[Advances in the application of ion chromatography-mass spectrometry in the fields of life and health].

Ion chromatography is a technique commonly used to separate strongly polar and ionizable substances; it can be used to separate, identify, and quantify ionizable compounds in complex samples when coupled with mass spectrometry, and is currently being used in the application of food analysis, drug analysis, metabolomics and clinical poisoning analysis. Herein, we review the development of ion chromatography-mass spectrometry (IC-MS), its progress over the past 20 years, and future trends in the abovementioned areas. The IC-MS research progress and applications for the determination of inorganic anions, organic acids, polar pesticides, biogenic amines, and sugars in the food field are discussed. Drug analysis applications are discussed mainly in relation to the analysis of drug impurities, identifying drug degradation products, and determination of plasma concentration, while the separation and analysis of strongly polar metabolites, such as organic acids, sugar phosphates, and nucleotides in biological matrices are discussed in relation to metabolomics. Advances in the analysis of strongly polar or ionizable toxic compounds, such as alkyl methylphosphonic acid, methylphosphonic acid, glyphosate, 3-nitropropionic acid, and indandione rodenticides, are mainly discussed in clinical poisoning analysis field. This paper is expected to become a useful reference for the further expansion and application of IC-MS in the life and health fields.

New analytical methods focusing on polar metabolite analysis in mass spectrometry and NMR-based metabolomics.

Following in the footsteps of genomics and proteomics, metabolomics has revolutionised the way we investigate and understand biological systems. Rapid development in the last 25 years has been driven largely by technical innovations in mass spectrometry and nuclear magnetic resonance spectroscopy. However, despite the modest size of metabolomes relative to proteomes and genomes, methodological capabilities for robust, comprehensive metabolite analysis remain a major challenge. Therefore, development of new methods and techniques remains vital for progress in the field. Here, we review developments in LC-MS, GC-MS and NMR methods in the last few years that have enhanced quantitative and comprehensive metabolome coverage, highlighting the techniques involved, their technical capabilities, relative performance, and potential impact.

Regulation of cardiac fibroblasts reprogramming into cardiomyocyte-like cells with a cocktail of small molecule compounds.

Myocardial infarction results in extensive cardiomyocyte apoptosis, leading to the formation of noncontractile scar tissue. Given the limited regenerative capacity of adult mammalian cardiomyocytes, direct reprogramming of cardiac fibroblasts (CFs) into cardiomyocytes represents a promising therapeutic strategy for myocardial repair, and small molecule drugs might offer a more attractive alternative to gene editing approaches in terms of safety and clinical feasibility. This study aimed to reprogram rat CFs into cardiomyocytes using a small molecular chemical mixture comprising CHIR99021, Valproic acid, Dorsomorphin, SB431542, and Forskolin. Immunofluorescence analysis revealed a significant increase in the expression of cardiomyocyte-specific markers, including cardiac troponin T (cTnT), Connexin 43 (Cx43), α-actinin, and Tbx5. Changes in intracellular calcium ion levels and Ca2+ signal transfer between adjacent cells were monitored using a calcium ion fluorescence probe. mRNA sequencing analysis demonstrated the upregulation of genes associated with cardiac morphogenesis, myocardial differentiation, and muscle fiber contraction during CF differentiation induced by the small-molecule compounds. Conversely, the expression of fibroblast-related genes was downregulated. These findings suggest that chemical-induced cell fate conversion of rat CFs into cardiomyocyte-like cells is feasible, offering a potential therapeutic solution for myocardial injury.

Activation and depression of neural and hemodynamic responses induced by the intracortical microstimulation and visual stimulation in the mouse visual cortex.

Objective. Intracortical microstimulation (ICMS) can be an effective method for restoring sensory perception in contemporary brain-machine interfaces. However, the mechanisms underlying better control of neuronal responses remain poorly understood, as well as the relationship between neuronal activity and other concomitant phenomena occurring around the stimulation site.Approach. Different microstimulation frequencies were investigatedin vivoon Thy1-GCaMP6s mice using widefield and two-photon imaging to evaluate the evoked excitatory neural responses across multiple spatial scales as well as the induced hemodynamic responses. Specifically, we quantified stimulation-induced neuronal activation and depression in the mouse visual cortex and measured hemodynamic oxyhemoglobin and deoxyhemoglobin signals using mesoscopic-scale widefield imaging.Main results. Our calcium imaging findings revealed a preference for lower-frequency stimulation in driving stronger neuronal activation. A depressive response following the neural activation preferred a slightly higher frequency stimulation compared to the activation. Hemodynamic signals exhibited a comparable spatial spread to neural calcium signals. Oxyhemoglobin concentration around the stimulation site remained elevated during the post-activation (depression) period. Somatic and neuropil calcium responses measured by two-photon microscopy showed similar dependence on stimulation parameters, although the magnitudes measured in soma was greater than in neuropil. Furthermore, higher-frequency stimulation induced a more pronounced activation in soma compared to neuropil, while depression was predominantly induced in soma irrespective of stimulation frequencies.Significance. These results suggest that the mechanism underlying depression differs from activation, requiring ample oxygen supply, and affecting neurons. Our findings provide a novel understanding of evoked excitatory neuronal activity induced by ICMS and offer insights into neuro-devices that utilize both activation and depression phenomena to achieve desired neural responses.

Differential stability of bacterial photosynthetic apparatus of Rhodobacter alkalitolerans strain JA916T under alkaline and light environment.

In purple bacteria, photosynthesis is performed by densely packed pigment-protein complexes, including the light-harvesting complexes known as RC-LH1 and LH2, with carotenoids to assist in the functioning of photosynthesis. Most photosynthetic bacteria are exposed to various abiotic stresses such as light, temperature, alkalinity-acidity, and salinity. Rhodobacter (R.) alkalitolerans was discovered from the alkaline pond; here, we report the comparative study of the photosynthetic apparatus of R. alkalitolerans in various light intensities in relation to its high pH tolerance ability. With increased light intensity, the stability of photosystem complexes decreased in normal pH (npH pH 6.80 ± 0.05) conditions, whereas in high pH (hpH pH 8.60 ± 0.05), acclimation was observed to high light. The content of bacteriochlorophyll a, absorbance spectra, and circular dichroism data shows that the integrity of photosystem complexes is less affected in hpH compared with npH conditions. Large pore blue native polyacrylamide gel electrophoresis of photosystem protein complexes and sucrose density gradient of n-dodecyl ß-D-maltoside solubilized intracytoplasmic membranes show that LH2 is more affected in npH than in hpH, whereas RC-LH1 monomer or dimer has shown interplay between monomer and dimer in hpH, although the dimer and monomer both increased in npH. Increased content and expression level of ATPase protein complex and subunit-"c" of ATPase, fast relaxation kinetics of p515, and relatively higher membrane lipid content in hpH along with less photooxidative stress and subsequently lesser superoxide dismutase activity exemplify photoprotection in hpH. Furthermore, the increased expression levels of antiporter NhaD in hpH signify its role in the maintenance of homeostatic balance in hpH.

Characterization of halogen species in seaweeds from the Antarctic using a multi-technique approach.

BACKGROUND: Despite the recognized importance, the determination of halogens in Antarctic seaweeds remains understudied. Limited research exists due to challenges associated with sample preparation, and reliable analytical techniques for this type of analysis. Therefore, further investigations are necessary to bridge this knowledge gap and gain a comprehensive understanding of halogen metabolism in Antarctic seaweeds. METHODS: In this study, seaweeds from the coast of the Antarctic continent were characterized concerning the total content of halogens and their species. For this purpose, different sample preparation methods, based on extraction and combustion, combining highly selective and sensitive chromatographic and spectrometric multi-technique approaches were used. RESULTS: By using optimized methods, it was possible to determine total halogens content, the distribution of bromine and iodine in different classes of species (lipids, water-soluble, proteins, carbohydrates, and residue), as well as the identification of iodinated amino acids (MIT and DIT) in ten brown and red seaweeds. Bromate and iodate were not detected in the samples, which presented only bromide and iodide species in their composition. Additionally, unknown bromine and iodine species were observed in different extracts evaluated. Furthermore, 25 halogenated polyphenols were identified in seaweeds, of which only four were already reported in the literature. CONCLUSION: The results obtained in this study comprise unprecedented data in the literature on species of halogens present in seaweeds from the Antarctic environment.

Identificando evasão fiscal em empresas de fachada e em créditos ilegais de ICMS / Identificación de evasión tributaria en empresas fachada y créditos ilegales del ICMS / Identifying tax evasion in shell companies and fraudulent credits of Brazil's state value-added tax (ICMS)

Resumo Empresas que emitem documentos fiscais para fraudar o fisco com a transferência de crédito do ICMS sem a circulação de mercadorias causam prejuízo ao erário público e, por conseguinte, à sociedade. Diversas iniciativas de combate a fraudes fiscais têm utilizado, com sucesso, técnicas de análise de dados e aprendizagem de máquina. Este trabalho buscou investigar o uso dessas técnicas na identificação de uma prática específica de fraude fiscal realizada por empresas popularmente conhecidas como "empresas noteiras", que formadas exclusivamente para emitir créditos não devidos de ICMS, imposto sobre operações relativas à circulação de mercadorias e sobre prestações de serviços de transporte interestadual, intermunicipal e de comunicação. Com base na análise documental e em consulta com auditores e especialistas, foram identificadas tipologias e variáveis relevantes na determinação de eventos de sonegação fiscal realizados pelas empresas noteiras. Em torno dessas variáveis, procedeu-se à coleta e à preparação de dados provenientes da Secretaria de Fazenda do Distrito Federal. Com esses dados, foi possível explorar o uso de modelos preditivos baseados em aprendizagem de máquina capazes de apontar comportamentos potencialmente fraudulentos. Os bons resultados obtidos por esses modelos demonstram seu potencial como parte de uma sistemática de monitoramento e auditorias fiscais realizadas pelos órgãos fazendários.

Resumen Las empresas que emiten documentos tributarios para defraudar al fisco con la transferencia de crédito del ICMS (impuesto a las operaciones relacionadas con la circulación. de bienes y de prestación de servicios interestatales, interurbanos y de comunicaciones) sin movimiento de mercancías causan daños al erario público y, por ende, a la sociedad en su conjunto. Varias iniciativas para combatir el fraude fiscal han utilizado con éxito técnicas de análisis de datos y aprendizaje automático. Este trabajo buscó investigar el uso de estas técnicas en la identificación de una práctica específica de fraude fiscal, practicada por empresas conocidas popularmente como 'empresas factureras', constituidas exclusivamente para emitir créditos no vencidos del ICMS. A partir del análisis documental y la consulta a auditores y especialistas, se identificaron tipologías y variables relevantes para la identificación de eventos de evasión fiscal realizados por empresas factureras. En torno a estas variables se recolectaron y prepararon datos desde la Secretaría de Hacienda del Distrito Federal. Con estos datos fue posible explorar el uso de modelos predictivos basados en machine learning capaces de señalar comportamientos potencialmente fraudulentos. Los buenos resultados obtenidos por estos modelos demuestran su potencial como parte de un seguimiento sistemático y auditorías fiscales por parte de las autoridades tributarias.

Abstract Companies that issue tax documents to defraud the tax authorities with the transfer of credits of Brazil's state value-added tax (ICMS) without the movement of goods cause financial losses to the government and, therefore, to society as a whole. Several initiatives to combat tax fraud have successfully used data analysis and Machine Learning techniques. This work sought to investigate the use of these techniques in identifying a specific practice of tax fraud, practiced by shell companies, formed exclusively to issue non-due ICMS credits, the tax on operations related to the circulation of goods, and the provision of interstate, intercity, and communication services. Based on document analysis and consultation with auditors and specialists, typologies and variables relevant to identifying tax evasion events carried out by shell companies were identified. Around these variables, data from the Finance Department of the Federal District were collected and prepared. With this data, it was possible to explore the use of predictive models based on Machine Learning capable of pointing out potentially fraudulent behavior. The good results obtained by these models demonstrate their potential as part of systematic monitoring and fiscal audits by tax authorities.

Analysis of environmental pollutants using ion chromatography coupled with mass spectrometry: A review.

The rise of emerging pollutants in the current environment and requirements of trace analysis in complex substrates pose challenges to modern analytical techniques. Ion chromatography coupled with mass spectrometry (IC-MS) is the preferred tool for analyzing emerging pollutants due to its excellent separation ability for polar and ionic compounds with small molecular weight and high detection sensitivity and selectivity. This paper reviews the progress of sample preparation and ion-exchange IC-MS methods in the analysis of several major categories of environmental polar and ionic pollutants including perchlorate, inorganic and organic phosphorus compounds, metalloids and heavy metals, polar pesticides, and disinfection by-products in past two decades. The comparison of various methods to reduce the influence of matrix effect and improve the accuracy and sensitivity of analysis are emphasized throughout the process from sample preparation to instrumental analysis. Furthermore, the human health risks of these pollutants in the environment with natural concentration levels in different environmental medias are also briefly discussed to raise public attention. Finally, the future challenges of IC-MS for analysis of environmental pollutants are briefly discussed.

Responses of Cortical Neurons to Intracortical Microstimulation in Awake Primates.

Intracortical microstimulation (ICMS) is commonly used in many experimental and clinical paradigms; however, its effects on the activation of neurons are still not completely understood. To document the responses of cortical neurons in awake nonhuman primates to stimulation, we recorded single-unit activity while delivering single-pulse stimulation via Utah arrays implanted in primary motor cortex (M1) of three macaque monkeys. Stimuli between 5 and 50 µA delivered to single channels reliably evoked spikes in neurons recorded throughout the array with delays of up to 12 ms. ICMS pulses also induced a period of inhibition lasting up to 150 ms that typically followed the initial excitatory response. Higher current amplitudes led to a greater probability of evoking a spike and extended the duration of inhibition. The likelihood of evoking a spike in a neuron was dependent on the spontaneous firing rate as well as the delay between its most recent spike time and stimulus onset. Tonic repetitive stimulation between 2 and 20 Hz often modulated both the probability of evoking spikes and the duration of inhibition; high-frequency stimulation was more likely to change both responses. On a trial-by-trial basis, whether a stimulus evoked a spike did not affect the subsequent inhibitory response; however, their changes over time were often positively or negatively correlated. Our results document the complex dynamics of cortical neural responses to electrical stimulation that need to be considered when using ICMS for scientific and clinical applications.

Exercise therapy guides cortical reorganization after midthoracic spinal contusion to enhance control of lower thoracic muscles, supporting functional recovery.

Postural control is critical for locomotion, allowing for gait changes, obstacle avoidance and navigation of rough terrain. A major problem after spinal cord injury (SCI) is regaining the control of balance to prevent falls and further injury. While the circuits for locomotor pattern generation reside in the spinal cord, postural control consists of multiple, complex networks that interact at the spinal, brainstem and cortical levels. After complete SCI, cortical reorganization establishes novel control of trunk musculature that is required for weight-supported stepping. In this study, we examined the impact of exercise therapy on cortical reorganization in the more clinically relevant models of both moderate and severe midthoracic contusion injury in the rat. Results demonstrate that both spontaneous recovery and therapy induced recovery of weight-supported stepping utilize cortical reorganization. Moreover, exercise therapy further improves outcome by enhancing cortical control of lower thoracic muscles enabling improvements in interlimb coordination associated with improved balance that increases weight-supported stepping. The outcome of this study suggest that cortical control of posture is key to functional improvement in locomotion. This information can be used to improve the timing and type of therapy after SCI by considering changes along the entire neural axis.

Cellular reprogramming of fibroblasts in heart regeneration.

Myocardial infarction causes the loss of cardiomyocytes and the formation of cardiac fibrosis due to the activation of cardiac fibroblasts, leading to cardiac dysfunction and heart failure. Unfortunately, current therapeutic interventions can only slow the disease progression. Furthermore, they cannot fully restore cardiac function, likely because the adult human heart lacks sufficient capacity to regenerate cardiomyocytes. Therefore, intensive efforts have focused on developing therapeutics to regenerate the damaged heart. Several strategies have been intensively investigated, including stimulation of cardiomyocyte proliferation, transplantation of stem cell-derived cardiomyocytes, and conversion of fibroblasts into cardiac cells. Resident cardiac fibroblasts are critical in the maintenance of the structure and contractility of the heart. Fibroblast plasticity makes this type of cells be reprogrammed into many cell types, including but not limited to induced pluripotent stem cells, induced cardiac progenitor cells, and induced cardiomyocytes. Fibroblasts have become a therapeutic target due to their critical roles in cardiac pathogenesis. This review summarizes the reprogramming of fibroblasts into induced pluripotent stem cell-derived cardiomyocytes, induced cardiac progenitor cells, and induced cardiomyocytes to repair a damaged heart, outlines recent findings in utilizing fibroblast-derived cells for heart regeneration, and discusses the limitations and challenges.

Spared Premotor Areas Undergo Rapid Nonlinear Changes in Functional Organization Following a Focal Ischemic Infarct in Primary Motor Cortex of Squirrel Monkeys.

Recovery of motor function after stroke is accompanied by reorganization of movement representations in spared cortical motor regions. It is widely assumed that map reorganization parallels recovery, suggesting a causal relationship. We examined this assumption by measuring changes in motor representations in eight male and six female squirrel monkeys in the first few weeks after injury, a time when motor recovery is most rapid. Maps of movement representations were derived using intracortical microstimulation techniques in primary motor cortex (M1), ventral premotor cortex (PMv), and dorsal premotor cortex (PMd) in 14 adult squirrel monkeys before and after a focal infarct in the M1 distal forelimb area. Maps were derived at baseline and at either 2 (n = 7) or 3 weeks (n = 7) postinfarct. In PMv the forelimb maps remained unchanged at 2 weeks but contracted significantly (-42.4%) at 3 weeks. In PMd the forelimb maps expanded significantly (+110.6%) at 2 weeks but contracted significantly (-57.4%) at 3 weeks. Motor deficits were equivalent at both time points. These results highlight two features of plasticity after M1 lesions. First, significant contraction of distal forelimb motor maps in both PMv and PMd is evident by 3 weeks. Second, an unpredictable nonlinear pattern of reorganization occurs in the distal forelimb representation in PMd, first expanding at 2 weeks, and then contracting at 3 weeks postinjury. Together with previous results demonstrating reliable map expansions in PMv several weeks to months after M1 injury, the subacute time period may represent a critical window for the timing of therapeutic interventions.SIGNIFICANCE STATEMENT The relationship between motor recovery and motor map reorganization after cortical injury has rarely been examined in acute/subacute periods. In nonhuman primates, premotor maps were examined at 2 and 3 weeks after injury to primary motor cortex. Although maps are known to expand late after injury, the present study demonstrates early map expansion at 2 weeks (dorsal premotor cortex) followed by contraction at 3 weeks (dorsal and ventral premotor cortex). This nonlinear map reorganization during a time of gradual behavioral recovery suggests that the relationship between map plasticity and motor recovery is much more complex than previously thought. It also suggests that rehabilitative motor training may have its most potent effects during this early dynamic phase of map reorganization.

Modulating Brain Activity with Invasive Brain-Computer Interface: A Narrative Review.

Brain-computer interface (BCI) can be used as a real-time bidirectional information gateway between the brain and machines. In particular, rapid progress in invasive BCI, propelled by recent developments in electrode materials, miniature and power-efficient electronics, and neural signal decoding technologies has attracted wide attention. In this review, we first introduce the concepts of neuronal signal decoding and encoding that are fundamental for information exchanges in BCI. Then, we review the history and recent advances in invasive BCI, particularly through studies using neural signals for controlling external devices on one hand, and modulating brain activity on the other hand. Specifically, regarding modulating brain activity, we focus on two types of techniques, applying electrical stimulation to cortical and deep brain tissues, respectively. Finally, we discuss the related ethical issues concerning the clinical application of this emerging technology.

Coupling an ion chromatography to high resolution mass spectrometry (IC-MS) for the discovery of potentially prebiotic oligosaccharides in Chardonnay grape marc.

Oligosaccharides are carbohydrates made of three to twenty monosaccharide units linked through glycosidic bonds. Emerging research into the potential prebiotic activity of oligosaccharides is creating opportunities to use industrial byproducts as value-added products. Grape marc is a residue left after winemaking and has been shown to provide health benefits to humans. In this study, we analyzed the oligosaccharides in Chardonnay grape marc by utilizing a hyphenated platform in which an ion chromatography (IC) system is coupled to an Orbitrap mass spectrometer (MS). With this platform, we obtained a structural library including 32 oligosaccharides with unique compositions of monosaccharides and 61 oligosaccharide structures. Notably, the ion chromatographic separation provided resolution of charged isomers while maintaining separation capacity for small, neutral oligosaccharides. High-quality tandem MS also facilitated the identification of oligosaccharides with structural modifications including methylation and the presence of sugar alditols and hexuronic acids. The data acquired by the IC-MS system were also compared with previously published LC-MS data. We found that these two platforms are largely complementary and, in combination, provide a more comprehensive characterization of oligosaccharides than either platform achieves alone.

The Causes and Control Measures of Extended Spectrum Beta-Lactamase Producing Enterobacteriaceae in Long-Term Care Facilities: A Systematic Review and Meta-Analysis.

Background: Due to extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE), infections among residents are increasing in long-term care facilities (LTCFs), resulting in a high rate of morbidity and healthcare costs. A designated infection control team is unavailable to control the disease. Methods: A systematic review and meta-analysis were conducted to characterize the causes of ESBL-PE and evaluate the infection control strategies within LTCFs. Multiple regression analysis (MRA) was included as supplementary statistical analysis to identify relationships between LTCFs, geographical locations, infection control measures (ICMs), and ESBL-PE. A systematic search was conducted for studies from January 2008 to December 2018. Twenty-two of the 3106 studies met the inclusion criteria. Results: The pooled prevalence for ESBL-PE among LTCFs residents was a mean difference (MD) of 15.78 (95% CI: 0.04, 31.53). Risk factors included the influence of regional areas was a standardized mean difference (SMD) of 0.61(95% CI: 0.32, 0.91) in Europe, SMD was 14.92 (95% CI: 9.17, 20.68) in Asia, and SMD was 0.51(95% CI: 0.35, 0.67) in other regions (North America and Australia). Nine of 22 studies reported ICMs were MD of 13.59 (95% CI: 5.32, 21.86). Conclusions: Meta-analysis and MRA revealed a statistically significant association between LTCF and ESBL-PE among residents (p = .05). Strict adherence to infection control measures in LTCFs is needed to address this ESBL-PE prevalence among residents. The potential positive social change is promoting knowledge about vulnerable residents in LTCFs and the community factors responsible for ESBL infection.

Motor cortex outputs evoked by long-duration microstimulation encode synergistic muscle activation patterns not controlled movement trajectories.

The effects of intracortical microstimulation (ICMS) parameters on the evoked electromyographic (EMG) responses and resulting limb movement were investigated. In ketamine-anesthetized cats, paw movement kinematics in 3D and EMG activity from 8 to 12 forelimb muscles evoked by ICMS applied to the forelimb area of the cat motor cortex (MCx) were recorded. The EMG responses evoked by ICMS were also compared to those evoked by focal ictal bursts induced by the iontophoretic ejection of the GABAA receptor antagonist bicuculline methochloride (BIC) at the same cortical point. The effects of different initial limb starting positions on movement trajectories resulting from long-duration ICMS were also studied. The ICMS duration did not affect the evoked muscle activation pattern (MAP). Short (50 ms) and long (500 ms) stimulus trains activated the same muscles in the same proportions. MAPs could, however, be modified by gradually increasing the stimulus intensity. MAPs evoked by focal ictal bursts were also highly correlated with those obtained by ICMS at the same cortical point. Varying the initial position of the forelimb did not change the MAPs evoked from a cortical point. Consequently, the evoked movements reached nearly the same final end point and posture, with variability. However, the movement trajectories were quite different depending on the initial limb configuration and starting position of the paw. The evoked movement trajectory was most natural when the forelimb lay pendant ~ perpendicular to the ground (i.e., in equilibrium with the gravitational force). From other starting positions, the movements did not appear natural. These observations demonstrate that while the output of the cortical point evokes a seemingly coordinated limb movement from a rest position, it does not specify a particular movement direction or a controlled trajectory from other initial positions.

Reducing Behavioral Detection Thresholds per Electrode via Synchronous, Spatially-Dependent Intracortical Microstimulation.

Intracortical microstimulation (ICMS) has shown promise in restoring quality of life to patients suffering from paralysis, specifically when used in the primary somatosensory cortex (S1). However, these benefits can be hampered by long-term degradation of electrode performance due to the brain's foreign body response. Advances in microfabrication techniques have allowed for the development of neuroprostheses with subcellular electrodes, which are characterized by greater versatility and a less detrimental immune response during chronic use. These probes are hypothesized to enable more selective, higher-resolution stimulation of cortical tissue with long-term implants. However, microstimulation using physiologically relevant charges with these smaller-scale devices can damage electrode sites and reduce the efficacy of the overall device. Studies have shown promise in bypassing this limitation by spreading the stimulation charge between multiple channels in an implanted electrode array, but to our knowledge the usefulness of this strategy in laminar arrays with electrode sites spanning each layer of the cortex remains unexplored. To investigate the efficacy of simultaneous multi-channel ICMS in electrode arrays with stimulation sites spanning cortical depth, we implanted laminar electrode arrays in the primary somatosensory cortex of rats trained in a behavioral avoidance paradigm. By measuring detection thresholds, we were able to quantify improvements in ICMS performance using a simultaneous multi-channel stimulation paradigm. The charge required per site to elicit detection thresholds was halved when stimulating from two adjacent electrode sites, although the overall charge used by the implant was increased. This reduction in threshold charge was more pronounced when stimulating with more than two channels and lessened with greater distance between stimulating channels. Our findings suggest that these improvements are based on the synchronicity and polarity of each stimulus, leading us to conclude that these improvements in stimulation efficiency per electrode are due to charge summation as opposed to a summation of neural responses to stimulation. Additionally, the per-site charge reductions are seen regardless of the cortical depth of each utilized channel. This evocation of physiological detection thresholds with lower stimulation currents per electrode site has implications for the feasibility of stimulation regimes in future advanced neuroprosthetic devices, which could benefit from reducing the charge output per site.

Cardiac regeneration by direct reprogramming in this decade and beyond.

Japan faces an increasing incidence of heart disease, owing to a shift towards a westernized lifestyle and an aging demographic. In cases where conventional interventions are not appropriate, regenerative medicine offers a promising therapeutic option. However, the use of stem cells has limitations, and therefore, "direct cardiac reprogramming" is emerging as an alternative treatment. Myocardial regeneration transdifferentiates cardiac fibroblasts into cardiomyocytes in situ.Three cardiogenic transcription factors: Gata4, Mef2c, and Tbx5 (GMT) can induce direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs), in mice. However, in humans, additional factors, such as Mesp1 and Myocd, are required. Inflammation and immune responses hinder the reprogramming process in mice, and epigenetic modifiers such as TET1 are involved in direct cardiac reprogramming in humans. The three main approaches to improving reprogramming efficiency are (1) improving direct cardiac reprogramming factors, (2) improving cell culture conditions, and (3) regulating epigenetic factors. miR-133 is a potential candidate for the first approach. For the second approach, inhibitors of TGF-ß and Wnt signals, Akt1 overexpression, Notch signaling pathway inhibitors, such as DAPT ((S)-tert-butyl 2-((S)-2-(2-(3,5-difluorophenyl) acetamido) propanamido)-2-phenylacetate), fibroblast growth factor (FGF)-2, FGF-10, and vascular endothelial growth factor (VEGF: FFV) can influence reprogramming. Reducing the expression of Bmi1, which regulates the mono-ubiquitination of histone H2A, alters histone modification, and subsequently the reprogramming efficiency, in the third approach. In addition, diclofenac, a non-steroidal anti-inflammatory drug, and high level of Mef2c overexpression could improve direct cardiac reprogramming.Direct cardiac reprogramming needs improvement if it is to be used in humans, and the molecular mechanisms involved remain largely elusive. Further advances in cardiac reprogramming research are needed to bring us closer to cardiac regenerative therapy.

Benefícios fiscais e sustentabilidade: um estudo dos municípios catarinenses / Beneficios fiscales y sostenibilidad: un estudio en los municipios catarinenses / Tax benefits and sustainability: a study of municipalities in the state of Santa Catarina

Resumo A relação entre benefícios fiscais e sustentabilidade não tem sido objeto de muitas pesquisas empíricas, apesar da importância da mensuração e do acompanhamento da efetividade dos gastos tributários. Assim, o objetivo deste artigo é analisar a influência dos benefícios fiscais de ICMS - imposto sobre circulação de mercadorias e prestação de serviços de transporte e de comunicação - na sustentabilidade dos municípios catarinenses. Para tanto, com base num conjunto de dados secundários em painel, coletados entre 2005 e 2017, emprega-se a modelagem de equações estruturais. A despeito de os resultados apontarem relações estatisticamente significativas, constata-se que os benefícios fiscais, em grau elevado, promovem a sustentabilidade econômica; em grau moderado, a sustentabilidade social; e, em grau baixo, a sustentabilidade ambiental.

Resumen La relación entre los beneficios fiscales y la sostenibilidad no ha sido objeto de mucha investigación empírica, a pesar de la importancia de medir y monitorear la efectividad de los gastos tributarios. Por lo tanto, el objetivo de este artículo es analizar la influencia de los beneficios fiscales del ICMS - impuesto sobre la circulación de bienes y la provisión de servicios de transporte y comunicación - sobre la sostenibilidad de los municipios catarinenses. Para ello, con base en un conjunto de datos secundarios en panel, recopilados entre 2005 y 2017, se emplea el modelado de ecuaciones estructurales. Aunque los resultados apuntan a relaciones estadísticamente significativas, parece que los beneficios fiscales, en un alto grado, promueven la sostenibilidad económica; en un grado moderado, la sostenibilidad social; y en un grado bajo, la sostenibilidad ambiental.

Abstract The relationship between tax benefits and sustainability is not well explored in empirical research, despite the importance of measuring and monitoring the effectiveness of tax expenditures. This article aims to analyze the influence of the ICMS tax benefits - tax on the circulation of goods and the provision of transport and communication services - on the sustainability of municipalities in the state of Santa Catarina. Structural equation modeling examined a set of secondary panel data collected between 2005 and 2017. Although the results point to statistically significant relationships, it appears that tax benefits promote economic sustainability to a high degree; social sustainability to a moderate degree; and environmental sustainability to a low degree.

Cortical direct current stimulation improves signal transmission between the motor cortices of rats.

Transcranial direct current (DC) stimulation is a noninvasive brain stimulation technique that is now widely used to improve motor and cognitive function. The neuromodulatory effects of DC is considered to extend to nearby as well as remote brain areas from the site of stimulation because of current flowing into the brain and/or signal transmission in neuronal networks. However, the effects of DC on cortico-cortical neuronal transmission are not well known. In the present study, we focused on signal transmission from the primary (M1) to secondary (M2) motor cortex of rats. Intra-cortical microstimulation (ICMS) was applied to the M1 under DC conditions, and changes in synaptic activity in the M2 were examined using current-source density analyses. The synaptic input to the M2 superficial layers was enhanced during DC stimulation, while the synaptic input to the M2 deeper layers was increased after DC stimulation. These results suggest that DC stimulation improves cortico-cortical neuronal transmission from M1 to M2, and that the effectiveness of DC may be different among different projection neuron types in the M1.