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Category: biotech/medical – Page 52

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.

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.

Turning MRI into a quantitative microscope to detect white matter injury

Early diagnosis and noninvasive monitoring of neurological disorders require sensitivity to elusive cellular-level alterations that emerge much earlier than volumetric changes observable with millimeter-resolution medical imaging.

Morphological changes in axons—the tube-like projections of neurons that transmit electrical signals and constitute the bulk of the brain’s white matter—are a common hallmark of a wide range of neurological disorders, as well as normal development and aging.

A study from the University of Eastern Finland (UEF) and the New York University (NYU) Grossman School of Medicine establishes a direct analytical link between the axonal microgeometry and noninvasive, millimeter-scale diffusion MRI (dMRI) signals—diffusion MRI measures the diffusion of water molecules within biological tissues and is sensitive to tissue microstructure.

A genetic breakthrough links early-onset diabetes to brain disorders

Paediatric teams are now facing babies whose diabetes appears in the first weeks of life, then rapidly reveals deep problems in brain growth and function. A new genetic finding sheds light on how a single molecular fault can disrupt both blood sugar control and early brain development.

Neonatal diabetes is diagnosed in the first six months of life, often within days or weeks after birth. Unlike the more common type 1 diabetes, which usually shows up in children and teenagers, neonatal diabetes is almost always genetic.

Doctors typically notice poor feeding, weight loss, dehydration and extremely high blood sugar. In many cases, the root cause is a mutation that stops the pancreas from making enough insulin. That alone makes neonatal diabetes a medical emergency.

Human heart regrows muscle cells after heart attack, world-first study shows

This study provides the first direct evidence of cardiomyocyte mitosis in the adult human heart following myocardial infarction, challenging the long-standing paradigm that cardiac muscle cells are incapable of regeneration. Utilizing live human heart tissue models, researchers from the University of Sydney demonstrated that while fibrotic scarring occurs post-ischemia, the heart simultaneously initiates a natural regenerative program characterized by active cell division. The investigation further identified specific regulatory proteins that drive this mitotic process, offering a molecular blueprint for endogenous tissue repair. These findings suggest that the human heart possesses a latent regenerative capacity that could be therapeutically harnessed to prevent heart failure and reverse post-infarct tissue damage, representing a significant shift in regenerative cardiovascular medicine.

A world‑first University of Sydney study reveals that the human heart can regrow muscle cells after a heart attack, paving the way for breakthrough regenerative therapies to reverse heart failure.

Proton Beam vs Intensity-Modulated Radiotherapy in Olfactory Neuroblastoma

In patients with advanced olfactory neuroblastoma, IMRT and PBRT yielded similar long-term outcomes and rates of grade 2 or higher radiation-related adverse events. Theoretical benefits of PBRT—such as organ sparing—require further study to clarify potential clinical advantages.

Question Does adjuvant proton beam radiotherapy (PBRT) provide equivalent oncologic effectiveness while reducing radiation toxic effects compared with adjuvant intensity-modulated radiotherapy (IMRT) for patients with olfactory neuroblastoma (ONB)?

Findings In this propensity score–matched cohort study of 54 patients, patients treated with adjuvant IMRT and PBRT had similar rates of radiation toxic effects and no statistical difference in overall survival and recurrence-free survival.

Meaning PBRT may not improve overall survival, recurrence-free survival, or radiation toxic effects relative to IMRT for patients with ONB.

Human heart regrows muscle cells after heart attack, researchers discover

Pioneering research by experts at the University of Sydney, the Baird Institute and the Royal Prince Alfred Hospital in Sydney has shown that heart muscle cells regrow after a heart attack, opening up the possibility of new regenerative treatments for cardiovascular disease.

Following the publication of the study in Circulation Research, first author Dr. Robert Hume, from the Faculty of Medicine and Health and Charles Perkins Center, and Lead of Translational Research at the Baird Institute for Applied Heart and Lung Research, explained the significance of the finding: Until now we’ve thought that, because heart cells die after a heart attack, those areas of the heart were irreparably damaged, leaving the heart less able to pump blood to the body’s organs.

Our research shows that while the heart is left scarred after a heart attack, it produces new muscle cells, which opens up new possibilities.

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