Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Mechanisms of Improving IVF Outcomes of Liu-Wei-Di-Huang Pill Acting on DOR Patients

Diminished ovarian reserve (DOR) is the weakening of ovarian oocyte production and quality. It will further become premature ovarian failure without timely cure. However, disease pathology and diagnostic markers are still incompletely understood. Liu-Wei-Di-Huang (LWDH) pill, a traditional Chinese medicine formula, is commonly used in the treatment of DOR in China. To explore the mechanism of the effect of LWDH on in vitro fertilization (IVF) outcomes in patients with DOR, a pseudotargeted metabolomics study combined with multivariate data processing strategy was carried out. A liquid chromatography tandem mass spectrometry-based metabolomics approach was applied to characterize metabolic biomarker candidates. Multiple pattern recognition was used to determine groups and confirm important variables. A total of 21 potential biomarkers were characterized, and related metabolic pathways were identified. The study displayed that the established pseudotargeted metabolomics strategy is a powerful approach for investigating the mechanism of DOR and LWDH. In addition, the approach may highlight biomarkers and metabolic pathways and can capture subtle metabolite changes from headache, which may lead to an improved mechanism understanding of DOR diseases and LWDH treatment

Dehydrogenative alpha-Oxygenation of Cyclic Ethers by a High-Valent Manganese(IV)-Oxo Species

High-valent metal-oxo species are typical catalytic cycle intermediates in mono-oxygenases and dioxygenases and commonly react through oxygen atom transfer to substrates. In this work we study a biomimetic model complex with a 1,1’-bis((3,5-dimethylpyridin-2-yl)methyl)-2,2’-bipiperidine ligand system bound to a manganese(IV)-oxo(hydroxo) species and study its formation from manganese(II)-hydroxo and H2O2 as well as its reaction with (S)-1-phenylisochromane through dehydrogenative α-oxygenation. The work utilizes density functional theory methods to explore its catalytic cycle and its reactivity patterns. We show that the manganese(IV)-oxo(hydroxo) species is an active oxidant and preferentially the oxo group abstracts a hydrogen atom from substrate with barriers well lower in energy than those found for hydrogen atom abstraction by the hydroxo group. Interestingly, the rate-determining step is the OH rebound rather than the hydrogen atom abstraction, which would imply they would have limited kinetic isotope effect for the replacement of the transferring hydrogen atom by deuterium

A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood

Background: Bilateral striatal necrosis (BSN) is characterized by symmetrical degeneration, predominantly of the caudate and putamen nucleus, in the basal ganglia. It is associated with numerous acquired and hereditary neuro-developmental and motor dysfunction-related pathological conditions. BSN results in high morbidity and mortality among infants and children, and its diagnosis is clinically challenging due to several overlapping disease phenotypes. Therefore, a precise genetic diagnosis is urgently needed for accurate genetic counseling and improved prognostic outcomes as well.Objective: To identify novel missense mutations in the NDUFAF5 gene as a cause of childhood BSN in members of a Chinese family and summarize the clinical characteristics of patients with the NDUFAF5 gene mutations.Methods: This study included a large family living in a remote northwestern area of China. Three siblings developed a neurological disorder characterized by generalized dystonia within the first decade of their lives. Cerebral computed tomography (CT) and magnetic resonance imaging (MRI) showed bilateral lesions of the putamen. Biochemical and genetic approaches were used to identify the cause of BSN.Results: Sequence analysis showed no pathogenic variation in PANK2, SLC25A19, SLC19A3, and NUP62 genes and in the entire mitochondrial genome as well. Whole-exome sequencing revealed compound heterozygous mutations consisting of NDUFAF5:c.425A > C(p.E142A) and c.836T > G (p.M279R). The father, a healthy sister, and a healthy brother of the affected siblings carried the c.836T > G mutation, and the mother carried the c.425A > C mutation. These variants were absent in 100 ethnically matched non-BSN controls. In silico analysis demonstrated that the E142A and M279R mutations in NDUFAF5 protein significantly perturbed the normal conformation of the protein due to alterations in the hydrogen bonding patterns around the evolutionarily conserved catalytic domains, leading to its loss of function in the early stage of mitochondrial complex I assembly.Conclusions: We identified a novel compound heterozygous mutation (c.425A > C and c.836T > G) in the NDUFAF5 gene as the potential cause of autosomal recessive childhood BSN, which extended the pathogenic variation spectrum of the NDUFAF5 gene. This study provides substantial evidence for further improvement of genetic counseling and better clinical management of BSN affected individuals

Cationic Nano-Fragrance with Sustained Release Property for Neuroregulation

Silk is a kind of textile with Chinese characteristics and widely used in clothing, decoration, military and medical fields. Recently, fragrances have been applied to silk to relieve anxiety and stress. However, the problems of too strong aroma and short scent lasting time seriously restrict the development of aromatic silk. Herein, Cationic nanoparticles encapsulating with linalool were prepared to prolong the scent lasting time. The fragrance-loaded nanoparticles are tightly attached to the silk by electrostatic interaction between cationic nanoparticles and anionic silk. Besides, the cationic nanoparticles could slow the release rate of linalool, thus extending the fragrance retention time. Subsequently, fragrant silk has been proven to have an effect of relieving stress. Therefore, this fragrance-loaded cationic nanoparticles-added silk has potential application value