Peptidyl arginine deiminase 4 (PAD4/PADI4) is a posttranslational modification enzyme that converts protein arginine or mono-methylarginine to citrulline. The PAD4-mediated hypercitrullination reaction in neutrophils causes the release of nuclear chromatin to form a chromatin network termed neutrophil extracellular traps (NET). NETs were first described as antimicrobial fibers that bind and kill bacteria. However, it is not known whether PAD4 can mediate the release of chromatin DNA into the extracellular space of cancer cells. Here, we report that murine breast cancer 4T1 cells expressing high levels of PADI4 can release cancer extracellular chromatin networks (CECN) in vitro and in vivo. Deletion of Padi4 using CRISPR/Cas9 abolished CECN formation in 4T1 cells. Padi4 deletion from 4T1 cells also reduced the rate of tumor growth in an allograft model, and decreased lung metastasis by 4T1 breast cancers. DNase I treatment, which degrades extracellular DNA including CECNs, also reduced breast to lung metastasis of Padi4 wild-type 4T1 cells in allograft experiments in the Padi4-knockout mice. We further demonstrated that DNase I treatment in this mouse model did not alter circulating tumor cells but decreased metastasis through steps after intravasation. Taken together, our genetic studies show that PAD4 plays a cell autonomous role in cancer metastasis, thus revealing a novel strategy for preventing cancer metastasis by inhibiting cancer cell endogenous PAD4.

Background and objectives

The effects of active case finding (ACF) models that mobilise community networks for early identification and treatment of tuberculosis (TB) remain unknown. We investigated and compared the effect of community-based ACF using a seed-and-recruit model with one-off roving ACF and passive case finding (PCF) on the time to treatment initiation and identification of bacteriologically confirmed TB.

Impaired insulin secretion from the pancreatic β-cells is central in the pathogenesis of type 2 diabetes (T2D), and microRNAs (miRNAs) are fundamental regulatory factors in this process. Differential expression of miRNAs contributes to β-cell adaptation to compensate for increased insulin resistance, but deregulation of miRNA expression can also directly cause β-cell impairment during the development of T2D. miRNAs are small noncoding RNAs that posttranscriptionally reduce gene expression through translational inhibition or mRNA destabilization. The nature of miRNA targeting implies the presence of complex and large miRNA–mRNA regulatory networks in every cell, including the insulin-secreting β-cell. Here we exemplify one such network using our own data on differential miRNA expression in the islets of T2D Goto-Kakizaki rat model. Several biological processes are influenced by multiple miRNAs in the β-cell, but so far most studies have focused on dissecting the mechanism of action of individual miRNAs. In this Perspective we present key islet miRNA families involved in T2D pathogenesis including miR-200, miR-7, miR-184, miR-212/miR-132, and miR-130a/b/miR-152. Finally, we highlight four challenges and opportunities within islet miRNA research, ending with a discussion on how miRNAs can be utilized as therapeutic targets contributing to personalized T2D treatment strategies.

Martha Wells's action-packed novel Network Effect puts you inside the head of a Murderbot. It raises fascinating questions you will think about for a long time, says Sally Adee

Expect expansion plans by the graphics card giant

A new study y reveals surprising findings about the function of circadian network neurons that undergo daily structural change. The research could lead to a better understanding of how to address circadian rhythm disruptions in humans and facilitate preventing a host of associated health problems, including increased risk for cancer and metabolic syndrome.

Chinese telecoms company Huawei has defended its role in the development of 5G in the UK and said disrupting its involvement would "do Britain a disservice".

Hundreds of O2 and Vodafone customers have reported problems with the networks.

Stop the fights over the connection with these tips

With over two million farmers on the platform, WeFarm has an essential place in the food supply chain

People don't talk enough about death and Untangle wants to change that

The app now counts 1.6 million users

OnlyFans recently received a nice bout of publicity thanks to Beyoncé

Historian Tony Comer says it is ‘a small insight into the real people behind the machinery of war’.

Trump's decision to air the selectively edited video clips led major US television networks to quickly cut away from his daily coronavirus briefing. 

Neither of the major football codes seem likely to emerge from the coronavirus outlook unscathed and nor do the free-to-air television networks that broadcast their matches.

The NRL announces it expects to restart the premiership season late next month, while the league comes under attack from one of its broadcast partners, who says it has "squandered" its finances.

Building upon the successes of earlier efforts, the Department today announced the opening in Bangkok of a regional conference of approximately 100 key law enforcement and industry officials from more than a dozen nations with the goal of strengthening international cooperation in fighting large-scale intellectual property crimes.

Christine A. Varney, Assistant Attorney General in charge of the Department’s Antitrust Division, will participate in the eighth annual International Competition Network (ICN) conference in Zurich, Switzerland, from June 3-5, 2009. At the conference, senior government antitrust officials, private-sector antitrust experts from around the world, and representatives from intergovernmental organizations will meet to discuss competition issues.

At the eighth annual International Competition Network (ICN) conference in Zurich, Switzerland, the ICN adopted new Recommended Practices for substantive merger analysis and presented two new reports on the analysis of tying and bundled discounting and loyalty discounts and rebates under unilateral conduct laws.

The former director of information technology for a non-profit organ and tissue donation center was sentenced today to two years in prison for hacking into her former employer’s computer network.

Albert Gonzalez, 28, of Miami, Fla., was indicted today for conspiring to hack into computer networks supporting major American retail and financial organizations, and stealing data relating to more than 130 million credit and debit cards. Among the corporate victims named in the indictment are Heartland Payment Systems, a New Jersey-based card payment processor; 7-Eleven Inc., a Texas-based nationwide convenience store chain; and Hannaford Brothers Co. Inc., a Maine-based supermarket chain.

An international computer hacker pleaded guilty today to multiple charges relating to hacking activity and credit card fraud. More than 40 million credit and debit card numbers were stolen from major U.S. retailers as a result of the hacking activity. Albert Gonzalez, 28, of Miami, pleaded guilty today to 19 counts of conspiracy, computer fraud, wire fraud, access device fraud and aggravated identity theft relating to hacks into numerous major U.S. retailers.

Albert Gonzalez pleaded guilty to conspiracy to gain unauthorized access to the payment card networks operated by, among others, Heartland Payment Systems, 7-Eleven and Hannaford Brothers Co. Inc.

Albert Gonzalez, of Miami, the leader of the largest hacking and identity theft ring ever prosecuted by the U.S. government, has been sentenced to 20 years and one day in prison for his role in a series of hacks into a major payment processor and several retail networks.

Christine Varney, Assistant Attorney General in charge of the Antitrust Division, will participate in the ninth annual International Competition Network (ICN) conference in Istanbul, Turkey, from April 27-29, 2010.

Operation Network Raider, a domestic and international enforcement initiative targeting the illegal distribution of counterfeit network hardware manufactured in China, has resulted in 30 felony convictions and more than 700 seizures of counterfeit Cisco network hardware and labels with an estimated retail value of more than $143 million.

"I’m proud that, for the first time, the Department is directing resources for the express purpose of reducing childhood exposure to violence and raising awareness of its ramifications, advancing scientific inquiry on its causes and characteristics, and, of course, countering its negative impact," said Attorney General Holder.

"The progress made in 20 years is remarkable. But our anniversary celebration must be marked by turning our attention to the next 20 years so that we can continue to create a nation where every individual has access to equal opportunity and equal justice," said Assistant Attorney General Thomas E. Perez

Steven Jinwoo Kim, 40, of Houston pleaded guilty on Nov. 16, 2009, to one count of intentionally accessing a protected computer without authorization and recklessly causing damage.

A Philadelphia man has pleaded guilty for his role in organizing and financing a network of high-tech, indoor marijuana grow facilities stretching from Florida to Connecticut.

The Justice Department today announced the settlement of a lawsuit filed to enforce the Americans with Disabilities Act (ADA) against Nobel Learning Communities, Inc. (NLC), a private, for-profit entity that operates a nationwide network of more than 180 preschools, elementary schools and secondary schools.

"...for two decades now, the National Action Network has been on the front lines of our nation’s fight to ensure security, opportunity, and justice for all. Today, this work goes on in your demands to those in power and in your aspirations for those in need."

Department of Justice Antitrust Division officials will participate in the 10th annual International Competition Network (ICN) conference in The Hague, The Netherlands, from May 18-20, 2011.

At its 10th annual conference in The Hague, the Netherlands, the International Competition Network (ICN) adopted new materials on how to assess market dominance, resolve cartel cases and manage competition projects effectively.

Chun-Yu Zhao, of Centreville, Va., and Donald H. Cone, of Frederick, Md., were convicted by a federal jury in Alexandria, Va., for their roles in a sophisticated scheme to import and sell counterfeit Cisco-branded computer networking equipment.

Seven individuals and five corporate entities based in the United States, France, the United Arab Emirates (U.A.E.) and Iran have been indicted in the Middle District of Georgia for their alleged roles in a conspiracy to illegally export military components for fighter jets and attack helicopters from the United States to Iran.

Attorney General Holder and Department of Homeland Security (DHS) Secretary Napolitano announced today the unsealing of three indictments and one complaint charging a total of 72 individuals for their participation in an international criminal network dedicated to the sexual abuse of children and the creation and dissemination of graphic images and videos of child sexual abuse throughout the world.

Donald H. Cone, 48, of Frederick, Md., was sentenced today in Alexandria, Va., to 30 months in prison for his role in a sophisticated conspiracy to import and sell counterfeit Cisco-branded computer networking equipment.

A Virginia woman was sentenced today to 60 months in prison for leading a sophisticated conspiracy to import and to sell counterfeit Cisco-branded computer networking equipment, laundering criminal proceeds and obtaining her citizenship through fraud.

"Although 44 years have passed since our nation first mourned the loss of Dr. King, it is clear that his spirit lives on. His enduring contributions have allowed me to stand on this stage as our nation’s first African-American Attorney General, and to serve alongside our first African-American President. And the dream that he shared – on the National Mall that now includes a memorial in his honor – has inspired countless acts of compassion and collaboration, including the creation of the National Action Network more than two decades ago," said Attorney General Holder.

The International Competition Network (ICN) launched and approved three new initiatives on international enforcement cooperation, the investigative process in competition cases and working with the courts.

John Wyss, aka “Bones,” 55, of Monroe, Wis., was found guilty of one count of engaging in a child exploitation enterprise, one count of conspiracy to advertise child pornography and one count of conspiracy to distribute child pornography.

"In the Civil Rights Division, we still see every single day barriers facing individuals with disabilities that stand in the way of allowing all people to maximize the contribution they can make to society," said Assistant Attorney General Perez.

John Wyss, aka “Bones,” 55, of Monroe, Wis., was sentenced by U.S. District Judge Maurice Hicks in the Western District of Louisiana.

A Massachusetts man was sentenced today to serve 45 years in prison for his participation in an international criminal network, known as Dreamboard, dedicated to the sexual abuse of children and the creation and dissemination of graphic images and videos of child sexual abuse throughout the world.

The company that operates Path, an online social networking application, agreed to pay an $800,000 penalty to settle charges that it violated the Federal Trade Commission (FTC) Act and the Children’s Online Privacy Protection Rule.

"I promised them I would never forget – just as I know you have not forgotten. On this, of all nights, let us dedicate ourselves, as Dr. King would expect us to do, to this new struggle," said Attorney General Holder.

The International Competition Network advanced convergence through important initiatives on international enforcement cooperation and investigative processes in competition cases.