Title: Overweight Teens Feel Stigmatized, Bullied: Study
Category: Health News
Created: 5/1/2014 9:35:00 AM
Last Editorial Review: 5/1/2014 12:00:00 AM

TNF-related apoptosis-inducing ligand (TRAIL) and an agonistic antibody against the death-inducing TRAIL receptor 5, DR5, are thought to selectively induce tumor cell death and therefore, have gained attention as potential therapeutics currently under investigation in several clinical trials. However, some tumor cells are resistant to TRAIL/DR5–induced cell death, even though they express DR5. Previously, we reported that DR5 is transported into the nucleus by importin β1, and knockdown of importin β1 upregulates cell surface expression of DR5 resulting in increased TRAIL sensitivity in vitro. Here, we examined the impact of importin β1 knockdown on agonistic anti-human DR5 (hDR5) antibody therapy. Drug-inducible importin β1 knockdown sensitizes HeLa cells to TRAIL-induced cell death in vitro, and exerts an antitumor effect when combined with agonistic anti-hDR5 antibody administration in vivo. Therapeutic importin β1 knockdown, administered via the atelocollagen delivery system, as well as treatment with the importin β inhibitor, importazole, induced regression and/or eradication of two human TRAIL-resistant tumor cells when combined with agonistic anti-hDR5 antibody treatment. Thus, these findings suggest that the inhibition of importin β1 would be useful to improve the therapeutic effects of agonistic anti-hDR5 antibody against TRAIL-resistant cancers.

ABSTRACT

Bacillus subtilis contains two known cyclic di-GMP (c-di-GMP)-dependent receptors, YdaK and DgrA, as well as three diguanylate cyclases (DGCs): soluble DgcP and membrane-integral DgcK and DgcW. DgrA regulates motility, while YdaK is responsible for the formation of a putative exopolysaccharide, dependent on the activity of DgcK. Using single-molecule tracking, we show that a majority of DgcK molecules are statically positioned in the cell membrane but significantly less so in the absence of YdaK but more so upon overproduction of YdaK. The soluble domains of DgcK and of YdaK show a direct interaction in vitro, which depends on an intact I-site within the degenerated GGDEF domain of YdaK. These experiments suggest a direct handover of a second messenger at a single subcellular site. Interestingly, all three DGC proteins contribute toward downregulation of motility via the PilZ protein DgrA. Deletion of dgrA also affects the mobility of DgcK within the membrane and also that of DgcP, which arrests less often at the membrane in the absence of DgrA. Both, DgcK and DgcP interact with DgrA in vitro, showing that divergent as well as convergent direct connections exist between cyclases and their effector proteins. Automated determination of molecule numbers in live cells revealed that DgcK and DgcP are present at very low copy numbers of 6 or 25 per cell, respectively, such that for DgcK, a part of the cell population does not contain any DgcK molecule, rendering signaling via c-di-GMP extremely efficient.

IMPORTANCE Second messengers are free to diffuse through the cells and to activate all responsive elements. Cyclic di-GMP (c-di-GMP) signaling plays an important role in the determination of the life style transition between motility and sessility/biofilm formation but involves numerous distinct synthetases (diguanylate cyclases [DGCs]) or receptor pathways that appear to act in an independent manner. Using Bacillus subtilis as a model organism, we show that for two c-di-GMP pathways, DGCs and receptor molecules operate via direct interactions, where a synthesized dinucleotide appears to be directly used for the protein-protein interaction. We show that very few DGC molecules exist within cells; in the case of exopolysaccharide (EPS) formation via membrane protein DgcK, the DGC molecules act at a single site, setting up a single signaling pool within the cell membrane. Using single-molecule tracking, we show that the soluble DGC DgcP arrests at the cell membrane, interacting with its receptor, DgrA, which slows down motility. DgrA also directly binds to DgcK, showing that divergent as well as convergent modules exist in B. subtilis. Thus, local-pool signal transduction operates extremely efficiently and specifically.

APHA member Elena Ong, PHN, MS, past president and founding CEO of the Asian & Pacific Islander Caucus for Public Health, a recent APHA Executive Board member, and a past vice president of the Southern California Public Health Association, discusses discrimination against Asians in the U.S. and beyond.

Objective

To investigate the pathogenicity of the TGM6 variant for spinocerebellar ataxia 35 (SCA35), which was previously reported to be caused by pathogenic mutations in the gene TGM6.

N-terminal (Nt) acetylation (NTA) is an ample and irreversible cotranslational protein modification catalyzed by ribosome-associated Nt-acetyltransferases. NTA on specific proteins can act as a degradation signal (called an Ac/N-degron) for proteolysis in yeast and mammals. However, in plants, the biological relevance of NTA remains largely unexplored. In this study, we reveal that Arabidopsis (Arabidopsis thaliana) SIGMA FACTOR-BINDING PROTEIN1 (SIB1), a transcription coregulator and a positive regulator of salicylic acid-primed cell death, undergoes an absolute NTA on the initiator Met; Nt-acetyltransferase B (NatB) partly contributes to this modification. While NTA results in destabilization of certain target proteins, our genetic and biochemical analyses revealed that plant NatB-involved NTA instead renders SIB1 more stable. Given that the ubiquitin/proteasome system stimulates SIB1 degradation, it seems that the NTA-conferred stability ensures the timely expression of SIB1-dependent genes, mostly related to immune responses. Taking our findings together, here we report a noncanonical NTA-driven protein stabilization in land plants.

The outer segments (OS) of rod and cone photoreceptor cells are specialized sensory cilia that contain hundreds of opsin-loaded stacked membrane disks that enable phototransduction. The biogenesis of these disks is initiated at the OS base, but the driving force has been debated. Here, we studied the function of the...

Noemie Liesch and Friedrich Ladich

In vocal fish species, males possess larger sound-generating organs and signal acoustically with pronounced sex-specific differences. Sound production is known in two out of three species of croaking gouramis (Trichopsis vittata and T. schalleri). The present study investigates sex-specific differences in sonic organs, vocalizing behaviour and sounds emitted in the third species, the pygmy gourami T. pumila, in order to test the hypothesis that females are able to vocalize despite their less-developed sonic organs, and despite contradictory reports. Croaking gouramis stretch and pluck two enhanced (sonic) pectoral fin tendons during alternate fin beating, resulting in a series of double-pulsed bursts termed croaking sound. We measured the diameter of the first and second sonic tendon and showed that male tendons were twice as large as in same-sized females. We also determined the duration of dyadic contests, visual displays, number of sounds and buttings. Sexes differ in all sound characteristics but in no behavioural variable. Male sounds consisted of twice as many bursts, a higher percentage of double-pulsed bursts and a higher burst period. Additionally, male sounds had a lower dominant frequency and a higher sound level. In summary, female pygmy gouramis possessed sonic organs and vocalized in most dyadic contests. The sexual dimorphism in sonic tendons is clearly reflected in sex-specific differences in sound characteristics, but not in agonistic behaviour, supporting the hypothesis that females are vocal.

Background

Studies have linked mutations in genes encoding the eight-protein exocyst protein complex to kidney disease, but the underlying mechanism is unclear. Because Drosophila nephrocytes share molecular and structural features with mammalian podocytes, they provide an efficient model for studying this issue.

Extensive studies have shown that the ₁ receptor (₁R) interacts with and modulates the activity of multiple proteins with important biological functions. Recent crystal structures of ₁R as a homotrimer differ from a dimer-tetramer model postulated earlier. It remains inconclusive whether ligand binding regulates ₁R oligomerization. Here, novel nondenaturing gel methods and mutational analysis were used to examine ₁R oligomerization. In transfected cells, ₁R exhibited as multimers, dimers, and monomers. Overall, ₁R agonists decreased, whereas ₁R antagonists increased ₁R multimers, suggesting that agonists and antagonists differentially affect the stability of ₁R multimers. Endogenous ₁R in rat liver membranes also showed similar regulation of oligomerization as in cells. Mutations at key residues lining the trimerization interface (Arg119, Asp195, Phe191, Trp136, and Gly91) abolished multimerization without disrupting dimerization. Intriguingly, truncation of the N terminus reduced ₁R to apparent monomer. These results demonstrate that multiple domains play crucial roles in coordinating high-order quaternary organization of ₁R. The E102Q ₁R mutant implicated in juvenile amyotrophic lateral sclerosis formed dimers only, suggesting that dysregulation of ₁R multimeric assembly may impair its function. Interestingly, oligomerization of ₁R was pH-dependent and correlated with changes in [³H](+)-pentazocine binding affinity and B_max. Combined with mutational analysis, it is reasoned that ₁R multimers possess high-affinity and high-capacity [³H](+)-pentazocine binding, whereas monomers likely lack binding. These results suggest that ₁R may exist in interconvertible oligomeric states in a dynamic equilibrium. Further exploration of ligand-regulated ₁R multimerization may provide novel approaches to modulate the function of ₁R and its interacting proteins.

Editor’s Note: This article is adapted from the address Ms. Valentine delivered as the recipient of the American Diabetes Association’s (ADA’s) Outstanding Educator in Diabetes Award for 2019. She delivered the address in June 2019 at the Association’s 79th Scientific Sessions in San Francisco, CA. A webcast of this speech is available for viewing at the ADA website (professional.diabetes.org/webcast/outstanding-educator-diabetes-award-lecture%E2%80%94-most-important-thing-we-give-people-hope).

Plasma DNA fragmentomics is an emerging area of research covering plasma DNA sizes, end points, and nucleosome footprints. In the present study, we found a significant increase in the diversity of plasma DNA end motifs in patients with hepatocellular carcinoma (HCC). Compared with patients without HCC, patients with HCC showed a preferential pattern of 4-mer end motifs. In particular, the abundance of plasma DNA motif CCCA was much lower in patients with HCC than in subjects without HCC. The aberrant end motifs were also observed in patients with other cancer types, including colorectal cancer, lung cancer, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma. We further observed that the profile of plasma DNA end motifs originating from the same organ, such as the liver, placenta, and hematopoietic cells, generally clustered together. The profile of end motifs may therefore serve as a class of biomarkers for liquid biopsy in oncology, noninvasive prenatal testing, and transplantation monitoring.

Escherichia coli DNA Pol I can carry out three enzymatic reactions: It possesses 5' -> 3' DNA polymerase activity and 3' -> 5' and 5' -> 3' exonuclease activity. Pol I can be cleaved by mild treatment with subtilisin into two fragments; the larger fragment is known as the Klenow fragment. The Klenow fragment retains the polymerizing activity and the 3' -> 5' exonuclease of the holo-enzyme but lacks its powerful 5' -> 3' exonuclease activity. These enzymes and their applications in molecular cloning are introduced here.

The Klenow fragment, which retains the template-dependent deoxynucleotide polymerizing activity and the 3' -> 5' exonuclease of the holo-enzyme but lacks its powerful 5' -> 3' exonuclease activity, is used to fill recessed 3' termini of dsDNA. In this protocol, fragments suitable as templates for the end-filling reaction are produced by digestion of DNA with an appropriate restriction enzyme. The Klenow enzyme is then used to catalyze the attachment of dNTPs to the recessed 3'-hydroxyl groups.

Many investors have shifted their money into real estate for lease or short-term deposit in banks as the liquidity of land lot segment has declined sharply.

When Earth and Venus formed, they both had global magma oceans deep underground. Earth’s has turned solid by now, but Venus’s may still remain hidden

Michael Apps ignores his new baby to podcast with us today. That’s ok because he’s played the new Fire Emblem. Learn if he sided with...

This interactive map for Assassin's Creed Odyssey will help you find everything you need, like ainigmata ostraka and tombs.

Consumer Gmail users are seeing a "Google Meet" section in the sidebar.

Hackers linked to Iran have targeted staff at U.S. drugmaker Gilead Sciences Inc in recent weeks, according to publicly-available web archives reviewed by Reuters and three cybersecurity researchers, as the company races to deploy a treatment for the COVID-19 virus.

Team RadioShack rider Gert Steegmans broke his left collarbone when a whirlwind caused him to crash during the prologue of the Paris-Nice race on Sunday.

Piers Morgan has accused the Government of "actively sending people out to get infected" at the start of the coronavirus outbreak during a heated interview with Culture Secretary Oliver Dowden.

Piers Morgan today hit out at the Government's "spectacular failure" for doing fewer coronavirus tests than 12 days ago.

Smart Education And Learning Market Size, Share & Trends Analysis Report By Age, By Component (Hardware, Software, Service), By Learning Mode, By End User, By Region, And Segment Forecasts, 2020 - 2027Read the full report: https://www.reportlinker.com/p05891723/?utm_source=PRN The global smart education and learning market size is expected to reach USD 680.1 billion by 2027. The market is anticipated to witness a CAGR of 17.9% from 2020 to 2027. Demand for smart education and learning solutions is increasing among the growing population in corporate and academic sectors, owing to benefits such as improved education quality and easy access to educational content. Increasing adoption of consumer electronics, such as smartphones, e-readers, laptops, and e-learning applications, has altered conventional education methodology and has enhanced the efficiency of an individual to learn. Additionally, there are enormous opportunities for advancements in the market, owing to improved internet accessibility.Also, the COVID - 19 outbreak has emerged an opportunity for the market with an increasing number of states and countries closing educational institutes. For instance, over 90.0% of the world's students are not attending their schools due to this pandemic, as mentioned by UNESCO (The United Nations Educational, Scientific, and Cultural Organization). Commonwealth of Learning (COL), an intergovernmental organization of The Commonwealth (Canada), has supported educational institutions and governments in building robust distance education solutions for quality e-learning practices. However, lack of awareness among end-users about the latest technologies and inadequate amount of resources for delivering quality education in developing regions is anticipated to hinder market growth.The simulation-based learning segment is anticipated to exhibit the highest CAGR because this mode enables corporate professional and educational institutions to create a realistic experience in a controlled environment.It also allows professionals and learners to practice, navigate, explore, and obtain more information through a virtual medium before they start working on real-life tasks.Growing awareness among people and the rising popularity of smart education are encouraging solution providers to invest in research and development for creating more reliable, better, and cost-effective solutions. Manufacturers are making substantial investments in developing new products for enhancing the user experience.Smart education and learning market report highlights:• Growing demand for smart educational practices can be accredited to factors, such as reducing expenses of online training, curbing geographic challenges in physically attending classes, and time constraints faced by aspirants• Increasing penetration of the Internet of Things (IoT), enhanced internet accessibility, and rapid adoption of mobile technology have encouraged users to adopt smart education and learning solutions• Innovative techniques, such as gamification, Massive Open Online Courses (MOOCs), microlearning, and adaptive learning, which improve the overall educational process, are expected to drive the market over the projected period• North America accounted for the largest market share in 2019 owing to its large consumer base for e-learning methodsRead the full report: https://www.reportlinker.com/p05891723/?utm_source=PRN About Reportlinker ReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place. __________________________ Contact Clare: clare@reportlinker.com US: (339)-368-6001 Intl: +1 339-368-6001

Hackers linked to Iran have targeted staff at U.S. drugmaker Gilead Sciences Inc in recent weeks, according to publicly-available web archives reviewed by Reuters and three cybersecurity researchers, as the company races to deploy a treatment for the COVID-19 virus. In one case, a fake email login page designed to steal passwords was sent in April to a top Gilead executive involved in legal and corporate affairs, according to an archived version on a website used to scan for malicious web addresses. Ohad Zaidenberg, lead intelligence researcher at Israeli cybersecurity firm ClearSky, who closely tracks Iranian hacking activity and has investigated the attacks, said the attempt was part of an effort by an Iranian group to compromise email accounts of staff at the company using messages that impersonated journalists.

By Allan Eastman The photographs of water bombers fighting the horrendous Ft. McMurray conflagration of 2016 invoked a sudden wash of memories having to do with two of the great Canadian cultural institutions that I had the good fortune to be involved with and a bizarre set of circumstances that led from a burned out […]

TV host has been playing music to her husband Derek Draper, who remains critically ill

Chef inadvertently started a blaze in his kitchen as Holly Willoughby and Phillip Schofield looked on in shock

Writer also said he has no plans for further episodes of 'Black Mirror'

The Kraftwerk co-founder remained a mystery even after death, but there is no doubting the impact he made with his group’s sublime, visionary music

• News: Florian Schneider, Kraftwerk co-founder, dies aged 73

Florian Schneider’s death came shrouded in a degree of secrecy. Gossip among fans about his health was first provoked at the end of April, when his fellow former Kraftwerk member Wolfgang Flür posted a sweet photo on social media of him and Schneider together in a bar, without explanation.

It had apparently been taken in 2016 – a decade and a half after Schneider and fellow founder member Ralf Hütter had served Flür with a lawsuit provoked by his autobiography I Was a Robot – and was subsequently deleted from Flür’s Facebook page. Then, a week later, another electronic musician based in Germany, the Manchester-born Mark Reeder, posted a brief eulogy; one commenter claimed that Schneider had died “several days ago”.

If only everyone was kinder we would all reap rewards

An interview with former Leicester City manager Claudio Ranieri encountered a rather odd technical difficulty on Thursday - with the feed cutting to his unsuspecting wife Rosanna.

Billionaire property developer Huang Xiangmo publishes a lengthy and scathing attack at the ATO, which is pursuing him over a $141 million tax bill, and ASIO, which revoked his permanent residency.

A Federal Court judge rules Chinese property developer Huang Xiangmo should declare his overseas assets as the ATO which alleges the billionaire has an unpaid $141 million tax debt closes in.

Around 15 people protesters gathered at a petrol forecourt in Stretford where the incident took place

Neither emerges from their handling of the pandemic with any honour.

Good Morning Britain's Charlotte Hawkins delighted fans on Friday as she shared a very...

The Department told the U.S. District Court for the District of Columbia today that it is necessary to extend the term of certain portions of the Microsoft final judgment by at least 18 months. The Department said that an extension is necessary to ensure the quality of the technical documentation Microsoft provides to licensees.

The United States has settled its claims filed under the False Claims Act against Lighthouse Disaster Relief and its partners, Gary Heldreth and Kerry Farmer. In its complaint, which was filed in the U.S. District Court for the Middle District of Louisiana, the United States alleged that Lighthouse, Heldreth, and Farmer accepted a $5.3 million payment for work that was not completely performed on a contract with the Department of Homeland Security.

The United States has obtained a $10 million consent judgment against Los Angeles businessman Robert Bourseau and Dr. Rudra Sabaratnam for a Medicare and Medi-Cal fraud scheme arising from their former ownership of the Los Angeles City of Angels Medical Center.