The national security adviser, a border tsar and UN ambassador are appointed but there are plenty more posts to fill.

World champions South Africa are aiming to have "the two best teams in the world", according to centre Andre Esterhuizen.

Known as Buz Stop Boys, the group's leader says they want "a cleaner, healthier, and prouder Ghana".

With her eye in the sky, Joanna Steidle captures images of the elusive creatures.

It has been a night of contrasting emotions as vote-counting continues across key swing states.

Watch the moment phone thieves were caught after stealing 35 phones in south-east London.

BBC Radio London's team of swimmers have completed their part of the 1,000-mile challenge.

After every round of Premier League matches this season, Troy Deeney gives us his team of the week. Do you agree with his choices?

Scotland are closing the gap on the world's top teams and can still finish second in their Nations League group despite their eight-game run without a win, assistant head coach John Carver insists.

1. 'There's a guy in Indian team whose Test average is 63...': Tim Paine wants Rohit and Gambhir to open their eyes  Hindustan Times
2. EXCLUSIVE | Dhruv Jurel can be the X-factor India are looking for in Australia, says Suresh Raina  The Times of India
3. Former Australia captain tips India youngster to shine Down Under  ICC Cricket
4. Not Rishabh Pant or Yashasvi Jaiswal; Ex- Australian captain backs this Indian young player to impress everyone in Border-Gavaskar Trophy, says 'class above all his teammates on this tour'  SportsTak
5. Why India should play Jurel as a specialist batsman at Perth  The Indian Express

The CEO of a California gay charity has been charged with embezzling almost a million bucks of the organization’s money. The charity official, Jacob Joseph Aaron Rostovsky, has been charged with 53 felony counts including fraudulent claims, grand theft, misappropriation of public funds, insurance fraud, perjury and money laundering, according to KTLA-TV. The DA said […]

The post CEO of Gay Nonprofit Charged for Stealing Organization’s Money appeared first on The Lid.

A “teacher” at Chino Valley School District launched into an unhinged rant after a student entered his classroom wearing a Trump hat. His name is Clyde J Colinco, who is also the girls golf course, and unfortunately, he still appears to be employed at Chino High School. “Trump Derangement Syndrome is a real thing. If […]

The post Teacher at Chino Valley School District Goes Off the Rails over a Student With a Trump Hat appeared first on The Lid.

velocityconf: Help your dev + ops teams be cross-functional and more successful. http://t.co/1mqGK3zh0U Free webcast 5/22 w/ @lnxchk

Teachers can use evidence-based strategies for delivering vocabulary instruction to improve reading comprehension and vice versa by integrating literacy across content areas. These should engage students in active processing, which is essential to student learning and retention.

A new children's book transforms a sad, scared and anxious little boy into a superhero. The book is called "Cape," in honor of the bright-red cape the little boy wears and finds comfort in following the death of his father. "Cape" is Kevin Johnson's debut picture book, and it's vividly illustrated by artist Kitt Thomas.

While many teachers are embracing generative artificial intelligence—the technology behind powerful new tools that analyze huge amounts of online data and then use it to create unique text and images from basic prompts—others are still wary of the technology and even feel overwhelmed by it. For that latter group, Kristen Brooks, a technology specialist in Cherokee County schools outside of Atlanta, has three simple strategies for teachers to get their feet wet.

In some parts of the capital, protesters negotiated with police. In other parts there was no talking.

Teacher question: I understand your claims that teaching students with grade-level texts instead of instructional level texts increases children’s opportunities to learn. However, what about children’s emotional needs, self-esteem, motivation, and self-starting skills when text is challenging. Children who struggle with sight words or sounding out words who are given a hard piece of text will shut down and refuse to try or will act out in the classroom.

I’m writing this blog because of the disarray I see over the topic of context instruction and the poor instructional practice that it seems to manifest. One confusion is already well recognized, but merits some mention here. The other befuddlement usually goes without remark, and yet it, too, has unfortunate consequences for young readers.

Teacher question: One of my colleagues told us that we should not be teaching guided reading lessons or comprehension skills or strategies. We’re using a core reading program that includes those kinds of things. He says that the science of reading proves that we would get higher reading achievement by teaching more social studies and science (he’s our science teacher) and dropping the comprehension instruction that we are providing. He’s really vocal about this. Can you help us shut him up? Shanahan’s response

This article describes the current findings on phonics and phonological awareness instruction. It uses a question & answer format to explore 10 common questions that teachers ask about teaching phonics and phonemic awareness. Here are a few key questions addressed in the article: What are phonics and phonemic awareness? Should phonemic awareness be paired with print and taught together? Should phonological awareness be coordinated with phonics instruction? What is the best sequence for teaching phonics?

The Gauteng education department has postponed the appointment of new office-based staff as well as teachers who applied to be promoted as heads of department, deputy principals and principals until April because of budget constraints.

TL;DR: If you still don't have a mouse for your WFH setup, get this ergonomic Logitech MX mouse for $89.99 (reg. $99)!

You know what part of you body seriously takes a beating after a long day or week of work? No, it's not your neck—though you need a more supportive office chair. — Read the rest

The post Your hand is cramping up! Use this ergonomic mouse instead appeared first on Boing Boing.

The following article, Teacher at Chino Valley School District Goes Off the Rails over a Student With a Trump Hat, was first published on Conservative Firing Line.

A “teacher” at Chino Valley School District launched into an unhinged rant after a student entered his classroom wearing a Trump hat. His name is Clyde J Colinco, who is also the girls golf course, and unfortunately, he still appears to be employed at Chino High School. “Trump Derangement Syndrome is a real thing. If …

Continue reading Teacher at Chino Valley School District Goes Off the Rails over a Student With a Trump Hat ...

It was supposed to be a push to help her over the finish line. It ended up giving Trump a free shot with their audience instead.

The post OOPS: SNL Tried To Help Kamala… But Boosted TRUMP Instead (VIDEO) appeared first on Clash Daily.

A.F. Branco Cartoon – The Media (CBS, MSNBC, CNN, ABC, etc. are showing their complete bias in support of Kamala..

New York Judge Juan Merchan — who is overseeing President-elect Donald Trump’s business records case — agreed to freeze the case until Nov. 19. There was to be a hearing […]

The post Judge Juan Merchan Grants Request from Trump's Legal Team and DA in NY Hush Money Case appeared first on The Western Journal.

Sri Lanka's cricket board named former South African batsman Neil McKenzie as a consultant coach ahead of their Test tour of South Africa.

The Springboks will continue to evolve their attack, but they must do so within the framework of what has made them so successful, says attack coach Tony Brown.

The main protease (3CL Mpro) from SARS–CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication. 3CL Mpro possesses an unusual catalytic dyad composed of Cys145 and His41 residues. A critical question in the field has been what the protonation states of the ionizable residues in the substrate-binding active-site cavity are; resolving this point would help understand the catalytic details of the enzyme and inform rational drug development against this pernicious virus. Here, we present the room-temperature neutron structure of 3CL Mpro, which allowed direct determination of hydrogen atom positions and, hence, protonation states in the protease. We observe that the catalytic site natively adopts a zwitterionic reactive form in which Cys145 is in the negatively charged thiolate state and His41 is doubly protonated and positively charged, instead of the neutral unreactive state usually envisaged. The neutron structure also identified the protonation states, and thus electrical charges, of all other amino acid residues and revealed intricate hydrogen-bonding networks in the active-site cavity and at the dimer interface. The fine atomic details present in this structure were made possible by the unique scattering properties of the neutron, which is an ideal probe for locating hydrogen positions and experimentally determining protonation states at near-physiological temperature. Our observations provide critical information for structure-assisted and computational drug design, allowing precise tailoring of inhibitors to the enzyme's electrostatic environment.

James M. Ntambi
Sep 1, 1999; 40:1549-1558
Reviews

Expert

Nigy Boy's management team was forced to put out a scam alert on Thursday as news surfaced that a promoter in the Turks and Caicos Islands, inadvertently wired thousands of US dollars to who he believed was the artiste's booking team as a deposit...

The Clarendon police have arrested and charged 25-year-old landscaper Anthony Marshall, of Lamparth district, Trout Hall in the parish for allegedly stealing oranges from a property in his community on Sunday.

Proteins in the α-macroglobulin (αM) superfamily use thiol esters to form covalent conjugation products upon their proteolytic activation. αM protease inhibitors use theirs to conjugate proteases and preferentially react with primary amines (e.g. on lysine side chains), whereas those of αM complement components C3 and C4B have an increased hydroxyl reactivity that is conveyed by a conserved histidine residue and allows conjugation to cell surface glycans. Human α2-macroglobulin–like protein 1 (A2ML1) is a monomeric protease inhibitor but has the hydroxyl reactivity–conveying histidine residue. Here, we have investigated the role of hydroxyl reactivity in a protease inhibitor by comparing recombinant WT A2ML1 and the A2ML1 H1084N mutant in which this histidine is removed. Both of A2ML1s' thiol esters were reactive toward the amine substrate glycine, but only WT A2ML1 reacted with the hydroxyl substrate glycerol, demonstrating that His-1084 increases the hydroxyl reactivity of A2ML1's thiol ester. Although both A2ML1s conjugated and inhibited thermolysin, His-1084 was required for the conjugation and inhibition of acetylated thermolysin, which lacks primary amines. Using MS, we identified an ester bond formed between a thermolysin serine residue and the A2ML1 thiol ester. These results demonstrate that a histidine-enhanced hydroxyl reactivity can contribute to protease inhibition by an αM protein. His-1084 did not improve A2ML1's protease inhibition at pH 5, indicating that A2ML1's hydroxyl reactivity is not an adaption to its acidic epidermal environment.

7 August 2020

Researchers use dynamic PET imaging with target-selective tracer molecules to probe molecular processes. Kinetic models have been developed to describe these processes. The models are typically fitted to the measured PET data with the assumption that the brain is in a steady-state condition for the duration of the scan. The end results are quantitative parameters that characterize the molecular processes. The most common kinetic modeling endpoints are estimates of volume of distribution or the binding potential of a tracer. If the steady state is violated during the scanning period, the standard kinetic models may not apply. To address this issue, time-variant kinetic models have been developed for the characterization of dynamic PET data acquired while significant changes (e.g., short-lived neurotransmitter changes) are occurring in brain processes. These models are intended to extract a transient signal from data. This work in the PET field dates back at least to the 1990s. As interest has grown in imaging nonsteady events, development and refinement of time-variant models has accelerated. These new models, which we classify as belonging to the first, second, or third generation according to their innovation, have used the latest progress in mathematics, image processing, artificial intelligence, and statistics to improve the sensitivity and performance of the earliest practical time-variant models to detect and describe nonsteady phenomena. This review provides a detailed overview of the history of time-variant models in PET. It puts key advancements in the field into historical and scientific context. The sum total of the methods is an ongoing attempt to better understand the nature and implications of neurotransmitter fluctuations and other brief neurochemical phenomena.

On October 24 and 25, SophosAI presents ideas on how to use models large and small—and defend against malignant ones.

Jessica Y. Franco
Dec 1, 2020; 19:1936-1951
Research

Yadong Yu
Dec 1, 2020; 19:1997-2014
Research

Leandro Xavier Neves
Nov 11, 2020; 0:RA120.002227v1-mcp.RA120.002227
Research

Neutrophils are primary host innate immune cells defending against pathogens. One proposed mechanism by which neutrophils prevent the spread of pathogens is NETosis, the extrusion of cellular DNA resulting in neutrophil extracellular traps (NETs). The protease neutrophil elastase (NE) has been implicated in the formation of NETs through proteolysis of nuclear proteins leading to chromatin decondensation. In addition to NE, neutrophils contain three other serine proteases that could compensate if the activity of NE was neutralized. However, whether they do play such a role is unknown. Thus, we deployed recently described specific inhibitors against all four of the neutrophil serine proteases (NSPs). Using specific antibodies to the NSPs along with our labeled inhibitors, we show that catalytic activity of these enzymes is not required for the formation of NETs. Moreover, the NSPs that decorate NETs are in an inactive conformation and thus cannot participate in further catalytic events. These results indicate that NSPs play no role in either NETosis or arming NETs with proteolytic activity.

Thibaut Bourgeois
Dec 11, 2020; 0:jlr.RA120000737v1-jlr.RA120000737
Research Articles

Abudukadier Abulizi
Dec 1, 2020; 61:1565-1576
Research Articles

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.

Recent studies have highlighted an important role for lysophosphatidylcholine acyltransferase 3 (LPCAT3) in controlling the PUFA composition of cell membranes in the liver and intestine. In these organs, LPCAT3 critically supports cell membrane-associated processes such as lipid absorption or lipoprotein secretion. However, the role of LPCAT3 in macrophages remains controversial. Here, we investigated LPCAT3’s role in macrophages both in vitro and in vivo in mice with atherosclerosis and obesity. To accomplish this, we used the LysMCre strategy to develop a mouse model with conditional Lpcat3 deficiency in myeloid cells (Lpcat3KOMac). We observed that partial Lpcat3 deficiency (approx. 75% reduction) in macrophages alters the PUFA composition of all phospholipid (PL) subclasses, including phosphatidylinositols and phosphatidylserines. A reduced incorporation of C20 PUFAs (mainly arachidonic acid [AA]) into PLs was associated with a redistribution of these FAs toward other cellular lipids such as cholesteryl esters. Lpcat3 deficiency had no obvious impact on macrophage inflammatory response or endoplasmic reticulum (ER) stress; however, Lpcat3KOMac macrophages exhibited a reduction in cholesterol efflux in vitro. In vivo, myeloid Lpcat3 deficiency did not affect atherosclerosis development in LDL receptor deficient mouse (Ldlr-/-) mice. Lpcat3KOMac mice on a high-fat diet displayed a mild increase in hepatic steatosis associated with alterations in several liver metabolic pathways and in liver eicosanoid composition. We conclude that alterations in AA metabolism along with myeloid Lpcat3 deficiency may secondarily affect AA homeostasis in the whole liver, leading to metabolic disorders and triglyceride accumulation.

Microsomal triglyceride transfer protein (MTTP) deficiency results in a syndrome of hypolipidemia and accelerated NAFLD. Animal models of decreased hepatic MTTP activity have revealed an unexplained dissociation between hepatic steatosis and hepatic insulin resistance. Here, we performed comprehensive metabolic phenotyping of liver-specific MTTP knockout (L-Mttp^–/–) mice and age-weight matched wild-type control mice. Young (10–12-week-old) L-Mttp^–/– mice exhibited hepatic steatosis and increased DAG content; however, the increase in hepatic DAG content was partitioned to the lipid droplet and was not increased in the plasma membrane. Young L-Mttp^–/– mice also manifested normal hepatic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps, no PKC activation, and normal hepatic insulin signaling from the insulin receptor through AKT Ser/Thr kinase. In contrast, aged (10-month-old) L-Mttp^–/– mice exhibited glucose intolerance and hepatic insulin resistance along with an increase in hepatic plasma membrane sn-1,2-DAG content and PKC activation. Treatment with a functionally liver-targeted mitochondrial uncoupler protected the aged L-Mttp^–/– mice against the development of hepatic steatosis, increased plasma membrane sn-1,2-DAG content, PKC activation, and hepatic insulin resistance. Furthermore, increased hepatic insulin sensitivity in the aged controlled-release mitochondrial protonophore-treated L-Mttp^–/– mice was not associated with any reductions in hepatic ceramide content. Taken together, these data demonstrate that differences in the intracellular compartmentation of sn-1,2-DAGs in the lipid droplet versus plasma membrane explains the dissociation of NAFLD/lipid-induced hepatic insulin resistance in young L-Mttp^–/– mice as well as the development of lipid-induced hepatic insulin resistance in aged L-Mttp^–/– mice.

α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson's disease (PD). It is an intrinsically disordered protein that binds acidic phospholipids. Growing evidence supports a role for α-Syn in membrane trafficking, including, mechanisms of endocytosis and exocytosis, although the exact role of α-Syn in these mechanisms is currently unclear. Here we investigate the associations of α-Syn with the acidic phosphoinositides (PIPs), phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2). Our results show that α-Syn colocalizes with PIP2 and the phosphorylated active form of the clathrin adaptor protein 2 (AP2) at clathrin-coated pits. Using endocytosis of transferrin as an indicator for clathrin-mediated endocytosis (CME), we find that α-Syn involvement in endocytosis is specifically mediated through PI(4,5)P2 levels on the plasma membrane. In accord with their effects on PI(4,5)P2 levels, the PD associated A30P, E46K, and A53T mutations in α-Syn further enhance CME in neuronal and nonneuronal cells. However, lysine to glutamic acid substitutions at the KTKEGV repeat domain of α-Syn, which interfere with phospholipid binding, are ineffective in enhancing CME. We further show that the rate of synaptic vesicle (SV) endocytosis is differentially affected by the α-Syn mutations and associates with their effects on PI(4,5)P2 levels, however, with the exception of the A30P mutation. This study provides evidence for a critical involvement of PIPs in α-Syn–mediated membrane trafficking.