How BRCA1 deficiency affects emergency granulopoeisis in cells

BRCA1 mutation carriers are predisposed to breast and ovarian cancer. Chemotherapy is a common treatment used in breast cancer patients. However, chemotherapy can cause damage to bone marrow. Bone marrow is responsible for the production of white blood cells, namely neutrophils, which are the first line of defense in the innate immune system2. When an infectious or inflammatory challenge presents itself, neutrophils are used up in large quantities, and the hematopoietic system in the body has to rapidly adapt to increased demands by switching from the process of steady-state granulopoeisis to emergency granulopoeisis3. Evidence has shown that BRCA1 mutation carriers who have undergone chemotherapy treatment experience low counts of neutrophils1. Additional evidence has shown that the Fanconi gene pathway contributes to genomic stability during emergency granulopoeisis, and increased Fanconi C (Fancc) gene expression contributes to emergency granulopoeisis4. Since the BRCA1 gene is downstream of the FANCC gene, a myeloid leukemia cell line (U937) was tested to determine whether BRCA1 deficiency contributes to emergency granulopoeisis as well. Different concentrations of the protein IL-1Beta was added to the cells in order to mimic the emergency granulopoeisis response, and both FANCC and BRCA1 gene expression was measured. The general trend for the expression of both genes was found to be different than has previously been reported4. Shanley S et al. Clin Cancer Res. 2006; 12(23): 7033-7038. Kolaczkowzka E et al. Nat Rev Immunol. 2013; 13(3): 159-175. Manz M et al. Nature Reviews Immunology. 2014; 14: 302-314. Hu L et al. J Clin Invest. 2013; 123(9): 3952-3966

Energy aware topology control protocols for wireless sensor networks

Wireless Sensor Network has emerged as an important technology of the future due to its potential for application across a wide array of domains. The collaborative power of numerous autonomousremote sensing nodes self configured into a multi hop network permits in-depth accurate observation of any physical phenomenon. A stringent set of computational and resource constraints make the design and implementation of sensor networks an arduous task. The issue of optimizing the limited and often non-renewable energy of sensor nodes due to its direct impact on network lifetime dominates every aspect of wireless sensor networks. Existing techniques for optimizing energy consumption are based on exploiting node redundancy, adaptive radio transmission power and topology control. Topology control protocols significantly impact network lifetime, routing algorithms and connectivity. We classify sensor nodes as strong and weak nodes based on their residual energy and propose a novel topology control protocol (NEC) which extends network lifetime while guarantying minimum connectivity. Extensive simulations in Network-Simulator (ns-2) show that our protocol outperforms the existing protocols in terms of various performance metrics. We further explore the effectiveness of data aggregation paradigm as a solution to the dominant problem of maximizing energy utilization and increasing network bandwidth utilization in sensor networks. We propose a novel energy efficient data aggregation protocol based on the well-known k-Means algorithm. Our protocol achieves energy efficiency by reduced number of data transmissions at each level of a hierarchical sensor network. Our protocol exploits the spatial and temporal coherence between the data sensed by neighboring sensor nodes in a cluster to reduce the number of packet transmissions. Sensor nodes apply k-Means algorithm to the raw data to generate a reduced set of mean values and forward this modified data set to cluster-head nodes. We further prove the effectiveness of our protocol in providing increased energy conservation in the network by extensive simulation results

Galectin-3 synergizes with CD47 to Suppress Phagocytosis and T cell immunity in Peritoneal Metastases of Gastric Adenocarcinoma

View full abstracthttps://openworks.mdanderson.org/leading-edge/1061/thumbnail.jp

Chemotherapy-Induced Late Transgenerational Effects in Mice

To our knowledge, there is no report on long-term reproductive and developmental side effects in the offspring of mothers treated with a widely used chemotherapeutic drug such as doxorubicin (DXR), and neither is there information on transmission of any detrimental effects to several filial generations. Therefore, the purpose of the present paper was to examine the long-term effects of a single intraperitoneal injection of DXR on the reproductive and behavioral performance of adult female mice and their progeny. C57BL/6 female mice (generation zero; G0) were treated with either a single intraperitoneal injection of DXR (G0-DXR) or saline (G0-CON). Data were collected on multiple reproductive parameters and behavioral analysis for anxiety, despair and depression. In addition, the reproductive capacity and health of the subsequent six generations were evaluated. G0-DXR females developed despair-like behaviors; delivery complications; decreased primordial follicle pool; and early lost of reproductive capacity. Surprisingly, the DXR-induced effects in oocytes were transmitted transgenerationally; the most striking effects being observed in G4 and G6, constituting: increased rates of neonatal death; physical malformations; chromosomal abnormalities (particularly deletions on chromosome 10); and death of mothers due to delivery complications. None of these effects were seen in control females of the same generations. Long-term effects of DXR in female mice and their offspring can be attributed to genetic alterations or cell-killing events in oocytes or, presumably, to toxicosis in non-ovarian tissues. Results from the rodent model emphasize the need for retrospective and long-term prospective studies of survivors of cancer treatment and their offspring

By

I would like to express my sincere gratitude to my major professor Dr. Rajgopal Kannan and the co-chair of my committee Dr. Anitra Wilson for their valuable insight, guidance and inspiration throughout this thesis work. I would further like to extend my gratitude to my committee members Dr. Arjan Durresi and Dr. Bijaya B. Karki for their invaluable suggestions and guidance. ii Table of Contents Acknowledgments....................................... i

Screening Unnatural Fluorescent Amino Acids for Incorporation into E. Coli Cellular Machinery

Fluorescence can be used in optical imaging to view cell activity in vivo. Fluorescent proteins and organic dyes are the primary method of visually tracking biomolecules in vivo. However, several research groups have also incorporated unnatural fluorescent amino acids (UFAAs) into proteins for in vivo analysis of said proteins. However, only a handful of UFAAs have been successfully incorporated into proteins using this method (sometimes called the amber suppression method)1. To expand the library of UFAAs viable for cell imaging, several UFAAs were tested in a Green Fluorescent Protein (GFP) screening system to determine if these UFAAs could be incorporated into GFP in response to an amber stop codon using previously developed ‘promiscuous’ tRNA-aaRS (aminoacyl tRNA synthetase) pairs2. This incorporation was quantified by fluorescence readings of mutated green fluorescent protein (GFP). The GFP was mutated to have a TAG (stop) codon deactivating its fluorescence. This deactivation could be overcome by the incorporation of a UFAA in response to the TAG codon, achieved by insertion of the UFAA by the tRNA specific to this codon. Several different UFAAs and several different amber suppression based tRNA/aaRS pairs were analyzed with this screening system, and the viability of these UFAAs to be incorporated into proteins using available amber suppression systems assessed. 1. Lampkowski, Jessica S.; Uthappa, Diya M.; Young, Douglas D.. Site-specific incorporation of a fluorescent terphenyl unnatural amino acid. Bioorg. Med. Chem. Lett. 2015, Available online 25 September 2015, accessed 10 October 2015. 2. Wang, Feng; Niu, Wei; Guo, Jianto; Schultz, Peter G.. Unnatural Amino Acid Mutagenesis of Fluorescent Proteins. Angew. Chem. Int. Ed. 2012, 51, 10132 –10135

GABAergic effect of valeric acid from Valeriana wallichii in amelioration of ICV STZ induced dementia in rats

Valeriana wallichii DC., Caprifoliaceae, is used to have anti-ulcer, anti-spasmodic, anti-epileptic, memory enhancer, anti-anxiety, anti-rheumatic, sedative, anti-asthmatic and diuretic activities. V. wallichii is reported to contain valpotriates, valeric acid, valerenic acid, valechlorine, valerianine, resins and alkaloids. Valeric acid, found in V. wallichii appears similar in structure to the neurotransmitter GABA. Valeric acid also acts as an NMDA-receptor antagonist. The aim of present study was to investigate the neuroprotective effect of V. wallichii containing valeric acid and its possible mechanism of action in amelioration of intracerebroventricular streptozotocin induced neurodegeneration in Wistar rats. The rhizomes of V. wallichii were powdered coarsely and extracted by percolation method using dichloromethane. Wistar rats (220⿿250 g) of either sex were divided into 5 groups, comprising 6 animals each. Valeric acid was isolated from plant extract and characterized using FT-IR. Picrotoxin (2 mg/kg) was used as GABA-A antagonist. Intracerebroventricular streptozotocin administration caused significant (p < 0.05) increase in escape latency, retention transfer latency on morris water maze on 17th, 18th, 19th and 20th day and elevated plus maze on 19th and 20th day respectively, as compared to normal untreated rats. Treatment with V. wallichii extract 100 and 200 mg/kg and valeric acid 20 and 40 mg/kg significantly decreased the escape latency and retention transfer latency, as compared to intracerebroventricular-streptozotocin group. Plant extract and valeric acid also decreased the level of lipid peroxidation and restored glutathione level in rat brains. Administration of picrotoxin significantly reversed the effects produced by plant extract and valeric acid in intracerebroventricular-streptozotocin treated rats. The findings may conclude that valeric acid present in V. wallichii has significant GABAergic effect in amelioration of experimental dementia. Keywords: GABA, Alzheimer's, Valeric acid, Dementia, Streptozotocin, Memor

Stability of non-proteinogenic amino acids to UV and gamma irradiation

Almost all living organisms on Earth utilize the same 20 amino acids to build their millions of different proteins, even though there are hundreds of amino acids naturally occurring on Earth. Although it is likely that both the prebiotic and the current environment of Earth shaped the selection of these 20 proteinogenic amino acids, environmental conditions on extraterrestrial planets and moons are known to be quite different than those on Earth. In particular, the surfaces of planets and moons such as Mars, Europa and Enceladus have a much greater flux of UV and gamma radiation impacting their surface than that of Earth. Thus, if life were to have evolved extraterrestrially, a different lexicon of amino acids may have been selected due to different environmental pressures, such as higher radiation exposure. One fundamental property an amino acid must have in order to be of use to the evolution of life is relative stability. Therefore, we studied the stability of three different proteinogenic amino acids (tyrosine, phenylalanine and tryptophan) as compared with 20 non-proteinogenic amino acids that were structurally similar to the aromatic proteinogenic amino acids, following ultraviolet (UV) light (254, 302, or 365 nm) and gamma-ray irradiation. The degree of degradation of the amino acids was quantified using an ultra-high performance liquid chromatography-mass spectrometer (UPLC-MS). The result showed that many non-proteinogenic amino acids had either equal or increased stability to certain radiation wavelengths as compared with their proteinogenic counterparts, with fluorinated phenylalanine and tryptophan derivatives, in particular, exhibiting enhanced stability as compared with proteinogenic phenylalanine and tryptophan amino acids following gamma and select UV irradiation