How many people have coronavirus in Carmel? The city soon may soon get a better picture — by testing residents' feces.

Especialistas apontam que propagação de vírus pode ter começado antes de 25 de fevereiro, quando primeiro paciente foi diagnosticado com a covid-19.

"I know he is going to do a great job of continuing to move Indiana athletics in the right direction," Steve Alford said of Scott Dolson.

Indiana workers could lose their eligibility for unemployment benefits if they are recalled to work but refuse to return over fears of the coronavirus

George Faerber still holds 17 records from his high school career, including a game with 52 points and 32 rebounds.

Chef Jonathan Brooks knows his new restaurant Beholder has a big act to follow. Milktooth put Indianapolis' food scene on the map.

The Indianapolis Metropolitan Police Department on Thursday night released more information about an exchange of gunfire that it says occurred between fatal shooting victim Dreasjon Reed and police.

Could the amount of fat in our body increase complications with Covid-19?

The Japanese island, which initially saw a drop in cases, is now facing a bigger wave of virus cases.

1. Coronavirus LIVE Updates: Maharashtra's Tally of Infections Crosses 20,000 with 1,165 New Cases, 48 Deaths in Last 24 Hours  News18
2. Coronavirus India News LIVE | Tamil Nadu COVID-19 tally zooms to 6,535 with 526 new cases; 44 die  Moneycontrol
3. Retirement age hiked for all Tamil Nadu government staff  Deccan Chronicle
4. Andra Prasdesh to Reduce Retail Liquor Outlets to 2,934 by May End  News18
5. In Pictures | Day-45 of coronavirus lockdown leaves people in limbo  The Hindu
6. View Full coverage on Google News

In Texas, abortions are resuming as virus restrictions ease - but for many, the damage has been done.

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Number of Covid-19 cases jumps by 245, the day Nigeria began phasing out emergency measures.

• As the coronavirus-led economic shutdown drags on, many investors have started counseling startups to have more than a years' worth of "runway" to avoid having to raise funding on poor terms.
• But VCs are split on how much startups should be socking away. Some have estimated 18 months oof reserves could suffice, while others say as much as 3 years' worth of runway is ideal.
• The different time frames depends on the age of the startup along with which industry they operate in. Younger startups typically have fewer overhead expenses, while older startups likely have more employees and pricey office leases.
• Also, those companies that may be able to resume work as essential services may need less cash if they are able to generate revenue.
• VCs are uniformly bracing for an economic slowdown, but the severity of downturn is still up for debate. 
• Click here for more BI Prime stories.

Startups are facing what could become the worst economic downturn in several decades, and VCs are begging them to take drastic measures to improve their chances of making it through. 

Most Americans who lived through the 2008 financial crisis will know that a savings stockpile or rainy day fund can mean the difference between surviving and thriving during tough times, but as recent studies have shown, many tech startups and VC firms don't have a similar first-hand experience; many have only known boom times and are now venturing into uncharted waters.

One thing VCs agree on is that startups need to quickly rein in growth plans — ideally as soon as yesterday — and start scrutinizing expenses. Anything nonessential should be cut or suspended indefinitely, headcount should be reduced, and pricey office leases eliminated if possible, all with the goal of extending a startup's "runway."

In Silicon Valley, runway refers to how much cash a startup has on hand to put against its operating expenses. If, for example, a startup has roughly $100,000 in monthly operating expenses and has $1 million in the bank, they are looking at a 10-month runway, assuming revenue stays roughly flat.

In the days before the coronavirus pandemic, a startup's runway dictated when it had to start looking for additional funding. Instead of cutting expenses, the popular solution was to simply put more VC money in the bank. This helped high flying startups like Uber and Airbnb expand at a breakneck pace — VC dollars kept pouring in and the companies remained unprofitable as they chased growth at all costs.

But now, VCs are saying that's no longer an option. Founders Fund general partner Keith Rabois said on a podcast recently that profitability is now being rewarded much more than high-growth. 

For startups that aren't profitable, that means hunkering down and ensuring there are enough reserves to last through the crisis.

So how long does the runway need to be? 

Many VCs that Business Insider has spoken to are advising their startups to have at least 18 months of runway. But some VCs say startups should have upwards of 3 years' of expenses saved up. 

The length of time can vary depending on the startup, one investor told Business Insider, pointing to the startup's age and industry as important factors. An early-stage company with a handful of employees and low-overhead costs might easily stretch a $500,000 seed check, whereas a growth-stage biotech startup with hundreds of employees, expensive hardware, and pricey office space might struggle to make tens of millions of dollars in funding make it through 12 months. Those that can't cut costs will be forced to fundraise with poor terms and risk the dreaded downround. 

"You can always easily dial back up the aggressiveness and risk profile if we get more optimistic visibility, but if you don't take action right away — to preserve capital, cut your burn rate, have fundamentally attractive unit economics, edit the product to make more sense in the new world order — if you don't do those right away, the opportunity to do those things and survive is probably lost forever," Rabois said in the April Talkshow broadcast.

Rabois is in the camp of pessimists, generally speaking, who think the economic downturn will not only drag on through 2020, but could eventually turn into an economic depression the likes of which could rival the Great Depression of the 1930s. He said that his VC peers are starting to rein in the freewheeling deal-making that has defined the last two decades of the Silicon Valley startup ecosystem, and are now treading cautiously. It's time that startups do the same, he said.

SEE ALSO: Lower valuations and a long wait for funding: Two top early-stage VCs dish on how they are counseling startups to withstand long-term economic uncertainty

Join the conversation about this story »

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Cosatu in the Western Cape says that it is deeply concerned over the "alarming rate on increase" in Covid-19 infections in the province.

You’ve probably attended a webinar or two (or more), but are you using them effectively as part of your overall content plan? In this blog post, we teach you the basics of hosting a webinar and how to use them effectively as you build out your content strategy and grow your business.

You’ve probably attended a webinar or two (or more), but are you using them effectively as part of your overall content plan? In this blog post, we teach you the basics of hosting a webinar and how to use them effectively as you build out your content strategy and grow your business.

Zoom has become a way of life for some people as of late (despite, uh, some safety concerns), especially when it comes to work meetings. Whether it's a company-wide all hands or a team check-in, it's likely that if you're working from home due to the coronavirus pandemic, you've had to see your coworkers' shining faces in a video call. 

Actor, writer, and Groundlings comedian Caitlin Reilly perfectly encapsulated that one co-worker you just can't stand during these video meetings:

It's so relevant it hurts. Who hasn't heard the phrase "to piggyback off of" during one of these calls?

The inspiration behind the 'tok was experiences Reilly had sitting in Zoom meetings on behalf of her boss. "I had actually never been in a zoom meeting before, so it was funny for me to see all the different 'personality' types in a situation like that," Reilly told Mashable. "And so it popped in my head one day and I just made the video." Read more...

An array of scientific evidence suggest that in some cases, the bacteria in your gut–your microbiome–could be tied to neurological and psychological disorders and differences, from anxiety and autism to Parkinson's and schizophrenia. The journal Science published a survey of the field and the Cambridge, Massachusetts start-up Holobiome that hopes to use insight into this "psychobiome" to develop treatments for depression, insomnia, and other conditions with a neurological side to them. From Science:

For example, many people with irritable bowel syndrome are also depressed, people on the autism spectrum tend to have digestive problems, and people with Parkinson’s are prone to constipation.

Researchers have also noticed an increase in depression in people taking antibiotics—but not antiviral or antifungal medications that leave gut bacteria unharmed. Last year, Jeroen Raes, a microbiologist at the Catholic University of Leuven, and colleagues analyzed the health records of two groups—one Belgian, one Dutch—of more then 1000 people participating in surveys of their types of gut bacteria. People with depression had deficits of the same two bacterial species, the authors reported in April 2019 in Nature Microbiology.

Researchers see ways in which gut microbes could influence the brain. Some may secrete messenger molecules that travel though the blood to the brain. Other bacteria may stimulate the vagus nerve, which runs from the base of the brain to the organs in the abdomen. Bacterial molecules might relay signals to the vagus through recently discovered “neuropod” cells that sit in the lining of the gut, sensing its biochemical milieu, including microbial compounds.

How Do Home Sales Affect the Economy in Your State?

Technology is continuously leaving an indelible mark on many conceivable fields and industries, and education hasn’t been left behind either. Today, you no longer need to take admission classes and physically attend all your classes to earn a degree. All that is required of you is a working web connection and an incontestable thirst for […]

The post 9 Online Resources for Effective Learning appeared first on Dumb Little Man.

Digital marketing is fast-paced with trends and new updates to existing systems continuously popping out. That’s why it is important to stay up-to-date with the latest strategies that can be beneficial in reaching new audiences. Keeping up to date with the marketing trends will also help a business stay ahead of their competition. The best […]

The post Five of the Best B2B Content Marketing Trends That Are Proven Effective To Gain New Clients appeared first on Dumb Little Man.

Mutations in retinaldehyde-binding protein 1 (RLBP1), encoding the visual cycle protein cellular retinaldehyde-binding protein (CRALBP), cause an autosomal recessive form of retinal degeneration. By binding to 11-cis-retinoid, CRALBP augments the isomerase activity of retinoid isomerohydrolase RPE65 (RPE65) and facilitates 11-cis-retinol oxidation to 11-cis-retinal. CRALBP also maintains the 11-cis configuration and protects against unwanted retinaldehyde activity. Studying a sibling pair that is compound heterozygous for mutations in RLBP1/CRALBP, here we expand the phenotype of affected individuals, elucidate a previously unreported phenotype in RLBP1/CRALBP carriers, and demonstrate consistencies between the affected individuals and Rlbp1/Cralbp−/− mice. In the RLBP1/CRALBP-affected individuals, nonrecordable rod-specific electroretinogram traces were recovered after prolonged dark adaptation. In ultrawide-field fundus images, we observed radially arranged puncta typical of RLBP1/CRALBP-associated disease. Spectral domain-optical coherence tomography (SD-OCT) revealed hyperreflective aberrations within photoreceptor-associated bands. In short-wavelength fundus autofluorescence (SW-AF) images, speckled hyperautofluorescence and mottling indicated macular involvement. In both the affected individuals and their asymptomatic carrier parents, reduced SW-AF intensities, measured as quantitative fundus autofluorescence (qAF), indicated chronic impairment in 11-cis-retinal availability and provided information on mutation severity. Hypertransmission of the SD-OCT signal into the choroid together with decreased near-infrared autofluorescence (NIR-AF) provided evidence for retinal pigment epithelial cell (RPE) involvement. In Rlbp1/Cralbp−/− mice, reduced 11-cis-retinal levels, qAF and NIR-AF intensities, and photoreceptor loss were consistent with the clinical presentation of the affected siblings. These findings indicate that RLBP1 mutations are associated with progressive disease involving RPE atrophy and photoreceptor cell degeneration. In asymptomatic carriers, qAF disclosed previously undetected visual cycle deficiency.

6 April 2020

Nucleoside analogues are a valuable experimental tool. Incorporation of these molecules into newly synthesized DNA (i.e. pulse-labeling) is used to monitor cell proliferation or to isolate nascent DNA. Some of the most common nucleoside analogues used for pulse-labeling of DNA in cells are the deoxypyrimidine analogues 5-ethynyl-2'-deoxyuridine (EdU) and 5-ethynyl-2'-deoxycytidine (EdC). Click chemistry enables conjugation of an azide molecule tagged with a fluorescent dye or biotin to the alkyne of the analog, which can then be used to detect incorporation of EdU and EdC into DNA. The use of EdC is often recommended because of the potential cytotoxicity associated with EdU during longer incubations. Here, by comparing the relative incorporation efficiencies of EdU and EdC during short 30-min pulses, we demonstrate significantly lower incorporation of EdC than of EdU in noninfected human fibroblast cells or in cells infected with either human cytomegalovirus or Kaposi's sarcoma-associated herpesvirus. Interestingly, cells infected with herpes simplex virus type-1 (HSV-1) incorporated EdC and EdU at similar levels during short pulses. Of note, exogenous expression of HSV-1 thymidine kinase increased the incorporation efficiency of EdC. These results highlight the limitations when using substituted pyrimidine analogues in pulse-labeling and suggest that EdU is the preferable nucleoside analogue for short pulse-labeling experiments, resulting in increased recovery and sensitivity for downstream applications. This is an important discovery that may help to better characterize the biochemical properties of different nucleoside analogues with a given kinase, ultimately leading to significant differences in labeling efficiency of nascent DNA.

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

Mitsunori Fukuda
Jun 1, 2008; 7:1031-1042
Research

The transfer of a phosphate from ATP to a protein substrate, a modification known as protein phosphorylation, is catalyzed by protein kinases. Protein kinases play a crucial role in virtually every cellular activity. Recent studies of atypical protein kinases have highlighted the structural similarity of the kinase superfamily despite notable differences in primary amino acid sequence. Here, using a bioinformatics screen, we searched for putative protein kinases in the intracellular bacterial pathogen Legionella pneumophila and identified the type 4 secretion system effector Lpg2603 as a remote member of the protein kinase superfamily. Employing an array of biochemical and structural biology approaches, including in vitro kinase assays and isothermal titration calorimetry, we show that Lpg2603 is an active protein kinase with several atypical structural features. Importantly, we found that the eukaryote-specific host signaling molecule inositol hexakisphosphate (IP6) is required for Lpg2603 kinase activity. Crystal structures of Lpg2603 in the apo-form and when bound to IP6 revealed an active-site rearrangement that allows for ATP binding and catalysis. Our results on the structure and activity of Lpg2603 reveal a unique mode of regulation of a protein kinase, provide the first example of a bacterial kinase that requires IP6 for its activation, and may aid future work on the function of this effector during Legionella pathogenesis.

Weerapan Khovidhunkit
Jul 1, 2004; 45:1169-1196
Thematic Reviews

K Schoonjans
May 1, 1996; 37:907-925
Reviews

Invitation Only Research Event

Event participants

Jude Webber, Mexico and Central America Correspondent, Financial Times
Michael Stott, Latin America Editor, Financial Times
Chair: Dr Christopher Sabatini, Senior Research Fellow for Latin America, US and the Americas Programme, Chatham House

6 May 2020

The respiratory epithelium comprises polarized cells at the interface between the environment and airway tissues. Polarized apical and basolateral protein secretions are a feature of airway epithelium homeostasis. Human respiratory syncytial virus (hRSV) is a major human pathogen that primarily targets the respiratory epithelium. However, the consequences of hRSV infection on epithelium secretome polarity and content remain poorly understood. To investigate the hRSV-associated apical and basolateral secretomes, a proteomics approach was combined with an ex vivo pediatric human airway epithelial (HAE) model of hRSV infection (data are available via ProteomeXchange and can be accessed at https://www.ebi.ac.uk/pride/ with identifier PXD013661). Following infection, a skewing of apical/basolateral abundance ratios was identified for several individual proteins. Novel modulators of neutrophil and lymphocyte activation (CXCL6, CSF3, SECTM1 or CXCL16), and antiviral proteins (BST2 or CEACAM1) were detected in infected, but not in uninfected cultures. Importantly, CXCL6, CXCL16, CSF3 were also detected in nasopharyngeal aspirates (NPA) from hRSV-infected infants but not healthy controls. Furthermore, the antiviral activity of CEACAM1 against RSV was confirmed in vitro using BEAS-2B cells. hRSV infection disrupted the polarity of the pediatric respiratory epithelial secretome and was associated with immune modulating proteins (CXCL6, CXCL16, CSF3) never linked with this virus before. In addition, the antiviral activity of CEACAM1 against hRSV had also never been previously characterized. This study, therefore, provides novel insights into RSV pathogenesis and endogenous antiviral responses in pediatric airway epithelium.

Members Event

Event participants

Dr Marja Lehto, Special Rapporteur, International Law Commission, UN
Doug Weir, Research and Policy Director, The Conflict and Environment Observatory
Chair: Elizabeth Wilmshurst CMG, Distinguished Fellow, International Law Programme, Chatham House
 

Membrane-bound proteins have been proposed to mediate the transport of long-chain FA (LCFA) transport through the plasma membrane (PM). These proposals are based largely on reports that PM transport of LCFAs can be blocked by a number of enzymes and purported inhibitors of LCFA transport. Here, using the ratiometric pH indicator (2',7'-bis-(2-carboxyethyl)-5-(and-6-)-carboxyfluorescein and acrylodated intestinal FA-binding protein-based dual fluorescence assays, we investigated the effects of nine inhibitors of the putative FA transporter protein CD36 on the binding and transmembrane movement of LCFAs. We particularly focused on sulfosuccinimidyl oleate (SSO), reported to be a competitive inhibitor of CD36-mediated LCFA transport. Using these assays in adipocytes and inhibitor-treated protein-free lipid vesicles, we demonstrate that rapid LCFA transport across model and biological membranes remains unchanged in the presence of these purported inhibitors. We have previously shown in live cells that CD36 does not accelerate the transport of unesterified LCFAs across the PM. Our present experiments indicated disruption of LCFA metabolism inside the cell within minutes upon treatment with many of the "inhibitors" previously assumed to inhibit LCFA transport across the PM. Furthermore, using confocal microscopy and a specific anti-SSO antibody, we found that numerous intracellular and PM-bound proteins are SSO-modified in addition to CD36. Our results support the hypothesis that LCFAs diffuse rapidly across biological membranes and do not require an active protein transporter for their transmembrane movement.

The autosomal dominant disorder Schnyder corneal dystrophy (SCD) is caused by mutations in UbiA prenyltransferase domain-containing protein-1 (UBIAD1), which uses geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K₂ subtype menaquinone-4 (MK-4). SCD is characterized by opacification of the cornea, owing to aberrant build-up of cholesterol in the tissue. We previously discovered that sterols stimulate association of UBIAD1 with ER-localized HMG-CoA reductase, which catalyzes a rate-limiting step in the synthesis of cholesterol and nonsterol isoprenoids, including GGpp. Binding to UBIAD1 inhibits sterol-accelerated ER-associated degradation (ERAD) of reductase and permits continued synthesis of GGpp in cholesterol-replete cells. GGpp disrupts UBIAD1-reductase binding and thereby allows for maximal ERAD of reductase as well as ER-to-Golgi translocation of UBIAD1. SCD-associated UBIAD1 is refractory to GGpp-mediated dissociation from reductase and remains sequestered in the ER to inhibit ERAD. Here, we report development of a biochemical assay for UBIAD1-mediated synthesis of MK-4 in isolated membranes and intact cells. Using this assay, we compared enzymatic activity of WT UBIAD1 with that of SCD-associated variants. Our studies revealed that SCD-associated UBIAD1 exhibited reduced MK-4 synthetic activity, which may result from its reduced affinity for GGpp. Sequestration in the ER protects SCD-associated UBIAD1 from autophagy and allows intracellular accumulation of the mutant protein, which amplifies the inhibitory effect on reductase ERAD. These findings have important implications not only for the understanding of SCD etiology but also for the efficacy of cholesterol-lowering statin therapy, which becomes limited, in part, because of UBIAD1-mediated inhibition of reductase ERAD.

Expert

Do biodiversity losses aggravate transmission of infectious diseases spread by animals to humans? The jury is still out but several scientists say there is a "biodiversity dilution effect" in which declining biodiversity results in increased infectious-disease transmission.