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Major depressive disorder is a devastating psychiatric disease that afflicts up to 17% of the world's population. Postmortem brain analyses and imaging studies of patients with depression have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, the circuit and molecular mechanisms through which BLA neurons modulate depressive behavior are largely uncharacterized. Here, in mice, we identified that BLA cholecystokinin (CCK) glutamatergic neurons mediated negative reinforcement via D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and that chronic social defeat selectively potentiated excitatory transmission of the CCKBLA-D2NAc circuit in susceptible mice via reduction of presynaptic cannabinoid type-1 receptor (CB1R). Knockdown of CB1R in the CCKBLA-D2NAc circuit elevated synaptic activity and promoted stress susceptibility. Notably, selective inhibition of the CCKBLA-D2NAc circuit or administration of synthetic cannabinoids in the NAc was sufficient to produce antidepressant-like effects. Overall, our studies reveal the circuit and molecular mechanisms of depression.

Differences in the gene mutation spectra of younger and older Chinese adult AML patients and the prognostic significance of these differentially presented gene mutations are rarely reported. One hundred and thirteen newly diagnosed Chinese adults with AML, divided into groups of younger and older patients, were enrolled in this study. Bone marrow samples from the patients were analyzed using targeted next-generation sequencing with a panel of 141 genes. Ninety-eight mutated genes were detected and the top 10 mutated genes were KMT2D, FLT3, FAT1, ASXL1, NRAS, DNMT3A, RELN, TET2, JAK2, and KRAS. The top five functional groups were the tyrosine kinase pathway, transcription factors, DNA methylation, chromatin modifiers, and the JAK-STAT signaling pathway. Younger patients exhibited higher incidences of KMT2D (33.8% vs 10.4%, P = 0.004) and KRAS (15.4% vs 2.1%, P = 0.042) mutations than older patients; whereas, older patients harbored more SRSF2 (20.8% vs 0%, P = 0.002), transcription factor (85.4% vs 67.7%, P = 0.031), DNA methylation (58.3% vs 36.9%, P = 0.024), and RNA splicing (31.3% vs 12.3%, P = 0.013) mutations than younger patients. Moreover, patients with SRSF2 mutations exhibited a lower rate of overall survival (P 0.001) and relapse-free survival (P 0.001) than patients carrying wild-type SRSF2. In conclusion, rarely reported KMT2D, FAT1, and RELN mutations were detected at high frequencies in our cohort. The gene mutation spectrum of older patients was different to that of younger patients. Moreover, older patients harbored more SRSF2 mutations, which predicted lower rates of overall and relapse-free survival.

In order to investigate the anti-aging effect and mechanism of Liuwei Dihuang Wan pill (LWDH) on natural aging rats, LWDH pill was abstracted by boiling and filtrating according to conventional method and became decoction. Adult male rats were divided into two groups randomly, the experimental group fed with decoction of LWDH (0.5 mg/ml/100 g body weight), and natural aging group fed with equivalent volume of tap water. Both groups were treated with respective material once each day for one year. Morris water maze was employed to examine the behavioral learning and memory ability of all rats in the experiment. The content of superoxide dismutase (SOD), an antioxidant, and acetylcholinesterase (AChE) in serum were tested with spectrophotometer. The activity of choline acetyltransferase (ChAT) in brain cortex was assayed by spectrophotometer. The thymus index and spleen index were analyzed. The results showed that LWDH can improve general behavior of aging rats. Compared with the control group, the weight of natural aging rats increased stably and was much higher (P ＜ 0.05). The LWDH-treated rats showed a shorter average escape latency in the navigation test (P ＜ 0.05) and higher percentage of swimming time spent in the target quadrant of Morris water maze and later spatial probe test (P ＜ 0.05). Higher thymus index and spleen index (P ＜ 0.05), increased SOD vigor in serum (P ＜ 0.05) as well as higher ChAT and AChE in cerebral cortex (P ＜ 0.05) were also observed. As above, LWDH can improve learning and memory ability and general behavior of natural aging rats; it can also reverse the metabolic capability and immunoregulation in natural aging rats.

In the version of this article originally published, there were several errors in Fig. 4. In Fig. 4a, the title read ‘3D repeated optical inhibition after CSDS.’ It should have read ‘3-day repeated optical inhibition after CSDS.’ In Fig. 4c, two labels that should have been aligned with the time axis appeared in the wrong place in the figure. The ticks labeled ‘SI’ and ‘Fiber implant’ should have also been labeled with ‘10’ and ‘14,’ respectively. Additionally, in Fig. 4j, a label that should have been aligned with the time axis appeared in the wrong place in the figure. The tick labeled ‘Fiber implant’ should have also been labeled with ‘14.’ The errors have been corrected in the print, PDF and HTML versions of the manuscript.

We reported previously that C-fibers innervating rat skin can be excited by short trains of electrical shocks ('tetanus') applied to neighboring nerves. Since these nerves were disconnected from the CNS, the cross-talk is located peripherally. Here we tested if low-threshold mechanoceptive (LTM) C-fibers can be excited by this cross-talk and if this process is mediated by substance P (SP) via neurokinin-1 (NK-1) receptors. In urethane anesthetized rats we found that 80% (56/71) of LTM C-fibers, recorded in the lateral cutaneous branch of the dorsal ramus (CBDR) of T10 spinal nerve, were excited by a 10s, 20 Hz tetanus of the T9 CBDR. Compared to the spontaneous pre-tetanic firing frequency of 1.62+/-0.40 impulses/30s, the frequency significantly increased to 3.74+/-0.99, 3.17+/-0.69 and 2.92+/-0.63 impulses/30s, at 30, 60 and 90 s after the tetanus, respectively, and declined to the baseline frequency thereafter. When injected into their receptive fields, SP mimicked the tetanically induced increase of firing rate, whereas the NK-1 receptor antagonist WIN 51708 blocked the excitation in most fibers. The excitation was significantly diminished in adult rats that were neonatally treated with capsaicin, a treatment that destroys most SP-expressing afferent fibers. Thus, we conclude that peptidergic primary afferents are functionally linked with adjacent LTM C-fibers in a non-synaptic, paracrine-like signaling pathway via SP and NK-1 receptors, and perhaps also other agents as well. We propose that this cross-talk has evolved as a mechanism regulating the mechanoceptive characteristics of LTM C-fibers, presumably contributing to pain sensation elicited by tactile stimuli ('allodynia').

To investigate the effect of bortezomib alone or combined with harringtonine (HT) or arsenic trioxide (As2O3) on the proliferation activity and apoptosis of HL60/ADM cell line and refractory/relapse acute leukemia primary cell. HL60/ADM cells or refractory/relapse acute leukemia primary cells were incubated with bortezomib at different doses alone and in combination with HT or As2O3. The proliferation activity was abserved by MTT assay, cell apoptosis was studied by fluorescence microscopy and flow cytometry. Intracellular concentration of daunorubicin (DNR) was determined by flow cytometry. In bortezomib-treated tumor cells, inhibition rate enhanced and apoptotic cells increased in mumber time- and dose-dependently. 40nM Bortezomib can best inhibit the proliferation activity of HL60/ADM cells when incubated for 48 hours. 15uM As2O3 or 752nM HT combined with different doses of bortezomib can inhibit the proliferation and induce the apoptosis of HL60/ADM cells, The dual inhibition of As2O3 plus bortezomib or HT plus bortezomib may present a superior anticancer efficancy to either inhibition of the drugs above alone (P

Objective To explore the apoptosis effect induced by bortezomib combined with homoharringtonine or arsenious acid in HL-60 cell line and the mechanism.Methods Cell' s apoptosis was demonstrated by MTT assay and Hoechst33342 staining.Expression of bcl-2,Caspase-9,Caspase-3 and PARP protein was detected by Western blot.Results HL-60 cells' apoptosis could be induced by bortezomib,homoharringtonine and arsenious acid respectively.Proliferation inhibition of HL-60 cells could be enhanced significantly when treated by bortezomib combined with homoharringtonine or arsenious acid compared with treated by any of the three drugs alone (P ＜ 0.05).At the same time morphology shows the apoptosis induced by drugs combined is more obviously than by one drug.Western blot showed bcl-2 protein was down-regulated and Caspase-9,Caspase-3 and PARP proteins were all cleaved activation when cells were treated by 15 μmol/ L arsenious acid alone,but only cleaved activation of PARP and down-regulation of bcl-2 protein be detected when cells were treated with 30 nmol/L homoharringtonine alone,expression of Caspase-9 and Caspase-3 had no change compared with the control.The changes of associated proteins were paralleled with the cell' s apoptosis when treated with combined drugs.Conclusion HL-60 cells' apoptosis effect is inhanced significantly when bortezomib combined with homoharringtonine or arsenious acid.Arsenious acid and bortezomib can inhibit caspase signaling pathway and down-regulate the expression of bcl-2 protein together,but homoharringtonine and bortezomib can only down-regulate the expression of bcl-2 protein and induce cleaved activation of PARP together. Key words: Cells, HL-60; Bortezomib; Homoharringtonine; Arsenious acid; Apoptosis