Structurally divergent and recurrently mutated regions of primate genomes.

We sequenced and assembled using multiple long-read sequencing technologies the genomes of chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, owl monkey, and marmoset. We identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. We estimate that 819.47 Mbp or ∼27% of the genome has been affected by SVs across primate evolution. We identify 1,607 structurally divergent regions wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (e.g., CARD, C4, and OLAH gene families) and additional lineage-specific genes are generated (e.g., CKAP2, VPS36, ACBD7, and NEK5 paralogs), becoming targets of rapid chromosomal diversification and positive selection (e.g., RGPD gene family). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species.

Systematic single-cell analysis reveals dynamic control of transposable element activity orchestrating the endothelial-to-hematopoietic transition.

BACKGROUND: The endothelial-to-hematopoietic transition (EHT) process during definitive hematopoiesis is highly conserved in vertebrates. Stage-specific expression of transposable elements (TEs) has been detected during zebrafish EHT and may promote hematopoietic stem cell (HSC) formation by activating inflammatory signaling. However, little is known about how TEs contribute to the EHT process in human and mouse. RESULTS: We reconstructed the single-cell EHT trajectories of human and mouse and resolved the dynamic expression patterns of TEs during EHT. Most TEs presented a transient co-upregulation pattern along the conserved EHT trajectories, coinciding with the temporal relaxation of epigenetic silencing systems. TE products can be sensed by multiple pattern recognition receptors, triggering inflammatory signaling to facilitate HSC emergence. Interestingly, we observed that hypoxia-related signals were enriched in cells with higher TE expression. Furthermore, we constructed the hematopoietic cis-regulatory network of accessible TEs and identified potential TE-derived enhancers that may boost the expression of specific EHT marker genes. CONCLUSIONS: Our study provides a systematic vision of how TEs are dynamically controlled to promote the hematopoietic fate decisions through transcriptional and cis-regulatory networks, and pre-train the immunity of nascent HSCs.

Abnormal expression of FOXM1 in carcinogenesis of renal cell carcinoma: From experimental findings to clinical applications.

Renal cell carcinoma (RCC) is a prevalent malignancy within the genitourinary system. At present, patients with high-grade or advanced RCC continue to have a bleak prognosis. Mounting research have emphasized the significant involvement of Forkhead box M1 (FOXM1) in RCC development and progression. Therefore, it is imperative to consolidate the existing evidence regarding the contributions of FOXM1 to RCC tumorigenesis through a comprehensive review. This study elucidated the essential functions of FOXM1 in promoting RCC growth, invasion, and metastasis by regulating cell cycle progression, DNA repair, angiogenesis, and epithelial-mesenchymal transition (EMT). Also, FOXM1 might serve as a novel diagnostic and prognostic biomarker as well as a therapeutic target for RCC. Clinical findings demonstrated that the expression of FOXM1 was markedly upregulated in RCC samples, while a high level of FOXM1 was found to be associated with a poor overall survival rate of RCC. Furthermore, it is worth noting that FOXM1 may have a significant impact on the resistance of renal cell carcinoma (RCC) to radiotherapy. This observation suggests that inhibiting FOXM1 could be a promising strategy to impede the progression of RCC and enhance its sensitivity to radiotherapy. The present review highlighted the pivotal role of FOXM1 in RCC development. FOXM1 has the capacity to emerge as not only a valuable diagnostic and prognostic tool but also a viable therapeutic option for unresectable RCC.

Arabidopsis cryptochrome 1 controls photomorphogenesis through regulation of H2A.Z deposition.

Light is a key environmental cue that fundamentally regulates plant growth and development, which is mediated by the multiple photoreceptors including the blue light (BL) photoreceptor cryptochrome 1 (CRY1). The signaling mechanism of Arabidopsis thaliana CRY1 involves direct interactions with CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1)/SUPPRESSOR OF PHYA-105 1 and stabilization of COP1 substrate ELONGATED HYPOCOTYL 5 (HY5). H2A.Z is an evolutionarily conserved histone variant, which plays a critical role in transcriptional regulation through its deposition in chromatin catalyzed by SWR1 complex. Here we show that CRY1 physically interacts with SWC6 and ARP6, the SWR1 complex core subunits that are essential for mediating H2A.Z deposition, in a BL-dependent manner, and that BL-activated CRY1 enhances the interaction of SWC6 with ARP6. Moreover, HY5 physically interacts with SWC6 and ARP6 to direct the recruitment of SWR1 complex to HY5 target loci. Based on previous studies and our findings, we propose that CRY1 promotes H2A.Z deposition to regulate HY5 target gene expression and photomorphogenesis in BL through the enhancement of both SWR1 complex activity and HY5 recruitment of SWR1 complex to HY5 target loci, which is likely mediated by interactions of CRY1 with SWC6 and ARP6, and CRY1 stabilization of HY5, respectively.

m1A regulator-mediated methylation modification patterns correlated with autophagy to predict the prognosis of hepatocellular carcinoma.

BACKGROUND: N1-methyladenosine (m1A), among the most common internal modifications on RNAs, has a crucial role to play in cancer development. The purpose of this study were systematically investigate the modification characteristics of m1A in hepatocellular carcinoma (HCC) to unveil its potential as an anticancer target and to develop a model related to m1A modification characteristics with biological functions. This model could predict the prognosis for patients with HCC. METHODS: An integrated analysis of the TCGA-LIHC database was performed to explore the gene signatures and clinical relevance of 10 m1A regulators. Furthermore, the biological pathways regulated by m1A modification patterns were investigated. The risk model was established using the genes that showed differential expression (DEGs) between various m1A modification patterns and autophagy clusters. These in vitro experiments were subsequently designed to validate the role of m1A in HCC cell growth and autophagy. Immunohistochemistry was employed to assess m1A levels and the expression of DEGs from the risk model in HCC tissues and paracancer tissues using tissue microarray. RESULTS: The risk model, constructed from five DEGs (CDK5R2, TRIM36, DCAF8L, CYP26B, and PAGE1), exhibited significant prognostic value in predicting survival rates among individuals with HCC. Moreover, HCC tissues showed decreased levels of m1A compared to paracancer tissues. Furthermore, the low m1A level group indicated a poorer clinical outcome for patients with HCC. Additionally, m1A modification may positively influence autophagy regulation, thereby inhibiting HCC cells proliferation under nutrient deficiency conditions. CONCLUSIONS: The risk model, comprising m1A regulators correlated with autophagy and constructed from five DEGs, could be instrumental in predicting HCC prognosis. The reduced level of m1A may represent a potential target for anti-HCC strategies.

Molecular Weights of Dissolved Organic Matter Significantly Affect Photoaging of Microplastics.

The fate of ubiquitous microplastics (MPs) is largely influenced by dissolved organic matter (DOM) in aquatic environments, which has garnered significant attention. The reactivity of DOM is reported to be greatly regulated by molecular weights (MWs), yet little is known about the effects of different MW DOM on MP aging. Here, the aging behavior of polystyrene MPs (PSMPs) in the presence of different MW fulvic acids (FAs) and humic acids (HAs) was systematically investigated. Under ultraviolet (UV) illumination, O/C of PSMPs aged for 96 h surged from 0.008 to 0.146 in the lower MW FA (FA<1kDa) treatment, suggesting significant PSMP aging. However, FA exhibited a stronger effect on facilitating PSMP photoaging than HA, which can be attributed to the fact that FA<1kDa contains more quinone and phenolic moieties, demonstrating a higher redox capacity. Meanwhile, compared to other fractions, FA<1kDa was more actively involved in the increase of different reactive species yields by 50-290%, including •OH, which plays a key role in PSMP photoaging, and contributed to a 25% increase in electron-donating capacity (EDC). This study lays a theoretical foundation for a better understanding of the environmental fate of MPs.

Genome-wide identification and analyses of ZmAPY genes reveal their roles involved in maize development and abiotic stress responses.

Apyrase is a class of enzyme that catalyzes the hydrolysis of nucleoside triphosphates/diphosphates (NTP/NDP), which widely involved in regulation of plant growth and stress responses. However, apyrase family genes in maize have not been identified, and their characteristics and functions are largely unknown. In this study, we identified 16 apyrases (named as ZmAPY1-ZmAPY16) in maize genome, and analyzed their phylogenetic relationships, gene structures, chromosomal distribution, upstream regulatory transcription factors and expression patterns. Analysis of the transcriptome database unveiled tissue-specific and abiotic stress-responsive expression of ZmAPY genes in maize. qPCR analysis further confirmed their responsiveness to drought, heat, and cold stresses. Association analyses indicated that variations of ZmAPY5 and ZmAPY16 may regulate maize agronomic traits and drought responses. Our findings shed light on the molecular characteristics and evolutionary history of maize apyrase genes, highlighting their roles in various biological processes and stress responses. This study forms a basis for further exploration of apyrase functions in maize. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01474-9.

Correction to: Genome­wide identification and analyses of ZmAPY genes reveal their roles involved in maize development and abiotic stress responses.

[This corrects the article DOI: 10.1007/s11032-024-01474-9.].

Ammonia energy fraction effect on the combustion and reduced NOX emission of ammonia/diesel dual fuel.

With stringent regulations of internal combustion engine on reducing CO2 emission, ammonia has been used as an alternative fuel. Investigating how engine-related performance is affected by partial ammonia replacement of diesel fuel is essential for understanding the combustion. Therefore, in this study, a three-dimensional numerical simulation model is developed for the burning of two fuels of diesel and ammonia based on relevant parameters (i.e., compression ratio, load, ammonia energy fraction, etc.) in a lab-made diesel engine. The consequences of load and compression proportion on combustion and pollutant emissions are investigated for ammonia energy fractions between 50% and 90%. When the ammonia portion rises, the increased ammonia equivalent ratio causes ammonia to move away from the dilute combustion boundary and accelerates the combustion rate of ammonia. An increase in compression ratio significantly increases the specified thermal performance and combustion efficacy. When the compression ratio is 16, as the ammonia energy fractions increases, due to the increase in the proportion of ammonia, that is, the proportion of nitrogen atoms increases, more NOx is generated during the combustion process. When the ammonia substitution rate is 90%, as the compression ratio increases, the cylinder pressure and temperature increase. The combustion efficiency of ammonia increases, generating more NOx and NOx emissions can reach 0.66 mg/m3. At a compression ratio of 18, the NOx emissions can reach 1.59 mg/m3. However, under medium and low load conditions, as the ammonia fraction increases, the total energy of fuel decreases, and the combustion efficiency of ammonia decreases, resulting in a decrease in the heat released during combustion and a decrease in NOx emissions. When the ammonia substitution rate is 90% and the load is 25%, NOx emissions reach 0.1 mg/m3. This research provides theoretical suggestions for the profitable and use ammonia fuel in internal combustion engines in a clean manner.

Role of NF-κB in cardiac changes of obstructive sleep apnoea rabbits treated by mandibular advancement device.

BACKGROUND: Obstructive sleep apnoea (OSA) is an independent risk factor for cardiovascular diseases. We aimed to investigate the role of nuclear factor-kappa B (NF-κB) in the changes of cardiac structures in OSA rabbits treated by mandibular advancement device (MAD). METHODS: Eighteen male New Zealand white rabbits aged 6 months were randomly divided into three groups: control group, group OSA and group MAD. Hyaluronate gel was injected into the soft palate of the rabbits in group OSA and group MAD to induce OSA. The cone beam computer tomography (CBCT) of the upper airway and polysomnography (PSG) was performed to ensure successful modelling. CBCT and PSG were applied again to detect the effects of MAD treatment. All animals were induced to sleep in a supine position for 4-6 h a day for 8 weeks. Then the levels of NF-κB, Interleukin 6 (IL-6), Interleukin 10 (IL-10) and the proportion of myocardial fibrosis (MF) were detected. RESULTS: The higher activation of NF-κB, IL-6 and IL-10 were found in the OSA group than in the control group, leading to the increase of collagen fibres compared with the control group. Furthermore, the apnoea-hypopnea index (AHI) was positively correlated with the above factors. There were no significant differences between group MAD and the control group. CONCLUSION: The NF-κB pathway was activated in the myocardium of OSA rabbits, which accelerated the development of MF. Early application of MAD could reduce the activation of NF-κB in the myocardium and prevent the development of MF.

A mandibular advancement device attenuates the abnormal morphology and function of mitochondria from the genioglossus in obstructive sleep apnea-hypopnea syndrome rabbits.

BACKGROUND: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a serious and potentially life-threatening disease. Mandibular advancement device (MAD) has the characteristics of non-invasive, comfortable, portable and low-cost, making it the preferred treatment for mild-to-moderate OSAHS. Our previous studies found that abnormal contractility and fibre type distribution of the genioglossus could be caused by OSAHS. However, whether the mitochondria participate in these tissue changes is unclear. The effect of MAD treatment on the mitochondria of the genioglossus in OSAHS is also uncertain. OBJECTIVE: To examine the morphology and function of mitochondria from the genioglossus in a rabbit model of obstructive sleep apnea-hypopnea syndrome (OSAHS), as well as these factors after insertion of a mandibular advancement device (MAD). METHODS: Thirty male New Zealand white rabbits were randomised into three groups: control, OSAHS and MAD, with 10 rabbits in each group. Animals in Group OSAHS and Group MAD were induced to develop OSAHS by injection of gel into the submucosal muscular layer of the soft palate. The rabbits in Group MAD were fitted with a MAD. The animals in the control group were not treated. Further, polysomnography (PSG) and cone-beam computed tomography (CBCT) scan were used to measure MAD effectiveness. CBCT of the upper airway and PSG suggested that MAD was effective. Rabbits in the three groups were induced to sleep for 4-6 h per day for eight consecutive weeks. The genioglossus was harvested and detected by optical microscopy and transmission electron microscopy. The mitochondrial membrane potential was determined by laser confocal microscopy and flow cytometry. Mitochondrial complex I and IV activities were detected by mitochondrial complex assay kits. RESULTS: OSAHS-like symptoms were induced successfully in Group OSAHS and rescued by MAD treatment. The relative values of the mitochondrial membrane potential, mitochondrial complex I activity and complex IV activity were significantly lower in Group OSAHS than in the control group; however, there was no significant difference between Group MAD and the control group. The OSAHS-induced injury and the dysfunctional mitochondria of the genioglossus muscle were reduced by MAD treatment. CONCLUSION: Damaged mitochondrial structure and function were induced by OSAHS and could be attenuated by MAD treatment.

Algorithm for the reconstruction of the parotid region: a single institution experience.

OBJECTIVE: This study aims to discuss the characteristics and treatment methods of malignant tumors in the parotid region, as well as the therapeutic effects of immediate free flap reconstruction of soft tissue for postoperative defects. MATERIALS AND METHODS: A retrospective review was conducted on 11 cases of soft tissue flap reconstruction for postoperative defects following the resection of malignant tumors in the parotid region. Statistical analysis was performed based on clinical data. RESULTS: Among the 11 cases of malignant tumors in the parotid region, there were 2 cases of secretory carcinoma (SC) of the salivary gland, 2 cases of squamous cell carcinoma (SCC), 2 cases of carcinosarcoma, 1 case of mucoepidermoid carcinoma (MEC), 1 case of epithelial-myoepithelial carcinoma (EMC), 1 case of salivary duct carcinoma (SDC), 1 case of basal cell carcinoma (BCC), and 1 case of osteosarcoma. Among these cases, 4 were initial diagnoses and 7 were recurrent tumors. The defect repairs involved: 8 cases with anterolateral thigh free flap (ALTF), 2 cases with pectoralis major muscle flaps, and 1 case with forearm flap. The size of the flaps ranged from approximately 1 cm × 3 cm to 7 cm × 15 cm. The recipient vessels included: 4 cases with the facial artery, 4 cases with the superior thyroid artery, and 1 case with the external carotid artery. The ratio of recipient vein anastomosis was: 57% for branches of the internal jugular vein, 29% for the facial vein, and 14% for the external jugular vein. Among the 8 cases that underwent neck lymph node dissection, one case showed lymph node metastasis on pathological examination. In the initial diagnosis cases, 2 cases received postoperative radiotherapy, and 1 case received 125I seed implantation therapeutic treatment after experiencing two recurrences. Postoperative follow-up revealed that 2 cases underwent reoperation due to local tumor recurrence, and there were 2 cases lost to follow-up. The survival outcomes after treatment included: one case of distant metastasis and one case of death from non-cancerous diseases. CONCLUSION: Immediate soft tissue flap reconstruction is an important and valuable option to address postoperative defects in patients afflicted with malignant tumors in the parotid region.

Disulfide-Directed Multicyclic Peptide Libraries for the Discovery of Peptide Ligands and Drugs.

Multicyclic peptides with stable 3D structures are a kind of novel and promising peptide formats for drug design and discovery as they have the potential to combine the best characteristics of small molecules and proteins. However, the development of multicyclic peptides is largely limited to naturally occurring products. It remains a big challenge to develop multicyclic peptides with new structures and functions without recourse to the existing natural scaffolds. Here, we report a general and robust method relying on the utility of new disulfide-directing motifs for designing and discovering diverse multicyclic peptides with potent protein-binding capability. These peptides, referred to as disulfide-directed multicyclic peptides (DDMPs), are tolerant to extensive sequence manipulations and variations of disulfide-pairing frameworks, enabling the development of de novo DDMP libraries useful for ligand and drug discovery. This study opens a new avenue for creating a new generation of multicyclic peptides in sequence and structure space inaccessible by natural scaffolds, thus would greatly benefit the field of peptide drug discovery.

Prevailing Charge Order in Overdoped La_{2-x}Sr_{x}CuO_{4} beyond the Superconducting Dome.

The extremely overdoped cuprates are generally considered to be Fermi liquid metals without exotic orders, whereas the underdoped cuprates harbor intertwined states. Contrary to this conventional wisdom, using Cu L_{3}-edge and O K-edge resonant x-ray scattering, we reveal a charge order (CO) correlation in overdoped La_{2-x}Sr_{x}CuO_{4} (0.35≤x≤0.6) beyond the superconducting dome. This CO has a periodicity of ∼6 lattice units with correlation lengths of ∼20 lattice units. It shows similar in-plane momentum and polarization dependence and dispersive excitations as the CO of underdoped cuprates, but its maximum intensity differs along the c direction and persists up to 300 K. This CO correlation cannot be explained by the Fermi surface instability and its origin remains to be understood. Our results suggest that CO is prevailing in the overdoped metallic regime and requires a reassessment of the picture of overdoped cuprates as weakly correlated Fermi liquids.

Untangling determinants of gut microbiota and tumor immunologic status through a multi-omics approach in colorectal cancer.

The changes in gut microbiota have been implicated in colorectal cancer (CRC). The interplays between the host and gut microbiota remain largely unclear, and few studies have investigated these interplays using integrative multi-omics data. In this study, large-scale multi-comic datasets, including microbiome, metabolome, bulk transcriptomics and single cell RNA sequencing of CRC patients, were analyzed individually and integrated through advanced bioinformatics methods. We further examined the clinical relevance of these findings in the mice recolonized with microbiota from human. We found that CRC patients had distinct microbiota compositions compared to healthy controls. A machine-learning model was developed with 28 biomarkers for detection of CRC, which had high accuracy and clinical applicability. We identified multiple significant correlations between genera and well-characterized genes, suggesting the potential role of gut microbiota in tumor immunity. Further analysis showed that specific metabolites worked as profound communicators between these genera and tumor immunity. Integrating microbiota and metabolome perspectives, we cataloged gut taxonomic and metabolomic features that represented the key multi-omics signature of CRC. Furthermore, gut microbiota transplanted from CRC patients compromised the response of CRC to immunotherapy. These phenotypes were strongly associated with the alterations in gut microbiota, immune cell infiltration as well as multiple metabolic pathways. The comprehensive interplays across multi-comic data of CRC might explain how gut microbiota influenced tumor immunity. Hence, we proposed that modifying the CRC microbiota using healthy donors might serve as a promising strategy to improve response to immunotherapy.

Host ALDH2 deficiency aggravates nonalcoholic steatohepatitis through gut-liver axis.

Nonalcoholic steatohepatitis (NASH) is the major cause of liver dysfunction. Animal and population studies have shown that mitochondrial aldehyde dehydrogenase (ALDH2) is implicated in fatty liver disease. However, the role of ALDH2 in NASH and the underlying mechanisms remains unclear. To address this issue, ALDH2 knockout (ALDH2-/-) mice and wild-type littermate mice were fed a methionine-and choline-deficient (MCD) diet to induce a NASH model. Fecal, serum, and liver samples were collected and analyzed to investigate the impact of the gut microbiota and bile acids on this process. We found that MCD-fed ALDH2-/- mice exhibited increased serum pro-inflammation cytokines, hepatic inflammation and fat accumulation than their wild-type littermates. MCD-fed ALDH2-/- mice exhibited worsened MCD-induced intestinal inflammation and barrier damage, and gut microbiota disorder. Furthermore, mice receiving microbiota from MCD-fed ALDH2-/- mice had increased severity of NASH compared to those receiving microbiota from MCD-fed wild-type mice. Notably, the intestinal Lactobacillus was significantly reduced in MCD-fed ALDH2-/- mice, and gavage with Lactobacillus cocktail significantly improved MCD-induced NASH. Finally, we found that ALDH2-/- mice had reduced levels of bile salt hydrolase and specific bile acids, especially lithocholic acid (LCA), accompanied by downregulated expression of the intestinal FXR-FGF15 pathway. Supplementation of LCA in ALDH2-/- mice upregulated intestinal FXR-FGF15 pathway and alleviated NASH. In summary, ALDH2 plays a critical role in the development of NASH through modulation of gut microbiota and bile acid. The findings suggest that supplementing with Lactobacillus or LCA could be a promising therapeutic approach for treating NASH exacerbated by ALDH2 deficiency.

Role of Impurities in Kaolinite Intercalation and Subsequent Formation of Nanoscrolls.

Kaolinite (Kaol)-methanol (MeOH) compounds (Kaol-Me) are widely used as the starting materials for further intercalation. The conventional approach to prepare Kaol-Me compounds is to wash dimethyl sulfoxide (DMSO)-intercalated Kaol (Kaol-DMSO) for 16 days, and MeOH must be refreshed every day. Herein, we report a new and much more efficient method to prepare Kaol-Me from Kaol-DMSO by the promotion of AlCl3 under mild conditions, and the corresponding mechanism is investigated. The X-ray diffraction (XRD), Fourier transform infrared spectroscopy, and X-ray fluorescence characterization results reveal that the electric double layer resulting from the impurities absorbed on the kaolinite surface prevents weakly polar molecules from entering the kaolinite interlayers, which is probably the key reason that MeOH must be refreshed daily in the preparation of Kaol-Me compounds. After being treated with HCl to remove the impurities, Kaol-Me-HCl was successfully intercalated by cetyltrimethyl ammonium bromide and subsequently predominantly curled into nanoscrolls.

The urban-rural disparities and factors associated with the utilization of public health services among diabetes patients in China.

BACKGROUND: Basic public health services for diabetes play an essential role in controlling glycemia in patients with diabetes. This study was conducted to understand the urban-rural disparities in the utilization of basic public health services for people with diabetes and the factors influencing them. METHODS: The data were obtained from the 2018 China Health and Retirement Longitudinal Study (CHARLS) with 2976 diabetes patients. Chi-square tests were used to examine the disparities in the utilization of diabetes physical examination and health education between urban and rural areas. Logistic regression was performed to explore the factors associated with the utilization of diabetes public health services. RESULTS: Among all participants, 8.4% used diabetes physical examination in the past year, and 28.4% used diabetes health education services. A significant association with age (OR = 0.64, 95% CI:0.49-0.85; P < 0.05) was found between patients' use of health education services. Compared with diabetes patients living in an urban area, diabetes patients living in a rural area used less diabetes health education. (χ2= 92.39, P < 0.05). Patients' self-reported health status (OR = 2.04, CI:1.24-3.35; P < 0.05) and the use of glucose control (OR = 9.33, CI:6.61-13.16; P < 0.05) were significantly positively associated with the utilization of diabetes physical examination. Patients with higher education levels were more likely to use various kinds of health education services than their peers with lower education levels (OR = 1.64, CI:1.21-2.22; P < 0.05). CONCLUSION: Overall, urban-rural disparities in the utilization of public health services existed. Vulnerable with diabetes, such as those in rural areas, are less available to use diabetes public health services. Providing convenient health service infrastructure facilitates the utilization of basic public health services for diabetes in older patients with diabetes, especially in rural areas.

Microtiter plate-based chemistry and in situ screening: SuFEx-enabled lead discovery of selective AChE inhibitors.

Sulphur fluoride exchange (SuFEx) is a category of click chemistry that enables covalent linking of modular units through sulphur connective hubs. Here, we reported an efficient synthesis and in situ screening method for building a library of sulphonamides on the picomolar scale by SuFEx reaction between a sulphonyl fluoride (RSO2F) core and primary or secondary amines. This biocompatible SuFEx reaction would allow us to rapidly synthesise sulphonamide molecules, and evaluate their ChE inhibitory activity. Compound T14-A24 was identified as a reversible, competitive, and selective AChE inhibitor (Ki = 22 nM). The drug-like evaluation showed that T14-A24 had benign BBB penetration, remarkable neuroprotective effect, and safe toxicological profile. In vivo behavioural study showed that T14-A24 treatment improved the Aß1 - 42-induced cognitive impairment, significantly prevented the effects of Aß1 - 42 toxicity. Therefore, this SuFEx click reaction can accelerate the discovery of lead compounds.

Arabidopsis cryptochrome 1 undergoes COP1 and LRBs-dependent degradation in response to high blue light.

Arabidopsis cryptochrome 1 (CRY1) is an important blue light photoreceptor that promotes photomorphogenesis under blue light. The blue light photoreceptors CRY2 and phototropin 1, and the red/far-red light photoreceptors phytochromes B and A undergo degradation in response to blue and red light, respectively. This study investigated whether and how CRY1 might undergo degradation in response to high-intensity blue light (HBL). We demonstrated that CRY1 is ubiquitinated and degraded through the 26S proteasome pathway in response to HBL. We found that the E3 ubiquitin ligase constitutive photomorphogenic 1 (COP1) is involved in mediating HBL-induced ubiquitination and degradation of CRY1. We also found that the E3 ubiquitin ligases LRBs physically interact with CRY1 and are also involved in mediating CRY1 ubiquitination and degradation in response to HBL. We further demonstrated that blue-light inhibitor of cryptochromes 1 interacts with CRY1 in a blue-light-dependent manner to inhibit CRY1 dimerization/oligomerization, leading to the repression of HBL-induced degradation of CRY1. Our findings indicate that the regulation of CRY1 stability in HBL is coordinated by COP1 and LRBs, which provides a mechanism by which CRY1 attenuates its own signaling and optimizes photomorphogenesis under HBL.