Molecular Evolution of the Deuterolysin (M35) Family Genes in Coccidioides

Coccidioides is a primary fungal pathogen of humans, causing life-threatening respiratory disease known as coccidioidomycosis (Valley fever) in immunocompromised individuals. Recently, Sharpton et al (2009) found that the deuterolysin (M35) family genes were significantly expanded in both the Coccidioides genus and in U. reesii, and that Coccidioides has acquired three more M35 family genes than U. reesii. In the present work, phylogenetic analyses based on a total of 28 M35 family genes using different alignments and tree-building methods consistently revealed five clades with high nodal supports. Interestingly, likelihood ratio tests suggested significant differences in selective pressure on the ancestral lineage of three additional duplicated M35 family genes from Coccidioides species compared to the other lineages in the phylogeny, which may be associated with novel functional adaptations of M35 family genes in the Coccidioides species, e.g., recent pathogenesis acquisition. Our study adds to the expanding view of M35 family gene evolution and functions as well as establishes a theoretical foundation for future experimental investigations

Changes of deep Pacific overturning circulation and carbonate chemistry during middle Miocene East Antarctic ice sheet expansion

East Antarctic ice sheet expansion (EAIE) at similar to 13.9 Ma in the middle Miocene represents a major climatic event during the long-term Cenozoic cooling, but ocean circulation and carbon cycle changes during this event remain unclear. Here, we present new fish teeth isotope (epsilon Nd) and benthic foraminiferal B/Ca records from the South China Sea (SCS), newly integrated meridional Pacific benthic foraminiferal delta O-18 and delta C-13 records and simulated results from a biogeochemical box model to explore the responses of deep Pacific Ocean circulation and carbon cycle across EAIE. The epsilon Nd and meridional benthic delta C-13 records reveal a more isolated Pacific Deep Water (PDW) and a sluggish Pacific meridional overturning circulation during the post-EAIE with respect to the pre-EAIE owing to weakened southern-sourced deep water formation. The deep-water [CO32-] and calcium carbonate mass accumulation rate in the SCS display markedly similar increases followed by recoveries to the pre-EAIE level during EAIE, which were probably caused by a shelf-basin shift of CaCO3 deposition and strengthened weathering due to a sea level fall within EAIE. The model results show that the similar to 1 parts per thousand positive delta C-13 excursion during EAIE could be attributed to increased weathering of high-delta C-13 shelf carbonates and a terrestrial carbon reservoir expansion. The drawdown of atmospheric CO2 over the middle Miocene were probably caused by combined effects of increased shelf carbonate weathering, expanded land biosphere carbon storage and a sluggish deep Pacific meridional overturning circulation. (C) 2017 Elsevier B.V. All rights reserved

A convenient tandem one-pot synthesis of donor-acceptor-type triphenylene 2,3-dicarboxylic esters from diarylacetylene

A tandem one-pot method for the direct synthesis of polysubstituted triphenylene 2,3-dicarboxylic esters with different substitution patterns was developed by enyne metathesis of diarylacetylene, followed by Diels–Alder, aromatization and a cyclization cascade

Intraperitoneal ropivacaine and early postoperative pain and postsurgical outcomes after laparoscoipc herniorrhaphy in toddlers: a randomized clinical trial

Background Postoperative pain can cause physiological distress, postoperative complications, and extended lengths of hospitalized stay. In children, management of postoperative pain is still recognized as being inadequate. Objective The aim of this trial was to investigate the effects of intraperitoneal ropivacaine on postoperative pain, and recovery of bowel function and emetic events after laparoscopic herniorrhaphy in toddlers. Methods Seventy-six children aged from 9 months to 3 years were recruited between August 2013 and June 2014 at Tongji Hospital and randomly assigned into two groups. One group received intraperitoneal ropivacaine right before surgery and the control group received intraperitoneal saline. A standard combined general anesthesia procedure was performed under regular monitoring. Postoperative pain was assessed by the FLACC scale. Postoperative analgesic consumption, time to flatus, time to first stool, and postoperative emetic events were also recorded. Results When compared with the control group, children who received intraperitoneal ropivacaine experienced less pain 0–4 h after surgery [P < 0.001, difference in median FLACC (95% CI) for 2 h time point is 2.00 (0.87–3.13), for 4 h time point is 1.00 (0.55–1.45)]. In addition, the number of toddlers who received analgesia 0–24 h after surgery in the ropivacaine group was lower than that in the control group [P < 0.001, difference in proportions (95% CI) is 0.575 (0.3865–0.7638)]. Compared with the control group, time to flatus in ropivacaine group was also much shorter [21.1 h vs 16.7 h, P = 0.04, difference in mean (95% CI) is 4.4 (1.49–7.28)], and the time to first stool after surgery was earlier in the ropivacaine group [30.7 h vs 25.6 h, P = 0.003, difference in mean (95% CI) is 5.1 (1.78–8.45)]. Furthermore, the incidence of emetic events in the ropivacaine group was significantly lower than the control group [32.4% vs 11.1%, P = 0.03, difference in proportions (95% CI) is 0.212 (0.0246–0.4002)]. Conclusion The present results indicate that intraperitoneal ropivacaine reduces early postoperative pain and improves recovery after laparoscopic herniorrhaphy in toddlers. Therefore, IPLA is a good stratagem for postoperative pain management after laparoscopic surgery in toddlers

Alkali burn induced corneal spontaneous pain and activated neuropathic pain matrix in the central nerve system in mice

Purpose: To explore whether alkali burn causes corneal neuropathic pain and activates neuropathic pain matrix in the central nerve system in mice. Methods: A corneal alkali burn mouse model (grade II) was used. Mechanical threshold in the cauterized area was tested using Von Frey hairs. Spontaneous pain behavior was investigated with conditioned place preference (CPP). Phosphor extracellular signal-regulated kinase (ERK), which is a marker for neuronal activation in chronic pain processing, was investigated in several representative areas of the neuropathic pain matrix: the two regions of the spinal trigeminal nucleus (subnucleus interpolaris/caudalis ,Vi/Vc; subnucleus caudalis/upper cervical cord , Vc/C1), insular cortex, anterior cingulated cortex (ACC), and the rostroventral medulla (RVM). Further, pharmacologically blocking pERK activation in ACC of alkali burn mice was performed in a separate study. Results: Corneal alkali burn caused long lasting damage to the corneal subbasal nerve fibers and mice exhibited spontaneous pain behavior. By testing in several representative areas of neuropathic pain matrix in the higher nerve system, phosphor extracellular signal-regulated kinase (ERK) was significantly activated in Vc/C1, but not in Vi/Vc. Also, ERK was activated in the insular cortex, ACC, and RVM. Furthermore, pharmacologically blocking ERK activation in ACC abolished alkali burn induced corneal spontaneous pain. Conclusion: Alkali burn could cause corneal spontaneous pain and activate neuropathic pain matrix in the central nerve system. Furthermore, activation of ERK in ACC is required for alkali burn induced corneal spontaneous pain

Src-family protein tyrosine kinases: a promising target for treating chronic pain

Abstract Despite growing knowledge of the mechanisms of chronic pain, it remains a major challenge facing clinical practice. Src-family protein tyrosine kinases (SFKs), a group of non-receptor protein tyrosine kinases, have been implicated in neuronal development and synaptic plasticity. SFKs are critically central to various transmembrane receptors e.g. G-protein coupled receptor (GPCR), EphB receptor (EphBR), increased intracellular calcium, epidermal growth factor (EGF) and other growth factors that regulate the phosphorylation of N-methyl-D-aspartic acid receptor (NMDAR) 2B subunit, thus contributing to the development of chronic pain. SFKs have also been regarded as an important point of convergence of intracellular signaling components that regulate microglia functions and the immune response. Additionally, intrathecal administration of SFKs inhibitors significantly alleviates mechanical allodynia in different chronic pain models. Thus, here we reviewed the current evidence of the role of SFKs in the development of chronic pain caused by complete Freund's adjuvant (CFA) injection, peripheral nerve injury (PNI), streptozotocin (STZ) injection and bone metastasis. Moreover, the role of SFKs on the development of morphine tolerance has also been discussed. Management of SFKs therefore emerged as a potential therapeutic target for the treatment of chronic pain in terms of safety and efficacy. Key words Chronic pain; Src-family protein tyrosine kinases; N-methyl-D-aspartic acid receptor; Microglia

The therapeutic potential of GABA in neuron-glia interactions of cancer-induced bone pain

Abstract: The development of effective therapeutics for cancer-induced bone pain (CIBP) remains a tremendous challenge owing to its unclear mechanisms. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. Emerging studies have shown that disinhibition in the spinal cord dorsal horn may account for the development of chronic pain. However, the role of GABA in the development of CIBP remains elusive. In addition, accumulating evidence has shown that neuroglial cells in the peripheral nervous system, especially astrocytes and microglial cells, play an important role in the maintenance of CIBP. In this study, we investigated the expression of GABA and Gamma-aminobutyric acid transporter-1 (GAT-1), a transporter of GABA. Our results demonstrate that GABA was decreased in CIBP rats as expected. However, the expression of glutamic acid decarboxylase (GAD) 65 was up-regulated on day 21 after surgery, while the expression of glutamic acid decarboxylase (GAD) 67 remained unchanged after surgery. We also found that the expression of GAT-1 was up-regulated mainly in the astrocytes of the spinal cord. Moreover, we evaluated the analgesic effect of exogenous GABA and the GAT-1 inhibitor. Intrathecal administration of exogenous GABA and NO-711(a GAT-1 selective inhibitor) significantly reversed CIBP-induced mechanical allodynia in a dose-dependent manner. These results firstly show that neuron-glia interactions, especially on the GABAnergic pathway, contribute to the development of CIBP. In conclusion, exogenous GABA and GAT-1 inhibitor might be alternative therapeutic strategies for the treatment of CIBP. Keywords: Cancer-induced bone pain; Gamma-Aminobutyric acid; Glutamic acid decarboxylases; GABA transporters; NO-711; Astrocyt

MHC-I promotes apoptosis of GABAergic interneurons in the spinal dorsal horn and contributes to cancer induced bone pain

Cancer induced bone pain (CIBP) remains one of the most intractable clinical problems due to poor understanding of its underlying mechanisms. Recent studies demonstrate the decline of inhibitory interneurons, especially GABAergic interneurons in the spinal cord, can evoke generation of chronic pain. It has also been reported that neuronal MHC-I expression renders neurons vulnerable to cytotoxic CD8+ T cells and finally lead to neurons apoptosis in a variety neurological disorders. However, whether MHC-I could induce the apoptosis of GABAergic interneurons in spinal cord and contribute to the development of CIBP remains unknown. In this study, we investigated roles of MHC-I and underlying mechanisms in CIBP on a rat model. Our results showed that increased MHC-I expression on GABAergic interneurons could deplete GABAergic interneurons by inducing their apoptosis in the spinal dorsal horn of tumor-bearing rats. Pretreatment of MHC-I RNAi-lentivirus could prevent the apoptosis of GABAergic interneurons and therefore alleviated mechanical allodynia induced by tumor cells intratibial injection. Additionally, we also found that CD8+ T cells were colocalized with MHC-I and GABAergic neurons and presented a significant and persistent increase in the spinal cord of tumor-bearing rats. Taken together, these findings indicated that MHC-I could evoke CIBP by promoting apoptosis of GABAergic interneurons in the dorsal horn, and this apoptosis was closely related to local CD8+ T cells