Immune checkpoint activity exacerbate renal interstitial fibrosis progression by enhancing PD-L1 expression in renal tubular epithelial cells.

Renal interstitial fibrosis (RIF) is often associated with inflammatory cell infiltration and no effective therapy. Programmed death cell-1 (PD-1) and its ligand PD-L1 were playing critical roles in T cell coinhibition and exhaustion, but the role in RIF is unclear. Here the data analyses of serum from 122 IgA nephrology (IgAN) patients showed that high level of soluble PD-1(sPD-1) was an independent risk factor for RIF and renal function progression. PD-L1 was also overexpressed in renal interstitial tissues from both IgAN patients with high level of sPD-1 and the unilateral ureteral obstruction (UUO) mouse. PD-L1 was significantly overexpressed in HK-2 cells with upregulated collagen and α-SMA when stimulated by inflammation or hypoxia in vitro. Additionally, matrix metalloproteinases (MMP-2) could increase the level of sPD-1 in culture supernatant when added in co-culture system of HK-2 and jurkat cells, which implied serum sPD-1 of IgAN might be cleaved by MMP-2 from T cells infiltrated into the tubulointerstitial inflammatory microenvironment. Crucially, injection of PD-L1 fusion protein, the blocker of sPD-1, could ameliorate kidney fibrosis in UUO mice by increasing T cell coinhibition and exhaustion, suggesting the therapeutic potential of PD-L1 fusion targeting for renal fibrosis. Take together, it reveals a novel causal role of sPD-1 in serum and PD-L1 of renal interstitial tissues in the development of renal fibrosis of IgAN, and targeting sPD-1 in serum by PD-L1 fusion protein is a potential therapeutic approach to prevent renal fibrosis of IgAN.

An oleanic acid decorated gold nanorod for highly efficient inhibition of hemagglutinin and visible rapid detection of the influenza virus.

Accurate diagnosis and effective antiviral treatments are urgently needed for the prevention and control of flu caused by influenza viruses. In this study, a novel oleanic acid (OA) functionalized gold nanorod OA-AuNP was prepared through a convenient ligand-exchange reaction. As hemagglutinin (HA) on the viral surface binds strongly to the multiple OA molecules on the surface of the nanoparticle, the prepared OA-AuNP was found to exhibit potent antiviral activity against a wide range of influenza A virus strains. Furthermore, the change in color resulting from the specific binding between HA and OA and the resultant aggregation of the OA-AuNP can be visually observed or measured by UV-vis spectra with a detection limit of 2 and 0.18 hemagglutination units (HAU), respectively, which is comparable to the commercially available influenza colloid gold rapid diagnostic kits. These findings demonstrate the potential of the OA-AuNP for the development of novel multivalent antiviral conjugates and the diagnosis of influenza virus.

"Triple-Punch" Strategy Exosome-Mimetic Nanovesicles for Triple Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is the most malignant breast cancer, with high rates of relapse and metastasis. Because of the nonspecific targeting of chemotherapy and insurmountable aggressiveness, TNBC therapy lacks an effective strategy. Exosomes have been reported as an efficient drug delivery system (DDS). CD82 is a tumor metastasis inhibitory molecule that is enriched in exosomes. Aptamer AS1411 specifically targets TNBC cells due to its high expression of nucleolin. We generated a "triple-punch" cell membrane-derived exosome-mimetic nanovesicle system that integrated with CD82 overexpression, AS1411 conjugation, and doxorubicin (DOX) delivery. CD82 enrichment effectively inhibits the migration of TNBC cells. AS1411 conjugation specifically targets TNBC cells. DOX loading effectively inhibits proliferation and induces apoptosis of TNBC cells. Our results demonstrate a system of exosome-mimetic nanovesicles with "triple-punch" that may facilitate TNBC therapeutics.

Impacts of Puppy Early Life Experiences, Puppy-Purchasing Practices, and Owner Characteristics on Owner-Reported Problem Behaviours in a UK Pandemic Puppies Cohort at 21 Months of Age.

Problem behaviours are a leading cause of relinquishment and euthanasia of young dogs. Previous research has identified associations between owner-reported problem behaviours and risk factors, including how dogs were acquired as puppies, early socialisation experiences, and owners' experience levels. Puppies acquired during the 2020 phase of the UK COVID-19 pandemic ("Pandemic Puppies") were more likely to be exposed to many of these risk factors compared to puppies acquired in 2019; however, consequences for their adult behaviour are, as yet, unexplored. This study aimed to investigate the impact of these early-life and provenance-based risk factors, in addition to owner management strategies (including training methods) into early adulthood, upon adult dog behaviour aged 21 months. An online longitudinal cohort study of n = 985 Pandemic Puppies was conducted, recruited from a cohort of n = 4369 puppies originally surveyed in November-December 2020, which included data on how and why they were acquired and their socialisation/habituation experiences <16 weeks of age. Nearly all owners (96.7%) reported that their dog had exhibited at least one problem behaviour up to 21 months of age (median: 5; IQR: 3-7). Almost one third of dogs (30.9%) were reported to have displayed separation-related behaviours. Multivariable linear regression modelling revealed that owners reporting more problem behaviours were more likely to use multiple aversive training techniques (e.g., physical punishment), the use of which was notably high in this population (82.3%) compared to previous studies. Attendance at online puppy classes was the sole protective factor against owner use of aversive training methods. Almost one third of owners had underestimated how hard training their dog would be; this view was more likely among first-time owners. Urgent efforts are required to support this vulnerable population of dogs, including providing owner education regarding humane training techniques, to improve canine emotional health and avoid future relinquishment and/or behavioural euthanasia.

Evaluation of packaging capacity at the genomic 2C/3A junction region in Porcine enterovirus G.

Porcine enterovirus G (EV-G) is endogenous to most pig farming countries worldwide. Reports that a papain-like protease (PLP) gene has been naturally inserted into the 2C/3A junction region of the EV-G genome, has increased the potential public health threats from this virus. We constructed a full-length infectious cDNA clone of EV-G, CH/17GXQZ/2017, in order to determine the packaging capacity at the 2C/3A insertion site. Subsequently, recombinants viruses containing the coding tags, GFP, iLOV and His at the 2C/3A junction region, were synthesized. The infectious virus was successfully rescued only with the insertion of the His-tag, which displayed similar virological and molecular properties to its parental strain. This study determined the packaging capacity of the 2C/3A insertion site, and it provides a practical tool for studying the functions and pathogenic mechanisms of EV-G in pigs.

Four-Color SERS Monitoring of Size-dependent Nanoparticle Delivery in the Same Tumor.

The physicochemical properties of nanoparticles (NPs) significantly influence their deposition at the disease site, ultimately impacting the overall therapeutic efficacy; however, precisely assessing the effects of various factors on NP accumulation within a single cell/tumor tissue is challenging due to the lack of appropriate labeling techniques. Surface-enhanced Raman spectroscopy (SERS) tag is a powerful encoding method that has recently been intensively employed for immunodetection of biomarkers. Herein, we introduce a multiplexed SERS tracking approach for systematic investigation of size-dependent accumulation and distribution of NPs within the same tumor. Four-sized (34, 60, 108, and 147 nm) NPs encoded with different SERS "colors" were fabricated, mixed, and incubated with monolayer tumor cells, multicellular tumor spheroids, or injected into mouse models bearing xenograft solid tumors in a single dose. Multicolor SERS detection of the specimens revealed that NP accumulation in tumor cells, tumor spheroids, and solid tumors was in the order of 34 nm > 60 nm > 108 nm > 147 nm, 60 nm > 34 nm > 108 nm > 147 nm, and 34 nm > 147 nm > 108 nm > 60 nm, respectively. Inductively coupled plasma mass spectroscopy determination performed in parallel samples were in alignment with the four-color SERS probing results, demonstrating the effectiveness of this multiplexed evaluation assay. Furthermore, in combination with fluorescence labeling of specific biomolecules, this method can be applied for the colocalization of different NPs in various pathological structures and provide additional information for analysis of the possible mechanisms.

2, 2-dimethylthiazolidine hydrochloride protects against experimental contrast-induced acute kidney injury via inhibition of tubular ferroptosis.

Contrast-induced acute kidney injury (CI-AKI) has become the third leading cause of AKI acquired in hospital, lacking of effective interventions. In the study, we identified the renal beneficial role of 2, 2-dimethylthiazolidine hydrochloride (DMTD), a safer compound which is readily hydrolyzed to cysteamine, in the rodent model of CI-AKI. Our data showed that administration of DMTD attenuated the impaired renal function and tubular injury induced by the contrast agent. Levels of MDA, 4-hydroxynonenal, ferrous iron and morphological signs showed that contrast agent induced ferroptosis, which could be inhibited in the DMTD group. In vitro, DMTD suppressed ferroptosis induced by ioversol in the cultured tubular cells. Treatment of DMTD upregulated glutathione (GSH) and glutathione peroxidase 4 (GPX4). Moreover, we found that DMTD promoted the ubiquitin-mediated proteasomal degradation of Keap1, and thus increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2). Mechanistically, increase of the ubiquitylation degradation of Keap1 mediates the upregulated effect of DMTD on Nrf2. Consequently, activated Nrf2/Slc7a11 results in the increase of GSH and GPX4, and therefore leads to the inhibition of ferroptosis. Herein, we imply DMTD as a potential therapeutic agent for the treatment of CI-AKI.

GsPKS24, a calcineurin B-like protein-interacting protein kinase gene from Glycine soja, positively regulates tolerance to pH stress and ABA signal transduction.

SOS2-like protein kinases (PKS/CIPK) family genes are known to be involved in various abiotic stresses in plants. Even though, its functions have been well characterized under salt and drought stresses. The roles of PKS genes associated with alkaline stress response are not fully established yet. In this study, we identified 56 PKS family genes which could be mainly classified into three groups in wild soybean (Glycine soja). PKS family genes transcript profiles revealed different expression patterns under alkali stress. Furthermore, we confirmed the regulatory roles of GsPKS24 in response to NaHCO3, pH and ABA treatments. Overexpression of GsPKS24 enhanced plant tolerance to pH stress in Arabidopsis and soybean hairy roots but conferred suppressed pH tolerance in Arabidopsis atpks mutant. Additionally, Overexpression of GsPKS24 decreased the ABA sensitivity compared to Arabidopsis atpks mutant which displayed more sensitivity towards ABA. Moreover, upregulated expression of stress responsive and ABA signal-related genes were detected in GsPKS24 overexpression lines. In conclusion, we identified the wild soybean PKS family genes, and explored the roles of GsPKS24 in positive response to pH stress tolerance, and in alleviation of ABA sensitivity.

Impacts of climate change on herpetofauna diversity in the Qinghai-Tibetan Plateau.

Although numerous studies on the impacts of climate change on biodiversity have been published, only a handful are focused on the intraspecific level or consider population-level models (separate models per population). We endeavored to fill this knowledge gap relative to the Qinghai-Tibetan plateau (QTP) by combining species distribution modeling (SDMs) with population genetics (i.e., population-level models) and phylogenetic methods (i.e., phylogenetic tree reconstruction and phylogenetic diversity analyses). We applied our models to 11 endemic and widely distributed herpetofauna species inhabiting high elevations in the QTP. We aimed to determine the influence of environmental heterogeneity on species' responses to climate change, the magnitude of climate-change impacts on intraspecific diversity, and the relationship between species range loss and intraspecific diversity losses under 2 shared socioeconomic pathways (SSP245 and SSP585) and 3 future periods (2050s, 2070s, and 2090s). The effects of global climatic change were more pronounced at the intraspecific level (22% of haplotypes lost and 36% of populations lost) than the morphospecies level in the SSP585 climate change scenario. Maintenance of genetic diversity was in general determined by a combination of factors including range changes, species genetic structure, and the part of the range predicted to be lost. This is owing to the fact that the loss and survival of populations were observed in species irrespective of the predicted range changes (contraction or expansion). In the southeast (mountainous regions), climate change had less of an effect on range size (>100% in 3 species) than in central and northern QTP plateau regions (range size <100% in all species). This may be attributed to environmental heterogeneity, which provided pockets of suitable climate in the southeast, whereas ecosystems in the north and central regions were homogeneous. Generally, our results imply that mountainous regions with high environmental heterogeneity and high genetic diversity may buffer the adverse impacts of climate change on species distribution and intraspecific diversity. Therefore, genetic structure and characteristics of the ecosystem may be crucial for conservation under climate change.

Impactos del cambio climático sobre la diversidad de herpetofauna en la meseta Qinghai-Tíbet Región Aunque se han publicado numerosos estudios sobre los impactos del cambio climática en la biodiversidad, son muy pocos los que se enfocan en el nivel intraespecífico o que consideran modelos a nivel poblacional (modelos separados por población). Intentamos cerrar este vacío de conocimiento en relación con la meseta Qinghai-Tíbet (MQT) con la combinación entre modelos de distribución de especies (MDE) y genética poblacional (modelos a nivel poblacional) y métodos filogenéticos (reconstrucción de árboles filogenéticos y análisis de diversidad filogenética). Aplicamos nuestros modelos a once especies endémicas de herpetofauna con distribución amplia en las elevaciones más altas de la MQT. Nos planteamos determinar la influencia de la heterogeneidad de las especies sobre la respuesta de las especies al cambio climático, la magnitud de los impactos del cambio climático sobre la diversidad intraespecífica y la relación entre la pérdida de distribución de la especie y las pérdidas de diversidad intraespecífica bajo dos vías socioeconómicas (SSP245 y SSP585) y tres periodos del futuro (2050s, 2070s y 2090s). Los efectos del cambio climático global fueron más pronunciados a nivel intraespecífico (22% de pérdida en los haplotipos y 36% en las poblaciones) que al nivel morfoespecie en el escenario de cambio climático SSP585. El mantenimiento de la diversidad genética casi siempre estuvo determinado por una combinación de factores que incluyen cambios en la distribución, estructura genética de las especies y la parte de la distribución que se pronosticó se perdería. Esto se debe a que observamos la pérdida y supervivencia de las poblaciones sin importar los cambios pronosticados en la distribución (contracción o expansión). En las regiones montañosas del sureste, el cambio climático tuvo un efecto menor sobre la distribución (>100% en tres especies) comparado con las regiones de la meseta central y del norte de la MQT (distribución <100% en todas las especies). Esto puede atribuirse a la heterogeneidad ambiental, la cual proporciona recovecos de clima adecuado en el sureste, mientras que los ecosistemas en las regiones central y norte fueron homogéneos. De manera general, nuestros resultados implican que las regiones montañosas con una elevada heterogeneidad ambiental y una gran diversidad genética podrían reducir los impactos adversos del cambio climático sobre la distribución de las especies y la diversidad intraespecífica. Por lo tanto, la estructura genética y las características del ecosistema pueden ser cruciales para conservar bajo el cambio climático.

Effects of dysregulated glucose metabolism on the occurrence and ART outcome of endometriosis.

BACKGROUND: Endometriosis is associated with systemic metabolic indicators, including body mass index (BMI), glucose metabolism and lipid metabolism, while the association between metabolic indexes and the occurrence and assisted reproductive technology (ART) outcome of endometriosis is unclear. We aimed to evaluate the characteristics of systemic metabolic indexes of endometriosis patients with infertility and their effects on pregnancy outcome after ART treatment. METHODS: A retrospective cohort study involve 412 endometriosis patients and 1551 controls was conducted. Primary outcome was metabolic indexes, and secondary measures consisted of the influence of metabolic indexes on the number of retrieved oocytes and ART outcomes. RESULTS: Endometriosis patients had higher insulin (INS) [6.90(5.10-9.50) vs 6.50(4.80-8.90) µU/mL, P = 0.005]. A prediction model for endometriosis combining the number of previous pregnancies, CA125, fasting blood glucose (Glu) and INS, had a sensitivity of 73.9%, specificity of 67.8% and area under curve (AUC) of 0.77. There were no significant differences in ART outcomes and complications during pregnancy. The serum levels of Glu before pregnancy were associated with GDM both in endometriosis group (aOR 12.95, 95% CI 1.69-99.42, P = 0.014) and in control group (aOR 4.15, 95% CI 1.50-11.53, P = 0.006). CONCLUSIONS: We found serum Glu is related to the number of retrieved oocytes in control group, serum INS is related to the number of retrieved oocytes in endometriosis group, while serum Glu and INS before pregnancy are related to the occurrence of GDM in two groups. A prediction model based on metabolic indexes was established, representing a promising non-invasive method to predict endometriosis patients with known pregnancy history.

Synthetic pentatrideca-valent triazolylsialoside inhibits influenza virus hemagglutinin/neuraminidase and aggregates virion particles.

A synthetic multivalent hemagglutinin and neuraminidase inhibitor was developed by the conjugation of a septa-valent triazolylsialoside to bovine serum albumin using di-(N-succinimidyl) adipate. Matrixassisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) confirmed the attachment of five septa-valent sialyl lactosides to the protein backbone, resulting in a pentatrideca-valent sialyl conjugate. This pseudo-glycoprotein demonstrated a high affinity for hemagglutinin/neuraminidase as well as for the drug-resistant NA mutation on the influenza virus surface due to the cluster effect. The conjugate also exhibited potent antiviral activity against a wide range of virus strains without cytotoxicity at high concentrations. Mechanistic studies revealed that the pentatrideca-valent sialyl conjugate bound strongly to the influenza virion particles through interactions with HA/NA on the virion surfaces. The KD of the interaction was approximately 1 µM, as determined by isothermal calorimetric titration, allowing the capture and trapping of the influenza virions and preventing their further infection of host cells. These findings provide insight into the development of new antiviral agents using multivalent sialic acid clusters.

Effects of incineration and pyrolysis on removal of organics and liberation of cathode active materials derived from spent ternary lithium-ion batteries.

Removing organics via thermal treatment to liberate active materials from spent cathode sheets is essential for recovering lithium-ion batteries. In this study, the effects of incineration, N2 pyrolysis, and CO2 pyrolysis on the removal of organics and liberation of ternary cathode active materials (CAMs) were compared. The results indicated that the organics in the spent ternary cathode sheets comprised a residual electrolyte and polyvinylidene fluoride (PVDF) binder. Moreover, the organics could be removed to promote the liberation of CAMs via incineration, N2 pyrolysis, and CO2 pyrolysis. When the temperature was <200 °C, the chemical properties of the volatilized ester electrolyte remained unchanged during both N2 and CO2 pyrolysis, indicating that the electrolyte can be collected by controlling the pyrolysis temperature and condensation. Furthermore, PVDF binder decomposition occurred at 200-600 °C. The optimal temperatures of incineration, N2 pyrolysis, and CO2 pyrolysis were 550, 500, and 450 °C, respectively, and these treatments increased the liberation efficiency of CAMs from 81.49 % to 98.75 %, 99.26 %, and 97.98 %, respectively. In addition, heat-treated CAMs required less time to achieve adequate liberation. Following three thermal treatment processes, the sizes of the CAM particles were mainly concentrated in the ranges of 0.075-0.1 mm and <0.075 mm. Furthermore, for all types of CAMs examined, the Al concentration decreased from 1.09 % to <0.35 %, which increased the separation efficiency and improved the chemical metallurgical performance.

Ultrasensitive iodide detection in biofluids based on hot electron-induced reduction of p-Nitrothiophenol on Au@Ag core-shell nanoparticles.

Surveillance of iodine intake is important because either inadequate or excessive amount of iodine may lead to thyroid malfunctions. Herein, we report a method for fast iodide quantification based on a plasmonic hot electron-driven chemical reaction, which occurs on Au@Ag core-shell nanoparticles (NPs) coated with p-nitrothiophenol (PNTP) molecules. Upon resonant light illumination, hot electron-hole pairs are generated in the NPs. The hot holes capture iodide ions (I-) and form AgI which decomposes under light; while the hot electrons are shifted to the electron orbital (LUMO) of PNTP and trigger its reduction to p-aminothiophenol (PATP). By measuring characteristic surface-enhanced Raman spectroscopic (SERS) peaks of PNTP and PATP, the concentration of I- in water can be quantitatively determined, with a linear response in the 0.5-20 µM range and a detection limit of 0.30 µM. The Au@Ag nanosensor was then applied for I- detection in various biofluids including urine, serum and saliva, exhibiting superior detection sensitivity and high selectivity. This sensing assay requires a small sample volume of ∼10 µL and completes the entire detection process in ∼2 min, and therefore holds significant potential for application in point-of-care settings.

Biological Characteristics and Pathogenicity Analysis of a Low Virulence G2a Porcine Epidemic Diarrhea Virus.

Since the outbreak caused by a porcine epidemic diarrhea virus (PEDV) variant in 2010, the current epidemic of PEDV genotype 2 (G2) has caused huge economic losses to the pig industry in China. In order to better understand the biological characteristics and pathogenicity of the current PEDV field strains, 12 PEDV isolates were collected and plaque purified during 2017 to 2018 in Guangxi, China. The neutralizing epitopes of the spike proteins and the ORF3 proteins were analyzed to evaluate genetic variations, and they were compared with the reported G2a and G2b strains. Phylogenetic analysis of the S protein showed that the 12 isolates were clustered into the G2 subgroup (with 5 and 7 strains in G2a and G2b, respectively) and that they shared 97.4 to 99.9% amino acid identities. Among them, one of the G2a strains, CH/GXNN-1/2018, which had a titer of 106.15 PFU/mL, was selected for pathogenicity analysis. Although piglets infected with the CH/GXNN-1/2018 strain exhibited severe clinical signs and the highest level of virus shedding within 24 h postinfection (hpi), recovery and decreased virus shedding were seen after 48 hpi, and no piglets died during the whole process. Thus, the CH/GXNN-1/2018 strain had low virulence in suckling piglets. Virus neutralizing antibody analysis showed that the CH/GXNN-1/2018 strain induced cross-protection against both homologous G2a and heterologous G2b PEDV strains as early as 72 hpi. These results are of great significance for understanding PEDV in Guangxi, China, and they provide a promising naturally occurring low-virulent vaccine candidate for further study. IMPORTANCE The current epidemic of porcine epidemic diarrhea virus (PEDV) G2 has caused huge economic losses to the pig industry. Evaluation for low virulence of the PEDV strains of subgroup G2a would be useful for the future development of effective vaccines. In this study, 12 field strains of PEDV were obtained successfully, and they were characterized from Guangxi, China. The neutralizing epitopes of the spike proteins and the ORF3 proteins were analyzed to evaluate antigenic variations. One of the G2a strains, CH/GXNN-1/2018, was selected for pathogenicity analysis, and it showed that the CH/GXNN-1/2018 strain had low virulence in suckling piglets. These results provide a promising naturally occurring low-virulent vaccine candidate for further study.

Empty and Full AAV Capsid Charge and Hydrophobicity Differences Measured with Single-Particle AFM.

Adeno-associated virus (AAV) is showing promise as a therapy for diseases that contain a single-gene deletion or mutation. One major scale-up challenge is the removal of empty or non-gene of interest containing AAV capsids. Analytically, the empty capsids can be separated from full capsids using anion exchange chromatography. However, when scaled up to manufacturing, the minute changes in conductivity are difficult to consistently obtain. To better understand the differences in the empty and full AAV capsids, we have developed a single-particle atomic force microscopy (AFM) method to measure the differences in the charge and hydrophobicity of AAV capsids at the single-particle level. The atomic force microscope tip was functionalized with either a charged or a hydrophobic molecule, and the adhesion force between the functionalized atomic force microscope tip and the virus was measured. We measured a change in the charge and hydrophobicity between empty and full AAV2 and AAV8 capsids. The charge and hydrophobicity differences between AAV2 and AAV8 are related to the distribution of charge on the surface and not the total charge. We propose that the presence of nucleic acids inside the capsid causes minor but measurable changes in the capsid structure that lead to measurable surface changes in charge and hydrophobicity.

A nomogram model based on pre-treatment and post-treatment MR imaging radiomics signatures: application to predict progression-free survival for nasopharyngeal carcinoma.

BACKGROUND: To establish a novel model using radiomics analysis of pre-treatment and post-treatment magnetic resonance (MR) images for prediction of progression-free survival in the patients with stage II-IVA nasopharyngeal carcinoma (NPC) in South China. METHODS: One hundred and twenty NPC patients who underwent chemoradiotherapy were enrolled (80 in the training cohort and 40 in the validation cohort). Acquiring data and screening features were performed successively. Totally 1133 radiomics features were extracted from the T2-weight images before and after treatment. Least absolute shrinkage and selection operator regression, recursive feature elimination algorithm, random forest, and minimum-redundancy maximum-relevancy (mRMR) method were used for feature selection. Nomogram discrimination and calibration were evaluated. Harrell's concordance index (C-index) and receiver operating characteristic (ROC) analyses were applied to appraise the prognostic performance of nomograms. Survival curves were plotted using Kaplan-Meier method. RESULTS: Integrating independent clinical predictors with pre-treatment and post-treatment radiomics signatures which were calculated in conformity with radiomics features, we established a clinical-and-radiomics nomogram by multivariable Cox regression. Nomogram consisting of 14 pre-treatment and 7 post-treatment selected features has been proved to yield a reliable predictive performance in both training and validation groups. The C-index of clinical-and-radiomics nomogram was 0.953 (all P < 0.05), which was higher than that of clinical (0.861) or radiomics nomograms alone (based on pre-treatment statistics: 0.942; based on post-treatment statistics: 0.944). Moreover, we received Rad-score of pre-treatment named RS1 and post-treatment named RS2 and all were used as independent predictors to divide patients into high-risk and low-risk groups. Kaplan-Meier analysis showed that lower RS1 (less than cutoff value, - 1.488) and RS2 (less than cutoff value, - 0.180) were easier to avoid disease progression (all P < 0.01). It showed clinical benefit with decision curve analysis. CONCLUSIONS: MR-based radiomics measured the burden on primary tumor before treatment and the tumor regression after chemoradiotherapy, and was used to build a model to predict progression-free survival (PFS) in the stage II-IVA NPC patients. It can also help to distinguish high-risk patients from low-risk patients, thus guiding personalized treatment decisions effectively.

STMHCpan, an accurate Star-Transformer-based extensible framework for predicting MHC I allele binding peptides.

Peptide-major histocompatibility complex I (MHC I) binding affinity prediction is crucial for vaccine development, but existing methods face limitations such as small datasets, model overfitting due to excessive parameters and suboptimal performance. Here, we present STMHCPan (STAR-MHCPan), an open-source package based on the Star-Transformer model, for MHC I binding peptide prediction. Our approach introduces an attention mechanism to improve the deep learning network architecture and performance in antigen prediction. Compared with classical deep learning algorithms, STMHCPan exhibits improved performance with fewer parameters in receptor affinity training. Furthermore, STMHCPan outperforms existing ligand benchmark datasets identified by mass spectrometry. It can also handle peptides of arbitrary length and is highly scalable for predicting T-cell responses. Our software is freely available for use, training and extension through Github (https://github.com/Luckysoutheast/STMHCPan.git).

Correlations of Omentin-1 and Leptin with Bone Metabolism and Plasma Glucose Upon Type 2 Diabetes Mellitus and Osteoporosis.

BACKGROUND: The goal was to investigate the correlations of peripheral blood Omentin-1 and leptin (LEP) levels with bone metabolism and plasma glucose in patients with type 2 diabetes mellitus (T2DM) complicated with oste-oporosis (OP). METHODS: One hundred patients with T2DM admitted from September 2019 to September 2021 were divided into group A (n = 36, OP with T-score ≤ -2.5), group B (n = 50, osteopenia with T-score between -1 and -2.5), and group C (n = 14, non-OP with T-score > -1) according to the values of bone mineral density (BMD). Thirty healthy adults physically examined in the same period were selected as group D. The levels of peripheral blood Omentin-1 and LEP, bone metabolism, and plasma glucose were compared among the four groups. The correlations of peripheral blood Omentin-1 and LEP levels with bone metabolism and plasma glucose were explored by Pearson's analysis. RESULTS: In group A, the levels of Omentin-1 and LEP in peripheral blood were lowest, the serum levels of beta C-terminal cross-linked telopeptides of type I collagen (ß-CTX) and osteocalcin (OCN) were highest, the serum level of total N-terminal propeptide of type I procollagen (tPINP) was lowest, and the levels of fasting plasma glucose (FPG), 2-hours postprandial plasma glucose (2hPG) and glycosylated hemoglobin A1c (HbA1c) were highest, se-quentially followed by those of group B, group C, and group D (p < 0.05). Omentin-1 and LEP in peripheral blood were negatively correlated with ß-CTX, OCN, 2hPG, and HbA1c and positively correlated with tPINP and FPG (p < 0.05). CONCLUSIONS: The expressions of Omentin-1 and LEP in peripheral blood have correlations with bone metabolism and plasma glucose in patients with T2DM complicated with OP.

PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma.

The prognosis of renal cell carcinoma (RCC) remains poor due to metastases and resistance to chemotherapy. Salinomycin (Sal) exhibits the potential of antitumor, while the underlying mechanism is not completely clear. Here, we found that Sal induced ferroptosis in RCCs and identified Protein Disulfide Isomerase Family A Member 4 (PDIA4) as a mediator of Sal's effect on ferroptosis. Sal suppressed PDIA4 by increasing its autophagic degradation. Downregulation of PDIA4 increased the sensitivity to ferroptosis, while ectopic overexpression of PDIA4 conferred ferroptosis resistance to RCCs. Our data showed that downregulation of PDIA4 suppressed activating transcription factor 4 (ATF4) and its downstream protein SLC7A11 (solute carrier family 7 member 11), thereby aggravating ferroptosis. In vivo, the administration of Sal promoted ferroptosis and suppressed tumor progress in the xenograft mouse model of RCC. Bioinformatical analyses based on clinical tumor samples and database indicated a positive correlation exists between PDIA4 and PERK/ATF4/SLC7A11 signaling pathway, as well as the malignant prognosis of RCCs. Together, our findings reveal that PDIA4 promotes ferroptosis resistance in RCCs. Treatment of Sal sensitizes RCC to ferroptosis via suppressing PDIA4, suggesting the potential therapeutical application in RCCs.

Hyperexcited limbic neurons represent sexual satiety and reduce mating motivation.

Transient sexual experiences can have long-lasting effects on behavioral decisions, but the neural coding that accounts for this change is unclear. We found that the ejaculation experience selectively activated estrogen receptor 2 (Esr2)-expressing neurons in the bed nucleus of the stria terminalis (BNST)-BNSTEsr2-and led to persistent decreases in firing threshold for days, during which time the mice displayed sexual satiety. Inhibition of hyperexcited BNSTEsr2 elicited fast mating recovery in satiated mice of both sexes. In males, such hyperexcitability reduced mating motivation and was partially mediated by larger HCN (hyperpolarization-activated cyclic nucleotide-gated) currents. Thus, BNSTEsr2 not only encode a specific mating action but also represent a persistent state of sexual satiety, and alterations in a neuronal ion channel contribute to sexual experience-dependent long-term changes to mating drive.