CSU Chancellor Timothy P. White and the presidents of the Northridge and East Bay campuses say they will stay on through fall 2020.

It isn't for lack of trying by teachers that some students aren't able to fully access the LAUSD's online learning curriculum.

A lawsuit announced Tuesday seeks refunds for students who, as a result of the coronavirus closures, lost out on in-person instruction, housing, meals and other elements of campus life and were not paid back tuition and fees.

Fire crews attended around 160 weather related incidents in a 12 hour period.

Read "Attack on Titan," "Somali & the Forest Spirit," "Fire Force," "Arte" and more with Mangamo, a new mobile manga subscription service.

An LAUSD teacher who once campaigned against Austin Beutner gives the superintendent credit for his leadership during the pandemic.

Exclusive: The airline is currently operating at just 5 per cent of its normal level

Corruption is both a major cause and a result of poverty around the world. It occurs at all levels of society, from local and national governments, civil society, judiciary functions, large and small businesses, military and other services and so on.

Some countries are seeing increasing protests at large scale corruption. In India, a largely non-violent movement has sprung up, which has also inspired anti-corruption campaigners in Nepal. In Brazil, inspired by the way protesters in Spain have used social networks, technology has been used to increasingly campaign against corruption there.

The global financial crisis has made conditions worse in many places for many people. Increasing food prices and other policy decisions governments are pushing through is leading to many volatile conditions, and it may be that this is giving a much needed push for large-scale grassroots and civil society movements against debilitating corruption.

This update to the corruption section includes an overview of some of the protests mentioned above.

Read full article: Corruption

19% of the world’s reptiles are estimated to be threatened with extinction according to a study by the International Union for Conservation of Nature (IUCN) and the Zoological Society of London. Reptiles include snakes, lizards, crocodiles, turtles and tortoises. But some species are at more risk than others. For example, freshwater turtles alone are at a 50% risk of extinction. Reasons vary, but include the usual suspects such as climate change and loss of habitat.

A recent study also estimated that some 100 million sharks are being killed each year — an unsustainable rate, given how long some species take to mature and reproduce. Much of the demand is driven by Chinese rising affluence and demand for shark fin soup in the mistaken belief it has various health benefits.

This small update to the biodiversity loss page has further details.

Read full article: Loss of Biodiversity and Extinctions

CELTIC captain Scott Brown insists David Turnbull’s chances of joining the Hoops are not dead and urged the midfielder to re-think his transfer snub because they are “the right club” for him.

Here are quarantine-friendly ways to get mom a perfect gift for Mother's Day.

It's the Caption Competition.

Caption competition is now closed. Full rules can be seen here [PDF].

This week, a new look is unveiled.

6. trisarahtops:
Catwalk face-off

5. StoneyMast:
We come, with our new look, in peace. Take me to your leader

4. George Huber:
Mannequin Skywalker

3. abz:
Terracotta Armani

2. Fi:
After 35 years, someone finally designed a collection to cover Morph's modesty...

1. SkarloeyLine:
Eighth new social class discovered - the faceless minority

Colleges across Indiana are navigating how to handle refunds for students who have had to vacate residence halls during the COVID-19 pandemic.

Woody Myers, the presumptive Democratic nominee for governor, thinks Gov. Eric Holcomb is making a big mistake in how he's reopening the economy.

After his name popped up in trade rumors the Colts spent a third-round pick on a safety. Are the Colts preparing for a future without Malik Hooker?

Tom Allen discusses how the Hoosiers move toward the fall when they can't work together. 'It's a universal challenge.'

Two Indianapolis restaurants have announced they will permanently close.

Teams will be allowed to use five substitutes when the season resumes after a Fifa proposal to help with fixture congestion was approved.

The director of "The Irishman" has criticized "comic book movies," but these titles show that such adaptations might be a perfect fit for him.

The dismissal of coach Hue Jackson seems to have given Duke Johnson Jr. new life with the Browns.

Sleep easy knowing that no matter what next week’s injury report reveals, you will have the players you need to secure a year’s worth of bragging rights.

Washington VIPs (hint: allll the Housewives) showed up for Cirque's ode to street sports, "Volta," which plays at Tysons II through Sept. 29.

TelcoTV released a preview of results from the annual Heavy Reading State of the Video Consumer Survey. Complete findings from the 2012 survey will be presented at the TelcoTV Conference and Expo taking place October 24 to 26, 2012 at the Las Vegas Hotel, Nevada. Aditya Kishore, Senior Analyst, Heavy Reading will present the findings during his keynote address on Wednesday, October 24, 2012.

Heavy Reading’s highly anticipated State of the Video Consumer Survey, now in its fifth year, is an annual report that reveals consumer opinions about video consumption across device platforms, provider perceptions and satisfaction levels with video services. In years past, it has proven to be a valuable planning tool for any organization serving the video distribution marketplace.

“It’s just so unfair that American companies aren’t allowed to pay bribes to get business overseas.”

Despite numerous unknowns and continued challenges, many agencies and advertisers say they have shifted gears for the next phase.

Please visit Search Engine Land for the full article.

‘The idea that what’s happening with searcher behavior is not causing these shifts means that Google is in there writing that code for every intent, every day, and I can’t believe that’s what’s happening,’ said Dr. Pete Meyers on Live with Search Engine Land.

Please visit Search Engine Land for the full article.

If you’re an entrepreneur nurturing your own company to a full-blown success, you are always looking for insights and ideas to take your business to the next level, right? But you’re probably super busy as well, and don’t always have the time to figure out where you should be looking for those insights.

This past year, I predicted the fall of both Zuck and Trump, not to mention the triumph of cannabis and rationale markets. But in 2019, the sociopaths won – bigly. Damn, was I wrong. One year ago this week, I sat down to write my annual list of ten or so predictions for the coming … Continue reading "Predictions Review: Trump, Zuck Crush My Optimism In 2019"

Last year, when we felt interest in artificial intelligence (AI) was approaching a fever pitch, we created a survey to ask about AI adoption. When we analyzed the results, we determined the AI space was in a state of rapid change, so we eagerly commissioned a follow-up survey to help find out where AI stands […]

NZ Rugby CEO Mark Robinson says there is still no clarity on the prospects for Test rugby in 2020, but said they will explore every avenue.

The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene–Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease.

Research Event

Event participants

Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B–E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B–E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS–PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.

For successful infection of their hosts, pathogenic bacteria recognize host-derived signals that induce the expression of virulence factors in a spatiotemporal manner. The fulminating food-borne pathogen Vibrio vulnificus produces a cytolysin/hemolysin protein encoded by the vvhBA operon, which is a virulence factor preferentially expressed upon exposure to murine blood and macrophages. The Fe-S cluster containing transcriptional regulator IscR activates the vvhBA operon in response to nitrosative stress and iron starvation, during which the cellular IscR protein level increases. Here, electrophoretic mobility shift and DNase I protection assays revealed that IscR directly binds downstream of the vvhBA promoter PvvhBA, which is unusual for a positive regulator. We found that in addition to IscR, the transcriptional regulator HlyU activates vvhBA transcription by directly binding upstream of PvvhBA, whereas the histone-like nucleoid-structuring protein (H-NS) represses vvhBA by extensively binding to both downstream and upstream regions of its promoter. Of note, the binding sites of IscR and HlyU overlapped with those of H-NS. We further substantiated that IscR and HlyU outcompete H-NS for binding to the PvvhBA regulatory region, resulting in the release of H-NS repression and vvhBA induction. We conclude that concurrent antirepression by IscR and HlyU at regions both downstream and upstream of PvvhBA provides V. vulnificus with the means of integrating host-derived signal(s) such as nitrosative stress and iron starvation for precise regulation of vvhBA transcription, thereby enabling successful host infection.

21 April 2020

Haploinsufficiency of Meis homeobox 2 (MEIS2), encoding a transcriptional regulator, is associated with human cleft palate, and Meis2 inactivation leads to abnormal palate development in mice, implicating MEIS2 functions in palate development. However, its functional mechanisms remain unknown. Here we observed widespread MEIS2 expression in the developing palate in mice. Wnt1Cre-mediated Meis2 inactivation in cranial neural crest cells led to a secondary palate cleft. Importantly, about half of the Wnt1Cre;Meis2f/f mice exhibited a submucous cleft, providing a model for studying palatal bone formation and patterning. Consistent with complete absence of palatal bones, the results from integrative analyses of MEIS2 by ChIP sequencing, RNA-Seq, and an assay for transposase-accessible chromatin sequencing identified key osteogenic genes regulated directly by MEIS2, indicating that it plays a fundamental role in palatal osteogenesis. De novo motif analysis uncovered that the MEIS2-bound regions are highly enriched in binding motifs for several key osteogenic transcription factors, particularly short stature homeobox 2 (SHOX2). Comparative ChIP sequencing analyses revealed genome-wide co-occupancy of MEIS2 and SHOX2 in addition to their colocalization in the developing palate and physical interaction, suggesting that SHOX2 and MEIS2 functionally interact. However, although SHOX2 was required for proper palatal bone formation and was a direct downstream target of MEIS2, Shox2 overexpression failed to rescue the palatal bone defects in a Meis2-mutant background. These results, together with the fact that Meis2 expression is associated with high osteogenic potential and required for chromatin accessibility of osteogenic genes, support a vital function of MEIS2 in setting up a ground state for palatal osteogenesis.

For successful infection of their hosts, pathogenic bacteria recognize host-derived signals that induce the expression of virulence factors in a spatiotemporal manner. The fulminating food-borne pathogen Vibrio vulnificus produces a cytolysin/hemolysin protein encoded by the vvhBA operon, which is a virulence factor preferentially expressed upon exposure to murine blood and macrophages. The Fe-S cluster containing transcriptional regulator IscR activates the vvhBA operon in response to nitrosative stress and iron starvation, during which the cellular IscR protein level increases. Here, electrophoretic mobility shift and DNase I protection assays revealed that IscR directly binds downstream of the vvhBA promoter PvvhBA, which is unusual for a positive regulator. We found that in addition to IscR, the transcriptional regulator HlyU activates vvhBA transcription by directly binding upstream of PvvhBA, whereas the histone-like nucleoid-structuring protein (H-NS) represses vvhBA by extensively binding to both downstream and upstream regions of its promoter. Of note, the binding sites of IscR and HlyU overlapped with those of H-NS. We further substantiated that IscR and HlyU outcompete H-NS for binding to the PvvhBA regulatory region, resulting in the release of H-NS repression and vvhBA induction. We conclude that concurrent antirepression by IscR and HlyU at regions both downstream and upstream of PvvhBA provides V. vulnificus with the means of integrating host-derived signal(s) such as nitrosative stress and iron starvation for precise regulation of vvhBA transcription, thereby enabling successful host infection.

Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses. We have recently reported a previously unappreciated role for HSF1 in the regulation of energy metabolism in fat tissues; however, whether HSF1 is differentially expressed in adipose depots and how its levels are regulated in fat tissues remain unclear. Here, we show that HSF1 levels are higher in brown and subcutaneous fat tissues than in those in the visceral depot and that HSF1 is more abundant in differentiated, thermogenic adipocytes. Gene expression experiments indicated that HSF1 is transcriptionally regulated in fat by agents that modulate cAMP levels, by cold exposure, and by pharmacological stimulation of β-adrenergic signaling. An in silico promoter analysis helped identify a putative response element for activating transcription factor 3 (ATF3) at −258 to −250 base pairs from the HSF1 transcriptional start site, and electrophoretic mobility shift and ChIP assays confirmed ATF3 binding to this sequence. Furthermore, functional assays disclosed that ATF3 is necessary and sufficient for HSF1 regulation. Detailed gene expression analysis revealed that ATF3 is one of the most highly induced ATFs in thermogenic tissues of mice exposed to cold temperatures or treated with the β-adrenergic receptor agonist CL316,243 and that its expression is induced by modulators of cAMP levels in isolated adipocytes. To the best of our knowledge, our results show for the first time that HSF1 is transcriptionally controlled by ATF3 in response to classic stimuli that promote heat generation in thermogenic tissues.

Michal Bassani-Sternberg
Mar 1, 2015; 14:658-673
Research

Ignat V. Shilov
Sep 1, 2007; 6:1638-1655
Technology

Martin R. Larsen
Jul 1, 2005; 4:873-886
Technology

Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
Research

Jürgen Cox
Sep 1, 2014; 13:2513-2526
Technological Innovation and Resources

SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes.

Invitation Only Research Event

Research Event

Event participants

Invitation Only Research Event

Event participants

Rebecca Wolfe, Lecturer, Harris School for Public Policy and Associate, Pearson Institute for the Study and Resolution of Global Conflicts, University of Chicago
Tom Gillhespy, Principal Consultant, Itad
Shodmon Hojibekov, Chief Executive Officer, Aga Khan Agency for Habitat (Afghanistan)
Chair: Champa Patel, Director, Asia-Pacific Programme, Chatham House

Nica M. Borradaile
Dec 1, 2006; 47:2726-2737
Research Articles