Morphological changes in the cerebellum during aging: evidence from convolutional neural networks and shape analysis.

The morphology and function of the cerebellum are associated with various developmental disorders and healthy aging. Changes in cerebellar morphology during the aging process have been extensively investigated, with most studies focusing on changes in cerebellar regional volume. The volumetric method has been used to quantitatively demonstrate the decrease in the cerebellar volume with age, but it has certain limitations in visually presenting the morphological changes of cerebellar atrophy from a three-dimensional perspective. Thus, we comprehensively described cerebellar morphological changes during aging through volume measurements of subregions and shape analysis. This study included 553 healthy participants aged 20-80 years. A novel cerebellar localized segmentation algorithm based on convolutional neural networks was utilized to analyze the volume of subregions, followed by shape analysis for localized atrophy assessment based on the cerebellar thickness. The results indicated that out of the 28 subregions in the absolute volume of the cerebellum, 15 exhibited significant aging trends, and 16 exhibited significant sex differences. Regarding the analysis of relative volume, only 11 out of the 28 subregions of the cerebellum exhibited significant aging trends, and 4 exhibited significant sex differences. The results of the shape analysis revealed region-specific atrophy of the cerebellum with increasing age. Regions displaying more significant atrophy were predominantly located in the vermis, the lateral portions of bilateral cerebellar hemispheres, lobules I-III, and the medial portions of the posterior lobe. This atrophy differed between sexes. Men exhibited slightly more severe atrophy than women in most of the cerebellar regions. Our study provides a comprehensive perspective for observing cerebellar atrophy during the aging process.

Comprehensive O-Glycan Analysis by Porous Graphitized Carbon Nanoliquid Chromatography-Mass Spectrometry.

The diverse and unpredictable structures of O-GalNAc-type protein glycosylation present a challenge for its structural and functional characterization in a biological system. Porous graphitized carbon (PGC) liquid chromatography (LC) coupled to mass spectrometry (MS) has become one of the most powerful methods for the global analysis of glycans in complex biological samples, mainly due to the extensive chromatographic separation of (isomeric) glycan structures and the information delivered by collision induced fragmentation in negative mode MS for structural elucidation. However, current PGC-based methodologies fail to detect the smaller glycan species consisting of one or two monosaccharides, such as the Tn (single GalNAc) antigen, which is broadly implicated in cancer biology. This limitation is caused by the loss of small saccharides during sample preparation and LC. Here, we improved the conventional PGC nano-LC-MS/MS-based strategy for O-glycan analysis, enabling the detection of truncated O-glycan species and improving isomer separation. This was achieved by the implementation of 2.7 µm PGC particles in both the trap and analytical LC columns, which provided an enhanced binding capacity and isomer separation for O-glycans. Furthermore, a novel mixed-mode PGC-boronic acid-solid phase extraction during sample preparation was established to purify a broad range of glycans in an unbiased manner, including the previously missed mono- and disaccharides. Taken together, the optimized PGC nano-LC-MS/MS platform presents a powerful component of the toolbox for comprehensive O-glycan characterization.

Physiological, cytological and multi-omics analysis revealed the molecular response of Fritillaria cirrhosa to Cd toxicity in Qinghai-Tibet Plateau.

Fritillaria cirrhosa, an endangered plant endemic to plateau regions, faces escalating cadmium (Cd) stress due to pollution in the Qinghai-Tibet Plateau. This study employed physiological, cytological, and multi-omics techniques to investigate the toxic effects of Cd stress and detoxification mechanisms of F. cirrhosa. The results demonstrated that Cd caused severe damage to cell membranes and organelles, leading to significant oxidative damage and reducing photosynthesis, alkaloid and nucleoside contents, and biomass. Cd application increased cell wall thickness by 167.89% in leaves and 445.78% in bulbs, leading to weight percentage of Cd increases of 76.00% and 257.14%, respectively. PER, CESA, PME, and SUS, genes responsible for cell wall thickening, were significantly upregulated. Additionally, the levels of metabolites participating in the scavenging of reactive oxygen species, including oxidized glutathione, D-proline, L-citrulline, and putrescine, were significantly increased under Cd stress. Combined multi-omics analyses revealed that glutathione metabolism and cell wall biosynthesis pathways jointly constituted the detoxification mechanism of F. cirrhosa in response to Cd stress. This study provides a theoretical basis for further screening of new cultivars for Cd tolerance and developing appropriate cultivation strategies to alleviate Cd toxicity.

In vitro digestion and fermentation behaviors of polysaccharides from Choerospondias axillaris fruit and its effect on human gut microbiota.

Choerospondias axillaris fruit has attracted more and more attention due to its various pharmacological activities, which are rich in polysaccharides. This study investigated the in vitro saliva-gastrointestinal digestion and fecal fermentation behaviors of polysaccharides from Choerospondias axillaris fruit (CAP), as well as its impact on human gut microbiota. The results showed that CAP could be partially degraded during the gastrointestinal digestion. The FT-IR spectra of the digested CAP didn't change significantly, however, the morphological feature of SEM changed to disordered flocculent and rod-like structures. 16S rRNA sequencing analysis found that after in vitro fermentation, CAP could increase the relative abundances of beneficial bacteria including Megasphaera, Megamonas and Bifidobacterium to produce short-chain fatty acids (SCFAs), while it can also reduce the abundances of harmful bacteria of Collinsella, Gemmiger, Klebsiella and Citrobacter, suggesting that CAP could modulate the composition and abundance of gut microbiota. These results implied that CAP can be developed as a potential prebiotic in the future.

Effects of extreme meteorological factors and high air pollutant concentrations on the incidence of hand, foot and mouth disease in Jining, China.

Background: The evidence on the effects of extreme meteorological conditions and high air pollution levels on incidence of hand, foot and mouth disease (HFMD) is limited. Moreover, results of the available studies are inconsistent. Further investigations are imperative to elucidate the specific issue. Methods: Data on the daily cases of HFMD, meteorological factors and air pollution were obtained from 2017 to 2022 in Jining City. We employed distributed lag nonlinear model (DLNM) incorporated with Poisson regression to explore the impacts of extreme meteorological conditions and air pollution on HFMD incidence. Results: We found that there were nonlinear relationships between temperature, wind speed, PM2.5, SO2, O3 and HFMD. The cumulative risk of extreme high temperature was higher at the 95th percentile (P95th) than at the 90th percentile(P90th), and the RR values for both reached their maximum at 10-day lag (P95th RR = 1.880 (1.261-2.804), P90th RR = 1.787 (1.244-2.569)), the hazardous effect of extreme low temperatures on HFMD is faster than that of extreme high temperatures. The cumulative effect of extreme low wind speeds reached its maximum at 14-day lag (P95th RR = 1.702 (1.389-2.085), P90th RR = 1.498(1.283-1.750)). The cumulative effect of PM2.5 concentration at the P90th was largest at 14-day lag (RR = 1.637 (1.069-2.506)), and the cumulative effect at the P95th was largest at 10-day lag (RR = 1.569 (1.021-2.411)). High SO2 concentration at the P95th at 14-day lag was associated with higher risk for HFMD (RR: 1.425 (1.001-2.030)). Conclusion: Our findings suggest that high temperature, low wind speed, and high concentrations of PM2.5 and SO2 are associated with an increased risk of HFMD. This study not only adds insights to the understanding of the impact of extreme meteorological conditions and high levels of air pollutants on HFMD incidence but also holds practical significance for the development and enhancement of an early warning system for HFMD.

Clinical characteristics and prognosis of patients with newly diagnosed primary central nervous system lymphoma: a multicentre retrospective analysis.

Bruton's tyrosine kinase inhibitors (BTKi) exhibit superior efficacy in relapsed/refractory primary central nervous system lymphoma (PCNSL), but few studies have evaluated patients with newly diagnosed PCNSL, and even fewer studies have evaluated differences in efficacy between treatment with BTKi and traditional chemotherapy. This study retrospectively analyzed the clinical characteristics of 86 patients with PCNSL and identified predictors of poor prognosis for overall survival (OS). After excluding patients who only received palliative care, 82 patients were evaluated for efficacy and survival. According to the induction regimen, patients were divided into the traditional chemotherapy, BTKi combination therapy, and radiotherapy groups; the objective response rates (ORR) of the three groups were 71.4%, 96.2%, and 71.4% (P = 0.037), respectively. Both median progression-free survival and median duration of remission showed statistically significant differences (P = 0.019 and P = 0.030, respectively). The median OS of the BTKi-containing therapy group was also longer than that of the traditional chemotherapy group (not reached versus 47.8 (32.5-63.1) months, P = 0.038).Seventy-one patients who achieved an ORR were further analyzed, and achieved an ORR after four cycles of treatment and maintenance therapy had prolonged OS (P = 0.003 and P = 0.043, respectively). In conclusion, survival, and prognosis of patients with newly diagnosed PCNSL are influenced by the treatment regimen, with the BTKi-containing regimen showing great potential.

Global burden of liver cirrhosis 1990-2019 and 20 years forecast: results from the global burden of disease study 2019.

BACKGROUND: Cirrhosis is a disease that imposes a heavy burden worldwide, but its incidence varies widely by region. Therefore, we analysed data on the incidence and mortality of cirrhosis in 204 countries and territories from 1990-2019 and projected the disease development from 2019-2039. METHODS: Data on the incidence and mortality of liver cirrhosis from 1990 to 2019 were acquired from the public Global Burden of Disease (GBD) study. In addition, the average annual percentage change (AAPC) and estimated annual percentage change (EAPC) of the age-standardized rate (ASR) of cirrhosis in different regions were calculated. The estimates of risk factor exposure were summarized, and the proportion of causes and risk factors of liver cirrhosis and their relationship with the human development index (HDI) and socio-demographic index (SDI) were analysed. Trends in the incidence of cirrhosis in 2019-2039 were predicted using Nordpred and BAPC models. RESULTS: Globally, the ASR of cirrhosis incidence decreased by 0.05% per year from 25.7/100,000 in 1990 to 25.3/100,000 in 2019. The mortality risk associated with cirrhosis is notably lower in females than in males (13 per 100,000 vs 25 per 100,000). The leading cause of cirrhosis shifted from hepatitis B to C. Globally, alcohol use increased by 14%. In line, alcohol use contributed to 49.3% of disability-adjusted life years (DALYs) and 48.4% of global deaths from liver cirrhosis. Countries with a low ASR in 1990 experienced a faster increase in cirrhosis, whereas in 2019, the opposite was observed. In countries with high SDI, the ASR of cirrhosis is generally lower. Finally, projections indicate that the number and incidence of cirrhosis will persistently rise from 2019-2039. CONCLUSIONS: Cirrhosis poses an increasing health burden. Given the changing etiology, there is an imperative to strengthen the prevention of hepatitis C and alcohol consumption, to achieve early reduce the incidence of cirrhosis.

This study is an updated assessment of liver cirrhosis prevalence trends in 204 countries worldwide and the first to project trends over the next 20 years.The disease burden of cirrhosis is still increasing, and despite the decline in ASR, the number and prevalence of cirrhosis will continue to increase over the next two decades after 2019.It is alarming that the global surge in alcohol use is accompanied by an increase in DALYs and deaths due to liver cirrhosis.Liver cirrhosis remains a noteworthy public health event, and our study can further guide the development of national healthcare policies and the implementation of related interventions.

Blended controlled-release nitrogen fertilizer increases rice post-anthesis nitrogen accumulation, translocation and nitrogen-use efficiency.

One-time application of blended controlled-release nitrogen fertilizer (CRN) has the potential to solve the difficulty of top-dressing fertilizer in the cultivation of rice and reduce the cost of CRN fertilizer application. However, its effects on rice dry matter and nitrogen (N) accumulation and translocation, yield and N-use efficiency (NUE) remain uncertain. Field experiments were carried out at three sites (Mingguang, Chaohu, and Guichi) in the Yangtze River Delta in China to compare the effects of the conventional split applications of urea and the blended CRN and on post-anthesis dry matter and N accumulation and translocation, yield, and NUE in rice at 0, 60, 120, 180, and 240 kg N ha-1. The results showed that at the equal N application rates, compared under the conventional N fertilizer treatment, the blended CRN application significantly increased the rice yield by an average of 0.9-6.9%, mainly due to increase the number of spikelets per panicle. The highest yield achieved with blended CRN treatment occurred at 200 kg N ha-1, with an NUE of 45.9%. Moreover, in comparison to the conventional N fertilizer, the blended CRN treatment increased pre-anthesis N translocation (Pre-NT) by 1.0-19.8%, and the contribution of pre-NT to grain N by 0.2-8.7%, and NUE by 3.2-28.4%. Meanwhile, the blended CRN treatment reduced labor costs by 1800 Yuan ha-1 and enhanced the economic gains by 21.5-68.8%. Therefore, one-time application of blended CRN ≤ 200 kg N ha-1 application rate improved rice yield, NUE, and economic profit compared to equivalent rates of split applied conventional N fertilizers.

Changes of bacterial communities and bile acid metabolism reveal the potential "intestine-hepatopancreas axis" in shrimp.

The interaction between the gut and the liver plays a significant role in individual health and diseases. Mounting evidence supports that bile acids are important metabolites in the bidirectional communication between the gut and the liver. Most of the current studies on the "gut-liver axis" have focused on higher vertebrates, however, few was reported on lower invertebrates such as shrimp with an open circulatory system. Here, microbiomic and metabolomic analyses were conducted to investigate the bacterial composition and bile acid metabolism in intestine, hemolymph and hepatopancreas of Penaeus vannamei fed diets supplemented with octanoic acid and oleic acid. After six days of feeding, the bacterial composition in intestine, hemolymph and hepatopancreas changed at different stages, with significant increases in the relative abundance of several genera such as Pseudomonas and Rheinheimera in intestine and hepatopancreas. Notably, there was a more similar bacterial composition in intestine and hepatopancreas at the genus level, which indicated the close communication between shrimp intestine and hepatopancreas. Meanwhile, higher content of some bile acids such as lithocholic acid (LCA) and α-muricholic acid (α-MCA) in intestine and lower content of some bile acids such as taurohyocholic acids (THCA) and isolithocholic acid (IsoLCA) in hepatopancreas were detected. Furthermore, Spearman correlation analysis revealed a significant correlation between bacterial composition and bile acid metabolism in intestine and hepatopancreas. The microbial source tracking analysis showed that there was a high proportion of intestine and hepatopancreas bacterial community as the source of each other. Collectively, these results showed a strong crosstalk between shrimp intestine and hepatopancreas, which suggests a unique potential "intestine-hepatopancreas axis" in lower invertebrate shrimp with an open circulatory system. Our finding contributed to the understanding of the interplay between shrimp intestine and hepatopancreas in the view of microecology and provided new ideas for shrimp farming and disease control.

Effectiveness of guselkumab in patients with moderate-to-severe plaque psoriasis: a retrospective study from China.

Data on guselkumab as treatment for moderate-to-severe plaque psoriasis, especially in different body regions, in China is limited. This study aimed to estimate the effectiveness of guselkumab in Chinese patients with moderate-to-severe plaque psoriasis, including effectiveness at different body regions. This multicentre, observational study retrospectively enrolled patients with moderate-to-severe plaque psoriasis. Effectiveness outcome was based on Psoriasis Area and Severity Index (PASI) response and improvement in Body Surface Area (BSA) and Dermatology Life Quality Index (DLQI). A total of 51 patients were included, with a median age of 44.00 (18.00, 74.00) years and median duration of psoriasis of 10.00 (0.50, 55.00) years. After 20 weeks of treatment, PASI response with 75% improvement from baseline (PASI 75) was reported in 96.1% of patients; 72.5% of patients achieved a DLQI score of 0-1 at week 20. The percentage of affected BSA was significantly decreased at week 4 (p<0.05), week 12 (p<0.001) and week 20 (p<0.001). PASI score significantly changed from baseline after four weeks (p<0.001), 12 weeks (p<0.001) and 20 weeks of treatment (p<0.001). DLQI score significantly increased at week 4 (p<0.001), week 12 (p<0.001) and week 20 (p<0.001). PASI 75 was achieved for the upper limbs in all cases and 100% PASI improvement (PASI 100) in 89.1%. The head and lower limbs were the areas least responsive to treatment, with PASI 100 achieved in only 68.6% and 70.6%, respectively. Guselkummab provided rapid and sustained PASI improvement, especially for the skin of the upper limbs and body trunk.

Profiling the role of m6A effectors in the regulation of pluripotent reprogramming.

The N6-methyladenosine (m6A) RNA modification plays essential roles in multiple biological processes, including stem cell fate determination. To explore the role of the m6A modification in pluripotent reprogramming, we used RNA-seq to map m6A effectors in human iPSCs, fibroblasts, and H9 ESCs, as well as in mouse ESCs and fibroblasts. By integrating the human and mouse RNA-seq data, we found that 19 m6A effectors were significantly upregulated in reprogramming. Notably, IGF2BPs, particularly IGF2BP1, were among the most upregulated genes in pluripotent cells, while YTHDF3 had high levels of expression in fibroblasts. Using quantitative PCR and Western blot, we validated the pluripotency-associated elevation of IGF2BPs. Knockdown of IGF2BP1 induced the downregulation of stemness genes and exit from pluripotency. Proteome analysis of cells collected at both the beginning and terminal states of the reprogramming process revealed that the IGF2BP1 protein was positively correlated with stemness markers SOX2 and OCT4. The eCLIP-seq target analysis showed that IGF2BP1 interacted with the coding sequence (CDS) and 3'UTR regions of the SOX2 transcripts, in agreement with the location of m6A modifications. This study identifies IGF2BP1 as a vital pluripotency-associated m6A effector, providing new insight into the interplay between m6A epigenetic modifications and pluripotent reprogramming.

Preterm Birth Alters the Regional Development and Structural Covariance of Cerebellum at Term-Equivalent Age.

Preterm birth is associated with increased risk for a spectrum of neurodevelopmental disabilities. The cerebellum is implicated in a wide range of cognitive functions extending beyond sensorimotor control and plays an increasingly recognized role in brain development. Morphometric studies based on volume analyses have revealed impaired cerebellar development in preterm infants. However, the structural covariance between the cerebellum and cerebral cortex has not been studied during the neonatal period, and the extent to which structural covariance is affected by preterm birth remains unknown. In this study, using the structural MR images of 52 preterm infants scanned at term-equivalent age and 312 full-term controls from the Developing Human Connectome Project, we compared volumetric growth, local cerebellum shape development and cerebello-cerebral structural covariance between the two groups. We found that although there was no significant difference in the overall volume measurements between preterm and full-term infants, the shape measurements were different. Compared with the control infants, preterm infants had significantly larger thickness in the vermis and lower thickness in the lateral portions of the bilateral cerebral hemispheres. The structural covariance between the cerebellum and frontal and parietal lobes was significantly greater in preterm infants than in full-term controls. The findings in this study suggested that cerebellar development and cerebello-cerebral structural covariance may be affected by premature birth.

Construction and validation of a hypoxia-related gene signature to predict the prognosis of breast cancer.

BACKGROUND: Among the most common forms of cancer worldwide, breast cancer posed a serious threat to women. Recent research revealed a lack of oxygen, known as hypoxia, was crucial in forming breast cancer. This research aimed to create a robust signature with hypoxia-related genes to predict the prognosis of breast cancer patients. The function of hypoxia genes was further studied through cell line experiments. MATERIALS AND METHODS: In the bioinformatic part, transcriptome and clinical information of breast cancer were obtained from The Cancer Genome Atlas(TCGA). Hypoxia-related genes were downloaded from the Genecards Platform. Differentially expressed hypoxia-related genes (DEHRGs) were identified. The TCGA filtered data was evenly split, ensuring a 1:1 distribution between the training and testing sets. Prognostic-related DEHRGs were identified through Cox regression. The signature was established through the training set. Then, it was validated using the test set and external validation set GSE131769 from Gene Expression Omnibus (GEO). The nomogram was created by incorporating the signature and clinicopathological characteristics. The predictive value of the nomogram was evaluated by C-index and receiver operating characteristiccurve. Immune microenvironment and mutation burden were also examined. In the experiment part, the function of the two most significant hypoxia-related genes were further explored by cell-line experiments. RESULTS: In the bioinformatic part, 141 up-regulated and 157 down-regulated DEHRGs were screened out. A prognostic signature was constructed containing nine hypoxia genes (ALOX15B, CA9, CD24, CHEK1, FOXM1, HOTAIR, KCNJ11, NEDD9, PSME2) in the training set. Low-risk patients exhibited a much more favorable prognosis than higher-risk ones (P < 0.001). The signature was double-validated in the test set and GSE131769 (P = 0.006 and P = 0.001). The nomogram showed excellent predictive value with 1-year OS AUC: 0.788, 3-year OS AUC: 0.783, and 5-year OS AUC: 0.817. Patients in the high-risk group had a higher tumor mutation burden when compared to the low-risk group. In the experiment part, the down-regulation of PSME2 inhibited cell growth ability and clone formation capability of breast cancer cells, while the down-regulation of KCNJ11 did not have any functions. CONCLUSION: Based on 9 DEHRGs, a reliable signature was established through the bioinformatic method. It could accurately predict the prognosis of breast cancer patients. Cell line experiment indicated that PSME2 played a protective role. Summarily, we provided a new insight to predict the prognosis of breast cancer by hypoxia-related genes.

Sensitive organic/inorganic polarized photodetectors enhanced by charge transfer with image sensing capacity.

Organic photodetectors (OPDs) have attracted increasing attention in the future wearable sensing and real-time health monitoring, due to their intrinsic features including the mechanical flexibility, low-cost processing and cooling-free operations; while their performances are lagging as the results of inferior carrier mobility and small exciton diffusion coefficient of organic molecules. Graphene exhibits the great photoresponse with wide spectral bandwidth and high response speed. However, weak light absorption and the absence of a gain mechanism have limited its photoresponsivity. Here, we report a sensitive organic/inorganic phototransistor with fast response speed by coupling PTCDA organic single crystal with the monolayer graphene. The long range exciton diffusion in highly ordered π-conjugated molecules, efficient exciton dissociation and charge transfer at the PTCDA/graphene heterointerfaces, and the high mobility of graphene enable a high responsivity (8 × 104A/W), short response time (220 µs) and excellent specific detectivity (>1011 Jones), which is higher than the level of commercial on-chip device. This interfacial photogating effect is verified by the high-resolution spatial photocurrent mapping experiment. In addition, the high sensitivity to polarization is clear and the ultrahigh photoconductive gain enables a near-infrared (NIR) response for 980 and 1550 nm. Finally, high-speed visible and NIR imaging applications are successfully demonstrated. This work suggests that high quality organic single crystal/graphene is a promising platform for future high performance optoelectronic systems and imaging applications.

Use of tumor markers in distinguishing lung adenocarcinoma-associated malignant pleural effusion from tuberculous pleural effusion.

BACKGROUND: The distinction between lung adenocarcinoma-associated malignant pleural effusion (MPE) and tuberculous pleural effusion (TPE) continues to pose a challenge. This study sought to assess the supplementary value of tumor markers in enabling a differential diagnosis. METHODS: Data concerning tumor markers, which included carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cancer antigen 153 (CA153), cancer antigen 724 (CA724), neuron-specific enolase (NSE), cytokeratin19 fragment (Cyfra21-1), and squamous cell carcinoma antigen (SCCA), in both serum and pleural effusion samples, were retrospectively compiled from lung adenocarcinoma-associated MPE and TPE patients. A comparative analysis of tumor marker concentrations between the two groups was performed to assess diagnostic utility, followed by a multiple logistic regression to control for confounding variables. RESULTS: While gender, serum CA125 and SCCA, and pleural effusion SCCA manifested comparability between the groups, distinctions were noted in patient age and the concentration of other tumor markers in serum and pleural effusion, which were notably elevated in the MPE group. Multiple logistic regression demonstrated a positive association between the risk of lung adenocarcinoma-associated MPE and levels of CEA and CA153 in serum and pleural effusion, as well as Cyfra21-1 in serum (P < 0.05). The odds ratio for CEA surpassed that of CA153 and Cyfra21-1. CONCLUSIONS: CEA and CA153 in serum and pleural effusion, and Cyfra21-1 in serum emerge as biomarkers possessing supplementary diagnostic value in distinguishing lung adenocarcinoma-associated MPE from TPE. The diagnostic efficacy of CEA is superior to CA153 and Cyfra21-1. Conversely, the utility of CA125, CA724, NSE, and SCCA appears constrained.

IgG1 glycosylation highlights premature aging in Down syndrome.

Down syndrome (DS) is characterized by lowered immune competence and premature aging. We previously showed decreased antibody response following SARS-CoV-2 vaccination in adults with DS. IgG1 Fc glycosylation patterns are known to affect the effector function of IgG and are associated with aging. Here, we compare total and anti-spike (S) IgG1 glycosylation patterns following SARS-CoV-2 vaccination in DS and healthy controls (HC). Total and anti-Spike IgG1 Fc N-glycan glycoprofiles were measured in non-exposed adults with DS and controls before and after SARS-CoV-2 vaccination by liquid chromatography-mass spectrometry (LC-MS) of Fc glycopeptides. We recruited N = 44 patients and N = 40 controls. We confirmed IgG glycosylation patterns associated with aging in HC and showed premature aging in DS. In DS, we found decreased galactosylation (50.2% vs. 59.0%) and sialylation (6.7% vs. 8.5%) as well as increased fucosylation (97.0% vs. 94.6%) of total IgG. Both cohorts showed similar bisecting GlcNAc of total and anti-S IgG1 with age. In contrast, anti-S IgG1 of DS and HC showed highly comparable glycosylation profiles 28 days post vaccination. The IgG1 glycoprofile in DS exhibits strong premature aging. The combination of an early decrease in IgG1 Fc galactosylation and sialylation and increase in fucosylation is predicted to reduce complement activity and decrease FcγRIII binding and subsequent activation, respectively. The altered glycosylation patterns, combined with decreased antibody concentrations, help us understand the susceptibility to severe infections in DS. The effect of premature aging highlights the need for individuals with DS to receive tailored vaccines and/or vaccination schedules.

Advancements in γδT cell engineering: paving the way for enhanced cancer immunotherapy.

Comprising only 1-10% of the circulating T cell population, γδT cells play a pivotal role in cancer immunotherapy due to their unique amalgamation of innate and adaptive immune features. These cells can secrete cytokines, including interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), and can directly eliminate tumor cells through mechanisms like Fas/FasL and antibody-dependent cell-mediated cytotoxicity (ADCC). Unlike conventional αßT cells, γδT cells can target a wide variety of cancer cells independently of major histocompatibility complex (MHC) presentation and function as antigen-presenting cells (APCs). Their ability of recognizing antigens in a non-MHC restricted manner makes them an ideal candidate for allogeneic immunotherapy. Additionally, γδT cells exhibit specific tissue tropism, and rapid responsiveness upon reaching cellular targets, indicating a high level of cellular precision and adaptability. Despite these capabilities, the therapeutic potential of γδT cells has been hindered by some limitations, including their restricted abundance, unsatisfactory expansion, limited persistence, and complex biology and plasticity. To address these issues, gene-engineering strategies like the use of chimeric antigen receptor (CAR) T therapy, T cell receptor (TCR) gene transfer, and the combination with γδT cell engagers are being explored. This review will outline the progress in various engineering strategies, discuss their implications and challenges that lie ahead, and the future directions for engineered γδT cells in both monotherapy and combination immunotherapy.

Characterization of polyamine metabolism predicts prognosis, immune profile, and therapeutic efficacy in lung adenocarcinoma patients.

Background: Polyamine modification patterns in lung adenocarcinoma (LUAD) and their impact on prognosis, immune infiltration, and anti-tumor efficacy have not been systematically explored. Methods: Patients from The Cancer Genome Atlas (TCGA) were classified into subtypes according to polyamine metabolism-related genes using the consensus clustering method, and the survival outcomes and immune profile were compared. Meanwhile, the geneCluster was constructed according to the differentially expressed genes (DEGs) of the subtypes. Subsequently, the polyamine metabolism-related score (PMRS) system was established using the least absolute shrinkage and selection operator (LASSO) multivariate regression analysis in the TCGA training cohort (n = 245), which can be applied to characterize the prognosis. To verify the predictive performance of the PMRS, the internal cohort (n = 245) and the external cohort (n = 244) were recruited. The relationship between the PMRS and immune infiltration and antitumor responses was investigated. Results: Two distinct patterns (C1 and C2) were identified, in which the C1 subtype presented an adverse prognosis, high CD8+ T cell infiltration, tumor mutational burden (TMB), immune checkpoint, and low tumor immune dysfunction and exclusion (TIDE). Furthermore, two geneClusters were established, and similar findings were observed. The PMRS, including three genes (SMS, SMOX, and PSMC6), was then constructed to characterize the polyamine metabolic patterns, and the patients were divided into high- and low-PMRS groups. As confirmed by the validation cohort, the high-PMRS group possessed a poor prognosis. Moreover, external samples and immunohistochemistry confirmed that the three genes were highly expressed in tumor samples. Finally, immunotherapy and chemotherapy may be beneficial to the high-PMRS group based on the immunotherapy cohorts and low half-maximal inhibitory concentration (IC50) values. Conclusion: We identified distinct polyamine modification patterns and established a PMRS to provide new insights into the mechanism of polyamine action and improve the current anti-tumor strategy of LUAD.

Construction of Risk Prediction Model of Type 2 Diabetic Kidney Disease Based on Deep Learning.

Background: This study aimed to develop a diabetic kidney disease (DKD) prediction model using long short term memory (LSTM) neural network and evaluate its performance using accuracy, precision, recall, and area under the curve (AUC) of the receiver operating characteristic (ROC) curve. Methods: The study identified DKD risk factors through literature review and physician focus group, and collected 7 years of data from 6,040 type 2 diabetes mellitus patients based on the risk factors. Pytorch was used to build the LSTM neural network, with 70% of the data used for training and the other 30% for testing. Three models were established to examine the impact of glycosylated hemoglobin (HbA1c), systolic blood pressure (SBP), and pulse pressure (PP) variabilities on the model's performance. Results: The developed model achieved an accuracy of 83% and an AUC of 0.83. When the risk factor of HbA1c variability, SBP variability, or PP variability was removed one by one, the accuracy of each model was significantly lower than that of the optimal model, with an accuracy of 78% (P<0.001), 79% (P<0.001), and 81% (P<0.001), respectively. The AUC of ROC was also significantly lower for each model, with values of 0.72 (P<0.001), 0.75 (P<0.001), and 0.77 (P<0.05). Conclusion: The developed DKD risk predictive model using LSTM neural networks demonstrated high accuracy and AUC value. When HbA1c, SBP, and PP variabilities were added to the model as featured characteristics, the model's performance was greatly improved.