Femtosecond laser ablation in liquid synthesis of iron-oxidation nanoparticles with saturable absorption performance.

"Naked" ferroferric-oxide nanoparticles (FONPs) synthesized by a femtosecond laser ablation on a bulk stainless steel in liquid were applied to the Nd: YVO4 laser to achieve passive Q-switched pulse laser output. Without the pollution of ligand, the inherent light characteristic of "naked" FONPs was unaffected. The analysis of the morphological characteristics, dominant chemical elements, and phase composition of the FONPs showed that they were mainly composed of Fe3O4, which was spherical with an average diameter of 40 nm. The electron transition and orbital splitting of the iron element's octahedral center position under the laser-driven were considered the primary mechanisms of saturable absorption of Fe3O4 nanoparticles.

Comparative Study on Interfacial Properties, Foam Stability, and Firefighting Performance of C6 Fluorocarbon Surfactants with Different Hydrophilic Groups.

Liquid fuel is flammable and hazardous, and a pool fire is one of the most serious disasters. Therefore, it is important to develop high-performance firefighting agents. To synthesize aqueous film-forming foam (AFFF) formulations, two C6 short-chain fluorocarbon surfactants Capstone 1157 (FC1157) and sodium perfluorohexylethyl sulfonate (SF852) with different hydrophilic groups were introduced, and three hydrocarbon surfactants sodium dodecyl sulfate (SDS), decyl glucoside (APG0810), and coco glucoside (APG0814) were chosen. The AFFF formulations based on the short-chain fluorocarbon-hydrocarbon compounding system were developed, and the firefighting performance of the formulations was assessed according to the standard pool fire extinction test. The results indicated that amphoteric FC1157 was slightly more effective than anionic SF852 in extinguishing small-scale pool fires and could reduce heat flux more effectively than SF852. Fluorocarbon surfactant FC1157 has been shown to suppress large pool fires much better than SF852, possibly due to its higher foam stability, higher foaming property, lower dynamic surface tension, and lower bubble coarsening rate. Both formulations we studied were more effective than commercial AFFF formulations. A concentration of 0.1-0.3% of FC1157 in an AFFF solution was optimal for extinguishing high-boiling-point oil fires.

Dynamic regulation of excitatory and inhibitory synaptic transmission by growth hormone in the developing mouse brain.

Normal sensory and cognitive function of the brain relies on its intricate and complex neural network. Synaptogenesis and synaptic plasticity are critical to neural circuit formation and maintenance, which are regulated by coordinated intracellular and extracellular signaling. Growth hormone (GH) is the most abundant anterior pituitary hormone. Its deficiencies could alter brain development and impair learning and memory, while GH replacement therapy in human patients and animal models has been shown to ameliorate cognitive deficits caused by GH deficiency. However, the underlying mechanism remains largely unknown. In this study, we investigated the neuromodulatory function of GH in young (pre-weaning) mice at two developmental time points and in two different brain regions. Neonatal mice were subcutaneously injected with recombinant human growth hormone (rhGH) on postnatal day (P) 14 or 21. Excitatory and inhibitory synaptic transmission was measured using whole-cell recordings in acute cortical slices 2 h after the injection. We showed that injection of rhGH (2 mg/kg) in P14 mice significantly increased the frequency of mEPSCs, but not that of mIPSCs, in both hippocampal CA1 pyramidal neurons and L2/3 pyramidal neurons of the barrel field of the primary somatosensory cortex (S1BF). Injection of rhGH (2 mg/kg) in P21 mice significantly increased the frequency of mEPSCs and mIPSCs in both brain regions. Perfusion of rhGH (1 µM) onto acute brain slices in P14 mice had similar effects. Consistent with the electrophysiological results, the dendritic spine density of CA1 pyramidal neurons and S1BF L2/3 pyramidal neurons increased following in vivo injection of rhGH. Furthermore, NMDA receptors and postsynaptic calcium-dependent signaling contributed to rhGH-dependent regulation of both excitatory and inhibitory synaptic transmission. Together, these results demonstrate that regulation of excitatory and inhibitory synaptic transmission by rhGH occurs in a developmentally dynamic manner, and have important implication for identifying GH treatment strategies without disturbing excitation/inhibition balance.

Environmental and occupational exposure to cadmium associated with male reproductive health risk: a systematic review and meta-analysis based on epidemiological evidence.

There is an abundance of epidemiological evidence and animal experiments concerning the correlation between cadmium exposure and adverse male reproductive health outcomes. However, the evidence remains inconclusive. We conducted a literature search from PubMed, Embase, and Web of Science over the past 3 decades. Pooled r and 95% confidence intervals (CIs) were derived from Cd levels of the type of biological materials and different outcome indicators to address the large heterogeneity of existing literature. Cd was negatively correlated with semen parameters (r = - 0.122, 95% CI - 0.151 to - 0.092) and positively correlated with sera sex hormones (r = 0.104, 95% CI 0.060 to 0.147). Among them, Cd in three different biological materials (blood, semen, and urine) was negatively correlated with semen parameters, while among sex hormones, only blood and urine were statistically positively correlated. In subgroup analysis, blood Cd was negatively correlated with semen density, sperm motility, sperm morphology, and sperm count. Semen Cd was negatively correlated with semen concentration. As for serum sex hormones, blood Cd had no statistical significance with three hormones, while semen Cd was negatively correlated with testosterone. In summary, cadmium exposure might be associated with the risk of a decline in sperm quality and abnormal levels of sex hormones.

Drosophila ZIP13 over-expression or transferrin1 RNAi influences the muscle degeneration of Pink1 RNAi by elevating iron levels in mitochondria.

Disruption of iron homeostasis in the brain of Parkinson's disease (PD) patients has been reported for many years, but the underlying mechanisms remain unclear. To investigate iron metabolism genes related to PTEN-induced kinase 1 (Pink1) and parkin (E3 ubiquitin ligase), two PD-associated proteins that function to coordinate mitochondrial turnover via induction of selective mitophagy, we conducted a genetic screen in Drosophila and found that altered expression of genes involved in iron metabolism, such as Drosophila ZIP13 (dZIP13) or transferrin1 (Tsf1), significantly influences the disease progression related to Pink1 but not parkin. Several phenotypes of Pink1 mutant and Pink1 RNAi but not parkin mutant were significantly rescued by over-expression (OE) of dZIP13 (dZIP13 OE) or silencing of Tsf1 (Tsf1 RNAi) in the flight muscles. The rescue effects of dZIP13 OE or Tsf1 RNAi were not exerted through mitochondrial disruption or mitophagy; instead, the iron levels in mitochondira were significantly increased, resulting in enhanced activities of enzymes participating in respiration and increased ATP synthesis. Consistently, the rescue effects of dZIP13 OE or Tsf1 RNAi on Pink1 RNAi can be inhibited by decreasing the iron levels in mitochondria through mitoferrin (dmfrn) RNAi. This study suggests that dZIP13, Tsf1, and dmfrn might act independently of parkin in a parallel pathway downstream of Pink1 by modulating respiration and indicates that manipulation of iron levels in mitochondria may provide a novel therapeutic strategy for PD associated with Pink1.

Development of a large-field streak tube for underwater imaging lidar.

Streak tube imaging lidar (STIL) can obtain 4-D images of a target, and its performance is mainly determined by the streak tube sensor. To obtain a large field of view, we developed a streak tube with a photocathode length as large as 35.3 mm, which is larger than the commonly used ST-HDR (30 mm). At the same time, the temporal resolution and dynamic spatial resolution are 60 ps and 12 lp/mm, which are very suitable to obtain accurate target coordinates for 4-D imaging. In addition, the streak tube has a high detection sensitivity of 46 mA/W at 500 nm and, hence, prospects in remote imaging. To test the performance of the streak tube, an underwater STIL experiment was conducted. Echo signal processing was performed by means of a bandpass filter and a matched filter, and then the peak detection algorithm was used to reconstruct the image. The results indicate that a spatial resolution better than 9 mm is achieved in the limpid water with a depth of 20 m, and a range accuracy of 1 cm is achieved in the turbid water with a depth of 10 m. Such a performance suggests that the large-field streak tube is of great potential for underwater target imaging and other remote imaging applications.

UBE3A-mediated PTPA ubiquitination and degradation regulate PP2A activity and dendritic spine morphology.

Deficiency in the E3 ubiquitin ligase UBE3A leads to the neurodevelopmental disorder Angelman syndrome (AS), while additional dosage of UBE3A is linked to autism spectrum disorder. The mechanisms underlying the downstream effects of UBE3A gain or loss of function in these neurodevelopmental disorders are still not well understood, and effective treatments are lacking. Here, using stable-isotope labeling of amino acids in mammals and ubiquitination assays, we identify PTPA, an activator of protein phosphatase 2A (PP2A), as a bona fide ubiquitin ligase substrate of UBE3A. Maternal loss of Ube3a (Ube3am-/p+) increased PTPA level, promoted PP2A holoenzyme assembly, and elevated PP2A activity, while maternal 15q11-13 duplication containing Ube3a down-regulated PTPA level and lowered PP2A activity. Reducing PTPA level in vivo restored the defects in dendritic spine maturation in Ube3am-/p+ mice. Moreover, pharmacological inhibition of PP2A activity with the small molecule LB-100 alleviated both reduction in excitatory synaptic transmission and motor impairment in Ube3am-/p+ mice. Together, our results implicate a critical role of UBE3A-PTPA-PP2A signaling in the pathogenesis of UBE3A-related disorders and suggest that PP2A-based drugs could be potential therapeutic candidates for treatment of UBE3A-related disorders.

Occurrence and removal of 25 antibiotics during sewage treatment processes and potential risk analysis.

The occurrence and removal of 25 antibiotics, including ten quinolones (QNs), four macrolides (MLs), four tetracyclines (TCs) and seven sulfonamides (SNs), were analysed at two sewage treatment plants (STPs) with different treatment units in Guangxi Province, China. The results showed that 14 and 16 antibiotics were detected in the influent of the two STPs, with concentrations ranging from 13.7-4265.2 ng/L and 14.5-10761.7 ng/L, respectively. Among the antibiotics, TCs were the main type in the study area, accounting for more than 79% of the total concentration of all antibiotics. The antibiotic removal efficiencies of the different process units ranged from -56.73% to 100.0%. It was found that the SN removal efficiency of the multistage composite mobile bed membrane bioreactor (MBBR) process was better than that of the continuous-flow Intermission biological reactor (IBR) process, while the IBR process was better than the MBBR process in terms of removing TCs and MLs; however, there was no obvious difference in the QN removal efficiencies of these two processes. Redundancy analysis (RDA) showed a strong correlation between antibiotic concentration and chemical oxygen demand (COD). Risk assessments indicated that algae, followed by invertebrates and fish, were the most sensitive aquatic organisms to the detected antibiotics.

Multiple Morphological Factors Underlie Experience-Dependent Cross-Modal Plasticity in the Developing Sensory Cortices.

Sensory experience regulates the structural and functional wiring of sensory cortices. In previous work, we showed that whisker deprivation (WD) from birth not only reduced excitatory synaptic transmission of layer (L) 2/3 pyramidal neurons of the correspondent barrel cortex in mice, but also cross-modally reduced synaptic transmission of L2/3 pyramidal neurons in other sensory cortices. Here, we used in utero electroporation, in combination with optical clearing, to examine the main morphological components regulating neural circuit wiring, namely presynaptic bouton density, spine density, as well as dendrite and axon arbor lengths. We found that WD from P0 to P14 reduced presynaptic bouton density in both L4 and L2/3 inputs to L2/3 pyramidal neurons, as well as spine density across the dendritic tree of L2/3 pyramidal neurons, in the barrel field of the primary somatosensory cortex. The cross-modal effects in the primary auditory cortex were manifested mostly as reduced dendrite and axon arbor size, as well as reduced bouton density of L2/3 inputs. Increasing sensory experience by rearing mice in an enriched environment rescued the effects of WD. Together, these results demonstrate that multiple morphological factors contribute to experience-dependent structural plasticity during early wiring of the sensory cortices.

Method of encapsulating silver nanodots using porous glass and its application in Q-switched all solid-state laser.

Here, we report on a packaging method for silver nanodots (SNDs) by using high-silicate porous glass. Millions of nanopores, which are randomly distributed in porous glass, are used as cells for SND nucleation and growth during the initial chemical-reduction process. Then, the sample is annealed at a high-temperature in a reducing atmosphere to impel the further SND growth and nanopore collapse. The compact SND-embedded transparent glass is synthesized in the end. Morphology characterization shows that the SNDs that are encapsulated in the sample have a uniform size of 1.5 to 4.5 nm. Both the sample's saturable and reverse saturable absorptions are observed under the irradiation of 100 fs laser pulses at 800 nm. Saturable absorption's threshhold is characterized to be 1.4 × 1011 W/cm2, which is much lower than what was ever reported. Furthermore, the SNDs-embedded silica as a saturable absorber (SA) has been demonstrated in the Q-switched Nd:YVO4 laser. The pulse duration as short as 53 nanoseconds is obtained. To our knowledge, it is the first time that SNDs are used as a SA in the passively Q-switched all solid-state laser.

[Subthalamic nucleus: from circuits, functions to a deep brain stimulation target for the treatment of Parkinson's disease].

The subthalamic nucleus (STN) is the only excitatory glutamatergic nucleus in the basal ganglia circuitry. It not only is a key node in the classical indirect pathway, but also forms the "hyperdirect" pathway directly connecting the cortex, and even is implicated as a pacemaker for activity of whole basal ganglia. Due to the key position of STN in the basal ganglia circuitry, the STN is an optimal target for deep brain stimulation (DBS) in the neurosurgical treatment of Parkinson's disease (PD). However, the therapeutic mechanisms underlying the amelioration of parkinsonian motor dysfunctions induced by DBS on STN remain enigmatic. This paper reviews recent progresses in the studies on the input-output configurations and functions of STN in the basal ganglia circuitry, and summarizes the hypotheses for mechanisms of DBS for the treatment of motor dysfunctions in PD. Studying on the DBS mechanisms will not only help to develop strategies for treatment of PD, but also contribute to the understanding of functions of the basal ganglia circuitry.

5-HT2A receptor-mediated excitation on cerebellar fastigial nucleus neurons and promotion of motor behaviors in rats.

It has long been known that serotonergic afferent inputs are the third largest afferent population in the cerebellum after mossy fibers and climbing fibers. However, the role of serotonergic inputs in cerebellar-mediated motor behaviors is still largely unknown. Here, we show that only 5-HT2A receptors among the 5-HT2 receptor subfamily are expressed and localized in the rat cerebellar fastigial nucleus (FN), one of the ultimate outputs of the spinocerebellum precisely regulating trunk and limb movements. Remarkably, selective activation of 5-HT2A receptors evokes a postsynaptic excitatory effect on FN neurons in a concentration-dependent manner in vitro, which is in accord with the 5-HT-elicited excitation on the same tested neurons. Furthermore, selective 5-HT2A receptor antagonist M100907 concentration-dependently blocks the excitatory effects of 5-HT and TCB-2, a 5-HT2A receptor agonist, on FN neurons. Consequently, microinjection of 5-HT into bilateral FNs significantly promotes rat motor performances on accelerating rota-rod and balance beam and narrows stride width rather than stride length in locomotion gait. All these motor behavioral effects are highly consistent with those of selective activation of 5-HT2A receptors in FNs, and blockage of the component of 5-HT2A receptor-mediated endogenous serotonergic inputs in FNs markedly attenuates these motor performances. All these results demonstrate that postsynaptic 5-HT2A receptors greatly contribute to the 5-HT-mediated excitatory effect on cerebellar FN neurons and promotion of the FN-related motor behaviors, suggesting that serotonergic afferent inputs may actively participate in cerebellar motor control through their direct modulation on the final output of the spinocerebellum.

The value of chromosome instability detected by low-pass whole-genome sequencing in preoperative prediction of sentinel lymph node metastasis in breast cancer.

Background: Breast cancer is a malignancy characterized by chromosomal instability (CIN). This study aimed to examine the potential diagnostic value of chromosomal instability, detected by low-pass whole-genome sequencing (LPWGS), in the preoperative evaluation of sentinel lymph node metastasis (SLNM) in breast cancer. Methods: A retrospective investigation of clinical records from 29 patients with breast cancer revealed two distinct groups based on sentinel lymph node biopsy (SLNB) results: the SLN metastasis group (24 cases) and the SLN non-metastasis group (five cases). CIN and CIN scores were evaluated using LPWGS. An analysis of univariate data and binary logistic regression was employed to identify factors influencing SLNM, and a curve with receiver operating characteristics (ROC) was constructed to assess the diagnostic utility of CIN in predicting SLNM. Results: A significant association between the SLNM and CIN high groups was observed in breast cancer (P=0.011). The CIN score in the metastasis group (17,665.055 ± 8,630.691) was higher than that in the non-metastasis group (9,247.973 ± 3,692.873), demonstrating a significant difference (P=0.044). Univariate binary logistic regression analysis indicated that CIN was a significant predictor for SLNM (odds ratio: 4.036, 95% CI: 1.015-16.047, P=0.048). The AUC of CIN for preoperative diagnosis of SLNM was 0.808 (95%CI: 0.635-0.982, P=0.033), with a sensitivity value of 67.0% and specificity of 100.0% at a threshold of 13,563. Conclusion: Detecting CIN through LPWGS demonstrates diagnostic potential in predicting SLNM in patients with breast cancer before surgery. This approach offers a novel method for assessing axillary lymph node status in clinical practice.

Variations in water use strategies of Tamarix ramosissima at coppice dunes along a precipitation gradient in desert regions of northwest China.

Introduction: The precipitation pattern has changed significantly in arid desert areas, yet it is not clear how the water use strategies of Tamarix ramosissima Ledeb. on coppice dunes along a natural precipitation gradient are affected. Methods: In this study, the hydrogen and oxygen isotope compositions of xylem water, soil water, precipitation, and groundwater were measured by stable isotope techniques in Huocheng, Mosuowan, and Tazhong. Additionally, the water use strategies of natural precipitation gradient were investigated in conjunction with the MixSIAR model. Results: The results indicated that the water sources of T. ramosissima exhibited significant variation from semi-arid to hyper-arid areas. In semi-arid areas, T. ramosissima mainly absorbed shallow, shallow-middle, and middle soil water; however, T. ramosissima shifted its primary water sources to middle and deep soil water in arid areas. In hyper-arid areas, it mainly utilized deep soil water and groundwater. In contrast, the water source contribution rate of T. ramosissima exhibited relative uniformity across each layer in an arid area. Notably, in hyper-arid areas, the proportion of groundwater by T. ramosissima was significantly high, reaching 60.2%. This is due to the relatively shallow groundwater supplementing the deep soil water content in the area. In conclusion, the proportion of shallow soil water decreased by 14.7% for T. ramosissima from semi-arid to hyper-arid areas, illustrating the occurrence of a gradual shift in potential water sources utilized by T. ramosissima from shallow to deep soil water and groundwater. Discussion: Therefore, T. ramosissima on coppice dunes shows flexible water use strategies in relation to precipitation and groundwater, reflecting its strong environmental adaptability. The findings hold significant implications for the conservation of water resources and vegetation restoration in arid areas.

Reassessment of capsaicin desensitization in the rodent spinal dorsal horn.

Capsaicin activates primary afferent transient receptor potential vanilloid 1 (TRPV1) in the spinal dorsal horn and induces exaggerated glutamate release. This capsaicin action is followed by a lasting refractory state referred to as "capsaicin desensitization", which is considered a presynaptic event. In this study, using whole-cell recordings and holographic photostimulation, we reassessed this notion by investigating presynaptic glutamate release and the postsynaptic glutamate response during capsaicin administration. We found that both presynaptic synchronous glutamate release and the postsynaptic glutamate response were largely attenuated in this refractory state; in contrast, asynchronous release was exaggerated. Further behavioral studies revealed a quick increase in the mechanical pain threshold with intrathecal capsaicin administration. Taken together, both presynaptic synchronous glutamate release and the postsynaptic response are downregulated during capsaicin desensitization, and this desensitization may transiently increase the pain threshold. Since both presynaptic synchronous release and postsynaptic glutamate responses are attenuated, the traditional electrophysiological evidence supporting capsaicin desensitization as a presynaptic event should be reassessed.

Polychlorinated biphenyls and risk of metabolic syndrome and comparison with the risk of diabetes: A systematic review and meta-analysis.

With the increasing incidence of metabolic syndrome (MetS) worldwide and no consistent results on PCBs and MetS. A meta-analysis to explore their relationship was conducted. Given the high correlation and overlap of MetS with diabetes, analysis of diabetes risk, was used as a supplement to compare with MetS. Seven studies included MetS, 15 studies for diabetes, and one study included both outcomes. It was found that PCBs may not be a risk factor for MetS, but their high heterogeneity indicates that they are under-represented. In addition, our results showed that total PCBs might be a protective factor against diabetes. In the whole blood subgroup, which can reflect the accumulation of more than one body load, heterogeneity was reduced, and its OR value suggested that PCBs increased the risk of MetS in the whole blood biomaterial. DL-PCBs were positively associated with MetS and diabetes, while NDL-PCBs were negatively associated with diabetes. In the subgroup analysis of PCBs homologs, DL-PCB-126 and DL-PCB-118 were risk factors for MetS and diabetes, respectively. In addition, PCB-153 and 180 showed a dose-response relationship between them and diabetes mellitus, respectively. The results of total analysis of MetS and diabetes mellitus and subgroup analysis of PCBs were mixed, and this reason might be attributed to the different mechanisms of action and effect sizes of different PCBs, so based on subgroup results and in vivo and in vitro experiments, we considered PCBs to be a risk factor for MetS and diabetes. Due to various reasons, there are still many shortcomings in the evaluation of PCBs impact on human health, and more high-quality research are needed to further explore the role of PCBs of different species and congeners in MetS and diabetes.

Nonlinear Absorption Response of Zirconium Carbide Films.

Zirconium carbide (ZrC), a novel representative of the MXene family, has attracted considerable interest because of its outstanding physicochemical properties and potential applications in optoelectronic devices. For improving its performance as an optical modulator for ultrashort lasers, there is a call to continue studying the nonlinear optical behavior of MXene ZrC. Herein, for the first time, MXene ZrC films were fabricated on fused silica by magnetron sputtering deposition technology and used as a saturable absorber (SA) optical modulator in a passive Q-switched Nd:YAG laser. The saturation absorption behaviors of the prepared ZrC films were characterized by the Z-scan method. Their morphology, band structure, damage threshold, carrier recovery time, and saturation absorption properties were analyzed. The experimental results show that the MXene ZrC SA films exhibit excellent nonlinear optical characteristics, with a saturation intensity of 48.4 MW/cm2, a large modulation depth of 6.9%, and an ultrashort recovery time of 2.72 ps. In addition, the damage threshold of MXene ZrC SA films was estimated to be greater than 0.2516 J/cm2. By integrating the ZrC SA film optical modulator into the oscillator of the Nd:YAG laser, we achieved stable operation of the Q-switched laser with a central wavelength at 1.06 µm, with the shortest pulse width of 78 ns. The results of this study demonstrate the potential use of MXene ZrC SA films as optical modulators in ultrashort lasers.

Association of saliva 3-methoxy-4-hydroxyphenylglycol levels and a later depressive state in older subjects living in a rural community: 3-year follow-up study.

OBJECTIVE: The aim of the study was to examine the association of saliva levels of 3-methoxy-4-hydroxyphenylglycol (sMHPG) with a later depressive state in older people living in a rural community. METHODS: Baseline sMHPG levels were measured in 214 older subjects followed by completion of the Beck Depression Inventory (BDI) from 2004 to 2006 (time A). The same cohort underwent BDI again from 2007 to 2009 (time B). RESULTS: One hundred forty-four subjects (44 men, 100 women) were reassessed by the BDI. Baseline sMHPG levels in men with a BDI score of ≤9 at time A and a BDI score of ≥10 at time B were significantly higher than those in men with a BDI score of ≤9 at times A and B. In men, there was a significant correlation between baseline sMHPG levels and BDI score at time B (r = 0.40, p = 0.007) but not at time A (r = 0.29, p = 0.06). This association was not significant in women. CONCLUSION: These data indicate that high sMHPG levels at time A could be associated with a later depressive state in older men living in a community.

Baseline saliva level of 3-methoxy-4-hydroxyphenylglycole (MHPG) associates with a consequent cognitive decline in non-demented elderly subjects: three-years follow-up study.

The aim of the study was to explore the relation between saliva level of 3-methoxy-4-hydroxy-phenylglycol (MHPG) and a later cognitive decline in non-demented elderly subjects. We have reported that sMHPG in 214 elderly subjects living in the community (age 74.5±5.9years) was associated with scores on the Mini-Mental State Examination (MMSE) and the Frontal Assessment Battery (FAB) in 2004 to 2006 (Time A). The same cohort underwent these cognitive tests again from 2007 to 2009 (Time B). The cognitive function of the 147 of 214 subjects could be reassessed by the same cognitive tests. The score on the FAB, but not the MMSE, was significantly reduced at Time B (14.6±2.6) compared with that of Time A (15.2±1.9). There was a significant negative correlation between the baseline sMHPG and the changes in the FAB score subtracted from Time B to Time A or the scores on the FAB at Time B in men, but not at Time A. These correlations were not found in women. These data indicate that high sMHPG might be associated with subsequent cognitive decline assessed by the FAB in non-demented elderly men living in the community.

Allosteric Modulation of the Sigma-1 Receptor Elicits Antipsychotic-like Effects.

Allosteric modulation represents an important approach in drug discovery because of its advantages in safety and selectivity. SOMCL-668 is the first selective and potent sigma-1 receptor allosteric modulator, discovered in our laboratory. The present work investigates the potential therapeutic effects of SOMCL-668 on phencyclidine (PCP)-induced schizophrenia-related behavior in mice and further elucidates underlying mechanisms for its antipsychotic-like effects. SOMCL-668 not only attenuated acute PCP-induced hyperactivity and PPI disruption, but also ameliorated social deficits and cognitive impairment induced by chronic PCP treatment. Pretreatment with the selective sigma-1 receptor antagonist BD1047 blocked the effects of SOMCL-668, indicating sigma-1 receptor-mediated responses. This was confirmed using sigma-1 receptor knockout mice, in which SOMCL-668 failed to ameliorate PPI disruption and hyperactivity induced by acute PCP and social deficits and cognitive impairment induced by chronic PCP treatment. Additionally, in vitro SOMCL-668 exerted positive modulation of sigma-1 receptor agonist-induced intrinsic plasticity in brain slices recorded by patch-clamp. Furthermore, in vivo lower dose of SOMCL-668 exerted positive modulation of improvement in social deficits and cognitive impairment induced by the selective sigma-1 agonist PRE084. Also, SOMCL-668 reversed chronic PCP-induced down-regulation in expression of frontal cortical p-AKT/AKT, p-CREB/CREB and BDNF in wide-type but not sigma-1 knockout mice. Moreover, administration of the PI3K/AKT inhibitor LY294002 abolished amelioration by SOMCL-668 of chronic PCP-induced schizophrenia-related behaviors by inhibition of BDNF expression. The present data provide initial, proof-of-concept evidence that allosteric modulation of the sigma-1 receptor may be a novel approach for the treatment of psychotic illness.