The progression of cancer is associated with increases in amino acid uptake by cancer cells. Upon their entry into cells through specific transporters, exogenous amino acids are used to synthesize ...proteins, nucleic acids and lipids and to generate ATP. The essential amino acid leucine is also important for maintaining cancer-associated signaling pathways. By upregulating amino acid transporters, cancer cells gain greater access to exogenous amino acids to support chronic proliferation, maintain metabolic pathways, and to enhance certain signal transduction pathways. Suppressing cancer growth by targeting amino acid transporters will require an in-depth understanding of how cancer cells acquire amino acids, in particular, the transporters involved and which cancer pathways are most sensitive to amino acid deprivation. L-Type Amino Acid Transporter 1 (LAT1) mediates the uptake of essential amino acids and its expression is upregulated during the progression of several cancers. We will review the upstream regulators of LAT1 and the downstream effects caused by the overexpression of LAT1 in cancer cells.
The Archaeology of Nucleation in the Old World explores
the role of the built environment in expressing and shaping
community organization and identity at prehistoric and historic
nucleated ...settlements and early cities in the Old World. The
spatial layout of large settlements results from the interaction of
social, political, economic, and religious orders. Subsequent
structural changes governed by the application, manipulation, and
challenges of these orders yield a dynamic built environment which
influences the processes of organization and identity formation.
Taking advantage of advances in archaeological methods and theory
that allow investigations of nucleated settlements to an extent and
depth of detail that was previously impossible, the contributors to
this volume address specific topics, such as how the built
environment and location of activity zones help us to understand
social configurations; how various scales of social units can be
recognized and the resulting patterns interpreted; how collective
actions contribute to settlement organization and community
integrity; how changes in social relations are reflected in the
development of the built environment; how cooperation and
competition as well as measures to mitigate social and
communication stress can be identified in the archaeological
record; and how the built environment was used to express or
manipulate identity.
The study of childhood diet, including breastfeeding and weaning, has important implications for our understanding of infant mortality and fertility in past societies
. Stable isotope analyses of ...nitrogen from bone collagen and dentine samples of infants have provided information on the timing of weaning
; however, little is known about which foods were consumed by infants in prehistory. The earliest known clay vessels that were possibly used for feeding infants appear in Neolithic Europe, and become more common throughout the Bronze and Iron Ages. However, these vessels-which include a spout through which liquid could be poured-have also been suggested to be feeding vessels for the sick or infirm
. Here we report evidence for the foods that were contained in such vessels, based on analyses of the lipid 'fingerprints' and the compound-specific δ
C and Δ
C values of the major fatty acids of residues from three small, spouted vessels that were found in Bronze and Iron Age graves of infants in Bavaria. The results suggest that the vessels were used to feed infants with milk products derived from ruminants. This evidence of the foodstuffs that were used to either feed or wean prehistoric infants confirms the importance of milk from domesticated animals for these early communities, and provides information on the infant-feeding behaviours that were practised by prehistoric human groups.
Burial rites of archaeological populations are frequently interpreted based on cremated remains of the human body and the urn they were deposited in. In comparison to inhumations, information about ...the deceased is much more limited and dependent on fragmentation, selection of body regions, taphonomic processes, and excavation techniques. So far, little attention has been paid to the context in which urns are buried. In this study, we combined archaeological techniques with anthropology, computed tomography, archaeobotany, zooarchaeology, geochemistry and isotopic approaches and conducted a detailed analysis on a case study of two Late Bronze Age urns from St. Pölten, Austria (c. 1430 and 1260 cal. BCE). The urns were recovered en-bloc and CT-scanned before the micro-excavation. Osteological and strontium isotope analysis revealed that the cremated remains comprised a young adult female and a child that died at the age of 10-12 years. Both individuals had been subject to physiological stress and were likely local. Animal bones burnt at different temperatures suggested different depositional pathways into the urn and pit as part of the pyre, food offerings, and unintentional settlement debris. Eight wild plant and five crop plant species appeared as part of the local landscape, as food offerings and fire accelerants. Sediment chemistry suggests that pyre remains were deposited around the urns during burial. Multi-element geochemistry, archaeobotany, and zooarchaeology provide insights into the Late Bronze Age environment, the process of cremation, the gathering of bones and final funerary deposition.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
The vertebrate brain consists of diverse neuronal types, classified by distinct anatomy and function, along with divergent transcriptomes and proteomes. Defining the cell-type specific ...neuroproteomes is important for understanding the development and functional organization of neural circuits. This task remains challenging in complex tissue, due to suboptimal protein isolation techniques that often result in loss of cell-type specific information and incomplete capture of subcellular compartments. Here, we develop a genetically targeted proximity labeling approach to identify cell-type specific subcellular proteomes in the mouse brain, confirmed by imaging, electron microscopy, and mass spectrometry. We virally express subcellular-localized APEX2 to map the proteome of direct and indirect pathway spiny projection neurons in the striatum. The workflow provides sufficient depth to uncover changes in the proteome of striatal neurons following chemogenetic activation of Gα
q
-coupled signaling cascades. This method enables flexible, cell-type specific quantitative profiling of subcellular proteome snapshots in the mouse brain.
Mammalian axonal development begins in embryonic stages and continues postnatally. After birth, axonal proteomic landscape changes rapidly, coordinated by transcription, protein turnover, and ...post-translational modifications. Comprehensive profiling of axonal proteomes across neurodevelopment is limited, with most studies lacking cell-type and neural circuit specificity, resulting in substantial information loss. We create a Cre-dependent APEX2 reporter mouse line and map cell-type-specific proteome of corticostriatal projections across postnatal development. We synthesize analysis frameworks to define temporal patterns of axonal proteome and phosphoproteome, identifying co-regulated proteins and phosphorylations associated with genetic risk for human brain disorders. We discover proline-directed kinases as major developmental regulators. APEX2 transgenic reporter proximity labeling offers flexible strategies for subcellular proteomics with cell type specificity in early neurodevelopment, a critical period for neuropsychiatric disease.
The insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor (IR) are receptor tyrosine kinases that are expressed in cancer cells. The results of different studies indicate that tumor ...proliferation and survival is dependent on the IGF1R and IR, and that their inhibition leads to reductions in proliferation and increases in cell death. Molecular targeting therapies that have been used in solid tumors include anti-IGF1R antibodies, anti-IGF1/IGF2 antibodies, and small molecule inhibitors that suppress IGF1R and IR kinase activity. New advances in the molecular basis of anti-IGF1R blocking antibodies reveal they are biased agonists and promote the binding of IGF1 to integrin β3 receptors in some cancer cells. Our recent reports indicate that pharmacological aryl hydrocarbon receptor (AHR) ligands inhibit breast cancer cell responses to IGFs, suggesting that targeting AHR may have benefit in cancers whose proliferation and survival are dependent on insulin/IGF signaling. Novel aspects of IGF1R/IR in cancer, such as biased agonism, integrin β3 signaling, AHR, and new therapeutic targeting strategies will be discussed.
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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is regulated by environmental toxicants that function as AHR agonists such as ...2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). L-Type Amino Acid Transporter 1 (LAT1) is a leucine transporter that is overexpressed in cancer. The regulation of LAT1 by AHR in MCF-7 and MDA-MB-231 breast cancer cells (BCCs) was investigated in this report. Ingenuity pathway analysis (IPA) revealed a significant association between TCDD-regulated genes (TRGs) and molecular transport. Overlapping the TCDD-RNA-Seq dataset obtained in this study with a published TCDD-ChIP-seq dataset identified LAT1 as a primary target of AHR-dependent TCDD induction. Short interfering RNA (siRNA)-directed knockdown of AHR confirmed that TCDD-stimulated increases in LAT1 mRNA and protein required AHR expression. TCDD-stimulated increases in LAT1 mRNA were also inhibited by the AHR antagonist CH-223191. Upregulation of LAT1 by TCDD coincided with increases in leucine uptake by MCF-7 cells in response to TCDD. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) assays revealed increases in AHR, AHR nuclear translocator (ARNT) and p300 binding and histone H3 acetylation at an AHR binding site in the LAT1 gene in response to TCDD. In MCF-7 and MDA-MB-231 cells, endogenous levels of LAT1 mRNA and protein were reduced in response to knockdown of AHR expression. Knockdown experiments demonstrated that proliferation of MCF-7 and MDA-MB-231 cells is dependent on both LAT1 and AHR. Collectively, these findings confirm the dependence of cancer cells on leucine uptake and establish a mechanism for extrinsic and intrinsic regulation of LAT1 by AHR.
The mechanistic target of rapamycin (mTOR) kinase is a component of two signaling complexes that are known as mTOR complex 1 (mTORC1) and mTORC2. We sought to identify mTOR-phosphorylated proteins ...that are differently expressed in clinically resected clear cell renal cell carcinoma (ccRCC) relative to pair-matched normal renal tissue. Using a proteomic array, we found N-Myc Downstream Regulated 1 (NDRG1) showed the greatest increase (3.3-fold) in phosphorylation (on Thr346) in ccRCC. This was associated with an increase in total NDRG1. RICTOR is a required subunit in mTORC2, and its knockdown decreased total and phospho-NDRG1 (Thr346) but not NDRG1 mRNA. The dual mTORC1/2 inhibitor, Torin 2, significantly reduced (by ~100%) phospho-NDRG1 (Thr346). Rapamycin is a selective mTORC1 inhibitor that had no effect on the levels of total NDRG1 or phospho-NDRG1 (Thr346). The reduction in phospho-NDRG1 (Thr346) due to the inhibition of mTORC2 corresponded with a decrease in the percentage of live cells, which was correlated with an increase in apoptosis. Rapamycin had no effect on ccRCC cell viability. Collectively, these data show that mTORC2 mediates the phosphorylation of NDRG1 (Thr346) in ccRCC. We hypothesize that RICTOR and mTORC2-mediated phosphorylation of NDRG1 (Thr346) promotes the viability of ccRCC cells.
Data on the beam asymmetry Σ in the photoproduction of η mesons off protons are reported for tagged photon energies from 1130 to 1790 MeV (mass range from W = 1748 MeV to W = 2045 MeV). The data ...cover the full solid angle that allows for a precise moment analysis. For the first time, a strong cusp effect in a polarization observable has been observed that is an effect of a branch-point singularity at the pη′ threshold Eγ = 1447 MeV (W = 1896 MeV). The latest BnGa partial wave analysis includes the new beam asymmetry data and yields a strong indication for the N (1895)1/2− nucleon resonance, demonstrating the importance of including all singularities for a correct determination of partial waves and resonance parameters.
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