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1.
Science ; 370(6512): 34-35, 2020 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-33004501
2.
Curr Opin Ophthalmol ; 31(6): 532-537, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33009086

RESUMEN

PURPOSE OF REVIEW: This article summarizes the systemic and ocular manifestations of Blau syndrome, its genetic basis, and reviews recently published literature. RECENT FINDINGS: A large multicenter prospective case series is underway, with 3-year preliminary results indicating the prevalence of uveitis, clinical characteristics and early data on its visual prognosis. Case reports have demonstrated the successful use of newer biologic agents. SUMMARY: Blau syndrome is an exceedingly rare autoinflammatory disorder with skin, joint and eye manifestations. It is caused by autosomal dominant mutations of the NOD2 protein. Eye involvement is typically a chronic bilateral granulomatous iridocyclitis, often with multifocal choroiditis in the posterior segment. Treatment starts with topical and systemic steroids and often requires antimetabolites or biologic agents.


Asunto(s)
Artritis , Sinovitis , Uveítis , Artritis/genética , Humanos , Coroiditis Multifocal , Mutación , Proteína Adaptadora de Señalización NOD2/genética , Sinovitis/genética , Uveítis/genética
3.
Drugs Today (Barc) ; 56(9): 561-571, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33025950

RESUMEN

Avapritinib is a tyrosine kinase inhibitor (TKI) that has recently received Food and Drug Administration (FDA) approval for the treatment of metastatic or unresectable gastrointestinal stromal tumors harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation. Mutations in the activation loop of PDGFRA or KIT confer resistance to conventional TKIs due to structural changes in the receptor. Avapritinib was developed to selectively target these mutations, thereby offering a new treatment option for patients in whom imatinib, sunitinib, and regorafenib have failed. This review covers the basic science and preclinical studies that guided avapritinib's development, in addition to the data currently available from early clinical studies as well as those later-stage trials that led to its approval.


Asunto(s)
Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirroles/uso terapéutico , Triazinas/uso terapéutico , Ensayos Clínicos como Asunto , Tumores del Estroma Gastrointestinal/genética , Humanos , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Estados Unidos
4.
Nat Commun ; 11(1): 4974, 2020 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-33009381

RESUMEN

Generation of bispecific antibodies (bsAbs) requires a combination of compatible binders in formats that support desired functionalities. Here, we report that bsAb-matrices can be generated by Format Chain Exchange (FORCE), enabling screening of combinatorial binder/format spaces. Input molecules for generation of bi/multi-valent bsAbs are monospecific entities similar to knob-into-hole half-antibodies, yet with complementary CH3-interface-modulated and affinity-tagged dummy-chains. These contain mutations that lead to limited interface repulsions without compromising expression or biophysical properties of educts. Mild reduction of combinations of educts triggers spontaneous chain-exchange reactions driven by partially flawed CH3-educt interfaces resolving to perfect complementarity. This generates large bsAb matrices harboring different binders in multiple formats. Benign biophysical properties and good expression yields of educts, combined with simplicity of purification enables process automation. Examples that demonstrate the relevance of screening binder/format combinations are provided as a matrix of bsAbs that simultaneously bind Her1/Her2 and DR5 without encountering binder or format-inflicted interferences.


Asunto(s)
Anticuerpos Biespecíficos/biosíntesis , Ensayos Analíticos de Alto Rendimiento , Anticuerpos Biespecíficos/aislamiento & purificación , Automatización , Células HEK293 , Humanos , Mutación/genética , Multimerización de Proteína
5.
Rev Med Liege ; 75(10): 639-643, 2020 Oct.
Artículo en Francés | MEDLINE | ID: mdl-33030838

RESUMEN

The Pierre-Marie Sainton syndrome or cleidocranial dysplasia is a rare congenital malformation due to a mutation in the RUNX2 gene, causing disruption in osteoblastic maturation, which results in various skeletal, dental and endocrine abnormalities. These various disorders may also have otorhinolaryngology and psychological consequences. We report the case of a patient with this rare birth defect.


Asunto(s)
Displasia Cleidocraneal , Displasia Cleidocraneal/diagnóstico , Displasia Cleidocraneal/genética , Humanos , Mutación
6.
Nat Commun ; 11(1): 4917, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-33004802

RESUMEN

Maternal mRNA clearance is an essential process that occurs during maternal-to-zygotic transition (MZT). However, the dynamics, functional importance, and pathological relevance of maternal mRNA decay in human preimplantation embryos have not yet been analyzed. Here we report the zygotic genome activation (ZGA)-dependent and -independent maternal mRNA clearance processes during human MZT and demonstrate that subgroups of human maternal transcripts are sequentially removed by maternal (M)- and zygotic (Z)-decay pathways before and after ZGA. Key factors regulating M-decay and Z-decay pathways in mouse have similar expression pattern during human MZT, suggesting that YAP1-TEAD4 transcription activators, TUT4/7-mediated mRNA 3'-oligouridylation, and BTG4/CCR4-NOT-induced mRNA deadenylation may also be involved in the regulation of human maternal mRNA stability. Decreased expression of these factors and abnormal accumulation of maternal transcripts are observed in the development-arrested embryos of patients who seek assisted reproduction. Defects of M-decay and Z-decay are detected with high incidence in embryos that are arrested at the zygote and 8-cell stages, respectively. In addition, M-decay is not found to be affected by maternal TUBB8 mutations, although these mutations cause meiotic cell division defects and zygotic arrest, which indicates that mRNA decay is regulated independent of meiotic spindle assembly. Considering the correlations between maternal mRNA decay defects and early developmental arrest of in vitro fertilized human embryos, M-decay and Z-decay pathway activities may contribute to the developmental potential of human preimplantation embryos.


Asunto(s)
Blastocisto/metabolismo , Desarrollo Embrionario/fisiología , Estabilidad del ARN/fisiología , ARN Mensajero Almacenado/metabolismo , Factores de Transcripción/metabolismo , Adulto , Animales , Técnicas de Cultivo de Embriones , Femenino , Fertilización In Vitro/métodos , Regulación del Desarrollo de la Expresión Génica , Humanos , Masculino , Meiosis/genética , Ratones , Mutación , Oocitos/metabolismo , Cultivo Primario de Células , RNA-Seq , Tubulina (Proteína)/genética , Cigoto/metabolismo
7.
Nat Commun ; 11(1): 4923, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-33004824

RESUMEN

A goal of biology is to predict how mutations combine to alter phenotypes, fitness and disease. It is often assumed that mutations combine additively or with interactions that can be predicted. Here, we show using simulations that, even for the simple example of the lambda phage transcription factor CI repressing a gene, this assumption is incorrect and that perfect measurements of the effects of mutations on a trait and mechanistic understanding can be insufficient to predict what happens when two mutations are combined. This apparent paradox arises because mutations can have different biophysical effects to cause the same change in a phenotype and the outcome in a double mutant depends upon what these hidden biophysical changes actually are. Pleiotropy and non-monotonic functions further confound prediction of how mutations interact. Accurate prediction of phenotypes and disease will sometimes not be possible unless these biophysical ambiguities can be resolved using additional measurements.


Asunto(s)
Fenómenos Biofísicos/genética , Estudios de Asociación Genética/métodos , Modelos Genéticos , Termodinámica , Bacteriófago lambda/genética , Regulación Viral de la Expresión Génica , Mutación , Fenotipo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteínas Reguladoras y Accesorias Virales/genética , Proteínas Reguladoras y Accesorias Virales/metabolismo
8.
Nat Commun ; 11(1): 5065, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-33033237

RESUMEN

The type VI protein secretion system (T6SS) is a powerful needle-like machinery found in Gram-negative bacteria that can penetrate the cytosol of receiving cells in milliseconds by physical force. Anchored by its membrane-spanning complex (MC) and a baseplate (BP), the T6SS sheath-tube is assembled in a stepwise process primed by TssA and terminated by TagA. However, the molecular details of its assembly remain elusive. Here, we systematically examined the initiation and termination of contractile and non-contractile T6SS sheaths in MC-BP, tssA and tagA mutants by fluorescence microscopy. We observe long pole-to-pole sheath-tube structures in the non-contractile MC-BP defective mutants but not in the Hcp tube or VgrG spike mutants. Combining overexpression and genetic mutation data, we demonstrate complex effects of TssM, TssA and TagA interactions on T6SS sheath-tube dynamics. We also report promiscuous interactions of TagA with multiple T6SS components, similar to TssA. Our results demonstrate that priming of the T6SS sheath-tube assembly is not dependent on TssA, nor is the assembly termination dependent on the distal end TssA-TagA interaction, and highlight the tripartite control of TssA-TssM-TagA on sheath-tube initiation and termination.


Asunto(s)
Proteínas Bacterianas/metabolismo , Sistemas de Secreción Tipo VI/metabolismo , Vibrio cholerae/metabolismo , Proteínas Bacterianas/química , Membrana Celular/metabolismo , Escherichia coli/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Proteínas de la Membrana/metabolismo , Viabilidad Microbiana , Modelos Biológicos , Mutación/genética , Unión Proteica , Dominios Proteicos
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1445-1450, 2020 Oct.
Artículo en Chino | MEDLINE | ID: mdl-33067935

RESUMEN

OBJECTIVE: To study the molecular characteristics and clinical significance of elderly patients with acute myeloid leukemia (AML). METHODS: Dideoxy sequencing was used to analyze the mutation spectrum and clinical significance of 51 hematopathy-related genes in 52 patients with newly diagnosed elderly AML. The efficacy of 39 patients receiving DCAG chemotherapy was also analyzed. RESULTS: The mutational frequency was high in elderly AML patients (98.1%, 51/52), and there were some coexistence or mutual exclusion between different mutations. Both the number of mutations and the incidence of epigenetic mutations DNMT3A, TET2 (P<0.01), as well as FLT3-ITD (P<0.05) increased with age. c-KIT mutations were most common in favorable-risk AML (P<0.01), while NPM1 and DNMT3A were common in intermediate-risk AML (P<0.05), especially in AML with normal karyotype. The complete remission rate of elderly AML patients receiving DCAG chemotherapy was 71.8% (28/39). CONCLUSION: Elderly AML patients have specific molecular characteristics, and the incidence of methylation-related gene mutations is very high, showing a certain significance for clinical diagnosis and treatment.


Asunto(s)
Leucemia Mieloide Aguda , Proteínas Nucleares , Anciano , Humanos , Leucemia Mieloide Aguda/genética , Mutación , Tasa de Mutación , Proteínas Nucleares/genética , Pronóstico
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1480-1485, 2020 Oct.
Artículo en Chino | MEDLINE | ID: mdl-33067941

RESUMEN

OBJECTIVE: To investigate the correlation of NK cell receptor-interacting serine/threonine kinase 1(RIPK1) activity and expression with prognosis of acute myeloid leukemia (AML) patients with FLT3-ITD mutation. METHODS: A total of 132 AML patients with FLT3-ITD mutation and 136 AML patients with FLT3-WT were selected. Clinical data and the number, length and rearrangement ratio of FLT3-ITD mutations were collected. The ratio of CD4+ T cells, regulatory T cells(Tregs), CD8+ T cells, B cells, natural killer cells(NK cells) and macrophage in peripheral blood(PB) were analyzed by flow cytometry. Correlation of NK cell ratio with FLT3-ITD mutation number, length and rearrangement ratio was analyzed by Pearson correlation analysis. Western blot and RT-qPCR were used to detect RIPK1 protein and mRNA levels in NK cells, respectively. Plasma RIPK activity was detected by ELISA, and Pearson corre-lation analysis was performed for the correlation of RIPK with FLT3-ITD mutation number, length and rearrangement ratio. Kaplan-Meier curve was used to analyze the survival rate of AML patients with FLT3-ITD mutation. RESULTS: Compared with AML patients with FLT3-WT, the white blood cell count in patients with FLT3-ITD mutation significantly increased, PB and BM blasts significantly decreased. There was no significant change in PB CD3+ T cells, Tregs, CD8+ T cells, B cells, M1 and M2 type macrophage of AML patients with FLT3-WT and FLT3-ITD mutation;Compared with AML patients with FLT3-WT, CD4+ T cells significantly decreased, NK cells significantly increased in AML patients wtih FLT3-ITD mutation. NK cells ratio in AML patients with FLT3-ITD mutation significantly positively correlated with the number of FLT3-ITD mutations and rearrangement bases. Plasma RIPK1 activity, RIPK1 protein and mRNA levels in NK cells of AML patients with FLT3-ITD were significantly lower than those of AML patients with FLT3-WT, and negatively correlated with the number of FLT3-ITD mutations, the length of rearranged bases (≥52 bp) and the ratio of rearranged bases. The survival rate of AML patients with FLT3-ITD mutation in low RIPK1 activity after Rydapt treatment was significantly higher than that in high RIPK1 activity. CONCLUSION: The prognosis of AML patients with FLT3-ITD mutation closely relates with plasma RIPK1 activity and RIPK1 expression in NK cells.


Asunto(s)
Linfocitos T CD8-positivos , Leucemia Mieloide Aguda , Humanos , Células Asesinas Naturales , Leucemia Mieloide Aguda/genética , Mutación , Pronóstico , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Tirosina Quinasa 3 Similar a fms/genética
11.
Nat Commun ; 11(1): 4977, 2020 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-33020483

RESUMEN

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.


Asunto(s)
Interleucina-6/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Transducción de Señal , Médula Ósea/patología , Mama/citología , Neoplasias de la Mama/patología , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Receptor gp130 de Citocinas/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Humanos , Interleucina-6/genética , Mutación , Metástasis de la Neoplasia/genética , Receptores de Interleucina-6/deficiencia , Receptores de Interleucina-6/metabolismo , Células del Estroma/metabolismo , Microambiente Tumoral
12.
Nat Commun ; 11(1): 4995, 2020 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-33020491

RESUMEN

Endometrioid ovarian carcinoma (EnOC) demonstrates substantial clinical and molecular heterogeneity. Here, we report whole exome sequencing of 112 EnOC cases following rigorous pathological assessment. We detect a high frequency of mutation in CTNNB1 (43%), PIK3CA (43%), ARID1A (36%), PTEN (29%), KRAS (26%), TP53 (26%) and SOX8 (19%), a recurrently-mutated gene previously unreported in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy is constructed, identifying clinically distinct EnOC subtypes: cases with TP53 mutation demonstrate greater genomic complexity, are commonly FIGO stage III/IV at diagnosis (48%), are frequently incompletely debulked (44%) and demonstrate inferior survival; conversely, cases with CTNNB1 mutation, which is mutually exclusive with TP53 mutation, demonstrate low genomic complexity and excellent clinical outcome, and are predominantly stage I/II at diagnosis (89%) and completely resected (87%). Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.


Asunto(s)
Carcinoma Endometrioide/genética , Neoplasias Ováricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/mortalidad , Carcinoma Endometrioide/patología , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Inestabilidad de Microsatélites , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Pronóstico , Transducción de Señal , Secuenciación del Exoma Completo
13.
Medicine (Baltimore) ; 99(41): e22606, 2020 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-33031315

RESUMEN

To determine effects of cryptococcal meningitis (CM) on human immunodeficiency virus (HIV)-1C cerebrospinal fluid (CSF) viral escape, CSF/plasma viral discordance, and drug resistance mutation (DRM) discordance between CSF and plasma compartments, we compared CSF and plasma viral load (VL) and DRMs in individuals with HIV-associated CM in Botswana.This cross-sectional study utilized 45 paired CSF/plasma samples from participants in a CM treatment trial (2014-2016). HIV-1 VL was determined and HIV-1 protease and reverse transcriptase genotyping performed. DRMs were determined using the Stanford HIV database. CSF viral escape was defined as HIV-1 ribonucleic acid ≥0.5 log10 higher in CSF than plasma and VL discordance as CSF VL > plasma VL.HIV-1 VL was successfully measured in 39/45 pairs, with insufficient sample volume in 6; 34/39 (87.2%) participants had detectable HIV-1 in plasma and CSF, median 5.1 (interquartile range: 4.7-5.7) and 4.6 (interquartile range:3.7-4.9) log10 copies/mL, respectively (P≤.001). CSF viral escape was present in 1/34 (2.9%) and VL discordance in 6/34 (17.6%). Discordance was not associated with CD4 count, antiretroviral status, fungal burden, CSF lymphocyte percentage nor mental status. Twenty-six of 45 (57.8%) CSF/plasma pairs were successfully sequenced. HIV-1 DRM discordance was found in 3/26 (11.5%); 1 had I84IT and another had M46MI in CSF only. The third had K101E in plasma and V106 M in CSF.Our findings suggest that HIV-1 escape and DRM discordance may occur at lower rates in participants with advanced HIV-disease and CM compared to those with HIV associated neurocognitive impairment.


Asunto(s)
Farmacorresistencia Viral/genética , Infecciones por VIH/sangre , Infecciones por VIH/líquido cefalorraquídeo , VIH-1/genética , Meningitis Criptocócica/virología , Adulto , Estudios Transversales , Femenino , Genes pol , Infecciones por VIH/virología , Humanos , Masculino , Meningitis Criptocócica/sangre , Meningitis Criptocócica/líquido cefalorraquídeo , Mutación , Estudios Retrospectivos , Carga Viral
14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1757-1761, 2020 Oct.
Artículo en Chino | MEDLINE | ID: mdl-33067986

RESUMEN

OBJECTIVE: To explore the clinical significance of G6PD gene mutation detection in female heterozygote with G6PD deficiency. METHODS: G6PD activity and fourteen common G6PD gene mutations in female blood samples were detected by biochemical phenotype detection and PCR-reverse dot blotting, respectively. Unidentified genotype of G6PD positive samples was further ascertained by direct DNA sequencing. The results from two methods were compared and analyzed. RESULTS: A total of 493 unrelated females were enrolled, and the G6PD activity and G6PD mutations was detected. Among them, 473 females were found to be normal in G6PD activity and 20 females with G6PD deficiency, and the detection rate by G6PD activity method was 4.06%. In all enrolled females, G6PD gene mutations, including the mutation of c.1311 C>T, were identified in 130 females, and the detection rate was 26.3%. Detection rate of the mutations that can lead to G6PD deficiency was 8.11%. The detection rates between the two methods were significantly different (P<0.01). The misdiagnosis rate of the G6PD activity detection reached 49. 94% for the female heterozygotes. Eight G6PD mutations and 13 mutation patterns were identified in the research, and most of mutation patterns were single nucleotide missense mutation. In addition to c.1311C>T mutation, the most common mutations were c.1376G>T, c.1388G>A and c.95 A>G. G6PD mutations were identified in 19 of 20 females with G6PD deficiency, and were also detected in 21 of 473 females with normal G6PD activity, of which the rate of heterozygous mutation was 90.88%. CONCLUSION: The phenotype detection based on G6PD enzyme activity alone is not sufficient for the diagnosis of female heterozygotes. The detection of G6PD mutations that covers the common mutations in specified region can effectively identify the female heterozygotes with normal G6PD activity.


Asunto(s)
Deficiencia de Glucosafosfato Deshidrogenasa , Femenino , Genotipo , Glucosafosfato Deshidrogenasa/genética , Deficiencia de Glucosafosfato Deshidrogenasa/genética , Heterocigoto , Humanos , Mutación
15.
Nat Commun ; 11(1): 4932, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-33004838

RESUMEN

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.


Asunto(s)
Predisposición Genética a la Enfermedad , Trastornos del Neurodesarrollo/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factor de Unión a CCCTC/genética , Estudios de Casos y Controles , Estudios de Cohortes , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Femenino , Estudios de Asociación Genética , Ribonucleoproteína Heterogénea-Nuclear Grupo U/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Canal de Potasio KCNQ3/genética , Masculino , Mutación , Proteínas de Unión al ARN/genética , Proteínas Represoras/genética , Factores de Transcripción/genética
16.
Nat Commun ; 11(1): 4627, 2020 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-33009389

RESUMEN

Animals have evolved responses to low oxygen conditions to ensure their survival. Here, we have identified the C. elegans zinc finger transcription factor PQM-1 as a regulator of the hypoxic stress response. PQM-1 is required for the longevity of insulin signaling mutants, but surprisingly, loss of PQM-1 increases survival under hypoxic conditions. PQM-1 functions as a metabolic regulator by controlling oxygen consumption rates, suppressing hypoxic glycogen levels, and inhibiting the expression of the sorbitol dehydrogenase-1 SODH-1, a crucial sugar metabolism enzyme. PQM-1 promotes hypoxic fat metabolism by maintaining the expression of the stearoyl-CoA desaturase FAT-7, an oxygen consuming, rate-limiting enzyme in fatty acid biosynthesis. PQM-1 activity positively regulates fat transport to developing oocytes through vitellogenins under hypoxic conditions, thereby increasing survival rates of arrested progeny during hypoxia. Thus, while pqm-1 mutants increase survival of mothers, ultimately this loss is detrimental to progeny survival. Our data support a model in which PQM-1 controls a trade-off between lipid metabolic activity in the mother and her progeny to promote the survival of the species under hypoxic conditions.


Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Hipoxia/metabolismo , Metabolismo de los Lípidos , Transactivadores/metabolismo , Animales , Caenorhabditis elegans/embriología , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Embrión de Mamíferos/metabolismo , Regulación de la Expresión Génica , Glucógeno/metabolismo , Insulina/metabolismo , Larva/metabolismo , Mutación/genética , Consumo de Oxígeno , Transducción de Señal , Estrés Fisiológico , Análisis de Supervivencia , Transactivadores/genética , Transcripción Genética , Vitelogeninas/metabolismo
17.
Nat Commun ; 11(1): 4941, 2020 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-33009412

RESUMEN

Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among these, small molecules including the drug-like compound PF-06446846 (PF846) selectively inhibit the synthesis of specific proteins, by stalling translation elongation. These molecules also inhibit translation termination by an unknown mechanism. Using cryo-electron microscopy (cryo-EM) and biochemical approaches, we show that PF846 inhibits translation termination by arresting the nascent chain (NC) in the ribosome exit tunnel. The arrested NC adopts a compact α-helical conformation that induces 28 S rRNA nucleotide rearrangements that suppress the peptidyl transferase center (PTC) catalytic activity stimulated by eukaryotic release factor 1 (eRF1). These data support a mechanism of action for a small molecule targeting translation that suppresses peptidyl-tRNA hydrolysis promoted by eRF1, revealing principles of eukaryotic translation termination and laying the foundation for new therapeutic strategies.


Asunto(s)
Terminación de la Cadena Péptídica Traduccional , Preparaciones Farmacéuticas/metabolismo , Línea Celular , Humanos , Modelos Moleculares , Mutación/genética , Conformación Proteica , ARN Ribosómico/metabolismo , Ribosomas/metabolismo , Ribosomas/ultraestructura
18.
Nat Commun ; 11(1): 5080, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-33033258

RESUMEN

Natural transformation is the process by which bacteria take up genetic material from their environment and integrate it into their genome by homologous recombination. It represents one mode of horizontal gene transfer and contributes to the spread of traits like antibiotic resistance. In Vibrio cholerae, a type IVa pilus (T4aP) is thought to facilitate natural transformation by extending from the cell surface, binding to exogenous DNA, and retracting to thread this DNA through the outer membrane secretin, PilQ. Here, we use a functional tagged allele of VcPilQ purified from native V. cholerae cells to determine the cryoEM structure of the VcPilQ secretin in amphipol to ~2.7 Å. We use bioinformatics to examine the domain architecture and gene neighborhood of T4aP secretins in Proteobacteria in comparison with VcPilQ. This structure highlights differences in the architecture of the T4aP secretin from the type II and type III secretion system secretins. Based on our cryoEM structure, we design a series of mutants to reversibly regulate VcPilQ gate dynamics. These experiments support the idea of VcPilQ as a potential druggable target and provide insight into the channel that DNA likely traverses to promote the spread of antibiotic resistance via horizontal gene transfer by natural transformation.


Asunto(s)
Sistemas de Secreción Bacterianos/ultraestructura , Microscopía por Crioelectrón , Fimbrias Bacterianas/ultraestructura , Secretina/química , Vibrio cholerae/metabolismo , Vibrio cholerae/ultraestructura , Cisteína/genética , Proteínas de la Membrana/ultraestructura , Modelos Moleculares , Mutación/genética , Filogenia , Dominios Proteicos , Transformación Bacteriana
19.
Artículo en Chino | MEDLINE | ID: mdl-33040498

RESUMEN

Objective:To explore the genetic cause of a Chinese autosomal dominant nonsyndromic hearing loss family and investigate the clinical features and molecular genetic characteristics of this family. Method:Detailed medical history and systematic audiology tests were carried out in the family members, and they were subjected to comprehensive genetic analyses using massively parallel sequencing, which targeted 139 known deafness genes and 6 mitochondrial DNA mutations associated with hearing loss. Result:This family's hearing loss was consistent with autosomal dominant nonsyndromic hearing loss. The affected family members appeared to have developed a high-frequency hearing loss with the onset of twenties. We identified a heterozygous missense mutation, c.418A>G/p. Thr140Ala in the CEACAM16 gene, segregating with the deafness in this family. Conclusion:In this study, we identified a new mutation of CEACAM16 gene, which was the second mutation identified in Chinese hearing loss population. It has enriched the mutation spectrum of this gene.


Asunto(s)
Artrogriposis , Sordera , Moléculas de Adhesión Celular , Sordera/genética , Humanos , Mutación , Linaje
20.
PLoS One ; 15(10): e0237689, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33006981

RESUMEN

Genomes of tens of thousands of SARS-CoV2 isolates have been sequenced across the world and the total number of changes (predominantly single base substitutions) in these isolates exceeds ten thousand. We compared the mutational spectrum in the new SARS-CoV-2 mutation dataset with the previously published mutation spectrum in hypermutated genomes of rubella-another positive single stranded (ss) RNA virus. Each of the rubella virus isolates arose by accumulation of hundreds of mutations during propagation in a single subject, while SARS-CoV-2 mutation spectrum represents a collection events in multiple virus isolates from individuals across the world. We found a clear similarity between the spectra of single base substitutions in rubella and in SARS-CoV-2, with C to U as well as A to G and U to C being the most prominent in plus strand genomic RNA of each virus. Of those, U to C changes universally showed preference for loops versus stems in predicted RNA secondary structure. Similarly, to what was previously reported for rubella virus, C to U changes showed enrichment in the uCn motif, which suggested a subclass of APOBEC cytidine deaminase being a source of these substitutions. We also found enrichment of several other trinucleotide-centered mutation motifs only in SARS-CoV-2-likely indicative of a mutation process characteristic to this virus. Altogether, the results of this analysis suggest that the mutation mechanisms that lead to hypermutation of the rubella vaccine virus in a rare pathological condition may also operate in the background of the SARS-CoV-2 viruses currently propagating in the human population.


Asunto(s)
Betacoronavirus/genética , Genoma Viral , ARN Viral/genética , Virus de la Rubéola/genética , Infecciones por Coronavirus/virología , Citidina Desaminasa/genética , Bases de Datos Genéticas , Evolución Molecular , Humanos , Mutación , Pandemias , Neumonía Viral/virología
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