Despite a rich African Plio-Pleistocene hominin fossil record, the ancestry of Homo and its relation to earlier australopithecines remain unresolved. Here we report on two partial skeletons with an ...age of 1.95 to 1.78 million years. The fossils were encased in cave deposits at the Malapa site in South Africa. The skeletons were found close together and are directly associated with craniodental remains. Together they represent a new species of Australopithecus that is probably descended from Australopithecus africanus. Combined craniodental and postcranial evidence demonstrates that this new species shares more derived features with early Homo than any other australopith species and thus might help reveal the ancestor of that genus.
Deficiency in several of the classical human RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3 is associated with cancer predisposition and Fanconi anemia. To investigate their functions, ...isogenic disruption mutants for each were generated in non-transformed MCF10A mammary epithelial cells and in transformed U2OS and HEK293 cells. In U2OS and HEK293 cells, viable ablated clones were readily isolated for each RAD51 paralog; in contrast, with the exception of RAD51B, RAD51 paralogs are cell-essential in MCF10A cells. Underlining their importance for genomic stability, mutant cell lines display variable growth defects, impaired sister chromatid recombination, reduced levels of stable RAD51 nuclear foci, and hyper-sensitivity to mitomycin C and olaparib, with the weakest phenotypes observed in RAD51B-deficient cells. Altogether these observations underscore the contributions of RAD51 paralogs in diverse DNA repair processes, and demonstrate essential differences in different cell types. Finally, this study will provide useful reagents to analyze patient-derived mutations and to investigate mechanisms of chemotherapeutic resistance deployed by cancers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Solar Orbiter mission seeks to make connections between the physical processes occurring at the Sun or in the solar corona and the nature of the solar wind created by those processes which is ...subsequently observed at the spacecraft. The mission also targets physical processes occurring in the solar wind itself during its journey from its source to the spacecraft. To meet the specific mission science goals, Solar Orbiter will be equipped with both remote-sensing and in-situ instruments which will make unprecedented measurements of the solar atmosphere and the inner heliosphere. A crucial set of measurements will be provided by the Solar Wind Analyser (SWA) suite of instruments. This suite consists of an Electron Analyser System (SWA-EAS), a Proton and Alpha particle Sensor (SWA-PAS), and a Heavy Ion Sensor (SWA-HIS) which are jointly served by a central control and data processing unit (SWA-DPU). Together these sensors will measure and categorise the vast majority of thermal and suprathermal ions and electrons in the solar wind and determine the abundances and charge states of the heavy ion populations. The three sensors in the SWA suite are each based on the top hat electrostatic analyser concept, which has been deployed on numerous space plasma missions. The SWA-EAS uses two such heads, each of which have 360° azimuth acceptance angles and ±45° aperture deflection plates. Together these two sensors, which are mounted on the end of the boom, will cover a full sky field-of-view (FoV) (except for blockages by the spacecraft and its appendages) and measure the full 3D velocity distribution function (VDF) of solar wind electrons in the energy range of a few eV to ∼5 keV. The SWA-PAS instrument also uses an electrostatic analyser with a more confined FoV (−24° to +42° × ±22.5° around the expected solar wind arrival direction), which nevertheless is capable of measuring the full 3D VDF of the protons and alpha particles arriving at the instrument in the energy range from 200 eV/q to 20 keV/e. Finally, SWA-HIS measures the composition and 3D VDFs of heavy ions in the bulk solar wind as well as those of the major constituents in the suprathermal energy range and those of pick-up ions. The sensor resolves the full 3D VDFs of the prominent heavy ions at a resolution of 5 min in normal mode and 30 s in burst mode. Additionally, SWA-HIS measures 3D VDFs of alpha particles at a 4 s resolution in burst mode. Measurements are over a FoV of −33° to +66° × ±20° around the expected solar wind arrival direction and at energies up to 80 keV/e. The mass resolution (
m
/Δ
m
) is > 5. This paper describes how the three SWA scientific sensors, as delivered to the spacecraft, meet or exceed the performance requirements originally set out to achieve the mission’s science goals. We describe the motivation and specific requirements for each of the three sensors within the SWA suite, their expected science results, their main characteristics, and their operation through the central SWA-DPU. We describe the combined data products that we expect to return from the suite and provide to the Solar Orbiter Archive for use in scientific analyses by members of the wider solar and heliospheric communities. These unique data products will help reveal the nature of the solar wind as a function of both heliocentric distance and solar latitude. Indeed, SWA-HIS measurements of solar wind composition will be the first such measurements made in the inner heliosphere. The SWA data are crucial to efforts to link the in situ measurements of the solar wind made at the spacecraft with remote observations of candidate source regions. This is a novel aspect of the mission which will lead to significant advances in our understanding of the mechanisms accelerating and heating the solar wind, driving eruptions and other transient phenomena on the Sun, and controlling the injection, acceleration, and transport of the energetic particles in the heliosphere.
For many years, immortalized cell lines have been used as model systems for cancer research. Cell line panels were established for basic research and drug development, but did not cover the full ...spectrum of leukemia and lymphoma. Therefore, we now developed a novel panel (LL-100), 100 cell lines covering 22 entities of human leukemia and lymphoma including T-cell, B-cell and myeloid malignancies. Importantly, all cell lines are unequivocally authenticated and assigned to the correct tissue. Cell line samples were proven to be free of mycoplasma and non-inherent virus contamination. Whole exome sequencing and RNA-sequencing of the 100 cell lines were conducted with a uniform methodology to complement existing data on these publicly available cell lines. We show that such comprehensive sequencing data can be used to find lymphoma-subtype-characteristic copy number aberrations, mRNA isoforms, transcription factor activities and expression patterns of NKL homeobox genes. These exemplary studies confirm that the novel LL-100 panel will be useful for understanding the function of oncogenes and tumor suppressor genes and to develop targeted therapies.
Histone demethylases are promising therapeutic targets as they play fundamental roles for survival of Mixed lineage leukemia rearranged acute leukemia (MLLr AL). Here we focused on the catalytic ...Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening. JMJD1C Jumonji domain inhibitor 4 (JDI‐4) and JDI‐12 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI‐4 and JDI‐12 bind to JMJD1C and its family homolog KDM3B with modest affinity. In vitro demethylation assays showed that JDI‐4 can reverse the H3K9 demethylation conferred by KDM3B. In vivo demethylation assays indicated that JDI‐4 and JDI‐12 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI‐4 and JDI‐12 kill MLLr AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI‐16, among multiple compounds structurally akin to JDI‐4/JDI‐12, exhibits superior killing activities against malignant hematopoietic cells compared to JDI‐4/JDI‐12. Mechanistically, JDI‐16 not only induces apoptosis but also differentiation of MLLr AL cells. RNA sequencing and quantitative PCR showed that JDI‐16 induced gene expression associated with cell metabolism; targeted metabolomics revealed that JDI‐16 downregulates lactic acids, NADP+ and other metabolites. Moreover, JDI‐16 collaborates with all‐trans retinoic acid to repress MLLr AML cells. In summary, we identified bona fide JMJD1C inhibitors that induce preferential death of MLLr AL cells.
What's new?
Histone demethylase JMJD1C represents one of the most promising therapeutic targets for a subtype of acute leukemia with inferior prognosis, MLLr AL. Here, the authors focused on the catalytic Jumonji domain of JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening. They identified structurally‐akin JMJD1C inhibitors with the ability to selectively kill MLLr AL cells, regulate MLLr AL cell metabolism, and collaborate with all‐trans retinoic acid to repress MLLr AL. The findings helped identify the backbone of an inhibitor class that holds promise for the treatment of MLLr AL.
Newly exposed cave sediments at the Malapa site include a flowstone layer capping the sedimentary unit containing the Australopithecus sediba fossils. Uranium-lead dating of the flowstone, combined ...with paleomagnetic and stratigraphic analysis of the flowstone and underlying sediments, provides a tightly constrained date of 1.977 ± 0.002 million years ago (Ma) for these fossils. This refined dating suggests that Au. sediba from Malapa predates the earliest uncontested evidence for Homo in Africa.
NKL homeobox genes encode developmental transcription factors regulating basic processes in cell differentiation. According to their physiological expression pattern in early hematopoiesis and ...lymphopoiesis, particular members of this homeobox gene subclass constitute an NKL-code. B-cell specific NKL-code genes generate a regulatory network and their deregulation is implicated in B-cell lymphomagenesis. Epstein-Barr virus (EBV) infects B-cells and influences the activity of signalling pathways including JAK/STAT and several genes encoding developmental regulators. Therefore, EBV-infection impacts the pathogenesis and the outcome of B-cell malignancies including Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL). Here, we isolated EBV-positive and EBV-negative subclones from the DLBCL derived cell line DOHH-2. These subclones served as models to investigate the role of EBV in deregulation of the B-cell specific NKL-code members HHEX, HLX, MSX1 and NKX6-3. We showed that the EBV-encoded factors LMP1 and LMP2A activated the expression of HLX via STAT3. HLX in turn repressed NKX6-3, SPIB and IL4R which normally mediate plasma cell differentiation. In addition, HLX repressed the pro-apoptotic factor BCL2L11/BIM and hence supported cell survival. Thus, EBV aberrantly activated HLX in DLBCL, thereby disturbing both B-cell differentiation and apoptosis. The results of our study appreciate the pathogenic role of EBV in NKL homeobox gene deregulation and B-cell malignancies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Leukemia–lymphoma cell lines are important research tools in a variety of fields. To represent adequate model systems it is of utmost importance that cell lines faithfully model the primary tumor ...material and are not cross‐contaminated with unrelated cell material (or contaminated with mycoplasma). As it has been previously reported that cross‐contaminated cell lines represent a significant problem, it is of interest to know whether any improvement in the prevalence of such “false cell lines” had occurred since we called the alert in 1999. A retrospective review of our data archives covered 848 cell lines received from 1990 to 2014 from 290 laboratories in 23 countries spanning the spectrum of leukemia–lymphoma entities. Two variables were considered: authenticity and freedom from mycoplasma infection. Regarding provenance, we separately considered primary sources (original investigators having established the cell lines or reference repositories) and secondary sources. The percentages of mycoplasma‐contaminated cell lines decreased significantly over the 25‐year timespan. Among primary sourced material: mycoplasma‐contamination fell from 23% to 0%; among secondary sourced: from 48% to 21%. The corresponding figures for cross‐contamination declined from 15% to 6%, while among material obtained from secondary sources prevalence remained remarkably high, throughout the time periods at 14–18%. Taken together, our data indicate that using non‐authenticated cell lines from secondary sources carries a risk of about 1:6 for obtaining a false cell line. The use of authentic leukemia–lymphoma cell lines holds important translational value for their model character and the reproducibility of the laboratory data in the clinical arena.
What's new?
Tumor cell lines are essential research tools, but a significant percentage is contaminated with other cell lines and/or mycoplasma. In our study of leukemia and lymphoma cell lines, the authors found that the incidence of mycoplasma‐contamination has decreased significantly over the past 25 years. However, cross‐contamination of cell lines still remains at an unacceptably high level, particularly among cell lines circulating unchecked between different laboratories. Researchers are urged to use authenticated cell lines, to ensure the accuracy of clinical and experimental results.
The Integrated Science Investigation of the Sun (ISIS) is a complete science investigation on the Solar Probe Plus (SPP) mission, which flies to within nine solar radii of the Sun’s surface. ISIS ...comprises a two-instrument suite to measure energetic particles over a very broad energy range, as well as coordinated management, science operations, data processing, and scientific analysis. Together, ISIS observations allow us to explore the mechanisms of energetic particles dynamics, including their: (1) Origins—defining the seed populations and physical conditions necessary for energetic particle acceleration; (2) Acceleration—determining the roles of shocks, reconnection, waves, and turbulence in accelerating energetic particles; and (3) Transport—revealing how energetic particles propagate from the corona out into the heliosphere. The two ISIS Energetic Particle Instruments measure lower (EPI-Lo) and higher (EPI-Hi) energy particles. EPI-Lo measures ions and ion composition from ∼20 keV/nucleon–15 MeV total energy and electrons from ∼25–1000 keV. EPI-Hi measures ions from ∼1–200 MeV/nucleon and electrons from ∼0.5–6 MeV. EPI-Lo comprises 80 tiny apertures with fields-of-view (FOVs) that sample over nearly a complete hemisphere, while EPI-Hi combines three telescopes that together provide five large-FOV apertures. ISIS observes continuously inside of 0.25 AU with a high data collection rate and burst data (EPI-Lo) coordinated with the rest of the SPP payload; outside of 0.25 AU, ISIS runs in low-rate science mode whenever feasible to capture as complete a record as possible of the solar energetic particle environment and provide calibration and continuity for measurements closer in to the Sun. The ISIS Science Operations Center plans and executes commanding, receives and analyzes all ISIS data, and coordinates science observations and analyses with the rest of the SPP science investigations. Together, ISIS’ unique observations on SPP will enable the discovery, untangling, and understanding of the important physical processes that govern energetic particles in the innermost regions of our heliosphere, for the first time. This paper summarizes the ISIS investigation at the time of the SPP mission Preliminary Design Review in January 2014.
We describe the geological, geochronological, geomorphological, and faunal context of the Malapa site and the fossils of Australopithecus sediba. The hominins occur with a macrofauna assemblage that ...existed in Africa between 2.36 and 1.50 million years ago (Ma). The fossils are encased in water-laid, clastic sediments that were deposited along the lower parts of what is now a deeply eroded cave system, immediately above a flowstone layer with a U-Pb date of 2.026 ± 0.021 Ma. The flowstone has a reversed paleomagnetic signature and the overlying hominin-bearing sediments are of normal polarity, indicating deposition during the 1.95-to 1.78-Ma Olduvai Subchron. The two hominin specimens were buried together in a single debris flow that lithified soon after deposition in a phreatic environment inaccessible to scavengers.
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