scholarly journals The non-essentiality of essential genes suggests a loss-of-function therapeutic strategy for loss-of-function human diseases

2016 ◽  
Author(s):  
Piaopiao Chen ◽  
Dandan Wang ◽  
Han Chen ◽  
Zhenzhen Zhou ◽  
Xionglei He
Keyword(s):  
Side Effects ◽  
Large Scale ◽  
Therapeutic Strategy ◽  
Essential Gene ◽  
Large Population ◽  
Essential Genes ◽  
Type I ◽  
Type Ii ◽  
Loss Of Function ◽  
Function Type

Essential genes refer to those whose null mutation leads to lethality or sterility. We propose that the fatal effect of inactivating an essential gene can be attributed to either the loss of indispensable core cellular function (type I), or the gain of fatal side effects after losing dispensable periphery function (type II). In principle, inactivation of the type I essential genes can be rescued only by re-gain of the core functions, whereas inactivation of the type II essential genes could be rescued by a further loss of function of another gene to eliminate the otherwise fatal side effects. Because such loss-of-function rescuing mutations may occur spontaneously, type II essential genes may become non-essential in a few individuals of a large population. We tested this idea in the yeastSacchromyces cerevisiae. Large-scale whole genome sequencing of such essentiality-reversing mutants reveals 14 cases where inactivation of an essential gene is rescued by loss-of-function mutations on another gene. In particular, the essential gene encoding the enzyme adenylosuccinate lyase (ADSL) is shown to be type II, suggesting a loss-of-function therapeutic strategy for the human disorder ADSL deficiency. A proof-of-principle test of this strategy in the nematodeCaenorhabditis elegansshows promising results.

scholarly journals Side Effects of mRNA-Based COVID-19 Vaccine: Nationwide Phase IV Study among Healthcare Workers in Slovakia

2021 ◽  
Vol 14 (9) ◽  
pp. 873
Author(s):  
Abanoub Riad ◽  
Barbora Hocková ◽  
Lucia Kantorová ◽  
Rastislav Slávik ◽  
Lucia Spurná ◽  
...  
Keyword(s):  
Side Effects ◽  
Side Effect ◽  
Healthcare Workers ◽  
Large Scale ◽  
Large Population ◽  
Medical Attention ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Post Vaccination ◽  
Phase Iv

mRNA-based COVID-19 vaccines such as BNT162b2 have recently been a target of anti-vaccination campaigns due to their novelty in the healthcare industry; nevertheless, these vaccines have exhibited excellent results in terms of efficacy and safety. As a consequence, they acquired the first approvals from drug regulators and were deployed at a large scale among priority groups, including healthcare workers. This phase IV study was designed as a nationwide cross-sectional survey to evaluate the post-vaccination side effects among healthcare workers in Slovakia. The study used a validated self-administered questionnaire that inquired about participants’ demographic information, medical anamneses, COVID-19-related anamnesis, and local, systemic, oral, and skin-related side effects following receiving the BNT162b2 vaccine. A total of 522 participants were included in this study, of whom 77% were females, 55.7% were aged between 31 and 54 years, and 41.6% were from Banska Bystrica. Most of the participants (91.6%) reported at least one side effect. Injection site pain (85.2%) was the most common local side effect, while fatigue (54.2%), headache (34.3%), muscle pain (28.4%), and chills (26.4%) were the most common systemic side effects. The reported side effects were of a mild nature (99.6%) that did not require medical attention and a short duration, as most of them (90.4%) were resolved within three days. Females and young adults were more likely to report post-vaccination side effects; such a finding is also consistent with what was previously reported by other phase IV studies worldwide. The role of chronic illnesses and medical treatments in post-vaccination side effect incidence and intensity requires further robust investigation among large population groups.

scholarly journals Tensile and fracture properties of NiAl/Ni micro-laminated composites prepared by reaction synthesis

2006 ◽  
Vol 21 (5) ◽  
pp. 1141-1149 ◽  
Author(s):  
Hee Y. Kim ◽  
Dong S. Chung ◽  
M. Enoki ◽  
Soon H. Hong
Keyword(s):  
Large Scale ◽  
Volume Fraction ◽  
Laminated Composites ◽  
Relative Strength ◽  
Type I ◽  
Reaction Synthesis ◽  
Type Ii ◽  
Composition Variation ◽  
Gradient Microstructure ◽  
Upward Curvature

The mechanical properties of NiAl/Ni micro-laminated composites with highly gradient microstructure have been investigated. Two types of composites with different gradient microstructures were prepared by reaction synthesis. Intermetallics of type I and type II composites mainly consisted of Al-rich Ni0.45Al0.55 with variable thickness and Ni-rich Ni0.58Al0.42 with similar thickness, respectively. As intermetallic volume fraction increased, yield strength of type II followed the rule-of-mixture well, while that of type I deviated due to the composition variation of intermetallic phases. Fracture toughness of type II was higher than that of type I, and all showed KR curves with upward curvature by large-scale bridging. Even though the relative strength of constituent phases in intermetallic/metal laminates was not constant due to the gradient microstructure, the fracture mode transition showed similar behavior to that of metal/ceramic laminates.

scholarly journals Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

1998 ◽  
pp. 96-100 ◽  
Author(s):  
M Peter ◽  
K Bunger ◽  
SL Drop ◽  
WG Sippell
Keyword(s):  
Genetic Study ◽  
Stop Codon ◽  
Molecular Genetic ◽  
Premature Stop Codon ◽  
Type I ◽  
Type Ii ◽  
Loss Of Function ◽  
Molecular Genetic Study ◽  
Base Exchange ◽  
Deficiency Type

We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2). presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.

scholarly journals The Effect of Multi-Scale Faults and Fractures on Oil Enrichment and Production in Tight Sandstone Reservoirs: A Case Study in the Southwestern Ordos Basin, China

2021 ◽  
Vol 9 ◽  
Author(s):  
Lianbo Zeng ◽  
Wenya Lyu ◽  
Yunzhao Zhang ◽  
Guoping Liu ◽  
Shaoqun Dong
Keyword(s):  
Large Scale ◽  
Ordos Basin ◽  
Oil Production ◽  
Small Scale ◽  
Type I ◽  
Type Ii ◽  
Tight Sandstone ◽  
Micro Scale ◽  
Multi Scale

The Chang 8 Member of the Upper Triassic Yanchang Formation in the southwestern Ordos Basin is a typical tight sandstone reservoir and has an average porosity of 8.60% and air permeability 0.20 mD. Multi-scale faults and fractures are widely developed in these reservoirs. In this study, three-dimensional seismic data, outcrops, cores, imaging logs, and thin sections were used to classify faults and fractures at multiple scales. Combined with the oil production data, the influence of multi-scale faults and fractures on the oil enrichment and production was analyzed. The results show multi-scale faults and fractures can be divided into six levels: type-I faults, type-II faults, large-scale fractures, mesoscale fractures, small-scale fractures, and micro-scale fractures. As the scale decreases, the number of fractures increases in a power function. Type-I faults cut the caprocks and are not conducive to the preservation of oil. Type-II faults connect the source rocks and reservoirs and are migration channels of the oil source. Large-scale fractures cut the mudstone interlayer and are the seepage channel inside the reservoir. Mesoscale fractures are controlled by thick interlayers, and small-scale fractures are restricted by thin interlayers or layer interfaces. These fractures are the main seepage channels and effective storage spaces. Micro-scale fractures serve as important storage spaces for these reservoirs. The case study of oil reservoir development proves that type-I faults have the greatest impact on fluid flow, while wells drilled into the type-II faults zone have a higher oil production capacity. The oil production changes with the development degree of fractures in different scales, strikes, and positions of faults. Meso- and small-scale fractures are the key to influencing the early single-well production, and micro-scale fractures are conducive to the stable production of single wells. Consequently, multi-scale faults and fractures have significantly different effects on the oil enrichment and production of tight sandstone reservoirs, and the research conclusions can guide to the exploration and development of such similar reservoirs.

scholarly journals A novel CRISPRi platform to study the role of essential genes in antifungal drug-resistant Candida albicans isolates

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
Lauren Wensing ◽  
Rebecca Shapiro ◽  
Deeva Uthayakumar ◽  
Viola Halder ◽  
Jehoshua Sharma ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Transcriptional Repression ◽  
Drug Targets ◽  
Large Scale ◽  
Essential Gene ◽  
Essential Genes ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Drug Resistant ◽  
Fungal Organisms

With the emergence of antifungal resistant Candida albicans strains, the need for new antifungal drugs is critical in combating this fungal pathogen. Investigating essential genes in C. albicans is a vital step in characterizing putative antifungal drug targets. As some of these essential genes are conserved between fungal organisms, developed therapies targeting these genes have the potential to be broad range antifungals. In order to study these essential genes, classical genetic knockout or CRISPR-based approaches cannot be used as disrupting essential genes leads to lethality in the organism. Fortunately, a variation of the CRISPR system (CRISPR interference or CRISPRi) exists that enables precise transcriptional repression of the gene of interest without introducing genetic mutations. CRISPRi utilizes an endonuclease dead Cas9 protein that can be targeted to a precise location but lacks the ability to create a double-stranded break. The binding of the dCas9 protein to DNA prevents the binding of RNA polymerase to the promoter through steric hindrance thereby reducing expression. We recently published the novel use of this technology in C. albicans and are currently working on expanding this technology to large scale repression of essential genes. Through the construction of an essential gene CRISPRi-sgRNA library, we can begin to study the function of essential genes under different conditions and identify genes that are involved in critical processes such as drug tolerance in antifungal resistant background strains. These genes can ultimately be characterized as putative targets for novel antifungal drug development, or targeted as a means to sensitize drug-resistant strains to antifungal treatment.

scholarly journals PHOTODYNAMIC THERAPY: NEW LIGHT IN MEDICINE WORLD

2010 ◽  
Vol 8 (2) ◽  
pp. 279-291 ◽  
Author(s):  
Venny Santosa ◽  
Leenawaty Limantara
Keyword(s):  
Reactive Oxygen Species ◽  
Photodynamic Therapy ◽  
Side Effects ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Type I ◽  
Oxygen Species ◽  
Type Ii ◽  
Light Spectrum ◽  
Medical Field

Photodynamic therapy (PDT) is a considerably new kind of photochemotherapeutic treatment in medical field. It combines the use of three components, which are a photosensitizer, light and oxygen. Photosensitizer is a compound activated by light. The application can be oral, topical or intravenous. It usually member of porphyrin group with ampiphilic characteristics. Photosensitizer can be of generation I, II or III, each generation step develops more specificity, selectivity and deeper tissue application. This review will discuss photosensitizer development consecutively, with its benefit and lackness. The light used is usually on red region, while the oxygen is involved in reactive oxygen species generation. Its mechanism action can go through either in type I or type II reaction. This kind of therapy is usually being used in oncology, especially in superficial and in-lining cancers, dermatology and ophthalmology field. This therapy can be safely given to patients with complication and has distinct advantages compare with other treatment such as chemotherapy and surgery. It also considerably has lesser side effects and risks. Broader application is being developed through various experiments and photosensitizer modification.   Keywords: light spectrum, photoactivation, photodynamic therapy, photosensitizer

scholarly journals Essential gene analysis in Acinetobacter baumannii by high-density transposon mutagenesis and CRISPR interference

2020 ◽  
Author(s):  
Jinna Bai ◽  
Yunfei Dai ◽  
Andrew Farinha ◽  
Amy Y. Tang ◽  
Sapna Syal ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Large Scale ◽  
Essential Gene ◽  
Essential Genes ◽  
Require Time ◽  
Crispr Interference ◽  
Genetic Manipulations ◽  
Multiple Processes ◽  
Life Threatening ◽  
Hospital Acquired

AbstractAcinetobacter baumannii is a poorly understood bacterium capable of life-threatening infections in hospitals. Few antibiotics remain effective against this highly resistant pathogen. Developing rationally-designed antimicrobials that can target A. baumannii requires improved knowledge of the proteins that carry out essential processes allowing growth of the organism. Unfortunately, studying essential genes has been challenging using traditional techniques, which usually require time-consuming recombination-based genetic manipulations. Here, we performed saturating mutagenesis with dual transposon systems to identify essential genes in A. baumannii and we developed a CRISPR-interference (CRISPRi) system for facile analysis of these genes. We show that the CRISPRi system enables efficient transcriptional silencing in A. baumannii. Using these tools, we confirmed the essentiality of the novel cell division protein AdvA and discovered a previously uncharacterized AraC-family transcription factor (ACX60_RS03245) that is necessary for growth. In addition, we show that capsule biosynthesis is a conditionally essential process, with mutations in late-acting steps causing toxicity in strain ATCC 17978 that can be bypassed by blocking early-acting steps or activating the BfmRS stress response. These results open new avenues for analysis of essential pathways in A. baumannii.ImportanceNew approaches are urgently needed to control A. baumannii, one of the most drug resistant pathogens known. To facilitate the development of novel targets that allow inhibition of the pathogen, we performed a large-scale identification of genes whose products the bacterium needs for growth. We also developed a CRISPR-based gene knockdown tool that operates efficiently in A. baumannii, allowing rapid analysis of these essential genes. We used these methods to define multiple processes vital to the bacterium, including a previously uncharacterized gene-regulatory factor and export of a protective polymeric capsule. These tools will enhance our ability to investigate processes critical for the essential biology of this challenging hospital-acquired pathogen.

scholarly journals Somatic mutation involving diverse genes leads to a spectrum of focal cortical malformations

2021 ◽  
Author(s):  
Dulcie Lai ◽  
Meethila Gade ◽  
Edward Yang ◽  
Hyun Yong Koh ◽  
Nicole M. Walley ◽  
...  
Keyword(s):  
Focal Cortical Dysplasia ◽  
Hippocampal Sclerosis ◽  
Cortical Development ◽  
Copy Number Variants ◽  
Cortical Dysplasia ◽  
Disease Genes ◽  
Type I ◽  
Type Ii ◽  
Loss Of Function ◽  
Brain Malformations

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT3-mTOR-signaling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n=16), focal cortical dysplasia type I and related phenotypes (n=48), focal cortical dysplasia type II (n=44), or focal cortical dysplasia type III (n=15) classified using imaging and pathological findings. We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel, and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1, and NIPBL, genes associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a very small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that FCD types I, II, and III, are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.

scholarly journals Biobank-scale inference of ancestral recombination graphs enables genealogy-based mixed model association of complex traits

2021 ◽  
Author(s):  
Brian C Zhang ◽  
Arjun Biddanda ◽  
Pier Francesco Palamara
Keyword(s):  
Complex Traits ◽  
Large Scale ◽  
Mixed Model ◽  
Large Population ◽  
Complex Trait ◽  
Genotype Imputation ◽  
Loss Of Function ◽  
Genome Wide ◽  
Wide Range ◽  
Ancestral Recombination Graphs

Accurate inference of gene genealogies from genetic data has the potential to facilitate a wide range of analyses. We introduce a method for accurately inferring biobank-scale genome-wide genealogies from sequencing or genotyping array data, as well as strategies to utilize genealogies within linear mixed models to perform association and other complex trait analyses. We use these new methods to build genome-wide genealogies using genotyping data for 337,464 UK Biobank individuals and to detect associations in 7 complex traits. Genealogy-based association detects more rare and ultra-rare signals (N = 133, frequency range 0.0004% - 0.1%) than genotype imputation from ~65,000 sequenced haplotypes (N = 65). In a subset of 138,039 exome sequencing samples, these associations strongly tag (average r = 0.72) underlying sequencing variants, which are enriched for missense (2.3×) and loss-of-function (4.5×) variation. Inferred genealogies also capture additional association signals in higher frequency variants. These results demonstrate that large-scale inference of gene genealogies may be leveraged in the analysis of complex traits, complementing approaches that require the availability of large, population-specific sequencing panels.

A Simulation Method to Estimate Two Types of Time-Varying Failure Rate of Dynamic Systems

2016 ◽  
Vol 138 (12) ◽  
Author(s):  
Zhonglai Wang ◽  
Xiaoqiang Zhang ◽  
Hong-Zhong Huang ◽  
Zissimos P. Mourelatos
Keyword(s):  
Failure Rate ◽  
Dynamic Systems ◽  
Saddlepoint Approximation ◽  
Simulation Method ◽  
Copula Function ◽  
Type I ◽  
Time Varying ◽  
Type Ii ◽  
Time Intervals ◽  
Function Type

The failure rate of dynamic systems with random parameters is time-varying even for linear systems excited by a stationary random input. In this paper, we propose a simulation-based method to estimate two types (type I and type II) of time-varying failure rate of dynamic systems. The input stochastic processes are discretized in time and the trajectories of the output stochastic process are calculated. The time of interest is partitioned into a series of time intervals and the saddlepoint approximation (SPA) is employed to estimate the probability of failure in each interval. Type I follows the commonly used definition of failure rate. It is estimated at discrete time intervals using SPA and the correlation information from a properly selected time-dependent copula function. Type II is a proposed new concept of time-varying failure rate. It provides a way to predict the failure rate considering a virtual “good-as-old” repair action of repairable dynamic systems. The effectiveness of the proposed method is illustrated with a vehicle vibration example.

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