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Galanin, a neuropeptide, regulates immune and inflammatory responses via GALR1-3. GALRs have emerged as potential therapeutic targets for inflammatory bowel disease (IBD), yet their mechanistic roles remain unclear. Based on evolutionary analysis, we identified a long galanin isoform (GAL53), generated by alternative splicing in non-mammalian vertebrates. Here we show that the chicken ortholog cGAL53 is robustly expressed in colonic tissue but downregulated upon dextran sulfate sodium (DSS)-induced colitis. Administration of cGAL53 alleviates colitis-associated weight loss, colon shortening, bleeding, and inflammation in both chickens and mice. These effects are abolished in Galr2 -deficient mice, highlighting receptor dependency. Moreover, epithelial cell-specific Arrb2 and Gnaq knockout models demonstrate that cGAL53 protects the gut barrier and reduces inflammation by activating β-arrestin2-biased GALR2 signaling. Our findings reveal a naturally occurring long galanin peptide with potent anti-inflammatory activity and propose evolutionary medicine-guided biased GALR2 agonism as a therapeutic strategy for IBD. GALRs, receptors for the neuropeptide galanin, have emerged as potential therapeutic targets for inflammatory bowel disease. Here the authors report that GAL53, a long galanin peptide derived from non-mammalian vertebrates, alleviates induced colitis in preclinical models by engaging GALR2 and activating the β-arrestin2-biased signalling pathway.

Aim This study aims to explore the effect of the ketogenic diet (KD) on the occurrence of end‐stage renal disease (ESRD) and the longitudinal relationship between circulating β‐hydroxybutyrate (β‐OHB) and kidney outcomes. Methods We used the dietary ketogenic ratio (DKR) to estimate the nutritional ketosis probability of KD and analyzed the association with ESRD using NHANES cross‐sectional data by Spearman correlation coefficient and multivariate logistic regression model. We also used the Kaplan–Meier method, Cox regression analysis, and restricted cubic splines (RCS) to analyze the relationship between circulating β‐OHB and renal outcomes in the T2DM‐DKD longitudinal cohort of West China Hospital. Mendelian randomization (MR) was also employed to evaluate potential causal associations. Results The cross‐sectional analysis revealed that non‐ESRD patients had significantly higher baseline age, BMI, serum albumin, and DKR values, with a weak negative correlation between DKR and serum creatinine (ρ = −0.072, p = 0.011). Logistic regression consistently indicated a reduced ESRD prevalence in higher DKR quartiles. In the longitudinal study, elevated β‐OHB levels were associated with improved renal survival and a lower risk of ESRD, with RCS analysis identifying the lowest risk at approximately 0.25 mmol/L. MR analyses supported these findings, showing inverse correlations between genetically predicted β‐OHB and creatinine (p = 0.007) and cystatin c (p < 0.001). Conclusion These findings suggest that KD may be associated with a lower incidence of ESRD in DKD patients, with elevated β‐OHB levels independently associated with a reduced risk of ESRD, warranting further research to confirm causality and elucidate underlying mechanisms. Ketogenic diet (KD) promotes nutritional ketosis and raises β‐hydroxybutyrate (β‐OHB) levels. Using cross‐sectional, longitudinal, and Mendelian randomization analyses, we found that elevated β‐OHB levels were independently associated with a reduced risk of ESRD. A nonlinear relationship between β‐OHB and ESRD risk was observed in DKD patients, suggesting that maintaining high‐normal β‐OHB levels may help delay DKD progression.

Human papillomavirus (HPV) is the causative agent in genital warts and nearly all cervical, anogenital, and oropharyngeal cancers. Nine HPV types (6, 11, 16, 18, 31, 33, 45, 52, and 58) are associated with about 90% of cervical cancers and 90% of genital warts. HPV neutralization by vaccine-elicited neutralizing antibodies can block viral infection and prevent HPV-associated diseases. However, there is only one commercially available HPV vaccine, Gardasil 9, produced from Saccharomyces cerevisiae that covers all nine types, raising the need for microbial production of broad-spectrum HPV vaccines. Here, we investigated whether N-terminal truncations of the major HPV capsid proteins L1, improve their soluble expression in Escherichia coli. We found that N-terminal truncations promoted the soluble expression of HPV 33 (truncated by 10 amino acids [aa]), 52 (15 aa), and 58 (10 aa). The resultant HPV L1 proteins were purified in pentamer form and extensively characterized with biochemical, biophysical, and immunochemical methods. The pentamers self-assembled into virus-like particles (VLPs) in vitro, and 3D cryo-EM reconstructions revealed that all formed T = 7 icosahedral particles having 50-60-nm diameters. Moreover, we formulated a nine-valent HPV vaccine candidate with aluminum adjuvant and L1 VLPs from four genotypes used in this study and five from previous work. Immunogenicity assays in mice and non-human primates indicated that this HPV nine-valent vaccine candidate elicits neutralizing antibody titers comparable to those induced by Gardasil 9. Our study provides a method for producing a nine-valent HPV vaccine in E. coli and may inform strategies for the soluble expression of other vaccine candidates. * N-terminal truncations promote the soluble expression of HPV L1 proteins in E. coli and their self-assembly of T = 7 icosahedral particle in vitro * An HPV 9-valent vaccine candidate was formulated with E. coli-derived HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 VLPs, and conferred comparable immunogenicity with Gardasil 9

For the DNA microarray datasets, tumor classification based on gene expression profiles has drawn great attention, and gene selection plays a significant role in improving the classification performance of microarray data. In this study, an effective hybrid gene selection method based on ReliefF and Ant colony optimization (ACO) algorithm for tumor classification is proposed. First, for the ReliefF algorithm, the average distance among k nearest or k non-nearest neighbor samples are introduced to estimate the difference among samples, based on which the distances between the samples in the same class or the different classes are defined, and then it can more effectively evaluate the weight values of genes for samples. To obtain the stable results in emergencies, a distance coefficient is developed to construct a new formula of updating weight coefficient of genes to further reduce the instability during calculations. When decreasing the distance between the same samples and increasing the distance between the different samples, the weight division is more obvious. Thus, the ReliefF algorithm can be improved to reduce the initial dimensionality of gene expression datasets and obtain a candidate gene subset. Second, a new pruning rule is designed to reduce dimensionality and obtain a new candidate subset with the smaller number of genes. The probability formula of the next point in the path selected by the ants is presented to highlight the closeness of the correlation relationship between the reaction variables. To increase the pheromone concentration of important genes, a new phenotype updating formula of the ACO algorithm is adopted to prevent the pheromone left by the ants that are overwhelmed with time, and then the weight coefficients of the genes are applied here to eliminate the interference of difference data as much as possible. It follows that the improved ACO algorithm has the ability of the strong positive feedback, which quickly converges to an optimal solution through the accumulation and the updating of pheromone. Finally, by combining the improved ReliefF algorithm and the improved ACO method, a hybrid filter-wrapper-based gene selection algorithm called as RFACO-GS is proposed. The experimental results under several public gene expression datasets demonstrate that the proposed method is very effective, which can significantly reduce the dimensionality of gene expression datasets, and select the most relevant genes with high classification accuracy.

PurposeSemaglutide is the only oral GLP-1 RA in the market, but oral bioavailability is generally limited in range of 0.4–1%. In this study, a new GLP-1RA named SHR-2042 was developed to gain higher oral bioavailability than semaglutide.MethodSelf-association of SHR-2042, semaglutide and liraglutide were assessed using SEC-MALS. The intestinal perfusion test in SD rats was used to select permeation enhancers (PEs) including SNAC, C10 and LCC. ITC, CD and DLS were used to explore the interaction between SHR-2042 and SNAC. Gastric administrated test in SD rats was used to screen SHR-2042 granules with different SHR-2042/SNAC ratios. The oral bioavailability of SHR-2042 was studied in rats and monkeys.ResultThe designed GLP-1RA, SHR-2042, gives a better solubility and lipophilicity than semaglutide. While it forms a similar oligomer with that of semaglutide. During the selection of PEs, SNAC shows better exposure than the other competing PEs including C10 and LCC. SHR-2042 and SNAC bind quickly and exhibit hydrophobic interaction. SNAC could promote monomerization of SHR-2042 and form micelles to trap the monomerized SHR-2042. The oral bioavailability of SHR-2042 paired with SNAC is 0.041% (1:0, w/w), 0.083% (1:10, w/w), 0.32% (1:30, w/w) and 2.83% (1:60, w/w) in rats. And the oral bioavailability of SHR-2042 matched with SNAC is 3.39% (1:30, w/w) in monkeys, which is over 10 times higher than that of semaglutide.ConclusionWe believe that the design and development of oral SHR-2042 will provide a new way to design more and more GLP-1RAs with high oral bioavailability in the future.

In this paper, a wireless communication system based on time-domain digital coding metasurface with Quadrature Phase Shift Keying (QPSK) modulation is proposed. The aperture-coupled resonant rings on the metal patches of the metasurface elements create an asymmetry along the x-axis, resulting in a phase difference. The Field Programmable Gate Array (FPGA) is used to change the conduction and cutoff states of pin diodes, which can control the phase responses of the metasurface elements, forming four coding states. Within a certain period, the FPGA dynamically modulates the high and low levels, thus controlling the reflection characteristics of the metasurface. When the information is converted into a binary bitstream and written into the FPGA, represented by high and low levels, the baseband signal is modulated onto the carrier by the metasurface. This system replaces the functionality of mixers in traditional wireless communication systems, further simplifying the architecture of wireless communication systems. The overall system is demonstrated by an experiment with a picture transmitted and received in real time, showing promise in future low-cost wireless communication transmission systems.

Background Paraquat and diquat are widely used in agricultural production in many countries, which are very toxic to human beings. Paraquat can be detected in some diquat solution sold in the market. The blood concentration of paraquat or diquat is an important indicator for clinical diagnosis of paraquat or diquat poisoning. So, it is very meaningful to develop a method for simultaneous determination of paraquat and diquat in human plasma. Objective To develop and validate a HPLC‐DAD method for simultaneous determination of paraquat and diquat in human plasma and to apply it in the acute poisoning patients by these two herbicides. Methods Paraquat and diquat were simultaneously determined by HPLC‐DAD. The plasma was treated using Waters OASIS® Column and then separated on a Thermo Hypersil GOLD (250 × 4.6 mm, 5 μm) Column with the mobile phase consisted of 75 mmol/L sodium heptane sulfonate (containing 0.1 mol/L phosphoric acid, pH 3.0) and acetonitrile (87:13, v:v) at a flow rate of 1.0 mL/min. The full‐wavelength scanning was 200‐400 nm, and the detection wavelength of paraquat and diquat was 257nm and 310nm, respectively. 120 and 30 plasma samples from patients with paraquat and diquat poisoning were collected and analyzed by the established method. Results The standard curve for paraquat and diquat ranged from 0.05 to 20 μg/mL, and the precision of LLOQ for paraquat was 16.49%, which was required to be less than 20%. The precision of other concentrations was less than 14.14%. The recovery of paraquat and diquat was 95.38%‐103.97% and 94.79%‐98.40%, respectively. The results showed that paraquat and diquat were stable under various storage conditions. 120 plasma samples of paraquat poisoning patients and 30 plasma samples of diquat poisoning patients were determined by the established method. The blood concentration of paraquat ranged from 0.10 to 20.62 μg/mL, with an average of 3.61 μg/mL, while for diquat, the concentration ranged from 0 to 26.59 μg/mL, with an average of 2.00 μg/mL. Among the diquat suspected poisoning samples, 5 samples were detected not only diquat but also paraquat, and 2 samples were detected only paraquat, no diquat. Conclusion The HPLC‐DAD method established in this study was high throughput, high sensitivity, simple operation, and wide linear ranges. It can be used for the screening analysis and quantitative detection of paraquat and diquat in acute poisoning patients, which can provide basis for the treatment and prognosis of these two herbicides poisoning patients. Both paraquat and diquat were determined in a suspected diquat poisoning patient plasma by the established method. The retention time of paraquat and diquat was 7.646 min and 8.771 min.

In this paper, an ultra-wideband (UWB) microwave absorber with robust angular stability is proposed. Each unit of the structure consists of three-layer stacked resistive films to effectively broaden the absorption bandwidth. A metallic via is inserted in the center of the structure, which effectively guides the TM polarization oblique incident wave power to propagate vertically and be absorbed by the resistive films, thus enhancing the angular stability of TM polarization. Within the frequency range of 3.2 GHz to 35.5 GHz, the absorptivity surpasses 90% and the fractional bandwidth reaches 167%. Within an incident angle range of 0∘ to 60∘, the absorptivity of TE polarization remains at about 80%, and the TM polarization can be maintained at over 90%. The absorption mechanism was analyzed by surface power loss and surface current distribution. A sample was fabricated, and the measured results are consistent with the simulated ones. The absorber displays good angular stability and broad bandwidth, making it ideal for electromagnetic stealth applications.

In this paper, a tunable metamaterial absorber (MMA) based on active frequency selective surface (FSS) is proposed, which can dynamically tune three absorption bands. The equivalent circuit model (ECM) was used to design the MMA and elucidate its mechanism of switchable absorption. By changing the state of the PIN diode in the lossy layer and FSS layer, the absorption frequency can be tuned continuously. The tuning of the three absorption bands from S- to C-band is achieved. The numerical simulation results show that the described MMA can achieve a bandwidth of 6.2 GHz and can dynamically tune between 1.86-2.70 GHz, 2.42-5.29 GHz, and 4.16-8.10 GHz. The reflectivity is lower than -10 dB, and the fractional bandwidth reaches 125.3%. In addition, the MMA’s prototype was produced and measured. The measurement results are generally consistent with the simulation results.

Human interleukin-2 (IL-2) stimulates the differentiation and expansion of diverse immune cells dose-dependently. As an immunotherapy agent to treat metastatic cancers, IL-2 has been used in clinical practice and has demonstrated clear antitumor effects; however, its short half-life, the risk of capillary leak syndrome, and the unintended activation of immunosuppressive T cells hinder its clinical application. To address these challenges, a novel PEGylated interleukin-2 analogue, SHR-1916, was designed. Its cellular selectivity, efficacy, and improved pharmacokinetic profiles were investigated. The binding affinities were characterized by surface plasmon resonance (SPR) in vitro. Subsequently, the stimulatory properties were investigated in a murine cell line (CTLL-2), a human cell line (M07e), and human peripheral blood mononuclear cells (PBMCs). To assess the anti-tumor efficacy, a CT-26 colon carcinoma syngeneic model in BALB/c mice and a A375 human melanoma xenograft model using PBMC humanized NCG mice were used in vivo. Moreover, the pharmacokinetic behavior following a single intravenous or subcutaneous dose was evaluated in Sprague-Dawley rats. SHR-1916 abolished binding to its receptor IL-2Rα, as evidenced by SPR assays, and exerted its activity mainly through binding to IL-2Rβγ, as confirmed by CTLL-2 and M07e cell proliferation assays. In contrast to IL-2, SHR-1916 exhibited a more biased activation of CD8 T and NK cells compared to T cells and stimulated an increase in IFNγ secretion in PBMCs dose-dependently without triggering the release of other potential side effect-associated cytokines. In CT26 colon carcinoma and A375 melanoma models, SHR-1916 significantly reduced the tumor burden. Pharmacokinetic results showed that SHR-1916 had a significantly prolonged half-life in rats. SHR-1916 exhibited excellent cellular selectivity, anti-tumor efficacies, and improved pharmacokinetics. It has the potential to serve as a novel immunotherapeutic agent designed to enhance IL-2's immune-stimulating activities and promote its tolerability while reducing the immunoregulatory function of T cells.