ABSTRACT

The clostridial neurotoxins (CNTs) comprise tetanus toxin (TT) and botulinum neurotoxin (BoNT [BT]) serotypes (A to G and X) and several recently identified CNT-like proteins, including BT/En and the mosquito BoNT-like toxin Pmp1. CNTs are produced as single proteins cleaved to a light chain (LC) and a heavy chain (HC) connected by an interchain disulfide bond. LC is a zinc metalloprotease (cleaving soluble N-ethylmaleimide-sensitive factor attachment protein receptors [SNAREs]), while HC contains an N-terminal translocation domain (HCN) and a C-terminal receptor binding domain (HCC). HCN-mediated LC translocation is the least understood function of CNT action. Here, β-lactamase (βlac) was used as a reporter in discovery-based live-cell assays to characterize TT-mediated LC translocation. Directed mutagenesis identified a role for a charged loop (⁷⁶⁷DKE⁷⁶⁹) connecting α15 and α16 (cis-loop) within HCN in LC translocation; aliphatic substitution inhibited LC translocation but not other toxin functions such as cell binding, intracellular trafficking, or HCN-mediated pore formation. K⁷⁶⁸ was conserved among the CNTs. In molecular simulations of the HCN with a membrane, the cis-loop did not bind with the cell membrane. Taken together, the results of these studies implicate the cis-loop in LC translocation, independently of pore formation.

IMPORTANCE How protein toxins translocate their catalytic domain across a cell membrane is the least understood step in toxin action. This study utilized a reporter, β-lactamase, that was genetically fused to full-length, nontoxic tetanus toxin (βlac-TT) in discovery-based live-cell assays to study LC translocation. Directed mutagenesis identified a role for K⁷⁶⁸ in LC translocation. K⁷⁶⁸ was located between α15 and α16 (termed the cis-loop). Cellular assays showed that K⁷⁶⁸ did not interfere with other toxin functions, including cell binding, intracellular trafficking, and pore formation. The equivalent K⁷⁶⁸ is conserved among the clostridial neurotoxin family of proteins as a conserved structural motif. The cis-loop appears to contribute to LC translocation.

Patients with systemic immunoglobulin light chain amyloidosis (AL) with no evidence of cardiac involvement by consensus criteria have excellent survival, but 20% will die within 5 years of diagnosis and prognostic factors remain poorly characterised. We report the outcomes of 378 prospectively followed Mayo stage I patients (N-terminal pro b-type natriuretic peptide <332 ng/L, high sensitivity cardiac troponin <55 ng/L). The median presenting N-terminal pro b-type natriuretic peptide was 161 ng/L, high sensitivity cardiac troponin 10 ng/L, creatinine 76 μmol/L and mean left ventricular septal wall thickness, 10 mm. Median follow up was 42 (1-117 months), with 71 deaths; median overall survival was not reached (78% survival at 5 years). Although no patients had cardiac involvement by echocardiogram, a proportion (n=25/90, 28%) had cardiac involvement by cardiac magnetic resonance imaging. Age, autonomic nervous system involvement, N-terminal pro b-type natriuretic peptide >152 ng/L, high sensitivity cardiac troponin >10 ng/L and cardiac involvement by magnetic resonance imaging were predictive for survival; on multivariate analysis only N-terminal pro b-type natriuretic peptide >152 ng/L (P<0.008, hazard ratio [HR] 3.180, confidence interval [CI]: 1.349-7.495) and cardiac involvement on magnetic resonance imaging (P=0.026, HR=5.360, CI: 1.219-23.574) were prognostic. At 5 years, 70% of patients with N-terminal pro b-type natriuretic peptide >152 ng/L were alive. In conclusion, N-terminal pro b-type natriuretic peptide is prognostic for survival in patients with no cardiac involvement by consensus criteria and cardiac involvement is detected by magnetic resonance imaging in such cases. This suggests that N-terminal pro b-type natriuretic peptide thresholds for cardiac involvement in AL may need to be redefined.

Biofilm formation by Pseudomonas aeruginosa contributes to its survival on surfaces and represents a major clinical threat because of the increased tolerance of biofilms to disinfecting agents. This study aimed to investigate the efficacy of 405-nm light-emitting diode (LED) illumination in eliminating P. aeruginosa biofilms formed on stainless steel coupons under different temperatures. Time-dependent killing assays using planktonic and biofilm cells were used to determine the antimicrobial and antibiofilm activities of LED illumination. We also evaluated the effects of LED illumination on the disinfectant susceptibility, biofilm structure, extracellular polymeric substance (EPS) structure and composition, and biofilm-related gene expression of P. aeruginosa biofilm cells. Results showed that the abundance of planktonic P. aeruginosa cells was reduced by 0.88, 0.53, and 0.85 log CFU/ml following LED treatment for 2 h compared with untreated controls at 4, 10, and 25°C, respectively. For cells in biofilms, significant reductions (1.73, 1.59, and 1.68 log CFU/cm²) were observed following LED illumination for 2 h at 4, 10, and 25°C, respectively. Moreover, illuminated P. aeruginosa biofilm cells were more sensitive to benzalkonium chloride or chlorhexidine than untreated cells. Scanning electron microscopy and confocal laser scanning microscopic observation indicated that both the biofilm structure and EPS structure were disrupted by LED illumination. Further, reverse transcription-quantitative PCR revealed that LED illumination downregulated the transcription of several genes associated with biofilm formation. These findings suggest that LED illumination has the potential to be developed as an alternative method for prevention and control of P. aeruginosa biofilm contamination.

IMPORTANCE Pseudomonas aeruginosa can form biofilms on medical implants, industrial equipment, and domestic surfaces, contributing to high morbidity and mortality rates. This study examined the antibiofilm activity of 405-nm light-emitting diode (LED) illumination against mature biofilms formed on stainless steel coupons. We found that the disinfectant susceptibility, biofilm structure, and extracellular polymeric substance structure and composition were disrupted by LED illumination. We then investigated the transcription of several critical P. aeruginosa biofilm-related genes and analyzed the effect of illumination temperature on the above characteristics. Our results confirmed that LED illumination could be developed into an effective and safe method to counter P. aeruginosa biofilm contamination. Further research will be focused on the efficacy and application of LED illumination for elimination of complicated biofilms in the environment.

Summary:

In this issue of Cancer Discovery, Li and colleagues provide a blueprint for the identification and functional validation of cancer-associated mutations in noncoding regions of the genome. Integration of whole-genome sequencing and high-throughput epigenome editing screens is starting to reveal the extent to which noncoding genetic lesions contribute to cancer.

See related article by Li et al., p. 724.

Summary:

Over the last two decades HER2 aberrations have been thoroughly investigated as potential therapeutic targets in advanced non–small cell lung cancer, with relatively modest results. Two articles published in this issue of Cancer Discovery further expand the knowledge on therapeutic exploitation of HER2 in lung cancer, addressing a large unmet medical need.

See related article by Li et al., p. 674.

See related article by Tsurutani et al., p. 688.

Summary:

The first basket clinical trial testing the BRAF inhibitor vemurafenib resulted in evidence of activity in 13 unique cancer types with BRAF^V600 mutations, but the response rates were variable. Therefore, different cancer histologies with the same driver oncogene display different degrees of oncogenic pathway addiction.

See related article by Subbiah et al., p. 657.

Background:

The impact of light-intensity physical activity (LPA) in preventing cancer mortality has been questioned. To address this concern, the present meta-analysis aimed to quantify the association between objectively-measured LPA and risk of cancer mortality.

An annual report released by the Ministry of Construction (MoC) at a press conference on Monday showed housing prices in the two mảo cities Hanoi and Ho Chi Minh (HCMC) rose slightly in the third quarter (Q3) of this year.

Developer Mirari & Co. announced the science-fiction action platformer Dark Light for Windows PC via Steam Early Access on May 8 and later for the Nintendo Switch when the game leaves Steam Early Access. 

Mirari & Co. is looking to release the game within one year of the Steam Early Access release, however, it depends "on how we are taking players suggestions and advice to shaping the game."

View the latest trailer of the game below:

Here is an overview of the game:

Dark Light is a science-fiction action-platformer with unique gameplay. Explore an apocalyptic cyberpunk world full of supernatural beings. Encounter and defeat creatures of darkness invisible to the naked eye, detected only with the light source from your drone. Experience the horror and feel their presence as they surround you.

As a Dark Hunter you were dropped into a wreaked world. To survive, you need to equip yourself, fight your way through, and collect ‘shards’ from killing supernatural creatures to reinforce your energy. Through survival, you will explore the mysterious dark zones of the apocalypse world.

Key Features:

• Cinematic quality graphic, detailed characters and environment design, and vivid animation with lush visual effect.
• A variety of range, melee, and throwable weapons; unique items; and multiple ways to upgrade weapons, special equipment, and the player to shape your own character skills.
• Non-linear map structure for you to choose your own path to explore the dark zones. Encounter horrifying supernatural enemies, fearsome bosses, and friendly NPCs, and fight with invisible creatures that can only be seen in a special light source.
• Detect invisible enemies and reveal hidden paths with the special light source from your drone.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443411/sci-fi-action-platformer-dark-light-launches-may-8-for-steam-early-access-later-for-switch/

Clothes that light up by themselves could be a high-tech replacement to high-visibility gear worn by cyclists and construction workers

A 3D printed grate can be used to make a smart window that blocks heat from sunlight out in the summer while letting it through in the winter, conserving energy

Spending at least six months in microgravity can cause astronauts’ brain volumes to increase, causing pressure to build up in their heads and creating vision problems

SpaceX’s first crewed launch is planned for 27 May and will be run from a mission control with desks set six feet apart to comply with social distancing protocols

Lab demoes of an all-optical neural network could lead to more powerful and less power-hungry AI

For the first time, NASA's Astrobee robot has demonstrated autonomous free flight in space

These are the vent dragons made and sold by artist David Lee Pancake. The dragons are available in a variety of dragony colors, cost $200 apiece, and are made to be hung on the wall, NOT cover an actual air vent. "But--" Hey, if you want to be hot all summer because the A/C isn't blowing in the living room, that's up to you.

Vent Dragons comes with a little remote control to light up the eyes of the two little monsters and surprise your guests and friends. The lights are powered by 3 AA batteries and should burn for 150 hours before you need to replace them. To replace the batteries unscrew the grate and lift off, the batteries are in a small pack inside. The lighted eyes have 8 different settings from fast blinking to continually glowing and there is a timer to turn them off in 6 hours. Enjoy! Size: 12x7 inches. Do NOT install in an actual heating/AC vent.

In there's no way Vader signed off on this news, this is the 'Nino Star Products Pool Float Black Outdoor' available from Amazon. It costs around $25, kinda looks like a Darth Vader a kid drew, and I can't imagine Darth doesn't wish they all melted in the destruction of the first Death Star. "What am I, a joke to you?!" I imagine him demanding as he Force-chokes the commander who signed off on using his likeness for a cartoony pool float as the other who signed off on the line of upcoming Vader sex toys casually backs out of the room intending to catch the first dropship to Tatooine. Keep going for one more shot of Vader at his most humiliated.

Cheap, printable photovoltaics might finally live up to their early promise.

There’s peanut butter in my chocolate in this week’s RPG Cast. We figure out how to solve the JRPG problem. Nintendo announces every RPG ever....

We're back and better* than ever! On this special episode of the RPGCast we do a deeper dive into what we've been playing and discuss our holiday hauls. *Note: RPG Cast 526 may not actually be better than any other previous RPG Cast.

Whether it’s printed and high-necked or floral and ruffled, brighten your lockdown by dressing up to stay in

New Dlehi, May 09: Several Indians, who are stranded in at least seven countries due to coronavirus outbreak, is all set to fly back to their home country on Saturday in special flights under Vande Bharat Mission. According to officials,

Noida Police Commissioner has written to national carrier Air India, requesting the airline to ensure that pilots and crew involved in repatriation flights should stay back in Delhi.

The stranded people hail from Tamil Nadu and they were working in the United Arab Emirates.

New Delhi, May 09 (ANI): An Air India flight carrying 129 passengers from Dhaka, Bangladesh has landed at Delhi airport. The stranded Indian nationals are being brought back to the country through government’s initiative, ‘Vande Bharat Mission’.

Around 250 Indian students and tourists were seen queuing with their luggage at the airport as they prepared for the journey home.

People with rheumatoid arthritis often take medicines that can have damaging side-effects, but a system that uses red light to deliver drugs exactly where they are needed could help

Researchers have found the weird exoplanet WASP-79b, nearly 800 light-years from Earth, does not have a blue sky as our planet does. Instead, its skies are yellow.

15 years after the first Twilight novel was released, author...

The post A New Book From The Twilight Saga Is Almost Here appeared first on Man's World India.

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.

Wildlife conservation efforts are essential to preventing outbreaks, scientists and advocates say

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For more than five years, wildlife conservationists in the US have been clamoring for the government to provide Endangered Species Act protections to pangolins, a group of imperiled ant-eating mammals that are widely, and often illicitly, trafficked for their scales and meat. The Trump administration, however, has refused to act and that refusal has suddenly taken on grave new implications.

Earlier this year, scientists in China identified pangolins, along with bats, as one of the possible animal hosts involved in the transmission of the deadly coronavirus from wildlife to humans.

You’ve got questions, we’ve got experts

Hydrogen is a possible next generation energy solution, and it can be produced from sunlight and water using photocatalysts. A research group has now developed a strategy that greatly increases the amount of hydrogen produced using hematite photocatalysts. In addition to boosting the high efficiency of what is thought to be the world's highest performing photoanode, this strategy will be applied to artificial photosynthesis and solar water-splitting technologies via university-industry collaborations.

Data centres and digital information processors are reaching their capacity limits and producing heat. Foundational work here on optical-acoustic microchips opens door to low-heat, low-energy, fast internet.

In physics, thermalization, or the trend of sub-systems within a whole to gain a common temperature, is typically the norm. There are situations, however, where thermalization is slowed down or virtually suppressed; examples are when considering the dynamics of electron and nuclear spins in solids. Understanding why this happens and how it can be controlled is presently at the center of a broad effort, particularly for applications in the emerging field of quantum information technologies.

As interest in the application of plasma medicine -- the use of low-temperature plasma (LTP) created by an electrical discharge to address medical problems -- continues to grow, so does the need for research advancements proving its capabilities and potential impacts on the health care industry. Across the world, many research groups are investigating plasma medicine for applications including cancer treatment and the accelerated healing of chronic wounds, among others.