Prolonged sleep deprivation induces a cytokine-storm-like syndrome in mammals.

Most animals require sleep, and sleep loss induces serious pathophysiological consequences, including death. Previous experimental approaches for investigating sleep impacts in mice have been unable to persistently deprive animals of both rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS). Here, we report a "curling prevention by water" paradigm wherein mice remain awake 96% of the time. After 4 days of exposure, mice exhibit severe inflammation, and approximately 80% die. Sleep deprivation increases levels of prostaglandin D2 (PGD2) in the brain, and we found that elevated PGD2 efflux across the blood-brain-barrier-mediated by ATP-binding cassette subfamily C4 transporter-induces both accumulation of circulating neutrophils and a cytokine-storm-like syndrome. Experimental disruption of the PGD2/DP1 axis dramatically reduced sleep-deprivation-induced inflammation. Thus, our study reveals that sleep-related changes in PGD2 in the central nervous system drive profound pathological consequences in the peripheral immune system.

Covalent targeted radioligands potentiate radionuclide therapy.

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1-4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted ß- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.

Role of oxidative stress-induced ferroptosis in cancer therapy.

Ferroptosis is a distinct mode of cell death, distinguishing itself from typical apoptosis by its reliance on the accumulation of iron ions and lipid peroxides. Cells manifest an imbalance between oxidative stress and antioxidant equilibrium during certain pathological contexts, such as tumours, resulting in oxidative stress. Notably, recent investigations propose that heightened intracellular reactive oxygen species (ROS) due to oxidative stress can heighten cellular susceptibility to ferroptosis inducers or expedite the onset of ferroptosis. Consequently, comprehending role of ROS in the initiation of ferroptosis has significance in elucidating disorders related to oxidative stress. Moreover, an exhaustive exploration into the mechanism and control of ferroptosis might offer novel targets for addressing specific tumour types. Within this context, our review delves into recent fundamental pathways and the molecular foundation of ferroptosis. Four classical ferroptotic molecular pathways are well characterized, namely, glutathione peroxidase 4-centred molecular pathway, nuclear factor erythroid 2-related factor 2 molecular pathway, mitochondrial molecular pathway, and mTOR-dependent autophagy pathway. Furthermore, we seek to elucidate the regulatory contributions enacted by ROS. Additionally, we provide an overview of targeted medications targeting four molecular pathways implicated in ferroptosis and their potential clinical applications. Here, we review the role of ROS and oxidative stress in ferroptosis, and we discuss opportunities to use ferroptosis as a new strategy for cancer therapy and point out the current challenges persisting within the domain of ROS-regulated anticancer drug research and development.

Genome-wide association analysis explores the genetic loci of amino acid content in duck's breast muscle.

BACKGROUND: Amino acids are the basic components of protein and an important index to evaluate meat quality. With the rapid development of genomics, candidate regions and genes affecting amino acid content in livestock and poultry have been gradually revealed. Hence, genome-wide association study (GWAS) can be used to screen candidate loci associated with amino acid content in duck meat. RESULT: In the current study, the content of 16 amino acids was detected in 358 duck breast muscles. The proportion of Glu to the total amino acid content was relatively high, and the proportion was 0.14. However, the proportion of Met content was relatively low, at just 0.03. By comparative analysis, significant differences were found between males and females in 3 amino acids, including Ser, Met, and Phe. In addition, 12 SNPs were significantly correlated with Pro content by GWAS analysis, and these SNPs were annotated by 7 protein-coding genes; 8 significant SNPs were associated with Tyr content, and these SNPs were annotated by 6 protein-coding genes. At the same time, linkage disequilibrium (LD) analysis was performed on these regions with significant signals. The results showed that three SNPs in the 55-56 Mbp region of chromosome 3 were highly correlated with the leader SNP (chr3:55526954) that affected Pro content (r2 > 0.6). Similarly, LD analysis showed that there were three SNPs in the 21.2-21.6 Mbp region of chromosome 13, which were highly correlated with leader SNP (chr13:21421661) (r2 > 0.6). Moreover, Through functional enrichment analysis of all candidate genes. The results of GO enrichment analysis showed that several significant GO items were associated with amino acid transport function, including amino acid transmembrane transport and glutamine transport. The results further indicate that these candidate genes are closely associated with amino acid transport. Among them, key candidate genes include SLC38A1. For KEGG enrichment analysis, CACNA2D3 and CACNA1D genes were covered by significant pathways. CONCLUSION: In this study, GWAS analysis found a total of 28 significant SNPs affecting amino acid content. Through gene annotation, a total of 20 candidate genes were screened. In addition, Through LD analysis and enrichment analysis, we considered that SERAC1, CACNA2D3 and SLC38A1 genes are important candidate genes affecting amino acid content in duck breast muscle.

Nickel-Catalyzed Carbonylative Negishi Cross-Coupling of Unactivated Secondary Alkyl Electrophiles with 1 atm CO Gas.

We describe a nickel-catalyzed carbonylative cross-coupling of unactivated secondary alkyl electrophiles with the organozinc reagent at atmospheric CO gas, thus allowing the expedient construction of unsymmetric dialkyl ketones with broad functional group tolerance. The leverage of a newly developed NN2-pincer type ligand enables the chemoselective three-component carbonylation by overcoming the competing Negishi coupling, the undesired ß-hydride elimination, and dehalogenation of alkyl iodides side pathways. Both alkyl iodides and alkyl tosylates are compatible in the single electron transfer involved mechanism.

Palladium-Catalyzed Enantioselective Multicomponent Cross-Coupling of Trisubstituted Olefins.

The development of a catalytic method for stereogenic carbon center formation holds immense significance in organic synthesis. Transition-metal-catalyzed cross-coupling reaction has been regarded as a straightforward and efficient tool for stereoselectively forging C-C bond. Nevertheless, the creation of acyclic all-carbon quaternary-containing vicinal stereocenters remains notoriously challenging within the domain of cross-coupling chemistry despite their prominence in various bioactive small molecules. Herein, we describe a palladium-catalyzed asymmetric multicomponent cross-coupling of trisubstituted alkene with aryl diazonium salts and arylboronic acids to realize the formation of tertiary-quaternary carbon centers with high regio-, distereo-, and enantioselectivity. Specifically, the precise manipulation of the stereoconfiguration of trisubstituted alkenes enables the divergent stereoselective cross-coupling reaction, thus allowing for the facile construction of all four enantiomers. Harnessing the ligand-swap strategy involving a chiral bisoxazoline and an achiral fumarate individually accelerates the enantioselective migratory insertion and reductive elimination step in the cross-coupling process, as supported by density functional theory (DFT) calculations, thus obviating the requirement for a neighboring directing group within the internal olefin skeleton.

Rev1 overexpression accelerates N-methyl-N-nitrosourea (MNU)-induced thymic lymphoma by increasing mutagenesis.

Rev1 has two important functions in the translesion synthesis pathway, including dCMP transferase activity, and acts as a scaffolding protein for other polymerases involved in translesion synthesis. However, the role of Rev1 in mutagenesis and tumorigenesis in vivo remains unclear. We previously generated Rev1-overexpressing (Rev1-Tg) mice and reported that they exhibited a significantly increased incidence of intestinal adenoma and thymic lymphoma (TL) after N-methyl-N-nitrosourea (MNU) treatment. In this study, we investigated mutagenesis of MNU-induced TL tumorigenesis in wild-type (WT) and Rev1-Tg mice using diverse approaches, including whole-exome sequencing (WES). In Rev1-Tg TLs, the mutation frequency was higher than that in WT TL in most cases. However, no difference in the number of nonsynonymous mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) genes was observed, and mutations involved in Notch1 and MAPK signaling were similarly detected in both TLs. Mutational signature analysis of WT and Rev1-Tg TLs revealed cosine similarity with COSMIC mutational SBS5 (aging-related) and SBS11 (alkylation-related). Interestingly, the total number of mutations, but not the genotypes of WT and Rev1-Tg, was positively correlated with the relative contribution of SBS5 in individual TLs, suggesting that genetic instability could be accelerated in Rev1-Tg TLs. Finally, we demonstrated that preleukemic cells could be detected earlier in Rev1-Tg mice than in WT mice, following MNU treatment. In conclusion, Rev1 overexpression accelerates mutagenesis and increases the incidence of MNU-induced TL by shortening the latency period, which may be associated with more frequent DNA damage-induced genetic instability.

Unlocking the power of Zc3h12c: Orchestrating Macrophage activation and elevating the innate immune response.

The activation of macrophages, essential for the innate defense against invading pathogens, revolves around Toll-like receptors (TLRs). Nevertheless, a comprehensive understanding of the molecular mechanisms governing TLR signaling in the course of macrophage activation remains to be fully clarified. Although Zc3h12c was originally identified as being enriched in organs associated with macrophages, its precise function remains elusive. In this study, we observed a significant induction of Zc3h12c in macrophages following stimulation with TLR agonists and pathogens. Overexpression of Zc3h12c significantly mitigated the release of TNF-α and IL-6 triggered by lipopolysaccharide (LPS), whereas depletion of Zc3h12c increased the production of the cytokines mentioned above. Notably, the expression of IFN-ß was not influenced by Zc3h12c. Luciferase reporter assays revealed that Zc3h12c could suppress the TNF-α promoter activity. Moreover, Zc3h12c exerted a notable inhibitory effect on JNK, ERK, p38, and NF-κB signaling induced by LPS. In summary, the findings of our study suggest that Zc3h12c functions as a robust suppressor of innate immunity, potentially playing a role in the pathogenesis of infectious diseases.

The outcomes of aortic arch repair between open surgical repair and debranching endovascular hybrid surgical repair: A systematic review and meta-analysis.

BACKGROUND: At present, open surgical aortic arch repair (OAR) and debranching hybrid surgical aortic arch repair (HAR) serve as significant therapeutic approaches for aortic arch aneurysm or dissection. It remains unclear which technique is preferable. Our study aimed to compare the short-term and long-term outcomes of these two procedures. METHODS: To identify comparison studies of debranching HAR and OAR, a systematic search of the PubMed, Embase, Web of Science, and Cochrane Library databases was performed from January 2002 to April 2022. This study was registered on PROSPERO (CRD42020218080). RESULTS: Sixteen publications (1316 patients), including six propensity score-matching (PSM) analysis papers, were included in this study. Compared with the HAR group, the patients who underwent OAR were younger (OAR vs HAR: 67.53 ± 12.81 vs 71.29 ± 11.0; P < .00001), had less coronary artery disease (OAR vs HAR: 22.45% vs 32.6%; P = .007), less chronic obstructive pulmonary disease (OAR vs HAR: 16.16% vs 23.92%; P = .001), lower rates of previous stroke (OAR vs HAR: 12.46% vs 18.02%; P = .05), and a lower EuroSCORE (European System for Cardiac Operative Risk Evaluation) score (OAR vs HAR: 6.27 ± 1.04 vs 6.9 ± 3.76; P < .00001). HAR was associated with less postoperative blood transfusion (OAR vs HAR: 12.23% vs 7.91%; P = .04), shorter length of intensive care unit stays (OAR vs HAR: 5.92 ± 7.58 days vs 4.02 ± 6.60 days; P < .00001) and hospital stays (OAR vs HAR: 21.59 ± 17.54 days vs 16.49 ± 18.45 days; P < .0001), lower incidence of reoperation for bleeding complications (OAR vs HAR: 8.07% vs 3.96%; P = .01), fewer postoperative pulmonary complication (OAR vs HAR: 14.75% vs 5.02%; P < .0001), and acute renal failure (OAR vs HAR: 7.54% vs 5.17%; P = .03). In the PSM subgroup, the rates of spinal cord ischemic (OAR vs HAR: 5.75% vs 11.49%; P = .02), stroke (OAR vs HAR: 5.1% vs 17.35%; P = .01), and permanent paraplegia (OAR vs HAR: 2.79% vs 6.08%; P = .006) were lower in the OAR group than that in the HAR group. Although there was no statistically significant difference in 1-year survival rates (HAR vs OAR: hazard ratio [HR]: 1.54; P = .10), the 3-year and 5-year survivals were significantly higher in the OAR group than that in the HAR group (HAR vs OAR: HR: 1.69; P = .01; HAR vs OAR: HR: 1.68; P = .01). In the PSM subgroup, the OAR group was also significantly superior to the HAR group in terms of 3-year and 5-year survivals (HAR vs OAR: HR: 1.73; P = .04; HAR vs OAR: HR: 1.67; P = .04). The reintervention rate in the HAR group was significantly higher than that in the OAR group (OAR vs HAR: 8.24% vs 16.01%; P = .01). The most common reintervention was postoperative bleeding (8.07%) in the OAR group and endoleak (9.67%) in the HAR group. CONCLUSIONS: Our meta-analysis revealed that debranching HAR was associated with fewer perioperative complications than the OAR group, except for postoperative permanent paraplegia, reintervention, and stroke events. The OAR group demonstrated better 3-year and 5-year survivals than the debranching HAR group. However, patients in the OAR group had fewer comorbid factors and were younger than those in the HAR group. High-quality studies and well-powered randomized trials are needed to further evaluate this evolving field.

Association of Dietary Polyunsaturated Fatty Acid Intake with Allergic Rhinitis in Adults: A Cross-Sectional Study of NHANES 2005-2006.

INTRODUCTION: The incidence of allergic rhinitis (AR) is increasing year by year, and the pathogenesis is complex, in which diet may play an important role. The role of polyunsaturated fatty acids (PUFAs) in AR is still controversial. Previous studies have looked at the effects of PUFA during pregnancy, childhood, and adolescence. In this study, we aimed to determine the association between dietary intake of PUFA and AR in adults. METHODS: We used the NHANES database from 2005 to 2006 to include a total of 4,211 adult subjects. We collected dietary PUFA intake data and information on AR. Logistic regression and restricted cubic spline models were constructed to examine the association between PUFA intake and AR in adults. The t test was used to compare daily PUFA intakes in patients with and without AR. RESULTS: In the fully adjusted model (OR: 1.016; 95% CI: 1.003; 1.028), PUFA intake was positively correlated with allergic symptoms, hay fever, and AR in adults (p < 0.05). In addition, daily PUFA intake was significantly higher in people with allergic symptoms, hay fever, and AR than in people without the disease (p < 0.01). CONCLUSIONS: Our results suggest a positive association between dietary PUFA intake and AR in adults to a certain extent. Future studies on dietary PUFA dose will provide new strategies for the prevention and treatment of allergic diseases such as AR related to non-pharmaceutical interventions.

Late gadolinium enhanced cardiac MR derived radiomics approach for predicting all-cause mortality in cardiac amyloidosis: a multicenter study.

OBJECTIVES: To evaluate the prognostic value of radiomics features based on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) images in patients with cardiac amyloidosis (CA). METHODS: This retrospective study included 120 CA patients undergoing CMR at three institutions. Radiomics features were extracted from global and three different segments (base, mid-ventricular, and apex) of left ventricular (LV) on short-axis LGE images. Primary endpoint was all-cause mortality. The predictive performance of the radiomics features and semi-quantitative and quantitative LGE parameters were compared by ROC. The AUC was used to observe whether Rad-score had an incremental value for clinical stage. The Kaplan-Meier curve was used to further stratify the risk of CA patients. RESULTS: During a median follow-up of 12.9 months, 30% (40/120) patients died. There was no significant difference in the predictive performance of the radiomics model in different LV sections in the validation set (AUCs of the global, basal, middle, and apical radiomics model were 0.75, 0.77, 0.76, and 0.77, respectively; all p > 0.05). The predictive performance of the Rad-score of the base-LV was better than that of the LGE total enhancement mass (AUC:0.77 vs. 0.54, p < 0.001) and LGE extent (AUC: 0.77 vs. 0.53, p = 0.004). Rad-score combined with Mayo stage had better predictive performance than Mayo stage alone (AUC: 0.86 vs. 0.81, p = 0.03). Rad-score (≥ 0.66) contributed to the risk stratification of all-cause mortality in CA. CONCLUSIONS: Compared to quantitative LGE parameters, radiomics can better predict all-cause mortality in CA, while the combination of radiomics and Mayo stage could provide higher predictive accuracy. CLINICAL RELEVANCE STATEMENT: Radiomics analysis provides incremental value and improved risk stratification for all-cause mortality in patients with cardiac amyloidosis. KEY POINTS: • Radiomics in LV-base was superior to LGE semi-quantitative and quantitative parameters for predicting all-cause mortality in CA. • Rad-score combined with Mayo stage had better predictive performance than Mayo stage alone or radiomics alone. • Rad-score ≥ 0.66 was associated with a significantly increased risk of all-cause mortality in CA patients.

Convolutional neural network for brachial plexus segmentation at the interscalene level.

BACKGROUND: Regional anesthesia with ultrasound-guided brachial plexus block is widely used for patients undergoing shoulder and upper limb surgery, but needle misplacement can result in complications. The purpose of this study was to develop and validate a convolutional neural network (CNN) model for segmentation of the brachial plexus at the interscalene level. METHODS: This prospective study included patients who underwent ultrasound-guided brachial plexus block in the Anesthesiology Department of Beijing Jishuitan Hospital between October 2019 and June 2022. A Unet semantic segmentation model was developed to train the CNN to identify the brachial plexus features in the ultrasound images. The degree of overlap between the predicted segmentation and ground truth segmentation (manually drawn by experienced clinicians) was evaluated by calculation of the Dice index and Jaccard index. RESULTS: The final analysis included 502 images from 127 patients aged 41 ± 14 years-old (72 men, 56.7%). The mean Dice index was 0.748 ± 0.190, which was extremely close to the threshold level of 0.75 for good overlap between the predicted and ground truth segregations. The Jaccard index was 0.630 ± 0.213, which exceeded the threshold value of 0.5 for a good overlap. CONCLUSION: The CNN performed well at segregating the brachial plexus at the interscalene level. Further development could allow the CNN to be used to facilitate real-time identification of the brachial plexus during interscalene block administration. CLINICAL TRIAL REGISTRATION: The trial was registered prior to patient enrollment at the Chinese Clinical Trial Registry (ChiCTR2200055591), the site url is https://www.chictr.org.cn/ . The date of trial registration and patient enrollment is 14/01/2022.

Multivariate analysis of prognostic factors in patients with lip squamous cell carcinoma after surgery.

BACKGROUND: Lip squamous cell carcinoma (LSCC) was one of the most common cancer types of head and neck tumors. This study aimed to find more predictors of the prognosis in postoperative LSCC patients. METHODS: A total of 147 LSCC patients between June 2012 and June 2018 were collected from two tertiary care institutions. There were 21 clinicopathological factors included and analyzed in our study. The univariate and multivariate Cox regression analyses were performed to find the independent prognostic factors for predicting progression-free survival (PFS) and overall survival (OS) in postoperative LSCC patients. The role of adjuvant radiotherapy in various subgroups was displayed by Kaplan-Meier plots. RESULTS: The 1-, 3-, and 5-year PFS of postoperative LSCC patients were 88.4%, 70.1%, and 57.8%, respectively. Similarly, the 1-, 3-, and 5-year OS of postoperative LSCC patients were 94.6%, 76.9%, and 69.4%, respectively. The results suggested that postoperative LSCC patients with age at diagnosis ≥ 70 years, grade with moderate or poor differentiate, the American Joint Committee on Cancer (AJCC) stage IV, higher systemic immune-inflammation index (SII), surgical margin < 5, and age-adjusted Charlson Comorbidity Index (ACCI) ≥ 5 tend to have a poorer PFS (all P < 0.05). Besides, postoperative LSCC patients with age at diagnosis ≥ 70 years, AJCC stage IV, higher GPS, higher SII, and ACCI ≥ 5 tend to have a worse OS (all P < 0.05). Additionally, postoperative patients with LSCC in the subgroup of ACCI < 5 and AJCC III-IV stage was more likely to benefit from adjuvant radiotherapy, but not for the other subgroups. CONCLUSION: We identified a series of significant immune-inflammation-related and comorbidity-related clinicopathological factors associated with the prognosis of postoperative LSCC patients by local data from two tertiary care institutions in China, which can be helpful for patients and surgeons to pay more attention to nutrition, inflammation, and complications and finally obtained a better prognosis.

Modulation of fried spring roll wrapper quality upon treatment of batter with maltogenic amylase, transglutaminase and bromelain.

BACKGROUND: Fried foods are favored for their unique crispiness, golden color and flavor, but they also face great challenge because of their high oil content, high calories and the existence of compounds such as acrylamide and polycyclic aromatic hydrocarbons. Long-term consumption of fried foods may adversely affect health. Therefore, it is necessary to explore fried foods with lower oil contents and a high quality to meet the demand. RESULTS: A method of enzyme treatment was explored to investigate the effects of maltogenic amylase (MA), transglutaminase (TG) and bromelain (BRO) on the physicochemical properties of the batter and the quality of fried spring roll wrapper (FSRW). The results showed that the MA-, TG- or BRO-treated batters had a significant shear-thinning behavior, especially with an increase in viscosity upon increasing TG contents. FSRW enhanced its fracturability from 419.19 g (Control) to 616.50 g (MA-6 U g-1), 623.49 g (TG-0.75 U g-1) and 644.96 g (BRO-10 U g-1). Meanwhile, in comparison with BRO and MA, TG-0.5 U g-1 endowed batter with the highest density and thermal stability. MA-15 U g-1 and TG-0.5 U g-1 displayed FSRW with uniform and dense pores, and significantly reduced its oil content by 18.05% and 25.02%, respectively. Moreover, compared to MA and TG, BRO-50 U g-1 improved the flavor of FSRW. CONCLUSION: MA, TG or BRO played a key role in affecting the physicochemical properties of the batter and the quality of FSRW. TG-0.5 U g-1 remarkly reduced the oil content of FSRW with a great potential in practical application. © 2024 Society of Chemical Industry.

A joint analysis of accessibility and household trip frequencies by travel mode.

This paper examines the endogenous relationship between residential level of accessibility and household trip frequencies to tease out the direct and indirect effects of observed behavioural differences. We estimate a multivariate ordered probit model system, which allows dependence in both observed and unobserved factors, using data from the 2016 Transportation Tomorrow Survey (TTS), a household travel survey in the Greater Golden Horseshoe Area (GGH) in Toronto. The modelling framework is used to analyse the influence of exogenous variables on eight outcome variables of accessibility levels and trip frequencies by four modes (auto, transit, bicycle and walk), and to explore the nature of the relationships between them. The results confirm our hypothesis that not only does a strong correlation exist between the residential level of accessibility and household trip frequency, but there are also direct effects to be observed. The complementarity effect between auto accessibility and transit trips, and the substitution effect observed between transit accessibility and auto trips highlight the residential neighbourhood dissonance of transit riders. It shows that locations with better transit service are not necessarily locations where people who make more transit trips reside. Essentially, both jointness (due to error correlations) as well as directional effects observed between accessibility and trip frequencies of multiple modes offer strong support for the notion that accessibility and trip frequency by mode constitute a bundled choice and need to be considered as such.

Finding Natural, Dense, and Stable Frustrated Lewis Pairs on Wurtzite Crystal Surfaces for Small-Molecule Activation.

The surface frustrated Lewis pairs (SFLPs) open up new opportunities for substituting noble metals in the activation and conversion of stable molecules. However, the applications of SFLPs on a larger scale are impeded by the complex construction process, low surface density, and sensitivity to the reaction environment. Herein, wurtzite-structured crystals such as GaN, ZnO, and AlP are found for developing natural, dense, and stable SFLPs. It is revealed that the SFLPs can naturally exist on the (100) and (110) surfaces of wurtzite-structured crystals. All the surface cations and anions serve as the Lewis acid and Lewis base in SFLPs, respectively, contributing to the surface density of SFLPs as high as 7.26×1014 cm-2. Ab initio molecular dynamics simulations indicate that the SFLPs can keep stable under high temperatures and the reaction atmospheres of CO and H2O. Moreover, outstanding performance for activating the given small molecules is achieved on these natural SFLPs, which originates from the optimal orbital overlap between SFLPs and small molecules. Overall, these findings not only provide a simple method to obtain dense and stable SFLPs but also unfold the nature of SFLPs toward the facile activation of small molecules.

Identification of the genetic basis of the duck growth rate in multiple growth stages using genome-wide association analysis.

BACKGROUND: The genetic locus responsible for duck body size has been fully explained before, but the growth trait-related genetic basis is still waiting to be explored. For example, the genetic site related to growth rate, an important economic trait affecting marketing weight and feeding cost, is still unclear. Here, we performed genome wide association study (GWAS) to identify growth rate-associated genes and mutations. RESULT: In the current study, the body weight data of 358 ducks were recorded every 10 days from hatching to 120 days of age. According to the growth curve, we evaluated the relative and absolute growth rates (RGR and AGR) of 5 stages during the early rapid growth period. GWAS results for RGRs identified 31 significant SNPs on autosomes, and these SNPs were annotated by 24 protein-coding genes. Fourteen autosomal SNPs were significantly associated with AGRs. In addition, 4 shared significant SNPs were identified as having an association with both AGR and RGR, which were Chr2: 11483045 C>T, Chr2: 13750217 G>A, Chr2: 42508231 G>A and Chr2: 43644612 C>T. Among them, Chr2: 11483045 C>T, Chr2: 42508231 G>A, and Chr2: 43644612 C>T were annotated by ASAP1, LYN and CABYR, respectively. ASAP1 and LYN have already been proven to play roles in the growth and development of other species. In addition, we genotyped every duck using the most significant SNP (Chr2: 42508231 G>A) and compared the growth rate difference among each genotype population. The results showed that the growth rates of individuals carrying the Chr2: 42508231 A allele were significantly lower than those without this allele. Moreover, the results of the Mendelian randomization (MR) analysis supported the idea that the growth rate and birth weight had a causal effect on the adult body weight, with the growth rate having a greater effect size. CONCLUSION: In this study, 41 SNPs significantly related to growth rate were identified. In addition, we considered that the ASAP1 and LYN genes are essential candidate genes affecting the duck growth rate. The growth rate also showed the potential to be used as a reliable predictor of adult weight, providing a theoretical reference for preselection.

Cholesterol induction in CD8+ T cell exhaustion in colorectal cancer via the regulation of endoplasmic reticulum-mitochondria contact sites.

BACKGROUND: Hypercholesterolemia is one of the risk factors for colorectal cancer (CRC). Cholesterol can participate in the regulation of human T cell function and affect the occurrence and development of CRC. OBJECTIVE: To elucidate the pathogenesis of CRC immune escape mediated by CD8+ T cell exhaustion induced by cholesterol. METHODS: CRC samples (n = 217) and healthy individuals (n = 98) were recruited to analyze the relationship between peripheral blood cholesterol levels and the clinical features of CRC. An animal model of CRC with hypercholesterolemia was established. Intraperitoneal intervention with endoplasmic reticulum stress (ERS) inhibitors in hypercholesterolemic CRC mice was performed. CD69, PD1, TIM-3, and CTLA-4 on CD8+ T cells of spleens from C57BL/6 J mice were detected by flow cytometry. CD8+ T cells were cocultured with MC38 cells (mouse colon cancer cell line). The proliferation, apoptosis, migration and invasive ability of MC38 cells were detected by CCK-8 assay, Annexin-V APC/7-AAD double staining, scratch assay and transwell assay, respectively. Transmission electron microscopy was used to observe the ER structure of CD8+ T cells. Western blotting was used to detect the expression of ERS and mitophagy-related proteins. Mitochondrial function and energy metabolism were measured. Immunoprecipitation was used to detect the interaction of endoplasmic reticulum-mitochondria contact site (ERMC) proteins. Immunofluorescence colocalization was used to detect the expression and intracellular localization of ERMC-related molecules. RESULTS: Peripheral blood cholesterol-related indices, including Tc, low density lipoproteins (LDL) and Apo(a), were all increased, and high density lipoprotein (HDL) was decreased in CRCs. The proliferation, migration and invasion abilities of MC38 cells were enhanced, and the proportion of tumor cell apoptosis was decreased in the high cholesterol group. The expression of IL-2 and TNF-α was decreased, while IFN-γ was increased in the high cholesterol group. It indicated high cholesterol could induce exhaustion of CD8+ T cells, leading to CRC immune escape. Hypercholesterolemia damaged the ER structure of CD8+ T cells and increased the expression of ER stress molecules (CHOP and GRP78), lead to CD8+ T cell exhaustion. The expression of mitophagy-related proteins (BNIP3, PINK and Parkin) in exhausted CD8+ T cells increased at high cholesterol levels, causing mitochondrial energy disturbance. High cholesterol enhanced the colocalization of Fis1/Bap31, MFN2/cox4/HSP90B1, VAPB/PTPIP51, VDAC1/IPR3/GRP75 in ERMCs, indicated that high cholesterol promoted the intermolecular interaction between ER and mitochondrial membranes in CD8+ T cells. CONCLUSION: High cholesterol regulated the ERS-ERMC-mitophagy axis to induce the exhaustion of CD8+ T cells in CRC.

Genetic fine-mapping reveals single nucleotide polymorphism mutations in the MC1R regulatory region associated with duck melanism.

Birds are among the most colourful terrestrial vertebrates, with various plumage colours and patterns. We conducted a genome-wide association study (GWAS) on an intercross F2 population of Pekin ducks and mallards (n = 722) and identified a 1.57-Mb genetic region (Chr11: 20,176,480-21,750,101 bp) related to duck melanism. Fine mapping by linkage disequilibrium (LD) and FST analysis narrowed the final candidate region to a region of 22,500 bp (Chr11: 20,677,500-20,700,000 bp) including three coding genes, TCF25, MC1R and TUBB3. Combined with transcriptome and qRT-PCR analysis, MC1R was identified as the unique genetic locus responsible for black plumage in ducks, and it was significantly more highly expressed in the feather bulbs of black ducks. We also identified 52G > A (Chr11: 20,696,354G > A) and 376G > A (Chr11: 20,696,678G > A) mutations in the MC1R coding region that have been widely studied in ducks. In addition, structural variations (SVs) were screened by nanopore sequencing, and no significant SV was found to be associated with the duck black plumage trait. However, we identified four novel single nucleotide polymorphisms in the MC1R regulator region (Chr11: 20,678,412G > A, Chr11: 20,679,236G > A, Chr11: 20,692,496 A > G and Chr11: 20,692,791 A > G) that had a strong association with the black plumage phenotype of ducks and combined with potential changes in transcription binding affinities. The luciferase reporter gene assay demonstrated that Chr11: 20,678,412G > A and Chr11: 20,679,236G > A led to significant promoter activity changes. Our research emphasizes the importance of MC1R regulatory region mutation in determining the duck black plumage phenotype, and these results expand our understanding of the genetic mechanism underlying duck plumage colour.

Progress on the study of Popeye domain-containing 3 (POPDC3) in malignancies and striated muscle function and homeostasis.

The Popeye domain-containing protein 3 (POPDC3), a transmembrane protein with a unique cyclic adenosine monophosphate (cAMP) binding site, is widely expressed in mammalian tissues, with the highest levels of expression in skeletal muscle. POPDC3 plays a key role in many physiological and pathological processes and is considered a candidate biomarker and potential therapeutic target of cancer. In addition, POPDC3 gene variants have been associated with limb-girdle muscular dystrophy (LGMD) type 26. However, there are only a few studies on the biological role of POPDC3, interacting proteins, potential downstream targets, and regulated signaling pathways. Therefore, this review focuses on the structure of POPDC3 protein, interacting molecules, and the role and mechanism in cancer, and in cardiac and skeletal muscle, and to review the current research progress of POPDC3 and propose possible future study directions.