To comprehensively characterize complement pathway activation in chronic inflammatory demyelinating polyneuropathy (CIDP) and its association with clinical disease features using advanced complement profiling.
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B cells play a more sinister role than believed in progression of type 1 diabetes
A recent study by Vanderbilt Health researchers has revealed a greater, detrimental role for B lymphocytes (B cells) in the progression of type 1 diabetes (T1D).
B cells are immune cells thought to drive the immune system’s attack on insulin-producing beta cells by activating anti-islet T cells. The study published in Diabetes suggests they play an even more sinister role by also interfering with and limiting the function of regulatory T cells (Tregs) that help calm the immune system.
“Our study showed B cells can weaken the body’s natural defenses by interfering with Tregs, which normally behave as peacekeepers to ward off immune attacks on the pancreas and the insulin-producing beta cells,” said Daniel Moore, MD, PhD, associate professor of Pediatrics at Vanderbilt Health and the study’s corresponding author.
Scientists identify cells by seeing how high they levitate
By Nina Bai
Stanford Medicine researchers invent an electromagnetic device that can gently sort different types of cells by levitating them to different heights.
MCM8- and MCM9 Deficiencies Cause Lifelong Increased Hematopoietic DNA Damage Driving p53-Dependent Myeloid Tumors
(Cell Reports 28, 2851–2865.e1–e4; September 10, 2019)
Our attention was called to an image duplication in the right panel of Figure 3C in our published paper. Note that the right panels are not new results but enlarged representative cases present in the left panel, as indicated in the figure legend. They show so-called Howell-Jolly bodies (faulty, dysplastic red blood cells that did not manage to expulse their cell nucleus completely). The first and second images show the same cell in question but in different clippings. We apologize for this inadvertent mistake and provide a revised Figure 3C depicting a fifth example of (two) erythrocytes displaying Howell-Jolly bodies in the right panel.
Intestinal epithelial TLR5 signaling promotes barrier-supportive macrophages
Crosstalk between commensal E. coli that express flagellin and intestinal epithelial cells coordinate intestinal macrophage recruitment to support gut barrier homeostasis in mice.
Learn more in ScienceImmunology.
The colonic epithelium is an important boundary between internal tissues and luminal contents including the microbiota. The gut microbiota drives immune cell accumulation and effector function (6, 10, 12), but how colonic epithelial cells mediate these processes is incompletely understood. To understand how intestinal epithelial sensing of adherent microbes regulates immune-supported intestinal barrier repair, we used the E. coli strain 541–15, which we previously found increased LP macrophages and promoted their IL-10 production, protecting against inflammatory pathology in mouse colitis models (12, 23, 24).
Here, we demonstrated that E. coli 541–15 colonization promotes LP recruitment of mature macrophages after antibiotic treatment. Using HCMs, we determined that E. coli 541–15 induced expression of immune regulatory genes including the monocyte-recruiting chemokine CCL2 exclusively in UD cells, which promote monocyte migration. In vivo, CCL2 produced by epithelial cells in response to E. coli 541–15 colonization promoted colon LP macrophage expansion and protected mice from DSS colitis. We further identified flagellin as the key microbial factor that induced epithelial CCL2 expression. Last, epithelial TLR5 and E. coli flagellin were both required for LP recruitment of mature macrophages and protection against DSS challenge. In both in vitro and in vivo systems, epithelial stem cells had higher TLR5 expression than mature IECs, indicating a crypt specific role for flagellated bacteria detection. Our findings are consistent with previous studies showing that TLR5-deficient mice develop spontaneous colitis in the presence of the pathobiont H. hepaticus (20), suggesting a potential protective role for TLR5 in intestinal homeostasis. Moreover, other studies report that H. hepaticus induces colitis in IL-10–deficient mice (52, 53), highlighting a possible link between TLR5 and IL-10+ macrophages in H. hepaticus pathogenesis. Here, we demonstrate that TLR5 signaling is essential for mucosal protection by promoting the recruitment of CCR2+ cells and the maturation of LP macrophages, which are key producers of IL-10 in the gut, highlighting a possible link between TLR5 and IL-10+ macrophages in H. hepaticus pathogenesis.
Previous work demonstrated that TLR5 expression differs by intestinal region, with expression restricted to Paneth cells in the small intestine crypt but distributed more broadly among colonic epithelial cells (54). Three-dimensional (3D) mouse Paneth cells enriched small intestinal organoids, and colonoids (which contain both undifferentiated and differentiated cells) responded to flagellin and up-regulated chemokines (54); however, the specific flagellin-responsive colonic cell types remained undefined. In addition, early studies using human epithelial cell lines showed that TLR5 localizes to the IEC basolateral surface, suggesting that flagellin sensing is limited to situations where bacterial products cross the epithelial barrier (55, 56). Our current study advances this understanding by using HCMs that allow for functional separation of DF IECs and UD stem-like cells, which express higher TLR5. After apical or basolateral treatment, UD, but not DF, HCMs responded to TLR5 stimulation. Similar to HCMs, in the mouse epithelium, we found higher Tlr5 expression in LGR5+ stem cells than mature LGR5− IECs. These results suggest that colonic stem cells in humans and mice, such as Paneth cells in the small intestine, act as critical sensors of flagellated microbes and highlight a conserved mechanism to spatially restrict microbial recognition to the crypt base to safeguard the stem cell niche. Under homeostatic conditions, stem cells are physically shielded from microbial stimulation by mucus, secretory immunoglobulin A (IgA), and antimicrobial peptides (13). However, multiple studies showed colonization of cecal and colonic crypts with select flagellated commensal bacteria at homeostasis, which could induce TLR5 signaling (47–49, 57). Furthermore, disruption of the epithelial barrier during injury and resulting expansion of the stem cell zone may increase stem cell and microbial interactions. We propose that compartmentalized TLR5 signaling provides a protective strategy, which promotes tonic macrophage expansion in the steady state and enables amplification when epithelial integrity is compromised or after colonization with microbes that can reach the base of the crypt.
The Singularity Countdown: AGI by 2029, Humans Merge with AI, Intelligence 1000x | Ray Kurzweil
Ray Kurzweil predicts humans will merge with artificial intelligence (AI) by 2045, resulting in a 1000x increase in intelligence and marking the beginning of a new era of unprecedented innovation, potentially transforming human life and society ## ## Questions to inspire discussion.
Preparing for AI Timeline.
🤖 Q: When should I expect human-level AI and what defines it? A: Human-level AI arrives by 2029, defined not by passing the Turing test (which only matches an ordinary person), but as AGI requiring expertise in thousands of fields and the ability to combine insights across disciplines.
🧠 Q: When will the singularity occur and what intelligence gain can I expect? A: The singularity happens by 2045 when humanity merges with AI to become 1000x more intelligent, creating a seamless merger where biological and computational thought processes become indistinguishable.
⚡ Q: How much change should I prepare for in the next decade? A: Expect as much change in the next 10 years as occurred in the last 100 years (1925−2025), with AGI and supercomputers by 2035 enabling merging with AI for 1000x intelligence increase.
Career and Economic Adaptation.
Tesla Robotaxis, AGI Myths, and the Real Economics of the Musk Economy
Elon Musk’s ventures, particularly Tesla’s robotaxis and advancements in AI, are poised to revolutionize the economy and society, with significant potential for growth, discovery, and profound implications for the future ##
## Questions to inspire discussion.
Robotaxi Economics & Business Model.
🚖 Q: What determines robotaxi success beyond achieving autonomy? A: Success depends on unit economics, fleet scalability, and supply elasticity during peak demand, not who reaches autonomy first, with the ability to integrate privately owned vehicles into a single economic system being critical.
💰 Q: What margin advantage does Tesla’s robotaxi model have over competitors? A: Tesla projects 35% margins by 2030, significantly higher than Uber’s 7.9% and Waymo’s break-even margins, enabling rapid revenue growth.
📈 Q: What revenue growth is expected for Tesla’s robotaxi business? A: Tesla expects 4.4-5x growth in robotaxi revenue over the next 5 years, potentially greater due to untapped use cases like long road trips.
