Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
57,373
result(s) for
"Thomas, Michael A"
Sort by:
The C9orf72 repeat expansion disrupts nucleocytoplasmic transport
The hexanucleotide repeat expansion (HRE) GGGGCC (G
4
C
2
) in
C9orf72
is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G
4
C
2
RNA including RanGAP1. A candidate-based genetic screen in
Drosophila
expressing 30 G
4
C
2
repeats identified RanGAP (
Drosophila
orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from
C9orf72
ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in
C9orf72
ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in
C9orf72
iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
A candidate-based genetic screen in
Drosophila
expressing 30 G
4
C
2
-repeat-containing RNAs finds that RanGAP, a key regulator of nucleocytoplasmic transport, is a potent suppressor of neurodegeneration; the defects caused by the G
4
C
2
repeat expansions can be rescued with antisense oligonucleotides or small molecules targeting the G-quadruplexes.
A novel mechanism of neurodegeneration
The most common cause of the debilitating disease amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion GGGGCC (G4C2) in the
C9orf72
gene. Two studies in this issue use contrasting methods to arrive at a molecular mechanism that may cause a familial form of the disease. Using a candidate-based genetic screen in
Drosophila
expressing 30 G
4
C
2
repeats (Ke Zhang
et al
.) or an unbiased genetic screen in
Drosophila
expressing 8, 28 or 58 G
4
C
2
repeat-containing transcripts (Brian Freibaum
et al
.), the two groups sought genes that enhance or suppress the disease phenotype. Zhang
et al
. identify the gene encoding RanGAP, a key regulator of nucleocytoplasmic transport, and Freibaum
et al
. identifies genes that encode components of the nuclear pore and the nucleocytoplasmic transport machinery. Both papers show deficits in nucleocytoplasmic transport in
Drosophila
cells expressing G
4
C
2
repeats and in iPSC-derived neurons from ALS patients. Zhang
et al
. show that these defects can be rescued with antisense oligonucleotides or small molecules targeting the G-quadruplexes.
Journal Article
A land transformed : the Arabian Peninsula, Saudi Arabia, and Saudi Aramco
Includes information on before the oil era, Architecture of ʼAsir and Tihamah, handicrafts, The Bedouin, Neolithic tools, who is an Arab, frankincense, the Tayma stone, The prayer rug, the five pillars of Islam, the Hijri calendar and the two festivals, how Islamic science reached Europe, Arabic numerals, Arabic language, Arabic literature, the development of Islamic law, tribal settlers and nomads, rood, dress, money, music, Saudi women today, climate, falconry, crude oil, gasoline, the search for oil and gas, geology of Arabia, environmental accountability, Saudi Arabia and world energy, Makkah (Mecca), etc.
Book
The adenovirus E4orf1 protein initiates a feedback loop involving insulin and growth factor receptors, AKT, and NF-κB, leading to abnormal DNA content in infected cells
Abnormal DNA levels, such as aneuploidy and polyploidy, can indicate cellular transformation and cancer; however, the mechanisms remain poorly understood. All tumor viruses inherently cause abnormal DNA content in cells due to their oncogenes. During infections, adenovirus (Ad) oncogenes—early region 1A (E1A), early region 4 open reading frame 3 (E4orf3), and E4 open reading frame 1 (E4orf1)—promote the abnormal buildup of cellular DNA. Previous studies have described how E1A and E4orf3 lead infected cells to accumulate abnormal DNA content; however, the role of E4orf1 remains speculative. In this study, we generated cells that express E4orf1 to investigate its role in abnormal DNA content. The E4orf1-expressing cells initially exhibited no increase in DNA content compared to the control group. However, after Ad infection, they displayed higher ploidy levels. To detail how E4orf1 influences ploidy levels in Ad-infected cells, we employed pharmacological agents that target E4orf1 signaling. Our results indicate that E4orf1 enhances signaling from insulin and growth factor receptors to AKT and NF-κB, creating a feedback loop that elevates levels of cellular DNA in Ad-infected cells.
Journal Article
The Eagle has landed : 50 years of lunar science fiction
\"In celebration of the 50th anniversary of the Apollo 11 landing, the endlessly-mysterious moon is explored in this reprint short science fiction anthology from award-winning editor and anthologist Neil Clarke ... On July 20, 1969, mankind made what had only years earlier seemed like an impossible leap forward: when Apollo 11 became the first manned mission to land on the moon, and Neil Armstrong the first person to step foot on the lunar surface. While there have only been a handful of new missions since, the fascination with our planet's satellite continues, and generations of writers and artists have imagined the endless possibilities of lunar life. From adventures in the vast gulf of space between the earth and the moon, to journeys across the light face to the dark side, to the establishment of permanent residences on its surface, science fiction has for decades given readers bold and forward-thinking ideas about our nearest interstellar neighbor and what it might mean to humankind, both now and in our future. [This book] collects the best stories written in the fifty years since mankind first stepped foot on the lunar surface, serving as a shining reminder that the moon is and always has been our most visible and constant example of all the infinite possibility of the wider universe\"-- Provided by publisher.
BOOK
Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice
It has been hypothesized that α-synuclein (αS) misfolding may begin in peripheral nerves and spread to the central nervous system (CNS), leading to Parkinson disease and related disorders. Although recent data suggest that αS pathology can spread within the mouse brain, there is no direct evidence for spread of disease from a peripheral site. In the present study, we show that hind limb intramuscular (IM) injection of αS can induce pathology in the CNS in the human Ala53Thr (M83) and wild-type (M20) αS transgenic (Tg) mouse models. Within 2–3 mo after IM injection in αS homozygous M83 Tg mice and 3–4 mo for hemizygous M83 Tg mice, these animals developed a rapid, synchronized, and predictable induction of widespread CNS αS inclusion pathology, accompanied by astrogliosis, microgliosis, and debilitating motor impairments. In M20 Tg mice, starting at 4 mo after IM injection, we observed αS inclusion pathology in the spinal cord, but motor function remained intact. Transection of the sciatic nerve in the M83 Tg mice significantly delayed the appearance of CNS pathology and motor symptoms, demonstrating the involvement of retrograde transport in inducing αS CNS inclusion pathology. Outside of scrapie-mediated prion disease, to our knowledge, this findiing is the first evidence that an entire neurodegenerative proteinopathy associated with a robust, lethal motor phenotype can be initiated by peripheral inoculation with a pathogenic protein. Furthermore, this facile, synchronized rapid-onset model of α-synucleinopathy will be highly valuable in testing disease-modifying therapies and dissecting the mechanism(s) that drive αS-induced neurodegeneration.
Journal Article
RNF8 and SCML2 cooperate to regulate ubiquitination and H3K27 acetylation for escape gene activation on the sex chromosomes
The sex chromosomes are enriched with germline genes that are activated during the late stages of spermatogenesis. Due to meiotic sex chromosome inactivation (MSCI), these sex chromosome-linked genes must escape silencing for activation in spermatids, thereby ensuring their functions for male reproduction. RNF8, a DNA damage response protein, and SCML2, a germline-specific Polycomb protein, are two major, known regulators of this process. Here, we show that RNF8 and SCML2 cooperate to regulate ubiquitination during meiosis, an early step to establish active histone modifications for subsequent gene activation. Double mutants of Rnf8 and Scml2 revealed that RNF8-dependent monoubiquitination of histone H2A at Lysine 119 (H2AK119ub) is deubiquitinated by SCML2, demonstrating interplay between RNF8 and SCML2 in ubiquitin regulation. Additionally, we identify distinct functions of RNF8 and SCML2 in the regulation of ubiquitination: SCML2 deubiquitinates RNF8-independent H2AK119ub but does not deubiquitinate RNF8-dependent polyubiquitination. RNF8-dependent polyubiquitination is required for the establishment of H3K27 acetylation, a marker of active enhancers, while persistent H2AK119ub inhibits establishment of H3K27 acetylation. Following the deposition of H3K27 acetylation, H3K4 dimethylation is established as an active mark on poised promoters. Together, we propose a model whereby regulation of ubiquitin leads to the organization of poised enhancers and promoters during meiosis, which induce subsequent gene activation from the otherwise silent sex chromosomes in postmeiotic spermatids.
Journal Article
Psychoactive Pharmaceuticals Induce Fish Gene Expression Profiles Associated with Human Idiopathic Autism
Idiopathic autism, caused by genetic susceptibility interacting with unknown environmental triggers, has increased dramatically in the past 25 years. Identifying environmental triggers has been difficult due to poorly understood pathophysiology and subjective definitions of autism. The use of antidepressants by pregnant women has been associated with autism. These and other unmetabolized psychoactive pharmaceuticals (UPPs) have also been found in drinking water from surface sources, providing another possible exposure route and raising questions about human health consequences. Here, we examined gene expression patterns of fathead minnows treated with a mixture of three psychoactive pharmaceuticals (fluoxetine, venlafaxine & carbamazepine) in dosages intended to be similar to the highest observed conservative estimates of environmental concentrations. We conducted microarray experiments examining brain tissue of fish exposed to individual pharmaceuticals and a mixture of all three. We used gene-class analysis to test for enrichment of gene sets involved with ten human neurological disorders. Only sets associated with idiopathic autism were unambiguously enriched. We found that UPPs induce autism-like gene expression patterns in fish. Our findings suggest a new potential trigger for idiopathic autism in genetically susceptible individuals involving an overlooked source of environmental contamination.
Journal Article
The Monosaccharide Transporter Gene Family in Arabidopsis and Rice: A History of Duplications, Adaptive Evolution, and Functional Divergence
Current hypotheses of gene duplicate divergence propose that surviving members of a gene duplicate pair may evolve, under conditions of purifying or nearly neutral selection, in one of two ways: with new function arising in one duplicate while the other retains original function (neofunctionalization [NF]) or partitioning of the original function between the 2 paralogs (subfunctionalization [SF]). More recent studies propose that SF followed by NF (subneofunctionalization [SNF]) explains the divergence of many duplicate genes. In this analysis, we evaluate these hypotheses in the context of the large monosaccharide transporter (MST) gene families in Arabidopsis and rice. MSTs have an ancient origin, predating plants, and have evolved in the seed plant lineage to comprise 7 subfamilies. In Arabidopsis, 53 putative MST genes have been identified, with one subfamily greatly expanded by tandem gene duplications. We searched the rice genome for members of the MST gene family and compared them with the MST gene family in Arabidopsis to determine subfamily expansion patterns and estimate gene duplicate divergence times. We tested hypotheses of gene duplicate divergence in 24 paralog pairs by comparing protein sequence divergence rates, estimating positive selection on codon sites, and analyzing tissue expression patterns. Results reveal the MST gene family to be significantly larger (65) in rice with 2 subfamilies greatly expanded by tandem duplications. Gene duplicate divergence time estimates indicate that early diversification of most subfamilies occurred in the Proterozoic (2500-540 Myr) and that expansion of large subfamilies continued through the Cenozoic (65-0 Myr). Two-thirds of paralog pairs show statistically symmetric rates of sequence evolution, most consistent with the SF model, with half of those showing evidence for positive selection in one or both genes. Among 8 paralog pairs showing asymmetric divergence rates, most consistent with the NF model, nearly half show evidence of positive selection. Positive selection does not appear in any duplicate pairs younger than 34 Myr. Our data suggest that the NF, SF, and SNF models describe different outcomes along a continuum of divergence resulting from initial conditions of relaxed constraint after duplication. [PUBLICATION ABSTRACT]
Journal Article
Predicting genome terminus sequences of Bacillus cereus-group bacteriophage using next generation sequencing data
Background
Most tailed bacteriophages (phages) feature linear dsDNA genomes. Characterizing novel phages requires an understanding of complete genome sequences, including the definition of genome physical ends.
Result
We sequenced 48
Bacillus cereus
phage isolates and analyzed Next-generation sequencing (NGS) data to resolve the genome configuration of these novel phages. Most assembled contigs featured reads that mapped to both contig ends and formed circularized contigs. Independent assemblies of 31 nearly identical I48-like
Bacillus
phage isolates allowed us to observe that the assembly programs tended to produce random cleavage on circularized contigs. However, currently available assemblers were not capable of reporting the underlying phage genome configuration from sequence data. To identify the genome configuration of sequenced phage
in silico
, a terminus prediction method was developed by means of ‘neighboring coverage ratios’ and ‘read edge frequencies’ from read alignment files. Termini were confirmed by primer walking and supported by phylogenetic inference of large DNA terminase protein sequences.
Conclusions
The Terminus package using phage NGS data along with the contig circularity could efficiently identify the proximal positions of phage genome terminus. Complete phage genome sequences allow a proposed characterization of the potential packaging mechanisms and more precise genome annotation.
Journal Article