Hexbyte  Tech News  Wired Drugs That Boost Our Circadian Rhythms Could Save Our Lives

Hexbyte Tech News Wired Drugs That Boost Our Circadian Rhythms Could Save Our Lives

Hexbyte Tech News Wired

This story is part of a series on how we make time—from productivity hacks and long walks to altering the function of our own circadian clocks.

Before there was electricity or the internet or screens illuminated by thousands of liquid crystals rotating polarized pulses of photons, humans mostly lived by the daily comings and goings of the yellow burning ball of gas in the sky. Like every other organism that walks, flies, swims, scurries, sways, or photosynthesizes on Earth, people evolved circadian rhythms tuned to this solar circuit.

Yours, like that of most other organisms, is controlled by waves of proteins encoded in just a handful of master clock genes. Every day, as if tracing the rise and fall of the sun through the firmament, concentrations of special timekeeping protein complexes surge and ebb inside nearly every cell in your body, in a sinusoidal curve that repeats itself every 24 hours. These proteins predictably bind and release your DNA, flipping thousands of genes on and off in synchronized choreography. They dictate more than just your sleep patterns. Fluctuations in most of your critical body functions, including blood pressure, body temperature, metabolism, and even your moods and behaviors all run on a meticulous 24-hour schedule.

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A Tour of How We Literally and Figuratively Make Time.

But lots of things can throw your clock out of whack—consuming calories at all hours of the day, binge-watching Netflix on a blue-tinged screen at 3 am, even just getting older. And when your internal timekeeper starts ticking off-beat, lots of other things start to go wrong, from depression and other mood disorders to metabolic malfunctions and heart disease. Which is why one of the newest ideas in the emerging field of circadian medicine is to create drugs that actually amplify the cadence of our internal timers. The scientists leading this charge think such “clock-enhancing molecules” could help astronauts in the future stay on Earth-time even as they’re up in orbit or en route to Mars. Closer to home, these drugs could one day be used to combat the obesity epidemic, stave off incurable diseases like Alzheimer’s, and even slow aging itself.

Up until the mid-2000s, circadian rhythm science had been mostly viewed as a kind of cute, niche little corner of biology. But advances in gene sequencing technologies post-Human Genome Project led scientists to realize that the clock controlled more than 10,000 genes in nearly every cell in the human body. Even more recently, they discovered that clock was malleable. “Almost all the important functions in your body have a temporal component that we can tweak through the power of circadian manipulation,” says Jake Chen, a biochemist at the University of Texas Health Science Center in Houston. He’s spent the last ten years hunting for compounds with circadian-boosting properties and testing the hypothesis that they can make people live happier, healthier, longer lives. If he’s right, curing or preventing some of society’s most common and costly diseases might come down to chemically resetting our clocks. “The time has come for the biomedical research community to recognize that biological timing is a bonafide therapeutic target.”

Chen’s interest in circadian-modifying molecules began back in 2008, when he was a postdoc in the lab of a biochemist named Steven McKnight. At that time, most of the genes that control our molecular clocks had already been mapped out by a few dedicated chronobiologists, including a trio of American scientists who would go on to win the 2017 Nobel Prize in medicine for their contributions. But no one was quite sure how to use that knowledge to help people live healthier lives. Chen thought if he could find compounds that nudged the hands of that clock by activating or deactivating the genes that control it—speeding it up, slowing it down, making it disappear altogether—he could help identify what happens inside the bodies of people whose clock genes turn on willy-nilly or not at all. What he found instead, after screening more than a quarter-million chemicals, was a class of molecules that supercharged cells’ clock functions. If you imagine the clock as an oscillating sine wave that represents the rate of timekeeping protein production, like a sound wave coming out of your Bluetooth speaker, these compounds make the peaks higher and the troughs lower, the molecular equivalent of turning the volume knob way up. And the louder the clock keeps time, the more the body’s tissues stick to their respective schedules.

The effects can be drastic. Take a chemical called nobiletin, which is found in the oily peel of some orange and kumquat species and has proven itself one of Chen’s most promising candidates. The small molecule binds to one of the core clock proteins responsible for stabilizing the 24-hour cycle. When his team administered nobiletin to mice that were fed a high-calorie diet (Chen describes it as an “all-McDonald’s every day” diet), they stayed slim, even as control mice packed on nearly twice their body weight in just 10 weeks. Nobiletin also improved other markers of healthy metabolism, like fasting glucose and cholesterol levels.

Megan Molteni covers DNA technologies, medicine, and genetic privacy for WIRED.

Chen’s team published those results in 2016, and more recently, they’ve tested nobiletin’s potential to reverse some of the common ailments associated with aging. As we get older our metabolism slows down, which impacts everything from exercise endurance and heat production to the ability to sleep for long stretches of time. Evidence suggests this metabolic tail-off is tied to mitochondrial burnout. Our cells’ energy factories just aren’t outputting as much as they used to. And why is that? Because mitochondrial function is closely regulated by our circadian clocks, which also get weaker as we age—they tick more quietly. In work that is currently under review, Chen’s group used nobiletin to restore the circadian clocks in muscle cells of aged mice. As a result, the mice were stronger, slept better, and lived longer than their untreated counterparts. “Chronologically they were 28 months, but they behaved much younger,” Chen says.

Encouraged by these results, he is now expanding into an even more ambitious project—testing whether or not circadian-enhancing drugs could be used to treat Alzheimer’s disease, the debilitating neurodegenerative condition that will affect about 10 percent of the US population before the middle of the century. Spurred by these projections, the National Institutes of Health and Congress have begun to aggressively fund Alzheimer’s research in the last few years, and Chen is a recipient of this spending bonanza. Last year he received a five-year, $3.6 million NIH grant to test his most promising molecules in mouse models of Alzheimer’s. It’s part of a larger project that will also look at genetic interventions that amp up the circadian clock by operating on the DNA that controls it directly. “We know that in Alzheimer’s disease patients, the circadian rhythm is dampened,” Chen says. “So we’re hoping that by rejuvenating the circadian rhythm it’s going to improve brain function, sleep cycles, and possibly even alleviate the behavioral deficits that are a hallmark of the disease.”

That work is just getting going. But it has other researchers in the field excited about the long-term prospects of circadian medicine. “Having drugs that reinforce and reset our clocks would be useful for combating the negative health effects of shift work, jet lag, and getting off the Earth,” says Carrie Partch, a structural biologist at the University of California Santa Cruz’s Center for Circadian Biology. On the International Space Station, astronauts have a 90-minute day, an unnatural environment that NASA’s recent Twin Study showed can alter both circadian rhythms and your DNA.

Back on Earth, scientists still don’t know whether the clock weakens because we get older, or if aging is itself a symptom of a diminishing circadian rhythm. And if it’s the latter, then invigorating our clocks could theoretically put more sand in the hourglass. “If a molecule can make that clock stronger so that our bodies can fight off all those changes, then 70 really would be the new 50,” Partch says. “That’s the promise of enhancing circadian rhythms.” Modern technology may have liberated the human species from millennia of obligate diurnality, but our bodies evolved to respond to the sun, not to screens.

So until science delivers some magic clock-boosting pill, maybe just, you know, go outside more often.

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Hexbyte  Tech News  Wired I Tweeted Out My Phone Number—and Rediscovered Humanity

Hexbyte Tech News Wired I Tweeted Out My Phone Number—and Rediscovered Humanity

Hexbyte Tech News Wired

The calls come in during twilight. At first, the tone is a whisper. They’re trying to see if I’m someone they’re comfortable with. I look for a common interest: food, film, music—anything that connects us as humans. After that, I let them lead.

I’ve been taking phone calls from strangers for a few months now. This practice started after I was digitally shamed on Twitter. I had written an op-ed in The New York Times worrying about our culture of shame. I empathized with a white teen growing up in a conservative, Midwestern home. In my heart, I know a couple things to be true. We’re all human beings that deserve the opportunity to change or grow. Speaking our truth is better than scolding or silencing the voices that we don’t like. It’s healthy to disagree.

Stefan Dinse/EyeEm/Getty Images (clouds)

Of course, there was a backlash. I was called racist. My mentions were filled with malice. Strangers tweeted about how they had lost respect for me. Close friends said nothing at all. I was being digitally shamed for arguing against digital shaming. A congressional candidate and internet influencers urged me to issue a public response. It’s a lonely experience to feel like the most hated person alive for just saying what was on my mind.

So I put my phone number in my bio on Twitter. Then, when no one called, I tweeted out my number with an invitation to reach out.

The first call came through around 9 at night. The caller was a librarian with an upbeat voice. I was prepared to answer as many questions as she needed to ask about my op-ed. Instead, she told me about the men in her life. I listened and offered any advice on men that I had—which, as a single woman, is not much. It was surprisingly normal and, after 20 minutes, we said our goodbyes.

The calls started to pour in. A soldier on a military base told me about his favorite films. We talked for two hours, and I loved every minute. A therapist had seen me tweet about my sobriety and called to talk through her own. A man in a loud Uber Pool called on his way home from drinks with coworkers. Like me, he was ashamed that as a teen he had identified as a Republican. A woman who had just moved to the United States for work called to talk about how hard it’s been to make new friends. Someone with an unlisted phone number called to say that I was an idiot and then hung up. Another softly asked if I was OK. Each conversation left me feeling more human, less shamed.

I’ve always loved talking on the phone. I adore the subtle ways a phone call can evoke intimacy. You hear the cracks in a voice, the sound of breath, and the patience of thinking. And there’s no audience. It’s the one-to-one connection that reassures we can correct our mistakes without fear of them following or haunting us. It’s a compassionate technology.

Before hanging up, I check in to see how my caller is feeling. It’s a closure that brings us closer. Surprisingly, no one ever mentioned the article. I merely listened and shared my feelings with dozens of strangers. I’d done this countless times on Twitter, too, but always seemed to miss what they were really saying; the connection between the human heart and human mind somehow got disconnected. Shouting online may bring us instant gratification, but a phone call helps us sleep at night.


Robyn Kanner (@robynkanner) is a writer and designer living in Brooklyn. You can reach her at 929-374-4003.

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Let us know what you think about this article. Submit a letter to the editor at mail@wired.com.


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Hexbyte  News  Computers NixOS/nixpkgs

Hexbyte News Computers NixOS/nixpkgs

Hexbyte News Computers

let maybePkgs = import ../../../../../. {}; in{ stdenv ? maybePkgs.stdenv, runCommand ? maybePkgs.runCommand, fetchurl ? maybePkgs.fetchurl, writeText ? maybePkgs.writeText, curl ? maybePkgs.curl, cacert ? maybePkgs.cacert, nix ? maybePkgs.nix}:let inherit (stdenv) lib; sources = if builtins.pathExists ./upstream-info.nix then import ./upstream-info.nix else {}; bucketURL = https://commondatastorage.googleapis.com/ + chromium-browser-official; mkVerURL = version: ${bucketURL}/chromium-${version}.tar.xz; debURL = https://dl.google.com/linux/chrome/deb/pool/main/g; getDebURL = channelName: version: arch: mirror: let packageSuffix = if channelName == dev then unstable else channelName; packageName = google-chrome-${packageSuffix}; in ${mirror}/${packageName}/${packageName}_${version}-1_${arch}.deb; # Untrusted mirrors, don’t try to update from them! debMirrors = [ http://95.31.35.30/chrome/pool/main/g http://mirror.pcbeta.com/google/chrome/deb/pool/main/g http://repo.fdzh.org/chrome/deb/pool/main/g ];in rec { getChannel = channel: let chanAttrs = builtins.getAttr channel sources; in { inherit channel; inherit (chanAttrs) version; main = fetchurl { url = mkVerURL chanAttrs.version; inherit (chanAttrs) sha256; }; binary = fetchurl (let mkUrls = arch: let mkURLForMirror = getDebURL channel chanAttrs.version arch; in map mkURLForMirror ([ debURL ] ++ debMirrors); in if stdenv.is64bit && chanAttrs ? sha256bin64 then { urls = mkUrls amd64; sha256 = chanAttrs.sha256bin64; } else if !stdenv.is64bit && chanAttrs ? sha256bin32 then { urls = mkUrls i386; sha256 = chanAttrs.sha256bin32; } else throw No Chrome plugins are available for your architecture.); }; update = let csv2nix = name: src: import (runCommand ${name}.nix { src = builtins.fetchurl src; } esc() { echo “”$(echo “$1″ | sed -e ‘s/”\$/\&/’)””; } # ohai emacs “ IFS=, read -r -a headings <<< "$(head -n1 "$src")" echo “[” > “$out” tail -n +2 “$src” | while IFS=, read -r -a line; do echo ” {“ for idx in “”${!headings[@]}”; do echo ” $(esc “”${headings[idx]}”) = $(esc ”${line[$idx]});” done echo ” }” done >> “$out” echo “]” >> “$out” ); channels = lib.fold lib.recursiveUpdate {} (map (attrs: { ${attrs.os}.${attrs.channel} = attrs // { history = let drvName = omahaproxy-${attrs.os}.${attrs.channel}-info; history = csv2nix drvName http://omahaproxy.appspot.com/history; cond = h: attrs.os == h.os && attrs.channel == h.channel && lib.versionOlder h.version attrs.current_version; # Note that this is a *reverse* sort! sorter = a: b: lib.versionOlder b.version a.version; sorted = builtins.sort sorter (lib.filter cond history); in map (lib.flip removeAttrs [os channel]) sorted; version = attrs.current_version; }; }) (csv2nix omahaproxy-info http://omahaproxy.appspot.com/all?csv=1)); /* XXX: This is essentially the same as: builtins.tryEval (builtins.fetchurl url) … except that tryEval on fetchurl isn’t working and doesn’t catch errors for fetchurl, so we go for a different approach. We only have fixed-output derivations that can have networking access, so we abuse SHA1 and its weaknesses to forge a fixed-output derivation which is not so fixed, because it emits different contents that have the same SHA1 hash. Using this method, we can distinguish whether the URL is available or whether it’s not based on the actual content. So let’s use tryEval as soon as it’s working with fetchurl in Nix. */ tryFetch = url: let # SHA1 hash collisions from https://shattered.io/static/shattered.pdf: collisions = runCommand sha1-collisions { outputs = [ out good bad ]; base64 = QlpoOTFBWSZTWbL5V5MABl///////9Pv///v////+/////HDdK739/677r+W3/75rUNr4 Aa/AAAAAAACgEVTRtQDQAaA0AAyGmjTQGmgAAANGgAaMIAYgGgAABo0AAAAAADQAIAGQ0 MgDIGmjQA0DRk0AaMQ0DQAGIANGgAAGRoNGQMRpo0GIGgBoGQAAIAGQ0MgDIGmjQA0DRk 0AaMQ0DQAGIANGgAAGRoNGQMRpo0GIGgBoGQAAIAGQ0MgDIGmjQA0DRk0AaMQ0DQAGIAN GgAAGRoNGQMRpo0GIGgBoGQAAIAGQ0MgDIGmjQA0DRk0AaMQ0DQAGIANGgAAGRoNGQMRp o0GIGgBoGQAABVTUExEZATTICnkxNR+p6E09JppoyamjGhkm0ammIyaekbUejU9JiGnqZ qaaDxJ6m0JkZMQ2oaYmJ6gxqMyE2TUzJqfItligtJQJfYbl9Zy9QjQuB5mHQRdSSXCCTH MgmSDYmdOoOmLTBJWiCpOhMQYpQlOYpJjn+wQUJSTCEpOMekaFaaNB6glCC0hKEJdHr6B mUIHeph7YxS8WJYyGwgWnMTFJBDFSxSCCYljiEk7HZgJzJVDHJxMgY6tCEIIWgsKSlSZ0 S8GckoIIF+551Ro4RCw260VCEpWJSlpWx/PMrLyVoyhWMAneDilBcUIeZ1j6NCkus0qUC Wnahhk5KT4GpWMh3vm2nJWjTL9Qg+84iExBJhNKpbV9tvEN265t3fu/TKkt4rXFTsV+Nc upJXhOhOhJMQQktrqt4K8mSh9M2DAO2X7uXGVL9YQxUtzQmS7uBndL7M6R7vX869VxqPu renSuHYNq1yTXOfNWLwgvKlRlFYqLCs6OChDp0HuTzCWscmGudLyqUuwVGG75nmyZhKpJ yOE/pOZyHyrZxGM51DYIN+Jc8yVJgAykxKCEtW55MlfudLg3KG6TtozalunXrroSxUpVL StWrWLFihMnVpkyZOrQnUrE6xq1CGtJlbAb5ShMbV1CZgqlKC0wCFCpMmUKSEkvFLaZC8 wHOCVAlvzaJQ/T+XLb5Dh5TNM67p6KZ4e4ZSGyVENx2O27LzrTIteAreTkMZpW95GS0CE JYhMc4nToTJ0wQhKEyddaLb/rTqmgJSlkpnALxMhlNmuKEpkEkqhKUoEq3SoKUpIQcDgW lC0rYahMmLuPQ0fHqZaF4v2W8IoJ2EhMhYmSw7qql27WJS+G4rUplToFi2rSv0NSrVvDU pltQ8Lv6F8pXyxmFBSxiLSxglNC4uvXVKmAtusXy4YXGX1ixedEvXF1aX6t8adYnYCpC6 rW1ZzdZYlCCxKEv8vpbqdSsXl8v1jCQv0KEPxPTa/5rtWSF1dSgg4z4KjfIMNtgwWoWLE sRhKxsSA9ji7V5LRPwtumeQ8V57UtFSPIUmtQdOQfseI2Ly1DMtk4Jl8n927w34zrWG6P i4jzC82js/46Rt2IZoadWxOtMInS2xYmcu8mOw9PLYxQ4bdfFw3ZPf/g2pzSwZDhGrZAl 9lqky0W+yeanadC037xk496t0Dq3ctfmqmjgie8ln9k6Q0K1krb3dK9el4Xsu44LpGcen r2eQZ1s1IhOhnE56WnXf0BLWn9Xz15fMkzi4kpVxiTKGEpffErEEMvEeMZhUl6yD1SdeJ YbxzGNM3ak2TAaglLZlDCVnoM6wV5DRrycwF8Zh/fRsdmhkMfAO1duwknrsFwrzePWeMw l107DWzymxdQwiSXx/lncnn75jL9mUzw2bUDqj20LTgtawxK2SlQg1CCZDQMgSpEqLjRM sykM9zbSIUqil0zNk7Nu+b5J0DKZlhl9CtpGKgX5uyp0idoJ3we9bSrY7PupnUL5eWiDp V5mmnNUhOnYi8xyClkLbNmAXyoWk7GaVrM2umkbpqHDzDymiKjetgzTocWNsJ2E0zPcfh t46J4ipaXGCfF7fuO0a70c82bvqo3HceIcRlshgu73seO8BqlLIap2z5jTOY+T2ucCnBt Atva3aHdchJg9AJ5YdKHz7LoA3VKmeqxAlFyEnQLBxB2PAhAZ8KvmuR6ELXws1Qr13Nd1 i4nsp189jqvaNzt+0nEnIaniuP1+/UOZdyfoZh57ku8sYHKdvfW/jYSUks+0rK+qtte+p y8jWL9cOJ0fV8rrH/t+85/p1z2N67p/ZsZ3JmdyliL7lrNxZUlx0MVIl6PxXOUuGOeArW 3vuEvJ2beoh7SGyZKHKbR2bBWO1d49JDIcVM6lQtu9UO8ec8pOnXmkcponBPLNM2CwZ9k NC/4ct6rQkPkQHMcV/8XckU4UJCy+VeTA== ; } echo “$base64” | base64 -d | tar xj mv good.pdf “$good” mv bad.pdf “$bad” touch “$out” ; cacheVal = let urlHash = builtins.hashString sha256 url; timeSlice = builtins.currentTime / 600; in ${urlHash}${toString timeSlice}; in { success = import (runCommand check-success { result = stdenv.mkDerivation { name = tryfetch-${cacheVal}; inherit url; outputHash = d00bbe65d80f6d53d5c15da7c6b4f0a655c5a86a; outputHashMode = flat; outputHashAlgo = sha1; nativeBuildInputs = [ curl ]; preferLocalBuild = true; inherit (collisions) good bad; buildCommand = if SSL_CERT_FILE=”${cacert}/etc/ssl/certs/ca-bundle.crt” curl -s -L -f -I “$url” > /dev/null; then cp “$good” “$out” else cp “$bad” “$out” fi ; impureEnvVars = lib.fetchers.proxyImpureEnvVars; }; inherit (collisions) good; } if cmp -s “$result” “$good”; then echo true > “$out” else echo false > “$out” fi ); value = builtins.fetchurl url; }; fetchLatest = channel: let result = tryFetch (mkVerURL channel.version); in if result.success then result.value else fetchLatest (channel // { version = if channel.history != [] then (lib.head channel.history).version else throw Unfortunately there’s no older version than + ${channel.version} available for channel + ${channel.channel} on ${channel.os}.; history = lib.tail channel.history; }); getHash = path: import (runCommand gethash.nix { inherit path; nativeBuildInputs = [ nix ]; } sha256=”$(nix-hash –flat –base32 –type sha256 “$path”)” echo “”$sha256″” > “$out” ); isLatest = channel: version: let ourVersion = sources.${channel}.version or null; in if ourVersion == null then false else lib.versionOlder version sources.${channel}.version || version == sources.${channel}.version; # We only support GNU/Linux right now. linuxChannels = let genLatest = channelName: channel: let newUpstream = { inherit (channel) version; sha256 = getHash (fetchLatest channel); }; keepOld = let oldChannel = sources.${channelName}; in { inherit (oldChannel) version sha256; } // lib.optionalAttrs (oldChannel ? sha256bin32) { inherit (oldChannel) sha256bin32; } // lib.optionalAttrs (oldChannel ? sha256bin64) { inherit (oldChannel) sha256bin64; }; in if isLatest channelName channel.version then keepOld else newUpstream; in lib.mapAttrs genLatest channels.linux; getLinuxFlash = channelName: channel: let inherit (channel) version; fetchArch = arch: tryFetch (getDebURL channelName version arch debURL); packages = lib.genAttrs [i386 amd64] fetchArch; isNew = arch: attr: !(builtins.hasAttr attr channel) && packages.${arch}.success; in channel // lib.optionalAttrs (isNew i386 sha256bin32) { sha256bin32 = getHash (packages.i386.value); } // lib.optionalAttrs (isNew amd64 sha256bin64) { sha256bin64 = getHash (packages.amd64.value); }; newChannels = lib.mapAttrs getLinuxFlash linuxChannels; dumpAttrs = indent: attrs: let mkVal = val: if lib.isAttrs val then dumpAttrs (indent + 1) val else ${lib.escape [$ \ ] (toString val)}; mkIndent = level: lib.concatStrings (builtins.genList (_: ) level); mkAttr = key: val: ${mkIndent (indent + 1)}${key} = ${mkVal val};n; attrLines = lib.mapAttrsToList mkAttr attrs; in {n + (lib.concatStrings attrLines) + (mkIndent indent) + }; in writeText chromium-new-upstream-info.nix # This file is autogenerated from update.sh in the same directory. ${dumpAttrs 0 newChannels}

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Hexbyte  News  Computers The mysterious crystal that melts at two different temperatures

Hexbyte News Computers The mysterious crystal that melts at two different temperatures

Hexbyte News Computers

Hexbyte  News  Computers Crystals of acetaldehyde phenylhydrazone, or APH.
Crystals of acetaldehyde phenylhydrazone appear colorful when exposed to polarized light under a microscope. Credit: Terry Threlfall

In a little-known paper published in 1896, Emil Fischer—the German chemist who would go on to win the 1902 Nobel Prize in Chemistry for synthesizing sugars and caffeine—said his laboratory had produced a crystal that seemed to break the laws of thermodynamics. To his puzzlement, the solid form of acetaldehyde phenylhydrazone (APH) kept melting at two very different temperatures. A batch he produced on Monday might melt at 65 °C, while a batch on Thursday would melt at 100 °C.

Colleagues and rivals at the time told him he must have made a mistake. Fischer didn’t think so. As far as he could tell, the crystals that melted at such different points were identical. A few groups in Britain and France repeated his work and got the same baffling results. But as those scientists died off, the mystery was forgotten, stranded in obscure academic journals published in German and French more than a century ago.

There it would probably have remained but for Terry Threlfall, an 84-year-old chemist at the University of Southampton, UK. Stumbling across Fischer’s 1896 paper in a library about a decade ago, Threlfall was intrigued enough to kick-start an international investigation of the mysterious crystal. Earlier this year in the journal Crystal Growth and Design, Threlfall and his colleagues published the solution: APH is the first recorded example of a solid that, when it melts, forms two structurally distinct liquids. Which liquid emerges comes down to contamination so subtle that it’s virtually undetectable.

A forgotten mystery

The quest began in 2008 when Threlfall, a fluent speaker of German and a keen student of the history of science, was searching the pages of the 140-year-old Berichte der deutschen chemischen Gesellschaft for interesting solid-state work relevant to his research on second-order phase transitions. After learning of the long-lost puzzle from Fischer’s paper, Threlfall followed the reported recipe and found that his own samples of APH melted according to the same peculiar pattern. One batch melted at around 60 °C, the other at 90–95 °C.

Hexbyte  News  Computers Emil Fischer
Nobel laureate Emil Fischer works in his lab in 1904, eight years after describing a mysterious solid with multiple melting points. Credit: Nicola Perscheid

As Fischer knew 125 years ago, the laws of thermodynamics do not allow such a molecule. If a pair of solids have different melting points, then they must be structurally distinct. Yet all the modern structural analysis techniques that Threlfall and some colleagues tried on Fischer’s compound confirmed the 19th-century claim. X-ray diffraction, nuclear magnetic resonance, IR spectroscopy: All showed the crystals that behaved so differently were identical.

“For two years we wondered whether to believe the evidence of our own eyes and think that we needed to rewrite the laws of the universe, or to believe thermodynamics and think that we were simply incompetent experimentalists,” Threlfall says.

Piecing together the puzzle

The first clue for solving the mystery came from the way APH crystals are prepared. The molecule (C8H10N2) is made up of a benzene ring attached to a pair of nitrogen atoms, one of which is attached to a hydrogen atom and a methyl group that can point either up or down. Chemists make APH by dissolving solid acetaldehyde (a precursor for many useful chemical reactions and a compound found naturally in fruit) into aqueous ethanol and adding drops of liquid phenylhydrazine (also first made and characterized by Fischer, who used it in his seminal studies of sugars). If the mixture is chilled and stirred, jagged flakes and then thicker chunks of APH crystals start to appear.

According to reports from Fischer’s time, there were hints that impurities could play a role in the puzzling behavior of APH. Adding drops of an acid could steer the crystallization process toward the low-melting-point version of the molecule; with added alkali, the high-melting-point crystal would emerge. Threlfall confirmed that claim and found that he could convert between the two forms. The low-melting version could be made to melt at the higher temperature by exposing it to ammonia vapor. And the high-melting crystal just needed a whiff of acid to bring its melting point down.

That behavior seemed to suggest that the acid worked like rock salt does in lowering the melting point of water ice. But for salt to make a difference, a significant amount must be added—certainly enough to show up in a close examination of the ice’s structure. At as little as a thousandth of a molar equivalent, the quantities of acid or alkali needed to make the switch in APH were vanishingly small. Whatever contamination occurred did so with no detectable physical change to the crystal structure.

Hexbyte  News  Computers Melting points of APH crystals.
Terry Threlfall and his colleagues confirmed that there are low-melting-point and high-melting-point forms of APH. The y axis represents the heat absorbed in melting; the measured absorption is the area under the curve. Credit: Terry Threlfall

Threlfall got some important help from Hugo Meekes, a solid-state physicist at Radboud University in Nijmegen, the Netherlands. After hearing of a 2012 lecture that Threlfall had given about the conundrum, Meekes wondered if the solution might relate to a different, but equally curious, phenomenon called the disappearing polymorph problem. A scourge of drug companies, the problem manifests as the production of a solid that’s slightly but consequentially different from the desired product. The polymorphs are identical except for varying crystalline structures, which can give them different properties. In the late 1990s, for example, Abbott Laboratories learned that it had produced a less-soluble polymorph of its antiviral crystalline compound ritonavir.

The cause of disappearing polymorphs is disputed, but Meekes says it seems to come down to imperceptible contamination—perhaps a single molecule in the air can disrupt the process by seeding crystallization of the problematic form. “It sounds rather unbelievable, but it’s the only explanation,” he says. “We thought the situation with the APH must be something like this.”

But the APH case didn’t fit the pattern. The crystals of APH that melted at different temperatures weren’t polymorphs; they were identical. The researchers failed to find any other structural discrepancies either. For example, some molecules show different physical properties when their same atoms are arranged in different patterns, which is called isomerization. But both solid forms of APH contained the Z isomer, in which the methyl group points down.

Meekes too was stumped.

Enter Manuel Minas da Piedade, a solid-state physicist and thermodynamics researcher at the University of Lisbon, whom Threlfall met at a conference in 2011. After initially offering a hunch that led to another dead end, the Portuguese physicist did what many scientists do when faced with something that doesn’t add up: He went back to first principles. Because it is impossible for the same material to melt at different temperatures if the initial and final states are the same, he says, “either we don’t have the same crystal state, or the final state cannot be the same.”

Hexbyte  News  Computers Simon Coles (left) and Terry Threlfall (right).
Study coauthors Simon Coles (left) and Terry Threlfall performed some of their APH detective work at the UK National Crystallography Service at the University of Southampton. Credit: Simon Coles

Until then, all the tests performed by Threlfall and a growing number of interested colleagues had focused on solid APH, since differences in melting point typically stem from differences in the solid form. But, out of options on the solid front, in 2015 the researchers took a look at the liquids that emerged.

Back in the Netherlands, Meekes spun tiny tubes of the hot, molten APH in a solid-state NMR machine, once with the low-melting-point sample and once with the high-melting-point one. Occasional forays to temperatures higher than the delicate equipment’s 100 °C limit led to “frowning technicians,” Meekes says, but the risk was worth it. He discovered that the spectra of the two liquids were different. The same solid crystal was melting to form two liquids with distinct compositions—an unprecedented finding. “We think we have a clue as to what’s going on,” Meekes recalls telling Threlfall at a conference.

Tricky liquid

The difference, Meekes, Threlfall, and colleagues soon found as they probed further, comes down to isomerization, but only in the liquid phase. Although solid APH consists of solely the Z isomer, liquid APH also contains E isomer, in which the methyl group points up. In the liquid state, with the molecules spaced farther apart and therefore with more room to maneuver, APH can flit between the two forms, and it does so until it finds the most stable mix. That turns out to be a blend of about one-third of the Z isomer and two-thirds of the E form.

The relative amounts of each isomer at equilibrium are determined by the molecules’ Gibbs free energies, a measure of their thermodynamic potential. As the difference in Gibbs energy increases, so does the ratio of one isomer to the other. What makes APH so unusual, Threlfall says, is that the optimal isomer combination for liquid APH doesn’t match that of the solid form. “That the [solid] crystal is composed entirely of Z molecules shows that these must have a more favorable packing,” he says.

Hexbyte  News  Computers NMR analysis of liquid APH.
An NMR analysis of liquid APH revealed structural differences between the low-melting-point (black line) and high-melting-point (red) forms. Credit: Terry Threlfall

Tests showed that the high-melting solid crystal melted to a liquid that was also all Z. Then the Z-type molecules started to flip to E-type and continued until they hit that stable mix. But when the low-melting solid APH melted, it did so almost immediately to the stable mix of two-thirds E. The two liquids are different—and so the melting points are different—only because one represents an intermediate stage.

It was a melting-point suppression effect, just like salt and ice, but it was much larger than anyone on the team had thought possible. So what was behind it? Like the salt, they thought it must be an impurity. And like the disappearing polymorphs that plague the pharmaceutical industry, that impurity is too small to see or measure. Threlfall says hydrogen ions must be clinging to the surface of the solid crystal and catalyzing the shift from the Z form to the E form. To do so, those protons shift the electron density of the nitrogen atoms, which loosens the connection between nitrogen and carbon atoms in the APH molecules from a strong double bond to a weaker single one. The bond is therefore free to rotate, allowing a much more rapid switch between the Z and E forms.

With no acid present, the Z-form solid melts to Z-form liquid, and then this Z-form liquid starts the transition to E-form liquid until it reaches the stable 1:2 ratio. But when acid is there, the catalysis effect speeds the switch from Z form to E form, so much so that it happens as the solid melts.

Hexbyte  News  Computers Z and E isomers of APH.
Two isomers of APH. As a solid, molecules of APH take the Z form (left), in which the methyl group points down. But liquid APH also contains the E isomer, in which the methyl group points up. Credit: Leyla-Cann Söğütoğlu and Hugo Meekes

Overall, the starting solid is the same, the finishing liquid is the same, and the amount of energy used is the same. The laws of the universe are safe. Gérard Coquerel, who works on thermodynamics and solid-state physics at the University of Rouen, France, and was not involved in the project, says it’s an important discovery that organic chemists and others who rely on melting points to help characterize compounds should take into account. “It shows that sometimes there is a need to be careful about what we consider as the melting point,” he says.

Fischer would have been delighted to see the answer, Threlfall says, and the 19th-century chemist would probably have understood it. Although the team’s work breaks genuinely new ground, Meekes cheerfully admits that the circumstances under which the melting-point suppression occurs are so specific that the research is unlikely to have useful applications. The team hasn’t even coined a name for the physical process by which identical solids can melt into distinct liquids. “If someone else wants to name it, then they can,” Threlfall says. “But if you ask me, the scientific literature is already cluttered with too many needless terms.”

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Hexbyte – Tech News – Ars Technica | Millions of machines affected by command execution flaw in Exim mail server

Hexbyte – Tech News – Ars Technica | Millions of machines affected by command execution flaw in Exim mail server

Hexbyte – Tech News – Ars Technica |

PATCH NOW! —

In some cases, it’s trivial for remote attackers to execute commands with root privileges.


Hexbyte - Tech News - Ars Technica | Close-up photo of police-style caution tape stretched across an out-of-focus background.

Millions of Internet-connected machines running the open source Exim mail server may be vulnerable to a newly disclosed vulnerability that, in some cases, allows unauthenticated attackers to execute commands with all-powerful root privileges.

The flaw, which dates back to version 4.87 released in April 2016, is trivially exploitable by local users with a low-privileged account on a vulnerable system running with default settings. All that’s required is for the person to send an email to “${run{…}}@localhost,” where “localhost” is an existing local domain on a vulnerable Exim installation. With that, attackers can execute commands of their choice that run with root privileges.

The command execution flaw is also exploitable remotely, albeit with some restrictions. The most likely scenario for remote exploits is when default settings have been made such as:

  • The “verify = recipient” is removed manually by an administrator, possibly to prevent username enumeration using RCPT TO functions. In such a case, the local exploitation method above works.
  • Exim is configured to recognize tags in the local part of a recipient’s address (through “local_part_suffix = +* : -*” for example). Attackers can exploit the vulnerability by reusing the local exploit method with an RCPT TO “balrog+${run{…}}@localhost” (where “balrog” is the name of a local