Sortilin deletion in the prefrontal cortex and hippocampus ameliorates depressive-like behaviors in mice via regulating ASM/ceramide signaling.

Major depressive disorder (MDD) is a common psychiatric disorder characterized by persistent mood despondency and loss of motivation. Although numerous hypotheses have been proposed, the possible pathogenesis of MDD remains unclear. Several recent studies show that a classic transporter protein, sortilin, is closely associated with depression. In the present study, we investigated the role of sortilin in MDD using a well-established rodent model of depression. Mice were subjected to chronic unpredictable mild stress (CUMS) for 6 weeks. We showed that the expression levels of sortilin were significantly increased in the prefrontal cortex and hippocampus of CUMS mice. The depressive-like behaviors induced by CUMS were alleviated by specific knockdown of sortilin in the prefrontal cortex and hippocampus. We revealed that sortilin facilitated acid sphingomyelinase (ASM)/ceramide signaling, which activated RhoA/ROCK2 signaling, ultimately causing the transformation of dendritic spine dynamics. Specific overexpression of sortilin in the prefrontal cortex and hippocampus induced depressive-like behaviors, which was mitigated by injection of ASM inhibitor SR33557 (4 µg/µL) into the prefrontal cortex and hippocampus. In conclusion, sortilin knockdown in the prefrontal cortex and hippocampus plays an important role in ameliorating depressive-like behavior induced by CUMS, which is mainly evidenced by decreasing the trafficking of ASM from the trans-Golgi network to the lysosome and reducing the ceramide levels. Our results provide a new insight into the pathology of depression, and demonstrate that sortilin may be a potential therapeutic target for MDD.

Reactions of Group 4 amide guanidinates with dioxygen or water. Studies of the formation of oxo products.

Reactions of the zirconium amide guanidinates (R2N)2M[(i)PrNC(NR2)N(i)Pr]2 (R = Me, M = Zr, 1; M = Hf, 2; R = Et, M = Zr, 3) with O2 or H2O give products that are consistent with the oxo dimers {M(µ-O)[(i)PrNC(NR2)N(i)Pr]2}2 (R = Me, M = Zr, 4; M = Hf, 5; R = Et, M = Zr, 6) and polymers {M(µ-O)[(i)PrNC(NR2)N(i)Pr]2}n (R = Me, M = Zr, 7; M = Hf, 8; R = Et, M = Zr, 9). Mass spectrometric (MS) analyses of the reactions of water in air with 1 and 2 show formation of the Zr monomer Zr(═O)[(i)PrNC(NMe2)N(i)Pr]2 (10), oxo dimers 4 and 5, and dihydroxyl complexes M(OH)2[(i)PrNC(NMe2)N(i)Pr]2 (M = Zr, 11; Hf, 12). Similar MS analyses of the reaction of diethylamide guanidinate 3 with water in air show the formation of Zr(═O)[(i)PrNC(NEt2)N(i)Pr]2 (13), Zr(OH)2[(i)PrNC(NEt2)N(i)Pr]2 (14), 6, and {(Et2N)Zr[(i)PrNC(NEt2)N(i)Pr]2}(+) (15). Kinetic studies of the reaction between 1 and a continuous flow of 1.0 atm of O2 at 80-105 °C indicate that it follows pseudo-first-order kinetics with ΔH(‡) = 8.7(1.1) kcal/mol, ΔS(‡) = -54(3) eu, ΔG(‡)(358 K) = 28(2) kcal/mol, and a half-life of 213(1) min at 85 °C.

Influence of reactive oxygen species on human sperm functions and fertilizing capacity including therapeutical approaches.

BACKGROUND: Reactive oxygen species (ROS) are an array of molecules including oxygen-centered radicals, which are endowed with one or more unpaired electrons and non-radical oxygen derivatives such as hydrogen peroxide, which behave, to a large extent, like a double-edged sword in human sperm biology. This study aimed to overview the current knowledge of ROS in sperm physiology and pathology, as well as related therapies in spermatozoal dysfunction. METHODS: We performed this study by searching for keywords from PUBMED, including reactive oxygen species, oxidative stress, sperm function, and antioxidant therapy. RESULTS AND CONCLUSIONS: Low levels of ROS exert critical function in normal sperm physiology, such as fertilizing ability (acrosome reaction, hyperactivation, capacitation, and chemotaxis) and sperm motility; while increased ROS generation and/or decreased antioxidant capacity leads to the imbalance between oxidation and reduction in living systems, which is called sperm oxidative stress. This condition was widely considered to be a significant contributory factor to sperm DNA damage/apoptosis, lipid peroxidation, and reduced motility, which in turn, increased risk of male factor infertility/subfertility and birth defects. Under the current status quo, numerous subsequent studies have concentrated on antioxidant therapy. Although utility of such a therapeutic strategy significantly improved sperm function and motility in a myriad of experimental and clinical reports, the overall effectiveness still remains controversial mainly due to non-standardized assay to measure the level of ROS and sperm DNA damage, various antioxidant supplementation strategies, and inadequate fertilization and pregnancy data after clinical treatment. Therefore, standardized assessment and evaluation of ROS and total antioxidant capacity in semen should be established to keep ROS in a physiological level and prevent over-treatment of antioxidants toward reductive stress, which should be kept in mind, especially in assisted reproductive procedure. Moreover, the significance of large sample size populations, double-blind randomized, placebo-controlled clinical trials of antioxidant therapies is emphasized in this review to achieve optimal ingredients and dosage of antioxidants for patients with reactive oxygen-induced male fertility/subfertility.

Formation of the imide [Ta(NMe2)3(µ-NSiMe3)]2 through an unprecedented α-SiMe3 abstraction by an amide ligand.

Ta(NMe(2))(4)[N(SiMe(3))(2)] (1) undergoes the elimination of Me(3)Si-NMe(2) (2), converting the -N(SiMe(3))(2) ligand to the ═NSiMe(3) ligand, to give the imide "Ta(NMe(2))(3)(═NSiMe(3))" (3) observed as its dimer 4. CyN═C═NCy captures 3 to yield guanidinates Ta(NMe(2))(3-n)(═NSiMe(3))[CyNC(NMe(2))NCy](n) [n = 1 (5), 2 (6)]. The kinetic study of α-SiMe(3) abstraction in 1 gives ΔH(‡) = 21.3(1.0) kcal/mol and ΔS(‡) = -17(2) eu.

Damage-tolerant material design motif derived from asymmetrical rotation.

Motifs extracted from nature can lead to significant advances in materials design and have been used to tackle the apparent exclusivity between strength and damage tolerance of brittle materials. Here we present a segmental design motif found in arthropod exoskeleton, in which asymmetrical rotational degree of freedom is used in damage control in contrast to the conventional interfacial shear failure mechanism of existing design motifs. We realise this design motif in a compression-resisting lightweight brittle material, demonstrating a unique progressive failure behaviour that preserves material integrity with 60-80% of load-bearing capacity at >50% of compressive strain. This rotational degree of freedom further enables a periodic energy absorbance pattern during failure yielding 200% higher strength than the corresponding cellular structure and up to 97.9% reduction of post-damage residual stress compared with ductile materials. Fifty material combinations covering 27 types of materials analysed display potential progressive failure behaviour by this design motif, thereby establishing a broad spectrum of potential applications of the design motif for advanced materials design, energy storage/conversion and architectural structures.

Formation of aminoxy and oxo complexes from the reaction of Nb(NMe2)5 with O2 and the crystal structure of Nb(NEt2)5.

The reaction of Nb(NMe(2))(5) with O(2) gives three complexes: monomeric (Me(2)N)(n)Nb(eta(2)-ONMe(2))(5-n) (n = 3, 4) and dimeric (Me(2)N)(4)Nb(2)[eta(2)-N(Me)CH(2)NMe(2)](2)(mu-O)(2). Nb(NEt(2))(5) was prepared in a mixture of pentane and THF, leading to its purification and characterization by single-crystal X-ray diffraction. Unlike Nb(NMe(2))(5), which adopts a square pyramidal structure, Nb(NEt(2))(5) is a distorted trigonal bipyramid. The reaction of Nb(NEt(2))(5) with O(2) gives an insoluble white solid.

Grid-based electron-solid interaction simulation for characterizing high-dimensional microstructures.

Three-dimensional (3D) micro- and nanostructural characterization using scanning electron microscope (SEM) and electron-solid interaction simulations (ESIS) has attracted broad interest in various research fields. However, 3D SEM-ESIS still faces key challenges in characterizing and modelling complex microstructures. In this paper, a new grid-based simulation scheme is developed to enable ESIS of complex microstructures. In contrast to the widely used region-based approach, the scheme presented here uses a grid of points to represent the spatial distribution of sample compositions, which allows numerical investigation of the effect of various geometric features such as interfacial diffusion zones and complex pores in the samples. The simulation results suggest that the interfacial diffusion zone and porosity significantly influence the scattering signals. It is believed that the presented scheme acts as a useful interpretation tool in understanding a wide range of materials and paves the way to SEM-based 3D reconstruction.

Synthesis and characterization of siloxy, aminoxy, and oxo complexes from the reaction of a tantalum amide silyl complex with oxygen.

(Me(2)N)(4)Ta-SiBu(t)Ph(2) (1) reacts with O(2) to give (Me(2)N)(4)Ta(OSiBu(t)Ph(2)) (2), (Me(2)N)(3)Ta(ONMe(2))(OSiBu(t)Ph(2)) (3), and the unusual mu-oxo amino (Me(2)N)(2)(Ph(2)Bu(t)SiO)(2)(mu,eta(2)-Me(2)NCH(2)NMe)(2)Ta(2)(mu-O)(2) (4) containing two bridging chelating (aminomethyl)amides -N(Me)CH(2)NMe(2). The dimer 4 was characterized by X-ray crystallography. 2 also reacts with O(2) to give both 3 and 4. Reaction pathways in the formation of these complexes are discussed. In reactions of O(2) with d(0) 1 and 2, oxidation of the ligands is the prevailing pathway.

Transitions between nanomechanical and continuum mechanical contacts: new insights from liquid structure.

The use of continuum mechanics to describe contacts involving nanoscale and atomic interactions has been one of the key controversies in nanoscience, tribology, and petrophysical and geological studies. By applying a novel nonequilibrium molecular dynamics scheme to wet quartz contacts, this study revealed the key transitions between continuum electrostatic, nanomechanical and Hertzian contact behaviors at around one nm of surface separation, which results in critical contact pressure fluctuations between -30 and 100 MPa. Using a novel liquid-structure analysis scheme based on the spatial distribution of water molecules, the nanomechanical behavior was found to originate from the collapse and localization of layers of water molecules. Moreover, the role of surface curvature on this effect was also quantified and explained based on a new topological descriptor. The findings of this study enrich our understanding of wet contacts and have a wide range of applications from the nanoscale to macroscale.

Exfoliation and dispersion of boron nitride nanosheets to enhance ordinary Portland cement paste.

Exfoliation and dispersion of boron nitride nanosheets (BNNSs) is the key to achieving desired reinforcing effects for ordinary Portland cement (OPC). Few studies exist, however, of the dispersion of BNNSs in a cement-induced alkaline environment and their effect on the mechanical properties of normal OPC paste. In this study, protocols were developed to prepare BNNS-reinforced OPC paste. Ultrasonication was used to exfoliate BNNSs from h-BN in water based suspensions. The addition of surfactants in the suspension was found to hinder the exfoliation of the BNNSs. The surfactants were, however, found to be essential for the dispersion of the BNNSs in pore solution. Among the three surfactants used in this study, polycarboxylate based superplasticizer was most suitable as it maintained over 40% of the BNNSs stable in the pore solution for 4 hours and increased the hydration flow peak over 20%. Atomic force microscopy results indicated that the thickness of the BNNSs was mostly under 10 nm. With the addition of 0.003 wt% BNNSs, the compressive and tensile strengths of the cement were increased by 13% and 8%, respectively. Besides the nucleation effect as indicated by hydration heat, pore structure refinement and chemical bonding were also found as the main reinforcing mechanisms of BNNSs in OPC matrix.

Quantification of evaporation induced error in atom probe tomography using molecular dynamics simulation.

Non-equilibrium molecular dynamics was used to simulate the dynamics of atoms at the atom probe surface and five objective functions were used to quantify errors. The results suggested that before ionization, thermal vibration and collision caused the atoms to displace up to 1Å and 25Å respectively. The average atom displacements were found to vary between 0.2 and 0.5Å. About 9 to 17% of the atoms were affected by collision. Due to the effects of collision and ion-ion repulsion, the back-calculated positions were on average 0.3-0.5Å different from the pre-ionized positions of the atoms when the number of ions generated per pulse was minimal. This difference could increase up to 8-10Å when 1.5ion/nm2 were evaporated per pulse. On the basis of the results, surface ion density was considered an important factor that needed to be controlled to minimize error in the evaporation process.

Quercetin promotes motor and sensory function recovery following sciatic nerve-crush injury in C57BL/6J mice.

Injuries and diseases that occur in the nervous system are common and have few effective treatments. Previous studies have shown that quercetin has a therapeutic effect on nervous system injuries, but its potential effects on and mechanisms of action related to behavioral recovery and axonal regrowth have not been investigated. Here, we showed that quercetin administration promotes behavioral recovery following sciatic nerve-crush injury in mice. Long-term evaluation showed that mice administered 20 mg·kg-1·day-1 quercetin for 35 days had a greater sensorimotor recovery compared with all other treatment groups. The mechanisms behind these effects were further investigated, and quercetin was found to regulate the expression of genes involved in regeneration and trophic support. Moreover, quercetin increased cyclic adenosine monophosphate expression and downstream pathway activation, which directly leads to neuronal growth activation in peripheral axon regeneration. In addition, quercetin enhanced axon remyelination, motor nerve conduction velocity and plantar muscle function, indicating that the degree of distal portion hypotrophy during the peripheral axon regeneration process was reduced. These results suggest that quercetin accelerates functional recovery by up-regulating neuronal intrinsic growth capacity and postponing distal atrophy. Overall, quercetin triggered multiple effects to promote behavioral recovery following sciatic nerve-crush injury in mice.

Treatment of severe Clonorchiasis sinensis by endoscopic nasobiliary drainage and oral praziquantel.

AIM: To assess the therapeutic value of endoscopic nasobiliary drainage (ENBD) and oral praziquantel for severe Clonorchiasis sinensis infection. METHODS: Of the 84 Clonorchiasis sinensis-infected patients enrolled, 58 were treated with ENBD (as observing group, ENBD group), 26 received operations (control group, operation group). Both of the two groups were comparable in terms of patient's age, body mass index. Before and one week after treatment, the average diameters of common bile ducts were measured by ultrasound, and serum bilirubin, ALP, gamma-GT and ALT were detected by biochemical methods. After ENBD or operation, the patients took praziquantel for two days. RESULTS: Compared with the patients in operation group, ENBD patients in ENBD group had higher recovery rates of abdominal pain and fever as well as jaundice, quicker remission, smaller trauma, fewer complications and lower cost. CONCLUSION: ENBD combined with oral praziquantel is an effective and safe method for the treatment of severe Clonorchiasis sinensis.

Reactions of d(0) tungsten alkylidyne complexes with O2 or H2O. Formation of an oxo siloxy complex through unusual silyl migrations.

(Me3SiCH2)3(Me3SiC≡)W←O=PMe3 (1), an adduct between (Me3SiCH2)3W≡CSiMe3 (2) and O=PMe3, reacts with O2 to give O=W(OSiMe3)(CH2SiMe3)3 (3) and CO2. Reaction of 2 with H2O yields 3 and the trimer [(µ-O)W(CH2SiMe3)2(=O)(THF)]3 (4). In the reaction of D2O with 2, 3-d(n) and methane isotopologues CH2D2, CHD3 and CD4 have been observed.

Unexpected formation of a trinuclear complex containing a Ta(IV)-Ta(IV) bond in the reactions of Bu(t)N=Ta(NMe2)3 with silanes.

A new trinuclear species containing a Ta(IV)-Ta(IV) bond, Ta(3)(µ-H)(µ-NMe(2))(µ=NBu(t))(2)(=NBu(t))(NMe(2))(5), has been formed by reductive elimination of H(2). Ta(2)H(2)(µ-NMe(2))(2)(NMe(2))(2)(=NBu(t))(2) has also been isolated. O(2) oxidizes the Ta(IV)-Ta(IV) bond to yield Ta(3)(µ(3)-O)(H)(µ=NBu(t))(µ-NMe(2))(2)(NMe(2))(4)(=NBu(t))(2) under ligand exchange. Delocalization of d electrons is discussed.

The role of mast cells in male infertility.

Increased numbers of mast cells (MCs) were described in the testes of males exhibiting infertility many years ago. Since beneficial effects of treatment with MC blockers on impaired male fertility were reported, more attention has been drawn on the role of MCs in the male reproductive tract. The main interest is focused on testicular MCs, however MCs also occur in the epididymis and seminal fluid, which may be relevant for fertility as well. The increase in testicular MCs in close contact to the seminiferous tubules indicates a relationship between MC proliferation and a dysfunction of the blood-testis barrier. Activated MCs not only coincide with fibrotic events, but also with elevated numbers of several types of immune cells in the testes of infertile men and may, therefore, be involved in the pathogenesis of testicular inflammatory processes as well. Outside the testis, MCs have really been assigned a key role in chronic protatitis/chronic pelvic pain syndrome. The occurrence of MCs in the seminal plasma of fertile/infertile men and negative effects on sperm functions has not been clarified so far and require further investigation. Optimistic reports on the beneficial effects of the treatment with MC blockers on disturbed male fertility also warrant further confirmation.

Reaction of Ta(NMe2)5 with O2: formation of aminoxy and unusual (aminomethyl)amide oxo complexes and theoretical studies of the mechanistic pathways.

Reaction of d0 Ta(NMe2)5 (1) with O2 yields two aminoxy complexes (Me2N)(n)Ta(eta2-ONMe2)(5-n) (n = 4, 2; 3, 3) as well as (Me2N)4Ta2[eta2-N(Me)CH2NMe2]2(mu-O)2 (4) and (Me2N)6Ta3[eta2-N(Me)CH2NMe2]2(eta2-ONMe2)(mu-O)3 (5) containing novel chelating (aminomethyl)amide-N(Me)CH2NMe2 ligands. The crystal structures of 2-5 have been determined by X-ray crystallography. (Me2N)4Ta(eta2-ONMe2) (2) converts to (Me2N)3Ta(eta2-ONMe2)2 (3) in its reaction with O2. In addition, the reaction of Ta(NMe2)5 with 3 gives 2 only at elevated temperatures. Density functional theory (DFT) calculations have been used to investigate the mechanistic pathways in the reactions of Ta(NMe2)5 (1) with triplet O2. Monomeric reaction pathways in the formation of 2-5 are proposed. A key step is the oxygen insertion into a Ta-N bond in 1 through an intersystem conversion from triplet to singlet energy surface to give an active peroxide complex (Me2N)4Ta(eta2-O-O-NMe2) (A4). The DFT studies indicate that the peroxide ligand plays an important role, including oxidizing an amide to an imine ligand through the abstraction of a hydride. Insertion of Me-N=CH2 into a Ta-amide bond yields the unusual -N(Me)CH2NMe2 ligands.

Reactions of d0 group 4 amides with dioxygen. Preparation of unusual oxo aminoxy complexes and theoretical studies of their formation.

Reactions of d0 amides M(NMe2)4 (M = Zr, 1; Hf, 2) with O2 have been found to yield unusual trinuclear oxo aminoxide complexes M3(NMe2)6(mu-NMe2)3(mu3-O)(mu3-ONMe2) (M = Zr, 3; Hf, 4) in high yields. Tetramethylhydrazine Me2N-NMe2 was also observed in the reaction mixtures. Crystal structures of 3 and 4 have been determined. Density functional theory calculations have been performed to explore the mechanistic pathways in the reactions of model complexes Zr(NR2)4 (R = H, 5; Me, 1) and [Zr(NR2)4]2 (R = H, 5a; Me, 1a) with triplet O2. Monomeric and dimeric reaction pathways in the formation of the Zr complex 3 are proposed.