Although a robust inflammatory response is needed to combat infection, this response must ultimately be terminated to prevent chronic inflammation. One mechanism that terminates inflammatory signaling is the production of alternative mRNA splice forms in the Toll-like receptor (TLR) signaling pathway. Whereas most genes in the TLR pathway encode positive mediators of inflammatory signaling, several, including that encoding the MyD88 signaling adaptor, also produce alternative spliced mRNA isoforms that encode dominant-negative inhibitors of the response. Production of these negatively acting alternatively spliced isoforms is induced by stimulation with the TLR4 agonist lipopolysaccharide (LPS); thus, this alternative pre-mRNA splicing represents a negative feedback loop that terminates TLR signaling and prevents chronic inflammation. In the current study, we investigated the mechanisms regulating the LPS-induced alternative pre-mRNA splicing of the MyD88 transcript in murine macrophages. We found that 1) the induction of the alternatively spliced MyD88 form is due to alternative pre-mRNA splicing and not caused by another RNA regulatory mechanism, 2) MyD88 splicing is regulated by both the MyD88- and TRIF-dependent arms of the TLR signaling pathway, 3) MyD88 splicing is regulated by the NF-κB transcription factor, and 4) NF-κB likely regulates MyD88 alternative pre-mRNA splicing per se rather than regulating splicing indirectly by altering MyD88 transcription. We conclude that alternative splicing of MyD88 may provide a sensitive mechanism that ensures robust termination of inflammation for tissue repair and restoration of normal tissue homeostasis once an infection is controlled.

Protease-activated receptor 2 (PAR-2) is activated by secreted proteases from immune cells or fungi. PAR-2 is normally expressed basolaterally in differentiated nasal ciliated cells. We hypothesized that epithelial remodeling during diseases characterized by cilial loss and squamous metaplasia may alter PAR-2 polarization. Here, using a fluorescent arrestin assay, we confirmed that the common fungal airway pathogen Aspergillus fumigatus activates heterologously-expressed PAR-2. Endogenous PAR-2 activation in submerged airway RPMI 2650 or NCI–H520 squamous cells increased intracellular calcium levels and granulocyte macrophage–colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-6 secretion. RPMI 2650 cells cultured at an air–liquid interface (ALI) responded to apically or basolaterally applied PAR-2 agonists. However, well-differentiated primary nasal epithelial ALIs responded only to basolateral PAR-2 stimulation, indicated by calcium elevation, increased cilia beat frequency, and increased fluid and cytokine secretion. We exposed primary cells to disease-related modifiers that alter epithelial morphology, including IL-13, cigarette smoke condensate, and retinoic acid deficiency, at concentrations and times that altered epithelial morphology without causing breakdown of the epithelial barrier to model early disease states. These altered primary cultures responded to both apical and basolateral PAR-2 stimulation. Imaging nasal polyps and control middle turbinate explants, we found that nasal polyps, but not turbinates, exhibit apical calcium responses to PAR-2 stimulation. However, isolated ciliated cells from both polyps and turbinates maintained basolateral PAR-2 polarization, suggesting that the calcium responses originated from nonciliated cells. Altered PAR-2 polarization in disease-remodeled epithelia may enhance apical responses and increase sensitivity to inhaled proteases.

Endorepellin, the C-terminal fragment of the heparan sulfate proteoglycan perlecan, influences various signaling pathways in endothelial cells by binding to VEGFR2. In this study, we discovered that soluble endorepellin activates the canonical stress signaling pathway consisting of PERK, eIF2α, ATF4, and GADD45α. Specifically, endorepellin evoked transient activation of VEGFR2, which, in turn, phosphorylated PERK at Thr980. Subsequently, PERK phosphorylated eIF2α at Ser51, upregulating its downstream effector proteins ATF4 and GADD45α. RNAi-mediated knockdown of PERK or eIF2α abrogated the endorepellin-mediated up-regulation of GADD45α, the ultimate effector protein of this stress signaling cascade. To functionally validate these findings, we utilized an ex vivo model of angiogenesis. Exposure of the aortic rings embedded in 3D fibrillar collagen to recombinant endorepellin for 2–4 h activated PERK and induced GADD45α vis à vis vehicle-treated counterparts. Similar effects were obtained with the established cellular stress inducer tunicamycin. Notably, chronic exposure of aortic rings to endorepellin for 7–9 days markedly suppressed vessel sprouting, an angiostatic effect that was rescued by blocking PERK kinase activity. Our findings unravel a mechanism by which an extracellular matrix protein evokes stress signaling in endothelial cells, which leads to angiostasis.

This report analyzes prenatal behaviors and birth outcomes of Black immigrant mothers, and finds that Black immigrant mothers are less likely to give birth to preterm or low-birth-weight infants than U.S.-born Black women, but more likely to experience these birth outcomes than other immigrant and U.S.-born women.

Last Thursday morning, I went to visit my youngest grandchild, three-year-old Morgan. As she emerged from her bedroom with her tablet in hand and a scream on her lips then saw me and barged towards me, I knew that a full embrace was not going to...

The current U.S. legal immigration system includes few visas for low-skilled workers, and employers have relied heavily on an unauthorized workforce in many low-skilled occupations. This issue brief explains the questions that policymakers must grapple with when designing programs for admission of low-skill workers, for temporary as well as permanent entry. The brief focuses in part on the recent agreement by the U.S. Chamber of Commerce and AFL-CIO regarding admission of future low-skilled workers.

State-of-the-art electron microscopy reveals the large-scale organization of the proteins that regulate neurotransmitter release

This spectacular image – which took the best part of a year to create – shows the fine structure of a nerve terminal at high resolution, revealing, for the very first time, an intricate network of fine filaments that controls the movements of synaptic vesicles.

The brain is soft and wet, with the consistency of a lump of jelly. Yet, it is the most complex and highly organized structure that we know of, containing hundreds of billions of neurons and glial cells, and something on the order of one quadrillion synaptic connections, all of which are arranged in a very specific manner.

Related: 3D model of a nerve terminal in atomic detail | Mo Costandi

Related: Blowing up the brain to reveal its finer details

Immigrants in the United Kingdom find work easily thanks to a flexible labor market, but often have trouble moving up the ladder into middle-skilled work. This report examines how workforce and integration policies affect immigrant workers in the United Kingdom.

Testimony of Marc R. Rosenblum, Deputy Director, U.S. Immigration Program, before the House Committee on Homeland Security Subcommittee on Oversight and Management Efficiency.

(May 1, 2020) On April 24, 2020, the Russian government portal for legal information published the text of the newly adopted Law on Amending the Law on Citizenship. (Federal Law No. 134-FZ of April 24, 2020, Concerning the Simplification of the Procedure for Acquisition of Russian Citizenship.) The new law, which will enter into force […]

(May 7, 2020) On February 18, 2020, Paraguayan President Mario Abdo Benítez signed Law No. 6501/2020, amending Law No. 4743/2012 Regulating Political Financing. Law No. 6501 creates a unit within the Superior Court of Electoral Justice (Tribunal Superior de Justicia Electoral, TSJE) to be in charge of arranging, coordinating, and supervising policies and procedures to prevent […]

RUTH Davidson, the Scottish Conservative leader, will take on Boris Johnson in the BBC's final EU debate, grandly entitled The Great Debate, which will be broadcast at 8pm tonight.

A pastor of a small community church was about to resign when God brought new hope through the work of OM El Salvador.

The North Central PA LaunchBox is driving collaborative relationships with and between local, regional and state organizations, as well as government, to drive economic development in the region.

In addition to the prizes and rewards, Hero MotoCorp may also make it a memorable experience for the participants by putting some of the entries into production.

The Benda Asura 400 comes with a single-sided swingarm, which is quite rare to see on a 400cc motorcycle.

The Audi A5 is one of the best looking and also one of the best driving cars money can buy in India. And here’s why!

Ask yourself why did you decide on studying abroad?

The decrease in WiFi usage can also be attributed to people staying at homes.

Airtel emerged on the top in terms of latency experience with an average response time of 54.1 milliseconds, followed by Jio at 56.3 ms.

The Indian rupee weakened by 31 paise to 62.64 against the US dollar today at the Interbank Foreign Exchange on month-end demand for the...

Transfer amounts should also be linked to CPI. While PM-KISAN covers only farmers and is much more expensive and exclusive, such a transfer would avoid narrow coverage, also avoiding inclusion/exclusion errors

The basic decision making on the ground must be left to the states and should involve municipal corporations and wards.

The scientists tested their vaccine on mice. The mice developed antibodies immediately after a single injection, which prevented the virus from infecting human cells. Researchers selected 2 of the five candidates for the vaccine after studying them with the best results.

A study by AdRoll and Priceonomics breaks down which cities and states are most and least likely to click.

PM Modi said that the action should be taken for a more proactive approach to handhold the investors.

After a lifetime high FPI withdrawal in the month of March, the foreign portfolio investors have once again pulled out nearly Rs 15,000 crore from the country's capital market in April.

In consumer goods, the textile and clothing sector; food products; and crop and animal production have the highest comparative advantage in India.

Hong Kong and Federal Republic of Germany have signed a Memorandum of Understanding (MOU) concerned with the automated clearance service usage on a shared basis. The MOU is considered as a new milestone in the collaboration between the countries in immigration…

The Government of Hong Kong is increasing its efforts to attract foreign talent, including the mainland China’s professionals, as working population of the city is supposed to get shrink in the year 2018.The Immigration Director, Chan Kwok-ki said…

The brand has released a new television commercial featuring the actor

Delhi recorded the maximum temperature of 40.9 degrees centigrade on Saturday, the IMD said. Due to the Western Disturbance, the IMD in its weather summary and forecast bulletin predicted isolated to scattered rain over the Western Himalayan region and plains of Northwest India, with peak activity on May 10, 2020.

Zoetis raised £20,000 for the nonprofit organization Hounds for Heroes with its ‘Pounds for Hounds’ fundraising campaign.

Zoetis recently launched its first-ever national, direct-to-consumer television advertising campaigns in the U.S. since becoming an independent company. Two brand-new Zoetis ads started airing on TVs across the U.S. this week, one featuring the company’s canine allergic itch tablet, Apoquel®, and the other starring Simparica®, a once-monthly chewable parasiticide that helps protect dogs from fleas and ticks.

Cadence is hosting a Front End Design Summit on Thursday, December 6, 2012 9:30am – 5:00pm at Cadence San Jose headquarters, 2655 Seely Avenue, Building 10. Logic designers will hear from customers including Cisco, Chelsio, PMC, Spansion, and Via Technologies...(read more)