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Tumor suppressor genes play critical roles in normal tissue homeostasis, and their dysregulation underlies human diseases including cancer. Besides human genetics, model organisms such as Drosophila have been instrumental in discovering tumor suppressor pathways that were subsequently shown to be highly relevant in human cancer. Here we show that hyperplastic disc (Hyd), one of the first tumor suppressors isolated genetically in Drosophila and encoding an E3 ubiquitin ligase with hitherto unknown substrates, and Lines (Lin), best known for its role in embryonic segmentation, define an obligatory tumor suppressor protein complex (Hyd-Lin) that targets the zinc finger-containing oncoprotein Bowl for ubiquitin-mediated degradation, with Lin functioning as a substrate adaptor to recruit Bowl to Hyd for ubiquitination. Interestingly, the activity of the Hyd-Lin complex is directly inhibited by a micropeptide encoded by another zinc finger gene, drumstick (drm), which functions as a pseudosubstrate by displacing Bowl from the Hyd-Lin complex, thus stabilizing Bowl. We further identify the epigenetic regulator Polycomb repressive complex1 (PRC1) as a critical upstream regulator of the Hyd-Lin-Bowl pathway by directly repressing the transcription of the micropeptide drm Consistent with these molecular studies, we show that genetic inactivation of Hyd, Lin, or PRC1 resulted in Bowl-dependent hyperplastic tissue overgrowth in vivo. We also provide evidence that the mammalian homologs of Hyd (UBR5, known to be recurrently dysregulated in various human cancers), Lin (LINS1), and Bowl (OSR1/2) constitute an analogous protein degradation pathway in human cells, and that OSR2 promotes prostate cancer tumorigenesis. Altogether, these findings define a previously unrecognized tumor suppressor pathway that links epigenetic program to regulated protein degradation in tissue growth control and tumorigenesis.

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LINS1 is the human homolog of the Drosophila segment polarity gene that encodes an essential regulator of the wingless/Wnt signaling. By 2011, only seven pedigrees (16 patients) with eight causative variants in LINS1 gene have been reported. These cases mainly presented with infancy-/child-onset neurodevelopmental disorders, facial dysmorphia, and other clinical features, and a wide spectrum of clinically distinct phenotypes were also manifested. In our study, two brothers in a family were admitted and diagnosed with child-onset movement disorders, slight intellectual disability, psychological symptoms, eye problems, urinary and bowel dysfunction, mitral value prolapse, and Q-T prolongation. By exome sequencing, we identified a nonsense homozygous pathogenic variant (LINS1: c.274C > T (p.Q92X)), which had been reported in a case diagnosed with intellectual disability and psychiatric disorders (such as schizophrenia and anxiety). Compared with this case, the clinical features of our cases were distinct. In particular, our cases displayed unusual features of heart and blood system. Furthermore, the genotype-phenotype relationship analysis suggested that distinct phenotypes presented in cases carrying variants in different domains of the LINS1 gene. In conclusions, our findings suggest the high clinical variations in the LINS1 variants-related disorders. Moreover, the Q92X might be a recurrent variant in Hans of Southern China.

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Excessive levels of dopamine in the synaptic cleft, induced by cocaine for example, activates dopaminergic receptors, mainly D1R, D2R, and D3R subtypes, contributing to neurotoxic effects. New synthetic 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine derivatives (the LINS01 compounds), designed as histaminergic receptor (H3R) ligands, are also dopaminergic receptor ligands, mainly D2R and D3R. This study aims to evaluate the neurotoxicity of these new synthetic LINS01 compounds (LINS01003, LINS01004, LINS01011, and LINS01018), as well as to investigate their protective potential on a cocaine model of dopamine-induced neurotoxicity using SH-SY5Y cell line culture. Neurotoxicity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and automated cell counting with fluorescent dyes (acridyl orange and propidium iodide) assays. Concentration-response curves (CRCs) were performed for all LINS compounds and cocaine using MTT assay. The results show that LINS series did not decrease cell viability after 48h of exposure-except for 100 µM LINS01018, which was discontinued from the study. Likewise, MTT, LDH, and fluorescent dyes staining showed no difference is cell viability for LINS compounds at 10 µM. When incubated with 2.5 mM cocaine (lethal concentration 50) for 48h, 10 µM of each LINS compound, metoclopramide (D2R antagonist) and haloperidol (D2R/D3R antagonist), ameliorated cocaine-induced neurotoxicity. However, only metoclopramide, haloperidol, and LINS01011 compound significantly decreased LDH released in the culture medium, suggesting that this new synthetic compound presents a more robust effect. This preliminary in vitro neurotoxicity study suggests that LINS01 compounds are not neurotoxic, and that they play a promising role in preventing cocaine-induced neurotoxicity.

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BACKGROUND: LINS1 encodes the lines homolog 1 protein that contains the Drosophila lines homologous domain. LINS1 mutations cause a rare recessive form of intellectual disability. So far, eight LINS1 mutations were reported in the literature. METHODS: We conducted a whole-genome sequencing analysis for a family with two sisters diagnosed with moderate intellectual disability, schizophrenia, and anxiety. RESULTS: We identified a novel homozygous nonsense mutation in the LINS1 in these two sisters. The mutation was a C-to-T substitution at the cDNA nucleotide position 274 that changed the amino acid glutamine at the codon 92 to stop codon (Gln92X). The mutation was transmitted from their unrelated parents, who were heterozygous carriers. CONCLUSIONS: We identified the first case of LINS1-associated neurodevelopmental disorder in Taiwan. Our findings suggest that besides intellectual disability, psychiatric diagnoses such as schizophrenia and anxiety disorder may also be part of clinical phenotypes of LINS1 mutations.

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Objective@#To explore the genetic basis of a child with idiopathic mental retardation.@*Methods@#Clinical data and peripheral blood sample of the child were collected. Genomic DNA was extracted and subjected to copy number analysis using single nucleotide polymrophism array comparative genome hybridization (SNP-aCGH) and targeted capture and next generation sequencing (NGS).@*Results@#No microdeletion/microduplication were detected by SNP-aCGH. NGS has detected homozygous c. 722delA(p.Asp241fs) variant of the LISN1 gene, which is known to underlie autosomal recessive mental retardation - 27 (MRT 27). Both parents are carriers of the variant, conforming to the autosomal recessive inheritance.@*Conclusion@#A novel pathogenic variant of the LINS1 gene has been identified, which probably underlies the MRT 27 in the patient.

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Worster-Drought syndrome is a congenital, pseudobulbar paresis. There is no identified molecular etiology despite familial cases reported. The authors report a boy who was diagnosed with Worster-Drought syndrome due to longstanding drooling, dysphagia, and impaired tongue movement. Magnetic resonance imaging of the brain was unrevealing. At 14 years old, he remains aphonic with normal facial and extraocular movements. Nonsense mutations in the LINS gene, p.Glu366X and p.Lys393X, were found. Results from neuropsychological testing at 14 years old were consistent with a diagnosis of intellectual disability and revealed nonverbal reasoning skills at a 5-year-old level with relative sparing of his receptive vocabulary and visual attention. Compared to prior testing at 9 years old, his receptive language improved from a 6-year-old to an 8.5-year-old level. The authors report LINS mutations associated with Worster-Drought syndrome. This highlights that despite severe and persistent aphonia, receptive language improvements can be observed within the context of intellectual disability.

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Newer sequencing technologies decipher molecular variations and increase the knowledge of pathogenesis of complex diseases like intellectual disability (ID), affecting 2-3% of the population. We report a novel family with a missense mutation in LINS1 as a cause for non-syndromic ID. Clinical exome sequencing for ID related genes carried out for a male with dysmorphism, mutism, and cognitive delay was uninformative. Subsequently, "pathogenic" and "likely pathogenic" variants associated with other inherited disorders were searched for as secondary findings. Further, PCR-RFLP carried out in other family members confirmed the result. A novel missense variant (c.937G>A) in exon 5 of LINS1 was detected in the proband. His affected elder brother was homozygous and the parents were heterozygous respectively, for the mutation. No mutation was observed in his unaffected sister. Mutations in LINS1 were suspected in this non-syndromic ID case with mutism. LINS1 alterations affect ELAV1 expression and result in reduction in the commissural axonal growth, thus affecting peripheral and central neuronal function. LINS1 acts in association with ß-catenin to influence WNT1 signaling. It is hypothesized that mutations in LINS1 may alter HuR expression during neural differentiation, leading to ID in humans. © 2017 Wiley Periodicals, Inc.

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Resumo Além do envolvimento com o futebol, outra característica típica da crônica de José Lins do Rego foi o diálogo (ou debates) com o círculo intelectual no qual estava inserido. As influências de Gilberto Freyre e Mário Filho foram as mais sensíveis, mas não foram poucos os seus interlocutores. Desta forma, perspectiva-se compreender o posicionamento de José Lins do Rego em suas crônicas esportivas, sem perder de vista esta interdependência estabelecida pela intelectualidade brasileira. Em caráter conclusivo, constatou-se que as crônicas de José Lins, permeadas pela racionalidade e pela paixão, exerceram funções múltiplas em se tratando do convívio com a intelectualidade brasileira.(AU)

Abstract Two major aspects of Jose Lins do Rego´s chronicles were the reference to soccer and the establishment of a dialogue (or discussion) with his intellectual circle. The influence of Gilberto Freyre and Mário Filho were the most prominent ones, but Rego had many other dialogic counterparts. Thus, this paper aims to understand José Lins do Rego´s stand in his sports chronicles at the same time it sheds light on the exchange of ideas within the Brazilian intelligentsia. Ultimately, we conclude that José Lins´ chronicles, full of rationality and passion, have played multiple roles when related to the Brazilian intellectual production.

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Confusion about strain classification and nomenclature permeates modern microbiology. Although taxonomists have traditionally acted as gatekeepers of order, the numbers of, and speed at which, new strains are identified has outpaced the opportunity for professional classification for many lineages. Furthermore, the growth of bioinformatics and database-fueled investigations have placed metadata curation in the hands of researchers with little taxonomic experience. Here I describe practical challenges facing modern microbial taxonomy, provide an overview of complexities of classification for environmentally ubiquitous taxa like Pseudomonas syringae, and emphasize that classification can be independent of nomenclature. A move toward implementation of relational classification schemes based on inherent properties of whole genomes could provide sorely needed continuity in how strains are referenced across manuscripts and data sets.

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Chromosomal microarray analysis is now commonly used in clinical practice to identify copy number variants (CNVs) in the human genome. We report our experience with the use of the 105 K and 180K oligonucleotide microarrays in 215 consecutive patients referred with either autism or autism spectrum disorders (ASD) or developmental delay/learning disability for genetic services at the University of Kansas Medical Center during the past 4 years (2009-2012). Of the 215 patients [140 males and 75 females (male/female ratio=1.87); 65 with ASD and 150 with learning disability], abnormal microarray results were seen in 45 individuals (21%) with a total of 49 CNVs. Of these findings, 32 represented a known diagnostic CNV contributing to the clinical presentation and 17 represented non-diagnostic CNVs (variants of unknown significance). Thirteen patients with ASD had a total of 14 CNVs, 6 CNVs recognized as diagnostic and 8 as non-diagnostic. The most common chromosome involved in the ASD group was chromosome 15. For those with a learning disability, 32 patients had a total of 35 CNVs. Twenty-six of the 35 CNVs were classified as a known diagnostic CNV, usually a deletion (n=20). Nine CNVs were classified as an unknown non-diagnostic CNV, usually a duplication (n=8). For the learning disability subgroup, chromosomes 2 and 22 were most involved. Thirteen out of 65 patients (20%) with ASD had a CNV compared with 32 out of 150 patients (21%) with a learning disability. The frequency of chromosomal microarray abnormalities compared by subject group or gender was not statistically different. A higher percentage of individuals with a learning disability had clinical findings of seizures, dysmorphic features and microcephaly, but not statistically significant. While both groups contained more males than females, a significantly higher percentage of males were present in the ASD group.

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Objective To explore the regularity of changes of plasma endothelin (ET), throm-boxame B2(TXB2) and 6-keto-prostaglandin F1α(6-keto-PGF1α) and restenosis after percutaneous transluminal angioplasty (PTCA) in patients with coronary heart disease. Methods Radioimmunoas-say was applied to measuring plasma levels of ET, TXB2and 6-keto-PGF1αat 0,30 min, 1 day and 3 days after PTCA in 41 patients with coronary heart disease. Results The level of ET in the patients with coronary heart disease was significantly decreased in 30 minutes after PTCA (P＜0.05), but no significant difference was observed in 1 day and 3 days after PTCA (P>0.05). The level of plasma TXB2has no statistical difference after PTCA in 30minutes, 1 day and 3 days (P>0.05). The level of 6-keto-prostaglandin F1α(6-keto-PGF1α) of the patients with coronary heart disease was significantly declined in 30 minutes after PTCA (P<0.05) ,but no significant difference was observed in 1 day and 3 days after PTCA (P>0.05). Conclusion PTCA may lead to fluctuation of plasma levels of ET, TXB2and 6-keto-PGF1αThe clarification of changing regularity of these vasoactive substances contrib-utes to prevention of acute artery occlusion or restenosis after PTCA.