Colorimetric sweat analysis using wearable hydrogel patch sensors for detection of chloride and glucose.

Sweat is a promising non-invasive biofluid that can provide valuable insights into the physiological state of the human body. However, a major obstacle to analyzing sweat in real-time is the fabrication of simple, fast-acting, accurate, and low-cost sensing constructs. To address this challenge, we introduced easily-prepared wearable hydrogel sensors that can be placed on the skin and used colorimetric techniques to assess sweat analytes without invasive procedures. Two typical sweat sensors, chloride ion (Cl-) responsive patches for cystic fibrosis (CF) analysis and glucose response patches for diabetic monitoring, were demonstrated for real sample analysis. The Cl- colorimetric sensor, with a detection limit down to 100 µM, shows a good linear response from 1.56 mM to 200 mM Cl-, and the glucose colorimetric sensor, with a detection limit down to 1 µM, exhibits an adequate linear response from 10 µM to 1 mM glucose. These colorimetric hydrogel sensors are also incorporated into a medical dressing to create wearable sensor devices for real-time sweat analysis. The acquired readings closely match the results obtained from the benchmark analyzing instrument, with a small deviation of less than 10%. Therefore, our simple colorimetric hydrogel sensing patches hold great potential to advance real-time sweat testing and contribute to the transitional development of wearable medical devices.

Saliva sampling strategies affecting the salivary glucose measurement.

Characterized by sustained elevated blood glucose levels, diabetes mellitus has become one of the largest global public health concerns by imposing a heavy global burden on socio-economic development. To date, regular blood glucose level check by performing a finger-prick test has been a routine strategy to monitor diabetes. However, the intrusive nature of finger blood prick tests makes it challenging for individuals to maintain consistent testing routines. Recently, salivary glucose measurement (SGM) has increasingly become a non-invasive alternative to traditional blood glucose testing for diabetes. Despite that, further research is needed to standardize the collection methods and address the issues of variability to ensure accurate and reliable SGM. To resolve possible remaining issues in SGM, we here thoroughly explored saliva sampling strategies that could impact the measurement results. Additionally, the effects of supplements taken, mouth washing, gum chewing, and smoking were collectively analyzed, followed by a continuous SGM over a long period, forming the stepping stone for the practical transitional development of SGM in non-invasive diabetes monitoring.

Paper-based colorimetric sensors for point-of-care testing.

By eliminating the need for sample transportation and centralized laboratory analysis, point-of-care testing (POCT) enables on-the-spot testing, with results available within minutes, leading to improved patient management and overall healthcare efficiency. Motivated by the rapid development of POCT, paper-based colorimetric sensing, a powerful analytical technique that exploits the changes in color or absorbance of a chemical species to detect and quantify analytes of interest, has garnered increasing attention. In this review, we strive to provide a bird's eye view of the development landscape of paper-based colorimetric sensors that harness the unique properties of paper to create low-cost, easy-to-use, and disposable analytical devices, thematically covering both fundamental aspects and categorized applications. In the end, we authors summarized the review with the remaining challenges and emerging opportunities. Hopefully, this review will ignite new research endeavors in the realm of paper-based colorimetric sensors.

A robust localization approach for Percutaneous Nephrolithotomy (PCNL): A single-center retrospective study.

BACKGROUND: Percutaneous Nephrolithotomy (PCNL) represents the gold standard treatment method for cases with large kidney stones. As a critical step in performing PCNL, the procedure of establishing a safe and accurate nephrostomy tract will dramatically impact the treatment quality of patients with large-sized kidney stones. OBJECTIVE: This work attempts to describe a new and improved process of establishing an accurate nephrostomy tract and clinically evaluate the effectiveness and safeness of this proposed methodology. METHODS: This work represents a retrospective single-center study carried out between August 2013 and November 2019. The collected samples consist of 937 patients who were operated on using PCNL coupled with our proposed procedure. Briefly, a preoperative B-ultrasonography was firstly performed to decide the puncture point in a simulated surgical position where was marked with ureteral catheter segments (2-3 cm). A computed tomography (CT) scan was followed to correct the anchor points in the simulated surgical position. After this, an accurate puncture operation was performed under the real-time guidance of intraoperative B ultrasound. RESULTS: Examining this study, 851 subjects with renal stones and 86 subjects with ureteropelvic junction stones were included for the PCNL operation project. All samples were grouped with Guy's grading system: grade I, II, III, and IV patients there were 0.00%, 42.69%, 51.01%, and 6.30%, respectively. Among these patients, the average age was 48.49 ± 10.80 years old, with a male to female ratio of around 1.73:1. CONCLUSIONS: This study showed that our developed method warrants an accurate and safe PCNL operation that involves the process of establishing the nephrostomy tract. Other advantageous attributes of this new PCNL process include negligible radiation exposure, lesser complications, and low failure rates. More importantly, this new localization approach is particularly attractive for hospitals that are new to the field of adopting PCNL considering its safeness, effectiveness, and learnability.

Prefrontal GABAA(δ)R Promotes Fear Extinction through Enabling the Plastic Regulation of Neuronal Intrinsic Excitability.

Extinguishing the previously acquired fear is critical for the adaptation of an organism to the ever-changing environment, a process requiring the engagement of GABAA receptors (GABAARs). GABAARs consist of tens of structurally, pharmacologically, and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically situated, δ-subunit-containing GABAARs [GABAA(δ)Rs], had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABAAR family. First, the fear extinction in individual mice was positively correlated with the level of GABAA(δ)R expression and function in their mPFC. Second, knockdown of GABAA(δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABAA(δ)R-deficient mice also showed fear extinction deficits, and re-expressing GABAA(δ)Rs in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABAA(δ)R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABAA(δ)R had little influence on the extinction-evoked plasticity of glutamatergic transmission in these cells. Altogether, our findings revealed an unconventional and permissive role of extrasynaptic GABAA receptors in fear extinction through a route relying on nonsynaptic plasticity.SIGNIFICANCE STATEMENT The medial prefrontal cortex (mPFC) is one of the kernel brain regions engaged in fear extinction. Previous studies have repetitively shown that the GABAA receptor (GABAAR) family in this region act to suppress fear extinction. However, the roles of specific GABAAR subtypes in mPFC are largely unknown. We observed that the GABAAR-containing δ-subunit [GABAA(δ)R], a subtype of GABAARs exclusively situated in the extrasynaptic membrane and mediating the tonic neuronal inhibition, works oppositely to the whole GABAAR family and promotes (but does not suppress) fear extinction. More interestingly, in striking contrast to the synaptic GABAARs that suppress fear extinction by breaking the extinction-evoked plasticity of glutamatergic transmission, the GABAA(δ)R promotes fear extinction through enabling the plastic regulation of neuronal excitability in the infralimbic subregion of mPFC. Our findings thus reveal an unconventional role of GABAA(δ)R in promoting fear extinction through a route relying on nonsynaptic plasticity.

A novel and sensitive DNA methylation marker for the urine-based liquid biopsies to detect bladder cancer.

BACKGROUND: Better prognostic outcome is closely correlated with early detection of bladder cancer. Current non-invasive urianalysis relies on simultaneously testing multiple methylation markers to achieve relatively high accuracy. Therefore, we have developed an easy-to-use, convenient, and accurate single-target urine-based DNA methylation test for the malignancy. METHODS: By analyzing TCGA data, 344 candidate markers with 424 primer pairs and probe sets synthesized were systematically screened in cancer cell lines, paired tissue specimens, and urine sediments from bladder cancer patients and normal controls. The identified marker was further validated in large case-control cohorts. Wilcoxon rank sum tests and c2 tests were performed to compare methylation levels between case-control groups and correlate methylation levels with demographic and clinical characteristics. In addition, MSP, qMSP, RT-PCR, western blot analysis, and immunohistochemistry were performed to measure levels of DNA methylation, mRNA transcription, and protein expression in cancer cell lines and tissues. RESULTS: A top-performing DMRTA2 marker identified was tested in both discovery and validation sets, showing similar sensitivity and specificity for bladder cancer detection. Overall sensitivity in the aggregate set was 82.9%(179/216). The specificity, from a control group consisting of patients with lithangiuria, prostatoplasia, and prostatitis, is 92.5%(468/506). Notably, the methylation assay had the highest sensitivities for tumors at stages of T1(90.4%) and T2(95.0%) compared with Ta (63.0%), T3(81.8%), and T4(81.8%). Furthermore, the test showed admirable detection rate of 80.0%(24/30) for recurring cancers. While methylation was observed in 39/54(72.2%) urine samples from patients with carcinomas of renal pelvis and ureter, it was detected at extremely low rate of 6.0%(8/133) in kidney and prostate cancers. Compared with SV-HUC-1, the normal bladder epithelial cell line, DMRTA2 was hypermethylated in 8/9 bladder cancer cell lines, consistent with the results of MSP and qMSP, but not correlated with mRNA and protein expression levels in these cell lines. Similarly, DMRTA2 immunostaining was moderate in some tissues but weak in others. Further studies are needed to address functional implications of DMRTA2 hypermethylation. CONCLUSIONS: Our data demonstrated that a single-target DNA methylation signature, mDMRTA2, could be highly effective to detect both primary and recurring bladder cancer via urine samples.

Individual differences in emotion differentiation modulate electrocortical dynamics of cognitive reappraisal.

Cognitive reappraisal plays an important role in individuals' mental health and adaptation and depends on individual differences in emotion differentiation. However, it is unclear how individual differences in emotion differentiation modulate the electrocortical dynamics of cognitive reappraisal. To this end, we employed event-related potentials (ERPs) and source analysis to characterize temporal dynamics and cortical functions of cognitive reappraisal related with positive emotion differentiation. The electroencephalogram (EEG) data from 36 participants (aged 18-25 years) were recorded when they were required to view neutral, pleasant emotional stimuli, or positively reappraise neutral emotional stimuli. Results showed that, compared with the individuals with low positive emotion differentiation, the individuals with high positive emotion differentiation presented larger late positive potential (LPP) amplitude enhancement during positive reappraisal. Source analysis further found that individuals with high positive emotion differentiation exhibited more activations in the middle frontal gyrus (Brodmann area [BA] 11), superior temporal gyrus (BA 38), and inferior frontal gurus (BA 47) when they implemented cognitive reappraisal as compared with their counterparts. Our findings deepen our understanding of the dynamic cortical organization of how positive emotion differentiation impacts cognitive reappraisal and informs cognitive reappraisal interventions for individuals with low emotion differentiation.

Emotional Contexts Modulate Anticipatory Late Positive Component and Reward Feedback Negativity in Adolescents With Major Depressive Disorder.

BACKGROUND: Neuroimaging research has determined deficits in the dopaminergic circuit of major depressive disorder (MDD) during adolescence. This study investigated how emotional contexts modulate the temporal dynamics of reward anticipation and feedback in adolescents. METHODS: EEG data from 35 MDD and 37 healthy adolescents were recorded when they conducted a gambling task after being presented with emotional pictures. RESULTS: The results demonstrated that both MDD and healthy adolescents exhibited the largest late positive component (LPC) in positive contexts at the frontal sites and the largest LPC in negative contexts at the central sites; however, MDD adolescents exhibited anticipatory LPC hypoactivation than healthy adolescents. However, MDD adolescents exhibited smaller gain feedback negativity (FN) than healthy adolescents independent of emotional contexts, positively correlating with the trait anhedonia according to the consummatory aspect of the Temporal Experience of Pleasure Scale. In contrast, MDD adolescents exhibited greater FN loss in positive and neutral contexts than healthy adolescents while no difference in FN loss was found between the two groups in negative contexts. Moreover, the FN loss amplitudes negatively correlated with hedonic tone according to the Snaith-Hamilton Pleasure Scale over the past week. CONCLUSIONS: These findings suggest that MDD adolescents exhibited dissociable deficits in reward anticipation and gain or loss feedback that are distinctly modulated by emotional contexts, and they deepen our understanding of the modulation of emotional contexts on the temporal dynamic reorganization of the reward circuit in MDD adolescents.

Chronic Stress Oppositely Regulates Tonic Inhibition in Thy1-Expressing and Non-expressing Neurons in Amygdala.

Chronic or prolonged exposure to stress ranks among the most important socioenvironmental factors contributing to the development of neuropsychiatric diseases, a process generally associated with loss of inhibitory tone in amygdala. Recent studies have identified distinct neuronal circuits within the basolateral amygdala (BLA) engaged in different emotional processes. However, the potential circuit involved in stress-induced dysregulation of inhibitory tones in BLA remains elusive. Here, a transgenic mouse model expressing yellow fluorescent protein under control of the Thy1 promoter was used to differentiate subpopulations of projection neurons (PNs) within the BLA. We observed that the tonic inhibition in amygdala neurons expressing and not expressing Thy1 (Thy1+/-) was oppositely regulated by chronic social defeat stress (CSDS). In unstressed control mice, the tonic inhibitory currents were significantly stronger in Thy1- PNs than their Thy1+ counterparts. CSDS markedly reduced the currents in Thy1- projection neurons (PNs), but increased that in Thy1+ ones. By contrast, CSDS failed to affect both the phasic A-type γ-aminobutyric acid receptor (GABAAR) currents and GABABR currents in these two PN populations. Moreover, chronic corticosterone administration was sufficient to mimic the effect of CSDS on the tonic inhibition of Thy1+ and Thy1- PNs. As a consequence, the suppression of tonic GABAAR currents on the excitability of Thy1- PNs was weakened by CSDS, but enhanced in Thy1+ PNs. The differential regulation of chronic stress on the tonic inhibition in Thy1+ and Thy1- neurons may orchestrate cell-specific adaptation of amygdala neurons to chronic stress.

Adolescents Exhibit Late Maturation of Long-Range Beta Coherences in Affective Processing.

We investigated whether intra-/interhemispheric long-range beta coherences mirror developmental changes in affective functional integration during adolescence. Electroencephalogram data were gathered from 15 young adolescents, 16 old adolescents, and 16 young adults during viewing affective pictures. The results indicated that both positive and negative pictures induced greater intra- and interhemispheric long-distance beta coherences than neutral pictures. However, opposite results were observed between young and old adolescents in terms of negative phase differences. Old adolescents exhibited greater beta coherences for positive and negative pictures than both young adolescents and young adults, but there was no difference between the groups for neutral pictures. These observations suggest that long-range beta coherence might reflect the late maturation of affective functional integration in adolescents.

Two-Photon Nanolithography of Tailored Hollow three-dimensional Microdevices for Biosystems.

Functional three-dimensional (3D) microstructures incorporating accessible interiors have emerged as a versatile platform for biosystem applications. By configuring their 3D geometric features, these biosystem microdevices can accurately evaluate and control targeted bioenvironments. However, classical fabrication techniques based on photolithography-etching processes cannot precisely and programmably control the geometric of the entire hollow 3D microstructures. Here, we proposed the use of a two-photon polymerization (TPP)-based technique for the precise, straightforward, and customizable preparation of hollow 3D microstructure devices with small opening(s). Factors governing the formation of hollow 3D biosystem microdevices, including material composition, laser input, and (post-) development treatment, have been systematically investigated and a set of optimized conditions are presented as a starting point for the development of novel hollow biosystem microdevices. To evaluate the broad applicability of this approach, a series of tailored hollow 3D microdevices with small opening(s), including a micropore, microneedle, microelectrode, microvalve, and micromachine, were successfully prepared using our direct laser writing-TPP technique. To further validate the feasibility of these biosystem microdevices in practical implementations, we demonstrated the use of hollow 3D micropore devices for the robust resistive-pulse analysis of nanoparticles.

Maskless 3D Ablation of Precise Microhole Structures in Plastics Using Femtosecond Laser Pulses.

Femtosecond laser ablation is a robust tool for the fabrication of microhole structures. This technique has several advantages compared to other microfabrication strategies for reliably preparing microhole structures of high quality and low cost. However, few studies have explored the use of femtosecond laser ablation in plastic materials because of the lack of controllability over the fabrication process in plastics. In particular, the depth profile of microhole structures prepared by conventional laser ablation techniques in plastics cannot be precisely and reproducibly controlled. In this paper, a novel three-dimensional femtosecond laser ablation technique was developed for the rapid fabrication of precise microhole structures in multiple plastics in air. Using a three-step fabrication scheme, microholes demonstrated extremely clean and sharp geometric features. This new technique also enables the precise creation of arbitrary-shaped microwell structures in plastic substrates through a rapid single-step ablation process, without the need for any masks. As a proof of concept for practical applications, precise microhole structures prepared by this novel femtosecond laser ablation technique were exploited for robust resistive-pulse sensing of microparticles.

Temperamental Effortful Control Modulates Gender Differences in Late Positive Potentials Evoked by Affective Pictures in Adolescents.

We investigated whether effort control (EC) modulates gender differences in late positive potential (LPP) evoked by affective pictures. We collected EEG data from 46 healthy adolescents while they viewed 90 affective pictures. Relative to neutral pictures, boys showed larger LPP amplitudes for positive pictures compared to girls while girls showed larger LPP amplitudes for negative pictures compared to boys. Temperamental EC in boys negatively predicted LPP amplitudes for positive pictures, whereas EC in girls negatively predicted LPP amplitudes for negative pictures. These observations increase our understanding of the relationship between EC and gender difference in electrocortical maturation.

Highly sensitive glucose sensors based on enzyme-modified whole-graphene solution-gated transistors.

Noninvasive glucose detections are convenient techniques for the diagnosis of diabetes mellitus, which require high performance glucose sensors. However, conventional electrochemical glucose sensors are not sensitive enough for these applications. Here, highly sensitive glucose sensors are successfully realized based on whole-graphene solution-gated transistors with the graphene gate electrodes modified with an enzyme glucose oxidase. The sensitivity of the devices is dramatically improved by co-modifying the graphene gates with Pt nanoparticles due to the enhanced electrocatalytic activity of the electrodes. The sensing mechanism is attributed to the reaction of H2O2 generated by the oxidation of glucose near the gate. The optimized glucose sensors show the detection limits down to 0.5 µM and good selectivity, which are sensitive enough for non-invasive glucose detections in body fluids. The devices show the transconductances two orders of magnitude higher than that of a conventional silicon field effect transistor, which is the main reason for their high sensitivity. Moreover, the devices can be conveniently fabricated with low cost. Therefore, the whole-graphene solution-gated transistors are a high-performance sensing platform for not only glucose detections but also many other types of biosensors that may find practical applications in the near future.

Flexible Organic Electronics in Biology: Materials and Devices.

At the convergence of organic electronics and biology, organic bioelectronics attracts great scientific interest. The potential applications of organic semiconductors to reversibly transmit biological signals or stimulate biological tissues inspires many research groups to explore the use of organic electronics in biological systems. Considering the surfaces of movable living tissues being arbitrarily curved at physiological environments, the flexibility of organic bioelectronic devices is of paramount importance in enabling stable and reliable performances by improving the contact and interaction of the devices with biological systems. Significant advances in flexible organic bio-electronics have been achieved in the areas of flexible organic thin film transistors (OTFTs), polymer electrodes, smart textiles, organic electrochemical ion pumps (OEIPs), ion bipolar junction transistors (IBJTs) and chemiresistors. This review will firstly discuss the materials used in flexible organic bioelectronics, which is followed by an overview on various types of flexible organic bioelectronic devices. The versatility of flexible organic bioelectronics promises a bright future for this emerging area.

Flexible organic electrochemical transistors for highly selective enzyme biosensors and used for saliva testing.

Flexible organic electrochemical transistors (OECTs) are successfully used as high-performance enzyme biosensors, such as uric acid (UA) and cholesterol sensors. The sensitivity and selectivity of the sensors can be simultaneously enhanced by co-modifying the gate electrodes with positively/negatively charged bilayer polymer films and enzymes. These OECT-based UA sensors are successfully utilized for non-invasive UA detection in human saliva.

Organic electrochemical transistors with graphene-modified gate electrodes for highly sensitive and selective dopamine sensors.

Organic electrochemical transistors (OECTs) are successfully used as highly sensitive and selective dopamine sensors. The selectivity of the OECT-based dopamine sensors is significantly improved by coating biocompatible polymer Nafion or chitosan on the surface of the gate electrodes. The interference induced by uric acid and ascorbic acid is effectively eliminated especially after the modification of Nafion. The sensitivity of the devices is improved by graphene flakes co-modified on the gate electrodes. The detection limit of the devices to dopamine is down to 5 nM, which is much lower than that of conventional electrochemical approaches. Because the OECT-based dopamine sensors are solution processable, they are suitable for low-cost and disposable sensing application.

Highly selective and sensitive glucose sensors based on organic electrochemical transistors with graphene-modified gate electrodes.

The sensitivity of glucose sensors based on organic electrochemical transistors (OECT) is increased by co-modifying graphene or reduced graphene oxide (rGO) and enzyme (glucose oxidase) on the gate electrodes for the first time. The optimized device shows linear responses to glucose in a broad concentration region from 10 nM to 1 µM and with a detection limit down to 10 nM, which is two orders of magnitude better than that for the device without the graphene modification. The selectivity of the device is systematically studied for the first time. The device selectivity is dramatically improved when the gate electrode is modified with biocompatible polymers (chitosan or Nafion). The interfering effect caused by uric acid and l-ascorbic acid is almost negligible for practical applications. Therefore, highly sensitive and selective OECT-based glucose sensors can be realized by functionalizing the gate electrodes. In addition, the devices are solution processable and low-cost, and are thus suitable for disposable sensing applications.