios de iPhone e iPad en las empresas.




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IBM es designada en el reporte MarketScape de IDC como líder mundial en Servicios de Desarrollo de Aplicaciones Móviles y de Consultoría de Pruebas

IBM anunció que fue designada como líder en el prestigiado modelo de evaluación de proveedores “IDC MarketScape: Worldwide Mobile Application Development and Testing Services 2014 Vendor Assessment”.




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Papel San Francisco garantiza la continuidad de operaciones aprovechando Servicios de IBM

Papel San Francisco garantiza la continuidad de operaciones aprovechando Servicios de IBM




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Crown apoyará su expansión en México con Servicios de TI y Nube híbrida de IBM

IBM y Crown Holdings, Inc., proveedor global líder en productos de empaques metálicos, anunciaron hoy la firma de un contrato de varios años que incluye servicios de TI y servicios administrados corriendo en la robusta plataforma de cómputo en la nube de clase empresarial de IBM.



  • Services and solutions

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Ecodex incrementa servicios de certificación tributaria para empresas con soluciones inteligentes de IBM

La empresa se afianza como líder de Proveedores Autorizados de Certificación (PAC) y logra procesar grandes volúmenes de transacciones de manera sencilla




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Dona IBM servicios de consultoría a organizaciones mexicanas para proyectos de impacto social

Con la finalidad de apoyar el desarrollo de proyectos de alto impacto en la Ciudad de México, la Asociación Mexiana de Ayuda a Niños con Cáncer (AMANC), Fondo Unido México, Fundación Carlos Slim, el Patronato del Museo Nacional de Antropología e IBM, ponen en marcha el día de hoy el programa de consultoría Corporate Service Corps (CSC), en su edición Ciudad de México.




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Organizaciones beneficiadas e IBM, comparten resultados de servicios de consultoría en proyectos de impacto social

Después de un mes de haber iniciado la consultoria pro-bono de IBM denominada Corporate Service Corps (CSC), el día de hoy se hizo la entrega del resumen ejecutivo de cada uno de los proyectos de las organizaciones receptoras de este apoyo: Asociación Mexiana de Ayuda a Niños con Cáncer (AMANC), Fondo Unido México, Fundación Carlos Slim, el Patronato del Museo Nacional de Antropología.




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Dona IBM Servicios de Consultoría a Organizaciones Queretanas para Proyectos de Impacto Social

IBM, Peace Corps y cuatro instituciones locales dieron inicio el día de hoy al programa de consultoría Corporate Service Corps (CSC), en su edición Cd. de Querétaro; con la finalidad de apoyar el desarrollo de proyectos de alto impacto en esta localidad. IBM y Peace Corps (PC) trabajarán en conjunto con la Secretaría de Desarrollo Social del Estado de Querétaro, el Instituto Queretano de las Mujeres, el Municipio de Querétaro - Delegación Santa Rosa Jáuregui, y la Universidad Politécnica de Santa Rosa Jáuregui (UPSRJ).




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Premian Banorte e IBM apps de estudiantes del Tec de Monterrey que transforman servicios bancarios dirigidos a los jóvenes

Tres proyectos que proponen mejorar la interacción y la experiencia de los jóvenes usuarios con servicios bancarios móviles, fueron reconocidos hoy por Banorte, IBM y el Tec de Monterrey como resultado del Reto Banorte en el marco de la Semana i, que la institución educativa llevó a cabo del 21 al 25 de septiembre en todo el país.




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Apple et IBM annoncent plus de 100 apps MobileFirst pour iOS !

Apple et IBM annoncent plus de 100 apps MobileFirst pour iOS !




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Таск-менеджер Wrike для iOS: отличный помощник в экспресс-работе над задачами

Проблема работы на ходу знакома и менеджерам, и исполнителям. Ведь дедлайн страшен любому специалисту и приходит всегда внезапно. Для тех, у кого смартфон под рукой 24/7 (то есть для всех) разработчики известного онлайн-менеджера задач Wrike создали мобильное приложение для iOS и Android. В этом обзоре речь пойдет о продукте для гаджетов Apple. С марта 2018 он «заговорил» на русском языке.




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Let Other Studios Race to VOD; Sony Pictures Classics Believes It’s Theaters or Nothing





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PM Studios "Stay Safe" Sale - Featuring Switch/PS4, and Limited Run Games.

PM Studios online store is back and they made a new sale featuring new reprints, overall deals and restock on rare out-of-print titles from Limited Run Games.

 

https://twitter.com/PMStudiosUSA/status/1253401043414781959

 

Also all orders over $49.99 will get Cytus Alpha Limited Edition Original Soundtrack CD for free with the Coupon "FREEGIFT".

 

Kinda sick move they did now.

 

https://www.pm-studios.com/store

 

Edit: Price list.

 

Reprints/Pre-Orders: 
 
Horizon Chase Turbo (Switch) - $29.99
Ministry of Broadcast (Steelbook Edition) (Switch) - $39.99 
 
Deals:
 
Deemo (Switch) $39.99 - $19.99
Opus Collection (Switch) $39.99 - 19.99
Horizon Chase Turbo (First Print - PS4) $29.99 - $14.99
Hover (Switch) - $29.99 - $24.99
WILL: A Wonderful World Limited Edition (Plush, 120 page Artbook, etc) : $79.99 $69.99
WILL: A Wonderful World - Artbook: $29.99 - $24.99

Limited Run Games products:
Mercenaries Series Double Pack (PAX Exclusive): $69.99
Mercenaries Wings Limited Edition (PS4 - LRG) : $59.99
Mercenaries Wings Limited Edition (Switch - LRG): $59.99
Musynx First Print (Vita - LRG): $29.99
Deemo: The Last Recital (Vita - LRG): $29.99
  • -->




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    PrideStudios: Jack Andy and Riley Mitchel

    After finding out about their co-worker’s secret on-the-job fuck spot, Riley Mitchel and Jack Andy sneak away the first chance they can get to check it out for themselves. They agree it’s a perfect spot where no one else would think to look for them, and not wanting to be outdone by their co-worker, they... View Article

    The post PrideStudios: Jack Andy and Riley Mitchel appeared first on QueerClick.




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    NextDoorStudios: Dean Hughes

    Mmm take a look. Sexy Dean Hughes is oh so fine to look at. But we all know that casting is about more than looks, so let’s find out. Does Dean have what it takes to blow your load? What do you think, does he pass or fail? See more at NextDoorStudios.

    The post NextDoorStudios: Dean Hughes appeared first on QueerClick.




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    La EPA y los CDC publican guía para limpiar y desinfectar espacios donde viven, trabajan y juegan los estadounidenses

    WASHINGTON (29 de abril de 2020) —  Hoy, la Agencia de Protección Ambiental (EPA, por sus siglas en inglés) y los Centros para el Control y la Prevención de Enfermedades (CDC) publicaron una 




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    Trinitarios takedown nabs seven reputed high-ranking gang-bangers

    The defendants were linked in a 15-page Manhattan court filing with a cornucopia of crimes committed between 2010-19, from murder to robbery, wire fraud to kidnapping, and drug dealing to identity theft.




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    Judson Studios, oldest family-run stained-glass maker in the U.S., weathers the storm

    Coronavirus stay-at-home orders shut down Judson Studios for the first time in 123 years, just as a new book celebrates its storied stained glass.




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    Review: The cowboys of Compton, first a curiosity and then a legacy

    Walter Thompson-Hernández's "The Compton Cowboys: The New Generation of Cowboys in America's Urban Heartland" tells a grand story in granular detail.




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    Battered by coronavirus, L.A.'s legendary recording studios prep for a post-shutdown 'resurgence'

    Stars from the Doors to Prince recorded at Sunset Sound. Now, the studio is closed for the first time in 60 years, joining hundreds of others shuttered across L.A.




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    What's on TV Monday: 'Breeders' on FX; coronavirus; Axios

    What's on TV Monday, April 27: Season finale of 'Breeders' on FX; coronavirus; Axios returns; Movies on TV; TV Talk Shows; 'Dispatches From Elsewhere' season finale




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    Australian Open contingency scenarios revealed amid Rafael Nadal fears for 2020 season



    Rafael Nadal expressed his worry this week that there may not be any more tennis in 2020 due to the coronavirus pandemic.




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    IU President McRobbie gives 5 scenarios for fall 2020 semester

    While a return to full, in-person classes is unlikely, IU President Michael McRobbie outlined five possibilities for the fall semester.

           




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    O culto religioso que levou o coronavírus a cidade de MS

    Cerimônia religiosa com mais de 30 pessoas foi organizada para receber dupla vinda de Osasco (SP); dias depois, os dois testaram positivo para covid-19.




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    Coronavírus: estudo com coquetel de remédios tem bons resultados contra a covid-19, mostra The Lancet

    Em estudo clínico randomizado controlado, pessoas que receberam as substâncias interferon beta 1-b, lopinavir-ritonavir e ribavirin tiveram tempo menor para alta e desaparecimento do vírus, na comparação com o grupo controle.




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    Beta 3 of iOS 13.5, iPadOS 13.5, MacOS Catalina 10.15.5 Released for Testing

    Apple has released the third beta versions of iOS 13.5, iPadOS 13.5, and MacOS Catalina 10.15.5. Separately, watchOS 6.2.5 beta 3 and tvOS 13.4.5 beta 3 are also available for testing. The third beta versions of iOS 13.5 and iPadOS 13.5 are actually reversioned from iOS 13.4.5 and iPadOS 13.4.5, so if you were testing ... Read More




    ios

    Beta 4 of iOS 13.5 & iPadOS 13.5 Released for Testing

    Apple has released the fourth beta versions of iOS 13.5 and ipadOS 13.5. Additionally, Apple also released the fourth beta builds for watchOS 6.2.5 and tvOS 13.4.5. As of writing, macOS Catalina 10.5.5 beta 4 is not yet available for testing, but presumably will arrive soon as well. iOS 13.5 beta 4 and ipadOS 13.5 ... Read More




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    strataconf: A roundup of healthcare tools used in the field from #hdpalooza http://t.co/0d2x3OlaeC including @MedCPU @SVBiosystems @CHRankings & more

    strataconf: A roundup of healthcare tools used in the field from #hdpalooza http://t.co/0d2x3OlaeC including @MedCPU @SVBiosystems @CHRankings & more




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    Biosynthesis of depsipeptides with a 3-hydroxybenzoate moiety and selective anticancer activities involves a chorismatase [Metabolism]

    Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B–E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B–E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS–PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.




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    NAD+ biosynthesis in bacteria is controlled by global carbon/nitrogen levels via PII signaling [Microbiology]

    NAD+ is a central metabolite participating in core metabolic redox reactions. The prokaryotic NAD synthetase enzyme NadE catalyzes the last step of NAD+ biosynthesis, converting nicotinic acid adenine dinucleotide (NaAD) to NAD+. Some members of the NadE family use l-glutamine as a nitrogen donor and are named NadEGln. Previous gene neighborhood analysis has indicated that the bacterial nadE gene is frequently clustered with the gene encoding the regulatory signal transduction protein PII, suggesting a functional relationship between these proteins in response to the nutritional status and the carbon/nitrogen ratio of the bacterial cell. Here, using affinity chromatography, bioinformatics analyses, NAD synthetase activity, and biolayer interferometry assays, we show that PII and NadEGln physically interact in vitro, that this complex relieves NadEGln negative feedback inhibition by NAD+. This mechanism is conserved in distantly related bacteria. Of note, the PII protein allosteric effector and cellular nitrogen level indicator 2-oxoglutarate (2-OG) inhibited the formation of the PII-NadEGln complex within a physiological range. These results indicate an interplay between the levels of ATP, ADP, 2-OG, PII-sensed glutamine, and NAD+, representing a metabolic hub that may balance the levels of core nitrogen and carbon metabolites. Our findings support the notion that PII proteins act as a dissociable regulatory subunit of NadEGln, thereby enabling the control of NAD+ biosynthesis according to the nutritional status of the bacterial cell.




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    Sir David Attenborough and the BBC Studios Natural History Unit awarded Chatham House Prize 2019 for ocean advocacy

    19 November 2019

    The 2019 Chatham House Prize is awarded to Sir David Attenborough and Julian Hector, head of BBC Studios Natural History Unit, for the galvanizing impact of the Blue Planet II series on tackling ocean plastic pollution.

    The Chatham House Prize is awarded to the person, persons or organization who is deemed to have made the most significant contribution to the improvement of international relations in the previous year. The presentation ceremony and panel discussion with the winners will be livestreamed on Wednesday.

    The Blue Planet II series highlighted the damage caused by discarded plastics to the world’s oceans and marine wildlife. It is estimated that there are more than 150 million tonnes of plastic in the world’s oceans; resulting in the deaths of 1 million birds and 100,000 sea mammals each year. 

    Dr Robin Niblett, director of Chatham House said: ‘Plastic pollution is one of the gravest challenges facing the world’s oceans, and undoubtedly an international issue. Sir David and the BBC Studios Natural History Unit played an instrumental role in helping to put this issue at the forefront of the public agenda. Blue Planet II spurred a passionate global response and generated clear behavioural and policy change.’

    This year the G20 agreed on an international framework to address marine plastic litter, acknowledging the increasing urgency of the issue and the need for an international solution. This follows action from the UK government, including a plan to ban common plastic items and investment in global research.

    See full award citation

    Read more about Chatham House's research work in this area

    Other nominees

    Dr Niblett thanked Chatham House members for voting and acknowledged the outstanding achievements of the 2019 nominees:

    Abiy Ahmed, prime minister of Ethiopia, nominated for his efforts to transform civic leadership and promote plural politics, free speech and peace in Ethiopia 

    Katrín Jakobsdóttir, prime minister of Iceland, nominated for her commitment to gender equality and women’s financial inclusion in Iceland 

    Event

    The Prize was presented to Sir David and Julian Hector by Her Majesty The Queen at Chatham House on Wednesday 20 November.

    Watch video from the event

    For more information please contact

    Chatham House Press Office
    pressoffice@chathamhouse.org
    +44 (0)207 957 5739

    BBC Studios Natural History Unit Communications Manager
    Lynn.li@bbc.co.uk
    +44 (0) 7513 137893

    About the Chatham House Prize

    The Chatham House Prize is voted for by Chatham House members, following nominations from the institute’s staff. The award is presented on behalf of the institute's patron, Her Majesty the Queen, representing the non-partisan and authoritative character of the Prize.

    The Chatham House Prize was launched in 2005. Previous recipients of the Prize include the Committee to Protect Journalists, Colombian president Juan Manuel Santos, president of Ghana John Kufuor, Médecins Sans Frontières and Melinda Gates, co-founder of the Bill and Melinda Gates Foundation.

    Chatham House is a world-leading policy institute based in London. Our mission is to help governments and societies build a sustainably secure, prosperous and just world. We engage governments, the private sector, civil society and our members in open debate and private discussions about the most significant developments in international affairs.  Our research and policy ideas involve rigorous analysis of critical global, regional and country-specific challenges and opportunities.

    About BBC Studios Natural History Unit 

    BBC Studios Natural History Unit produces the world’s most iconic natural history programmes, such as Blue Planet II and Planet Earth II, which have been watched by more than a billion people globally. Ranging from technically challenging live shows and super-landmarks to long-running series and children’s content, The Natural History Unit programmes include Dynasties, Blue Planet Live, Springwatch, Animal Babies: First Year On Earth, Andy’s Dinosaur Adventures as well as the currently on air Seven Worlds, One Planet presented by Sir David Attenborough and third-party commissions for Discovery, Apple, Quibi, National Geographic and BBC America. 

    The Natural History Unit is part of BBC Studios, a subsidiary of the BBC, which develops, produces and distributes bold, British content, making over 2,500 hours of content each year, operating in 22 markets globally and generating revenue of around £1.4bn. In the year to March 2019, it returned £243m to the BBC Group, complementing the BBC’s licence fee and enhancing programmes for UK audiences.




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    Biosecurity: Preparing for the Aftermath of Global Health Crises

    9 January 2020

    Professor David R Harper CBE

    Senior Consulting Fellow, Global Health Programme

    Benjamin Wakefield

    Research Associate, Global Health Programme
    The Ebola outbreak in the Democratic Republic of the Congo is a reminder that the security of samples taken during global health emergencies is a vital part of safeguarding biosecurity.

    2020-01-09-DRC.jpg

    A nurse prepares a vaccine against Ebola in Goma in August 2019. Photo: Getty Images.

    The world’s second-largest Ebola outbreak is ongoing in the Democratic Republic of the Congo (DRC) and experts from around the world have been parachuted in to support the country’s operation to stamp out the outbreak. The signs are encouraging, but we need to remain cautious.

    In such emergencies, little thought is usually given to what happens to the body-fluid samples taken during the course of the outbreak after the crisis is over. What gets left behind has considerable implications for global biosecurity.

    Having unsecured samples poses the obvious risk of accidental exposures to people who might come into contact with them, but what of the risk of malicious use? Bioterrorists would have ready access to materials that have the characteristics essential to their purpose: the potential to cause disease that is transmissible from person to person, the capacity to result in high fatality rates and, importantly, the ability to cause panic and social disruption at the very mention of them.

    Comparisons can be drawn with the significant international impact of the anthrax attacks in the US in 2001. Not only was there a direct effect in the US with five deaths and a further 17 people infected, but there was a paralysis of public health systems in other countries involved in the testing of countless samples from the so-called ‘white-powder incidents’ that followed.

    Many laboratory tests were done purely on a precautionary basis to eliminate any possibility of a risk, no matter how remote. However, the UK was also hit when a hoaxer sent envelopes of white powder labelled as anthrax to 15 MPs.

    The threat of the pathogen alone resulted in widespread fear, the deployment of officers trained in response to chemical, biological, radiological and nuclear incidents and the evacuation of a hospital emergency department.

    We learned from the 2014–16 West Africa Ebola outbreaks that during the emergency, the future biosecurity implications of the many thousands of samples taken from people were given very little consideration. It is impossible to be sure where they all are and whether they have been secured.

    It is widely recognized that the systems needed at the time for tracking and monitoring resources, including those necessary for samples, were weak or absent, and this has to be addressed urgently along with other capacity-building initiatives.

    In Sierra Leone, for example, the remaining biosecurity risk is only being addressed after the fact. To help achieve this, the government of Canada is in the process of providing a secure biobank in the Sierra Leonean capital of Freetown. The aim is to provide the proper means of storage for these hazardous samples and to allow them to remain in-country, with Sierra Leonean ownership.

    However, it is already more three years since the emergency was declared over by the then director-general of the World Health Organization (WHO), Margaret Chan, and the biobank and its associated laboratory are yet to be fully operational.

    There are many understandable reasons for this delay, including the critical issue of how best to ensure the sustainability of any new facility. But what is clear is that these solutions take time to implement and must be planned for in advance.

    The difficulties of responding to an outbreak in a conflict zone have been well documented, and the frequent violence in DRC has undoubtedly caused delays in controlling the outbreak. According to figures from WHO, during 2019 approximately 390 attacks on health facilities in DRC killed 11 and injured 83 healthcare workers and patients.

    Not only does the conflict inhibit the response, but it could also increase the risk posed by unsecured samples. There are two main potential concerns.

    First is the risk of accidental release during an attack on a health facility, under which circumstances sample containers may be compromised or destroyed. Second is that the samples may be stolen for malicious use or to sell them to a third-party for malicious use. It is very important in all outbreaks to ensure the necessary measures are in place to secure samples; in conflict-affected areas, this is particularly challenging.

    The sooner the samples in the DRC are secured, the sooner this risk to global biosecurity is reduced. And preparations for the next emergency must be made without further delay.

    The following steps need to be taken:

    • Affected countries must ‘own’ the problem, with clear national government commitment to take the required actions.
    • Funding partners must coordinate their actions and work closely with the countries to find the best solutions.
    • If samples are to be kept in-country, secure biobanks must be established to contain them.
    • Sustainable infrastructure must be built for samples to be kept secure into the future.
    • An international agreement should be reached on the best approach to take to prepare for the aftermath of global health emergencies.




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    NAD+ biosynthesis in bacteria is controlled by global carbon/nitrogen levels via PII signaling [Microbiology]

    NAD+ is a central metabolite participating in core metabolic redox reactions. The prokaryotic NAD synthetase enzyme NadE catalyzes the last step of NAD+ biosynthesis, converting nicotinic acid adenine dinucleotide (NaAD) to NAD+. Some members of the NadE family use l-glutamine as a nitrogen donor and are named NadEGln. Previous gene neighborhood analysis has indicated that the bacterial nadE gene is frequently clustered with the gene encoding the regulatory signal transduction protein PII, suggesting a functional relationship between these proteins in response to the nutritional status and the carbon/nitrogen ratio of the bacterial cell. Here, using affinity chromatography, bioinformatics analyses, NAD synthetase activity, and biolayer interferometry assays, we show that PII and NadEGln physically interact in vitro, that this complex relieves NadEGln negative feedback inhibition by NAD+. This mechanism is conserved in distantly related bacteria. Of note, the PII protein allosteric effector and cellular nitrogen level indicator 2-oxoglutarate (2-OG) inhibited the formation of the PII-NadEGln complex within a physiological range. These results indicate an interplay between the levels of ATP, ADP, 2-OG, PII-sensed glutamine, and NAD+, representing a metabolic hub that may balance the levels of core nitrogen and carbon metabolites. Our findings support the notion that PII proteins act as a dissociable regulatory subunit of NadEGln, thereby enabling the control of NAD+ biosynthesis according to the nutritional status of the bacterial cell.




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    A single amino acid substitution uncouples catalysis and allostery in an essential biosynthetic enzyme in Mycobacterium tuberculosis [Enzymology]

    Allostery exploits the conformational dynamics of enzymes by triggering a shift in population ensembles toward functionally distinct conformational or dynamic states. Allostery extensively regulates the activities of key enzymes within biosynthetic pathways to meet metabolic demand for their end products. Here, we have examined a critical enzyme, 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS), at the gateway to aromatic amino acid biosynthesis in Mycobacterium tuberculosis, which shows extremely complex dynamic allostery: three distinct aromatic amino acids jointly communicate occupancy to the active site via subtle changes in dynamics, enabling exquisite fine-tuning of delivery of these essential metabolites. Furthermore, this allosteric mechanism is co-opted by pathway branchpoint enzyme chorismate mutase upon complex formation. In this study, using statistical coupling analysis, site-directed mutagenesis, isothermal calorimetry, small-angle X-ray scattering, and X-ray crystallography analyses, we have pinpointed a critical node within the complex dynamic communication network responsible for this sophisticated allosteric machinery. Through a facile Gly to Pro substitution, we have altered backbone dynamics, completely severing the allosteric signal yet remarkably, generating a nonallosteric enzyme that retains full catalytic activity. We also identified a second residue of prime importance to the inter-enzyme communication with chorismate mutase. Our results reveal that highly complex dynamic allostery is surprisingly vulnerable and provide further insights into the intimate link between catalysis and allostery.




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    Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

    Chi-Liang Eric Yen
    Nov 1, 2008; 49:2283-2301
    Thematic Reviews




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    Negative Emissions and Managing Climate Risks Scenarios

    Research Event

    4 July 2019 - 1:30pm to 5:00pm

    Chatham House | 10 St James's Square | London | SW1Y 4LE

    This half-day strategic workshop, organized by Chatham House and E3G, brought together key climate experts, policymakers and influential actors, especially in Europe, for a focused and facilitated discussion on the roles, risks and potentials of negative emissions technologies (NETs). 

    An interactive scenario exercise will be conducted, drawing on a climate simulation tool developed by Climate Interactive, to consider the potential roles and risks of different NETs deployments to meet the Paris Agreement targets and to consider the international co-operation required to manage the pathway to net-zero emissions. Participants will explore the political opportunities, discuss different scenarios and risks and identify areas of interventions and collective action.

    The meeting is part of a series of events being held at Chatham House as part of London Climate Action Week (LCAW).




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    Biosecurity: Preparing for the Aftermath of Global Health Crises

    9 January 2020

    Professor David R Harper CBE

    Senior Consulting Fellow, Global Health Programme

    Benjamin Wakefield

    Research Associate, Global Health Programme
    The Ebola outbreak in the Democratic Republic of the Congo is a reminder that the security of samples taken during global health emergencies is a vital part of safeguarding biosecurity.

    2020-01-09-DRC.jpg

    A nurse prepares a vaccine against Ebola in Goma in August 2019. Photo: Getty Images.

    The world’s second-largest Ebola outbreak is ongoing in the Democratic Republic of the Congo (DRC) and experts from around the world have been parachuted in to support the country’s operation to stamp out the outbreak. The signs are encouraging, but we need to remain cautious.

    In such emergencies, little thought is usually given to what happens to the body-fluid samples taken during the course of the outbreak after the crisis is over. What gets left behind has considerable implications for global biosecurity.

    Having unsecured samples poses the obvious risk of accidental exposures to people who might come into contact with them, but what of the risk of malicious use? Bioterrorists would have ready access to materials that have the characteristics essential to their purpose: the potential to cause disease that is transmissible from person to person, the capacity to result in high fatality rates and, importantly, the ability to cause panic and social disruption at the very mention of them.

    Comparisons can be drawn with the significant international impact of the anthrax attacks in the US in 2001. Not only was there a direct effect in the US with five deaths and a further 17 people infected, but there was a paralysis of public health systems in other countries involved in the testing of countless samples from the so-called ‘white-powder incidents’ that followed.

    Many laboratory tests were done purely on a precautionary basis to eliminate any possibility of a risk, no matter how remote. However, the UK was also hit when a hoaxer sent envelopes of white powder labelled as anthrax to 15 MPs.

    The threat of the pathogen alone resulted in widespread fear, the deployment of officers trained in response to chemical, biological, radiological and nuclear incidents and the evacuation of a hospital emergency department.

    We learned from the 2014–16 West Africa Ebola outbreaks that during the emergency, the future biosecurity implications of the many thousands of samples taken from people were given very little consideration. It is impossible to be sure where they all are and whether they have been secured.

    It is widely recognized that the systems needed at the time for tracking and monitoring resources, including those necessary for samples, were weak or absent, and this has to be addressed urgently along with other capacity-building initiatives.

    In Sierra Leone, for example, the remaining biosecurity risk is only being addressed after the fact. To help achieve this, the government of Canada is in the process of providing a secure biobank in the Sierra Leonean capital of Freetown. The aim is to provide the proper means of storage for these hazardous samples and to allow them to remain in-country, with Sierra Leonean ownership.

    However, it is already more three years since the emergency was declared over by the then director-general of the World Health Organization (WHO), Margaret Chan, and the biobank and its associated laboratory are yet to be fully operational.

    There are many understandable reasons for this delay, including the critical issue of how best to ensure the sustainability of any new facility. But what is clear is that these solutions take time to implement and must be planned for in advance.

    The difficulties of responding to an outbreak in a conflict zone have been well documented, and the frequent violence in DRC has undoubtedly caused delays in controlling the outbreak. According to figures from WHO, during 2019 approximately 390 attacks on health facilities in DRC killed 11 and injured 83 healthcare workers and patients.

    Not only does the conflict inhibit the response, but it could also increase the risk posed by unsecured samples. There are two main potential concerns.

    First is the risk of accidental release during an attack on a health facility, under which circumstances sample containers may be compromised or destroyed. Second is that the samples may be stolen for malicious use or to sell them to a third-party for malicious use. It is very important in all outbreaks to ensure the necessary measures are in place to secure samples; in conflict-affected areas, this is particularly challenging.

    The sooner the samples in the DRC are secured, the sooner this risk to global biosecurity is reduced. And preparations for the next emergency must be made without further delay.

    The following steps need to be taken:

    • Affected countries must ‘own’ the problem, with clear national government commitment to take the required actions.
    • Funding partners must coordinate their actions and work closely with the countries to find the best solutions.
    • If samples are to be kept in-country, secure biobanks must be established to contain them.
    • Sustainable infrastructure must be built for samples to be kept secure into the future.
    • An international agreement should be reached on the best approach to take to prepare for the aftermath of global health emergencies.




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