Galacturonic acid-capsaicin prodrug for prolonged nociceptive-selective nerve blockade.

There is an urgent clinical need to develop nerve-blocking agents capable of inducing long duration sensory block without muscle weakness or paralysis to treat post-operative and chronic pain conditions. Here, we report a galacturonic acid-capsaicin (GalA-CAP) prodrug as an effective nociceptive-selective axon blocking agent. Capsaicin selectively acts on nociceptive signaling without motor nerve blockade or disruption of proprioception and touch sensation, and the galacturonic acid moiety enhance prodrug permeability across the restrictive peripheral nerve barriers (PNBs) via carrier-mediated transport by the facilitative glucose transporters (GLUTs). In addition, following prodrug transport across PNBs, the inactive prodrug is converted to active capsaicin through linker hydrolysis, leading to sustained drug release. A single injection of GalA-CAP prodrug at the sciatic nerves of rats led to nociceptive-selective nerve blockade lasting for 234 ± 37 h, which is a sufficient duration to address the most intense period of postsurgical pain. Furthermore, the prodrug markedly mitigated capsaicin-associated side effects, leading to a notable decrease in systemic toxicity, benign local tissue reactions, and diminished burning and irritant effects.

Lignin-Derived Lightweight Carbon Aerogels for Tunable Epsilon-Negative Response.

Electromagnetic (EM) metamaterials have garnered considerable attention due to their capacity to achieve negative parameters, significantly influencing the integration of natural materials with artificially structural media. The emergence of carbon aerogels (CAs) offers an opportunity to create lightweight EM metamaterials, notable for their promising EM shielding or absorption effects. This paper introduces an efficient, low-cost method for fabricating CAs without requiring stringent drying conditions. By finely tuning the ZnCl2/lignin ratio, the porosity is controlled in CAs. This control leads to an epsilon-negative response in the radio-frequency region, driven by the intrinsic plasmonic state of the 3D carbon network, as opposed to traditional periodic building blocks. This approach yields a tunable and weakly epsilon-negative response, reaching an order of magnitude of -103 under MHz frequencies. Equivalent circuit analysis highlights the inductive characteristics of CAs, correlating their significant dielectric loss at low frequencies. Additionally, EM simulations are performed to evaluate the distribution of the electric field vector in epsilon-negative CAs, showcasing their potential for effective EM shielding. The lignin-derived, lightweight CAs with their tunable epsilon-negative response hold promise for pioneering new directions in EM metamaterials and broadening their application in diverse extreme conditions.

From waste corn straw to graphitic porous carbon: A trade-off between specific surface area and graphitization degree for efficient peroxydisulfate activation.

Electron transfer pathways have been verified as overriding regimes when peroxydisulfate (PDS) was activated by porous carbon. The incorporation of graphitic structure into carbon matrix was favorable to the rapid electron transfer, but excessive graphitization would deteriorate the specific surface area (SSA), weakening the catalytic performance. The reasonable trade-off between SSA and graphitization degree was necessary and challenging for the preparation of efficient carbon based PS-activators. Herein, a series of graphitic porous carbon with discrepant SSA and graphitic structure were fabricated. The incorporation of graphitization tracks into ultra-thin edges on porous carbon film was verified by multifarious structural characterization. After trade-off, the optimum catalyst exhibited superior catalytic performance with degradation rate constant (kobs) exceeding that of ungraphitized precursor by up to 16.0 times. Mechanistic investigations substantiated that the sufficient SSA of catalyst provided favorable conditions for its affinity towards PDS and sulfadiazine (SDZ), resulting in the formation of PDS* complexes and SDZ adsorption, while the appropriate graphitization degree ensured the reinforced electron transfer rate, which collectively accelerated SDZ oxidation through electron-transfer pathway. The multivariate linear regression model linking kobs to SSA and graphitization degree was established providing basis to construct efficient catalysts for PDS activation.

Single-nucleus transcriptomic mapping uncovers targets for traumatic brain injury.

The subventricular zone (SVZ) is a neurogenic niche that contributes to homeostasis and repair after brain injury. However, the effects of mild traumatic brain injury (mTBI) on the divergence of the regulatory DNA landscape within the SVZ and its link to functional alterations remain unexplored. In this study, we mapped the transcriptome atlas of murine SVZ and its responses to mTBI at the single-cell level. We observed cell-specific gene expression changes following mTBI and unveiled diverse cell-to-cell interaction networks that influence a wide array of cellular processes. Moreover, we report novel neurogenesis lineage trajectories and related key transcription factors, which we validate through loss-of-function experiments. Specifically, we validate the role of Tcf7l1, a cell cycle gene regulator, in promoting neural stem cell differentiation toward the neuronal lineage after mTBI, providing a potential target for regenerative medicine. Overall, our study profiles an SVZ transcriptome reference map, which underlies the differential cellular behavior in response to mTBI. The identified key genes and pathways that may ameliorate brain damage or facilitate neural repair serve as a comprehensive resource for drug discovery in the context of mTBI.

Single-nucleus transcriptomic mapping of blast-induced traumatic brain injury in mice hippocampus.

As a significant type of traumatic brain injury (TBI), blast-induced traumatic brain injury (bTBI) frequently results in severe neurological and psychological impairments. Due to its unique mechanistic and clinical features, bTBI presents diagnostic and therapeutic challenges compared to other TBI forms. The hippocampus, an important site for secondary injury of bTBI, serves as a key niche for neural regeneration and repair post-injury, and is closely associated with the neurological outcomes of bTBI patients. Nonetheless, the pathophysiological alterations of hippocampus underpinning bTBI remain enigmatic, and a corresponding transcriptomic dataset for research reference is yet to be established. In this investigation, the single-nucleus RNA sequencing (snRNA-seq) technique was employed to sequence individual hippocampal nuclei of mice from bTBI and sham group. Upon stringent quality control, gene expression data from 17,278 nuclei were obtained, with the dataset's reliability substantiated through various analytical methods. This dataset holds considerable potential for exploring secondary hippocampal injury and neurogenesis mechanisms following bTBI, with important reference value for the identification of specific diagnostic and therapeutic targets for bTBI.

Intermittent fasting ameliorates neuronal ferroptosis and cognitive impairment in mice after traumatic brain injury.

Ferroptosis, a newly characterized form of programmed cell death that results from lipid peroxidation and mitochondrial dysfunction, has been demonstrated to be involved in the pathogenesis of traumatic brain injury (TBI). Scientific evidence has shown that intermittent fasting (IF) reduces both the lipid peroxidation and the mitochondrial dysfunction, raising the question of whether IF affects the ferroptosis induced by TBI. Here, based on an established TBI animal model, we examine the effects of IF on the activation of ferroptosis pathway as well as related outcomes. We uncovered that a 1-mo IF elevated the protective Gpx4 and Hspb1 expression, and partly abolished the increase of Nfe2l2, Slc7a11, Alox8, Steap3, and Nox2 in the cortex, which were induced by TBI. Furthermore, the characteristic cellular damage induced by ferroptosis was alleviated by IF, as revealed by Perls' Prussian blue staining, Nissl staining, and transmission electron microscope examination. Consistently, we examined the outcomes of mice subjected to TBI and found an improved cognitive function of the IF mice. In sum, our study demonstrated, to our knowledge for the first time, that a 1-mo IF regimen partly ameliorates ferroptosis in the cortex of mice subjected to TBI, which potentially contributes to a lessening of cognitive impairment.

Single-nucleus profiling of adult mice sub-ventricular zone after blast-related traumatic brain injury.

Explosive blast-related traumatic brain injuries (bTBI) are common in war zones and urban terrorist attacks. These bTBIs often result in complex neuropathologic damage and neurologic complications. However, there is still a lack of specific strategies for diagnosing and/or treating bTBIs. The sub-ventricular zone (SVZ), which undergoes adult neurogenesis, is critical for the neurological maintenance and repair after brain injury. However, the cellular responses and mechanisms that trigger and modulate these activities in the pathophysiological processes following bTBI remain poorly understood. Here we employ single-nucleus RNA-sequencing (snRNA-seq) of the SVZ from mice subjected to a bTBI. This data-set, including 15272 cells (7778 bTBI and 7494 control) representing all SVZ cell types and is ideally suited for exploring the mechanisms underlying the pathogenesis of bTBIs. Additionally, it can serve as a reference for future studies regarding the diagnosis and treatment of bTBIs.

Single-cell transcriptome study in forensic medicine: prospective applications.

Next-generation sequencing and single-cell RNA sequencing (scRNA-seq) technologies have advanced rapidly in recent years. scRNA-seq reveals the unique gene expression of each cell type, providing directions for exploring cell heterogeneity, cell type-specific responses to injury/disease, and the mechanisms underlying these processes. The development of sequencing technology and improved sequencing throughput have brought about a revolution in single-cell transcriptome study, bringing great benefits to the fields of medicine and biomedical science. From our perspective, certain issues in forensic medicine may potentially be addressed using single-cell transcriptome studies; however, this powerful technique has not yet attracted sufficient attention in forensic medicine-associated research. Therefore, examining and reviewing the latest developments and applications of single-cell transcriptome studies, we present our views on the future directions of forensic research using this technology, aiming to expand the frontiers of forensic science.

Chinese expert consensus on the clinical applications of aminolevulinic acid-based photodynamic therapy in female lower genital tract diseases (2022).

INTRODUCTION: With the younger onset age of female lower genital tract diseases, there are increasing demands for protecting organ and tissue structures to preserve fertility and, therefore, effective fertility-sparing treatments that cause minimal normal tissue damage and less adverse reactions are urgently needed. OBJECTIVE: This study is aimed at reviewing information and achieving consensus on recommendations on the clinical applications of aminolevulinic acid-based photodynamic therapy (ALA-PDT) in female lower genital tract diseases. METHODS: Members of the expert panel held online and in-person meetings to discuss and revise drafts created by the steering committee based on the literature review and the clinical experiences of the expert panel. Opinions of the experts were transcribed and discussed in detail to ensure that the consensus statement best reflects the current advances in the field and the experts' view. RESULTS: After numerous rounds of meetings, experts unanimously agreed on the importance of ALA-PDT in the treatment of cervical squamous intraepithelial lesions (SIL), vaginal SIL, vulvar SIL, vulvar lichen sclerosus (VLS), and condyloma acuminatumon (CA). Experts also reached consensus on the recommended treatment regimen and treatment methods. CONCLUSION: This consensus aimed to provide practical basis and guidance for the clinical applications of ALA-PDT in female lower genital tract diseases in China. Of note, this is the only expert consensus prepared by board-certified specialists in gynecology and obstetrics in China. More evidence-based clinical studies should be made to update and expand the current recommendations.

Cyanine-flavonol hybrids as NIR-light activatable carbon monoxide donors in methanol and aqueous solutions.

Here we report on carbon monoxide-photoreleasable compounds (photoCORMs) that combine heptamethine cyanine and flavonol chromophores and are activated upon irradiation with near-infrared light. Excellent CO-release yields and uncaging cross sections in aqueous solutions, enhanced water solubilities thanks to polar substituents or a host-guest approach using cucurbit[7]uril are demonstrated. The hybrids display outstanding biocompatibility and diverse, structure-dependent cell penetrability and internalization.

The complex photochemistry of coumarin-3-carboxylic acid in acetonitrile and methanol.

Irradiation of coumarin-3-carboxylic acid in acetonitrile and methanol solutions at 355 nm results in complex multistep photochemical transformations, strongly dependent on the solvent properties and oxygen content. A number of reaction intermediates, which themselves undergo further (photo)chemical reactions, were identified by steady-state and transient absorption spectroscopy, mass spectrometry, and NMR and product analyses. The triplet excited compound in acetonitrile undergoes decarboxylation to give a 3-coumarinyl radical that traps molecular oxygen to form 3-hydroxycoumarin as the major but chemically reactive intermediate. This compound is oxygenated by singlet oxygen, produced by coumarin-3-carboxylic acid sensitization, followed by a pyrone ring-opening reaction to give an oxalic acid derivative. The subsequent steps lead to the production of salicylaldehyde, carbon monoxide, and carbon dioxide as the final products. When 3-coumarinyl radical is not trapped by oxygen in degassed acetonitrile, it abstracts hydrogen from the solvent and undergoes triplet-sensitized [2 + 2] cycloaddition. The reaction of 3-coumarinyl radical with oxygen is largely suppressed in aerated methanol as a better H-atom donor, and coumarin is obtained as the primary product in good yields. Because coumarin derivatives are used in many photophysical and photochemical applications, this work provides detailed and sometimes surprising insights into their complex phototransformations.

Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation.

Ras-related C3 botulinum toxin substrate 2 (RAC2) is a GTPase exclusively expressed in hematopoietic cells that acts as a pivotal regulator of several aspects of cell behavior via various cellular processes. RAC2 undergoes a tightly regulated GTP-binding/GTP-hydrolysis cycle, enabling it to function as a molecular switch. Mutations in RAC2 have been identified in 18 patients with different forms of primary immunodeficiency, ranging from phagocyte defects caused by dominant negative mutations to common variable immunodeficiency resulting from autosomal recessive loss-of-function mutations, or severe combined immunodeficiency due to dominant activating gain-of-function mutations. Here, we describe an 11-year-old girl with combined immunodeficiency presenting with recurrent respiratory infections and bronchiectasis. Immunological investigations revealed low T-cell receptor excision circle/K-deleting recombination excision circles numbers, lymphopenia, and low serum immunoglobulin G. Targeted next-generation sequencing identified a novel heterozygous mutation in RAC2, c.86C > G (p.P29R), located in the highly conserved Switch I domain. The mutation resulted in enhanced reactive oxygen species production, elevated F-actin content, and increased RAC2 protein expression in neutrophils, as well as increased cytokine production and a dysregulated phenotype in T lymphocytes. Furthermore, the dominant activating RAC2 mutation led to accelerated apoptosis with augmented intracellular active caspase 3, impaired actin polarization in lymphocytes and neutrophils, and diminished RAC2 polarization in neutrophils. We present a novel RAC2 gain-of-function mutation with implications for immunodeficiency and linked to functional dysregulation, including abnormal apoptosis and cell polarization arising from altered RAC2 expression. Thus, our findings broaden the spectrum of known RAC2 mutations and their underlying mechanisms.

Activated Phosphoinositide 3-Kinase δ Syndrome: a Large Pediatric Cohort from a Single Center in China.

PURPOSE: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a primary immunodeficiency first described in 2013, which is caused by gain-of-function mutations in PIK3CD or PIK3R1, and characterized by recurrent respiratory tract infections, lymphoproliferation, herpesvirus infection, autoimmunity, and enteropathy. We sought to review the clinical phenotypes, immunological characteristics, treatment, and prognosis of APDS in a large genetically defined Chinese pediatric cohort. METHODS: Clinical records, radiology examinations, and laboratory investigations of 40 APDS patients were reviewed. Patients were contacted via phone call to follow up their current situation. RESULTS: Sinopulmonary infections and lymphoproliferation were the most common complications in this cohort. Three (10.3%) and five (12.5%) patients suffered localized BCG-induced granulomatous inflammation and tuberculosis infection, respectively. Twenty-seven patients (67.5%) were affected by autoimmunity, while malignancy (7.5%) was relatively rare to be seen. Most patients in our cohort took a combined treatment of anti-infection prophylaxis, immunoglobulin replacement, and immunosuppressive therapy such as glucocorticoid or rapamycin administration. Twelve patients underwent hematopoietic stem cell transplantation (HSCT) and had a satisfying prognosis. CONCLUSION: Clinical spectrum of APDS is heterogeneous. This cohort's high incidence of localized BCG-induced granulomatous inflammation and tuberculosis indicates Mycobacterial susceptibility in APDS patients. Rapamycin is effective in improving lymphoproliferation and cytopenia. HSCT is an option for those who have severe complications and poor response to other treatments.

Obesity modulates cell-cell interactions during ovarian folliculogenesis.

Obesity is known to affect female reproduction, as evidenced by obese patients suffering from subfertility and abnormal oogenesis. However, the underlying mechanisms by which obesity impairs folliculogenesis are poorly documented. Here, we performed comprehensive single-cell transcriptome analysis in both regular diet (RD) and obese mouse models to systematically uncover how obesity affects ovarian follicle cells and their interactions. We found an increased proportion of Inhbb highly expressed granulosa cells (GCs) among all the GC subpopulations in obese mice. Under obese conditions, excessive androgen secreted from endocrine theca cells (ETCs) may contribute to the imbalanced change of GC subtypes through ETCs-GCs interactions. This is alleviated by enzalutamide, an androgen receptor antagonist. We also identified and confirmed typical GC markers, such as Marcks and Prkar2b, for sensitive evaluation of female fertility in obesity. These data represent a resource for studying transcriptional networks and cell-cell interactions during folliculogenesis under physiological and pathological conditions.

Phenotypic characterization of patients with activated PI3Kδ syndrome 1 presenting with features of systemic lupus erythematosus.

Activated phosphoinositide 3-kinase δ syndrome 1 (APDS1) is a primary immunodeficiency disease caused by gain-of-function mutations in PIK3CD. Clinical features of autoimmune disease have been reported in patients with APDS1. In this study, we reported three patients with APDS1 presenting with systemic lupus erythematosus (SLE) phenotype. The clinical manifestations included recurrent respiratory tract infection, lymphoproliferation, Coombs-positive hemolytic anemia, decreased complement fractions, positive antinuclear antibodies, renal complications related to SLE associated diseases, which met the clinical spectrum of APDS1 and the classification criteria of SLE. The immunological phenotype included an inversion in the CD4:CD8 ratio, an increase in both non-circulating Tfh CD4+ memory T and circulating Tfh populations, a low level of recent thymic emigrant T cells, overexpression of CD57 on T cells, and a decrease in B cells with fewer antibody class switch recombination. These phenotypes detected in patients with APDS1 presenting with SLE were resemble that in patients with APDS1 presenting without SLE. Meanwhile, we described the effect of glucocorticoids and rapamycin therapy on patients with APDS1. The phosphorylation of S6 at Ser235/236 was inhibited in patients with APDS1 who underwent glucocorticoids therapy, including two who presented with SLE phenotype. The phosphorylation of AKT at Ser473 and phosphorylation of S6 at Ser235/236 were inhibited in other patients with APDS1 who underwent rapamycin therapy. Here, we showed the coexistence of immunodeficiency and SLE phenotype in APDS1, and the inhibition of rapamycin in activated Akt-mTOR signaling pathway.

ZnO-Co3O4/N-C Cage Derived from the Hollow Zn/Co ZIF for Enhanced Degradation of Bisphenol A with Persulfate.

The zeolitic imidazolate framework (ZIF)-67 microcrystal was employed as a precursor to synthesize the hollow ZIF-8/ZIF-67 composite via the epitaxial growth of ZIF-8 on ZIF-67, in situ self-sacrifice, and excavation of ZIF-67. The hollow ZIF-8/ZIF-67 composite was successfully transformed to the ZnO-Co3O4/N-C cage by thermal treatment, which was further used as the catalyst for the oxidative degradation of bisphenol A (BPA) in the presence of potassium persulfate (PS). In comparison with the Co3O4/N-C and Co3O4 obtained from pure ZIF-67 and cobalt nitrate, the ZnO-Co3O4/N-C cage demonstrated a more than four fold-higher activity and robust reusability. Based on structural analysis, the enhanced catalytic performance could be ascribed to the small, highly dispersed cobalt oxide particles, the hollow structure that facilitated the transportation of the molecules, and the synergistic effect between cobalt oxide and nitrogen-doped carbon in the composite. Besides, the effect of dosage of PS, BPA, and the co-existing components such as chloride ion, methanol, and t-butyl alcohol was carefully investigated to propose the possible mechanism. This study would give new insights into the design of functional composite materials from metal organic frameworks and the development of their application in environmental pollution disposal.

Plant Metabolites Drive Different Responses in Caterpillars of Two Closely Related Helicoverpa Species.

The host acceptances of insects can be determined largely by detecting plant metabolites using insect taste. In the present study, we investigated the gustatory sensitivity and feeding behaviors of two closely related caterpillars, the generalist Helicoverpa armigera (Hübner) and the specialist H. assulta (Guenée), to different plant metabolites by using the single sensillum recording technique and the dual-choice assay, aiming to explore the contribution of plant metabolites to the difference of diet breadth between the two species. The results depicted that the feeding patterns of caterpillars for both plant primary and secondary metabolites were significantly different between the two Helicoverpa species. Fructose, glucose, and proline stimulated feedings of the specialist H. assulta, while glucose and proline had no significant effect on the generalist H. armigera. Gossypol and tomatine, the secondary metabolites of host plants of the generalist H. armigera, elicited appetitive feedings of this insect species but drove aversive feedings of H. assulta. Nicotine and capsaicin elicited appetitive feedings of H. assulta, but drove aversive feedings of H. armigera. For the response of gustatory receptor neurons (GRNs) in the maxillary styloconic sensilla of caterpillars, each of the investigated primary metabolites induced similar responding patterns between the two Helicoverpa species. However, four secondary metabolites elicited different responding patterns of GRNs in the two species, which is consistent with the difference of feeding preferences to these compounds. In summary, our results of caterpillars' performance to the plant metabolites could reflect the difference of diet breadth between the two Helicoverpa species. To our knowledge, this is the first report showing that plant secondary metabolites could drive appetitive feedings in a generalist insect species, which gives new insights of underscoring the adaptation mechanism of herbivores to host plants.

Decoding dynamic epigenetic landscapes in human oocytes using single-cell multi-omics sequencing.

Developing female human germ cells undergo genome-wide epigenetic reprogramming, but de novo DNA methylation dynamics and their interplay with chromatin states and transcriptional activation in developing oocytes is poorly understood. Here, we developed a single-cell multi-omics sequencing method, scChaRM-seq, that enables simultaneous profiling of the DNA methylome, transcriptome, and chromatin accessibility in single human oocytes and ovarian somatic cells. We observed a global increase in DNA methylation during human oocyte growth that correlates with chromatin accessibility, whereas increases of DNA methylation at specific features were associated with active transcription. Integrated analyses of multi-omics data from humans and mice revealed species-specific gene expression, and promoter accessibility contributes to gene body methylation programs. Alu elements retained low DNA methylation levels and high accessibility in early growing oocytes and were located near developmental genes in humans and mice. Together, these findings show how scChaRM-seq can provide insight into DNA methylation pattern establishment.

Hyperactive PI3Kδ predisposes naive T cells to activation via aerobic glycolysis programs.

Activated phosphoinositide 3-kinase δ syndrome (APDS) is an autosomal-dominant combined immunodeficiency disorder resulting from pathogenic gain-of-function (GOF) mutations in the PIK3CD gene. Patients with APDS display abnormal T cell homeostasis. However, the mechanisms by which PIK3CD GOF contributes to this feature remain unknown. Here, with a cohort of children with PIK3CD GOF mutations from multiple regions of China and a corresponding CRISPR/Cas9 gene-edited mouse model, we reported that hyperactive PI3Kδ disrupted TNaive cell homeostasis in the periphery by intrinsically promoting the growth, proliferation, and activation of TNaive cells. Our results showed that PIK3CD GOF resulted in loss of the quiescence-associated gene expression profile in naive T cells and promoted naive T cells to overgrow, hyperproliferate and acquire an activated functional status. Naive PIK3CD GOF T cells exhibited an enhanced glycolytic capacity and reduced mitochondrial respiration in the resting or activated state. Blocking glycolysis abrogated the abnormal splenic T cell pool and reversed the overactivated phenotype induced by PIK3CD GOF in vivo and in vitro. These results suggest that enhanced aerobic glycolysis is required for PIK3CD GOF-induced overactivation of naive T cells and provide a potential therapeutic approach for targeting glycolysis to treat patients with APDS as well as other immune disorders.