The transfer of a phosphate from ATP to a protein substrate, a modification known as protein phosphorylation, is catalyzed by protein kinases. Protein kinases play a crucial role in virtually every cellular activity. Recent studies of atypical protein kinases have highlighted the structural similarity of the kinase superfamily despite notable differences in primary amino acid sequence. Here, using a bioinformatics screen, we searched for putative protein kinases in the intracellular bacterial pathogen Legionella pneumophila and identified the type 4 secretion system effector Lpg2603 as a remote member of the protein kinase superfamily. Employing an array of biochemical and structural biology approaches, including in vitro kinase assays and isothermal titration calorimetry, we show that Lpg2603 is an active protein kinase with several atypical structural features. Importantly, we found that the eukaryote-specific host signaling molecule inositol hexakisphosphate (IP6) is required for Lpg2603 kinase activity. Crystal structures of Lpg2603 in the apo-form and when bound to IP6 revealed an active-site rearrangement that allows for ATP binding and catalysis. Our results on the structure and activity of Lpg2603 reveal a unique mode of regulation of a protein kinase, provide the first example of a bacterial kinase that requires IP6 for its activation, and may aid future work on the function of this effector during Legionella pathogenesis.

If you google "The NHS" you'll see screaming headlines from the Daily Mail about cost and waste - debate in parliament is about how much of our GDP we should be spending - and each year, hospital trusts go cap in hand to ask for more funding. Against this backdrop, a new analysis, and a first in a series, published on bmj.com, looks at what it...

Looking after a young child is hard enough, but when that child has learning difficulties and displays challenging behaviour - the burden on parents can be extreme. That behaviour may prompt a visit to the doctor, and in this podcast we’re talking about how parents can be supported in that - what services are available. We’ll also be discussing...

R A DeFronzo
Dec 1, 1981; 30:1000-1007
Original Contribution

Thomas A. Buchanan
Sep 1, 2002; 51:2796-2803
Pathophysiology

This study aims to model genetic, immunologic, metabolomics, and proteomic biomarkers for development of islet autoimmunity (IA) and progression to type 1 diabetes in a prospective high-risk cohort. We studied 67 children: 42 who developed IA (20 of 42 progressed to diabetes) and 25 control subjects matched for sex and age. Biomarkers were assessed at four time points: earliest available sample, just prior to IA, just after IA, and just prior to diabetes onset. Predictors of IA and progression to diabetes were identified across disparate sources using an integrative machine learning algorithm and optimization-based feature selection. Our integrative approach was predictive of IA (area under the receiver operating characteristic curve [AUC] 0.91) and progression to diabetes (AUC 0.92) based on standard cross-validation (CV). Among the strongest predictors of IA were change in serum ascorbate, 3-methyl-oxobutyrate, and the PTPN22 (rs2476601) polymorphism. Serum glucose, ADP fibrinogen, and mannose were among the strongest predictors of progression to diabetes. This proof-of-principle analysis is the first study to integrate large, diverse biomarker data sets into a limited number of features, highlighting differences in pathways leading to IA from those predicting progression to diabetes. Integrated models, if validated in independent populations, could provide novel clues concerning the pathways leading to IA and type 1 diabetes.

Invitation Only Research Event

Event participants

Paula Hodges QC, Partner; Head, Global Arbitration Practice, Herbert Smith Freehills
Stéphane Brabant, Partner; Chairman, Africa Practice Group, Herbert Smith Freehills

Invitation Only Research Event

Research Event

Event participants

Toby Fisher, Barrister, Landmark Chambers; Representative of the South African Human Rights Commission, Marikana Commission of Inquiry
Gary White, Director of Operations, Ineqe Group; Expert Witness on Policing, Marikana Commission of Inquiry
Chair: Muzong Kodi, Associate Fellow, Africa Programme

5 November 2019

This ethnographic study is the first of its kind to analyse energy access and resilience strategies deployed in two refugee camps in Kenya and Burkina Faso. It highlights the need for new methodological approaches to expand the evidence base for humanitarian energy interventions and policies.

Cas12a (Cpf1) is an RNA-guided endonuclease in the bacterial type V-A CRISPR-Cas anti-phage immune system that can be repurposed for genome editing. Cas12a can bind and cut dsDNA targets with high specificity in vivo, making it an ideal candidate for expanding the arsenal of enzymes used in precise genome editing. However, this reported high specificity contradicts Cas12a's natural role as an immune effector against rapidly evolving phages. Here, we employed high-throughput in vitro cleavage assays to determine and compare the native cleavage specificities and activities of three different natural Cas12a orthologs (FnCas12a, LbCas12a, and AsCas12a). Surprisingly, we observed pervasive sequence-specific nicking of randomized target libraries, with strong nicking of DNA sequences containing up to four mismatches in the Cas12a-targeted DNA-RNA hybrid sequences. We also found that these nicking and cleavage activities depend on mismatch type and position and vary with Cas12a ortholog and CRISPR RNA sequence. Our analysis further revealed robust nonspecific nicking of dsDNA when Cas12a is activated by binding to a target DNA. Together, our findings reveal that Cas12a has multiple nicking activities against dsDNA substrates and that these activities vary among different Cas12a orthologs.

Nearly 6 million Afghans fled after violence erupted in the late 1970s, primarily to Iran and Pakistan. While millions returned after the collapse of the Taliban in 2001, the security situation has since deteriorated and the government struggles to meet the needs of vulnerable populations, particularly the internally displaced. This country profile explores Afghanistan’s complex migration and displacement history as well as ongoing challenges.

With nearly 1.4 million internally displaced persons (IDPs), Ukraine is home to one of the largest IDP populations in the world. Five years after Russia's annexation of Crimea, displaced Ukrainians continue to face challenges related to national identity, social cohesion, and political participation. While the Ukrainian government has had some success integrating IDPs, the conflict’s end remains uncertain, and many are unlikely to return to their communities of origin no matter the outcome.

From earthquakes to drought, natural disasters and climate change played a key role in migration flows in 2015. Climate-induced migration surfaced as a concern at the United Nations Climate Change Conference (known as COP21) as international organizations and policymakers have begun to recognize the growing challenges, and potential protection obligations, of such movement.

Climate-related displacement is not hypothetical: An average of 21.5 million people per year have been displaced since 2008 by natural disasters, and thousands more have fled slow-onset environmental hazards. While migration can serve as a safety valve to adapt to changing conditions, few orderly, legal channels exist for climate migrants (also known as environmental migrants), as this article explores.

Edward A. Chow
Jul 1, 2012; 30:130-133
Diabetes Advocacy

Katherine M Flegal
Jul 1, 1991; 14:628-638
Supplement 3: Diabetes in Hispanic Americans

Being female is a risk factor for Alzheimer’s. Why?

-- Read more on ScientificAmerican.com

Shortly after the Sept. 11, 2001, attacks, psychologist Jennifer Lerner conducted a national field experiment: She asked a random sampling of Americans how likely it was that they would be the victim of a terrorist attack in the next 12 months.

Six million immigrant workers are at the frontlines of keeping U.S. residents healthy and fed during the COVID-19 pandemic, representing disproportionate shares of physicians, home health aides, and retail-store pharmacists, for example. They also are over-represented in sectors most immediately devastated by mass layoffs, yet many will have limited access to safety-net systems and to federal relief, as this fact sheet details.

WASHINGTON — Six million immigrant workers are at the frontlines of keeping U.S. residents healthy, safe and fed during the COVID-19 pandemic, according to a Migration Policy Institute (MPI) analysis of U.S. Census Bureau data issued today. While the foreign born represented 17 percent of the 156 million civilians working in 2018, they account for larger shares in pandemic-response frontline occupations: 29 percent of all physicians in the United States, 38 percent of home health aides and 23 percent of retail-store pharmacists, for example.

This recipe was featured on Foodie Tuesday, a weekly segment with Raf Epstein on Drive, 774 ABC Melbourne, 3:30 PM, courtesy of George Calombaris. George's new book is called "Greek."

4 salmon fillets, skin on (175g per portion) 2 tbs soy sauce 1 tbs rice wine vinegar 1 tbs olive oil 1 clove garlic, minced 1 tbs ginger, mined 1 small red chilli 1 lime, juiced

Salmon with a twist.

Love this time of year where our makers are abundant with the sweet aroma of fresh basil . Here is my take on a fancy potato salad of macadamia pesto , crispy prosciutto, sweet cherry tomatoes

Delicious summer tuna dish.

Edward A. Chow
Jul 1, 2012; 30:130-133
Diabetes Advocacy

Ohio is seeking to recoup millions of dollars in funds from now-defunct online charter school, the Electronic Classroom of Tomorrow.

Ohio's attorney general last week filed suit against the founder of the Electronic Classroom of Tomorrow, aiming to recover millions of dollars in public funding that the state claims wrongfully went to the cyber charter school.

The supreme court put an end to five years of legal wrangling that landed the state's public school system with millions more dollars from the state and teachers with a pay raise.

Minister for Asylum Deterrence & Foreign Investment, Peter Ruddick, is en route to the remote Pulcherrima Island, the site of his latest privately-run, fast food chain-inspired detention centre. But chaos ensues when Peter misses his connecting flight and finds himself confined to the visa-free zone of the Turgrael airport, without a business lounge in sight.

Common good.

A new report has found Indiana's school voucher program ran up a $53.2 million deficit, but backers of the program say it actually represents a net savings to taxpayers.

Birmingham : printed by M. Billing, 1847.

Marburg : Elwert'sche, 1879.

Leipzig : F.C.W. Vogel, 1889.

Lipsiae : Sumtibus Baumgaertneri, 1829.

Argentorati : Sumtibus Amandi Koenig, 1786-1787.

London : J. & A. Churchill, 1875.

Halifax : Milner and Sowerby, 1856.

Halifax : Milner and Sowerby, 1860.

London : printed for A. Strahan, T. Cadell, 1790.

London : And J. Balfour, and W. Creech, Edinburgh, 1791.

London : printed for A. Strahan and T. Cadell, London, 1794.