KCNQ2/3 Gain-of-Function Variants and Cell Excitability: Differential Effects in CA1 versus L2/3 Pyramidal Neurons.

Gain-of-function (GOF) pathogenic variants in the potassium channels KCNQ2 and KCNQ3 lead to hyperexcitability disorders such as epilepsy and autism spectrum disorders. However, the underlying cellular mechanisms of how these variants impair forebrain function are unclear. Here, we show that the R201C variant in KCNQ2 has opposite effects on the excitability of two types of mouse pyramidal neurons of either sex, causing hyperexcitability in layer 2/3 (L2/3) pyramidal neurons and hypoexcitability in CA1 pyramidal neurons. Similarly, the homologous R231C variant in KCNQ3 leads to hyperexcitability in L2/3 pyramidal neurons and hypoexcitability in CA1 pyramidal neurons. However, the effects of KCNQ3 gain-of-function on excitability are specific to superficial CA1 pyramidal neurons. These findings reveal a new level of complexity in the function of KCNQ2 and KCNQ3 channels in the forebrain and provide a framework for understanding the effects of gain-of-function variants and potassium channels in the brain.SIGNIFICANCE STATEMENT KCNQ2/3 gain-of-function (GOF) variants lead to severe forms of neurodevelopmental disorders, but the mechanisms by which these channels affect neuronal activity are poorly understood. In this study, using a series of transgenic mice we demonstrate that the same KCNQ2/3 GOF variants can lead to either hyperexcitability or hypoexcitability in different types of pyramidal neurons [CA1 vs layer (L)2/3]. Additionally, we show that expression of the recurrent KCNQ2 GOF variant R201C in forebrain pyramidal neurons could lead to seizures and SUDEP. Our data suggest that the effects of KCNQ2/3 GOF variants depend on specific cell types and brain regions, possibly accounting for the diverse range of phenotypes observed in individuals with KCNQ2/3 GOF variants.

Autosomal dominant ApoA4 mutations present as tubulointerstitial kidney disease with medullary amyloidosis.

Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m2, including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m2. Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies.

Improving Public Health Emergency Communication Along the U.S. Southern Border: Insights From a COVID-19 Pilot Campaign With Truck Drivers.

Tens of thousands of trucks cross the U.S.-Mexico border every day. Cross-border truckers' high mobility puts them at risk of acquiring and transmitting infectious diseases and creates challenges reaching them with emergency public health messaging due to their everchanging locations and limited English proficiency. Despite this community-level transmission risk and documented health disparities related to various infectious and noninfectious diseases experienced by truckers themselves, little has been published to provide practical recommendations on better reaching this audience through innovative outreach methods. This article describes a COVID-19 health promotion campaign that aimed to (1) identify, pilot test, and evaluate effective messages, channels, sources, and settings for reaching truckers on both sides of the U.S.-Mexico border and (2) build capacity and sustainability for messaging around future health emergencies. The pilot program ran for 6 weeks, June to August 2023, in three key commercial border crossings and delivered approximately 50,000,000 impressions, nearly 45% more impressions than expected. Considerations for practitioners include the areas of design, implementation, and evaluation. The results provide insight into how to design health promotion messages that resonate with cross-border truckers and how to place these messages where they will be seen, heard, and understood. This includes working effectively with community health workers (CHW), known locally as promotores; identifying local partners that allow CHW to set up onsite; and, working with partner organizations including employers. Practical insights for building evaluation metrics into traditional and grassroots outreach strategies to facilitate real-time optimization as well as continued learning across efforts are also described.

Mechanistic Insights into the Oxidative Degradation of Formic and Oxalic Acids with Ozone and OH Radical. A Computational Rationale.

Gas-phase and aqueous oxidations of formic and oxalic acids with ozone and OH radicals have been thoroughly examined by DFT methods. Such acids are not only important feedstocks for the iterative construction of other organic compounds but also final products generated by mineralization and advanced oxidation of higher organics. Our computational simulation unravels both common and distinctive reaction channels, albeit consistent with known H atom abstraction pathways and formation of hydropolyoxide derivatives. Notably, reactions with neutral ozone and OH radical proceed through low-energy concerted mechanisms involving asynchronous transition structures. For formic acid, carbonylic H-abstraction appears to be more favorable than the dissociative abstraction of the acid proton. Formation of long oxygen chains does not cause a significant energy penalty and highly oxygenated products are stable enough, even if subsequent decomposition releases environmentally benign side substances like O2 and H2O.

Cellulase and chitinase activities and antagonism against Fusarium oxysporum f.sp. cubense race 1 of six Trichoderma strains isolated from Mexican maize cropping.

OBJECTIVE: To evaluate the enzymatic and biocontrol capacity of native Trichoderma strains isolated from corn crops in Irapuato (state of Guanajuato) and Napízaro (state of Michoacán), Mexico. RESULTS: Six native strains from Irapuato and Napízaro were tested, with five of them identified as T. harzianum and one as T. tomentosum. The six strains qualitatively and quantitatively showed enzyme activity for cellulase and chitinase. The best results were obtained for strains IrV6SIC7 and MichV6S2C2 with 878 IU L-1 of chitinase and 1323 IU L-1 of cellulase, respectively. All Trichoderma strains acted antagonistically toward Fusarium oxysporum f.sp. cubense race 1 (FocR1), with percentages of inhibition that ranged from 9 to 54%. In addition, the microscopic analysis allowed visualizing the mechanisms of mycoparasitism and antibiosis by either IrV6SIC7 or MichV6S2C2. The latter effects indicate that the tested native Trichoderma strains isolated from corn crops possessed enzymatic mechanisms as a strategy for biocontrolling FocR1 strains. CONCLUSION: The enzyme production by the Trichoderma strains represents a potential biotechnological utilization for either agricultural or industrial purposes.

Implementation of a Fuzzy Inference System to Enhance the Measurement Range of Multilayer Interferometric Sensors.

This work presents a novel methodology to implement a fuzzy inference system (FIS) to overcome the measurement ambiguity that is typically observed in interferometric sensors. This ambiguity occurs when the measurand is determined by tracing the wavelength position of a peak or dip of a spectral fringe. Consequently, the sensor measurement range is typically limited to the equivalent of 1 free spectral range (FSR). Here, it is demonstrated that by using the proposed methodology, the measurement range of this type of sensor can be widened several times by overcoming the ambiguity over some FSR periods. Furthermore, in order to support the viability of the methodology, it was applied to a couple of temperature interferometric sensors. Finally, experimental results demonstrated that it was possible to quintuple the measurement range of one of the tested sensors with a mean absolute error of MAE = 0.0045 °C, while for the second sensor, the measurement range was doubled with an MAE = 0.0073 °C.

Towards an Optimal Methodology for Basidiomes Production of Naturally Occurring Species of the Genus Oudemansiella (Basidiomycetes).

Oudemansiella species are worldwide distributed and they are characterized for having attractive appearance, a soft fleshy context and mild taste and odor, what makes them interesting for mushroom intensive production. However, studies on their cultivation are scarce and there is no information regarding productive and morphological parameters of fruiting bodies obtained in culture. Here, we propose a methodology to determine the best production technique for the cultivation of not only Oudemansiella species but also of other xylophagous species assaying five different mushroom cultivation systems. Also, the optimal temperature of vegetative growth, the optimal lignocellulosic substrates and the nutritional properties of two naturally occurring Oudemansiella species were determined. As a result, bags with holes-system proved to be the most appropriate technique for the production of fruiting bodies, 25 °C was determined as the optimal temperature for mycelial growth and wheat straw as the best substrate. The evaluated species showed a higher content of fats and fiber and a lower content of proteins and carbohydrates compared to other mushrooms. Furthermore, this is the first report of the cultivation of O. cubensis on agricultural wastes in the world.

Optical Fiber FP Sensor for Simultaneous Measurement of Refractive Index and Temperature Based on the Empirical Mode Decomposition Algorithm.

In this work, a dual refractive index and temperature sensor based on an interferometric system and on the empirical mode decomposition (EMD) algorithm is presented. Here, it is shown that the EMD provides a comprehensive way to analyze and decompose complex reflection spectra produced by an interferometric filter build at the tip of an optical fiber. By applying the EMD algorithm, the spectrum can be decomposed into a set of intrinsic mode functions (IMF) from which the temperature and the refractive index can be easily extracted. Moreover, the proposed methodology provides a detailed insight of the behavior of this type of interferometric sensors and allows widening of the dynamic measurement ranges of both variables. Here, for proof of principle purposes, a filter based on a stack of three layers (two of them were thermo-sensitive) was fabricated. Finally, it is shown that the proposed methodology can decompose the experimental measured spectra and to determine the refractive index and the temperature, supporting the mathematical model.

[Gastric mucormycosis in an immunocompetent child]. / Mucormicosis gástrica en un niño inmunocompetente.

Mucormycosis is a rare, usually fatal, opportunistic infection that mostly affects people with immune deficiency or associated pathologies. There are few reports of this disease in patients without the traditional risk factors, still unknown what could be the real predisposing causes involved. The forms of presentation are rhinocerebral, cutaneous, pulmonary, gastrointestinal and disseminated. This is why, due to the difficult diagnosis, high mortality and uncommon presentation, we report the case of a 4-year-old child without immunodeficiency or background pathologies who developed an esophagogastric mucormycosis.

Tailored Algorithm for Sensitivity Enhancement of Gas Concentration Sensors Based on Tunable Laser Absorption Spectroscopy.

In this work, a novel tailored algorithm to enhance the overall sensitivity of gas concentration sensors based on the Direct Absorption Tunable Laser Absorption Spectroscopy (DA-ATLAS) method is presented. By using this algorithm, the sensor sensitivity can be custom-designed to be quasi constant over a much larger dynamic range compared with that obtained by typical methods based on a single statistics feature of the sensor signal output (peak amplitude, area under the curve, mean or RMS). Additionally, it is shown that with our algorithm, an optimal function can be tailored to get a quasi linear relationship between the concentration and some specific statistics features over a wider dynamic range. In order to test the viability of our algorithm, a basic C 2 H 2 sensor based on DA-ATLAS was implemented, and its experimental measurements support the simulated results provided by our algorithm.

A Core-Offset Mach Zehnder Interferometer Based on A Non-Zero Dispersion-Shifted Fiber and Its Torsion Sensing Application.

In this paper, an all-fiber Mach-Zehnder interferometer (MZI) based on a non-zero dispersion-shifted fiber (NZ-DSF) is presented. The MZI was implemented by core-offset fusion splicing one section of a NZ-DSF fiber between two pieces of single mode fibers (SMFs). Here, the NZ-DSF core and cladding were used as the arms of the MZI, while the core-offset sections acted as optical fiber couplers. Thus, a MZI interference spectrum with a fringe contrast (FC) of about 20 dB was observed. Moreover, its response spectrum was experimentally characterized to the torsion parameter and a sensitivity of 0.070 nm/° was achieved. Finally, these MZIs can be implemented in a compact size and low cost.

Analytical modelling of a refractive index sensor based on an intrinsic micro Fabry-Perot interferometer.

In this work a refractive index sensor based on a combination of the non-dispersive sensing (NDS) and the Tunable Laser Spectroscopy (TLS) principles is presented. Here, in order to have one reference and one measurement channel a single-beam dual-path configuration is used for implementing the NDS principle. These channels are monitored with a couple of identical optical detectors which are correlated to calculate the overall sensor response, called here the depth of modulation. It is shown that this is useful to minimize drifting errors due to source power variations. Furthermore, a comprehensive analysis of a refractive index sensing setup, based on an intrinsic micro Fabry-Perot Interferometer (FPI) is described. Here, the changes over the FPI pattern as the exit refractive index is varied are analytically modelled by using the characteristic matrix method. Additionally, our simulated results are supported by experimental measurements which are also provided. Finally it is shown that by using this principle a simple refractive index sensor with a resolution in the order of 2.15 × 10(-4) RIU can be implemented by using a couple of standard and low cost photodetectors.

Effects of a Single Session of Mindfulness and Compassion on Skin Temperature in Breast Cancer Survivors.

Previous studies have suggested that mindfulness programs can be useful, in a significant sector of the population, to reduce stress when practiced for at least 8 weeks. The objective of the present investigation was to explore the effect of a single session of mindfulness practice in reducing stress in female cancer survivors. Two repeated measures studies were applied; in the first one, it was performed individually, while in the second one, it was performed in a group. Psychosocial measures were administered, and skin temperature was recorded as a marker of autonomic nervous activity. The results indicate that only when the mindfulness exercise was presented did the skin temperature increase (p < 0.05), with a large effect size (d > 0.8) during compassion, suggesting sympathetic decline. Furthermore, the psychosocial functioning of the group of female cancer survivors was like that of the non-clinical population. The data are discussed in the context of Polyvagal Theory, a theoretical model of biopsychosocial functioning, and evidence is provided on the effect of mindfulness and compassion on reducing stress and inducing positive affect in female cancer survivors.

Kinetic modelling of UVC and UVC/H2O2 oxidation of an aqueous mixture of antibiotics in a completely mixed batch photoreactor.

The removal kinetics of an aqueous mixture of thirteen antibiotics (i.e., ampicillin, cefuroxime, ciprofloxacin, flumequine, metronidazole, ofloxacin, oxytetracycline, sulfadimethoxine, sulfamethoxazole, sulfamethazine, tetracycline, trimethoprim and tylosin) by batch UVC and UVC/H2O2 processes has been modeled in this work. First, molar absorption coefficients (ε), direct quantum yields (Φ) and the rate constants of the reaction of antibiotics with hydroxyl radical (kHO•) (model inputs) were determined for each antibiotic and compared with literature data. The values of these parameters range from 0.3 to 21.8 mM-1 cm-1 for ε, < 0.01 to 67.8 mmol·E-1 for Φ and 3.8 × 109 to 1.7 × 1010 M-1 s-1 for kHO•. Second, a regression model was developed to compute the rate constants of the reactions of the antibiotics with singlet oxygen (k1O2) from experimental data obtained in batch UVC experiments treating a mixture of the antibiotics. k1O2 values in the 1-50 × 106 M-1 s-1 range were obtained for the antibiotics studied. Finally, a semi-empirical kinetic model comprising a set of ordinary differential equations was solved to simulate the evolution of the residual concentration of antibiotics and hydrogen peroxide (model outputs) in a completely mixed batch photoreactor. Model predictions were reasonably consistent with the experimental data. The kinetic model developed might be combined with computational fluid dynamics to predict process performance and energy consumption in UVC and UVC/H2O2 applications at full scale.

Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with increased prevalence and incidence in recent decades. Its etiology remains largely unclear, but it seems to involve a strong genetic component and environmental factors that, in turn, induce epigenetic changes during embryonic and postnatal brain development. In recent decades, clinical studies have shown that inutero exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug, is an environmental factor associated with an increased risk of ASD. Subsequently, prenatal VPA exposure in rodents has been established as a reliable translational model to study the pathophysiology of ASD, which has helped demonstrate neurobiological changes in rodents, non-human primates, and brain organoids from human pluripotent stem cells. This evidence supports the notion that prenatal VPA exposure is a valid and current model to replicate an idiopathic ASD-like disorder in experimental animals. This review summarizes and describes the current features reported with this animal model of autism and the main neurobiological findings and correlates that help elucidate the pathophysiology of ASD. Finally, we discuss the general framework of the VPA model in comparison to other environmental and genetic ASD models.

(-)-epicatechin treatment did not modify the thermogenic pathway in the gastrocnemius muscle of male rat offspring obeses by programming.

The aim of this study was to analyse the expression of genes related to the regulation of energy metabolism in skeletal muscle tissue by comparing male offspring in two age groups [at 110 and 245 postnatal days (pnd)] from a mother with obesity induced by a high-fat diet and (-)-epicatechin (Epi) administration. Four groups of six male offspring from different litters were randomly selected for the control groups [C and offspring of mothers with maternal obesity (MO)] or Epi intervention groups. We evaluated the effect of Epi on gastrocnemius tissue by analysing the mRNA and protein expression levels of Fndc5/irisin, Pgc-1α, Ucp3, and Sln. Epi significantly increased the Pgc-1α protein in the MO group of offspring at 110 pnd (p < 0.036, MO vs. MO+Epi), while at 245 pnd, Epi increased Fndc5/irisin mRNA expression in the MO+Epi group versus the MO group (p = 0.006).No differences were detected in Fndc5/irisin, Ucp3 or Sln mRNA or protein levels (including Pgc-1α mRNA) in the offspring at 110 pnd or in Pgc-1α, Ucp3, or Sln mRNA or protein levels (including Fndc5/irisin protein) at 245 pnd among the experimental groups. In conclusion, (-)-epicatechin treatment increased Fndc5/irisin mRNA expression and Pgc-α protein levels in the gastrocnemius muscle of offspring at postnatal days 110 and 245. Furthermore, it is suggested that the flavonoid effect in a model of obesity and its impact on thermogenesis in skeletal muscle are regulated by a different pathway than Fndc5/irisin.

Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy.

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.

High temperature optical fiber sensor based on compact fattened long-period fiber gratings.

A compact high temperature fiber sensor where the sensor head consists of a short fattened long period fiber grating (F-LPFG) of at least 2 mm in length and background loss of -5 dBm is reported. On purpose two different F-LPFGs were used to measure temperature variations, taking advantage of their broad spectrum and the slope characteristics of the erbium light source. This approach affected the spectrum gain as the linear band shifting took place. The measured sensitivity of the long period fiber gratings were about 72 pm/°C in a range from 25 to 500 °C. Here, the temperature rate of the experiment was 0.17 °C/s and the temperature response time was within 3 s. Moreover, temperature changes were detected with an InGaAs photodetector, where a sensitivity of 0.05 mV/°C was achieved.

Importance of multiplanar reformation angiographic images for the detection of carotid web: A case series.

Carotid web (CW) is considered a variant of intimal fibromuscular dysplasia. CW represents between 9.4% and 37% of ischemic strokes that were initially misclassified as "cryptogenic." However, in Latin America, there is a lack of detection. We present 5 cases of ischemic stroke due to CW and discuss the usefulness of multiplanar reformatting (MPR) imaging in computed tomography angiography. The identification of CW with the use of tridimensional (3D) reconstructions and maximum intensity projection was 20%, the rest was misdiagnosed as atherosclerotic plaque. With the MPR, the identification of typical CW findings was improved, such as a thin septum, a shelf-like image, and a mountain shadow-like image. However, one must be alert to changes in the 3D disposition of the carotid bifurcation, as they may mask the typical CW findings. A good practice is to align the internal carotid artery exactly posterior to the external carotid artery in the sagittal plane.