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As the main reserve carbohydrate in garlic, fructan contributes to garlic’s yield and quality formation. Numerous studies have shown that plant fructan metabolism induces a stress response to adverse environments. However, the transcriptional regulation mechanism of garlic fructan in low-temperature environments is still unknown. In this study, the fructan metabolism of garlic seedlings under low-temperature stress was revealed by transcriptome and metabolome approaches. With the extension of stress time, the number of differentially expressed genes and metabolites increased. Using weighted gene co-expression network analysis (WGCNA), three key enzyme genes related to fructan metabolism were screened (a total of 12 transcripts): sucrose: sucrose 1-fructosyltransferase (1-SST) gene; fructan: fructan 6G fructosyltransferase (6G-FFT) gene; and fructan 1-exohydrolase (1-FEH) gene. Finally, two hub genes were obtained, namely Cluster-4573.161559 (6G-FFT) and Cluster-4573.153574 (1-FEH). The correlation network and metabolic heat map analysis between fructan genes and carbohydrate metabolites indicate that the expression of key enzyme genes in fructan metabolism plays a positive promoting role in the fructan response to low temperatures in garlic. The number of genes associated with the key enzyme of fructan metabolism in trehalose 6-phosphate was the highest, and the accumulation of trehalose 6-phosphate content may mainly depend on the key enzyme genes of fructan metabolism rather than the enzyme genes in its own synthesis pathway. This study not only obtained the key genes of fructan metabolism in garlic seedlings responding to low temperatures but also preliminarily analyzed its regulatory mechanism, providing an important theoretical basis for further elucidating the cold resistance mechanism of garlic fructan metabolism.

Background Transformed lymphoma occurs when indolent lymphoma transforms into more aggressive lymphoma usually associated with poor prognosis. Methods In this study, we analyzed the immunophenotypes, prognostic factors, and outcomes of 35 patients with transformed lymphoma from among 306 marginal zone lymphoma (MZL), 544 follicular lymphoma (FL), and 871 chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) cases. In addition, we performed whole-exome sequencing study of 7 transformed MZL (tMZL) cases. Results Our results demonstrate that the median time from indolent lymphoma diagnosis to transformed DLBCL was 35 months (range, 14–53 months). The 5-year overall survival (OS) and progression-free survival (PFS) rates after histological transformation (HT) were 50% and 26%, respectively. Kaplan-Meier survival analysis revealed that asynchronous HT and transformed CLL/SLL (tCLL/SLL) were significant adverse prognostic factors for OS after DLBCL HT. Our study found that TNFAIP3 was the most frequently mutated gene in tMZL samples. We identified mutations involvement in chromatin remodeling (CREBBP and EP300) and regulators of NF-κB signaling(TNFAIP3, BCL10, MYD88, CD79B, and CARD11) were affected in tMZL. Conclusion Whole-exome sequencing and copy-number analysis revealed that tMZL derives from the divergent evolution of an ancestral common progenitor clone (CPC). Collectively, this study provides clinicopathological characteristics of three common types of transformed lymphomas and the genetic profile of tMZL with diagnostic and therapeutic implications.

Objective To use the service quality gap model to analyze the information communication service in perioperative period and formulate management measures to improve the experience for surgery patients in perioperative period. Method 114 families of level 3 and level 4 elective surgical patients in a Grade-A Tertiary Hospital from January to March in 2022 were analyzed by cross-sectional cluster sampling. The assessment scale of the information communication service in perioperative period, which involved 5 dimensions and 22 items in total, was made by referring to the model framework and combining the positioning and characteristics of operating theatre service. The expectation scale was distributed 1 day prior to surgery, and the perception scale was distributed 1 day after operation. The gap between the expected and perceived service quality was analyzed, classified and ranked, the multi-factor analysis method was used to determine the effect of patients’ general state on patients’ perceived service, and the service quality gap model was also used to analyze the survey result to determine the demand attributes. Result The perception level of family-centered information communication service in perioperative period is (6.23±0.32), the mean of expectation is (6.72±0.30), and the score difference is significant statistically (P＜0.05); the average SQ of 5 dimensions is ranked as follows: responsiveness, assurance, tangibility, reliability, empathy; age, times of medical treatment and self-care ability are all factors that affect nursing service. Conclusion: The service quality gap model is a method of service quality evaluation from the perspective of patients’ families. The application of the model to the analysis of service subject’s expectations and actual feelings can be used to help managers to find out the root that results in quality problems and look for the proper measures with pertinence that eliminate the gap.

Background This study aims to explore the information chain management model of large instrument and equipment inter-working in the operating room (OR) led by information nurses. Methods Through the chain management process of large instruments and equipment in the OR, which was based on information nurses, the management model of inter-working and integrating information chain was established, the key links were controlled, and the whole life cycle management of instruments and equipment from expected procurement to scrapping treatment was realized. Using the cluster sampling method, 1562 surgical patients were selected. Among these patients, 749 patients were assigned to the control group before the running mode, and 813 patients were assigned to the observation group after the running mode. The related indexes for large instrument and equipment management in the department before and after the running mode were compared. Results In the observation group, the average time of equipment registration was (22.05 ± 2.36), the cost was reduced by 2220 yuan/year, and the satisfaction rate of the nursing staff was 97.62%. These were significantly better, when compared to the control group (P P Conclusion The integrated management model of large instrument and equipment interworking in the OR based on chain flow realizes the whole life cycle management of instruments and equipment, which is essential to improve management efficiency.

Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain.

Botulism is caused by potent and specific bacterial neurotoxins that infect host neurons and block neurotransmitter release. Treatment for botulism is limited to administration of an antitoxin within a short time window, before the toxin enters neurons. Alternatively, current botulism drug development targets the toxin light chain, which is a zinc-dependent metalloprotease that is delivered into neurons and mediates long-term pathology. Several groups have identified inhibitory small molecules, peptides, or aptamers, although no molecule has advanced to the clinic due to a lack of efficacy in advanced models. Here we used a homogeneous high-throughput enzyme assay to screen three libraries of drug-like small molecules for new chemotypes that modulate recombinant botulinum neurotoxin light chain activity. High-throughput screening of 97088 compounds identified numerous small molecules that activate or inhibit metalloprotease activity. We describe four major classes of inhibitory compounds identified, detail their structure-activity relationships, and assess their relative inhibitory potency. A previously unreported chemotype in any context of enzyme inhibition is described with potent submicromolar inhibition (Ki = 200-300 nM). Additional detailed kinetic analyses and cellular cytotoxicity assays indicate the best compound from this series is a competitive inhibitor with cytotoxicity values around 4-5 μM. Given the potency and drug-like character of these lead compounds, further studies, including cellular activity assays and DMPK analysis, are justified.

Protein disulfide isomerase (PDI, PDIA1) is an emerging therapeutic target in oncology. PDI inhibitors have demonstrated a unique propensity to selectively induce apoptosis in cancer cells and overcome resistance to existing therapies, although drug candidates have not yet progressed to the stage of clinical development. We recently reported the discovery of lead indene compound E64FC26 as a potent pan-PDI inhibitor that enhances the cytotoxic effects of proteasome inhibitors in panels of Multiple Myeloma (MM) cells and MM mouse models. An extensive medicinal chemistry program has led to the generation of a diverse library of indene-containing molecules with varying degrees of proteasome inhibitor potentiating activity. These compounds were generated by a novel nucleophilic aromatic ring cyclization and dehydration reaction from the precursor ketones. The results provide detailed structure activity relationships (SAR) around this indene pharmacophore and show a high degree of correlation between potency of PDI inhibition and bortezomib (Btz) potentiation in MM cells. Inhibition of PDI leads to ER and oxidative stress characterized by the accumulation of misfolded poly-ubiquitinated proteins and the induction of UPR biomarkers ATF4, CHOP, and Nrf2. This work characterizes the synthesis and SAR of a new chemical class and further validates PDI as a therapeutic target in MM as a single agent and in combination with proteasome inhibitors.

Multiple Myeloma (MM) is highly sensitive to disruptions in cellular protein homeostasis. Proteasome inhibitors (PIs) are initially effective in the treatment of MM, although cures are not achievable and the emergence of resistance limits the durability of responses. New therapies are needed for refractory patients, and those that combat resistance to standard of care agents would be particularly valuable. Screening of multiple chemical libraries for PI re-sensitizing compounds identified E61 as a potent enhancer of multiple PIs and MM specific activity. Using a tandem approach of click chemistry and peptide mass fingerprinting, we identified multiple protein disulfide isomerase (PDI) family members as the primary molecular targets of E61. PDIs mediate oxidative protein folding, and E61 treatment induced robust ER and oxidative stress responses as well as the accumulation of ubiquitinylated proteins. A chemical optimization program led to a new structural class of indene (exemplified by lead E64FC26), which are highly potent pan-style inhibitors of PDIs. In mice with MM, E64FC26 improved survival and enhanced the activity of bortezomib without any adverse effects. This work demonstrates the potential of E64FC26 as an early drug candidate and the strategy of targeting multiple PDI isoforms for the treatment of refractory MM and beyond.

We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition.

A series of indole-O-glucosides and C-glucosides was synthesized and evaluated in SGLT1 and SGLT2 cell-based functional assays. Compounds 2a and 2o were identified as potent SGLT2 inhibitors and screened in ZDF rats.

A series of indole-O-glucosides and C-glucosides was synthesized and evaluated in SGLT1 and SGLT2 cell-based functional assays. Compounds 2a and 2o were identified as potent SGLT2 inhibitors and screened in ZDF rats.

A series of benzo-fused heteroaryl-O-glucosides was synthesized and evaluated in SGLT1 and 2 cell-based functional assays. Indole-O-glucoside 10a and benzimidazole-O-glucoside 18 exhibited potent in vitro SGLT2 inhibitory activity.

A series of benzo-fused heteroaryl-O-glucosides was synthesized and evaluated in SGLT1 and 2 cell-based functional assays. Indole-O-glucoside 10a and benzimidazole-O-glucoside 18 exhibited potent in vitro SGLT2 inhibitory activity.

We have explored the basic theory and quantitative methods for the measurement of motorcycle exhaust using a Fourier transform infrared interferometer system. Remote sensing direct measurements were made and the species carbon monoxide, carbon dioxide, nonmethane paraffinic carbon(CHx) and unburned additional harmful species in motorcycle exhaust were determined. Typical concentrations observed in absorption for carbon monoxide, carbon dioxide and nonmethane paraffinic carbon were about 1.11%, 1.91%, 0.54% respectively. Furthemore, this paper describes the remote sensing Fourier transform infrared spectrometer system. The system covers the infrared spectral region from 700 to 6000 cin−1 at a maxim resolution of 0.06 cm−1 for beamsplitter of gerrniuiirun coated zinc selenide and receiver telescope with zinc selriide leis. For air multipollutant monitoring the analytica1 methods have the potential and become important. The remote measurements usirig the Fourier transform inf raid spectroscopy could...