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PubMed2001

Differential expression of cytotoxic molecules and killer cell inhibitory receptors in CD8+ and CD56+ cutaneous lymphomas.

Cutaneous lymphomas of the cytotoxic phenotype, including CD8+ and CD56+ lymphomas, have only recently been recognized. To characterize the phenotypic profile of these lymphomas, we investigated the expression of both cytotoxic molecules and killer cell inhibitory receptors by immunohistochemistry techniques. Frozen sections from four CD8+ and from three CD56+ cutaneous lymphomas were stained for the cytotoxicity markers including T-cell restricted intracellular antigen-1, perforin, granzyme B, and for expression of the inhibitory receptors including p58.1, p58.2, p70, p140, CD94, NKG2, and leukocyte immunoglobulin-like receptor (LIR-1). Apart from LIR-1, the CD8+ lymphomas in our series express p70 and p140 from the inhibitory receptors and only one or two of the cytotoxic proteins. The CD56+ lymphomas, on the other hand, express only LIR-1 of the set of inhibitory receptors and the whole panel of cytotoxic antigens. Various subtypes of cytotoxic cutaneous lymphomas (CD8+ and CD56+) differ in regard to their phenotypic and functional profile, which may explain differences in their biological behavior.

Adult↗
PubMed1997

Immunophenotypic and functional characterization of human tonsillar mast cells.

Mast cells (MC) are proinflammatory immune cells residing in various organs. Tissue-specific heterogeneity of MC has been described. The aim of this study was to establish the phenotype and functional profile of human tonsillar mast cells (ToMC) and to compare ToMC with lung-, skin-, and uterus MC. Tonsillar tissue was obtained from 23 patients suffering from hyperplastic tonsils and dispersed by enzymatic digestion. With the use of a combined toluidine blue/immunofluorescence staining technique, isolated ToMC were found to react with monoclonal antibodies (mAb) to immunoglobulin E, CD9, CD43, CD44, CD46, CD54, CD55, and CD59, as well as mAb to stem cell factor (SCF) receptor (CD117/c-kit). ToMC were not recognized by mAb to other cytokine receptors or mAb to CD3, CD11b, CD14, CDw17, the skin MC marker CD88 (C5aR) or CD89 (Fc alphaR). Activation of ToMC by recombinant human (rh) SCF or anti-IgE resulted in histamine secretion, whereas no effects were seen with rhC5a, rh granulocyte-macrophage colony-stimulating factor, or rh interleukin-1 through -10. In summary, ToMC exhibit functional and phenotypic properties similar to lung- or uterus MC. Unlike skin MC, ToMC lack C5aR and are unresponsive to rhC5a.

Antigens, Surface↗
PubMed1999

Nicotinic acetylcholine receptors assembled from the alpha7 and beta3 subunits.

Intracellular recordings were performed in voltage-clamped Xenopus oocytes upon injection with a mixture of cDNAs encoding the beta3 and mutant alpha7 (L247Talpha7) neuronal nicotinic acetylcholine receptor (nAChR) subunits. The expressed receptors maintained sensitivity to methyllycaconitine and to alpha-bungarotoxin but exhibited a functional profile strikingly different from that of the homomeric L247Talpha7 receptor. The heteromeric L247Talpha7beta3 nAChR had a lower apparent affinity and a faster rate of desensitization than L247Talpha7 nAChR, exhibited nonlinearity in the I-V relationship, and was inhibited by 5-hydroxytryptamine, much like wild type alpha7 (WTalpha7) nAChR. Single channel recordings in cell-attached mode revealed unitary events with a slope conductance of 19 picosiemens and a lifetime of 5 ms, both values being much smaller than those of the homomeric receptor channel. Upon injection with a mixture of WTalpha7 and beta3 cDNAs, clear evidence was obtained for the plasma membrane assembly of heteromeric nAChRs, although ACh could not activate these receptors. It is concluded that beta3, long believed to be an orphan subunit, readily co-assembles with other subunits to form heteromeric receptors, some of which may be negative regulators of cholinergic function.

Aconitine↗
PubMed1986

Functionally distinct monoclonal antibodies reactive with enzymatically active and binding domains of Pseudomonas aeruginosa toxin A.

Monoclonal antibodies (MAbs) are described which react with two discrete structural domains of Pseudomonas aeruginosa toxin A and which have two distinct functional profiles. The MAbs designated T3-1C7 and T4-1F2 reacted with a 46,000-dalton peptide similar to the putative B or binding fragment of toxin A. These antibodies neutralized the cytotoxic and lethal properties of toxin but had no effect on its ADP-ribosyl transferase activity. T4-1F2 interfered with the binding of toxin A to membrane receptors on mouse fibroblasts (L cells), although the epitope for the antibody appears to be distinct from the actual receptor binding site. The MAb designated T2-1H2 reacted with intact toxin A and with a cloned, enzymatically active carboxy-terminal polypeptide similar to the toxin A fragment. This MAb neutralized the ADP-ribosyl transferase activity of activated holotoxin and of the cloned peptide, but inhibited neither binding of toxin to membrane receptors nor its cytotoxic and lethal actions. The complementary specificity and function of these MAbs confirm the functional specialization of discrete structural domains within the toxin A molecule. Our findings suggest the greater antitoxic potential of antibodies that block binding, compared with those which inhibit the enzymatic activity of toxin A.

ADP Ribose Transferases↗
PubMed1996

Correlation of the topographical arrangement and the functional pattern of tissue-infiltrating macrophages in giant cell arteritis.

End organ ischemia, fragmentation of elastic membranes, and aneurysm formation in patients with giant cell vasculitis results from an inflammation destroying the mural layers of large and medium sized arteries. Although the inflammatory infiltrate extends through all layers of the affected blood vessel, the most pronounced changes involve the intima and the internal elastic lamina. Analysis of the functional profile of tissue infiltrating CD68+ cells demonstrates that different subsets of macrophages can be distinguished. TGFbeta1-expressing CD68+ cells coproduce IL-1beta and IL-6, are negative for inducible nitric oxide synthase (iNOS), and exhibit a strong preference for localization in the adventitia. The adventitial homing of TGFbeta1+ CD68+ cells places them in the vicinity of IFN-gamma secreting CD4+ T cells which also accumulate in the exterior layer of the artery. Conversely, iNOS expressing CD68+ cells are negative for TGFbeta and are almost exclusively found in the intimal layer of the inflamed artery. The intimal-medial junction is the preferred site for 72-kD collagenase expressing CD68+ cells. Thus, TGFbeta1-producing macrophages colocalize with activated CD4+ T cells and home to an area of inflammation which is distant from the site of tissue damage but critical in regulating cellular influx, suggesting that TGFbeta1 functions as a proinflammatory mediator in this disease. iNOS- and 72-kD collagenase-producing macrophages accumulate at the center of pathology implying a role of these products in tissue destruction. These data indicate that the microenvironment controls the topographical arrangement as well as the functional commitment of macrophages.

Antigens, CD↗
PubMed1997

P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed tissues.

When activated, T helper cells differentiate into one of two subsets, Th1 and Th2, characterized by distinct profiles of cytokine production. Th1 cells activate pro-inflammatory effector mechanisms involved in protection and autoimmunity, whereas Th2 cells induce humoral and allergic responses and downregulate local inflammation. Apart from differences in the repertoire of cytokines, no phenotypic attributes are established that distinguish the two subsets. Here we show that Th1 cells, but not Th2 cells, are able to bind to P-selectin and E-selectin. Moreover, only Th1 cells can efficiently enter inflamed sites in Th1-dominated models, such as sensitized skin or arthritic joints, but not in a Th2-dominated allergic response. Immigration of Th1 cells into inflamed skin can be blocked by antibodies against P- and E-selectin. These results provide evidence for adhesion mechanisms to distinguish between the two T helper subsets and mediate their differential trafficking. They indicate that selective recruitment is an additional level of regulation for both effector function profile and character of a local immune response.

Animals↗
PubMed1997

Giant cell vasculitis is a T cell-dependent disease.

BACKGROUND: Giant cell arteritis (GCA) is a systemic vasculitis that preferentially targets medium-sized and large arteries. The etiopathogenesis of the syndrome is not known, and because of the paucity of information concerning the mechanisms of blood vessel wall damage, treatment options are limited. Clues to pathogenic events in this arteritis may derive from understanding the function of tissue-infiltrating cells. Arterial injury in GCA is associated with the formation of granulomas that are composed of T cells, activated macrophages, and multinucleated giant cells. To examine the role of T cells, we implanted inflamed temporal arteries from patients with GCA into severe combined immunodeficiency (SCID) mice and studied whether the vascular lesions were T cell-dependent. MATERIALS AND METHODS: Temporal artery specimens from patients with GCA were engrafted into SCID mice. The histomorphologic appearance of fresh arteries and grafts retrieved from the mice was compared by two-color immunohistochemistry, and the functional profile of tissue-infiltrating cells was analyzed by semiquantifying cytokine transcription with a polymerase chain reaction (PCR)-based assay system. The repertoire of tissue-infiltrating T cells was assessed for the presence of dominant T cell populations by using T cell receptor beta-chain-specific PCR followed by sequencing. To investigate the role of T cells in the activation of tissue-infiltrating macrophages, T cells were depleted from the arterial grafts by treating the mice with T cell-specific antibodies and the production of monokines was monitored. To demonstrate the disease relevance of T cells expanding in the implants, T cells were isolated from tissue segments and adoptively transferred into mice implanted with syngeneic arteries. The in situ production of lymphokines was then determined. RESULTS: The inflammatory infiltrate penetrating all layers of the arterial wall persisted in the xenotransplants, indicating that the inflammatory foci represent independent functional units. Similar quantities of T cell- and macrophage-derived cytokines were detected in fresh and engrafted tissue. However, the diversity of tissue-infiltrating T cells decreased following implantation. T cells with identical T cell receptors were expanded in different mice that had been engrafted with tissue fragments from the same patient, indicating that T cell survival in the arterial wall was a nonrandom process. To confirm the disease relevance of these T cells, T cell depletion and reconstitution experiments were performed. Antibody-mediated elimination of T cells from the xenotransplants resulted in the attenuation of the production of the monokines, IL-1 beta and IL-6. Adoptive transfer of syngeneic tissue-derived T cells, but not of peripheral blood T cells, into engrafted SCID mice enhanced the transcription of IL-2 and IFN-gamma in the implanted arteries. CONCLUSIONS: The vascular lesions of GCA are maintained in human artery-mouse chimeras, indicating that all cellular and noncellular components necessary for the disease are present in the temporal artery. Activation of tissue-infiltrating T cells and macrophages depends upon an infrequent subpopulation of lesional T cells that have a survival advantage in the xenotransplants. The selective proliferation of these T cells in the arteries suggests that there is recognition of a locally expressed antigen. Therefore, these T cells should be candidate targets for the development of novel therapeutic strategies in GCA.

Adoptive Transfer↗
PubMed2004

Chronic antidepressant treatment causes a selective reduction of mu-opioid receptor binding and functional coupling to G Proteins in the amygdala of fawn-hooded rats.

We have previously documented that chronic alcohol consumption or alcohol withdrawal affects mu-opioid receptor density and receptor-mediated G protein coupling in Fawn-Hooded (FH) rat brain, especially in mesolimbic regions. FH rats demonstrate comorbid depression and high voluntary alcohol consumption; treatment with standard antidepressants improves both facets of this phenotype. Accordingly, we sought to examine whether mu-opioid receptor binding and the receptor-mediated functional coupling to G protein is affected by this drug treatment. Using quantitative autoradiography, binding of mu-opioid receptors labeled by [125I]FK33,824 (D-Ala2,N-Me-Phe4,Met(O)5-ol enkephalin) and the coupling between receptors and G proteins determined by agonist-stimulated guanosine 5'-O -(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding was mapped throughout brain sections of FH rats after 10-day treatment with vehicle, desipramine, or sertraline. Both desipramine and sertraline produced significant decreases of [125I]FK33,824 binding in many brain regions; 13 of 20 measured regions for desipramine and 16 of 20 measured regions for sertraline. The coupling efficiency of mu-opioid receptors to G proteins was determined by an increase of [35S]GTPgammaS binding induced by stimulation with the mu-opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10 microM). In contrast to the receptor binding profile, functional coupling of receptors to G proteins was only significantly reduced in the amygdala, whereas it remained unchanged in other regions compared with control. The present findings suggest that antidepressants regulate opioid systems; however, this occurs differentially, and region-specific alteration of functional coupling of mu-opioid receptors to G proteins in the amygdala suggests that opioid function within the amygdala may be modulated by antidepressants.

Amygdala↗
PubMed2004

Role of cyclic GMP on inhibition by nitric oxide donors of human eosinophil chemotaxis in vitro.

1. This study was designed to investigate the effects of the nitric oxide (NO) donors sodium nitroprusside (SNP), 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP) on N-formyl-L-methionyl-L-leucyl-phenylalanine (fMLP, 1 x 10(-7) M)-induced human eosinophil chemotaxis, cyclic guanosine-3',5'-monophosphate (cGMP) levels, protein nitration and cytotoxicity. 2. Human eosinophils were exposed to SNP, SIN-1 and SNAP (0.001-1.0 mM) for either short (10 min) or prolonged (90 min) time periods. Exposition of eosinophils with these NO donors significantly inhibited the eosinophil chemotaxis irrespective of whether cells were exposed to these agents for 10 or 90 min. No marked differences were detected among them regarding the profile of chemotaxis inhibition. 3. Exposition of eosinophils to SNP, SIN-1 and SNAP (0.001-1.0 mM) markedly elevated the cGMP levels above basal levels, but the 90-min exposition resulted in significantly higher levels compared with the 10-min protocols (5.3+/-0.6 and 2.6+/-0.2 nM 1.5 x 10(6) cells(-1), respectively). The cGMP levels achieved with SNAP were greater than SNP and SIN-1. 4. The NO donors did not induce cell toxicity in any experimental condition used. Additionally, eosinophils exposed to SNP, SIN-1 and SNAP (1.0 mM each) either for 10 or 90 min did not show any tyrosine nitration in conditions where a strong nitration of bovine serum albumin was observed. 5. Our findings show that inhibitory effects of fMLP-induced human eosinophil chemotaxis by NO donors at short or prolonged exposition time were accompanied by significant elevations of cGMP levels. However, additional elevations of cGMP levels do not change the functional profile (chemotaxis inhibition) of stimulated eosinophils.

Adolescent↗
PubMed2004

Human aldolase A natural mutants: relationship between flexibility of the C-terminal region and enzyme function.

We have identified a new mutation in the FBP (fructose 1,6-bisphosphate) aldolase A gene in a child with suspected haemolytic anaemia associated with myopathic symptoms at birth and with a subsequent diagnosis of arthrogryposis multiplex congenita and pituitary ectopia. Sequence analysis of the whole gene, also performed on the patient's full-length cDNA, revealed only a Gly346-->Ser substitution in the heterozygous state. We expressed in a bacterial system the new aldolase A Gly346-->Ser mutant, and the Glu206-->Lys mutant identified by others, in a patient with an aldolase A deficit. Analysis of their functional profiles showed that the Gly346Ser mutant had the same Km as the wild-type enzyme, but a 4-fold lower kcat. The Glu206-->Lys mutant had a Km approx. 2-fold higher than that of both the Gly346-->Ser mutant and the wild-type enzyme, and a kcat value 40% less than the wild-type. The Gly346-->Ser and wild-type enzymes had the same Tm (melting temperature), which was approx. 6-7 degrees C higher than that of the Glu206-->Lys enzyme. An extensive molecular graphic analysis of the mutated enzymes, using human and rabbit aldolase A crystallographic structures, suggests that the Glu206-->Lys mutation destabilizes the aldolase A tetramer at the subunit interface, and highlights the fact that the glycine-to-serine substitution at position 346 limits the flexibility of the C-terminal region. These results also provide the first evidence that Gly346 is crucial for the correct conformation and function of aldolase A, because it governs the entry/release of the substrates into/from the enzyme cleft, and/or allows important C-terminal residues to approach the active site.

Amino Acid Substitution↗
PubMed1984

Small airways changes in workers exposed to asbestos.

Although restriction is considered the classic pulmonary function profile of asbestosis, studies suggest that obstruction of the peripheral airways not revealed by standard spirometry is equally frequent and indicative of peribronchiolar fibrosis. We recorded flows and volumes from maximal expiratory flow volume (MEFV) curves, closing volume data and the phase III slope of the alveolar plateau for 610 litigants, 575 men and 35 women, exposed to asbestos for varying periods in a single workplace in northern New Jersey. Smokers (260) included current smokers and subjects who had stopped within the previous 10 years; nonsmokers (350) had either never smoked or had given up for more than 10 years. Analyses were made for both groups according to years worked. Compared to predicted, smokers and nonsmokers had significantly higher closing capacities (p less than 0.01) and delta N2% (p less than 0.001) means, and lower forced vital capacity (FVC), forced expiratory volume for the first second (FEV1.0, maximal expiratory flow rate (MEFR) and peak expiratory flow rate (PEFR) functions (p less than 0.05); the flow rate after 75% of the FVC had been exhaled (FEF75%) values were significantly reduced (p less than 0.01) only for workers exposed for more than 30 years. The change from predicted was significantly more rapid for smokers, compared with nonsmokers, for FVC, FEV1.0, PEFR, MEFR and FEF75% means, while the increase in closing capacity (CC) was twice as rapid for nonsmokers and the two groups did not differ in their mean rates of rise for delta N2%. CC and the slope of the alveolar plateau appeared to be the measures best able to discriminate between the data for both smoking and nonsmoking asbestos workers and their lung function prediction means.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2001

A high-resolution phantom for MRI.

Assessment of spatial resolution is an important step to test the performance of new sequence techniques-especially ultrafast techniques with dedicated k-space trajectories or interpolation algorithms. Measurement of the modulation transfer function (MTF) is a rather difficult procedure, but using suitable resolution phantoms allows a simple visual evaluation of spatial resolution. In contrast to commonly used test objects with a very restricted number of resolution patterns we developed a phantom containing resolution patterns from 0.1 to 1.5 mm in steps of 0.1 mm. One resolution pattern consists of five parallel Plexiglas strips with the distance of the strips being equal to their thickness. Together with a Plexiglas cuboid the resolution patterns are mounted on a Plexiglas plate on the bottom of the cylindrical phantom. An aqueous solution of manganese chloride is used to fill the phantom. High resolution cross sections (pixel size: 50 microm) through the resolution patterns were measured to confirm the correct dimensions of the phantom. To verify the appropriateness of the 0.1 and 0.2 mm stacks micro-CT images with a pixel size of 25 microm were acquired additionally for both patterns. Besides visual inspection evaluation of the profile function of signal intensity across the stacks demonstrates that the resolution patterns are sufficiently correct. T(1)-weighted SE sequences with slightly different pixel sizes as well as T(1)- and T(2*)- weighted gradient echo sequences were applied to demonstrate some possible applications of this phantom. In conclusion, the proposed phantom is well suited to assess the spatial resolution qualitatively (i.e., visually) and quantitatively over a wide range in steps of 0.1 mm.

Humans↗
PubMed2007

Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases.

We have used microarray technology to identify the transcriptional targets of Rho subfamily guanosine 5'-triphosphate (GTP)ases in NIH3T3 cells. This analysis indicated that murine fibroblasts transformed by these proteins show similar transcriptomal profiles. Functional annotation of the regulated genes indicate that Rho subfamily GTPases target a wide spectrum of functions, although loci encoding proteins linked to proliferation and DNA synthesis/transcription are upregulated preferentially. Rho proteins promote four main networks of interacting proteins nucleated around E2F, c-Jun, c-Myc and p53. Of those, E2F, c-Jun and c-Myc are essential for the maintenance of cell transformation. Inhibition of Rock, one of the main Rho GTPase targets, leads to small changes in the transcriptome of Rho-transformed cells. Rock inhibition decreases c-myc gene expression without affecting the E2F and c-Jun pathways. Loss-of-function studies demonstrate that c-Myc is important for the blockage of cell-contact inhibition rather than for promoting the proliferation of Rho-transformed cells. However, c-Myc overexpression does not bypass the inhibition of cell transformation induced by Rock blockage, indicating that c-Myc is essential, but not sufficient, for Rock-dependent transformation. These results reveal the complexity of the genetic program orchestrated by the Rho subfamily and pinpoint protein networks that mediate different aspects of the malignant phenotype of Rho-transformed cells.

Amino Acid Substitution↗
PubMed1990

Combined effect of silica dust exposure and tobacco smoking on the prevalence of respiratory impairments among gold miners.

The combined effect of underground gold mining dust with a high content of free silica and tobacco smoking on the prevalence of respiratory impairment was examined among 2209 South African gold miners and 483 nonminers. The subjects were grouped as having normal function; minimal, moderate or marked obstruction; marked obstruction with restriction; or pure restriction on the basis of their lung function profiles. Each profile group was compared with the normal group for exposure prevalences, and additive and multiplicative relative risk models were applied to test for departure from the additivity of individual effects. Departure from additivity was found to increase progressively with the severity of obstructive impairment. The results indicated that approximately 94% of the cases with the most severe respiratory impairment (N = 191) could have been prevented through the elimination of tobacco smoking. In conclusion, tobacco smoking was found to potentiate the effect of dust on respiratory impairments.

Bronchitis↗
PubMed2005

Genome-wide introgression lines and their use in genetic and molecular dissection of complex phenotypes in rice (Oryza sativa L.).

Tremendous efforts have been taken worldwide to develop genome-wide genetic stocks for rice functional genomic (FG) research since the rice genome was completely sequenced. To facilitate FG research of complex polygenic phenotypes in rice, we report the development of over 20,000 introgression lines (ILs) in three elite rice genetic backgrounds for a wide range of complex traits, including resistances/tolerances to many biotic and abiotic stresses, morpho-agronomic traits, physiological traits, etc., by selective introgression. ILs within each genetic background are phenotypically similar to their recurrent parent but each carries one or a few traits introgressed from a known donor. Together, these ILs contain a significant portion of loci affecting the selected complex phenotypes at which allelic diversity exists in the primary gene pool of rice. A forward genetics strategy was proposed and demonstrated with examples on how to use these ILs for large-scale FG research. Complementary to the genome-wide insertional mutants, these ILs opens a new way for highly efficient discovery, candidate gene identification and cloning of important QTLs for specific phenotypes based on convergent evidence from QTL position, expression profiling, functional and molecular diversity analyses of candidate genes, highlights the importance of genetic networks underlying complex phenotypes in rice that may ultimately lead to more complete understanding of the genetic and molecular bases of quantitative trait variation in rice.

Adaptation, Physiological↗
PubMed2026

Data-driven approaches in green microbiology: strategies for plant growth-promoting bacteria.

Plant growth-promoting bacteria (PGPB) are gaining attention as scalable biological solutions to enhance crop productivity and resilience. However, accurately identifying and characterizing PGPB remains challenging, particularly under variable environmental conditions where microbial functions are context-dependent and shaped by complex plant-microbe interactions. Advances in high-throughput sequencing have shifted the field from culture-dependent approaches to genome-informed strategies, enabling large-scale taxonomic and functional profiling. Although trait-based databases support the prediction of plant-beneficial genes, they capture only a fraction of the underlying biological complexity and often require labor-intensive analyses. Machine learning (ML) and deep learning (DL) have emerged as powerful tools to integrate genomic, physiological, and ecological data, enabling the prioritization of candidate strains with plant growth-promoting potential. To evaluate advances in the field, we conducted a systematic review of studies integrating ML and DL with PGPB characterization, assessing algorithm selection, performance, and target plant systems. Across 248 observations, only 6.0% of studies directly addressed PGPB screening, whereas the majority (77.4%) focused on plant disease detection, revealing a substantial gap in the application of AI to beneficial microorganisms for plant growth. Convolutional neural networks (CNNs) were the most frequently applied algorithms, largely driven by image-based phenotyping tasks. Overall, the field is constrained by limited datasets, high computational demands, and challenges in modeling multispecies and host-associated interactions. We highlight the need for integrative and interpretable ML and DL frameworks that bridge genomic data and functional validation. Such approaches represent a promising path toward scalable, data-driven discovery and deployment of bioinoculants in sustainable agriculture.

Agriculture↗
PubMed2026

Resistant starch types 2 and 4 induce distinct and reversible changes in the human gut microbiome.

Resistant starch (RS) can confer benefits for the gut microbiome and host cardiometabolic health. However, different types of resistant starch can differentially affect gut microbiome composition and functional capacity, especially given interindividual variability in responses, thus limiting the application of resistant starch in dietary strategies. We used shotgun metagenomics to perform a secondary analysis of samples collected during a previously reported randomized clinical trial to determine the effects of dietary supplementation with two types of resistant starch (RS2 and RS4) and a digestible starch (control) on the gut microbiome. Both resistant starch types induced distinct but transient alterations in the gut microbial community. RS2 enriched the keystone degrader, Ruminococcus bromii, and Blautia glucerasea, whereas RS4 favored Parabacteroides distasonis and known but uncharacterized microbial species such as a Lachnospiraceae bacterium. Moreover, we detected strain-level differences in the response of Bifidobacterium adolescentis to resistant starch. Microbial functional profiling revealed an enhanced capacity for complex carbohydrate utilization following resistant starch intake, including increased abundance of specific α-amylases, glycoside hydrolases, starch utilization systems, and other currently uncharacterized genes. Identifying the bacterial strains and genes that respond to different RS types will help to more accurately predict who will benefit from a given RS type. Our findings demonstrate that RS2 and RS4 differentially shape microbial ecology and metabolic capacity and provide a foundation for microbiome-informed personalization of resistant starch-based dietary interventions.IMPORTANCEDietary intake influences human health by modulating metabolism, partly by shaping the microbiota inhabiting the gut. Resistant starch (RS), a dietary fiber, is associated with metabolic improvements. While previous research has explored how RS alters the gut microbiome, RS comprises five types with differing physical and chemical characteristics, and the distinct impacts of each type on the microbiome and host health have not been fully characterized, particularly using high-resolution approaches such as shotgun metagenomics. In this secondary analysis of samples from a longitudinal crossover intervention study, we link dietary supplementation with RS2 and RS4 with distinct and transient changes in the composition and functional potential of the human gut microbiome. Specifically, we identify species that increase in abundance with each RS type, accompanied by increases in genes and pathways involved in complex carbohydrate utilization. The findings support the development of precision nutrition strategies utilizing RS supplementation to improve metabolic health.This study is registered with ClinicalTrials.gov as NCT05743790.

Humans↗
PubMed1996

Genomic responses to 5-HT1A or 5-HT2A/2C receptor activation is differentially regulated in four regions of rat brain.

The functional profiles of brain 5-HT1A and 5-HT2A/C receptors were assessed by quantitating changes in the immediate early genes -c-fos, ngf1c and tis1, following receptor activation with either 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) or DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane). Stimulation of either class of 5-HT receptor elicited an induction of all three immediate early genes to varying extents in cortex, hippocampus and cerebellum, but not in striatum. The responses to 8-OH-DPAT peaked earlier than those to DOI. WAY 100135 (N-tertiobutyl-3-[4-(2-methoxyphenyl)-piperazinyl]-2-phenylpropana mide), the putative 5-HT1A receptor antagonist blocked the 8-OH-DPAT effect but not the responses to DOI. WAY 100135 by itself also elicited a relatively smaller genomic response. Ketanserin completely abolished the DOI-induced genomic responses. The results support the earlier findings that 5-HT1A receptor sites are abundant in frontal cortex and hippocampus. In addition, the robust genomic responses to 8-OH-DPAT as well as Northern hybridization with a cDNA probe for 5-HT1A mRNA in the cerebellum clearly implicate the functional expression of 5-HT1A receptors in this brain region. The responses to the 5-HT2 receptor agonist, DOI support a greater abundance of these receptors in the cortex, and relatively lower levels in hippocampus and cerebellum. The results suggest a differential induction pattern among the three immediate-early genes depending on the brain region and the 5-HT receptor subtype involved.

8-Hydroxy-2-(di-n-propylamino)tetralin↗