The only time Indianapolis will be in prime time will be a Thursday night showdown with the rival Tennessee Titans. At their place in Nashville.

Notre Dame's national/international visibility would seem to give Irish student-athletes an edge.

Hoosiers are scheduled to start the season against Wisconsin and finish with the traditional Old Oaken Bucket game.

Indiana Pacers are coming off a second straight season with 48 regular-season wins and a first-round playoff loss

Celebrate National Hot Dog Day with loaded dogs that howl with flavor.

Purdue men's basketball is coming off of an Elite Eight season as Matt Painter enters his 15th season as coach

Indiana Pacers are coming off a second straight season with 48 regular-season wins and a first-round playoff loss

Celebrate National Hot Dog Day with loaded dogs that howl with flavor.

Mark Drakeford said "we should all be anxious" about how long lockdown can be sustained.

"The numbers are still going up," San Francisco Mayor London Breed said, emphasizing that Bay Area health officers can continue to enforce tighter restrictions.

With parts of the California economy poised to reopen Friday, cities will be taking it slow over concerns that COVID-19 remains a significant threat.

Pool parties are frowned on, as health officials offer guidelines for the use of apartment and HOA pools and spas.

California allows some retailers to open with curbside service, including bookstores, florists and toy stores. Many parks will reopen Saturday.

A federal judge overseeing the college admissions case on Friday declined to dismiss charges against Lori Loughlin and her co-defendants.

Indianapolis Colts will play their AFC South foes twice each, and also the Baltimore Ravens and Green Bay Packers

The Indianapolis Colts play every team from the AFC North and AFC North, as well as each AFC South foe twice, the New York Jets and Las Vegas Raiders.

Notre Dame's national/international visibility would seem to give Irish student-athletes an edge.

The only time Indianapolis will be in prime time will be a Thursday night showdown with the rival Tennessee Titans. At their place in Nashville.

The Indianapolis Colts start and finish the 2020 season against the Jacksonville Jaguars; the Colts are on the road to start the year and at home to finish it.

Ministers are reportedly considering relaxing the two-metre rule for social distancing in workplaces.

The City of Ottawa is launching a “Parks Ambassador Program” to educate residents on the do’s and don’ts in parks during the COVID-19 pandemic.

Milwaukee has embraced the modern NBA.

The Ravens' Ty Montgomery figures to take on a larger share of the workload in Baltimore over the remainder of the season.

• Dating apps like Tinder, Bumble, and Hinge have reported increased use amid the coronavirus pandemic, while touting virtual dating alternatives for users instead of meeting up in person.
• Swaths of users are still encouraging matches to break quarantine to have sex and go on dates, despite social distancing guidelines and fines to comply with them.
• An illustrator on Instagram has been collecting screenshots of these situations, and told Business Insider that users will brand themselves as "badasses," dispute the effectiveness of isolating, and lash out in anger and hurl abusive language when they're rejected.
• Spokespeople for Grindr, Tinder and Bumble told Business Insider they've informed users to adhere to social-distancing guidelines, but did not respond to inquiries about actions they're taking against users in places where violating lockdown orders can be against the law.
• Visit Business Insider's homepage for more stories.

As millions remain confined to their homes to prevent the spread of coronavirus, the desire for human contact and connection has risen dramatically and led some to search for ways to break those social distancing rules.

Popular dating apps — including Tinder, Bumble, and Hinge — have reported significant increases during the outbreak of swiping activity, matches between users, and messages exchanged. It's also led to the introduction of a breed of users who are interested in shirking lockdown orders, and are encouraging their matches to join them in doing the same.

Dating app users have shared stories across social media, and recently with Mashable, about messages they've received from matches who ask them to come over or want to hook up. Artist Samantha Rothenberg, who uses the handle @violetclair on Instagram, has been collecting these screenshots from followers, and told Business Insider she's received close to a thousand of such stories.

"Because of how common it is, I can honestly say that anyone who is on a dating app right now has dealt with this," Rothenberg told Business Insider. "People are horny, and a lot of people are putting that ahead of the risk and the danger."

For dating platforms whose end goal is inherently to bring its millions of users together in real life, the coronavirus outbreak has put them in a curious predicament. Dating apps are forced to balance a desire to keep people on their platform for the sake of business, with a moral responsibility to discourage users to engage in behavior with potential life-or-death implications.

Since the start of the outbreak, apps have rolled out in-app virtual dating options and touted ways users can go on virtual dates. However, the prevalence of users who are trying to meet up in person, as documented by Rothenberg and screenshots across social media, raise questions about whether these dating platforms are doing enough to stymie such behavior in the time of coronavirus.

Rothenberg has long collected screenshots of users' horror stories from dating app interactions, which she often will depict in illustrations she posts to her Instagram account. But ever since the pandemic led states to instill lockdown orders starting in March, nearly all of the screenshots she's received have had to do with coronavirus.

These lockdown-violating users fall into a few general categories, according to Rothenberg. There's the users who try to paint themselves as "badasses" for breaking the rules, though Rothenberg says they're more like "a--holes." There are the matches who propose meeting up and, after getting rejected, reverse course to say they're were joking or "testing" you, she says. You'll also encounter the anti-quarantine user, whose reasoning is based on claims about herd immunity and the ineffectiveness of social distancing measures.

The last group is made up of users who react to "no" with anger and verbal abuse, Rothenberg told Business Insider. Women told Mashable recently about encounters with men on dating apps who badgered and harassed them after they turned down in-person meetings, going to the point of gaslighting.

These types of users are what led Rothenberg to launch a petition on Change.org to hold dating apps responsible for enforcing social distancing guidelines during the pandemic. She's also been active about calling out dating apps in her Instagram Stories she posts with screenshots she receives.

"People are angry, they tell me, 'can you believe this, this is disgusting, this is wrong,'" Rothenberg said. "Because I have this platform, I feel I have a bit of a responsibility to put these [stories] out in the open and share, and bring some light into what's going on out there to people who may not know."

In late March, platforms sent out various messages and alerts to their users that Rothenberg documented on Instagram. A message to Bumble users from CEO Whitney Wolfe Herd said: "Please don't meet your Bumble matches IRL for now." Hinge users were told to "stay safe and keep connected."

Tinder, arguably the most well-know dating app, also discouraged users to meet up in a platform-wide message sent March 26.

"We know there's a lot to stay to each other as we all do our best to stay healthy and prevent the spread of the coronavirus," the message from Tinder said. "We hope to be a place for connecting during this challenging time, but it's important to stress that now is not the time to meet IRL with your match."

Dating apps' responsibilities to pivot from IRL to TXT

As companies across industries adjust business to stay afloat, dating apps have transitioned to emphasize alternatives to in-person meetups. Although online dating success has long been measured by the amount of conversations that turn to real-life connections, platforms are forced to rethink their strategy as users continue turning to them en masse. A poll conducted by Hinge found that 70% of its users said they were open to going on dates on Zoom, FaceTime, and other video platforms.

Some dating brands have introduced new features amid the pandemic. Hinge launched "Date from Home" in April, where users can indicate to a match they're ready to move their conversation off-app. Plenty of Fish started rolling out a livestreaming feature in March to users in the U.S. to allow matches to go on short virtual dates. Tinder, relatively late to the game, announced this week it was launching a video chat feature by the end of June.

A spokesperson for Match Group — the parent company on Tinder, Hinge, Plenty of Fish, and other dating platforms — told Business Insider that it made updates to its products "to help users better navigate stay-from-home policies and date digitally via phone or video."

Other apps that already enabled video chat and voice call, like The League and Bumble, are pushing these features to their users more than ever. 

But while users on these dating apps are swiping and messaging at new highs, the transition to virtual-only hasn't been as seamless for those on Grindr, the most popular dating app for gay men. Steve, a 26-year-old living in Washington, D.C., told Business Insider that activity on Grindr is "completely dead." He said he doesn't check the app nearly as often any more, but messages he does get on the app are largely from people who say they want to meet up despite the quarantine.

Grindr, like other apps, has attempted to pivot to virtual dating: The platform recently introduced Circles, where groups of up to 20 users can join chats centered around certain topics and interests. However, Steve said he's seen these groups largely dissolve into "all d--k pics."

"I dont think Grindr has the ability to rebrand itself honestly at this point for something other than hookups," Steve said. "They tried to take the opportunity to rebrand itself as something else, and it just right away became sexual."

A Grindr spokesperson told Business Insider it had sent in-app notifications to all users asking them to "refrain from in-person meetings right now."Nonetheless, an app-wide message sent to users — and shared by users on Twitter — made no mention of asking users to social distance. 

For users across these dating apps who encourage the violating of social distancing guidelines, it's unclear how much responsibility platforms have to keep their users' indoors. In some states under lockdown, authorities have doled out fines and even arrested residents found failing to follow at-home guidelines.

Grindr, Bumble and Match Group — the parent company of Tinder, Hinge, Plenty of Fish and others — told Business Insider in statements they have encouraged users to adhere to coronavirus guidelines from the World Health Organization and the Center for Disease Control.

None of the companies responded to Business Insider's requests for comment about whether asking to violate social-distancing guidelines on the platforms is a breach of policy or would garner any ban or suspension on a user.

SEE ALSO: What you need to know about Grimes, the Canadian musician who just had a baby with tech billionaire Elon Musk

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Discover the (sometimes surprising!) things you can no longer do on a cruise and cruise ship. How many of these did you know about? Got any to add that I missed? I look forward to you listening (or watching the video version: https://youtu.be/zas6F4wMD0Q )

The latest immigration rule is based on obvious lies.

Establishing daily and weekly routines provides a structure for learning at home. Parents and children know how the day will unfold; routines create predictability and also anticipation for the fun and comforting things that will happen throughout the day. It can be helpful to identify a learning theme to explore together over the course of two weeks. You'll find a sample daily schedule below, with ideas for how to bring in the theme into every part of the day, from breakfast to read alouds to art and science activities. 

The Washington Post’s rules for comments, reader discussions and communities.

WhatsApp on Tuesday placed new limits on message forwarding as part of an effort to curb the spread of misinformation about the coronavirus pandemic.

The health expert who helped shaped Britain’s lockdown policies in response to the coronavirus has resigned after admitting he broke his own rules by having his married lover visit him at his home. Professor Neil Ferguson, 51, of Imperial College in London was a prominent member of the Scientific Advisory Group for Emergencies. The Telegraph…

The post Scientist Behind Social Distancing Breaks Own Rules To Cheat with Married Woman, Resigns appeared first on The Western Journal.

Philadelphia Phillies star Bryce Harper believes Major League Baseball should relax its "dumb" rule preventing top players from competing in the Olympics.

The Mycobacterium tuberculosis virulence factor EsxA and its chaperone EsxB are secreted as a heterodimer (EsxA:B) and are crucial for mycobacterial escape from phagosomes and cytosolic translocation. Current findings support the idea that for EsxA to interact with host membranes, EsxA must dissociate from EsxB at low pH. However, the molecular mechanism by which the EsxA:B heterodimer separates is not clear. In the present study, using liposome-leakage and cytotoxicity assays, LC-MS/MS–based proteomics, and CCF-4 FRET analysis, we obtained evidence that the Nα-acetylation of the Thr-2 residue on EsxA, a post-translational modification that is present in mycobacteria but absent in Escherichia coli, is required for the EsxA:B separation. Substitutions at Thr-2 that precluded Nα-acetylation inhibited the heterodimer separation and hence prevented EsxA from interacting with the host membrane, resulting in attenuated mycobacterial cytosolic translocation and virulence. Molecular dynamics simulations revealed that at low pH, the Nα-acetylated Thr-2 makes direct and frequent “bind-and-release” contacts with EsxB, which generates a force that pulls EsxB away from EsxA. In summary, our findings provide evidence that the Nα-acetylation at Thr-2 of EsxA facilitates dissociation of the EsxA:B heterodimer required for EsxA membrane permeabilization and mycobacterial cytosolic translocation and virulence.

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.

Yi Zhang
Sep 1, 2005; 4:1240-1250
Research

Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development.

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31 July 2014 , Volume 70, Number 4

A long view of the problems of modern migration

Webinar Research Event

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Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development.

Knowledge of the molecular events in mitochondrial DNA (mtDNA) replication is crucial to understanding the origins of human disorders arising from mitochondrial dysfunction. Twinkle helicase is an essential component of mtDNA replication. Here, we employed atomic force microscopy imaging in air and liquids to visualize ring assembly, DNA binding, and unwinding activity of individual Twinkle hexamers at the single-molecule level. We observed that the Twinkle subunits self-assemble into hexamers and higher-order complexes that can switch between open and closed-ring configurations in the absence of DNA. Our analyses helped visualize Twinkle loading onto and unloading from DNA in an open-ringed configuration. They also revealed that closed-ring conformers bind and unwind several hundred base pairs of duplex DNA at an average rate of ∼240 bp/min. We found that the addition of mitochondrial single-stranded (ss) DNA–binding protein both influences the ways Twinkle loads onto defined DNA substrates and stabilizes the unwound ssDNA product, resulting in a ∼5-fold stimulation of the apparent DNA-unwinding rate. Mitochondrial ssDNA-binding protein also increased the estimated translocation processivity from 1750 to >9000 bp before helicase disassociation, suggesting that more than half of the mitochondrial genome could be unwound by Twinkle during a single DNA-binding event. The strategies used in this work provide a new platform to examine Twinkle disease variants and the core mtDNA replication machinery. They also offer an enhanced framework to investigate molecular mechanisms underlying deletion and depletion of the mitochondrial genome as observed in mitochondrial diseases.

T-type (Cav3) Ca2+ channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca2+ channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1–IS2 and IS3–IS4 loops of domain I and a cluster of extracellular cysteines in the IS1–IS2 loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and N-ethylmaleimide, as well as a reactive oxygen species–producing neuropeptide, substance P (SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His191 in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1–IS2 loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1–IS2 loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc.

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.

Publication Date: Apr 10 2020 The SEC will withdraw the existing approval order and the fund will become subject to the requirements of Rule 6c-11 and Nasdaq Rule 5704....

Publication Date: Apr 10 2020 Yes. According to the SEC, once an ETF becomes eligible to operate under Rule 6c-11 and elects to list on Nasdaq under Nasdaq Rule 5704, the existing order related to that fund (and all other funds under that exemptive order) will be rescinded. Once a fund is listed under Nasdaq Rule 5704, it will not be able to relist under Nasdaq Rule 5705(b) (Index Fund Shares) or Nasdaq Rule 5735 (Managed Fund Shares) unless a new exemptive relief order is obtained from the SEC....

Publication Date: Apr 10 2020 Funds listed under Nasdaq Rule 5704 are required to submit an annual certification regarding the funds compliance with Rule 6c-11 during the most recent fiscal year. The certification is required within 30 calendar days of a fund’s fiscal year end. The certification can be found here....

Publication Date: Apr 10 2020 On or before December 22, 2020, all ETFs that meet the definition of "Exchange Traded Fund" in Nasdaq Rule 5704(a)(1)(A) will need to be compliant with Rule 6c-11. If it is determined that an ETF no longer complies with Rule 6c-11 and therefore no longer complies Nasdaq Rule 5704, Nasdaq will generally issue a letter of deficiency. The ETF will generally be given 45 days to submit a plan to regain compliance. If the plan is accepted, Nasdaq Staff can grant an...

Publication Date: Apr 10 2020 ETFs that meet the definition of “Exchange Traded Fund” in Nasdaq Rule 5704(a)(1)(A) are eligible to be considered for listing pursuant to Nasdaq Rule 5704. ETFs that are excluded from operating pursuant to Rule 6c-11 under the Investment Company Act of 1940 are not eligible to list under Nasdaq Rule 5704....

Publication Date: Apr 10 2020 New Fund Launches In addition to completing the Listing Application, new funds are required to complete a certification prior to receiving approval of an initial listing application. The certification can be found here. Listing Transfers In addition to completing the Listing Application, funds switching from another market to Nasdaq are required to complete a certification regarding compliance with SEC Rule 6c-11. The certification must be completed prior to...

New Publication: Rules, Procedures and Mechanisms Applicable to Processes under the Cartagena Protocol on Biosafety.