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  • 1
    Publication Date: 2015-04-22
    Description: Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528969/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528969/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Najm, Fadi J -- Madhavan, Mayur -- Zaremba, Anita -- Shick, Elizabeth -- Karl, Robert T -- Factor, Daniel C -- Miller, Tyler E -- Nevin, Zachary S -- Kantor, Christopher -- Sargent, Alex -- Quick, Kevin L -- Schlatzer, Daniela M -- Tang, Hong -- Papoian, Ruben -- Brimacombe, Kyle R -- Shen, Min -- Boxer, Matthew B -- Jadhav, Ajit -- Robinson, Andrew P -- Podojil, Joseph R -- Miller, Stephen D -- Miller, Robert H -- Tesar, Paul J -- F30 CA183510/CA/NCI NIH HHS/ -- F30CA183510/CA/NCI NIH HHS/ -- NS026543/NS/NINDS NIH HHS/ -- NS030800/NS/NINDS NIH HHS/ -- NS085246/NS/NINDS NIH HHS/ -- P30 CA043703/CA/NCI NIH HHS/ -- P30CA043703/CA/NCI NIH HHS/ -- R01 NS026543/NS/NINDS NIH HHS/ -- R01 NS030800/NS/NINDS NIH HHS/ -- R21 NS085246/NS/NINDS NIH HHS/ -- T32 GM007250/GM/NIGMS NIH HHS/ -- T32 GM008056/GM/NIGMS NIH HHS/ -- T32GM008056/GM/NIGMS NIH HHS/ -- UL1 TR000439/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Jun 11;522(7555):216-20. doi: 10.1038/nature14335. Epub 2015 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. ; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. ; 1] Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA [2] Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA [3] Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. ; PerkinElmer, 940 Winter Street, Waltham, Massachusetts 02451, USA. ; Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. ; Drug Discovery Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237, USA. ; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA. ; Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, Illinois 60611, USA. ; 1] Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA [2] Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25896324" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation/drug effects ; Cerebellum/drug effects/metabolism/pathology ; Clobetasol/*pharmacology ; Demyelinating Diseases/drug therapy/metabolism/pathology ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental/drug therapy/metabolism/pathology ; Female ; Germ Layers/drug effects/metabolism/pathology ; Humans ; Lysophosphatidylcholines ; MAP Kinase Signaling System ; Male ; Mice ; Miconazole/*pharmacology ; Mitogen-Activated Protein Kinases/metabolism ; Multiple Sclerosis/*drug therapy/*metabolism/pathology ; Myelin Sheath/*drug effects/*metabolism ; Oligodendroglia/cytology/drug effects/metabolism ; Phenotype ; Pluripotent Stem Cells/cytology/*drug effects/metabolism ; Receptors, Glucocorticoid/metabolism ; Regeneration/drug effects ; Tissue Culture Techniques
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2019-07-13
    Description: The present paper investigates the temperature structure of the X-ray emitting plasma in the core of the Perseus cluster using the 1.8-20.0 keV data obtained with the Soft X-ray Spectrometer (SXS) onboard the Hitomi Observatory. A series of four observations were carried out, with a total effective exposure time of 338 ks and covering a central region _ 7 in diameter. The SXS was operated with an energy resolution of _5 eV (full width at half maximum) at 5.9 keV. Not only fine structures of K-shell lines in He-like ions but also transitions from higher principal quantum numbers are clearly resolved from Si through Fe. This enables us to perform temperature diagnostics using the line ratios of Si, S, Ar, Ca, and Fe, and to provide the first direct measurement of the excitation temperature and ionization temperature in the Perseus cluster. The observed spectrum is roughly reproduced by a single temperature thermal plasma model in collisional ionization equilibrium, but detailed line ratio diagnostics reveal slight deviations from this approximation. In particular, the data exhibit an apparent trend of increasing ionization temperature with increasing atomic mass, as well as small differences between the ionization and excitation temperatures for Fe, the only element for which both temperatures can be measured. The best-fit two-temperature models suggest a combination of 3 and 5 keV gas, which is consistent with the idea that the observed small deviations from a single temperature approximation are due to the effects of projection of the known radial temperature gradient in the cluster core along the line of sight. Comparison with the Chandra/ACIS and the XMM-Newton/RGS results on the other hand suggests that additional lower-temperature components
    Keywords: Astrophysics
    Type: GSFC-E-DAA-TN54095 , Publications of the Astronomical Society of Japan (ISSN 0004-6264) (e-ISSN 2053-051X); 70; 2
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  • 3
    Publication Date: 2019-07-13
    Description: We present a detailed spectral analysis of XMM-Newton and NuSTAR observations of the accreting transient black hole GRS1739278 during a very faint low hard state at 0.02% of the Eddington luminosity (for a distance of 8.5 kpc and a mass of 10 solar mass). The broadband X-ray spectrum between 0.5 and 60 keV can be well-described by a power-law continuum with an exponential cutoff. The continuum is unusually hard for such a low luminosity, with a photon index of =1.39+/-0.04. We find evidence for an additional reflection component from an optically thick accretion disk at the 98% likelihood level. The reflection fraction is low, with R(sub refl) = 0.043(exp + 0.033)(sub - 0.023). In combination with measurements of the spin and inclination parameters made with NuSTAR during a brighter hard state by Miller et al., we seek to constrain the accretion disk geometry. Depending on the assumed emissivity profile of the accretion disk, we find a truncation radius of 15-35 R(sub g) (5-12 R(sub ISCO)) at the 90% confidence limit. These values depend strongly on the assumptions and we discuss possible systematic uncertainties.
    Keywords: Astrophysics
    Type: GSFC-E-DAA-TN60680 , The Astrophysical Journal (ISSN 0004-637X) (e-ISSN 1538-4357); 832; 2; 115
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  • 4
    Publication Date: 2019-07-13
    Description: The Large Observatory For x-ray Timing (LOFT) is a mission concept which was proposed to ESA as M3 and M4 candidate in the framework of the Cosmic Vision 2015-2025 program. Thanks to the unprecedented combination of effective area and spectral resolution of its main instrument and the uniquely large field of view of its wide field monitor, LOFT will be able to study the behaviour of matter in extreme conditions such as the strong gravitational field in the innermost regions close to black holes and neutron stars and the supra-nuclear densities in the interiors of neutron stars. The science payload is based on a Large Area Detector (LAD, is greater than 8m2 effective area, 2-30 keV, 240 eV spectral resolution, 1 degree collimated field of view) and a Wide Field Monitor (WFM, 2-50 keV, 4 steradian field of view, 1 arcmin source location accuracy, 300 eV spectral resolution). The WFM is equipped with an on-board system for bright events (e.g., GRB) localization. The trigger time and position of these events are broadcast to the ground within 30 s from discovery. In this paper we present the current technical and programmatic status of the mission.
    Keywords: Astrophysics
    Type: GSFC-E-DAA-TN44111 , SPIE Astronomical Telescopes + Instrumentation; Jun 26, 2016 - Jul 01, 2016; Edinburgh, Scotland; United Kingdom|Space Telescopes and Instrumentation 2016: Ultraviolet to Gamma Ray; 9905; 99051R
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  • 5
    Publication Date: 2019-07-13
    Description: Arcus will be proposed to the NASA Explorer program as a free-flying satellite mission that will enable high-resolution soft X-ray spectroscopy (8-50 Angstroms) with unprecedented sensitivity-effective areas of greater than 500 sq cm and spectral resolution greater than 2500. The Arcus key science goals are (1) to determine how baryons cycle in and out of galaxies by measuring the effects of structure formation imprinted upon the hot gas that is predicted to lie in extended halos around galaxies, groups, and clusters, (2) to determine how black holes influence their surroundings by tracing the propagation of out-flowing mass, energy and momentum from the vicinity of the black hole out to large scales and (3) to understand how accretion forms and evolves stars and circumstellar disks by observing hot infalling and outflowing gas in these systems. Arcus relies upon grazing incidence silicon pore X-ray optics with the same 12m focal length (achieved using an extendable optical bench) that will be used for the ESA Athena mission. The focused X-rays from these optics will then be diffracted by high-efficiency off-plane reflection gratings that have already been demonstrated on sub-orbital rocked flights, imaging the results with flight-proven CCD detectors and electronics. The power and telemetry requirements on the spacecraft are modest. The majority of mission operations will not be complex, as most observations will be long (~100 ksec), uninterrupted, and pre-planned, although there will be limited capabilities to observe targets of opportunity, such as tidal disruption events or supernovae with a 3-5 day turnaround. After the end of prime science, we plan to allow guest observations to maximize the science return of Arcus to the community.
    Keywords: Astrophysics
    Type: GSFC-E-DAA-TN43826 , Space Telescopes and Instrumentation 2016; Edinburgh; United Kingdom|Proceedings of SPIE (ISSN 0277-786X); 9905; 99054M
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Plant systematics and evolution 214 (1999), S. 103-130 
    ISSN: 1615-6110
    Keywords: Solanaceae ; sect.Petota ; Solanum brevicaule ; Domestication ; hybridization ; potatoes ; systematics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract TheSolanum brevicaule complex is a group of morphologically very similar wild and cultivated potato taxa (Solanum sect.Petota). This study uses single to low-copy nuclear RFLPs and RAPDs to investigate their species boundaries and relationships. Cladistic analyses of both data sets are largely concordant with each other and with a recently published phenetic analyses of the same accessions using morphology. All three data sets separate members of the complex into populations from Peru and immediately adjacent northwestern Bolivia, including most cultivated species accessions, and populations from northwestern Bolivia to Argentina. The molecular results suggest that the complex is paraphyletic as currently circumscribed. Many species of theS. brevicaule complex should be relegated to synonymy.
    Type of Medium: Electronic Resource
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  • 7
    Publication Date: 2002-02-09
    Description: Primary open-angle glaucoma (POAG) affects 33 million individuals worldwide and is a leading cause of blindness. In a study of 54 families with autosomal dominantly inherited adult-onset POAG, we identified the causative gene on chromosome 10p14 and designated it OPTN (for "optineurin"). Sequence alterations in OPTN were found in 16.7% of families with hereditary POAG, including individuals with normal intraocular pressure. The OPTN gene codes for a conserved 66-kilodalton protein of unknown function that has been implicated in the tumor necrosis factor-alpha signaling pathway and that interacts with diverse proteins including Huntingtin, Ras-associated protein RAB8, and transcription factor IIIA. Optineurin is expressed in trabecular meshwork, nonpigmented ciliary epithelium, retina, and brain, and we speculate that it plays a neuroprotective role.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rezaie, Tayebeh -- Child, Anne -- Hitchings, Roger -- Brice, Glen -- Miller, Lauri -- Coca-Prados, Miguel -- Heon, Elise -- Krupin, Theodore -- Ritch, Robert -- Kreutzer, Donald -- Crick, R Pitts -- Sarfarazi, Mansoor -- EY-09947/EY/NEI NIH HHS/ -- New York, N.Y. -- Science. 2002 Feb 8;295(5557):1077-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Ophthalmic Genetics Laboratory, Surgical Research Center, Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11834836" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Alternative Splicing ; Amino Acid Sequence ; Brain/metabolism ; Chromosome Mapping ; Chromosomes, Human, Pair 10/genetics ; Ciliary Body/metabolism ; Exons ; Eye Proteins/analysis/chemistry/*genetics/physiology ; Female ; Glaucoma, Open-Angle/*genetics ; Golgi Apparatus/chemistry ; Heterozygote ; Humans ; Intraocular Pressure ; Male ; Middle Aged ; *Mutation ; *Mutation, Missense ; Nerve Tissue Proteins/analysis/chemistry/*genetics/physiology ; Ocular Hypertension/genetics ; Pedigree ; Polymorphism, Single-Stranded Conformational ; Retina/metabolism ; Trabecular Meshwork/metabolism ; *Transcription Factor TFIIIA ; Zinc Fingers
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2002-11-09
    Description: Rapid evolution of reproductive traits has been attributed to sexual selection arising from interaction between the sexes. However, little is known about the nature of selection driving the evolution of interacting sex-specific phenotypes. Using populations of Drosophila melanogaster selected for divergent sperm length or female sperm-storage organ length, we experimentally show that male fertilization success is determined by an interaction between sperm and female morphology. In addition, sperm length evolution occurred as a correlated response to selection on the female reproductive tract. Giant sperm tails are the cellular equivalent of the peacock's tail, having evolved because females evolved reproductive tracts that selectively bias paternity in favor of males with longer sperm.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miller, Gary T -- Pitnick, Scott -- New York, N.Y. -- Science. 2002 Nov 8;298(5596):1230-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Syracuse University, 108 College Place, Syracuse, NY 13244, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12424377" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Copulation ; Drosophila melanogaster/*anatomy & histology/genetics/*physiology ; Female ; Fertilization ; Genitalia, Female/anatomy & histology/physiology ; Linkage Disequilibrium ; Male ; Selection, Genetic ; Sexual Behavior, Animal ; Sperm Tail/ultrastructure ; Spermatozoa/*cytology/physiology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 1999-11-13
    Description: In sexual transmission of simian immunodeficiency virus, and early and later stages of human immunodeficiency virus-type 1 (HIV-1) infection, both viruses were found to replicate predominantly in CD4(+) T cells at the portal of entry and in lymphoid tissues. Infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells. The infected proliferating cells correspond to the short-lived population that produces the bulk of HIV-1. Most of the HIV-1-infected resting T cells persisted after antiretroviral therapy. Latently and chronically infected cells that may be derived from this population pose challenges to eradicating infection and developing an effective vaccine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Z -- Schuler, T -- Zupancic, M -- Wietgrefe, S -- Staskus, K A -- Reimann, K A -- Reinhart, T A -- Rogan, M -- Cavert, W -- Miller, C J -- Veazey, R S -- Notermans, D -- Little, S -- Danner, S A -- Richman, D D -- Havlir, D -- Wong, J -- Jordan, H L -- Schacker, T W -- Racz, P -- Tenner-Racz, K -- Letvin, N L -- Wolinsky, S -- Haase, A T -- AI 28246/AI/NIAID NIH HHS/ -- AI 38565/AI/NIAID NIH HHS/ -- RR 00168/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 1999 Nov 12;286(5443):1353-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10558989" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-HIV Agents/therapeutic use ; CD4-Positive T-Lymphocytes/cytology/immunology/*virology ; Cell Cycle ; Cervix Uteri/virology ; Epithelial Cells/virology ; Female ; HIV Infections/drug therapy/*transmission/virology ; HIV-1/*physiology ; Lymph Nodes/virology ; *Lymphocyte Activation ; Macaca mulatta ; RNA, Viral/analysis ; Simian Acquired Immunodeficiency Syndrome/*transmission/virology ; Simian Immunodeficiency Virus/*physiology ; Time Factors ; Virus Replication
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2001-03-17
    Description: Caenorhabditis elegans oocytes, like those of most animals, arrest during meiotic prophase. Sperm promote the resumption of meiosis (maturation) and contraction of smooth muscle-like gonadal sheath cells, which are required for ovulation. We show that the major sperm cytoskeletal protein (MSP) is a bipartite signal for oocyte maturation and sheath contraction. MSP also functions in sperm locomotion, playing a role analogous to actin. Thus, during evolution, MSP has acquired extracellular signaling and intracellular cytoskeletal functions for reproduction. Proteins with MSP-like domains are found in plants, fungi, and other animals, suggesting that related signaling functions may exist in other phyla.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miller, M A -- Nguyen, V Q -- Lee, M H -- Kosinski, M -- Schedl, T -- Caprioli, R M -- Greenstein, D -- CA09592/CA/NCI NIH HHS/ -- GM57173/GM/NIGMS NIH HHS/ -- GM58008/GM/NIGMS NIH HHS/ -- HD07043/HD/NICHD NIH HHS/ -- HD25614/HD/NICHD NIH HHS/ -- R01 GM057173/GM/NIGMS NIH HHS/ -- R01 HD025614/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 2001 Mar 16;291(5511):2144-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11251118" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Caenorhabditis elegans/*physiology ; Carrier Proteins/chemistry/physiology ; Cytoskeleton/chemistry/physiology ; Disorders of Sex Development ; Enzyme Activation ; Evolution, Molecular ; Female ; Gonads/cytology/physiology ; Helminth Proteins/chemistry/immunology/pharmacology/*physiology ; MAP Kinase Signaling System ; Male ; *Meiosis ; Membrane Proteins/chemistry/physiology ; Microinjections ; Mitogen-Activated Protein Kinases/metabolism ; Molecular Sequence Data ; Oocytes/*physiology ; Ovulation ; Phylogeny ; Protein Folding ; Protein Structure, Tertiary ; Pseudopodia/physiology ; Recombinant Proteins/pharmacology ; Signal Transduction ; Sperm Motility ; Spermatozoa/chemistry/*physiology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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