Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations / 中华耳鼻咽喉头颈外科杂志

Objective: To analyze the phenotypic-genotypic characteristics of hereditary deafness caused by OTOA gene variations. Methods: Family histories, clinical phenotypes and gene variations of six pedigrees were analyzed, which were diagnosed with hearing loss caused by OTOA gene variations at the PLA General Hospital from September 2015 to January 2022. The sequence variations were verified by Sanger sequencing and the copy number variations were validated by multiplex ligation-dependent probe amplification (MLPA) in the family members. Results: The hearing loss phenotype caused by OTOA variations ranged from mild to moderate in the low frequencies, and from moderate to severe in the high frequencies in the probands, which came from six sporadic pedigrees, among which a proband was diagnosed as congenital deafness and five were diagnosed as postlingual deafness. One proband carried homozygous variations and five probands carried compound heterozygous variations in OTOA gene. Nine pathogenic variations (six copy number variations, two deletion variations and one missense variation) and two variations with uncertain significance in OTOA were identified in total, including six copy number variations and five single nucleotide variants, and three of the five single nucleotide variants were firstly reported [c.1265G>T(p.Gly422Val),c.1534delG(p.Ala513Leufs*11) and c.3292C>T(p.Gln1098fs*)]. Conclusions: OTOA gene variations can lead to autosomal recessive nonsyndromic hearing loss. In this study, the hearing loss caused by OTOA defects mostly presents as bilateral, symmetrical, and postlingual, and that of a few presents as congenital. The pathogenic variations of OTOA gene are mainly copy number variations followed by deletion variations and missense variations.

Mutation characteristics of osteosarcoma: a single center study of 64 cases using next-generation sequencing / 中华病理学杂志

Objective: To investigate the distribution and characteristics of gene mutations in osteosarcoma, and to analyze the frequency and types of detectable mutations, and to identify potential targets for individualized treatment of osteosarcoma. Methods: The fresh tissue or paraffin-embedded tissue samples of 64 cases of osteosarcoma that were surgically resected or biopsied and then subject to next generation sequencing, were collected from Beijing Jishuitan Hospital, China from November 2018 to December 2021. The tumor DNA was extracted to detect the somatic and germline mutations using targeted sequencing technology. Results: Among the 64 patients, 41 were males and 23 were females. The patient age ranged from 6 to 65 years with a median age of 17 years, including 36 children (under 18 years old) and 28 adults. There were 52 cases of conventional osteosarcoma, 3 cases of telangiectatic osteosarcoma, 7 cases of secondary osteosarcoma, and 2 cases of parosteosarcoma. The detection rate of gene mutations was overall 84.4% (54/64). There were 324 variations in 180 mutated genes, including 125 genes with copy number variations, 109 single nucleotide variants, 83 insertions or deletions, and 7 gene fusions. The most common mutated genes were TP53, VEGFA, CCND3, ATRX, MYC, RB1, PTEN, GLI1, CDK4 and PTPRD. Among them, TP53 had the highest mutation rate (21/64, 32.8%), single nucleotide variant was the main mutation type (14/23, 60.9%), and 2 cases carried the TP53 germline mutation. VEGFA and CCND3 showed copy number amplification simultaneously in 7 cases. Conclusions: The high-frequency mutation of TP53 suggests that it plays an important role in the pathogenesis and development of osteosarcoma. VEGFA, CCND3 and ATRX are mutated genes in osteosarcoma and worthy of further studies. Combination of pathologic diagnosis and next generation sequencing with clinical practice can guide individualized treatment for patients with refractory, recurrent and metastatic osteosarcoma.

Genetic characterization of varicella-zoster virus in people aged 20 years and under in Yichang City of Hubei Province, 2019-2020 / 中华流行病学杂志

Objective: To analyze the genetic characteristics of varicella-zoster virus (VZV) in people aged 20 years and under in Yichang City of Hubei Province from 2019 to 2020. Methods: Based on the Yichang Health Big Data Platform, we investigated cases 20 and under clinically diagnosed as herpes zoster in three hospitals from March 2019 to September 2020. Collecting vesicle fluid and throat swab samples of the cases and completing questionnaires to obtain basic information. Real-time fluorescent quantitative PCR was used for positive identification of the virus. PCR amplification of VZV's open reading frame (ORF) and sequencing of the products to determine the VZV genotype. Analyze mutations at some specific single nucleotide polymorphism (SNP) sites. Results: Among 46 cases of herpes zoster, the male to female ratio was 1.3∶1 (26∶20) and the age ranged from 7 to 20 years old. Fifteen cases had been vaccinated against varicella, including 13 and 2 cases of 1 and 2 doses, respectively. VZV strains were detected in 34 samples (73.91%), all belonging to Clade 2. Phylogenetic tree analysis of the nucleotide of ORF22 showed, compared with Clade 2 referenced strains, the sequence matching degree of nucleotide for all 34 samples was 99.0% to 100.0%. Conclusion: The main VZV strain causing herpes zoster in people aged 20 years and under in Yichang from 2019 to 2020 was Clade 2.

Research progress on the nucleoside/nucleotide-loaded nanomedicines / 浙江大学学报·医学版

Nucleoside drugs play an essential role in treating major diseases such as tumor and viral infections, and have been widely applied in clinics. However, the effectiveness and application of nucleoside drugs are significantly limited by their intrinsic properties such as low bioavailability, lack of targeting ability, and inability to enter the cells. Nanocarriers can improve the physiological properties of nucleoside drugs by improving drug delivery efficiency and availability, maintaining drug efficacy and system stability, adjusting the binding ability of the carrier and drug molecules, as well as modifying specific molecules to achieve active targeting. Starting from the design strategy of nucleoside drug nanodelivery systems, the design and therapeutic effect of these nanomedicines are described in this review, and the future development directions of nucleoside/nucleotide-loaded nanomedicines are also discussed.

Effect of procalcitonin on lipopolysaccharide-induced expression of nucleotide-binding oligomerization domain-like receptor protein 3 and caspase-1 in human umbilical vein endothelial cells / 中国当代儿科杂志

OBJECTIVES@#To study the effect of procalcitonin (PCT) on lipopolysaccharide (LPS)-induced expression of the pyroptosis-related proteins nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and caspase-1 in human umbilical vein endothelial cells (HUVECs).@*METHODS@#HUVECs were induced by LPS to establish a model of sepsis-induced inflammatory endothelial cell injury. The experiment was divided into two parts. In the first part, HUVECs were randomly divided into four groups: normal control, LPS (1 μg/mL), PCT (10 ng/mL), and LPS+PCT (n=3 each). In the second part, HUVECs were randomly grouped: normal control, LPS, and LPS+PCT of different concentrations (0.1, 1, 10, and 100 ng/mL) (n=3 each). Quantitative real-time PCR and Western blot were used to measure the mRNA and protein expression levels of NLRP3 and caspase-1 in each group.@*RESULTS@#In the first experiment: compared with the normal control group, the PCT, LPS, and LPS+PCT groups had significantly upregulated mRNA and protein expression levels of NLRP3 and caspase-1 (P<0.05); compared with the LPS group, the LPS+PCT group had significantly downregulated mRNA and protein expression levels of NLRP3 and caspase-1 (P<0.05). In the second experiment: compared with those in the LPS group, the mRNA and protein expression levels of NLRP3 and caspase-1 in the LPS+PCT of different concentrations groups were significantly downregulated in a concentration-dependent manner (P<0.05).@*CONCLUSIONS@#LPS can promote the expression of the pyroptosis-related proteins NLRP3 and caspase-1 in HUVECs, while PCT can inhibit the LPS-induced expression of the pyroptosis-related proteins NLRP3 and caspase-1 in HUVECs in a concentration-dependent manner.

Genetic analysis and reproductive intervention of 7 families with gonadal mosaicism for Duchenne muscular dystrophy / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for 7 families with gonadal mosaicism for Duchenne muscular dystrophy (DMD).@*METHODS@#For the 7 families presented at the CITIC Xiangya Reproductive and Genetic Hospital from September 2014 to March 2022, clinical data were collected. Preimplantation genetic testing for monogenic disorders (PGT-M) was carried out for the mother of the proband from family 6. Peripheral venous blood samples of the probands, their mothers and other patients from the families, amniotic fluid samples from families 1 ~ 4 and biopsied cells of embryos cultured in vitro from family 6 were collected for the extraction of genomic DNA. Multiplex ligation-dependent probe amplification (MLPA) was carried out for the DMD gene, and short tandem repeat (STR)/single nucleotide polymorphism (SNP)-based haplotypes were constructed for the probands, other patients, fetuses and embryos.@*RESULTS@#The results of MLPA showed that the probands and the fetuses/probands' brothers in families 1 ~ 4, 5, 7 had carried the same DMD gene variants, whilst the probands' mothers were all normal. The proband in family 6 carried the same DMD gene variant with only 1 embryo (9 in total) cultured in vitro, and the DMD gene of the proband's mother and the fetus obtained through the PGT-M were normal. STR-based haplotype analysis showed that the probands and the fetuses/probands' brothers in families 1 ~ 3 and 5 have inherited the same maternal X chromosome. SNP-based haplotype analysis showed that the proband from family 6 has inherited the same maternal X chromosome with only 1 embryo (9 in total) cultured in vitro. The fetuses in families 1 and 6 (via PGT-M) were both confirmed to be healthy by follow up, whilst the mothers from families 2 and 3 had chosen induced labor.@*CONCLUSION@#Haplotype analysis based on STR/SNP is an effective method for judging gonad mosaicism. Gonad mosaicisms should be suspected for women who have given births to children with DMD gene variants but with a normal peripheral blood genotype. Prenatal diagnosis and reproductive intervention may be adapted to reduce the births of further affected children in such families.

Clinical phenotypes and genetic features of epilepsy children with MBD5 gene variants / 中华儿科杂志

Objective: To summarize the phenotypes of epilepsy in patients with MBD5 gene variants. Methods: A total of 9 epileptic patients, who were treated in the Department of Pediatrics, Peking University First Hospital from July 2016 to September 2021 and detected with MBD5 gene pathogenic variants, were enrolled. The features of clinical manifestations, electroencephalogram (EEG), and neuroimaging were analyzed retrospectively. Results: Among 9 patients, 6 were male and 3 were female. Age at seizure onset ranged from 5 to 89 months. Multiple seizure types were observed, including generalized tonic clonic seizures (GTCS) in 7 patients, myoclonic seizures in 5 patients, focal seizures in 5 patients, atypical absence seizures in 3 patients, atonic seizures in 2 patients, myoclonus absence seizures in 1 patient, epileptic spasms in 1 patient, and tonic seizures in 1 patient. There were 8 patients with multiple seizure types, 2 patients with sensitivity to fever and 5 patients with clustering of seizures. Two patients had a history of status epilepticus. All patients had developmental delay before seizure onset. Nine patients had obvious language delay, and 6 patients had autism-like manifestations. Five patients had slow background activity in EEG. Interictal EEG showed abnormal discharges in 9 patients. Brain magnetic resonance imaging (MRI) was normal in all patients. A total of 9 epileptic patients carried MBD5 gene variants, all of them were de novo variants. There were MBD5 gene overall heterozygous deletion in 1 patient, large fragment deletions including MBD5 gene in 3 patients and single nucleotide variations (c.300C>A/p.C100X, c.1775delA/p.N592Tfs*29, c.1759C>T/p.Q587X, c.150_151del/p.Lys51Asnfs*6, c.113+1G>C) in 5 patients. The age at last follow-up ranged from 2 years and 9 months to 11 years and 11 months. At the last follow-up, 2 patients were seizure-free for more than 11 months to 4 years 6 months, 7 patients still had seizures. Conclusions: The initial seizure onset in patients with MBD5 gene variants usually occurs in infancy. Most patients have multiple seizure types. The seizures may be fever sensitive and clustered. Developmental delays, language impairments, and autistic behaviors are common. MBD5 gene variants include single nucleotide variations and fragment deletions. Epilepsy associated with MBD5 gene variants is usually refractory.

Strategy Optimization and Clinical Analyze of Multiple Nucleotide Polymorphism Analysis in the Chimerism Detection after Allogeneic Hematopoietic Stem Cell Transplantation / 中国实验血液学杂志

AbstractObjective: To investigate the sample selection, result correction and clinical application value of multi nucleotide polymorphism chimerism detection method based on Next-generation sequencing.@*METHODS@#The chimerism samples from November 2018 to June 2020 were collected, and Pearson correlation coefficient (r) was used to analyze the consistency of bone marrow and peripheral blood results detected by MNPseq; according to the different information integrity before transplantation, the calibration model was constructed to analyze the correction value of the micro chimerism results in each model; the clinical results were retrospectively analyzed to verify the reliability and practicability of chimerism results correction and the clinical value of MNPseq method.@*RESULTS@#The results of bone marrow and peripheral blood chimerism detected by MNPseq method were consistent with each other and showed significant correlation (r=0.985, P<0.01). The three groups of calibration models were constructed according to different pre-transplant information. For the no donor and pre-transplant patients information group, the correction value was 1%; while for the group with pre-transplant patients and without donor information, 0.61% of the chimerism rate and 13 heterotopic points were used as the correction value; 0.26% of the chimerism rate and 21.57% of the heterotopic points were used as the correction value for the group with pre-transplantation patients and donor information. After correction, the number of the patients with incomplete chimerism decreased from 276 (74.19%) to 141 (37.91%) (P<0.01). Among 18 (18/141, 12.77%) patients with incomplete chimerism, the results of MNPseq in the patients were 25-39 days earlier than those in STR and flow MRD, and the result showed statistical significance.@*CONCLUSION@#MNPseq method can be used to monitor chimerism with peripheral blood instead of bone marrow samples, and the results can be corrected to detect the changes of graft status in vivo in a more timely manner.

Molecular analysis of 23 cases of B subgroup / 中华医学遗传学杂志

OBJECTIVE@#To explore the molecular reasons of weak expression of B antigen on the red cell.@*METHODS@#Serological test for blood group was carried out, including red cell and plasma grouping, and anti-A1 and anti-H testing, and confirming weak A or B antigens by adsorption and elution. Exons 1-7 were sequenced directly, and one of them was cloned and sequenced.@*RESULTS@#All of the 23 samples showed the weak B antigen by serological method. The alleles of the subgroups were identified by DNA sequencing, including 2 Bel subgroup, 4 B3 subgroup, 14 Bw subgroup, 2 CisAB subgroup and a novel allele. The novel allele showed a nucleotide substitution 662G>A in the exon 7, and the sequence was submitted to Blood Group Antigen Gene Mutation Database, and the novel allele was named Bel10.@*CONCLUSION@#Nucleotide substitution in exon results in blood subgroup, which showed that the antigens were weakened, and Bw phenotype was the most frequently subgroup.

Análisis genético de cinco polimorfismos de nucleótido simple de caseínas lácteas obtenidos con chips genómicos en ganado Holstein de Antioquia, Colombia / Genetic analysis of five single nucleotide polymorphisms of dairy caseins obtained with genomic chips in Holstein cattle from Antioquia, Colombia

RESUMEN Los polimorfismos genéticos asociados con las caseínas de la leche son de gran importancia, ya que pueden ser usados como marcadores genéticos para mejorar el rendimiento productivo en los hatos lecheros. El objetivo de este estudio fue evaluar la diversidad y estructura genética de 5 SNP de caseínas de la leche, obtenidos con chips genómicos en vacas y toros de raza Holstein en Antioquia (Colombia). Fueron muestreados 113 animales de raza Holstein en 3 regiones del departamento de Antioquia (norte, centro y oriente) y un cuarto grupo de sementales comerciales. Los animales fueron genotipificados con chips genómicos de alta densidad (Illumina BovineHD e Illumina SNP50 v2), a partir de los cuales se identificaron 5 SNP (ARS-BFGL-NGS-8140, BTA-77380-no-rs, BTA-32346-no-rs, BTB-00821654 y ARS-BFGL-NGS-15809). Para cada SNP se realizó un análisis genético mediante un análisis de varianza molecular (amova) usando el software GenAIEx 6.501. Los SNP con mayor heterocigosidad total (HT) fueron ARS-BFGL-NGS-8140 y BTA-32346-no-rs, con resultados cercanos al 45%; sin embargo, la Ht para ARS-BFGL-NGS-15809, BTA-77380-no-rs y BTB-00821654 estuvo por debajo del 15%. El SNP con mayor diversidad genética fue BTA-32346-no-rs (Ho-He = 0,06; p < 0,05). En esta investigación se evaluó una subpoblación de toros comerciales extranjeros, en la cual se obtuvieron frecuencias alélicas y genotípicas similares a las obtenidas para las subpoblaciones locales, sugiriendo que los alelos de los toros muy posiblemente están fijados en dichas subpoblaciones, por lo que la estructura y diversidad genética tienden a ser bajas en la muestra de estudio.

ABSTRACT Genetic polymorphisms associated with milk caseins have a great importance since they can be used as genetic markers to improve productive performance in dairy herds. The main goal of the present study was to evaluate the diversity and genetic structure of 5 SNPs of milk caseins, obtained with genomic chip in Holstein cows and bulls from Antioquia (Colombia). 113 Holstein animals were sampled in 3 regions of Antioquia (north, center, and east), and a fourth group of commercial sires. Animals were geno-typed with high-density SNP chips (Illumina BovineHD and Illumina SNP50 v2), from which 5 SNPs were identified (ARS-BFGL-NGS-8140, BTA-77380-no-rs, BTA-32346-no-rs, BTB-00821654 and ARS-BFGL-NGS-15809). For each SNP, a genetic analysis was performed by means of an analysis of molecular variance (AMOVA) using the GenAIEx 6.501 software. The SNPs with the highest total heterozygosity (Ht) were ARS-BFGL-NGS-8140 and BTA-32346-no-rs, with results close to 45%; however, the HT for ARS-BFGL-NGS-15809, BTA-77380-no-rs, and BTB-00821654 were below 15%. The SNP with the highest genetic diversity was BTA-32346-no-rs (Ho-He = 0,06; p < 0,05). In this research a subpopulation of foreign commercial bulls was evaluated, in which similar allelic and genotypic frequencies to those for local subpopulations were obtained, suggesting that the alleles of the bulls are very possibly fixed in these subpopulations, so that the structure and genetic diversity tend to be low in the study sample.

Polimorfismos genéticos de nucleotídeo único relacionados a sintomas depressivos em pacientes oncológicos: uma scoping review / Single nucleotide genetic polymorphisms related to depressive symptoms in cancer patients: a scoping review

Trata-se de uma revisão de escopo que objetivou relatar as evidências científicas reportadas na literatura referentes a polimorfismos genéticos de nucleotídeo único (SNPs) e a sua relação com o desenvolvimento de sintomas depressivos em pessoas com câncer. A pergunta de pesquisa que norteou esta revisão foi: "Quais polimorfismos genéticos de nucleotídeo único estão relacionados ao desenvolvimento de sintomas depressivos em pacientes oncológicos?". Para a sua condução foi utilizado o referencial teórico proposto por Arksey & O'Malley (2005), acrescido de ampliações de Levac, Colquhoun & O'Brien (2010) e Colquhoun, Levac & O'Brien (2014). Realizou-se buscas sistematizadas nas seguintes bases de dados: PubMed, Embase, PsychInfo, Web of Science e Scopus. Encontrou-se 1946 referências únicas e, após rigorosa seleção, 10 artigos atenderam aos três critérios de inclusão propostos: (1) estudos clínicos conduzidos com pacientes oncológicos; (2) apresentar relação entre SNPs e o desenvolvimento de sintomas depressivos; (3) publicados em português, inglês ou espanhol. Dos 10 artigos incluídos na amostra final, 70% tratava-se de estudos longitudinais, a maioria produzidos nos Estados Unidos (40%), com publicação predominante entre os anos 2012-2014 (60%). A população predominantemente estudada foram mulheres acometidas por câncer de mama (60%) e os sintomas depressivos foram, em sua maioria, avaliados por intermédio de instrumentos validados cientificamente (80%). Os SNPs relacionados aos sintomas depressivos foram encontrados, sobretudo, em genes da via inflamatória (6/11, 54,5%), e o polimorfismo mais estudado foi o rs6265 do gene BDNF, da via de transdução de sinais (4/11, 36,3%). Os principais achados dessa revisão, demonstram que portadores do genótipo Met-BDNF tendem a apresentar maior risco de desenvolvimento e agravamento dos sintomas depressivos. Além disso, os SNPs de genes da via da inflamação, especialmente aqueles relacionados à produção de citocinas pró-inflamatórias, podem desempenhar um importante papel preditivo de sintomas depressivos, na referida população. Portanto, pode-se concluir que as evidências disponíveis na literatura apontam que o polimorfismo do gene BDNF Val66Met (rs6265) e SNPs do sistema imunológico, em especial da via inflamatória, despontam como potenciais marcadores biológicos, no contexto do desenvolvimento de sintomas depressivos em pacientes oncológicos

This is a scoping review that aimed to report the scientific evidence reported in the literature regarding single nucleotide genetic polymorphisms (SNPs) and their relation with the development of depressive symptoms in people with cancer. The research question that guided this review was: "Which single nucleotide genetic polymorphisms are related to the development of depressive symptoms in cancer patients?". The theoretical reference proposed by Arksey & O'Malley (2005) was used to conduct it, plus extensions by Levac, Colquhoun & O'Brien (2010) and Colquhoun, Levac & O'Brien (2014). Systematic searches were carried out in the following databases: PubMed, Embase, PsychInfo, Web of Science, and Scopus. 1946 unique references were found and, after rigorous selection, 10 articles met the three proposed inclusion criteria: (1) clinical studies conducted with cancer patients; (2) presenting a relation between SNPs and the development of depressive symptoms; (3) published in Portuguese, English or Spanish. Of the 10 articles included in the final sample, 70% were longitudinal studies, most of them produced in the United States (40%), with a predominant publication between the years 2012-2014 (60%). The predominantly studied population were women affected by breast cancer (60%) and the depressive symptoms were mostly evaluated using scientifically validated instruments (80%). SNPs related to depressive symptoms were found, mainly, in genes of the inflammatory pathway (6/11, 54.5%), and the most studied polymorphism was the rs6265 of the BDNF gene, of the signal transduction pathway (4/11, 36.3%). The main findings of this review demonstrate that patients with the Met-BDNF genotype tend to have a higher risk of developing and worsening depressive symptoms. In addition, the SNPs of genes in the inflammation pathway, especially those related to the production of pro-inflammatory cytokines, can play an important predictive role of depressive symptoms in this population. Therefore, it can be concluded that the evidence available in the literature indicates that the polymorphism of the BDNF gene Val66Met (rs6265) and SNPs of the immune system, especially of the inflammatory pathway, emerge as potential biological markers, in the context of the development of depressive symptoms in oncological patients

Nucleotide-binding Oligomerization Domain-like Receptor Family Pyrin Domain Containing 3 Inflammasome in Alzheimer's Disease / 中国医学科学院学报

Alzheimer's disease(AD)is a chronic neurodegenerative disease whose cause remains unclear.The β-amyloid plaques in the brain are one of the major pathological features of AD.However,the drugs targeting extracellular β-amyloid plaques have failed to cure the disease.Innate immunity and neuroinflammation play a role in the pathogenesis and progression of AD.As the macrophages existing in the central nervous system,microglia are related with extracellular β-amyloid deposition,intracellular neurofibrillary tangle formation,and neuron injury.Accumulating evidence demonstrates that the activation of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3(NLRP3)inflammasome in microglia plays a role in AD,suggesting new therapeutic target for AD in this signaling pathway.This article reviewed the studies about the activation and regulation of NLRP3 inflammasome in the pathogenesis and progression of AD as well as the development of AD therapies targeting this pathway,aiming to provide reference for further studies in this field.

Identification of a novel HLA-DQB1*03 allele caused by variant of a single nucleotide / 中华医学遗传学杂志

OBJECTIVE@#To delineate the characteristics of a novel HLA-DQB1 allele identified during routine HLA matching in a leukemia family.@*METHODS@#The mother and brother of the patient were subjected to PCR sequence-specific oligonucleotide probe (SSOP), PCR sequence-based typ1ing (SBT), as well as next-generation sequencing (NGS).@*RESULTS@#PCR-SBT revealed that the patient's mother and brother's HLA-DQB1 sequences did not fully match with any known allele combination. NGS revealed that the novel allele has differed from the closest matched DQB1*03:02 with a T>G substitution at position 233 in exon 2, which resulted in substitution of Valine at codon 46 by Glycine. Pedigree analysis confirmed that the novel HLA-DQB1 allele was inherited from his mother.@*CONCLUSION@#A novel HLA-DQB1 allele has been identified through next generation sequencing and was officially named as HLA-DQB1*03:362 by the World Health Organization HLA Factor Nomenclature Committee.

Genetic Influence in Disc Degeneration - Systematic Review of Literature / A influência genética na degeneração discal - Revisão sistemática da literatura

Abstract Disc degeneration is a condition that compromises the intervertebral disc functions, which can lead to several important pathological processes, such as disc herniation and canal stenosis. Although its etiology is still unknown, more and more studies have demonstrated the preponderant role of genetic factors to the detriment of environmental factors. Aiming to review the current knowledge about the genes associated with intervertebral disc degeneration, we have performed a narrative review based on the medical literature in the English language from the last 10 years regarding this subject. We have concluded that several genes have been associated with disc degeneration in humans, including the genes for collagen I α-1 (COL1A1), collagen IX (COL9A2 and COL9A3), collagen XI (COL11A2), interleukin 6 (IL-6), aggrecan (AGC1), vitamin D receptor (VDR), and matrix metalloproteinase 3 (MMP-3), in addition to microRNAs. Therefore, the present review emphasizes the latest advancements in the association of genes with specific phenotypes of degenerated discs, single-nucleotide polymorphisms, heritage and genetic-environmental interactions in relation to disc degeneration to help future reviews regarding the genetic mechanisms underlying these processes.

Resumo A degeneração discal é uma condição que compromete as funções do disco intervertebral, podendo levar a vários processos patológicos importantes, como hérnias discais e estenoses de canal. Apesar de sua etiologia ainda ser desconhecida, cada vez mais estudos têm demonstrado o papel preponderante de fatores genéticos em detrimento de fatores ambientais. Com o objetivo de revisar o conhecimento atual sobre os genes associados à degeneração do disco intervertebral, foi realizada uma revisão narrativa da literatura inglesa nos últimos 10 anos sobre o tema. Concluímos que há uma série de genes que foram associados à degeneração discal em seres humanos, incluindo genes codificando colágeno I α-1 (COL1A1), colágeno IX (COL9A2 e COL9A3), colágeno XI (COL11A2), interleucina 6 (IL-6), agrecano (AGC1), receptor de vitamina D (VDR), metaloproteinase de matriz 3 (MMP-3), além de microRNAs. Dessa forma, a presente revisão enfatiza os últimos avanços na associação de genes com fenótipos de discos degenerados específicos, polimorfismos de nucleotídeos únicos, hereditariedade e interações genético-ambientais em relação à degeneração discal, com o intuito de permitir ao clínico entender esse mecanismo de degeneração e estar preparado para as novas terapêuticas que estão por vir baseadas na genética.

Gene sequence analysis of toxins from the spider Phoneutria nigriventer revealed an intronless feature

Phoneutria nigriventer spider venom contains several cysteine-rich peptide toxins that act on different ion channels. Despite extensive studies on its venom and description of cDNA sequences of several of its toxin precursors, the gene structure of these toxins remains unknown. Methods: Genomic regions encoding the precursors of three previously characterized P. nigriventer toxins - PnTx1, PnTx2-5 and PnTx4(5-5) - were amplified by PCR using specific primers. PCR fragments were cloned and sequenced. Obtained sequences were compared with their corresponding cDNA sequences. Results: The size of PCR fragments obtained and sequences corresponding to genomic regions encoding for the toxin precursors matched their cDNA sequences. Conclusions: Despite a few nucleotide substitutions in the genomic regions encoding for the toxin precursors when compared with cDNA sequences, the results of the present work indicate that P. nigriventer toxins do not contain introns in their genes sequences.(AU)

In vitro-induction of metronidazole-resistant Giardia duodenalis is not associated with nucleotide alterations in the genes involved in pro-drug activation

Giardiasis is an infectious disease caused by Giardia duodenalis. The pro-drug metronidazole (MTZ) is the first-line treatment for giardiasis. Parasite's proteins as pyruvate:ferredoxin oxidoreductase (PFOR), ferredoxin (Fd), nitroreductase-1 (NR-1) and thioredoxin reductase (TrxR) participate in MTZ activation. Here, we showed Giardia trophozoites long-term exposed to MTZ presented higher IC50 than controls, showing the drug influenced the parasite survival. That reduction in MTZ's susceptibility does not seem to be related to mutations in the genes pfor, fd, nr-1 or trxr. It points that different mechanism as alterations in other metabolic pathways can account for Giardia resistance to MTZ therapy.

Recomendaciones en el tratamiento actual de la infección crónica por el virus de la hepatitis B / Current recommendations for the treatment of chronic hepatitis B infection

La infección crónica por el virus de la hepatitis B (VHB) se considera un problema de salud pública mundial. Se estima que al menos dos mil millones de personas han estado expuestas al VHB, y a pesar de una vacuna efectiva, 300 millones de personas están infectadas crónicamente a nivel mundial. Aunque el virus no es directamente citopático, la infección puede desencadenar cirrosis hepática y aun, carcinoma hepatocelular (CHC). El ADN circular cerrado covalentemente (ADNccc) en el núcleo de los hepatocitos y la incapacidad del sistema inmunitario para eliminar la infección crónica por el virus son los mecanismos más importantes de la infección por VHB. Las diferentes entidades, como la Asociación Europea para el Estudio del Hígado (EASL) y la Asociación Americana para el Estudio de las Enfermedades Hepáticas (AASLD), ponen a disposición las pautas para el manejo de esta enfermedad. A pesar de los avances en el tratamiento de la infección crónica por el VHB, en particular con el desarrollo de los análogos de los nucleótidos/ nucleósidos, quedan aún muchos interrogantes. Las investigaciones continúan para el desarrollo de nuevas opciones de tratamiento enfocadas principalmente en evitar que la suspensión de la terapia conlleve a un incremento de la carga viral, con el consecuente aumento del riesgo de progresión de la enfermedad hepática, y un eventual CHC.

Chronic hepatitis B virus (HBV) infection is considered a global public health problem. It is estimated that at least two billion people have been exposed to HBV, and despite an effective vaccine, 300 million people are chronically infected worldwide. Although the virus is not directly cytopathic, the infection can trigger liver cirrhosis and even hepatocellular carcinoma (HCC). Covalently closed circular DNA (cccDNA) in the nucleus of hepatocytes and the inability of the immune system to eliminate chronic virus infection are the most important mechanisms of chronic HBV infection. Different entities, such as the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), provide guidelines for the management of this disease. Despite advances in the treatment of chronic HBV infection, including the development of nucleotide and nucleoside analogs, many questions remain. Research continues for the development of new treatment options focused mainly on avoiding a relapse on viral load after therapy discontinuation, with an increased risk of liver disease progression, and an eventual CHC.

MicroRNAs in Asthma and Respiratory Infections: Identifying Common Pathways

MicroRNAs (miRs) are single-stranded RNAs of 18-25 nucleotides. These molecules regulate gene expression at the post-transcriptional level; several of these are differentially expressed in asthma as well as in viral acute respiratory infections (ARIs), the main triggers of acute asthma exacerbations. In recent years, miRs have been studied in order to discover drug targets as well as biomarkers for diagnosis, disease severity and prognosis. We describe recent findings on miR expression and function in asthma and their role in the regulation of viral ARIs, according to cell tissue specificity and asthma severity. By combining the above information, we identify miRs that may be important in virus-induced asthma exacerbations. This is the first attempt to link miR profiles of asthmatic patients and ARI-induced miRs, addressing the question of whether there might be a specific miR deficit in asthmatic subjects that make them more susceptible and/or reactive to infection.

Potential Implications of Long Noncoding RNAs in Autoimmune Diseases

Long noncoding RNAs (lncRNAs) are non-protein coding RNAs of more than 200 nucleotides in length. Despite the term “noncoding”, lncRNAs have been reported to be involved in gene expression. Accumulating evidence suggests that lncRNAs play crucial roles in the regulation of immune system and the development of autoimmunity. lncRNAs are expressed in various immune cells including T lymphocytes, B lymphocytes, macrophages, neutrophils, dendritic cells, and NK cells, and are also involved in the differentiation and activation of these immune cells. Here, we review recent studies on the role of lncRNAs in immune regulation and the differential expression of lncRNAs in various autoimmune diseases.