Eyad Naser
Mar 10, 2020; 0:jlr.RA120000682v1-jlr.RA120000682
Research Articles

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Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM’s catalytic activity in cultured cells, a mechanism which differs from that of functional inhibitors of ASM (FIASMAs). We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASMpromoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.

Analyzing global steroid metabolism in humans can shed light on the etiologies of steroid-related diseases. However, existing methods require large amounts of serum and lack the evaluation of accuracy. Here, we developed an LC/MS/MS method for the simultaneous quantification of 12 steroid hormones: testosterone, pregnenolone, progesterone, androstenedione, corticosterone, 11-deoxycortisol, cortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, estriol, and estradiol. Steroids and spiked internal standards in 100 μl serum were extracted by protein precipitation and liquid-liquid extraction. The organic phase was dried by evaporation, and isonicotinoyl chloride was added for steroid derivatization, followed by evaporation under nitrogen and redissolution in 50% methanol. Chromatographic separation was performed on a reverse-phase PFP column, and analytes were detected on a triple quadrupole mass spectrometer with ESI. The lower limits of quantification ranged from 0.005 ng/ml for estradiol to 1 ng/ml for cortisol. Apparent recoveries of steroids at high, medium, and low concentrations in quality control samples were between 86.4% and 115.0%. There were limited biases (–10.7% to 10.5%) between the measured values and the authentic values, indicating that the method has excellent reliability. An analysis of the steroid metabolome in pregnant women highlighted the applicability of the method in clinical serum samples. We conclude that the LC/MS/MS method reported here enables steroid metabolome analysis with high accuracy and reduced serum consumption, indicating that it may be a useful tool in both clinical and scientific laboratory research.

The actin cytoskeleton is extremely dynamic and supports diverse cellular functions in many physiological and pathological processes, including tumorigenesis. However, the mechanisms that regulate the actin-related protein 2/3 (ARP2/3) complex and thereby promote actin polymerization and organization in cancer cells are not well-understood. We previously implicated the proline-rich 11 (PRR11) protein in lung cancer development. In this study, using immunofluorescence staining, actin polymerization assays, and siRNA-mediated gene silencing, we uncovered that cytoplasmic PRR11 is involved in F-actin polymerization and organization. We found that dysregulation of PRR11 expression results in F-actin rearrangement and nuclear instability in non-small cell lung cancer cells. Results from molecular mechanistic experiments indicated that PRR11 associates with and recruits the ARP2/3 complex, facilitates F-actin polymerization, and thereby disrupts the F-actin cytoskeleton, leading to abnormal nuclear lamina assembly and chromatin reorganization. Inhibition of the ARP2/3 complex activity abolished irregular F-actin polymerization, lamina assembly, and chromatin reorganization due to PRR11 overexpression. Notably, experiments with truncated PRR11 variants revealed that PRR11 regulates F-actin through different regions. We found that deletion of either the N or C terminus of PRR11 abrogates its effects on F-actin polymerization and nuclear instability and that deletion of amino acid residues 100–184 or 100–200 strongly induces an F-actin structure called the actin comet tail, not observed with WT PRR11. Our findings indicate that cytoplasmic PRR11 plays an essential role in regulating F-actin assembly and nuclear stability by recruiting the ARP2/3 complex in human non-small cell lung carcinoma cells.

AS ARTISTES and musicians try to manage the situation brought on by COVID-19’s stranglehold on the world and its economy, in the interim, many have resorted to hosting live-stream events. But that only succeeds to a point. Performers retain their...

There has been an outpouring of grief following the death of legendary Jamaican singer Millicent Dolly May Small, popularly known as Millie Small. She died in the United Kingdom today at the age of 73 after suffering a stroke. The voice...

BEFORE MILLIE Small became the ‘lollipop girl’, she was a ‘sugar plum’. Not only is it a term of endearment, it is also the title of her first song – a duet as it was called back in 1960 – with singer Owen Gray. This collab was born out of the time...

The actin cytoskeleton is extremely dynamic and supports diverse cellular functions in many physiological and pathological processes, including tumorigenesis. However, the mechanisms that regulate the actin-related protein 2/3 (ARP2/3) complex and thereby promote actin polymerization and organization in cancer cells are not well-understood. We previously implicated the proline-rich 11 (PRR11) protein in lung cancer development. In this study, using immunofluorescence staining, actin polymerization assays, and siRNA-mediated gene silencing, we uncovered that cytoplasmic PRR11 is involved in F-actin polymerization and organization. We found that dysregulation of PRR11 expression results in F-actin rearrangement and nuclear instability in non-small cell lung cancer cells. Results from molecular mechanistic experiments indicated that PRR11 associates with and recruits the ARP2/3 complex, facilitates F-actin polymerization, and thereby disrupts the F-actin cytoskeleton, leading to abnormal nuclear lamina assembly and chromatin reorganization. Inhibition of the ARP2/3 complex activity abolished irregular F-actin polymerization, lamina assembly, and chromatin reorganization due to PRR11 overexpression. Notably, experiments with truncated PRR11 variants revealed that PRR11 regulates F-actin through different regions. We found that deletion of either the N or C terminus of PRR11 abrogates its effects on F-actin polymerization and nuclear instability and that deletion of amino acid residues 100–184 or 100–200 strongly induces an F-actin structure called the actin comet tail, not observed with WT PRR11. Our findings indicate that cytoplasmic PRR11 plays an essential role in regulating F-actin assembly and nuclear stability by recruiting the ARP2/3 complex in human non-small cell lung carcinoma cells.

Israel's Ministry of Defense ordered small drones for its ground forces working in urban areas, maker Rafael Advanced Defense Systems Ltd. said Monday.

The ADA, along with a large group of other dental organizations, told the U.S. Department of Labor that they are concerned about provisions in HR 6201, the Families First Coronavirus Response Act as related to family and medical leave and paid sick leave.

As Congress works on a third legislation package in response to the coronavirus pandemic, the ADA is asking lawmakers to include provisions on how to assist dental practices and other small businesses facing economic burdens.

The Association continues to wait for clear guidance from the U.S. Department of Treasury and Small Business Administration on the best way to help dentists considering applying for Paycheck Protection Program 7(a) loans and Economic Injury Disaster Loans.

Dentists can apply for both Economic Injury Disaster Loans and Paycheck Protection Program 7(a) loans, the Small Business Administration told the American Dental Association on April 6.

The ADA webinar, Small Business Administration Loans: Understanding the Options for Dentist Owners, is available online.

The ADA is urging Congress to continue supporting small businesses during the COVID-19 pandemic by increasing funding and streamlining the application process for Small Business Administration loans.

The Senate passed new coronavirus relief legislation April 21 calling for much-needed funding for depleted federal loan programs that could help businesses nationwide, including dentists and dental practices, recover from the economic fallout of the pandemic.

"Real Housewives of New York" star Tinsley Mortimer gave an update on her wedding plans amid the coronavirus pandemic.

In five northern U.S. states, black students comprise more than a fifth of ELL enrollment.

A school district in a small Arkansas city has installed steel safe rooms in every classroom.

Museums -- Collection management -- United States.

A little-known monument in Emporia, Kan., which recently received federal recognition, will add 10 new names to the list of teachers and support staff who’ve died on the job.

In five northern U.S. states, black students comprise more than a fifth of ELL enrollment.

Emily Berg, Danhyang Lee.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2158--2188.

Abstract:
Quantiles of the distributions of several measures of erosion are important parameters in the Conservation Effects Assessment Project, a survey intended to quantify soil and nutrient loss on crop fields. Because sample sizes for domains of interest are too small to support reliable direct estimators, model based methods are needed. Quantile regression is appealing for CEAP because finding a single family of parametric models that adequately describes the distributions of all variables is difficult and small area quantiles are parameters of interest. We construct empirical Bayes predictors and bootstrap mean squared error estimators based on the linearly interpolated generalized Pareto distribution (LIGPD). We apply the procedures to predict county-level quantiles for four types of erosion in Wisconsin and validate the procedures through simulation.

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Over the past years, we have often been reminded that we must leave no one behind as we strive to cement our plans for a sustainable future. Most recent data indicate that many of the Small Island Developing States (SIDS) have achieved undernourishment levels of less than 5 percent. Good governance is perhaps the most essential factor in increasing food [...]

The crustaceans' guts pulverize plastics into tiny bits that can be consumed by even smaller creatures at the base of the ocean food chain

The Beatles guitarist visited his sister in southern Illinois just months before he'd become world famous

From gas stations to public libraries, these celebrity architect-designed buildings are worth a road trip

Since early 2019, the Russell 2000, the primary index for small cap stocks, has lagged mid and large cap benchmarks....

The post Why Small Caps Lag In This Economic Downturn appeared first on OpenMarkets.

Michell Jesse said the personal care home operators she represents have been frustrated trying to keep up with the government's direction during an already stressful time.

Curbside pickups offer a bit of hope after months of being shuttered by COVID-19, but while retailers are happy to start getting back to business some are raising questions of fairness and access to opportunity.

She only came for a week, but impacted lives of several families with children with autism. Isabel Black shares about her experiences in Montenegro.

God answers the prayers of OM Guatemala and a partnering church with a Christmas celebration for children and families with OM’s Project Rescue.

A change of plans for OM Panama volunteers leads to a powerful prayer meeting.

During Easter, the oldest town in Austria celebrated the life of Jesus and furthered the dream of planting a church.

Millie Small, who died Tuesday at age 73 in London, was the first Jamaican artiste to score a hit on the British pop chart. Her version of My Boy Lollipop reached number two in 1964 and was also successful in the United States, Ireland, Canada, Australia, and New Zealand.

MOST people's memories of Millie Small in 1964 are of her climbing international charts with the massive hit song, My Boy Lollipop. But for Dennis Smith, it was her return to Jamaica that year that made the greatest impression.

Participants of OM Costa Rica's Pearl Process programme start their own small groups to impact more women in high-risk communities.

THE most important lesson in life is to always travel in hope rather than expectation. That way the almost inevitable disappointment that follows isn’t quite as crushing. A cheery thought for these troubled times.

The free literacy app Khan Academy Kids boosted early literacy skills in children and parents said it improved their home-teaching skills.

Smaller classes could help bridge the gap between home and school, writes former teacher Marc Vincenti.

Stand-up Romesh Ranganathan is back with a second series of topical comedy show The Ranganation. He talks to Sherna Noah about filming the show in lockdown, the place of comedy in a crisis, and spending so much time with his family.

In five northern U.S. states, black students comprise more than a fifth of ELL enrollment.

Children born small for gestational age (SGA) have increased risk of perinatal morbidity and mortality, neonatal death, and cerebral palsy (CP). Causes of SGA, such as congenital malformations, intrauterine infections, and preeclampsia, are also risk factors for the same outcomes.

In 90% of singletons born SGA, CP is apparently of prenatal origin. Low proportions of intrapartum events leading to CP could not be fully explained by a higher neonatal mortality rate in SGA than in non-SGA children. (Read the full article)

Acquired widespread pain syndromes of youth are prevalent, disabling, usually unexplained, and untreatable. Small-fiber polyneuropathy causes widespread pain and multisystem complaints in older adults. Some causes are treatable. Neurodiagnostic skin biopsy, autonomic function testing, and nerve biopsy permit objective diagnosis.

It identifies definite (in 59%) and probable (in 17%) small-fiber polyneuropathy among 41 young patients with otherwise-unexplained, childhood-onset widespread pain. It characterizes this new disease’s clinical features, diagnostic, and treatment options. Some cases appeared immune mediated and responded to immunomodulatory therapies. (Read the full article)

Prescribing patterns in the US pediatric population are changing but not uniformly. A detailed examination of prescription variation is needed to better understand pharmacotherapy of children and to inform future exploration of the causes and consequences of diverse practices.

We examine pediatric pharmacotherapy and quantify payer type differences and small geographic area variation. Substantial payer-type differences and regional variations were found, likely reflecting local practice cultures. Variation was greatest for medications used in situations of diagnostic and therapeutic uncertainty. (Read the full article)

Small-for-gestational-age neonates are at risk for thrombocytopenia during the first days and weeks after birth. However, the incidence, duration, severity, responsible mechanism, value of platelet transfusions, and risk of death from this variety of neonatal thrombocytopenia are unknown.

Ten percent of thrombocytopenic small-for-gestational-age neonates have a recognized cause for low platelets (aneuploidy, extracorporeal membrane oxygenation, disseminated intravascular coagulation); they have a high mortality rate (65%). Ninety percent have a moderate, transient (2 weeks), hyporegenerative thrombocytopenia with a low mortality rate (2%). (Read the full article)