The cholesterol metabolite 25-hydroxycholesterol restrains the transcriptional regulator SREBP2 and limits intestinal IgA plasma cell differentiation.

Diets high in cholesterol alter intestinal immunity. Here, we examined how the cholesterol metabolite 25-hydroxycholesterol (25-HC) impacts the intestinal B cell response. Mice lacking cholesterol 25-hydroxylase (CH25H), the enzyme generating 25-HC, had higher frequencies of immunoglobulin A (IgA)-secreting antigen-specific B cells upon immunization or infection. 25-HC did not affect class-switch recombination but rather restrained plasma cell (PC) differentiation. 25-HC was produced by follicular dendritic cells and increased in response to dietary cholesterol. Mechanistically, 25-HC restricted activation of the sterol-sensing transcription factor SREBP2, thereby regulating B cell cholesterol biosynthesis. Ectopic expression of SREBP2 in germinal center B cells induced rapid PC differentiation, whereas SREBP2 deficiency reduced PC output in vitro and in vivo. High-cholesterol diet impaired, whereas Ch25h deficiency enhanced, the IgA response against Salmonella and the resulting protection from systemic bacterial dissemination. Thus, a 25-HC-SREBP2 axis shapes the humoral response at the intestinal barrier, providing insight into the effect of high dietary cholesterol in intestinal immunity.

All roads lead to IgA: Mapping the many pathways of IgA induction in the gut.

The increasing prevalence of food allergy and related pathologies in recent years has underscored the need to understand the factors affecting adverse reactions to food. Food allergy is caused when food-specific IgE triggers the release of histamine from mast cells. However, other food-specific antibody isotypes exist as well, including IgG and IgA. IgA is the main antibody isotype in the gut and mediates noninflammatory reactions to toxins, commensal bacteria, and food antigens. It has also been thought to induce tolerance to food, thus antagonizing the role of food-specific IgE. However, this has remained unclear as food-specific IgA generation is poorly understood. Particularly, the location of IgA induction, the role of T cell help, and the fates of food-specific B cells remain elusive. In this review, we outline what is known about food-specific IgA induction and highlight areas requiring further study. We also explore how knowledge of food-specific IgA induction can be informed by and subsequently contribute to our overall knowledge of gut immunity.

Surface patches induce nonspecific binding and phase separation of antibodies.

Nonspecific interactions are a key challenge in the successful development of therapeutic antibodies. The tendency for nonspecific binding of antibodies is often difficult to reduce by rational design, and instead, it is necessary to rely on comprehensive screening campaigns. To address this issue, we performed a systematic analysis of the impact of surface patch properties on antibody nonspecificity using a designer antibody library as a model system and single-stranded DNA as a nonspecificity ligand. Using an in-solution microfluidic approach, we find that the antibodies tested bind to single-stranded DNA with affinities as high as KD = 1 µM. We show that DNA binding is driven primarily by a hydrophobic patch in the complementarity-determining regions. By quantifying the surface patches across the library, the nonspecific binding affinity is shown to correlate with a trade-off between the hydrophobic and total charged patch areas. Moreover, we show that a change in formulation conditions at low ionic strengths leads to DNA-induced antibody phase separation as a manifestation of nonspecific binding at low micromolar antibody concentrations. We highlight that phase separation is driven by a cooperative electrostatic network assembly mechanism of antibodies with DNA, which correlates with a balance between positive and negative charged patches. Importantly, our study demonstrates that both nonspecific binding and phase separation are controlled by the size of the surface patches. Taken together, these findings highlight the importance of surface patches and their role in conferring antibody nonspecificity and its macroscopic manifestation in phase separation.

TGF-ß1 impairs IgA class switch recombination and production in porcine Peyer's patches B cells.

Secretory IgA is crucial for preventing the invasion of entero-pathogens via intestinal mucosa. While it is well-established that Transforming growth factor ß1 (TGF-ß1) regulates IgA production in human and mouse B cells, our previous investigation revealed different functions of TGF-ß1 in IgA generation in pigs compared with humans and mice, with the underlying mechanism remaining elusive. In this study, IgM+ B cells from porcine Peyer's patches (PPs) were isolated and stimulated with recombinant porcine TGF-ß1 to evaluate the effect of TGF-ß1 on pigs. The results showed that antibody production from B cells of PPs was impaired by TGF-ß1 ex vivo. Furthermore, TGF-ß1 treatment led to a decrease in the expression of germ-line transcript αand postswitch transcript α. Moreover, we observed that TGF-ß1 predominantly inhibited the phosphorylation of p38-mitogen-activated protein kinases (MAPK), confirming the involvement of the p38-MAPK pathway in porcine IgA generation and IgA class switch recombination. The application of p38-MAPK inhibitor resulted in decreased B-cell differentiation levels. Collectively, this study demonstrates that exogenous TGF-ß1 restrains the production and class switch recombination of IgA antibodies by inhibiting p38-MAPK signaling in porcine PPs B cells, which may constitute a component of TGF-ß1-mediated inhibition of B-cell activation.

Lessons of Vascular Specialization From Secondary Lymphoid Organ Lymphatic Endothelial Cells.

Secondary lymphoid organs, such as lymph nodes, harbor highly specialized and compartmentalized niches. These niches are optimized to facilitate the encounter of naive lymphocytes with antigens and antigen-presenting cells, enabling optimal generation of adaptive immune responses. Lymphatic vessels of lymphoid organs are uniquely specialized to perform a staggering variety of tasks. These include antigen presentation, directing the trafficking of immune cells but also modulating immune cell activation and providing factors for their survival. Recent studies have provided insights into the molecular basis of such specialization, opening avenues for better understanding the mechanisms of immune-vascular interactions and their applications. Such knowledge is essential for designing better treatments for human diseases given the central role of the immune system in infection, aging, tissue regeneration and repair. In addition, principles established in studies of lymphoid organ lymphatic vessel functions and organization may be applied to guide our understanding of specialization of vascular beds in other organs.

Brain-wide functional connectivity of face patch neurons during rest.

The brain is a highly organized, dynamic system whose network architecture is often assessed through resting functional magnetic resonance imaging (fMRI) functional connectivity. The functional interactions between brain areas, including those observed during rest, are assumed to stem from the collective influence of action potentials carried by long-range neural projections. However, the contribution of individual neurons to brain-wide functional connectivity has not been systematically assessed. Here we developed a method to concurrently measure and compare the spiking activity of local neurons with fMRI signals measured across the brain during rest. We recorded spontaneous activity from neural populations in cortical face patches in the macaque during fMRI scanning sessions. Individual cells exhibited prominent, bilateral coupling with fMRI fluctuations in a restricted set of cortical areas inside and outside the face patch network, partially matching the pattern of known anatomical projections. Within each face patch population, a subset of neurons was positively coupled with the face patch network and another was negatively coupled. The same cells showed inverse correlations with distinct subcortical structures, most notably the lateral geniculate nucleus and brainstem neuromodulatory centers. Corresponding connectivity maps derived from fMRI seeds and local field potentials differed from the single unit maps, particularly in subcortical areas. Together, the results demonstrate that the spiking fluctuations of neurons are selectively coupled with discrete brain regions, with the coupling governed in part by anatomical network connections and in part by indirect neuromodulatory pathways.

Dynamics and drivers of fungal communities in a multipartite ant-plant association.

BACKGROUND: Fungi and ants belong to the most important organisms in terrestrial ecosystems on Earth. In nutrient-poor niches of tropical rainforests, they have developed steady ecological relationships as a successful survival strategy. In tropical ant-plant mutualisms worldwide, where resident ants provide the host plants with defense and nutrients in exchange for shelter and food, fungi are regularly found in the ant nesting space, inhabiting ant-made dark-colored piles ("patches"). Unlike the extensively investigated fungus-growing insects, where the fungi serve as the primary food source, the purpose of this ant-fungi association is less clear. To decipher the roles of fungi in these structures within ant nests, it is crucial to first understand the dynamics and drivers that influence fungal patch communities during ant colony development. RESULTS: In this study, we investigated how the ant colony age and the ant-plant species affect the fungal community in the patches. As model we selected one of the most common mutualisms in the Tropics of America, the Azteca-Cecropia complex. By amplicon sequencing of the internal transcribed spacer 2 (ITS2) region, we analyzed the patch fungal communities of 93 Azteca spp. colonies inhabiting Cecropia spp. trees. Our study demonstrates that the fungal diversity in patches increases as the ant colony grows and that a change in the prevalent fungal taxa occurs between initial and established patches. In addition, the ant species significantly influences the composition of the fungal community in established ant colonies, rather than the host plant species. CONCLUSIONS: The fungal patch communities become more complex as the ant colony develops, due to an acquisition of fungi from the environment and a substrate diversification. Our results suggest a successional progression of the fungal communities in the patches during ant colony growth and place the ant colony as the main driver shaping such communities. The findings of this study demonstrate the unexpectedly complex nature of ant-plant mutualisms in tropical regions at a micro scale.

Fantastic IgA plasma cells and where to find them.

IgA is produced in large quantities at mucosal surfaces by IgA+ plasma cells (PC), protecting the host from pathogens, and restricting commensal access to the subepithelium. It is becoming increasingly appreciated that IgA+ PC are not constrained to mucosal barrier sites. Rather, IgA+ PC may leave these sites where they provide both host defense and immunoregulatory function. In this review, we will outline how IgA+ PC are generated within the mucosae and how they subsequently migrate to their "classical" effector site, the gut lamina propria. From there we provide examples of IgA+ PC displacement from the gut to other parts of the body, referencing examples during homeostasis and inflammation. Lastly, we will speculate on mechanisms of IgA+ PC displacement to other tissues. Our aim is to provide a new perspective on how IgA+ PC are truly fantastic beasts of the immune system and identify new places to find them.

Plant-Derived Chinese Herbal Hydrogel Microneedle Patches for Wound Healing.

Several natural Chinese herbal medicines have demonstrated considerable potential in facilitating wound healing, while the primary concern remains centered around optimizing formulation and structure to maximize their efficacy. To address this, a natural microneedles drug delivery system is proposed that harnesses gelatinized starch and key Chinese herbal ingredients-aloe vera and berberine. After gelatinized and aged in a well-designed mold, the starch-based microneedles are fabricated with suitable mechanical strength to load components. The resulting Chinese herbal hydrogel microneedles, enriched with integrated berberine and aloe, exhibit antibacterial, anti-inflammatory, and fibroblast growth-promoting properties, thereby facilitating wound healing in the whole process. In vivo experimental results underscore the notable achievements of the microneedles in early-stage antibacterial effects and subsequent tissue reconstruction, contributing significantly to the overall wound healing process. These results emphasize the advantageous combination of traditional Chinese medicine with microneedles, presenting a novel strategy for wound repair and opening new avenues for the application of traditional Chinese medicine.

Engineering Ultrasoft Interactions in Stiff All-DNA Dendrimers by Site-Specific Control of Scaffold Flexibility.

A combined experimental and theoretical study of the structural correlations in moderately concentrated suspensions of all-DNA dendrimers of the second generation (G2) with controlled scaffold rigidity is reported here. Small-angle X-ray scattering experiments in concentrated aqueous saline solutions of stiff all-DNA G2 dendritic constructs reveal a novel anomalous liquid-like phase behavior which is reflected in the calculated structure factors as a two-step increase at low scattering wave vectors. By developing a new design strategy for adjusting the particle's internal flexibility based on site-selective incorporation of single-stranded DNA linkers into the dendritic scaffold, it is shown that this unconventional type of self-organization is strongly contingent on the dendrimer's stiffness. A comprehensive computer simulation study employing dendritic models with different levels of coarse-graining, and two theoretical approaches based on effective, pair-potential interactions, remarkably confirmed the origin of this unusual liquid-like behavior. The results demonstrate that the precise control of the internal structure of the dendritic scaffold conferred by the DNA can be potentially used to engineer a rich palette of novel ultrasoft interaction potentials that could offer a route for directed self-assembly of intriguing soft matter phases and experimental realizations of a host of unusual phenomena theoretically predicted for ultrasoft interacting systems.

Toward Molecular Textiles: Synthesis and Characterization of Molecular Patches.

This works describes a new step into the assembly of molecular textiles by the use of covalent templating. To establish a well-founded base and to tackle pre-mature obstacles, expected during the fabrication of the desired 2D-material, we opted to investigate the in-solution synthesis of molecular patches e.g. cut-outs of a textile. A bi-functional cross-shaped monomer was designed, synthesized and was in-detail characterized by means of 1H-NMR and chiro-optical spectroscopy. In addition, x-ray structure crystallography was used to assess the absolute configuration. The monomer was used in an in-solution oligomerization to assemble the molecular patches via imine condensation, which revealed the formation of predominately dimeric patches.  The imine-oligomer mixtures were further analyzed by reduction and cleaved to investigate the conditions required post mono-layer assembly. All reaction stages were followed by FT-IR and 1H-NMR analysis. Finally, we address the adsorption of the cross-shaped monomer onto a Au(111) surface, via high vacuum electrospray deposition. The subsequent annealing of the interface induced the on-surface imine condensation reaction, leading to unidimensional oligomers co-adsorbed with clusters of cyclic-dimers. Nc-AFM analysis revealed the tridimensional molecular structures, and together with electrospray deposition technique showed to be a promising pathway to investigate potential monomer candidates.

Enteric-Coated Capsules Providing Reliable Site-Specific Drug Delivery to the Distal Ileum.

Nefecon, a targeted-release capsule formulation of budesonide approved for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy, targets overproduction of galactose-deficient immunoglobulin A type 1 in the Peyer's patches at the gut mucosal level. To investigate whether the commercial formulation of Nefecon capsules reliably releases budesonide to the distal ileum, a human study was conducted with test capsules reproducing the delayed-release function of Nefecon capsules. Caffeine was included in the test capsules as a marker for capsule opening in the gut since it appears rapidly in saliva after release from orally administered dosage forms. Magnetic resonance imaging with black iron oxide was used to determine the capsule's position in the gut at the time caffeine was first measured in saliva and additionally to directly visualize dispersion of the capsule contents in the gut. In vitro dissolution results confirmed that the test capsules had the same delayed-release characteristics as Nefecon capsules. In 10 of 12 human volunteers, the capsule was demonstrated to open in the distal ileum; in the other two subjects, it opened just past the ileocecal junction. These results compared favorably with the high degree of variability seen in other published imaging studies of delayed-release formulations targeting the gut. The test capsules were shown to reliably deliver their contents to the distal ileum, the region with the highest concentration of Peyer's patches.

Regulation of maize root growth by local phosphorus availability, sucrose metabolism, and partitioning.

BACKGROUND AND AIMS: Understanding how maize roots proliferate in phosphorus (P)-rich soil patches is critical for improving nutrient acquisition and crop productivity. This study explores the mechanisms of root adaptation to heterogeneous P availability, focusing on sucrose metabolism and the role of local P signals. METHODS: A split-root system with chambers of differing Pi concentrations (0 and 500 µM) was used to examine maize root responses. Various physiological and biochemical parameters, including root growth, sucrose partitioning, enzyme activities, and gene expression, were measured to elucidate the underlying mechanisms. KEY RESULTS: Root proliferation, particularly of second-order lateral roots, was markedly enhanced in P-rich patches. Sucrose was preferentially allocated to the Pi-supplied side, as confirmed by Fourier-transform infrared (FTIR) microscopy. Sucrose content in these roots decreased, indicating active metabolism. Higher activities of cell-wall invertase and sucrose synthase were observed in the Pi-supplied roots, supporting enhanced carbohydrate utilization. CONCLUSIONS: Local P availability triggers significant adjustments in sucrose metabolism and allocation, enhancing the sink capacity of maize roots in P-rich patches. These changes facilitate efficient lateral root proliferation and Pi utilization, highlighting the critical role of local P signals in nutrient acquisition strategies. This research provides deeper insights into the adaptive responses of maize to heterogeneous P environments, offering potential strategies for improving crop nutrient efficiency.

Implantable Patch of Oxidized Nanofibrillated Cellulose and Lysozyme Amyloid Nanofibrils for the Regeneration of Infarcted Myocardium Tissue and Local Delivery of RNA-Loaded Nanoparticles.

Biopolymeric implantable patches are popular scaffolds for myocardial regeneration applications. Besides being biocompatible, they can be tailored to have required properties and functionalities for this application. Recently, fibrillar biobased nanostructures prove to be valuable in the development of functional biomaterials for tissue regeneration applications. Here, periodate-oxidized nanofibrillated cellulose (OxNFC) is blended with lysozyme amyloid nanofibrils (LNFs) to prepare a self-crosslinkable patch for myocardial implantation. The OxNFC:LNFs patch shows superior wet mechanical properties (60 MPa for Young's modulus and 1.5 MPa for tensile stress at tensile strength), antioxidant activity (70% scavenging activity under 24 h), and bioresorbability ratio (80% under 91 days), when compared to the patches composed solely of NFC or OxNFC. These improvements are achieved while preserving the morphology, required thermal stability for sterilization, and biocompatibility toward rat cardiomyoblast cells. Additionally, both OxNFC and OxNFC:LNFs patches reveal the ability to act as efficient vehicles to deliver spermine modified acetalated dextran nanoparticles, loaded with small interfering RNA, with 80% of delivery after 5 days. This study highlights the value of simply blending OxNFC and LNFs, synergistically combining their key properties and functionalities, resulting in a biopolymeric patch that comprises valuable characteristics for myocardial regeneration applications.

R 0 May Not Tell Us Everything: Transient Disease Dynamics of Some SIR Models Over Patchy Environments.

This paper examines the short-term or transient dynamics of SIR infectious disease models in patch environments. We employ reactivity of an equilibrium and amplification rates, concepts from ecology, to analyze how dispersals/travels between patches, spatial heterogeneity, and other disease-related parameters impact short-term dynamics. Our findings reveal that in certain scenarios, due to the impact of spatial heterogeneity and the dispersals, the short-term disease dynamics over a patch environment may disagree with the long-term disease dynamics that is typically reflected by the basic reproduction number. Such an inconsistence can mislead the public, public healthy agencies and governments when making public health policy and decisions, and hence, these findings are of practical importance.

Two cases of small bowel necrosis due to intussusception secondary to abnormal proliferation of intestinal Peyer's patches in infants after MMR vaccination.

BACKGROUND: Intussusception is one of the most common acute abdominal conditions in pediatric patients, and if left untreated, it may result in intestinal necrosis and even death. The etiology of the disease is unknown and may be related to a variety of factors, and there are only limited reports of small bowel necrosis secondary to abnormal Peyer's node hyperplasia after MMR vaccination. CASE PRESENTATION: In this report, we present two infants who had an abnormal proliferation of Peyer's nodes secondary to intussusception eventually leading to small bowel necrosis after MMR vaccination. CONCLUSIONS: Intestinal necrosis and infectious shock are the most common causes of infant mortality, and early detection and management are critical.

Pharmacodynamic Studies of Pravastatin Sodium Nanoemulsion Loaded Transdermal Patch for Treatment of Hyperlipidemia.

Pravastatin sodium (PVS) is a hypolipidemic drug with poor oral bioavailability due to the first-pass effect. Therefore, this study aims to formulate and evaluate transdermal patches containing PVS-loaded nanoemulsions (PVS-NEs) to increase PVS's hypolipidemic and hepatoprotective activities. PVS-NEs were prepared using the aqueous titration method, where oleic acid was chosen as an oil phase, and span 80 and tween 80 were used as surfactant and cosurfactant respectively. Droplet size (DS), polydispersity index (PDI), zeta potential (ZP), clarity, and thermodynamic stability of NEs were all characterized. Also, PVS-NEs (NE2) with 50% oil phase, 40% SC mix 2:1, and 10% water were selected as an optimum formula based on the results of DS (251 ± 16), PDI (0.4 ± 0.16), and ZP (-70 ± 10.4) to be incorporated into a transdermal patch, and PVS-NE2 loaded transdermal patches (PVS-NE2-TDPs) were prepared by solvent evaporation method. F1 patch with HPMC E15 and PVP K30 in a ratio of 3:1 represented satisfactory patch properties with good drug-excipients compatibility. Thus, it was selected as an optimum patch formula. The optimized F1 patch was characterized for thickness, moisture content, weight variation, and drug-excipients incompatibility. Therefore, it was subjected to ex vivo skin permeation and finally pharmacodynamic studies. Ex vivo permeation studies of F1 revealed that the cumulative amount of PVS permeated across rat skin was 271.66 ± 19 µg/cm2 in 72 h, and the pharmacodynamic studies demonstrated that the F1 patch was more effective in treating hyperlipidemia than PVS-TDP (control patch) based on both blood analysis and histopathological examination. .

Evaluation of caffeic acid mucoadhesive tablets on minor recurrent aphthous stomatitis: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Oral aphthous stomatitis is a chronic inflammatory condition. Numerous medications have been investigated to treat the symptoms of the disease. However, these days patients prefer herbal medicines due to lower side effects. Considering the anti-inflammatory, analgesic, and anti-oxidant properties of Caffeic acid and its few side effects, the aim of this study was to assess the impact of Caffeic acid on recurrent aphthous stomatitis (RAS). investigating the effect of caffeic acid mucoadhesive tablets on the size and pain intensity of the aphthous lesions. METHODS: in this double-blinded clinical trial study, 47 patients who met the inclusion criteria were selected by convenient sampling method. The patients were assigned to two groups randomly; the control group (placebo recipients) and the intervention group (Caffeic acid recipients). Patients were followed up for 7 days following the intervention. The diameter of the inflammatory lesion was measured in millimeters, and the pain intensity was recorded based on the VAS scale (Visual Analogue Scale). This trial was approved by the medical ethics committee of Mazandaran University of Medical Sciences (Ethical code: IR.MAZUMS.REC.1401.261) and received IRCT code of IRCT20220815055700N1on 03/09/2022. RESULTS: the diameter of the lesion in both groups decreased over time, and there was no significant difference between the intervention and control groups, except on the fifth day when the diameter of the lesion was significantly greater in the control group (P = 0.012). From the second day, the control group's average pain intensity was significantly higher than the intervention group's pain intensity (P < 0.05). CONCLUSIONS: when comparing mucoadhesive tablets containing Caffeic acid and placebo, the findings demonstrated that Caffeic acid has a significant efficacy in reducing aphthous lesions' diameter and pain intensity of the patients and are suggested for palliative oral aphthous lesions treatment since they showed significant anti-inflammatory and analgesic effects on recurrent aphthous stomatitis.

Consistent spatial scaling of high-severity wildfire can inform expected future patterns of burn severity.

Increasing wildfire activity in forests worldwide has driven urgency in understanding current and future fire regimes. Spatial patterns of area burned at high severity strongly shape forest resilience and constitute a key dimension of fire regimes, yet remain difficult to predict. To characterize the range of burn severity patterns expected within contemporary fire regimes, we quantified scaling relationships relating fire size to patterns of burn severity. Using 1615 fires occurring across the Northwest United States between 1985 and 2020, we evaluated scaling relationships within fire regimes and tested whether relationships vary across space and time. Patterns of high-severity fire demonstrate consistent scaling behaviour; as fire size increases, high-severity patches consistently increase in size and homogeneity. Scaling relationships did not differ substantially across space or time at the scales considered here, suggesting that as fire-size distributions potentially shift, stationarity in patch-size scaling can be used to infer future patterns of burn severity.

Transnuclear mice reveal Peyer's patch iNKT cells that regulate B-cell class switching to IgG1.

Tissue-resident iNKT cells maintain tissue homeostasis and peripheral surveillance against pathogens; however, studying these cells is challenging due to their low abundance and poor recovery from tissues. We here show that iNKT transnuclear mice, generated by somatic cell nuclear transfer, have increased tissue resident iNKT cells. We examined expression of PLZF, T-bet, and RORγt, as well as cytokine/chemokine profiles, and found that both monoclonal and polyclonal iNKT cells differentiated into functional subsets that faithfully replicated those seen in wild-type mice. We detected iNKT cells from tissues in which they are rare, including adipose, lung, skin-draining lymph nodes, and a previously undescribed population in Peyer's patches (PP). PP-NKT cells produce the majority of the IL-4 in Peyer's patches and provide indirect help for B-cell class switching to IgG1 in both transnuclear and wild-type mice. Oral vaccination with α-galactosylceramide shows enhanced fecal IgG1 titers in iNKT cell-sufficient mice. Transcriptional profiling reveals a unique signature of PP-NKT cells, characterized by tissue residency. We thus define PP-NKT as potentially important for surveillance for mucosal pathogens.