Mendelian randomization and colocalization analysis reveal novel drug targets for myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is a complex autoimmune disease affecting the neuromuscular junction with limited drug options, but the field of MG treatment recently benefits from novel biological agents. We performed a drug-targeted Mendelian randomization (MR) study to identify novel therapeutic targets of MG. METHODS: Cis-expression quantitative loci (cis-eQTL), which proxy expression levels for 2176 druggable genes, were used for MR analysis. Causal relationships between genes and disease, identified by eQTL MR analysis, were verified by comprehensive sensitivity, colocalization, and protein quantitative loci (pQTL) MR analyses. The protein-protein interaction (PPI) analysis was also performed to extend targets, followed by enzyme-linked immunosorbent assay (ELISA) to explore the serum level of drug targets in MG patients. A phenome-wide MR analysis was then performed to assess side effects with a clinical trial review assessing druggability. RESULTS: The eQTL MR analysis has identified eight potential targets for MG, one for early-onset MG and seven for late-onset MG. Further colocalization analyses indicated that CD226, CDC42BPB, PRSS36, and TNFSF12 possess evidence for colocalization with MG or late-onset MG. pQTL MR analyses identified the causal relations of TNFSF12 and CD226 with MG and late-onset MG. Furthermore, PPI analysis has revealed the protein interaction between TNFSF12-TNFSF13(APRIL) and TNFSF12-TNFSF13B(BLyS). Elevated TNFSF13 serum level of MG patients was also identified by ELISA experiments. This study has ultimately proposed three promising therapeutic targets (TNFSF12, TNFSF13, TNFSF13B) of MG. CONCLUSIONS: Three drug targets associated with the BLyS/APRIL pathway have been identified. Multiple biological agents, including telitacicept and belimumab, are promising for MG therapy.

Circular RNA vaccines against monkeypox virus provide potent protection against vaccinia virus infection in mice.

Since the outbreak of monkeypox (mpox) in 2022, widespread concern has been placed on imposing an urgent demand for specific vaccines that offer safer and more effective protection. Using an efficient and scalable circular RNA (circRNA) platform, we constructed four circRNA vaccines that could induce robust neutralizing antibodies as well as T cell responses by expressing different surface proteins of mpox virus (MPXV), resulting in potent protection against vaccinia virus (VACV) in mice. Strikingly, the combination of the four circular RNA vaccines demonstrated the best protection against VACV challenge among all the tested vaccines. Our study provides a favorable approach for developing MPXV-specific vaccines by using a circular mRNA platform and opens up novel avenues for future vaccine research.

Seroepidemiology of measles and rubella among Hong Kong young adults and the humoral responses of an MMR booster among participants with low antibody levels.

BACKGROUND: Some individuals may not retain adequate immunity against measles and rubella years after two doses of measles, mumps, and rubella (MMR) vaccination due to vaccine failure. This study aimed to investigate the rates of vaccine failure and seroconversion by administering an MMR booster to young adults. METHODS: We first assessed measles and rubella antibody levels using the Luminex multiplex assay, VIDAS IgG assay, and plaque reduction neutralization test (PRNT) among individuals aged 18-30 years old who had received two doses of MMR vaccine. Participants with low measles and/or rubella antibody levels as confirmed by VIDAS received an MMR booster. Antibody levels were measured at 1-month post-booster. RESULTS: Among 791 participants, the measles and rubella seroprevalence rates were 94.7% (95% CI: 92.9%-96.0%) and 97.3% (95% CI: 96.0%-98.3%), respectively. Lower seroprevalence rates were observed among older participants. 113 participants who received an MMR booster acquired higher measles and rubella antibody levels at 1-month post-booster compared to baseline. CONCLUSIONS: Although measles and rubella vaccine failures were observed among 5.3% and 2.7% of young adults, respectively, an MMR booster triggered a significant antibody response.

Engineering an (R)-selective transaminase for asymmetric synthesis of (R)-3-aminobutanol.

(R)-selective transaminases show promise as catalysts for the asymmetric synthesis of chiral amines, which are building blocks of various small molecule drugs. However, their application is limited by poor substrate acceptance and low catalytic efficiency. Here, a potential (R)-selective transaminase from Fodinicurvata sediminis (FsTA) was identified through a substrate truncating strategy, and used as starting point for enzyme engineering toward catalysis of 4-hydroxy-2-butanone, a substrate that poses challenges in catalysis. Molecular docking and dynamics simulations revealed Y90 as the key residue responsible for poor substrate binding. Starting from the variant (Y90F, mut1) with initial activity, FsTA was systematically modified to improve substrate-binding through active site reshaping and consensus sequence strategy, yielding three variants (H30R, V152K, and Y156F) with improved activity. A quadruple mutation variant H30R/Y90F/V152K/Y156F (mut4) was also found to show a 7.95-fold greater catalytic efficiency (kcat/KM) than the initial variant mut1. Furthermore, mut4 also enhanced the thermostability of enzyme significantly, with the Tm value increasing by 10 °C. This variant also exhibited significantly improved activity toward a series of ketones that are either not accepted or poorly accepted by the wild-type. This study provides a basis for the rational design of an active to creating variants that can accommodate novel substrates.

A Retrospective Cohort Study on the Comorbidity in 19,264 Chinese Patients of Different Ages with Urticaria.

To examine the prevalence of comorbidities in Chinese urticaria patients and assess medication use patterns across different ages (6-11 years, 12-17 years, above 18 years), a retrospective cohort study was performed in 192,647 urticaria patients within the Health Database. After 1:1 propensity score matching, 166,921 people were divided into the urticaria group and the control group, and the follow-up data were collected within 2 years. During the 12-month and 24-month follow-up period, significant comorbidities identified included allergic rhinitis and asthma, with distinct patterns observed across age groups. Chronic urticaria patients often have complications, such as allergic rhinitis, upper respiratory infection, oropharyngeal infection, and dental caries. The study underscores the need for age-specific treatment strategies in urticaria management.

Screening and analysis of the targeted compounds in Choerospondias axillaris extract by receptor chromatographic column with immobilized angiotensin II type 1 receptor.

As a result of the lack of modern techniques, the study of Tibetan medicine has been hindered in identifying bioactive compounds. Herein, we established a chromatographic approach using an immobilized angiotensin II type 1 receptor (AT1R) via a one-step method triggered by haloalkane dehalogenase. The bioactive compounds from Choerospondias axillaris (Guangzao) were screened and identified using the immobilized AT1R followed by MS. Frontal analysis (FA) and adsorption energy distribution (AED) were used to evaluate the association constants. Molecular docking was used to investigate the binding configurations, and the surface efficiency index, binding efficiency index, and ligand-lipophilicity efficiency (LLE) were calculated to assess the drug-like properties. The results identified naringenin, pinocembrin, and chrysin as the compounds that specifically bind to AT1R in Guangzao. FA and AED confirmed that there is only one type of binding site between these compounds and AT1R. The association constants were (2.40 ± 0.02) × 104 M-1 for naringenin (5.22 ± 0.26) × 104 M-1 for pinocembrin, and (4.27 ± 0.14) × 104 M-1 for chrysin, respectively. These compounds can bind with AT1R through the orthosteric binding pocket. Naringenin exhibited better LLE than pinocembrin and chrysin. These results confirmed the feasibility of using the immobilized AT1R column for screening and analyzing bioactive compounds in Tibetan medicines.

Regulated Surface Electronic States of CuNi Nanoparticles through Metal-Support Interaction for Enhanced Electrocatalytic CO2 Reduction to Ethanol.

Developing stable catalysts with higher selectivity and activity within a wide potential range is critical for efficiently converting CO2 to ethanol. Here, the carbon-encapsulated CuNi nanoparticles anchored on nitrogen-doped nanoporous graphene (CuNi@C/N-npG) composite are designedly prepared and display the excellent CO2 reduction performance with the higher ethanol Faradaic effiency (FEethanol  ≥ 60%) in a wide potential window (600 mV). The optimal cathodic energy efficiency (47.6%), Faradaic efficiency (84%), and selectivity (96.6%) are also obtained at -0.78 V versus reversible hydrogen electrode (RHE). Combining with the density functional theory (DFT) calculations, it is demonstrated that the stronger metal-support interaction (Ni-N-C) can regulate the surface electronic structure effectively, boosting the electron transfer and stabilizing the active sites (Cu0 -Cuδ+ ) on the surface of CuNi@C/N-npG, finally realizing the controllable transition of reaction intermediates. This work may guide the designs of electrocatalysts with highly catalytic performance for CO2 reduction to C2+ products.

A Simple Way to Incorporate Target Structural Information in Molecular Generative Models.

Deep learning generative models are now being applied in various fields including drug discovery. In this work, we propose a novel approach to include target 3D structural information in molecular generative models for structure-based drug design. The method combines a message-passing neural network model that predicts docking scores with a generative neural network model as its reward function to navigate the chemical space searching for molecules that bind favorably with a specific target. A key feature of the method is the construction of target-specific molecular sets for training, designed to overcome potential transferability issues of surrogate docking models through a two-round training process. Consequently, this enables accurate guided exploration of the chemical space without reliance on the collection of prior knowledge about active and inactive compounds for the specific target. Tests on eight target proteins showed a 100-fold increase in hit generation compared to conventional docking calculations and the ability to generate molecules similar to approved drugs or known active ligands for specific targets without prior knowledge. This method provides a general and highly efficient solution for structure-based molecular generation.

Occurrence of Tomato Leaf Curl New Delhi Virus in Cucurbit Plants in China.

In August 2022, melon (Cucumis melo), cucumber (Cucumis sativus) and luffa (Luffa aegyptiaca) plants showed virus-like symptoms characteristic of geminiviruses (yellowish green, mosaic patterns and severe curling of leaves, short internodes, and stunting) in 10 greenhouses in Fengxian district and 20 greenhoues in Jiading district of Shanghai, China. Fifty symptomatic leaf samples were randomly collected: 28 from melon, 17 from cucumber, and 5 from luffa. To investigate the etiology of the observed disease, total DNA and RNA was extracted via a DNA extraction kit (Tiangen, Not: DP350) and TRIzol reagent (Sigma-Aldrich, Not: T9424), respectively. Healthy melon plants grown in a growth chamber served as negative control. The DNA and RNA samples were screened for the presence of geminiviruses, Cucurbit chlorotic yellow virus (CCYV), Melon yellow spot virus (MYSV), Cucumber mosaic virus (CMV), Zucchini yellow mosaic virus (ZYMV) and Cucumber green mottle mosaic virus (CGMMV) through PCR or RT‒PCR with geminiviruses (Deng et al. 1994), CCYV, MYSV, CMV, ZYMV and CGMMV (Zeng et al. 2011, 2019) primers. The PCR results showed that 28 melon leaves and 17 cucumber leaves were positive for geminivirus and CCYV, respectively, 5 luffa samples were infected with only geminivirus, and virus was not detected from the healthy plants. These results indicate that these two viruses are widely distributed throughout cucurbit crops in Shanghai, China. All the geminiviruses sequences (approximately 510 bp) were quite similar to each other and were most similar (99.4%) to the Tomato leaf curl New Delhi virus (ToLCNDV) sequence (GenBank Accession No. OP356207) (Li et al. 2022). To confirm the presence of geminiviruses, the segments of DNA-A and DNA-B were amplified by PCR with 4 ToLCNDV-specific primer sets (Mizutani et al. 2011) and sequenced from 10 samples (4 melon, 4 cucumber and 2 luffa). Both DNA-A and DNA-B of the ToLCNDV sequences and features were deposited in GenBank under the accession numbers OQ190939-OQ190948 (DNA-A, 2739 nt) and OQ190949-OQ190958 (DNA-B, 2693 nt). BLASTn analysis of Shanghai isolates of ToLCNDV (DNA-A and DNA-B) showed that the sequences shared nucleotide identities ranged from 99.3% to 100% among them and with values of more than 99.4% nucleotide identity with ToLCNDV isolates from tomato in China (OP356207 and OP356208) (Li et al. 2022). To confirm the virus infection, we have successfully constructed an infectious clone for 0823-1 isolate in the binary plasmid and inoculated melon with and without an infectious clone. The melon plants inoculated with ToLCNDV 15 dpi showed the high accumulation of the virus and displayed symptoms similar to viruses in greenhouse. Based on the complete sequences, results of the molecular phylogenetic analysis (Fig. 2) and infectious clone, these geminiviruses were identified as ToLCNDV. ToLCNDV has been reported to occur and spread by the whitefly (Bemisia tabaci) in many Asian countries (Sohrab et al. 2003; Sohrab et al. 2011; Aamir et al. 2020) and Europe (Juárez et al. 2014; Ruiz et al. 2015; Luigi et al. 2019). Large populations of whiteflies were also present in all our surveyed areas. However, to our knowledge, this is the first report of the occurrence of ToLCNDV in cucurbit plants in China. The presence of ToLCNDV and CCYV can cause severe losses in crop yields or even crop failure. In addition to TYLCV, ToLCNDV is another major geminivirus-induced disease threatening cucurbit and other vegetable production in China.

Gallic acid improves the metformin effects on diabetic kidney disease in mice.

OBJECTIVES: Metformin is an antidiabetic agent that is used as the first-line treatment of type 2 diabetes mellitus. Gallic acid is a type of phenolic acid that has been shown to be a potential drug candidate to treat diabetic kidney disease, an important complication of diabetes. We aimed to test whether a combination of gallic acid and metformin can exert synergetic effect on diabetic kidney disease in diabetic mice model. METHODS: Streptozotocin (65 mg/kg) intraperitoneal injection was used to induce diabetic kidney disease in mice. The diabetic mice were treated with saline (Vehicle), gallic acid (GA) (30 mg/kg), metformin (MET) (200 mg/kg), or the combination of gallic acid (30 mg/kg) and metformin (200 mg/kg) (GA + MET). RESULTS: Our results demonstrated that compared to the untreated diabetic mice, all three strategies (GA, MET, and GA + MET) exhibited various effects on improving renal morphology and functions, reducing oxidative stress in kidney tissues, and restoring AMP-activated protein kinase (AMPK)/silent mating type information regulation 2 homolog 1 (SIRT1) signaling in kidney tissues of diabetic mice. Notably, the combination strategy (GA + MET) provided the most potent renal protection effects than any single strategies (GA or MET). CONCLUSION: Our results support the hypothesis that gallic acid might serve as a potential supplement to metformin to enhance the therapeutical effect of metformin.

Isoindigo-Thiophene D-A-D-Type Conjugated Polymers: Electrosynthesis and Electrochromic Performances.

Four novel isoindigo-thiophene D-A-D-type precursors are synthesized by Stille coupling and electrosynthesized to yield corresponding hybrid polymers with favorable electrochemical and electrochromic performances. Intrinsic structure-property relationships of precursors and corresponding polymers, including surface morphology, band gaps, electrochemical properties, and electrochromic behaviors, are systematically investigated. The resultant isoindigo-thiophene D-A-D-type polymer combines the merits of isoindigo and polythiophene, including the excellent stability of isoindigo-based polymers and the extraordinary electrochromic stability of polythiophene. The low onset oxidation potential of precursors ranges from 1.10 to 1.15 V vs. Ag/AgCl, contributing to the electrodeposition of high-quality polymer films. Further kinetic studies illustrate that isoindigo-thiophene D-A-D-type polymers possess favorable electrochromic performances, including high optical contrast (53%, 1000 nm), fast switching time (0.8 s), and high coloration efficiency (124 cm2 C-1). These features of isoindigo-thiophene D-A-D-type conjugated polymers could provide a possibility for rational design and application as electrochromic materials.

Antibacterial Activity and the Mechanism of the Z-Scheme Bi2MoO6/Bi5O7I Heterojunction under Visible Light.

Z-scheme Bi2MoO6/Bi5O7I heterojunction was constructed by an in situ solvothermal method, which was composed of Bi2MoO6 nanosheets growing on the surface of Bi5O7I microrods. The antibacterial activities under illumination towards Escherichia coli (E. coli) were investigated. The Bi2MoO6/Bi5O7I composites exhibited more outstanding antibacterial performance than pure Bi2MoO6 and Bi5O7I, and the E. coli (108 cfu/mL) was completely inactivated by BM/BI-3 under 90 min irradiation. Additionally, the experiment of adding scavengers revealed that h+, •O2- and •OH played an important role in the E. coli inactivation process. The E. coli cell membrane was damaged by the oxidation of h+, •O2- and •OH, and the intracellular components (K+, DNA) subsequently released, which ultimately triggered the apoptosis of the E. coli cell. The enhanced antibacterial performance of Bi2MoO6/Bi5O7I heterojunction is due to the formation of Z-scheme heterojunction with the effective charge transfer via the well-contacted interface of Bi2MoO6 and Bi5O7I. This study provides useful guidance on how to construct Bi5O7I-based heterojunction for water disinfection with abundant solar energy.

Construction of S-Scheme CuS/Bi5O7I Heterojunction for Boosted Photocatalytic Disinfection with Visible Light Exposure.

In this paper, a novel S-scheme CuS/Bi5O7I heterojunction was successfully constructed using a two-step approach comprising the alkaline hydrothermal method and the adsorption-deposition method, and it consisted of Bi5O7I microrods with CuS particles covering the surface. The photocatalytic antibacterial effects on Escherichia coli (E. coli) were systematically examined with visible light exposure. The results suggested that the 3%-CuS/Bi5O7I composite showed the optimal antibacterial activity, completely inactivating E. coli (5 × 108 cfu/mL) in 180 min of irradiation. Moreover, the bacterial inactivation process was scientifically described. •O2- and h+ were the major active species for the inactivation of the bacteria. In the early stages, SOD and CAT initiated the protection system to avoid the oxidative destruction of the active species. Unfortunately, the antioxidant protection system was overwhelmed thereafter, which led to the destruction of the cell membrane, as evidenced by the microstructure changes in E. coli cells. Subsequently, the leakage of intracellular components including K+, proteins, and DNA resulted in the unavoidable death of E. coli. Due to the construction of the S-scheme heterojunction, the CuS/Bi5O7I composite displayed the boosted visible light harvesting, the high-efficiency separation of photogenerated electrons and holes, and a great redox capacity, contributing to an outstanding photocatalytic disinfection performance. This work offers a new opportunity for S-scheme Bi5O7I-based heterojunctions with potential application in water disinfection.

Study of the Mechanism of Astragali Radix in Treating Type 2 Diabetes Mellitus and Its Renal Protection Based on Enzyme Activity, Network Pharmacology, and Experimental Verification.

Astragali Radix (AR) is a common Chinese medicine and food. This article aims to reveal the active role of AR in treating Type 2 diabetes mellitus (T2DM) and its renal protective mechanism. The hypoglycemic active fraction was screened by α-glucosidase and identified by UPLC-QE-Orbitrap-MS spectrometry. The targets and KEGG pathway were determined through the application of network pharmacology methodology. Molecular docking and molecular dynamics simulation technology were used for virtual verification. Subsequently, a mouse model of T2DM was established, and the blood glucose and renal function indexes of the mice after administration were analyzed to further prove the pharmacodynamic effect and mechanism of AR in the treatment of T2DM. HA was determined as the best hypoglycemic active fraction by the α-glucosidase method, with a total of 23 compounds identified. The main active components, such as calycoside-7-O-ß-D-glucoside, methylnisoline, and formononetin, were revealed by network pharmacology. In addition, the core targets and the pathway have also been determined. Molecular docking and molecular dynamics simulation techniques have verified that components and targets can be well combined. In vivo studies have shown that AR can reduce blood sugar levels in model mice, enhance the anti-inflammatory and antioxidant activities of kidney tissue, and alleviate kidney damage in mice. And it also has regulatory effects on proteins such as RAGE, PI3K, and AKT. AR has a good therapeutic effect on T2DM and can repair disease-induced renal injury by regulating the RAGE/PI3K/Akt signaling pathway. This study provides ideas for the development of new drugs or dietary interventions for the treatment of T2DM.

UPLC-QE-Orbitrap-Based Cell Metabolomics and Network Pharmacology to Reveal the Mechanism of N-Benzylhexadecanamide Isolated from Maca (Lepidium meyenii Walp.) against Testicular Dysfunction.

Testicular dysfunction (TDF) is characterized by testosterone deficiency and is caused by oxidative stress injury in Leydig cells. A natural fatty amide named N-benzylhexadecanamide (NBH), derived from cruciferous maca, has been shown to promote testosterone production. Our study aims to reveal the anti-TDF effect of NBH and explore its potential mechanism in vitro. This study examined the effects of H2O2 on cell viability and testosterone levels in mouse Leydig cells (TM3) under oxidative stress. In addition, cell metabolomics analysis based on UPLC-Q-Exactive-MS/MS showed that NBH was mainly involved in arginine biosynthesis, aminoacyl-tRNA biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, the TCA cycle and other metabolic pathways by affecting 23 differential metabolites, including arginine and phenylalanine. Furthermore, we also performed network pharmacological analysis to observe the key protein targets in NBH treatment. The results showed that its role was to up-regulate ALOX5, down-regulate CYP1A2, and play a role in promoting testicular activity by participating in the steroid hormone biosynthesis pathway. In summary, our study not only provides new insights into the biochemical mechanisms of natural compounds in the treatment of TDF, but also provides a research strategy that integrates cell metabolomics and network pharmacology in order to promote the screening of new drugs for the treatment of TDF.

Single-Atom Iron Anchored on 2-D Graphene Carbon to Realize Bridge-Adsorption of O-O as Biomimetic Enzyme for Remarkably Sensitive Electrochemical Detection of H2O2.

Single-atom catalysis is mainly focused on its dispersed high-density catalytic sites, but delicate designs to realize a unique catalysis mechanism in terms of target reactions have been much less investigated. Herein an iron single atomic site catalyst anchored on 2-D N-doping graphene (Fe-SASC/G) was synthesized and further employed as a biomimetic sensor to electrochemically detect hydrogen peroxide, showing an extremely high sensitivity of 3214.28 µA mM-1 cm-2, which is much higher than that (6.5 µA mM-1 cm-2) of its dispersed on 1-D carbon nanowires (Fe-SASC/NW), ranking the best sensitivity among all reported Fe based catalyst at present. The sensor was also used to successfully in situ monitor H2O2 released from A549 living cells. The mechanism was further systematically investigated. Results interestingly indicate that the distance between adjacent single Fe atomic catalytic sites on 2-D graphene of Fe-SASC/G matches statistically well with the outer length of bioxygen of H2O2 to promote a bridge adsorption of -O-O- for simultaneous 2-electron transfer, while the single Fe atoms anchored on distant 1-D nanowires in Fe-SASC/NW only allow an end-adsorption of oxygen atoms for 1-electron transfer. These results demonstrate that Fe-SASC/G holds great promise as an advanced electrode material in selective and sensitive biomimetic sensor and other electrocatalytic applications, while offering scientific insights in deeper single atomic catalysis mechanisms, especially the effects of substrate dimensions on the mechanism.

Antigen Capture and Immune Modulation by Bacterial Outer Membrane Vesicles as In Situ Vaccine for Cancer Immunotherapy Post-Photothermal Therapy.

Tumor antigens released from tumor cells after local photothermal therapy (PTT) can activate the tumor-specific immune responses, which are critical for eliminating the residual lesions and distant metastases. However, the limited recognition efficiency of released tumor antigens by the immune system and the immunosuppressive microenvironment lead to ineffective antitumor immunity. Here, an in situ multifunctional vaccine based on bacterial outer membrane vesicles (OMVs, 1-MT@OMV-Mal) is developed by surface conjunction of maleimide groups (Mal) and interior loading with inhibitor of indoleamine 2, 3-dioxygenase (IDO), 1-methyl-tryptophan (1-MT). 1-MT@OMV-Mal can bind to the released tumor antigens after PTT, and be efficiently recognized and taken up by dendritic cells. Furthermore, in situ injection of 1-MT@OMV-Mal simultaneously overcomes the immune inhibition of IDO on tumor-infiltrating effector T cells, leading to remarkable inhibition on both primary and distant tumors. Together, a promising in situ vaccine based on OMVs to facilitate immune-mediated tumor clearance after PTT through orchestrating antigen capture and immune modulation is presented.

Principles of Amino-Acid-Nucleotide Interactions Revealed by Binding Affinities between Homogeneous Oligopeptides and Single-Stranded DNA Molecules.

We have determined the binding strengths between nucleotides of adenine, thymine, guanine and cytosine in homogeneous single stranded DNAs and homo-octapeptides consisting of 20 common amino acids. We use a bead-based fluorescence assay for these measurements in which octapeptides are immobilized on the bead surface and ssDNAs are in solutions. Comparative analyses of the distribution of the binding energies reveal unique binding strength patterns assignable to each DNA nucleotide and amino acid originating from the chemical structures. Pronounced favorable (such as Arg-G, etc.) and unfavorable (such as Ile-T, etc.) binding interactions can be identified in selected groups of amino acid and nucleotide pairs that could provide basis to elucidate energetics of amino-acid-nucleotide interactions. Such interaction selectivity, specificity and polymorphism establish the contributions from DNA backbone, DNA bases, as well as main chain and side chain of the amino acids.

HOP1 and HOP2 are involved in salt tolerance by facilitating the brassinosteroid-related nucleo-cytoplasmic partitioning of the HSP90-BIN2 complex.

The co-chaperone heat shock protein (HSP)70-HSP90 organizing protein (HOP) is involved in plant thermotolerance. However, its function in plant salinity tolerance was not yet studied. We found that Arabidopsis HOP1 and HOP2 play critical roles in salt tolerance by affecting the nucleo-cytoplasmic partitioning of HSP90 and brassinosteroid-insensitive 2 (BIN2). A hop1/2 double mutant was hypersensitive to salt-stress. Interestingly, this sensitivity was remedied by exogenous brassinolide application, while the application of brassinazole impeded growth of both wild-type (WT) and hop1/2 plants under normal and salt stress conditions. This suggested that the insufficient brassinosteroid (BR) content was responsible for the salt-sensitivity of hop1/2. After WT was transferred to salt stress conditions, HOP1/2, BIN2 and HSP90 accumulated in the nucleus, brassinazole-resistant 1 (BZR1) was phosphorylated and accumulated in the cytoplasm, and BR content significantly increased. This initial response resulted in dephosphorylation of BZR1 and BR response. This dynamic regulation of BR content was impeded in salt-stressed hop1/2. Thus, we propose that HOP1 and HOP2 are involved in salt tolerance by affecting BR signalling.

A Nomogram of Combining IVIM-DWI and MRI Radiomics From the Primary Lesion of Rectal Adenocarcinoma to Assess Nonenlarged Lymph Node Metastasis Preoperatively.

BACKGROUND: Lymph node (LN) staging plays an important role in treatment decision-making. Current problem is that preoperative detection of LN involvement is always highly challenging for radiologists. PURPOSE: To explore the value of the nomogram model combining intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and radiomics features from the primary lesion of rectal adenocarcinoma in assessing the non-enlarged lymph node metastasis (N-LNM) preoperatively. STUDY TYPE: Retrospective. POPULATION: A total of 126 patients (43% female) comprising a training group (n = 87) and a validation group (n = 39) with pathologically confirmed rectal adenocarcinoma. FIELD STRENGTH/SEQUENCE: A 3.0 Tesla (T); T2 -weighted imaging (T2 WI) with fast spin-echo (FSE) sequence; IVIM-DWI spin-echo echo-planar imaging sequence. ASSESSMENT: Based on pathological analysis of the surgical specimen, patients were classified into negative LN (LN-) and positive LN (LN+) groups. Apparent diffusion coefficient (ADC), diffusion coefficient (D), pseudo diffusion coefficient (D*) and microvascular volume fraction (f) values of primary lesion of rectal adenocarcinoma were measured. Three-dimensional (3D) radiomics features were measured on T2 WI and IVIM-DWI. A nomogram model including IVIM-DWI and radiomics features was developed. STATISTICAL TESTS: General_univariate_analysis and multivariate logistic regression were used for radiomics features selection. The performance of the nomogram was assessed by the receiver operating characteristic (ROC) curve, calibration, and decision curve analysis (DCA). RESULTS: The LN+ group had a significantly lower D* value ([13.20 ± 13.66 vs. 23.25 ± 18.71] × 10-3  mm2 /sec) and a higher f value (0.43 ± 0.12 vs. 0.34 ± 0.10) than the LN- group in the training cohort. The nomogram model combined D*, f, and radiomics features had a better evaluated performance (AUC = 0.864) than any other model in the training cohort. DATE CONCLUSION: The nomogram model including IVIM-DWI and MRI radiomics features in the primary lesion of rectal adenocarcinoma was associated with the N-LNM. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.