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The Governing Committee for the Workers’ Compensation Insurance Rating Bureau will review pending legislative, regulatory and judicial actions during a Sept. 25 meeting. Committee members will hear reports on the annual…

TORONTO - The Canadian Securities Administrators (CSA) today published its biennial

In this episode, Markus talks to Rebecca Wirfs-Brock on what she has learned from architecture reviews. This is a very complement to the earlier episode on architecture evaluation.

Michaela Greiler spoke with SE Radio’s Felienne about code review best practices and how to improve the effectiveness of your reviews.

Billing software for the Mac. A review by Kenneth S. Pope, Ph.D., for psychologists and mental health practitioners.

Office productivity software- A review of Dragon NaturallySpeaking by W. E. Benet, Ph.D., Psy.D., for psychologists and mental health practitioners.

Jim Grisanzio from Oracle Developer Relations talks with Mirela Ardelean about building the Oracle developer community and also the upcoming Oracle Groundbreakers EMEA Virtual Tour 2021 — October 15-29. There will be 70 speakers presenting Oracle technologies over 11 days to 10 UGs! Video on YouTube. Get involved with the event here.

Mirela Ardelean, Oracle ACE, Founder and VP of the Romanian Oracle User Group, Board member of EOUC

• https://twitter.com/Mirela_RoOUG
• http://ogbemea.com

Jim Grisanzio, Oracle Developer Relations

• https://twitter.com/jimgris
• https://www.linkedin.com/in/jimgris/
• https://developer.oracle.com/team/
• https://oraclegroundbreakers.libsyn.com/

Jim Grisanzio from Oracle Developer Relations talks with Oracle ACE Director Francisco Alvarez Munoz about the upcoming APAC Oracle Groundbreakers APAC Virtual Tour. The event takes place over two weeks starting on November 22 and running through December 7. Thousands of developers are expected to participate along with 100 speakers talking about a variety of topics, such as Java, Database, Cloud, APEX, Developer Tools, Data Science, and more. The event schedule will be posted soon. Check the links below and get involved. Video on YouTube.

Francisco Alvarez Munoz, Oracle ACE Director & President of the APAC Oracle User Community

• https://twitter.com/fcomunoz
• https://twitter.com/apacouc
• https://apacgbt.mykommu.com/

Jim Grisanzio, Oracle Developer Relations

• https://twitter.com/jimgris
• https://www.linkedin.com/in/jimgris/
• https://developer.oracle.com/team/
• https://oraclegroundbreakers.libsyn.com/

Jim Grisanzio from Oracle Developer Relations talks with Oracle ACE Director Rita Nunez from Argentina to preview the upcoming 2021 LAOUC Evento de Primavera November 9-10. The event will be held online in Spanish, Portuguese, and English, and it's free and open to developers globally. Technologies discussed will be Oracle Database, security, APEX, Java, development tools, cloud, and more. Get involved here.

Rita Nunez, Oracle ACE Director

• https://twitter.com/ritan2000 

Jim Grisanzio, Oracle Developer Relations

• https://twitter.com/jimgris 
• https://www.linkedin.com/in/jimgris/ 
• https://developer.oracle.com/team/ 
• https://oraclegroundbreakers.libsyn.com/ 

Show reboots can be a hit-or-miss when released because they may not live up to the original. Students share their opinions on reboots they have watched and whether they support the continuation of reboots being produced.

The post Students Share Mixed Reviews on Childhood Show Reboots appeared first on Pepperdine Graphic.

Applied Brain Research's self-contained, single-chip speech recognition solution?can perform real-time low latency automatic speech recognition.

What Danielle Smith posted on her subscribers-only social media; how litter boxes in schools became a Republican talking point; Yankee scented candle reviews as COVID indicator; a surgeon struggles to care for patients through Ethiopia's civil war; Brent Bambury returns and more.

Most recent Reviews and Interviews

St. Vincent has released the new single 'El Mero Cero,' a Spanish language version of her song 'Big Time Nothing.'

New reviews have been added to our Reviews section. These are: AVG Anti-Virus + Firewall, AVG Anti-Malware and Kaspersky Anti-Virus. These reviews are not in depth reviews like the reviews done on the Internet Security products, they only give the user a basic overview of the differences between these products and the more comprehensive versions that's available.

The Book Club: "The Ministry of Time" and more short reviews from readers

This author is best known for her Harry Potter series, but she’s a fine writer for adults, too.

Liz Moore’s latest suspense novel is so compelling I pretty much couldn’t put it down.

It’s rare that I read a book in one day, but Held's writing grabbed me and held on.

Sadly, this is the final installment of the Maisie Dobbs mystery series.

Part mystery, part science fiction, this novel rests upon the alarming premise that time is more than a concept.

"It's a brutal world for all of us, really, and some aspects of it are not comfortable for the sentimental or the squeamish. Somehow that's never dimmed my love for all animals. I celebrate their beauty, even the darker side of it." (Introduction, The Book of Deadly Animals)

"The predators far outnumbered the vegetarians."
(last words, The Red Hourglass: Lives of the Predators)

It's October, the "spooky" month with Halloween at the end of it; I sometimes take advantage of that to bring to light something a bit more horror themed than the usual Flayrah fare.

This year, I'd like to share the non-fiction books of Gordon Grice, which are about animals and their sometimes very tense relationship with man, because they are some of the scariest things I've ever read, and so appropriate enough under the "it's about animals and it's spooky" month to stretch the boundaries of what a furry publication can cover. Furthermore, from a personal angle, Grice spent much of his life where I'm originally from, the Oklahoma Panhandle (we share a birth town), and I occasionally like to shine a light on what would be to me local authors.

"The Red Hourglass: Lives of the Predators", Delacourte Press, 1998, 259 pages, Kindle $5.99, hardcover $19.32, paperback $17.10
"The Book of Deadly Animals", Penguin Books Ltd., 2010, xxvii + 383 pages, Kindle $4.99, paperback $24.00, illustrated, originally published as Deadly Kingdom

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For years TIFF has been intentionally or otherwise making it incrementally more difficult to do the event diehard style, as we have always done. Often it announces changes that blindside longtime loyalists—sometimes, as this year, after they’ve purchased their expensive memberships and ticket packages. This time around they surprised us by taking a tier of titles that any other year would be available through the package we purchased and moving them into a premium package previously reserved for the most publicized Gala films. For good measure, they threw in a couple of other medium-sized irritants.

To recreate something closer to our usual experience, we programmed another 25 titles already available on streaming platforms. Some actually played TIFF in the past; others were the types of movies that could have played the fest but didn’t.

I’m glad that we did, because the TIFF titles we were allowed to choose from included all of the duds of a normal year and none of the surprise masterpieces. Granted, it was a miracle that any films got made this year, and those that did tended toward the sorts of modest chamber pieces that could be produced under COVID protocol conditions.

This year crystallized a gradually growing realization we’ve been trying to suppress. So much has changed in the world of international cinema, from the festival’s position in their life cycle, to their subsequent availability, and even the style of the movies themselves, has completely changed since we started doing this in the mid 80s.

We have always gone to the fest for great films that we could otherwise never see, and started doing it in the VHS era. We don’t care about seeing things before anyone else does, or seeing the stars wave at us from the stage beforehand, or hearing audience members ask directors rambling questions afterwards. Even the virtues of a big screen experience are blunted by a dirty secret — a packed TIFF venue is not actually an ideal place to see a movie. Talkers and smartphone screens abound in every screening, and the bigger venues they convert into movie theaters for ten days are universally terrible.

You’d think that programming films from existing streaming platforms eliminates the other key part of fest-going, the surprise from out of nowhere. Except we got more of those with our alternate schedule than we did with the official titles this year.

In other words, after 36 years we are retiring from our vacation. Next year we’ll be doing a fully alternate replica of TIFF as we think of it from the past. The old rodeo is dead. Long live the new rodeo.

Here then is my final set of Toronto International Film Festival capsule reviews.

(Capsules for the 2021 Robin and Valerie International Film Festival will drop over time in Ken and Robin Consume Media.)

Recommended

Murina (Croatia, Antoneta Alamat Kusijanović) Teen (Gracija Filipovic) chafes at the agitated authority of her command-barking father (Leon Lucev) as he hosts a rich, glamorous old friend (Cliff Curtis) to try to sell him on a resort proposal. Taut, superbly acted family drama set against the stunning yet slightly sinister beauty of the rocky Croatian coastline.

Saloum (Senegal, Jean Luc Herbulot) Three gunslingers—the mastermind, the hard case, and the magic user—take an unscheduled pit stop at an eccentric communal resort, which harbors horrible secrets of both the man-made and supernatural varieties. Gorgeously shot, tightly edited contemporary horror western with political resonance and cool monster design.

Compartment No. 6 (Finland, Juho Kuosmanen) Traveling alone on a trip she was supposed to take with her Muscovite professor girlfriend, a Finnish archaeology student finds herself sharing a compartment on the train to Murmansk with a loutish miner. Naturalistic light romantic drama of human connection overcoming barriers of class and personality.

OUT OF SYNC (Spain, Juanjo Giménez Peña) Isolated sound mixer (Marta Nieto) is unnerved to suffer a strange delay in her hearing, which becomes all the more inexplicable as it worsens. Realist weird tale makes smart use of cinema’s relationship between sight and sound. 

Zalava (Iran, Arsalan Amiri) In pre-Revolutionary Iranian Kurdistan, a pig-headed police sergeant interferes with a djinn exorcism, sparking village hysteria. Tale of communal terror and its hazards generates suspense by skillfully modulating its pace.

Vengeance is Mine, All Others Pay Cash (Indonesia, Edwin) After meeting cute by beating the crap out of each other at a construction site, two lovers navigate the vicissitudes of fidelity, vengeance, and impotence. A martial arts flick that isn’t an action movie, but rather an allegorical romantic drama with elements of satire and magic realism to go with its bruising 70s style fights.

Hold Your Fire (US, Stefan Forbes) Documentary recreates the 1973 robbery-turned-hostage incident in which a group of young black Sunni men hoped to steal guns from a sporting goods shop to protect themselves from the Nation of Islam, in which the beginnings of hostage negotiation techniques were created and implemented on the fly. Archival footage and compelling retrospective interviews illuminate a complicated narrative with resonances into the present day.

A Banquet (UK, Ruth Paxton) After her husband’s death, a brittle woman (Sienna Guillory) struggles with her eldest daughter’s (Jessica Alexander) visionary transformation, which has taken away her need to eat. Slow burn realist cosmic horror filters eating disorders, emotional control and female rage.

Kicking Blood (Canada, Blaine Thurier) Vampire (Alanna Bale) connects with a detoxing alcoholic, prompting her to reconsider preying on humans. Frosty supernatural indie drama extends the vampire-as-addiction metaphor.

Yuni (Indonesia, Kamila Andini) High schooler with a yen for purple chafes at the narrow expectations her religious school, family and village have for her.  Observational social drama enlivened by a vivid color palette.

Good

The Daughter (Spain, Manuel Martín Cuenca) Teacher at a juvenile detention center helps a pregnant 14-year old escape so she can live secretly with him and his wife at their mountain home and give them the baby when it is born. Ultra-restrained domestic thriller could stand a notch or two less restraint.

Dug Dug (India, Ritwik Pareek)  A local saint cult springs up when a motorbike keeps mysteriously returning to the site of its owner’s death. Gentle satire of faith and religious merchandising shows the sort of color and verve that raises hopes for a fresh wave of Indian art cinema.

Tug of War (Tanzania, Amil Shivji) A callow Marxist subversive falls for an Indian girl who has escaped her arranged marriage in British-controlled 1950s Zanzibar. Political romantic drama adopts the language of classic Hollywood glamor, albeit without the magnetic movie star performances the style depends on. Based on a classic Tanzanian novel.

Okay

Earwig (France, Lucile Hadžihalilović) In a creepy manor, an anxious loner (Paul Hilton) looks after a girl with teeth made of ice, at the behest of mysterious masters. The director’s first English language film pushes her dream narratives of childhood transformation into the far fringes of austerity.

Not Recommended

You Are Not My Mother (Ireland, Kate Dolan) A withdrawn teen’s depressed mother briefly disappears, prefiguring the revelation of a supernatural family secret. Contemporary folk horror with stronger direction than script, with extensive foreshadowing genre fans will be well ahead of and an inactive menace that doesn’t do enough to propel the story.

Snakehead (US, Evan Jackson Leong) Smuggled immigrant (Shuya Chang) works off her debt by acting as the right hand to the matriarch (Jade Wu) of an NYC Chinatown crime family. Socially conscious gangland drama features the bane of longtime documentarians turning their hand to fiction:  awkward, exposition-heavy scripting.

Arthur Rambo (France, Laurent Cantet) Rising literary star (Rabah Nait Oufella) plummets when the hate-filled tweets of his old alter ego resurface. Refined, uncinematic debate film presents thesis, antithesis, and credits.

Medusa (Brazil, Anita Rocha da Silveira) Member of AN ultra-right Christian school’s violent, pallid-masked theocratic girl gang  goes undercover at a coma ward in search of a disfigured model. Overlong, unfocused political allegory references the horror genre, chiefly by adopting Dario Argento’s color palette.

After Blue (Dirty Paradise) (France, Bertrand Mandico) On a psychedelic alien world, a young outcast (Paula Luna) frees the statuesque, wish-granting death-dealer Kate Bush and she must accompany her hairdresser mother (Elina Löwensohn) on a quest to hunt her down. Invokes the spirits of Jodorowsky and Barbarella for a sleepwalk trudge through an arbitrary sequence of dream-logic events. Like its influences it is perhaps intended for a chemically altered audience.

La Soga 2 (US, Manny Perez) Dominican hitman (Perez) has gotten out and is living with a devoted new girlfriend, until a corrupt CIA officer pulls him back in. Scrappy microbudget crime flick is Dominican. 

Driving more reviews to your profile for a local listing has always been a great way and still is a great way to increase your local listing visibility. The problem with this is when people started trying to game the system by posting fake reviews. Some companies were posting so many reviews that Google had […]

Reviews of The Cure's Songs of a Lost World. Video sent out by The Cure via Whatsapp.

This article has been withdrawn by the authors as part of this review overlapped with the contents of Pietrangelo A and Ridgway ND. 2018. Cellular and Molecular Life Sciences. 75; 3079-98.

Photoreceptors have high energy-demands and a high density of mitochondria that produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) of fuel substrates. Although glucose is the major fuel for central nervous system (CNS) brain neurons, in photoreceptors (also CNS), most glucose is not metabolized through OXPHOS but is instead metabolized into lactate by aerobic glycolysis. The major fuel sources for photoreceptor mitochondria remained unclear for almost six decades. Similar to other tissues (like heart and skeletal muscle) with high metabolic rates, photoreceptors were recently found to metabolize fatty acids (palmitate) through OXPHOS. Disruption of lipid entry into photoreceptors leads to extracellular lipid accumulation, suppressed glucose transporter expression, and a duel lipid/glucose fuel shortage. Modulation of lipid metabolism helps restore photoreceptor function. However, further elucidation of the types of lipids used as retinal energy sources, the metabolic interaction with other fuel pathways, as well as the crosstalk among retinal cells to provide energy to photoreceptors is not yet known. In this review, we will focus on the current understanding of photoreceptor energy demand and sources, and potential future investigations of photoreceptor metabolism.

Vitamin A aldehyde covalently bound to opsin protein is embedded in a phospholipid-rich membrane that supports photon absorption and phototransduction in photoreceptor cell outer segments. Following absorption of a photon, the 11-cis-retinal chromophore of visual pigment in photoreceptor cells isomerizes to all-trans-retinal. To maintain photosensitivity 11-cis-retinal must be replaced. At the same time, however, all-trans-retinal has to be handled so as to prevent nonspecific aldehyde activity. Some molecules of retinaldehyde upon release from opsin are efficiently reduced to retinol. Other molecules are released into the lipid phase of the disc membrane where they form a conjugate (N-retinylidene-PE, NRPE) through a Schiff base linkage with phosphatidylethanolamine (PE). The reversible formation of NRPE serves as a transient sink for retinaldehyde that is intended to return retinaldehyde to the visual cycle. However, if instead of hydrolyzing to PE and retinaldehyde, NRPE reacts with a second molecule of retinaldehyde a synthetic pathway is initiated that leads to the formation of multiple species of unwanted bisretinoid fluorophores. We report on recently identified members of the bisretinoid family some of which differ with respect to the acyl chains associated with the glycerol backbone. We discuss processing of the lipid moieties of these fluorophores in lysosomes of retinal pigment epithelial (RPE) cells, their fluorescence characters and new findings related to light and iron-associated oxidation of bisretinoids.

Driven by the energy of a photon, the visual pigments in rod and cone photoreceptor cells isomerize 11-cis-retinal to the all-trans configuration. This photochemical reaction initiates the signal transduction pathway that eventually leads to the transmission of a visual signal to the brain and leaves the opsins insensitive to further light stimulation. For the eye to restore light sensitivity, opsins require recharging with 11-cis-retinal. This trans–cis back conversion is achieved through a series of enzymatic reactions composing the retinoid (visual) cycle. Although it is evident that the classical retinoid cycle is critical for vision, the existence of an adjunct pathway for 11-cis-retinal regeneration has been debated for many years. Retinal pigment epithelium (RPE)–retinal G protein-coupled receptor (RGR) has been identified previously as a mammalian retinaldehyde photoisomerase homologous to retinochrome found in invertebrates. Using pharmacological, genetic, and biochemical approaches, researchers have now established the physiological relevance of the RGR in 11-cis-retinal regeneration. The photoisomerase activity of RGR in the RPE and Müller glia explains how the eye can remain responsive in daylight. In this review, we will focus on retinoid metabolism in the eye and visual chromophore regeneration mediated by RGR.  

The field of phosphoinositide signaling has expanded significantly in recent years. Phosphoinositides (PIs) are universal signaling molecules that directly interact with membrane proteins or with cytosolic proteins containing domains that directly bind phosphoinositides and are recruited to cell membranes. Through the activities of PI kinases and PI phosphatases, seven distinct phosphoinositide lipid molecules are formed from the parent molecule phosphatidylinositol. PI signals regulate a wide range of cellular functions, including cytoskeletal assembly, membrane binding and fusion, ciliogenesis, vesicular transport, and signal transduction. Given the many excellent reviews on phosphoinositide kinases, phosphoinositide phosphatases, and PIs in general, in this review, we discuss recent studies and advances in PI lipid signaling in the retina. We specifically focus on PI lipids from vertebrate (e.g. bovine, rat, mice, toad, and zebrafish) and invertebrate (e.g. drosophila, horseshoe crab, and squid) retinas. We also discuss the importance of PIs revealed from animal models and human diseases, and methods to study PI levels both in vitro and in vivo. We propose that future studies should investigate the function and mechanism of activation of PI-modifying enzymes/phosphatases and further unravel PI regulation and function in the different cell types of the retina.

     Lens and tear film lipids are as unique as the systems they reside in. The major lipid of the human lens is dihydrosphingomylein, found in quantity only in the lens. The lens contains a cholesterol to phospholipid molar ratio as high as 10:1, more than anywhere in the body. Lens lipids contribute to maintaining lens clarity, and alterations in lens lipid composition due to age are likely to contribute to cataract. Lens lipid composition reflects adaptations to the unique characteristics of the lens: no turnover of lens lipids or proteins; the lowest amount of oxygen than any other tissue and contains almost no intracellular organelles. The tear film lipid layer (TFLL) is also unique. The TFLL is a thin, 100 nm layer of lipid on the surface of tears covering the cornea that contributes to tear film stability. The major lipids of the TFLL are wax esters and cholesterol esters that are not found in the lens. The hydrocarbon chains associated with the esters are longer than those found anywhere in the body, as long as 32 carbons, and many are branched. Changes in the composition and structure of the 30,000 different moieties of TFLL contribute to the instability of tears. The focus of the current review is how spectroscopy has been used to elucidate the relationships between lipid composition, conformational order and function and the etiology of cataract and dry eye.

Abstract

After training as a gastroenterologist in the UK the author became interested in lipidology while he was a research fellow in the USA and switched careers after returning home. Together with Nick Myant he introduced the use of plasma exchange to treat FH homozygotes and undertook non-steady state studies of LDL kinetics, which showed that the fractional catabolic rate of LDL remained constant irrespective of pool size. Subsequent steady-state turnover studies showed that FH homozygotes had an almost complete lack of receptor-mediated LDL catabolism, providing in vivo confirmation of the Nobel Prize-winning discovery by Goldstein and Brown that LDL receptor dysfunction was the cause of FH. Further investigation of metabolic defects in FH revealed that a significant proportion of LDL in homozygotes and heterozygotes was produced directly via a VLDL-independent pathway.

Management of heterozygous FH has been greatly facilitated by statins and PCSK9 inhibitors but remains dependent upon lipoprotein apheresis in homozygotes. In a recent analysis of a large cohort treated with a combination of lipid-lowering measures survival was markedly enhanced in homozygotes in the lowest quartile of on-treatment serum cholesterol. Emerging therapies could further improve the prognosis of homozygous FH whereas in heterozygotes the current need is better detection.

Since the publication of the Age-Related Eye Disease Study (AREDS2) in 2013, the macular pigment carotenoids lutein and zeaxanthin have become well known to both the eye care community and the public. It is a fascinating aspect of evolution that primates have repurposed photoprotective pigments and binding proteins from plants and insects to protect and enhance visual acuity. Moreover, utilization of these plant-derived nutrients has been widely embraced for preventing vision loss from age-related macular degeneration (AMD). More recently, there has been growing awareness that these nutrients can also play a role in improving visual performance in adults. On the other hand, the potential benefits of lutein and zeaxanthin supplementation at very young ages have been underappreciated. In this review, we examine the biochemical mechanisms and supportive data for lutein and zeaxanthin supplementation throughout the lifespan, with particular emphasis on prenatal supplementation. We propose that prenatal nutritional recommendations may aim at improving maternal and infant carotenoid status. Prenatal supplementation with lutein and zeaxanthin might enhance infant visual development and performance and may even prevent retinopathy of prematurity, possibilities that should be examined in future clinical studies.

The cornea is densely innervated, mainly by sensory nerves of the ophthalmic branch of the trigeminal ganglia (TG). These nerves  are important to maintain corneal homeostasis, and nerve damage can lead to a decrease in wound healing, an increase in corneal ulceration and dry eye disease (DED), and neuropathic pain. Pathologies, such as diabetes, aging, viral and bacterial infection, as well as  prolonged use of contact lenses and surgeries to correct vision can produce nerve damage. There are no effective therapies to alleviate DED (a multifunctional disease) and several clinical trials using -3 supplementation show unclear and sometimes negative results. Using animal models of corneal nerve damage, we show that treating corneas with pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) increases nerve regeneration, wound healing, and tear secretion. The mechanism involves the activation of a calcium-independent phospholipase A2 (iPLA2) that releases the incorporated DHA from phospholipids and enhances the synthesis of docosanoids neuroprotectin D1 (NPD1) and a new resolvin stereoisomer  RvD6i. NPD1 stimulates the synthesis of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and of semaphorin 7A (Sema7A).  RvD6i treatment of injured corneas modulates gene expression in the TG resulting in enhanced neurogenesis; decreased neuropathic pain and increased sensitivity. Taken together, these results represent a promising therapeutic option to re-establish the homeostasis of the cornea.

Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is, therefore, crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) emerges as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine-1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide-1-phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.

Cholesterol is a quantitatively and biologically significant constituent of all mammalian cell membrane, including those that comprise the retina. Retinal cholesterol homeostasis entails the interplay between de novo synthesis, uptake, intra-retinal sterol transport, metabolism and efflux. Defects in these complex processes are associated with several congenital and age-related disorders of the visual system. Herein, we provide an overview of the following topics: a) cholesterol synthesis in the neural retina; b) lipoprotein uptake and intraretinal sterol transport in the neural retina and the retinal pigment epithelium (RPE); c) cholesterol efflux from the neural retina and the RPE; and d) biology and pathobiology of defects in sterol synthesis and sterol oxidation in the neural retina and the RPE. We focus, in particular, on studies involving animal models of monogenic disorders pertinent to the above topics, as well as in vitro models using biochemical, metabolic, and omic approaches. We also identify current knowledge gaps as well as opportunities in the field that beg further research in this topic area.

The essential fatty acid DHA (22:6, omega-3 or n-3) is enriched in and required for the membrane biogenesis and function of photoreceptor cells (PRC), synapses, mitochondria, etc. of the CNS. PRC DHA becomes an acyl chain at the sn-2 of phosphatidylcholine (PC), amounting to more than 50% of the PRC outer segment phospholipids, where phototransduction takes place. Very long chain PUFAs (VLC-PUFAs,n-3, ≥ 28 carbons) are at the sn-1 of this PC molecular species and interact with rhodopsin. PRC shed their tips (DHA-rich membrane disks) daily, which in turn are phagocytized by the retinal pigment epithelium (RPE), where DHA is recycled back to PRC inner segments to be used for the biogenesis of new photoreceptor membranes. Here, we review the structures and stereochemistry of novel elovanoid (ELV)-N32 and ELV-N34 to be ELV-N32: (14Z,17Z,20R,21E,23E,25Z,27S,29Z)-20,27-dihydroxydo-triaconta-14,17,21,23,25,29-hexaenoic acid; ELV-N34: (16Z,19Z,22R,23E,25E,27Z,29S,31Z)-22,29-dihydroxytetra-triaconta-16,19,23,25,27,31-hexaenoic acid. ELVs are low-abundance, high-potency, protective mediators. Their bioactivity includes enhancing of anti-apoptotic and pro-survival protein expression with concomitant downregulation of pro-apoptotic proteins when RPE is confronted with uncompensated oxidative stress (UOS). ELVs also target PRC/RPE senescence gene programming, the senescence secretory phenotype in the interphotoreceptor matrix (IPM), as well as inflammaging (chronic, sterile, low-grade inflammation). An important lesson on neuroprotection is highlighted by the ELV mediators that target the terminally differentiated PRC and RPE, sustaining a beautifully synchronized renewal process. The role of ELVs in PRC and RPE viability and function uncovers insights on disease mechanisms and the development of therapeutics for age-related macular degeneration (AMD), Alzheimer’s disease (AD), and other pathologies.

Lipid metabolic abnormalities have emerged as potential risk factors for the development and progression of diabetic complications, including diabetic retinopathy (DR).  This review article provides an overview of the results of clinical trials evaluating the potential benefits of lipid lowering drugs, such as fibrates, omega 3 fatty acids, and statins, for the prevention and treatment of DR. Although several clinical trials demonstrated that treatment with fibrates leads to improvement of DR, there is a dissociation between the protective effects of fibrates in the retina, and the intended blood lipid classes, including plasma triglycerides, total cholesterol or HDL/LDL cholesterol ratio. Guided by these findings, plasma lipid and lipoprotein-independent mechanisms are addressed based on clinical, cell culture and animal model studies. Potential retinal-specific effects of fatty acids oxidation products, cholesterol, and ceramide, as well as lipid independent effects of PPAR alpha activation are summarized based on current literature. Overall, this review highlights promising potential of lipid-based treatment strategies further enhanced by the new knowledge of intra-retinal lipids and lipoproteins in DR.

Some cases of chylomicronemia are caused by autoantibodies against glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), an endothelial cell protein that shuttles LPL to the capillary lumen. GPIHBP1 autoantibodies prevent binding and transport of LPL by GPIHBP1, thereby disrupting the lipolytic processing of triglyceride-rich lipoproteins. Here, we review the "GPIHBP1 autoantibody syndrome" and summarize clinical and laboratory findings in 22 patients. All patients had GPIHBP1 autoantibodies and chylomicronemia, but we did not find a correlation between triglyceride levels and autoantibody levels. Many of the patients had a history of pancreatitis, and most had clinical and/or serological evidence of autoimmune disease. IgA autoantibodies were present in all patients, and IgG4 autoantibodies were present in 19 of 22 patients. Patients with GPIHBP1 autoantibodies had low plasma LPL levels, consistent with impaired delivery of LPL into capillaries. Plasma levels of GPIHBP1, measured with a monoclonal antibody–based ELISA, were very low in 17 patients, reflecting the inability of the ELISA to detect GPIHBP1 in the presence of autoantibodies (immunoassay interference). However, GPIHBP1 levels were very high in five patients, indicating little capacity of their autoantibodies to interfere with the ELISA. Recently, several GPIHBP1 autoantibody syndrome patients were treated successfully with rituximab, resulting in the disappearance of GPIHBP1 autoantibodies and normalization of both plasma triglyceride and LPL levels. The GPIHBP1 autoantibody syndrome should be considered in any patient with newly acquired and unexplained chylomicronemia.

Phosphatidate phosphatase (PAP) catalyzes the penultimate step in the synthesis of triacylglycerol and regulates the synthesis of membrane phospholipids. There is much interest in this enzyme because it controls the cellular levels of its substrate, phosphatidate (PA), and product, DAG; defects in the metabolism of these lipid intermediates are the basis for lipid-based diseases such as obesity, lipodystrophy, and inflammation. The measurement of PAP activity is required for studies aimed at understanding its mechanisms of action, how it is regulated, and for screening its activators and/or inhibitors. Enzyme activity is determined through the use of radioactive and nonradioactive assays that measure the product, DAG, or P_i. However, sensitivity and ease of use are variable across these methods. This review summarizes approaches to synthesize radioactive PA, to analyze radioactive and nonradioactive products, DAG and P_i, and discusses the advantages and disadvantages of each PAP assay.

Resurrecting an old idea about assessing school quality could allow schools to examine a broad range of data on performance and practices and lead to improvement.

The Apex Committee of the Special Investment Facilitation Council (SIFC) met to evaluate advancements in fostering investments in Pakistan. Chaired by the caretaker prime minister, discussions encompassed strategies such as the privatization of financially struggling government institutions. In a separate interaction, the Army Chief reiterated the armed forces’ dedication to supporting the nation’s economic stability. ... Read more

The post Special Investment Facilitation Council Reviews Progress and Strategies for Economic Stability in Pakistan appeared first on Pakistan Tribune.

Massively parallel reporter assays (MPRAs) are powerful tools for quantifying the impacts of sequence variation on gene expression. Reading out molecular phenotypes with sequencing enables interrogating the impact of sequence variation beyond genome scale. Machine learning models integrate and codify information learned from MPRAs and enable generalization by predicting sequences outside the training data set. Models can provide a quantitative understanding of cis-regulatory codes controlling gene expression, enable variant stratification, and guide the design of synthetic regulatory elements for applications from synthetic biology to mRNA and gene therapy. This review focuses on cis-regulatory MPRAs, particularly those that interrogate cotranscriptional and post-transcriptional processes: alternative splicing, cleavage and polyadenylation, translation, and mRNA decay.

Cellular plasticity in adult multicellular organisms is a protective mechanism that allows certain tissues to regenerate in response to injury. Considering that aging involves exposure to repeated injuries over a lifetime, it is conceivable that cell identity itself is more malleable—and potentially erroneous—with age. In this review, we summarize and critically discuss the available evidence that cells undergo age-related shifts in identity, with an emphasis on those that contribute to age-associated pathologies, including neurodegeneration and cancer. Specifically, we focus on reported instances of programs associated with dedifferentiation, biased differentiation, acquisition of features from alternative lineages, and entry into a preneoplastic state. As some of the most promising approaches to rejuvenate cells reportedly also elicit transient changes to cell identity, we further discuss whether cell state change and rejuvenation can be uncoupled to yield more tractable therapeutic strategies.