A 44-Year-Old Female With Overwhelming Sepsis

(See pages 1813–4 for the Answer to the Photo Quiz.)

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A 44-Year-Old Female With Overwhelming Sepsis

(See page 1812 for the Photo Quiz.)

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Refinement of the endogenous epitope tagging technology allows the identification of a novel NRAS binding partner in melanoma

Pigment Cell &Melanoma Research, EarlyView.

A Commentary on: “Effects of Regular Physical Activity on the Cognitive Performance of Type 2 Diabetic Patients: A systematic Review” by Podolski et al. (Metab Syndr Relat Disord 2017;15:481–493)

Metabolic Syndrome and Related Disorders, Ahead of Print.

Efficacy of punarnavine in restraining organ-specific tumour progression in 4T1-induced murine breast tumour model

Abstract

Most of the breast cancer deaths occur when cancer cells depart from their tumour of origin and spread systemically and colonise distant organs. The present study was to find out whether punarnavine, the quinolizidine alkaloid, with already proven antimetastatic effect on spontaneous B16F10 pulmonary metastasis has got any effect on a drastic organ-specific breast cancer spread. For the study, we selected a syngenic mouse 4T1 breast tumour model that mimics stage four of human breast cancer. The metastatic progression of 4T1 to lymph nodes, lungs, and liver was reduced by punarnavine (40 mg/kg body weight) administration in BALB/c mice. This was evident from the histopathology of these organs as well as from the reduction in the metastatic cell density of cultured 6-thioguanine-resistant 4T1 cells in the punarnavine-treated group compared to the control group. There was also a significant (p < 0.0001) inhibition of the primary breast tumour growth in the orthotopic site of induction with a simultaneous increase (p < 0.0001) in the life span of treated animals. The assessment of biochemical parameters such as hydroxyproline, hexosamine, uronic acid, sialic acid and γ-glutamyl transferase and the analysis of various cytokines VEGF, IL-1β, TNF-α and GM-CSF showed a similar pattern of reduction in punarnavine (p < 0.0001) treated group compared to the control group. The gene expression study revealed the inhibitory effect of punarnavine on the major genes MMP-2, MMP-9, TIMP-1, TIMP-2 and VEGF involved in the metastatic process. These findings undeniably proved the potential of this quinolizidine alkaloid in combating breast tumour development and its progression in the studied murine model.

Contamination of Scots pine forests with polycyclic aromatic hydrocarbons on the territory of industrial city of Siberia, Russia

Abstract

Anthropogenic contamination with polycyclic aromatic hydrocarbons (PAH) coming from a powerful aluminum smelter has been estimated by the accumulation of these substances (17 substances: phenanthrene, fluoranthene, pyrene, chrysene, acenaphthylene, acenaphthene, anthracene, fluorene, benz[а]anthracene, benz[b]fluoranthene, benz[k]fluoranthene, benz[а]pyrene, benz[е]pyrene, perylene, indeno[1,2,3-c,d]pyrene, benz[g,h,i]perylene, dibenz[a,h]anthracene) in needles of Scots pine (Pinus sylvestris L.) in the residential areas of Bratsk, East Siberia, Russia. It has been found that the total PAH amount reaches the maximum values (982 ng/g) in the needles of trees growing in a residential zone, remote from the smelter up to 10 km (Central Urban District), where more than half of the city's population lives. On the territory remote up to 25 km (Padunsky District), PAH needle levels decline, but are still 14.5–17.5 times higher than the background ones and at a distance of 45 km (Pravoberezhny District), they still exceed background levels (30 ng/g) by 4.7–8.1 times. Qualitative analysis of PAH showed the prevalence (up to 90% of the total amount) of 3–4 ring PAHs in pine needles on the entire studied territory. PAH concentrations increase when approaching the smelter with the highest values in the Central City District. Within the urban area, the content of PAHs with 5–6 rings (benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene (B[a]P), benz[a]anthracene, dibenz[a,h]anthracene, indeno[1,2,3-c,d]pyrene, benzo[g,h,i]perylene) is also significantly increased. In the Central District, needle concentration of B[a]P, which is a class 1 carcinogen, exceeds the background one by 22 times, the Padunsky District—by 7 times, and the Pravoberezhny District—by 3 times. In the territories of the Central Districts, needle level of perylene, which is a marker of territory pollution by aluminum smelter emissions, is 18 times, the Padunsky District—by 10 times, Pravoberezhny District—by 2.5–3 times higher than in the background, where the perylene level is below the detection limit (< 0.2 ng/g).

Facile preparation of nitrogen and sulfur co-doped graphene-based aerogel for simultaneous removal of Cd 2+ and organic dyes

Abstract

The need in simultaneous removal of heavy metals and organic compounds dictates the development of synthetic adsorbents with tailor-made properties. A nitrogen (N) and sulfur (S) co-doped graphene-based aerogel (GBA) modified with 2,5-dithiobisurea was synthesized hydrothermally for simultaneous adsorption of Cd²⁺ and organic dyes—safranin-O (SO), crystal violet (CV), and methylene blue (MB). 2,5-Dithiobisurea was used as nitrogen and sulfur sources to introduce N and S-containing functional group onto graphene oxide. The adsorption mechanism of GBA towards Cd²⁺ and organic dyes was studied by Dumwald-Wagner models and the results showed that surface and intraparticle diffusion was the key factor in controlling the rate of adsorption. The maximum adsorption capacities of GBA towards Cd²⁺, SO, CV, and MB comprised 1.755, 0.949, 0.538, and 0.389 mmol/g in monocomponent system, respectively. Adsorption synergism was observed with respect to Cd²⁺ in presence of the dyes. The performance of GBA with respect to Cd²⁺ removal from binary solutions, Cd²⁺-SO, Cd²⁺-CV, and Cd²⁺-MB, was enhanced by the presence of the dyes significantly, while the adsorption capacities towards the dyes were not affected by the presence of Cd²⁺.

Degradation of ampicillin antibiotic by electrochemical processes: evaluation of antimicrobial activity of treated water

Abstract

Ampicillin (AMP) is an antibiotic widely used in hospitals and veterinary clinics around the world for treating infections caused by bacteria. Therefore, it is common to find traces of this antibiotic in wastewater from these entities. In this work, we studied the mineralization of this antibiotic in solution as well as the elimination of its antimicrobial activity by comparing different electrochemical advanced oxidation processes (EAOPs), namely electro-oxidation with hydrogen peroxide (EO-H₂O₂), electro-Fenton (EF), and photo electro-Fenton (PEF). With PEF process, a high degradation, mineralization, and complete elimination of antimicrobial activity were achieved in 120-min electrolysis with high efficiency. In the PEF process, fast mineralization rate is caused by hydroxyl radicals (·OH) that are generated in the bulk, on the anode surface, by UV radiation, and most importantly, by the direct photolysis of complexes formed between Fe³⁺ and some organic intermediates. Moreover, some products and intermediates formed during the degradation of the antibiotic Ampicillin, such as inorganic ions, carboxylic acids, and aromatic compounds, were determined by photometric and chromatographic methods. An oxidation pathway is proposed for the complete conversion to CO₂.

Identification of a contact-dependent growth inhibition system in the probiotic Escherichia coli Nissle 1917

Abstract

Contact-dependent growth inhibition (CDI) is a type of competitive mechanisms and has been identified in various strains including Burkholderia, Dickeya, E. coli and Yersinia. Classical CDI systems contain three genes, cdiB, cdiA and cdiI. CdiB encoded by cdiB gene is a conserved β-barrel protein and required for export of CdiA. CdiA protein encoded by cdiA gene includes a conserved N-terminal domain and variable C-terminal toxic domain (CdiA-CT). Immunity protein CdiI binds and inactivates toxin protein CdiA-CT. Here, we identified two CDI systems, an intact cdiBAI operon with a truncated CdiB due to an unexpected mutation and an 'orphan' cdiA-CT/cdiI module in the probiotic Escherichia coli Nissle 1917 (EcN) genome. Both CdiA-CTs from EcN showed auto-inhibition activity when transferring into E. coli DH5α, as well the sequential deletion of amino acid residues resulted in the generation of the most potent mutant of CdiA-CT. CdiI neutralized the toxicity activity of CdiA and was immunity protein as previous report. In conclusion, this is the first report that the functional CDI system is in probiotic EcN and might provide a potential competitive mechanism for probiotic EcN in intestinal microenvironment.

Effluent composition prediction of a two-stage anaerobic digestion process: machine learning and stoichiometry techniques

Abstract

Computational self-adapting methods (Support Vector Machines, SVM) are compared with an analytical method in effluent composition prediction of a two-stage anaerobic digestion (AD) process. Experimental data for the AD of poultry manure were used. The analytical method considers the protein as the only source of ammonia production in AD after degradation. Total ammonia nitrogen (TAN), total solids (TS), chemical oxygen demand (COD), and total volatile solids (TVS) were measured in the influent and effluent of the process. The TAN concentration in the effluent was predicted, this being the most inhibiting and polluting compound in AD. Despite the limited data available, the SVM-based model outperformed the analytical method for the TAN prediction, achieving a relative average error of 15.2% against 43% for the analytical method. Moreover, SVM showed higher prediction accuracy in comparison with Artificial Neural Networks. This result reveals the future promise of SVM for prediction in non-linear and dynamic AD processes.

Graphical abstract

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Biomonitoring levels of airborne metals around Urmia Lake using deciduous trees and evaluation of their tolerance for greenbelt development

Abstract

In the northwest of Iran, the dust of salty and toxic metals possibly caused due to drying Urmia Lake is threatening the health of surrounding communities. This study aimed to employ leaves of local deciduous trees for biomonitoring of toxic elements and to evaluate air pollution tolerance of the trees for greenbelt application. Sampling from leaves of four dominant tree species including Vitis vinifera, Juglans regia, Ulmus umbraculifera, and Popolus alba was carried out from gardens in two radial distances (5 and 10 km) around the Urmia Lake accounting for 16 sites. The concentration of metals in the leaves were extracted according to method USEPA method 3050B and measured by ICP AES technique. According to the levels of air pollution tolerance index (APTI), Popolus alba showed to be more sensitive to air pollution and can be applied for biomonitoring. The ranks of heavy metals and sodium concentrations in the leaves gained in the order of Na > Zn > Cu > Ni > Pb > As > Cd. The mean enrichment factor for the elements was calculated from 1 to 3, suggesting minor enrichment for them. As, Pb, and Na with similar spatial distribution were dominantly observed in northwest and center-east of the Urmia Lake. Potential ecological risk (PER) index showed a moderate risk in 6% of sampling zones, where Cd and As were identified as responsible pollutants. Principle component and correlation analysis between the elements depicted human sources such as industrial activity and road traffic for Cd, Cu, Ni, Pb, and Zn, whereas As and Na were most likely originated from the aerosols of Urmia Lake. Our findings showed that Popolus alba can be applied as a local biomonitor and Vitis vinifera with moderate tolerance can be used as a good air pollutant sink in greenbelt development around the drying Urmia Lake in the northwest of Iran.

Remediation of lead-contaminated water by geological fluorapatite and fungus Penicillium oxalicum

Abstract

Phosphate-solubilizing fungi (PSF) can secrete large amounts of organic acids. In this study, the application of the fungus Penicillium oxalicum and geological fluorapatite (FAp) to lead immobilization was investigated. The formation and morphology of the lead-related minerals were analyzed by ATR-IR, XRD, Raman, and SEM. The quantity of organic acids secreted by P. oxalicum reached the maximum on the fourth day, which elevated soluble P concentrations from 0.4 to 108 mg/L in water. The secreted oxalic acid dominates the acidity in solution. P. oxalicum can survive in the solution with Pb concentration of ~ 1700 mg/L. In addition, it was shown that ~ 98% lead cations were removed while the fungus was cultured with Pb (~ 1700 mg/L) and FAp. The mechanism is that the released P from FAp (enhanced by organic acids) can react with Pb²⁺ to form the stable pyromorphite mineral [Pb₅(PO₄)₃F]. The precipitation of lead oxalate also contributes to Pb immobilization. However, lead oxalate is more soluble due to its relatively high solubility. P. oxalicum has a higher rate of organic acid secretion compared with other typical PSF, e.g., Aspergillus niger. This study sheds light on bright future of applying P. oxalicum in Pb remediation.

Evaluating a 5-year metal contamination remediation and the biomonitoring potential of a freshwater gastropod along the Xiangjiang River, China

Abstract

Effective remediation of heavy metal pollution in aquatic systems is desired in many regions, but it requires integrative assessments of sediments, water, and biota that can serve as robust biomonitors. We assessed the effects of a 5-year metal contamination remediation along the Xiangjiang River, China, by comparing concentrations of trace metals in water and surface sediments between 2010–2011 and 2016. We also explored the trace metal biomonitoring potential of a freshwater gastropod (Bellamya aeruginosa). Metal concentrations in water (means and ranges) dropped over time to within permissible limits of drinking water guidelines set by China, USEPA, and WHO in 2016. Although sediment means and ranges of Cd, Pb, Zn, and Mn also diminished with remediation, those for Cr and Cu slightly increased, and all six metals retained concentrations higher than standards set by China. All metals in sediments could also be associated with anthropogenic inputs using a hierarchical clustering analysis, and they generate high potential ecological risks based on several indices, especially for Cd and As. The bio-sediment accumulation factors of all measured trace metals in gastropod soft tissues and shells were lower than 1.0, except for Ca. Trace metal contents in gastropods were positively correlated with those in water and surface sediments for As (soft tissues) and Cr (shells). Collectively, our results do not yet highlight strong beneficial effects of 5-year remediation and clearly illustrate the heavy metal pollution remaining in Xiangjiang River sediment. Additional physical, chemical, and biological measurements should be implemented to improve sediment quality. We further conclude that gastropod soft tissues and shells can be suitable biomonitors of spatial differences in some heavy metals found within river sediments (e.g., As, Cr).

Total and methyl-mercury seasonal particulate fluxes in the water column of a large lake (Lake Geneva, Switzerland)

Abstract

Concentrations and fluxes of total and methylmercury were determined in surface sediments and associated with settling particles at two sites in Lake Geneva to evaluate the sources and dynamics of this toxic contaminant. Total mercury concentrations measured in settling particles were different throughout the seasons and were greatly influenced by the Rhone River particulate inputs. Total mercury concentrations closer to shore (NG2) ranged between 0.073 ± 0.001 and 0.27 ± 0.01 μg/g, and between 0.038 ± 0.001 and 0.214 ± 0.008 μg/g at a site deeper in the lake (NG3). Total mercury fluxes ranged between 0.144 ± 0.002 and 3.0 ± 0.1 μg/m²/day at NG2, and between 0.102 ± 0.008 and 1.32 ± 0.08 μg/m²/day at NG3. Combined results of concentrations and fluxes showed that total mercury concentrations in settling particles are related to the season and particle inputs from the Rhone River. Despite an observed decrease in total mercury fluxes from the coastal zone towards the open lake, NG3 (~ 3 km from the shoreline) was still affected by the coastal boundary, as compared to distal sites at the center of the lake. Thus, sediment focusing is not efficient enough to redistribute contaminant inputs originating from the coastal zones, to the lake center. Methylmercury concentrations in settling particles largely exceeded the concentrations found in sediments, and their fluxes did not show significant differences with relation to the distance from shore. The methylmercury found associated with settling particles would be related to the lake's internal production rather than the effect of transport from sediment resuspension.

Source identification and spatial distribution of metals in soils in a typical area of the lower Yellow River, eastern China

Abstract

In this study, 234 soil samples were recently collected from Gaoqing County (a typical area of the lower Yellow River) to determine the contents of As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn. Multivariate statistical analyses such as correlation analysis, principal components analysis, and one-way ANOVA were applied to identify the source of metals in the soil. Geostatistical methods were used to analyze the spatial structure and distribution of the metals. The results indicated that the mean contents of all metals exceeded the background value of the lower Yellow River, especially for As, Cu, and Hg (1.23, 1.20, and 1.29 times that of the BV, respectively), indicating that these metals were enriched in the study area to different degrees. The results derived from multivariate analysis suggested that As, Cd, Cr, Cu, Ni, Pb, and Zn were mainly controlled by the combination of human activities and soil parent material, and the human activities included industrial emissions, traffic emissions, and agricultural practices. In addition, Hg mainly originated from anthropogenic inputs, such as textile printing, plastics processing, and petrochemical engineering. The contents of metals in different types of land use and parent materials are clearly different. The mean content for eight elements in urban construction land was significantly higher than that of the other land use types; in addition to Hg, the mean content of the other elements was the highest in the lacustrine deposit. The elements of As, Cd, Cr, Cu, Ni, Pb, and Zn had similar hotspots in the urban area, indicating the significant human influence. In addition, these seven metals showed high values in the southeast lacustrine deposit area. The high-value areas of Hg were concentrated in the southwest and northeast study area, which were consistent with the spatial pattern of the industrial sites.

Insight into elemental mercury (Hg 0 ) removal from flue gas using UV/H 2 O 2 advanced oxidation processes

Abstract

Elemental mercury (Hg⁰) emitted from coal-fired power plants and municipal solid waste (MSW) incinerators has caused great harm to the environment and human beings. The strong oxidized ^•OH radicals produced by UV/H₂O₂ advanced oxidation processes were studied to investigate the performance of Hg⁰ removal from simulated flue gases. The results showed that when H₂O₂ concentration was 1.0 mol/L and the solution pH value was 4.1, the UV/H₂O₂ system had the highest Hg⁰ removal efficiency. The optimal reaction temperature was approximately 50 °C and Hg⁰ removal was inhibited when the temperature was higher or lower. The yield of ^•OH radicals during UV/H₂O₂ reaction was studied by electron paramagnetic resonance (EPR) analysis. UV radiation was the determining factor to remove Hg⁰ in UV/H₂O₂ system due to ^•OH generation during H₂O₂ decomposition. SO₂ had little influence on Hg⁰ removal whereas NO had an inhibitory effect on Hg⁰ removal. The detailed findings for Hg⁰ removal reactions over UV/H₂O₂ make it an attractive method for mercury control from flue gases.

Altered Excitability and Local Connectivity of mPFC-PAG Neurons in a Mouse Model of Neuropathic Pain

The medial prefrontal cortex (mPFC) plays a major role in both sensory and affective aspects of pain. There is extensive evidence that chronic pain produces functional changes within the mPFC. However, our understanding of local circuit changes to defined subpopulations of mPFC neurons in chronic pain models remains unclear. A major subpopulation of mPFC neurons project to the periaqueductal gray (PAG), which is a key midbrain structure involved in endogenous pain suppression and facilitation. Here, we used laser scanning photostimulation of caged glutamate to map cortical circuits of retrogradely labeled cortico-PAG (CP) neurons in layer 5 (L5) of mPFC in brain slices prepared from male mice having undergone chronic constriction injury (CCI) of the sciatic nerve. Whole-cell recordings revealed a significant reduction in excitability for L5 CP neurons contralateral to CCI in the prelimbic (PL), but not infralimbic (IL), region of mPFC. Circuit mapping showed that excitatory inputs to L5 CP neurons in both PL and IL arose primarily from layer 2/3 (L2/3) and were significantly reduced in CCI mice. Glutamate stimulation of L2/3 and L5 elicited inhibitory inputs to CP neurons in both PL and IL, but only L2/3 input was significantly reduced in CP neurons of CCI mice. We also observed significant reduction in excitability and L2/3 inhibitory input to CP neurons ipsilateral to CCI. These results demonstrating region and laminar specific changes to mPFC-PAG neurons suggest that a unilateral CCI bilaterally alters cortical circuits upstream of the endogenous analgesic network, which may contribute to persistence of chronic pain.

SIGNIFICANCE STATEMENT Chronic pain is a significant unresolved medical problem that is refractory to traditional analgesics and can negatively affect emotional health. The role of central circuits in mediating the persistent nature of chronic pain remains unclear. Local circuits within the medial prefrontal cortex (mPFC) process ascending pain inputs and can modulate endogenous analgesia via direct projections to the periaqueductal gray (PAG). However, the mechanisms by which chronic pain alters intracortical circuitry of mPFC-PAG neurons are unknown. Here, we report specific changes to local circuits of mPFC-PAG neurons in mice displaying chronic pain behavior after nerve injury. These findings provide evidence for a neural mechanism by which chronic pain disrupts the descending analgesic system via functional changes to cortical circuits.

Neural Representations of Sensorimotor Memory- and Digit Position-Based Load Force Adjustments Before the Onset of Dexterous Object Manipulation

Anticipatory load forces for dexterous object manipulation in humans are modulated based on visual object property cues, sensorimotor memories of previous experiences with the object, and, when digit positioning varies from trial to trial, the integrating of this sensed variability with force modulation. Studies of the neural representations encoding these anticipatory mechanisms have not considered these mechanisms separately from each other or from feedback mechanisms emerging after lift onset. Here, representational similarity analyses of fMRI data were used to identify neural representations of sensorimotor memories and the sensing and integration of digit position. Cortical activity and movement kinematics were measured as 20 human subjects (11 women) minimized tilt of a symmetrically shaped object with a concealed asymmetric center of mass (CoM, left and right sided). This task required generating compensatory torques in opposite directions, which, without helpful visual CoM cues, relied primarily on sensorimotor memories of the same object and CoM. Digit position was constrained or unconstrained, the latter of which required modulating forces beyond what can be recalled from sensorimotor memories to compensate for digit position variability. Ventral premotor (PMv), somatosensory, and cerebellar lobule regions (CrusII, VIIIa) were sensitive to anticipatory behaviors that reflect sensorimotor memory content, as shown by larger voxel pattern differences for unmatched than matched CoM conditions. Cerebellar lobule I–IV, Broca area 44, and PMv showed greater voxel pattern differences for unconstrained than constrained grasping, which suggests their sensitivity to monitor the online coincidence of planned and actual digit positions and correct for a mismatch by force modulation.

SIGNIFICANCE STATEMENT To pick up a water glass without slipping, tipping, or spilling requires anticipatory planning of fingertip load forces before the lift commences. This anticipation relies on object visual properties (e.g., mass/mass distribution), sensorimotor memories built from previous experiences (especially when object properties cannot be inferred visually), and online sensing of where the digits are positioned. There is limited understanding of how the brain represents each of these anticipatory mechanisms. We used fMRI measures of regional brain patterns and digit position kinematics before lift onset of an object with nonsalient visual cues specifically to isolate sensorimotor memories and integration of sensed digit position with force modulation. In doing so, we localized neural representations encoding these anticipatory mechanisms for dexterous object manipulation.

The Role of the Microglial Cx3cr1 Pathway in the Postnatal Maturation of Retinal Photoreceptors

Microglia are the resident immune cells of the CNS, and their response to infection, injury and disease is well documented. More recently, microglia have been shown to play a role in normal CNS development, with the fractalkine-Cx3cr1 signaling pathway of particular importance. This work describes the interaction between the light-sensitive photoreceptors and microglia during eye opening, a time of postnatal photoreceptor maturation. Genetic removal of Cx3cr1 (Cx3cr1^GFP/GFP) led to an early retinal dysfunction soon after eye opening [postnatal day 17 (P17)] and cone photoreceptor loss (P30 onward) in mice of either sex. This dysfunction occurred at a time when fractalkine expression was predominantly outer retinal, when there was an increased microglial presence near the photoreceptor layer and increased microglial–cone photoreceptor contacts. Photoreceptor maturation and outer segment elongation was coincident with increased opsin photopigment expression in wild-type retina, while this was aberrant in the Cx3cr1^GFP/GFP retina and outer segment length was reduced. A beadchip array highlighted Cx3cr1 regulation of genes involved in the photoreceptor cilium, a key structure that is important for outer segment elongation. This was confirmed with quantitative PCR with specific cilium-related genes, Rpgr and Rpgrip1, downregulated at eye opening (P14). While the overall cilium structure was unaffected, expression of Rpgr, Rpgrip1, and centrin were restricted to more proximal regions of the transitional zone. This study highlighted a novel role for microglia in postnatal neuronal development within the retina, with loss of fractalkine–Cx3cr1 signaling leading to an altered distribution of cilium proteins, failure of outer segment elongation and ultimately cone photoreceptor loss.

SIGNIFICANCE STATEMENT Microglia are involved in CNS development and disease. This work highlights the role of microglia in postnatal development of the light-detecting photoreceptor neurons within the mouse retina. Loss of the microglial Cx3cr1 signaling pathway resulted in specific alterations in the cilium, a key structure in photoreceptor outer segment elongation. The distribution of key components of the cilium transitional zone, Rpgr, Rpgrip1, and centrin, were altered in retinae lacking Cx3cr1 with reduced outer segment length and cone photoreceptor death observed at later postnatal ages. This work identifies a novel role for microglia in the postnatal maturation of retinal photoreceptors.

Correction: Suarez et al., "Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease"

mTORC1 Is Transiently Reactivated in Injured Nerves to Promote c-Jun Elevation and Schwann Cell Dedifferentiation

Schwann cells (SCs) are endowed with a remarkable plasticity. When peripheral nerves are injured, SCs dedifferentiate and acquire new functions to coordinate nerve repair as so-called repair SCs. Subsequently, SCs redifferentiate to remyelinate regenerated axons. Given the similarities between SC dedifferentiation/redifferentiation in injured nerves and in demyelinating neuropathies, elucidating the signals involved in SC plasticity after nerve injury has potentially wider implications. c-Jun has emerged as a key transcription factor regulating SC dedifferentiation and the acquisition of repair SC features. However, the upstream pathways that control c-Jun activity after nerve injury are largely unknown. We report that the mTORC1 pathway is transiently but robustly reactivated in dedifferentiating SCs. By inducible genetic deletion of the functionally crucial mTORC1-subunit Raptor in mouse SCs (including male and female animals), we found that mTORC1 reactivation is necessary for proper myelin clearance, SC dedifferentiation, and consequently remyelination, without major alterations in the inflammatory response. In the absence of mTORC1 signaling, c-Jun failed to be upregulated correctly. Accordingly, a c-Jun binding motif was found to be enriched in promoters of genes with reduced expression in injured mutants. Furthermore, using cultured SCs, we found that mTORC1 is involved in c-Jun regulation by promoting its translation, possibly via the eIF4F-subunit eIF4A. These results provide evidence that proper c-Jun elevation after nerve injury involves also mTORC1-dependent post-transcriptional regulation to ensure timely dedifferentiation of SCs.

SIGNIFICANCE STATEMENT A crucial evolutionary acquisition of vertebrates is the envelopment of axons in myelin sheaths produced by oligodendrocytes in the CNS and Schwann cells (SCs) in the PNS. When myelin is damaged, conduction of action potentials along axons slows down or is blocked, leading to debilitating diseases. Unlike oligodendrocytes, SCs have a high regenerative potential, granted by their remarkable plasticity. Thus, understanding the mechanisms underlying SC plasticity may uncover new therapeutic targets in nerve regeneration and demyelinating diseases. Our work reveals that reactivation of the mTORC1 pathway in SCs is essential for efficient SC dedifferentiation after nerve injury. Accordingly, modulating this signaling pathway might be of therapeutic relevance in peripheral nerve injury and other diseases.

Canonical TGF-{beta} Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression

Functional neuronal connectivity requires proper neuronal morphogenesis and its dysregulation causes neurodevelopmental diseases. Transforming growth factor-β (TGF-β) family cytokines play pivotal roles in development, but little is known about their contribution to morphological development of neurons. Here we show that the Smad-dependent canonical signaling of TGF-β family cytokines negatively regulates neuronal morphogenesis during brain development. Mechanistically, activated Smads form a complex with transcriptional repressor TG-interacting factor (TGIF), and downregulate the expression of a neuronal polarity regulator, collapsin response mediator protein 2. We also demonstrate that TGF-β family signaling inhibits neurite elongation of human induced pluripotent stem cell-derived neurons. Furthermore, the expression of TGF-β receptor 1, Smad4, or TGIF, which have mutations found in patients with neurodevelopmental disorders, disrupted neuronal morphogenesis in both mouse (male and female) and human (female) neurons. Together, these findings suggest that the regulation of neuronal morphogenesis by an evolutionarily conserved function of TGF-β signaling is involved in the pathogenesis of neurodevelopmental diseases.

SIGNIFICANCE STATEMENT Canonical transforming growth factor-β (TGF-β) signaling plays a crucial role in multiple organ development, including brain, and mutations in components of the signaling pathway associated with several human developmental disorders. In this study, we found that Smads/TG-interacting factor-dependent canonical TGF-β signaling regulates neuronal morphogenesis through the suppression of collapsin response mediator protein-2 (CRMP2) expression during brain development, and that function of this signaling is evolutionarily conserved in the mammalian brain. Mutations in canonical TGF-β signaling factors identified in patients with neurodevelopmental disorders disrupt the morphological development of neurons. Thus, our results suggest that proper control of TGF-β/Smads/CRMP2 signaling pathways is critical for the precise execution of neuronal morphogenesis, whose impairment eventually results in neurodevelopmental disorders.

NMDA Receptor Signaling Is Important for Neural Tube Formation and for Preventing Antiepileptic Drug-Induced Neural Tube Defects

Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that during Xenopus laevis neural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that NMDA receptors are important for the formation of the neural tube and that the loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation.

SIGNIFICANCE STATEMENT Neural tube defects are one of the most common birth defects. Clinical investigations have determined that the use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that they are side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy.

Genetic Ablation of All Cerebellins Reveals Synapse Organizer Functions in Multiple Regions Throughout the Brain

Cerebellins are synaptic organizer molecules that bind to presynaptic neurexins and postsynaptic receptors. They are well studied in the cerebellum, but three of the four cerebellins (Cbln1, Cbln2, and Cbln4) are also broadly expressed outside of the cerebellum, suggesting that they perform general functions throughout the brain. Here, we generated male and female constitutive single (KO), double KO (dKO), and triple KO (tKO) mice of Cbln1, Cbln2, and Cbln4. We found that all constitutive cerebellin-deficient mice were viable and fertile, suggesting that cerebellins are not essential for survival. Cbln1/2 dKO mice exhibited salience-induced seizures that were aggravated in Cbln1/2/4 tKO mice, suggesting that all cerebellins contribute to brain function. As described previously, Cbln1 KO mice displayed major motor impairments that were aggravated by additional KO of Cbln2. Strikingly, the Cbln1/2 dKO did not cause alterations in synapse density in the hippocampus of young adult (1- and 2-month-old) mice, but produced a selective ~50% decrease in hippocampal synapse density in the stratum lacunosum moleculare of the CA1 region and in the dentate gyrus of aging, 6-month-old mice. A similar decrease in excitatory synapse density was observed in the striatum and retrosplenial cortex. Behaviorally, the Cbln1 KO produced dramatic changes in motor behaviors that were partly aggravated by additional deletion of Cbln2 and/or Cbln4. Our results show that cerebellins are not essential for survival and do not contribute to initial synapse formation, but perform multiple functions throughout the brain; as a consequence, their ablation results in a delayed loss of synapses and in behavioral impairments.

SIGNIFICANCE STATEMENT Cerebellins (Cbln1-4) are trans-synaptic cell adhesion molecules. In the cerebellum, Cbln1 functions as a bidirectional organizer of parallel fiber–Purkinje cell synapses by binding to presynaptic neurexins and postsynaptic GluR2. Little is known about the function of cerebellins outside of the cerebellum; therefore, the present study used single, double, and triple constitutive KO mice of Cbln1, Cbln2, and Cbln4 to analyze the overall function of cerebellins. We show that cerebellins act as important synaptic organizers in specific subsets of neurons and likely contribute to many different brain functions. We also show that cerebellins are not initially required for synapse formation, but rather for specification and long-term synapse maintenance and demonstrate that all cerebellins, not just Cbln1, contribute to brain function.

Cortical Mechanisms of Prioritizing Selection for Rejection in Visual Search

In visual search, the more one knows about a target, the faster one can find it. Surprisingly, target identification is also faster with knowledge about distractor-features. The latter is paradoxical, as it implies that to avoid the selection of an item, the item must somehow be selected to some degree. This conundrum has been termed the "ignoring paradox", and, to date, little is known about how the brain resolves it. Here, in data from four experiments using neuromagnetic brain recordings in male and female humans, we provide evidence that this paradox is resolved by giving distracting information priority in cortical processing. This attentional priority to distractors manifests as an enhanced early neuromagnetic index, which occurs before target-related processing, and regardless of distractor predictability. It is most pronounced on trials for which a response rapidly occurred, and is followed by a suppression of the distracting information. These observations together suggest that in visual search items cannot be ignored without first being selected.

SIGNIFICANCE STATEMENT How can we ignore distracting stimuli in our environment? To do this successfully, a logical hypothesis is that as few neural resources as possible should be devoted to distractor processing. Yet, to avoid devoting resources to a distractor, the brain must somehow mark what to avoid; this is a philosophical problem, which has been termed the "ignoring paradox" or "white bear phenomenon". Here, we use MEG recordings to determine how the human brain resolves this paradox. Our data show that distractors are not only processed, they are given temporal priority, with the brain building a robust representation of the to-be-ignored items. Thus, successful suppression of distractors can only be achieved if distractors are first strongly neurally represented.

Rapid Disinhibition by Adjustment of PV Intrinsic Excitability during Whisker Map Plasticity in Mouse S1

Rapid plasticity of layer (L) 2/3 inhibitory circuits is an early step in sensory cortical map plasticity, but its cellular basis is unclear. We show that, in mice of either sex, 1 d whisker deprivation drives the rapid loss of L4-evoked feedforward inhibition and more modest loss of feedforward excitation in L2/3 pyramidal (PYR) cells, increasing the excitation-inhibition conductance ratio. Rapid disinhibition was due to reduced L4-evoked spiking by L2/3 parvalbumin (PV) interneurons, caused by reduced PV intrinsic excitability. This included elevated PV spike threshold, which is associated with an increase in low-threshold, voltage-activated delayed rectifier (presumed Kv1) and A-type potassium currents. Excitatory synaptic input and unitary inhibitory output of PV cells were unaffected. Functionally, the loss of feedforward inhibition and excitation was precisely coordinated in L2/3 PYR cells, so that peak feedforward synaptic depolarization remained stable. Thus, the rapid plasticity of PV intrinsic excitability offsets early weakening of excitatory circuits to homeostatically stabilize synaptic potentials in PYR cells of sensory cortex.

SIGNIFICANCE STATEMENT Inhibitory circuits in cerebral cortex are highly plastic, but the cellular mechanisms and functional importance of this plasticity are incompletely understood. We show that brief (1 d) sensory deprivation rapidly weakens parvalbumin (PV) inhibitory circuits by reducing the intrinsic excitability of PV neurons. This involved a rapid increase in voltage-gated potassium conductances that control near-threshold spiking excitability. Functionally, the loss of PV-mediated feedforward inhibition in L2/3 pyramidal cells was precisely balanced with the separate loss of feedforward excitation, resulting in a net homeostatic stabilization of synaptic potentials. Thus, rapid plasticity of PV intrinsic excitability implements network-level homeostasis to stabilize synaptic potentials in sensory cortex.

Distribution of Spinal Neuronal Networks Controlling Forward and Backward Locomotion

Higher vertebrates, including humans, are capable not only of forward (FW) locomotion but also of walking in other directions relative to the body axis [backward (BW), sideways, etc.]. Although the neural mechanisms responsible for controlling FW locomotion have been studied in considerable detail, the mechanisms controlling steps in other directions are mostly unknown. The aim of the present study was to investigate the distribution of spinal neuronal networks controlling FW and BW locomotion. First, we applied electrical epidural stimulation (ES) to different segments of the spinal cord from L2 to S2 to reveal zones triggering FW and BW locomotion in decerebrate cats of either sex. Second, to determine the location of spinal neurons activated during FW and BW locomotion, we used c-Fos immunostaining. We found that the neuronal networks responsible for FW locomotion were distributed broadly in the lumbosacral spinal cord and could be activated by ES of any segment from L3 to S2. By contrast, networks generating BW locomotion were activated by ES of a limited zone from the caudal part of L5 to the caudal part of L7. In the intermediate part of the gray matter within this zone, a significantly higher number of c-Fos-positive interneurons was revealed in BW-stepping cats compared with FW-stepping cats. We suggest that this region of the spinal cord contains the network that determines the BW direction of locomotion.

SIGNIFICANCE STATEMENT Sequential and single steps in various directions relative to the body axis [forward (FW), backward (BW), sideways, etc.] are used during locomotion and to correct for perturbations, respectively. The mechanisms controlling step direction are unknown. In the present study, for the first time we compared the distributions of spinal neuronal networks controlling FW and BW locomotion. Using a marker to visualize active neurons, we demonstrated that in the intermediate part of the gray matter within L6 and L7 spinal segments, significantly more neurons were activated during BW locomotion than during FW locomotion. We suggest that the network determining the BW direction of stepping is located in this area.

Striatal Direct and Indirect Pathway Output Structures Are Differentially Altered in Mouse Models of Huntington's Disease

The present study examined synaptic communication between direct and indirect output pathway striatal medium-sized spiny neurons (MSNs) and their target structures, the substantia nigra pars reticulata (SNr) and the external globus pallidus (GPe) in two mouse models of Huntington's disease (HD). Cre recombination, optogenetics, and whole-cell patch-clamp recordings were used to determine alterations in intrinsic and synaptic properties of SNr and GPe neurons from both male and female symptomatic R6/2 (>60 d) and presymptomatic (2 months) or symptomatic (10–12 months) YAC128 mice. Cell membrane capacitance was decreased, whereas input resistance was increased in SNr neurons from R6/2, but not YAC128 mice. The amplitude of GABAergic responses evoked by optogenetic stimulation of direct pathway terminals was reduced in SNr neurons of symptomatic mice of both models. A decrease in spontaneous GABA synaptic activity, in particular large-amplitude events, in SNr neurons also was observed. Passive membrane properties of GPe neurons were not different between R6/2 or YAC128 mice and their control littermates. Similarly, the amplitude of GABA responses evoked by activation of indirect pathway MSN terminals and the frequency of spontaneous GABA synaptic activity were similar in HD and control animals. In contrast, the decay time of the evoked GABA response was significantly longer in cells from HD mice. Interestingly, activation of indirect pathway MSNs within the striatum evoked larger-amplitude responses in direct pathway MSNs. Together, these results demonstrate differential alterations in responses evoked by direct and indirect pathway terminals in SNr and GPe leading to striatal output imbalance and motor dysfunction.

SIGNIFICANCE STATEMENT Previous work on Huntington's disease (HD) focused on striatal medium-sized spiny neurons (MSNs) almost exclusively. Little is known about the effects that alterations in the striatum have on output structures of the direct and indirect pathways, the substantia nigra pars reticulata (SNr) and the external segment of the globus pallidus (GPe), respectively. We combined electrophysiological and optogenetic methods to examine responses evoked by selective activation of terminals of direct and indirect pathway MSNs in SNr and GPe neurons in two mouse models of HD. We show a differential disruption of synaptic communication between the direct and indirect output pathways of the striatum with their target regions leading to an imbalance of striatal output, which will contribute to motor dysfunction.

MCU Interacts with Miro1 to Modulate Mitochondrial Functions in Neurons

Mitochondrial Ca²⁺ uptake is gated by the mitochondrial calcium uniplex, which is comprised of mitochondrial calcium uniporter (MCU), the Ca²⁺ pore-forming subunit of the complex, and its regulators. Ca²⁺ influx through MCU affects both mitochondrial function and movement in neurons, but its direct role in mitochondrial movement has not been explored. In this report, we show a link between MCU and Miro1, a membrane protein known to regulate mitochondrial movement. We find that MCU interacts with Miro1 through MCU's N-terminal domain, previously thought to be the mitochondrial targeting sequence. Our results show that the N-terminus of MCU has a transmembrane domain that traverses the outer mitochondrial membrane, which is dispensable for MCU localization into mitochondria. However, this domain is required for Miro1 interaction and is critical for Miro1 directed movement. Together, our findings reveal Miro1 as a new component of the MCU complex, and that MCU is an important regulator of mitochondrial transport.

SIGNIFICANCE STATEMENT Mitochondrial calcium level is critical for mitochondrial metabolic activity and mitochondrial transport in neurons. While it has been established that calcium influx into mitochondria is modulated by mitochondrial calcium uniporter (MCU) complex, how MCU regulates mitochondrial movement still remains unclear. Here, we discover that the N-terminus of MCU plays a different role than previously thought; it is not required for mitochondrial targeting but is essential for interaction with Miro1, an outer mitochondrial membrane protein important for mitochondrial movement. Furthermore, we show that MCU–Miro1 interaction is required to maintain mitochondrial transport. Our data identify that Miro1 is a novel component of the mitochondrial calcium uniplex and demonstrate that coupling between MCU and Miro1 as a novel mechanism modulating both mitochondrial Ca²⁺ uptake and mitochondrial transport.

Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers

The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in Dcc-haploinsufficient mice. The human volunteers were 20 DCC^+/– mutation carriers, 16 DCC^+/+ relatives, and 20 DCC^+/+ unrelated healthy volunteers (UHVs; 28 females). The mice were 11 Dcc^+/– and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human DCC^+/– carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [DCC^+/+: p = 0.0005, r(effect size) = 0.60; UHV: p = 0.0029, r = 0.48] and ventral medial prefrontal cortex (DCC^+/+: p = 0.0031, r = 0.53; UHV: p = 0.034, r = 0.35); (2) lower novelty-seeking scores (DCC^+/+: p = 0.034, d = 0.82; UHV: p = 0.019, d = 0.84); and (3) reduced striatal volume (DCC^+/+: p = 0.0009, d = 1.37; UHV: p = 0.0054, d = 0.93). Striatal volumetric reductions were also present in Dcc^+/– mice, and these were seen during adolescence (p = 0.0058, d = 1.09) and adulthood (p = 0.003, d = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders.

SIGNIFICANCE STATEMENT Opportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene, DCC, enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in DCC-haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders.

FLP-18 Functions through the G-Protein-Coupled Receptors NPR-1 and NPR-4 to Modulate Reversal Length in Caenorhabditis elegans

Animal behavior is critically dependent on the activity of neuropeptides. Reversals, one of the most conspicuous behaviors in Caenorhabditis elegans, plays an important role in determining the navigation strategy of the animal. Our experiments on hermaphrodite C. elegans show the involvement of a neuropeptide FLP-18 in modulating reversal length in these hermaphrodites. We show that FLP-18 controls the reversal length by regulating the activity of AVA interneurons through the G-protein-coupled neuropeptide receptors, NPR-4 and NPR-1. We go on to show that the site of action of these receptors is the AVA interneuron for NPR-4 and the ASE sensory neurons for NPR-1. We further show that mutants in the neuropeptide, flp-18, and its receptors show increased reversal lengths. Consistent with the behavioral data, calcium levels in the AVA neuron of freely reversing C. elegans were significantly higher and persisted for longer durations in flp-18, npr-1, npr-4, and npr-1 npr-4 genetic backgrounds compared with wild-type control animals. Finally, we show that increasing FLP-18 levels through genetic and physiological manipulations causes shorter reversal lengths. Together, our analysis suggests that the FLP-18/NPR-1/NPR-4 signaling is a pivotal point in the regulation of reversal length under varied genetic and environmental conditions.

SIGNIFICANCE STATEMENT In this study, we elucidate the circuit and molecular machinery required for normal reversal behavior in hermaphrodite Caenorhabditis elegans. We delineate the circuit and the neuropeptide receptors required for maintaining reversal length in C. elegans. Our work sheds light on the importance of a single neuropeptide, FLP-18, and how change in levels in this one peptide could allow the animal to change the length of its reversal, thereby modulating how the C. elegans explores its environment. We also go on to show that FLP-18 functions to maintain reversal length through the neuropeptide receptors NPR-4 and NPR-1. Our study will allow for a better understanding of the complete repertoire of behaviors shown by freely moving animals as they explore their environment.

Learning-Dependent and -Independent Enhancement of Mitral/Tufted Cell Glomerular Odor Responses Following Olfactory Fear Conditioning in Awake Mice

Associative fear learning produces fear toward the conditioned stimulus (CS) and often generalization, the expansion of fear from the CS to similar, unlearned stimuli. However, how fear learning affects early sensory processing of learned and unlearned stimuli in relation to behavioral fear responses to these stimuli remains unclear. We subjected male and female mice expressing the fluorescent calcium indicator GCaMP3 in olfactory bulb mitral and tufted cells to a classical olfactory fear conditioning paradigm. We then used awake, in vivo calcium imaging to quantify learning-induced changes in glomerular odor responses, which constitute the first site of olfactory processing in the brain. The results demonstrate that odor-shock pairing nonspecifically enhances glomerular odor representations in a learning-dependent manner and increases representational similarity between the CS and nonconditioned odors, potentially priming the system toward generalization of learned fear. Additionally, CS-specific glomerular enhancements remain even when associative learning is blocked, suggesting two separate mechanisms lead to enhanced glomerular responses following odor-shock pairings.

SIGNIFICANCE STATEMENT In the olfactory bulb (OB), odors are uniquely coded in a spatial map that represents odor identity, making the OB a unique model system for investigating how learned fear alters sensory processing. Classical fear conditioning causes fear of the conditioned stimulus (CS) and of neutral stimuli, known as generalization. Combining fear conditioning with fluorescent calcium imaging of OB glomeruli, we found enhanced glomerular responses of the CS as well as neutral stimuli in awake mice, which mirrors fear generalization. We report that CS and neutral stimuli enhancements are, respectively, learning-independent and learning-dependent. Together, these results reveal distinct mechanisms leading to enhanced OB processing of fear-inducing stimuli and provide important implications for altered sensory processing in fear generalization.

This Week in The Journal

Whole-Body Distribution and Clinical Association of Telangiectases in Systemic Sclerosis

This cross-sectional study evaluates the association between the presence and distribution of telangiectases and the severity of vasculopathy in patients with systemic sclerosis.

Improvement in Ulcerative Necrobiosis Lipoidica After JAK-Inhibitor Therapy for Polycythemia Vera

This case report describes a patient whose ulcerative necrobiosis lipoidica improved after being treated for a different condition, polycythemia vera, with Janus kinase inhibitor.

Necrotizing Anogenital Ulcer in a Healthy 8-Month-Old Male

A healthy 8-month-old male infant was admitted for management of a rapidly progressive, painful anogenital ulcer; the lesion had developed acutely over 48 hours and had an associated symptom, but no fevers, chills, or other systemic symptoms. What is your diagnosis?

Teaching Intuitive Visual Diagnosis of Melanoma

This diagnostic study compares the training efficacy of a novel web-based application to the publicly available Internet Curriculum For Melanoma Early Detection Skin Education Series to determine if intuitive visual diagnosis training is superior to a traditional rule-based algorithm in the diagnosis of melanomas.

Timing and Number of Cutaneous Squamous Cell Carcinomas in Transplant Recipients

This cohort study of 3652 recipients of solid organ transplants examines the timing and number of cutaneous squamous cell carcinomas that developed after transplantation.

Frontalis Myocutaneous Transposition Flap for Forehead Defect Reconstruction

This case series of 12 patients with large, deep forehead defects secondary to Mohs surgery assesses whether the frontalis myocutaneous transposition flap represents a good alternative for the reconstruction of forehead defects.

Efficacy of Guselkumab Compared With Adalimumab and Placebo for Psoriasis in Specific Body Regions

This secondary analysis of 2 randomized clinical trials evaluates the effect of guselkumab vs adalimumab or placebo on psoriasis in specific difficult-to-treat body regions.

Nicorandil‐induced ulcerations: a 10‐year observational study of all cases spontaneously reported to the French pharmacovigilance network

International Wound Journal, EarlyView.

Books Received

ARISTOTLE, Poetics. (New York: W.W. Norton and Co). 2018. pp. 224. £12.54 (pbk).

Journals Received

JTLA, Journal of the Faculty of Letters, The University of Tokyo: Prolegomena, Society for the Advancement of Philosophy, Aesthetics. University of Zagreb.

Notes on Contributors

CRAIG BOURNE is a reader in philosophy at the University of Hertfordshire. His research interests are in metaphysics, philosophy of language and aesthetics. His publications include A Future for Presentism (2006) and, with Emily Caddick Bourne, Time in Fiction (2016). He is currently co-editing, with Emily Caddick Bourne, the Routledge Companion to Shakespeare and Philosophy.

Toluene degradation by Cupriavidus metallidurans CH34 in nitrate-reducing conditions and in Bioelectrochemical Systems

Abstract

Bioelectrochemical remediation of hydrocarbons is a technology that exploits the ability of specific microorganisms to use as electron acceptor an electrode, thus potentially lowering the operational costs related to classical bioremediation. Several well-characterized hydrocarbonoclastic strains might be electroactive, thus their biodegradation performances in Bioelectrochemical Systems should be studied. Cupriavidus metallidurans CH34 is a model metal-resistant strain whose capacity to degrade benzene aerobically has recently been described. In this study, toluene degradation under anaerobic conditions and the exoelectrogenic capacity of Cupriavidus metallidurans CH34 were determined. Strain CH34 was grown anaerobically with toluene as sole carbon source in sealed serum bottles and then inoculated in a Microbial Electrolysis Cell (MEC) to assess its exoelectrogenic capacity. It was demonstrated for the first time that strain CH34 is able to degrade toluene under nitrate-reducing conditions (up to 45 mg_toluene/L were removed within 17 days, corresponding to 73% of toluene amended). Nitrate consumption and cellular growth were observed during toluene removal. In the MEC, toluene degradation was linked to current production, showing current peaks after every toluene addition (maximum current density 48 mA/m²). Coulombic efficiency of the toluene biodegradation process increased with time, from 11% (first batch cycle), up to 77% (last batch cycle).

The rheumatic disease‐associated FAM167A‐BLK locus encodes DIORA‐1, a novel disordered protein expressed highly in bronchial epithelium and alveolar macrophages

Clinical &Experimental Immunology, EarlyView.

Comparison of Blue and White Lamp Light with Sunlight for Daylight‐Mediated, 5‐ALA Photodynamic Therapy, in vivo

Photochemistry and Photobiology, EarlyView.

Identification of Chronic Obstructive Pulmonary Disease Axes That Predict All-Cause Mortality: The COPDGene Study

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a syndrome caused by damage to the lungs resulting in decreased pulmonary function and reduced structural integrity. Pulmonary function testing (PFT) is currently used to diagnose and stratify COPD into severity groups and chest computed tomography (CT) imaging is often used to assess structural changes in the lungs. We hypothesized that the combination of PFT and CT phenotypes would provide a more powerful tool for assessing underlying morphologic differences associated with pulmonary function in COPD than PFT alone. We used factor analysis of 26 variables to classify 8,157 participants recruited into the COPDGene cohort between January 2008 and June 2011 from 21 Clinical Centers across the United States. These factors were then used as predictors of all-cause mortality using Cox Proportional Hazards modeling. Five factors explained 80% of the covariance and represented domains for increased emphysema and decreased pulmonary function (Factor 1); airway disease and decreased pulmonary function (Factor 2); gas trapping (Factor 3); CT variability (Factor 4); and hyperinflation (Factor 5). Over 46,079 person-years of follow-up, Factors 1 through 4 were associated with mortality and there was a significant synergistic interaction between Factor 1 and Factor 2 on mortality. Considering CT measures along with PFT in the assessment of COPD can identify patients at particularly high risk for mortality.

Erratum

Erratum to Park et al. Sprouty2 enhances the tumorigenic potential of glioblastoma cells. Neuro Oncol (doi: 10.1093/neuonc/noy028) (2018) first published online 23 February 2018

Oncolytic virotherapy in glioblastoma patients induces a tumor macrophage phenotypic shift leading to an altered glioblastoma microenvironment

Abstract

Background

Immunosuppressive pro-tumorous M2 macrophages are important in pathogenesis, progression and therapy resistance in glioblastoma (GBM) and provide a target for therapy. Recently oncolytic virotherapy in murine models was shown to change these M2 macrophages towards the pro-inflammatory and anti-tumorous M1 phenotype. Here we study the effects of the oncolytic virotherapy Delta24-RGD in humans using both in vitro models and patient material.

Methods

Human monocyte-derived macrophages were co-cultured with Delta24-RGD-infected primary glioma stem cells (GSCs) and were analyzed for their immunophenotype, cytokine expression and secretion profiles. Cerebrospinal fluid (CSF) from 18 Delta24-RGD-treated patients was analyzed for inflammatory cytokine levels and the effects of these CSF samples on macrophage phenotype in vitro were determined. In addition, tumor macrophages in resected material from a Delta-24-RGD-treated GBM patient were compared to 5 control GBM patient samples by flow cytometry.

Results

Human monocyte-derived M2 macrophages co-cultured with Delta24-RGD-infected GSCs shifted towards an M1-immunophenotype, coinciding with pro-inflammatory gene expression and cytokine production. This phenotypic switch was induced by the concerted effects of a change in tumor-produced soluble factors and the presence of viral particles. CSF samples from Delta24-RGD-treated GBM patients revealed cytokine levels indicative of a pro-inflammatory microenvironment. Furthermore, tumoral macrophages in a Delta24-RGD-treated patient showed significantly greater M1 characteristics then in control GBM tissue.

Conclusion

Together these in vitro and patient studies demonstrate that local Delta24-RGD therapy may provide a therapeutic tool to promote a prolonged shift in the pro-tumoral M2 macrophages towards M1 in human GBM, inducing a pro-inflammatory and potentially tumor-detrimental microenvironment.

Immunotherapy in CNS Cancers: the Role of Immune Cell Trafficking

Abstract

Glioblastoma (GBM) is a highly malignant CNS tumor with very poor survival despite intervention with conventional therapeutic strategies. Although the CNS is separated from the immune system by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), emerging evidence of immune surveillance and the selective infiltration of GBMs by immune suppressive cells indicates that there is breakdown or compromise of these physical barriers. This in turn offers hope that immunotherapy can be applied to specifically target and reduce tumor burden. One of the major setbacks in translating immunotherapy strategies is the hostile microenvironment of the tumor that inhibits trafficking of effector immune cells such as cytotoxic T lymphocytes into the CNS. Incorporating important findings from autoimmune disorders such as multiple sclerosis to understand and thereby enhance cytotoxic lymphocyte infiltration into GBM could augment immunotherapy strategies to treat this disease. However, although these therapies are designed to evoke a potent immune response, limited space in the brain and cranial vault reduces tolerance for immune therapy induced inflammation and resultant brain edema. Therefore, successful immunotherapy requires that a delicate balance be maintained between activating and retaining lasting anti-tumor immunity.

CO2 laser and photodynamic therapy: Study of efficacy in periocular BCC

Dermatologic Therapy, EarlyView.

Malignes Melanom

The removal of silver nanoparticle by titanium tetrachloride and modified sodium alginate composite coagulants: floc properties, membrane fouling, and floc recycle

Abstract

In this study, a modified sodium alginate (MSA) composited with TiCl₄ was used to treat the synthetic Ag nanoparticles (AgNPs) water in coagulation-ultrafiltration process. The floc properties and membrane fouling of TiCl₄ and MSA composite coagulants (TiCl₄ + MSA) were investigated by a laser diffraction instrument and ultrafiltration fouling model. The recycle of the AgNP-containing flocs was evaluated by XRD and photocatalytic experiments. The results showed that TiCl₄ + MSA could achieve better coagulation performance than TiCl₄ alone with AgNP and DOC removal up to 97 and 59% at the optimum condition (pH = 5 and dosage = 12 mg TiCl₄/L). TiCl₄ + MSA produced larger and looser flocs than TiCl₄ and TiCl₄ + SA composite coagulant (TiCl₄ + SA), which was benefit for the inhibition of subsequence membrane fouling. The strongly attached external fouling resistance (R_ef-s) and the reversible internal fouling resistance (R_if-r) of TiCl₄ + MSA were only 43 and 39.2% of those achieved by TiCl₄ at the optimal coagulation condition. Besides, the adopted AgCl-TiO₂ could be recycled from AgNP-containing flocs. And MSA could promote the form of TiO₂ anatase. It gives us a possible way for silver nanoparticle recycle.

Developing a non-point source P loss indicator in R and its parameter uncertainty assessment using GLUE: a case study in northern China

Abstract

Uncertainty analysis is an important prerequisite for model application. However, the existing phosphorus (P) loss indexes or indicators were rarely evaluated. This study applied generalized likelihood uncertainty estimation (GLUE) method to assess the uncertainty of parameters and modeling outputs of a non-point source (NPS) P indicator constructed in R language. And the influences of subjective choices of likelihood formulation and acceptability threshold of GLUE on model outputs were also detected. The results indicated the following. (1) Parameters RegR₂, RegSDR₂, PlossDP_fer , PlossDP_man , DPDR, and DPR were highly sensitive to overall TP simulation and their value ranges could be reduced by GLUE. (2) Nash efficiency likelihood (L₁) seemed to present better ability in accentuating high likelihood value simulations than the exponential function (L₂) did. (3) The combined likelihood integrating the criteria of multiple outputs acted better than single likelihood in model uncertainty assessment in terms of reducing the uncertainty band widths and assuring the fitting goodness of whole model outputs. (4) A value of 0.55 appeared to be a modest choice of threshold value to balance the interests between high modeling efficiency and high bracketing efficiency. Results of this study could provide (1) an option to conduct NPS modeling under one single computer platform, (2) important references to the parameter setting for NPS model development in similar regions, (3) useful suggestions for the application of GLUE method in studies with different emphases according to research interests, and (4) important insights into the watershed P management in similar regions.

The usefulness integrity testing in children: A single institution experience of 86 tests over a period of 20 years

Clinical Otolaryngology, EarlyView.

The limits of Humeanism

Abstract

Humeans take reality to be devoid of 'necessary connections': things just happen. Laws of nature are to be understood in terms of what 'just happens', not vice versa. Here the Humean needs some conception of what it is that 'just happens' – a conception of the Humean mosaic. Lewis's Humeanism incorporates such a conception in the form of a Lewis-style metaphysics of objects, properties, and modality. Newer versions of Humeanism about laws of nature, such as the Better Best Systems approach (BBS), typically reject such a Lewisian metaphysics, but it remains unclear what they can offer in its place. By exploring different candidate conceptions, this paper sheds light on the limits of Humeanism about laws of nature: not all conceptions of the Humean mosaic form a suitable basis for a Humean theory of laws. In fact, only a metaphysics roughly in line with Lewis's will do. The paper ends with a tentative generalization of this result, thus pointing to the 'limit' of Humeanism in general: taking the Humean way of thinking to its limit results in a rejection of the whole idea of such a mosaic – and hence of Humean mosaic-based accounts of anything.

Case of generalized pustular psoriasis that might have progressed from terbinafine‐induced acute generalized exanthematous pustulosis

The Journal of Dermatology, EarlyView.