2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea

Abstract

These guidelines are intended for use by healthcare professionals who care for children and adults with suspected or confirmed infectious diarrhea. They are not intended to replace physician judgement regarding specific patients or clinical or public health situations. This document does not provide detailed recommendations on infection prevention and control aspects related to infectious diarrhea.

2017 Infectious Diseases Society of America Infectious Diarrhea Guidelines: A View From the Clinical Laboratory

gastroenteritisculture-independent diagnostic testsmultiplex panelsIDSA guidelinesdiagnosis

Cancer characterization and diagnosis with SERS-encoded particles

Early diagnosis, monitoring and treatment selection of cancer represent major challenges in medicine. The definition of the complex clinical and molecular landscape of cancer requires the combination of multip...

Spatial distributions, fractionation characteristics, and ecological risk assessment of trace elements in sediments of Chaohu Lake, a large eutrophic freshwater lake in eastern China

Abstract

The concentrations, spatial distribution, fractionation characteristics, and potential ecological risks of trace elements (Cu, Pb, Zn, Cr, Ni, and Co) in the surface sediment samples collected from 32 sites in Chaohu Lake were investigated. The improved BCR sequential extraction procedure was applied to analyze the chemical forms of trace elements in sediments. The enrichment factor (EF), sediment quality guidelines (SQGs), potential ecological risk index (PERI), and risk assessment code (RAC) were employed to evaluate the pollution levels and the potential ecological risks. The results found that the concentrations of Cu, Pb, Zn, Cr, Ni, and Co in the surface sediments were 78.59, 36.91, 161.84, 98.87, 38.92, and 10.09 mg kg⁻¹, respectively. The lower concentrations of Cu, Pb, Zn, Cr, and Ni were almost found in the middle part of the lake, while Co increased from the western toward the eastern parts of the lake. Cr, Ni, Co, and Zn predominantly existed in the residual fractions, with the average values of 76.35, 59.22, 45.60, and 44.30%, respectively. Cu and Pb were mainly combined with Fe/Mn oxides in reducible fraction, with the average values of 66.4 and 69.1%, respectively. The pollution levels were different among the selected elements. Cu had the highest potential ecological risk, while Cr had the lowest potential ecological risk.

Spatial distribution and potential biological risk of some metals in relation to granulometric content in core sediments from Chilika Lake, India

Abstract

The article presents first systematic report on the concentration of selected major elements [iron (Fe) and manganese (Mn)] and minor elements [zinc (Zn), copper (Cu), chromium (Cr), lead (Pb), nickel (Ni), and cobalt (Co)] from the core sediment of Chilika Lake, India. The analyzed samples revealed higher content of Pb than the background levels in the entire study area. The extent of contamination from minor and major elements is expressed by assessing (i) the metal enrichments in the sediment through the calculations of anthropogenic factor (AF), pollution load index (PLI), Enrichment factor (EF), and geoaccumulation index (Igeo) and (ii) potential biological risks by the use of sediment quality guidelines like effect range median (ERM) and effect range low (ERL) benchmarks. The estimated indices indicated that sediment is enriched with Pb, Ni, Cr, Cu and Co. The enrichment of these elements seems to be due to the fine granulometric characteristics of the sediment with Fe and Mn oxyhydroxides being the main metal carriers and fishing boats using low grade paints, fuel, and fishing technology using lead beads fixed to fishing nets. Trace element input to the Chilika lake needs to be monitored with due emphasis on Cr and Pb contaminations since the ERM and ERL benchmarks indicated potential biological risk with these metals.

First determination of fullerenes in the Austrian market and environment: quantitative analysis and assessment

Abstract

This study forms the first report on analyzing fullerenes in the Austrian environment and cosmetic products available on the Austrian market. We developed, optimized, and validated a novel method for the analysis of C₆₀ and C₇₀ fullerenes and N-methylfulleropyrrolidine C₆₀ (NMFP) for measuring sensitivities in the low nanograms per liter range in order to prove their presence in the environment (12 wastewater- and 12 sewage sludge samples) and in 11 selected fullerene-containing cosmetic products from three different brands. The optimized method relies on a liquid-liquid extraction (LLE) or solid-liquid extraction (SLE) and, for the first time, introduced the Carrez-clarification, followed by liquid chromatography (LC) and coupled to a hybrid triple quadrupole mass spectrometry (MS) quantification. The total variability of the new established LC-MS/MS method based on all the tested matrices was below 10%. We found recoveries generally higher than 70% for both tap water and surface water. The limits of quantitation (LOQ) for the wastewater samples were measured to be from 0.8 to 1.6 ng/L, for the sewage sludge samples, from 1.4 to 2.6 ng/g DM (drymass), and for the cosmetic samples from 0.2 to 0.4 ng/g. None of the analyzed samples of wastewater or sewage sludge samples contained fullerenes. But in 70% of the tested cosmetics, fullerene concentrations between 10 and 340 ng/g were detected. These values were much lower than concentrations causing toxicity in water animals.

Combined Gluteus and Pudendal Thigh Flap Reconstruction of Vaginal Defects following Robotic Abdominoperineal Resection

Summary: Low-lying rectal cancers are being treated more frequently with robotic-assisted abdominoperineal resection, obviating the need for laparotomy and the ability to raise vertical rectus abdominis musculocutaneous flaps. For female patients, posterior vaginectomy often accompanies the resection. Combined pudendal thigh flaps as an extension of bilateral gluteus advancement flaps allow for posterior vaginal resurfacing with thin pliable fasciocutaneous flaps, which rest on the gluteal flap soft-tissue bulk that obliterates the pelvic dead space. For patients with advanced cancers who have had neoadjuvant chemoradiation, the pudendal skin paddle can be planned more laterally to bring in healthier medial thigh skin. The donor incisions lie within the gluteal cleft and crease and groin creases recapitulating normal perineal anatomy and aesthetics.

Optimizing Nipple Position following Nipple-Sparing Mastectomy

Background: The best treatment for nipple malposition following nipple-sparing mastectomy is prevention. This article reviews basic elements for success in nipple-sparing mastectomy and offers an option to patients with grade 2–3 breast ptosis who strongly desire to preserve the nipple. Methods: Retrospective review identified patients undergoing nipple-sparing mastectomy and immediate reconstruction. Results: Patient selection centered on realistic goals for postoperative breast size, nipple position, and when not to save the nipple. The choice of device considered projection and nipple centralization as equal components and led to wider, lower profile devices selectively for the first stage of reconstruction. In severe grade 2–3 nipple ptosis, an inferior vertical incision or wedge excision was used to enhance nipple position postoperatively. Eighteen consecutive patients underwent 32 implant-based breast reconstructions following nipple-sparing mastectomy with the vertical incision. The average age was 45 years old, and the average body mass index was 26.7. Direct-to-implant reconstruction was performed in 25%, whereas 75% had tissue expander-implant reconstruction. Overall complications included infection (3%) and nipple necrosis (3%) leading to explant in 1 reconstruction. Conclusions: The final nipple position following nipple-sparing mastectomy can be optimized with preoperative planning. The vertical incision, combined with proper patient selection and choice of device, may increase eligibility for nipple-sparing procedures in patients with grade 2–3 ptosis who desire nipple preservation.

La enfermedad dermatológica en urgencias y su importante impacto sobre la calidad de vida de los pacientes

Publication date: Available online 18 October 2017
Source:Actas Dermo-Sifiliográficas
Author(s): E. Martínez García

La bibliometría como herramienta de conocimiento de la situación de la investigación clínica española en dermatología y sus implicaciones futuras

Publication date: Available online 18 October 2017
Source:Actas Dermo-Sifiliográficas
Author(s): I. Belinchón Romero

Risk of hepatitis B virus reactivation in patients treated with anti-TNFα agents for immune-mediated inflammatory diseases

Publication date: Available online 18 October 2017
Source:Actas Dermo-Sifiliográficas
Author(s): R. Pereira, I. Raposo, F. Nery, T. Torres

A single-centre retrospective proof of concept review of salvage of infected or exposed implant breast reconstructions with explantation and one-stage free flap replacement

Implant-based breast reconstruction has relatively high complication rates. Removal of infected implants and immediate autologous reconstruction is a safe single stage procedure that preserves the native breast skin envelope.

Effects of infraorbital nerve's anatomical course on fracture pattern of the orbital floor

In this study, details of the infraorbital nerve's (ION's) anatomical course variants were compared using computed tomography (CT) and relationships between the variants and fracture patterns in the orbital floor were investigated. Fifty-two normal individuals and 50 patients with unilateral isolated orbital floor fractures were enrolled in this study. Four measurements in normal individuals and 5 measurements in fracture patients were obtained in parasagittal sections. The anatomical variations of the ION were categorized into 3 types based on the classification by Ferences et al.

Localization of collagen type 5 in the papillary dermis and its role in maintaining stem cell functions

Letter to the Editor

Effects of kestose on gut mucosal immunity in an atopic dermatitis mouse model

Atopic dermatitis has markedly increased in western countries and has been investigated with respect to the relationship between environmental factors and the human immune system [1,2]. Allergic diseases could be driven by in response to environmental or food antigens [2]; however, the mechanisms are not clearly understood. Recently, one of the more interesting studies investigating intestinal microbiota reported that commensal bacteria and their metabolites interact with the development of the immune system.

A Single-arm Open-label Clinical Trial of Autologous Epidermal Cell Transplantation for Stable Vitiligo: A 30-month Follow-Up

Vitiligo is a common pigmentation disorder with a worldwide prevalence of 0.4%–2% [1] characterized by white patches on the skin and mucus membrane [2]. The disease negatively impacts on the patients' quality of life, psychological health and social activities [2,3]. Various therapies are available for vitiligo including local or systemic immunosuppressive drugs, light-based and surgical therapies. However, all the patients do not show satisfactory response to the current treatments [4–7].

Anacardic acid reduces lipogenesis in human differentiated adipocytes via inhibition of histone acetylation

Adipose tissue is a dynamic endocrine organ that has a great impact on overall energy and metabolic homeostasis. Recent studies have suggested that the maintenance of adequate fat volume without excessive accumulation or loss is important for energy homeostasis. Intracellular lipid accumulation and homeostasis in adipocytes is determined by lipogenesis (triglyceride synthesis) and lipolysis (triglyceride breakdown) [1]. Lipogenesis is mediated by increased expression and activity of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC).

Turkish dermatologists' approach for chronic spontaneous urticaria: A questionnaire based study

Publication date: Available online 18 October 2017
Source:Dermatologica Sinica
Author(s): Emek Kocatürk, Etikan Piril, Taskapan Oktay, Atakan Nilgun, Erdem Teoman, Utas Serap, Savk Ekin, Bulbul Baskan Emel, Koca Rafet, Aktan Sebnem
Background/ObjectivesChronic spontaneous urticaria (CSU) is a common skin disorder which represents a challenge both for the patients and physicians. Guidelines and treatment algorithms have been created to help physicians to ease management. Our aim was to determine Turkish dermatologists' approach to CSU with regard to treatment, search for causative factors and use of instruments to assess the quality of life and severity of the disease.MethodsThis was a cross-sectional methodological study which was performed by delivery of a questionnaire including ten questions about the management of CSU.ResultsAnalyses of 314 questionnaires revealed that the most common first-line treatments were non-sedating antihistamines in standard doses (65.6%), while second-line treatment was updosing antihistamines (59.9%) followed by addition of sedative-antihistamines (26.4%) and systemic steroids (19.1%). Third-line treatment option was omalizumab in 35% followed by systemic steroids. Twenty-two percent of the dermatologists referred the patients to a center experienced in urticaria. Most of them were performing laboratory testing for underlying causes including thyroid function tests, C-reactive protein, thyroid auto-antibodies, stool analyses, infection markers. Urticaria activity score and chronic urticaria quality of life questionnaire were used by 30 and 13%, respectively, while 56% were using none of the instruments.ConclusionOur study showed that the therapeutic management of Turkish dermatologists was parallel to the European Urticaria Guidelines. The high utility of omalizumab as a third line regimen improved patient care. Nevertheless there is a need for centers experienced in urticaria to refer antihistamine-resistant patients where third-line treatment options can not be implemented.

Are distinct nitrous oxide emission factors required for cattle urine and dung deposited on pasture in western Canada?

Abstract

While some countries disaggregate N₂O emission factors for urine and dung deposited onto pastures, in Canada, distinct N₂O emission factors for beef cattle urine and dung have not been defined. To help address this knowledge gap, we conducted a 1-year study to quantify N₂O fluxes from beef cattle urine and dung patches on a semiarid tame pasture in western Canada, as well as to quantify the N₂O emission factors (EF3) for urine and dung as the percentage of applied N emitted as N₂O-N. Urine and dung were deposited when soil water-filled pore space was nearly 60%, a wet soil condition for the grazing season in the semiarid study region, which led to a burst of N₂O from urine in the first 14 days of the study (42% of total N emitted). Urine emitted more cumulative N₂O (P < 0.001) and had a greater N₂O emission factor (P = 0.002) than dung. The urine patch emitted 1.30 ± 0.47 g N₂O-N m⁻² year⁻¹, while the dung patch emitted 0.083 ± 0.020 g N₂O-N m⁻² year⁻¹ (mean values ± SD). The N₂O emission factor for urine was 1.32 ± 0.49%, while for dung it was 0.03 ± 0.02%. We conclude that more study is needed to determine if distinct N₂O emission factors are required for urine and dung deposited onto pasture in western Canada to more accurately estimate national N₂O inventories.

A single-centre retrospective proof of concept review of salvage of infected or exposed implant breast reconstructions with explantation and one-stage free flap replacement

Publication date: Available online 18 October 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Russell J. Bramhall, Izaro Hernan, Paul A. Harris
IntroductionImplant-based breast reconstruction has relatively high complication rates. Removal of infected implants and immediate autologous reconstruction is a safe single stage procedure that preserves the native breast skin envelope.MethodsA single-centre retrospective proof of concept review of all salvage procedures performed for acute/chronic infected or exposed implant-based reconstructions by a single surgeon over a 6 year period.ResultsWe present 13 cases of a particularly difficult subgroup over a 6 year period that were for acute/chronic infection/extrusion. All were successfully salvaged in one procedure by implant removal and immediate free flap reconstruction with no significant complications. All patients had a change of pocket from subpectoral to subcutaneous and partial capsulectomies. 4 patients had unilateral DIEP flaps for unilateral reconstruction, 3 bi-pedicle DIEP flaps for unilateral reconstruction, 2 bilateral TUG flaps for unilateral reconstruction, 3 bilateral DIEP flaps for bilateral reconstruction and 1 patient had a unilateral DIEP and implant for unilateral reconstruction.ConclusionsThese patients are often slim with limited donor sites and pose technical challenges, often requiring double free flap reconstructions. Single stage implant removal and autologous reconstruction preserves the breast skin envelope to maximise cosmesis in a single procedure. The introduction of healthy, well vascularised tissue may also help to treat the infection.

Effects of infraorbital nerve's anatomical course on fracture pattern of the orbital floor

Publication date: Available online 18 October 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Junhyung kim, Sang Woo Park, Jaehoon Choi, Woonhyeok Jeong, Ryeolwoo kim
In this study, details of the infraorbital nerve's (ION's) anatomical course variants were compared using computed tomography (CT) and relationships between the variants and fracture patterns in the orbital floor were investigated. Fifty-two normal individuals and 50 patients with unilateral isolated orbital floor fractures were enrolled in this study. Four measurements in normal individuals and 5 measurements in fracture patients were obtained in parasagittal sections. The anatomical variations of the ION were categorized into 3 types based on the classification by Ferences et al. Among the normal individuals, 42 orbits were classified as type 1 ION, 48 orbits as type 2 and 14 orbits as type 3. The distance from the inferior orbital rim to the upper border of the inferior orbital foramen and the length of descension portion of the ION in type 1 ION were significantly shorter than in type 2 and type 3 IONs. In patients with orbital floor fractures, the distance from the inferior orbital rim to the upper border of the inferior orbital foramen was positively correlated with herniation level of bone and soft tissue. The ION had 3 anatomical variants based on the degree of descension in the anterior portion of the orbit. When fracture of the orbital floor occurs in patients with type 1 ION, inferior displacement of the fractured orbital bone and orbital soft tissue may be less severe than in patients with other ION types.

Individual Alpha Peak Frequency Predicts 10 Hz Flicker Effects on Selective Attention

Rhythmic visual stimulation ("flicker") is primarily used to "tag" processing of low-level visual and high-level cognitive phenomena. However, preliminary evidence suggests that flicker may also entrain endogenous brain oscillations, thereby modulating cognitive processes supported by those brain rhythms. Here we tested the interaction between 10 Hz flicker and endogenous alpha-band (~10 Hz) oscillations during a selective visuospatial attention task. We recorded EEG from human participants (both genders) while they performed a modified Eriksen flanker task in which distractors and targets flickered within (10 Hz) or outside (7.5 or 15 Hz) the alpha band. By using a combination of EEG source separation, time-frequency, and single-trial linear mixed-effects modeling, we demonstrate that 10 Hz flicker interfered with stimulus processing more on incongruent than congruent trials (high vs low selective attention demands). Crucially, the effect of 10 Hz flicker on task performance was predicted by the distance between 10 Hz and individual alpha peak frequency (estimated during the task). Finally, the flicker effect on task performance was more strongly predicted by EEG flicker responses during stimulus processing than during preparation for the upcoming stimulus, suggesting that 10 Hz flicker interfered more with reactive than proactive selective attention. These findings are consistent with our hypothesis that visual flicker entrained endogenous alpha-band networks, which in turn impaired task performance. Our findings also provide novel evidence for frequency-dependent exogenous modulation of cognition that is determined by the correspondence between the exogenous flicker frequency and the endogenous brain rhythms.

SIGNIFICANCE STATEMENT Here we provide novel evidence that the interaction between exogenous rhythmic visual stimulation and endogenous brain rhythms can have frequency-specific behavioral effects. We show that alpha-band (10 Hz) flicker impairs stimulus processing in a selective attention task when the stimulus flicker rate matches individual alpha peak frequency. The effect of sensory flicker on task performance was stronger when selective attention demands were high, and was stronger during stimulus processing and response selection compared with the prestimulus anticipatory period. These findings provide novel evidence that frequency-specific sensory flicker affects online attentional processing, and also demonstrate that the correspondence between exogenous and endogenous rhythms is an overlooked prerequisite when testing for frequency-specific cognitive effects of flicker.

This Week in The Journal

On Myelinated Axon Plasticity and Neuronal Circuit Formation and Function

Studies of activity-driven nervous system plasticity have primarily focused on the gray matter. However, MRI-based imaging studies have shown that white matter, primarily composed of myelinated axons, can also be dynamically regulated by activity of the healthy brain. Myelination in the CNS is an ongoing process that starts around birth and continues throughout life. Myelin in the CNS is generated by oligodendrocytes and recent evidence has shown that many aspects of oligodendrocyte development and myelination can be modulated by extrinsic signals including neuronal activity. Because modulation of myelin can, in turn, affect several aspects of conduction, the concept has emerged that activity-regulated myelination represents an important form of nervous system plasticity. Here we review our increasing understanding of how neuronal activity regulates oligodendrocytes and myelinated axons in vivo, with a focus on the timing of relevant processes. We highlight the observations that neuronal activity can rapidly tune axonal diameter, promote re-entry of oligodendrocyte progenitor cells into the cell cycle, or drive their direct differentiation into oligodendrocytes. We suggest that activity-regulated myelin formation and remodeling that significantly change axonal conduction properties are most likely to occur over timescales of days to weeks. Finally, we propose that precise fine-tuning of conduction along already-myelinated axons may also be mediated by alterations to the axon itself. We conclude that future studies need to analyze activity-driven adaptations to both axons and their myelin sheaths to fully understand how myelinated axon plasticity contributes to neuronal circuit formation and function.

Enhanced Nociception in Angelman Syndrome Model Mice

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutation or deletion of the maternal UBE3A allele. The maternal UBE3A allele is expressed in nearly all neurons of the brain and spinal cord, whereas the paternal UBE3A allele is repressed by an extremely long antisense transcript (UBE3A-ATS). Little is known about expression of UBE3A in the peripheral nervous system, where loss of maternal UBE3A might contribute to AS phenotypes. Here we sought to examine maternal and paternal Ube3a expression in DRGs neurons and to evaluate whether nociceptive responses were affected in AS model mice (global deletion of maternal Ube3a allele; Ube3a^m–/p+). We found that most large-diameter proprioceptive and mechanosensitive DRG neurons expressed maternal Ube3a and paternal Ube3a-ATS. In contrast, most small-diameter neurons expressed Ube3a biallelically and had low to undetectable levels of Ube3a-ATS. Analysis of single-cell DRG transcriptomes further suggested that Ube3a is expressed monoallelically in myelinated large-diameter neurons and biallelically in unmyelinated small-diameter neurons. Behavioral responses to some noxious thermal and mechanical stimuli were enhanced in male and female AS model mice; however, nociceptive responses were not altered by the conditional deletion of maternal Ube3a in the DRG. These data suggest that the enhanced nociceptive responses in AS model mice are due to loss of maternal Ube3a in the central, but not peripheral, nervous system. Our study provides new insights into sensory processing deficits associated with AS.

SIGNIFICANCE STATEMENT Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss or mutation of the maternal UBE3A allele. While sensory processing deficits are frequently associated with AS, it is currently unknown whether Ube3a is expressed in peripheral sensory neurons or whether maternal deletion of Ube3a affects somatosensory responses. Here, we found that Ube3a is primarily expressed from the maternally inherited allele in myelinated large-diameter sensory neurons and biallelically expressed in unmyelinated small-diameter neurons. Nociceptive responses to select noxious thermal and mechanical stimuli were enhanced following global, but not sensory neuron-specific, deletion of maternal Ube3a in mice. These data suggest that maternal loss of Ube3a affects nociception via a central, but not peripheral mechanism, with implications for AS.

Stress and Exploitative Decision-Making

Primary Generators of Visually Evoked Field Potentials Recorded in the Macaque Auditory Cortex

Prior studies have reported "local" field potential (LFP) responses to faces in the macaque auditory cortex and have suggested that such face-LFPs may be substrates of audiovisual integration. However, although field potentials (FPs) may reflect the synaptic currents of neurons near the recording electrode, due to the use of a distant reference electrode, they often reflect those of synaptic activity occurring in distant sites as well. Thus, FP recordings within a given brain region (e.g., auditory cortex) may be "contaminated" by activity generated elsewhere in the brain. To determine whether face responses are indeed generated within macaque auditory cortex, we recorded FPs and concomitant multiunit activity with linear array multielectrodes across auditory cortex in three macaques (one female), and applied current source density (CSD) analysis to the laminar FP profile. CSD analysis revealed no appreciable local generator contribution to the visual FP in auditory cortex, although we did note an increase in the amplitude of visual FP with cortical depth, suggesting that their generators are located below auditory cortex. In the underlying inferotemporal cortex, we found polarity inversions of the main visual FP components accompanied by robust CSD responses and large-amplitude multiunit activity. These results indicate that face-evoked FP responses in auditory cortex are not generated locally but are volume-conducted from other face-responsive regions. In broader terms, our results underscore the caution that, unless far-field contamination is removed, LFPs in general may reflect such "far-field" activity, in addition to, or in absence of, local synaptic responses.

SIGNIFICANCE STATEMENT Field potentials (FPs) can index neuronal population activity that is not evident in action potentials. However, due to volume conduction, FPs may reflect activity in distant neurons superimposed upon that of neurons close to the recording electrode. This is problematic as the default assumption is that FPs originate from local activity, and thus are termed "local" (LFP). We examine this general problem in the context of previously reported face-evoked FPs in macaque auditory cortex. Our findings suggest that face-FPs are indeed generated in the underlying inferotemporal cortex and volume-conducted to the auditory cortex. The note of caution raised by these findings is of particular importance for studies that seek to assign FP/LFP recordings to specific cortical layers.

Conditional Deletion of the L-Type Calcium Channel Cav1.2 in NG2-Positive Cells Impairs Remyelination in Mice

Exploring the molecular mechanisms that drive the maturation of oligodendrocyte progenitor cells (OPCs) during the remyelination process is essential to developing new therapeutic tools to intervene in demyelinating diseases such as multiple sclerosis. To determine whether L-type voltage-gated calcium channels (L-VGCCs) are required for OPC development during remyelination, we generated an inducible conditional knock-out mouse in which the L-VGCC isoform Cav1.2 was deleted in NG2-positive OPCs (Cav1.2^KO). Using the cuprizone (CPZ) model of demyelination and mice of either sex, we establish that Cav1.2 deletion in OPCs leads to less efficient remyelination of the adult brain. Specifically, Cav1.2^KO OPCs mature slower and produce less myelin than control oligodendrocytes during the recovery period after CPZ intoxication. This reduced remyelination was accompanied by an important decline in the number of myelinating oligodendrocytes and in the rate of OPC proliferation. Furthermore, during the remyelination phase of the CPZ model, the corpus callosum of Cav1.2^KO animals presented a significant decrease in the percentage of myelinated axons and a substantial increase in the mean g-ratio of myelinated axons compared with controls. In addition, in a mouse line in which the Cav1.2^KO OPCs were identified by a Cre reporter, we establish that Cav1.2^KO OPCs display a reduced maturational rate through the entire remyelination process. These results suggest that Ca²⁺ influx mediated by L-VGCCs in oligodendroglial cells is necessary for normal remyelination and is an essential Ca²⁺ channel for OPC maturation during the remyelination of the adult brain.

SIGNIFICANCE STATEMENT Ion channels implicated in oligodendrocyte differentiation and maturation may induce positive signals for myelin recovery. Voltage-gated Ca²⁺ channels (VGCCs) are important for normal myelination by acting at several critical steps during oligodendrocyte progenitor cell (OPC) development. To determine whether voltage Ca²⁺ entry is involved in oligodendrocyte differentiation and remyelination, we used a conditional knockout mouse for VGCCs in OPCs. Our results indicate that VGCCs can modulate oligodendrocyte maturation in the demyelinated brain and suggest that voltage-gated Ca²⁺ influx in OPCs is critical for remyelination. These findings could lead to novel approaches for obtaining a better understanding of the factors that control OPC maturation in order to stimulate this pool of progenitors to replace myelin in demyelinating diseases.

Sublaminar Subdivision of Mouse Auditory Cortex Layer 2/3 Based on Functional Translaminar Connections

The cerebral cortex is subdivided into six layers based on morphological features. The supragranular layers 2/3 (L2/3) contain morphologically and genetically diverse populations of neurons, suggesting the existence of discrete classes of cells. In primates and carnivores L2/3 can be subdivided morphologically, but cytoarchitectonic divisions are less clear in rodents. Nevertheless, discrete classes of cells could exist based on their computational requirement, which might be linked to their associated functional microcircuits. Through in vitro slice recordings coupled with laser-scanning photostimulation we investigated whether L2/3 of male mouse auditory cortex contains discrete subpopulations of cells with specific functional microcircuits. We use hierarchical clustering on the laminar connection patterns to reveal the existence of multiple distinct classes of L2/3 neurons. The classes of L2/3 neurons are distinguished by the pattern of their laminar and columnar inputs from within A1 and their location within L2/3. Cells in superficial L2 show more extensive columnar integration than deeper L3 cells. Moreover, L3 cells receive more translaminar input from L4. In vivo imaging in awake mice revealed that L2 cells had higher bandwidth than L3 cells, consistent with the laminar differences in columnar integration. These results suggest that similar to higher mammals, rodent L2/3 is not a homogenous layer but contains several parallel microcircuits.

SIGNIFICANCE STATEMENT Layer 2/3 of auditory cortex is functionally diverse. We investigated whether L2/3 cells form classes based on their functional connectivity. We used in vitro whole-cell patch-clamp recordings with laser-scanning photostimulation and performed unsupervised clustering on the resulting excitatory and inhibitory connection patterns. Cells within each class were located in different sublaminae. Superficial cells showed wider integration along the tonotopic axis and the amount of L4 input varied with sublaminar location. To identify whether sensory responses varied with sublaminar location, we performed in vivo Ca²⁺ imaging and found that L2 cells were less frequency-selective than L3 cells. Our results show that the diversity of receptive fields in L2/3 is likely due to diversity in the underlying functional circuits.

Disruption of Bmal1 Impairs Blood-Brain Barrier Integrity via Pericyte Dysfunction

Circadian rhythm disturbances are well established in neurological diseases. However, how these disruptions cause homeostatic imbalances remains poorly understood. Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) is a major circadian clock transcriptional activator, and Bmal1 deficiency in male Bmal1_nestin^–/– mice induced marked astroglial activation without affecting the number of astrocytes in the brain and spinal cord. Bmal1 deletion caused blood–brain barrier (BBB) hyperpermeability with an age-dependent loss of pericyte coverage of blood vessels in the brain. Using Nestin-green fluorescent protein (GFP) transgenic mice, we determined that pericytes are Nestin-GFP⁺ in the adult brain. Bmal1 deletion caused Nestin-GFP⁺ pericyte dysfunction, including the downregulation of platelet-derived growth factor receptor β (PDGFRβ), a protein necessary for maintaining BBB integrity. Knockdown of Bmal1 downregulated PDGFRβ transcription in the brain pericyte cell line. Thus, the circadian clock component Bmal1 maintains BBB integrity via regulating pericytes.

SIGNIFICANCE STATEMENT Circadian rhythm disturbances may play a role in neurodegenerative disorders, such as Alzheimer's disease. Our results revealed that one of the circadian clock components maintains the integrity of the blood–brain barrier (BBB) by regulating vascular-embedded pericytes. These cells were recently identified as a vital component for the control of BBB permeability and cerebral blood flow. Our present study demonstrates the involvement of circadian clock component Bmal1 in BBB homeostasis and highlights the role of Bmal1 dysfunction in multiple neurological diseases.

Correction: Clarkson et al., "AMPA Receptor-Induced Local Brain-Derived Neurotrophic Factor Signaling Mediates Motor Recovery after Stroke"

Dopamine D2 Receptors Modulate Pyramidal Neurons in Mouse Medial Prefrontal Cortex through a Stimulatory G-Protein Pathway

Dopaminergic modulation of prefrontal cortex (PFC) is thought to play key roles in many cognitive functions and to be disrupted in pathological conditions, such as schizophrenia. We have previously described a phenomenon whereby dopamine D2 receptor (D2R) activation elicits afterdepolarizations (ADPs) in subcortically projecting (SC) pyramidal neurons within L5 of the PFC. These D2R-induced ADPs only occur following synaptic input, which activates NMDARs, even when the delay between the synaptic input and ADPs is relatively long (e.g., several hundred milliseconds). Here, we use a combination of electrophysiological, optogenetic, pharmacological, transgenic, and chemogenetic approaches to elucidate cellular mechanisms underlying this phenomenon in male and female mice. We find that knocking out D2Rs eliminates the ADP in a cell-autonomous fashion, confirming that this ADP depends on D2Rs. Hyperpolarizing current injection, but not AMPA receptor blockade, prevents synaptic stimulation from facilitating D2R-induced ADPs, suggesting that this phenomenon depends on the recruitment of voltage-dependent currents (e.g., NMDAR-mediated Ca²⁺ influx) by synaptic input. Finally, the D2R-induced ADP is blocked by inhibitors of cAMP/PKA signaling, insensitive to pertussis toxin or β-arrestin knock-out, and mimicked by G_s-DREADD stimulation, suggesting that D2R activation elicits the ADP by stimulating cAMP/PKA signaling. These results show that this unusual physiological phenomenon, in which D2Rs enhance cellular excitability in a manner that depends on synaptic input, is mediated at the cellular level through the recruitment of signaling pathways associated with G_s, rather than the G_i/o-associated mechanisms that have classically been ascribed to D2Rs.

SIGNIFICANCE STATEMENT Dopamine D2 receptors (D2Rs) in the prefrontal cortex (PFC) are thought to play important roles in behaviors, including working memory and cognitive flexibility. Variation in D2Rs has also been implicated in schizophrenia, Tourette syndrome, and bipolar disorder. Recently, we described a new mechanism through which D2R activation can enhance the excitability of pyramidal neurons in the PFC. Here, we explore the underlying cellular mechanisms. Surprisingly, although D2Rs are classically assumed to signal through G_i/o-coupled G-proteins and/or scaffolding proteins, such as β-arrestin, we find that the effects of D2Rs on prefrontal pyramidal neurons are actually mediated by pathways associated with G_s-mediated signaling. Furthermore, we show how, via this D2R-dependent phenomenon, synaptic input can enhance the excitability of prefrontal neurons over timescales on the order of seconds. These results elucidate cellular mechanisms underlying a novel signaling pathway downstream of D2Rs that may contribute to prefrontal function under normal and pathological conditions.

Contralateral Bias of High Spatial Frequency Tuning and Cardinal Direction Selectivity in Mouse Visual Cortex

Binocular mechanisms for visual processing are thought to enhance spatial acuity by combining matched input from the two eyes. Studies in the primary visual cortex of carnivores and primates have confirmed that eye-specific neuronal response properties are largely matched. In recent years, the mouse has emerged as a prominent model for binocular visual processing, yet little is known about the spatial frequency tuning of binocular responses in mouse visual cortex. Using calcium imaging in awake mice of both sexes, we show that the spatial frequency preference of cortical responses to the contralateral eye is ~35% higher than responses to the ipsilateral eye. Furthermore, we find that neurons in binocular visual cortex that respond only to the contralateral eye are tuned to higher spatial frequencies. Binocular neurons that are well matched in spatial frequency preference are also matched in orientation preference. In contrast, we observe that binocularly mismatched cells are more mismatched in orientation tuning. Furthermore, we find that contralateral responses are more direction-selective than ipsilateral responses and are strongly biased to the cardinal directions. The contralateral bias of high spatial frequency tuning was found in both awake and anesthetized recordings. The distinct properties of contralateral cortical responses may reflect the functional segregation of direction-selective, high spatial frequency-preferring neurons in earlier stages of the central visual pathway. Moreover, these results suggest that the development of binocularity and visual acuity may engage distinct circuits in the mouse visual system.

SIGNIFICANCE STATEMENT Seeing through two eyes is thought to improve visual acuity by enhancing sensitivity to fine edges. Using calcium imaging of cellular responses in awake mice, we find surprising asymmetries in the spatial processing of eye-specific visual input in binocular primary visual cortex. The contralateral visual pathway is tuned to higher spatial frequencies than the ipsilateral pathway. At the highest spatial frequencies, the contralateral pathway strongly prefers to respond to visual stimuli along the cardinal (horizontal and vertical) axes. These results suggest that monocular, and not binocular, mechanisms set the limit of spatial acuity in mice. Furthermore, they suggest that the development of visual acuity and binocularity in mice involves different circuits.

Visual Motion Discrimination by Propagating Patterns in Primate Cerebral Cortex

Visual stimuli can evoke waves of neural activity that propagate across the surface of visual cortical areas. The relevance of these waves for visual processing is unknown. Here, we measured the phase and amplitude of local field potentials (LFPs) in electrode array recordings from the motion-processing medial temporal (MT) area of anesthetized male marmosets. Animals viewed grating or dot-field stimuli drifting in different directions. We found that, on individual trials, the direction of LFP wave propagation is sensitive to the direction of stimulus motion. Propagating LFP patterns are also detectable in trial-averaged activity, but the trial-averaged patterns exhibit different dynamics and behaviors from those in single trials and are similar across motion directions. We show that this difference arises because stimulus-sensitive propagating patterns are present in the phase of single-trial oscillations, whereas the trial-averaged signal is dominated by additive amplitude effects. Our results demonstrate that propagating LFP patterns can represent sensory inputs at timescales relevant to visually guided behaviors and raise the possibility that propagating activity patterns serve neural information processing in area MT and other cortical areas.

SIGNIFICANCE STATEMENT Propagating wave patterns are widely observed in the cortex, but their functional relevance remains unknown. We show here that visual stimuli generate propagating wave patterns in local field potentials (LFPs) in a movement-sensitive area of the primate cortex and that the propagation direction of these patterns is sensitive to stimulus motion direction. We also show that averaging LFP signals across multiple stimulus presentations (trial averaging) yields propagating patterns that capture different dynamic properties of the LFP response and show negligible direction sensitivity. Our results demonstrate that sensory stimuli can modulate propagating wave patterns reliably in the cortex. The relevant dynamics are normally masked by trial averaging, which is a conventional step in LFP signal processing.

Site-Specific Regulation of P2X7 Receptor Function in Microglia Gates Morphine Analgesic Tolerance

Tolerance to the analgesic effects of opioids is a major problem in chronic pain management. Microglia are implicated in opioid tolerance, but the core mechanisms regulating their response to opioids remain obscure. By selectively ablating microglia in the spinal cord using a saporin-conjugated antibody to Mac1, we demonstrate a causal role for microglia in the development, but not maintenance, of morphine tolerance in male rats. Increased P2X7 receptor (P2X7R) activity is a cardinal feature of microglial activation, and in this study we found that morphine potentiates P2X7R-mediated Ca²⁺ responses in resident spinal microglia acutely isolated from morphine tolerant rats. The increased P2X7R function was blocked in cultured microglia by PP2, a Src family protein tyrosine kinase inhibitor. We identified Src family kinase activation mediated by μ-receptors as a key mechanistic step required for morphine potentiation of P2X7R function. Furthermore, we show by site-directed mutagenesis that tyrosine (Y_382–384) within the P2X7R C-terminus is differentially modulated by repeated morphine treatment and has no bearing on normal P2X7R function. Intrathecal administration of a palmitoylated peptide corresponding to the Y_382–384 site suppressed morphine-induced microglial reactivity and preserved the antinociceptive effects of morphine in male rats. Thus, site-specific regulation of P2X7R function mediated by Y_382–384 is a novel cellular determinant of the microglial response to morphine that critically underlies the development of morphine analgesic tolerance.

SIGNIFICANCE STATEMENT Controlling pain is one of the most difficult challenges in medicine and its management is a requirement of a large diversity of illnesses. Although morphine and other opioids offer dramatic and impressive relief of pain, their impact is truncated by loss of efficacy (analgesic tolerance). Understanding why this occurs and how to prevent it are of critical importance in improving pain therapies. We uncovered a novel site (Y_382–384) within the P2X7 receptor that can be targeted to blunt the development of morphine analgesic tolerance, without affecting normal P2X7 receptor function. Our findings provide a critical missing mechanistic piece, site-specific modulation by Y_382–384, that unifies P2X7R function to the activation of spinal microglia and the development of morphine tolerance.

Rubrocerebellar Feedback Loop Isolates the Interposed Nucleus as an Independent Processor of Corollary Discharge Information in Mice

Understanding cerebellar contributions to motor coordination requires deeper insight into how the output structures of the cerebellum, the cerebellar nuclei, integrate their inputs and influence downstream motor pathways. The magnocellular red nucleus (RNm), a brainstem premotor structure, is a major target of the interposed nucleus (IN), and has also been described in previous studies to send feedback collaterals to the cerebellum. Because such a pathway is in a key position to provide motor efferent information to the cerebellum, satisfying predictions about the use of corollary discharge in cerebellar computations, we studied it in mice of both sexes. Using anterograde viral tracing, we show that innervation of cerebellum by rubrospinal neuron collaterals is remarkably selective for the IN compared with the cerebellar cortex. Optogenetic activation of the pathway in acute mouse brain slices drove IN activity despite small amplitude synaptic currents, suggesting an active role in IN information processing. Monosynaptic transsynaptic rabies tracing indicated the pathway contacts multiple cell types within the IN. By contrast, IN inputs to the RNm targeted a region that lacked inhibitory neurons. Optogenetic drive of IN inputs to the RNm revealed strong, direct excitation but no inhibition of RNm neurons. Together, these data indicate that the cerebellar nuclei are under afferent control independent of the cerebellar cortex, potentially diversifying its roles in motor control.

SIGNIFICANCE STATEMENT The common assumption that all cerebellar mossy fibers uniformly collateralize to the cerebellar nuclei and cortex underlies classic models of convergent Purkinje influence on cerebellar output. Specifically, mossy fibers are thought to both directly excite nuclear neurons and drive polysynaptic feedforward inhibition via Purkinje neurons, setting up a fundamental computational unit. Here we present data that challenge this rule. A dedicated cerebellar nuclear afferent comprised of feedback collaterals from premotor rubrospinal neurons can directly modulate IN output independent of Purkinje cell modulation. In contrast to the IN-RNm pathway, the RNm-IN feedback pathway targets multiple cell types, potentially influencing both motor output pathways and nucleo-olivary feedback.

Mitochondrial DNA Double-Strand Breaks in Oligodendrocytes Cause Demyelination, Axonal Injury, and CNS Inflammation

Mitochondrial dysfunction has been implicated in the pathophysiology of neurodegenerative disorders, including multiple sclerosis (MS). To date, the investigation of mitochondrial dysfunction in MS has focused exclusively on neurons, with no studies exploring whether dysregulation of mitochondrial bioenergetics and/or genetics in oligodendrocytes might be associated with the etiopathogenesis of MS and other demyelinating syndromes. To address this question, we established a mouse model where mitochondrial DNA (mtDNA) double-strand breaks (DSBs) were specifically induced in myelinating oligodendrocytes (PLP:mtPstI mice) by expressing a mitochondrial-targeted endonuclease, mtPstI, starting at 3 weeks of age. In both female and male mice, DSBs of oligodendroglial mtDNA caused impairment of locomotor function, chronic demyelination, glial activation, and axonal degeneration, which became more severe with time of induction. In addition, after short transient induction of mtDNA DSBs, PLP:mtPstI mice showed an exacerbated response to experimental autoimmune encephalomyelitis. Together, our data demonstrate that mtDNA damage can cause primary oligodendropathy, which in turn triggers demyelination, proving PLP:mtPstI mice to be a useful tool to study the pathological consequences of mitochondrial dysfunction in oligodendrocytes. In addition, the demyelination and axonal loss displayed by PLP:mtPstI mice recapitulate some of the key features of chronic demyelinating syndromes, including progressive MS forms, which are not accurately reproduced in the models currently available. For this reason, the PLP:mtPstI mouse represents a unique and much needed platform for testing remyelinating therapies.

SIGNIFICANCE STATEMENT In this study, we show that oligodendrocyte-specific mitochondrial DNA double-strand breaks in PLP:mtPstI mice cause oligodendrocyte death and demyelination associated with axonal damage and glial activation. Hence, PLP:mtPstI mice represent a unique tool to study the pathological consequences of mitochondrial dysfunction in oligodendrocytes, as well as an ideal platform to test remyelinating and neuroprotective agents.

Visual Experience Shapes the Neural Networks Remapping Touch into External Space

Localizing touch relies on the activation of skin-based and externally defined spatial frames of reference. Psychophysical studies have demonstrated that early visual deprivation prevents the automatic remapping of touch into external space. We used fMRI to characterize how visual experience impacts the brain circuits dedicated to the spatial processing of touch. Sighted and congenitally blind humans performed a tactile temporal order judgment (TOJ) task, either with the hands uncrossed or crossed over the body midline. Behavioral data confirmed that crossing the hands has a detrimental effect on TOJ judgments in sighted but not in early blind people. Crucially, the crossed hand posture elicited enhanced activity, when compared with the uncrossed posture, in a frontoparietal network in the sighted group only. Psychophysiological interaction analysis revealed, however, that the congenitally blind showed enhanced functional connectivity between parietal and frontal regions in the crossed versus uncrossed hand postures. Our results demonstrate that visual experience scaffolds the neural implementation of the location of touch in space.

SIGNIFICANCE STATEMENT In daily life, we seamlessly localize touch in external space for action planning toward a stimulus making contact with the body. For efficient sensorimotor integration, the brain has therefore to compute the current position of our limbs in the external world. In the present study, we demonstrate that early visual deprivation alters the brain activity in a dorsal parietofrontal network typically supporting touch localization in the sighted. Our results therefore conclusively demonstrate the intrinsic role that developmental vision plays in scaffolding the neural implementation of touch perception.

The Neural Basis of Aversive Pavlovian Guidance during Planning

Important real-world decisions are often arduous as they frequently involve sequences of choices, with initial selections affecting future options. Evaluating every possible combination of choices is computationally intractable, particularly for longer multistep decisions. Therefore, humans frequently use heuristics to reduce the complexity of decisions. We recently used a goal-directed planning task to demonstrate the profound behavioral influence and ubiquity of one such shortcut, namely aversive pruning, a reflexive Pavlovian process that involves neglecting parts of the decision space residing beyond salient negative outcomes. However, how the brain implements this important decision heuristic and what underlies individual differences have hitherto remained unanswered. Therefore, we administered an adapted version of the same planning task to healthy male and female volunteers undergoing functional magnetic resonance imaging (fMRI) to determine the neural basis of aversive pruning. Through both computational and standard categorical fMRI analyses, we show that when planning was influenced by aversive pruning, the subgenual cingulate cortex was robustly recruited. This neural signature was distinct from those associated with general planning and valuation, two fundamental cognitive components elicited by our task but which are complementary to aversive pruning. Furthermore, we found that individual variation in levels of aversive pruning was associated with the responses of insula and dorsolateral prefrontal cortices to the receipt of large monetary losses, and also with subclinical levels of anxiety. In summary, our data reveal the neural signatures of an important reflexive Pavlovian process that shapes goal-directed evaluations and thereby determines the outcome of high-level sequential cognitive processes.

SIGNIFICANCE STATEMENT Multistep decisions are complex because initial choices constrain future options. Evaluating every path for long decision sequences is often impractical; thus, cognitive shortcuts are often essential. One pervasive and powerful heuristic is aversive pruning, in which potential decision-making avenues are curtailed at immediate negative outcomes. We used neuroimaging to examine how humans implement such pruning. We found it to be associated with activity in the subgenual cingulate cortex, with neural signatures that were distinguishable from those covarying with planning and valuation. Individual variations in aversive pruning levels related to subclinical anxiety levels and insular cortex activation. These findings reveal the neural mechanisms by which basic negative Pavlovian influences guide decision-making during planning, with implications for disrupted decision-making in psychiatric disorders.

Approaching the Ground Truth: Revealing the Functional Organization of Human Multisensory STC Using Ultra-High Field fMRI

Integrating inputs across sensory systems is a property of the brain that is vitally important in everyday life. More than two decades of fMRI research have revealed crucial insights on multisensory processing, yet the multisensory operations at the neuronal level in humans have remained largely unknown. Understanding the fine-scale spatial organization of multisensory brain regions is fundamental to shed light on their neuronal operations. Monkey electrophysiology revealed that the bimodal superior temporal cortex (bSTC) is topographically organized according to the modality preference (visual, auditory, and bimodal) of its neurons. In line with invasive studies, a previous 3 Tesla fMRI study suggests that the human bSTC is also topographically organized according to modality preference (visual, auditory, and bimodal) when analyzed at 1.6 x 1.6 x 1.6 mm³ voxel resolution. However, it is still unclear whether this resolution is able to unveil an accurate spatial organization of the human bSTC. This issue was addressed in the present study by investigating the spatial organization of functional responses of the bSTC in 10 participants (from both sexes) at 1.5 x 1.5 x 1.5 mm³ and 1.1 x 1.1 x 1.1 mm³ using ultra-high field fMRI (at 7 Tesla). Relative to 1.5 x 1.5 x 1.5 mm³, the bSTC at 1.1 x 1.1 x 1.1 mm³ resolution was characterized by a larger selectivity for visual and auditory modalities, stronger integrative responses in bimodal voxels, and it was organized in more distinct functional clusters indicating a more precise separation of underlying neuronal clusters. Our findings indicate that increasing the spatial resolution may be necessary and sufficient to achieve a more accurate functional topography of human multisensory integration.

SIGNIFICANCE STATEMENT The bimodal superior temporal cortex (bSTC) is a brain region that plays a crucial role in the integration of visual and auditory inputs. The aim of the present study was to investigate the fine-scale spatial organization of the bSTC by using ultra-high magnetic field fMRI at 7 Tesla. Mapping the functional topography of bSTC at a resolution of 1.1 x 1.1 x 1.1 mm³ revealed more accurate representations than at lower resolutions. This result indicates that standard-resolution fMRI may lead to wrong conclusions about the functional organization of the bSTC, whereas high spatial resolution is essential to more accurately approach neuronal operations of human multisensory integration.

Multiple Signaling Pathways Coordinately Regulate Forgetting of Olfactory Adaptation through Control of Sensory Responses in Caenorhabditis elegans

Forgetting memories is important for animals to properly respond to continuously changing environments. To elucidate the mechanisms of forgetting, we used one of the behavioral plasticities of Caenorhabditis elegans hermaphrodite, olfactory adaptation to an attractive odorant, diacetyl, as a simple model of learning. In C. elegans, the TIR-1/JNK-1 pathway accelerates forgetting of olfactory adaptation by facilitating neural secretion from AWC sensory neurons. In this study, to identify the downstream effectors of the TIR-1/JNK-1 pathway, we conducted a genetic screen for suppressors of the gain-of-function mutant of tir-1 (ok1052), which shows excessive forgetting. Our screening showed that three proteins—a membrane protein, MACO-1; a receptor tyrosine kinase, SCD-2; and its putative ligand, HEN-1—regulated forgetting downstream of the TIR-1/JNK-1 pathway. We further demonstrated that MACO-1 and SCD-2/HEN-1 functioned in parallel genetic pathways, and only MACO-1 regulated forgetting of olfactory adaptation to isoamyl alcohol, which is an attractive odorant sensed by different types of sensory neurons. In olfactory adaptation, odor-evoked Ca²⁺ responses in olfactory neurons are attenuated by conditioning and recovered thereafter. A Ca²⁺ imaging study revealed that this attenuation is sustained longer in maco-1 and scd-2 mutant animals than in wild-type animals like the TIR-1/JNK-1 pathway mutants. Furthermore, temporal silencing by histamine-gated chloride channels revealed that the neuronal activity of AWC neurons after conditioning is important for proper forgetting. We propose that distinct signaling pathways, each of which has a specific function, may coordinately and temporally regulate forgetting by controlling sensory responses.

SIGNIFICANCE STATEMENT Active forgetting is an important process to understand the whole mechanisms of memories. Recent papers have reported that the noncell autonomous regulations are required for proper forgetting in invertebrates. We found that in Caenorhabditis elegans hermaphrodite, the noncell autonomous regulations of forgetting of olfactory adaptation is regulated by three conserved proteins: a membrane protein, MACO-1; a receptor tyrosine kinase, SCD-2: and its ligand, HEN-1. MACO-1 and SCD-2/HEN-1, working in coordination, accelerate forgetting by controlling sensory responses in parallel. Furthermore, temporal regulation of neuronal activity is important for proper forgetting. We suggest that multiple pathways may coordinately and temporally regulate forgetting through control of sensory responses. This study should lead to a better understanding of forgetting in higher organisms.

Life-cycle impacts of shower water waste heat recovery: case study of an installation at a university sport facility in the UK

Abstract

Recovering heat from waste water discharged from showers to preheat the incoming cold water has been promoted as a cost-effective, energy-efficient, and low-carbon design option which has been included in the UK's Standard Assessment Procedure (SAP) for demonstrating compliance with the Building Regulation for dwellings. Incentivized by its carbon cost-effectiveness, waste water heat exchangers (WWHX) have been selected and incorporated in a newly constructed Sports Pavilion at the University of Brighton in the UK. This £2-m sports development serving several football fields was completed in August 2015 providing eight water- and energy-efficient shower rooms for students, staff, and external organizations. Six of the shower rooms are located on the ground floor and two on the first floor, each fitted with five or six thermostatically controlled shower units. Inline type of WWHX were installed, each consisted of a copper pipe section wound by an external coil of smaller copper pipe through which the cold water would be warmed before entering the shower mixers. Using the installation at Sport Pavilion as the case study, this research aims to evaluate the environmental and financial sustainability of a vertical waste heat recovery device, over a life cycle of 50 years, with comparison to the normal use of a PVC-u pipe. A heat transfer mathematical model representing the system has been developed to inform the development of the methodology for measuring the in-situ thermal performance of individual and multiple use of showers in each changing room. Adopting a system thinking modeling technique, a quasi-dynamic simulation computer model was established enabling the prediction of annual energy consumptions under different shower usage profiles. Data based on the process map and inventory of a functional unit of WWHX were applied to a proprietary assessment software to establish the relevant outputs for the life-cycle environmental impact assessment. Life-cycle cost models were developed and industry price book data were applied. The results indicated that the seasonal thermal effectiveness was over 50% enabling significant energy savings through heat recovery that led to short carbon payback time of less than 2 years to compensate for the additional greenhouse gas emissions associated with the WWHX. However, the life-cycle cost of the WWHX is much higher than using the PVC pipe, even with significant heat recovered under heavy usage, highlighting the need to adopt more economic configurations, such as combining waste water through fewer units, in order to maximize the return on investment and improve the financial viability.

Release and kinetics of arsenic and plumbum in the Songhua River surficial sediments

Abstract

To estimate the pollution of As and Pb in the Songhua River which flows through the major rice-producing regions in China, the present study investigated the level and release of As and Pb in surficial sediments which collected from nine sites in Songhua River (M₁–M₉). The concentration of As and Pb was ranged as follows: As = 3.104~15.01 μg/g, Pb = 20.10~37.42 μg/g; the average concentration: As = 6.466 ± 3.077 μg/g, Pb = 28.88 ± 5.077 μg/g. By analysis vertically, the average concentration of As was 5.166 ± 1.496 μg/g in the upstream, 5.815 ± 1.793 μg/g in the midstream, and 9.716 ± 4.977 μg/g in the downstream. The average concentration of Pb was 27.83 ± 4.552 μg/g in the upstream, 28.66 ± 6.333 μg/g in the midstream, and 30.99 ± 4.837 μg/g in the downstream. It indicated that the concentration of As and Pb increased gradually from upstream to downstream. As existed mainly as insoluble state and Pb existed mainly as sulfide and organic combining state in surficial sediments, and the species of As and Pb could transform with the change of the circumstance. The release of quantity of As was higher than Pb. The pH of 6 was not conducive to the release of As and Pb. When the temperature was 35 and 6 °C, the release of As and Pb in surficial sediments were restrained, respectively. Fumaric acid and citric acid played an important role in promoting the release of As, but not conducive to Pb. Furthermore, the reasonable aeration rate was beneficial to the release process of As and Pb in surficial sediment. By kinetic analysis, the Elovich equation (Ct = 84.931–8.952lnt) could be used to describe the dynamic process of the release of As in a relatively short time. The Elovich equation (C _t  = 2.724 + 1.3724lnt) and double constant rate equation (lnC _T  = 1.4646 + 0.1522lnT) could well describe the dynamics process of the release of Pb.

Fungicidal activity of slow-release P(3HB)/TEB formulations in wheat plant communities infected by Fusarium moniliforme

Abstract

Fungicidal activity of experimental tebuconazole (TEB) formulations was investigated in laboratory soil ecosystems in wheat plant communities infected by Fusarium moniliforme. TEB was embedded in the matrix of poly-3-hydroxybutyrate, shaped as films and microgranules. These formulations were buried in the soil with wheat plants, and their efficacy was compared with that of commercial formulation Raxil and with the effect of pre-sowing treatment of seeds. In the experiment with the initially infected seeds and a relatively low level of natural soil infection caused by Fusarium fungi, the effects of the experimental P(3HB)/TEB formulations and Raxil were comparable. However, when the level of soil infection was increased by adding F. moniliforme spores, P(3HB)/TEB granules and films reduced the total counts of fungi and the abundance of F. moniliforme more effectively than Raxil. Seed treatment or soil treatment with Raxil solution showed an increase in the percentage of rot-damaged roots in the later stages of the experiment. In the early stage (between days 10 and 20), the percentage of rot-damaged roots in the soil with TEB embedded in the slowly degraded P(3HB) matrix was similar to that in the soil with Raxil. However, the efficacy of P(3HB)/TEB formulations lasted longer, and in later stages (between days 20 and 30), the percentage of rot-damaged roots in that group did not grow. In experiments with different TEB formulations and, hence, different fungicidal activities, the increase in plant biomass was 15–17 to 40–60% higher than in the groups where TEB was applied by using conventional techniques.

Self-calibrated fluorescent probe resembled as an indicator of the lysosomal phosphatase pertaining to the cancer cells

Publication date: Available online 18 October 2017
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Arup Podder, Susan M. Alex, Mrinmoy Maiti, Kaustabh Kumar Maiti, Sankarprasad Bhuniya
A self-calibrated fluorescent probe Lyso-Phos has synthesized followed by a straightforward synthetic pathway. Lyso-Phos acts as an indicator for lysosomal phosphatase. Its photophysical property including cellular imaging was described. Lyso-Phos showed ratiometric UV–Vis- absorption changes from λabs 370nm to λabs 450nm in the presence of alkaline phosphatase (ALP). On the other hand, fluorescence intensity λem 560nm of Lyso-Phos has increased around 45-fold in the presence of ALP. The probe Lyso-Phos was found to be highly chemoselective toward the phosphatase compared with other ubiquitous entities in cellular milieu. The non-toxic nature of the Lyso-phos has accounted by observing higher cell viability in prostate cancer- LnCap, fibrosarcoma HT1080 and normal mouse embryo fibroblast NIH3T3 cells. Further, the probe Lyso-Phos was utilized for tracking of cellular phosphatase in live-cells. Lyso-Phos enabled to track cellular phosphatase by the extent of fluorescence labeling of LnCap cells which showed reasonable uptake efficiency in the presence of Lyso–Phos as indicated by the intracellular fluorescence. The phosphoester bond in the probe was cleaved by intracellular alkaline phosphatase leading to turn on fluorescence of the fluorescent probe Lyso–Phos. Finally, cellular colocalization with Lyso-Tracker empowered our speculation that Lyso-Phos can track endogenous phosphatase in the lysosomes. Altogether these findings suggest that Lyso-Phos would be powerful probe to detect phosphates in cancer cells.

Graphical abstract

Association between coal consumption and urbanization in a coal-based region: a multivariate path analysis

Abstract

This study examines causal relationship between urbanization and coal consumption. By taking Shanxi Province, China, as a typical case area, a multivariate path analysis model is used to seek for the key driving factors of coal consumption throughout its urbanization during the period of 1978 to 2014. The result indicates that the key factors are urban household disposable income and residential area per capita, which are closely related to urban construction and household lifestyle. It is expected that the study may inform better policies on coal consumption reduction and energy structure improvement.

Characterization of carbonaceous fractions in PM 2.5 and PM 10 over a typical industrial city in central China

Abstract

Aerosol samples of PM_2.5 and PM₁₀ were collected every 6 days from March 2012 to February 2013 in Huangshi, a typical industrial city in central China, to investigate the characteristics, relationships, and sources of carbonaceous species. The PM_2.5 and PM₁₀ samples were analyzed for organic carbon (OC), elemental carbon (EC), char, and soot using the thermal/optical reflectance (TOR) method following the IMPROVE_A protocol. PM_2.5 and PM₁₀ concentrations ranged from 29.37 to 501.43 μg m⁻³ and from 50.42 to 330.07 μg m⁻³, with average levels of 104.90 and 151.23 μg m⁻³, respectively. The 24-h average level of PM_2.5 was about three times the US EPA standard of 35 μg m⁻³, and significantly exceeds the Class II National Air Quality Standard of China of 75 μg m⁻³. The seasonal cycles of PM mass and OC concentrations were higher during winter than in summer. EC and char concentrations were generally highest during winter but lowest in spring, while higher soot concentrations occurred in summer. This seasonal variation could be attributed to different seasonal meteorological conditions and changes in source contributions. Strong correlations between OC and EC were found for both PM_2.5 and PM₁₀ in winter and fall, while char and soot showed a moderate correlation in summer and winter. The average OC/EC ratios were 5.11 and 4.46 for PM_2.5 and PM₁₀, respectively, with individual OC/EC ratios nearly always exceeding 2.0. Higher char/soot ratios during the four seasons indicated that coal combustion and biomass burning were the major sources for carbonaceous aerosol in Huangshi. Contrary to expectations, secondary organic carbon (SOC) which is estimated using the EC tracer method exhibited spring maximum and summer minimum, suggesting that photochemical activity is not a leading factor in the formation of secondary organic aerosols in the study area. The contribution of SOC to OC concentration for PM_2.5 and PM₁₀ were 47.33 and 45.38%, respectively, implying that SOC was an important component of OC mass. The serious air pollution in haze-fog episode was strongly correlated with the emissions of pollutants from biomass burning and the meteorological conditions.

Chemical elements as fingerprints of geographical origin in cultivars of Vitis vinifera L. raised on the same SO4 rootstock

Abstract

The uptake of major and trace elements in grapevine (Vitis vinifera L.) can be influenced by soil, climate, geographic origin, and rootstock type. Rootstocks were mainly selected to resist phylloxera and for specific tolerance to lime, mineral uptake, drought, and salinity. The relationship among concentrations of major, trace, and rare earth elements was studied in soil and leaves from two Italian grapevine cultivars, "Cabernet Sauvignon" and "Corvina," employed to produce renowned controlled designation of origin (DOC) wines. The cultivars were raised on the same rootstock SO4 in two different areas of the Veneto Region (Northern Italy). The elements were studied by X-ray fluorescence and inductively coupled plasma mass spectrometry, and data were elaborated by non-parametric tests and multivariate linear discrimination analysis. The related index of bioaccumulation was calculated to define the specific assimilation of the elements from soil to leaves. A statistically significant correspondence between soil and leaf samples was observed for Mg, Sm, V, and Zr. The results allowed to discriminate soil and leaf samples of the two cultivars according to geographical provenance, possibly providing geochemical markers (fingerprints) useful against fraudulent use of DOC wine labels.

Strategies of heavy metal uptake by three Armeria species growing on different geological substrates in Serbia

Abstract

This study surveyed three species of the genus Armeria Willd. from five ultramafic outcrops, two non-ultramafic (schist) soils, and one tailing heap of an abandoned iron-copper mine from Serbia. Similarities and differences among the three Armeria species growing on different geological substrates in the ability to control uptake and translocate nine metals were examined. Chemical characteristics of the soil and plant samples (concentrations of P₂O_5, K₂O, Ca, Fe, Mn, Ni, Zn, Cu, Cr, Co, Cd, and Pb) are presented. In order to assess accumulative potential of these three Armeria species, biological concentration, accumulation, as well as translocation factors were used. Three investigated Armeria species growing on eight different localities showed large differences in heavy metal uptake, translocation, and accumulation. The differences were present among the plant samples of the same species and even more among three different Armeria species and were primarily the result of the different contents of available heavy metals in the investigated soils. Additionally, differences might be the consequence of diverse responses and possible presence of supplementary resistance mechanisms in the plants from the ultramafic soils. None of the three Armeria species showed shoot hyperaccumulative potential for any of the investigated heavy metals and they could be considered as root accumulators, considering their potential to accumulate medium to large amounts of Zn (BCF up to 134), Cr (BCF up to 148), and Cd (BCF up to 9) in their roots.

Lead in roadway dusts from different functional areas in a typical valley city, NW China: contamination and exposure risk

Abstract

Lead contamination and exposure risk assessment in roadway dusts from four different functional areas in a typical valley city in northwest China (Xi'an) were conducted in this study. A total of 130 roadway dust samples from park area (PA), traffic area (TA), educational area (EA), and residential area (RA) were collected and Pb concentrations in the samples were determined by using XRF (X-ray fluorescence). Geo-accumulation index (I _geo) and enrichment factor (EF) were applied to assess Pb contamination level and the hazard indexes (HI) of Pb were calculated to evaluate the exposure risks to children and adults. The results showed that roadway dusts from all four functional areas had elevated Pb concentrations and pollution characteristics of Pb were discrepant in different functional areas. The mean concentration of Pb in roadway dusts from PA, TA, EA, and RA was 147.4, 74.8, 119.6, and 161.0 mg kg⁻¹, respectively. The I _geo and EF of Pb were mostly 1–3 and 2–20, which indicated moderate to high Pb contamination in roadway dusts. High contamination level of Pb in RA and EA should receive priority for prevention and control. Exposure risk assessment of Pb from roadway dusts was mainly in the acceptable range, but the potential risk of Pb exposure to children should be continuously concerned.

Token physicalism and functional individuation

Abstract

Token physicalism is often viewed as a modest and unproblematic physicalist commitment, as contrasted with type physicalism. This paper argues that the prevalence of functional individuation in biology creates serious problems for token physicalism, because the latter requires that biological entities can be individuated physically and without reference to biological functioning. After characterizing the main philosophical roles for token physicalism, I describe the distinctive uses of functional individuation in models of biological processes. I then introduce some requirements on token identity claims that arise from a position on individuation and identity known as sortalism. An examination of biological examples shows that these sortalist requirements cannot be plausibly met due to differences between individuation by functional biological criteria and by physical criteria. Even without assuming sortalism, token physicalism faces the more basic problem of excluding functionally irrelevant detail from the individuation of biological tokens. I close by suggesting that the philosophical roles for token identity are better fulfilled by a notion of token composition, which promotes a hierarchical picture of individuality.

Experimental investigations on a diesel engine operated with fuel blends derived from a mixture of Pakistani waste tyre oil and waste soybean oil biodiesel

Abstract

The waste tyre and waste cooking oils have a great potential to be used as alternative fuels for diesel engines. The aim of this study was to convert light fractions of pyrolysis oil derived from Pakistani waste vehicle tyres and waste soybean oil methyl esters into valuable fuel and to reduce waste disposal-associated environmental problems. In this study, the waste tyre pyrolysis liquid (light fraction) was collected from commercial tyre pyrolysis plant and biodiesel was prepared from waste soybean oil. The fuel blends (FMWO10, FMWO20, FMWO30, FMWO40 and FMWO50) were prepared from a 30:70 mixture of waste tyre pyrolysis liquid and waste soybean oil methyl esters with different proportions of mineral diesel. The mixture was named as the fuel mixture of waste oils (FMWO). FT-IR analysis of the fuel mixture was carried out using ALPHA FT-IR spectrometer. Experimental investigations on a diesel engine were carried out with various FMWO blends. It was observed that the engine fuel consumption was marginally increased and brake thermal efficiency was marginally decreased with FMWO fuel blends. FMWO10 has shown lowest NOx emissions among all the fuel blends tested. In addition, HC, CO and smoke emissions were noticeably decreased by 3.1–15.6%, 16.5–33.2%, and 1.8–4.5%, respectively, in comparison to diesel fuel, thereby qualifying the blends to be used as alternative fuel for diesel engines.

Residual degradation and toxicity of insecticides against Bactrocera oleae

Abstract

Field and lab trials took place in Crete (July to September 2016), concerning the residual degradation and toxicity of seven active ingredients applied as bait sprays against the olive fruit fly. Highest residues were recorded in olive leaves for dimethoate and phosmet (~ 60 mg/kg) immediately after application (day 1+), while a threefold and fivefold reduction was observed 1 week later, respectively. Residues of pyrethroids were determined at lower levels (< 10 mg/kg) but remained almost stable for a longer period of time. Finally, thiacloprid and spinosad residues were determined at 5.81 and 0.19 mg/kg respectively (day 1+), and rapidly decreased below the LOQ. Highest toxicity against the olive fruit fly was observed just right after the application of dimethoate (100%), a-cypermethrin (80%), and l-cyhalothrin (72.92%). Although the toxicity of dimethoate was significantly reduced 1 week after the application (80%) and then minimized, toxicity of pyrethroids remained almost stable (> 60%) for the first 2 weeks and then decreased to 30–40%, which remained stable up to the end of the study (8 weeks). Concerning phosmet, its toxicity ranged from 35 to 56% for 3 weeks with no significant reduction, while spinosad presented a lower toxicity profile (50% only for 1 week). The benefits of these results in the knowledge of insecticide residues and their toxicity against olive fruit fly can be used for improving olive fruit fly control.