Porcine reproductive and respiratory syndrome (PRRS) is a serious viral disease affecting the global swine industry. Its causative agent, PRRS virus (PRRSV), is an enveloped virus, and therefore membrane fusion between its envelope and host cell target membrane is critical for viral infection. Though much research has focused on PRRSV infection, the detailed mechanisms involved in its membrane fusion remain to be elucidated. In the present study, we performed confocal microscopy in combination with a constitutively active (CA) or dominant negative (DN) mutant, specific inhibitors, and small interfering RNAs (siRNAs), as well as multiple other approaches, to explore PRRSV membrane fusion. We first observed that PRRSV membrane fusion occurred in Rab11-recycling endosomes during early infection using labeled virions and subcellular markers. We further demonstrated that low pH and cathepsin E in Rab11-recycling endosomes are critical for PRRSV membrane fusion. Moreover, PRRSV glycoprotein 5 (GP5) is identified as being cleaved by cathepsin E during this process. Taken together, our findings provide in-depth information regarding PRRSV pathogenesis, which support a novel basis for the development of antiviral drugs and vaccines.

IMPORTANCE PRRS, caused by PRRSV, is an economically critical factor in pig farming worldwide. As PRRSV is a lipid membrane-wrapped virus, merging of the PRRSV envelope with the host cell membrane is indispensable for viral infection. However, there is a lack of knowledge on its membrane fusion. Here, we first explored when and where PRRSV membrane fusion occurs. Furthermore, we determined which host cell factors were involved in the process. Importantly, PRRSV GP5 is shown to be cleaved by cathepsin E during membrane fusion. Our work not only provides information on PRRSV membrane fusion for the first time but also deepens our understanding of the molecular mechanisms of PRRSV infection, which provides a foundation for future applications in the prevention and control of PRRS.

Group II introns are mobile genetic elements that perform both self-splicing and intron mobility reactions. These ribozymes are comprised of a catalytic RNA core that binds to an intron-encoded protein (IEP) to form a ribonucleoprotein (RNP) complex. Splicing proceeds through two competing reactions: hydrolysis or branching. Group IIC intron ribozymes have a minimal RNA architecture, and splice almost exclusively through hydrolysis in ribozyme reactions. Addition of the IEP allows the splicing reaction to form branched lariat RNPs capable of intron mobility. Here we examine ribozyme splicing, IEP-dependent splicing, and mobility reactions of a group IIC intron from the thermophilic bacterium Thermoanerobacter italicus (Ta.it.I1). We show that Ta.it.I1 is highly active for ribozyme activity, forming linear hydrolytic intron products. Addition of purified IEP switches activity to the canonical lariat forming splicing reaction. We demonstrate that the Ta.it.I1 group IIC intron coordinates the progression of the forward splicing reaction through a –' interaction between intron domains II and VI. We further show that branched splicing is supported in the absence of the IEP when the –' interaction is mutated. We also investigated the regulation of the two steps of reverse splicing during intron mobility into DNA substrates. Using a fluorescent mobility assay that simultaneously visualizes all steps of intron integration into DNA, we show that completion of reverse splicing is tightly coupled to cDNA synthesis regardless of mutation of the –' interaction.

Objective

To assess the impact of APOE polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS).

Serological testing for nasopharyngeal carcinoma (NPC) has recently been reinvigorated by the implementation of novel Epstein-Barr virus (EBV)-specific IgA and IgG antibodies from a proteome array. Although proteome arrays are well suited for comprehensive antigen selection, they are not applicable for large-scale studies. We adapted a 13-marker EBV antigen signature for NPC risk identified by proteome arrays to multiplex serology to establish an assay for large-scale studies. Taiwanese NPC cases (n = 175) and matched controls (n = 175) were used for assay validation. Spearman’s correlation was calculated, and the diagnostic value of all multiplex markers was assessed independently using the area under the receiver operating characteristic curve (AUC). Two refined signatures were identified using stepwise logistic regression and internally validated with 10-fold cross validation. Array and multiplex serology showed strong correlation for each individual EBV marker, as well as for a 13-marker combined model on continuous data. Two refined signatures with either four (LF2 and BGLF2 IgG, LF2 and BMRF1 IgA) or two (LF2 and BGLF2 IgG) antibodies on dichotomous data were identified as the most parsimonious set of serological markers able to distinguish NPC cases from controls with AUCs of 0.992 (95% confidence interval [CI], 0.983 to 1.000) and 0.984 (95% CI, 0.971 to 0.997), respectively. Neither differed significantly from the 13-marker model (AUC, 0.992; 95% CI, 0.982 to 1.000). All models were internally validated. Multiplex serology successfully validated the original EBV proteome microarray data. Two refined signatures of four and two antibodies were capable of detecting NPC with 99.2% and 98.4% accuracy.

Sepsis causes an activation of the human contact system, an inflammatory response mechanism against foreign surfaces, proteins and pathogens. The serine proteases of the contact system, factor XII and plasma kallikrein, are decreased in plasma of septic patients, which was previously associated with an unfavorable outcome. However, the precise mechanisms and roles of contact system factors in bacterial sepsis are poorly understood. We, therefore, studied the physiological relevance of factor XII and plasma kallikrein in a mouse model of experimental sepsis. We show that decreased plasma kallikrein concentration in septic mice is a result of reduced mRNA expression plasma prekallikrein gene, indicating that plasma kallikrein belong to negative acute phase proteins. Investigations regarding the pathophysiological function of contact system proteases during sepsis revealed different roles for factor XII and plasma kallikrein. In vitro, factor XII decelerated bacteria induced fibrinolysis, whereas plasma kallikrein supported it. Remarkably, depletion of plasma kallikrein (but not factor XII) by treatment with antisense-oligonucleotides, dampens bacterial dissemination and growth in multiple organs in the mouse sepsis model. These findings identify plasma kallikrein as a novel host pathogenicity factor in Streptococcus pyogenes sepsis.

Want to sell a house but do not know how to sell it quickly? Some suggestions below may help you sell property faster.

As any good Guardian knows, Destiny 2 isn’t just a jargon-filled sci-fi loot ’em up. It’s just as much, if not more so, a far-future fashion show. But in a game about constantly trading out new gear, keeping a fresh look has always felt a little contentious. This week, Bungie revealed that Year 4 will […]

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The new coronavirus is upending our lives, but simple actions can slow its spread, help our neighbours, foster a sense of togetherness and rejuvenate our immune systems

BORIS JOHNSON will give garden centres the go-ahead to reopen from next Wednesday in one of the first steps out of the coronavirus lockdown, Downing Street sources told the Daily Express on Friday night.

Coronavirus restrictions are lifting across the nation, and before long you’ll get back to some normalcy. I’m not taking any chances with bringing germs into my house. Tap or click for the at-home “airlock” trick I use to make sure everything is disinfected, inspired by NASA astronaut Scott Kelly.

Follow our live coronavirus updates here Coronavirus: the symptoms

Spain's prime minister has revealed his government's plans to start winding down the country's coronavirus lockdown in the second half of May.

Labour leader Sir Keir Starmer has called for a coronavirus lockdown "exit strategy" with the Government facing increasing pressure to reveal its next steps.

Sex offender Jeffrey Epstein visited Harvard University dozens of times after his conviction - and was even given his own office.

UK arrivals could be told to self-isolate for 14-days PM will reportedly recommend face masks while at work or on public transport More money will be set aside for cycle lanes to limit rush hour travel

Most are doing their best to avoid other people's germs right now. But for cleaners and those who get rid of that trash, they're coming into contact with COVID-19 every shift.

Adam Silver outlined a potentially grim future for the NBA in a call with players, calling the pandemic the "single greatest challenge of all our lives."

Antle believes that animal rights activists are behind the threats

The YouTube star spent the weekend in hospital after having wires removed from his hand

Emma Glass's book set in an isolation ward is both terrific and timely. She talks to Katie Law

Forget a virtual haircut, all you need is this foolproof, three-step hack

"All of my work has been cancelled [because of the crisis] and I was just missing shooting people and thought it would be a nice way for the community to come together and have a memory of this time.

Bunga’s MOCA exhibit is the first piece of art in a series featuring one piece of art we can share and enjoy together each week

Todd Greenberg resigns with immediate effect after four years leading the NRL, in a decision the sporting body says was mutually agreed.

The genetic mutations that cause epilepsy don’t stop there. Praxis Precision Medicines CEO Marcio Souza says research also links these genes to other neurological conditions. The biotech startup is turning that research into new neuro drugs and it’s coming out of stealth to share details about its science and its pipeline, which already has two […]

Gilead has said that Dr John McHutchison is stepping down after nine years at the firm.

Gilead’s Chief Scientific Officer and Head of Research and Development has decided to leave the company next month, Gilead said.

Under McHutchinson, Gilead developed five new hepatitis drugs, which have been used by as many as 3.2 million people around the world.

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Dr Reshma Kewalramani has been made the new Vertex CEO.

Vertex’s Chief Medical Officer Dr Kewalramani will succeed current CEO Jeffrey Leiden who has is now stepping aside from the role after seven years as Chief executive at the Boston-based firm. In stepping down Leiden will serve as executive chairman until the first quarter of 2023.     

Fourty-six year old Dr Kewalramani, who has been at Vertex since 2017, will thus become the first woman to head the firm. Prior to joining Vertex, Kewalramani spent more than 12 years at Amgen.

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Chief Executive of Gulf Pharmaceutical Industries, Jerome Carle, is stepping down from his post at the United Arab Emirates drug manufacturer facing mounting pressure.

Julphar, one of the biggest generic drugs manufacturers in the Middle East and North Africa said Jerome Carle has “tendered his resignation” and the board has accepted it. His last working day will be December 8th.

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The Japanese pharma development firm will harness risk-based quality management solutions to help sponsors improve trial quality and safety.

When Gilead Sciences scored a groundbreaking FDA emergency use authorization for COVID-19 therapy remdesivir, the company made the unusual move of handing distribution rights to the U.S. government. But the federal rollout has gotten off to a rocky start. 

The owner of a Costa Rica-based telemarketing call center and two employees of another Costa Rica call center were sentenced for their roles in schemes that targeted and defrauded thousands of American victims of more than $10 million.

Japanese electronics manufacturer Epson Imaging Devices Corporation (Epson) agreed to plead guilty and pay a $26 million criminal fine for its role in a conspiracy to fix prices in the sale of Thin Film Transistor-Liquid Crystal Display panels (TFT-LCD) sold to Motorola Inc.

Four owners of Costa Rica-based telemarketing call centers, an employee and a Texas-based list broker have been sentenced for their roles in defrauding thousands of U.S. victims of more than $20 million through a phony sweepstakes scheme.

Today, in response to a letter from the Justice Department, the Massachusetts Board of Elementary and Secondary Education voted to grant the Commissioner of Education authority to draft state regulations that will require training of all Sheltered English Immersion teachers who instruct English Language Learner students.

The Department of Justice today announced it is proposing a regulation that will clarify who, due to mental health reasons, is prohibited under federal law from receiving, possessing, shipping or transporting firearms. In addition to providing general guidance on the federal law, this clarification will help states determine what information may be appropriately shared with the federal background check system for firearms transfers – the National Instant Criminal Background Check System (NICS) – in order to keep guns out of the hands of individuals who may be a danger to themselves or others.

The Department of Justice Civil Rights Division and the U.S. Attorney’s Office for the District of New Jersey will announce the results and next steps following its investigation into the Newark Police TODAY, TUESDAY, JULY 22, 2014, at 12:00 p.m. EDT, at the Newark office of the U.S. Attorney for the District of New Jersey

A North Carolina couple pleaded guilty for leading a Costa Rican sweepstakes fraud scheme that defrauded hundreds of elderly Americans

Attorney General Eric Holder announced today that the Justice Department has launched two initiatives to address concerns about police services in the city of Ferguson and in St. Louis County, Missouri.

A dual United States-Costa Rican citizen pleaded guilty today for his role in a $1.88 million sweepstakes fraud scheme that defrauded hundreds of elderly Americans.

Today's Daily Dose brings you news about aTyr Pharma joining the COVID-19 battle; Cara's pivotal KALM-2 trial; LabCorp's at-home collection kit for COVID-19 testing securing Emergency Use Authorization from the FDA, and Myovant's much-awaited clinical trial catalyst.

APEC economies, data privacy regulators, and other stakeholders are exploring ways to bolster the Cross-Border Privacy Rules (CBPR) system.

Force India does not expect to make its biggest development strides until the European season as it continues to recover from its late start to 2015

At the beginning of this century, about one in four of the world's extreme poor lived in fragile and conflict affected situations (FCS). By the end of this year, FCS will be home to the majority of the world's extreme poor. Increasingly, we live in a "two-speed world." This is the key finding of a…