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BackgroundWilliams syndrome (WS) is a neurodevelopmental disorder that has been attributed to heterozygous deletions in chromosome 7q11.23 and exhibits a variety of physical, cognitive, and behavioral features. However, the genetic basis of this phenotypic variability is unclear. In this study, we identified genetic clues underlying these complex phenotypes.MethodsNeurobehavioral function was assessed in WS patients and healthy controls. Total RNA was extracted from peripheral blood and subjected to microarray analysis, RNA-sequencing, and qRT-PCR. Weighted gene co-expression network analysis was performed to identify specific alterations related to intermediate disease phenotypes. To functionally interpret each WS-related module, gene ontology and disease-related gene enrichment were examined. We also investigated the micro (mi)RNA expression profiles and miRNA co-expression networks to better explain the regulation of the transcriptome in WS.ResultsOur analysis identified four significant co-expression modules related to intermediate WS phenotypes. Notably, the three upregulated WS-related modules were composed exclusively of genes located outside the 7q11.23 region. They were significantly enriched in genes related to B-cell activation, RNA processing, and RNA transport. BCL11A, which is known for its association with speech disorders and intellectual disabilities, was identified as one of the hub genes in the top WS-related module. Finally, these key upregulated mRNA co-expression modules appear to be inversely correlated with a specific downregulated WS-related miRNA co-expression module.ConclusionsDysregulation of the mRNA/miRNA network involving genes outside of the 7q11.23 region is likely related to the complex phenotypes observed in WS patients.

Simple Summary: Despite the heterogeneity of resistance mechanisms to tyrosine kinase inhibitor (TKI)-targeting Epidermal Growth Factor Receptor (EGFR)-activating mutations, many induce the activation of MAPK signaling in the presence of EGFR-TKIs. ARAF gene amplification is identified as one such mechanism that activates MAPK signaling by directly interacting with RAS, yet its clinicopathologic characteristics remain poorly understood. In this study, we characterized nine cases with ARAF amplification resistant to EGFR-TKIs. Overall, these ARAF-amplified resistant tumors retained their original founder EGFR mutation and lacked secondary alterations. Furthermore, ARAF amplification was predominantly observed in female patients with EGFR exon 19 deletion. We also identified two cases showing a histologic transformation from lung adenocarcinoma to small-cell lung cancer (SCLC). ARAF amplification potentially fosters conditions that promote tumor cell survival and neuroendocrine marker transcription under EGFR-TKIs. Background/Objectives: Although tyrosine kinase inhibitors (TKIs) targeting EGFR-activating mutations significantly improved the outcome of EGFR-mutant NSCLC, resistance inevitably emerges. Despite the heterogeneity of these resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. While ARAF gene amplification is identified as a resistance mechanism that activates MAPK signaling by directly interacting with RAS, little is known about its clinicopathologic characteristics. Methods: We conducted a single-center retrospective analysis of the presence of ARAF amplification in re-biopsied samples in patients with EGFR-mutant NSCLC resistant to EGFR-TKIs. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. ARAF amplification was determined using a gene copy number assay. RNA sequence analysis was performed in patients with ARAF amplification as well as presenting histologic transformations to small-cell lung carcinoma (SCLC). Results: ARAF amplification was identified in five of ninety-seven patients resistant to erlotinib or gefitinib, and four of forty-eight patients resistant to Osimertinib. ARAF amplification was dominantly observed in female patients with EGFR exon 19 deletion. All ARAF-amplified tumors retained their founder EGFR mutation and were absent of secondary mutations. Two cases were found where ARAF amplification correlated with a histological transformation to SCLC. Conclusions: ARAF amplification was identified in 5–8% of EGFR-TKI-resistant tumors. The possible roles of ARAF in SCLC transformation warrant further investigation. [ABSTRACT FROM AUTHOR]

Aim: The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case–control sample. Method: Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP‐CNVs) in PRKN and examined their association with SCZ and ASD. Results: In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP‐CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP‐CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early‐onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit. Conclusion: The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted. [ABSTRACT FROM AUTHOR]

Abstract. We propose an exact optimization method for home healthcare delivery that relies on logic-based Benders decomposition (LBBD). The objective is to match patients with healthcare aides and schedule multiple [...]

To estimate the impact of C[O.sub.2]-driven ocean acidification on the early life stages of gastropods, the effects of increased partial pressure of seawater carbon dioxide (pC[O.sub.2]) (800-2,000 µatm) on the early developmental stages and larval shell length of the commercially important gastropod, the horned turban snail, Turbo cornutus were investigated. Increase in experimental seawater pC[O.sub.2] had an increasingly negative impact on the early developmental rate; the proportion of embryos or larvae displaying retarded development increased at higher pC[O.sub.2]. The proportion of embryos that developed to the 4-cell stage at 2 h after fertilization decreased linearly with increasing pC[O.sub.2]. At ~1,000 µatm pC[O.sub.2], retarded development was observed in ~50 % of larvae. No embryos developed to the 4-cell stage at 2,000 µatm pC[O.sub.2] within 2 h of fertilization. A similar trend continued until 24-26 h after fertilization; the proportion of larvae attaining veliger stage by 24-26 h also decreased with increasing pC[O.sub.2]. The shell length of T. cornutus veligers decreased gradually as seawater pC[O.sub.2] increased, but markedly decreased in seawater under nearly unsaturated and unsaturated conditions (≤ 1.04) of the aragonite saturation state ([Ω.sub.aragonite]). The results indicate that increased pC[O.sub.2] seawater has a progressive and acute effect on embryonic and larval T. cornutus, and imply that the extended early developmental period and/or the downsized larval shell produced by ocean acidification will have a negative impact on survival, settlement and recruitment well into the future., Introduction Since the Industrial Revolution (1760-1840), the increase in anthropogenic carbon dioxide (C[O.sub.2]) emissions from fossil-fuel burning has rapidly raised the C[O.sub.2] concentration in the atmosphere. At the same time, [...]