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Journal of Crohn's & Colitis Jul 2024Biomarkers that integrate genetic and environmental factors and predict outcome in complex immune diseases such as inflammatory bowel disease (IBD; including Crohn's...
BACKGROUND & AIMS
Biomarkers that integrate genetic and environmental factors and predict outcome in complex immune diseases such as inflammatory bowel disease (IBD; including Crohn's disease [CD] and ulcerative colitis [UC]) are needed. We showed that morphologic patterns of ileal Paneth cells (Paneth cell phenotype [PCP]; a surrogate for PC function) is one such cellular biomarker for CD. Given the shared features between CD and UC, we hypothesized that PCP is also associated with molecular/genetic features and outcome in UC. Because PC density is highest in the ileum, we further hypothesized that PCP predicts outcome in UC subjects who underwent total colectomy and ileal pouch-anal anastomosis (IPAA).
METHODS
Uninflamed ileal resection margins from UC subjects with colectomy and IPAA were used for PCP and transcriptomic analyses. PCP was defined using defensin 5 immunofluorescence. Genotyping was performed using Immunochip. UC transcriptomic and genotype associations of PCP were incorporated with data from CD subjects to identify common IBD-related pathways and genes that regulate PCP.
RESULTS
The prevalence of abnormal ileal PCP was 27%, comparable to that seen in CD. Combined analysis of UC and CD subjects showed that abnormal PCP was associated with transcriptomic pathways of secretory granule maturation and polymorphisms in innate immunity genes. Abnormal ileal PCP at the time of colectomy was also associated with pouch complications including de novo CD in the pouch and time to first episode of pouchitis.
CONCLUSIONS
Ileal PCP is biologically and clinically relevant in UC and can be used as a biomarker in IBD.
PubMed: 38953127
DOI: 10.1093/ecco-jcc/jjae105 -
Research and Practice in Thrombosis and... May 2024Congenital fibrinogen disorders (CFDs) are rare bleeding disorders (RBDs) caused by mutations in 1 of the 3 fibrinogen genes (, , and ).
BACKGROUND
Congenital fibrinogen disorders (CFDs) are rare bleeding disorders (RBDs) caused by mutations in 1 of the 3 fibrinogen genes (, , and ).
OBJECTIVES
To investigate the clinical phenotype, laboratory features, diagnosis, treatment, and prognosis of CFDs.
METHODS
Clinical data of 93 subjects with CFDs identified from June 2018 to December 2023 were retrospectively analyzed.
RESULTS
Among the 93 patients, there were 46 males (49.5%) and 47 females (50.5%), with a median age of 23 years. Fifty-three of 93 (57%) subjects experienced bleeding, 3/93 (3.2%) experienced thrombosis, and 37/93 (39.8%) were asymptomatic. Females were more prone to experience bleeding ( < .0001). The 93 patients exhibited prolonged thrombin time, significantly decreased fibrinogen activity (Fg:C), and normal or decreased fibrinogen antigen. The 93 patients included 3 with hypofibrinogenemia, 16 with hypodysfibrinogenemia, and 74 with dysfibrinogenemia. Among the 53 patients with bleeding, bleeding episodes were identified in 3.8% (2/53), 20.8% (11/53), and 75.5% (40/53) patients with hypofibrinogenemia, hypodysfibrinogenemia, and dysfibrinogenemia, respectively. Genetic analysis was performed on 22 cases from 8 pedigrees, revealing 10 mutations, including 1 novel splice mutation. Twenty-eight (30.1%) subjects received replacement therapy to treat or prevent bleeding, consisting of 8 fresh frozen plasma transfusions, 3 packing and suture treatment, and 61 fibrinogen infusions.
CONCLUSION
Most patients with CFDs have mild or no bleeding symptoms. Fg:C combined with fibrinogen antigen and pedigree investigation can improve the feasibility and accuracy of diagnosis of CFDs. The severity of bleeding symptoms was negatively correlated with Fg:C.
PubMed: 38953055
DOI: 10.1016/j.rpth.2024.102445 -
Frontiers in Immunology 2024Antiglycine receptor (anti-GlyR) antibody mediates multiple immune-related diseases. This study aimed to summarize the clinical features to enhance our understanding of... (Review)
Review
BACKGROUND AND OBJECTIVES
Antiglycine receptor (anti-GlyR) antibody mediates multiple immune-related diseases. This study aimed to summarize the clinical features to enhance our understanding of anti-GlyR antibody-related disease.
METHODS
By collecting clinical information from admitted patients positive for glycine receptor (GlyR) antibody, the clinical characteristics of a new patient positive for GlyR antibody were reported in this study. To obtain additional information regarding anti-GlyR antibody-linked illness, clinical data and findings on both newly reported instances in this study and previously published cases were merged and analyzed.
RESULTS
A new case of anti-GlyR antibody-related progressive encephalomyelitis with rigidity and myoclonus (PERM) was identified in this study. A 20-year-old man with only positive cerebrospinal fluid anti-GlyR antibody had a good prognosis with first-line immunotherapy. The literature review indicated that the common clinical manifestations of anti-GlyR antibody-related disease included PERM or stiff-person syndrome (SPS) (n = 179, 50.1%), epileptic seizure (n = 94, 26.3%), and other neurological disorders (n = 84, 24.5%). Other neurological issues included demyelination, inflammation, cerebellar ataxia and movement disorders, encephalitis, acute psychosis, cognitive impairment or dementia, celiac disease, Parkinson's disease, neuropathic pain and allodynia, steroid-responsive deafness, hemiballism/tics, laryngeal dystonia, and generalized weakness included respiratory muscles. The group of PERM/SPS exhibited a better response to immunotherapy than others.
CONCLUSIONS
The findings suggest the presence of multiple clinical phenotypes in anti-GlyR antibody-related disease. Common clinical phenotypes include PERM, SPS, epileptic seizure, and paraneoplastic disease. Patients with RERM/SPS respond well to immunotherapy.
Topics: Humans; Male; Receptors, Glycine; Autoantibodies; Young Adult; Encephalomyelitis; Muscle Rigidity; Myoclonus; Stiff-Person Syndrome; Adult
PubMed: 38953026
DOI: 10.3389/fimmu.2024.1387591 -
Frontiers in Immunology 2024The immune system plays an important role in the development and treatment of thyroid cancer(THCA).However, the correlation between immune cells and THCA has not been...
BACKGROUND
The immune system plays an important role in the development and treatment of thyroid cancer(THCA).However, the correlation between immune cells and THCA has not been systematically studied.
METHODS
This study used a two-sample Mendelian randomization (MR) study to determine the causal relationship between immune cell characteristics and THCA. Based on a large sample of publicly available genetic data, we explored the causal relationship between 731 immune cell characteristics and THCA risk. The 731 immunophenotypes were divided into 7 groups, including B cell panel(n=190),cDC panel(n=64),Maturation stages of T cell panel(n=79),Monocyte panel(n=43),Myeloid cell panel(n=64),TBNK panel(n=124),and Treg panel(n=167). The sensitivity of the results was analyzed, and heterogeneity and horizontal pleiotropy were excluded.
RESULTS
After FDR correction, the effect of immunophenotype on THCA was not statistically significant. It is worth mentioning, however, that there are some unadjusted low P-values phenotypes. The odds ratio (OR) of CD62L on monocyte on THCA risk was estimated to be 0.953 (95% CI=0.930~0.976, =1.005×10),and which was estimated to be 0.975(95% CI=0.961-0.989, =7.984×10) for Resting Treg%CD4 on THCA risk. Furthermore, THCA was associated with a reduced risk of 5 immunophenotype:CD25 on CD39+ CD4 on Treg (OR=0.871, 95% CI=0.812~0.935, =1.274×10), activated Treg AC (OR=0.884, 95% CI=0.820~0.953, =0.001), activated & resting Treg % CD4 Treg (OR=0.872, 95%CI=0.811~0.937,=2.109×10),CD28- CD25++ CD8br AC(OR=0.867,95% CI=0.809~0.930,=6.09×10),CD28-CD127-CD25++CD8brAC(OR=0.875,95%CI=0.814~0.942,=3.619×10).THCA was associated with an increased risk of Secreting Treg % CD4 Treg (OR=1.143, 95% CI=1.064~1.229, =2.779×10) and CD19 on IgD+ CD24+ (OR=1.118, 95% CI=1.041~1.120, =0.002).
CONCLUSIONS
These findings suggest the causal associations between immune cells and THCA by genetic means. Our results may have the potential to provide guidance for future clinical research.
Topics: Humans; Mendelian Randomization Analysis; Thyroid Neoplasms; Immunophenotyping; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Monocytes
PubMed: 38953025
DOI: 10.3389/fimmu.2024.1425873 -
Frontiers in Immunology 2024P2X receptors are a family of homo- and heterotrimeric cation channels gated by extracellular ATP. The P2X4 and P2X7 subunits show overlapping expression patterns and...
INTRODUCTION
P2X receptors are a family of homo- and heterotrimeric cation channels gated by extracellular ATP. The P2X4 and P2X7 subunits show overlapping expression patterns and have been involved in similar physiological processes, such as pain and inflammation as well as various immune cell functions. While formation of P2X2/P2X3 heterotrimers produces a distinct pharmacological phenotype and has been well established, functional identification of a P2X4/P2X7 heteromer has been difficult and evidence for and against a physical association has been found. Most of this evidence stems, however, from model systems.
METHODS
Here, we used a P2X7-EGFP BAC transgenic mouse model as well as P2X4 and P2X7 knock-out mice to re-investigate a P2X4-P2X7 interaction in mouse lung by biochemical and immunohistochemical experiments as well as quantitative expression analysis.
RESULTS
No detectable amounts of P2X4 could be co-purified from mouse lung via P2X7-EGFP. In agreement with these findings, immuno-histochemical analysis using a P2X7-specific nanobody revealed only limited overlap in the cellular and subcellular localizations of P2X4 and P2X7 in both the native lung tissue and primary cells. Comparison of P2X4 and P2X7 transcript and protein levels in the respective gene-deficient and wild type mice showed no mutual interrelation between their expression levels in whole lungs. However, a significantly reduced expression was found in alveolar macrophages of mice.
DISCUSSION
In summary, our detailed analysis of the cellular and subcellular P2X4 and P2X7 localization and expression does not support a physiologically relevant direct association of P2X4 and P2X7 subunits or receptors .
Topics: Animals; Receptors, Purinergic P2X4; Receptors, Purinergic P2X7; Mice; Lung; Mice, Knockout; Mice, Transgenic; Mice, Inbred C57BL; Protein Binding
PubMed: 38953020
DOI: 10.3389/fimmu.2024.1425938 -
Practical Laboratory Medicine May 2024Prader-Willi syndrome (PWS) is a complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region, known as the...
Prader-Willi syndrome (PWS) is a complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region, known as the Prader Willi critical region. Nutritional clinical manifestations change with age and are described in four different phases. The phases span both extremes of the nutritional spectrum, beginning with an infant with poor sucking reflexes and failure to thrive then progressing to an adolescent who may have hyperphagia and be at risk for obesity. The phenotype is likely due to hypothalamic dysfunction due to genetic changes in the Prader Willi critical region. Researchers are examining the pathological mechanisms that determine the disease course.
PubMed: 38953015
DOI: 10.1016/j.plabm.2024.e00405 -
Frontiers in Plant Science 2024Phenotypic complexity in species complexes and recently radiated lineages has resulted in a diversity of forms that have historically been classified into separate taxa....
INTRODUCTION
Phenotypic complexity in species complexes and recently radiated lineages has resulted in a diversity of forms that have historically been classified into separate taxa. Increasingly, with the proliferation of high-throughput sequencing methods, additional layers of complexity have been recognized, such as frequent hybridization and reticulation, which may call into question the previous morphological groupings of closely related organisms.
METHODS
We investigated Northern European, Asian, and Beringian populations of agg. with phylogenomic analysis of 736 genes and 27,586 SNPs in order to deduce the interrelatedness and hybrid origin of this phenotypically and taxonomically complicated group from Europe characterized by a history of hybridization, polyploidy, apomixis, and recent radiation. The ploidy levels and the reproductive mode of the Northern European populations were assessed via flow cytometric seed screening. In addition, in order to examine the phenotypic plasticity of the dwarf forms previously described as species and summarized as the group, we conducted climate chamber experiments under cold (northern) and warm (temperate) conditions.
RESULTS
The Northern European populations are tetra- to hexaploid and propagate primarily through apomixis. The complex is characterized by highly reticulate relationships. Genetic differentiation of the main clusters has occurred between the above-mentioned geographical regions. We find evidence for the hybrid origin of the taxa in these areas with differing genomic contributions from the geographically nearest European sexual progenitor species. Furthermore, polyphyly in the taxa of the group is supported. Experiments show low lability in the traits associated with the group.
DISCUSSION
We conclude that multiple adaptations of hybrids to colder climates and shorter vegetation periods have shaped the phenotypes of the group, and we suggest a formal classification as nothotaxa within the group.
PubMed: 38952845
DOI: 10.3389/fpls.2024.1415059 -
Behavioral Ecology : Official Journal... 2024It is well known that maternal age at reproduction affects offspring lifespan and some other fitness-related traits, but it remains understudied whether maternal...
It is well known that maternal age at reproduction affects offspring lifespan and some other fitness-related traits, but it remains understudied whether maternal senescence affects how offspring respond to their environments. Early environment often plays a significant role in the development of an animal's behavioral phenotype. For example, complex environments can promote changes in cognitive ability and brain morphology in young animals. Here, we study whether and how maternal effect senescence influences offspring plasticity in cognition, group behavior, and brain morphology in response to environmental complexity. For this, juvenile 3-spined sticklebacks from young and old mothers (i.e. 1-yr and 2-yr-old) were exposed to different levels of environmental enrichment and complexity (i.e. none, simple, and complex), and their behavior, cognitive ability, and brain size were measured. Exposing fish to enriched conditions improved individual learning ability assessed by a repeated detour-reaching task, increased the size of the whole brain, and decreased aggressive interactions in the shoal. Maternal age did not influence the inhibitory control, learning ability, and group behavioral responses of offspring to the experimental environmental change. However, maternal age affected how some brain regions of offspring changed in response to environmental complexity. In offspring from old mothers, those exposed to the complex environment had larger telencephalons and cerebellums than those who experienced simpler environments. Our results suggest that maternal effect senescence may influence how offspring invest in brain functions related to cognition in response to environmental complexity.
PubMed: 38952837
DOI: 10.1093/beheco/arae049 -
Network Neuroscience (Cambridge, Mass.) 2024Canonical correlation analysis (CCA) and partial least squares correlation (PLS) detect linear associations between two data matrices by computing latent variables (LVs)...
Canonical correlation analysis (CCA) and partial least squares correlation (PLS) detect linear associations between two data matrices by computing latent variables (LVs) having maximal correlation (CCA) or covariance (PLS). This study compared the similarity and generalizability of CCA- and PLS-derived brain-behavior relationships. Data were accessed from the baseline Adolescent Brain Cognitive Development (ABCD) dataset ( > 9,000, 9-11 years). The brain matrix consisted of cortical thickness estimates from the Desikan-Killiany atlas. Two phenotypic scales were examined separately as the behavioral matrix; the Child Behavioral Checklist (CBCL) subscale scores and NIH Toolbox performance scores. Resampling methods were used to assess significance and generalizability of LVs. LV for the CBCL brain relationships was found to be significant, yet not consistently stable or reproducible, across CCA and PLS models (singular value: CCA = .13, PLS = .39, < .001). LV for the NIH brain relationships showed similar relationships between CCA and PLS and was found to be stable and reproducible (singular value: CCA = .21, PLS = .43, < .001). The current study suggests that stability and reproducibility of brain-behavior relationships identified by CCA and PLS are influenced by the statistical characteristics of the phenotypic measure used when applied to a large population-based pediatric sample.
PubMed: 38952810
DOI: 10.1162/netn_a_00363 -
BioRxiv : the Preprint Server For... May 2024Biological sex shapes the manifestation and progression of neurodevelopmental disorders (NDDs). These disorders often demonstrate male-specific vulnerabilities; however,...
UNLABELLED
Biological sex shapes the manifestation and progression of neurodevelopmental disorders (NDDs). These disorders often demonstrate male-specific vulnerabilities; however, the identification of underlying mechanisms remains a significant challenge in the field. Hemideletion of the 16p11.2 region (16p11.2 del/+) is associated with NDDs, and mice modeling 16p11.2 del/+ exhibit sex-specific striatum-related phenotypes relevant to NDDs. Striatal circuits, crucial for locomotor control, consist of two distinct pathways: the direct and indirect pathways originating from D1 dopamine receptor (D1R) and D2 dopamine receptor (D2R) expressing spiny projection neurons (SPNs), respectively. In this study, we define the impact of 16p11.2 del/+ on striatal circuits in male and female mice. Using snRNA-seq, we identify sex- and cell type-specific transcriptomic changes in the D1- and D2-SPNs of 16p11.2 del/+ mice, indicating distinct transcriptomic signatures in D1-SPNs and D2-SPNs in males and females, with a ∼5-fold greater impact in males. Further pathway analysis reveals differential gene expression changes in 16p11.2 del/+ male mice linked to synaptic plasticity in D1- and D2-SPNs and GABA signaling pathway changes in D1-SPNs. Consistent with our snRNA-seq study revealing changes in GABA signaling pathways, we observe distinct changes in miniature inhibitory postsynaptic currents (mIPSCs) in D1- and D2-SPNs from 16p11.2 del/+ male mice. Behaviorally, we utilize conditional genetic approaches to introduce the hemideletion selectively in either D1- or D2-SPNs and find that conditional hemideletion of genes in the 16p11.2 region in D2-SPNs causes hyperactivity in male mice, but hemideletion in D1-SPNs does not. Within the striatum, hemideletion of genes in D2-SPNs in the dorsal lateral striatum leads to hyperactivity in males, demonstrating the importance of this striatal region. Interestingly, conditional 16p11.2 del/+ within the cortex drives hyperactivity in both sexes. Our work reveals that a locus linked to NDDs acts in different striatal circuits, selectively impacting behavior in a sex- and cell type-specific manner, providing new insight into male vulnerability for NDDs.
HIGHLIGHTS
- 16p11.2 hemideletion (16p11.2 del/+) induces sex- and cell type-specific transcriptomic signatures in spiny projection neurons (SPNs). - Transcriptomic changes in GABA signaling in D1-SPNs align with changes in inhibitory synapse function. - 16p11.2 del/+ in D2-SPNs causes hyperactivity in males but not females. - 16p11.2 del/+ in D2-SPNs in the dorsal lateral striatum drives hyperactivity in males. - 16p11.2 del/+ in cortex drives hyperactivity in both sexes.
PubMed: 38952795
DOI: 10.1101/2024.05.17.594746