Natural rubber (NR), principally comprising
cis
-1,4-polyisoprene, is an industrially important natural hydrocarbon polymer because of its unique physical properties, which render it suitable for ...manufacturing items such as tires. Presently, industrial NR production depends solely on latex obtained from the Pará rubber tree,
Hevea brasiliensis
. In latex, NR is enclosed in rubber particles, which are specialized organelles comprising a hydrophobic NR core surrounded by a lipid monolayer and membrane-bound proteins. The similarity of the basic carbon skeleton structure between NR and dolichols and polyprenols, which are found in most organisms, suggests that the NR biosynthetic pathway is related to the polyisoprenoid biosynthetic pathway and that rubber transferase, which is the key enzyme in NR biosynthesis, belongs to the
cis
-prenyltransferase family. Here, we review recent progress in the elucidation of molecular mechanisms underlying NR biosynthesis through the identification of the enzymes that are responsible for the formation of the NR backbone structure.
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset intractable myopathy, characterized by slowly progressive ptosis, dysphagia, and proximal limb weakness. It is caused by the abnormal ...expansion of the alanine-encoding (GCN)n trinucleotide repeat in the exon 1 of the
gene (11-18 repeats in OPMD instead of the normal 10 repeats). As the disease progresses, the patients gradually develop a feeling of suffocation, regurgitation of food, and aspiration pneumonia, although the initial symptoms and the progression patterns vary among the patients. Autologous myoblast transplantation may provide therapeutic benefits by reducing swallowing problems in these patients. Therefore, it is important to assemble information on such patients for the introduction of effective treatments in nonendemic areas. Herein, we present a concise review of recent progress in clinical and pathological studies of OPMD and introduce an idea for setting up a nation-wide OPMD disease registry in Japan. Since it is important to understand patients' unmet medical needs, realize therapeutically targetable symptoms, and identify indices of therapeutic efficacy, our attempt to establish a unique patient registry of OPMD will be a helpful tool to address these urgent issues.
Vibrational energy flow in the many degrees of freedom in proteins governs energy-barrier-crossing processes, such as conformational exchanges and thermal reactions. The intensity of anti-Stokes ...Raman bands arises from vibrationally excited populations and can thus function as a selective probe for the excess energy. Time-resolved observations of the anti-Stokes ultraviolet resonance Raman (UVRR) intensity of amino acid residues provide information about the flow of excess energy in proteins, with the spatial resolution of an amino acid residue. The answer to the question of whether the extent of vibrational excitation in any given vibrational modes reflects the extent of excitation in the whole molecule under nonequilibrium conditions is not straightforward. Here, we calculated the occupation probabilities of vibrational states for model compounds of amino acids under equilibrium and nonequilibrium conditions. At a given temperature, the occupation probability of the model compound of tryptophan under nonequilibrium conditions was nearly identical to that under equilibrium conditions at high temperature. Thus, the anti-Stokes band intensities of Trp residues in the nonequilibrium condition indicate the temperature of the molecules with equivalent energy in the equilibrium condition. In addition, we showed that the temperatures calculated on the basis of two UVRR bands of tryptophan in a time-resolved spectrum agreed with each other within the experimental uncertainty. The present results demonstrate that anti-Stokes UVRR bands of Trp residues serve as an excellent spectroscopic thermometer for determining the local temperature in proteins under nonequilibrium conditions.
In frustrated magnetic systems, long-range ordering is forbidden and degeneracy of energy states persists, even at extremely low temperatures. Under certain conditions, these systems form an exotic ...quantum spin-liquid ground state, in which strongly correlated spins fluctuate in the spin lattices. Here we investigate the thermodynamic properties of an anion radical spin liquid of EtMe(3)SbPd(dmit)(2)(2), where dmit represents 1,3-dithiole-2-thione-4,5-dithiolate. This compound is an organic dimer-based Mott insulator with a two-dimensional triangular lattice structure. We present distinct evidence for the formation of a gapless spin liquid by examining the T-linear heat capacity coefficient, γ , in the low-temperature heat capacity. Using comparative analyses with κ-(BEDT-TTF)(2)Cu(2)(CN)(3), a generalized picture of the new spin liquid in dimer-based organic systems is discussed. We also report anomalous enhancement of γ, produced by a kind of criticality inherent to the Pd(dmit)(2) phase diagram.
Land plants produce diverse flavonoids for growth, survival, and reproduction. Chalcone synthase is the first committed enzyme of the flavonoid biosynthetic pathway and catalyzes the production of ...2',4,4',6'-tetrahydroxychalcone (THC). However, it also produces other polyketides, including p-coumaroyltriacetic acid lactone (CTAL), because of the derailment of the chalcone-producing pathway. This promiscuity of CHS catalysis adversely affects the efficiency of flavonoid biosynthesis, although it is also believed to have led to the evolution of stilbene synthase and p-coumaroyltriacetic acid synthase. In this study, we establish that chalcone isomerase-like proteins (CHILs), which are encoded by genes that are ubiquitous in land plant genomes, bind to CHS to enhance THC production and decrease CTAL formation, thereby rectifying the promiscuous CHS catalysis. This CHIL function has been confirmed in diverse land plant species, and represents a conserved strategy facilitating the efficient influx of substrates from the phenylpropanoid pathway to the flavonoid pathway.
Background
Traditional serrated adenoma (TSA) is the least common type of colorectal serrated polyp, which exhibits considerable morphological and molecular diversity.
Methods
We examined the spectra ...of alterations in MAPK and WNT pathway genes and their relationship with clinicopathological features in 128 TSAs.
Results
Sequencing analyses identified
BRAF
V600E,
BRAF
non-V600E,
KRAS
, and
NRAS
mutations in 77, 3, 45, and 1 lesion, respectively. Collectively, 124 lesions (97%) had mutations in MAPK pathway genes. Alterations in WNT pathway genes were identified in 107 lesions (84%), including
RSPO
fusions/overexpression,
RNF43
mutations,
ZNRF3
mutations,
APC
mutations, and
CTNNB1
mutations in 47, 45, 2, 13, and 2 lesions, respectively. Ten lesions (8%) harbored
GNAS
mutations. There was significant interdependence between the altered MAPK and WNT pathway genes.
RSPO
fusions/overexpression was significantly associated with
KRAS
mutations (31/47, 66%), whereas most
RNF43
mutations coexisted with the
BRAF
V600E mutation (40/45, 89%). Histologically, extensive slit-like serration was more common in lesions with the
BRAF
V600E mutation (71%) and those with
RNF43
mutations (87%). Prominent ectopic crypt formation was more prevalent in lesions with
RSPO
fusions/overexpression (58%) and those with
GNAS
mutations (100%).
Conclusions
Our observations indicate that TSAs mostly harbor various combinations of concurrent WNT and MAPK gene alterations. The associations between genetic and morphological features suggest that the histological diversity of TSA reflects the underlying molecular heterogeneity.
Pediatric cancers such as neuroblastoma are thought to involve a dysregulation of embryonic development. However, it has been difficult to identify the critical events that trigger tumorigenesis and ...differentiate them from normal development. In this study, we report the establishment of a spheroid culture method that enriches early-stage tumor cells from TH-MYCN mice, a preclinical model of neuroblastoma. Using this method, we found that tumorigenic cells were evident as early as day E13.5 during embryo development, when the MYC and PRC2 transcriptomes were significantly altered. Ezh2, an essential component of PRC2, was expressed in embryonic and postnatal tumor lesions and physically associated with N-MYC and we observed that H3K27me3 was increased at PRC2 target genes. PRC2 inhibition suppressed
sphere formation, derepressed its target genes, and suppressed
tumor growth. In clinical specimens, expression of MYC and PRC2 target genes correlated strongly and predicted survival outcomes. Together, our findings highlighted PRC2-mediated transcriptional control during embryogenesis as a critical step in the development and clinical outcome of neuroblastoma.
.
Background
Diffuse-type gastric cancers (DGC) typically have a poor prognosis related to their invasion and metastasis, in which the epithelial–mesenchymal transition (EMT) is the initiation step. ...ULK2 plays a role in the autophagy initiation, which might provide a survival advantage in cancer cells. Although knock-down of
ULK2
reportedly induces autophagy and EMT in a lung cancer cell line, the mechanism of EMT via the down-regulation of
ULK2
, as well as its clinical significance, remains yet unclear. The present study, therefore, aims at clarifying this mechanism and its clinical significance in gastric cancers.
Methods
We examined
ULK2
mRNA expression in gastric cancer tissues and normal gastric tissues of healthy people. The effects of knock-downed
ULK2
were examined in two gastric cancer cells, which were investigated in terms of their gene expression changes by the mRNA microarray.
Results
ULK2 was strongly expressed in intestinal-type cancers but was scarcely expressed in DGC by immunohistochemical staining. Furthermore, we found that
ULK2
was methylated in DGC and was unmethylated in corresponding adjacent normal tissues. Then, we validated whether knock-down of
ULK2
could induce autophagy, cell migration, and EMT in NUGC3 and MKN45 cells. Using mRNA microarray analysis, we confirmed that knock-down of
ULK2
changed expressions of oncogenic genes associated with cell migration and EMT. Autophagy inhibitor suppressed cell migration and EMT induced by knock-down of
ULK2
in NUGC3 and MKN45.
Conclusion
Methylation silencing of
ULK2
could induce cell migration and EMT by means of autophagy induction, causing transformation to poorly differentiated cancers.
Dynamic metabolic changes occur in the liver during the transition between fasting and feeding. Here we show that transient ER stress responses in the liver following feeding terminated by Sdf2l1 are ...essential for normal glucose and lipid homeostasis. Sdf2l1 regulates ERAD through interaction with a trafficking protein, TMED10. Suppression of Sdf2l1 expression in the liver results in insulin resistance and increases triglyceride content with sustained ER stress. In obese and diabetic mice, Sdf2l1 is downregulated due to decreased levels of nuclear XBP-1s, whereas restoration of Sdf2l1 expression ameliorates glucose intolerance and fatty liver with decreased ER stress. In diabetic patients, insufficient induction of Sdf2l1 correlates with progression of insulin resistance and steatohepatitis. Therefore, failure to build an ER stress response in the liver may be a causal factor in obesity-related diabetes and nonalcoholic steatohepatitis, for which Sdf2l1 could serve as a therapeutic target and sensitive biomarker.
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