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Article ; Online: The Eµ-hnRNP K Murine Model of Lymphoma: Novel Insights into the Role of hnRNP K in B-Cell Malignancies.

Malaney, Prerna / Velasco-Estevez, María / Aguilar-Garrido, Pedro / Aitken, Marisa J L / Chan, Lauren E / Zhang, Xiaorui / Post, Sean M / Gallardo, Miguel

Frontiers in immunology

2021 Volume 12, Page(s) 634584

Abstract: ... In this article, we discuss a new driver of B-cell lymphomas - hnRNP K (heterogenous nuclear ribonucleoprotein K ...

Abstract	B-cell lymphomas are one of the most biologically and molecularly heterogeneous group of malignancies. The inherent complexity of this cancer subtype necessitates the development of appropriate animal model systems to characterize the disease with the ultimate objective of identifying effective therapies. In this article, we discuss a new driver of B-cell lymphomas - hnRNP K (heterogenous nuclear ribonucleoprotein K)-an RNA-binding protein. We introduce the
MeSH term(s)	Animals ; Animals, Genetically Modified ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; B-Lymphocytes/pathology ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/immunology ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease ; Heterogeneous-Nuclear Ribonucleoprotein K/genetics ; Heterogeneous-Nuclear Ribonucleoprotein K/metabolism ; Lymphoma, B-Cell/genetics ; Lymphoma, B-Cell/immunology ; Lymphoma, B-Cell/metabolism ; Lymphoma, B-Cell/pathology ; Phenotype ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Up-Regulation
Chemical Substances	Heterogeneous-Nuclear Ribonucleoprotein K ; MYC protein, human ; Proto-Oncogene Proteins c-myc
Language	English
Publishing date	2021-04-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.634584
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Article ; Online: Heterogeneous nuclear ribonucleoprotein K is overexpressed in acute myeloid leukemia and causes myeloproliferation in mice via altered

Aitken, Marisa J L / Malaney, Prerna / Zhang, Xiaorui / Herbrich, Shelley M / Chan, Lauren / Benitez, Oscar / Rodriguez, Ashley G / Ma, Huaxian / Jacamo, Rodrigo / Duan, Ruizhi / Link, Todd M / Kornblau, Steven M / Kanagal-Shamanna, Rashmi / Bueso-Ramos, Carlos E / Post, Sean M

NAR cancer

2022 Volume 4, Issue 4, Page(s) zcac039

Abstract: ... to disease progression. Herein, we identify hnRNP K overexpression as a recurrent abnormality in AML that negatively ... correlates with patient survival. Overexpression of hnRNP K in murine fetal liver cells results in altered ... self-renewal and differentiation potential. Further, murine transplantation models reveal that hnRNP K ...

Abstract	Acute myeloid leukemia (AML) is driven by numerous molecular events that contribute to disease progression. Herein, we identify hnRNP K overexpression as a recurrent abnormality in AML that negatively correlates with patient survival. Overexpression of hnRNP K in murine fetal liver cells results in altered self-renewal and differentiation potential. Further, murine transplantation models reveal that hnRNP K overexpression results in myeloproliferation
Language	English
Publishing date	2022-12-09
Publishing country	England
Document type	Journal Article
ISSN	2632-8674
ISSN (online)	2632-8674
DOI	10.1093/narcan/zcac039
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Article ; Online: Uncovering the Role of RNA-Binding Protein hnRNP K in B-Cell Lymphomas.

Journal of the National Cancer Institute

2019 Volume 112, Issue 1, Page(s) 95–106

Abstract: Background: Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an RNA-binding protein that is ... aberrantly expressed in cancers. We and others have previously shown that reduced hnRNP K expression ... downmodulates tumor-suppressive programs. However, overexpression of hnRNP K is the more commonly observed ...

Abstract	Background: Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an RNA-binding protein that is aberrantly expressed in cancers. We and others have previously shown that reduced hnRNP K expression downmodulates tumor-suppressive programs. However, overexpression of hnRNP K is the more commonly observed clinical phenomenon, yet its functional consequences and clinical significance remain unknown. Methods: Clinical implications of hnRNP K overexpression were examined through immunohistochemistry on samples from patients with diffuse large B-cell lymphoma who did not harbor MYC alterations (n = 75). A novel transgenic mouse model that overexpresses hnRNP K specifically in B cells was generated to directly examine the role of hnRNP K overexpression in mice (three transgenic lines). Molecular consequences of hnRNP K overexpression were determined through proteomics, formaldehyde-RNA-immunoprecipitation sequencing, and biochemical assays. Therapeutic response to BET-bromodomain inhibition in the context of hnRNP K overexpression was evaluated in vitro and in vivo (n = 3 per group). All statistical tests were two-sided. Results: hnRNP K is overexpressed in diffuse large B-cell lymphoma patients without MYC genomic alterations. This overexpression is associated with dismal overall survival and progression-free survival (P < .001). Overexpression of hnRNP K in transgenic mice resulted in the development of lymphomas and reduced survival (P < .001 for all transgenic lines; Line 171[n = 30]: hazard ratio [HR] = 64.23, 95% confidence interval [CI] = 26.1 to 158.0; Line 173 [n = 31]: HR = 25.27, 95% CI = 10.3 to 62.1; Line 177 [n = 25]: HR = 119.5, 95% CI = 42.7 to 334.2, compared with wild-type mice). Clinical samples, mouse models, global screening assays, and biochemical studies revealed that hnRNP K's oncogenic potential stems from its ability to posttranscriptionally and translationally regulate MYC. Consequently, Hnrnpk overexpression renders cells sensitive to BET-bromodomain-inhibition in both in vitro and transplantation models, which represents a strategy for mitigating hnRNP K-mediated c-Myc activation in patients. Conclusion: Our findings indicate that hnRNP K is a bona fide oncogene when overexpressed and represents a novel mechanism for c-Myc activation in the absence of MYC lesions.
MeSH term(s)	Adult ; Aged ; Animals ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Disease Models, Animal ; Disease Susceptibility ; Female ; Gene Expression ; Gene Expression Regulation, Neoplastic ; Heterogeneous-Nuclear Ribonucleoprotein K/chemistry ; Heterogeneous-Nuclear Ribonucleoprotein K/genetics ; Heterogeneous-Nuclear Ribonucleoprotein K/metabolism ; Humans ; Lymphoma, B-Cell/etiology ; Lymphoma, B-Cell/metabolism ; Lymphoma, B-Cell/mortality ; Lymphoma, B-Cell/pathology ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Neoplasm Staging ; Phenotype ; Protein Binding ; Protein Interaction Domains and Motifs/drug effects ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism
Chemical Substances	Antineoplastic Agents ; Heterogeneous-Nuclear Ribonucleoprotein K ; RNA-Binding Proteins ; HNRNPK protein, human (146410-60-8)
Language	English
Publishing date	2019-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djz078
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Book ; Online: A new non-extensive equation of state for the fluid phases of argon for temperatures from the melting line to 2300 K and pressures up to 50 GPa, based on an original approach including the metastable states

Aitken, F. / Denat, A. / Volino, F.

2015

Abstract: ... The new formulation is valid for the whole fluid region from the melting line to 2300 K and for pressures ... between the triple point temperature and 148 K. ... Comment: 93 pages, 53 figures, 12 tables, 3 appendix ...

Abstract	A new equation of state for argon has been developed in view to extend the range of validity of the equation of state previously proposed by Tegeler et al. (Ref. 4) and to obtain a better physical description of the experimental thermodynamic data for the whole fluid region (single-phase, metastable and saturation states). As proposed by Tegeler et al., this equation is also based on a functional form of the residual part of the reduced Helmholtz free energy. However in this work, the fundamental equation for the Helmholtz free energy has been derived from the measured quantities CV(rho,T) and P(rho,T). The empirical description of the isochoric heat capacity CV(rho,T) is based on an original empirical description containing explicitly the metastable states. The thermodynamic properties (internal energy, entropy, free energy) are then obtained by combining integration of CV(rho,T). The arbitrary functions introduced by the integration process have been deduced from a comparison between calculated and experimental pressure P(rho,T) data. The new formulation is valid for the whole fluid region from the melting line to 2300 K and for pressures up to 50 GPa. It also predicts existence of a maximum of the isochoric heat capacity CV along isochors as experimentally observed in several other fluids. For many applications, an approximate form of the equation of state for the liquid phase may be sufficient. A Tait-Tammann equation is therefore proposed between the triple point temperature and 148 K. Comment: 93 pages, 53 figures, 12 tables, 3 appendix
Keywords	Condensed Matter - Statistical Mechanics ; Condensed Matter - Materials Science ; Condensed Matter - Soft Condensed Matter
Subject code	541
Publishing date	2015-03-31
Publishing country	us
Document type	Book ; Online
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Article: History and Development of Molecular Markers for Sugarcane Breeding

Aitken, K. S.

Sugar tech. 2022 Feb., v. 24, no. 1

2022

Abstract: Sugarcane (Saccharum spp. hybrids) is one of the world’s most important economic crops for both the food and biofuel industries. It has one of the most complex genomes of any crop plant, varieties are unbalanced polyploids and derived from interspecific ... ...

Abstract	Sugarcane (Saccharum spp. hybrids) is one of the world’s most important economic crops for both the food and biofuel industries. It has one of the most complex genomes of any crop plant, varieties are unbalanced polyploids and derived from interspecific hybridisation between the domesticated Saccharum officinarum and a wild relative S. spontaneum. Here I review sugarcane’s complex genetics and chart the history of DNA marker development in sugarcane over the last 30 years. Despite its complex autopolyploid genome of over 100 chromosomes, marker development has spanned the first hybridisation-based markers, restriction fragment length polymorphism markers (RFLP) to the high-throughput next generation sequence methods currently used to detect single nucleotide polymorphism (SNP). Although there is a long history of research and development in sugarcane, it is only comparatively recently that marker technology has caught up with the need for discovery of large numbers of single-dose SNP markers and methods for genotyping that are fast, efficient and cost-effective that can be used for selection in a breeding program. The choice of genotyping platform depends on the breeding application and both whole genome SNP methods (array-based and genotype-by-sequencing (GBS)) and low density scalable and cost-effective platform technologies have a place in sugarcane breeding.
Keywords	Saccharum officinarum ; autopolyploidy ; biofuels ; cost effectiveness ; crops ; genetic markers ; genome ; genotyping ; interspecific hybridization ; research and development ; restriction fragment length polymorphism ; single nucleotide polymorphism ; sugarcane ; sugars ; wild relatives
Language	English
Dates of publication	2022-02
Size	p. 341-353.
Publishing place	Springer India
Document type	Article
ZDB-ID	2433394-3
ISSN	0974-0740 ; 0972-1525
ISSN (online)	0974-0740
ISSN	0972-1525
DOI	10.1007/s12355-021-01000-7
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Article ; Online: When Less is More: The Rising Tide of Hypofractionation.

Aitken, K / Mukherjee, S

Clinical oncology (Royal College of Radiologists (Great Britain))

2022 Volume 34, Issue 5, Page(s) 277–279

MeSH term(s)	Dose Fractionation, Radiation ; Humans ; Radiation Dose Hypofractionation
Language	English
Publishing date	2022-03-16
Publishing country	England
Document type	Editorial
ZDB-ID	1036844-9
ISSN	1433-2981 ; 0936-6555
ISSN (online)	1433-2981
ISSN	0936-6555
DOI	10.1016/j.clon.2022.03.002
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Article: Identification, characterization and deduced amino acid sequence of the dominant protease from Kudoa paniformis and K. thyrsites: a unique cytoplasmic cysteine protease.

Funk, Valerie A / Olafson, Robert W / Raap, Monique / Smith, Derek / Aitken, Laura / Haddow, Jody D / Wang, Diana / Dawson-Coates, Jennifer A / Burke, Robert D / Miller, Kristina M

Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology

2008 Volume 149, Issue 3, Page(s) 477–489

Abstract: ... terminal sequence analysis of partially purified protease from hake muscle infected with K. paniformis and ... K. thyrsites revealed a 23 amino acid sequence that aligned with cysteine proteases ... Enzyme inhibition assays confirmed the presence of an essential active site cysteine residue. Using the above K ...

Abstract	Kudoa paniformis and Kudoa thyrsites (Myxozoa: Myxosporea) infections are associated with severe proteolysis of host muscle tissue post-mortem. The present study was undertaken to identify and characterize the protease responsible for myoliquefaction and determine mechanisms controlling protease function in vivo. N-terminal sequence analysis of partially purified protease from hake muscle infected with K. paniformis and K. thyrsites revealed a 23 amino acid sequence that aligned with cysteine proteases. Enzyme inhibition assays confirmed the presence of an essential active site cysteine residue. Using the above K. paniformis amino acid sequence data, a corresponding cDNA sequence from K. thyrsites plasmodia was elucidated revealing a cathepsin L proenzyme (Kth-CL). The translated amino acid sequence lacked a signal sequence characteristic of lysosomal and secreted proteins suggesting a unique cytoplasmic location. Only the proenzyme form of Kth-CL was present in Atlantic salmon muscle anti-mortem but this form became processed in vivo when infected muscle was stored at 4 degrees C. The proenzyme of Kth-CL showed uninhibited activity at pH 6.0, negligible activity at pH 6.5 and no measurable activity at pH 7.0 whilst the processed protease showed stability and function over a broad pH range (pH 4.5-8.8). The pH dependent processing and function of Kth-CL was consistent with histidine residues in the proregion playing a critical role in the regulation of Kth-CL.
MeSH term(s)	Amino Acid Sequence ; Animals ; Cathepsin L ; Cathepsins/chemistry ; Cathepsins/metabolism ; Chromatography, High Pressure Liquid ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/metabolism ; Cytoplasm/drug effects ; Cytoplasm/enzymology ; DNA, Complementary/genetics ; Electrophoresis, Polyacrylamide Gel ; Eukaryota/drug effects ; Eukaryota/enzymology ; Fluorescent Antibody Technique ; Gadiformes/parasitology ; Hydrogen-Ion Concentration ; Molecular Sequence Data ; Muscle Proteins/isolation & purification ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/parasitology ; Protease Inhibitors/pharmacology ; Protozoan Infections, Animal/enzymology ; Protozoan Infections, Animal/parasitology ; Salmo salar/parasitology ; Sequence Analysis, DNA
Chemical Substances	DNA, Complementary ; Muscle Proteins ; Protease Inhibitors ; Cathepsins (EC 3.4.-) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Cathepsin L (EC 3.4.22.15)
Language	English
Publishing date	2008-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	121247-3
ISSN	1879-1107 ; 1096-4959 ; 0305-0491
ISSN (online)	1879-1107
ISSN	1096-4959 ; 0305-0491
DOI	10.1016/j.cbpb.2007.11.011
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Article ; Online: Neural population dynamics of computing with synaptic modulations.

Aitken, Kyle / Mihalas, Stefan

eLife

2023 Volume 12

Abstract: In addition to long-timescale rewiring, synapses in the brain are subject to significant modulation that occurs at faster timescales that endow the brain with additional means of processing information. Despite this, models of the brain like recurrent ... ...

Abstract	In addition to long-timescale rewiring, synapses in the brain are subject to significant modulation that occurs at faster timescales that endow the brain with additional means of processing information. Despite this, models of the brain like recurrent neural networks (RNNs) often have their weights frozen after training, relying on an internal state stored in neuronal activity to hold task-relevant information. In this work, we study the computational potential and resulting dynamics of a network that relies solely on synapse modulation during inference to process task-relevant information, the multi-plasticity network (MPN). Since the MPN has no recurrent connections, this allows us to study the computational capabilities and dynamical behavior contributed by synapses modulations alone. The generality of the MPN allows for our results to apply to synaptic modulation mechanisms ranging from short-term synaptic plasticity (STSP) to slower modulations such as spike-time dependent plasticity (STDP). We thoroughly examine the neural population dynamics of the MPN trained on integration-based tasks and compare it to known RNN dynamics, finding the two to have fundamentally different attractor structure. We find said differences in dynamics allow the MPN to outperform its RNN counterparts on several neuroscience-relevant tests. Training the MPN across a battery of neuroscience tasks, we find its computational capabilities in such settings is comparable to networks that compute with recurrent connections. Altogether, we believe this work demonstrates the computational possibilities of computing with synaptic modulations and highlights important motifs of these computations so that they can be identified in brain-like systems.
MeSH term(s)	Brain/physiology ; Neural Networks, Computer ; Synapses ; Neuronal Plasticity
Language	English
Publishing date	2023-02-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.83035
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Article ; Online: Open Approach to the Transversus Abdominis Plane in Horses: A Cadaver Feasibility Study.

Aitken, Maia R / Floriano, Dario A / Hopster, Klaus

Veterinary sciences

2024 Volume 11, Issue 1

Abstract: The study's objective was to evaluate the feasibility and dispersion of an open approach to the transversus abdominis plane (TAP) block in eight adult equine cadavers. A ventral midline incision was made, starting 2 cm cranial to the umbilicus and ... ...

Abstract	The study's objective was to evaluate the feasibility and dispersion of an open approach to the transversus abdominis plane (TAP) block in eight adult equine cadavers. A ventral midline incision was made, starting 2 cm cranial to the umbilicus and extending 25 cm cranially. In total, 0.5 mL/kg of new methylene blue (NMB) was injected per horse, divided into six injections. Using an 18 g, 8 cm Tuohy needle, three injections were made per side. The needle was guided blindly into the TAP using palpation. A 60 mL syringe was attached directly to the needle, depositing ~0.08 mL/kg at each site. The time to complete the injections was recorded for each cadaver. Following injection, the ventral body wall was dissected to determine if the dye was present within the TAP space as well as to measure the extent of the dispersion of the dye, the cranial to caudal extent, and the width of the dye's spread. Complete deposition of NMB into the TAP (six of six sites) was achieved in 5/8 horses. The median time needed to perform all the injections was 263 s. Increased adiposity (retroperitoneal fat) was associated with unsuccessful injections. This approach to the TAP was easily and quickly performed, though less successful in horses with increased retroperitoneal fat and increased BCS.
Language	English
Publishing date	2024-01-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2768971-2
ISSN	2306-7381 ; 2306-7381
ISSN (online)	2306-7381
ISSN	2306-7381
DOI	10.3390/vetsci11010051
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Article: Block of (Na+,K+)ATPase with ouabain induces spreading depression-like depolarization in hippocampal slices.

Balestrino, M / Young, J / Aitken, P

Brain research

1999 Volume 838, Issue 1-2, Page(s) 37–44

Abstract: We used ouabain (100 microM) to block Na+,K(+)ATPase of in vitro rat hippocampal slices ... and sudden increase in [K](o), also reminiscent of that observed during both SD and AD. Ouabain ... induced SD did not require a complete inactivation of Na+,K(+)ATPase, as it occurred when the enzyme was ...

Abstract	We used ouabain (100 microM) to block Na+,K(+)ATPase of in vitro rat hippocampal slices. This treatment was sufficient to cause the sudden depolarization that is the hallmark of both spreading depression (SD) and of the SD-like anoxic depolarization (AD). This depolarization was accompanied by a large and sudden increase in [K](o), also reminiscent of that observed during both SD and AD. Ouabain-induced SD did not require a complete inactivation of Na+,K(+)ATPase, as it occurred when the enzyme was still capable of providing recovery of both V(o) and [K](o). The data indicate that functional inactivation of Na+,K(+)ATPase per se initiates events that lead to an SD-like AD. This ouabain-induced depolarization was not affected by block of synaptic transmission, instead it was abolished by hyperosmolarity of the extracellular space. The possible relevance of these findings to the pathophysiology of AD is discussed.
MeSH term(s)	Animals ; Cortical Spreading Depression ; Evoked Potentials/drug effects ; Female ; Hippocampus/drug effects ; In Vitro Techniques ; Male ; Membrane Potentials/drug effects ; Ouabain/pharmacology ; Potassium/pharmacology ; Rats ; Rats, Sprague-Dawley ; Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors
Chemical Substances	Ouabain (5ACL011P69) ; Sodium-Potassium-Exchanging ATPase (EC 3.6.3.9) ; Potassium (RWP5GA015D)
Language	English
Publishing date	1999-08-14
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/s0006-8993(99)01674-1
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