Unconventional spectral signature of Tc in a pure d-wave superconductor.

In conventional superconductors, the phase transition into a zero-resistance and perfectly diamagnetic state is accompanied by a jump in the specific heat and the opening of a spectral gap1. In the high-transition-temperature (high-Tc) cuprates, although the transport, magnetic and thermodynamic signatures of Tc have been known since the 1980s2, the spectroscopic singularity associated with the transition remains unknown. Here we resolve this long-standing puzzle with a high-precision angle-resolved photoemission spectroscopy (ARPES) study on overdoped (Bi,Pb)2Sr2CaCu2O8+δ (Bi2212). We first probe the momentum-resolved electronic specific heat via spectroscopy and reproduce the specific heat peak at Tc, completing the missing link for a holistic description of superconductivity. Then, by studying the full momentum, energy and temperature evolution of the spectra, we reveal that this thermodynamic anomaly arises from the singular growth of in-gap spectral intensity across Tc. Furthermore, we observe that the temperature evolution of in-gap intensity is highly anisotropic in the momentum space, and the gap itself obeys both the d-wave functional form and particle-hole symmetry. These findings support the scenario that the superconducting transition is driven by phase fluctuations. They also serve as an anchor point for understanding the Fermi arc and pseudogap phenomena in underdoped cuprates.

Differentiated roles of Lifshitz transition on thermodynamics and superconductivity in La2-xSrxCuO4.

The effect of Lifshitz transition on thermodynamics and superconductivity in hole-doped cuprates has been heavily debated but remains an open question. In particular, an observed peak of electronic specific heat is proposed to originate from fluctuations of a putative quantum critical point p* (e.g., the termination of pseudogap at zero temperature), which is close to but distinguishable from the Lifshitz transition in overdoped La-based cuprates where the Fermi surface transforms from hole-like to electron-like. Here we report an in situ angle-resolved photoemission spectroscopy study of three-dimensional Fermi surfaces in La2-xSrxCuO4 thin films (x = 0.06 to 0.35). With accurate kz dispersion quantification, the said Lifshitz transition is determined to happen within a finite range around x = 0.21. Normal state electronic specific heat, calculated from spectroscopy-derived band parameters, reveals a doping-dependent profile with a maximum at x = 0.21 that agrees with previous thermodynamic microcalorimetry measurements. The account of the specific heat maximum by underlying band structures excludes the need for additionally dominant contribution from the quantum fluctuations at p*. A d-wave superconducting gap smoothly across the Lifshitz transition demonstrates the insensitivity of superconductivity to the dramatic density of states enhancement.

Sanyensin with an Unprecedented Architecture: An Effective Strategy from Discovery to Stereochemical Identification of Flexible Natural Products.

Under the guidance of genome mining combined with bioassay-coupled metabolomic analyses, an unprecedented macrodiolide sanyensin (1), with two flexible macrolides fused by the rigid oxabicyclo[3.3.1]nonane core, was isolated from the deep-sea-derived Streptomyces sp. OUCT16-30. The stereochemistry of 1 was established by NOEs (nuclear Overhauser effects), J-based configuration analysis, Marfey's analysis, and together with a newly introduced stereochemical study workflow, which greatly shortens the time to obtain correct conformations of flexible structures based on the NMR constraints, thus leading to reliable quantum chemical calculations to establish the absolute configurations. This workflow is expected to have broad applicability for elucidating the stereochemistry of flexible natural products. The macrodiolide framework of 1 is proposed to be formed through a biocatalytic cyclodimerization, followed by a series of nonenzymatic reactions. This work leads to new insights into the unexplored biosynthetic potential of deep-sea microbes and also provides a practical streamline for efficient mining of novel natural products, from discovery to stereochemical finalization.

Construction of a three-dimensional inflammation model of human bronchial epithelial cells BEAS-2B by using the self-assembling D-form peptide Sciobio-â ¢.

Human bronchial epithelial cells in the airway system, as the primary barrier between humans and the surrounding environment, assume a crucial function in orchestrating the processes of airway inflammation. Target to develop a new three-dimensional (3D) inflammatory model to airway system, and here we report a strategy by using self-assembling D-form peptide to cover the process. By testing physicochemical properties and biocompatibility of Sciobio-Ⅲ, we confirmed that it can rapidly self-assembles under the trigger of ions to form a 3D nanonetwork-like scaffold, which supports 3D cell culture including the cell strains like BEAS-2B cells. Subsequently, inflammation model was established by lipopolysaccharide (LPS), the expression of some markers of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interleukin-8 (IL-8), the levels of relevant inflammatory factors were measured by RT-qPCR and the secretion profile of inflammatory cytokines by ELISA, are obtained the quite difference effects in 2D and 3D microenvironment, which suggested Sciobio-Ⅲ hydrogel is an ideal scaffold that create the microenvironment for 3D cell culture. Here we are success to establish a 3D inflammation model for airway system. This innovative model allows for rapid and accurate evaluation of drug metabolism and toxicological side effects, hope to use in drug screening for airway inflammatory diseases and beyond.

Engineering Self-Assembling Peptide Hydrogel to Enhance the Capacity of Dendritic Cells to Activate In Vivo T-Cell Immunity.

The efficacy of the dendritic cell (DC) has failed to meet expectations thus far, and crucial problems such as the immature state of DCs, low targeting efficiency, insufficient number of dendritic cells, and microenvironment are still the current focus. To address these problems, we developed two self-assembling peptides, RLDI and RQDT, that mimic extracellular matrix (ECM). These peptides can be self-assembled into highly ordered three-dimensional nanofiber scaffold structures, where RLDI can form gelation immediately. In addition, we found that RLDI and RQDT enhance the biological function of DCs, including releasing antigens sustainably, adhering to DCs, promoting the maturation of DCs, and increasing the ability of DC antigen presentation. Moreover, peptide hydrogel-based DC treatment significantly achieved prophylactic and treatment effects on colon cancer. These results have certain implications for the design of new broad-spectrum vaccines in the future.

Multiple high-risk HPV infections probably associated with a higher risk of low-grade cytological abnormalities but not with high-grade intraepithelial lesions of the cervix.

BACKGROUND: For women diagnosed with HR-HPV DNA positivity in community hospitals, the necessity of investigating the potential presence of multiple HR-HPV infections upon referral to tertiary medical institutions remains unclear. METHODS: In our cohort, women tested positive for HR-HPV DNA during examinations in community hospitals, were subsequently referred to tertiary medical facilities, reevaluated HR-HPV genotype and categorized based on cytological and histopathological results. The risk of cytologic/histopathology abnormalities and ≧ high grade squamous intraepithelial lesion(HSIL) or Cervical Intraepithelial Neoplasia (CIN) 2 associated with individual genotypes and related multiple HPV infections are calculated. RESULTS: A total of 1677 women aged between 21 and 77 were finally included in the present study. The cytology group included 1202 women and the histopathological group included 475 women with at least one HR-HPV infection of any genotype. We only observed a higher risk of low grade cytological abnormalities in women with multiple infections than those in corresponding single infections (for all population with an OR of 1.85[1.39-2.46]; p < 0.05). However, this phenomenon was not observed in histopathology abnormalities (CIN1). The risk of developing of ≥ HSIL/CIN2 in women who were infected with multiple HR-HPV also showed a similar profile to those with a single HR-HPV genotype. CONCLUSION: Multiple HR-HPV infections is only associated with a higher associated risk of low grade cytological abnormalities. There is no evidence of clinical benefit to identify the possible presence of multiple HR-HPV infection frequently in a short period of time for women with HR-HPV-DNA positive.

A Rapid Self-Assembling Peptide Hydrogel for Delivery of TFF3 to Promote Gastric Mucosal Injury Repair.

Self-assembled peptide-based nanobiomaterials exhibit promising prospects for drug delivery applications owing to their commendable biocompatibility and biodegradability, facile tissue uptake and utilization, and minimal or negligible unexpected toxicity. TFF3 is an active peptide autonomously secreted by gastric mucosal cells, possessing multiple biological functions. It acts on the surface of the gastric mucosa, facilitating the repair process of gastric mucosal damage. However, when used as a drug, TFF3 faces significant challenges, including short retention time in the gastric mucosal cavity and deactivation due to degradation by stomach acid. In response to this challenge, we developed a self-assembled short peptide hydrogel, Rqdl10, designed as a delivery vehicle for TFF3. Our investigation encompasses an assessment of its properties, biocompatibility, controlled release of TFF3, and the mechanism underlying the promotion of gastric mucosal injury repair. Congo red/aniline blue staining revealed that Rqdl10 promptly self-assembled in PBS, forming hydrogels. Circular dichroism spectra indicated the presence of a stable ß-sheet secondary structure in the Rqdl10 hydrogel. Cryo-scanning electron microscopy and atomic force microscopy observations demonstrated that the Rqdl10 formed vesicle-like structures in the PBS, which were interconnected to construct a three-dimensional nanostructure. Moreover, the Rqdl10 hydrogel exhibited outstanding biocompatibility and could sustainably and slowly release TFF3. The utilization of the Rqdl10 hydrogel as a carrier for TFF3 substantially augmented its proliferative and migratory capabilities, while concurrently bolstering its anti-inflammatory and anti-apoptotic attributes following gastric mucosal injury. Our findings underscore the immense potential of the self-assembled peptide hydrogel Rqdl10 for biomedical applications, promising significant contributions to healthcare science.

Shedding Light on Lysosomal Malondialdehyde Affecting Vitamin B12 Transport during Cerebral Ischemia/Reperfusion Injury.

Cerebral ischemia-reperfusion injury (CIRI) is often accompanied by upregulation of homocysteine (Hcy). Excessive Hcy damages cerebral vascular endothelial cells and neurons, inducing neurotoxicity and even neurodegeneration. Normally, supplementation of vitamin B12 is an ideal intervention to reduce Hcy. However, vitamin B12 therapy is clinically inefficacious for CIRI. Considering oxidative stress is closely related to CIRI, the lysosome is the pivotal site for vitamin B12 transport. Lysosomal oxidative stress might hinder the transport of vitamin B12. Whether lysosomal malondialdehyde (lysosomal MDA), as the authoritative biomarker of lysosomal oxidative stress, interferes with the transport of vitamin B12 has not been elucidated. This is ascribed to the absence of effective methods for real-time and in situ measurement of lysosomal MDA within living brains. Herein, a fluorescence imaging agent, Lyso-MCBH, was constructed to specifically monitor lysosomal MDA by entering the brain and targeting the lysosome. Erupting the lysosomal MDA level in living brains of mice under CIRI was first observed using Lyso-MCBH. Excessive lysosomal MDA was found to affect the efficacy of vitamin B12 by blocking the transport of vitamin B12 from the lysosome to the cytoplasm. More importantly, the expression and function of the vitamin B12 transporter LMBD1 were proved to be associated with excessive lysosomal MDA. Altogether, the revealing of the lysosomal MDA-LMBD1 axis provides a cogent interpretation of the inefficacy of vitamin B12 in CIRI, which could be a prospective therapeutic target.

Novel AP2238-clorgiline hybrids as multi-target agents for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation.

Cholinesterase and monoamine oxidase are potential targets for the therapy of Alzheimer's disease. A series of novel AP2238-clorgiline hybrids as multi-target agents were designed, synthesized and investigated in vitro for their inhibition of cholinesterases and monoamine oxidases. Many compounds displayed balanced and good inhibitory activity against AChE, BuChE and MAO-B with an obvious selective inhibitory effect on MAO-B. Among them, Compound 5l showed the most balanced potency to inhibit ChEs (eeAChE: IC50 = 4.03 ± 0.03 µM, eqBuChE: IC50 = 5.64 ± 0.53 µM; hAChE: IC50 = 8.30 ± 0.04 µM, hBuChE: IC50 = 1.91 ± 0.06 µM) and hMAO-B (IC50 = 3.29 ± 0.09 µM). Molecular modeling and kinetic studies showed that 5l was a mixed inhibitor for both AChE and BuChE, and a competitive MAO-B inhibitor. Compound 5l exhibited no toxicity to PC12 and BV-2 cells at 12.5 µM and no acute toxicity at a dosage of 2500 mg/kg. Moreover, 5l can improve the memory function of mice with scopolamine-induced memory impairment and have an excellent ability to cross the blood-brain barrier. Overall, these findings suggested that compound 5l could be deemed as a promising, balanced multi-target drug candidate against Alzheimer's disease.

Metallic surface states in a correlated d-electron topological Kondo insulator candidate FeSb2.

The resistance of a conventional insulator diverges as temperature approaches zero. The peculiar low-temperature resistivity saturation in the 4f Kondo insulator (KI) SmB6 has spurred proposals of a correlation-driven topological Kondo insulator (TKI) with exotic ground states. However, the scarcity of model TKI material families leaves difficulties in disentangling key ingredients from irrelevant details. Here we use angle-resolved photoemission spectroscopy (ARPES) to study FeSb2, a correlated d-electron KI candidate that also exhibits a low-temperature resistivity saturation. On the (010) surface, we find a rich assemblage of metallic states with two-dimensional dispersion. Measurements of the bulk band structure reveal band renormalization, a large temperature-dependent band shift, and flat spectral features along certain high-symmetry directions, providing spectroscopic evidence for strong correlations. Our observations suggest that exotic insulating states resembling those in SmB6 and YbB12 may also exist in systems with d instead of f electrons.

[Physicochemical properties of a novel chiral self-assembling peptide R-LIFE-1 and its controlled release to exosomes].

This research aims to investigate the encapsulation and controlled release effect of the newly developed self-assembling peptide R-LIFE-1 on exosomes. The gelling ability and morphological structure of the chiral self-assembling peptide (CSAP) hydrogel were examined using advanced imaging techniques, including atomic force microscopy, transmission electron microscopy, and cryo-scanning electron microscopy. The biocompatibility of the CSAP hydrogel was assessed through optical microscopy and fluorescent staining. Exosomes were isolated via ultrafiltration, and their quality was evaluated using Western blot analysis, nanoparticle tracking analysis, and transmission electron microscopy. The controlled release effect of the CSAP hydrogel on exosomes was quantitatively analyzed using laser confocal microscopy and a BCA assay kit. The results revealed that the self-assembling peptide R-LIFE-1 exhibited spontaneous assembly in the presence of various ions, leading to the formation of nanofibers. These nanofibers were cross-linked, giving rise to a robust nanofiber network structure, which further underwent cross-linking to generate a laminated membrane structure. The nanofibers possessed a large surface area, allowing them to encapsulate a substantial number of water molecules, thereby forming a hydrogel material with high water content. This hydrogel served as a stable spatial scaffold and loading matrix for the three-dimensional culture of cells, as well as the encapsulation and controlled release of exosomes. Importantly, R-LIFE-1 demonstrated excellent biocompatibility, preserving the growth of cells and the biological activity of exosomes. It rapidly formed a three-dimensional network scaffold, enabling the stable loading of cells and exosomes, while exhibiting favorable biocompatibility and reduced cytotoxicity. In conclusion, the findings of this study support the notion that R-LIFE-1 holds significant promise as an ideal tissue engineering material for tissue repair applications.

Janus-Faced Fluorescence Imaging Agent for Malondialdehyde and Formaldehyde in Brains.

Carbonyl stress caused by reactive carbonyl species (RCS) is closely related to various brain diseases. As the highly reactive, highly toxic, and lipophilic RCS, malondialdehyde (MDA) and formaldehyde (FA) could easily cross the blood-brain barrier (BBB) and induce protein dysfunction or cross-linking in the brain. Do MDA and FA coordinately regulate the physio-pathological processes of the brain? To answer the question, first of all, powerful identification and sensing tools are needed. However, competent probes for simultaneously analyzing MDA and FA in living brains are lacking, which originates from the following three challenges: (1) MDA and FA are difficult to distinguish due to their great similarity in structure and reactivity; (2) to achieve simultaneous and discriminable imaging, same excitation and different emissions are preferable; and (3) the detection of MDA and FA in living brains require the materials to pass through the BBB. Thus, we created a two-photon fluorescent agent, TFCH, for MDA/FA. The hydrazine group in TFCH could successfully differentiate MDA/FA at 440/510 nm under same excitation. Moreover, the lipophilic trifluoromethyl group (-CF3) in TFCH prompts it to traverse the BBB, thereby realizing the coinstantaneous visualization of MDA and FA in the living brain. Using TFCH, we observed the excessive production of MDA and FA in living PC12 cells under carbonyl stress and oxidative stress. Notably, for the first time, two-photon fluorescence imaging indicated the synchronous increase of MDA and FA in living brains of mice with depression. Altogether, this work provides a promising tool for revealing the carbonyl stress-related molecular mechanism involved in brain diseases.

Unconventional Hysteretic Transition in a Charge Density Wave.

Hysteresis underlies a large number of phase transitions in solids, giving rise to exotic metastable states that are otherwise inaccessible. Here, we report an unconventional hysteretic transition in a quasi-2D material, EuTe_{4}. By combining transport, photoemission, diffraction, and x-ray absorption measurements, we observe that the hysteresis loop has a temperature width of more than 400 K, setting a record among crystalline solids. The transition has an origin distinct from known mechanisms, lying entirely within the incommensurate charge density wave (CDW) phase of EuTe_{4} with no change in the CDW modulation periodicity. We interpret the hysteresis as an unusual switching of the relative CDW phases in different layers, a phenomenon unique to quasi-2D compounds that is not present in either purely 2D or strongly coupled 3D systems. Our findings challenge the established theories on metastable states in density wave systems, pushing the boundary of understanding hysteretic transitions in a broken-symmetry state.

A Rapid Self-Assembly Peptide Hydrogel for Recruitment and Activation of Immune Cells.

Self-assembly peptide nanotechnology has attracted much attention due to its regular and orderly structure and diverse functions. Most of the existing self-assembly peptides can form aggregates with specific structures only under specific conditions and their assembly time is relatively long. They have good biocompatibility but no immunogenicity. To optimize it, a self-assembly peptide named DRF3 was designed. It contains a hydrophilic and hydrophobic surface, using two N-terminal arginines, leucine, and two c-terminal aspartate and glutamic acid. Meanwhile, the c-terminal of the peptide was amidated, so that peptide segments were interconnected to increase diversity. Its characterization, biocompatibility, controlled release effect on antigen, immune cell recruitment ability, and antitumor properties were examined here. Congo red/aniline blue staining revealed that peptide hydrogel DRF3 could be immediately gelled in PBS. The stable ß-sheet secondary structure of DRF3 was confirmed by circular dichroism spectrum and IR spectra. The observation results of cryo-scanning electron microscopy, transmission electron microscopy, and atomic force microscopy demonstrated that DRF3 formed nanotubule-like and vesicular structures in PBS, and these structures interlaced with each other to form ordered three-dimensional nanofiber structures. Meanwhile, DRF3 showed excellent biocompatibility, could sustainably and slowly release antigens, recruit dendritic cells and promote the maturation of dendritic cells (DCs) in vitro. In addition, DRF3 has a strong inhibitory effect on clear renal cell carcinoma (786-0). These results provide a reliable basis for the application of peptide hydrogels in biomedical and preclinical trials.

Validation of the Chinese Version of the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults.

BACKGROUND: The number of individuals with potential gender dysphoria (GD) being referred to specialized gender identity clinics or programs is increasing internationally; these cases are initially screened using the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults (GIDYQ-AA). AIM: The current study aimed to assess the psychometric properties of the GIDYQ-AA in a sample of adolescents and young adults from China. METHODS: A cross-sectional study was conducted in October 2020. Sociodemographic information of the participants was first collected. Participants then completed the GIDYQ-AA, the Generalized Anxiety Disorder-7 scale, the Patient Health Questionnaire-9, and a suicidal ideation assessment. A total of 2,533 participants with a mean age of 19.30 (SD = 1.19) years were recruited. Of the participants, 841 (33.2%) were cis men, 1,589 (62.7%) were cis women, 66 (2.6%) self-identified as transgender, 17 (0.7%) self-identified as non-binary, and 20 (0.8%) self-identified as gender queer. RESULTS: The GIDYQ-AA had high internal consistency with a Cronbach's alpha = 0.89. Exploratory factor analysis showed that the GIDYQ-AA had a four-factor structure in China. The GIDYQ-AA was significantly correlated with anxiety symptoms (r = -0.32, P < .01), depressive symptoms (r = -0.33, P < .01), and suicidal ideation (r = -0.20, P < .01). CLINICAL TRANSLATION: The Chinese version of GIDYQ-AA is a useful measurement with high practical value, which could promote the assessment and research of GD across China or among Chinese migrants in other countries. STRENGTHS AND LIMITATIONS: This is the first study assessing the psychometric properties of the GIDYQ-AA in Chinese adolescents and young adults. The convergent and divergent validity of the GIDYQ-AA were not examined due to the unavailability of data. Also, the sample did not have an equal distribution of male to males and female to females. CONCLUSION: The Chinese version of GIDYQ-AA is a useful measure, which could promote both the assessment and research of GD in the Chinese population. Wang Y, Feng Y, Su D, et al. Validation of the Chinese Version of the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults. J Sex Med 2021;18:1632-1640.

Highly sensitive detection of DNA methyltransferase activity and its inhibitor screening by coupling fluorescence correlation spectroscopy with polystyrene polymer dots.

DNA methylation is a critical part of epigenetics and plays a vital role in maintaining normal cell function, genetic imprinting, and human tumorigenesis. Thus, it is important to develop a sensitive method for the determination of DNA methyltransferase (MTase) activity. Here, we present a simple and sensitive method based on single molecule fluorescence correlation spectroscopy (FCS) and polystyrene polymer dots (PS Pdots) for the quantitative detection of DNA adenine methylation (Dam) MTase activity and its inhibitor screening in homogeneous solution without separation. Its principle is based on the measurement of the characteristic diffusion time (τD) of unmethylated and methylated DNA-fluorescent probes by FCS. A hairpin DNA probe including the 5'-GATC-3' sequence is used by doubly labelling fluorophore Alexa Fluor 488 (Alexa 488) and biotin at the 5'- and 3'-terminus, respectively. Dam MTase catalyzed the methylation of the sequence of 5'-GATC-3', and DpnI cleaved the sequence of 5'-G-Am-TC-3'. Streptavidin conjugated PS Pdots were used to react with DNA probes without methylation to further increase the difference in τD values between methylated and unmethylated DNA-Alexa 488 probes. We used the FCS method to measure the τD values of DNA-Alexa 488 probes and further obtained the activity of Dam MTase. It is found that the τD value of the methylated DNA probe is negatively correlated with the logarithm of Dam MTase concentration in the range from 0.025 U mL-1 to 3 U mL-1. The detection limit is as low as 0.025 U mL-1. Furthermore, we evaluated the inhibition effect of drug-related DNA methylation and the half-maximal inhibitory concentration (IC50) value is consistent with a previous study. The results demonstrated that our proposed method will become a promising platform for the determination of Dam MTase activity and inhibitor screening.

Oxidative Damage of Tryptophan Hydroxylase-2 Mediated by Peroxisomal Superoxide Anion Radical in Brains of Mouse with Depression.

Depression is intimately linked with oxidative stress in the brains. Peroxisome plays vital roles in the regulation of intracellular redox balance by keeping reactive oxygen species (ROS) homeostasis. Available evidence indicates a possible relationship between peroxisomal ROS and depression. Even so, the underlying modulation mechanisms of peroxisomal ROS in depression are still rudimentary due to the limitations of the existing detecting methods. Hence, we developed a two-photon fluorescent probe TCP for the real-time visualization of the first produced ROS superoxide anion radical (O2•-) in peroxisome. Using the two-photon fluorescence imaging, we found that peroxisomal O2•- rose during oxidative stress in the mouse brains, resulting in the inactivation of catalase (CAT). Subsequently, the intracellular H2O2 level elevated, which further oxidized tryptophan hydroxylase-2 (TPH2). Then the decrease contents of TPH2 caused the dysfunction of 5-hydroxytryptamine (5-HT) system in the mouse brains, eventually leading to depression-like behaviors. Our work provides evidence of a peroxisomal O2•- mediated signaling pathway in depression, which will conduce to pinpoint potential targets for the treatment of depression.

Simultaneous Fluorescence Imaging Reveals N-Methyl-d-aspartic Acid Receptor Dependent Zn2+/H+ Flux in the Brains of Mice with Depression.

Depression is immensely attributed to the overactivation of N-methyl-d-aspartic acid (NMDA) receptor in the brains. As regulatory binding partners of NMDA receptor, both Zn2+ and H+ are intimately interrelated to NMDA receptor's activity. Therefore, exploring synergistic changes on the levels of Zn2+ and H+ in brains will promote the knowledge and treatment of depression. However, the lack of efficient, appropriate imaging tools limits simultaneously tracking Zn2+ and H+ in living mouse brains. Thus, a well-designed dual-color fluorescent probe (DNP) was fabricated for the simultaneous monitoring of Zn2+ and H+ in the brains of mice with depression. Encountering Zn2+, the probe evoked bright blue fluorescence at 460 nm. Meanwhile, the red fluorescence at 680 nm was decreased with H+ addition. With blue/red dual fluorescence signal of DNP, we observed the synchronous increased Zn2+ and H+ in PC12 cells under oxidative stress. Notably, in vivo imaging for the first time revealed the simultaneous reduction of Zn2+ and pH in brains of mice with depression-like behaviors. Further results implied that the NMDA receptor might be responsible for the coinstantaneous fluctuation of Zn2+ and H+ during depression. Altogether, this work is conducive to the knowledge of neural signal transduction mechanisms, advancing our understanding of the pathogenesis in depression.

Observing Malondialdehyde-Mediated Signaling Pathway in Cerebral Ischemia Reperfusion Injury with a Specific Nanolight.

Cerebral ischemia reperfusion injury (CIRI) is closely related to lipid peroxidation. Malondialdehyde (MDA), as a biomarker of lipid peroxidation, is prone to addition with biomacromolecules, resulting in a secondary cerebral injury. However, desirable tools for in vivo-determining cerebral MDA are scarce. Thus, we devised innovative polymer carbon dots carbonized by benzoyl hydrazine and named them BH-PCDs. BH-PCDs covered with hydrazine groups directly form from one-pot synthesis. The functional nanoparticle specifically identifies MDA via a photoinduced electron transfer (PET) mechanism from other similar biological species, especially reactive carbonyl species. BH-PCDs afforded several valuable traits of a simple preparation, a large two-photon absorption cross section, and exceptional biocompatibility, as well as the ability of traversing the blood-brain barrier. Relying on BH-PCDs, we real-time portrayed the increased cerebral MDA under CIRI. Furthermore, combining with a commercial indicator of the superoxide anion (O2•-), an O2•--regulated MDA level under CIRI was visualized in vivo. Moreover, we demonstrated MDA inactivated glutamine synthetase under CIRI, mediating the glutamate level. Overall, we provide a perspective nanolight serviceable for treating CIRI, which could reveal the physiopathology mechanism of brain MDA.

Highly Specific Cys Fluorescence Probe for Living Mouse Brain Imaging via Evading Reaction with Other Biothiols.

Depression is characterized by oxidative stress in the brain. As the crucial reductive biothiol, cysteine (Cys) directly regulates the occurrence of oxidative stress in the brain. Despite its significance, the precise exploration of Cys in mouse brains remains a challenge, primarily owing to the limitations of Cys-monitoring tools, especially the interference from unavoidable reaction with other biothiols. Thus, we developed a novel two-photon fluorescence probe for Cys based on a new specific recognition site, thiobenzoate. Encountering Cys, the carbon-sulfur double bond in the probe formed a stable five-membered ring via the selective nucleophilic addition reaction, triggering a remarkable fluorescence increase. Notably, this reaction cannot occur with other biothiols, which afford the probe unprecedented selectivity to Cys. With two-photon excitation at 754 nm, we achieved in situ visualization of the increased Cys in PC12 cells under dithiothreitol stimulation. Furthermore, we directly visualized the precipitous reduction of Cys in the brains of mice with depression phenotypes for the first time. This work opens up new vistas for Cys imaging and expands the understanding of pathogenesis of depression.