170 research outputs found
Copper-catalyzed reaction of aziridine for the synthesis of substituted imidazolidine and imidazolidinone
Herein we report a copper-catalyzed synthesis of imidazolidine by employing the reaction of aziridine with imine. The reaction smoothly provided a diverse range of 2-substituted imidazolidines with high compatibility with various functional groups. Moreover, during our investigation, we discovered that isocyanate also reacted with aziridine to yield substituted imidazolidinones efficiently. The versatility of these reactions was further demonstrated by their application in the synthesis of hybrid molecules derived from two pharmaceutical compounds. This approach opens new possibilities for the discovery of novel classes of bioactive molecules
The brightest UV-selected galaxies in protoclusters at : Ancestors of Brightest Cluster Galaxies?
We present the results of a survey of the brightest UV-selected galaxies in
protoclusters. These proto-brightest cluster galaxy (proto-BCG) candidates are
drawn from 179 overdense regions of -dropout galaxies at from the
Hyper Suprime-Cam Subaru Strategic Program identified previously as good
protocluster candidates. This study is the first to extend the systematic study
of the progenitors of BCGs from to . We carefully remove
possible contaminants from foreground galaxies and, for each structure, we
select the brightest galaxy that is at least 1 mag brighter than the fifth
brightest galaxy. We select 63 proto-BCG candidates and compare their
properties with those of galaxies in the field and those of other galaxies in
overdense structures. The proto-BCG candidates and their surrounding galaxies
have different rest-UV color distributions to field galaxies and
other galaxies in protoclusters that do not host proto-BCGs. In addition,
galaxies surrounding proto-BCGs are brighter than those in protoclusters
without proto-BCGs. The image stacking analysis reveals that the average
effective radius of proto-BCGs is larger than that of field
galaxies. The color differences suggest that proto-BCGs and their
surrounding galaxies are dustier than other galaxies at . These results
suggest that specific environmental effects or assembly biasses have already
emerged in some protoclusters as early as , and we suggest that
proto-BCGs have different star formation histories than other galaxies in the
same epoch.Comment: 18 pages, 11 figures, Accepted for publication in Ap
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Exquisite Tumor Targeting by Salmonella A1-R in Combination with Caffeine and Valproic Acid Regresses an Adult Pleomorphic Rhabdomyosarcoma Patient-Derived Orthotopic Xenograft Mouse Model.
Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor. Recently, we developed a patient-derived orthotopic xenograft (PDOX) model of adult pleomorphic RMS. In the present study, we evaluated the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R combined with caffeine (CAF) and valproic acid (VPA) on the adult RMS PDOX. An adult pleomorphic RMS cell line was established from the PDOX model. Cell survival after exposure to CAF and VPA was assessed, and the IC50 value was calculated for each drug. The RMS PDOX models were randomized into five groups: untreated control; tumor treated with cyclophosphamide (CPA); tumor treated with CAF + VPA; tumor treated with S. typhimurium A1-R; and tumor treated with S. typhimurium A1-R + CAF + VPA. Tumor size and body weight was measured twice a week. VPA caused a concentration-dependent cytocidal effect. A synergistic effect of combination treatment with CAF was observed against the RMS cell line. For the in vivo study, all treatments significantly inhibited tumor growth compared with the untreated control. S. typhimurium A1-R combined with VPA and CAF was significantly more effective than CPA, VPA combined with CAF, or S. typhimurium A1-R alone and significantly regressed the tumor volume compared with day 0. These results suggest that S. typhimurium A1-R together with VPA and CAF could regresses an adult pleomorphic RMS in a PDOX model and therefore has important future clinical potential
Microstructural and Genetic Insights Into the Formation of the “Winter Diffusion Layer” in Japanese Pearl Oyster Pinctada fucata and Its Relation to Environmental Temperature Changes
金沢大学国際基幹教育院 GS教育系Phenotypic plasticity in molluscan shell microstructures may be related to environmental changes. The “winter diffusion layer,” a shell microstructure of the Japanese pearl oyster Pinctada fucata, is an example of this phenomenon. In this study, we used P. fucata specimens with shared genetic background to evaluate the seasonal plasticity of shell microstructures, at molecular level. To detect the seasonal changes in shell microstructure and mineral composition, shells of multiple individuals were periodically collected and analyzed using scanning electron microscopy and Raman spectrophotometry. Our observations of the winter diffusion layer revealed that this irregular shell layer, located between the outer and middle shell layers, had a sphenoid shape in radial section. This distinct shape might be caused by the internal extension of the outer shell layer resulting from growth halts. The winter diffusion layer could be distinguished from the calcitic outer shell layer by its aragonitic components and microstructures. Moreover, the components of the winter diffusion layer were irregular simple prismatic (the outer and inner sublayers) and homogeneous structures (the middle sublayer). This irregular formation occurred until April, when the animals resumed their “normal” shell formation after hibernation. To check for a correlation between gene expression and the changes in microstructures, we conducted qPCR of seven major biomineralization-related shell matrix protein-coding genes (aspein, prismalin-14, msi7, msi60, nacrein, n16, and n19) in the shell-forming mantle tissue. Tissue samples were collected from the mantle edge (tissue secreting the outer shell layer) and mantle pallium (where the middle shell layer is constructed) of the same individuals used for microstructural observation and mineral identification that were collected in January (winter growth break period), April (irregular shell formation period), and August (normal shell formation period). Statistically significant differences in gene expression levels were observed between mantle edge and mantle pallium, but no seasonal differences were detected in the seasonal expression patterns of these genes. These results suggest that the formation of the irregular shell layer in P. fucata is caused by a currently unknown genetic mechanism unrelated to the genes targeted in the present study. Further studies using big data (transcriptomics and manipulation of gene expression) are required to answer the questions herein raised. Nevertheless, the results herein presented are essential to unravel the intriguing mystery of the formation of the winter diffusion layer, which may allow us to understand how marine mollusks adapt or acclimate to climate changes. Copyright © 2022 Sato, Setiamarga, Yonemitsu and Higuchi
Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making
「何を買うんだっけ」と「どれにしよう」を処理する2つの脳回路を明らかに --霊長類の生体脳で神経経路を可視化・操作する技術で解明、高次脳機能の理解へ大きく前進--. 京都大学プレスリリース. 2021-06-24.The primate prefrontal cortex (PFC) is situated at the core of higher brain functions via neural circuits such as those linking the caudate nucleus and mediodorsal thalamus. However, the distinctive roles of these prefronto-subcortical pathways remain elusive. Combining in vivo neuronal projection mapping with chemogenetic synaptic silencing, we reversibly dissected key pathways from dorsolateral part of the PFC (dlPFC) to the dorsal caudate (dCD) and lateral mediodorsal thalamus (MDl) individually in single monkeys. We found that silencing the bilateral dlPFC-MDl projections, but not the dlPFC-dCD projections, impaired performance in a spatial working memory task. Conversely, silencing the unilateral dlPFC-dCD projection, but not the unilateral dlPFC-MDl projection, altered preference in a decision-making task. These results revealed dissociable roles of the prefronto-subcortical pathways in working memory and decision-making, representing the technical advantage of imaging-guided pathway-selective chemogenetic manipulation for dissecting neural circuits underlying cognitive functions in primates
Impact of pathogenic mutations of the GLUT1 glucose transporter on solute carrier dynamics using ComDYN enhanced sampling
Background: The solute carrier (SLC) family of membrane proteins is a large class of transporters for many small molecules that are vital for cellular function. Several pathogenic mutations are reported in the glucose transporter subfamily SLC2, causing Glut1-deficiency syndrome (GLUT1DS1, GLUT1DS2), epilepsy (EIG2) and cryohydrocytosis with neurological defects (Dystonia-9). Understanding the link between these mutations and transporter dynamics is crucial to elucidate their role in the dysfunction of the underlying transport mechanism, which we investigate using molecular dynamics simulations.
\nMethods: We studied pathogenic and non-pathogenic mutations, using a newly developed coarse-grained simulation approach \xe2\x80\x98ComDYN\xe2\x80\x99, which captures the \xe2\x80\x98COMmon constraints DYNamics\xe2\x80\x99 between both states of the solute carrier protein. To guarantee the sampling of large conformational changes, we only include common constraints of the elastic network introduced upon coarse-graining, which showed similar reference distances between both conformational states (\xe2\x89\xa41 \xc3\x85 difference).
\nResults: ComDYN is computationally efficient and sufficiently sensitive to capture effects of different mutations. Our results clearly indicate that the pathogenic mutation in GLUT1, G91D, situated at the highly conserved RXGRR motif between helices 2 and 3, has a strong impact on transporter function, as it blocks the protein from sampling both conformational states. In comparison, predictions from SIFT and PolyPhen only provided an impression of the impact upon mutation in the highly conserved RXGRR motifs, but yielded no clear differentiation between pathogenic and non-pathogenic mutations.
\nConclusions: Using our approach, we can explain the pathogenicity of the mutation G91D and some of the effects of other known pathogenic mutations, when we observe the configurations of the transmembrane helices, suggesting that their relative position is crucial for the correct functioning of the GLUT1 protein. To fully understand the impact of other mutations in the future, it is necessary to consider the effect of ligands, e.g., glucose, within the transport mechanism
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Recombinant methioninase combined with doxorubicin (DOX) regresses a DOX-resistant synovial sarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model.
Synovial sarcoma (SS) is a recalcitrant subgroup of soft tissue sarcoma (STS). A tumor from a patient with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) mouse model. The PDOX mice were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks; G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G4 DOX (3mg/kg), i.p. weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks). On day 14 after treatment initiation, all therapies significantly inhibited tumor growth compared to untreated control, except DOX: (DOX: p = 0.48; rMETase: p < 0.005; DOX combined with rMETase < 0.0001). DOX combined with rMETase was significantly more effective than both DOX alone (p < 0.001) and rMETase alone (p < 0.05). The relative body weight on day 14 compared with day 0 did not significantly differ between any treatment group or untreated control. The results indicate that r-METase can overcome DOX-resistance in this recalcitrant disease
Current and future perspectives on functional molecular imaging in nephro-urology: theranostics on the horizon
In recent years, a paradigm shift from single-photon-emitting radionuclide radiotracers toward positron-emission tomography (PET) radiotracers has occurred in nuclear oncology. Although PET-based molecular imaging of the kidneys is still in its infancy, such a trend has emerged in the field of functional renal radionuclide imaging. Potentially allowing for precise and thorough evaluation of renal radiotracer urodynamics, PET radionuclide imaging has numerous advantages including precise anatomical co-registration with CT images and dynamic three-dimensional imaging capability. In addition, relative to scintigraphic approaches, PET can allow for significantly reduced scan time enabling high-throughput in a busy PET practice and further reduces radiation exposure, which may have a clinical impact in pediatric populations. In recent years, multiple renal PET radiotracers labeled with C-11, Ga-68, and F-18 have been utilized in clinical studies. Beyond providing a precise non-invasive read-out of renal function, such radiotracers may also be used to assess renal inflammation. This manuscript will provide an overview of renal molecular PET imaging and will highlight the transformation of conventional scintigraphy of the kidneys toward novel, high-resolution PET imaging for assessing renal function. In addition, future applications will be introduced, e.g. by transferring the concept of molecular image-guided diagnostics and therapy (theranostics) to the field of nephrology
Salt, Hot Water, and Silicon Compounds Tracing Massive Twin Disks
We report results of 0.05"-resolution observations toward the O-type
proto-binary system IRAS 16547-4247 with the Atacama Large
Millimeter/submillimeter Array (ALMA). We present dynamical and chemical
structures of the circumbinary disk, circumstellar disks, outflows and jets,
illustrated by multi-wavelength continuum and various molecular lines. In
particular, we detect sodium chloride, silicon compounds, and
vibrationally-excited water lines as probes of the individual protostellar
disks at a scale of 100 au. These are complementary to typical hot-core
molecules tracing the circumbinary structures on a 1000-au scale. The H2O line
tracing inner-disks has an upper-state energy of Eu/k>3000K, indicating a high
temperature of the disks. On the other hand, despite the detected transitions
of NaCl, SiO, and SiS not necessarily having high upper-state energies, they
are enhanced only in the vicinity of the protostars. We interpret that these
molecules are the products of dust destruction, which only happens in the inner
disks. This is the second detection of alkali metal halide in protostellar
systems after the case of the disk of Orion Source I, and also one of few
massive protostellar disks associated with high-energy transition water and
silicon compounds. These new results suggest these "hot-disk" lines may be
common in innermost disks around massive protostars, and have great potential
for future research of massive star formation. We also tentatively find that
the twin disks are counter-rotating, which might give a hint of the origin of
the massive proto-binary system IRAS 16547-4247.Comment: 15 pages, 5 figures, 2 appendix figures. Published in ApJ Letter
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