Early T-cell precursor-acute lymphoblastic leukemia (ETP-ALL) has been identified as a high-risk subtype of pediatric T-cell acute lymphoblastic leukemia (T-ALL). Conventional chemotherapy is not fully effective for this subtype of leukemia; therefore, potential therapeutic targets need to be explored. Analysis of the gene expression patterns of the transcription factors in pediatric T-ALL revealed that MEF2C and FLT3 were expressed at higher levels in ETP-ALL than typical T-ALL. Using human T-ALL and BaF3 cell lines with high expression levels of MEF2C, the present study tested whether the BCL2 inhibitor (ABT-737) restores the sensitivity to prednisolone (PSL), because MEF2C causes PSL resistance, possibly by augmenting the anti-apoptotic activity of BCL2. Treatment with PSL and ABT-737 caused a significant reduction in the IC50 of PSL in the MEF2C-expressing LOUCY cells, in addition to the MEF2C-transduced BaF3 cells, but not in the non-MEF2C-expressing Jurkat cells. The combination treatment significantly accelerated the killing of primary leukemic blast cells of ETP-ALL with high expression levels of MEF2C, which were co-cultured with murine stromal cells. These findings suggest that BCL2 inhibitors may be a therapeutic candidate in vivo for patients with ETP-ALL with high expression levels of MEF2C.
The structures of two isomeric compounds of isoquinoline with 3-chloro-2-nitrobenzoic acid and 4-chloro-2-nitrobenzoic acid have been determined at 190 K. In each compound, the acid and base molecules are held together by a short hydrogen bond between a carboxy O atom and a base N atom. In the hydrogen-bonded unit of the former, the H atom is disordered over two positions, while in the latter, an acid–base interaction involving H-atom transfer occurs and the H atom is located at the N site.
In each of the title isomeric compounds, C9H7.3N·C7H3.7ClNO4, (I), and C9H8N·C7H3ClNO4, (II), of isoquinoline with 3-chloro-2-nitrobenzoic acid and 4-chloro-2-nitrobenzoic acid, the two components are linked by a short hydrogen bond between a base N atom and a carboxy O atom. In the hydrogen-bonded unit of (I), the H atom is disordered over two positions with N and O site occupancies of 0.30 (3) and 0.70 (3), respectively, while in (II), an acid–base interaction involving H-atom transfer occurs and the H atom is located at the N site. In the crystal of (I), the acid–base units are connected through C—H⋯O hydrogen bonds into a tape structure along the b-axis direction. Inversion-related adjacent tapes are further linked through π–π interactions [centroid–centroid distances = 3.6389 (7)–3.7501 (7) Å], forming a layer parallel to (001). In the crystal of (II), the acid–base units are connected through C—H⋯O hydrogen bonds into a ladder structure along the a-axis direction. The ladders are further linked by another C—H⋯O hydrogen bond into a layer parallel to (001).
crystal structure; short hydrogen bond; chloro- and nitro-substituted benzoic acid; isoquinoline
It is unclear whether combined leg and arm high-intensity interval training (HIIT) improves fitness and morphological characteristics equal to those of leg-based HIIT programs. The aim of this study was to compare the effects of HIIT using leg-cycling (LC) and arm-cranking (AC) ergometers with an HIIT program using only LC. Effects on aerobic capacity and skeletal muscle were analyzed. Twelve healthy male subjects were assigned into two groups. One performed LC-HIIT (n=7) and the other LC- and AC-HIIT (n=5) twice weekly for 16 weeks. The training programs consisted of eight to 12 sets of >90% VO2 (the oxygen uptake that can be utilized in one minute) peak for 60 seconds with a 60-second active rest period. VO2 peak, watt peak, and heart rate were measured during an LC incremental exercise test. The cross-sectional area (CSA) of trunk and thigh muscles as well as bone-free lean body mass were measured using magnetic resonance imaging and dual-energy X-ray absorptiometry. The watt peak increased from baseline in both the LC (23%±38%; P<0.05) and the LC–AC groups (11%±9%; P<0.05). The CSA of the quadriceps femoris muscles also increased from baseline in both the LC (11%±4%; P<0.05) and the LC–AC groups (5%±5%; P<0.05). In contrast, increases were observed in the CSA of musculus psoas major (9%±11%) and musculus anterolateral abdominal (7%±4%) only in the LC–AC group. These results suggest that a combined LC- and AC-HIIT program improves aerobic capacity and muscle hypertrophy in both leg and trunk muscles.
arm-cranking ergometer; cycling ergometer; aerobic capacity; skeletal muscle
Autophagy is an intracellular process leading to vacuolar degradation of cytoplasmic components, which is important for nutrient recycling. Autophagic degradation of chloroplastic proteins via Rubisco-containing bodies is activated in leaves upon low sugar availability in Arabidopsis and our recent study reveals the contribution of autophagy to nighttime energy availability for growth. Whereas metabolic analysis supports that autophagic proteolysis provides a supply of alternative energy sources such as amino acids during sugar deficit, changes in a large number of metabolites due to autophagy deficiency are also observed. Here, we performed statistical characterization of that metabolic data. Principal component analysis clearly separated wild type and autophagy-deficient atg5 mutant samples, pointing to significant effects of autophagy deficiency on metabolite profiles in Arabidopsis leaves. Thirty-six and four metabolites were significantly increased and decreased in atg5 compared with wild type, respectively. These results imply that autophagic proteolysis is linked to plant metabolic processes.
Arabidopsis; autophagy; chloroplast; energy availability; metabolite profiling; Rubisco-containing body
In the title compound [systematic name: bis(4-methoxy-3,4-dihydroquinazolin-1-ium) 2,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,4-diolate], 2C9H11N2O+·C6Cl2O4
2−, the chloranilate anion lies about an inversion center. The 4-methoxy-3,4-dihydroquinazolin-1-ium cations are linked on both sides of the anion via bifurcated N—H⋯(O,O) and weak C—H⋯O hydrogen bonds, giving a centrosymmetric 2:1 aggregate. The 2:1 aggregates are linked by another N—H⋯O hydrogen bond into a tape running along [1-10]. The tapes are further linked by a C—H⋯O hydrogen bond into a layer parallel to the ab plane.
In the crystal structure of the title compound [systematic name: bis(triethylammonium) 2,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,4-diolate], 2C6H16N+·C6Cl2O4
2−, the chloranilate anion lies on an inversion center. The triethylammonium cations are linked on both sides of the anion via bifurcated N—H⋯(O,O) and weak C—H⋯O hydrogen bonds to give a centrosymmetric 2:1 aggregate. The 2:1 aggregates are further linked by C—H⋯O hydrogen bonds into a zigzag chain running along [01-1].
In the title compound, C14H13ClN2O, the fused hydropyrimidine ring adopts an envelope conformation with one of the methylene C atoms at the flap. The three-membered ring is approximately perpendicular to the attached isoquinoline ring system, with a dihedral angle of 89.44 (11)°. In the crystal, molecules are linked by a weak C—H⋯π interaction, forming a helical chain along the c axis.
The asymmetric unit of the triclinic polymorph of the title compound (systematic name: 4-cyanopyridinium 2,5-dichloro-4-hydroxy-3,6-dioxocyclohexa-1,4-dien-1-olate), C6H5N2
−, consists of two crystallographically independent cation–anion units, in each of which the cation and the anion are linked by an N—H⋯O hydrogen bond. In the units, the dihedral angles between the cation and anion rings are 78.43 (11) and 80.71 (11)°. In the crystal, each unit independently forms a chain through N—H⋯O and O—H⋯N hydrogen bonds; one chain runs along the c axis while the other runs along . Weak C—H⋯O, C—H⋯N and C—H⋯Cl interactions are observed between the chains.
The asymmetric unit of the title compound, C13H9NO3, consists of two crystallographically independent molecules. In each molecule, the tetrahydrofuran (THF) ring adopts an envelope conformation with one of the methylene C atoms positioned at the flap. The dihedral angles between the mean plane of the THF and the benzofuran ring system are 70.85 (5) and 89.59 (6)°. In the crystal, molecules are stacked in a column along the a-axis direction through C—H⋯O hydrogen bonds, with columns further linked by C—H⋯N and C—H⋯O interactions.
Ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) small subunit (RBCS) is encoded by a nuclear RBCS multigene family in many plant species. The contribution of the RBCS multigenes to accumulation of Rubisco holoenzyme and photosynthetic characteristics remains unclear. T-DNA insertion mutants of RBCS1A (rbcs1a-1) and RBCS3B (rbcs3b-1) were isolated among the four Arabidopsis RBCS genes, and a double mutant (rbcs1a3b-1) was generated. RBCS1A mRNA was not detected in rbcs1a-1 and rbcs1a3b-1, while the RBCS3B mRNA level was suppressed to ∼20% of the wild-type level in rbcs3b-1 and rbcs1a3b-1 leaves. As a result, total RBCS mRNA levels declined to 52, 79, and 23% of the wild-type level in rbcs1a-1, rbcs3b-1, and rbcs1a3b-1, respectively. Rubisco contents showed declines similar to total RBCS mRNA levels, and the ratio of Rubisco-nitrogen to total nitrogen was 62, 78, and 40% of the wild-type level in rbcs1a-1, rbcs3b-1, and rbcs1a3b-1, respectively. The effects of RBCS1A and RBCS3B mutations in rbcs1a3b-1 were clearly additive. The rates of CO2 assimilation at ambient CO2 of 40 Pa were reduced with decreased Rubisco contents in the respective mutant leaves. Although the RBCS composition in the Rubisco holoenzyme changed, the CO2 assimilation rates per unit of Rubisco content were the same irrespective of the genotype. These results clearly indicate that RBCS1A and RBCS3B contribute to accumulation of Rubisco in Arabidopsis leaves and that these genes work additively to yield sufficient Rubisco for photosynthetic capacity. It is also suggested that the RBCS composition in the Rubisco holoenzyme does not affect photosynthesis under the present ambient [CO2] conditions.
Arabidopsis; RbcL; RBCS multigene family; Rubisco
In the crystal structure of the title compound, C4H10NO+·C6HCl2O4
−·CH4O, the components are held together by bifurcated O—H⋯(O,O), O—H⋯(O,Cl) and N—H⋯(O,O) hydrogen bonds into a centrosymmetric 2+2+2 aggregate. The aggregates are further connected by another bifurcated N—H⋯(O, O) hydrogen bond, forming a double-tape structure along the b axis. A weak C—H⋯O interaction is observed between the tapes.
In the title co-crystal, 2C7H4ClNO4·C4H4N2, the pyrazine molecule is located on an inversion centre, so that the asymmetric unit consists of one molecule of 4-chloro-2-nitrobenzoic acid and a half-molecule of pyrazine. The components are connected by O—H⋯N and C—H⋯O hydrogen bonds, forming a 2:1 unit. In the hydrogen-bonded unit, the dihedral angle between the pyrazine ring and the benzene ring of the benzoic acid is 16.55 (4)°. The units are linked by intermolecular C—H⋯O hydrogen bonds, forming a sheet structure parallel to (04). A C—H⋯O hydrogen-bond linkage is also observed between these sheets.
Autophagy is an intracellular process for the vacuolar degradation of cytoplasmic components and is important for nutrient recycling during starvation. Chloroplasts can be partially mobilized to the vacuole by autophagy via spherical bodies named Rubisco-containing bodies (RCBs). Although chloroplasts contain approximately 80% of total leaf nitrogen and represent a major carbon and nitrogen source for recycling, the relationship between leaf nutrient status and RCB production remains unclear. We analyzed the effects of nutrient factors on the appearance of RCBs in Arabidopsis leaves and postulated that a close relationship exists between the autophagic degradation of chloroplasts via RCBs and leaf carbon status but not nitrogen status in autophagy. The importance of carbohydrates in RCB production during leaf senescence can be further argued. During nitrogen-limited senescence, as leaf carbohydrates were accumulated, RCB production was strongly suppressed. During the life span of leaves, RCB production increased with the progression of leaf expansion and senescence, while the production declined in late senescent leaves with a remarkable accumulation of carbohydrates, glucose and fructose. These results suggest that RCB production may be controlled by leaf carbon status during both induced and natural senescence.
arabidopsis (Arabidopsis thaliana); autophagy; chloroplast; nutrient response; leaf senescence; carbohydrate
In the title compound, C7H4ClNO4·C9H7N, the two components are connected by an O—H⋯N hydrogen bond. In the hydrogen-bonded unit, the dihedral angle between the quinoline ring system and the benzene ring of benzoic acid is 3.15 (7)°. In the crystal, units are linked by intermolecular C—H⋯O hydrogen bonds, forming a tape along the c axis. The tapes are stacked along the b axis through a C—H⋯O hydrogen bond into a layer parallel to the bc plane.
In the crystal structure of the title compound, C18H18O4, the full molecule is generated by the application of an inversion centre. The molecule is essentially planar, with an r.m.s. deviation of 0.017 (1) Å for all non-H atoms. The molecules are linked through intermolecular C—H⋯O interactions to form a molecular sheet parallel to the (02) plane.
The crystal structures of two solid phases of the title compound, C4H5N2
−·H2O, have been determined at 225 and 120 K. In the high-temperature phase, stable above 198 K, the transition temperature of which has been determined by 35Cl nuclear quadrupole resonance and differential thermal analysis measurements, the three components are held together by O—H⋯O, N⋯H⋯O, C—H⋯O and C—H⋯Cl hydrogen bonds, forming a centrosymmetric 2+2+2 aggregate. In the N⋯H⋯O hydrogen bond formed between the pyrimidin-1-ium cation and the water molecule, the H atom is disordered over two positions, resulting in two states, viz. pyrimidin-1-ium–water and pyrimidine–oxonium. In the low-temperature phase, the title compound crystallizes in the same monoclinic space group and has a similar molecular packing, but the 2+2+2 aggregate loses the centrosymmetry, resulting in a doubling of the unit cell and two crystallographically independent molecules for each component in the asymmetric unit. The H atom in one N⋯H⋯O hydrogen bond between the pyrimidin-1-ium cation and the water molecule is disordered, while the H atom in the other hydrogen bond is found to be ordered at the N-atom site with a long N—H distance [1.10 (3) Å].
In the crystal structure of the title compound (systematic name: triethylammonium 2,5-dichloro-4-hydroxy-3,6-dioxocyclohexa-1,4-dien-1-olate), C6H16N+·C6HCl2O4
−, two hydrogen chloranilate anions are connected by a pair of bifurcated O—H⋯O hydrogen bonds into a dimeric unit. The triethylammonium cations are linked on both sides of the dimer via bifurcated N—H⋯O hydrogen bonds into a centrosymmetric 2:2 aggregate. The 2:2 aggregates are further linked by intermolecular C—H⋯O hydrogen bonds.
In the title compound, C7H5ClO2·C9H7N, the 4-chlorobenzoic acid molecule is almost planar, with a dihedral angle of 2.9 (14)° between the carboxy group and the benzene ring. In the crystal, the two components are connected by an O—H⋯N hydrogen bond. In the hydrogen-bonded unit, the dihedral angle between the quinoline ring system and the benzene ring of the benzoic acid is 44.75 (4)°. The two components are further linked by intermolecular C—H⋯O hydrogen bonds, forming a layer parallel to the ab plane.
In the title compound, C11H9ClN2O, the fused-ring system is essentially planar, with a maximum deviation of 0.0323 (16) Å. In the crystal, molecules are connected by N—H⋯O hydrogen bonds forming a zigzag chain along the c axis. Molecules are further stacked along the a axis through weak π–π interactions, the shortest distance between ring centroids being 3.6476 (8) Å.
In the asymmetric unit of the title compound, 2C7H9ClN+·C9H6O4
2−·2H2O, there are two crystallographically independent cations, one dianion and two water molecules. The dihedral angle between the two carboxylate groups of the dianion is 78.1 (2)°. In the crystal, the components are held together by N—H⋯O, O—H⋯O and C—H⋯O hydrogen bonds, forming a layer parallel to the bc plane, with the hydrophilic and hydrophobic groups located in the inner and outer regions of the layers, respectively.
We recently reported that autophagy plays a role in chloroplasts degradation in individually-darkened senescing leaves. Chloroplasts contain approximately 80% of total leaf nitrogen, mainly as photosynthetic proteins, predominantly ribulose 1, 5-bisphosphate carboxylase/oxygenase (Rubisco). During leaf senescence, chloroplast proteins are degraded as a major source of nitrogen for new growth. Concomitantly, while decreasing in size, chloroplasts undergo transformation to non-photosynthetic gerontoplasts. Likewise, over time the population of chloroplasts (gerontoplasts) in mesophyll cells also decreases. While bulk degradation of the cytosol and organelles is mediated by autophagy, the role of chloroplast degradation is still unclear. In our latest study, we darkened individual leaves to observe chloroplast autophagy during accelerated senescence. At the end of the treatment period chloroplasts were much smaller in wild-type than in the autophagy defective mutant, atg4a4b-1, with the number of chloroplasts decreasing only in wild-type. Visualizing the chloroplast fractions accumulated in the vacuole, we concluded that chloroplasts were degraded by two different pathways, one was partial degradation by small vesicles containing only stromal-component (Rubisco containing bodies; RCBs) and the other was whole chloroplast degradation. Together, these pathways may explain the morphological attenuation of chloroplasts during leaf senescence and describe the fate of chloroplasts.
Arabidopsis; autophagy; chloroplast; dark treatment; leaf senescence; nutrients recycling
In the title salt hydrate, C5H6NO+·C6HCl2O4
−·H2O, the three components are held together by O—H⋯O and N—H⋯O hydrogen bonds, as well as by C—H⋯O contacts, forming a double-tape structure along the c axis. Within each tape, the pyridinium ring and the chloranilate ring are almost coplanar, forming a dihedral angle of 2.35 (7)°.
In the crystal structure of the title compound, 2C6H4N2·C6H2Cl2O4·2C2H3N, the two symmetry-related pyridine-3-carbonitrile molecules are linked to either side of a chloranilic acid (systematic name: 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone) molecule via intermolecular O—H⋯N hydrogen bonds, giving a centrosymmetric 2:1 unit. The dihedral angle between the pyridine ring and the chloranilic acid plane is 26.71 (6)°. In addition, the two acetonitrile molecules are linked to either side of the 2:1 unit through C—H⋯N hydrogen bonds, forming a 2:1:2 aggregate. These 2:1:2 aggregates are further linked by weak intermolecular C—H⋯N and C—H⋯O hydrogen bonds, forming a tape along the c axis.
Hereditary spherocytosis (HS) is a genetic disorder of the red blood cell membrane clinically characterized by anemia, jaundice and splenomegaly. Evans' syndrome is a clinical syndrome characterized by autoimmune hemolytic anemia (AIHA) accompanied by immune thrombocytopenic purpura (ITP). It results from a malfunction of the immune system that produces multiple autoantibodies targeting at least red blood cells and platelets. HS and Evans' syndrome have different mechanisms of pathophysiology one another. We reported the quite rare case of an infant who had these diseases concurrently. Possible explanations of the unexpected complication are discussed.
In the crystal structure of the title salt, C6H6NO2
−, the pyridine ring and the mean plane of the hydrogen chloranilate anion form a dihedral angle of 77.40 (8)°. The ionic components are held together by N—H⋯O and O—H⋯O hydrogen bonds, forming a supramolecular ladder. C—H⋯O interactions are also present.