Cell-Surface Proteomic Profiling in the Fly Brain Uncovers Wiring Regulators.

Molecular interactions at the cellular interface mediate organized assembly of single cells into tissues and, thus, govern the development and physiology of multicellular organisms. Here, we developed a cell-type-specific, spatiotemporally resolved approach to profile cell-surface proteomes in intact tissues. Quantitative profiling of cell-surface proteomes of Drosophila olfactory projection neurons (PNs) in pupae and adults revealed global downregulation of wiring molecules and upregulation of synaptic molecules in the transition from developing to mature PNs. A proteome-instructed in vivo screen identified 20 cell-surface molecules regulating neural circuit assembly, many of which belong to evolutionarily conserved protein families not previously linked to neural development. Genetic analysis further revealed that the lipoprotein receptor LRP1 cell-autonomously controls PN dendrite targeting, contributing to the formation of a precise olfactory map. These findings highlight the power of temporally resolved in situ cell-surface proteomic profiling in discovering regulators of brain wiring.

Classifying Drosophila Olfactory Projection Neuron Subtypes by Single-Cell RNA Sequencing.

The definition of neuronal type and how it relates to the transcriptome are open questions. Drosophila olfactory projection neurons (PNs) are among the best-characterized neuronal types: different PN classes target dendrites to distinct olfactory glomeruli, while PNs of the same class exhibit indistinguishable anatomical and physiological properties. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomes of most PN classes and unequivocally mapped transcriptomes to specific olfactory function for six classes. Transcriptomes of closely related PN classes exhibit the largest differences during circuit assembly but become indistinguishable in adults, suggesting that neuronal subtype diversity peaks during development. Transcription factors and cell-surface molecules are the most differentially expressed genes between classes and are highly informative in encoding cell identity, enabling us to identify a new lineage-specific transcription factor that instructs PN dendrite targeting. These findings establish that neuronal transcriptomic identity corresponds with anatomical and physiological identity defined by connectivity and function.

The TGF-ß superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation.

Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor ß1 (TGF-ß1) is instrumental for Th17 cell differentiation, it is dispensable for generation of pathogenic Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-ß superfamily member closely related to TGF-ß1, in pathogenic Th17 cell differentiation. Activin-A expression was increased in individuals with relapsing-remitting multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic Th17 cells and was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic Th17 cell differentiation in vitro and in vivo. Mechanistically, extracellular-signal-regulated kinase (ERK) phosphorylation, which was essential for pathogenic Th17 cell differentiation, was suppressed by TGF-ß1-ALK5 but not Activin-A-ALK4 signaling. Thus, Activin-A drives pathogenic Th17 cell differentiation, implicating the Activin-A-ALK4-ERK axis as a therapeutic target for Th17 cell-related diseases.

RAS P21 Protein Activator 3 (RASA3) Specifically Promotes Pathogenic T Helper 17 Cell Generation by Repressing T-Helper-2-Cell-Biased Programs.

Pathogenic Th17 (pTh17) cells drive inflammation and immune-pathology, but whether pTh17 cells are a Th17 cell subset whose generation is under specific molecular control remains unaddressed. We found that Ras p21 protein activator 3 (RASA3) was highly expressed by pTh17 cells relative to non-pTh17 cells and was required specifically for pTh17 generation in vitro and in vivo. Mice conditionally deficient for Rasa3 in T cells showed less pathology during experimental autoimmune encephalomyelitis. Rasa3-deficient T cells acquired a Th2 cell-biased program that dominantly trans-suppressed pTh17 cell generation via interleukin 4 production. The Th2 cell bias of Rasa3-deficient T cells was due to aberrantly elevated transcription factor IRF4 expression. RASA3 promoted proteasome-mediated IRF4 protein degradation by facilitating interaction of IRF4 with E3-ubiquitin ligase Cbl-b. Therefore, a RASA3-IRF4-Cbl-b pathway specifically directs pTh17 cell generation by balancing reciprocal Th17-Th2 cell programs. These findings indicate that a distinct molecular program directs pTh17 cell generation and reveals targets for treating pTh17 cell-related pathology and diseases.

Body mass index, waist circumference, and mortality in subjects older than 80 years: a Mendelian randomization study.

BACKGROUND AND AIMS: Emerging evidence has raised an obesity paradox in observational studies of body mass index (BMI) and health among the oldest-old (aged ≥80 years), as an inverse relationship of BMI with mortality was reported. This study was to investigate the causal associations of BMI, waist circumference (WC), or both with mortality in the oldest-old people in China. METHODS: A total of 5306 community-based oldest-old (mean age 90.6 years) were enrolled in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) between 1998 and 2018. Genetic risk scores were constructed from 58 single-nucleotide polymorphisms (SNPs) associated with BMI and 49 SNPs associated with WC to subsequently derive causal estimates for Mendelian randomization (MR) models. One-sample linear MR along with non-linear MR analyses were performed to explore the associations of genetically predicted BMI, WC, and their joint effect with all-cause mortality, cardiovascular disease (CVD) mortality, and non-CVD mortality. RESULTS: During 24 337 person-years of follow-up, 3766 deaths were documented. In observational analyses, higher BMI and WC were both associated with decreased mortality risk [hazard ratio (HR) 0.963, 95% confidence interval (CI) 0.955-0.971 for a 1-kg/m2 increment of BMI and HR 0.971 (95% CI 0.950-0.993) for each 5 cm increase of WC]. Linear MR models indicated that each 1 kg/m2 increase in genetically predicted BMI was monotonically associated with a 4.5% decrease in all-cause mortality risk [HR 0.955 (95% CI 0.928-0.983)]. Non-linear curves showed the lowest mortality risk at the BMI of around 28.0 kg/m2, suggesting that optimal BMI for the oldest-old may be around overweight or mild obesity. Positive monotonic causal associations were observed between WC and all-cause mortality [HR 1.108 (95% CI 1.036-1.185) per 5 cm increase], CVD mortality [HR 1.193 (95% CI 1.064-1.337)], and non-CVD mortality [HR 1.110 (95% CI 1.016-1.212)]. The joint effect analyses indicated that the lowest risk was observed among those with higher BMI and lower WC. CONCLUSIONS: Among the oldest-old, opposite causal associations of BMI and WC with mortality were observed, and a body figure with higher BMI and lower WC could substantially decrease the mortality risk. Guidelines for the weight management should be cautiously designed and implemented among the oldest-old people, considering distinct roles of BMI and WC.

Extremely Durable K-Ion Batteries Enabled by Heteroatom Co-Doped Highly-Ordered Porous Carbon Spheres with Nearly 100% Capacity Retention up to 11,000 Cycles.

Currently, one major target for exploring K-ion batteries (KIBs) is enhancing their cycle stability due to the intrinsically sluggish kinetics of large-radius K+ ions. Herein, we report a rationally designed electrode, the S/O co-doped hard carbon spheres with highly ordered porous characteristics (SPC), for extremely durable KIBs. Experimental results and theory calculations confirm that this structure offers exceptional advantages for high-performance KIBs, facilitating rapid K+ diffusion and (de)-intercalation, efficient electrolyte penetration and transport, improved K+ storage sites, and enhanced redox reaction kinetics, thus ensuring the long-term cycle stability. As a result, the as-constructed SPC anode delivers a high reversible capacity of ca. 200 mAh g-1 at a high current density of 2.0 A g-1 and robust stability with ∼100% capacity retention up to 11,000 cycles, outperforming most carbon-based KIB anodes. This work offers insight into developing advanced KIBs with durable stability toward practical applications.

Enantioselective Total Synthesis of (-)-Daphenylline.

A concise enantioselective total synthesis of (-)-daphenylline, a hexacyclic Daphniphyllum alkaloid with a unique benzene ring, was achieved in 14 steps. The synthesis commences with two chiral stereocenters, C2 and C18, readily installed via Carreira's Ir/amine dual-catalyzed allylation. The allylic bridgehead amine 6 was rapidly prepared through Wickens' photoredox-catalyzed hydrocarboxylation of olefin and CuBr2-catalyzed α-amination of ketone. The tetracycle 4 was formed via Pd-catalyzed reductive Heck reaction or, more concisely, by Krische's Rh-catalyzed reductive 1,6-enyne cyclization. In this synthesis, newly reported Wickens' photoredox-catalyzed hydrocarboxylation was used twice, and Friedel-Crafts acylation thrice.

Dynamic Bubbling Balanced Proactive CO2 Capture and Reduction on a Triple-Phase Interface Nanoporous Electrocatalyst.

The formation and preservation of the active phase of the catalysts at the triple-phase interface during CO2 capture and reduction is essential for improving the conversion efficiency of CO2 electroreduction toward value-added chemicals and fuels under operational conditions. Designing such ideal catalysts that can mitigate parasitic hydrogen generation and prevent active phase degradation during the CO2 reduction reaction (CO2RR), however, remains a significant challenge. Herein, we developed an interfacial engineering strategy to build a new SnOx catalyst by invoking multiscale approaches. This catalyst features a hierarchically nanoporous structure coated with an organic F-monolayer that modifies the triple-phase interface in aqueous electrolytes, substantially reducing competing hydrogen generation (less than 5%) and enhancing CO2RR selectivity (∼90%). This rationally designed triple-phase interface overcomes the issue of limited CO2 solubility in aqueous electrolytes via proactive CO2 capture and reduction. Concurrently, we utilized pulsed square-wave potentials to dynamically recover the active phase for the CO2RR to regulate the production of C1 products such as formate and carbon monoxide (CO). This protocol ensures profoundly enhanced CO2RR selectivity (∼90%) compared with constant potential (∼70%) applied at -0.8 V (V vs RHE). We further achieved a mechanistic understanding of the CO2 capture and reduction processes under pulsed square-wave potentials via in situ Raman spectroscopy, thereby observing the potential-dependent intensity of Raman vibrational modes of the active phase and CO2RR intermediates. This work will inspire material design strategies by leveraging triple-phase interface engineering for emerging electrochemical processes, as technology moves toward electrification and decarbonization.

The neurophysiological mechanisms of medial prefrontal-perirhinal cortex circuit mediating temporal order memory decline in early stage of AD rats.

The temporal component of episodic memory has been recognized as a sensitive behavioral marker in early stage of Alzheimer's disease (AD) patients. However, parallel studies in AD animals are currently lacking, and the underlying neural circuit mechanisms remain poorly understood. Using a novel AppNL-G-F knock-in (APP-KI) rat model, the developmental changes of temporal order memory (TOM) and the relationship with medial prefrontal cortex and perirhinal cortex (mPFC-PRH) circuit were determined through in vivo electrophysiology and microimaging technique. We observed a deficit in TOM performance during the object temporal order memory task (OTOMT) in APP-KI rats at 6 month old, which was not evident at 3 or 4 months of age. Alongside behavioral changes, we identified a gradually extensive and aggravated regional activation and functional alterations in the mPFC and PRH during the performance of OTOMT, which occurred prior to the onset of TOM deficits. Moreover, coherence analysis showed that the functional connectivity between the mPFC and PRH could predict the extent of future behavioral performance. Further analysis revealed that the aberrant mPFC-PRH interaction mainly attributed to the progressive deterioration of synaptic transmission, information flow and network coordination from mPFC to PRH, suggesting the mPFC dysfunction maybe the key area of origin underlying the early changes of TOM. These findings identify a pivotal role of the mPFC-PRH circuit in mediating the TOM deficits in the early stage of AD, which holds promising clinical translational value and offers potential early biological markers for predicting AD memory progression.

B-cell characteristics define HCV reinfection outcome.

BACKGROUND & AIMS: In individuals highly exposed to HCV, reinfection is common, suggesting that natural development of sterilising immunity is difficult. In those that are reinfected, some will develop a persistent infection, while a small proportion repeatedly clear the virus, suggesting natural protection is possible. The aim of this study was to characterise immune responses associated with rapid natural clearance of HCV reinfection. METHODS: Broad neutralising antibodies (nAbs) and Envelope 2 (E2)-specific memory B cell (MBC) responses were examined longitudinally in 15 individuals with varied reinfection outcomes. RESULTS: Broad nAb responses were associated with MBC recall, but not with clearance of reinfection. Strong evidence of antigen imprinting was found, and the B-cell receptor repertoire showed a high level of clonality with ongoing somatic hypermutation of many clones over subsequent reinfection events. Single-cell transcriptomic analyses showed that cleared reinfections featured an activated transcriptomic profile in HCV-specific B cells that rapidly expanded upon reinfection. CONCLUSIONS: MBC quality, but not necessarily breadth of nAb responses, is important for protection against antigenically diverse variants, which is encouraging for HCV vaccine development. IMPACT AND IMPLICATIONS: HCV continues to have a major health burden globally. Limitations in the health infrastructure for diagnosis and treatment, as well as high rates of reinfection, indicate that a vaccine that can protect against chronic HCV infection will greatly complement current efforts to eliminate HCV-related disease. With alternative approaches to testing vaccines, such as controlled human inoculation trials under consideration, we desperately need to identify the correlates of immune protection. In this study, in a small but rare cohort of high-risk injecting drug users who were reinfected multiple times, breadth of neutralisation was not associated with ultimate clearance of the reinfection event. Alternatively, characteristics of the HCV-specific B-cell response associated with B-cell proliferation were. This study indicates that humoral responses are important for protection and suggests that for genetically very diverse viruses, such as HCV, it may be beneficial to look beyond just antibodies as correlates of protection.

Powering the Future: Unleashing the Potential of MXene-Based Dual-Functional Photoactive Cathodes in Photo-Rechargeable Zinc-Ion Capacitor.

Dual-functional photo-rechargeable (photo-R) energy storage devices, which acquire stored energy from solar energy harvesting, are being developed to battle the current energy crisis. In this study, these findings on the photo-driven characteristics of MXene-based photocathodes in photo-R zinc-ion capacitors (ZICs) are presented. Along with the pristine Ti3 C2 Tx MXene, tellurium/Ti3 C2 Tx (Te/Ti3 C2 Tx ) hybrid nanostructure is synthesized via facile chemical vapor transport technique to examine them for photocathodes in ZICs. Interestingly, the evaluated self-powered photodetector devices using MXene-based samples revealed a pyro-phototronic behavior introduced into the samples, with higher desirability observed in Te/Ti3 C2 Tx . The photo-R ZICs results exhibited a capacitance enhancement of 50.86% for Te/Ti3 C2 Tx at two scan rates of 5 and 10 mV s-1 under illumination, compared to dark conditions. In contrast, a capacitance enhancement of 30.20% is obtained for the pristine Ti3 C2 Tx at only a 5 mV s-1 scan rate. Furthermore, both samples achieved photo-charging voltage responses of ≈960 mV, and photoconversion efficiencies of 0.01% (for Te/ Ti3 C2 Tx ) and 0.07% (for Ti3 C2 Tx ). These characteristics in MXene-based single photo-R ZICs are significant and considerable with the distinguished integrated photo-R supercapacitors with solar cells, or coupled energy-harvesting and energy-storing devices reported recently in the literature.

Surfactant-Mediated Crystalline Structure Evolution Enabling the Ultrafast Green Synthesis of Bismuth-MOF in Aqueous Condition.

Green synthesis of stable metal-organic frameworks (MOFs) with permanent and highly ordered porosity at room temperature without needing toxic and harmful solvents and long-term high-temperature reactions is crucial for sustainable production. Herein, a rapid and environmentally friendly synthesis strategy is reported to synthesize the complex topological bismuth-based-MOFs (Bi-MOFs), [Bi9(C9H3O6)9(H2O)9] (denoted CAU-17), in water under ambient conditions by surfactant-mediated sonochemical approach, which could also be applicable to other MOFs. This strategy explores using cetyltrimethylammonium bromide (CTAB) amphiphilic molecules as structure-inducing agents to control the removal of non-coordinated water (dehydration) and enhance the degree of deprotonation of the ligands, thereby regulating the coordination and crystallization in aqueous solutions. In addition, another two new strategies for synthesizing CAU-17 by crystal reconstruction and one-step synthesis in binary solvents are provided, and the solvent-induced synthesis mechanism of CAU-17 is studied. The as-prepared CAU-17 presents a competitive iodine capture capability and effective delivery of the antiarrhythmic drug procainamide (PA) for enteropatia due to the broad pH tolerance and the unique phosphate-responsive destruction in the intestine. The findings will provide valuable ideas for the follow-up study of surfactant-assisted aqueous synthesis of MOFs and their potential applications.

Transforming Undesired Corrosion Products into a Nanoflake-Array Functional Layer: A Gelatin-Assistant Modification Strategy for High Performance Zn Battery Anodes.

As corrosion products of Zn anodes in ZnSO4 electrolytes, Zn4SO4 (OH)6·xH2O with loose structure cannot suppress persistent side reactions but can increase the electrode polarization and induce dendrite growth, hindering the practical applications of Zn metal batteries. In this work, a functional layer is built on the Zn anode by a gelatin-assistant corrosion and low-temperature pyrolysis method. With the assistant of gelatin, undesired corrosion products are converted into a uniform nanoflake array comprising ZnO coated by gelatin-derived carbon on Zn foil (denoted Zn@ZnO@GC). It is revealed that the gelatin-derived carbons not only enhance the electron conductivity, facilitate Zn2+ desolvation, and boost transport/deposition kinetics, but also inhibit the occurrence of hydrogen evolution and corrosion reactions on the zincophilic Zn@ZnO@GC anode. Moreover, the 3D nanoflake array effectively homogenizes the current density and Zn2+ concentration, thus inhibiting the formation of dendrites. The symmetric cells using the Zn@ZnO@GC anodes exhibit superior cycling performance (over 7000 h at 1 mA cm-2/1 mAh cm-2) and without short-circuiting even up to 25 mAh cm-2. The Zn@ZnO@GC||NaV3O8 full cell works stably for 5000 cycles even with a limited N/P ratio of ≈5.5, showing good application prospects.

Encapsulation of Uranium Oxide in Multiwall WS2 Nanotubes.

Uranium is a high-value energy element, yet also poses an appreciable environmental burden. The demand for a straightforward, low energy, and environmentally friendly method for encapsulating uranium species can be beneficial for long-term storage of spent uranium fuel and a host of other applications. Leveraging on the low melting point (60 °C) of uranyl nitrate hexahydrate and nanocapillary effect, a uranium compound is entrapped in the hollow core of WS2 nanotubes. Followingly, the product is reduced at elevated temperatures in a hydrogen atmosphere. Nanocrystalline UO2 nanoparticles anchor within the WS2 nanotube lumen are obtained through this procedure. Such methodology can find utilization in the processing of spent nuclear fuel or other highly active radionuclides as well as a fuel for deep space missions. Moreover, the low melting temperatures of different heavy metal-nitrate hydrates, pave the way for their encapsulation within the hollow core of the WS2 nanotubes, as demonstrated herein.

Effects of fetal growth restriction on the perinatal neurovascular unit and possible treatment targets.

The neurovascular unit (NVU) within the brain is a multicellular unit that synergistically acts to maintain blood-brain barrier function and meet cerebral metabolic demand. Recent studies have indicated disruption to the NVU is associated with neuropathology in the perinatal brain. Infants with fetal growth restriction (FGR) are known to be at increased risk of neurodevelopmental conditions including motor, learning, and behavioural deficits. There are currently no neuroprotective treatments for these conditions. In this review, we analyse large animal studies examining the effects of FGR on the perinatal NVU. These studies show altered vascularity in the FGR brain as well as blood-brain barrier dysfunction due to underlying cellular changes, mediated by neuroinflammation. Neuroinflammation is a key mechanism associated with pathological effects in the FGR brain. Hence, targeting inflammation may be key to preserving the multicellular NVU and providing neuroprotection in FGR. A number of maternal and postnatal therapies with anti-inflammatory components have been investigated in FGR animal models examining targets for amelioration of NVU disruption. Each therapy showed promise by uniquely ameliorating the adverse effects of FGR on multiple aspects of the NVU. The successful implementation of a clinically viable neuroprotective treatment has the potential to improve outcomes for neonates affected by FGR. IMPACT: Disruption to the neurovascular unit is associated with neuropathology in fetal growth restriction. Inflammation is a key mechanism associated with neurovascular unit disruption in the growth-restricted brain. Anti-inflammatory treatments ameliorate adverse effects on the neurovascular unit and may provide neuroprotection.

Construction and validation of a nomogram for predicting diabetes remission at 3 months after bariatric surgery in patients with obesity combined with type 2 diabetes mellitus.

AIM: Bariatric metabolic surgery (BMS) is a proven treatment option for patients with both obesity and type 2 diabetes mellitus (T2DM). However, there is a lack of comprehensive reporting on the short-term remission rates of diabetes, and the existing data are inadequate. Hence, this study aimed to investigate the factors that may contribute to diabetes remission (DR) in patients with obesity and T2DM, 3 months after undergoing BMS. Furthermore, our objective was to develop a risk-predicting model using a nomogram. METHODS: In total, 389 patients with obesity and T2DM, who had complete preoperative information and underwent either laparoscopic sleeve gastrectomy or laparoscopic gastric bypass surgery between January 2014 and May 2023, were screened in the Chinese Obesity and Metabolic Surgery Database. The patients were randomly divided into a training set (n = 272) and a validation set (n = 117) in a 7:3 ratio. Potential factors for DR were analysed through univariate and multivariate logistic regression analyses and then modelled using a nomogram. The model's performance was evaluated using receiver operating characteristic curves and the area under the curve (AUC). Calibration plots were used to assess prediction accuracy and decision curve analyses were conducted to evaluate the clinical usefulness of the model. RESULTS: Glycated haemoglobin, triglycerides, duration of diabetes, insulin requirement and hypercholesterolaemia were identified as independent factors influencing DR. We have incorporated these five indicators into a nomogram, which has shown good efficacy in both the training cohort (AUC = 0.930) and validation cohort (AUC = 0.838). The calibration plots indicated that the model fits well in both the training and the validation cohorts, and decision curve analyses showed that the model had good clinical applicability. CONCLUSION: The prediction model developed in this study holds predictive value for short-term DR following BMS in patients with obesity and T2DM.

Mitochondria fission accentuates oxidative stress in hyperglycemia-induced H9c2 cardiomyoblasts in vitro by regulating fatty acid oxidation.

Oxidative stress plays a pivotal role in the development of diabetic cardiomyopathy (DCM). Previous studies have revealed that inhibition of mitochondrial fission suppressed oxidative stress and alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. However, no research has confirmed whether mitochondria fission accentuates hyperglycemia-induced cardiomyoblast oxidative stress through regulating fatty acid oxidation (FAO). We used H9c2 cardiomyoblasts exposed to high glucose (HG) 33 mM to simulate DCM in vitro. Excessive mitochondrial fission, poor cell viability, and lipid accumulation were observed in hyperglycemia-induced H9c2 cardiomyoblasts. Also, the cells were led to oxidative stress injury, lower adenosine triphosphate (ATP) levels, and apoptosis. Dynamin-related protein 1 (Drp1) short interfering RNA (siRNA) decreased targeted marker expression, inhibited mitochondrial fragmentation and lipid accumulation, suppressed oxidative stress, reduced cardiomyoblast apoptosis, and improved cell viability and ATP levels in HG-exposed H9c2 cardiomyoblasts, but not in carnitine palmitoyltransferase 1 (CPT1) inhibitor etomoxir treatment cells. We also found subcellular localization of CPT1 on the mitochondrial membrane, FAO, and levels of nicotinamide adenine dinucleotide phosphate (NADPH) were suppressed after exposure to HG treatment, whereas Drp1 siRNA normalized mitochondrial CPT1, FAO, and NADPH. However, the blockade of FAO with etomoxir abolished the above effects of Drp1 siRNA in hyperglycemia-induced H9c2 cardiomyoblasts. The preservation of mitochondrial function through the Drp1/CPT1/FAO pathway is the potential mechanism of inhibited mitochondria fission in attenuating oxidative stress injury of hyperglycemia-induced H9c2 cardiomyoblasts.

Investigating the causal association between systemic lupus erythematosus and migraine using Mendelian randomization analysis.

OBJECTIVE: To assess whether systemic lupus erythematosus (SLE) may be genetically causally associated with migraine, including the two primary subtypes: migraine with aura (MWA) and migraine without aura (MWoA). BACKGROUND: The association between SLE and migraine has been investigated extensively. Previous studies have shown a higher prevalence of migraine in patients with SLE, although the exact relationship remains unclear. This study investigated the potential causal association between SLE and migraine using the powerful analytical tool of Mendelian randomization (MR). METHODS: We performed two-sample MR analysis of publicly available summary statistic datasets using inverse variance-weighted (IVW), weighted median, and MR-Egger methods based on an SLE genome-wide association study (GWAS; 5201 cases; 9066 controls; the exposure frequency is 36.5%) as an exposure and migraine GWAS (15,905 cases; 264,662 controls) in individuals with European ancestry as outcomes, focusing on the two migraine subtypes MWA (6780 cases; 264,662 controls) and MWoA (5787 cases; 264,662 controls). Thepleiotropy and heterogeneity were performed. RESULTS: We selected 42 single-nucleotide polymorphisms from SLE GWAS as instrumental variables (IVs) for SLE on migraine, and 41 SNP IVs for SLE on MWA or MWoA. The IVW (odds ratio [OR] = 1.01, 95% confidence interval [CI] = [0.99, 1.03], p = 0.271), weighted median (OR = 1.00, 95% CI = [0.97, 1.03], p = 0.914), and MR-Egger (OR = 1.04, 95% CI = [0.99, 1.09], p = 0.153) methods showed no causal effect of SLE on migraine. A causal effect of SLE was observed on MWA (IVW: OR = 1.05, 95% CI = [1.02, 1.08], p = 0.001; weighted median: OR = 1.05, 95% CI = [1.01, 1.10], p = 0.018; MR-Egger: OR = 1.07, 95% CI = [1.01, 1.14], p = 0.035 and pIVW < 0.017 [Bonferroni correction]) but not MWoA (IVW: OR = 0.99, 95% CI = [0.96, 1.02], p = 0.331; weighted median: OR = 0.98, 95% CI = [0.94, 1.03], p = 0.496; MR-Egger: OR = 1.02, 95% CI = [0.95, 1.09], p = 0.652). The results showed no significant pleiotropy or heterogeneity. CONCLUSION: Our MR analysis demonstrated the complex relationship between SLE and migraine, suggesting a potential effect of SLE on the risk of MWA but not MWoA. These findings can aid in the development of improved subtype-specific management of migraine in patients with SLE.

Associations of Serum Per- and Polyfluoroalkyl Substances with Hyperuricemia in Adults: A Nationwide Cross-Sectional Study.

There has been widespread concern about the health hazards of per- and polyfluoroalkyl substances (PFAS), which may be the risk factor for hyperuricemia with evidence still insufficient in the general population in China. Here, we conducted a nationwide study involving 9,580 adults aged 18 years or older from 2017 to 2018, measured serum concentrations of uric acid and PFAS (PFOA, PFOS, 6:2 Cl-PFESA, PFNA, PFHxS) in participants, to assess the associations of individual PFAS with hyperuricemia, and estimated a joint effect of PFAS mixtures. We found positive associations of higher serum PFAS with elevated odds of hyperuricemia in Chinese adults, with the greatest contribution from PFOA (69.37%). The nonmonotonic dose-response (NMDR) relationships were observed for 6:2 Cl-PFESA and PFHxS with hyperuricemia. Participants with less marine fish consumption, overweight, and obesity may be the sensitive groups to the effects of PFAS on hyperuricemia. We highlight the potential health hazards of legacy long-chain PFAS (PFOA) once again because of the higher weights of joint effects. This study also provides more evidence about the NMDR relationships in PFAS with hyperuricemia and emphasizes a theoretical basis for public health planning to reduce the health hazards of PFAS in sensitive groups.

Therapeutic Effect of Anti-CD52 Monoclonal Antibody in Multiple Sclerosis and Its Animal Models Is Mediated via T Regulatory Cells.

The objective of this study is to determine the mechanism of action of anti-CD52 mAb treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Experimental autoimmune encephalomyelitis (EAE), an animal model of the disease, was used to address the role of T regulatory cells (Tregs) in the anti-CD52 mAb-induced suppression of the disease. In vitro studies on PBMCs from RRMS patients and matched healthy controls determined the effect of IL-7 on the expansion of CD4+CD25+CD127- Tregs and induction of their suppressive phenotype. This study using EAE animal models of MS has shown that mouse anti-CD52 mAb suppression of clinical disease was augmented by coadministration of IL-7 and partially reversed by anti-IL-7 mAb. In vitro human studies showed that IL-7 induced expansion of CD4+CD25+CD127- Tregs and increased their FOXP3, GITIR, CD46, CTLA-4, granzyme B, and perforin expression. Anti-CD52 mAb treatment of mice with relapsing-remitting EAE induced expansion of Foxp3+CD4+ Tregs and the suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in peripheral immune organs and CNS infiltrates. The effect was detected immediately after the treatment and maintained over long-term follow-up. Foxp3+CD4+ Treg-mediated suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in the spinal cord infiltrates was reversed after inducible Foxp3 depletion. Our results demonstrated that the therapeutic effect of U.S. Food and Drug Administration-approved anti-CD52 mAb is dependent on the presence of Tregs.