Mechanisms underlying capsulotomy for refractory obsessive-compulsive disorder: neural correlates of negative affect processing overlap with deep brain stimulation targets.

Ablative procedures such as anterior capsulotomy are potentially effective in refractory obsessive-compulsive disorder (OCD). Converging evidence suggests the ventral internal capsule white matter tracts traversing the rostral cingulate and ventrolateral prefrontal cortex and thalamus is the optimal target for clinical efficacy across multiple deep brain stimulation targets for OCD. Here we ask which prefrontal regions and underlying cognitive processes might be implicated in the effects of capsulotomy by using both task fMRI and neuropsychological tests assessing OCD-relevant cognitive mechanisms known to map across prefrontal regions connected to the tracts targeted in capsulotomy. We tested OCD patients at least 6 months post-capsulotomy (n = 27), OCD controls (n = 33) and healthy controls (n = 34). We used a modified aversive monetary incentive delay paradigm with negative imagery and a within session extinction trial. Post-capsulotomy OCD subjects showed improved OCD symptoms, disability and quality of life with no differences in mood or anxiety or cognitive task performance on executive, inhibition, memory and learning tasks. Task fMRI revealed post-capsulotomy decreases in the nucleus accumbens during negative anticipation, and in the left rostral cingulate and left inferior frontal cortex during negative feedback. Post-capsulotomy patients showed attenuated accumbens-rostral cingulate functional connectivity. Rostral cingulate activity mediated capsulotomy improvement on obsessions. These regions overlap with optimal white matter tracts observed across multiple stimulation targets for OCD and might provide insights into further optimizing neuromodulation approaches. Our findings also suggest that aversive processing theoretical mechanisms may link ablative, stimulation and psychological interventions.

Risk and aversion coding in human habenula high gamma activity.

Neurons in the primate lateral habenula fire in response to punishments and are inhibited by rewards. Through its modulation of midbrain monoaminergic activity, the habenula is believed to play an important role in adaptive behavioural responses to punishment and underlie depressive symptoms and their alleviation with ketamine. However, its role in value-based decision-making in humans is poorly understood due to limitations with non-invasive imaging methods which measure metabolic, not neural, activity with poor temporal resolution. Here, we overcome these limitations to more closely bridge the gap between species by recording local field potentials directly from the habenula in 12 human patients receiving deep brain stimulation treatment for bipolar disorder (n = 4), chronic pain (n = 3), depression (n = 3) and schizophrenia (n = 2). This allowed us to record neural activity during value-based decision-making tasks involving monetary rewards and losses. High-frequency gamma (60-240 Hz) activity, a proxy for population-level spiking involved in cognitive computations, increased during the receipt of loss and decreased during receipt of reward. Furthermore, habenula high gamma also encoded risk during decision-making, being larger in amplitude for high compared to low risk. For both risk and aversion, differences between conditions peaked approximately between 400 and 750 ms after stimulus onset. The findings not only demonstrate homologies with the primate habenula but also extend its role to human decision-making, showing its temporal dynamics and suggesting revisions to current models. The findings suggest that habenula high gamma could be used to optimize real-time closed-loop deep brain stimulation treatment for mood disturbances and impulsivity in psychiatric disorders.

Subthalamic Oscillatory Activity of Reward and Loss Processing Using the Monetary Incentive Delay Task in Parkinson Disease.

BACKGROUND: The subthalamic nucleus (STN) is an effective deep brain stimulation target for Parkinson disease (PD) and obsessive-compulsive disorder and has been implicated in reward and motivational processing. In this study, we assessed the STN and prefrontal oscillatory dynamics in the anticipation and receipt of reward and loss using a task commonly used in imaging. MATERIALS AND METHODS: We recorded intracranial left subthalamic local field potentials from deep brain stimulation electrodes and prefrontal scalp electroencephalography in 17 patients with PD while they performed a monetary incentive delay task. RESULTS: During the expectation phase, enhanced left STN delta-theta activity was observed in both reward and loss vs neutral anticipation, with greater STN delta-theta activity associated with greater motivation specifically to reward. In the consummatory outcome phase, greater left STN delta activity was associated with a rewarding vs neutral outcome, particularly with more ventral contacts along with greater delta-theta coherence with the prefrontal cortex. We highlight a differential activity in the left STN to loss vs reward anticipation, demonstrating a distinct STN high gamma activity. Patients with addiction-like behaviors show lower left STN delta-theta activity to loss vs neutral outcomes, emphasizing impaired sensitivity to negative outcomes. CONCLUSIONS: Together, our findings highlight a role for the left STN in reward and loss processing and a potential role in addictive behaviors. These findings emphasize the cognitive-limbic function of the STN and its role as a physiologic target for neuropsychiatric disorders.

Evaluation of the Antioxidant Activities and Phenolic Profile of Shennongjia Apis cerana Honey through a Comparison with Apis mellifera Honey in China.

This study evaluates the phenolic profile as well as the antioxidant properties of Shennongjia Apis cerana honey through a comparison with Apis mellifera honey in China. The total phenolic content (TPC) ranges from 263 ± 2 to 681 ± 36 mg gallic acid/kg. The total flavonoids content (TFC) ranges from 35.9 ± 0.4 to 102.2 ± 0.8 mg epicatechin/kg. The correlations between TPC or TFC and the antioxidant results (FRAP, DPPH, and ABTS) were found to be statistically significant (p < 0.01). Furthermore, the phenolic compounds are quantified and qualified by high performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS), and a total of 83 phenolic compounds were tentatively identified in this study. A metabolomics analysis based on the 83 polyphenols was carried out and subjected to principal component analysis and orthogonal partial least squares-discriminant analysis. The results showed that it was possible to distinguish Apis cerana honey from Apis mellifera honey based on the phenolic profile.

A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome.

Recessive mutations in the genes encoding the four subunits of the tRNA splicing endonuclease complex (TSEN54, TSEN34, TSEN15, and TSEN2) cause various forms of pontocerebellar hypoplasia, a disorder characterized by hypoplasia of the cerebellum and the pons, microcephaly, dysmorphisms, and other variable clinical features. Here, we report an intronic recessive founder variant in the gene TSEN2 that results in abnormal splicing of the mRNA of this gene, in six individuals from four consanguineous families affected with microcephaly, multiple craniofacial malformations, radiological abnormalities of the central nervous system, and cognitive retardation of variable severity. Remarkably, unlike patients with previously described mutations in the components of the TSEN complex, all the individuals that we report developed atypical hemolytic uremic syndrome (aHUS) with thrombotic microangiopathy, microangiopathic hemolytic anemia, thrombocytopenia, proteinuria, severe hypertension, and end-stage kidney disease (ESKD) early in life. Bulk RNA sequencing of peripheral blood cells of four affected individuals revealed abnormal tRNA transcripts, indicating an alteration of the tRNA biogenesis. Morpholino-mediated skipping of exon 10 of tsen2 in zebrafish produced phenotypes similar to human patients. Thus, we have identified a novel syndrome accompanied by aHUS suggesting the existence of a link between tRNA biology and vascular endothelium homeostasis, which we propose to name with the acronym TRACK syndrome (TSEN2 Related Atypical hemolytic uremic syndrome, Craniofacial malformations, Kidney failure).

Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis.

Nephronophthisis (NPHP), the leading genetic cause of end-stage renal failure in children and young adults, is a group of autosomal recessive diseases characterized by kidney-cyst degeneration and fibrosis for which no therapy is currently available. To date, mutations in >25 genes have been identified as causes of this disease that, in several cases, result in chronic DNA damage in kidney tubular cells. Among such mutations, those in the transcription factor-encoding GLIS2 cause NPHP type 7. Loss of function of mouse Glis2 causes senescence of kidney tubular cells. Senescent cells secrete proinflammatory molecules that induce progressive organ damage through several pathways, among which NF-κB signaling is prevalent. Herein, we show that the NF-κB signaling is active in Glis2 knockout kidney epithelial cells and that genetic inactivation of the toll-like receptor (TLR)/IL-1 receptor or pharmacologic elimination of senescent cells (senolytic therapy) reduces tubule damage, fibrosis, and apoptosis in the Glis2 mouse model of NPHP. Notably, in Glis2, Tlr2 double knockouts, senescence was also reduced and proliferation was increased, suggesting that loss of TLR2 activity improves the regenerative potential of tubular cells in Glis2 knockout kidneys. Our results further suggest that a combination of TLR/IL-1 receptor inhibition and senolytic therapy may delay the progression of kidney disease in NPHP type 7 and other forms of this disease.

Coordinately Co-opted Multiple Transposable Elements Constitute an Enhancer for wnt5a Expression in the Mammalian Secondary Palate.

Acquisition of cis-regulatory elements is a major driving force of evolution, and there are several examples of developmental enhancers derived from transposable elements (TEs). However, it remains unclear whether one enhancer element could have been produced via cooperation among multiple, yet distinct, TEs during evolution. Here we show that an evolutionarily conserved genomic region named AS3_9 comprises three TEs (AmnSINE1, X6b_DNA and MER117), inserted side-by-side, and functions as a distal enhancer for wnt5a expression during morphogenesis of the mammalian secondary palate. Functional analysis of each TE revealed step-by-step retroposition/transposition and co-option together with acquisition of a binding site for Msx1 for its full enhancer function during mammalian evolution. The present study provides a new perspective suggesting that a huge variety of TEs, in combination, could have accelerated the diversity of cis-regulatory elements involved in morphological evolution.

Efficacy of Antihypertensive Therapy in the Acute Stage of Cerebral Infarction - A Prospective, Randomized Control Trial.

BACKGROUND: This study investigated whether patients in the acute stage of cerebral infarction (ACI) might benefit from single-drug antihypertensive therapy (AT) without the use of preset target levels. METHODS: A total of 320 ACI patients were randomly divided into an AT group and a control group (group C) (160 patients in each group). The AT group received single antihypertensive drug treatment after the first 48 hours of onset with 5 mg of amlodipine besylate or 150 mg of irbesartan once a day. The primary end-point event was mortality on the 14th day and in the 6th month after onset, significant dependent-survival status (SDS, Barthel Index ≤ 60), mortality/disability ratio (modified Rankin Scale ≥ 3), and recurrence rate of cardio-cerebral vascular events (RR-CVE). RESULTS: The National Institutes of Health Stroke Scale (NIHSS) score was 8.39 ± 3.21 vs. 8.16 ± 3.27 in the AT and C groups on entry to the study. On day 14, there were no significant differences in mortality (2.5% vs. 3.1%, p = 0.9994), SDS (50.0% vs. 49.0%, p = 0.864), and mortality/disability ratio (61.3% vs. 66.3%, p = 0.352) between the two groups, however the RR-CVE in the AT group was lower than in group C (4.4% vs. 11.9%, p = 0.014). In month 6, there were no significant difference in mortality rate between the two groups (3.1% vs. 3.8%, p = 0.767), however the SDS (23.4% vs. 34.4%, p = 0.033), mortality/disability ratio (32.1% vs. 45.0%, p = 0.018), and RR-CVE in group AT were lower than in group C (10.7% vs. 19.4%, p = 0.030). CONCLUSIONS: Appropriate AT for patients with ACI does not worsen the disease condition and may improve the prognosis for the patients with moderate or mild stroke severity.

NCAM affects directional lamellipodia formation of BMSCs via ß1 integrin signal-mediated cofilin activity.

The neural cell adhesion molecule (NCAM), a key member of the immunoglobulin-like CAM family, was reported to regulate the migration of bone marrow-derived mesenchymal stem cells (BMSCs). However, the detailed cellular behaviors including lamellipodia formation in the initial step of directional migration remain largely unknown. In the present study, we reported that NCAM affects the lamellipodia formation of BMSCs. Using BMSCs from Ncam knockout mice we found that Ncam deficiency significantly impaired the migration and the directional lamellipodia formation of BMSCs. Further studies revealed that Ncam knockout decreased the activity of cofilin, an actin-cleaving protein, which was involved in directional protrusions. To explore the molecular mechanisms involved, we examined protein tyrosine phosphorylation levels in Ncam knockout BMSCs by phosphotyrosine peptide array analyses, and found that the tyrosine phosphorylation level of ß1 integrin, a protein upstream of cofilin, was greatly upregulated in Ncam-deficient BMSCs. Notably, by blocking the function of ß1 integrin with RGD peptide or ROCK inhibitor, the cofilin activity and directional lamellipodia formation of Ncam knockout BMSCs could be rescued. Finally, we found that the effect of NCAM on tyrosine phosphorylation of ß1 integrin was independent of the fibroblast growth factor receptor. These results indicated that NCAM regulates directional lamellipodia formation of BMSCs through ß1 integrin signal-mediated cofilin activity.

Three dimensional Eulerian-Eulerian simulation on hydrodynamics in dissolved air flotation tank with different turbulence models.

The Eulerian-Eulerian approach is used to simulate the two phase flow of air and water in a dissolved air flotation (DAF) tank. Unsteady simulation is adopted to obtain the quasi-steady result. The two dimensional model cannot capture the three dimensional feature of flow pattern in the tank. The three dimensional model reproduces the stratification structure observed in the experiment and obtains the satisfactory volume fraction of air bubbles in the separation zone. To account for the turbulence effect, four two-equation turbulence models are evaluated. Although all turbulence models capture the stratification structure in the separation zone, the re-normalization group theory (RNG) k-ɛ model obtains the best agreement with the experimental data. The effect of bubble diameter on the performance of DAF tank is simulated. Small air bubbles can form a big range of high volume fraction of air bubbles, which helps to remove the suspended matters.

[Quality Control and Biological Assessment of Automated Synthesized 3'-deoxy-3'-¹8F-fluorothymidine using CFN-MPS-200 Module].

OBJECTIVES: To synthesize 3'-deoxy-3'-¹8F-fluorotyhymidine)(¹8F-FLT) using CFN-MPS-200 automatic synthesis module, and evaluate its distribution in Wistar rats. METHODS: We used 3-N-Boc-5!d-O-dimethoxytrityl-3!d-O-nosyl-thymidine (Boc-FLT)-percursor as raw material to synthesize ¹8F-FLT without residual solvents. Its radiochemical purity was confirmed with radio-HPLC and thin layer chromatography (TLC). Normal Wistar rats were injected with 18 F-FLT and underwent PET scanning. RESULTS: The entire preparation procedure took about 60 min, which resulted in a radio chemical yield of (24±5)% (after attenuation correction, n =20) and radiochemical purity of over 99%, with 1.11×108 Bq/mL specific activity. The ¹8F-FLT solution was colorless and had a pH value between 7.0-8.0. ¹8F-FLT was mainly concentrated in the kidney, bladder, liver, bone marrow and Liver of normal Wistar rats. CONCLUSION: Automated synthesis of ¹8F-FLT using CFN-MPS-200 is a stable method, with high yield, safety without solvent, and acceptable quality.

[Two sample pooling strategies revealed different root-associated fungal diversity of Rhododendron species].

Objective: ooling of multiple samples is widely used in studying general patterns of microbial communities that are heterogeneously structured in space. Pooling strategies and the number of sequence reads generate biases in the description of diversity and community structure of root-associated fungi. Therefore, we developed a molecular toolbox for fast and accurate identification of the root-associated fungal community of Rododendron species. Methods: Multiple root samples of R. lutescens and R. bureavii were collected for DNA extraction. Effects of two different pooling strategies, i.e. pooling samples prior to vs. post PCR, on fungal species composition were studied by comparing results within host species. Results: Species richness and Shannon-Wiener index of fungal communities of clone library constructed by pooling samples after PCR were higher than that of pooling prior to PCR. High frequency fungal species were detected by both pooling strategies, whereas infrequent species detected by the two strategies differed. Notably, the prior to PCR pooling strategy effectively alleviated the unwanted amplification of host plant sequences when fungal specific primer ITS1f and ITS4 were used. Accumulation curves of fungal species suggested that sequencing at least 50 clones can fully reflect species composition of clone library of the two Rhododendron root-associated fungal community. Conclusion: Clone library constructed by post PCR pooling of samples is better in providing accurate views of fungal diversity and community structure of Rhododendron species.

Characterization of an IncA/C Multidrug Resistance Plasmid in Vibrio alginolyticus.

Cephalosporin-resistant Vibrio alginolyticus was first isolated from food products, with ß-lactamases encoded by blaPER-1, blaVEB-1, and blaCMY-2 being the major mechanisms mediating their cephalosporin resistance. The complete sequence of a multidrug resistance plasmid, pVAS3-1, harboring the blaCMY-2 and qnrVC4 genes was decoded in this study. Its backbone exhibited genetic homology to known IncA/C plasmids recoverable from members of the family Enterobacteriaceae, suggesting its possible origin in Enterobacteriaceae.

Community assembly of ectomycorrhizal fungi along a subtropical secondary forest succession.

Environmental selection and dispersal limitation are two of the primary processes structuring biotic communities in ecosystems, but little is known about these processes in shaping soil microbial communities during secondary forest succession. We examined the communities of ectomycorrhizal (EM) fungi in young, intermediate and old forests in a Chinese subtropical ecosystem, using 454 pyrosequencing. The EM fungal community consisted of 393 operational taxonomic units (OTUs), belonging to 21 EM fungal lineages, in which three EM fungal lineages and 11 EM fungal OTUs showed significantly biased occurrence among the young, intermediate and old forests. The EM fungal community was structured by environmental selection and dispersal limitation in old forest, but only by environmental selection in young, intermediate, and whole forests. Furthermore, the EM fungal community was affected by different factors in the different forest successional stages, and the importance of these factors in structuring EM fungal community dramatically decreased along the secondary forest succession series. This study suggests that different assembly mechanisms operate on the EM fungal community at different stages in secondary subtropical forest succession.

Distribution of Hg, As and Se in material and flue gas streams from preheater-precalciner cement kilns and vertical shaft cement kilns in China.

The aim of this study was to evaluate the behavior of Hg, As, and Se in cement production. Two types of cement plants were studied, including the vertical shaft kiln (VSK) and preheater-precalciner kiln (PPK) processes. Determination of Hg, As, and Se in the main material and gas streams were performed. It was found that recycling of particulate matter captured by an air pollution control device caused a significant enrichment of Hg and As inside both processes. The total quantity of Hg entering the process and the quantity emitted to the atmosphere were found to be 10-109 and 6.3-38 mg, respectively, per ton of clinker produced. The average Hg emission was calculated to be around 41% of the total mercury input. The emissions found complied with the European Union (EU) limit and exceeded partly the U.S. limit. Furthermore, it was found that oxidized mercury was the dominant species in the PPK process, whereas the reduced form was dominant in the VSK process, due to the oxidizing and reducing gas conditions, respectively. Regarding the distribution of As and Se, the major amounts were bound to the solid materials, that is, cement clinker and particulate matter. Based on cement production data in China in 2013, the annual emissions of Hg and As were estimated to be in the range of 8.6-52 and 4.1-9.5 tons, respectively.

Host plant richness explains diversity of ectomycorrhizal fungi: Response to the comment of Tedersoo et al. (2014).

Exploring the relationships between the biodiversity of groups of interacting organisms yields insight into ecosystem stability and function (Hooper et al. ; Wardle ). We demonstrated positive relationships between host plant richness and ectomycorrhizal (EM) fungal diversity both in a field study in subtropical China (Gutianshan) and in a meta-analysis of temperate and tropical studies (Gao et al. ). However, based on re-evaluation of our data sets, Tedersoo et al. () argue that the observed positive correlation between EM fungal richness and EM plant richness at Gutianshan and also in our metastudies was based mainly from (i) a sampling design with inconsistent species pool and (ii) poor data compilation for the meta-analysis. Accordingly, we checked our data sets and repeated the analysis performed by Tedersoo et al. (). In contrast to Tedersoo et al. (), our re-analysis still confirms a positive effect of plant richness on EM fungal diversity in Gutianshan, temperate and tropical ecosystems, respectively.

MicroRNA-200c Release from Gelatin-Coated 3D-Printed PCL Scaffolds Enhances Bone Regeneration.

The fabrication of clinically relevant synthetic bone grafts relies on combining multiple biodegradable biomaterials to create a structure that supports the regeneration of defects while delivering osteogenic biomolecules that enhance regeneration. MicroRNA-200c (miR-200c) functions as a potent osteoinductive biomolecule to enhance osteogenic differentiation and bone formation; however, synthetic tissue-engineered bone grafts that sustain the delivery of miR-200c for bone regeneration have not yet been evaluated. In this study, we created novel, multimaterial, synthetic bone grafts from gelatin-coated 3D-printed polycaprolactone (PCL) scaffolds. We attempted to optimize the release of pDNA encoding miR-200c by varying gelatin types, concentrations, and polymer crosslinking materials to improve its functions for bone regeneration. We revealed that by modulating gelatin type, coating material concentration, and polymer crosslinking, we effectively altered the release rates of pDNA encoding miR-200c, which promoted osteogenic differentiation in vitro and bone regeneration in a critical-sized calvarial bone defect animal model. We also demonstrated that crosslinking the gelatin coatings on the PCL scaffolds with low-concentration glutaraldehyde was biocompatible and increased cell attachment. These results strongly indicate the potential use of gelatin-based systems for pDNA encoding microRNA delivery in gene therapy and further demonstrate the effectiveness of miR-200c for enhancing bone regeneration from synthetic bone grafts.

Host plant genus-level diversity is the best predictor of ectomycorrhizal fungal diversity in a Chinese subtropical forest.

Microbial diversity is generally far higher than plant diversity, but the relationship between microbial diversity and plant diversity remains enigmatic. To shed light on this problem, we examined the diversity of a key guild of root-associated microbes,that is, ectomycorrhizal (EM) fungi along a plant diversity gradient in a Chinese subtropical forest. The results indicated that EM fungal diversity was positively correlated with host plant diversity. Furthermore, this relationship was best predicted by host genus-level diversity, rather than species-level diversity or family-level diversity. The generality of this finding was extended beyond our study system through the analyses of 100 additional studies of EM fungal communities from tropical and temperate forests.Here as well, EM fungal lineage composition was significantly affected by EM plant diversity levels, and some EM fungal lineages were co-associated with some host plant genera. These results suggest a general diversity maintenance mechanism for host-specific microbes based on higher order host plant phylogenetic diversity.

Major controlling factors and predictions for cadmium transfer from the soil into spinach plants.

Predicting the mobility, bioavailability and transfer of cadmium (Cd) in the soil-plant system is of great importance with regards to food safety and environmental management. In this study, the transfer characteristics of Cd (exogenous salts) from a wide range of Chinese soils to spinach (Spinacia oleracea L.) were investigated. The major controlling factors and prediction equations for Cd transfer in the soil-plant system were also investigated. The results showed that plant Cd concentration was positively correlated with soil Cd concentration. The maximum transfer factor (ratio of the Cd concentration in the plant to that in the soil) was found in acid soils. The extended Freundlich-type function was able to describe the Cd transfer from soil to spinach plants. Combining soil total Cd, pH and organic carbon (OC) content in the prediction equation greatly improved the correlation performance compared with predictions based on total Cd only. A slight protection effect of OC on Cd uptake was observed at low soil Cd concentrations. The results are a useful tool that can be used to predict Cd transfer from soil to plant.

China action of "Cleanup Plan for Polychlorinated Biphenyls Burial Sites": emissions during excavation and thermal desorption of a capacitor-burial site.

Scarce data are available so far on emissions in a given scenario for excavation and thermal desorption, a common practice, of soils contaminated with polychlorinated biphenyls (PCBs). As part of China action of "Cleanup Plan for PCBs Burial Sites", this study roughly estimated PCBs emissions in the scenario for a capacitor-burial site. The concentrations of total PCBs (22 congeners) in soils were in the range of 2.1-16,000µg/g with a mean of 2300µg/g, among the same order of magnitude as the highest values obtained in various PCBs-contaminated sites. Only six congeners belonging to Di-, Tri-, and Tetra-CBs were observed above limits of detection in air samples in the scenario, partially which can be estimated by the USEPA air emission model. Comparing concentrations and composition profiles of PCBs in the soil and air samples further indicated a leaked source of commercial PCBs formulations of trichlorobiphenyl (China PCB no. 1). The measures taken if any to mitigate the volatilization and movement of PCBs and to minimize worker exposure were discussed for improvements of the excavation practice.