The ongoing miniaturization of spectrometers creates a perfect synergy with the common advantages of near-infrared (NIR) spectroscopy, which together provide particularly significant benefits in the field of food analysis. The combination of portability and direct onsite application with high throughput and a noninvasive way of analysis is a decisive advantage in the food industry, which features a diverse production and supply chain. A miniaturized NIR analytical framework is readily applicable to combat various food safety risks, where compromised quality may result from an accidental or intentional  origin. In this review, the characteristics of miniaturized NIR sensors are discussed in comparison to benchtop laboratory spectrometers regarding their performance, applicability, and optimization of methodology. Miniaturized NIR spectrometers remarkably increase the flexibility of analysis; however, various factors affect the performance of these devices in different analytical scenarios. Currently, it is a focused research direction to perform systematic evaluation studies of the accuracy and reliability of various miniaturized spectrometers that are based on different technologies; e.g., Fourier transform (FT)-NIR, micro-optoelectro-mechanical system (MOEMS)-based Hadamard mask, or linear variable filter (LVF) coupled with an array detector, among others. Progressing technology has been accompanied by innovative data-analysis methods integrated into the package of a micro-NIR analytical framework to improve its accuracy, reliability, and applicability. Advanced calibration methods  and nonlinear regression) directly improve the performance of miniaturized instruments in challenging analyses, and balance the accuracy of these instruments toward laboratory spectrometers. The quantum-mechanical simulation of NIR spectra reveals the wavenumber regions where the best-correlated spectral information resides and unveils the interactions of the target analyte with the surrounding matrix, ultimately enhancing the information gathered from the NIR spectra. A data-fusion framework offers a combination of spectral information from sensors that operate in different wavelength regions and enables parallelization of spectral pretreatments. This set of methods enables the intelligent design of future NIR analyses using miniaturized instruments, which is critically important for samples with a complex matrix typical of food raw material and shelf products. Re. Re54]. ervision . Exemplaervision . The othervision ; the micervision ; or the ervision . Mini-NIervision  or the Xervision .−1) seem sufficient for the intended applications of this device, as a number of essential quality parameters of foods can be effectively predicted from these spectra. In connection with the ultraminiaturized, consumer-oriented instruments described above, the much-anticipated NIR sensor fully integrated with a smartphone has remained a vivid concept in the past decade [In the context of food analysis, attention should be given to specialized, consumer-oriented NIR spectrometers designed to accept somewhat limited overall performance with the greatest benefit of cost-effectiveness. These are the necessary trade-offs to fit the instruments into their specific niche of the market, where they are offered as “pocket food analyzers” for use by the general public . The sent decade . While tt decade ,67, so ft decade , suggestMiniaturized spectrometers, in general, can be adopted to perform well in all modes of spectral acquisition established in NIR spectroscopy; i.e., diffuse reflectance a and traThat being said, most miniaturized NIR spectrometers are factory-configured to operate in diffuse reflectance mode, and some of them are offered with additional accessories for transflectance measurements, as in the case of, e.g., the VIAVI MicroNIR. Typically, spectral acquisition in this mode is performed by using an external reflector and holder designed for maximizing the optical gain of a specific instrument. Such an accessory may be also custom-made; e.g., a gold-plated surface with a geometrical shape tailored to a specific analysis . On the MVA groups various mathematical methods capable of correlating many variables at one time . Every sExploratory data analysis (EDA) groups techniques for data mining ) used to gain a general overview of the variance in the dataset and explore the statistical properties  of high volume, complex data; e.g., sets of spectra.Pattern-recognition (classification) techniques are used for separation (grouping) of the samples according to the statistical specificity of the sample set. Supervised classification methods include, e.g., linear discriminant analysis (LDA) or support vector machine (SVM) classification . ClusterRegression analysis groups the methods used for quantitative prediction of a sample’s properties; e.g., quantification of chemical content (either one or a group of constituents) present in the sample. The most popular techniques include multiple linear regression (MLR), principal component regression (PCR), and partial least-squares regression (PLSR). Nonlinear regression methods ) and ANNs can perform very well and improve the analytical performance of miniaturized sensors, in which a lower resolution and spectral region limit the amount of information available for the analysis ,73.R2), root-mean-square of calibration (RMSEC), and root-mean-square error of cross-validation (RMSECV) describe the robustness of the model. The ultimate prediction power of the model is best assessed by evaluating the root-mean-square error of prediction (RMSEP) on the basis of an independent one, or preferably more test sets of samples. Finally, the level of detection (LOD) and level of quantification (LOQ) are essential parameters that indicate a sensor’s performance  toward low-concentrated constituents, which often receive most focus in certain applications. Furthermore, statistical parameters can be used to directly compared different approaches or various instruments being used; e.g., to describe the performance of the sensing device in different conditions .The statistical parameters of trained classification or regression models need to be evaluated to assess their validity  and predictive performance. The coefficient of determination  could be successfully analyzed using miniaturized NIR instruments in a rapid manner with no need for destructive sampling procedures . On the Quantitative predictions often focus on the analysis of the fat content in meat, as well as the microbiological status, or the quantitative prediction of the level of fat adulteration . FurtherCountering seafood mislabeling is receiving increased attention, as numerous cases of food fraud involving fish and seafood products were reported lately ,149,150.To reflect state-of-the-art and currently undertaken research directions, Pennisi et al.  recentlyFruits and vegetables are also among the most-studied items in the development of analytical miniaturized NIR spectroscopy, with equal interests in both the food and agriculture sectors. Most often, the aim of the analyses was directed towards the prediction of the quality parameters of fruits and vegetables . SeveralConsidering the success of miniaturized NIR spectroscopy in predicting critical qualitative and quantitative properties of foods that feature considerable complexity, such as meat, fresh fruits, or vegetables, one should expect that the analysis of beverages or syrups should be within reach of this technology as well. An inspection of the recent literature indicated that miniaturized NIR sensors can provide the rapid assessment of sugar content in such samples in a wide range of concentrations, and in a robust manner . The preNoteworthy classification examples that included discrimination between different beer brands or sake varieties using miniaturized NIR spectroscopy should be mentioned as well ,180.Other examples of recent food-analysis studies should also be noted that further demonstrated the versatility of miniaturized NIR spectrometers, in which they were successfully applied to qualitative and quantitative analyses in a variety of cases, from whole foods to highly processed products . ContentAn inspection of the available literature well demonstrated the versatility and superior utility of miniaturized NIR spectrometers in the diverse realm of food analysis and quality control. On the other hand, attention should be also given to some of the limitations in the applicability of handheld NIR instruments; for example, chlorophyll content could not be accurately predicted in canola seed, as determined by Barthet et al. .In parallel to their revolutionary practical advantages, miniaturized technologies also impose inevitable limitations on the optical/spectral capabilities of the very compact NIR instruments. Spectra measured in narrow wavenumber regions with a relatively low resolution and an often-inferior S/N ratio, as compared with benchtop spectrometers, place a particular need on performing systematic feasibility studies of miniaturized NIR spectrometers in given analytical scenarios. In this case, the evaluation of numerous spectral pretreatments and calibration algorithms, including artificial neural networks (ANNs) and nonlinear regression methods ) is recommended to establish the best data-analytical approach for a given sensor in a specific analytical scenario. As demonstrated, this may result in a sizeable improvement in the predictive performance of portable NIR spectrometers, surpassing PLSR with minimal or no penalties to the prediction performance of handheld vs. benchtop spectroscopy in difficult analyses . Advanced calibration enables miniaturized spectrometers to nearly match the performance of benchtop instruments.As shown by Mayr et al. , the anaData-fusion methodologies offer considerable potential, effectively combining strengths of different analytical techniques. The opportunities stemming from this concept for food and beverage authentication and quality assessment were discussed in detail by Borràs et al. . HoweverFor example, an integrated analytical framework using fused physicochemical analyses, benchtop NIR spectroscopy, and melissopalynology  was recently presented by Bodor et al. . An analOn the other hand, a direct improvement of the performance of NIR sensors with mutually exclusive operational spectral regions can be accomplished by data fusion as well. Several cost-effective miniaturized NIR sensors appeared on the market that were specifically intended for food analysis ,6,7,77. Although still relatively scarce, studies of effective data-fusion strategies that integrated miniaturized NIR spectrometers have begun to attract growing attention in the fields of food and agriculture. In the study of Bec et al. , a benchA further increase in the reliability of the analysis can be achieved by low-level fusion of the spectra from spectrometers measuring largely different, only partially overlapping fragments of NIR spectrum, such as the SCiO and Tellspec instruments considered in that study . The TelFurthermore, Cavallini et al.  recentlyThe conclusions that might be drawn from the data-fusion studies involving miniaturized NIR sensors suggest that the profound instrumental differences often observed for these devices create a particular opportunity for fusion approaches to provide direct gains in analytical performance. On the other hand, a different approach to reinforcing an analytical framework using miniaturized NIR spectrometers through a data-fusion approach stems from parallelization of spectra pretreatments. As concluded in numerous case studies, and as outlined in other sections of this review, miniaturized sensors often provide spectra of inferior quality, in various terms, compared to full-scale benchtop instruments. Often, most of the resulting distortions of the spectra  can be corrected or suppressed by separately applied algorithms. However, a promising alternative is provided by applying the pretreatments in parallel and fusing the resulting datasets for further calibration and prediction. The methodological background of this concept was recently exhaustively presented by Mishra et al. . Given tWith the recently provided availability of in silico simulated NIR spectra, it has become feasible to elucidate in detail the sensor sensitivity to specific chemical information, and thus gain a deeper insight into the critical factors that affect its prediction performance in a given analytical application. Accordingly, the differences in the prediction power of caffeine and L-theanine content in black tea using the microPHAZIR and MicroNIR instruments were analyzed in detail in a recent investigation by Mayr et al. . The aut−1) was just enough to acquire the most meaningful absorption of piperine, with only weak second overtones and ternary combination bands populating the spectrum above 6150 cm−1. Firstly, as expected, the structure of the loading plots for all factors indicated a clear correspondence with the absorption features of piperine. Interestingly, exclusion of the region between 5550 and 4950 cm−1 improved the performance of the prediction for the microPHAZIR. Comparing this information with the determined vibrational assignments, one may conclude that the contributions from weak CH combination bands of piperine to the NIR spectrum of black pepper were not acquired to a satisfactory degree by the microPHAZIR. The model constructed for the microPHAZIR required four factors to obtain the maximum predictive performance, while for the dataset from the benchtop spectrometer, the optimal number of factors was three. The structures of the first factors for both cases are quite similar, and these seem to capture the most intense bands of piperine. Note, the structure of the third factor in the case of benchtop spectrometer clearly stands out from the remaining ones, e.g., above 6000 cm−1 and in the region of 5300–4900 cm−1. At these wavenumbers, one may see, standing out from the rest as well, the contributions from the combination bands involving CH and, to lesser extent, the ring deformation bands of piperine. The presence of the combinations involving ring deformation were also viable in the second factor for the benchtop spectrometer, where a distinct structure was observed near 4750–4500 cm−1.Another good example of how the comprehension of chemical information can be used in such scenario was provided by the further investigation by Grabska et al. into the patterns unveiled in the above-discussed studies . In thatThe conclusions drawn in this study indicated that the laboratory spectrometer appeared to be more sensitive to the specific vibrations of piperine in black pepper. As shown, for example, by the factor 3 corresponding to νCH combination bands of piperine that was clearly distinct from the others . There was also a significant part of the ring-deformation bands that contributed to the second and third factors in the PLSR model calibrated for the spectral set measured by the benchtop NIRFlex N-500 spectrometer. Therefore, in this case, a more accurate association between the distinct chemical information and the particular factors in the regression model was recorded.In contrast, the factors in the PLSR model constructed for the spectral set from the microPHAZIR appeared to be less specific to individual vibrations of piperine. Consequently, the microPHAZIR was less capable of following fine spectral variations representing intensity changes in the spectrum related to a specific chemical constituent.w/w, respectively) [It is likely that the poorer spectral resolution of the miniaturized spectrometer also played a role here. It remains to be seen whether this observation can explain, at least in part, the poorer performance of the microPHAZIR spectrometer compared to the laboratory spectrometer in the analysis under discussion  .A calibration model, regardless of whether the intended problem to solve concerns classification  or quantification  is generally valid only if the spectra used for predicting the property of interest is measured by the same spectrometer by which the calibration set was obtained. The critical difference here results from the disparity between two or more instruments with respect to key optical performance parameters such as the operating spectral region, wavelength accuracy, dynamic range, distance between sample and optics, the photometric response of the detector, etc. These differences are very likely to invalidate the prediction model when used with a different instrument, thus necessitating time-consuming calibration and validation for each specific spectrometer. On the other hand, in practical routines, often more than one NIR instrument; e.g., benchtop and miniaturized, or several miniaturized ones, are available at the site. Considerable gains in the efficiency of the analytical framework can be provided by the ability to perform calibration procedure on just one master instrument, which is then subsequently used for predictions from the spectra collected by the other sensors.Various mathematical algorithms known as calibration-transfer or standardization strategies help convert models or data measured by a particular instrument for use by other instruments . For thiExamples demonstrating the utility value of calibration transfer in food analysis and quality control appeared in literature shortly after the first miniaturized spectrometers were popularized on the market. For example, the aim of the study of Pierna et al.  was to aIn another example, Zamora-Rojaset et al.  evaluateNIR spectroscopy is a powerful tool for qualitative and quantitative analyses involving different types of samples used in various industries. The canonical advantages of NIR spectroscopy; i.e., nondestructive analysis, high-throughput capacity, cost-effectiveness, and its “green” nature , form a perfect synergy with the novel, miniaturized sensor technology. With the advent of portable spectrometers, decisive enhancement of NIR spectroscopy in its utility in the agri-food sector was offered. The unique value of miniaturized NIR spectroscopy is best manifested in this sector, on which the analysis of complex, chemically and physically diverse samples of natural origin is focused; i.e., raw food materials, whole and highly processed foods, and agricultural crops. Importantly, this technology permits the persistent monitoring of food quality at every stage of its complex production and supply chain, from the farm to the shelf. In these applications, the revolutionary advantage of miniaturized sensors is manifested by the capacity to perform rapid, high-throughput analyses with no need for sample preparation directly onsite.Accompanying progress in technology, recent breakthroughs in spectral-analysis methods and fundamental science have decisively changed our understanding of NIR spectra and largely expanded the potential for new applications. Comprehension of chemical information enables the interpretation of calibration models, while sensor fusion enhances the availability of the information correlated with food-quality parameters. The progress in data-analytical methods and the fundamental science underlying NIR spectra permit the knowledge-based design and optimization of the analytical application of NIR spectroscopy. These qualities have directly translated to a thriving development of new applications of miniaturized NIR spectroscopy, as it is readily available to combat food-safety risks resulting from the globalization of the food market. Hence, it has become widely adopted in this critically important sector of public interest.While immensely successful and widespread, the technology and applications of miniaturized NIR spectroscopy still face certain challenges that should be considered in the future. Unexplored areas such as sensor deterioration and transferability of the models to new generations of instruments have been signaled by recent reviews published in the field. On the other hand, ultraminiaturization and the trend aiming at providing ordinary consumers with a spectrometer in their pocket urge the reinforced reliability of precalibrated models, as well as the user-friendliness and accessibility of cloud-based services that are intended for the processing and analysis of the spectra from such sensors. The reliable and fail-proof operation of NIR spectrometers integrated with smartphones by nonexpert personnel and ordinary consumers would mark the next cornerstone of this technology in food analysis, provided that the outlined challenges are successfully addressed.


Childhood obesity is a major public health problem worldwide, and the relationship between obesity and central precocious puberty has long been confirmed, however, the mechanisms underlying this association remain elusive. This review provides an overview of the recent progress regarding how childhood obesity impacts on hypothalamic-pituitary-gonadal axis and pubertal onset, focusing on adipokines (leptin and ghrelin), hormone (insulin), and lipid (ceramide), as well as critical signaling pathways  that integrate the peripheral metabolism and central circuits. Notably, prevention of obesity and CPP is beneficial for the adult life of the children, thus we further summarize the potential strategies in treating and preventing childhood obesity and CPP. The updated understanding of metabolic stress and pediatric endocrine disease will arise the attention of society, and also contribute to preventing more serious comorbidities in the later period of life in children. Precocious puberty refers to the early onset of puberty, manifests as early secondary sexual characteristics and physical development, and is a pediatric endocrine disease. Precocious puberty can be mainly classified as central precocious puberty (CPP) and peripheral precocious puberty (PPP) according to whether the hypothalamic-pituitary-gonadal (HPG) axis is activated. The initiation of the HPG axis is usually considered true precocious puberty, therefore, CPP is the dominant diagnosis. The development of secondary sexual characteristics before the age of 8 in girls and 9 in boys is defined as CPP. CPP shows an obvious gender dimorphism, which is a conserved feature of puberty in higher mammals, possibly due to environmental and psychological factors. A recent systematic review and meta-analysis indicated that pooled prevalence is 25% in girls less than 6 years of age, although significant heterogeneity exists in different age groups . FemalesDetailed descriptions of the HPG axis in controlling puberty can be found in many excellent reviews. In brief, GnRH neurons in the hypothalamus release GnRH pulse to the hypophyseal portal blood system, while the gonadotroph cells in the pituitary respond to the signal and release the gonadotrophins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which reach the gonads to drive puberty onwards. Therefore, the evaluation of LH peaks after GnRH testing is the gold standard in the biochemical diagnosis of CPP. The combined detection of secondary sexual characters, bone age, hormone levels, pelvic ultrasound and cranial MRI could increase the sensitivity and accuracy for CPP diagnosis , 5.The development of CPP is both determined by genetic and environmental factors. The past decade has confirmed a series of core genes of CPP, such as the kisspeptin gene (KISS1), the kisspeptin receptor gene (KISS1R), the makorin ring finger protein 3 (MKRN3), and the Delta-like non-canonical Notch ligand 1 (DLK1). It is reported that DLK1 gene mutation is associated with the prevalence of family CPP, and MKRN3 gene loss-of-function mutations are the most prevalent genetic etiology of CPP. Apart from rare genetic variants, the occurrence of metabolic comorbidities rises as the dominant cause of CPP in recent years. The epidemic of childhood obesity serves as the major companion for CPP, suggesting the impact of nutritional and metabolic cues on the HPG axis. There is clear evidence to support the effects of higher childhood body mass index (BMI) on the onset and development of puberty in both boys and girls . ChildhoPalaeolithic Ages. Whereas individuals with anorexia or malnutrition are often related to delay or absence of puberty onset and perturbed fertility , MKRN3 are acted as inhibitors of GnRH release .Clinical and experimental work further provide evidence to support the interaction of energy reserves and CPP. The age of menarche was approximately 17 years in the early 19th century, while it dramatically declined to approximately 13 years by the mid-20th century, largely attributed to improved nutrition, personal hygiene, and better socioeconomic conditions . StudiesObesity is accompanied by a series of metabolic alterations, and different metabolic cytokines and hormones, such as leptin, ghrelin, insulin, as well as certain central lipids may impact the HPG axis, and participate in the fine-tuning of puberty.ob) gene, and secreted from the adipocytes into the circulation, the level of leptin is directly related to the amount of body fat stores. Leptin can pass the blood-brain barrier, and take the action at certain neurons in the hypothalamus. Physiologically, circulating leptin is a sensitive maker of metabolic status, and transports the signal to the control center . Upon binding with leptin receptor (LepRb), leptin activates pathways such as JAK2/STAT3, PI3K/IRS/AKT, and SHP2/MAPK in the hypothalamus, and exerts anorexigenic and thermogenic functions to alleviate the metabolic burden in the peripheral. Simultaneously, the accumulation of phosphorylated STAT3 dimers induces the transcription of SOCS3, which inhibits the JAK2/STAT3 pathway. This efficient work of the leptin signaling feedback loop guarantees metabolic homeostasis. Accordingly, leptin deficiency (ob/ob mice) and leptin receptor deficiency (db/db mice) animals spontaneously develop into obesity and/or type 2 diabetes.Leptin is the first identified adipose cytokine, which is a peptide hormone (16kDa) encoded by the product of the obese  synthesis and secretion in the anterior pituitary, or indirectly elevates ACTH through paracrine stimulation of hypothalamic corticotropin-releasing hormone synthesis and secretion. It is reported that plasma ghrelin is negatively correlated with BMI and body fat percentage, and circulating ghrelin levels are decreased in human obesity . ConsistEvery other day fasting (EODF) is reported to delay the Di-(2-ethylhexyl) phthalate-induced puberty onset acceleration in female rats, accompanied by the decrease of serum leptin, luteinizing hormone and estradiol . ConsideInsulin is another important hormone that affects both childhood obesity and CPP. Insulin is a pancreatic hormone, and secreted in response to the increase of blood concentration of glucose (hyperglycemia), to promote circulating glucose to enter effector cells. Reduced sensitivity of cells to insulin is termed insulin resistance, which often occurs in obesity and related T2DM. The inefficient glucose uptake in conditions of insulin resistance causes hyperglycemia, which further stimulates insulin secretion to compensate the insulin insensitivity. However, continuous hyperglycemia and insulin resistance in obesity has been shown to conduct stimulatory/permissive actions on the HPG axis. Actually, conditions of low or null insulin levels, such as uncontrolled diabetes, are usually associated with suppressed GnRH levels and reproductive activity . Mice laDuring development, nutrient consumption promotes growth as well as the production of required hormones through insulin-like systems . The horKiss1, and its receptor Gpr54 is considered to be a breakthrough in puberty. Kiss1 governs the secretion of kisspeptin, which directly acts on GnRH neurons in promoting puberty activation. The Kiss1 system is sensitive to metabolic conditions, and an important transmitter for impacting puberty. Therefore, hypothalamic kisspeptin neurons have been postulated to be a key nodal nexus between metabolism and puberty  will inhibit AMPK activity.AMPK is a fundamental nutrition sensor that is essential for cellular energy homeostasis, alteration of cellular AMP/ATP ratio determines the status of AMPK. Upon energy deficiency, an increased AMP/ATP ratio directly activates AMPK AMPK is widely expressed in metabolic organs and also co-expressed in Kiss 1 neurons, therefore the brain AMPK is likely to integrate metabolic/nutritional status and the onset of puberty in obesity. Chronic energy deficiency at puberty activates hypothalamic AMPK, and pharmacological or virogenetic activation of AMPK delays pubertal onset to a variable extent in rodent models . AMPK isCentral AMPK activity also regulates peripheral metabolism. Estrogens (E2) are reported to inhibit hypothalamic AMPK through estrogen receptor alpha (ERα), which leads to the promotion of thermogenesis in brown adipose tissue in a feeding-independent manner. Genetic activation of AMPK in the VMH prevented E2-induced increase in brown adipose tissue-mediated thermogenesis and weight loss .Mammalian target of rapamycin (mTOR) is atypical serine/threonine protein kinase, and is an evolutionally conserved protein. mTOR can integrate multiple intracellular signals , and is involved in the transcriptional and translational regulating processes.In conditions of energy sufficiency, timely eviction of SIRT1 from the Kiss1 promoter, together with the presumable activation of mammalian target of rapamycin (mTOR), allows increased Kiss1 expression and the normal occurrence of puberty. Activation of PI3K/Akt/mTOR pathway in the hypothalamus is associated with the increased GnRH release and CPP in adolescent female rats, whereas inhibition of mTOR in the hypothalamus could block the activation of Kiss1, Grp54, and GnRH . In addide novo ceramide synthesis, the increased ceramide level further results ovarian sympathetic output, whereas blockade of ceramide synthesis normalized the timing of puberty and ovarian sympathetic tone  and sympathetic ovarian innervation. Obese female rats with CPP show higher expression of serine palmitoyltransferase long-chain base subunit 1 (SPTLC1), a crucial component for tic tone . Consisttic tone .Puberty is a crucial biological process normally occurring at a specific time, therefore, the aim of CPP treatment is to normalize the course of puberty, preserve the adult height, and alleviate the associated complications. GnRH secretion is considered the initial drive for the development of CPP, therefore, GnRH analog (GnRHa) is the primary option for CPP. GnRHa treatment shows efficacy in suppressing gonadotrophin and slowing the progression of secondary sexual characteristics . HoweverPrevention is the first and foremost strategy for CPP and obesity. A healthy lifestyle is crucial for the development of children. Away from “junk food” should be highlighted. Overconsumption of high-fat high-fructose food is the driving force of obesity, especially in children. It is reported that high-fructose corn syrup consumption  during childhood has stronger metabolic effects than in other generations, which is closely associated with CPP . An animGuaranteeing the quality and duration of sleep of the children is equally important for preventing obesity and CPP. The circadian timing system regulates a variety of biological actions including metabolism, hormone, immunity, and reproductive function. Sleep quality and duration determine the hypothalamic melatonin secretion, which impacts the transcription of kisspeptin and GnRH . In addiExogenous chemicals that interfere with the endocrine system are defined as endocrine disruptors. Endocrine disruptors may affect the synthesis, metabolism, and the action of endogenous hormones, leading to the dysregulation of normal physiological processes and promoting the development of disease . EndocriThe obesity epidemic and CPP are associated with a series of metabolic and endocrine diseases, and might also impact the quality of life in adults. In this review, we have focused on the peripheral cytokines, hormones, lipids, as well as energy-sensitive molecules to integrating the metabolic and endocrine functions during CPP Figure 1LZ conceptualized the manuscript, LS and ZJ collected the literature and drafted the manuscript, LZ revised the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by grants from the National Natural Science Foundation of China (No. 82205181).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


High-throughput Determination of Interdiffusion Coefficients) code was adopted in a high-throughput and automatic manner for accommodating a dataset of composition profiles with up to 87 diffusion couples. A good convergence for the optimization process was achieved, while satisfactory results regarding the composition profiles and previously evaluated diffusion properties were obtained. Here, we present an investigation into the elemental effect of Al towards interdiffusion and tracer diffusion, and their potential effect on creep and precipitation processes.This study aims to incorporate a big dataset of composition profiles of fcc AlCoCrFeNi alloys, in addition to those of the related subsystem, to develop a self-consistent kinetic description for quinary high-entropy alloys. The latest feature of the HitDIC ( High-entropy alloys (HEAs) represent one of the most appealing research interests in the materials community ,2,3. ResFor applications at moderate or high temperatures, creep resistance is an important research priority, especially for traditional superalloy systems . The creIn recent years, several contributions have been devoted to investigating the diffusion behaviors of AlCoCrFeNi HEAs ,20,21,22In order to obtain reliable diffusion coefficients covering wide composition and temperature regions, the experimental composition profiles of the AlCoCrFeNi alloys, in addition to those of the related subsystem, are considered simultaneously. Despite the large number of composition profiles, the assessment of diffusion descriptions of HEAs is concerned with many descriptors, i.e., binary and ternary interaction parameters of the Relich–Kister polynomial, according to the CALPAHD convention. The assessed results are therefore prone to overfitting and non-uniqueness without a rational strategy for dimensionality reduction and regularization. As the important features of the HitDIC code ,25,26,27Consequently, in this study, the diffusion descriptions of the AlCoCrFeNi alloys have been updated using the latest developed parameter selection and regularization strategies  to pursuix is the composition and R is the ideal gas constant, T the temperature, iM the atomic mobility and A0 is the structure factor and s might be assigned with 0 when the attribution is of minimal effect. Furthermore, the atomic mobility can be expanded according to the CALPHAD convention, i.e.,To determine the diffusion properties underlying the diffusion phenomenon, numerical inverse methods are adopted, which are feasible for determining the interdiffusion coefficients for systems with any number of components. HitDIC code is developed on the numerical inverse methods and equipped with advanced algorithms for addressing inverse coefficients problem of diffusion. Relatively, the forward problem of diffusion in multi-component systems can be read asN is the number of diffusion couples, iC denotes the number of components for the i-th diffusion couple, jn is the number of experimental points for the i-th diffusion couple, where From the point view of the numerical inverse method, interdiffusion coefficients can be retrieved by solving the inverse problem related to the diffusion processes during the annealing processes of the diffusion couples. It can be achieved by iteratively adapting the interdiffusion coefficient matrices and simultaneously minimizing the difference between the predictions, based on Equation (1) and observations from diffusion couple experiments. After parametrization, a PDE-constrained optimization problem can be establishedK is number of activated parameters of interest and M is the number of independent observations. K is determined according to the auxiliary genes in addition to the genes in the canonical genetic algorithms, which share the same operators in the evolution processes of the genetic algorithm. After parameter selection, the regularization strategy is further introduced to reduce the complexity of the diffusion models, i.e., the L2 norm of the parameters of interest. The regularization process starts from the optimal output from the parameter selection process, while the regularization term −9. During the regularization process, the penalized target is adopted as the optimization criterionFor dimensionality reduction or parameter selection, the variable selection strategy based on genetic algorithm in HitDIC is employed, where the corrected AIC (Akaike information criterion) is used as the optimization criterionA re-evaluation study case was carried out, where the composition profiles of fcc AlCoCrFeNi alloy and related quaternary sub-system were joined, as listed in In addition to the expanded experimental dataset, advanced algorithms, i.e., parameter-selection strategy and regularization strategy, were applied for rigorous assessment over the related interaction parameters of the kinetic database. The convergence sequence of the parameter selection strategy is shown in To be clear, goodness of fit was observed between the model-predicted results and experimental composition profiles, as shown in the For equal-atomic high-entropy alloys, the ideal mixing theory was applied and the related tracer diffusion coefficients towards the quinary systems were retrieved, as shown in Addition of Al is an important strategy for achieving lightweight high-entropy alloys, while precipitations are likely introduced due to their promising mechanical performance. However, complex thermodynamic, kinetic and mechanical effects might emerge with varying amounts of Al ,10,11. FWith the assessed diffusion description for the fcc AlCoCrFeNi alloy in the present work, the surface of the main terms of the interdiffusion coefficient matrices are shown in x(CoCrFeNi)1−x is calculated as shown in In addition to the interdiffusivities, the corresponding tracer diffusion coefficients for the AlFor HEAs, the diffusion coefficient is an important transport coefficient for describing many diffusion-controlled processes, i.e., solidification, aging and creep processes at a moderate service temperature. For solidification, the diffusion rates are attributed to the subtle micro-segregation of the alloying components in the concerned system. Generally, numerical simulation techniques, i.e., Scheil solidification simulation and phase-field modeling, are able to provide a good representation of the state in a material during solidification, which usually occurs in non-equilibrium conditions. Such application scenarios of the diffusion database resemble the demands of other preparation or service processes, where the quantitative description of mass transportation is indispensable.In addition to the above computation intensive simulation techniques, efforts have also been paid to the development of empirical or semi-empirical models for evaluating the performance indexes of the corresponding processes, i.e., creep processes. Zhu et al.  introducFollowing the above convention, the evaluated creep merit index is calculated and illustrated in To efficiently employ the principle of the assessed description, a precipitation factor is proposed, referring to the convention of the creep merit index. For the coarsening process during the precipitation period, Morral and Purdy  proposesAs a brief summary, the assessed diffusion database of AlCoCrFeNi alloys can successfully capture the composition and temperature dependency for kinetic essence. That is, the deduced properties, i.e., interdiffusion coefficients and tracer diffusion coefficients, are consistent with the reported calculation or experimental results. Moreover, the inferred quantities, i.e., the creep merit index and precipitation factor, also demonstrate a common tendency to influence the alloying component, i.e., Al, though the relevancy of this argument is yet to be further determined. Such a priority is considered to originate from the adopted strategy of parameter selection and regularization, which can efficiently facilitate the big dataset of diffusion information.The diffusion description of the fcc AlCoCrFeNi alloy is automatically evaluated using the latest version of HitDIC software based on a big dataset of composition profiles, composed of fcc AlCoCrFeNi HEA and the related subsystem. Good convergence behaviors are achieved for the automation strategies of parameter selection and regularization, while the obtained diffusion description can reasonably reproduce all composition profiles in the dataset related to the fcc AlCoCrFeNi HEAs.Model-predicted interdiffusion and tracer diffusion coefficients shows good consistency with the reported interdiffusion coefficients and tracer diffusion coefficients, respectively. Generality and accuracy of the employed parameter selection and regularization strategies are therefore proved, as well as the robustness of the HitDIC code.Related diffusion properties, including the interdiffusion coefficients, tracer diffusion coefficients, creep index and the precipitation factor, are subsequently evaluated. Addition of Al tends to provide lower activation energies for Al, Co and Ni components, while no significant contribution is noted towards Cr and Fe, especially for tracer diffusion. Addition of Al is found to result in the decline in creep resistance, while the related coarsening rate tends to increase with the increment of Al amount.


Under the trend of the rapid development of the internet of things (IoT), sensing for dynamic behaviors is widely needed in many fields such as traffic management, industrial production, medical treatment, building health monitoring, etc. Due to the feature of power supply independence and excellent working performance under a low-frequency environment, triboelectric nanogenerators (TENGs) as sensors are attracting more and more attention. In this paper, a comprehensive review focusing on the recent advance of TENGs as sensors for dynamic behaviors is conducted. The structure and material are two major factors affecting the performance of sensors. Different structure designs are proposed to make the sensor suitable for different sensing occasions and improve the working performance of the sensors. As for materials, new materials with stronger abilities to gain or lose electrons are fabricated to obtain higher surface charge density. Improving the surface roughness of material by surface engineering techniques is another strategy to improve the output performance of TENG. Based on the advancement of TENG structures and materials, plenty of applications of TENG-based sensors have been developed such as city traffic management, human–computer interaction, health monitoring of infrastructure, etc. It is believed that TENG-based sensors will be gradually commercialized and become the mainstream sensors for dynamic sensing. W. W25]. WIn addition to the four basic modes and hybrid generators introduced above, there are several other typical structures such as the sphere, fiber, and rotation structures, etc. Some typical sphere-based sensors are illustrated in The second typical structure is fiber. In fiber-based TENG, the tribo-pair is integrated into a slender and long fiber. There is a core fiber taken as the substrate with the electrode and dielectric material wrapped layer by layer from inside to outside, forming a coaxial fiber b 27,63,,63,64. TThe rotator-stator structure is another special structural design in which the tribo-pair is integrated into the rotator and stator, respectively ,66. The Tribo-pair and electrodes are two indispensable parts of all kinds of TENGs, and the materials of them will influence the output performance of TENGs. Plenty of materials and technologies have been developed and applied to TENG sensors.Materials for tribo-pair directly affect the device output due to the difference in triboelectric characteristics. For materials of tribo-pair, their triboelectric characteristics are the most important influencing factors. To further enhance the output of the device, different technologies of surface engineering have been applied to the tribo-pair or electrodes.The influence of tribo-pair on the performance of TENG devices is mainly determined by surface charge density. According to the theoretical models of TENG, the surface charge density of dielectric material shows a linear relationship between the transferred charge and output voltage . The surThe materials close to the top of 2  or or33] orvelocity . Then thvelocity .Voc). Another is the one between the instantaneous velocity of the freestanding layer and the short-circuit current (Isc). However, the linear relationships only exist in the condition of open-circuit or short circuit. In the latest study, Zhang et al. proposed a real-time sensing system based on TENG, in which the analytical relationship between the relative displacement of tribo-pair and the output voltage (voltage-transferred charge-displacement model) is derived [Deriving the relationship between the dynamic behaviors and the detected electrical signals through theoretical models is the third strategy. In FTENG, there are two linear relationships between the mechanical indexes and the electrical outputs according to the mechanical-electric conversion theory of FTENG ,105. The derived . Based oThe trajectory tracking is usually realized by TENG arrays ,106,107,Rotational motion widely exists in mechanical equipment, such as engines, downhole turbodrills, and bearings. The TENG sensors have been applied in monitoring rotating speed and angle on many occasions, such as steering wheels  and downThe sensing of the rotating angle could be realized with interdigital electrodes ,112 or pThe TENG-based pressure sensors have been applied in tactile sensing for human–computer interaction ,98, humaIn this paper, we have reviewed recent advances in TENG as self-powered sensors for dynamic behaviors. The structures, materials, and applications of the sensors are introduced, which can be summarized as follows.(1) To meet the application demands of TENGs in various fields, lots of structural designs of TENGs have been developed. Through special structural design, TENGs can be more effectively combined with the host to drive the relative motion of tribo-pair. Additionally, by combining the piezoelectric or magnetoelectric mechanism with the triboelectric mechanism through structural design, the output performance of the sensor will be improved and the detecting range will be broadened.(2) The material design of TENG sensors mainly depends on the output performance of the device or the functional requirements of the applications on different occasions. The output performance of TENGs is affected by the intrinsic character of the tribo-pair materials for gaining or losing electrons. The larger the difference between the abilities of gaining or losing electrons, the higher the surface charge density will be. To obtain higher output performance, some special materials are applied. To meet the special needs of some applications such as wearable devices and human–computer interaction, some transparent, stretchable, or low-elastic modulus materials are applied in TENGs.(3) The micro/nano structures on the tribo-pair surfaces can improve the output performance of TENGs by enhancing the ability to accommodate charges. The surface engineering technologies are applied to fabricate rough textures or regular patterns on the material surface, including electrospinning, ICP etching, photolithography, etc. The output performance of TENG sensors could be improved by the increase in the roughness of the tribo-pair surfaces.(4) TENG-based sensors for dynamic behaviors are applied in many fields such as city traffic management, human–computer interaction, health monitoring of infrastructure, industrial machinery, the human body, etc. To realize quantitative sensing, the linear relationship between the peak values of electric output and the sensing indexes is utilized. However, only peak values of the indexes to be tested could be obtained, with most of the information in response time history lost. To realize real-time monitoring, grating structures and interdigitated electrodes are developed. For this kind of sensor, the sensing resolution depends on the size of gratings or interdigitated electrodes.(5) The advances of TENG sensors in this review show great potential for TENG to be the mainstream of the next generation of sensors. To achieve a deeper understanding of the sensing mechanism and full-time domain sensing, the quantitative sensing techniques based on mechanical-electric conversion theory should be improved. Secondly, for better integration with precision equipment, the structures should be more compact and easier to manufacture. Thirdly, to improve the service stability, the durability of TENG sensors in the actual environment remains to be enhanced.


Infectious diseases, which often result in deadly sepsis or septic shock, represent a major global health problem. For understanding the pathophysiology of sepsis and developing new treatment strategies, reliable and clinically relevant animal models of the disease are necessary. In this review, two large animal (porcine) models of sepsis induced by either peritonitis or bacteremia are introduced and their strong and weak points are discussed in the context of clinical relevance and other animal models of sepsis, with a special focus on cardiovascular and immune systems, experimental design, and monitoring. Especially for testing new therapeutic strategies, the large animal (porcine) models represent a more clinically relevant alternative to small animal models, and the findings obtained in small animal (transgenic) models should be verified in these clinically relevant large animal models before translation to the clinical level. Infectious diseases and their associated sepsis and septic shock remain a global health problem, with a steadily growing yearly incidence of up to 20 million cases and 5 million sepsis-related deaths worldwide . They ar2/FiO2), hemostasis (number of thrombocytes), the liver (plasma levels of bilirubin), the kidneys (plasma levels of creatinine and urine volume), the central nervous system , and the cardiovascular system  (Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (SEPSIS-3) , which csupport) . Septic support) . For a qsupport) .Animal models allow for a detailed investigation of the pathophysiological mechanisms of the disease; however, the translation of the findings to the clinical level is often complicated. Therefore, in this review, animal models of sepsis were analyzed with an emphasis on their clinical relevance. Small and large animal models of sepsis were compared to reveal their main advantages and disadvantages with special focus on cardiovascular and immune systems. As highly clinically relevant models, two porcine models of sepsis (peritonitis- and bacteremia-induced), which are used routinely in our lab, were scrutinized in detail, including methodological aspects of the experiments.Despite significant progress in our understanding of this clinical syndrome, the pathophysiology of sepsis remains unclear and there is an increasing need to improve our understanding of sepsis and develop new effective treatments for this deadly condition. Obviously, reliable and clinically relevant animal models are necessary for understanding the complex pathophysiological concepts of sepsis as well as for developing new effective treatment options. Many preclinical studies have been conducted, with promising results; however, most of them could not be successfully transferred to clinical situations. Knowledge transfer is complicated by the heterogeneity and complexity of the animal models used . Small pCardiovascular system has been extensively studied in both small and large animal models, which allows for a fair comparison with humans and a proper assessment of the possibility of clinical translation. From a practical point of view, large animal models  have an obvious advantage in that their size and macroanatomy resemble those of the human cardiovascular system. That allows for the easy use of clinical devices and tools in large animal models, including their experimental testing. Also, microstructural studies show similar characteristics for the human and porcine myocardium , with doto,f and Ito,s), together with the rapidly activating, slowly inactivating delayed rectifier potassium currents , whereas the main repolarization currents of human ventricular myocardium IKr (rapid delayed rectifier potassium current) and IKs (slow delayed rectifier potassium current) are functionally irrelevant (to) that is responsible for early repolarization in human ventricular myocytes is missing in the porcine myocardium , which is associated with a faster kinetics of both cardiac contraction and excitation . Cardiacrelevant . On the relevant . Major cocardium .High resting heartrates in mice and rats limit the extent of additional heartrate increase, i.e., heartrate reserve, which is significantly smaller in mice and rats (∼40%) than in humans or pigs (∼150%) . The limin vivo discrepancy, however, was not paralleled by the in vitro response of macrophages in cell culture. The studies of the response of mouse and human macrophages in the microenvironment of mouse and human serum indicated that proteins in mouse serum markedly suppress the induction of proinflammatory cytokines compared to human serum ; a femoral arterial catheter for blood pressure recording and blood sampling; a fiberoptic catheter for thermal-dye double-indicator dilution measurements; ultrasound transit time flow probes ; catheters in the portal, renal, and hepatic veins; laser Doppler flowmetry for monitoring ileal mucosal and renal cortex microcirculation; and a cystostomy catheter for urine collection (percutaneous insertion under ultrasound guidance). In case hemofiltration techniques are investigated, a dialysis catheter  may be inserted into the right femoral vein and serve for hemofiltration access (An important advantage of large (porcine) animal models is that extensive monitoring of vital functions is plausible , 3. A stn access . Such exn access  with theP. aeruginosa  was used  is technically simple and reproduces many pathophysiological features of human sepsis. This type of modeling allows for a tightly regulated load of bacterial exposure, and, therefore, severity of insult. Clinically, it replicates conditions such as acute endocarditis or overwhelming infections with Pneumococcus or Meningococcus. In addition, the specific host response to Gram-positive or Gram-negative bacterial challenge can be investigated. On the other hand, the intravenous application of live bacteria leads to a rapid immune-inflammatory and hemodynamic response, usually not seen in sepsis induced by an infectious focus. Hence, more complex, and perhaps more clinically relevant models include locally induced sepsis such as peritonitis. These models of polymicrobial sepsis allow for more protracted immune-inflammatory, metabolic, and hemodynamic alterations to be observed in a clinical setting. Autologous fecal material challenges the animals with its individual gut flora. However, marked intra- and interindividual variations in gut microbial diversity might predispose animals to significant heterogeneity in their host response. Another problem is the difficulty of controlling the quantity of bacteria introduced into the peritoneum.Three broad categories of experimental models of sepsis include locally induced sepsis , endotoxemia, and the intravenous administration of a viable pathogen (intermittent or continuous bacteremia). Each model has its strengths and limitations. Intravenous application of single live bacteria  models represent a more clinically relevant alternative to small animal  models, especially for testing novel therapeutic strategies with not so clear cellular and molecular mechanisms. In a number of studies, porcine models of sepsis have shown a high level of correspondence with clinical situations and human disease progression, thus allowing for the easy and reliable translation of experimental findings to a clinical setting. On the other hand, small animal models, especially transgenic models, allow researchers to obtain mechanistic proof-of-principle insights into the molecular mechanisms of disease in a much faster and more cost-effective way. Obviously, the relationship between small and large models is not competitive but complementary, and the optimal translation should include both steps, with the verification of small animal model findings in large animal models.


Objective: We examine the impact of financial distress caused by the COVID-19 pandemic on mental health and psychological well-being.Methods: We analyze cross-sectional survey data  from the Life during Pandemic study in Chile. We estimate linear probability models to analyze the relationship between economic fragility, financial distress, and psychological well-being.Results: Our findings show unemployment and income loss are highly predictive of experiencing a range of financial problems, such as a lack of savings, as well as difficulties paying bills, consumer debt, and mortgage loans. In turn, financial distress leads to a higher prevalence of poor well-being and mental health deterioration, and sleep problems.Conclusion: Expansion of mental health assistance services are needed, as new diagnosis of mental health conditions has increased, but treatment has not, pointing to a barrier in the access to some mental health care services during the pandemic. Policies designed with the objective of improving financial education are necessary to increase precautionary savings and financial resilience, and alleviate the psychological burden of debt in the future. The COVID-19 pandemic produced an unprecedented and long-lasting shock to households around the world. Most countries have seen severe declines in income and higher rates of unemployment . In lineVida en Pandemia (Life during Pandemic) survey in Chile, which combines labor outcomes, financial fragility, and mental health information. We hypothesize that pandemic-induced unemployment and loss of income increases financial hardship, which in turn increases vulnerability to mental health difficulties and illnesses.In this paper we investigate the economic effects of the COVID-19 pandemic and the role of financial distress in the mental health and well-being of individuals, using a novel dataset from the Typically, measures of financial hardship include difficulty paying bills, purchasing basic goods such as food and clothing, and affording suitable housing, utilities, health care, and transportation . PersonaSymptoms of depression increased with job loss among older workers during the Great Recession, and wealth has a mitigating effect in this relationship . UnemploRecent studies have documented the effect of the COVID-19 pandemic on mental health and well-being in different countries and circumstances. There are several reviews on mental health early consequences of the COVID-19 pandemic –28. TherChile provides an interesting case study as a country that has experienced significant economic growth over the past few decades, but where high levels of income inequality and informality are still pervasive . Poor ecThe paper’s major findings indicate unemployment and income loss are highly predictive of experiencing a range of financial problems, such as a lack of savings and difficulty paying bills, consumer debt, and mortgage loans. In turn, financial distress leads to a higher prevalence of mental health and well-being complaints, including feelings of depression, anxiety, and sleep problems. Our main findings are robust to alternative measures of financial distress, mental health and well-being, and potential endogeneity bias.This study contributes to the new body of research that explores how economic and financial fragility is one of the main stressors contributing to widespread emotional stress during the pandemic, and how some specific groups are more vulnerable than others to the psychological effects of pandemics. The understanding of the nexus between financial fragility and mental health is important, and we add evidence that is relatively scarce outside developed countries. Our results suggest the effects of the COVID-19 pandemic has worrying implications for those in more vulnerable economic and financial situations.Vida en Pandemia survey in Chile . Note that although the survey design is cross-sectional, this variable allows us to capture the change in well-being as reported by individuals.Utilization of mental health-care services is measured with a set of indicator variables that capture a new diagnosis, new treatment, and/or new medication , after the start of the pandemic . Finally, we consider two variables that measure conflict within the household: an indicator for higher frequency of conflicts relative to before the pandemic, and a variable that measures severity of conflicts. Severity of the conflicts is a variable that goes from 0 to 5, where 0 indicates there is not an increase in conflicts, 1 indicates an increase in conflicts of low intensity, and 5 indicates an increase in conflicts of high intensity.First, we analyze the relationship between economic fragility and financial distress, following a linear probability model (LPM):via logit/probit models (results available upon request).We then analyze the relationship between financial distress and psychological well-being, according to the following equation:The relationship between financial distress and unemployment or income drop is highly statistically significant and economically meaningful regardless of the model specification. Our estimates indicate unemployment increases the probability of having problems paying a mortgage loan or a consumer loan by roughly 23 and 24 percentage points, respectively, after controlling for pre-pandemic income, a comprehensive set of variables, education, and region fixed effects. Our estimates also suggest that, on average, unemployment increases roughly by 0.6 the number of different basic goods or services one may have problems paying for . Finally, unemployment increases by 5 percentage points the probability of having insufficient savings to pay for basic needs for at least 3 months. Overall, results are qualitatively similar when we use an indicator of income drop as a measure of economic hardship.Most of the coefficients associated with the control variables have the expected sign and are statistically significant. Older individuals have fewer financial problems and are less likely to have a lack of savings. Households with more children have more financial problems and less savings. Individuals with a higher pre-pandemic income are less likely to face any financial problem or lack savings. Finally, individuals with a family member who became unemployed also face a more difficult financial situation during the pandemic.In Relatedly, in We examine conflict within the household as one potential mechanism linking financial distress and mental health outcomes. Specifically, In view of our previous results, we augment in In this paper, we analyze the effects of the COVID-19 pandemic on financial distress and mental health in Chile. We first show how the pandemic affected economic fragility, which in turn increased financial distress . We then present evidence that financial distress negatively affects mental health and well-being, using a range of variables and controlling for individual-level characteristics, including pre-pandemic income. Our results are in line with evidence showing that over-indebtedness and the prevalence of depressive symptoms are associated , and thaThe pandemic disrupted mental health services in most countries . In our An exploration of the mechanisms linking financial distress and mental health points to a higher frequency of conflicts within the household, consistent with the general finding that domestic violence increased during the pandemic  and lockOur results highlight the need for new public policies to improve mental health in the short run, for those most vulnerable to the economic impact of the pandemic: younger, female, unemployed individuals. Policies should consider the heterogeneous factors affecting mental health. Our paper also points to the key role of financial education, as a change in financial behavior can improve financial well-being of individuals , and finAn important limitation in our study is that the survey was not designed around a validated instrument to screen for anxiety and depression such as the Patient Health Questionnaire 4 (PHQ-4). We argue that the variables used in our study do a good job in assessing subjective well-being, as modeled by OECD Guidelines on Measuring Subjective Well-being . AnotherUnderstanding the effects on mental health from the pandemic, as well as the effects of the policies implemented, is vital. Relief policies targeting economically fragile and vulnerable individuals are necessary. One key lesson of our findings is that financial assistance in the form of more loans increases debt and may worsen mental health and psychological well-being. Interventions designed with the objective of improving financial education are necessary to increase levels of precautionary savings, build financial resilience, and alleviate the psychological burden of debt in the future.


Due to their advantageous features, the CRISPR-Cas systems are already employed in several biological and medical research fields as the most suitable technique for genome engineering. In this review, we aim to describe the CRISPR-Cas systems that have been identified among prokaryotic organisms and engineered for genome manipulation studies. Furthermore, a comprehensive comparison between the innovative CRISPR-Cas methodology and the previously utilized ZFN and TALEN editing nucleases is also discussed. Ultimately, we highlight the contribution of CRISPR-Cas methodology in modern biomedicine and the current plethora of available applications for gene KO, repression and/or overexpression, as well as their potential implementation in therapeutical strategies that aim to improve patients’ quality of life.In October 2020, the chemistry Nobel Prize was awarded to Emmanuelle Charpentier and Jennifer A. Doudna for the discovery of a new promising genome-editing tool: the genetic scissors of CRISPR-Cas9. The identification of CRISPR arrays and the subsequent identification of  In October 2020, the chemistry Nobel Prize was awarded to Emmanuelle Charpentier and Jennifer A. Doudna for the discovery of a new promising genome-editing tool: the genetic scissors of CRISPR-Cas9 . The intEscherichia coli (E. coli) genome . F. FGRN) gor cells . Furtheror cells . The devor cells ,130. Foror cells ,132.The introduction of CRISPR-Cas technologies paved the way for the development of novel approaches that aim to facilitate genomic and epigenomic studies, providing us the ability to decipher in depth the function of genes as well as their regulator mechanisms. More specifically, the development of diverse methods grounded on CRISPR-Cas systems laid the groundwork for the study of the genetic information in multiple levels since these technologies enabled us to mediate KO in vital genes, alter the epigenomic profile of the DNA, and correct the sequence of mutated genes that are responsible for hereditary diseases. Of note, the attempt to utilize CRISPR-Cas systems in clinical practice proved promising since it gave new insights into therapeutics, suggesting that these systems could be exploited for the development of novel therapeutic approaches for many human diseases.


Treatment of these lesions is difficult due to the complexity of the posterior circulation, with frequent anatomic variations and perforators supplying the brainstem. Microsurgical resection can be challenging, with the potential need for complex surgical approaches with limited access to the lesion through narrow working corridors. We are honored to have been selected to edit this important issue of Neurosurgical Focus: Video. We have selected 15 videos from four continents. These videos were chosen for their demonstration of state-of-the-art techniques in the treatment of posterior fossa AVMs via microsurgical resection. This collection of videos by masters in the field of neurovascular surgery illustrates surgical decision-making, technical mastery, operative nuances, technological innovations, and complication avoidance, demonstrating the beauty and danger of AVMs in the posterior fossa location.AIt is our hope that this collection of videos serves as an educational tool for neurosurgical trainees in understanding these lesions, while also providing an update on the current state of surgical treatments for more experienced clinicians. This compendium shows novel vascular treatment concepts, innovative approaches, the evolution of intraoperative imaging, and advanced technologies. While these new techniques expand the options for treating posterior fossa AVMs, microsurgical excellence founded in a detailed understanding of neuroanatomy forms the basis of the surgical mastery apparent in these videos. We thank all the authors for their excellent contributions.


Stroke is a global health and socio-economic problem. However, no efficient preventive and/or palliative treatments have yet been found. Neuroglobin (Ngb) is an endogen neuroprotective protein, but it only exerts its beneficial action against stroke after increasing its basal levels. Therefore, its systemic administration appears to be an efficient therapy applicable to stroke and other neurodegenerative pathologies. Unfortunately, Ngb cannot cross the blood-brain barrier (BBB), making its direct pharmacological use unfeasible. Thus, the association of Ngb with a drug delivery system (DDS), such as nanoparticles (NPs), appears to be a good strategy for overcoming this handicap. NPs are a type of DDS which efficiently transport Ngb and increase its bioavailability in the infarcted area. Hence, we previously built hyaluronate NPS linked to Ngb (Ngb-NPs) as a therapeutic tool against stroke. This nanoformulation induced an improvement of the cerebral infarct prognosis. However, this innovative therapy is still in development, and a more in-depth study focusing on its long-lasting neuroprotectant and neuroregenerative capabilities is needed. In short, this review aims to update the state-of-the-art of stroke therapies based on Ngb, paying special attention to the use of nanotechnological drug-delivering tools. Moreover, stroke generates a large number of hospital admissions , and is a leading cause of serious disability, with 15% to 30% of victims remaining permanently disabled. Consequently, the annual costs for stroke treatment and care in the EU are estimated at 27 billion euros per year, with 18.5 billion accounting for direct medical costs and 8.5 billion for indirect costs . An additional 11.1 billion euros are estimated to account for informal care [Stroke is the second leading cause of death and the third most common long-term disability worldwide. While two-thirds of stroke deaths occur in less developed countries, stroke is the second most common cause of death in Europe, accounting for 650,000 deaths per year ; [Although mortality rates have decreased in the last two decades, it is estimated that in 2035 the number of cases will increase by 39% in the EU and the total direct medical costs for stroke will triple (There are two major types of stroke: (i) Hemorrhagic stroke (15–20%), that involves the rupture of a blood vessel causing bleeding in the brain, thus inhibiting oxygen and nutrients from reaching brain cells; and (ii) ischemic stroke, by far the most common type of stroke (80–85%), and caused by a blood clot or by the narrowing of a blood vessel thus leading to deprivation of oxygen and nutrients in an area of the brain. This last type of stroke produces infarcts, generally in the territory irrigated by the middle cerebral artery, affecting mainly the parietal cortex and striatum. The infarcted zone has a core and a penumbra, which is susceptible to recovery. The severity of damage depends both on the duration of the ischemia and on the level of reduction of the blood flow.There are several ways to classify the severity of the infarct, but the best one consists in a combination of neuroimaging  or computed tomography (CT)), and neurological evaluation using specific functional outcomes to identify behavioral deficits. The results of imaging and pathological parameters are correlated to the results of learning and memory/mood studies .The first occurs during the initial hours after the onset of stroke and represents an opportunity to salvage the tissue, eliminate clots , and restore the normal blood flow. The harmful consequences of stroke (ischemic cascade) begin as soon as the ischemia occurs and continue during the reperfusion onset. The prognosis of the stroke depends on the severity of the ischemia in this stage and determines the outcomes of the following stages.The second phase lasts from days to weeks following the stroke. The reperfusion damage may continue  but spontaneous neural auto-reparation mechanisms also occur. This stage is crucial for treatments focused on the induction of neural repair (neurogenesis and synaptogenesis).The third stage is a chronic period lasting from months to years. The brain is relatively stable regarding the endogenous repair-related events, but modifications in brain structure and function are still possible with specific neuroprotectant interventions.The response of the brain to stroke can be roughly organized into three temporal stages :The firsThese three stages delineate distinct biological states and have clinical implications concerning the delivery of restorative therapies ,6.Neuronal injury in ischemic stroke is the consequence of a two-step process: (i) ischemia and (ii) reperfusion (I/R) . IschemiWhile stroke injury results in a devastating set of damages, it also induces growth-related events in the perilesional zone that enable repair and the formation of new connections in the injured area. Adult neurogenesis occurs mainly at the subventricular zone of the walls of the lateral ventricle and the subgranular zone of the dentate gyrus. In pathological conditions such as stroke, increased neurogenesis has been reported in adult animal models and even in stroke patients . ProlifeHence, any protective action, either prophylactic or therapeutic, should not only aim to restore blood circulation in the affected area, but also to enhance those mechanisms that prevent cell and tissue damage and/or potentiate neural repair and neuroregeneration. In this way, controlling the production of free radicals, and therefore the oxidative damage, is a possible therapeutic target that has been investigated for years. Moreover, strategies addressed to reduce neuronal death and the consequent inflammatory signals, as well as to activate the processes of neurogenesis and synaptogenesis may also help in the recovery of lost neuronal circuits.Effective treatments for ischemic stroke are limited, despite the plethora of attempts and therapies assayed . CurrentSpecifically, treatments such as decompressive surgery or even hypothermia have been used , but theIn this context, the use of blood glutamate grabbers, such as riboflavin, have already been clinically validated, demonstrating their efficacy in patients with stroke ,26. MoreIn any case, most of the pharmacological treatments tackle the BBB, a cellular interface that separates the central nervous system (CNS) from the periphery. The BBB regulates the trafficking of fluid, solutes, and cells between blood and the nervous tissue; it is integrated by endothelial cells, pericytes, glia, and neuronal cells. All these cells form the so-called “neurovascular unit”, contributing to the modulation of permeability after ischemic stroke . Hence, One of the most innovative pharmaceutical strategies to overcome the BBB is the use of different types of nanocarriers that may increase the lifespan of the associated therapeutic drugs in the bloodstream, enhancing their permeation through the BBB to effectively reach the ischemic brain site . In addiOther popular noninvasive DDS are nanoparticles (NPs), whose most common design is based on lipids or polymers . NPs areLiposomes and solid lipid nanoparticles (SLN) are NPs that can easily deliver different drugs throughout the organism . CertainRegarding polymeric NPs, they are also biocompatible and biodegradable, and have been used to deliver different drugs in I/R models of injury with good results. In this sense, Liu and collaborators  delivereNgb is an oxygen-binding-heme protein of 17 kDa  with a mAccumulating evidence has clearly demonstrated that Ngb acts as an endogenous neuroprotective molecule in numerous neurological diseases, including some hypoxic/ischemic (H/I) and oxidative stress-related insults . This neSeveral strategies have been used in animal model to increase Ngb in the damaged brain; some include genetic manipulations  or the use of DDS (see below). Other options consist in up-regulating the expression of Ngb using molecules such as deferoxamine, hemin, or valproic acid, ,69,82, aDespite the fact that the neuroprotective action of Ngb after the ischemic damage is well documented, the mechanisms underlying this role are not well known yet  Figure .2− to NO, contributing to the cellular pool of this molecule [3− by means of a heme-bound peroxynitrite intermediate, acting as an NO scavenger [2 and NO have led Brunori and collaborators (2005) [One of the most prevalent hypotheses is the defensive role of Ngb against oxidative stress, probably through the scavenging of ROS and RNS ,87,88,89molecule . Howevercavenger . Besidescavenger , some stcavenger ,94. Morecavenger . These dcavenger . Indeed,cavenger . Thus, tcavenger . Therefocavenger , which cs (2005)  to propoInterestingly, it has been reported that Ngb can directly interact with components of the respiratory chain (ETC), i.e., complex III, leading to a better mitochondrial functionality . The neuIn this sense, different authors have reported the involvement of Ngb in the regulation of the PTEN/PI3K/Akt pathway. Specifically, an improvement of the neurological functions with a reduced infarct volume was achieved using a treatment with hemin to induce Ngb overexpression in a rat model of unilateral MCAO. Delving into the neuroprotective mechanisms of Ngb in this model, the activation of the PI3K/Akt signaling pathway has been pointed out . Other sThe involvement of Ngb in the death pathways triggered by stroke may be also based on other molecular mechanisms. Specifically, the upregulation of Ngb expression in mice cortical neurons reduced the aperture of the mitochondrial permeability transition pore (MPTP), thus avoiding Cytc3 release after I/R . Accordi+/K+ ATPases, preserving cellular homeostasis and membrane excitability [On the other hand, when Ngb is upregulated after neuronal injury, it shows other neuronal localizations and possible neuroprotective actions. In this sense, at a nuclear level, Ngb overexpression promotes neurogenesis in mice brains after ischemia; this effect was studied in cultured neural progenitor cells, and further validated in mice stroke models. In these studies, it has been suggested that the role of Ngb might be mediated through Dvl1 up-regulation, previous activation of the Wnt signaling pathway, leading to an increased nuclear localization of beta-catenin . On the tability . Ngb is tability . Moreovetability . Finallytability  or astrotability , contribtability ).Proteomics and other omics studies can provide valuable information about the protective role of Ngb. In fact, monitoring the changes on key proteins not only helps to deepen the molecular bases of ischemia ,116,117,In this regard, we have carried out proteomic studies in an animal model of MCAO, detecting a total of 219 proteins that significantly changed their expression after stroke and treatment with nanoencapsulate-Ngb . InteresConsequently, the neuroprotective role of Ngb, supported by its function as oxygen sensor, as well as its capacity to interact with other proteins involved in modulating reparative processes such as dendritogenesis, neuritogenesis, or synaptogenesis, allows Ngb to be assigned a central role in neuroregenerative therapy against stroke.The easiest way to use Ngb as a therapeutic drug in stroke would be its direct pharmacological administration via intravenous (IV) injection; however, its molecular size and conformation prevent its crossing through the BBB ,121. CerA feasible strategy to overcome this problem, as previously pointed out, is the use of DDS that may deliver Ngb into the ischemic neurons. In this regard, exogenous Ngb has been linked to CPPs. This sort of DDS has been demonstrated to facilitate the entry of Ngb from blood into the damaged brain parenchyma . ParticuOther strategies to transport Ngb through the BBB include their association to different DDS, such as biodegradable nano-vehicles. This is the case of the polymeric NPs, which are completely free of toxicity and can easily deliver the protein into the ischemic neurons. In this sense, polymer based nanocarriers can be labeled with different functional groups to monitor their specific targets . They alAfter their formulation and characterization, our experimental purpose continued with the biosynthesis of rat-recombinant Ngb to complete the pharmaceutical preparation of nanoencapsulated Ngb-NPs. Then, Ngb-charged NPs were characterized by size, ζ-potential, encapsulation efficiently, in vitro release and kinetic liberation . The NPsIn our experiments, bioengineered Ngb-NPs were systemically injected in the MCAO animals immediately after the surgery at the onset of reperfusion. Their neuroprotective role against stroke was monitored during the next 24 h. These Ngb-NPs colocalized with the neuronal marker NeuN. They appeared grouped in clusters that showed the typical endosomal morphology. However, only a few of them colocalized with GFAP, a specific marker of astrocytes . On the Obviously, the next step should be to extend this study along the three temporal stroke stages to monitor the effects of Ngb-NPs in the long term. However, it will also be important to analyze the way in which Ngb-NPs reached the damaged tissue in the first hours of the reperfusion period. In this sense, and considering the different pathways by which molecules and ions cross the BBB to reach neurons , and theGiven the optimum size of the Ngb-NPs and its decoration with chitosan and glycerol tripalmitin, it could be thought that they might cross the BBB and reach the neuron endosomal compartment via several cell-penetrability mechanisms, including macropinocytosis, adsorptive-mediated transcytosis, or tight junctions opening at the neurovascular unit level of the BBB . MoreoveA second matter, concerning the intraneuronal traffic of the Ngb-NPs, refers to the endosomal escape mechanism. Knowledge about this mechanism comes mainly from experiments in cultured tumor cells  which hAlthough further research will be needed to elucidate all these questions, the fact that a nanopharmaceutical preparation of systemic Ngb capable of reaching the neurons is already available is an important step in stroke therapy and possibly in the therapy of other neurodegenerative diseases.Ngb is an oxygen sensor protein with neuroprotective activity against many brain injuries, including neurodegeneration, toxicity, nutrient deprivation, and ischemia. Although Ngb is an endogenous protein, its protective effects seem to rely on its overexpression or increase in the damaged tissue. Thereby, the injection of exogenous Ngb into the blood stream could be a good therapeutic option in some neurological diseases, including stroke. However, Ngb cannot cross the BBB itself, so therapeutic approaches using nanotechnological tools have arisen as promising alternatives. In fact, the use of nanoparticles as a contrast agent or as drug carriers for a specific target are some of the most common approaches developed in nanomedicine for stroke . In addiMore specifically, polymeric sodium hyaluronate NPs fulfill all the characteristics of DDS, as they protect exogenous Ngb from the endothelial system in blood and facilitate the passage of Ngb through the neurovascular unit of the BBB. This path depends on numerous cellular processes such as membrane permeability, cytoskeletal motility, endosomal and mitochondrial dynamics, and homeostatic energy or ion regulation, among others. In fact, the bioengineered Ngb-NPs assayed by our group seemed to overcome all these processes reaching their intracellular targets as soon as 2 h after injection. What is more, the Ngb delivered this way exerts its neuroprotective role in stroke for as long as 24 h after the onset of reperfusion.Although these nanotherapeutic strategies against stroke are very promising, further research is needed. Hence, we have identified the following points for further investigation: (i) More in-depth study of the neuroprotective mechanisms exerted by Ngb in the ischemic tissue. (ii) Comprehensive identification of the many pathways and processes involved in the long journey that the Ngb-NPs run from the blood to their final destinations in the ischemic damaged neurons. (iii) Detailed follow up of the evolution of this nanotechnological treatment along the different post-stroke stages.Thereafter, the therapeutic horizon of these nanotechnological tools is hopeful. Notwithstanding, further scientific findings are needed in order to optimize these therapies in stroke.


Stroke is among the leading causes of disability of worldwide. Gait dysfunction is common in stroke survivors, and substantial advance is yet to be made in stroke rehabilitation practice to improve the clinical outcome of gait recovery. The role of the upper limb in gait recovery has been emphasized in the literature. Recent studies proposed that four limbs coordinated interventions, coined the term “interlimb-coordinated interventions,” could promote gait function by increasing the neural coupling between the arms and legs. A high-quality review is essential to examine the clinical improvement and neurophysiological changes following interlimb-coordinated interventions in patients with stroke.Systematic review and meta-analysis will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The literature will be retrieved from the databases of OVID, MEDLINE, PubMed, Web of Science, EMBASE, and PsycINFO. Studies published in English over the past 15 years will be included. All of the clinical studies  that employed interlimb intervention and assessed gait function of patients with stroke will be included. Clinical functions of gait, balance, lower limb functions, and neurophysiologic changes are the outcome measures of interest. Statistical analyses will be performed using the Comprehensive Meta-Analysis version 3.The findings of this study will provide insight into the clinical benefits and the neurophysiological adaptations of the nervous system induced by interlimb-coordinated intervention in patients with stroke. This would guide clinical decision-making and the future development of targeted neurorehabilitation protocol in stroke rehabilitation to improve gait and motor function in patients with stroke. Increasing neuroplasticity through four-limb intervention might complement therapeutic rehabilitation strategies in this patient group. The findings could also be insightful for other cerebral diseases. Gait reThe pendula motion of the upper extremities plays a vital role in gait . The rolThe rhythmic control of gait motion is primarily modulated by the central pattern generator (CPG) and the peripheral sensory feedback that provides the basic synchronous movements of the arms and legs . CPG is The spinal cord itself has central pattern generators and is able to generate coordinated locomotor electromyography (EMG) activity . It contTo date, there seems to be no systematic review or meta-analysis that investigated the strength of the evidence on interlimb-coordinated interventions, and the neurophysiological and clinical changes induced by such intervention program. A high-quality review examining the clinical improvements and neurophysiological changes following interlimb-coordinated interventions may instigate the establishment of future clinical practice guidelines for clinicians and practitioners. Thus, we present our protocol to critically evaluate the evidence on the change in clinical and neurophysiology measures induced by interlimb-coordinated interventions in patients with stroke. Our review question is “What are the clinical benefits and neurophysiological changes at the cortical and spinal level associated with interlimb coordinated interventions in patients with stroke?”* OR reflex OR electromyography OR EMG). Studies published in English over the past 15 years, from August 2021, will be considered for inclusion.The systematic review of the literature will follow the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. It is registered on the International Platform of Registered Systematic Review and Meta-analysis Protocols  Registr (RegistrParticipants with chronic stroke (more than 6 months of stroke onset)  who are The inclusion criteria are as follows:Full-text studies published in english 15 years prior to August 2021.Studies conducted on individuals aged between forty and eighty with chronic stroke.Studies that investigated the neurophysiological changes in patients with stroke, including peripheral nerve stimulation to assess the hoffman-reflex pathway, electromyography to examine the heteronymous and contralateral muscle activity and reflex amplitudes, and neural imaging to assess cortical activities.The exclusion criteria are as follows:Studies that included unilateral intervention.Studies that did not mention the screening of medications that might affect muscle tone. previous study reported spatiotemporal parameters of gait could be improved by releasing the upper extremity spasticity . therefoStudies that did not exclude participants with musculoskeletal , cardiovvia nerve stimulation, and EMG signals of muscle activities of the muscle bellies of interest. Neurophysiological data refer to parameters that reflect the properties of neurons, glia, and neural network , and any duplicates will be removed.The main data to be extracted and analyzed are the descriptive information of article title, journal title, authors, target population, and host institute. The cohort characteristics of sample size, sex, age, stroke onset duration, and infarction location will be recorded. The methodological characteristics of study design, randomization procedures, intervention type, intervention period, and follow-up will be extracted. The outcome measures regarding clinical functions of gait, balance, lower limb motor functions, and neurophysiological assessment will be recorded and analyzed. A minimum of two independent reviewers will extract and summarize the data from all of the studies.The quality of all included articles will be assessed by the Mixed Methods Appraisal Tool (MMAT) . It is ap < 0.05. A narrative synthesis will be written if a meta-analysis is not possible due to the heterogeneity of the studies.Effect sizes at 95% confidence intervals will be collected to assess the relationships within the data, as well as Cohen's d for estimates of effect size. Quantitative data will be extracted from each article, and a chi-squared analysis will be used to determine homogeneity between observed and expected frequencies. Statistical significance will be set at This systematic review will be among the first to provide a comprehensive assessment of the neurophysiological changes and clinical benefits of interlimb-coordinated interventions in patients with chronic stroke. Specifically, we aim to explore the effects of interlimb-coordinated intervention on neural coupling as measured by the H-reflex and EMG muscle activities. Changes in cutaneous reflex and muscle activities could be considered as a proxy of spinal plasticity resulting from interlimb training . Reflex Another potential underpinning mechanism of interlimb-coordinated intervention is the increase in neural activation of cortices. The activations of the supplementary motor area (SMA), premotor area , and cerSeveral studies utilized different functional tasks, neurophysiological tools, and measurements which provided insights on the potential clinical benefits of interlimb coordination , 47. HowDL, YL, QY, and KL contribute to the data analysis and drafting of the manuscript. MD and WL managed the research and adjudicate any dispute. WL, MD, and QY contribute to funding acquisition. All authors fulfill the four authorship criteria and involved in a specific aspect of the study. All authors had read and approved the final manuscript.This study was supported by the National Natural Science Foundation of China (Grant Nos. 81971224 and 82002375) and the Guangzhou Science and Technology Project (Grant No. 201803010083).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.