Tranylcypromine upregulates Sestrin 2 expression to ameliorate NLRP3-related noise-induced hearing loss.

JOURNAL/nrgr/04.03/01300535-202505000-00030/figure1/v/2024-07-28T173839Z/r/image-tiff Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction. However, there are currently no effective pharmacological interventions for patients with noise-induced hearing loss. Here, we present evidence suggesting that the lysine-specific demethylase 1 inhibitor-tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss, and elucidate its underlying regulatory mechanisms. We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 dB for 4 hours. We found that tranylcypromine treatment led to the upregulation of Sestrin2 (SESN2) and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine. The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click, 4, 8, and 16 kHz frequencies compared with the noise exposure group treated with saline. These findings indicate that tranylcypromine treatment resulted in increased SESN2, light chain 3B, and lysosome-associated membrane glycoprotein 1 expression after noise exposure, leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3, thereby reducing noise-induced hair cell loss. Additionally, immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway. Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domain-containing 3 (NLRP3) production. In conclusion, our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2, which induced autophagy, thereby restricting NLRP3-related inflammasome signaling, alleviating cochlear hair cell loss, and protecting hearing function. These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.

Association of Methylenetetrahydrofolate Reductase rs1801133 Polymorphism with osteoporosis and fracture risk in Taiwan.

Introduction: Osteoporosis is a prevalent skeletal disorder influenced by age, hormonal changes, medication use, nutrition, and genetics. The relationship between MTHFR and osteoporosis remains unclear, especially in Asians. The aim of our study was to elucidate the impact of MTHFR on osteoporosis and fracture risk. Materials and Methods: Participants were recruited from the Taiwan Precision Medicine Initiative at Taichung Veterans General Hospital. A total of 3,503 subjects with available bone mineral density measurements were selected. Using the Axiom Genome-Wide TWB 2.0 Array, we identified the MTHFR rs1801133 variant. Among these subjects, 1,624 patients carrying the variant were included in the case group, while the remaining 1,879 patients without the variant served as the control group. Results: Overall, individuals carrying the MTHFR rs1801133 variant exhibited a significantly elevated risk of developing osteoporosis. Stratified analysis by different genotypes, the results revealed a statistically significant association between the heterozygous genotype of MTHFR rs1801133 and osteoporosis. However, there was no significant correlation between MTHFR genotypes and fracture risk. Furthermore, subgroup analysis of female patients revealed age, a known risk factor, was associated with both osteoporosis and fractures. Interestingly, the presence of the MTHFR rs1801133 variant did not confer an increased risk of osteoporosis or fractures in females. Conclusion: Our study revealed a notable increase in the prevalence of osteoporosis among individuals carrying the MTHFR rs1801133 variant. Nevertheless, these individuals did not exhibit a heightened risk of major or hip fractures compared to non-carriers. Our findings could be of value in raising awareness of the increased risk of osteoporosis among individuals with this genetic variant.

Fluorescence hyperspectral imaging technology combined with chemometrics for kiwifruit quality attribute assessment and non-destructive judgment of maturity.

Dry matter content (DMC), firmness and soluble solid content (SSC) are important indicators for assessing the quality attributes and determining the maturity of kiwifruit. However, traditional measurement methods are time-consuming, labor-intensive, and destructive to the kiwifruit, leading to resource wastage. In order to solve this problem, this study has tracked the flowering, fruiting, maturing and collecting processes of Ya'an red-heart kiwifruit, and has proposed a non-destructive method for kiwifruit quality attribute assessment and maturity identification that combines fluorescence hyperspectral imaging (FHSI) technology and chemometrics. Specifically, first of all, three different spectral data preprocessing methods were adopted, and PLSR was used to evaluate the quality attributes (DMC, firmness, and SSC) of kiwifruit. Next, the differences in accuracy of different models in discriminating kiwifruit maturity were compared, and an ensemble learning model based on LightGBM and GBDT models was constructed. The results indicate that the ensemble learning model outperforms single machine learning models. In addition, the application effects of the 'Convolutional Neural Network'-'Multilayer Perceptron' (CNN-MLP) model under different optimization algorithms were compared. To improve the robustness of the model, an improved whale optimization algorithm (IWOA) was introduced by modifying the acceleration factor. Overall, the IWOA-CNN-MLP model performs the best in discriminating the maturity of kiwifruit, with Accuracytest of 0.916 and Loss of 0.23. In addition, compared with the basic model, the accuracy of the integrated learning model SG-MSC-SEL was improved by about 12%-20 %. The research findings will provide new perspectives for the evaluation of kiwifruit quality and maturity discrimination using FHSI and chemometric methods, thereby promoting further research and applications in this field.

Diagnostic Significance of Serum Long Noncoding HOX Antisense Intergenic Ribonucleic Acid in Patients with Hepatitis B Virus Related Hepatocellular Carcinoma.

BACKGROUND/AIMS:  Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third leading cause of cancer-related mortality. Extensive literature suggests that long noncoding RNAs play a role in the progression of HCC and hold potential as diagnostic biomarkers for this disease. MATERIALS AND METHODS:  We examined the serum levels of HOX antisense intergenic RNA (HOTAIR) in 49 hepatitis patients, 31 liver cirrhosis (LC), and 37 HCC patients using quantitative real-time polymerase chain reaction. Correlations between serum HOTAIR levels and clinical data were evaluated in HCC patients. The receiver operating characteristic curve was utilized to analyze the diagnostic potency of HOTAIR. RESULTS:  The HOTAIR levels in serum were significantly higher in HCC patients compared to those with hepatitis (P = .003) and LC patients (P = .048). There was a significant association between the serum levels of HOTAIR and positivity of hepatitis B e antigen (HBeAg) (P = .039) as well as portal vein tumor thrombus (P = .040) in HCC patients. The area under the curve (AUC) for HOTAIR for distinguishing HCC from hepatitis and LC was 0.697. The combined AUC for HOTAIR, HBeAg, and alpha-fetoprotein (AFP) was 0.777. CONCLUSION:  Serum HOTAIR functions as a potential diagnostic marker for hepatitis B virus-related HCC. Combining HOTAIR with clinical data and AFP can reinforce the diagnostic precision on HCC.

Transoral Robotic Surgery and Human Papillomavirus Infection: Impact on Oropharyngeal Cancer Prognosis.

Background/Objective: The incidence of oropharyngeal cancer (OPC) remains significant, with a rising prevalence of HPV-positive (HPV+) cases, underscoring the growing importance of appropriate treatment approaches for this condition. While HPV+ OPC typically exhibits a more favorable prognosis than HPV-negative (HPV-) OPC, certain HPV+ OPC patients still face adverse outcomes. This study aimed to assess the effectiveness of TORS versus traditional surgery in treating OPC patients and investigate the prognostic implications of specific variants in the HPV genome. Methods: The clinical information, including pathological features, treatments, and outcomes (death), of 135 OPC patients treated with traditional surgery from 2008 to 2018 (the non-TORS group) and 130 OPC patients treated with TORS from 2017 to 2021 (the TORS group) were obtained from Sun Yat-sen University Cancer Center (SYSUCC). A comparative analysis of 3-year overall survival (OS) was performed between these two groups. Furthermore, we conducted next-generation sequencing for the HPV16 genome of the 68 HPV+ OPC cases to characterize single-nucleotide variations (SNVs) in the HPV16 genome and evaluate its association with HPV+ OPC patient survival. Results: The comparative analysis of 3-year OS between the two groups (TORS vs. non-TORS) revealed a significant prognostic improvement in the TORS group for OPC patients with a T1-T2 classification (89.3% vs. 72.0%; p = 1.1 × 10-2), stages I-II (92.1% vs. 82.2%; p = 4.6 × 10-2), and stages III-IV (82.8% vs. 62.2%; p = 5.7 × 10-2) and for HPV- patients (85.5% vs. 33.3%; p < 1.0 × 10-6). Furthermore, three SNVs (SNV1339A>G, SNV1950A>C, and SNV4298A>G) in the HPV16 genome were identified as being associated with worse survival. These SNVs could alter protein interactions and weaken the binding affinity for MHC-II, promoting viral amplification and immune evasion. Conclusions: TORS exhibited a superior prognosis to traditional surgery in OPC patients. Additionally, identifying specific SNVs within the HPV16 genome provided potential prognostic markers for HPV+ OPC. These significant findings hold clinical relevance for treatment decision-making and prognostic assessment in patients with OPC.

Ultra-Sensitive Simultaneous Detection of Dopamine and Acetaminophen over Hollow Porous AuAg Alloy Nanospheres.

Hollow porous AuAg nanospheres (AuAg HPNSs) were obtained through a simple solvothermal synthesis, complemented by a dealloying strategy. The hollow interior, open pore voids, and integral interconnected skeleton shell in AuAg HPNSs are beneficial for providing sufficient electrolyte diffusion and contacts, abundant active sites, and efficient electron transport. This specific structure and the favorable alloy synergism contribute to the superior electrocatalytic activity toward dopamine (DA) and acetaminophen (AC). AuAg HPNSs show high sensitivity, good selectivity, excellent sensing durability, and outstanding repeatability for amperometric assays of AC and DA. In particular, the AuAg-based sensors achieve effective ultrasensitive simultaneous analyses of AC and DA, exhibiting the characteristics of the wide linear range and low detection limit. With their prominent electrocatalytic activity and simple preparation methods, AuAg HPNSs present broad application prospects for constructing a highly responsive electrochemical sensing system.

Research on nondestructive detection of sweet-waxy corn seed varieties and mildew based on stacked ensemble learning and hyperspectral feature fusion technology.

The variety and quality of corn seeds are crucial factors affecting crop yield and farmers' economic benefits. This study adopts an innovative method based on a hyperspectral imaging system combined with stacked ensemble learning, aiming to achieve varieties classification and mildew detection of sweet-waxy corn seeds. First, data interference is eliminated by extracting the spectral and texture information of each corn sample and preprocessing the data. Secondly, a stacked ensemble learning model (Stack) was constructed by stacking base models and meta-models. Its results were compared with those of the base models, including Gradient Boosting Decision Tree (GBDT), Extreme Gradient Boosting (XGBoost), Light Gradient Boosting Machine (LightGBM), and Random Forest (RF).Finally, the overall performance of the model is improved through the information fusion strategy of hyperspectral data and texture information. The research results indicate that the GBDT-Stack model, which integrates spectral and texture data, demonstrated optimal performance in the comprehensive classification of both corn seed varieties and mold detection. On the test set, the model achieved an average prediction accuracy of 97.01%. Specifically, the model achieved a test set accuracy ranging from 94.49% to 97.58% for different corn seed varieties and a test set accuracy of 98.89% for mildew detection. This model not only classifies corn seed varieties but also accurately detects mildew, demonstrating its wide applicability. The method has huge potential and is of great significance for improving crop yield and quality.

Sestrin2 plays a protective role in age-related hearing loss by inhibiting NLRP3-inflammasome activity.

Age-related hearing loss (ARHL) is an auditory disease characterized by gradual loss of high-frequency hearing sensitivity. Excessive reactive oxygen species trigger NLRP3-inflammasome activation that may be crucial for ARHL pathogenesis. The antioxidant factor Sestrin2 (SESN2) has been reported to be involved in the remission of oxidative stress and ARHL. However, the mechanism by which SESN2 protects auditory cells in the aging mouse cochlea remains unknown. Here, we observed that ectopic overexpression of SESN2 delayed ARHL, whereas SESN2 knockdown accelerated it. Importantly, we elucidated that SESN2 exerts a hearing-protective effect by inhibiting the production of NLRP3 by acting as a mitophagy agonist. Our study proposes a new theoretical basis for SESN2 prevention of ARHL and provides a novel therapeutic strategy for maintaining SESN2 activity in the aging cochlea.

Structural variant landscapes reveal convergent signatures of evolution in sheep and goats.

BACKGROUND: Sheep and goats have undergone domestication and improvement to produce similar phenotypes, which have been greatly impacted by structural variants (SVs). Here, we report a high-quality chromosome-level reference genome of Asiatic mouflon, and implement a comprehensive analysis of SVs in 897 genomes of worldwide wild and domestic populations of sheep and goats to reveal genetic signatures underlying convergent evolution. RESULTS: We characterize the SV landscapes in terms of genetic diversity, chromosomal distribution and their links with genes, QTLs and transposable elements, and examine their impacts on regulatory elements. We identify several novel SVs and annotate corresponding genes (e.g., BMPR1B, BMPR2, RALYL, COL21A1, and LRP1B) associated with important production traits such as fertility, meat and milk production, and wool/hair fineness. We detect signatures of selection involving the parallel evolution of orthologous SV-associated genes during domestication, local environmental adaptation, and improvement. In particular, we find that fecundity traits experienced convergent selection targeting the gene BMPR1B, with the DEL00067921 deletion explaining ~10.4% of the phenotypic variation observed in goats. CONCLUSIONS: Our results provide new insights into the convergent evolution of SVs and serve as a rich resource for the future improvement of sheep, goats, and related livestock.

A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues.

High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterize transcriptional changes of all genes in each tissue, and examine multi-tissue temporal dynamics and transcriptional interactions among genes. Particularly, we identify critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identify TAD-constrained cis-regulatory elements, which suppress the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicate that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provide time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.

Advanced optimal tracking integrating a neural critic technique for asymmetric constrained zero-sum games.

This paper investigates the optimal tracking issue for continuous-time (CT) nonlinear asymmetric constrained zero-sum games (ZSGs) by exploiting the neural critic technique. Initially, an improved algorithm is constructed to tackle the tracking control problem of nonlinear CT multiplayer ZSGs. Also, we give a novel nonquadratic function to settle the asymmetric constraints. One thing worth noting is that the method used in this paper to solve asymmetric constraints eliminates the strict restriction on the control matrix compared to the previous ones. Further, the optimal controls, the worst disturbances, and the tracking Hamilton-Jacobi-Isaacs equation are derived. Next, a single critic neural network is built to estimate the optimal cost function, thus obtaining the approximations of the optimal controls and the worst disturbances. The critic network weight is updated by the normalized steepest descent algorithm. Additionally, based on the Lyapunov method, the stability of the tracking error and the weight estimation error of the critic network is analyzed. In the end, two examples are offered to validate the theoretical results.

Tea Polyphenol Epigallocatechin Gallate Protects Against Nonalcoholic Fatty Liver Disease and Associated Endotoxemia in Rats via Modulating Gut Microbiota Dysbiosis and Alleviating Intestinal Barrier Dysfunction and Related Inflammation.

Nonalcoholic fatty liver disease (NAFLD) is characterized by fat accumulation and inflammation. Epigallocatechin gallate (EGCG) has been proven to be effective against NAFLD, but its hepatoprotective mechanisms based on the "gut microbiota-barrier-liver axis" are still not fully understood. Herein, the results demonstrated that EGCG effectively ameliorated NAFLD phenotypes and metabolic disorders in rats fed a high-fat diet (HFD), and inhibited intestinal barrier dysfunction and inflammation, which is also supported in the experiment of Caco-2 cells. Moreover, EGCG could restore gut microbiota diversity and composition, particularly promoting beneficial microbes, including short-chain fatty acids (SCFAs) producers, such as Lactobacillus, and suppressing Gram-negative bacteria, such as Desulfovibrio. The microbial modulation raised SCFA levels, decreased lipopolysaccharide levels, inhibited the TLR4/NF-κB pathway, and strengthened intestinal barrier function via Nrf2 pathway activation, thereby alleviating liver steatosis and inflammation. Spearman's correlation analysis showed that 24 key OTUs, negatively or positively associated with NAFLD and metabolic disorders, were also reshaped by EGCG. Our results suggested that a combinative improvement of EGCG on gut microbiota dysbiosis, intestinal barrier dysfunction, and inflammation might be a potential therapeutic target for NAFLD.

Series of Viologen-Based Metal-Organic Polyhedra with Photo/Electrochromic Behavior for Inkless Printing and UV Detection.

The fabrication of molecular crystalline materials with fast, multistimuli-responsive behavior and the construction of the corresponding structure-activity relationship are of extraordinary significance for the development of smart materials. In this context, three multistimuli-responsive functional metal-organic polyhedra (MOP), {[Dy2(bcbp)3(NO3)1.5(H2O)7]·Cl4.2·(NO3)0.3·H2O}n (1), {[Dy2(bcbp)4(H2O)8]Cl6}n (2), and {[Eu2(bcbp)4(H2O)10]Cl6·H2O}n (3; bcbp = 1,1'-bis(4-carboxyphenyl)-4,4'-bipyridinium), were successfully prepared and characterized. All of the compounds exhibit rapid and reversible photochromic and electrochromic dual-responsive behaviors. Furthermore, benefiting from the well-defined crystal structure and different responsive behaviors, the photoinduced electron transfer (PIET) process and structure-activity relationship were explored. In addition, considering the excellent photochromic performance, function filter paper and smart organic glass were successfully prepared and used for ink-free printing and UV light detection.

The characterization and comorbidities of heterozygous Bardet-Biedl syndrome carriers.

Introduction: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with clinical features of retinal dystrophy, obesity, postaxial polydactyly, renal anomalies, learning disabilities, hypogonadism, and genitourinary abnormalities. Nevertheless, previous studies on the phenotypic traits of BBS heterozygous carriers have generated inconclusive results. The aim of our study was to investigate the impact of BBS heterozygosity on carriers when compared to non-carriers within the Taiwanese population. Materials and Methods: This study follows a hospital-based case-control design. We employed the Taiwan Biobank version 2 (TWBv2) array to identify three specific loci associated with BBS (rs773862084, rs567573386, and rs199910690). In total, 716 patients were included in the case group, and they were compared to a control group of 2,864 patients who lacked BBS alleles. The control group was selected through gender and age matching at a ratio of 1:4. The association between BBS-related loci and comorbidity was assessed using logistic regression models. Results: We found that BBS heterozygous carriers exhibited a significant association with elevated BMI levels, especially the variant rs199910690 in MKS1 (p=0.0037). The prevalence of comorbidities in the carriers' group was not higher than that in the non-carriers' group. Besides, the average values of the biochemistry data showed no significant differences, except for creatinine level. Furthermore, we conducted a BMI-based analysis to identify specific risk factors for chronic kidney disease (CKD). Our findings revealed that individuals carrying the CA/AA genotype of the BBS2 rs773862084 variant or the CT/TT genotype of the MKS1 rs199910690 variant showed a reduced risk of developing CKD, irrespective of their BMI levels. When stratified by BMI level, obese males with the MKS1 rs199910690 variant and obese females with the BBS2 rs773862084 variant exhibited a negative association with CKD development. Conclusion: We found that aside from the association with overweight and obesity, heterozygous BBS mutations did not appear to increase the predisposition of individuals to comorbidities and metabolic diseases. To gain a more comprehensive understanding of the genetic susceptibility associated with Bardet-Biedl Syndrome (BBS), further research is warranted.

Inversion of heavy metal content in soil using hyperspectral characteristic bands-based machine learning method.

The global concern regarding the adverse effects of heavy metal pollution in soil has grown significantly. Accurate prediction of heavy metal content in soil is crucial for environmental protection. This study proposes an inversion analysis method for heavy metals (As, Cd, Cr, Cu, Ni, Pb) in soil based on hyperspectral and machine learning algorithms for 21 soil reference materials from multiple provinces in China. On this basis, an integrated learning model called Stacked RF (the base model is XGBoost, LightGBM, CatBoost, and the meta-model is RF) was established to perform soil heavy metal inversion. Specifically, three popular algorithms were initially employed to preprocess the spectral data, then Random Forest (RF) was used to select the best feature bands to reduce the impact of noise, finally Stacking and four basic machine learning algorithms were used to establish comparisons and analysis of inversion model. Compared with traditional machine learning methods, the stacking model showcases enhanced stability and superior accuracy. Research results indicate that machine learning algorithms, especially ensemble learning models, have better inversion effects on heavy metals in soil. Overall, the MF-RF-Stacking model performed best in the inversion of the six heavy metals. The research results will provide a new perspective on the ensemble learning model method for soil heavy metal content inversion using data of hyperspectral characteristic bands collected from soil reference materials.

Changes in the Physicochemical Properties and Microbial Communities of Air-Fried Hairtail Fillets during Storage.

This study assessed the physicochemical properties of air-fried hairtail fillets (190 °C, 24 min) under different storage temperatures (4, 25, and 35 °C). The findings revealed a gradual decline in sensory scores across all samples during storage, accompanied by a corresponding decrease in thiobarbituric acid reactive substances (TBARS) and total viable count over time. Lower storage temperatures exhibited an effective capacity to delay lipid oxidation and microbiological growth in air-fried hairtail fillets. Subsequently, alterations in the microbiota composition of air-fried hairtail fillets during cold storage were examined. Throughout the storage duration, Achromobacter, Escherichia-Shigella, and Pseudomonas emerged as the three dominant genera in the air-fried hairtail samples. Additionally, Pearson correlation analysis demonstrated that among the most prevalent microbial genera in air-fried hairtail samples, Achromobacter and Psychrobacter exhibited positive correlations with the L* value, a* value, and sensory scores. Conversely, they displayed negative correlations with pH, b* value, and TBARS. Notably, air-fried samples stored at 4 °C exhibited prolonged freshness compared with those stored at 25 °C and 35 °C, suggesting that 4 °C is an optimal storage temperature. This study offers valuable insights into alterations in the physicochemical properties and microbial distribution in air-fried hairtail fillets during storage, facilitating the improvement of meat quality by adjusting microbial communities in air-fried hairtail fillets.

Clinical characteristics of autoimmune encephalitis with co-existence of multiple anti-neuronal antibodies.

BACKGROUND: An increasing number of cases of autoimmune encephalitis (AE) with co-existing multiple anti-neuronal antibodies have been reported in recent years. However, the clinical significance of the concurrent presence of multiple anti-neuronal antibodies in patients with AE remains unclear. METHODS: We retrospectively enrolled AE patients with multiple anti-neuronal antibodies treated at our center between August 2019 and February 2022. We also reviewed cases reported in multiple literature databases. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed on selection process. And then the clinical and laboratory data of these cases were collected for review and summary. RESULTS: A total of 83 AE cases with multiple antibodies (9 cases from our center and 74 cases from the literatures reviewed) were identified. In our center, nine patients presented with encephalitis symptoms, clinically characterized as disturbed consciousness, seizures, cognitive impairment, and psychiatric disorders. Of the 83 cases, 73 cases had co-existence of 2 types of antibodies, 8 cases had 3 types, and 2 cases had 4 types. Thirty-nine cases (39/83, 46.9%) were confirmed or suspected of also having a tumor, of which the most common was lung cancer (28/83, 33.7%). Partial or complete recovery was achieved in 57 cases (57/83, 68.6%), while 26 cases (26/83, 31.3%) died during treatment or follow-up. CONCLUSIONS: AE with co-existing multiple anti-neuronal antibodies is a specific subgroup, that is increasingly recognized in clinical practice. The co-existence of multiple anti-neuronal antibodies has a major impact on clinical features, disease progression, and prognosis.

PD-1: A critical player and target for immune normalization.

Immune system imbalances contribute to the pathogenesis of several different diseases, and immunotherapy shows great therapeutic efficacy against tumours and infectious diseases with immune-mediated derivations. In recent years, molecules targeting the programmed cell death protein 1 (PD-1) immune checkpoint have attracted much attention, and related signalling pathways have been studied clearly. At present, several inhibitors and antibodies targeting PD-1 have been utilized as anti-tumour therapies. However, increasing evidence indicates that PD-1 blockade also has different degrees of adverse side effects, and these new explorations into the therapeutic safety of PD-1 inhibitors contribute to the emerging concept that immune normalization, rather than immune enhancement, is the ultimate goal of disease treatment. In this review, we summarize recent advancements in PD-1 research with regard to immune normalization and targeted therapy.

IBD sharing patterns as intra-breed admixture indicators in small ruminants.

In this study, we investigated how IBD patterns shared between individuals of the same breed could be informative of its admixture level, with the underlying assumption that the most admixed breeds, i.e. the least genetically isolated, should have a much more fragmented genome. We considered 111 goat breeds (i.e. 2501 individuals) and 156 sheep breeds (i.e. 3304 individuals) from Europe, Africa and Asia, for which beadchip SNP genotypes had been performed. We inferred the breed's level of admixture from: (i) the proportion of the genome shared by breed's members (i.e. "genetic integrity level" assessed from ADMIXTURE software analyses), and (ii) the "AV index" (calculated from Reynolds' genetic distances), used as a proxy for the "genetic distinctiveness". In both goat and sheep datasets, the statistical analyses (comparison of means, Spearman correlations, LM and GAM models) revealed that the most genetically isolated breeds, also showed IBD profiles made up of more shared IBD segments, which were also longer. These results pave the way for further research that could lead to the development of admixture indicators, based on the characterization of intra-breed shared IBD segments, particularly effective as they would be independent of the knowledge of the whole genetic landscape in which the breeds evolve. Finally, by highlighting the fragmentation experienced by the genomes subjected to crossbreeding carried out over the last few generations, the study reminds us of the need to preserve local breeds and the integrity of their adaptive architectures that have been shaped over the centuries.