Simvastatin ameliorates synaptic plasticity impairment in chronic mild stress-induced depressed mice by modulating hippocampal NMDA receptor.

BACKGROUND: In our previous study, we showed simvastatin exerts an antidepressant effect and inhibits neuroinflammation. Given the role of synaptic impairment in depression development, we investigate the effect of simvastatin on synaptic plasticity in depression and the related mechanisms. METHODS: Electrophysiological analysis, Golgi staining, and transmission electron microscope were performed to analyze the effect of simvastatin on synaptic impairment in depression. In addition, the localization and reactivity of N-methyl-D-aspartate receptor (NMDAR) subunits and the downstream signaling were investigated to explore the mechanism of simvastatin's effect on synaptic plasticity. RESULTS: Simvastatin ameliorated the reduction of the magnitude of long-term potentiation (LTP) in Schaffer collateral-CA1, restored hippocampal dendritic spine density loss, improved the number of spine synapses, reversed the reduction in BrdU-positive cells in chronic mild stress (CMS)-induced depressed mice, and ameliorated NMDA-induced neurotoxicity in hippocampal neurons. Dysfunction of NMDAR activity in the hippocampus is associated with depression. Simvastatin treatment reversed the surface expression and phosphorylation changes of NMDAR subunits in NMDA-treated hippocampal neurons and depressed mice. In addition, simvastatin further increased the levels of mature BDNF, activating TrkB-Akt-mTOR signaling, which is critical for synaptic plasticity. CONCLUSIONS: These findings suggest that simvastatin can improve the dysfunction of NMDAR and ameliorate hippocampal synaptic plasticity impairment in depressed mice.

Economic evaluation of serplulimab plus chemotherapy as the first-line treatment of oesophageal squamous cell carcinoma in China.

OBJECTIVE: The ASTRUM-007 study confirmed the significant efficacy and safety of serplulimab plus chemotherapy for patients with locally advanced/metastatic, programmed cell death-ligand 1 positive oesophageal squamous cell carcinoma (OSCC). The economics of this regimen, however, is unclear. Therefore, this study aimed to evaluate the cost-effectiveness of adding serplulimab to chemotherapy for the treatment of advanced OSCC from the perspective of the Chinese healthcare system. DESIGN: A partitioned survival model was established to simulate the costs and outcomes of chemotherapy versus serplulimab plus chemotherapy. The survival data came from the ASTRUM-007 study. Only direct medical costs were considered, and utility values were referred to the literature. Sensitivity analysis was performed to assess the effect of parameter uncertainty on the model. OUTCOME MEASURES: Total costs, incremental costs, life years, quality-adjusted life years (QALYs), incremental QALYs and incremental cost-effectiveness ratio (ICER). RESULTS: The base case analysis showed that the cost of serplulimab plus chemotherapy (US$69 356) was US$41 607 higher than that of chemotherapy (US$27 749), but it also gained 0.38 QALYs more (1.38 vs 1 QALYs), with an ICER of US$110 744.36/QALY, which was higher than the willingness to pay. The factors that most influenced the ICER were the price of serplulimab, weight and utility value of the progression-free survival stage. The subgroup analysis and scenario analysis also demonstrated that serplulimab plus chemotherapy was not economical. CONCLUSIONS: Compared with chemotherapy, serplulimab coupled with chemotherapy was not cost-effective for the treatment of advanced OSCC in China.

A new one-dimensional NiII coordination polymer with a two-dimensional supra-molecular architecture.

A new one-dimensional NiII coordination polymer of 1,3,5-tris-(imidazol-1-ylmeth-yl)benzene, namely catena-poly[[aqua-(sulfato-κO)hemi(µ-ethane-1,2-diol-κ2O:O')[µ3-1,3,5-tris-(1H-imidazol-1-ylmeth-yl)benzene-κ3N3,N3',N3'']nickel(II)] ethane-1,2-diol monosolvate monohydrate], {[Ni(SO4)(C18H18N6)(C2H6O2)0.5(H2O)]·C2H6O2·H2O} n , was synthesized and characterized by elemental analysis, IR spectroscopy and single-crystal X-ray diffraction. The NiII cation is coordinated by three N atoms of three different 1,3,5-tris-(imidazol-1-ylmeth-yl)benzene ligands, one O atom of an ethane-1,2-diol mol-ecule, by a sulfate anion and a water mol-ecule, forming a distorted octa-hedral NiN3O3 coordination geometry. The tripodal 1,3,5-tris-(imidazol-1-ylmeth-yl)benzene ligands link the NiII cations, generating metal-organic chains running along the [100] direction. Adjacent chains are further connected by O-H⋯O hydrogen bonds, resulting in a two-dimensional supermolecular architecture running parallel to the (001) plane. Another water mol-ecule and a second ethane-1,2-diol mol-ecule are non-coordinating and are linked to the coordinating sulfate ions via O-H⋯O hydrogen bonds.

Bis(6-nitro-1,10-phenanthrolin-1-ium) 2,5-di-carb-oxy-terephthalate.

In the structure of the title 2:1 proton-transfer compound, 2C12H8N3O2 (+)·C10H4O8 (2-), the 6-nitro-1,10-phenanthroline mol-ecules act as proton sponges, accepting protons from pyromellitic acid. The -NO2 group of one of the 6-nitro-1,10-phenanthrolin-1-ium cations is disordered and was refined with a site-occupancy ratio of 0.624 (15):0.376 (15). Two -COOH(-COO(-)) groups of the 2,5-di-carb-oxy-terephthalate dianion are disordered and were refined with site-occupancy ratios of 0.769 (4):0.231 (4) and 0.766 (5):0.234 (5). The -NO2 group of the second cation is also disordered about a pseudo-twofold rotation axis and was refined with a site-occupancy ratio of 0.903 (3):0.097 (3). There is an intra-molecular O-H⋯O hydrogen bond in the anion. The phenanthroline rings of the two cations are inclined to one another by 31.3 (1)°. In the anions, considering the major components only, the carb-oxy-lic acid groups (-COOH) are inclined to the benzene ring by 17.3 (2) and 22.3 (3)°. The carboxyl-ate groups (-COO(-)) are twisted by 9.3 (2) and 13.6 (6)° with respect to the benzene ring. In the crystal, adjacent 2,5-di-carb-oxy-terephthalate anions are linked via O-H⋯O hydrogen bonds, forming chains propagating along [010]. The cations are attached to the chain of anions by N-H⋯O hydrogen bonds.

A novel three-dimensional Zn(II) coordination polymer with 1,3,5-tris(imidazol-1-ylmethyl)benzene and cyclohexane-1,3,5-tricarboxylate ligands.

In the Zn(II) compound poly[[bis(µ3-cyclohexane-1,3,5-tricarboxylato)bis[µ3-1,3,5-tris(imidazol-1-ylmethyl)benzene]trizinc(II)] hexahydrate], {[Zn3(C18H18N6)2(C9H9O6)2]·6H2O}n, based on mixed 1,3,5-tris(imidazol-1-ylmethyl)benzene and cyclohexane-1,3,5-tricarboxylate ligands, there are two types of crystallographically independent Zn(II) centres, one in a general position and one on a crystallographic twofold axis. They have similar fourfold distorted tetrahedral coordination geometries, ligated by two monodentate carboxylate groups from two cyclohexane-1,3,5-tricarboxylate ligands and by two N atoms from two 1,3,5-tris(imidazol-1-ylmethyl)benzene ligands. The cyclohexane-1,3,5-tricarboxylate anions link the Zn(II) cations to generate a two-dimensional layered metal-organic structure running parallel to the (201) plane. Adjacent layers are further connected by tripodal 1,3,5-tris(imidazol-1-ylmethyl)benzene ligands, resulting in a three-dimensional network. The solvent water molecules are linked to the cyclohexane-1,3,5-tricarboxylate ligands via water-carboxylate O-H···O hydrogen bonds.

Two-dimensional hydrogen-bonded supramolecular networks in the compounds of benzene-1,2,4,5-tetracarboxylic acid (pyromellitic acid) with 2,2'-biimidazole and 4,4'-dimethyl-2,2'-bipyridine.

Two products from the proton-transfer reactions of benzene-1,2,4,5-tetracarboxylic acid (pyromellitic acid, PMA) with 2,2'-biimidazole and 4,4'-dimethyl-2,2'-bipyridine, namely 2,2'-biimidazole-3,3'-diium 2,5-dicarboxybenzene-1,4-dicarboxylate, C6H8N4(2+),C10H4O8(2-), (I), and 4-methyl-2-(4-methylpyridin-2-yl)pyridinium 2,4,5-tricarboxybenzoate monohydrate, C12H13N2(+)·C10H5O8(-)·H2O, (II), have been prepared and their structures determined. Both compounds crystallize in the space group P1. The asymmetric unit of (I) is composed of two independent ion pairs. Both the 2,2'-biimidazole-3,3'-diium dication and the PMA(2-) anion are located on special positions (inversion centres). The protonated 2,2'-biimidazole-3,3'-diium ring H atoms are involved in hydrogen bonding with carboxylate O atoms to form one-dimensional hydrogen-bonded chain structures. Adjacent chains are further linked via carboxyl-carboxyl O-H···O hydrogen bonding, resulting in a two-dimensional supramolecular sheet with the R6(5)(34) motif extending in the (1-21) plane. In (II), classical O-H···O hydrogen-bond-linked anion-anion units are extended into a one-dimensional chain running parallel to the [100] direction, giving an R2(2)(8)R4(4)(30) motif. The chains are connected by water-carboxyl O-H···O hydrogen bonds to form a two-dimensional network parallel to the (011) plane. The 4-methyl-2-(4-methylpyridin-2-yl)pyridinium cations lie between the two-dimensional supramolecular layers linked via N-H···O hydrogen-bonding interactions.

Bis(1,10-phenanthroline-κ(2) N,N')(sulfato-κO)zinc(II) propane-1,2-diol monosolvate.

In the title compound, [Zn(SO4)(C12H8N2)2]·C3H8O2, the Zn(II) ion is in a distorted square-pyramidal coordination environment composed of four N atoms from two chelating 1,10-phenanthroline ligands and one O atom from a monodentate sulfate ligand. The Zn(II) ion lies on a twofold rotation axis. The sulfate ligand and propane-1,2-diol mol-ecules are disordered across the twofold rotation axis. The dihedral angle between the two chelating N2C2 groups is 83.26 (13)°. In the crystal, the complex mol-ecule and the propane-1,2-diol mol-ecule are connected through a pair of O-H⋯O hydrogen bonds.

Poly[diaqua-bis-(µ-4,4'-bipyridine-κ(2) N:N')bis-(ethane-1,2-diol-κO)bis(µ-sulfato-κ(2) O:O')dicobalt(II)].

In the title compound, [Co2(SO4)2(C10H8N2)2(C2H6O2)2(H2O)2] n , there are two crystallographically independent Co(II) ions, each of which lies on a twofold rotation axis and has a slightly distorted octa-hedral environment. One Co(II) ion is coordinated by two N atoms from two bridging 4,4'-bipyridine (4,4'-bipy) ligands, two O atoms from two sulfate ions and two O atoms from aqua ligands. The second Co(II) ion is similar but with ethane-1,2-diol ligands in place of water mol-ecules. The sulfate anions act as bridging ligands to link two adjacent Co(II) ions together, leading to the formation of linear ⋯Co1Co2Co1Co2⋯chains along the a axis. Adjacent chains are further bridged by 4,4'-bipy ligands, which are also located on the twofold rotation axis, resulting in a two-dimensional layered polymer extending parallel to (001). In the crystal, the layers are linked by extensive O-H⋯O hydrogen-bonding inter-actions involving the O atoms of the water mol-ecules and ethane-1,2-diol mol-ecules, resulting in a three-dimensional supra-molecular network.

Bis(1,10-phenanthroline-κ(2) N,N')(sulfato-κ(2) O,O')cobalt(II) propane-1,2-diol monosolvate.

In the title compound, [Co(SO4)(C12H8N2)2]·C3H8O2, the Co(II) atom (site symmetry 2) has a distorted octa-hedral coordination composed of four N atoms from two chelating 1,10-phenanthroline ligands and two O atoms from an O,O'-bidentate sulfate ligand, in which the S atom has site symmetry 2. The dihedral angle between the two chelating N2C2 groups is 84.46 (15)°. The complex and solvent mol-ecules are connected through O-H⋯O hydrogen bonds. The solvent mol-ecule is equally disordered over two positions and is also located on a twofold axis.

Bis(1,10-phenanthroline-κ(2) N,N')(sulfato-O)copper(II) butane-2,3-diol monosolvate.

The title compound, [Cu(SO4)(C12H8N2)2]·C4H10O2, is comprised of neutral monomeric complex and butane-2,3-diol solvent mol-ecules. In the complex, the Cu(II) ion is in a distorted square-pyramidal coordination environment defined by four N atoms from two chelating 1,10-phenanthroline ligands and one O atom from a monodentate sulfate anion; the O atom is at the apex. The two chelating N2C2 groups subtend a dihedral angle of 85.8 (4)°. In the crystal, the neutral monomeric complex and butane-2,3-diol solvent mol-ecules are held together by O-H⋯O hydrogen bonding, which leads to additional stabilization of the structure. The presence of pseudosymmetry in the structure suggests the higher symmetry space group C2/c, but attempts to refine the structure in this space group resulted in an unsatisfactory model and high R and wR values. The sulfate anion is disordered over two sets of sites with occupancies of 0.55 (1) and 0.45 (1).

Poly[aqua-(µ2-4,4'-bipyridine-κ(2) N:N')(ethane-1,2-diol-κO)(µ2-sulfato-κ(2) O:O')nickel(II)].

The title compound, [Ni(SO4)(C10H8N2)(C2H6O2)(H2O)] n , contains two crystallographically unique Ni(II) atoms, each lying on a twofold rotation axis and having a slightly distorted octa-hedral environment. It is isotypic with the previously reported Cu(II) analog [Zhong et al. (2011 ▶). Acta Cryst. C67, m62-m64]. One Ni(II) atom is coordinated by two N atoms from two bridging 4,4'-bipyridine (4,4'-bipy) ligands, two O atoms from two sulfate ions and two aqua O atoms. The second Ni(II) atom is surrounded by two N atoms from 4,4'-bipy ligands and four O atoms, two from bridging sulfate ions and from two ethane-1,2-diol ligands. The sulfate anion acts as a bridging ligand, linking adjacent Ni(II) atoms, leading to the formation of linear ⋯Ni1-Ni2-Ni1-Ni2⋯ chains along the a-axis direction. Adjacent chains are further bridged by 4,4'-bipy ligands, resulting in a two-dimensional layered polymer parallel to (001). In the crystal, the polymeric layers are linked by extensive O-H⋯O hydrogen-bonding inter-actions involving the O atoms of the water mol-ecules and the ethane-1,2-diol mol-ecules, resulting in a three-dimensional supra-molecular network.

Bis(1,10-phenanthroline-κ(2) N,N')(sulfato-κ(2) O,O')nickel(II) propane-1,2-diol monosolvate.

In the title compound, [Ni(SO4)(C12H8N2)2]·C3H8O2, the Ni(II) atom exhibits a distorted octa-hedral coordination by four N atoms from two chelating 1,10-phenanthroline ligands and two O atoms from an O,O'-bidentate sulfate group. A twofold rotation axis passes through the Ni and S atoms and the mid-point of the hydroxyl C-C bond of the propane-1,2-diol solvent mol-ecule. The dihedral angle between the two chelating N2C2 groups is 85.61 (8)°. The [NiSO4(C10H8N2)2] and propane-1,2-diol units are held together by a pair of symmetry-related inter-molecular O-H⋯O hydrogen bonds involving the uncoordinating O atoms of the sulfate ion. Due to symmetry, the solvent mol-ecule is equally disordered over two positions.

2,9-Dimethyl-1,10-phenanthrolin-1-ium 2,4,5-tri-carb-oxy-benzoate monohydrate.

In the preparation of the title hydrated salt, C14H13N2 (+)·C10H5O8 (-)·H2O, a proton has been transfered to the 2,9-dimethyl-1,10-phenanthrolinium cation, forming a 2,4,5-tri-carb-oxy-benzoate anion. In the anion, the mean planes of the protonated carboxyl-ate groups form dihedral angles of 11.0 (5), 4.4 (5) and 80.3 (4)° with the benzene ring to which they are attached. The mean plane of the deprotonated carboxyl-ate group forms a dihedral angle of 10.6 (5)° with the benzene ring. In the crystal, the anions are involved in carb-oxy-lic acid O-H⋯Ocarbox-yl hydrogen bonds, generating a two-dimensional network parallel to (001) containing R 4 (4)(28) and R 4 (4)(32) motifs. The 2,9-dimethyl-1,10-phenanthrolinium cations and water mol-ecules reside between the anion layers and are connected to the anions via N-H⋯Owater and Owater-H⋯Ocarbox-yl hydrogen bonds. An intra-molecular O-H⋯O hydrogen bond is also observed in the anion.

Tris(1,10-phenanthroline-κ2N,N')iron(II) bis(2,4,5-tricarboxybenzoate) monohydrate and tris(2,2'-bipyridine-κ2N,N')iron(II) 2,5-dicarboxybenzene-1,4-dicarboxylate-benzene-1,2,4,5-tetracarboxylic acid-water (1/1/2).

The title compounds, tris(1,10-phenanthroline-κ(2)N,N')iron(II) bis(2,4,5-tricarboxybenzoate) monohydrate, [Fe(C(12)H(8)N(2))(3)](C(10)H(5)O(8))(2)·H(2)O, (I), and tris(2,2'-bipyridine-κ(2)N,N')iron(II) 2,5-dicarboxybenzene-1,4-dicarboxylate-benzene-1,2,4,5-tetracarboxylic acid-water (1/1/2), [Fe(C(10)H(8)N(2))(3)](C(10)H(4)O(8))·C(10)H(6)O(8)·2H(2)O, (II), were obtained during an attempt to synthesize a mixed-ligand complex of Fe(II) with an N-containing ligand and benzene-1,2,4,5-tetracarboxylic acid via a solvothermal reaction. In both mononuclear complexes, each Fe(II) metal ion is six-coordinated in a distorted octahedral manner by six N atoms from three chelating 1,10-phenanthroline or 2,2'-bipyridine ligands. In compound (I), the Fe(II) atom lies on a twofold axis in the space group C2/c, whereas (II) crystallizes in the space group P2(1)/n. In both compounds, the uncoordinated carboxylate anions and water molecules are linked by typical O-H···O hydrogen bonds, generating extensive three-dimensional hydrogen-bond networks which surround the cations.

A novel one-dimensional Co(II) coordination polymer: catena-poly[[hexaaquacobalt(II)] [[diaquabis(sulfato-κO)cobalt(II)]-µ-4,4'-bipyridine-κ2N:N'] [[triaqua(sulfato-κO)cobalt(II)]-µ-4,4'-bipyridine-κ2N:N']].

The title compound, {[Co(H(2)O)(6)][Co(SO(4))(C(10)H(8)N(2))(H(2)O)(3)][Co(SO(4))(2)(C(10)H(8)N(2))(H(2)O)(2)]}(n), contains three crystallographically unique Co(II) centres, all of which are in six-coordinated environments. One Co(II) centre is coordinated by two bridging 4,4'-bipyridine (4,4'-bipy) ligands, one sulfate ion and three aqua ligands. The second Co(II) centre is surrounded by two N atoms of two 4,4'-bipy ligands and four O atoms, i.e. two O atoms from two monodentate sulfate ions and two from water molecules. The third Co(II) centre forms part of a hexaaquacobalt(II) ion. In the crystal structure, there are two different one-dimensional chains, one being anionic and the other neutral, and adjacent chains are arranged in a cross-like fashion around the mid-point of the 4,4'-bipy ligands. The structure features O-H···O hydrogen-bonding interactions between sulfate anions and water molecules, resulting in a three-dimensional supramolecular network.

Poly[diaqua-(µ(4)-2,5-dicarb-oxy-benzene-1,4-dicarboxyl-ato-κ(4)O(1):O(2):O(4):O(5))(µ(2)-2,5-dicarb-oxy-benzene-1,4-dicarboxyl-ato-κ(2)O(1):O(4))bis-(1,10-phenanthroline-κ(2)N,N')dimanganese(II)].

In the title compound, [Mn(2)(C(10)H(4)O(8))(2)(C(12)H(8)N(2))(2)(H(2)O)(2)](n), the Mn(2+) ion has a slightly distorted octa-hedral N(2)O(4) coordination geometry being coordinated by one aqua O atom, two N atoms of the chelating 1,10-phenanthroline ligand and three carboxyl O atoms from three 2,5-dicarb-oxy-benzene-1,4-dicarboxyl-ate (H(2)btec(2-)) ligands. The H(2)btec(2-) anion exhibits two different coordination modes, viz. µ(2) and µ(4). Both of the H(2)btec(2-) anions are located on special positions (inversion centers). The µ(4)-anion bridges adjacent Mn(II) atoms, forming a chain along the a axis. Adjacent chains are further bridged by µ(2)-anions, resulting in a two-dimensional layered polymer parallel to (011). In the crystal, extensive carb-oxy-carboxyl-ate O-H⋯O and water-carboxyl-ate O-H⋯O inter-actions lead to the formation of a three-dimensional supra-molecular network.

Bis(1,10-phenanthroline-κ(2) N,N')(sulfato-κ(2) O,O')nickel(II) butane-2,3-diol monosolvate.

In the title compound, [Ni(SO4)(C12H8N2)2]·C4H10O2, the Ni(II) ion is six-coordinated by four N atoms from two chelating 1,10-phenanthroline ligands and two O atoms from an O,O'-bidentate sulfate anion, resulting in a distorted octa-hedral geometry for the metal ion. The dihedral angle between the two chelating N2C2 groups is 83.82 (12)°. The Ni(II) ion, the S atom and the mid-point of the central C-C bond of the butane-2,3-diol solvent mol-ecule lie on a twofold rotation axis. In the crystal, the complex mol-ecules and solvent mol-ecules are held together by pairs of symmetry-related Odiol-H⋯Osulfate hydrogen bonds involving the uncoordinating O atoms of the sulfate ions. The solvent mol-ecule is disordered over two sets of sites with site occupancies of 0.450 (9) and 0.550 (9).

Bis(1,10-phenanthroline-κ(2) N,N')(sulfato-O)copper(II) propane-1,3-diol monosolvate.

In the title compound, [Cu(SO4)(C12H8N2)2]·C3H8O2, the Cu(II) ion is bonded to two chelating 1,10-phenanthroline (phen) ligands and one O atom from a monodentate sulfate ligand in a distorted square-based pyramidal arrangement, with the O atom in a basal site. The two chelating N2C2 groups subtend a dihedral angle of 71.10 (15)°. In the crystal, the solvent mol-ecule forms two O-H⋯O hydrogen bonds to its adjacent complex mol-ecule. The chosen crystal was found to be a racemic twin; the presence of pseudosymmetry in the structure suggests the higher symmetry space group C2/c, but attempts to refine the structure in this space group resulted in an unsatisfactory model and high R and wR values.

Tris(1,10-phenanthroline-κN,N')nickel(II) bis-(2,4,5-tricarb-oxy-benzo-ate) monohydrate.

In the title compound, [Ni(C(12)H(8)N(2))(3)](C(10)H(5)O(8))(2)·H(2)O, the Ni(II) cation is coordinated by six N atoms of the three bidentate chelating 1,10-phenanthroline ligands in a slightly distorted octa-hedral coordination geometry. The Ni-N bond lengths range from 2.074 (2) to 2.094 (2) Å. The dihedral angles between the three chelating NCCN groups to each other are 85.71 (3), 73.75 (2) and 85.71 (3)°, respectively. The Ni cation, the phenyl ring of the 1,10-phenanthroline ligand and the lattice water molecule are located on special positions (site symmetry 2). In the crystal, the uncoordinated 2,4,5-tricarb-oxy-benzeno-ate anions join with each other through O-H⋯O hydrogen bonds, forming a two-dimensional hydrogen-bonded layer structure along the bc plane. The layers are further linked via additional O-H⋯O inter-actions between water and carboxyl groups, resulting in a three-dimensional supra-molecular network.

Bis(1,10-phenanthroline-κN,N')(sulfato-O)copper(II) ethane-1,2-diol monosolvate.

In the title compound, [Cu(SO(4))(C(12)H(8)N(2))(2)]·C(2)H(6)O(2), the Cu(II) ion is five-coordinated in a distorted square-pyramidal manner by four N atoms from two chelating 1,10-phenanthroline (phen) ligands and one O atom from a monodentate sulfate anion. The four N atoms comprise a square and the one O atom the apex of a square pyramid. The two chelating N(2)C(2) groups are oriented at 71.1 (2)°. In the crystal, the components are connected by inter-molecular O-H⋯O hydrogen bonding. The presence of pseudosymmetry in the structure suggests the higher symmetry space group C2/c, but attempts to refine the structure in this space group resulted in an unsatisfactory model.