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Molecular Psychiatry Jun 2022Inhibitory control deficits are prevalent in multiple neuropsychiatric conditions. The communication- as well as the connectivity- between corticolimbic regions of the...
Inhibitory control deficits are prevalent in multiple neuropsychiatric conditions. The communication- as well as the connectivity- between corticolimbic regions of the brain are fundamental for eliciting inhibitory control behaviors, but early markers of vulnerability to this behavioral trait are yet to be discovered. The gradual maturation of the prefrontal cortex (PFC), in particular of the mesocortical dopamine innervation, mirrors the protracted development of inhibitory control; both are present early in life, but reach full maturation by early adulthood. Evidence suggests the involvement of the Netrin-1/DCC signaling pathway and its associated gene networks in corticolimbic development. Here we investigated whether an expression-based polygenic score (ePRS) based on corticolimbic-specific DCC gene co-expression networks associates with impulsivity-related phenotypes in community samples of children. We found that lower ePRS scores associate with higher measurements of impulsive choice in 6-year-old children tested in the Information Sampling Task and with impulsive action in 6- and 10-year-old children tested in the Stop Signal Task. We also found the ePRS to be a better overall predictor of impulsivity when compared to a conventional PRS score comparable in size to the ePRS (4515 SNPs in our discovery cohort) and derived from the latest GWAS for ADHD. We propose that the corticolimbic DCC-ePRS can serve as a novel type of marker for impulsivity-related phenotypes in children. By adopting a systems biology approach based on gene co-expression networks and genotype-gene expression (rather than genotype-disease) associations, these results further validate our methodology to construct polygenic scores linked to the overall biological function of tissue-specific gene networks.
Topics: Adult; Child; DCC Receptor; Dopamine; Gene Regulatory Networks; Genes, DCC; Humans; Impulsive Behavior; Prefrontal Cortex
PubMed: 35388180
DOI: 10.1038/s41380-022-01533-7 -
Acta Neuropathologica Communications Mar 2022Autosomal-dominant Alzheimer's disease (ADAD) is caused by pathogenic mutations in APP, PSEN1, and PSEN2, which usually lead to an early age at onset (< 65). Circular...
BACKGROUND
Autosomal-dominant Alzheimer's disease (ADAD) is caused by pathogenic mutations in APP, PSEN1, and PSEN2, which usually lead to an early age at onset (< 65). Circular RNAs are a family of non-coding RNAs highly expressed in the nervous system and especially in synapses. We aimed to investigate differences in brain gene expression of linear and circular transcripts from the three ADAD genes in controls, sporadic AD, and ADAD.
METHODS
We obtained and sequenced RNA from brain cortex using standard protocols. Linear counts were obtained using the TOPMed pipeline; circular counts, using python package DCC. After stringent quality control (QC), we obtained the counts for PSEN1, PSEN2 and APP genes. Only circPSEN1 passed QC. We used DESeq2 to compare the counts across groups, correcting for biological and technical variables. Finally, we performed in-silico functional analyses using the Circular RNA interactome website and DIANA mirPath software.
RESULTS
Our results show significant differences in gene counts of circPSEN1 in ADAD individuals, when compared to sporadic AD and controls (ADAD = 21, AD = 253, Controls = 23-ADADvsCO: logFC = 0.794, p = 1.63 × 10, ADADvsAD: logFC = 0.602, p = 8.22 × 10). The high gene counts are contributed by two circPSEN1 species (hsa_circ_0008521 and hsa_circ_0003848). No significant differences were observed in linear PSEN1 gene expression between cases and controls, indicating that this finding is specific to the circular forms. In addition, the high circPSEN1 levels do not seem to be specific to PSEN1 mutation carriers; the counts are also elevated in APP and PSEN2 mutation carriers. In-silico functional analyses suggest that circPSEN1 is involved in several pathways such as axon guidance (p = 3.39 × 10), hippo signaling pathway (p = 7.38 × 10), lysine degradation (p = 2.48 × 10) or Wnt signaling pathway (p = 5.58 × 10) among other KEGG pathways. Additionally, circPSEN1 counts were able to discriminate ADAD from sporadic AD and controls with an AUC above 0.70.
CONCLUSIONS
Our findings show the differential expression of circPSEN1 is increased in ADAD. Given the biological function previously ascribed to circular RNAs and the results of our in-silico analyses, we hypothesize that this finding might be related to neuroinflammatory events that lead or that are caused by the accumulation of amyloid-beta.
Topics: Humans; Alzheimer Disease; Amyloid beta-Protein Precursor; Brain; Mutation; Presenilin-1; RNA, Circular
PubMed: 35246267
DOI: 10.1186/s40478-022-01328-5 -
Journal of Clinical Laboratory Analysis Apr 2022The present study aimed to explore the changes in the expressions of six tumor-related genes in myeloproliferative neoplasms (MPNs). The study population included 130...
BACKGROUND
The present study aimed to explore the changes in the expressions of six tumor-related genes in myeloproliferative neoplasms (MPNs). The study population included 130 patients with MPNs (52 with chronic myeloid leukemia (CML), 49 with essential thrombocythemia (ET), 20 with polycythemia vera (PV), and 9 with primary myelofibrosis (PMF)) and 51 healthy individuals.
METHODS
The expression profiling of six genes (ADAMTS18, CMTM5, CDKN2B, DCC, FHIT, and WNT5B) in the peripheral blood granulocyte cells was explored by real-time quantitative reverse transcription polymerase chain reaction.
RESULTS
The patients with MPNs showed significant downregulation of CMTM5 (EFC = 0.66) and DCC (EFC = 0.65) genes in contrast to a non-significant upregulation of ADAMTS18, CDKN2B, FHIT, and WNT5B genes. Downregulation of DCC was consistent in all subtypes of MPN (EFC range: 0.591-0.860). However, CMTM5 had a 1.22-fold upregulation in PMF in contrast to downregulation in other MPN subtypes (EFC range: 0.599-0.775). The results revealed a significant downregulation in CMTM5 and DCC at below 60-years of age. Furthermore, female patients showed a clear-cut downregulation in both CMTM5 and DCC (EFC DCC: 0.436 and CMTM5: 0.570), while male patients presented a less prominent downregulation with a borderline p-value only in DCC (EFC: 0.69; p = 0.05).
CONCLUSIONS
Chronic myeloid leukemia cases showed a significant upregulation of WNT5B, as a known oncogenesis gene. Two tumor suppressor genes, namely DCC and CMTM5, were downregulated in the patients with MPNs, especially in females and patients below 60 years of age.
Topics: ADAMTS Proteins; Carcinogenesis; Chemokines; Female; Genes, Tumor Suppressor; Humans; Janus Kinase 2; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; MARVEL Domain-Containing Proteins; Male; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis
PubMed: 35176183
DOI: 10.1002/jcla.24289 -
Frontiers in Genetics 2021In a recently published genome-wide association study (GWAS) chronic back pain was associated with three loci; and . This GWAS was based on a heterogeneous sample of...
In a recently published genome-wide association study (GWAS) chronic back pain was associated with three loci; and . This GWAS was based on a heterogeneous sample of back pain disorders, and it is unknown whether these loci are of clinical relevance for low back pain (LBP) with persistent radiculopathy. Thus, we examine if LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy is associated with the selected single nucleotide polymorphisms (SNPs); rs34616559, rs7833174 and rs4384683. In this prospective cohort study, subjects admitted to a secondary health care institution due to an acute episode of LBP with radiculopathy, reported back pain, leg pain, and Oswestry Disability Index (ODI), were genotyped and followed up at 12 months ( = 338). Kruskal-Wallis H test showed no association between the SNPs and back pain, leg pain or ODI. In conclusion, LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy, is not associated with the selected SNPs; rs34616559, rs7833174 and rs4384683. This absent or weak association suggests that the SNPs previously associated with chronic back pain are not useful as prognostic biomarkers for LBP with persistent radiculopathy.
PubMed: 35140737
DOI: 10.3389/fgene.2021.757632 -
Journal of Neurochemistry May 2022Mechanisms that determine the survival of midbrain dopaminergic (mDA) neurons in the adult central nervous system (CNS) are not fully understood. Netrins are a family of...
Mechanisms that determine the survival of midbrain dopaminergic (mDA) neurons in the adult central nervous system (CNS) are not fully understood. Netrins are a family of secreted proteins that are essential for normal neural development. In the mature CNS, mDA neurons express particularly high levels of netrin-1 and its receptor Deleted in Colorectal Cancer (DCC). Recent findings indicate that overexpressing netrin-1 protects mDA neurons in animal models of Parkinson's disease (PD), with a proposed pro-apoptotic dependence function for DCC that triggers cell death in the absence of a ligand. Here, we sought to determine if DCC expression influences mDA neuron survival in young adult and ageing mice. To circumvent the perinatal lethality of DCC null mice, we selectively deleted DCC from mDA neurons utilizing DAT /loxP gene-targeting and examined neuronal survival in adult and aged animals. Reduced numbers of mDA neurons were detected in the substantia nigra pars compacta (SNc) of young adult DAT /DCC mice, with further reduction in aged DAT /DCC animals. In contrast to young adults, aged mice also exhibited a gene dosage effect, with fewer SNc mDA neurons in DCC heterozygotes (DAT /DCC ). Notably, loss of mDA neurons in the SN was not uniform. Neuronal loss in the SN was limited to ventral tier mDA neurons, while mDA neurons in the dorsal tier of the SN, which resist degeneration in PD, were spared from the effect of DCC deletion in both young and aged mice. In the ventral tegmental area (VTA), young adult mice with conditional deletion of DCC had normal mDA neuronal numbers, while significant loss occurred in aged DAT /DCC and DAT /DCC mice compared to age-matched wild-type mice. Our results indicate that expression of DCC is required for the survival of subpopulations of mDA neurons and may be relevant to the degenerative processes in PD.
Topics: Aging; Animals; DCC Receptor; Dopaminergic Neurons; Mesencephalon; Mice; Netrin Receptors; Netrin-1; Parkinson Disease
PubMed: 35118677
DOI: 10.1111/jnc.15579 -
Frontiers in Immunology 2021Immune checkpoint inhibitor (ICI) therapy dramatically prolongs melanoma survival. Currently, the identified ICI markers are sometimes ineffective. The objective of this...
BACKGROUND
Immune checkpoint inhibitor (ICI) therapy dramatically prolongs melanoma survival. Currently, the identified ICI markers are sometimes ineffective. The objective of this study was to identify novel determinants of ICI efficacy.
METHODS
We comprehensively curated pretreatment somatic mutational profiles and clinical information from 631 melanoma patients who received blockade therapy of immune checkpoints (i.e., CTLA-4, PD-1/PD-L1, or a combination). Significantly mutated genes (SMGs), mutational signatures, and potential molecular subtypes were determined. Their association with ICI responses was assessed simultaneously.
RESULTS
We identified 27 SMGs, including four novel SMGs (, , , and ) that are associated with ICI efficacy and well-known driver genes. mutations were associated with improved ICI overall survival (hazard ratio (HR): 0.64, 95% CI: 0.45-0.91, = 0.012), whereas immune resistance was observed in patients with mutations (HR: 1.42, 95% CI: 1.10-1.82, = 0.006). The presence of the tobacco smoking-related signature was significantly correlated with inferior prognoses (HR: 1.42, 95% CI: 1.11-1.82, = 0.005). In addition, the signature resembling that of alkylating agents and a newly discovered signature both exhibited extended prognoses (both HR < 1, < 0.05). Based on the activities of the extracted 6 mutational signatures, we identified one immune subtype that was significantly associated with better ICI outcomes (HR: 0.44, 95% CI: 0.23-0.87, = 0.017).
CONCLUSION
We uncovered several novel SMGs and re-annotated mutational signatures that are linked to immunotherapy response or resistance. In addition, an immune subtype was found to exhibit favorable prognoses. Further studies are required to validate these findings.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Drug Resistance, Neoplasm; Female; Gene Ontology; Humans; Immune Checkpoint Inhibitors; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Transcriptome; Young Adult
PubMed: 35087523
DOI: 10.3389/fimmu.2021.798474 -
International Journal of Molecular... Jan 2022Increased bone marrow adiposity is widely observed in patients with obesity and osteoporosis and reported to have deleterious effects on bone formation. Dracunculin...
Increased bone marrow adiposity is widely observed in patients with obesity and osteoporosis and reported to have deleterious effects on bone formation. Dracunculin (DCC) is a coumarin isolated from spp. but, until now, has not been studied for its bioactive potential except antitrypanosomal activity. In this context, current study has reported the anti-adipogenic effect of DCC in human bone marrow-derived mesenchymal stromal cells (hBM-MSCs). DCC dose-dependently inhibited the lipid accumulation and expression of adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) in hBM-MSCs induced to undergo adipogenesis. To elucidate its action mechanism, the effect of DCC on Wnt/β-catenin and AMPK pathways was examined. Results showed that DCC treatment activated Wnt/β-catenin signaling pathway via AMPK evidenced by increased levels of AMPK phosphorylation and Wnt10b expression after DCC treatment. In addition, DCC treated adipo-induced hBM-MSCs exhibited significantly increased nuclear levels of β-catenin compared with diminished nuclear PPARγ levels. In conclusion, DCC was shown to be able to hinder adipogenesis by activating the β-catenin via AMPK, providing potential utilization of DCC as a nutraceutical against bone marrow adiposity.
Topics: AMP-Activated Protein Kinases; Adipogenesis; Artemisia; CCAAT-Enhancer-Binding Proteins; Cell Differentiation; Cell Proliferation; Cell Survival; Cells, Cultured; Coumarins; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation; Humans; Mesenchymal Stem Cells; Molecular Structure; PPAR gamma; Phosphorylation; Wnt Signaling Pathway
PubMed: 35054838
DOI: 10.3390/ijms23020653 -
PLoS Pathogens Dec 2021Influenza virus infection is dependent on host cellular factors, and identification of these factors and their underlying mechanisms can provide important information...
Influenza virus infection is dependent on host cellular factors, and identification of these factors and their underlying mechanisms can provide important information for the development of strategies to inhibit viral infection. Here, we used a highly pathogenic H5N1 influenza virus to perform a genome-wide CRISPR/Cas9 gene knockout screen in human lung epithelial cells (A549 cells), and found that knockout of transmembrane protein immunoglobulin superfamily DCC subclass member 4 (IGDCC4) significantly reduced the replication of the virus in A549 cells. Further studies showed that IGDCC4 interacted with the viral hemagglutinin protein and facilitated virus internalization into host cells. Animal infection studies showed that replication of H5N1 virus in the nasal turbinates, lungs, and kidneys of IGDCC4-knockout mice was significantly lower than that in the corresponding organs of wild-type mice. Half of the IGDCC4-knockout mice survived a lethal H5N1 virus challenge, whereas all of the wild-type mice died within 11 days of infection. Our study identifies a novel host factor that promotes influenza virus infection by facilitating internalization and provides insights that will support the development of antiviral therapies.
Topics: A549 Cells; Animals; CRISPR-Cas Systems; DCC Receptor; Endocytosis; Gene Knockout Techniques; Humans; Influenza A Virus, H5N1 Subtype; Mice; Mice, Knockout; Orthomyxoviridae Infections; Virus Internalization
PubMed: 34871331
DOI: 10.1371/journal.ppat.1010141 -
Medicina (Kaunas, Lithuania) Nov 2021: Recurrence of atrial fibrillation (AF) within six months after sinus rhythm restoration with direct current cardioversion (DCC) is a significant treatment challenge....
: Recurrence of atrial fibrillation (AF) within six months after sinus rhythm restoration with direct current cardioversion (DCC) is a significant treatment challenge. Currently, the factors influencing outcome are mostly unknown. Studies have found a link between genetics and the risk of AF and efficacy of rhythm control. The aim of this study was to examine the association between eight single-nucleotide variants (SNVs) and the risk of AF development and recurrence after DCC. Regarding the occurrence of AF, 259 AF cases and 108 controls were studied. Genotypes for the eight SNVs located in the genes , , , , , and were determined using high-resolution melting analysis and confirmed with Sanger sequencing. Six months after DCC, a telephone interview was conducted to determine whether AF had recurred. A polygenic risk score (PRS) was calculated as the unweighted sum of risk alleles. Multivariate regression analyses were performed to assess SNV and PRS association with AF occurrence and recurrence after DCC. The risk allele of rs2200733 () was significantly associated with the development of AF ( = 0.012, OR = 2.31, 95% CI = 1.206-4.423). AF recurred in 60% of patients and the allele generally associated with a decreased risk of AF of rs11047543 () was associated with a greater risk of AF recurrence ( = 0.014, OR = 0.223, 95% CI = 0.067-0.738). A PRS of greater than 7 was significantly associated ( = 0.008) with a higher likelihood of developing AF after DCC (OR = 4.174, 95% CI = 1.454-11.980). : A higher PRS is associated with increased odds of AF recurrence after treatment with DCC. (rs2200733) is significantly associated with an increased risk of AF. The protective allele of rs11047543 () is associated with a greater risk of AF recurrence. Further studies are needed to predict the success of rhythm control and guide patient selection towards the most efficacious treatment.
Topics: Atrial Fibrillation; Electric Countershock; Humans; Recurrence; Risk Factors; Small-Conductance Calcium-Activated Potassium Channels; Treatment Outcome
PubMed: 34833481
DOI: 10.3390/medicina57111263 -
Biomedicines Nov 2021There is a need for sensitive and specific biomarkers for the early detection of colorectal cancer. In this retrospective study, we assessed whether a high blood copper...
There is a need for sensitive and specific biomarkers for the early detection of colorectal cancer. In this retrospective study, we assessed whether a high blood copper level was associated with the presence of colorectal cancer. The blood copper level was measured among 187 colorectal cancer patients and 187 matched controls. Cases and controls were matched for sex, smoking status (yes/no) and year of birth. Among the cases, the mean blood copper level was 1031 µg/L (range 657 µg/L to 2043 µg/L) and among the controls, the mean blood copper level was 864 µg/L (range 589 µg/L to 1433 µg/L). The odds ratio for colorectal cancer for those in the highest quartile of copper level (versus the lowest) was 12.7 (95% CI: 4.98-32.3; < 0.001). Of the patients with stage I-II colon cancer, 62% had a copper level in the highest quartile. A blood copper level in excess of 930 µg/L is associated with an increase in the prevalence of colorectal cancer in the Polish population and its potential use in early detection programs should be considered.
PubMed: 34829856
DOI: 10.3390/biomedicines9111628