The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13-2 (Munc13-2), which is highly expressed in the brain-predominantly in the cerebral cortex-and plays an ...essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of the UNC13B mutation in human disease is not known. In this study, we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed a favourable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database (gnomAD). Computational modelling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiological recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results indicate that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favourable outcome under anti-epileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.
Mitochondrial diseases (MDs) were a large group multisystem disorders, attributable in part to the dual genomic control. The advent of massively sequencing has improved diagnostic rates and speed, ...and was increasingly being used as a first-line diagnostic test. Paediatric patients (aged < 18 years) who underwent dual genomic sequencing were enrolled in this retrospective multicentre study. We evaluated the mitochondrial disease criteria (MDC) and molecular diagnostic yield of dual genomic sequencing. Causative variants were identified in 177 out of 503 (35.2%) patients using dual genomic sequencing. Forty-six patients (9.1%) had mitochondria-related variants, including 25 patients with nuclear DNA (nDNA) variants, 15 with mitochondrial DNA (mtDNA) variants, and six with dual genomic variants (MT-ND6 and POLG; MT-ND5 and RARS2; MT-TL1 and NARS2; MT-CO2 and NDUFS1; MT-CYB and SMARCA2; and CHRNA4 and MT-CO3). Based on the MDC, 15.2% of the patients with mitochondria-related variants were classified as "unlikely to have mitochondrial disorder". Moreover, 4.5% of the patients with non-mitochondria-related variants and 1.43% with negative genetic tests, were classified as "probably having mitochondrial disorder". Dual genomic sequencing in suspected MDs provided a more comprehensive and accurate diagnosis for pediatric patients, especially for patients with dual genomic variants.
Macrobrachium rosenbergii
is a typical aquatic organism with reversible gonadal development that is regulated by gene expression. The role of transcription factors in gonadal in adult shrimps remains ...unclear in
M. rosenbergii
. In this study, we sequenced the transcriptomes of adult shrimp testes, ovaries, and androgenic glands using second-generation sequencing. In total, 24,007 genes were identified and 9,199 differentially expressed genes (DEGs) were identified by pairwise comparison. There were 272 differentially expressed transcription factors (TFs); 107, 152, and 13 differentially expressed TFs were identified in the testes, ovaries, and androgenic glands by three pairwise comparisons, respectively. GO and KEGG analyses of the TFs and DEGs involved in the MAPK signaling and transcriptional regulation pathways and play key roles in the cell cycle of the testes, whereas involved in the thyroid hormone signaling pathway and neuroactive ligand–receptor interaction play important roles in the ovary. We determined the existence of networks comprising important TFs related to sex development in adult
M. rosenbergii
gonads. The key TFs were
Piwi
(expressed only in the testes and ovaries) and
Argonaute 3
(expressed only in the ovaries), which might be involved in the regulation of testes and ovary development.
Genome-wide association studies (GWAS) have identified ∼100 genetic loci associated with prostate cancer risk. Less than a dozen of these loci were initially identified from GWAS in two Asian ...populations, likely because of smaller sample sizes of these individual GWAS in Asians. Here, we conduct a large-scale meta-analysis of two GWAS from the Japanese population (1,583 cases and 3,386 controls) and the Chinese population (1,417 cases and 1,008 controls), followed by replication in three independent sample sets. We identify two independent susceptibility loci for prostate cancer at 11p15.4 (rs12791447, P=3.59 × 10(-8); PPFIBP2) and 14q23.2 (rs58262369, P=6.05 × 10(-10); ESR2). The mRNA levels of PPFIBP2 and ESR2 are differentially expressed in prostate tumours and paired normal tissues. Our study adds two new loci to the limited number of prostate cancer risk-associated variants in Asians and provides important insight into potential biological mechanisms of prostate cancer.
Bone metabolism can be influenced by a range of factors. We selected children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and lifestyles similar to those of healthy children to ...control for the confounding factors that may influence bone metabolism. We aimed to identify the specific effects of epilepsy and/or anti-seizure medications (ASMs) on bone metabolism.
Patients with SeLECTS were divided into an untreated group and a monotherapy group, and the third group was a healthy control group. We determined the levels of various biochemical markers of bone metabolism, including procollagen type I nitrogenous propeptide (PINP), alkaline phosphatase (ALP), osteocalcin (OC), collagen type I cross-linked C-telopeptide (CTX), calcium, magnesium, phosphorus, parathyroid hormone (PTH), and vitamin D
(VD
).
A total of 1487 patients (from 19 centers) were diagnosed with SeLECTS; 1032 were analyzed, including 117 patients who did not receive any ASMs (untreated group), 643 patients who received only one ASM (monotherapy group), and 272 children in the healthy control group. Except for VD
, other bone metabolism of the three groups were different (p < .001). Bone metabolism was significantly lower in the untreated group than the healthy control group (p < .05). There were significant differences between the monotherapy and healthy control group in the level of many markers. However, when comparing the monotherapy and untreated groups, the results were different; oxcarbazepine, levetiracetam, and topiramate had no significant effect on bone metabolism. Phosphorus and magnesium were significantly lower in the valproic acid group than the untreated group (adjusted p < .05, Cliff's delta .282-.768). CTX was significantly higher in the lamotrigine group than in the untreated group (adjusted p = .012, Cliff's delta = .316).
Epilepsy can affect many aspects of bone metabolism. After controlling epilepsy and other confounders that affect bone metabolism, we found that the effects of ASMs on bone metabolism differed. Oxcarbazepine, levetiracetam, and topiramate did not affect bone metabolism, and lamotrigine corrected some of the abnormal markers of bone metabolism in patients with epilepsy.
To investigate the characteristics of gene mutations in unexplained infantile epileptic encephalopathy (EE).
A total of 47 infants with unexplained infantile EE were enrolled, and next-generation ...sequencing was used to analyze gene mutations in these infants and their parents.
Of all 47 infants, 23 were found to have gene mutations, among whom 13 had de novo mutations and 10 had heterozygous mutations inherited from their father or mother. Among the 23 infants with gene mutations, 17 were found to have the gene mutations related to EE (among whom 14 had ion channel gene mutations), 2 had the gene mutations related to congenital inherited metabolic diseases, 2 had the gene mutations related to brain structural abnormality, and 2 had the gene mutations related to mental retardation.
Unexplained infantile EE may have gene mutations, mainly ion channel gene mutations.
The -2proPSA （p2PSA） and its derivatives, the p2PSA-to-free PSA ratio （%p2PSA）, and the Prostate Health Index （PHI） have greatly improved discrimination between men with and without prostate cancer ...（PCa） in prostate biopsies. However, little is known about their performance in cases where a digital rectal examination （DRE） and transrectal ultrasonography （TRUS） are negative. A prospective cohort of 261 consecutive patients in China with negative DRE and TRUS were recruited and underwent prostate biopsies. A serum sample had collected before the biopsy was used to measure various PSA derivatives, including total prostate-specific antigen （tPSA）, free PSA, and p2PSA. For each patient, the free-to-total PSA ratio （%fPSA）, PSA density （PSAD）, p2PSA-to-free PSA ratio （%p2PSA）, and PHI were calculated. Discriminative performance was assessed using the area under the receiver operating characteristic curve （AUC） and the biopsy rate at 91% sensitivity. The AUC scores within the entire cohort with respect to age, tPSA, %fPSA, PSAD, p2PSA, %p2PSA, and PHI were 0.598, 0.751, 0.646, 0.789, 0.814, 0.808, and 0.853, respectively. PHI was the best predictor of prostate biopsy results, especially in patients with a tPSA of 10.1-20 ng ml-1. Compared with other markers, at a sensitivity of 91%, PHI was the most useful for determining which men did not need to undergo biopsy, thereby avoiding unnecessary procedures. The use of PHI could improve the accuracy of PCa detection by predicting prostate biopsy outcomes among men with a negative DRE and TRUS in China.
Prostate cancer risk-associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically ...investigate prostate cancer risk-associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10(-14)) and 19q13.4 (rs103294, P = 5.34 × 10(-16)) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10(-4)). These findings may advance the understanding of genetic susceptibility to prostate cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
To explore the association between chorioamnionitis and brain injury in preterm infants.
A total of 88 preterm infants (28-34 weeks), who were born between June 2008 and June 2011, were divided into ...a case group (n=41) and a control group (n=47) according to whether or not they had chorioamnionitis. All the infants were examined by brain ultrasonography periodically after birth and underwent brain diffusion weighted imaging (DWI) between 3 and 7 days after birth. The two groups were compared in terms of the incidence of periventricular leukomalacia (PVL) and periventricular and intraventricular hemorrhage (PVH-IVH) by brain magnetic resonance imaging (MRI) at the corrected gestational age of 40 weeks.
There was statistical significance in the incidence of PVL between the case and the control groups (32% vs 6%; P<0.05), but no significant difference in the incidence of PVH-IVH between the two groups (27% vs 23%; P>0.05).
Chorioamnionitis is associated with brain injury in preterm infants, increasing the incide
To investigate pathological changes in the epileptogenic foci of children with intractable epilepsy and their clinical significance.
Thirty children with intractable epilepsy were included in the ...study. The epileptogenic foci were surgically resected and pathological changes in the obtained specimens were observed under a light microscope (LM) and a transmission electron microscope (TEM).
Under the LM, cortical dysplasia was found in 14 cases (47%), hippocampal sclerosis in 11 cases (37%), dysembryoplastic neuroepithelial tumor in 1 case (3%), ganglioglioma in 1 case (3%), and encephalomalacia in 3 cases (10%). The TEM observation revealed pathological changes in the ultrastructure of the hippocampus and extra-hippocampal cortex, such as changes in the number of synapses and synaptic structure, decrease in neurons and karyopyknosis, swelling and degeneration of astrocytes, and changes in mitochondrial structures.
Pathological changes in the hippocampus and extra-hippocampal cortex, especially synaptic remodel
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