Characterization of metallothionein genes from Broussonetia papyrifera: metal binding and heavy metal tolerance mechanisms.

BACKGROUND: Broussonetia papyrifera is an economically significant tree with high utilization value, yet its cultivation is often constrained by soil contamination with heavy metals (HMs). Effective scientific cultivation management, which enhances the yield and quality of B. papyrifera, necessitates an understanding of its regulatory mechanisms in response to HM stress. RESULTS: Twelve Metallothionein (MT) genes were identified in B. papyrifera. Their open reading frames ranged from 186 to 372 bp, encoding proteins of 61 to 123 amino acids with molecular weights between 15,473.77 and 29,546.96 Da, and theoretical isoelectric points from 5.24 to 5.32. Phylogenetic analysis classified these BpMTs into three subclasses: MT1, MT2, and MT3, with MT2 containing seven members and MT3 only one. The expression of most BpMT genes was inducible by Cd, Mn, Cu, Zn, and abscisic acid (ABA) treatments, particularly BpMT2e, BpMT2d, BpMT2c, and BpMT1c, which showed significant responses and warrant further study. Yeast cells expressing these BpMT genes exhibited enhanced tolerance to Cd, Mn, Cu, and Zn stresses compared to control cells. Yeasts harboring BpMT1c, BpMT2e, and BpMT2d demonstrated higher accumulation of Cd, Cu, Mn, and Zn, suggesting a chelation and binding capacity of BpMTs towards HMs. Site-directed mutagenesis of cysteine (Cys) residues indicated that mutations in the C domain of type 1 BpMT led to increased sensitivity to HMs and reduced HM accumulation in yeast cells; While in type 2 BpMTs, the contribution of N and C domain to HMs' chelation possibly corelated to the quantity of Cys residues. CONCLUSION: The BpMT genes are crucial in responding to diverse HM stresses and are involved in ABA signaling. The Cys-rich domains of BpMTs are pivotal for HM tolerance and chelation. This study offers new insights into the structure-function relationships and metal-binding capabilities of type-1 and - 2 plant MTs, enhancing our understanding of their roles in plant adaptation to HM stresses.

Alleviation of migraine related pain and anxiety by inhibiting calcium-stimulating AC1-dependent CGRP in the insula of adult rats.

BACKGROUND: Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood. METHODS: The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats. RESULTS: The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application. CONCLUSIONS: Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.

Enhanced breast cancer treatment using phototherapy and RNS therapy with macrophage membrane-coated liposomes.

Breast cancer, the predominant malignancy afflicting women, continues to pose formidable challenges despite advancements in therapeutic interventions. This study elucidates the potential of phototherapy, comprising both photothermal and photodynamic therapy (PTT/PDT), as a novel and promising modality. To achieve this goal, we devised liposomes coated with macrophage cell membranes including macrophage-associated membrane proteins, which have demonstrated promise in biomimetic delivery systems for targeting tumors while preserving their inherent tumor-homing capabilities. This integrated biomimetic delivery system comprised IR780, NONOate, and perfluorocarbon. This strategic encapsulation aims to achieve a synergistic combination of photodynamic therapy (PDT) and reactive nitrogen species (RNS) therapy. Under near-infrared laser irradiation at 808 nm, IR780 demonstrates its ability to prolifically generate reactive oxygen species (ROS), including superoxide anion (O2•-), singlet oxygen, and hydroxyl radical (·OH). Simultaneously, NONOate releases nitric oxide (NO) gas upon the same laser irradiation, thereby engaging with IR780-induced ROS to facilitate the formation of peroxynitrite anion (ONOO-), ultimately inducing programmed cell death in cancer cells. Additionally, the perfluorocarbon component of our delivery system exhibits a notable affinity for oxygen and demonstrates efficient oxygen-carrying capabilities. Our results demonstrate that IR780-NO-PFH-Lip@M significantly enhances breast cancer cell toxicity, reducing proliferation and in vivo tumor growth through simultaneous heat, ROS, and RNS production. This study contributes valuable insights to the ongoing discourse on innovative strategies for advancing cancer therapeutics.

Gut microbiome and metabolome profiling in Framingham heart study reveals cholesterol-metabolizing bacteria.

Accumulating evidence suggests that cardiovascular disease (CVD) is associated with an altered gut microbiome. Our understanding of the underlying mechanisms has been hindered by lack of matched multi-omic data with diagnostic biomarkers. To comprehensively profile gut microbiome contributions to CVD, we generated stool metagenomics and metabolomics from 1,429 Framingham Heart Study participants. We identified blood lipids and cardiovascular health measurements associated with microbiome and metabolome composition. Integrated analysis revealed microbial pathways implicated in CVD, including flavonoid, γ-butyrobetaine, and cholesterol metabolism. Species from the Oscillibacter genus were associated with decreased fecal and plasma cholesterol levels. Using functional prediction and in vitro characterization of multiple representative human gut Oscillibacter isolates, we uncovered conserved cholesterol-metabolizing capabilities, including glycosylation and dehydrogenation. These findings suggest that cholesterol metabolism is a broad property of phylogenetically diverse Oscillibacter spp., with potential benefits for lipid homeostasis and cardiovascular health.

Unveiling the therapeutic potential of Dl-3-n-butylphthalide in NTG-induced migraine mouse: activating the Nrf2 pathway to alleviate oxidative stress and neuroinflammation.

BACKGROUND: Migraine stands as a prevalent primary headache disorder, with prior research highlighting the significant involvement of oxidative stress and inflammatory pathways in its pathogenesis and chronicity. Existing evidence indicates the capacity of Dl-3-n-butylphthalide (NBP) to mitigate oxidative stress and inflammation, thereby conferring neuroprotective benefits in many central nervous system diseases. However, the specific therapeutic implications of NBP in the context of migraine remain to be elucidated. METHODS: We established a C57BL/6 mouse model of chronic migraine (CM) using recurrent intraperitoneal injections of nitroglycerin (NTG, 10 mg/kg), and prophylactic treatment was simulated by administering NBP (30 mg/kg, 60 mg/kg, 120 mg/kg) by gavage prior to each NTG injection. Mechanical threshold was assessed using von Frey fibers, and photophobia and anxious behaviours were assessed using a light/dark box and elevated plus maze. Expression of c-Fos, calcitonin gene-related peptide (CGRP), Nucleus factor erythroid 2-related factor 2 (Nrf2) and related pathway proteins in the spinal trigeminal nucleus caudalis (SP5C) were detected by Western blotting (WB) or immunofluorescence (IF). The expression of IL-1ß, IL-6, TNF-α, Superoxide dismutase (SOD) and malondialdehyde (MDA) in SP5C and CGRP in plasma were detected by ELISA. A reactive oxygen species (ROS) probe was used to detect the expression of ROS in the SP5C. RESULTS: At the end of the modelling period, chronic migraine mice showed significantly reduced mechanical nociceptive thresholds, as well as photophobic and anxious behaviours. Pretreatment with NBP attenuated nociceptive sensitization, photophobia, and anxiety in the model mice, reduced expression levels of c-Fos and CGRP in the SP5C and activated Nrf2 and its downstream proteins HO-1 and NQO-1. By measuring the associated cytokines, we also found that NBP reduced levels of oxidative stress and inflammation. Most importantly, the therapeutic effect of NBP was significantly reduced after the administration of ML385 to inhibit Nrf2. CONCLUSIONS: Our data suggest that NBP may alleviate migraine by activating the Nrf2 pathway to reduce oxidative stress and inflammation in migraine mouse models, confirming that it may be a potential drug for the treatment of migraine.

The crucial role of locus coeruleus noradrenergic neurons in the interaction between acute sleep disturbance and headache.

BACKGROUND: Both epidemiological and clinical studies have indicated that headache and sleep disturbances share a complex relationship. Although headache and sleep share common neurophysiological and anatomical foundations, the mechanism underlying their interaction remains poorly understood. The structures of the diencephalon and brainstem, particularly the locus coeruleus (LC), are the primary sites where the sleep and headache pathways intersect. To better understand the intricate nature of the relationship between headache and sleep, our study focused on investigating the role and function of noradrenergic neurons in the LC during acute headache and acute sleep disturbance. METHOD: To explore the relationship between acute headache and acute sleep disturbance, we primarily employed nitroglycerin (NTG)-induced migraine-like headache and acute sleep deprivation (ASD) models. Initially, we conducted experiments to confirm that ASD enhances headache and that acute headache can lead to acute sleep disturbance. Subsequently, we examined the separate roles of the LC in sleep and headache. We observed the effects of drug-induced activation and inhibition and chemogenetic manipulation of LC noradrenergic neurons on ASD-induced headache facilitation and acute headache-related sleep disturbance. This approach enabled us to demonstrate the bidirectional function of LC noradrenergic neurons. RESULTS: Our findings indicate that ASD facilitated the development of NTG-induced migraine-like headache, while acute headache affected sleep quality. Furthermore, activating the LC reduced the headache threshold and increased sleep latency, whereas inhibiting the LC had the opposite effect. Additional investigations demonstrated that activating LC noradrenergic neurons further intensified pain facilitation from ASD, while inhibiting these neurons reduced this pain facilitation. Moreover, activating LC noradrenergic neurons exacerbated the impact of acute headache on sleep quality, while inhibiting them alleviated this influence. CONCLUSION: The LC serves as a significant anatomical and functional region in the interaction between acute sleep disturbance and acute headache. The involvement of LC noradrenergic neurons is pivotal in facilitating headache triggered by ASD and influencing the effects of headache on sleep quality.

AMPK activation attenuates central sensitization in a recurrent nitroglycerin-induced chronic migraine mouse model by promoting microglial M2-type polarization.

BACKGROUND: Energy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM. METHODS: Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention. RESULTS: Repeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1ß, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway. CONCLUSIONS: AMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine.

Novel FOXP2 variant associated with speech and language dysfunction in a Chinese family and literature review.

Since its initial identification, the Forkhead Box P2 gene (FOXP2) has maintained its singular status as the archetypal monogenic determinant implicated in Mendelian forms of human speech and language impairments. Despite the passage of two decades subsequent to its discovery, extant literature remains disproportionately sparse with regard to case-specific instances and loci of mutational perturbations. The objective of the current investigation centers on furnishing an enriched delineation of both its clinical manifestations and its mutational heterogeneity. Clinical phenotypes and peripheral blood samples were assiduously amassed from familial subjects. Whole-exome sequencing and Sanger sequencing methodologies were deployed for the unambiguous identification of potential genetic variants and for corroborating their co-segregation within the family pedigree. An exhaustive review of published literature focusing on patients manifesting speech and language disorders consequent to FOXP2 genetic anomalies was also undertaken. The investigation yielded the identification of a novel heterozygous variant, c.661del (p.L221Ffs*41), localized within the FOXP2 gene in the proband, an inheritance from his symptomatic mother. The proband presented with an array of symptoms, encompassing dysarthric speech, deficits in instruction comprehension, and communicative impediments. In comparison, the mother exhibited attenuated symptoms, including rudimentary verbalization capabilities punctuated by pronounced stuttering and dysarthria. A comprehensive analysis of articles archived in the Human Gene Mutation Database (HGMD) classified under "DM" disclosed the existence of 74 patients inclusive of the subjects under current examination, sub-divided into 19 patients with null variants, 5 patients with missense variants, and 50 patients with gross deletions or complex genomic rearrangements. A conspicuous predominance of delayed speech, impoverished current verbal abilities, verbal comprehension deficits, and learning difficulties were observed in patients harboring null or missense FOXP2 variants, as compared to their counterparts with gross deletions or complex rearrangements. Developmental delays, hypotonia, and craniofacial aberrations were exclusive to the latter cohort. The elucidated findings augment the existing corpus of knowledge on the genetic architecture influencing both the proband and his mother within this specified familial context. Of critical importance, these discoveries furnish a robust molecular framework conducive to the prenatal diagnostic evaluations of prospective progeny within this familial lineage.

Achieving Bright and Long-Lived Aqueous Room-Temperature Phosphorescence of Carbon Nitrogen Dots Through In Situ Host-Guest Binding.

The development of bright and long-lived aqueous room-temperature phosphorescent (RTP) materials holds paramount importance in broadening the application scope of RTP material system. However, the conventional RTP materials usually exhibit low efficiency and short lifetime in aqueous solution. Herein, an in situ host-guest strategy is proposed to achieve cyanuric acid (CA)-derived phosphorescent carbon nitrogen dots (CNDs) composite (CNDs@CA) that demonstrates a significant enhancement of both quantum yield (QY) and lifetime mediated by water. Detailed investigations reveal that the robust hydrogen bonding networks between CNDs@CA and water effectively stabilize triplet excitons and suppress nonradiative decays, as well as facilitate efficient energy transfer from CA to CNDs, thereby prolonging the lifetime and enhancing the efficiency of RTP. The phosphorescent QY and lifetime of CNDs@CA can be increased to 26.89% (3.9-fold increase) and 951.25 ms (5.5-fold increase), respectively, with the incorporation of 50 wt% water under ambient conditions. Even in fully aqueous environments (with up to 400 wt% water added), CNDs@CA exhibits persistent water-boosted RTP properties, demonstrating exceptional stability. The robust water-boosted RTP property of CNDs@CA in aqueous solutions presents significant potential for high signal-to-noise ratio afterglow bioimaging as well as advanced information encryption.

Leukocyte telomere length and sarcopenia-related traits: A bidirectional Mendelian randomization study.

Accumulating evidence indicated that leukocyte telomere length (LTL) was related to sarcopenia. However, it is still not clear whether the association of changes in LTL with sarcopenia is likely to be causal, or could be explained by reverse causality. Thus, we carried on bidirectional Mendelian randomization (MR) and multivariable MR analyses to identify the causal relationship between LTL and sarcopenia-related traits. Summary-level data and independent variants used as instruments came from large genome-wide association studies of LTL (472,174 participants), appendicular lean mass (450,243 participants), low grip strength (256,523 participants), and walking pace (450,967 participants). We identified suggestive association of longer LTL with larger appendicular lean mass [odds ratio (OR) = 1.053; 95% confidence interval (CI), 1.009-1.099; P = 0.018], and causal association of longer LTL with a lower risk of low grip strength (OR = 0.915; 95% CI, 0.860-0.974; P = 0.005). In the reverse MR analysis, we also observed a positive causal association between walking pace and LTL (OR = 1.252; 95% CI, 1.121-1.397; P < 0.001). Similar results can be repeated in sensitivity analyses. While in the multivariable MR analysis, the estimate of the impact of walking pace on LTL underwent a transformation after adjusting for T2DM (OR = 1.141; 95%CI: 0.989-1.317; P = 0.070). The current MR analysis supported a causal relationship between shorter telomere length and both low muscle mass and strength. Additionally, walking pace may affect LTL through T2DM.

Migraine-like headache in subjects with isolated Lambl's excrescences: a case series and literature review.

AIM: Lambl's excrescences are mobile, thin, fibrinous connective tissue strands typically found on left-sided cardiac values. Migraine is positively associated with structural cardiac anomalies. However, it remains unclear whether Lambl's excrescences are associated with migraine. METHODS: Retrospective review of 182 inpatients with Lambl's excrescences confirmed by transesophageal echocardiogram in Chinese PLA General Hospital since January 2010. Among them, those with isolated Lambl's excrescences presented with migraine-like headache were included. We collected information on the demographics and clinical profiles of all participants, and performed follow-up visits. RESULTS: A total of 8 patients presented with migraine-like headache among 15 patients with isolated Lambl's excrescences. They included 2 men and 6 women, with an average age of 44.63 ± 12.24 years. Among these patients, 3 had visual aura, and 6 manifested infarct-like lesions on magnetic resonance imaging, of which 2 developed lesions after first visit. During follow-up, 4 patients suffering from intervention for Lambl's excrescences dramatically reduced headache recurrence compared to the other 4 patients only receiving migraine preventive medications. CONCLUSIONS: This study supports the hypothesis that microemboli from isolated Lambl's excrescences could cause migraine-like headache. And intervention for Lambl's excrescences may be crucial for preventing headache recurrence.

This study supports the hypothesis that microemboli from isolated Lambl's excrescences could cause migraine-like headache.The small sample size study fails to make management recommendations.

Visible Light-Activated Ultralong-Lived Triplet Excitons of Carbon Dots for White-Light Manipulated Anti-Counterfeiting.

Room temperature phosphorescence (RTP) has emerged as an interesting but rare phenomenon with multiple potential applications in anti-counterfeiting, optoelectronic devices, and biosensing. Nevertheless, the pursuit of ultralong lifetimes of RTP under visible light excitation presents a significant challenge. Here, new phosphorescent materials that can be excited by visible light with record-long lifetimes are demonstrated, realized through embedding nitrogen doped carbon dots (N-CDs) into a poly(vinyl alcohol) (PVA) film. The RTP lifetime of the N-CDs@PVA film is remarkably extended to 2.1 s excited by 420 nm, representing the highest recorded value for visible light-excited phosphorescent materials. Theoretical and experimental studies reveal that the robust hydrogen bonding interactions can effectively reduce the non-radiative decay rate and radiative transition rate of triplet excitons, thus dramatically prolong the phosphorescence lifetime. Notably, the RTP emission of N-CDs@PVA film can also be activated by easily accessible low-power white-light-emitting diode. More significantly, the practical applications of the N-CDs@PVA film in state-of-the-art anti-counterfeiting security and optical information storage domains are further demonstrated. This research offers exciting opportunities for utilizing visible light-activated ultralong-lived RTP systems in a wide range of promising applications.

The emergence and prospects of carbon dots with solid-state photoluminescence for light-emitting diodes.

The significant features of carbon dots (CDs), such as bright and tunable photoluminescence, high thermal stability, and low toxicity, endow them with tremendous potential for application in next generation optoelectronics. Despite great progress achieved in the design of high-performance CDs so far, the practical applications in solid-state lighting and displays have been retarded by the aggregation-caused quenching (ACQ) effect ascribed to direct π-π interactions. This review provides a comprehensive overview of the recent progress made in solid-state CD emitters, including their synthesis, optical properties and applications in light-emitting diodes (LEDs). Their triplet-excited-state-involved properties, as well as their recent advances in phosphor-converted LEDs and electroluminescent LEDs, are mainly reviewed here. Finally, the prospects and challenges of solid-state CD-based LEDs are discussed with an eye on future development. We hope that this review will provide critical insights to inspire new exciting discoveries on solid-state CDs from both fundamental and practical standpoints so that the realization of their potential in optoelectronic areas can be facilitated.

Progression of Myopic Maculopathy Based on the ATN Classification System.

INTRODUCTION: Myopic maculopathy is a sight-threatening disease, which causes irreversible vision faults and central vision loss. The purpose of this study is evaluating the risk factors of the myopic maculopathy progression according to the ATN classification system. METHODS: Clinic data of 69 high myopia patients aged older than 40 years with a follow-up time of more than 2 years, who underwent fundus photography and OCT examination were retrospectively collected. Fundus changes were evaluated with ATN classification at the first and last follow-up times. The related factors affecting progress including axial length (AL), spherical equivalence (SE), subfoveal choroidal thickness (SFCT), disc-foveal distance (DFD), optic disc tilt, and parapapillary atrophy (PPA) were analyzed. RESULTS: This study included 69 high-myopia patients with mean age 54.29 ± 10.41 years. The progression rate of myopic maculopathy (MM) was approximately 25.56%. Elongated DFD (5.37 ± 0.11 mm vs. 4.86 ± 0.37 mm; p < 0.001) and thinner SFCT (138.52 ± 29.38 µm vs. 184.87 ± 48.72 µm; p = 0.008) at baseline were linked with MM progression. In multiple logistic regression analysis, DFD was a substantial hazard risk factor (adjusted OR = 1.672, 95% CI: 1.135-2.498, p < 0.05) after adjusting for age, AL and SFCT. Receiver operating characteristic curve showed that DFD might serve as a predictor to discriminate the MM progression with a cut-off value of 5.15 mm and a substantial receiver operating characteristic curve area (AUC: 0.794). Compared with the non-progression group, the progression group had older age (p < 0.001), longer AL (p = 0.001), higher optic disc tilt rate (p < 0.001), and higher proportion of pre-existing PPA (p = 0.038) at baseline, the differences were statistically significant. CONCLUSION: Based on the ATN classification system, we found that the progression of MM was related to older age, longer AL, high disc tilt, pre-existing PPA, thinner SFCT, and longer DFD. The parameter of DFD was an important factor affecting the progression of MM, which is considered to have a higher probability of progression when the length is beyond 5.15 mm.

Dopaminergic Projections from the Hypothalamic A11 Nucleus to the Spinal Trigeminal Nucleus Are Involved in Bidirectional Migraine Modulation.

Clinical imaging studies have revealed that the hypothalamus is activated in migraine patients prior to the onset of and during headache and have also shown that the hypothalamus has increased functional connectivity with the spinal trigeminal nucleus. The dopaminergic system of the hypothalamus plays an important role, and the dopamine-rich A11 nucleus may play an important role in migraine pathogenesis. We used intraperitoneal injections of glyceryl trinitrate to establish a model of acute migraine attack and chronicity in mice, which was verified by photophobia experiments and von Frey experiments. We explored the A11 nucleus and its downstream pathway using immunohistochemical staining and neuronal tracing techniques. During acute migraine attack and chronification, c-fos expression in GABAergic neurons in the A11 nucleus was significantly increased, and inhibition of DA neurons was achieved by binding to GABA A-type receptors on the surface of dopaminergic neurons in the A11 nucleus. However, the expression of tyrosine hydroxylase and glutamic acid decarboxylase proteins in the A11 nucleus of the hypothalamus did not change significantly. Specific destruction of dopaminergic neurons in the A11 nucleus of mice resulted in severe nociceptive sensitization and photophobic behavior. The expression levels of the D1 dopamine receptor and D2 dopamine receptor in the caudal part of the spinal trigeminal nucleus candalis of the chronic migraine model were increased. Skin nociceptive sensitization of mice was slowed by activation of the D2 dopamine receptor in SP5C, and activation of the D1 dopamine receptor reversed this behavioral change. GABAergic neurons in the A11 nucleus were activated and exerted postsynaptic inhibitory effects, which led to a decrease in the amount of DA secreted by the A11 nucleus in the spinal trigeminal nucleus candalis. The reduced DA bound preferentially to the D2 dopamine receptor, thus exerting a defensive effect against headache.

Metafiber transforming arbitrarily structured light.

Structured light has proven useful for numerous photonic applications. However, the current use of structured light in optical fiber science and technology is severely limited by mode mixing or by the lack of optical elements that can be integrated onto fiber end-faces for wavefront engineering, and hence generation of structured light is still handled outside the fiber via bulky optics in free space. We report a metafiber platform capable of creating arbitrarily structured light on the hybrid-order Poincaré sphere. Polymeric metasurfaces, with unleashed height degree of freedom and a greatly expanded 3D meta-atom library, were 3D laser nanoprinted and interfaced with polarization-maintaining single-mode fibers. Multiple metasurfaces were interfaced on the fiber end-faces, transforming the fiber output into different structured-light fields, including cylindrical vector beams, circularly polarized vortex beams, and arbitrary vector field. Our work provides a paradigm for advancing optical fiber science and technology towards fiber-integrated light shaping, which may find important applications in fiber communications, fiber lasers and sensors, endoscopic imaging, fiber lithography, and lab-on-fiber technology.

Genetic vulnerability to Crohn's disease reveals a spatially resolved epithelial restitution program.

Effective tissue repair requires coordinated intercellular communication to sense damage, remodel the tissue, and restore function. Here, we dissected the healing response in the intestinal mucosa by mapping intercellular communication at single-cell resolution and integrating with spatial transcriptomics. We demonstrated that a risk variant for Crohn's disease, hepatocyte growth factor activator (HGFAC) Arg509His (R509H), disrupted a damage-sensing pathway connecting the coagulation cascade to growth factors that drive the differentiation of wound-associated epithelial (WAE) cells and production of a localized retinoic acid (RA) gradient to promote fibroblast-mediated tissue remodeling. Specifically, we showed that HGFAC R509H was activated by thrombin protease activity but exhibited impaired proteolytic activation of the growth factor macrophage-stimulating protein (MSP). In Hgfac R509H mice, reduced MSP activation in response to wounding of the colon resulted in impaired WAE cell induction and delayed healing. Through integration of single-cell transcriptomics and spatial transcriptomics, we demonstrated that WAE cells generated RA in a spatially restricted region of the wound site and that mucosal fibroblasts responded to this signal by producing extracellular matrix and growth factors. We further dissected this WAE cell-fibroblast signaling circuit in vitro using a genetically tractable organoid coculture model. Collectively, these studies exploited a genetic perturbation associated with human disease to disrupt a fundamental biological process and then reconstructed a spatially resolved mechanistic model of tissue healing.