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Objectives: The aim of this study was to investigate executive skills in children with dystrophinopathy and to examine the association between executive functions and dystrophin gene mutation position. Methods: Fifty boys with dystrophinopathy (mean age, 11 years 0 months; ages range, 5 to 17 years) completed measures of intellectual functioning (IF), working memory and executive functioning [including Digit Span (working memory) and measures from the NIH Toolbox (selective attention/inhibitory control, set shifting, working memory, and processing speed)]. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). Mutation positions were categorized into three groups (upstream exon 30, 31–62, and downstream exon 63). Paired-samples t tests compared performance on executive measures to IF, and a one-way (three-group) multivariate analysis of covariance compared cognitive performance with mutation location controlling for motor functioning. Results: Mean performance on all executive measures was significantly lower than IF. Parents were also more likely to rate their child with dystrophinopathy as having clinically significant executive difficulties on the Shift, Emotional Control, and Behavior Regulation indices of the BRIEF. Mutation analyses resulted in small groups limiting power to detect subtle differences. Those with a downstream mutation position had significantly poorer performance on IF and Total Digit Span, but not on other measures of executive function including behavior. Conclusions: Individuals with dystrophinopathy have executive skill deficits, but they are not generally associated with more distal mutations. (JINS, 2019, 25, 146–155)
HBsAg reappearance may constitute not only a risk for liver disease but also an infectious source. We aimed to determine whether HBsAg may reappear after spontaneous HBsAg seroclearance. A cohort of 2999 HBsAg-positive subjects aged 30–55 years was recruited in Guangxi, China in 2004. HBsAg was tested every 6 months from July 2004 to June 2007, then, one more time in December 2013. The results showed that spontaneous HBsAg seroclearance occurred in 41 subjects in the first 3 years, giving a 0·54% annual seroclearance rate. Thirteen of the 41 subjects were randomly tested for HBsAg in 2013. Four subjects became HBsAg positive. S gene sequences of HBV were analysed from serum collected before seroclearance and after reappearance, respectively, for subject QS840 (11 and 12 clones), subject TN98 (13 and 13 clones) and subject WX227 (10 and 8 clones). Serotype, subgenotype and amino-acid substitution pattern in each sample collected after reappearance was observed in the sample collected before HBsAg seroclearance. Nucleotide similarity between the two sequences from each subject was >99% and five sequences from subject TN98 were the same. In conclusion, following reactivation, HBsAg may reappear in individuals with spontaneous HBsAg seroclearance many years previously.
GJB2 gene mutations are highly prevalent in pre-lingual hearing loss patients from China. Pre-lingual deafness is a sensorineural disorder that can only be treated with cochlear implantation.
The prevalence of GJB2 gene mutations was examined in 330 randomly selected patients treated with cochlear implantation.
Overall, 276 patients (83.64 per cent) carried variations in the GJB2 gene. Seventeen different genotypes were identified, including 10 confirmed pathogenic mutations (c.235delC, c.299delAT, c.176del16, p.E47X, p.T123N, p.V167M, p.C218Y, p.T86R, p.V63L and p.R184Q), 3 polymorphisms (p.V27I, p.E114 G and p.I203 T) and 2 unidentified mutations (p.V37I and c.571 T > C).
A total of 103 patients (31.2 per cent) carried 2 confirmed pathogenic mutations. The frequency of c.235delC was higher than that reported previously in the Jiangsu province. The two novel mutations identified, 69C > G and 501G > A, are likely to be polymorphisms.
A significant number of patients with schizophrenia fail to respond to antipsychotic medication. Although several studies have investigated associated patient characteristics, the emerging findings from genetic studies offer further scope for study.
In 612 schizophrenia patients with detailed clinical information, common genetic variants indexed by polygenic risk scores, and rare variants indexed by deletion and duplication burden genomewide, we explored potential genetic predictors alongside other established risk factors for treatment resistance. Clinical outcomes of treatment resistance were also calculated using lifetime measures of positive, negative/disorganized and mood symptoms as well as number of hospitalizations and suicide attempts.
Logistic regression models identified a significant relationship between treatment resistance and total duplication burden genomewide, years of formal schooling and age at onset. Clinically, treatment-resistant patients were characterized by greater negative/disorganized and positive symptoms and greater number of hospitalizations.
Taken together, these findings suggest genetic information, specifically the genomewide burden of rare copy number variants, may increase our understanding and clinical management of patients with treatment-resistant schizophrenia.
An integro-differential model for evolutionary dynamics with mutations is investigated by improving the understanding of its behaviour using numerical simulations. The proposed numerical approach can handle also density dependent fitness, and gives new insights about the role of mutation in the preservation of cooperation.
Mutations in the major hydrophilic region (MHR) of the surface antigen of hepatitis B virus (HBV) may result in vaccine escape, failure of immunotherapy and antiviral resistance. These mutants may be transmitted and constitute a public health threat. We aimed to determine the prevalence of MHR mutations of HBV in areas of high endemicity in Guangxi, China. HBV surface gene was analysed from 278 HBsAg-positive asymptomatic individuals recruited from Guangxi using cluster sampling. Three genotypes, B, C and I, were identified. The overall prevalence of MHR mutations is 17·6%. The prevalence of MHR mutations in genotype B (15·1%) is not significantly different from that in genotype C (16·4%). However, the prevalence in subgenotype C5 (31·1%) is significantly higher than in subgenotype C2 (13·0%) (χ2 = 6·997, P < 0·05). The prevalence of escape mutations and overlapping polymerase substitutions in subgenotype C5 is significantly higher than in subgenotypes B2 and C2. In total, 7·9% of MHR mutants are escape mutations and 72·1% of MHR mutations produced amino-acid changes in the overlapping polymerase, including resistance mutations to entecavir. Our results suggest that the prevalence of MHR mutations varies with subgenotype. The prevalence of escape mutations and polymerase mutations may be associated with subgenotype.
Genetic resources form the basis of the new era of global food security. The food crises in many developing countries, reflected by food riots correlated with food prices, have been termed the Silent Tsunami. Plant genetic resources are clearly essential to food security for the future. Fortunately, genetic resources are generally considered a public good and shared internationally. Wild relatives of crop species and their derivatives represent the reservoir of genetic diversity that will help to meet the food demands of nine billion people by 2050. New technologies from genomics bolster conventional plant breeding for enhancing traits to meet these food demands. Genetic diversity is the lifeblood of traditional and modern plant breeding. The dramatic increase in the number of biotech crops reveals the value of new genetic resources. Genetic resources will provide a gateway to a new era of global food security. Although 7.4 million plant accessions are stored in 1750 germplasm banks around the world, only a small portion of the accessions has been used so far to produce commercial varieties. Our challenge is to find better ways to make more efficient use of gene bank materials for meeting food demands in the future.
Hereditary sensorineural hearing loss is the most frequently occurring birth defect. It has profound effects for the individual and is a substantial burden on society. Insight into disease mechanisms can help to broaden therapeutic options and considerably lower lifetime social costs. In the past few decades, the identification of genes that can cause this type of hearing loss has developed rapidly.
This paper provides a concise overview of the currently known genes involved in non-syndromic hereditary hearing loss and their function in the inner ear.
An insertion (In)/deletion (Del) polymorphism in the fatty acid desaturase 2 (FADS2) gene, which codes for Δ6-desaturase, was for the first time observed in fish. The polymorphism is located in the seventh intron of FADS2 and the insertion consists of eleven repeats of CTGT (44 bp) with an allelic frequency, for the insertion, of 39 %. The polymorphism was associated with a modulation in Δ6-desaturase activity as significant effects on the ratio of EPA or DHA to their precursors were found (P< 0·001). A different distribution of SFA, MUFA and PUFA among the In/In, In/Del and Del/Del groups was also detected in fish fillet. The results suggest that genetic selection for this marker might improve the ability of European grayling to utilise dietary n-3 long-chain PUFA precursors, as Δ6-desaturase is the rate-limiting enzyme in the production of EPA and DHA from α-linolenic acid.
This chapter reviews the biology of adenoviruses, clinical trials of oncolytic viral gene therapy in ovarian cancer and recent developments that may give cause for cautious optimism. There are 49 serotypes of human adenoviruses, divided into six groups. There have only been a small number of clinical trials of gene therapy in ovarian cancer. Mutations in p53 are almost universal in high-grade serous ovarian cancer, there were early attempts to re-introduce wild-type p53 gene expression using a non-replicating adenovirus. Following primary debulking surgery, women whose tumours had demonstrable p53 mutations were randomised to conventional platinum and paclitaxel chemotherapy with or without IP SCH58500. Most importantly, there remain many questions about the biology of adenoviruses that are unanswered-many of these relate to the role of host cell factors in determining cell fate following infection and the potential role of immune responses in cell death in whole organisms.
Massese is an Italian dairy sheep breed characterized by animals with black skin and horns and black or apparent grey hairs. Owing to the presence of these two coat colour types, this breed can be considered an interesting model to evaluate the effects of coat colour gene polymorphisms on this phenotypic trait. Two main loci have been already shown to affect coat colour in sheep: Agouti and Extension coding for the agouti signalling protein (ASIP) and melanocortin 1 receptor (MC1R) genes, respectively. The Agouti locus is affected by a large duplication including the ASIP gene that may determine the Agouti white and tan allele (AWt). Other disrupting or partially inactivating mutations have been identified in exon 2 (a deletion of 5 bp, D5; and a deletion of 9 bp, D9) and in exon 4 (g.5172T>A, p.C126S) of the ASIP gene. Three missense mutations in the sheep MC1R gene cause the dominant black ED allele (p.M73K and p.D121N) and the putative recessive e allele (p.R67C). Here, we analysed these ASIP and MC1R mutations in 161 Massese sheep collected from four flocks. The presence of one duplicated copy allele including the ASIP gene was associated with grey coat colour (P = 9.4E-30). Almost all animals with a duplicated copy allele (37 out of 41) showed uniform apparent grey hair and almost all animals without a duplicated allele (117 out of 120) were completely black. Different forms of duplicated alleles were identified in Massese sheep including, in almost all cases, copies with exon 2 disrupting or partially inactivating mutations making these alleles different from the AWt allele. A few exceptions were observed in the association between ASIP polymorphisms and coat colour: three grey sheep did not carry any duplicated copy allele and four black animals carried a duplicated copy allele. Of the latter four sheep, two carried the ED allele of the MC1R gene that may be the cause of their black coat colour. The coat colour of all other black animals may be determined by non-functional ASIP alleles (non-agouti alleles, Aa) and in a few cases by the EDExtension allele. At least three frequent ASIP haplotypes ([D5:g.5172T], [N:g.5172A] and [D5:g.5172A]) were detected (organized into six different diplotypes). In conclusion, the results indicated that coat colours in the Massese sheep breed are mainly derived by combining ASIP and MC1R mutations.
A small proportion of malignancies have a clear genetic aetiology resulting from mutations in genes inherited usually as an autosomal dominant trait. Risk assessment and genetic counselling around genetic testing and reproductive decision-making should be undertaken in a regional genetic service. If a mutation is identified within an individual, it should be confirmed in another affected member of the family, if possible. A predictive genetic test is then available for unaffected adult members of the family. Adoption or conception using donor gametes may be alternatives for families with genetic conditions who wish to avoid prenatal diagnosis. The issue of the appropriateness of prenatal diagnosis and of preimplantation genetic diagnosis (PGD) for inherited conditions with an onset in adulthood is controversial. PGD may be more acceptable than prenatal diagnosis as it obviates the need for termination of an affected pregnancy.
Obesity originates from a failure of the body-weight control systems, which may be affected by changing environmental influences. Basically, the obesity risk depends on two important mutually-interacting factors: (1) genetic variants (single-nucleotide polymorphisms, haplotypes); (2) exposure to environmental risks (diet, physical activity etc.). Common single-nucleotide polymorphisms at candidate genes for obesity may act as effect modifiers for environmental factors. More than 127 candidate genes for obesity have been reported and there is evidence to support the role of twenty-two genes in at least five different populations. Gene–environment interactions imply that the synergy between genotype and environment deviates from either the additive or multiplicative effect (the underlying model needs to be specified to appraise the nature of the interaction). Unravelling the details of these interactions is a complex task. Emphasis should be placed on the accuracy of the assessment methods for both genotype and lifestyle factors. Appropriate study design (sample size) is crucial in avoiding false positives and ensuring that studies have enough power to detect significant interactions, the ideal design being a nested case–control study within a cohort. A growing number of studies are examining the influence of gene–environmental interactions on obesity in either epidemiological observational or intervention studies. Positive evidence has been obtained for genes involved in adiposity, lipid metabolism or energy regulation such as PPARγ2 (Pro12Ala), β-adrenoceptor 2 (Gln27Glu) or uncoupling proteins 1, 2 and 3. Variants on other genes relating to appetite regulation such as melanocortin and leptin receptors have also been investigated. Examples of some recently-identified interactions are discussed.
Embryonic loss occurring in the first week of the incubation is termed early embryonic mortality. Environmental, technological and genetic factors can be responsible forits appearance. The examination of genetic background of embryonic death is justified when the breeding and hatching technological parameters are optimal. Disposition of early embryonic mortality can be inherited and it can accumulate in a stock, which will finally deteriorate its fertility indices. Although the heritability value of reproductiveness is poor, h2=0.1−0.2, even so, during the selection still should be considered. This paper offers a short review on the special features of early embryonic development in poultry and examination methods forpossible genetic background of early embryonic abnormalities and mortality. The application of cytogenetical and embryological methods may be of major relevance in the improvement of the reproduction traits of poultry species.
Dihydrofolate reductase-thymidylate synthase (DHFR-TS) from Plasmodium falciparum, a validated target for antifolate antimalarials, is a dimeric enzyme with interdomain interactions significantly mediated by the junction region as well as the Plasmodium-specific additional sequences (inserts) in the DHFR domain. The X-ray structures of both the wild-type and mutant enzymes associated with drug resistance, in complex with either a drug which lost, or which still retains, effectiveness for the mutants, reveal features which explain the basis of drug resistance resulting from mutations around the active site. Binding of rigid inhibitors like pyrimethamine and cycloguanil to the enzyme active site is affected by steric conflict with the side-chains of mutated residues 108 and 16, as well as by changes in the main chain configuration. The role of important residues on binding of inhibitors and substrates was further elucidated by site-directed and random mutagenesis studies. Guided by the active site structure and modes of inhibitor binding, new inhibitors with high affinity against both wild-type and mutant enzymes have been designed and synthesized, some of which have very potent antimalarial activities against drug-resistant P. falciparum bearing the mutant enzymes.
Cerebrovascular diseases can causes cognitive impairment and dementia by loss of neurons and synaptic connections, destruction of axons, and demyelinization. Biological markers including genetic tests, brain imaging techniques, and biochemical assays in the CSF are valuable for the identification and quantification of cerebrovascular diseases. Genetic tests may be used to detect mutations that cause hereditary cerebral amyloid angiopathies or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Structural CT and MR imaging is routinely used to visualize and quantify infarcts and white-matter changes. Functional SPET and PET imaging can demonstrate focal and remote effects of vascular lesions on cerebral blood flow and metabolism. Biochemical imaging using proton MRS is a nonspecific marker for neuronal and axonal damage. Among biochemical markers in the CSF, tau protein, phospho-tau, and beta amyloid protein are helpful to differentiate vascular dementia from Alzheimer's disease.
Quantum-chemical methods are used to shed light on the
functional role of residues involved in the resistance
of HIV-1 reverse transcriptase against nucleoside-analog
drugs. Ab initio molecular dynamics simulations are carried
out for models representing the adduct between the triphosphate
substrate and the nucleoside binding site. The triphosphate
is considered either deprotonated or protonated at the
γ-position. Although the protonated form already experiences
large rearrangements in the ps time scale, the fully deprotonated
state exhibits a previously unrecognized low-barrier hydrogen
bond between Lys65 and γ-phosphate. Absence of this
interaction in Lys65→Arg HIV-1 RT might play a prominent
role in the resistance of this mutant for nucleoside analogs
(Gu Z et al., 1994b, Antimicrob Agents Chemother 38:275–281;
Zhang D et al., 1994, Antimicrob Agents Chemother 38:282–287).
Water molecules present in the active site, not detected
in the X-ray structure, form a complex H-bond network.
Among these waters, one may be crucial for substrate recognition
as it bridges Gln151 and Arg72 with the β-phosphate.
Absence of this stabilizing interaction in Gln151→Met
HIV-1 RT mutant may be a key factor for the known drug
resistance of this mutant toward dideoxy-type drugs and
AZT (Shirasaka T et al., 1995, Proc Natl Acad Sci USA
92:2398–2402; Iversen AK et al., 1996, J
In this study, we employed a mutation scanning approach for the
direct visual display of genetic variability in mitochondrial
DNA (mtDNA) fragments within and among populations of Schistosoma japonicum
from the People's Republic of
China. Fragments of the NADH dehydrogenase 1 gene (ND1) and the cytochrome
c oxidase subunit I (COI) were
individually amplified from parasite DNA by polymerase chain reaction (PCR),
denatured and subjected to single-strand
conformation polymorphism (SSCP) analysis. Using ND1 and COI fragments,
individuals representing different genotypes
could be readily identified based on characteristic and reproducible SSCP
profiles. The results demonstrated the
usefulness of SSCP for the direct visual display of low-level sequence
variation in mtDNA of S. japonicum prior to DNA
sequence analysis. This approach has important implications for studying
the genetic structure and biology of S. japonicum
populations, and for analysing the inheritance of mitochondrial DNA.
Fucosidosis is an autosomal recessive disorder caused by a deficiency of alpha-L-fucosidase. Up to now 79 cases have been described and several others identified but not yet published. The higher incidence of the disease is in Italy, where nearly 20 patients have been identified. Fourteen disease-causing mutations have been detected and four of them, Q422X, G60D, E375X, P141fs are present in more than 70% of the forty patients studied. In Italian patients, only seven mutations have been described and P141fs and G60D mutations are present in more than 50% of the cases. The P141fs mutation is absent in other ethnic groups. It has been impossible to establish genotype-phenotype correlation so far and the clinical variability of the disease cannot be explained only by genetic heterogeneity.