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Michael Hunter, MD

Michael Hunter, MD

3 years ago

5 Drugs That May Increase Your Risk of Dementia

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Sara_Mednick

Sara_Mednick

3 years ago

Since I'm a scientist, I oppose biohacking

Understanding your own energy depletion and restoration is how to truly optimize

Photo: Towfiqu barbhuiya / Unsplash

Hack has meant many bad things for centuries. In the 1800s, a hack was a meager horse used to transport goods.

Modern usage describes a butcher or ax murderer's cleaver chop. The 1980s programming boom distinguished elegant code from "hacks". Both got you to your goal, but the latter made any programmer cringe and mutter about changing the code. From this emerged the hacker trope, the friendless anti-villain living in a murky hovel lit by the computer monitor, eating junk food and breaking into databases to highlight security system failures or steal hotdog money.

Remember the 1995 movie, Hackers, in which a bunch of super cool programmers (said no one ever) get caught up in a plot to destroy the world and only teenybopper Angelina Jolie and her punk rock gang of nerd-bots can use their lightening quick typing skills to save the world? Remember public phones?

Now, start-a-billion-dollar-business-from-your-garage types have shifted their sights from app development to DIY biology, coining the term "bio-hack". This is a required keyword and meta tag for every fitness-related podcast, book, conference, app, or device.

Bio-hacking involves bypassing your body and mind's security systems to achieve a goal. Many biohackers' initial goals were reasonable, like lowering blood pressure and weight. Encouraged by their own progress, self-determination, and seemingly exquisite control of their biology, they aimed to outsmart aging and death to live 180 to 1000 years (summarized well in this vox.com article).

With this grandiose north star, the hunt for novel supplements and genetic engineering began.

Companies selling do-it-yourself biological manipulations cite lab studies in mice as proof of their safety and success in reversing age-related diseases or promoting longevity in humans (the goal changes depending on whether a company is talking to the federal government or private donors).

The FDA is slower than science, they say. Why not alter your biochemistry by buying pills online, editing your DNA with a CRISPR kit, or using a sauna delivered to your home? How about a microchip or electrical stimulator?

What could go wrong?


I'm not the neo-police, making citizen's arrests every time someone introduces a new plumbing gadget or extrapolates from animal research on resveratrol or catechins that we should drink more red wine or eat more chocolate. As a scientist who's spent her career asking, "Can we get better?" I've come to view bio-hacking as misguided, profit-driven, and counterproductive to its followers' goals.

We're creatures of nature. Despite all the new gadgets and bio-hacks, we still use Roman plumbing technology, and the best way to stay fit, sharp, and happy is to follow a recipe passed down since the beginning of time. Bacteria, plants, and all natural beings are rhythmic, with alternating periods of high activity and dormancy, whether measured in seconds, hours, days, or seasons. Nature repeats successful patterns.

During the Upstate, every cell in your body is naturally primed and pumped full of glycogen and ATP (your cells' energy currencies), as well as cortisol, which supports your muscles, heart, metabolism, cognitive prowess, emotional regulation, and general "get 'er done" attitude. This big energy release depletes your batteries and requires the Downstate, when your subsystems recharge at the cellular level.

Downstates are when you give your heart a break from pumping nutrient-rich blood through your body; when you give your metabolism a break from inflammation, oxidative stress, and sympathetic arousal caused by eating fast food — or just eating too fast; or when you give your mind a chance to wander, think bigger thoughts, and come up with new creative solutions. When you're responding to notifications, emails, and fires, you can't relax.

Every biological plant and animal is regulated by rhythms of energy-depleting Upstate and energy-restoring Downstates.

Downstates aren't just for consistently recharging your battery. By spending time in the Downstate, your body and brain get extra energy and nutrients, allowing you to grow smarter, faster, stronger, and more self-regulated. This state supports half-marathon training, exam prep, and mediation. As we age, spending more time in the Downstate is key to mental and physical health, well-being, and longevity.

When you prioritize energy-demanding activities during Upstate periods and energy-replenishing activities during Downstate periods, all your subsystems, including cardiovascular, metabolic, muscular, cognitive, and emotional, hum along at their optimal settings. When you synchronize the Upstates and Downstates of these individual rhythms, their functioning improves. A hard workout causes autonomic stress, which triggers Downstate recovery.

This zig-zag trajectory of performance improvement illustrates that getting better at anything in life isn’t a straight shot. The close-up box shows how prioritizing Downstate recovery after an Upstate exertion (e.g., hard workout) leads to RECOVERYPLUS. Image from The Power of the Downstate by Sara C. Mednick PhD.

By choosing the right timing and type of exercise during the day, you can ensure a deeper recovery and greater readiness for the next workout by working with your natural rhythms and strengthening your autonomic and sleep Downstates.

Morning cardio workouts increase deep sleep compared to afternoon workouts. Timing and type of meals determine when your sleep hormone melatonin is released, ushering in sleep.

Rhythm isn't a hack. It's not a way to cheat the system or the boss. Nature has honed its optimization wisdom over trillions of days and nights. Stop looking for quick fixes. You're a whole system made of smaller subsystems that must work together to function well. No one pill or subsystem will make it all work. Understanding and coordinating your rhythms is free, easy, and only benefits you.

Dr. Sara C. Mednick is a cognitive neuroscientist at UC Irvine and author of The Power of the Downstate (HachetteGO)

Laura Sanders

Laura Sanders

3 years ago

Xenobots, tiny living machines, can duplicate themselves.

Strange and complex behavior of frog cell blobs


A xenobot “parent,” shaped like a hungry Pac-Man (shown in red false color), created an “offspring” xenobot (green sphere) by gathering loose frog cells in its opening.

Tiny “living machines” made of frog cells can make copies of themselves. This newly discovered renewal mechanism may help create self-renewing biological machines.

According to Kirstin Petersen, an electrical and computer engineer at Cornell University who studies groups of robots, “this is an extremely exciting breakthrough.” She says self-replicating robots are a big step toward human-free systems.

Researchers described the behavior of xenobots earlier this year (SN: 3/31/21). Small clumps of skin stem cells from frog embryos knitted themselves into small spheres and started moving. Cilia, or cellular extensions, powered the xenobots around their lab dishes.

The findings are published in the Proceedings of the National Academy of Sciences on Dec. 7. The xenobots can gather loose frog cells into spheres, which then form xenobots.
The researchers call this type of movement-induced reproduction kinematic self-replication. The study's coauthor, Douglas Blackiston of Tufts University in Medford, Massachusetts, and Harvard University, says this is typical. For example, sexual reproduction requires parental sperm and egg cells. Sometimes cells split or budded off from a parent.

“This is unique,” Blackiston says. These xenobots “find loose parts in the environment and cobble them together.” This second generation of xenobots can move like their parents, Blackiston says.
The researchers discovered that spheroid xenobots could only produce one more generation before dying out. The original xenobots' shape was predicted by an artificial intelligence program, allowing for four generations of replication.

A C shape, like an openmouthed Pac-Man, was predicted to be a more efficient progenitor. When improved xenobots were let loose in a dish, they began scooping up loose cells into their gaping “mouths,” forming more sphere-shaped bots (see image below). As many as 50 cells clumped together in the opening of a parent to form a mobile offspring. A xenobot is made up of 4,000–6,000 frog cells.

Petersen likes the Xenobots' small size. “The fact that they were able to do this at such a small scale just makes it even better,” she says. Miniature xenobots could sculpt tissues for implantation or deliver therapeutics inside the body.

Beyond the xenobots' potential jobs, the research advances an important science, says study coauthor and Tufts developmental biologist Michael Levin. The science of anticipating and controlling the outcomes of complex systems, he says.

“No one could have predicted this,” Levin says. “They regularly surprise us.” Researchers can use xenobots to test the unexpected. “This is about advancing the science of being less surprised,” Levin says.

Jamie Ducharme

3 years ago

How monkeypox spreads (and doesn't spread)

Monkeypox was rare until recently. In 2005, a research called a cluster of six monkeypox cases in the Republic of Congo "the longest reported chain to date."

That's changed. This year, over 25,000 monkeypox cases have been reported in 83 countries, indicating widespread human-to-human transmission.

What spreads monkeypox? Monkeypox transmission research is ongoing; findings may change. But science says...

Most cases were formerly animal-related.

According to the WHO, monkeypox was first diagnosed in an infant in the DRC in 1970. After that, instances were infrequent and often tied to animals. In 2003, 47 Americans contracted rabies from pet prairie dogs.

In 2017, Nigeria saw a significant outbreak. NPR reported that doctors diagnosed young guys without animal exposure who had genital sores. Nigerian researchers highlighted the idea of sexual transmission in a 2019 study, but the theory didn't catch on. “People tend to cling on to tradition, and the idea is that monkeypox is transmitted from animals to humans,” explains research co-author Dr. Dimie Ogoina.

Most monkeypox cases are sex-related.

Human-to-human transmission of monkeypox occurs, and sexual activity plays a role.

Joseph Osmundson, a clinical assistant professor of biology at NYU, says most transmission occurs in queer and gay sexual networks through sexual or personal contact.

Monkeypox spreads by skin-to-skin contact, especially with its blister-like rash, explains Ogoina. Researchers are exploring whether people can be asymptomatically contagious, but they are infectious until their rash heals and fresh skin forms, according to the CDC.

A July research in the New England Journal of Medicine reported that of more than 500 monkeypox cases in 16 countries as of June, 95% were linked to sexual activity and 98% were among males who have sex with men. WHO Director-General Tedros Adhanom Ghebreyesus encouraged males to temporarily restrict their number of male partners in July.

Is monkeypox a sexually transmitted infection (STI)?

Skin-to-skin contact can spread monkeypox, not simply sexual activities. Dr. Roy Gulick, infectious disease chief at Weill Cornell Medicine and NewYork-Presbyterian, said monkeypox is not a "typical" STI. Monkeypox isn't a STI, claims the CDC.

Most cases in the current outbreak are tied to male sexual behavior, but Osmundson thinks the virus might also spread on sports teams, in spas, or in college dorms.

Can you get monkeypox from surfaces?

Monkeypox can be spread by touching infected clothing or bedding. According to a study, a U.K. health care worker caught monkeypox in 2018 after handling ill patient's bedding.

Angela Rasmussen, a virologist at the University of Saskatchewan in Canada, believes "incidental" contact seldom distributes the virus. “You need enough virus exposure to get infected,” she says. It's conceivable after sharing a bed or towel with an infectious person, but less likely after touching a doorknob, she says.

Dr. Müge evik, a clinical lecturer in infectious diseases at the University of St. Andrews in Scotland, says there is a "spectrum" of risk connected with monkeypox. "Every exposure isn't equal," she explains. "People must know where to be cautious. Reducing [sexual] partners may be more useful than cleaning coffee shop seats.

Is monkeypox airborne?

Exposure to an infectious person's respiratory fluids can cause monkeypox, but the WHO says it needs close, continuous face-to-face contact. CDC researchers are still examining how often this happens.

Under precise laboratory conditions, scientists have shown that monkeypox can spread via aerosols, or tiny airborne particles. But there's no clear evidence that this is happening in the real world, Rasmussen adds. “This is expanding predominantly in communities of males who have sex with men, which suggests skin-to-skin contact,” she explains. If airborne transmission were frequent, she argues, we'd find more occurrences in other demographics.

In the shadow of COVID-19, people are worried about aerosolized monkeypox. Rasmussen believes the epidemiology is different. Different viruses.

Can kids get monkeypox?

More than 80 youngsters have contracted the virus thus far, mainly through household transmission. CDC says pregnant women can spread the illness to their fetus.

Among the 1970s, monkeypox predominantly affected children, but by the 2010s, it was more common in adults, according to a February study. The study's authors say routine smallpox immunization (which protects against monkeypox) halted when smallpox was eradicated. Only toddlers were born after smallpox vaccination halted decades ago. More people are vulnerable now.

Schools and daycares could become monkeypox hotspots, according to pediatric instances. Ogoina adds this hasn't happened in Nigeria's outbreaks, which is encouraging. He says, "I'm not sure if we should worry." We must be careful and seek evidence.

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Ben Chino

Ben Chino

3 years ago

100-day SaaS buildout.

We're opening up Maki through a series of Medium posts. We'll describe what Maki is building and how. We'll explain how we built a SaaS in 100 days. This isn't a step-by-step guide to starting a business, but a product philosophy to help you build quickly.

Focus on end-users.

This may seem obvious, but it's important to talk to users first. When we started thinking about Maki, we interviewed 100 HR directors from SMBs, Next40 scale-ups, and major Enterprises to understand their concerns. We initially thought about the future of employment, but most of their worries centered on Recruitment. We don't have a clear recruiting process, it's time-consuming, we recruit clones, we don't support diversity, etc. And as hiring managers, we couldn't help but agree.

Co-create your product with your end-users.

We went to the drawing board, read as many books as possible (here, here, and here), and when we started getting a sense for a solution, we questioned 100 more operational HR specialists to corroborate the idea and get a feel for our potential answer. This confirmed our direction to help hire more objectively and efficiently.

Survey findings

Back to the drawing board, we designed our first flows and screens. We organized sessions with certain survey respondents to show them our early work and get comments. We got great input that helped us build Maki, and we met some consumers. Obsess about users and execute alongside them.

Using whiteboards

Don’t shoot for the moon, yet. Make pragmatic choices first.

Once we were convinced, we began building. To launch a SaaS in 100 days, we needed an operating principle that allowed us to accelerate while still providing a reliable, secure, scalable experience. We focused on adding value and outsourced everything else. Example:

Concentrate on adding value. Reuse existing bricks.

When determining which technology to use, we looked at our strengths and the future to see what would last. Node.js for backend, React for frontend, both with typescript. We thought this technique would scale well since it would attract more talent and the surrounding mature ecosystem would help us go quicker.

Maki's tech

We explored for ways to bootstrap services while setting down strong foundations that might support millions of users. We built our backend services on NestJS so we could extend into microservices later. Hasura, a GraphQL APIs engine, automates Postgres data exposing through a graphQL layer. MUI's ready-to-use components powered our design-system. We used well-maintained open-source projects to speed up certain tasks.

We outsourced important components of our platform (Auth0 for authentication, Stripe for billing, SendGrid for notifications) because, let's face it, we couldn't do better. We choose to host our complete infrastructure (SQL, Cloud run, Logs, Monitoring) on GCP to simplify our work between numerous providers.

Focus on your business, use existing bricks for the rest. For the curious, we'll shortly publish articles detailing each stage.

Most importantly, empower people and step back.

We couldn't have done this without the incredible people who have supported us from the start. Since Powership is one of our key values, we provided our staff the power to make autonomous decisions from day one. Because we believe our firm is its people, we hired smart builders and let them build.

Maki Camp 2 team

Nicolas left Spendesk to create scalable interfaces using react-router, react-queries, and MUI. JD joined Swile and chose Hasura as our GraphQL engine. Jérôme chose NestJS to build our backend services. Since then, Justin, Ben, Anas, Yann, Benoit, and others have followed suit.

If you consider your team a collective brain, you should let them make decisions instead of directing them what to do. You'll make mistakes, but you'll go faster and learn faster overall.

Invest in great talent and develop a strong culture from the start. Here's how to establish a SaaS in 100 days.

Sukhad Anand

Sukhad Anand

3 years ago

How Do Discord's Trillions Of Messages Get Indexed?

They depend heavily on open source..

Photo by Alexander Shatov on Unsplash

Discord users send billions of messages daily. Users wish to search these messages. How do we index these to search by message keywords?

Let’s find out.

  1. Discord utilizes Elasticsearch. Elasticsearch is a free, open search engine for textual, numerical, geographical, structured, and unstructured data. Apache Lucene powers Elasticsearch.

  2. How does elastic search store data? It stores it as numerous key-value pairs in JSON documents.

  3. How does elastic search index? Elastic search's index is inverted. An inverted index lists every unique word in every page and where it appears.

4. Elasticsearch indexes documents and generates an inverted index to make data searchable in near real-time. The index API adds or updates JSON documents in a given index.

  1. Let's examine how discord uses Elastic Search. Elasticsearch prefers bulk indexing. Discord couldn't index real-time messages. You can't search posted messages. You want outdated messages.

6. Let's check what bulk indexing requires.
1. A temporary queue for incoming communications.
2. Indexer workers that index messages into elastic search.

  1. Discord's queue is Celery. The queue is open-source. Elastic search won't run on a single server. It's clustered. Where should a message go? Where?

8. A shard allocator decides where to put the message. Nevertheless. Shattered? A shard combines elastic search and index on. So, these two form a shard which is used as a unit by discord. The elastic search itself has some shards. But this is different, so don’t get confused.

  1. Now, the final part is service discovery — to discover the elastic search clusters and the hosts within that cluster. This, they do with the help of etcd another open source tool.

A great thing to notice here is that discord relies heavily on open source systems and their base implementations which is very different from a lot of other products.

Erik Engheim

Erik Engheim

3 years ago

You Misunderstand the Russian Nuclear Threat

Many believe Putin is simply sabre rattling and intimidating us. They see no threat of nuclear war. We can send NATO troops into Ukraine without risking a nuclear war.

I keep reading that Putin is just using nuclear blackmail and that a strong leader will call the bluff. That, in my opinion, misunderstands the danger of sending NATO into Ukraine.
It assumes that once NATO moves in, Putin can either push the red nuclear button or not.
Sure, Putin won't go nuclear if NATO invades Ukraine. So we're safe? Can't we just move NATO?

No, because history has taught us that wars often escalate far beyond our initial expectations. One domino falls, knocking down another. That's why having clear boundaries is vital. Crossing a seemingly harmless line can set off a chain of events that are unstoppable once started.
One example is WWI. The assassin of Archduke Franz Ferdinand could not have known that his actions would kill millions. They couldn't have known that invading Serbia to punish them for not handing over the accomplices would start a world war. Every action triggered a counter-action, plunging Europe into a brutal and bloody war. Each leader saw their actions as limited, not realizing how they kept the dominos falling.

Nobody can predict the future, but it's easy to imagine how NATO intervention could trigger a chain of events leading to a total war. Let me suggest some outcomes.
NATO creates a no-fly-zone. In retaliation, Russia bombs NATO airfields. Russia may see this as a limited counter-move that shouldn't cause further NATO escalation. They think it's a reasonable response to force NATO out of Ukraine. Nobody has yet thought to use the nuke.
Will NATO act? Polish airfields bombed, will they be stuck? Is this an article 5 event? If so, what should be done?

It could happen. Maybe NATO sends troops into Ukraine to punish Russia. Maybe NATO will bomb Russian airfields.

Putin's response Is bombing Russian airfields an invasion or an attack? Remember that Russia has always used nuclear weapons for defense, not offense. But let's not panic, let's assume Russia doesn't go nuclear.

Maybe Russia retaliates by attacking NATO military bases with planes. Maybe they use ships to attack military targets. How does NATO respond? Will they fight Russia in Ukraine or escalate? Will they invade Russia or attack more military installations there?
Seen the pattern? As each nation responds, smaller limited military operations can grow in scope.

So far, the Russian military has shown that they begin with less brutal methods. As losses and failures increase, brutal means are used. Syria had the same. Assad used chemical weapons and attacked hospitals, schools, residential areas, etc.
A NATO invasion of Ukraine would cost Russia dearly. “Oh, this isn't looking so good, better pull out and finish this war,” do you think? No way. Desperate, they will resort to more brutal tactics. If desperate, Russia has a huge arsenal of ugly weapons. They have nerve agents, chemical weapons, and other nasty stuff.

What happens if Russia uses chemical weapons? What if Russian nerve agents kill NATO soldiers horribly? West calls for retaliation will grow. Will we invade Russia? Will we bomb them?

We are angry and determined to punish war criminal Putin, so NATO tanks may be heading to Moscow. We want vengeance for his chemical attacks and bombing of our cities.
Do you think the distance between that red nuclear button and Putin's finger will be that far once NATO tanks are on their way to Moscow?

We might avoid a nuclear apocalypse. A NATO invasion force or even Western cities may be used by Putin. Not as destructive as ICBMs. Putin may think we won't respond to tactical nukes with a full nuclear counterattack. Why would we risk a nuclear Holocaust by launching ICBMs on Russia?

Maybe. My point is that at every stage of the escalation, one party may underestimate the other's response. This war is spiraling out of control and the chances of a nuclear exchange are increasing. Nobody really wants it.

Fear, anger, and resentment cause it. If Putin and his inner circle decide their time is up, they may no longer care about the rest of the world. We saw it with Hitler. Hitler, seeing the end of his empire, ordered the destruction of Germany. Nobody should win if he couldn't. He wanted to destroy everything, including Paris.

In other words, the danger isn't what happens after NATO intervenes The danger is the potential chain reaction. Gambling has a psychological equivalent. It's best to exit when you've lost less. We humans are willing to take small risks for big rewards. To avoid losses, we are willing to take high risks. Daniel Kahneman describes this behavior in his book Thinking, Fast and Slow.

And so bettors who have lost a lot begin taking bigger risks to make up for it. We get a snowball effect. NATO involvement in the Ukraine conflict is akin to entering a casino and placing a bet. We'll start taking bigger risks as we start losing to Russian retaliation. That's the game's psychology.

It's impossible to stop. So will politicians and citizens from both Russia and the West, until we risk the end of human civilization.

You can avoid spiraling into ever larger bets in the Casino by drawing a hard line and declaring “I will not enter that Casino.” We're doing it now. We supply Ukraine. We send money and intelligence but don't cross that crucial line.

It's difficult to watch what happened in Bucha without demanding NATO involvement. What should we do? Of course, I'm not in charge. I'm a writer. My hope is that people will think about the consequences of the actions we demand. My hope is that you think ahead not just one step but multiple dominos.

More and more, we are driven by our emotions. We cannot act solely on emotion in matters of life and death. If we make the wrong choice, more people will die.

Read the original post here.