The ATP Level in the Medial Prefrontal Cortex Regulates Depressive-like Behavior via the Medial Prefrontal Cortex-Lateral Habenula Pathway.

BACKGROUND: Depression is the most common mental illness. Mounting evidence suggests that dysregulation of extracellular ATP (adenosine triphosphate) is involved in the pathophysiology of depression. However, the cellular and neural circuit mechanisms through which ATP modulates depressive-like behavior remain elusive. METHODS: By use of ex vivo slice electrophysiology, chemogenetic manipulations, RNA interference, gene knockout, behavioral testing, and two depression mouse models, one induced by chronic social defeat stress and one caused by a IP3R2-null mutation, we systematically investigated the cellular and neural circuit mechanisms underlying ATP deficiency-induced depressive-like behavior. RESULTS: Deficiency of extracellular ATP in both defeated susceptible mice and IP3R2-null mutation mice led to reduced GABAergic (gamma-aminobutyric acidergic) inhibition and elevated excitability in lateral habenula-projecting, but not dorsal raphe-projecting, medial prefrontal cortex (mPFC) neurons. Furthermore, the P2X2 receptor in GABAergic interneurons mediated ATP modulation of lateral habenula-projecting mPFC neurons and depressive-like behavior. Remarkably, chemogenetic activation of the mPFC-lateral habenula pathway induced depressive-like behavior in C57BL/6J mice, while inhibition of this pathway was sufficient to alleviate the behavioral impairment in both defeated susceptible and IP3R2-null mutant mice. CONCLUSIONS: Overall, our study provides compelling evidence that ATP level in the mPFC is critically involved in regulating depressive-like behavior in a pathway-specific manner. These results shed new light on the mechanisms underlying depression and the antidepressant effect of ATP.

PV network plasticity mediated by neuregulin1-ErbB4 signalling controls fear extinction.

Neuroplasticity in the medial prefrontal cortex (mPFC) is essential for fear extinction, the process of which forms the basis of the general therapeutic process used to treat human fear disorders. However, the underlying molecules and local circuit elements controlling neuronal activity and concomitant induction of plasticity remain unclear. Here we show that sustained plasticity of the parvalbumin (PV) neuronal network in the infralimbic (IL) mPFC is required for fear extinction in adult male mice and identify the involvement of neuregulin 1-ErbB4 signalling in PV network plasticity-mediated fear extinction. Moreover, regulation of fear extinction by basal medial amygdala (BMA)-projecting IL neurons is dependent on PV network configuration. Together, these results uncover the local molecular circuit mechanisms underlying mPFC-mediated top-down control of fear extinction, suggesting alterative therapeutic approaches to treat fear disorders.

A discrete serotonergic circuit regulates vulnerability to social stress.

Exposure to social stress and dysregulated serotonergic neurotransmission have both been implicated in the etiology of psychiatric disorders. However, the serotonergic circuit involved in stress vulnerability is still unknown. Here, we explored whether a serotonergic input from the dorsal raphe (DR) to ventral tegmental area (VTA) influences vulnerability to social stress. We identified a distinct, anatomically and functionally defined serotonergic subpopulation in the DR that projects to the VTA (5-HTDR→VTA neurons). Moreover, we found that susceptibility to social stress decreased the firing activity of 5-HTDR→VTA neurons. Importantly, the bidirectional manipulation of 5-HTDR→VTA neurons could modulate susceptibility to social stress. Our findings reveal that the activity of 5-HTDR→VTA neurons may be an essential factor in determining individual levels of susceptibility to social stress and suggest that targeting specific serotonergic circuits may aid the development of therapies for the treatment of stress-related disorders.

The gut microbiota regulates autism-like behavior by mediating vitamin B6 homeostasis in EphB6-deficient mice.

BACKGROUND: Autism spectrum disorder (ASD) is a developmental disorder, and the effective pharmacological treatments for the core autistic symptoms are currently limited. Increasing evidence, particularly that from clinical studies on ASD patients, suggests a functional link between the gut microbiota and the development of ASD. However, the mechanisms linking the gut microbiota with brain dysfunctions (gut-brain axis) in ASD have not yet been full elucidated. Due to its genetic mutations and downregulated expression in patients with ASD, EPHB6, which also plays important roles in gut homeostasis, is generally considered a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 in regulating the gut microbiota and the development of ASD are unclear. RESULTS: Here, we found that the deletion of EphB6 induced autism-like behavior and disturbed the gut microbiota in mice. More importantly, transplantation of the fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotic-treated C57BL/6J mice, and transplantation of the fecal microbiota from wild-type mice ameliorated the autism-like behavior in EphB6-deficient mice. At the metabolic level, the disturbed gut microbiota in EphB6-deficient mice led to vitamin B6 and dopamine defects. At the cellular level, the excitation/inhibition (E/I) balance in the medial prefrontal cortex was regulated by gut microbiota-mediated vitamin B6 in EphB6-deficient mice. CONCLUSIONS: Our study uncovers a key role for the gut microbiota in the regulation of autism-like social behavior by vitamin B6, dopamine, and the E/I balance in EphB6-deficient mice, and these findings suggest new strategies for understanding and treating ASD. Video abstract.

[Spatiotemporal Variations of Chlorophyll a and Its Relationship to Environmental Factors in Shiyan Reservoir].

The spatial-temporal characteristics of chlorophyll a concentration[ρ(Chla)] were analyzed in Shiyan Reservoir, based on the monthly monitoring data from April 2013 to June 2014. The correlation between ρ(Chla) and key environmental factors were also studied using correlation analysis and canonical correspondence analysis.The results showed that ρ(TChla) was 9.59-123.29 µg·L-1, with an average of 52.03 µg·L-1. The ρ(Chla) of cyanobacteria was 4.54-76.30 µg·L-1, with an average of 28.39 µg·L-1. The ρ(Chla) of bacillariophyta was 3.16-46.09 µg·L-1, with an average of 15.02 µg·L-1. The ρ(Chla) of chlorophyta was 0.77-26.2 µg·L-1, with an average of 8.62 µg·L-1. Cyanobacteria was the primary species from April to December in 2013 and May, June in 2014 while bacillariophyta was the primary species in other months. The spatial heterogeneity of ρ(Chla) was unconspicuous and ρ(Chla) decreased gradually from south to north. There was a risk of algal blooming for the whole reservoir during flood season and south part of reservoir in autumn. The storm runoff pollutant washout was the leading cause of the spatial heterogeneity of ρ(Chla) in Shiyan Reservoir. Analysis revealed that water temperature was the most important driving factor for seasonal succession of phytoplankton. Significant correlation was found between ρ(Chla) and surface runoff in flood season. TN:TP was negatively related to phytoplankton biomass and phosphorus was the restrictive factor for phytoplankton. Cyanophyta were affected water temperature, TOC, TN, pH, transparency, turbidity and NO3--N. However silicate, TOC, NO3--N, and COD were the main environmental factor of bacillariophyta while TOC, COD, pH, transparency and NO3--N were the main factor of chlorophyta.

Value of R2* obtained from T2*-weighted imaging in predicting the prognosis of advanced cervical squamous carcinoma treated with concurrent chemoradiotherapy.

BACKGROUND: To prospectively investigate the value of R2* in predicting the prognosis of advanced cervical squamous carcinoma treated with concurrent chemoradiotherapy. METHODS: Sixty-five patients with biopsy-proven cervical squamous carcinoma were enrolled in our study. All these subjects underwent multi-echo T2*-weighted MR imaging on a 3.0 Tesla MR scanner, and tumor R2* was calculated. The patients were divided into the responders and the nonresponders according to treatment effect. Tumor R2* values of these two groups were compared. The relationship between tumor R2* and prognosis after therapy was analyzed. RESULTS: The responder group had lower R2* value than the nonresponder group (P = 0.02). The area under the receiver operating characteristics curve for tumor R2* in discriminating responders from nonresponders was 0.769. A cutoff value of 23.87 Hz for tumor R2* resulted in a sensitivity of 78.3% and a specificity of 67.6%. The low R2* group (≤28.37 Hz) had longer median progression-free survival period and overall survival period (P = 0.01, 0.03). Multivariate analysis showed that tumor R2* was a significant prognostic factor for progression-free survival and overall survival (adjusted hazards ratio = 5.34, 4.78; P = 0.02, 0.01). CONCLUSION: R2* value obtained from T2*-weighted imaging, as an imaging biomarker, may be an important predictor for the prognosis of advanced cervical squamous carcinoma treated with concurrent chemoradiotherapy.

Value of whole-tumor dual-input perfusion CT in predicting the effect of multiarterial infusion chemotherapy on advanced non-small cell lung cancer.

OBJECTIVE: The purposes of this study were to prospectively evaluate tumor perfusion using whole-tumor dual-input perfusion CT in advanced non-small cell lung cancer treated with multiarterial infusion chemotherapy and to determine whether treatment effect can be predicted in light of perfusion parameters. SUBJECTS AND METHODS: Forty-two patients with advanced non-small cell lung cancer were enrolled in this study. Whole-tumor dual-input perfusion CT was performed for all these patients, who subsequently received multiarterial infusion chemotherapy. The patients were divided into responders and nonresponders according to response to treatment. The relation between baseline perfusion parameters and prognosis after therapy was analyzed. RESULTS: The responder group had higher bronchial flow than the nonresponder group (p = 0.02). The AUC for bronchial flow was 0.83; pulmonary flow, 0.71; and perfusion index, 0.66. The higher bronchial flow group (≥ 65.34 mL/min/100 mL) and lower pulmonary flow group (< 23.05 mL/min/100 mL) had longer median progression-free survival periods (p = 0.01, p = 0.03) and overall survival periods (p = 0.04, p = 0.04). Multivariate analysis showed that bronchial flow was a significant prognostic factor for progression-free survival and overall survival (p = 0.01, p = 0.02) and that pulmonary flow may be helpful for predicting progression-free survival (p = 0.04) and overall survival (p = 0.03). CONCLUSION: Whole-tumor dual-input perfusion CT can provide information on the dual blood supply of tumors, which is helpful for predicting the treatment effect of multiarterial infusion chemotherapy for advanced non-small cell lung cancer.

Hippolachnin A, a new antifungal polyketide from the South China Sea sponge Hippospongia lachne.

Hippolachnin A (1), a polyketide possessing an unprecedented carbon skeleton with a four-membered ring, was isolated from the South China Sea sponge Hippospongia lachne. The structure was elucidated using MS and NMR spectroscopic analyses, and the absolute configuration was determined using a calculated ECD method. Hippolachnin A demonstrated potent antifungal activity against three pathogenic fungi, Cryptococcus neoformans, Trichophyton rubrum, and Microsporum gypseum, with a MIC value of 0.41 µM for each fungus.

The value of perfusion CT in predicting the short-term response to synchronous radiochemotherapy for cervical squamous cancer.

OBJECTIVE: To determine the value of the perfusion parameters in predicting short-term tumour response to synchronous radiochemotherapy for cervical squamous carcinoma. METHODS: Ninety-three patients with cervical squamous carcinoma later than stage IIB were included in this study. Perfusion CT was performed for all these patients who subsequently received the same synchronous radiochemotherapy. The patients were divided into responders and non-responders according to short-term response to treatment. Baseline perfusion parameters of the two groups were compared. The perfusion parameters that might affect treatment effect were analysed by using a multivariate multi-regression analysis. RESULTS: The responders group had higher baseline permeability-surface area product (PS) and blood volume (BV) values than the non-responders group (P < 0.05). There was no statistical difference in baseline mean transit time (MTT) and blood flow (BF) value between the two groups (P >0.05). At multivariate multi-regression analysis, BV, PS and tumour size were significant factors in the prediction of treatment effect. Small tumours usually had high PS and BV values, and thus had a good treatment response. CONCLUSION: Perfusion CT can provide some helpful information for the prediction of the short-term effect. Synchronous radiochemotherapy may be more effective in cervical squamous carcinoma with higher baseline PS and BV. KEY POINTS: • Perfusion CT can reflect tumour vascular physiology in cervical squamous carcinoma. • Perfusion CT helps predict the short-term effect before treatment • Synchronous radiochemotherapy may be more effective in patients with higher baseline BV and PS.

Pulmonary fungal infections after bone marrow transplantation: the value of high-resolution computed tomography in predicting their etiology.

BACKGROUND: The correct diagnosis of etiology of fungal infection after bone marrow transplantation is very important to the choice of antifungal drugs and a premise for improvement of therapeutic efficacy. This study aimed to compare high-resolution computed tomography (HRCT) findings of the pulmonary fungal infections to determine whether the etiology of various fungal infections could be diagnosed with HRCT. METHODS: Eighty-five cases were enrolled. According to the pathogens responsible for fungal infections, the patients were classified into three groups including invasive aspergillosis (n = 52), candidiasis (n = 19) and cryptococcosis (n = 14) groups. All the patients underwent HRCT scans. Two independent radiologists retrospectively analyzed the HRCT scans regarding CT patterns and distribution of lung abnormality. RESULTS: Most fungal infections in the three groups occurred in the neutropenic phase. There was no significant difference in the constituent ratio of fungal infections at different phases after bone marrow transplantation among the three groups. Agreement between the two observers for all the CT characteristics of fungal infections was excellent (k > 0.75). There was a significant difference in occurrence ratio of mass among the three groups (P = 0.02). Occurrence ratio of mass (43.3%, 13/30) in the group with invasive aspergillosis was higher than in each of other two groups (20.0%, 2/10; 14.3%, 1/7). There was no significant difference in other CT characteristics of nodules or masses; including number, margin, halo sign, cavitation and air-crescent sign. There was no significant difference in number, margin, air bronchogram and distribution of air-space consolidation. CONCLUSIONS: The HRCT appearance of various pulmonary fungal infections has a great deal of overlap and is nonspecific. Mass is more common in invasive aspergillosis, which is helpful to the diagnosis of invasive aspergillosis after bone marrow transplantation.

Simplextones A and B, unusual polyketides from the marine sponge Plakortis simplex.

Two novel polyketides, simplextones A (1) and B (2), were isolated from the sponge Plakortis simplex. Their structures were established by spectroscopic methods. The absolute configurations were assigned by modified Mosher's method, X-ray crystallographic analysis, and quantum mechanical calculation of the electronic circular dichroism (ECD) spectrum. Compounds 1 and 2 featured an unprecedented polyketide skeleton via the connection of a single carbon-carbon bond to form a cyclopentane. These compounds also exhibited moderate cytotoxicity.

Construction of a three-dimensional pharmacophore for Bcl-2 inhibitors by flexible docking and the multiple copy simultaneous search method.

B-Cell lymphoma-2 (Bcl-2) protein is a new promising target for anticancer drugs. A number of anticancer Bcl-2 inhibitors with diverse chemical structures have been discovered in recent years. In this paper, the flexible docking was performed to determine the binding modes of the representative inhibitors from different structural types. Subsequently, the binding modes of inhibitor were used to construct a primary three- dimensional (3D) pharmacophore model. It proved that this model can effectively disrupt the binding of the BH3 domain of proapoptotic Bcl-2 family members to Bcl-2, and match the structural requirement of a new type of Bcl-2 inhibitors. However, these distances between pharmacophoric points are not optimal due to the fact that not all of individual functional groups are located in the ideal position when inhibitors bind to its receptor. In this paper, we proposed a new idea to improve the quality of the pharmacophore model: the multiple copy simultaneous search (MCSS) method was performed to determine the energetically favorable distribution of functional groups with similar features to these pharmacophoric points in the active site of Bcl-2 first. Then their most energetically favorable minima in the positions near the pharmacophoric points were used to optimize the distances between pharmacophoric points. By examining the binding modes of several inhibitors from the same structural type, it was found that the more potent the inhibitor was, the closer it was to the optimized distances between pharmacophoric points. The optimized 3D pharmacophore model obtained in this paper may provide a good starting point for further rational design of Bcl-2 inhibitors.

Annexin B1 from Taenia solium metacestodes is a newly characterized member of the annexin family.

We previously reported cloning of the Taenia solium annexin B1 gene from a metacestode cDNA expression library and demonstrated that it acts as a protective antigen for effective vaccine development against cysticercosis. In the present study we produced recombinant annexin B1 and antiserum against the protein to investigate its structural and functional properties. Western blotting of metacestode fractions indicated that T. solium annexin B1, similar to vertebrate annexins, associates with acid phospholipids in the presence of Ca(2+). This property was confirmed by the recognition of apoptotic cells by labeled annexin B1. CD spectroscopy results demonstrated that alpha-helices are the main secondary structures of the protein. Ca(2+) binding increases the alpha-helix content and causes significant thermal stabilization with a melting temperature increase of approximately 10 degrees C. Functional Ca(2+)-dependent phospholipid binding sites of annexin B1 were investigated using mutant proteins. By changing a conserved acidic amino acid residue that putatively combines Ca(2+) in each domain of annexin B1 singly or in combination, we found that Ca(2+) binding in the first domain is more important than that at the other Ca(2+) binding sites. Annexin B1 is a metacestode stage-specific antigen, with the protein being mainly localized in the teguments and surrounding cyst wall of T. solium metacestodes, suggesting a role in the parasite-host interaction.

[Synthesis and antifungal activity of novel triazole antifungal agents].

AIM: A series of triazole antifungal agents were synthesized to search for novel triazole antifungal agents with more potent activity, less toxicity and broader spectrum. METHODS: Twenty-one 1-(1H-1, 2, 4-triazolyl)-2-(2, 4-diflurophenyl)-3-(4-substituted-1-piperazinyl)-2-propanols were synthesized, on the basis of the three dimensional structure of P450 cytochrome 14alpha-sterol demethylase (CYP51) and their antifungal activities were also evaluated. RESULTS: Results of preliminary biological tests showed that most of title compounds exhibited activity against the eight common pathogenic fungi to some extent and the activities against deep fungi were higher than that against shallow fungi. In general, phenyl and pyridinyl analogues showed higher antifungal activity than that of the phenylacyl analogues. CONCLUSION: Several title compounds showed higher antifungal activities than fluconazole and terbinafine. Compound VIII-1, 4, 5 and IX-3 showed the best antifungal activity with broad antifungal spectrum and were chosen for further study.

[Synthesis and antifungal activity of 1-(1,2,4-triazolyl-1H-1-yl)-2-(2,4-diflurophenyl)-3-(4-substituted benzyl-1-piperazinyl)-2-propanols].

AIM: A series of triazole antifungals were synthesized to search for novel triazole antifungals with more potent activity, less toxicity and broader spectrum. METHODS: Nineteen 1-(1,2,4-triazolyl-1H-1-yl)-2-(2,4-diflurophenyl)-3-(4-substituted benzyl-1-piperazinyl)-2-propanols were designed and synthesized, on basis of the three dimensional structure of P450 cytochrome 14 alpha-sterol demethylase (CYP51) and their antifungal activities were also evaluated. RESULTS: All the title compounds were first reported. Results of preliminary biological tests showed that most of the title compounds exhibited high activity against the eight common pathogenic fungi and the activities against deep fungi were higher than that against shallow fungi. CONCLUSION: Most of the title compounds showed higher antifungal activities than Fluconazole and Terbinafine. Compound VIII-1, 10, 12, 17 showed best antifungal activity with broad antifungal spectrum and were chosen for further development.