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Constellations
I.
We had crash-landed on the planet. We were far from home. The spaceship could not be repaired, and the rescue beacon had failed. Besides me, only the astrogator, part of the captain, and the ship’s AI mind were left.
Outside, the atmosphere registered as hostile to most organisms. We huddled in the lifeboat, which was inoperable but still held air. Vast storms buffeted our cockleshell shelter, although we knew from prior readings that other areas remained calm. All that remained to us was to explore, if we wanted to live. The captain gave me the sole weapon. She tasked the astrogator with carrying some tools that would not unduly weigh him down.
Little existed on the planet except deserts of snow. But alien artifacts lay in an area near us. We were an exploration team, so this discovery had oddly comforted us, even though we had been on our way elsewhere. The massive systems failure had no discernible source, and the planet had been our only choice for landfall.
The artifacts took the form of 13 domes, spread out over that hostile terrain. The domes had been linked by cables just below shoulder level, threaded through the tops of metal posts at irregular intervals. Whether intended or not, these cables and rods formed a series of paths between the domes.
Before our instruments failed, the AI had reported that the domes appeared to have a heat signature. The cables pulsed under our grip in a way that teased promised warmth far ahead. It took some time to get used to the feeling.
The shortest path between domes was a thousand miles long. The longest path was 10 thousand miles long. Our suit technology was good: A suit could recycle water, generate food, create oxygen. It could push us into various states of near hibernation while motors in the legs drove us forward. For the captain, the suit would compensate for having lost her legs and ease her pain. We estimated we could reach the nearest path and follow it to the nearest dome … and that was it. If the dome had life support capabilities, or even just a way to replenish our suits, we would live. Otherwise, we would probably die.
We revised the estimate of our survival downward when we reached the path and soon encountered the skeletons of dead astronauts littering the way. In all shapes and sizes, cocooned within their suits. Their huddled forms under the snow displayed a serenity at odds with their fate. But when I wiped the frost from face plates, we saw the extremity of their suffering.
It is difficult to explain how we felt walking among so many fatalities. So many dead first contacts.
We no longer had to puzzle over the systems failure. Spaceships came here to crash, and intelligent entities came here to die, for whatever reason. We could not presume our fate would be any different, and adjusted our expectations accordingly. The AI’s platitudes about courage did not raise morale. There were too many lost there in the frozen wastes.
Here were the ghastly emissaries of hundreds of spacefaring species we had never before encountered.
The number of the bodies and their haphazard positioning hampered our ability to make progress to the dome. The AI estimated our chances of survival at below 50% for the first time. We would starve in our suits as the motors propelled us forward. We would become desiccated and exist in an elongation of our thoughts that made us weak and stupid until the light winked out. But still, we had no choice. So even in places where the dead in their suits were piled high, we would simply plunge forward, over and through them, headed for the dome.
What we would find there, as I have said, we did not know. But we were in an area of the galaxy where ancient civilizations had died out millions of years ago. We had been on our way to a major site, an ancient city on a moon with no atmosphere in a wilderness of stars.
Although our emotions fluctuated, a professional awe and curiosity about the dead eventually came over us. This created much debate over the comms. We had made a discovery for the ages, but our satisfaction was bittersweet. Even if we lived longer than expected, we would never return home, never see our friends or family again. The AI might continue on after we were dead, but I doubt it envied being the one to report on our discovery centuries hence. And to who?
Here were the ghastly emissaries of hundreds of spacefaring species we had never before encountered. Their suits displayed an extraordinary range, although our examination was cursory. Some even appeared to be made out of scales and other biological substances from their home worlds, giving us further clues as to their origins.
The burial of the suits by snow and the lack of access to anything other than a screaming face or faces, often distorted by time and ice, worked against recording much usable data. This issue was compounded in those cases where the suit was part of the organism and they had not needed any “artificial skin,” as the AI put it, to survive harsh conditions. That many had died despite appearing well-prepared for the planet’s environment sobered us up even before our own suits dispensed drugs to help our mental states.
After a time, each face seemed to express some aspect of our own stress and terror at the seriousness of our situation. After a time, the sheer welter of detail defeated us and caused us extreme distress. The captain made the observation that even one instance of alien contact might cause physiological and mental conditions, including anxiety, stress, fatigue. Here, we were constantly encountering the alien dead of what seemed at times an infinite number of civilizations.
We stopped recording. We recommitted ourselves to the slog toward the nearest dome.
The captain’s drugs unit had failed, but the AI found a way to help her by turning off the heating element in select panels of her suit. Some parts of her would soon be lost to the cold, but the system would allow her to live on with some measure of comfort.
I must admit, we were just glad the screaming had stopped and welcomed her counsel.
II.
For a long time, as we labored in our spacesuits on that planet—following the path, beleaguered by snowstorms—we could not understand why we found so many dead astronauts, of so many unknown alien types, and yet no spaceships. During good visibility, our line of sight reached, unbroken, for 500 miles. Where were the crash sites?
But one day we chanced upon an antenna sticking up out of the ground. Clumsy attempts at excavation soon revealed that below this antenna lay a vast dead spaceship of a kind we had never seen before. The gash that had opened it to the elements had laid bare its unique architecture, but also gave the illusion that the snow had spilled out of it to create the world around us rather than having infiltrated and accumulated inside over time.
Aspects of the spaceship’s texture gave the startling suggestion that it had been made of some ultra-hard wood or wood equivalent. Clambering partway up to stare at the inner compartments, we all felt the strangeness of the dimensions and proportions of the living quarters. There was no sign of the occupants. Perhaps, I suggested, they had headed for the domes. Perhaps they had even made it to the domes. I tried and failed to keep hope from my voice.
But the captain had ordered the AI to perform a materials analysis. The “snow” in this region had been contaminated by ash and tiny particles of bone. The AI estimated that more than 70% of the white surrounding us was made of the remains of vertebrate sentient life and the remnants of suits. Of invertebrates there was no telling. A thaw might bring not just the drip, drip of water but a shushing sound indicative of bone particulate in the mixture. I imagined there might even be the clink of small objects not rendered down by whatever intense heat had created the ash.
The astrogator had insisted on digging deeper into the ship, with the idea that some recognizable commonality between technologies might yield a part or parts with which he could fix our ship. The rest of us allowed this delusion for the obvious reasons. But upon his return, he held in his hands ovals of snow not much larger than the space formed by the circle between a thumb and finger. Many of them had soft indentations, as one might find in the afterbirth of reptiles from eggs. A kind of ghostly cilia-like tread appeared along the bottoms of these objects.
The astrogator did not find any technology of use to us. Instead, he discovered that the species piloting the spaceship had been so different from us as to be safely encapsuled in suits the size of eggs. Much of what had spilled into or spilled out of the gash constituted the bodies of the crew, in their hundreds of thousands. Their suits had been inadequate to the conditions. They had died en masse attempting to escape their own ship.
The AI speculated that it had been a generation ship, perhaps fleeing a planet with a dying star. If we wondered how the AI had reached this conclusion, it was because we did not want it to be true.
The captain became silent upon receiving this further news and did not speak to us for more than 100 miles of further progress.
As we left that site, unsure exactly what we stepped upon, we also knew that since the spaceship was entirely covered by snow, it had been falling into the sediment for days or months or years. We knew then that our ship might not be visible against the horizon should we retrace our steps. The already bleak probability of rescue through visual identification of a crash site from above would be lost to us in time, even as the line of cables remained perpetually visible to the horizon. We now thought of the planet as a trap. But of what sort?
III.
We could not be sure, but in the absence of the captain’s voice, it may have been the AI that put forward the idea of the planet’s being “duplicitous.” The phrasing concerned us, for there was a duplicity in using the planet as the subject of the spoken sentence. A sphere rotating around a sun in deep space could not exhibit forethought or premeditation or other qualities of sentience.
The AI meant whoever or whatever had created the conditions on the planet that allowed spacecraft to be trapped and then the occupants placed in a perilous situation with no recourse. But I distinctly recall the AI using the words “the planet.” In addition to being inaccurate, this also let us know that the AI did not have any analysis available that might help us understand the agency and motivations acting upon us.
But in a sense, the AI only voiced something I had felt for several miles: that there existed an overlay to the planet’s surface, an area or space or different landscape unavailable to us. This overlay had also not been available to any of the prior astronauts who had died here. In this area or space or different landscape existed a wealth of the usual hoped-for things: a breathable atmosphere and abundant food and water.
While we struggled with the line through the snow and through the storms that welled up, others could see us but chose to ignore us for reasons or perhaps just for their own well-being. For hundreds, possibly thousands of years, as explorers had died here in merciless and terrible ways, there raged a sumptuous feast for the senses, as excessive as it was ancient and unending.
I cannot tell you how powerfully the AI’s words struck us, so that our mouths watered at the thought of real food and of clean, unrecycled water, of a freedom unencumbered by suits and breathing apparatus. Even at our intended destination, we would have spent most of our days aboard a small space station. This tedium would have been broken only by the arduous process of reaching the unbreathable surface and its ancient ruins of jagged black stone.
This vision that overtook us functioned not just as tantalizing delusion. It scared us so much that we could not compartmentalize it in our thoughts. It continued to overwhelm us like a wave.
We fought for the first time, with the astrogator expressing the wish to return to the ruined spacecraft and explore nearby areas for parts, while the captain broke silence to order us to continue to make progress toward the nearest dome. The AI, which had brought us to this point, stole the captain’s silence and said no more.
For each of us, those endless white plains with no real elevation, just the metal rope and the metal posts, had become a kind of repetition that hurt the brain, and the mind with it.
As I looked out across the white, I could not help seeing the impression of shapes in the wind, as if invisible entities fled by, carried there by gusts, unable to get purchase, swept up for hundreds and hundreds of miles before being dashed to the ground.
We did not give up, however.
IV.
About halfway to the nearest dome, amid a storm that reduced our progress incrementally and our line of sight to nothing, we came upon a peculiar tableau.
Six astronaut suits had fallen across and around the metal rope. With the flurries of snow, it took us, even with our powerful headlamps, some minutes to determine the nature of the obstruction. The six suits had been created for a humanoid species that must have had torsos like nine-foot-long slabs, attached to six limbs, three for walking. Their heads had flared out like thick fans. All the helmets were cracked open, and curled inside were the skeletons of some other intelligent species no larger than 40 or 50 pounds, possibly warm-blooded. With no sign of the original occupants.
After a brief analysis cut short by the conditions, we postulated that the warm-blooded species had worn breathable skin suits that, as they failed, required these intruders to seek shelter. All they could find were these six dead astronauts. Because we could discover no trace of the original occupants, the AI put forward the theory that this smaller species had eaten every scrap of the remains within the suits.
Then they too had perished, and in time, the AI suggested, something smaller would take up residence inside those bodies, then smaller still within those, and smaller still—
At this point, the captain attempted a soft reboot of the AI using a coded question. We could hear the concern in her voice.
Yet the AI continued undeterred, suggesting that we might find this to be a common situation. It might be replicated across the planet, depending on a system’s ability to break down and process meat that had not evolved alongside the devourer for millions of years. In all likelihood, most who attempted to eat in this way died soon after, poisoned by alien flesh.
The astrogator had taken to muttering inside his suit, off comms, as if he no longer thought we functioned as a team. No amount of castigation from the captain served to change his mind.
In the terse harshness of the captain’s reprimand, I recognized that her pain levels had spiked once again.
V.
The AI began to talk to us in strange alien voices at mile 700, as we labored through the snowstorm to hold onto the cables and thus the path. The AI warbled and chirped and howled and hummed and clucked. The AI spoke in voices like fossilized choruses of beasts, vast and harmonious. And in voices like dry grass spun to fire by the sun. And in voices like the dissolution of all things, darkness in the blinding white that scared me.
At first we thought the AI was deranged. Then that the AI channeled voices from the dome 300 miles ahead. But finally, the AI managed to make known to us that these were the voices of the dead astronauts we had come across from time to time. Huddled frozen. The suits in so many shapes and sizes. That the voices of the dead were channeled through the AI, and nothing could stop them.
We chose to believe that the AI had begun to malfunction. We did not waste time with a response. The captain asked the AI to perform self-shutdown and whispered the numbers in the correct sequence. We knew what we lost with this act, and yet we knew if we did not shut down the AI it might become harmful to us beyond the mental distress of what it had just conveyed to us.
Soon after, the AI gave up its own voice, and all that came from it were the sounds of the others.
A little later, the AI no longer spoke at all.
VI.
The snow began to betray us, as the storms created different forms of ice. Often, our arms became weary, our legs cramping, and we had to rest with greater frequency. We came to accept the solid crunch that could support our weight. We came to reject the feather-light freshness that felt effortless underfoot but could give way just as easily as if it were air. In some places, slick purple-hued ice welled up in sluggish layers as if something half-alive. In others, we discovered strange islands of elevation, with brutal curls and curves that suggested two continental shelves had clashed in that space.
As we adapted to these conditions, and as conditions worsened and still we adapted, we came to feel an illusion of competency, one that made even the astrogator temporarily cheerful. The sounds through the comms of our efforts, the deeper breathing, the occasional muffled curse, seduced us in this regard. We felt that we were becoming adroit at handling the snow. We began to believe if we could only make it to the dome, we would be saved.
Yet this uptick in morale ran parallel to, rather than intersected with, the idea of our ultimate survival.
VII.
We lost track of the distance left to us without the AI to tell us. Or the captain, in her pain, no longer thought to issue updates. But across the distance left to us came sights beyond reckoning: three giant astronauts spaced 50 miles apart. Larger than most starships, each body lay sprawled across an area larger than several fields and in very different conditions.
The first had been badly burned and was thus unrecoverable, even in terms of salvage. The astronaut had crawled or pulled itself along for some distance. It had left a long smudge of black and red across that expanse. The alien species was, as ever, unknown to us, but the five arms were sunk in the ground as if in agony. The skull had once held three eyes, and the face plate had been cracked by force so strong it resembled a meteor strike. The body was bloated, the fabric of the suit gray with a shimmer of green that came and went, linked to photosensitive skin cells. The way the flesh took up space, and how it exhibited aspects more plant than animal, made it impossible to study further.
The second was a sprawl of limbs, with the suggestion of a defensive posture. The debris of conflict flared out to the side in an incomprehensible display. The suit had an intactness that surprised us, but a similar crack in the face plate without any trace of body within. The rest of the suit had become inhabited by a wealth of other dead astronauts of varying sizes and shapes, who had sought shelter or sustenance and then become trapped or simply … given up. As the AI had predicted, we had once again encountered bodies providing other bodies with temporary sustenance and shelter.
I felt like a parasite who beheld a god. Or was the scale even more ludicrous?
But this condition was not at first evident to us, becoming apparent only after we had clambered for an hour to reach the cracked face plate and the entry hole extended like a broken archway before us.
Despite the number of remains within, and the difficulty in moving through them to explore, the captain ordered an exhaustive recon. Her pulse in the readings had a thready quality. Sometimes I felt, and the astrogator too when we took private comms, that the captain had begun to say things similar to the AI’s delusions. Yet we obeyed the order, on the chance that some internal calculation on the captain’s part meant she believed this was the only way we would survive.
What did we expect to find in the dead body of a once-intelligent giant? Food? Oxygen? Some cause of death? To put off the thought of our own death by seeking shelter with a death so large we could not comprehend it?
I felt like a parasite who beheld a god. Or was the scale even more ludicrous? I had trouble envisioning the way the body must have twisted as it pitched forward into that icy ground. I had trouble holding onto my own thoughts.
More and more pressure moved through my skull as I contemplated that scene. We were in the midst of something none of my kind had ever known. We might be the only ones, ever. I better understood the unraveling of the AI and of the captain. My sharpness had dulled, taking my calm with it.
It was impossible to tell how long the astronaut had taken to die. Unless somewhere within that fallen figure some hint of life hid that we would never find.
The storms fell away, rose, then fell away again.
VIII.
The third huge astronaut was full of light and life and shone out across the wasteland of snow like a beacon. For a moment, I thought we had pierced the invisible layer and could see what lay beyond the veil. We would have comforts beyond anything found on our ruined spaceship even when it had been fit to cross galactic space. There would not be recycled urine for our water. There would not be the faint stink of sweat creeping into our suits as the ventilation system began to fail. Our liquid food would not taste stale and moldy.
As we approached, the suit extended almost to the horizon in that foreshortened perspective created by the left foot. We noted through our remaining instrumentation that the suit remained intact. The pressure told us a kind of air circulated within its sealed surfaces.
We climbed with a renewed energy, the promise of sanctuary so close making us giddy. We each exhorted the others on with such exuberance that it made me a little afraid. What lay on the other side of this state of mind but a fall?
When we reached the helmet plate, we could see inside not a face or a skull, but instead such a richness of healthy growth that we fell silent before it. None of us could, I believe, understand exactly what we saw, except that it equaled ecosystem—resplendent with vibrant greens and blues, stippled with other colors. There might be some parallel to a terrarium full of moss and exotic plants. There might be some sense of life moving amongst those plants, as of jewel-like amphibians or even tiny shy sapphire birds. We could not smell or taste or hear what lay behind the face plate. We could not experience it in that way, but somehow we each imagined enough to be calmed and comforted by it.
The astrogator said he might be able to create a hole in the plate or elsewhere on the body to let us in, and then patch the surface such that not too much air or vitality would spill out. This workaround might take an hour or two, due to the delicate nature of what we saw within. But it was possible.
The captain considered the astrogator’s proposal and then agreed. The weather had begun to turn dangerous again. That we should begin immediately did not need to be said. With the proper pressure brought to bear, we would have some measure of sanctuary from which to recover for a final push to the dome. It could be the difference between life and death, the astrogator said. If the atmosphere was breathable, we might even be able to give the captain some better solution to her pain.
I unclipped the astrogator’s equipment from his waist and threw it off the mountain that was the astronaut and watched it sail through the air and into the snow. Then I used my weapon to fry it where it lay. Then I threw my weapon into the snow, too, in a place where the featheriness would cover it and hide it forever.
We were a team and I had helped my team while showing them I posed no threat—although I knew the astrogator and the captain would not see it that way. I stood there on the face plate that we could no longer open with the diminished tools at our disposal as they both yelled at me through the comms. It’s unimportant what they said to me. They were admonishing me for something that had already happened and that they had no power to stop. I did not bother to explain, but began to make the descent to the ground so we could once again take up the metal rope and make for the dome.
Will you follow, I asked them from the ground, when I saw they still stood on the heights. There came no reply, but when they saw me take up the rope, they climbed down to take up the rope too.
I waited then, and let them catch up.
IX.
The captain died not long after. The pain was too great or the wounds she had suffered too damaging. I had known for some time she would never make it to the dome, but there was no point in emphasizing that to her. Nothing she had done until the end had required her to be removed from command. Her last words were the name of our ship and giving her love to someone who would be dead of old age even if we found a way to escape this place and return home. But the astrogator told her he would carry those words forward.
Then we left her by the marker that meant we had 100 miles left to the dome. We knew the snow would cover her for burial. It had done so faithfully for all the rest.
That in that frozen hellscape, the persistence of life in that manner, an oasis in the midst of nothing, could be categorized as a miracle.
As the astrogator followed me down the rope line, he cried out for explanation. The captain’s death required it for some reason, in his mind. The captain had not deserved my betrayal. The captain would not rest easy until I told him why.
You must believe in ghosts, I replied.
This reply incensed him and he castigated me in words not used among members of a team that respect each other. Once more, I ignored him, but told him if our oxygen got low, he could have mine if we calculated he could make it to the base. I meant this, as I knew the odds were low anyway. I had hurt my knee taking the equipment from the astrogator and then making my way so rapidly down from the dead astronaut.
The astrogator did not reply, by which I knew he did not accept my answer.
The reason I took the tools and destroyed them is because the wind had told me something it had not whispered to the captain or the astrogator. The wind had not spoken to me before, so I believed what it told me. That the astronaut within the suit lived on, if unable to move. That what we saw on the outside and registered as ecosystem, as separate “plants” and “animals,” instead formed a composite life-form and that to crack open the suit or cut through the suit at a leg would have been a violation.
That in that frozen hellscape, the persistence of life in that manner, an oasis in the midst of nothing, could be categorized as a miracle.
I would not snuff that out. I could not allow that to be snuffed out. But I remembered too how I felt looking at that vast and alien country behind the face plate. So calm, so comforted, overcome by the depths of an emotion I could not place. Would I replace that feeling with the feeling of seeing all those explorers dead within the other vast suit? Even as I become one of them?
Because the planet had already told us the rules, the consequences, and the ultimate outcome. There are no odds so terrible that they could not be experienced, and in dozens of ways, in this place.
So I trudged on and the astrogator cursed me and cursed me and called out my childhood and how badly I must have been brought up and how I must have cheated to pass the psych exams, and yet I had thought the same of him at various points during our journey.
See how beautiful the snow is, falling now, I said to him over the comms. See how precise and geometric this line we follow across this expanse.
He did not reply, but a little later he told me he no longer believed in the line at all, and by his calculations he would get to the dome faster if he abandoned it and struck out on his own.
I could not stop the astrogator and did not want to, so I watched him become a smaller and smaller figure against the white until the white ate him up and I was alone.
X.
I have been walking a long time, visiting with the dead. Here, against an arch of heaven that appears no different than what I see directly in front of me.
Jeff VanderMeer is the author of the critically acclaimed, bestselling Southern Reach series, translated into 38 languages. His short fiction has appeared in Vulture, Slate, New York Magazine, Black Clock, Interzone, American Fantastic Tales (Library of America), and many others.
AI Finds Unreported Side Effects of GLP-1 Drugs in Reddit Posts
A study of more than 400,000 posts in the social media platform Reddit has identified previously unreported side effects from the increasingly popular GLP-1 weight loss and diabetes drugs. Users reported symptoms affecting menstrual cycles and body temperature, which have not yet been described in clinical trials or included in drug labels.
Published today in Nature Health, the study covers over five years of public online posts from nearly 70,000 Reddit users discussing their personal experience taking the GLP-1 drugs semaglutide and tirzepatide.
“Some of the side effects we found, like nausea, are well known, and that shows that the method is picking up a real signal,” says Sharath Chandra Guntuku, PhD, research associate professor in computer and information science at Penn Engineering and the study’s senior author. “The underreported symptoms are leads that came from patients themselves, unprompted, and clinicians could potentially pay attention to them.”
Although the study is not representative of the broader population—Reddit users are generally younger, more likely male and based in the U.S.—the symptoms reported collectively match known side effects of semaglutide and tirzepatide. About 44% of users described at least one known side effect, most commonly symptoms of gastrointestinal distress.
“Clinical trials generally identify the most dangerous side effects of drugs, but they can fail to find what symptoms patients are most concerned about,” says Lyle H. Ungar, PhD, professor in computer and information science at Penn Engineering. “Online patient communities work a lot like a neighborhood grapevine. People who are living with these medications are swapping notes with each other in real time, sharing experiences that rarely make it into a doctor’s office visit or an official report. Even though social media is not necessarily representative, a large collection of posts may reflect additional concerns.”
The study uncovered a series of side effects that were previously unreported for these drugs. This included discussions of menstrual cycle changes, such as intermenstrual bleeding, heavy bleeding, and irregular cycles. Other users reported chills, hot flashes, fever, and other temperature-related symptoms. In addition, fatigue symptoms ranked as the second most common complaint in these online posts despite rarely being reported in clinical trials.
“We can’t say that GLP-1s are actually causing these symptoms,” says Neil K. R. Sehgal, doctoral student at the University of Pennsylvania and the study’s lead author. “But nearly 4% of the Reddit users in our sample reported menstrual irregularities, which would be even higher in a female-only sample. We think that’s a signal worth investigating.”
While efforts to scour the internet for self-reported drug side effects have been ongoing for more than a decade, screening through social media posts at scale remained challenging until the arrival of large language models such as ChatGPT or Gemini. In particular, these tools can prove instrumental in mapping the language users use to describe their symptoms to clinical terminology defined in the Medical Dictionary for Regulatory Activities (MedDRA), used to officially report symptoms in clinical trials.
“Large language models have made it possible to do this kind of analysis much faster with a level of standardization that could be difficult to achieve before,” says Sehgal.
The researchers hope these findings will encourage researchers and drug developers to investigate the side effects discussed by users online. In future work, the team plans to expand beyond Reddit and English-language discussions to confirm whether the same symptoms appear across different social media platforms and populations.
While this approach is not intended as a replacement for clinical trials, screening social media posts for clues on unreported side effects can make a significant difference in terms of speed. This can be especially relevant for drugs like semaglutide and tirzepatide, originally diabetes drugs that quickly became mainstream when the FDA granted them approval as weight loss drugs.
“Clinical trials are the gold standard, but by design, they are slow,” says Guntuku. “The whole point of this kind of approach is that it can move quickly, and that’s exactly when it’s most valuable.”
The post AI Finds Unreported Side Effects of GLP-1 Drugs in Reddit Posts appeared first on Inside Precision Medicine.
Opinion: I’m a MAHA activist. I went into the public health lion’s den — and it changed how I think
The past few weeks have been nothing but discouraging for those of us who helped create the Make America Healthy Again movement, including a silly executive order on glyphosate that feels anathema to what we have fought for. I’d be lying if I said that my heart hasn’t been bent toward repentance for my part in the whole thing. I helped champion Bobby Kennedy as a campaign volunteer, and when he joined up with then-candidate Donald Trump, I reluctantly decided that the trade-offs were worth what I believed Kennedy could advocate for within the walls of a Trump White House: the best fixes for a very sick and broken nation.
Yet I found myself recently, and reluctantly, headed to the citadel of arrogance: Washington (well, Arlington, Va., to be more specific). At the invitation of Brinda Adhikari — one of the hosts of the podcast “Why Should I Trust You?” — I attended the Association of Schools and Programs of Public Health’s annual meeting, where I spoke on a panel about engaging in civil conversation in a session called “A Dialogue Between Academic Public Health and MAHA.”
Artificial Sweeteners Could Alter Metabolism over Generations
Popular low-calorie sugar substitutes can negatively affect both the balance of microbes in the gut and gene expression in a heritable way, preclinical research suggests.
The findings in mice, published in Frontiers in Nutrition, challenge long-standing assumptions that non-nutritive sweeteners (NNS) are metabolically inert and underscore their potential to influence health across generations through microbial and molecular pathways.
Both sugar alternatives studied had an impact: sucralose, a popular artificial sweetener that is around 600 times sweeter than sugar, and stevia, a no-calorie natural alternative extracted from the leaves of a South American plant.
Lead researcher Francisca Concha Celume, PhD, from the University of Chile, said the changes seen in glucose tolerance and gene expression could be interpreted as early biological signals related to metabolic or inflammatory diseases.
“For example, the animals did not develop diabetes. Instead, what we observed were subtle changes in how the body regulates glucose and in the activity of genes associated with inflammation and metabolic regulation,” she explained.
“It is possible that such changes could increase susceptibility to metabolic disturbances under certain conditions, such as a high-fat diet.”
Celume and team divided 47 male and female mice into three groups receiving either plain water, or water with sucralose or stevia added over 16 weeks at levels comparable to those seen in a usual human diet.
These mice were then bred, with each of the two subsequent generations just receiving plain water.
The team found there were no differences in glycemic response in the initial group, but that it had mildly altered in the male offspring of those fed sucralose in both successive generations. By the second generation, female mice with stevia-consuming grandparents had elevated fasting blood sugar.
Fecal microbiomes in both sets of animals receiving sweeteners were more diverse than in those given plain water. But sweetener-fed mice also had lower levels of short-chain fatty acids, which could signal epigenetic changes and could indicate that bacteria may be generating less beneficial metabolites and that this was passed on to subsequent generations.
Mice that had consumed sucralose were particularly affected and had more pathogenic bacteria and fewer beneficial species in their fecal microbiomes. The impact of this sweetener tended to be more consistent and persistent across generations.
The researchers also examined the impact of five genes relating to inflammation, gut barrier function, and metabolism in the liver and intestines.
Overexpression in the inflammation-linked toll-like receptor-4 (tlr4) and tumor necrosis factor (tnf) genes was seen both in animals that consumed sucralose and stevia. This was also seen in the immediate offspring of the former but not the latter.
The expression of sterol regulatory element-binding protein 1 (Srepb1), which is linked with regulation of lipid and carbohydrate metabolism, was decreased in the liver of sucralose-fed animals and subsequent generations.
“In summary, our findings demonstrate that parental consumption of sucralose or stevia induces persistent, intergenerational changes in host metabolism, intestinal and hepatic gene expression, gut microbiota composition, and microbial metabolite production in unexposed offspring,” the researchers concluded.
They added: “Given the widespread use of NNS during critical developmental periods, these findings raise important questions about their safety and long-term impact.”
The post Artificial Sweeteners Could Alter Metabolism over Generations appeared first on Inside Precision Medicine.
Cancer Drug Shortfalls Tied to How BET Inhibitors Hit BRD2 and BRD4 Differently
For more than a decade, BET inhibitors have been touted as one of cancer therapy’s most promising drug classes. The logic was straightforward: many tumors rely on oncogenes that depend on BET (bromo- and extra-terminal domain) proteins—chromatin‑binding regulators that help switch genes on. Block the BET family, the thinking went, and cancer cells should lose their transcriptional fuel. In the lab, the strategy often worked. But in clinical trials, the results were far more uneven: modest responses, substantial side effects, and little clarity about which patients might benefit.
A new study from the Max Planck Institute of Immunobiology and Epigenetics (MPI‑IE) may finally explain why. Published in Nature Genetics, the work uncovers a previously underappreciated division of labor within the BET family—one that helps clarify why drugs that block all BET proteins at once have struggled in the clinic. The paper is titled, “Histone acetylation-dependent clustering of BRD2 instructs transcription dynamics.”
Most BET inhibitors were designed to block a shared bromodomain that all BET proteins use to bind chromatin. That approach assumed the proteins—BRD2, BRD3, BRD4, and BRDT—perform similar roles. But the new study paints a more nuanced picture. Using rapid protein degradation, chemogenomics, and super‑resolution microscopy in mouse embryonic stem cells, the team dissected the distinct contributions of BRD2 and BRD4 to transcription.

Their findings reveal that BRD4 drives the well‑known step of releasing paused RNA polymerase II into productive elongation. BRD2, however, acts earlier. It helps recruit and organize the transcription initiation machinery at promoters, particularly under conditions where pause‑release is impaired. As the authors wrote, BRD2’s role becomes “particularly critical under the conditions of impaired pause release,” a mechanistic insight that reframes how BET proteins collaborate during gene activation.
The MPI‑IE team likens BRD2 to a stage manager. “BRD2 sets up the stage: assembling the props, costumes, and actors to ensure preparations run smoothly. BRD2 then gives BRD4, the actor, the ‘start’ signal to begin with the performance,” said senior author Asifa Akhtar, PhD. Blocking both proteins simultaneously—exactly what current BET inhibitors do—disrupts two different steps of transcription at once, producing unpredictable and context‑dependent effects.
“Our data shows that the setup work happening before is just as critical for gene activation,” explained Akhtar.
A key discovery is that BRD2’s recruitment depends on histone H4 acetylation placed by the enzyme MOF. When MOF was rapidly depleted or deleted, BRD2 lost its grip on chromatin, while BRD3 and BRD4 remained largely unaffected. “The findings support a model in which acetylated chromatin creates a platform that allows regulatory proteins like BRD2 to concentrate and prepare the transcription machinery,” noted first author Umut Erdogdu, PhD.
The team also showed that BRD2 forms dynamic clusters at promoters. Removing only the BRD2 region responsible for clustering stalled transcription almost as completely as deleting the entire protein.
The study suggests a path forward: instead of blocking all BET proteins indiscriminately, future therapies may need to distinguish between BRD2‑ and BRD4‑specific functions. “Thus, these findings support a model in which histone acetylation-dependent spatiotemporal dynamics of BRD2 coordinate the transcription machinery to regulate transcription initiation,” the authors wrote.
For a field long puzzled by the uneven performance of BET inhibitors, BRD2’s newly revealed role offers a compelling piece of the puzzle—and a clearer blueprint for next‑generation cancer therapeutics.
The post Cancer Drug Shortfalls Tied to How BET Inhibitors Hit BRD2 and BRD4 Differently appeared first on GEN – Genetic Engineering and Biotechnology News.

