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Structural connections among the hubs of the revised Papez circuit remain to be elucidated in the human brain. As the original Papez circuit failed to explain functional imaging findings, a more detailed investigation is needed to delineate connections among the circuit’s key hubs. Here we acquired diffusion spectrum imaging (DSI) from eight normal subjects and used data from the Human Connectome Project (HCP) to elucidate connections among hubs in the retrosplenial gyrus, hippocampus, mammillary bodies, and anterior thalamic nuclei. Our results show that the ventral hippocampal commissure (VHC) was visualized in all eight individual DSI datasets, as well as in the DSI and HCP group datasets, but a strictly defined VHC was only visualized in one individual dataset. Thalamic fibers were observed to connect with both the posterior cingulate cortex (PCC) and retrosplenial cortex (RSC). The RSC was mainly responsible for direct hippocampal connections, while the PCC was not. This indicates that the RSC and PCC represent separate functional hubs in humans, as also shown by previous primate axonal tracing studies and functional magnetic resonance imaging observations. [ABSTRACT FROM AUTHOR]

A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine–quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC 50 value of 0.28 ± 0.07 μM against HIV-1 III B . A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules. [ABSTRACT FROM AUTHOR]

Abstract: In prior studies, Eph/ephrin system was demonstrated to be involved in inflammatory and neuropathic pain modulation. The present study was to investigate whether the spinal Eph/ephrin signaling was involved in modulation of spinal inflammatory cytokines in bone cancer pain (BCP) of rats. BCP was induced by intra-tibial inoculation of Walker 256 mammary gland carcinoma cells. The expressions of EphB1/ephrinB1 in spinal cord (SC) and dorsal root ganglia (DRG) were determined. At 16 days post inoculation, the pain relieving effect and the mRNA levels of inflammatory cytokines were detected after intrathecal administration of EphB1-Fc (blocker of EphB1 receptor, 10μg). The results showed that the EphB1/ephrinB1 expression was significantly increased in SC, but ephrinB1 was decreased in DRG after Walker 256 inoculation. The mechanical allodynia induced by bone cancer was significantly alleviated by intrathecal administration of EphB1-Fc. Furthermore, the RT-PCR analysis showed that the mRNA levels of IL-1β, IL-6 and TNF-α were significantly increased at 16 days post Walker 256 inoculation and were significantly suppressed by intrathecal administration of EphB1-Fc in SC. We concluded that Eph/ephrin might be involved in the maintenance of mechanical allodynia, via modulating the expression of spinal inflammatory cytokines, in the present rat model of BCP. This study suggested that Eph/ephrin signaling would be a potential target for the treatment of BCP. [Copyright &y& Elsevier]

Abstract: Kisspeptin/GPR54 system plays a crucial role in the control of puberty onset and reproductive function. In the present study, we gave the first report that kisspeptin and GPR54 were expressed in the small- to large-sized neurons, and co-localized with Bandeiraea simplicifolia isolectin B4 (IB4), calcitonin-gene-related peptide (CGRP) and neurofilament 200 (NF200) in the L4/5 dorsal root ganglion (DRG) of naïve rats, detected by the double immunofluorescent staining. Interestingly, a marked elevation in the levels of KiSS-1 and GPR54 mRNA as well as protein was observed in the spinal dorsal horn and DRG 4 and 14 days following intra-articular injection of complete Freund''s adjuvant (CFA), indicating a possible involvement of the kisspeptin/GPR54 system in chronic inflammatory pain. [Copyright &y& Elsevier]

Abstract: Electroacupuncture (EA) can effectively control the exaggerated pain in humans with inflammatory disease and animals with experimental inflammatory pain. However, there have been few investigations on the effect of co-administration of EA and analgesics and the underlying synergistic mechanism. Using behavioral test, RT-PCR analysis, enzyme immunoassay (EIA) and enzyme-linked immunosorbent assay (ELISA), the present study demonstrated that (1) Unilateral intra-articular injection of complete Freund''s adjuvant (CFA) produced a constant hyperalgesia and an up-regulation of the prostaglandin E2 (PGE2) level as well as the tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels in the spinal cord; (2) Celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2), at a dose of 2, 10, and 20mg/kg (twice daily, p.o.), presented a dose-dependent anti-hyperalgesic effect; (3) Repeated EA stimulation of ipsilateral ‘Huan-Tiao’ (GB30) and ‘Yang-Ling-Quan’ (GB34) acupoints significantly suppressed CFA-induced hyperalgesia, and markedly inhibited the CFA-induced increase of the level of PGE2 as well as IL-1β, IL-6, and TNF-α in the spinal cord; (4) EA combined with low dose of celecoxib (2mg/kg, twice daily, p.o.) greatly enhanced the anti-hyperalgesic effects of EA, with a synergistic reversing effect on CFA-induced up-regulation of spinal PGE2, but not on the IL-1β, IL-6, or TNF-α. These data indicated that repeated EA combined with low dose of celecoxib produced synergistic anti-hyperalgesic effect in the CFA-induced monoarthritic rats, which could be made possible by regulating the activity of spinal COX, hence the spinal PGE2 level. Thus, this combination may provide an effective strategy for pain management. [Copyright &y& Elsevier]

To evaluate the long-term efficacy, prognostic factors, and safety of posteroventral globus pallidus internus deep brain stimulation (DBS) in patients with refractory Tourette syndrome (RTS). This retrospective study recruited 61 patients with RTS who underwent posteroventral globus pallidus internus (GPi) DBS from January 2010 to December 2020 at the Chinese People's Liberation Army General Hospital. The Yale Global Tic Severity Scale (YGTSS), Yale-Brown Obsessive-Compulsive Scale (YBOCS), Beck Depression Inventory (BDI), Gilles de la Tourette Syndrome Quality-of-Life Scale (GTS-QOL) were used to evaluate the preoperative and postoperative clinical condition in all patients. Prognostic factors and adverse events following surgery were analyzed. Patient follow up was conducted for an average of 73.33 ± 28.44 months. The final postoperative YGTSS (32.39 ± 22.34 vs 76.61 ± 17.07), YBOCS (11.26 ± 5.57 vs 18.31 ± 8.55), BDI (14.36 ± 8.16 vs 24.79 ± 11.03) and GTS-QOL (39.69 ± 18.29 vs 78.08 ± 14.52) scores at the end of the follow-up period were significantly lower than those before the surgery (p < 0.05). While age and the duration of follow-up were closely related to prognosis, the disease duration and gender were not. No serious adverse events were observed and only one patient exhibited symptomatic deterioration. Posteroventral-GPI DBS provides long-term effectiveness, acceptable safety and can improve the quality of life in RTS patients. Moreover, DBS is more successful among younger patients and with longer treatment duration. [ABSTRACT FROM AUTHOR]

Based on molecular simulation, the etravirine–VRX-480773 hybrids previously disclosed by our group were optimized to yield novel pyrimidine sulfonylacetanilides 8 with improved activity against a panel of seven clinically relevant single and double mutant strains of HIV-1. The improvement in potency in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits the reverse transcriptase (RT), and represents a remarkable step forward in the development of anti-HIV drugs. [ABSTRACT FROM AUTHOR]

The improvement of microstructure and mechanical properties of Ti alloys is of great significance for their industrial application. In this study, a developed multi-step hot deformation process was employed to regulate the grain boundaries (GBs), hetero-phase boundaries (PBs) and dislocation structure for dual-phase titanium alloy. The effects of accumulative thermal deformation ratios from 33% to 75% (2–8 cycles) on the microstructure and mechanical properties have been investigated. It is found that the sintered sample shows a typical Widmanstätten structure without obvious pores and micro-cracks. However, with the increase of the deformation ratio, for the hexagonal close packed (HCP) Ti, the crystal orientations of { 01 1 ‾ 0 } and { 1 ‾ 2 1 ‾ 0 } were gradually transformed into {0001}, with the change of high-angle grain boundaries (HAGBs) to low-angle grain boundaries (LAGBs). The density of stored geometrically necessary dislocations (GNDs) density raised dramatically from 1.95 × 1014 m−2 to 6.5 × 1014 m−2, and various types of dislocations have been characterized. For the β phase, in the thermal deformation process, high density α-precipitates with an average thickness below 20 nm had formed with Burgers relationship of {110} BCC //{0001} HCP and < 1 ‾ 11 > BCC //< 2 1 ‾ 1 ‾ 0 > HCP. Finally, the yield strength of the dual-phase titanium alloy increased dramatically from 881 MPa to 1178 MPa, and the ductility can still maintain at above 8.5%. The enhanced strength was mainly contributed by the increase of geometrically necessary boundaries (GNBs) and nano-lamellae boundaries (NLBs). Therefore, this strategy of combining hetero-phase boundaries (PBs) and dislocation engineering could open up new avenues to designing strong and ductile titanium matrix materials. [ABSTRACT FROM AUTHOR]

Abstract: Cumulative evidences suggest that electroacupuncture (EA) can modulate immune function, but the mechanism needs further study. In the present study, the contribution of EA on toll-like receptors 2 and 4 (TLR2/TLR4) and pro-inflammatory cytokine expression after surgical trauma stress were investigated. The mRNA level of both TLR2/4 and pro-inflammatory cytokine was measured by quantitative real-time PCR. ELISA and Western blot assay were chosen for TLR2/TLR4 protein expression and pro-inflammatory cytokine production, respectively. The results showed that surgical trauma stress increased TLR2 mRNA and TLR2/4 proteins in the spleen and augmented pro-inflammatory cytokines (e.g. IL-1β) mRNA and protein expression in the spleen and plasma. These effects could be deteriorated by adrenalectomy (ADX). EA at “Zusanli” acupoint significantly inhibited surgical trauma-induced TLR2 mRNA and TLR2/4 protein expression in spleen and pro-inflammatory cytokine expression in the spleen and plasma. ADX, however, could not block the effect of EA. These results suggested that surgical trauma stress primes the innate immune system for enhanced TLR2 expression and pro-inflammatory cytokine production. EA inhibits TLR2/4 and pro-inflammatory cytokines to produce an anti-inflammatory effect in a surgical trauma stress model, without adrenal gland involvement. [Copyright &y& Elsevier]

Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized by intermittent and recurrent upper airway collapse during sleep that leads to chronic intermittent hypoxia (CIH). The genioglossus (GG) is the largest dilator muscle, which controls the upper airway and plays an important role in OSA pathology. Elucidating its genetic alterations may help identify potential targets for OSA. However, the genetic aspects of the GG in CIH mice remain unclear. Here, we have conducted an RNA sequencing (RNA-Seq) analysis to assess the differentially expressed genes (DEGs) in the GG between CIH mice and normoxia (NOR) mice. A total of 637 DEGs were identified to be dysregulated in CIH mice compared with control mice. Bioinformatics analysis showed that the DEGs were related to various physiological processes, such as the endogenous stimulus responses, cellular component organization and metabolic processes. Extracellular matrix (ECM)–receptor interaction was the top KEGG pathway in the environmental information processing category with high significance and large fold changes. From the gene weight distributions of collagen (Col)-related biological processes (BPs), we found several significant DEGs, such as Col1a1, Col1a2, Mmp2, Col3a1, Col5a1, Fmod, and Col5a2. A PPI network showed that Col1a1 was linked to ECM–receptor interactions, responses to reactive oxygen species (ROS) and Col-related BPs. It was verified in vivo and in vitro that hypoxia can induce excess ROS and reduce Col expression levels. Moreover, we found NAC can effectively scavenge ROS and restore collagen synthesis. These findings contribute to a better understanding of the mechanisms linking OSA and upper airway muscle injury and may help identify potential therapeutic targets. • 637 DEGs were identified in mouse genioglossus of chronic intermittent hypoxia model. • ECM–receptor interactions was highly enriched with transcriptional changes in collagen synthesis. • A PPI network showed that Col1a1 was linked to ECM–receptor interactions, responses to ROS and Col-related BPs. [ABSTRACT FROM AUTHOR]

Pseudomonas plecoglossicida NyZ12 (CCTCC AB 2015057), a Gram-negative bacterium isolated from soil, has the ability to degrade cyclohexylamine. The complete genome sequence of this strain (6,233,254 bp of chromosome length) is presented, with information about the genes of characteristic enzymes responsible for cyclohexylamine oxidation to cyclohexanone and the integrated gene cluster for the metabolic pathway of cyclohexanone oxidation to adipate. [ABSTRACT FROM AUTHOR]

The Gram-negative strain of Pseudomonas plecoglossicida NyZ12 isolated from soil has the ability to degrade cyclohexylamine (CHAM). The genes encoding CHAM degradation by gram-negative bacteria, however, have not been reported previously. In this study, ORFs predicted to encode CHAM degradation by NyZ12 were identified by bioinformatics analysis. Differential expression of the proposed ORFs was analyzed via RNA-seq and quantitative reverse transcription-PCR (qRT-PCR), using RNA extracted from NyZ12 cultured with or without CHAM addition. One CHAM-inducible ORF, RK21_02867 predicted to encode a cyclohexanone monooxygenase (ChnB) was disrupted, as were five ORFs, RK21_00425, RK21_02631, RK21_04207, RK21_04637 and RK21_05539, that had weak homology to the only known cyclohexylamine oxidase (CHAO encoded by chaA ) found in Brevibacterium oxydans IH-35A. We also found that a tandem array of five ORFs (RK21_02866-02870) shared homology with those in an operon responsible for oxidation of cyclohexanone to adipic acid, although the ORFs in strain NyZ12 were arranged in a different order with previously found in cyclohexane, cyclohexanol or cyclohexanone degradation strains. The ORFs in this cluster were all up-regulated when CHAM was supplied as the sole carbon source. When one of these five genes, RK21_02867 encoding cyclohexanone (CHnone) monooxygenase, was knocked out, NyZ12 could not grow on CHAM, but it accumulated equimolar amounts of CHnone. Our results show that strain NyZ12 metabolized CHAM directly to CHnone which was then further metabolized to adipate. Despite clearly identifying genes encoding the steps for metabolism of CHAM metabolites, not every one of the putative chaAs was differentially expressed in the presence of CHAM and deletion of each one individually did not completely eliminate the capacity of NyZ12 to degrade CHAM, though it did reduce its growth in several instances. Our results suggest that there is genetic redundancy encoding the initial step in the oxidation of CHAM to CHnone in NyZ12 and that its CHAOs differ considerably from the ChaA, originally described in Brevibacterium oxydans IH-35A. [ABSTRACT FROM AUTHOR]

A novel series of etravirine–VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N -(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC 50 = 0.24 , SI >1225), was more potent than delavirdine (EC 50 = 0.66 μM, SI >67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group. [ABSTRACT FROM AUTHOR]

A novel series of piperidin-4-yl-aminopyrimidine derivatives were designed fusing the pharmacophore templates of etravirine–VRX-480773 hybrids our group previously described and piperidine-linked aminopyrimidines. Most compounds displayed significantly improved activity against wild-type HIV-1 with EC 50 values in single-digit nanomolar concentrations compared to etravirine–VRX-480773 hybrids. Selected compounds were also evaluated for activity against reverse transcriptase, and had lower IC 50 values than that of nevirapine. The improved potency observed in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits reverse transcriptase, and represents a remarkable step forward in the development of AIDS therapeutics. [ABSTRACT FROM AUTHOR]

Abstract: RNA activation is a promising discovery that promoter-targeted double-stranded small RNAs, termed small activating RNAs (saRNAs), can induce gene expression, which represents a novel approach to gene over-expression without traditional vector-based systems. PAWR is a tumor suppressing gene essential for apoptosis and a cancer-selective target for cancer therapeutics. Here our study identified synthetic saRNAs that could activate the expression of PAWR in human cancer cells. Functional analysis of PAWR induction revealed that saRNA treatment induced growth inhibition and apoptosis of cancer cells, and predictably modulated the expression of known downstream target gene Bcl-2. New functional saRNAs can also be harvested by one or two-base shifting of the original target sites. Chromatin immunoprecipitation assays indicated that activation of PAWR is accompanied by reduced dimethylation at histone H3K9 and increased dimethylation at histone H3K4. Moreover, the existence of transcripts in PAWR promoter was detected but its relationship with RNA activation needs more lucubration. These data have enlarged the gene pool of RNAa and hold great promise as an alternative for PAWR-targeted therapeutics. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: The herbal analgesic gel Tong-Luo-San-Jie (TLSJ) and its modifications are used in traditional Chinese medicine to manage cancer pain. However, its mechanisms are still unknown. Aim of the study: To investigate the effects and mechanisms of TLSJ gel on bone cancer pain in a rat model. Materials and methods: A bone cancer pain rat model was established by inoculating Walker 256 rat carcinoma cells directly into the right tibial medullary cavity of Sprague–Dawley rats (150–170g); Phosphate buffered saline (PBS) tibial inoculation was used as control. Cancer-bearing rats were treated twice a day with external TLSJ gel (0.5g/cm2/day) or inert gel control for 21 day (n=10/group). Behavioral tests such as mechanical threshold and paw withdrawal latency (PWL) were carried out. Osteoclastic activities were determined and carboxyterminal pyridinoline cross-linked type I collagen telopeptides (ICTP) and bone-specific alkaline phosphatase (BAP) concentrations were detected with ELISA after treatment. Adverse effects were monitored, and biochemical and histological tests were performed in naïve rats treated with local TLSJ gel for six weeks. Results: TLSJ treatment significantly restored bone cancer-induced decrease of PWL and mechanical threshold compared to inert gel. It also decreased the level of blood serum ICTP and BAP and inhibited osteoclast activities. No adverse effects or abnormal biochemical and histological changes were detected after TLSJ treatment. Conclusion: The present study shows that TLSJ significantly inhibits bone cancer-induced thermal and mechanical sensitization. It suggests that the gel may be useful in managing cancer pain and that it may act by inhibiting osteoclastic activity. [Copyright &y& Elsevier]

Abstract: Osteomyelitis is an acute or chronic inflammatory process of bone accompanied with mild to severe pain. Generally, mild to moderate pain induced by osteomyelitis can be relieved, yet severe pain cannot. Therefore, a further investigation into the mechanism of severe pain induced by osteomyelitis is needed. In this study, a traditional rat model of osteomyelitis was induced by intra-tibial injection of Staphylococcus aureus. Then, a series of tests including bone histology, blood analysis, mechanical allodynia, thermal hyperalgesia, and immunohistochemistry were performed. Four days after an intra-tibial bacterial injection, acute inflammation was observed in the bone marrow, which developed into chronic inflammation 12 days after the procedure. The results from the blood analysis confirmed the existence of bone inflammation. Significant mechanical allodynia and thermal hyperalgesia developed shortly after the injection. This osteomyelitis-induced pain behavior was reversed by Celecoxib, a selective COX-2 inhibitor. Furthermore, significant increase of both microglia and astrocytes was observed in the spinal cord. Our results suggest that osteomyelitis-induced rats display pain related behaviors and associated neurochemical changes. This study thus provides a novel practical rat model of bone inflammation induced pain. [Copyright &y& Elsevier]

Abstract: In prior studies, models of inflammatory pain were produced through injecting complete Freund''s adjuvant (CFA) or capsaicin directly into either the deep somatic tissue or the animal''s hind paw. In contrast, bone cancer-induced pain (BCIP) was simulated through injecting tumor cells into the cavity of the femur or the tibia. It has been reported that, due to differences in afferent innervation, the same stimulus to various tissue types might result in differing patterns of pain response. Hence, the aim of this study is to establish a rat model of bone inflammation-induced pain (BIIP) by injecting CFA into the tibial cavity, the same site involved in the BCIP model. The differences in body weight, bone histology, mechanical allodynia, thermal hyperalgesia, and the pain relieving effects of Celebrex on this model of BIIP were evaluated. The results showed that there was evidence of significant inflammation seen in the bone marrow two days after intra-tibial CFA injection, including nuclear condensation and fragmentation, massive neutrophilic granulocytes, and prominent fibrinous exudates. Fourteen days after injection, marked fibrosis of the bone was detected by histological staining. After unilateral CFA injection, behavioral studies showed mechanical allodynia to von Frey hair stimulation, but no thermal hyperalgesia was observed. Celebrex showed significant anti-allodynic effects on the BIIP model. The results demonstrated that CFA is an effective agent for inducing bone inflammation and subsequent pain-related behavior in rat models, and, thus, provides a practical and valuable contrast for BCIP research. [Copyright &y& Elsevier]

Abstract: Very recent studies have reported that chemically synthesized small duplex RNAs complementary to the promoters of target genes can activate gene expression in different cancer cell lines. Such dsRNA have been referred to as saRNA for small activating RNA. The present study was conducted to evaluate the potential of p21WAF1/Cip1 (p21) induction by small activating RNA targeting the p21 promoter in the treatment of bladder cancer. Using T24 human bladder cancer cells, we found that p21 saRNA caused dose- and time-dependent inhibition of cell proliferation and viability which was associated with induced G1-phase cell cycle arrest and apoptosis. The decreased anti-apoptotic protein Bcl-xL and activation of caspase-3 and PARP also supported the efficacy of the treatment. These data suggest that up-regulation of p21 by saRNA may be an effective way for treating human bladder and other types of cancers. [Copyright &y& Elsevier]

Abstract: The present study was designed to investigate whether electroacupuncture (EA) was beneficial to extenuate the behavioral deficit in a rat model of depression induced by chronic unpredictable stress (CUS) and to observe the effect of EA on progenitor cell proliferation in the dentate gyrus (DG) of hippocampus. EA was performed on acupoints “Bai-Hui” (Du 20) and unilateral “An-Mian” (EX 17) once daily for 3 consecutive weeks, 2 weeks post CUS procedure. Open field test and forced swimming test were employed to evaluate the behavioral activity during a stress period or EA treatment. The results revealed that exposure to CUS resulted in a decrease of behavioral activity, whilst a daily session of EA treatment significantly reversed the behavioral deficit of these depression model rats. Moreover, as shown by 5-bromo-2-deoxyuridine (BrdU) labeling immunohistochemistry, hippocampal progenitor cell proliferation was decreased in the DG of depression model rats. Intriguingly, EA treatment effectively blocked this decrease. The study demonstrated a potential antidepressant-like effect of EA treatment on CUS induced depression model rats, which might be mediated by up-regulating the hippocampal progenitor cell proliferation. [Copyright &y& Elsevier]

Profile of cybersickness and balance disturbance induced by virtual ship motion alone and in combination with galvanic vestibular stimulation (GVS) remained unclear. Subjects were exposed to a ship deck vision scene under simulated Degree 5 or 3 sea condition using a head-mounted virtual reality display with or without GVS. Virtual ship motion at Degree 5 induced significant cybersickness with symptom profile: nausea syndrome > central (headache and dizziness) > peripheral (cold sweating) > increased salivation. During a single session of virtual ship motion exposure, GVS aggravated balance disturbance but did not affect most cybersickness symptoms except cold sweating. Repeated exposure induced cybersickness habituation which was delayed by GVS, while the temporal change of balance disturbance was unaffected. These results suggested that vestibular inputs play different roles in cybersickness and balance disturbance during virtual reality exposure. GVS might not serve as a potential countermeasure against cybersickness induced by virtual ship motion. [ABSTRACT FROM AUTHOR]