Efficacy and safety of vunakizumab in moderate-to-severe chronic plaque psoriasis: a randomized, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Vunakizumab, a novel anti-IL-17A antibody, has showed promising efficacy for moderate-to-severe plaque psoriasis in a phase 2 trial. OBJECTIVE: We conducted a double-blind, randomized phase 3 trial (NCT04839016) to further evaluate vunakizumab in this population. METHODS: 690 subjects were randomized (2:1) to receive vunakizumab 240 mg or placebo at weeks 0, 2, 4 and 8. At week 12, subjects on placebo were switched to vunakizumab 240 mg (weeks 12, 14, 16 and q4w thereafter). The co-primary endpoints were ≥90% improvement from baseline in the psoriasis area-and-severity index score (PASI 90) and a static Physicians Global Assessment score of 0/1 (sPGA 0/1) at week 12. RESULTS: At week 12, the vunakizumab group showed higher PASI 90 (76.8% vs 0.9%) and sPGA 0/1 (71.8% vs 0.4%) response rates, as well as higher PASI 75 (93.6% vs 4.0%), PASI 100 (36.6% vs 0.0%) and sPGA 0 (38.2% vs 0.0%) response rates (all two-sided P<0.0001 vs placebo). Efficacy was maintained through week 52 with continuous vunakizumab. Possible treatment-related serious adverse events occurred in 0.9% of vunakizumab-treated subjects. LIMITATIONS: Chinese subjects only; no active comparator. CONCLUSION: Vunakizumab demonstrated robust clinical response at week 12 and through week 52, with good tolerability in moderate-to-severe plaque psoriasis.

Association between serum potassium, risk and prognosis of peritonitis in peritoneal dialysis patients - results from the Peritoneal Dialysis Telemedicine-assisted Platform Cohort (PDTAP) Study.

BACKGROUND: Hypokalemia has been associated with an increased risk of peritoneal dialysis (PD)-associated peritonitis. However, hypokalemia is commonly associated with malnutrition, inflammation, and severe coexisting comorbidities, which thus are suspected of being potential confounders. This study was aimed at testing whether hypokalemia was independently associated with the occurrence and prognosis of PD-associated peritonitis. METHODS: A national-level dataset from the Peritoneal Dialysis Telemedicine-assisted Platform Cohort (PDTAP) Study was used to explore the independent association of serum potassium with PD-associated peritonitis. Unmatched and propensity score-adjusted multivariate competing risk models, as well as univariate competing risk models following 1:1 propensity score matching, were conducted to balance potential biases between patients with and without hypokalemia. The association between potassium levels prior to peritonitis and treatment failure due to peritonitis was also investigated. RESULTS: During a median follow-up of 25.7 months in 7220 PD patients, there was a higher incidence of peritonitis in patients with serum potassium below 4.0 mmol/L compared to those with higher serum levels (677 [0.114/patient-year] vs. 914 [0.096/patient-year], P = 0.001). After adjusting for demographics, laboratory tests, residual renal function, and medication use, baseline potassium levels below 4.0 mmol/L were not linked to an increased risk of peritonitis, with a hazard ratio of 0.983 (95% CI 0.855-1.130, P = 0.810). This result remained consistent in both the propensity score adjusted multivariate competing risk regression (HR = 0.974, 95% CI 0.829-1.145, P = 0.750) and the univariate competing risk regression after 1:1 propensity score matching (Fine-Gray test, P = 0.218). The results were similar when analyzing patients with serum potassium level above or below 3.5 mmol/L. Lastly, hypokalemia before the occurrence of peritonitis was not independently associated with treatment failure. CONCLUSION: Hypokalemia was not found to be an independent risk factor for PD-associated peritonitis or treatment failure of peritonitis in China.

Superlattice cathodes endow cation and anion co-intercalation for high-energy-density aluminium batteries.

Conventionally, rocking-chair batteries capacity primarily depends on cation shuttling. However, intrinsically high-charge-density metal-ions, such as Al3+, inevitably cause strong Coulombic ion-lattice interactions, resulting in low practical energy density and inferior long-term stability towards rechargeable aluminium batteries (RABs). Herein, we introduce tunable quantum confinement effects and tailor a family of anion/cation co-(de)intercalation superlattice cathodes, achieving high-voltage anion charge compensation, with extra-capacity, in RABs. The optimized superlattice cathode with adjustable van der Waals not only enables facile traditional cation (de)intercalation, but also activates O2- compensation with an extra anion reaction. Furthermore, the constructed cathode delivers high energy-density (466 Wh kg-1 at 107 W kg-1) and one of the best cycle stability (225 mAh g-1 over 3000 cycles at 2.0 A g-1) in RABs. Overall, the anion-involving redox mechanism overcomes the bottlenecks of conventional electrodes, thereby heralding a promising advance in energy-storage-systems.

Dock4 contributes to neuropathic pain by regulating spinal synaptic plasticity in mice.

Introduction: Neuropathic pain (NP) conditions arising from injuries to the nervous system due to trauma, disease, or neurotoxins are chronic, severe, debilitating, and exceedingly difficult to treat. However, the mechanisms of NP are not yet clear. Here we explored the role of Dock4, an atypical Rac1 GEF, in the development of NP. Methods: Mechanical allodynia was assessed as paw withdrawal threshold by a dynamic plantar aesthesiometer. Immunofluorescence staining was conducted to investigate the expression and localization of Dock4, Rac1 and GluN2B. Quantitative analysis of Dock4, Rac1 and GluN2B were determined by qRT-PCR and Western blot assay. Spontaneous excitatory and inhibitory postsynaptic currents in spinal cord slices were examined using whole cell patch clam. Dendritic spine remodeling and synaptogenesis were detected in cultured dorsal spinal neurons. Results and discussion: We found that SNL caused markedly mechanical allodynia accompanied by increase of Dock4, GTP-Rac1and GluN2B, which was prevented by knockdown of Dock4. Electrophysiological tests showed that SNL facilitated excitatory synaptic transmission, however, this was also inhibited by Dock RNAi-LV. Moreover, knockdown of Dock4 prevented dendritic growth and synaptogenesis. Conclusion: In summary, our data indicated that Dock4 facilitated excitatory synaptic transmission by promoting the expression of GluN2B at the synaptic site and synaptogenesis, leading to the occurrence of NP.

Estimator-Based Reinforcement Learning Consensus Control for Multiagent Systems With Discontinuous Constraints.

This article focuses on the optimal consensus control problem for multiagent systems (MASs) with discontinuous constraints. The case of discontinuous constraints is a particular instance of state constraints, which has been studied less but occurs in many practical situations. Due to the discontinuous constraint boundaries, the traditional barrier function-based backstepping methods cannot be used directly. In response to this thorny problem, a novel constraint boundary reconstruction technique is proposed by designing a class of switch-like functions. The technique can convert discontinuous constraint boundaries into continuous ones, and it strictly proves that when the states satisfy the transformed constraint boundaries, the original constraints are also absolutely fulfilled. Meanwhile, with the aid of the barrier function and distributed event-triggered estimator, an improved coordinate transformation is constructed, which can remove the "feasibility condition" and simplify the controller design. In addition, by introducing prediction error and revised term into the learning process of neural networks (NNs), the optimal consensus problem is resolved by constructing a modified reinforcement learning strategy. Finally, the stability of the MASs is testified through the Lyapunov stability theory, and a simulation example verifies the effectiveness of the proposed method.

Assessing traffic emissions during the summer world university games 2023: Insights for multisectoral synergetic decontamination.

Implementing temporary traffic control measures is a common strategy to prevent air pollution and alleviate traffic congestion during mega-events. Accurate assessment of event-time vehicular emissions is useful for local authorities to develop effective policies. However, many previous assessments were based on policy-based scenarios, which often failed to capture the synergistic impact from other sectors (e.g., the industrial sector). Here, we conducted both traditional scenario-based ex-ante evaluation and data-driven real-time emissions tracking to evaluate the impacts of traffic restriction policies during the Summer World University Games 2023 in Chengdu, China. Real-time tracking revealed that average vehicle kilometers traveled (VKT), traffic emissions of nitrogen oxides (NOX), and volatile organic compound (VOC) decreased by 18.3 %, 37.9 %, and 18.4 %, respectively, compared to the non-event period. The scenario-based ex-ante evaluation substantially underestimated NOX emission reduction from the truck fleet due to the lack of consideration for multisectoral synergistic effects. Event-time interventions in the industrial sector accounted for an additional 18.1 % reduction in truck NOX emissions. This study underscores the importance of considering cross-sectoral synergy when establishing policies for future mega events.

Computationally-Assisted Discovery and Assignment of a New Class of 6/6/5/5 Fused-Ring Diterpene Acting as Pregnane X Receptor Ligands from Isodon serra.

We report here the orchestration of molecular ion networking (MoIN) and a set of computationally assisted structural elucidation approaches in the discovery and assignment of a new class of rearranged 4,5-seco-abietane diterpenoids including serra A (1), which possesses an unusual 6/6/5/5 fused-ring skeleton system, together with two previously unreported diterpenoids serras B-C (2-3) and five known compounds were isolated from Isodon serra (I. serra). The structures were elucidated by spectroscopic analysis in conjunction with computationally assisted structure elucidation tools. In silico, serras A-C (1-3) bind well to PXR, suggesting their potential role in reducing inflammation. The results of serra A (1) with hPXR demonstrated agonist activity with an EC50 value of 15 µM. Serra A (1), graciliflorin F (4), gerardianin C (5), 11,12,15-trihydroxy-8,11,13-abietatrien-7-one (6), rabdosin D (7), and 15-hydroxysalprionin (8) exhibited promising anti-inflammatory activities in lipopolysaccharide (LPS)-induced RAW 267.4 cells, and their inhibition rates on NO production were more than 65% at 10 µM.

ADP-based fault-tolerant consensus control for multiagent systems with irregular state constraints.

This paper investigates the consensus control issue for nonlinear multiagent systems (MASs) subject to irregular state constraints and actuator faults using an adaptive dynamic programming (ADP) algorithm. Unlike the regular state constraints considered in previous studies, this paper addresses irregular state constraints that may exhibit asymmetry, time variation, and can emerge or disappear during operation. By developing a system transformation method based on one-to-one state mapping, equivalent unconstrained MASs can be obtained. Subsequently, a finite-time distributed observer is designed to estimate the state information of the leader, and the consensus control problem is transformed into the tracking control problem for each agent to ensure that actuator faults of any agent cannot affect its neighboring agents. Then, a critic-only ADP-based fault tolerant control strategy, which consists of the optimal control policy for nominal system and online fault compensation for time-varying addictive faults, is proposed to achieve optimal tracking control. To enhance the learning efficiency of critic neural networks (NNs), an improved weight learning law utilizing stored historical data is employed, ensuring the convergence of critic NN weights towards ideal values under a finite excitation condition. Finally, a practical example of multiple manipulator systems is presented to demonstrate the effectiveness of the developed control method.

Correlation Analysis of ApoB, ApoA1, and ApoB/ApoA1 with Cortical Morphology in Patients with Memory Complaints.

Background: Apolipoproteins and cortical morphology are closely associated with memory complaints, and both may contribute to the development of Alzheimer's disease. Objective: To examine whether apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA1), and their ratio (ApoB/ApoA1) are associated with cortical morphology in patients with memory complaints. Methods: Ninety-seven patients underwent neuropsychological testing, measurements of ApoB, ApoA1, ApoB/ApoA1, plasma Alzheimer's biomarker, apolipoprotein E (ApoE) genotyping, and 3T structural magnetic resonance imaging (sMRI) scans. Based on sMRI scanning locations, patients were categorized into the University of Electronic Science and Technology (UESTC) and the Fourth People's Hospital of Chengdu (FPHC). The Computational Anatomy Toolbox within Statistical Parametric Mapping was used to calculate each patient's cortical morphology index based on sMRI data. The cortical morphology index and apolipoproteins were also analyzed. Results: Significant positive correlations were found between ApoB and sulcal depth in the lateral occipital cortex among the UESTC, the FPHC, and the total sample groups, and negative correlations were observed between sulcal depth in the lateral occipital cortex and the scores of the Shape Trails Test Part A and B. In the FPHC group, the scores of the Montreal Cognitive Assessment Basic, delayed recall of the Auditory Verbal Learning Test, Animal Fluency Test and Boston Naming Test were positively correlated with the sulcal depth. Conclusions: ApoB is associated with the sulcal depth in the lateral occipital cortex, potentially relating to speed/executive function in individuals with memory complaints.

Targeting NPM1 inhibits proliferation and promotes apoptosis of hepatic progenitor cells via suppression of mTOR signalling pathway.

BACKGROUND: Hepatic progenitor cells serve not only as the origin of combined hepatocellular cholangiocarcinoma (cHCC-CCA) but are also responsible for malignancy recurrence after surgical resection. Nucleophosmin 1 (NPM1) has been implicated in cancer metastasis and poor prognosis. This study aimed to determine the expression of NPM1 by hepatic progenitor cells in cHCC-CCA and the effects of targeting NPM1 on hepatic progenitor cells and BEL-7402 cells with characteristics of both progenitor cells and cHCC-CCA. METHODS: First, NPM1 was detected by RT‒PCR, western blotting, and double-immunofluorescence staining in cHCC-CCA tissues. NPM1 expression was subsequently analysed in rat hepatic progenitor cells cultured in vitro and in interleukin 6 (IL6)-treated cells. The effects and mechanism of NPM1 on hepatic progenitor cells were determined by knocking down NPM1 and performing RNA sequencing analysis. Finally, NSC348884, a small-molecule inhibitor that disrupts NPM1 dimer formation, was used to confirm the function of NPM1 in BEL-7402 cells. RESULTS: Both human hepatic progenitor cells in cHCC-CCA tissues and rat in vitro cultured hepatic progenitor cells highly expressed NPM1. IL6, a cytokine involved in the malignant transformation of hepatic progenitor cells, dose-dependently increased NPM1 and PCNA expression. Knocking down NPM1 reduced IL6R transcription (P < 0.0001) and inhibited the proliferation (P = 0.0065) of hepatic progenitor cells by suppressing the mTOR signalling pathway and activating the apoptosis pathway. Furthermore, knocking down NPM1 in hepatic progenitor cells resulted in more apoptotic cells (7.33 ± 0.09% vs. 3.76 ± 0.13%, P < 0.0001) but fewer apoptotic cells in the presence of NSC348884 (47.57 ± 0.49% vs. 63.40 ± 0.05%, P = 0.0008) than in the control cells, suggesting that low-NPM1-expressing cells are more resistant to NSC348884. In addition, NSC348884 induced the apoptosis of BEL-7402 cells with an IC50 of 2.77 µmol/L via the downregulation of the IL-6R and mTOR signalling pathways and inhibited the growth of BEL-7402 cells in a subcutaneous xenograft tumour model (P = 0.0457). CONCLUSIONS: Targeting NPM1 inhibits proliferation and induces apoptosis in hepatic progenitor cells and BEL-7402 cells, thus serving as a potential therapy for cHCC-CCA.

Transition Metal Parent Alumylene Complexes: Synthesis, Structures, and XPS Characterization of Aluminum Oxidation State.

The first isolation and characterization of transition metal complexes with the parent Al(I)-H unit were achieved in base-stabilized forms. W and Fe complexes, Cp*(CO)n(H)M←:AlH(NHC)2 (NHC = N-heterocyclic carbene, n = 1 or 2), were synthesized in 43-63% yields by the one-step reaction of Cp*M(CO)n(py)Me with H3Al·NHC. The characterization included 1H and 27Al nuclear magnetic resonance (NMR), and infrared (IR) spectroscopic analysis, as well as DFT calculations, which revealed the extremely strong σ-donating ability of the :AlH(NHC)2 ligand, and the highly polarized M(δ-)←:Al(δ+) coordination bonds. The monovalent oxidation state of the Al center of these complexes was confirmed by X-ray photoelectron spectroscopy (XPS). The hydroalumination of carbodiimide and the reduction of CO2 to CO were also demonstrated.

Construction of Risk-Prediction Models for Autogenous Arteriovenous Fistula Thrombosis in Patients on Maintenance Hemodialysis.

INTRODUCTION: Autogenous arteriovenous fistula (AVF) is the preferred vascular access in patients undergoing maintenance hemodialysis (MHD). However, complications such as thrombosis may occur. This study aimed to construct and validate a machine learning-based risk-prediction model for AVF thrombosis, hypothesizing that such a model can effectively predict occurrences, providing a foundation for early clinical intervention. METHODS: The retrospective longitudinal study included a total of 270 patients who underwent MHD at the Hemodialysis Center of the Second Affiliated Hospital of Harbin Medical University between March 2021 and December 2022. During this study, baseline data and scale information of patients between March 2020 and December 2021 were collected. We recorded outcome indicators between March 2021 and December 2022 for subsequent analyses. Five machine learning models were developed (artificial neural network, logistic regression, ridge classification, random forest, and adaptive boosting). The sensitivity (recall), specificity, accuracy, and precision of each model were evaluated. The effect size of each variable was analyzed and ranked. Models were assessed using the area under the receiver-operating characteristic (AUROC) curve. RESULTS: Among the 270 included patients, 105 had AVF thrombosis (55 male and 50 female patients; age range, 29-79 years; mean age, 56.72 years; standard deviation [SDs], ±13.10 years). Conversely, 165 patients did not have AVF thrombosis (99 male and 66 female patients; age range, 23-79 years; mean age, 53.58 years; SD, ± 13.33 years). During the observation period, approximately 52.6% of patients with AVF experienced long-term complications. The most common complications associated with AVF were thrombosis (105; 38.9%), aneurysm formation (27; 10%), and excessively high output flow (10; 3.7%). Fifty-four (20%) patients with AVF required intervention because of complications associated with vascular access. The AUROC curve of the testing set was between 0.858 and 0.903. CONCLUSION: In this study, we developed five machine learning models to predict the risk of AVF thrombosis, providing a reference for early clinical intervention.

Relationship Between Excessive Daytime Sleepiness and Caudate Nucleus Volume in Patients with Subjective Cognitive Decline: A Study from the SILCODE Using the Volbrain.

Background: Excessive daytime sleepiness (EDS) and caudate nucleus volume alterations have been linked to Alzheimer's disease (AD), but their relationship remains unclear under the context of subjective cognitive decline (SCD). Objective: This study aimed to investigate the relationship between EDS and caudate nucleus volume in patients with SCD. Methods: The volume of entire brain was measured in 170 patients with SCD, including 37 patients with EDS and 133 non-EDS, from the Sino Longitudinal Study on Cognitive Decline (SILCODE). Participants underwent a comprehensive assessment battery, including neuropsychological and clinical evaluations, blood tests, genetic analysis for APOE ɛ4, and structural MRI scans analyzed using the fully automated segmentation tool, volBrain. Results: Patients with EDS had significantly increased volume in the total and left caudate nucleus compared to non-EDS. The most significant cognitive behavioral factor associated with caudate nucleus volume in the EDS was the Auditory Verbal Learning Test-recognition. Conclusions: These findings suggest that EDS may be associated with alterations in caudate nucleus volume, particularly in the left hemisphere, in the context of SCD. Further research is necessary to understand the underlying mechanisms of this relationship and its implications for clinical management.

Seating accuracy of removable partial denture frameworks fabricated by different digital workflows in comparison to conventional workflow.

PURPOSE: To evaluate the seating accuracy of removable partial denture (RPD) frameworks fabricated by two digital workflows involving selective laser melting (SLM) in comparison to the conventional workflow. MATERIALS AND METHODS: A Kennedy class III modification 1 partially edentulous mandibular arch was used as a master model. Three RPD framework groups were included: (1) a conventional workflow group with conventional impression and casting (CC), (2) a partial digital workflow group with conventional impression and digital fabrication (CD), and (3) a complete digital workflow group with digital impression and digital fabrication (DD). A total of 10 frameworks were produced for each group. The marginal gaps at the occlusal rests, retention arms, and reciprocating arms were measured by a traveling microscope. The data were analyzed with the one-way analysis of variance test. RESULTS: At the framework level, the most superior fit was observed for the CD group (79.5 µm) followed by DD (85.3 µm) and CC (114.2 µm) groups. The CD and DD groups were significantly superior to CC (p < 0.001). This fit pattern was consistent for the retention and reciprocating arms, while the occlusal rest fit was similar among all the groups. CONCLUSIONS: The SLM frameworks had a promising seating accuracy in comparison to conventional frameworks. The type of impression, conventional or digital, did not affect the accuracy of SLM frameworks. The differences observed in the present study are likely to be of minimal clinical significance.

Diagnostic Accuracy of Ultra-Low Dose CT Compared to Standard Dose CT for Identification of Fresh Rib Fractures by Deep Learning Algorithm.

The present study aimed to evaluate the diagnostic accuracy of ultra-low dose computed tomography (ULD-CT) compared to standard dose computed tomography (SD-CT) in discerning recent rib fractures using a deep learning algorithm detection of rib fractures (DLADRF). A total of 158 patients undergoing forensic diagnosis for rib fractures were included in this study: 50 underwent SD-CT, and 108 were assessed using ULD-CT. Junior and senior radiologists independently evaluated the images to identify and characterize the rib fractures. The sensitivity of rib fracture diagnosis by radiologists and radiologist + DLADRF was better using SD-CT than ULD-CT. However, the diagnosis sensitivity of DLADRF using ULD-CT alone was slightly more than SD-CT. Nonetheless, no substantial differences were observed in specificity, positive predictive value, and negative predictive value between SD-CT and ULD-CT by the same radiologist, radiologist + DLADRF, and DLADRF (P > 0.05). The area under the curve (AUC) of receiver operating characteristic indicated that senior radiologist + DLADRF was significantly better than senior and junior radiologists, junior radiologists + DLADRF, and DLADRF alone using SD-CT or ULD-CT (all P < 0.05). Also, junior radiologists + DLADRF was better with ULD-CT than senior and junior radiologists (P < 0.05). The AUC of the rib fracture diagnosed by senior radiologists did not differ from DLADRF using ULD-CT. Also, no significant differences were observed between junior + AI and senior and between junior and DLADRF using SD-CT. DLADRF enhanced the diagnostic performance of radiologists in detecting recent rib fractures. The diagnostic outcomes between SD-CT and ULD-CT across radiologists' experience and DLADRF did not differ significantly.

Tri-signal CdS@SiO2 nanoprobes for accurate and sensitive detection of human immunoglobulin G with enhanced flexibility and internal validation.

Accurate and sensitive determination of human immunoglobulin G (HIgG) level is critical for diagnosis and treatment of various diseases, including rheumatoid arthritis, humoral immunodeficiencies, and infectious disease. In this study, versatile tri-signal probes were developed by preparing CdS@SiO2 nanorods that integrate photoluminescence (PL), multi-phonon resonant Raman scattering (MRRS) and infrared absorption (IRA) properties. Through the coating of multiple CdS nanoparticles as cores within SiO2 shells, the PL and MRRS properties of CdS were improved, resulting in a significantly lowered limit of detection (LOD), with the lowest LOD of 12.37 ag mL-1. Integration with the distinctive IRA property of SiO2 shells widened the detection range towards higher concentrations, establishing a final linear range of 50 ag mL-1 to 10 µg mL-1. The remarkable consistency among the three signals highlighted the robust internal verification capability for accurate detection. This approach enhances flexibility in selecting detection methodologies to suit diverse scenarios, facilitating HIgG detection. The tri-signal nanoprobes also exhibited excellent detection selectivity, specificity and repeatability. This study presents a fresh idea for developing high-performance detection strategies.

Recent Advances in Hydrogel Technology in Delivering Mesenchymal Stem Cell for Osteoarthritis Therapy.

Osteoarthritis (OA), a chronic joint disease affecting over 500 million individuals globally, is characterized by the destruction of articular cartilage and joint inflammation. Conventional treatments are insufficient for repairing damaged joint tissue, necessitating novel therapeutic approaches. Mesenchymal stem cells (MSCs), with their potential for differentiation and self-renewal, hold great promise as a treatment for OA. However, challenges such as MSC viability and apoptosis in the ischemic joint environment hinder their therapeutic effectiveness. Hydrogels with biocompatibility and degradability offer a three-dimensional scaffold that support cell viability and differentiation, making them ideal for MSC delivery in OA treatment. This review discusses the pathological features of OA, the properties of MSCs, the challenges associated with MSC therapy, and methods for hydrogel preparation and functionalization. Furthermore, it highlights the advantages of hydrogel-based MSC delivery systems while providing insights into future research directions and the clinical potential of this approach.

A two-sample Mendelian randomization study of mutual relations of six types of diets in atopic dermatitis.

BACKGROUND: In the continuous endeavor to find safe and efficient treatments for Atopic Dermatitis (AD), there remains a considerable focus on dietary adjustments. Nevertheless, the limited availability of research and conflicting findings in the academic literature pose a hurdle in establishing conclusive recommendations. METHOD: Mendelian randomization (MR) was applied to the most comprehensive genome-wide association studies (GWAS) data on tea intake (447 485), green tea intake (n = 64 949), flavored milk intake (n = 64 941), never eat eggs, dairy, wheat, sugar: Wheat products(n = 461 046), never eat eggs, dairy, wheat, sugar: Sugar or foods/drinks containing sugar (n = 461 046), never eat eggs, dairy, wheat, sugar: I eat all of the above (n = 461 046) and atopic dermatitis (n = 218 467). We used the inverse-variance weighted method (IVW) as the primary method. RESULTS: The IVW analyses have demonstrated an increased tea intake was genetically associated with a reduced risk of AD (odds ratio [OR]: 0.646, 95% confidence interval [CI]: 0.430-0.968, p = 0.034). Furthermore, green tea intake was significantly negatively associated with AD (IVW OR: 0.986, 95% CI: 0.975-0.998; p = 0.024) in the IVW model. AD risk could be reduced by never eating wheat products (IVW OR: 8.243E-04, 95% CI: 7.223E-06-9.408E-02, p = 0.003). There was no association between never eating eggs, dairy, wheat, sugar: Sugar, or foods/drinks containing sugar, I eat all of the above and AD. CONCLUSIONS: Our MR study suggests a causal relationship between tea intake, green tea intake, and the avoidance of eating wheat products with atopic dermatitis. Our findings recommend that preventing and managing atopic dermatitis may be achieved by never eating wheat products while increasing tea and green tea intake.

Engineering viral vectors for acoustically targeted gene delivery.

Targeted gene delivery to the brain is a critical tool for neuroscience research and has significant potential to treat human disease. However, the site-specific delivery of common gene vectors such as adeno-associated viruses (AAVs) is typically performed via invasive injections, which limit its applicable scope of research and clinical applications. Alternatively, focused ultrasound blood-brain-barrier opening (FUS-BBBO), performed noninvasively, enables the site-specific entry of AAVs into the brain from systemic circulation. However, when used in conjunction with natural AAV serotypes, this approach has limited transduction efficiency and results in substantial undesirable transduction of peripheral organs. Here, we use high throughput in vivo selection to engineer new AAV vectors specifically designed for local neuronal transduction at the site of FUS-BBBO. The resulting vectors substantially enhance ultrasound-targeted gene delivery and neuronal tropism while reducing peripheral transduction, providing a more than ten-fold improvement in targeting specificity in two tested mouse strains. In addition to enhancing the only known approach to noninvasively target gene delivery to specific brain regions, these results establish the ability of AAV vectors to be evolved for specific physical delivery mechanisms.

Effects of emulsifiers on lipid metabolism and performance of yellow-feathered broilers.

BACKGROUND: Reducing production costs while producing high-quality livestock and poultry products is an ongoing concern in the livestock industry. The addition of oil to livestock and poultry diets can enhance feed palatability and improve growth performance. Emulsifiers can be used as potential feed supplements to improve dietary energy utilization and maintain the efficient productivity of broilers. Therefore, further investigation is warranted to evaluate whether dietary emulsifier supplementation can improve the efficiency of fat utilization in the diet of yellow-feathered broilers. In the present study, the effects of adding emulsifier to the diet on lipid metabolism and the performance of yellow-feathered broilers were tested. A total of 240 yellow-feasted broilers (21-day-old) were randomly divided into 4 groups (6 replicates per group, 10 broilers per replicate, half male and half female within each replicate). The groups were as follows: the control group (fed with basal diet), the group fed with basal diet supplemented with 500 mg/kg emulsifier, the group fed with a reduced oil diet (reduced by 1%) supplemented with 500 mg/kg emulsifier, and the group fed with a reduced oil diet supplemented with 500 mg/kg emulsifier. The trial lasted for 42 days, during which the average daily feed intake, average daily gain, and feed-to-gain ratio were measured. Additionally, the expression levels of lipid metabolism-related genes in the liver, abdominal fat and each intestinal segment were assessed. RESULTS: The results showed that compared with the basal diet group, (1) The average daily gain of the basal diet + 500 mg/kg emulsifier group significantly increased (P < 0.05), and the half-even-chamber rate was significantly increased (P < 0.05); (2) The mRNA expression levels of Cd36, Dgat2, Apob, Fatp4, Fabp2, and Mttp in the small intestine were significantly increased (P < 0.05). (3) Furthermore, liver TG content significantly decreased (P < 0.05), and the mRNA expression level of Fasn in liver was significantly decreased (P < 0.05), while the expression of Apob, Lpl, Cpt-1, and Pparα significantly increased (P < 0.05). (4) The mRNA expression levels of Lpl and Fatp4 in adipose tissue were significantly increased (P < 0.05), while the expression of Atgl was significantly decreased (P < 0.05). (5) Compared with the reduced oil diet group, the half-evading rate and abdominal fat rate of broilers in the reduced oil diet + 500 mg/kg emulsifier group were significantly increased (P < 0.05), and the serum level of LDL-C increased significantly (P < 0.05)0.6) The mRNA expression levels of Cd36, Fatp4, Dgat2, Apob, and Mttp in the small intestine were significantly increased (P < 0.05). 7) The mRNA expression levels of Fasn and Acc were significantly decreased in the liver (P < 0.05), while the mRNA expression levels of Lpin1, Dgat2, Apob, Lpl, Cpt-1, and Pparα were significantly increased (P < 0.05). CONCLUSIONS: These results suggest that dietary emulsifier can enhance the fat utilization efficiency of broilers by increasing the small intestinal fatty acid uptake capacity, inhibiting hepatic fatty acid synthesis and promoting hepatic TG synthesis and transport capacity. This study provides valuable insights for the potential use of emulsifier supplementation to improve the performance of broiler chickens.