Hematological and histopathological effects of silver nanoparticles in rainbow trout ( Oncorhynchus mykiss )—how about increase of salinity?

Abstract

Hematological and histopathological toxicities of silver nanoparticles (Ag-NPs) to rainbow trout were assessed in three water salinities: 0.4 ppt (low salinity), 6 ± 0.3 ppt (moderate salinity), and 12 ± 0.2 ppt (high salinity). The concentrations of Ag-NPs in the low salinity were 0.032, 0.1, 0.32, and 1 ppm, and in the moderate and high salinities were 3.2, 10, 32, and 100 ppm. The results indicated a concentration-dependently increased (thrombocyte, monocyte, and large lymphocyte) and decreased (neutrophil and small lymphocyte) white blood cell count in the Ag-NP treatments in the low salinity than the other ones in the moderate and high salinities. Red blood cell volume significantly increased in all of the experimental groups exposed to higher Ag-NP concentrations, especially those in the low salinity. In the moderate and high salinities, blood plasma total protein decreased in 10 and 32 ppm Ag-NP treatments, but albumin increased in the groups in the low salinity. Blood plasma ions (Cl⁻, Na⁺, K⁺, Ca²⁺, and Mg²⁺) showed high changes in the higher Ag-NP treatments. In all treatments, gill histological analysis demonstrated a time- and Ag-NP concentration-dependent extent of abnormalities, with the highest epithelial lifting in 1 ppm Ag-NPs in the low salinity and also the highest necrosis and aneurism in the 32 ppm treatments in other salinities. Lower Ag-NP concentrations in the low salinity led to fibrosis, villus fusion, inflammation, vacuolization, and microvillus hyperplasia in the gut, yet villi lifting and necrosis in 0.32 and 1 ppm of Ag-NPs were the main anomalies. In addition to the mentioned alterations, villi abolitions predominantly occurred in 32 ppm Ag-NP concentrations in the moderate and high salinities. Overall, despite exposing to lower Ag-NP concentrations, the fish kept in the low salinity demonstrated more vulnerability to Ag-NPs than those in the other salinities.

Alterations of antioxidant indexes and inflammatory cytokine expression aggravated hepatocellular apoptosis through mitochondrial and death receptor-dependent pathways in Gallus gallus exposed to arsenic and copper

Abstract

In this study, we sought to investigate the effects of sub-chronic exposure of arsenic (As) and copper (Cu) on oxidative stress, inflammatory response, and mitochondria and death receptor apoptosis pathways in chicken liver. Seventy-two 1-day-old male Hy-line chickens were treated with basal diet, 30 mg/kg arsenic trioxide (As₂O₃), or/and 300 mg/kg copper sulfate (CuSO₄) for 4, 8, and 12 weeks. Study revealed that exposure to As or/and Cu undermined the antioxidant function and increased lipid peroxidation. Worse yet, liver cell swollen, vacuolar degeneration, and inflammatory cell infiltration were accompanied by an increase of the nuclear factor-κB (NF-κB) and its downstream inflammation-related genes after exposure to As or/and Cu. Furthermore, mitochondria swollen and chromatin condensation were found in As and Cu groups, and hepatocyte nuclear membrane rupture and markedly increased (P < 0.01) apoptosis index were observed in As combined with Cu group. Meanwhile, the transcription and protein expression levels of Bcl-2-associated X protein (Bax), p53, cytochrome c (Cyt c), and caspase-3, 8, 9 were upregulated and B cell lymphoma-2 (Bcl-2) was downregulated in As, Cu, and As + Cu groups in the liver tissues (P < 0.05, P < 0.01). Our results indicated that exposure to As or/and Cu could lead to oxidative stress, inflammatory response, and tissue damage and aggravate hepatocellular apoptosis through mitochondrial and death receptor-dependent pathways in chicken liver. And As and Cu showed a possible synergistic relationship in liver damage.

Detection of 2-aminoethylphosphonic acid in suspended particles in an ultraoligotrophic lake: a two-dimensional nuclear magnetic resonance (2D-NMR) study

Abstract

Particulate organic phosphorus (P) compounds were examined in ultraoligotrophic Lake Saiko, Japan. A cartridge filter was used to collect sufficient amount of suspended particles for analysis by a two-dimensional NMR (¹H-³¹P heteronuclear multiple bond correlation). 2-Aminoethylphosphonic acid (2-AEP), a phosphonate, was detected in suspended particles in Lake Saiko. The identity of the phosphonate was confirmed by comparison with a commercially available compound. Because 2-AEP is bioavailable, microorganisms can store and use this compound under extremely P-limited conditions. This is the first study to detect 2-AEP in an ultra-oligotrophic environment.

Correction to: Subcutaneous lipomas: A minimally invasive method for resection of subcutaneous lipomas preserving retaining ligaments

Abstract

The article Subcutaneous lipomas: A minimally invasivemethod for resection of subcutaneous lipomas preserving retaining ligaments, written by Akio Sakamoto, Takeshi Okamoto, Shuichi Matsuda, was originally published electronically on the publisher's internet portal (currently SpringerLink).

Implementation of GPU accelerated SPECT reconstruction with Monte Carlo-based scatter correction

Abstract

Objective

Statistical SPECT reconstruction can be very time-consuming especially when compensations for collimator and detector response, attenuation, and scatter are included in the reconstruction. This work proposes an accelerated SPECT reconstruction algorithm based on graphics processing unit (GPU) processing.

Methods

Ordered subset expectation maximization (OSEM) algorithm with CT-based attenuation modelling, depth-dependent Gaussian convolution-based collimator-detector response modelling, and Monte Carlo-based scatter compensation was implemented using OpenCL. The OpenCL implementation was compared against the existing multi-threaded OSEM implementation running on a central processing unit (CPU) in terms of scatter-to-primary ratios, standardized uptake values (SUVs), and processing speed using mathematical phantoms and clinical multi-bed bone SPECT/CT studies.

Results

The difference in scatter-to-primary ratios, visual appearance, and SUVs between GPU and CPU implementations was minor. On the other hand, at its best, the GPU implementation was noticed to be 24 times faster than the multi-threaded CPU version on a normal 128 × 128 matrix size 3 bed bone SPECT/CT data set when compensations for collimator and detector response, attenuation, and scatter were included.

Conclusions

GPU SPECT reconstructions show great promise as an every day clinical reconstruction tool.

Innovative Clinical Investigations: featured papers in IJCARS

Oral exposure of deltamethrin and/or lipopolysaccharide (LPS) induced activation of the pulmonary immune system in Swiss albino mice

Abstract

The deltamethrin, a synthetic pyrethroid, is used worldwide and has been linked with several type of acute toxicity. However, effect of low level of deltamethrin alone or in combination with the microbial antigen on pulmonary system is not understood. Lipopolysaccharide (LPS) was used as antigen which is a key inflammatory component of gram-negative bacteria, which induces a distinctive pattern of cytokine release that regulates inflammation. The aim was to determine whether chronic exposure to a low level of deltamethrin alone or in combination with LPS impair the lung response in adult male Swiss albino mice. The mice were orally exposed to different doses of deltamethrin (0.1, 0.05, 0.005, 0.001 mg/kg bwt) and then immunized with LPS at the 60th day. None of the treatment groups contained residues of deltamethrin above the limits of quantification. Deltamethrin combined with LPS challenge caused significant lymphocytosis and neutropenia in group 1 (0.1 mg/kg) mice (P < 0.05). The highest dose of deltamethrin exposure (0.1 mg/kg bwt) alone altered the total cell count significantly in blood and total leukocyte count (TLC) and macrophage count in bronchoalveolar lavage fluid. Microscopic pulmonary damage was evaluated by H&E staining and EM which indicated that two higher doses of deltamethrin, i.e., 0.1 and 0.05 mg/kg bwt, distinctly increased inflammatory cell infiltration and caused alveolar septa thickening and leukocyte infiltration into the alveolar septum (septal cell infiltration) in the lungs. Deltamethrin exposure alone and/or with endotoxin revealed different degrees of immunopositive reaction for Toll-like receptor 4 (TLR4) and pro-inflammatory cytokine-like tumor necrosis factor-alpha (TNFα) in different parts of the lungs. The expression of TLR4 and TNFα in the lung tissue was more pronounced in two higher dose groups. Thus, chronic low-level deltamethrin exposure may impair the main pro-inflammatory response in the lungs which is more pronounced in combination with LPS. Further research is required in direction of the mechanism of action of deltamethrin on the immune cell lineage and their differentiation.

Synthesis of NiO nanoparticles via a green route using Monsonia burkeana: The physical and biological properties

Publication date: Available online 21 March 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): P. Kganyago, L.M. Mahlaule-Glory, M.M. Mathipa, B. Ntsendwana, N. Mketo, Z. Mbita, N.C. Hintsho-Mbita
NiO nanoparticles have emerged as ideal candidates in various fields due to their magnetic, electrical and optical properties. The coupling of plant extracts that have anticancer and antibacterial properties with NiO nanoparticles has increased their usage in the biomedical field. In this work, we report on the novel synthesis of NiO nanoparticles using a local medicinal plant, Monsonia burkenea. The nickel nanoparticles were characterized using Fourier transform infrared spectroscopy (FTIR), Energy dispersive X-ray analysis (EDX), Scanning electron microscope (SEM), High-resolution transmission electron microscope (HRTEM) and X-ray diffraction (XRD). FTIR showed that the extraction of the plant phytochemicals was successful and the green synthesized nanoparticles from plants contained the phytochemical groups that are found in the Monsonia burkeana plant. XRD and HRTEM confirmed the successful formation of NiO nanoparticles with an average particle size range of 20 nm. These results were also corroborated by elemental mapping and EDX, where the dominant groups were identified.The Monsonia burkeana NiO particles exhibited selective bactericidal activity against Gram-negative strains, such as E. coli and P. aeruginosa. Additionally, cytotoxicity studies showed the materials did not have any anti proliferative effect against A549 lung cancer cells but could be used as potential drug delivery vehicles against human cancers.

Graphical abstract

Authentication of an Italian PDO hazelnut (“Nocciola Romana”) by NIR spectroscopy

Abstract

Common hazelnuts are widely present in human diet all over the world, and their beneficial effects on the health have been extensively investigated and demonstrated. Different in-depth researches have highlighted that the harvesting area can define small variations in the chemical composition of the fruits, affecting their quality. As a consequence, it has become relevant to develop methodologies which would allow authenticating and tracing hazelnuts. In the light of this, the present work aims to develop a non-destructive method for the authentication of a specific high-quality Italian hazelnut, "Nocciola Romana," registered with a protected designation of origin (PDO). Thus, different samples of this fruit have been analyzed by near-infrared (NIR) spectroscopy and then classification models have been built, in order to distinguish between the PDO fruits and the hazelnuts not coming from the designated region. In particular, two different classification approaches have been tested, a discriminant one, partial least squares-discriminant analysis, and a class-modeling one, soft independent modeling of class analogies. Both methods led to very high prediction capability in external validation on a test set (classification accuracy in one case, and sensitivity and specificity in the other, all higher than 92%), suggesting that the proposed methodologies are suitable for a rapid and non-destructive authentication of the product.

Biopsia selectiva del ganglio centinela de la región inguinal: técnica quirúrgica

Publication date: Available online 21 March 2018
Source:Actas Dermo-Sifiliográficas
Author(s): D. Moreno-Ramírez, J. Pérez-Anker, A. Perissinotti, R. Pigem, S. Podlipnik, I. Fragakis, T. Toledo Pastrana

Long-Term Neuroinflammation Induced by Influenza A Virus Infection and the Impact on Hippocampal Neuron Morphology and Function

Acute influenza infection has been reported to be associated with neurological symptoms. However, the long-term consequences of an infection with neurotropic and non-neurotropic influenza A virus (IAV) variants for the CNS remain elusive. We can show that spine loss in the hippocampus after infection with neurotropic H7N7 (rSC35M) and non-neurotropic H3N2 (maHK68) in female C57BL/6 mice persists well beyond the acute phase of the disease. Although spine number was significantly reduced at 30 d postinfection (dpi) with H7N7 or H3N2, full recovery could only be observed much later at 120 dpi. Infection with H1N1 virus, which was shown previously to affect spine number and hippocampus-dependent learning acutely, had no significant long-term effects. Spine loss was associated with an increase in the number of activated microglia, reduced long-term potentiation in the hippocampus, and impairment in spatial memory formation, indicating that IAV-associated inflammation induced functional and structural alterations in hippocampal networks. Transcriptome analyses revealed regulation of many inflammatory and neuron- and glia-specific genes in H3N2- and H7N7-infected mice at day 18 and in H7N7-infected mice at day 30 pi that related to the structural and functional alterations. Our data provide evidence that neuroinflammation induced by neurotropic H7N7 and infection of the lung with a non-neurotropic H3N2 IAV result in long-term impairments in the CNS. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS.

SIGNIFICANCE STATEMENT In the acute phase of influenza infection, neuroinflammation can lead to alterations in hippocampal neuronal morphology and cognitive deficits. The results of this study now also provide evidence that neuroinflammation induced by influenza A virus (IAV) infection can induce longer-lasting, virus-specific alterations in neuronal connectivity that are still detectable 1 month after infection and are associated with impairments in spatial memory formation. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS.

Alzheimer's Disease and Sleep-Wake Disturbances: Amyloid, Astrocytes, and Animal Models

Sleep–wake abnormalities are common in patients with Alzheimer's disease, and can be a major reason for institutionalization. However, an emerging concept is that these sleep–wake disturbances are part of the causal pathway accelerating the neurodegenerative process. Recently, new findings have provided intriguing evidence for a positive feedback loop between sleep–wake dysfunction and β-amyloid (Aβ) aggregation. Studies in both humans and animal models have shown that extended periods of wakefulness increase Aβ levels and aggregation, and accumulation of Aβ causes fragmentation of sleep. This perspective is aimed at presenting evidence supporting causal links between sleep–wake dysfunction and aggregation of Aβ peptide in Alzheimer's disease, and explores the role of astrocytes, a specialized type of glial cell, in this context underlying Alzheimer's disease pathology. The utility of current animal models and the unexplored potential of alternative animal models for testing mechanisms involved in the reciprocal relationship between sleep disruption and Aβ are also discussed.

Dual Perspectives Companion Paper: Microglia-Mediated Synapse Loss in Alzheimer's Disease by Lawrence Rajendran and Rosa Paolicelli

This Week in The Journal

Microglia-Mediated Synapse Loss in Alzheimer's Disease

Microglia are emerging as key players in neurodegenerative diseases, such as Alzheimer's disease (AD). Thus far, microglia have rather been known as modulator of neurodegeneration with functions limited to neuroinflammation and release of neurotoxic molecules. However, several recent studies have demonstrated a direct role of microglia in "neuro" degeneration observed in AD by promoting phagocytosis of neuronal, in particular, synaptic structures. While some of the studies address the involvement of the β-amyloid peptides in the process, studies also indicate that this could occur independent of amyloid, further elevating the importance of microglia in AD. Here we review these recent studies and also speculate about the possible cellular mechanisms, and how they could be regulated by risk genes and sleep. Finally, we deliberate on possible avenues for targeting microglia-mediated synapse loss for therapy and prevention.

Dual Perspectives Companion Paper: Alzheimer's Disease and Sleep-Wake Disturbances: Amyloid, Astrocytes, and Animal Models by William M. Vanderheyden, Miranda M. Lim, Erik S. Musiek, and Jason R. Gerstner

Visual Working Memory Is Independent of the Cortical Spacing Between Memoranda

The sensory recruitment hypothesis states that visual short-term memory is maintained in the same visual cortical areas that initially encode a stimulus' features. Although it is well established that the distance between features in visual cortex determines their visibility, a limitation known as crowding, it is unknown whether short-term memory is similarly constrained by the cortical spacing of memory items. Here, we investigated whether the cortical spacing between sequentially presented memoranda affects the fidelity of memory in humans (of both sexes). In a first experiment, we varied cortical spacing by taking advantage of the log-scaling of visual cortex with eccentricity, presenting memoranda in peripheral vision sequentially along either the radial or tangential visual axis with respect to the fovea. In a second experiment, we presented memoranda sequentially either within or beyond the critical spacing of visual crowding, a distance within which visual features cannot be perceptually distinguished due to their nearby cortical representations. In both experiments and across multiple measures, we found strong evidence that the ability to maintain visual features in memory is unaffected by cortical spacing. These results indicate that the neural architecture underpinning working memory has properties inconsistent with the known behavior of sensory neurons in visual cortex. Instead, the dissociation between perceptual and memory representations supports a role of higher cortical areas such as posterior parietal or prefrontal regions or may involve an as yet unspecified mechanism in visual cortex in which stimulus features are bound to their temporal order.

SIGNIFICANCE STATEMENT Although much is known about the resolution with which we can remember visual objects, the cortical representation of items held in short-term memory remains contentious. A popular hypothesis suggests that memory of visual features is maintained via the recruitment of the same neural architecture in sensory cortex that encodes stimuli. We investigated this claim by manipulating the spacing in visual cortex between sequentially presented memoranda such that some items shared cortical representations more than others while preventing perceptual interference between stimuli. We found clear evidence that short-term memory is independent of the intracortical spacing of memoranda, revealing a dissociation between perceptual and memory representations. Our data indicate that working memory relies on different neural mechanisms from sensory perception.

Expression of Bona Fide Epithelial Stem Cell Marker in Postmitotic Olfactory Bulb Neurons Suggest Novel Roles for Wnt Signaling in the Brain

Dendritic A-Current in Rhythmically Active PreBötzinger Complex Neurons in Organotypic Cultures from Newborn Mice

The brainstem preBötzinger complex (preBötC) generates the inspiratory rhythm for breathing. The onset of neural activity that precipitates the inspiratory phase of the respiratory cycle may depend on the activity of type-1 preBötC neurons, which exhibit a transient outward K⁺ current, I_A. Inspiratory rhythm generation can be studied ex vivo because the preBötC remains rhythmically active in vitro, both in acute brainstem slices and organotypic cultures. Advantageous optical conditions in organotypic slice cultures from newborn mice of either sex allowed us to investigate how I_A impacts Ca²⁺ transients occurring in the dendrites of rhythmically active type-1 preBötC neurons. The amplitude of dendritic Ca²⁺ transients evoked via voltage increases originating from the soma significantly increased after an I_A antagonist, 4-aminopyridine (4-AP), was applied to the perfusion bath or to local dendritic regions. Similarly, glutamate-evoked postsynaptic depolarizations recorded at the soma increased in amplitude when 4-AP was coapplied with glutamate at distal dendritic locations. We conclude that I_A is expressed on type-1 preBötC neuron dendrites. We propose that I_A filters synaptic input, shunting sparse excitation, while enabling temporally summated events to pass more readily as a result of I_A inactivation. Dendritic I_A in rhythmically active preBötC neurons could thus ensure that inspiratory motor activity does not occur until excitatory synaptic drive is synchronized and well coordinated among cellular constituents of the preBötC during inspiratory rhythmogenesis. The biophysical properties of dendritic I_A might thus promote robustness and regularity of breathing rhythms.

SIGNIFICANCE STATEMENT Brainstem neurons in the preBötC generate the oscillatory activity that underlies breathing. PreBötC neurons express voltage-dependent currents that can influence inspiratory activity, among which is a transient potassium current (I_A) previously identified in a rhythmogenic excitatory subset of type-1 preBötC neurons. We sought to determine whether I_A is expressed in the dendrites of preBötC. We found that dendrites of type-1 preBötC neurons indeed express I_A, which may aid in shunting sparse non-summating synaptic inputs, while enabling strong summating excitatory inputs to readily pass and thus influence somatic membrane potential trajectory. The subcellular distribution of I_A in rhythmically active neurons of the preBötC may thus be critical for producing well coordinated ensemble activity during inspiratory burst formation.

Subretinal Human Umbilical Tissue-Derived Cell Transplantation Preserves Retinal Synaptic Connectivity and Attenuates Müller Glial Reactivity

Human umbilical tissue-derived cells (hUTC or palucorcel) are currently under clinical investigation for the treatment of geographic atrophy, a late stage of macular degeneration, but how hUTC transplantation mediates vision recovery is not fully elucidated. Subretinal administration of hUTC preserves visual function in the Royal College of Surgeons (RCS) rat, a genetic model of retinal degeneration caused by Mertk loss of function. hUTC secrete synaptogenic and neurotrophic factors that improve the health and connectivity of the neural retina. Therefore, we investigated the progression of synapse and photoreceptor loss and whether hUTC treatment preserves photoreceptors and synaptic connectivity in the RCS rats of both sexes. We found that RCS retinas display significant deficits in synaptic development already by postnatal day 21 (P21), before the onset of photoreceptor degeneration. Subretinal transplantation of hUTC at P21 is necessary to rescue visual function in RCS rats, and the therapeutic effect is enhanced with repeated injections. Synaptic development defects occurred concurrently with morphological changes in Müller glia, the major perisynaptic glia in the retina. hUTC transplantation strongly diminished Müller glia reactivity and specifically protected the α2-1-containing retinal synapses, which are responsive to thrombospondin family synaptogenic proteins secreted by Müller glia. Müller glial reactivity and reduced synaptogenesis observed in RCS retinas could be recapitulated by CRISPR/Cas9-mediated loss-of-Mertk in Müller glia in wild-type rats. Together, our results show that hUTC transplantation supports the health of retina at least in part by preserving the functions of Müller glial cells, revealing a previously unknown aspect of hUTC transplantation-based therapy.

SIGNIFICANCE STATEMENT Despite the promising effects observed in clinical trials and preclinical studies, how subretinal human umbilical tissue-derived cell (hUTC) transplantation mediates vision improvements is not fully known. Using a rat model of retinal degeneration, the RCS rat (lacking Mertk), here we provide evidence that hUTC transplantation protects visual function and health by protecting photoreceptors and preserving retinal synaptic connectivity. Furthermore, we find that loss of Mertk function only in Müller glia is sufficient to impair synaptic development and cause activation of Müller glia. hUTC transplantation strongly attenuates the reactivity of Müller glia in RCS rats. These findings highlight novel cellular and molecular mechanisms within the neural retina, which underlie disease mechanisms and pinpoint Müller glia as a novel cellular target for hUTC transplantation.

Detecting Unattended Stimuli Depends on the Phase of Prestimulus Neural Oscillations

Neural oscillations appear important for perception and attention processes because stimulus detection is dependent upon the phase of 7–11 Hz oscillations before stimulus onset. Previous work has examined stimulus detection at attended locations, but it is unknown whether unattended locations are also subject to phasic modulation by ongoing oscillatory activity, as would be predicted by theories proposing a role for neural oscillations in organizing general neural processing. Here, we recorded brain activity with EEG while human participants of both sexes detected brief visual targets preceded by a spatial cue and determined whether performance for cued (attended) and uncued (unattended) targets was influenced by oscillatory phase across a range of frequencies. Detection of both attended and unattended targets depended upon an ~5 Hz theta rhythm and an ~11–15 Hz alpha rhythm. Critically, detection of unattended stimuli was more strongly modulated by the phase of theta oscillations than was detection of attended stimuli, suggesting that attentional allocation involves a disengagement from ongoing theta sampling. There was no attention-related difference in the strength of alpha phase dependence, consistent with a perceptual rather than attentional role of oscillatory phase in this frequency range. These results demonstrate the importance of neural oscillations in modulating visual processing at both attended and unattended locations and clarify one way in which attention may produce its effects: through disengagement from low-frequency sampling at attended locations.

SIGNIFICANCE STATEMENT Past work on the interaction between oscillatory phase and neural processing has shown the involvement of posterior ~7–11 Hz oscillations in visual processing. Most studies, however, have presented stimuli at attended locations, making it difficult to disentangle frequencies related to attention from those related to perception. Here, we compared the oscillatory frequencies involved in the detection of attended and unattended stimuli and found that ~11–15 Hz oscillations were related to perception independently of attention, whereas ~5 Hz oscillations were more prominent for the detection of unattended stimuli. This work demonstrates the importance of neural oscillations for mediating stimulus processing at both attended and unattended locations and clarifies the different oscillatory frequencies involved in attention and perception.

Neurobiological Mechanisms of Responding to Injustice

People are particularly sensitive to injustice. Accordingly, deeper knowledge regarding the processes that underlie the perception of injustice, and the subsequent decisions to either punish transgressors or compensate victims, is of important social value. By combining a novel decision-making paradigm with functional neuroimaging, we identified specific brain networks that are involved with both the perception of, and response to, social injustice, with reward-related regions preferentially involved in punishment compared with compensation. Developing a computational model of punishment allowed for disentangling the neural mechanisms and psychological motives underlying decisions of whether to punish and, subsequently, of how severely to punish. Results show that the neural mechanisms underlying punishment differ depending on whether one is directly affected by the injustice, or whether one is a third-party observer of a violation occurring to another. Specifically, the anterior insula was involved in decisions to punish following harm, whereas, in third-party scenarios, we found amygdala activity associated with punishment severity. Additionally, we used a pharmacological intervention using oxytocin, and found that oxytocin influenced participants' fairness expectations, and in particular enhanced the frequency of low punishments. Together, these results not only provide more insight into the fundamental brain mechanisms underlying punishment and compensation, but also illustrate the importance of taking an explorative, multimethod approach when unraveling the complex components of everyday decision-making.

SIGNIFICANCE STATEMENT The perception of injustice is a fundamental precursor to many disagreements, from small struggles at the dinner table to wasteful conflict between cultures and countries. Despite its clear importance, relatively little is known about how the brain processes these violations. Taking an interdisciplinary approach, we combine methods from neuroscience, psychology, and economics to explore the neurobiological mechanisms involved in both the perception of injustice as well as the punishment and compensation decisions that follow. Using a novel behavioral paradigm, we identified specific brain networks, developed a computational model of punishment, and found that administrating the neuropeptide oxytocin increases the administration of low punishments of norm violations in particular. Results provide valuable insights into the fundamental neurobiological mechanisms underlying social injustice.

Correction: Araujo et al., "Foxp1 in Forebrain Pyramidal Neurons Controls Gene Expression Required for Spatial Learning and Synaptic Plasticity"

Human Sensorimotor Cortex Control of Directly Measured Vocal Tract Movements during Vowel Production

During speech production, we make vocal tract movements with remarkable precision and speed. Our understanding of how the human brain achieves such proficient control is limited, in part due to the challenge of simultaneously acquiring high-resolution neural recordings and detailed vocal tract measurements. To overcome this challenge, we combined ultrasound and video monitoring of the supralaryngeal articulators (lips, jaw, and tongue) with electrocorticographic recordings from the cortical surface of 4 subjects (3 female, 1 male) to investigate how neural activity in the ventral sensory-motor cortex (vSMC) relates to measured articulator movement kinematics (position, speed, velocity, acceleration) during the production of English vowels. We found that high-gamma activity at many individual vSMC electrodes strongly encoded the kinematics of one or more articulators, but less so for vowel formants and vowel identity. Neural population decoding methods further revealed the structure of kinematic features that distinguish vowels. Encoding of articulator kinematics was sparsely distributed across time and primarily occurred during the time of vowel onset and offset. In contrast, encoding was low during the steady-state portion of the vowel, despite sustained neural activity at some electrodes. Significant representations were found for all kinematic parameters, but speed was the most robust. These findings enabled by direct vocal tract monitoring demonstrate novel insights into the representation of articulatory kinematic parameters encoded in the vSMC during speech production.

SIGNIFICANCE STATEMENT Speaking requires precise control and coordination of the vocal tract articulators (lips, jaw, and tongue). Despite the impressive proficiency with which humans move these articulators during speech production, our understanding of how the brain achieves such control is rudimentary, in part because the movements themselves are difficult to observe. By simultaneously measuring speech movements and the neural activity that gives rise to them, we demonstrate how neural activity in sensorimotor cortex produces complex, coordinated movements of the vocal tract.

The Nucleus Reuniens Controls Long-Range Hippocampo-Prefrontal Gamma Synchronization during Slow Oscillations

Gamma oscillations are involved in long-range coupling of distant regions that support various cognitive operations. Here we show in adult male rats that synchronized bursts of gamma oscillations bind the hippocampus (HPC) and prefrontal cortex (mPFC) during slow oscillations and slow-wave sleep, a brain state that is central for consolidation of memory traces. These gamma bursts entrained the firing of the local HPC and mPFC neuronal populations. Neurons of the nucleus reuniens (NR), which is a structural and functional hub between HPC and mPFC, demonstrated a specific increase in their firing before gamma burst onset, suggesting their involvement in HPC–mPFC binding. Chemical inactivation of NR disrupted the temporal pattern of gamma bursts and their synchronization, as well as mPFC neuronal firing. We propose that the NR drives long-range hippocampo–prefrontal coupling via gamma bursts providing temporal windows for information exchange between the HPC and mPFC during slow-wave sleep.

SIGNIFICANCE STATEMENT Long-range coupling between hippocampus (HPC) and prefrontal cortex (mPFC) is believed to support numerous cognitive functions, including memory consolidation occurring during sleep. Gamma-band synchronization is a fundamental process in many neuronal operations and is instrumental in long-range coupling. Recent evidence highlights the role of nucleus reuniens (NR) in consolidation; however, how it influences hippocampo–prefrontal coupling is unknown. In this study, we show that HPC and mPFC are synchronized by gamma bursts during slow oscillations in anesthesia and natural sleep. By manipulating and recording the NR–HPC–mPFC network, we provide evidence that the NR actively promotes this long-range gamma coupling. This coupling provides the hippocampo–prefrontal circuit with a novel mechanism to exchange information during slow-wave sleep.

Auditory Input Shapes Tonotopic Differentiation of Kv1.1 Expression in Avian Cochlear Nucleus during Late Development

Tonotopic differentiation is fundamental for signal processing in the auditory system. However, when and how this differentiation arises remain elusive. We addressed this issue using electrophysiology and immunohistochemistry in nucleus magnocellularis of chickens of both sexes, which is known to differ in the expression of Kv1.1 channels depending on characteristic frequency (CF). Just after hearing onset (embryonic day 12–14), Kv1 current gradually increased to a slightly larger extent in neurons with higher CF, causing a tonotopic difference of Kv1 current before hatch. However, after hatch, a much larger increase of Kv1 current occurred, particularly in higher-CF neurons, due to an augmentation of Kv1.1 expression at the plasma membrane. This later change in expression led to the large tonotopic difference of Kv1 current characteristic of mature animals. Attenuation of auditory input by inducing conductive or sensorineural hearing loss around hatch suppressed the differentiation in a level-dependent manner. Moreover, elevation of auditory input during embryonic periods could not reproduce the differentiation, suggesting that the capacity of neurons to drive Kv1.1 expression via auditory input develops in a cell-specific manner, thus underlying the frequency-specific expression of the channel within the nucleus. The results indicated that the tonotopic differentiation of Kv1.1 in nucleus magnocellularis is partially determined before hatch, but largely driven by afferent input after hatch. Our results highlight the importance of neuronal capacity for sound to drive ion channel expression as well as the level of auditory experience in the frequency tuning of brainstem auditory circuits.

SIGNIFICANCE STATEMENT Tuning-frequency-specific expression of ion channels is a prerequisite for auditory system function, but its underlying mechanisms remain unclear. Here, we revealed in avian cochlear nucleus that the expression of Kv1.1 became more dependent on auditory input at a late period of maturation in neurons tuned to higher-frequency sound, leading to frequency-specific Kv1.1 expression. Attenuation of auditory input during this period suppressed the differentiation in a level-dependent manner, whereas elevation of input in earlier periods could not reproduce the differentiation. Thus, the capacity of neurons to drive Kv1.1 expression via auditory input develops in a cell-specific manner and directs differentiation, highlighting the importance of neuronal character as well as the level of input in the frequency tuning of auditory circuits.

The Effect of Locomotion on Early Visual Contrast Processing in Humans

Most of our knowledge about vision comes from experiments in which stimuli are presented to immobile human subjects or animals. In the case of human subjects, movement during psychophysical, electrophysiological, or neuroimaging experiments is considered to be a source of noise to be eliminated. Animals used in visual neuroscience experiments are typically restrained and, in many cases, anesthetized. In reality, however, vision is often used to guide the motion of awake, ambulating organisms. Recent work in mice has shown that locomotion elevates visual neuronal response amplitudes (Niell and Stryker, 2010; Erisken et al., 2014; Fu et al., 2014; Lee et al., 2014; Mineault et al., 2016) and reduces long-range gain control (Ayaz et al., 2013). Here, we used both psychophysics and steady-state electrophysiology to investigate whether similar effects of locomotion on early visual processing can be measured in humans. Our psychophysical results show that brisk walking has little effect on subjects' ability to detect briefly presented contrast changes and that co-oriented flankers are, if anything, more effective masks when subjects are walking. Our electrophysiological data were consistent with the psychophysics indicating no increase in stimulus-driven neuronal responses while walking and no reduction in surround suppression. In summary, we have found evidence that early contrast processing is altered by locomotion in humans but in a manner that differs from that reported in mice. The effects of locomotion on very low-level visual processing may differ on a species-by-species basis and may reflect important differences in the levels of arousal associated with locomotion.

SIGNIFICANCE STATEMENT Mice are the current model of choice for studying low-level visual processing. Recent studies have shown that mouse visual cortex is modulated by behavioral state: primary visual cortex neurons in locomoting mice tend to be more sensitive and less influenced by long-range gain control. Here, we tested these effects in humans by measuring psychophysical detection thresholds and electroencephalography (EEG) responses while subjects walked on a treadmill. We found no evidence of increased contrast sensitivity or reduced surround suppression in walking humans. Our data show that fundamental measurements of early visual processing differ between humans and mice and this has important implications for recent work on the links among arousal, behavior, and vision in these two species.

Individual Differences in Reading Skill Are Related to Trial-by-Trial Neural Activation Variability in the Reading Network

Recent work has suggested that variability in levels of neural activation may be related to behavioral and cognitive performance across a number of domains and may offer information that is not captured by more traditional measures that use the average level of brain activation. We examined the relationship between reading skill in school-aged children and neural activation variability during a functional MRI reading task after taking into account average levels of activity. The reading task involved matching printed and spoken words to pictures of items. Single trial activation estimates were used to calculate the mean and standard deviation of children's responses to print and speech stimuli; multiple regression analyses evaluated the relationship between reading skill and trial-by-trial activation variability. The reliability of observed findings from the discovery sample (n = 44; ages 8–11; 18 female) was then confirmed in an independent sample of children (n = 32; ages 8–11; 14 female). Across the two samples, reading skill was positively related to trial-by-trial variability in the activation response to print in the left inferior frontal gyrus pars triangularis. This relationship held even when accounting for mean levels of activation. This finding suggests that intrasubject variability in trial-by-trial fMRI activation responses to printed words accounts for individual differences in human reading ability that are not fully captured by traditional mean levels of brain activity. Furthermore, this positive relationship between trial-by-trial activation variability and reading skill may provide evidence that neural variability plays a beneficial role during early reading development.

SIGNIFICANCE STATEMENT Recent work has suggested that neural activation variability, or moment-to-moment changes in the engagement of brain regions, is related to individual differences in behavioral and cognitive performance across multiple domains. However, differences in neural activation variability have not yet been evaluated in relation to reading skill. In the current study, we analyzed data from two independent groups of children who performed an fMRI task involving reading and listening to words. Across both samples, reading skill was positively related to trial-by-trial variability in activation to print stimuli in the left inferior frontal gyrus pars triangularis, even when accounting for the more conventional measure of mean levels of brain activity. This finding suggests that neural variability could be beneficial in developing readers.

Ultrasound Elicits Behavioral Responses through Mechanical Effects on Neurons and Ion Channels in a Simple Nervous System

Focused ultrasound has been shown to stimulate excitable cells, but the biophysical mechanisms behind this phenomenon remain poorly understood. To provide additional insight, we devised a behavioral-genetic assay applied to the well-characterized nervous system of Caenorhabditis elegans nematodes. We found that pulsed ultrasound elicits robust reversal behavior in wild-type animals in a pressure-, duration-, and pulse protocol-dependent manner. Responses were preserved in mutants unable to sense thermal fluctuations and absent in mutants lacking neurons required for mechanosensation. Additionally, we found that the worm's response to ultrasound pulses rests on the expression of MEC-4, a DEG/ENaC/ASIC ion channel required for touch sensation. Consistent with prior studies of MEC-4-dependent currents in vivo, the worm's response was optimal for pulses repeated 300–1000 times per second. Based on these findings, we conclude that mechanical, rather than thermal, stimulation accounts for behavioral responses. Further, we propose that acoustic radiation force governs the response to ultrasound in a manner that depends on the touch receptor neurons and MEC-4-dependent ion channels. Our findings illuminate a complete pathway of ultrasound action, from the forces generated by propagating ultrasound to an activation of a specific ion channel. The findings further highlight the importance of optimizing ultrasound pulsing protocols when stimulating neurons via ion channels with mechanosensitive properties.

SIGNIFICANCE STATEMENT How ultrasound influences neurons and other excitable cells has remained a mystery for decades. Although it is widely understood that ultrasound can heat tissues and induce mechanical strain, whether or not neuronal activation depends on heat, mechanical force, or both physical factors is not known. We harnessed Caenorhabditis elegans nematodes and their extraordinary sensitivity to thermal and mechanical stimuli to address this question. Whereas thermosensory mutants respond to ultrasound similar to wild-type animals, mechanosensory mutants were insensitive to ultrasound stimulation. Additionally, stimulus parameters that accentuate mechanical effects were more effective than those producing more heat. These findings highlight a mechanical nature of the effect of ultrasound on neurons and suggest specific ways to optimize stimulation protocols in specific tissues.

GUCY2D Cone-Rod Dystrophy-6 Is a "Phototransduction Disease" Triggered by Abnormal Calcium Feedback on Retinal Membrane Guanylyl Cyclase 1

The Arg838Ser mutation in retinal membrane guanylyl cyclase 1 (RetGC1) has been linked to autosomal dominant cone–rod dystrophy type 6 (CORD6). It is believed that photoreceptor degeneration is caused by the altered sensitivity of RetGC1 to calcium regulation via guanylyl cyclase activating proteins (GCAPs). To determine the mechanism by which this mutation leads to degeneration, we investigated the structure and function of rod photoreceptors in two transgenic mouse lines, 362 and 379, expressing R838S RetGC1. In both lines, rod outer segments became shorter than in their nontransgenic siblings by 3–4 weeks of age, before the eventual photoreceptor degeneration. Despite the shortening of their outer segments, the dark current of transgenic rods was 1.5–2.2-fold higher than in nontransgenic controls. Similarly, the dim flash response amplitude in R838S⁺ rods was larger, time to peak was delayed, and flash sensitivity was increased, all suggesting elevated dark-adapted free cGMP in transgenic rods. In rods expressing R838S RetGC1, dark-current noise increased and the exchange current, detected after a saturating flash, became more pronounced. These results suggest disrupted Ca²⁺ phototransduction feedback and abnormally high free-Ca²⁺ concentration in the outer segments. Notably, photoreceptor degeneration, which typically occurred after 3 months of age in R838S RetGC1 transgenic mice in GCAP1,2^+/+ or GCAP1,2^+/– backgrounds, was prevented in GCAP1,2^–/– mice lacking Ca²⁺ feedback to guanylyl cyclase. In summary, the dysregulation of guanylyl cyclase in RetGC1-linked CORD6 is a "phototransduction disease," which means it is associated with increased free-cGMP and Ca²⁺ levels in photoreceptors.

SIGNIFICANCE STATEMENT In a mouse model expressing human membrane guanylyl cyclase 1 (RetGC1, GUCY2D), a mutation associated with early progressing congenital blindness, cone–rod dystrophy type 6 (CORD6), deregulates calcium-sensitive feedback of phototransduction to the cyclase mediated by guanylyl cyclase activating proteins (GCAPs), which are calcium-sensor proteins. The abnormal calcium sensitivity of the cyclase increases cGMP-gated dark current in the rod outer segments, reshapes rod photoresponses, and triggers photoreceptor death. This work is the first to demonstrate a direct physiological effect of GUCY2D CORD6-linked mutation on photoreceptor physiology in vivo. It also identifies the abnormal regulation of the cyclase by calcium-sensor proteins as the main trigger for the photoreceptor death.

Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences

Pain associates both sensory and emotional aversive components, and often leads to anxiety and depression when it becomes chronic. Here, we characterized, in a mouse model, the long-term development of these sensory and aversive components as well as anxiodepressive-like consequences of neuropathic pain and determined their electrophysiological impact on the anterior cingulate cortex (ACC, cortical areas 24a/24b). We show that these symptoms of neuropathic pain evolve and recover in different time courses following nerve injury in male mice. In vivo electrophysiological recordings evidence an increased firing rate and bursting activity within the ACC when anxiodepressive-like consequences developed, and this hyperactivity persists beyond the period of mechanical hypersensitivity. Whole-cell patch-clamp recordings also support ACC hyperactivity, as shown by increased excitatory postsynaptic transmission and contribution of NMDA receptors. Optogenetic inhibition of the ACC hyperactivity was sufficient to alleviate the aversive and anxiodepressive-like consequences of neuropathic pain, indicating that these consequences are underpinned by ACC hyperactivity.

SIGNIFICANCE STATEMENT Chronic pain is frequently comorbid with mood disorders, such as anxiety and depression. It has been shown that it is possible to model this comorbidity in animal models by taking into consideration the time factor. In this study, we aimed at determining the dynamic of different components and consequences of chronic pain, and correlated them with electrophysiological alterations. By combining electrophysiological, optogenetic, and behavioral analyses in a mouse model of neuropathic pain, we show that the mechanical hypersensitivity, ongoing pain, anxiodepressive consequences, and their recoveries do not necessarily exhibit temporal synchrony during chronic pain processing, and that the hyperactivity of the anterior cingulate cortex is essential for driving the emotional impact of neuropathic pain.

Basolateral Amygdala Neurons Maintain Aversive Emotional Salience

BLA neurons serve a well-accepted role in fear conditioning and fear extinction. However, the specific learning processes related to their activity at different times during learning remain poorly understood. We addressed this using behavioral tasks isolating distinct aspects of fear learning in male rats. We show that brief optogenetic inhibition of BLA neurons around moments of aversive reinforcement or nonreinforcement causes reductions in the salience of conditioned stimuli, rendering these stimuli less able to be learned about and less able to control fear or safety behaviors. This salience reduction was stimulus-specific, long-lasting, and specific to learning about, or responding to, the same aversive outcome, precisely the goals of therapeutic interventions in human anxiety disorders. Our findings identify a core learning process disrupted by brief BLA optogenetic inhibition. They show that a primary function of the unconditioned stimulus-evoked activity of BLA neurons is to maintain the salience of conditioned stimuli that precede it. This maintenance of salience is a necessary precursor for these stimuli to gain and maintain control over fear and safety behavior.

SIGNIFICANCE STATEMENT The amygdala is essential for learning to fear and learning to reduce fear. However, the specific roles served by activity of different amygdala neurons at different times during learning is poorly understood. We used behavioral tasks isolating distinct aspects of learning in rats to show that brief optogenetic inhibition of BLA neurons around moments of reinforcement or nonreinforcement disrupts maintenance of conditioned stimulus salience. This causes a stimulus-specific and long-lasting deficit in the ability of the conditioned stimulus to be learned about or control fear responses. These consequences are the precisely goals of therapeutic interventions in human anxiety disorders. Our findings identify a core learning process disrupted by brief BLA optogenetic inhibition.

Zinc in an ultraoligotrophic lake food web

Abstract

Zinc (Zn) bioaccumulation and trophic transfer were analyzed in the food web of Lake Nahuel Huapi, a deep, unpolluted ultraoligotrophic system in North Patagonia. Benthic macroinvertebrates, plankton, and native and introduced fish were collected at three sites. The effect of pyroclastic inputs on Zn levels in lacustrine food webs was assessed by studying the impact of the eruption of Puyehue-Cordón Caulle volcanic complex (PCCVC) in 2011, by performing three sampling campaigns immediately before and after the PCCVC eruption, and after 2 years of recovery of the ecosystem. Zinc trophodynamics in L. Nahuel Huapi food web was assessed using nitrogen stable isotopes (δ¹⁵N). There was no significant increase of Zn concentrations ([Zn]) in L. Nahuel Huapi biota after the PCCVC eruption, despite the evidence of [Zn] increase in lake water that could be associated with volcanic ash leaching. The organisms studied exhibited [Zn] above the threshold level considered for dietary deficiency, regulating Zn adequately even under a catastrophic situations like PCCVC 2011 eruption. Zinc concentrations exhibited a biodilution pattern in the lake's food web. To the best of our knowledge, present research is the first report of Zn biodilution in lacustrine systems, and the first to study Zn transfer in a freshwater food web including both pelagic and benthic compartments.

Transcriptome analysis reveals the molecular mechanism of hepatic metabolism disorder caused by chromium poisoning in chickens

Abstract

Chromium (Cr) is one of the most important environmental pollutants which are released into the environment due to their wide usage in numerous industries. The excess of Cr (VI) can induce hepatotoxicity, while the molecular mechanism that is involved in Cr (VI)-induced hepatotoxicity is unclear. We demonstrated the induction of chromium poisoning model in chickens to identify the differentially expressed genes (DEGs), and their functions were analyzed under different physiological and pathological conditions. Histopathological examination and transcriptome data for chromium-poisoned livers and control livers were annotated with Illumina® HiSeq 2000. The histopathological examination in chromium poisoning groups showed diapedesis, hemolysis, degeneration, nucleus pycnosis, and central phlebectasia in the liver. A total of 334 genes were upregulated and 509 genes were downregulated. The most strongly upregulated genes were HKDC1, DDX4, ACACA, FDFT1, CYYR1, PPP1R3C, and SLC16A14, while the most downregulated genes were MYBPC3, CCKAR, PCK1, and CPT1A. A Gene Ontology (GO) term with the highest enrichment of DEGs is small molecule metabolic process. In cell component domain, the term with the highest enrichment is extracellular matrix. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways showed that glucose metabolism, lipid metabolism, and protein metabolism were the most important metabolic pathways in the liver. The current study first time provides important clues and evidence for identifying the differentially expressed genes in livers due to Cr (VI)-induced liver injury in chickens.

Vascular Malformations and Health-Related Quality of Life

This systematic review and meta-analysis uses validated health-related quality-of-life instruments to compare the health-related quality of life of patients with vascular malformations with that of the US general population.

Favre-Racouchot Syndrome Following Long-term Exposure to Infrared Waves

This case report describes a patient with monolateral Favre-Racouchot syndrome following long-term exposure to infrared waves.

Quality of Life and the Dermatologist

This Editorial discusses factors that affect quality of life in those with vascular malformations, and dermatologists' goal of improving these aspects for patients.

Urticaria and Episcleritis in a Woman With Chronic Cough

A woman in her 30s presented with a 10-month history of painful pruritic eruption and painful red eyes; the eruption was exacerbated by stress but unrelated to time of day, ambient temperature, or sunlight exposure. She also reported recent worsening of a chronic cough. What is your diagnosis?

Utility of Baseline Transaminase Monitoring During Systemic Terbinafine Therapy for Pediatric Onychomycosis

To the Editor We applaud the important research findings by Patel et al regarding pediatric onychomycosis. In this study, the authors appropriately conclude that routine laboratory monitoring of children during treatment with terbinafine may be unnecessary, considering (1) the low incidence of clinically significant adverse effects; (2) the costs of laboratory tests; (3) workup of spurious laboratory abnormalities; and (4) patient discomfort.

Utility of Baseline Transaminase Monitoring During Systemic Terbinafine Therapy for Pediatric Onychomycosis—Reply

In Reply We appreciate the comments of Li and Mostaghimi regarding our study. While we generally agree that baseline monitoring of laboratory values in children prior to systemic therapy for onychomycosis may not be cost-effective or informative in otherwise healthy children, we would like to emphasize that, in our opinion, clinicians should be adherent to medication-use directives and current guidelines for patient safety, which at this time are unambiguous with regard to the recommendation for pretreatment laboratory screening for terbinafine. The package insert, which was last revised in January 2017, states "before prescribing Lamisil Tablets, perform liver function tests because hepatotoxicity may occur in patients with and without preexisting liver disease." Furthermore, the US Food and Drug Administration medication guide for terbinafine, which was last issued in August 2016, states "your doctor should do a blood test to check you for liver problems before you start treatment with LAMISIL Tablets." With these guidelines in place, we currently do not feel comfortable, based on this one study, to advise clinicians to dismiss these recommendations. Importantly, this study does give us the opportunity to open up lines of communication with the US regulatory bodies to consider altering the terbinafine medication guidance specifically for pediatric patients and consider additional studies that would help solidify these data. We want to maintain the highest standard of care and safety for the treatment of pediatric patients while continuing to practice cost-effective and evidence-based medicine.

Chronic Urticaria Associated With Methylisothiazolinone Type IV Hypersensitivity

This case report describes a patient with chronic urticaria associated with methylisothiazolinone type IV hypersensitivity.

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Toxicity interactions between manganese (Mn) and lead (Pb) or cadmium (Cd) in a model organism the nematode C. elegans

Abstract

Manganese (Mn) is considered as an emerging metal contaminant in the environment. However, its potential interactions with companying toxic metals and the associated mixture effects are largely unknown. Here, we investigated the toxicity interactions between Mn and two commonly seen co-occurring toxic metals, Pb and Cd, in a model organism the nematode Caenorhabditis elegans. The acute lethal toxicity of mixtures of Mn+Pb and Mn+Cd were first assessed using a toxic unit model. Multiple toxicity endpoints including reproduction, lifespan, stress response, and neurotoxicity were then examined to evaluate the mixture effects at sublethal concentrations. Stress response was assessed using a daf-16::GFP transgenic strain that expresses GFP under the control of DAF-16 promotor. Neurotoxicity was assessed using a dat-1::GFP transgenic strain that expresses GFP in dopaminergic neurons. The mixture of Mn+Pb induced a more-than-additive (synergistic) lethal toxicity in the worm whereas the mixture of Mn+Cd induced a less-than-additive (antagonistic) toxicity. Mixture effects on sublethal toxicity showed more complex patterns and were dependent on the toxicity endpoints as well as the modes of toxic action of the metals. The mixture of Mn+Pb induced additive effects on both reproduction and lifespan, whereas the mixture of Mn+Cd induced additive effects on lifespan but not reproduction. Both mixtures seemed to induce additive effects on stress response and neurotoxicity, although a quantitative assessment was not possible due to the single concentrations used in mixture tests. Our findings demonstrate the complexity of metal interactions and the associated mixture effects. Assessment of metal mixture toxicity should take into consideration the unique property of individual metals, their potential toxicity mechanisms, and the toxicity endpoints examined.

Nephrotoxicity in Hybrid sparrow ( Passer domesticus × Passer hispaniolensis ) living near a phosphate treatment factory complex in southern Tunisia: a biochemical and histological study

Abstract

Our study was designed to evaluate impacts of exposure to pollutants, released by the Gabès–Ghannouche factory complex of phosphate treatment, on biochemical biomarkers and histopathological indices in kidney tissues of Hybrid sparrow (Passer domesticus × Passer hispaniolensis) in Gabès city. Our results show evidence of a pronounced impairment in kidney function which is confirmed by remarkable blood chemical alterations in sparrows living in Ghannouche, the most polluted site. Moreover, superoxide dismutase and catalase activities were found to be decreased in birds sampled from the contaminated site when compared to less polluted areas. The population of sparrows feeding in Ghannouche had enhanced renal thiobarbituric acid reactive substance levels, indicating oxidative damage to membrane lipids. Some histopathological alterations were also observed including kidney interstitial dilatations. Overall, our findings demonstrated that the exposure to pollutants released by the factory complex possessed nephrotoxic by depleting renal antioxidant defense system and promoting kidney morphometric damage in sparrows. These results constitute an early warning of an ecological change in relation to human health.

Adsorptive removal of fluoride from water by granular zirconium–aluminum hybrid adsorbent: performance and mechanisms

Abstract

Granular zirconium–aluminum hybrid adsorbent (GZAHA) was fabricated for efficient defluoridation of groundwater in filter application. GZAHA was formed through the aggregation of massive Zr/Al oxide nanoparticles with an amorphous pattern. This adsorbent has a satisfactory mechanical strength, a specific surface area of 29.55 m²/g, and numerous hydroxyl groups on the surface. F adsorption equilibrium could be achieved within 12 h, and the sorption process followed a pseudo-second-order reaction rate. The maximum adsorption capacity of F estimated from the Langmuir model was 65.07 mg/g at 25 °C, being greater than most of other granular adsorbents. The removal efficiency of F could be maintained in a wide pH range of 5~9. The presence of phosphate posed an adverse effect on F adsorption due to the competition mechanisms. The saturated adsorbents could be regenerated and reused for four times by using sodium hydroxide solution as an eluent, and the adsorption capacity remained around 80%. Besides electrostatic attraction and Al–F complex, surface complexation and anion exchange were also involved in the adsorption process. Continuous adsorption experiments illustrated that 808 bed volumes of F-contaminated water (F = 5 mg/L) were treated successfully by a GZAHA-packed column without second pollution.

Role of fuel additives on reduction of NO X emission from a diesel engine powered by camphor oil biofuel

Abstract

The present study intends to explore the effect of the addition of fuel additives with camphor oil (CMO) on the characteristics of a twin-cylinder compression ignition (CI) engine. The lower viscosity and boiling point of CMO when compared to diesel could improve the fuel atomization, evaporation, and air/fuel mixing process. However, the lower cetane index of CMO limits its use as a drop in fuel for diesel in CI engine. In general, NO_X emission increases for less viscous and low cetane (LVLC) fuels due to pronounced premixed combustion phase. To improve the ignition characteristics and decrease NO_X emissions, fuel additives such as diglyme (DGE)—a cetane enhancer, cumene (CU)—an antioxidant, and eugenol (EU) and acetone (A)—bio-additives, are added 10% by volume with CMO. The engine used for the experimentation is a twin-cylinder tractor engine that runs at a constant speed of 1500 rpm. The engine was operated with diesel initially to attain warm-up condition, which facilitates the operation of neat CMO. At full load condition, brake thermal efficiency (BTE) for CMO is higher (29.6%) than that of diesel (28.1%), while NO_X emission is increased by 9.4%. With DGE10 (10% DGE + 90% CMO), the ignition characteristics of CMO are improved and BTE is increased to 31.7% at full load condition. With EU10 (10% EU + 90% CMO) and A10 (10% A + 90% CMO), NO_X emission is decreased by 24.6 and 17.8% when compared to diesel, while BTE is comparable to diesel. While HC and CO emission decreased for DGE10 and CU10, they increased for EU10 and A10 when compared to baseline diesel and CMO.

Absorption and subcellular distribution of cadmium in tea plant ( Camellia sinensis cv. “Shuchazao”)

Abstract

A hydroponic experiment was performed to investigate the Cd absorption and subcellular distribution in tea plant, Camellia sinensis. Increased Cd accumulation potential was observed in the tea plant in a Cd-enriched environment, but most of the Cd was absorbed by the roots of C. sinensis. The Cd in all the root fractions was mostly distributed in the soluble fraction, followed by the cell wall fraction. By contrast, the Cd was least distributed in the organelle fraction. The adsorption of Cd onto the C. sinensis roots was described well by the Langmuir isotherm model than the Freundlich isotherm. Most of the Cd (38.6 to 59.4%) was integrated with pectates and proteins in the roots and leaves. Fourier transform infrared spectroscopy (FTIR) analysis showed that small molecular organic substances, such as amino acids, organic acids, and carbohydrates with N–H, C=O, C–N, and O–H functional groups in the roots, bonded with Cd(II). The Cd accumulation in the C. sinensis leaves occurred in the cell wall and organelle fractions. C. sinensis has great capability to transport Cd, thereby indicating pollution risk. The metal homeostasis of Fe, Mn, Ca, and Mg in C. sinensis was affected when the Cd concentration was 1.0–15.0 mg/L.

Thinking About Events: A Pragmatist Account of the Objects of Episodic Hypothetical Thought

Abstract

The debate over the objects of episodic memory has for some time been stalled, with few alternatives to familiar forms of direct and indirect realism being advanced. This paper moves the debate forward by building on insights from the recent psychological literature on memory as a form of episodic hypothetical thought (or mental time travel) and the recent philosophical literature on relationalist and representationalist approaches to perception. The former suggests that an adequate account of the objects of episodic memory will have to be a special case of an account of the objects of episodic hypothetical thought more generally. The latter suggests that an adequate account of the objects of episodic hypothetical thought will have to combine features of direct realism and representationalism. We develop a novel pragmatist-inspired account of the objects of episodic hypothetical thought that has the requisite features.

The relationship between mitotic rate and depth of invasion in biopsies of malignant melanoma

Onkologische Chirurgie 4.0

Zusammenfassung

Hintergrund

Die Fortschritte in der Digitalisierung und der Informationsverarbeitung nehmen auch Einfluss auf die interventionelle Medizin. Sich dieser Entwicklung anzupassen, wird eine zentrale Herausforderung der modernen (onkologischen) Chirurgie sein, um weiterhin optimierte Therapieverfahren anbieten zu können.

Ziel und Schlussfolgerung

Im Hinblick auf die technologische Entwicklung innerhalb und auch außerhalb der Medizin schlagen die Autoren eine „Chirurgie 4.0" vor, die ein besonderes Augenmerk auf die Sammlung, Aufbereitung und Analyse von perioperativen Daten legt, um durch intelligente Assistenzsysteme die Eingriffe effizienter und sicherer zu machen. Hierzu werden – bezogen auf die 3 operativen Phasen Planung, Durchführung und Nachbehandlung – die Bedeutung der Datengenerierung, Analyse und Interpretation und die möglichen Anwendungen für kontextsensitive mechatronische oder softwarebasierte Unterstützungssysteme dargestellt.

Therapie des rezidivierten und refraktären multiplen Myeloms

Zusammenfassung

Hintergrund

Die Rezidivbehandlung beim multiplen Myelom (MM) ist durch Zulassung vieler neuer Substanzen komplexer geworden.

Ziel

Es sollen aktuelle Therapieoptionen für das rezidivierte und refraktäre MM (RRMM) dargestellt werden.

Material und Methoden

Nach aktueller Literaturrecherche internationaler Studien- bzw. Übersichtsartikel werden Antimyelomtherapien beim RRMM beschrieben.

Ergebnisse und Schlussfolgerungen

Aufgrund des deutlich verlängerten Überlebens von MM-Patienten erleiden nahezu alle ein oder mehrere Rezidive während ihres Krankheitsverlaufs. Zahlreiche neue zugelassene Substanzen im Rezidiv sowie zahlreiche Substanzen in klinischen Studien haben die Prognose beim RRMM erheblich verbessert, lassen die Therapiewahl aber auch komplexer ausfallen. Zu berücksichtigen sind hierbei patienten-, krankheits- und therapiespezifische Faktoren. Interdisziplinäre Tumorboards zur Planung eines bestmöglichen therapeutischen Vorgehens sind dabei hilfreich. Zahlreiche neue zugelassene Substanzen, die im Rezidiv auch bei intensiv vorbehandelten Patienten eingesetzt werden, umfassen neue immunmodulatorische Substanzen wie Pomalidomid, neue Proteasomeninhibitoren wie Carfilzomib und Ixazomib, Antikörper wie Daratumumab und Elotuzumab sowie den Histondeacetylase(HDAC)-Inhibitor Panobinostat. Die autologe Stammzelltransplantation (SZT) spielt in der Rezidivsituation bei genügend fitten Patienten ebenfalls eine Rolle, insbesondere, um eine tiefe Remission zu induzieren oder – nach bereits durchgeführter erster SZT und bei mindestens 18 Monaten Remissionsinduktion – um eine länger anhaltende Remission erneut zu erreichen. Neben der Antimyelomtherapie ist auch die Supportivtherapie essenziel und umfasst u. a. die suffiziente Schmerztherapie, die Vermeidung bzw. Behandlung von Osteolysen oder Frakturen und von Infektkomplikationen.

EPH Receptor Signaling as a Novel Therapeutic Target in NF2-deficient Meningioma

Abstract

Background

Meningiomas are the most common primary brain tumor in adults, and somatic loss of the NF2 tumor suppressor gene is a frequent genetic event. There is no effective treatment for tumors that recur or continue to grow despite surgery and/or radiation. Therefore, targeted therapies that either delay tumor progression or cause tumor shrinkage are much needed. Our earlier work established mTORC1/mTORC2 activation in NF2-deficient meningiomas.

Methods

High-throughput kinome analyses were performed in NF2-null human arachnoidal and meningioma cell lines to identify functional kinome changes upon NF2 loss. Immunoblotting confirmed the activation of kinases and demonstrated effectiveness of drugs to block the activation. Drugs, singly and in combination, were screened in cells for their growth inhibitory activity. Anti-tumor drug efficacy was tested in an orthotopic meningioma model.

Results

EPH receptor tyrosine kinases (EPH RTKs), c-KIT and Src family kinase (SFK) members, which are biological targets of dasatinib, were among the top candidates activated in NF2-null cells. Dasatinib significantly inhibited phospho-EPHA2 (pEPHA2), pEPHB1, c-KIT and Src/SFK in NF2-null cells, showing no cross-talk with mTORC1/2 signaling. Post-treatment kinome analyses showed minimal adaptive changes. While dasatinib treatment showed some activity, dual mTORC1/2 inhibitor and its combination with dasatinib elicited stronger growth inhibition in meningiomas.

Conclusion

Co-targeting mTORC1/2 and EPH RTK/SFK pathways could be a novel effective treatment strategy for NF2-deficient meningiomas.

Fungal Fragments and Fungal Aerosol Composition in Sawmills

Abstract

Assessment of exposure to fungi has commonly been limited to fungal spore measurements that have shown associations between fungi and development or exacerbation of different airway diseases. Because large numbers of submicronic fragments can be aerosolized from fungal cultures under laboratory conditions, it has been suggested that fungal exposure is more complex and higher than that commonly revealed by spore measurements. However, the assessment of fungal fragments in complex environmental matrix remain limited due to methodological challenges. With a recently developed immunolabeling method for field emission scanning electron microscope (FESEM), we could assess the complex composition of fungal aerosols present in personal thoracic samples collected from two Norwegian sawmills. We found that large fungal fragments (length >1 µm) dominated the fungal aerosols indicating that the traditional monitoring approach of spores severely underestimate fungal exposure. The composition of fungal aerosols comprised in average 9% submicronic fragments, 62% large fragments, and 29% spores. The average concentrations of large and submicronic fragments (0.2–1 µm) were 3 × 10⁵ and 0.6 × 10⁵ particles m⁻³, respectively, and correlated weakly with spores (1.4 × 10⁵ particles m⁻³). The levels of fragments were 2.6 times higher than the average spore concentration that was close to the proposed hazardous level of 10⁵ spores per m³. The season influenced significantly the fungal aerosol concentrations but not the composition. Furthermore, the ratio of spores in the heterogeneous fungal aerosol composition was significantly higher in saw departments as compared to sorting of green timber departments where the fungal fragments were most prevalent. Being the dominating particles of fungal aerosols in sawmills, fungal fragments should be included in exposure-response studies to elucidate their importance for health impairments. Likewise, the use of fungal aerosol composition in such studies should be considered.

Credal pragmatism

Abstract

According to doxastic pragmatism, certain perceived practical factors, such as high stakes and urgency, have systematic effects on normal subjects' outright beliefs. Upholders of doxastic pragmatism have so far endorsed a particular version of this view, which we may call threshold pragmatism. This view holds that the sensitivity of belief to the relevant practical factors is due to a corresponding sensitivity of the threshold on the degree of credence necessary for outright belief. According to an alternative but yet unrecognised version of doxastic pragmatism, practical factors affect credence rather than the threshold on credence. Let's call this alternative view credal pragmatism. In this paper, I argue that credal pragmatism is more plausible than threshold pragmatism. I show that the former view better accommodates a cluster of intuitive and empirical data. I conclude by considering the issue of whether our doxastic attitudes' sensitivity to practical factors can be considered rational, and if yes, in what sense.

Revealing the Hidden Curriculum in Higher Education

Abstract

The so-called 'hidden curriculum' (HC) is often presented as a counterproductive element in education, and many scholars argue that it should be eliminated, by being made explicit, in education in general and specifically in higher education (HE). The problem of the HC has not been solved by the transition from a teacher-centered education to a student-centered educational model that takes the student's experience as the starting point of learning. In this article we turn to several philosophers of education (Dewey, Kohlberg, Whitehead, Peters and Knowles) to propose that HC can be made explicit in HE when the teacher recognizes and lives his/her teaching as a personal issue, not merely a technical one; and that the students' experience of the learning process is not merely individual but emerges through their interpersonal relationship with the teacher. We suggest ways in which this interpersonal relationship can be strengthened despite current challenges in HE.