Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

Resolving the overlooked photochemical nitrophenol transformation mechanism induced by nonradical species under visible light.

Nitrophenols present on the surface of particulates are ubiquitous in the atmosphere. However, its atmospheric photochemical transformation pathway remains unknown, for which the crucial effect of visible light is largely overlooked, resulting in an incomplete understanding of the effects of nitrophenols in the atmospheric environment. This study delves into the photolysis mechanism of 4-nitrophenol (4NP), one of the most abundant atmospheric nitrophenol compounds, on the surface of photoactive particulates under visible light irradiation. Unexpectedly, the nonradical species (singlet oxygen, 1O2) was identified as a dominant factor in driving the visible photolysis of 4NP. The pathways of HONO and p-benzoquinone (C6H4O2) generation were clarified by acquiring direct evidence of C-N and O-H bond breakage in the nitro (-NO2) and hydroxyl (-OH) groups of 4NP. The further decomposition of HONO results in the generation of NO and hydroxyl radicals, which could directly contribute to atmospheric oxidizing capacity and complicate the PM2.5 composition. Significantly, the behavior of 1O2-induced visible photolysis of 4NP was universal on the surface of common particulates in the atmosphere, such as A1 dust and Fe2O3. This work advances the understanding of the photochemical transformation mechanism of particulate-phase atmospheric nitrophenols, which is indispensable in elucidating the role of nitrophenols in atmospheric chemistry.

Inflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity.

Inflammation causes pain by shifting the balance of ionic currents in nociceptors toward depolarization, leading to hyperexcitability. The ensemble of ion channels within the plasma membrane is regulated by processes including biogenesis, transport, and degradation. Thus, alterations in ion channel trafficking may influence excitability. Sodium channel NaV1.7 and potassium channel KV7.2 promote and oppose excitability in nociceptors, respectively. We used live-cell imaging to investigate mechanisms by which inflammatory mediators (IM) modulate the abundance of these channels at axonal surfaces through transcription, vesicular loading, axonal transport, exocytosis, and endocytosis. Inflammatory mediators induced a NaV1.7-dependent increase in activity in distal axons. Further, inflammation increased the abundance of NaV1.7, but not of KV7.2, at axonal surfaces by selectively increasing channel loading into anterograde transport vesicles and insertion at the membrane, without affecting retrograde transport. These results uncover a cell biological mechanism for inflammatory pain and suggest NaV1.7 trafficking as a potential therapeutic target.

Molecular interactions of the chaperone CcmS and carboxysome shell protein CcmK1 that mediate ß-carboxysome assembly.

The carboxysome is a natural proteinaceous organelle for carbon fixation in cyanobacteria and chemoautotrophs. It comprises hundreds of protein homologs that self-assemble to form a polyhedral shell structure to sequester cargo enzymes, ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) and carbonic anhydrases. How these protein components assemble to construct a functional carboxysome is a central question in not only understanding carboxysome structure and function but also synthetic engineering of carboxysomes for biotechnological applications. Here, we determined the structure of the chaperone protein CcmS, which has recently been identified to be involved in ß-carboxysome assembly, and its interactions with ß-carboxysome proteins. The crystal structure at 1.99 Å resolution reveals CcmS from Nostoc sp. PCC 7120 forms a homodimer, and each CcmS monomer consists of five α-helices and four ß-sheets. Biochemical assays indicate that CcmS specifically interacts with the C-terminal extension of the carboxysome shell protein CcmK1, but not the shell protein homolog CcmK2 or the carboxysome scaffolding protein CcmM. Moreover, we solved the structure of a stable complex of CcmS and the C-terminus of CcmK1 at 1.67 Å resolution and unveiled how the CcmS dimer interacts with the C-terminus of CcmK1. These findings allowed us to propose a model to illustrate CcmS-mediated ß-carboxysome assembly by interacting with CcmK1 at the outer shell surface. Collectively, our study provides detailed insights into the accessory factors that drive and regulate carboxysome assembly, thereby improving our knowledge of carboxysome structure, function, and bioengineering.

miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts.

MicroRNAs and heterogeneous ribonucleoproteins (hnRNPs) are posttranscriptional gene regulators that bind mRNA in a sequence-specific manner. Here, we report that loss of miR-328 occurs in blast crisis chronic myelogenous leukemia (CML-BC) in a BCR/ABL dose- and kinase-dependent manner through the MAPK-hnRNP E2 pathway. Restoration of miR-328 expression rescues differentiation and impairs survival of leukemic blasts by simultaneously interacting with the translational regulator poly(rC)-binding protein hnRNP E2 and with the mRNA encoding the survival factor PIM1, respectively. The interaction with hnRNP E2 is independent of the microRNA's seed sequence and it leads to release of CEBPA mRNA from hnRNP E2-mediated translational inhibition. Altogether, these data reveal the dual ability of a microRNA to control cell fate both through base pairing with mRNA targets and through a decoy activity that interferes with the function of regulatory proteins.

The fates of internalized NaV1.7 channels in sensory neurons: Retrograde cotransport with other ion channels, axon-specific recycling, and degradation.

Neuronal function relies on the maintenance of appropriate levels of various ion channels at the cell membrane, which is accomplished by balancing secretory, degradative, and recycling pathways. Neuronal function further depends on membrane specialization through polarized distribution of specific proteins to distinct neuronal compartments such as axons. Voltage-gated sodium channel NaV1.7, a threshold channel for firing action potentials in nociceptors, plays a major role in human pain, and its abundance in the plasma membrane is tightly regulated. We have recently characterized the anterograde axonal trafficking of NaV1.7 channels in Rab6A-positive vesicles, but the fate of internalized channels is not known. Membrane proteins that have undergone endocytosis can be directed into multiple pathways including those for degradation, recycling to the membrane, and transcytosis. Here, we demonstrate NaV1.7 endocytosis and dynein-dependent retrograde trafficking in Rab7-containing late endosomes together with other axonal membrane proteins using real-time imaging of live neurons. We show that some internalized NaV1.7 channels are delivered to lysosomes within the cell body, and that there is no evidence for NaV1.7 transcytosis. In addition, we show that NaV1.7 is recycled specifically to the axonal membrane as opposed to the soma membrane, suggesting a novel mechanism for the development of neuronal polarity. Together, these results shed light on the mechanisms by which neurons maintain excitable membranes and may inform efforts to target ion channel trafficking for the treatment of disorders of excitability.

Multi-cohort validation of Ascore: an anoikis-based prognostic signature for predicting disease progression and immunotherapy response in bladder cancer.

Bladder cancer ranks as the 10th most common cancer worldwide, with deteriorating prognosis as the disease advances. While immune checkpoint inhibitors (ICIs) have shown promise in clinical therapy in both operable and advanced bladder cancer, identifying patients who will respond is challenging. Anoikis, a specialized form of cell death that occurs when cells detach from the extracellular matrix, is closely linked to tumor progression. Here, we aimed to explore the anoikis-based biomarkers for bladder cancer prognosis and immunotherapeutic decisions. Through consensus clustering, we categorized patients from the TCGA-BLCA cohort into two clusters based on anoikis-related genes (ARGs). Significant differences in survival outcome, clinical features, tumor immune environment (TIME), and potential ICIs response were observed between clusters. We then formulated a four-gene signature, termed "Ascore", to encapsulate this gene expression pattern. The Ascore was found to be closely associated with survival outcome and served as an independent prognosticator in both the TCGA-BLCA cohort and the IMvigor210 cohort. It also demonstrated superior predictive capacity (AUC = 0.717) for bladder cancer immunotherapy response compared to biomarkers like TMB and PD-L1. Finally, we evaluated Ascore's independent prognostic performance as a non-invasive biomarker in our clinical cohort (Gulou-Cohort1) using circulating tumor cells detection, achieving an AUC of 0.803. Another clinical cohort (Gulou-Cohort2) consisted of 40 patients undergoing neoadjuvant anti-PD-1 treatment was also examined. Immunohistochemistry of Ascore in these patients revealed its correlation with the pathological response to bladder cancer immunotherapy (P = 0.004). Impressively, Ascore (AUC = 0.913) surpassed PD-L1 (AUC = 0.662) in forecasting immunotherapy response and indicated better net benefit. In conclusion, our study introduces Ascore as a novel, robust prognostic biomarker for bladder cancer, offering a new tool for enhancing immunotherapy decisions and contributing to the tailored treatment approaches in this field.

Constructing Directional Electrostatic Potential Difference via Gradient Nitrogen Doping for Efficient Oxygen Reduction Reaction.

Nitrogen doping has been recognized as an important strategy to enhance the oxygen reduction reaction (ORR) activity of carbon-encapsulated transition metal catalysts (TM@C). However, previous reports on nitrogen doping have tended to result in a random distribution of nitrogen atoms, which leads to disordered electrostatic potential differences on the surface of carbon layers, limiting further control over the materials' electronic structure. Herein, a gradient nitrogen doping strategy to prepare nitrogen-deficient graphene and nitrogen-rich carbon nanotubes encapsulated cobalt nanoparticles catalysts (Co@CNTs@NG) is proposed. The unique gradient nitrogen doping leads to a gradual increase in the electrostatic potential of the carbon layer from the nitrogen-rich region to the nitrogen-deficient region, facilitating the directed electron transfer within these layers and ultimately optimizing the charge distribution of the material. Therefore, this strategy effectively regulates the density of state and work function of the material, further optimizing the adsorption of oxygen-containing intermediates and enhancing ORR activity. Theoretical and experimental results show that under controlled gradient nitrogen doping, Co@CNTs@NG exhibits significantly ORR performance (Eonset = 0.96 V, E1/2 = 0.86 V). At the same time, Co@CNTs@NG also displays excellent performance as a cathode material for Zn-air batteries, with peak power density of 132.65 mA cm-2 and open-circuit voltage (OCV) of 1.51 V. This work provides an effective gradient nitrogen doping strategy to optimize the ORR performance.

Characteristics of human papillomavirus prevalence and infection patterns among women aged 25-64 according to age groups and cytology results in Ordos City, China.

BACKGROUND: The assessment of human papillomavirus (HPV) genotype distribution in terms of age and cervical lesions could contribute to the adoption of more targeted preventive approaches to specific populations against cervical cancer. The current study was conducted in Ordos City, China, with the aim of analyzing the HPV genotypes prevalence and infection patterns within a hospital-based population. METHODS: The analysis included a total of 26,692 women aged 25-64 who underwent cervical cancer screening between January 1st, 2019, and June 30th, 2022, in Ordos City. These women had valid results for both the polymerase chain reaction (PCR)-reverse dot blot (RDB) HPV test and the liquid-based cytology (thinprep cytologic test/TCT). Data were extracted from the database of KingMed Diagnostics laboratories. The prevalence of HPV genotypes within different age groups and cytology diagnoses were calculated. RESULTS: Among 26,692 women, 7136 (26.73%) women were HPV positive, 5696 (21.34%) women were high-risk HPV (HR-HPV) positive, and 2102 (7.88%) women had multiple HPV infections. The most frequently detected HPV genotypes were HPV16 (4.72%) and HPV52 (4.15%), ranking as the first and second most prevalent genotypes, respectively. The prevalence of HR-HPV increased with age groups and severity of cervical lesions. Notably, the positive rate of HR-HPV among women aged 35-64 years showed a decreasing trend over the respective years, ranging from 26.00 to 19.70% (Ptrend < 0.001). CONCLUSION: In conclusion, the epidemiology of HPV genotypes partly reflects the effectiveness of regional cervical cancer prevention and control efforts in the past. These findings can inform future initiatives concerning HPV vaccination and screening in the region.

Dissecting the Photochemical Reactivity of Metal Ions during Atmospheric Nitrate Transformations on Photoactive Mineral Dust.

Dissecting the photochemical reactivity of metal ions is a significant contribution to understanding secondary pollutant formation, as they have a role to be reckoned with atmospheric chemistry. However, their photochemical reactivity has received limited attention within the active nitrogen cycle, particularly at the gas-solid interface. In this study, we delve into the contribution of magnesium ion (Mg2+) and ferric ion (Fe3+) to nitrate decomposition on the surface of photoactive mineral dust. Under simulated sunlight irradiation, the observed NOX production rate differs by an order of magnitude in the presence of Mg2+ (6.02 × 10-10 mol s-1) and Fe3+ (2.07 × 10-11 mol s-1). The markedly decreased fluorescence lifetime induced by Mg2+ and the change in the valence of Fe3+ revealed that Mg2+ and Fe3+ significantly affect the concentration of nitrate decomposition products by distinct photochemical reactivity with photogenerated electrons. Mg2+ promotes NOX production by accelerating charge transfer, while Fe3+ hinders nitrate decomposition by engaging in a redox cyclic reaction with Fe2+ to consume photogenerated carriers continuously. Furthermore, when Fe3+ coexists with other metal ions (e.g., Mg2+, Ca2+, Na+, and K+) and surpasses a proportion of approximately 12%, the photochemical reactivity of Fe3+ tends to be dominant in depleting photogenerated electrons and suppressing nitrate decomposition. Conversely, below this threshold, the released NOX concentration increases sharply as the proportion of Fe3+ decreases. This research offers valuable insights into the role of metal ions in nitrate transformation and the generation of reactive nitrogen species, contributing to a deep understanding of atmospheric photochemical reactions.

Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability.

Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. NaV1.7 has been genetically and functionally validated as a mediator of pain. Preclinical studies of NaV1.7-selective blockers have shown limited success and translation to clinical studies has been limited. The degree of NaV1.7 channel blockade necessary to attenuate neuronal excitability and ameliorate pain is an unanswered question important for drug discovery. Here, we utilize dynamic clamp electrophysiology and induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) to answer this question for inherited erythromelalgia, a pain disorder caused by gain-of-function mutations in Nav1.7. We show that dynamic clamp can produce hyperexcitability in iPSC-SNs associated with two different inherited erythromelalgia mutations, NaV1.7-S241T and NaV1.7-I848T. We further show that blockade of approximately 50% of NaV1.7 currents can reverse neuronal hyperexcitability to baseline levels.

Knowledge, Attitude, and Uptake of Human Papillomavirus (HPV) Vaccination among Chinese Female Adults: A National Cross-sectional Web-Based Survey Based on a Large E-commerce Platform.

BACKGROUND: Human papillomavirus (HPV) vaccination is a promising step toward cervical cancer elimination. This study was conducted to investigate the knowledge, attitude, and HPV vaccine uptake among female adults in mainland China based on a large e-commerce platform. METHODS: We conducted a cross-sectional online survey of female adults between March 4 to April 20, 2022. The survey consisted of sociodemographic information, related knowledge, vaccination uptake, and attitudes toward vaccination. We included women aged 18-45 years in the final analysis. Logistic regressions were conducted to explore influencing factors associated with related knowledge, HPV vaccination uptake, and willingness to be vaccinated. RESULTS: In total, 3,572 female adults (34 years, IQR 30-39) were included in the analysis. The majority of the participants were highly educated (78.7%) with a high monthly family income (79.0%). The median HPV knowledge score was 8.25 out of 11. More than 75% of respondents were unvaccinated, while 95.8% of unvaccinated female adults are willing to be vaccinated. Variables such as age, insurance, vaccination history, and whether one had heard of the HPV vaccine influence HPV vaccination practice (all p-values < 0.05). The main barriers to vaccination were vaccine inaccessibility and the high cost of the vaccine. CONCLUSION: The findings of our study highlight a moderate knowledge level, poor vaccination rate, and strong willingness to be vaccinated among Chinese female adults who were better educated and wealthier. Targeted health education and practical support should be provided in the future, to reduce gaps between vaccine uptake and vaccine acceptance.

Discovery of Novel Marine-Derived Phidiandine/Lipoic Acid Hybrid as a Potential Anti-Atherosclerosis Agent: Design, Synthesis and in Vitro/in Vivo Evaluation.

In the present study, a novel derivative, IOP-LA, was prepared by hybridizing antioxidant lipoic acid (LA) and our recently reported antioxidative marine phidianidine B-inspired indole/1,2,4-oxadiazole derivative. Our results demonstrated that IOP-LA could protect vascular endothelial cells (VECs) from oxidized low-density lipoprotein (oxLDL)-induced oxidative stress by activating the Nrf2 pathway, inhibit the production of atherosclerotic plaque, and promote the stability of atherosclerotic plaque in apoE-/- mice. Moreover, the protective effect of IOP-LA was superior to LA at the same concentration. Mechanistic studies revealed that IOP-LA significantly inhibited the increase of reactive oxygen species (ROS) levels and the translocation of nuclear factor kappa-B (NF-κB) nuclear induced by oxLDL through the nuclear factor erythroid2-related factor 2 (Nrf2) pathway. In summary, the data demonstrate that IOP-LA, as a new antioxidant, protects VECs from oxLDL-induced oxidative stress by activating the Nrf2 pathway. It is worth noting that this study provides a promising lead compound for the prevention and treatment of atherosclerosis.

Association of the dietary inflammation index DII with the prevalence of chronic kidney disease in patients with hypertension.

BACKGROUND AND OBJECTIVE: Chronic kidney disease (CKD) is a global health concern that is frequently associated with hypertension. Inflammation is an important factor in the development of both illnesses. The Dietary Inflammation Index (DII) has evolved as a way to measure how much a diet can cause inflammation, which may impact CKD, especially in hypertensive persons. The study's goal is to investigate the link between DII and the occurrence of CKD in hypertensive individuals. METHODS: This study examined data from 22940 hypertensive patients from 1999 to 2018 of the National Health and Nutrition Examination Survey (NHANES). The DII was computed using 28 dietary components. CKD was diagnosed based on the estimated glomerular filtration rate and urine albumin-to-creatinine ratio. The link between DII and CKD was explored using sampling-weighted logistic regression and restricted cubic splines. RESULTS: Higher DII scores were shown to be strongly related with an increased risk of CKD. In the fully adjusted model, this connection remained consistent across demographic and clinical categories. CONCLUSIONS: The study found a strong association between a pro-inflammatory diet and an elevated risk of CKD in hypertensive individuals, emphasizing the potential of dietary changes in CKD management.

Accelerated Reversible Conversion of Li2S2 to Li2S by Spidroin Regulated Li+ Flux for High-performance Li-Sulfur Batteries.

Regulating the transformation of sulfur species is the key to improving the electrochemical performance of lithium-sulfur (Li-S) batteries, in particular, to accelerate the reversible conversion between solid phase Li2S2 and Li2S. Herein, we introduced Spidroin, which is a main protein in spider silk, as a dual functional separator coating in Li-S batteries to effectively adsorb polysulfides via the sequence of amino acids in its primary structure and regulate Li+ flux through the ß-sheet of its secondary structure, thus accelerating the reversible transformation between Li2S2 and Li2S. Spidroin-based Li-S cells exhibited an exceptional electrochemical performance with a high specific capacity of  744.1 mAh g-1 at 5C and a high areal capacity of 7.5 mAh cm-2 at a low electrolyte-to-sulfur (E/S) ratio of 6 µL mgs-1 and a sulfur loading of 8.6 mgs cm-2.

Depolarizing NaV and hyperpolarizing KV channels are co-trafficked in sensory neurons.

Neuronal excitability relies on coordinated action of functionally distinct ion channels. Voltage-gated sodium (NaV) and potassium (KV) channels have distinct but complementary roles in firing action potentials: NaV channels provide depolarizing current while KV channels provide hyperpolarizing current. Mutations and dysfunction of multiple NaV and KV channels underlie disorders of excitability, including pain and epilepsy. Modulating ion channel trafficking may offer a potential therapeutic strategy for these diseases. A fundamental question, however, is whether these channels with distinct functional roles are transported independently or packaged together in the same vesicles in sensory axons. We have used Optical Pulse-Chase Axonal Long-distance (OPAL) imaging to investigate trafficking of NaV and KV channels and other axonal proteins from distinct functional classes in live rodent sensory neurons (from male and female rats). We show that, similar to NaV1.7 channels, NaV1.8 and KV7.2 channels are transported in Rab6a-positive vesicles, and that each of the NaV channel isoforms expressed in healthy, mature sensory neurons - NaV1.6, NaV1.7, NaV1.8, and NaV1.9 - are co-transported in the same vesicles. Further, we show that multiple axonal membrane proteins with different physiological functions - NaV1.7, KV7.2, and TNFR1 - are co-transported in the same vesicles. However, vesicular packaging of axonal membrane proteins is not indiscriminate, since another axonal membrane protein - NCX2 - is transported in separate vesicles. These results shed new light on the development and organization of sensory neuron membranes, revealing complex sorting of axonal proteins with diverse physiological functions into specific transport vesicles.Significance StatementNormal neuronal excitability is dependent on precise regulation of membrane proteins including NaV and KV channels, and imbalance in the level of these channels at the plasma membrane could lead to excitability disorders. Ion channel trafficking could potentially be targeted therapeutically, which would require better understanding of the mechanisms underlying trafficking of functionally diverse channels. Optical Pulse-chase Axonal Long-distance (OPAL) imaging in live neurons permitted examination of the specificity of ion channel trafficking, revealing co-packaging of axonal proteins with opposing physiological functions into the same transport vesicles. This suggests that additional trafficking mechanisms are necessary to regulate levels of surface channels and reveals an important consideration for therapeutic strategies that target ion channel trafficking for the treatment of excitability disorders.

Ih current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain.

We show here that hyperpolarization-activated current (Ih ) unexpectedly acts to inhibit the activity of dorsal root ganglion (DRG) neurons expressing WT Nav1.7, the largest inward current and primary driver of DRG neuronal firing, and hyperexcitable DRG neurons expressing a gain-of-function Nav1.7 mutation that causes inherited erythromelalgia (IEM), a human genetic model of neuropathic pain. In this study we created a kinetic model of Ih and used it, in combination with dynamic-clamp, to study Ih function in DRG neurons. We show, for the first time, that Ih increases rheobase and reduces the firing probability in small DRG neurons, and demonstrate that the amplitude of subthreshold oscillations is reduced by Ih . Our results show that Ih , due to slow gating, is not deactivated during action potentials (APs) and has a striking damping action, which reverses from depolarizing to hyperpolarizing, close to the threshold for AP generation. Moreover, we show that Ih reverses the hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes IEM. In the aggregate, our results show that Ih unexpectedly has strikingly different effects in DRG neurons as compared to previously- and well-studied cardiac cells. Within DRG neurons where Nav1.7 is present, Ih reduces depolarizing sodium current inflow due to enhancement of Nav1.7 channel fast inactivation and creates additional damping action by reversal of Ih direction from depolarizing to hyperpolarizing close to the threshold for AP generation. These actions of Ih limit the firing of DRG neurons expressing WT Nav1.7 and reverse the hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes IEM. KEY POINTS: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, the molecular determinants of hyperpolarization-activated current (Ih ) have been characterized as a 'pain pacemaker', and thus considered to be a potential molecular target for pain therapeutics. Dorsal root ganglion (DRG) neurons express Nav1.7, a channel that is not present in central neurons or cardiac tissue. Gain-of-function mutations (GOF) of Nav1.7 identified in inherited erythromelalgia (IEM), a human genetic model of neuropathic pain, produce DRG neuron hyperexcitability, which in turn produces severe pain. We found that Ih increases rheobase and reduces firing probability in small DRG neurons expressing WT Nav1.7, and demonstrate that the amplitude of subthreshold oscillations is reduced by Ih . We also demonstrate that Ih reverses the hyperexcitability of DRG neurons expressing a GOF Nav1.7 mutation (L858H) that causes IEM. Our results show that, in contrast to cardiac cells and CNS neurons, Ih acts to stabilize DRG neuron excitability and prevents excessive firing.

Interleukin 4-driven reversal of self-reactive B cell anergy contributes to the pathogenesis of systemic lupus erythematosus.

OBJECTIVES: Reactivation of anergic autoreactive B cells (BND cells) is a key aetiological process in systemic lupus erythematosus (SLE), yet the underlying mechanism remains largely elusive. This study aimed to investigate how BND cells participate in the pathogenesis of SLE and the underlying mechanism. METHODS: A combination of phenotypical, large-scale transcriptome and B cell receptor (BCR) repertoire profiling were employed at molecular and single cell level on samples from healthy donors and patients with SLE. Isolated naïve B cells from human periphery blood were treated with anti-CD79b mAb in vitro to induce anergy. IgM internalisation was tracked by confocal microscopy and was qualified by flow cytometer. RESULTS: We characterised the decrease and disruption of BND cells in SLE patients and demonstrated IL-4 as an important cytokine to drive such pathological changes. We then elucidated that IL-4 reversed B cell anergy by promoting BCR recycling to the cell surface via STAT6 signalling. CONCLUSIONS: We demonstrated the significance of IL-4 in reversing B cell anergy and established the scientific rationale to treat SLE via blocking IL-4 signalling, also providing diagnostic and prognostic biomarkers to identify patients who are most likely going to benefit from such treatments.

Cyclosporin A improves the hyperosmotic response in an experimental dry eye model by inhibiting the HMGB1/TLR4/NF-κB signaling pathway.

Hyperosmolarity is closely related to dry eye disease (DED), which induces corneal epithelial cell structure and dysfunction leading to ocular surface inflammation. Cyclosporine A (CSA) is a cyclopeptide consisting of 11 deduced amino acids. It has an immunosuppressive effect and shows a vital function in inhibiting the inflammatory response. The mechanism of CSA in DED is still not entirely clear. This experiment aimed to investigate the possible mechanism of CSA in the hyperosmotic DED model. This study found that CSA can inhibit the transcript levels of DED high mobility group protein 1 (HMGB1), Toll-like receptor 4 (TLR4) and nuclear transcription factor κB (NF-κB) in signaling pathways. In addition, the study also found that 550 mOsm/L can induce the formation of DED models in vivo or in vitro. Furthermore, different concentrations of CSA have different effects on the expression of HMGB1 in human corneal epithelial cells under hyperosmotic stimulation, and high concentrations of CSA may increase the expression of HMGB1. In addition, CSA effectively reduced the corneal fluorescence staining score of the DE group and increased the tear volume of mice. Therefore, this experimental investigation might supply new evidence for the mechanism of CSA in DED, provide a potential new therapy for treating DED, and provide a theoretical basis for CSA treatment of DED.

Acute uveitis caused by abnormal glucose and lipid metabolism: a case report.

PURPOSE: This report describes a rare case of acute uveitis with severe anterior chamber inflammation due to abnormal glucose and lipid metabolism. CASE PRESENTATION: A 31-year-old male patient complained of redness in the right eye with decreased visual acuity for 3 days. Ocular examination revealed a milky white clouding of the right anterior chamber of the eye. Two clusters of yellowish-white exudates were visible on the surface of the iris in the upper nasal and temporal areas in addition to elevated intraocular pressure. He had a previous diagnosis of type 2 diabetes mellitus (T2DM). Laboratory tests suggested hyperlipidemia and ketoacidosis. After admission, topical glucocorticoids, mydriasis, and intraocular pressure-lowering drugs combined with hypoglycemic and lipid-lowering therapy and fluid replacement therapy were given immediately. After 10 days of treatment, the uveitis and systemic condition of the right eye were effectively controlled and improved. CONCLUSION: Abnormal glucose and lipid metabolism leads to impairment of the blood-aqueous barrier, which causes a severe uveitis response in the anterior chamber. After the use of topical steroids and mydriatic eye drops combined with systemic hypoglycemic and lipid-lowering interventions, the condition was significantly relieved.