Association of Nutritional Risk Index With Infection-Related Hospitalization and Death After Hospitalization in Patients Undergoing Maintenance Hemodialysis.

OBJECTIVE: Patients undergoing dialysis frequently experience hospitalization due to cardiovascular disease (CVD) and infection. This population is also at high risk of rehospitalization and subsequent death. In addition to serious outcomes, hospitalization incurs substantial medical cost. Prevention of hospitalization is accordingly an urgent matter. Here, we examined whether nutritional disorder was associated with hospitalization and subsequent death. METHODS: The study was conducted under a prospective design using data from the Japanese Dialysis Outcomes and Practice Pattern Study. The exposure was the Nutritional Risk Index for Japanese Hemodialysis (NRI-JH), through which patients were divided into low-, medium-, and high-risk groups, with the low-risk group as referent. The primary outcome was CVD-related or infection-related hospitalization. Secondary outcome was all-cause mortality. For exploratory analyses, the associations of baseline or latest NRI-JH just before hospitalization, with death after hospitalizations, were examined. RESULTS: Of 4021 patients, 566 patients had CVD-related hospitalization and 375 had infection-related hospitalization during a median follow-up of 2.6 years. NRI-JH at baseline was significantly associated with infection-related hospitalization but not with CVD-related hospitalization, in multivariable Cox models (hazard ratio [HR] 1.46, 95% confidential interval [CI]: 1.09 to 1.97, P = .012 for medium-risk vs. low-risk group) (HR 2.46, 95% CI: 1.81 to 3.35, P < .001 for high-risk vs. low-risk group). NRI-JH was also associated with all-cause mortality. In addition, the baseline and latest high-risk NRI-JH groups were significantly associated with death after both CVD-related and infection-related hospitalizations. CONCLUSIONS: A higher nutritional risk as evaluated by NRI-JH was associated with infection-related hospitalization but not with CVD-related hospitalization. However, NRI-JH was significantly associated with death after both CVD-related and infection-related hospitalizations, suggesting that nutritional risk may be separately involved in hospitalization or subsequent death. NRI-JH may be useful in the planning of individual care to improve outcomes.

Characterization of cotinine degradation in a newly isolated Gram-negative strain Pseudomonas sp. JH-2.

Cotinine, the primary metabolite of nicotine in the human body, is an emerging pollutant in aquatic environments. It causes environmental problems and is harmful to the health of humans and other mammals; however, the mechanisms of its biodegradation have been elucidated incompletely. In this study, a novel Gram-negative strain that could degrade and utilize cotinine as a sole carbon source was isolated from municipal wastewater samples, and its cotinine degradation characteristics and kinetics were determined. Pseudomonas sp. JH-2 was able to degrade 100 mg/L (0.56 mM) of cotinine with high efficiency within 5 days at 30 ℃, pH 7.0, and 1% NaCl. Two intermediates, 6-hydroxycotinine and 6-hydroxy-3-succinoylpyridine (HSP), were identified by high-performance liquid chromatography and liquid chromatograph mass spectrometer. The draft whole genome sequence of strain JH-2 was obtained and analyzed to determine genomic structure and function. No homologs of proteins predicted in Nocardioides sp. JQ2195 and reported in nicotine degradation Pyrrolidine pathway were found in strain JH-2, suggesting new enzymes that responsible for cotinine catabolism. These findings provide meaningful insights into the biodegradation of cotinine by Gram-negative bacteria.

Cyp6g2 is the major P450 epoxidase responsible for juvenile hormone biosynthesis in Drosophila melanogaster.

BACKGROUND: Juvenile hormones (JH) play crucial role in regulating development and reproduction in insects. The most common form of JH is JH III, derived from MF through epoxidation by CYP15 enzymes. However, in the higher dipterans, such as the fruitfly, Drosophila melanogaster, a bis-epoxide form of JHB3, accounted most of the JH detected. Moreover, these higher dipterans have lost the CYP15 gene from their genomes. As a result, the identity of the P450 epoxidase in the JH biosynthesis pathway in higher dipterans remains unknown. RESULTS: In this study, we show that Cyp6g2 serves as the major JH epoxidase responsible for the biosynthesis of JHB3 and JH III in D. melanogaster. The Cyp6g2 is predominantly expressed in the corpus allatum (CA), concurring with the expression pattern of jhamt, another well-studied gene that is crucial in the last steps of JH biosynthesis. Mutation in Cyp6g2 leads to severe disruptions in larval-pupal metamorphosis and exhibits reproductive deficiencies, exceeding those seen in jhamt mutants. Notably, Cyp6g2-/-::jhamt2 double mutants all died at the pupal stage but could be rescued through the topical application of JH analogs. JH titer analyses revealed that both Cyp6g2-/- mutant and jhamt2 mutant lacking JHB3 and JH III, while overexpression of Cyp6g2 or jhamt caused a significant increase in JHB3 and JH III titer. CONCLUSIONS: These findings collectively established that Cyp6g2 as the major JH epoxidase in the higher dipterans and laid the groundwork for the further understanding of JH biosynthesis. Moreover, these findings pave the way for developing specific Cyp6g2 inhibitors as insect growth regulators or insecticides.

Discovery of selective TYK2 inhibitors: Design, synthesis, in vitro and in silico studies of promising hits with triazolopyrimidinone scaffold.

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway mediates many cytokine and growth factor signals. Tyrosine kinase 2 (TYK2), one of the members of this pathway and the first described member of the JAK family. TYK2 associates with inflammatory and autoimmune diseases, cancer and diabetes. Here, we present novel compounds as selective inhibitors of the canonical kinase domain of TYK2 enzyme. These compounds were rationally designed and synthesized with appropriate reactions. Molecular modeling techniques were used to design and optimize the candidates for TYK2 inhibition and to determine the estimated binding orientations of them inside JAKs. Designed compounds potently inhibited TYK2 with good selectivity against other JAKs as determined by in vitro assays. In order to verify its selectivity properties, compound A8 was tested against 58 human kinases (KinaseProfiler™ assay). The effects of the selected seven compounds on the protein levels of members of the JAK/STAT family were also detected in THP-1 monocytes although the basal level of these proteins is poorly detectable. Therefore, their expression was induced by lipopolysaccharide treatment and compounds A8, A15, A18, and A19 were found to be potent inhibitors of the TYK2 enzyme, (9.7 nM, 6.0 nM, 5.0 nM and 10.3 nM, respectively), and have high selectivity index for the JAK1, JAK2, and JAK3 enzymes. These findings suggest that triazolo[1,5-a]pyrimidinone derivatives may be lead compounds for developing potent TYK2-selective inhibitors targeting enzymes' active site.

Study on the dynamic response characteristics of lining structures in large-section tunnel blasting using JH-2 model analysis.

The lining structures of tunnels are typically constructed using sprayed or cast concrete materials, and their performance and quality during tunnel excavation and blasting are crucial for the stability and safety of tunnels. Therefore, the safe distance between the lining structure and blasting source should be determined to avoid concrete damage caused by blasting vibrations. In this study, taking the subway tunnel of Danshan Station in Qingdao as an example, the JH-2 model is introduced as the constitutive model of the tunnel blasting simulation, and the JH-2 model parameters of the local surrounding rock are obtained by experiments, and finally the numerical simulation and theoretical verification are carried out to study the safety distance of shotcrete under various safety judgment standards. The results indicate that the JH-2 model can effectively simulate the propagation of stress waves under different media conditions, and the closer the strength parameters and pressure constant of the lining structure are to those of the surrounding rock, the safer the concrete-rock bonding interface. During tunnel blasting construction using the ring blasting method, the peak particle velocity (PPV) of the lining structure increases with an increase in the arch angle. Based on the numerical simulation results, we recommend that concrete lining be constructed at a distance of at least 62 m from the blasting source to avoid damage caused by vibrations. The effect of concrete tensile failure caused by longitudinal stress is much smaller than the damage to the bonding interface caused by the PPV and can be neglected.

Spray-induced and nanocarrier-delivered gene silencing system targeting juvenile hormone receptor components: potential application as fertility inhibitors for Adelphocoris suturalis management.

BACKGROUND: Adelphocoris suturalis is a destructive pest that attacks > 270 plants, including cotton, maize, soybean, and fruit trees. Adelphocoris suturalis can cause tremendous crop losses when the density exceeds economic thresholds, but because it can be both phytophagous and zoophytophagous it can serve as a natural enemy of other pests when the density is below the economic threshold. Effective control of its population is beneficial for maximizing yield and profits. RNA interference (RNAi) has potential to be a viable alternative to conventional pesticide-based pest management, but the lack of efficient double-stranded RNA (dsRNA) delivery systems and candidate genes are currently limiting factors for field applications. RESULTS: In this study, RNAi of juvenile hormone (JH) receptor components methoprene-tolerant (Met)/Taiman (Tai) in Adelphocoris suturalis reduced fertility. Based on this reproductive role, we targeted Adelphocoris suturalis Met and Tai for knockdown by coupling nanomaterial-dsRNA complexes with a transdermal spray delivery system. Within 12 h of adult emergence, females were sprayed with star polycation (SPc)-dsRNA formulations and the RNAi effects were assessed over time. RNAi knockdown efficiencies of 39-58% were observed at 5 days post-treatment and abnormal ovarian development was apparent by 10 days post-treatment. CONCLUSION: Our results show that spray-induced and nanocarrier-delivered gene silencing (SI-NDGS) system targeting JH signal genes effectively impaired oviposition, thus developing a novel RNA fertility inhibitor to control Adelphocoris suturalis populations. These results give new perspective on pest management and suggest broad prospects for field applications. © 2024 Society of Chemical Industry.

Mamestra brassicae Multiple Nucleopolyhedroviruses Prevents Pupation of Helicoverpa armigera by Regulating Juvenile Hormone Titer.

Baculovirus infection can prevent the pupation of insects. Juvenile hormone (JH) plays a vital role in regulating insect molting and metamorphosis. However, the molecular mechanism of baculovirus preventing the pupation of larvae by regulating the Juvenile hormone (JH) pathway is still unclear. In this study, we found that the Mamestra brassicae multiple nucleopolyhedroviruses (MbMNPV) infection prolonged the larval stage of fourth instar Helicoverpa armigera (H. armigera) by 0.52 d and caused an increase in JH titer. To identify the genes that contribute to the JH increase in H. armigera-MbMNPV interaction, we analyzed mRNA expression profiles of the fat bodies of H. armigera infected by MbMNPV. A total of 3637 differentially expressed mRNAs (DE-mRNAs) were filtered out through RNA-seq analysis. These DE-mRNAs were mainly enriched in Spliceosome, Ribosome biogenesis in eukaryotes, Aminoacyl-tRNA biosynthesis, Mismatch repair, and RNA degradation signaling pathway, which are related to the virus infection. Real-time PCR was used to verify the RNA sequencing results. To find out which genes caused the increase in JH titer, we analyzed all the DE-mRNAs in the transcriptome and found that the JHE and JHEH genes, which were related to JH degradation pathway, were down-regulated. JHE and JHEH genes in the larvae of MbMNPV-infected group were significantly down-regulated compared with the control group by RT-qPCR. We further proved that the JH is degraded by JHE in H. armigera larvae by RNAi, ELISA, RT-qPCR and bioassay, while the hydrolysis of JH by JHEH in H. armigera larvae can almost be ignored. Knocking down of HaJHE promoted the expression of the JH receptor gene Met and the downstream gene Kr-h1, and the replication of MbMNPV. This study clarified that JH is mainly degraded by JHE in H. armigera larvae. The MbMNPV infection of H. armigera larvae leads to the increase of JH titer by inhibiting the expression of JHE. The increase in JH titer promotes the expression of the JH receptor gene Met and the downstream gene Kr-h1, which prevents the pupation of H. armigera, and promotes MbMNPV replication. This study provides new insights into H. armigera and MbMNPV interaction mechanisms.

Farnesol, a component of plant-derived honeybee-collected resins, shows JH-like effects in Apis mellifera workers.

Farnesol, a sesquiterpene found in all eukaryotes, precursor of juvenile hormone (JH) in insects, is involved in signalling, communication, and antimicrobial defence. Farnesol is a compound of floral volatiles, suggesting its importance in pollination and foraging behaviour. Farnesol is found in the resin of Baccharis dracunculifolia, from which honeybees elaborate the most worldwide marketable propolis. Bees use propolis to seal cracks in the walls, reinforce the wax combs, and as protection against bacteria and fungi. The introduction within a honeybee hive of a compound with potential hormonal activity can be a challenge to the colony survival, mainly because the transition from within-hive to outside activities of workers is controlled by JH. Here, we tested the hypothesis that exogenous farnesol alters the pacing of developing workers. The first assays showed that low doses of the JH precursor (0.1 and 0.01 µg) accelerate pharate-adult development, with high doses being toxic. The second assay was conducted in adult workers and demonstrated bees that received 0.2 µg farnesol showed more agitated behaviour than the control bees. If farnesol was used by corpora allata (CA) cells as a precursor of JH and this hormone was responsible for the observed behavioural alterations, these glands were expected to be larger after the treatment. Our results on CA measurements after 72 h of treatment showed bees that received farnesol had glands doubled in size compared to the control bees (p < 0.05). Additionally, we expected the expression of JH synthesis, JH degradation, and JH-response genes would be upregulated in the treated bees. Our results showed that indeed, the mean transcript levels of these genes were higher in the treated bees (significant for methyl farnesoate epoxidase and juvenile hormone esterase, p < 0.05). These results suggest farnesol is used in honeybees as a precursor of JH, leading to increasing JH titres, and thus modulating the pacing of workers development. This finding has behavioural and ecological implications, since alterations in the dynamics of the physiological changes associated to aging in young honeybees may significantly impact colony balance in nature.

Structural Insights into the Substrate Binding of Farnesyl Diphosphate Synthase FPPS1 from Silkworm, Bombyx mori.

Farnesyl diphosphate synthase (FPPS) is an important enzyme involved in the juvenile hormone (JH) biosynthesis pathway. Herein, we report the crystal structure of a type-I Lepidopteran FPPS from Bombyx mori (BmFPPS1) at 2.80 Å resolution. BmFPPS1 adopts an α-helix structure with a deep cavity at the center of the overall structure. Computational simulations combined with biochemical analysis allowed us to define the binding mode of BmFPPS1 to its substrates. Structural comparison revealed that BmFPPS1 adopts a structural pattern similar to that of type-II FPPS but exhibits a distinct substrate-binding site. These findings provide a structural basis for understanding substrate preferences and designing FPPS inhibitors. Furthermore, the expression profiles and RNA interference of BmFPPSs indicated that they play critical roles in the JH biosynthesis and larval-pupal metamorphosis. These findings enhance our understanding of the structural features of type-I Lepidopteran FPPS while providing direct evidence for the physiological role of BmFPPSs in silkworm development.

JH degradation pathway participates in hormonal regulation of larval development of Bombyx mori following λ-cyhalothrin exposure.

λ-Cyhalothrin (λ-cyh), a widely utilized pyrethroid insecticide, poses serious threats to non-target organisms due to its persistence nature in the environment. Exposure to low concentrations of λ-cyh has been observed to result in prolonged larval development in Bombyx mori, leading to substantial financial losses in sericulture. The present study was undertaken to elucidate the underlying mechanisms for prolonged development caused by λ-cyh (LC10) exposure. The results showed that the JH Ⅲ titer was significantly increased at 24 h of λ-cyh exposure, and the JH interacting genes Methoprene-tolerant 2, Steroid Receptor Co-activator, Krüppel-homolog 1, and JH binding proteins were also up-regulated. Although the target of rapamycin (Tor) genes were induced by λ-cyh, the biosynthesis of JH in the corpora allata was not promoted. Notably, 13 JH degradation genes were found to be significantly down-regulated in the midgut of B. mori. The mRNA levels and enzyme activity assays indicated that λ-cyh had inhibitory effects on JH esterase, JH epoxide hydrolase, and JH diol kinase (JHDK). Furthermore, the suppression of JHDK (KWMTBOMO01580) was further confirmed by both western blot and immunohistochemistry. This study has offered a comprehensive perspective on the mechanisms underlying the prolonged development caused by insecticides, and our results also hold significant implications for the safe production of sericulture.

Corrigendum: Two small-molecule inhibitors of Toxoplasma gondii proliferation in vitro.

[This corrects the article DOI: 10.3389/fcimb.2023.1145824.].

Juvenile hormone receptor Methoprene tolerant: Functions and applications.

During the past 15years, after confirming Methoprene tolerant (Met) as a juvenile hormone (JH) receptor, tremendous progress has been made in understanding the function of Met in supporting JH signal transduction. Met role in JH regulation of development, including metamorphosis, reproduction, diapause, cast differentiation, behavior, im`munity, sleep and epigenetic modifications, have been elucidated. Met's Heterodimeric partners involved in performing some of these functions were discovered. The availability of JH response elements (JHRE) and JH receptor allowed the development of screening assays in cell lines and yeast. These screening assays facilitated the identification of new chemicals that function as JH agonists and antagonists. These new chemicals and others that will likely be discovered in the near future by using JH receptor and JHRE will lead to highly effective species-specific environmentally friendly insecticides for controlling pests and disease vectors.

Recent progress on tyrosine kinase 2 JH2 inhibitors.

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which can regulate the signaling of multiple pro-inflammatory cytokines, including IL12, IL23 and type I interferon (IFNα/ß), and its inhibitors can treat autoimmune diseases caused by the abnormal expression of IL12 and IL23. Interest in TYK2 JH2 inhibitors has increased as a result of safety concerns with JAK inhibitors. This overview introduces TYK2 JH2 inhibitors that are already on the market, including Deucravactinib (BMS-986165), as well as those currently in clinical trials, such as BMS-986202, NDI-034858, and ESK-001.

Structure-activity relationship study of central pyridine-derived TYK2 JH2 inhibitors: Optimization of the PK profile through C4' and C6 variations.

Efforts directed at improving potency and preparing structurally different TYK2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central pyridyl based analogs 2-4. The current SAR study resulted in the identification of 4h as a potent and selective TYK2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described. The hWB IC50 of 4h was shown as 41 nM with 94% bioavailability in the mouse PK study.

Citrinin Is a Potential Quorum Sensing Inhibitor against Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an opportunistic pathogen that infects patients by regulating virulence factors and biofilms through a quorum sensing (QS) system to protect itself from antibiotics and environmental stress. Therefore, the development of quorum sensing inhibitors (QSIs) is expected to become a new strategy for studying drug resistance to P. aeruginosa infections. Marine fungi are valuable resources for screening QSIs. A marine fungus, Penicillium sp. JH1, with anti-QS activity was isolated from the offshore waters of Qingdao (China), and citrinin, a novel QSI, was purified from secondary metabolites of this fungus. Citrinin could significantly inhibit the production of violacein in Chromobacterium violaceum CV12472 and the production of three virulence factors (elastase, rhamnolipid and pyocyanin) in P. aeruginosa PAO1. It could also inhibit the biofilm formation and motility of PAO1. In addition, citrinin downregulated the transcript levels of nine genes (lasI, rhlI, pqsA, lasR, rhlR, pqsR, lasB, rhlA and phzH) associated with QS. Molecular docking results showed that citrinin bound to PqsR and LasR with better affinity than the natural ligands. This study laid a foundation for the further study of the structure optimization and structure-activity relationship of citrinin.

Two small-molecule inhibitors of Toxoplasma gondii proliferation in vitro.

Background: Toxoplasmosis caused by Toxoplasma gondii is a globally distributed zoonosis. Most infections appear asymptomatic in immunocompetent individuals, but toxoplasmosis can be fatal in fetuses and immunocompromised adults. There is an urgent need to research and develop effective and low-toxicity anti-T. gondii drugs because of some defects in current clinical anti-T. gondii drugs, such as limited efficacy, serious side effects and drug resistance. Methods: In this study, 152 autophagy related compounds were evaluated as anti-T. gondii drugs. The activity of ß-galactosidase assay based on luminescence was used to determine the inhibitory effect on parasite growth. At the same time, MTS assay was used to further detect the effects of compounds with over 60% inhibition rate on host cell viability. The invasion, intracellular proliferation, egress and gliding abilities of T. gondii were tested to assess the inhibitory effect of the chosen drugs on the distinct steps of the T. gondii lysis cycle. Results: The results showed that a total of 38 compounds inhibited parasite growth by more than 60%. After excluding the compounds affecting host cell activity, CGI-1746 and JH-II-127 were considered for drug reuse and further characterized. Both CGI-1746 and JH-II-127 inhibited tachyzoite growth by 60%, with IC50 values of 14.58 ± 1.52 and 5.88 ± 0.23 µM, respectively. TD50 values were 154.20 ± 20.15 and 76.39 ± 14.32 µM, respectively. Further research found that these two compounds significantly inhibited the intracellular proliferation of tachyzoites. Summarize the results, we demonstrated that CGI-1746 inhibited the invasion, egress and especially the gliding abilities of parasites, which is essential for the successful invasion of host cells, while JH-II-127 did not affect the invasion and gliding ability, but seriously damaged the morphology of mitochondria which may be related to the damage of mitochondrial electron transport chain. Discussion: Taken together, these findings suggest that both CGI-1746 and JH-II-127 could be potentially repurposed as anti-T. gondii drugs, lays the groundwork for future therapeutic strategies.

JAK1 Pseudokinase V666G Mutant Dominantly Impairs JAK3 Phosphorylation and IL-2 Signaling.

Overactive Janus kinases (JAKs) are known to drive leukemia, making them well-suited targets for treatment. We sought to identify new JAK-activating mutations and instead found a JAK1-inactivating pseudokinase mutation, V666G. In contrast to other pseudokinase mutations that canonically lead to an active kinase, the JAK1 V666G mutation led to under-activation seen by reduced phosphorylation. To understand the functional role of JAK1 V666G in modifying kinase activity we investigated its influence on other JAK kinases and within the Interleukin-2 pathway. JAK1 V666G not only inhibited its own activity, but its presence could inhibit other JAK kinases. These findings provide new insights into the potential of JAK1 pseudokinase to modulate its own activity, as well as of other JAK kinases. Thus, the features of the JAK1 V666 region in modifying JAK kinases can be exploited to allosterically inhibit overactive JAKs.

Cloning and characterization of Aedes aegypti blood downregulated chymotrypsin II.

Aedes aegypti adult and larval blood downregulated chymotrypsin II was cloned, sequenced and its 3D conformation modeled. Cloning of the enzymes from adult and larval guts indicated that both genes sit at the same location on Chromosome 2. Genomic analyses showed that larval and adult genes are the same and both have four exons and three introns that are located on an 8.32 Kb DNA in direction with the Ae. aegypti genome. The adult and larval transcript synthesis is controlled by alternative splicing explaining small difference in the amino acids sequences. Chymotrypsin II that was extracted from guts of sugar-fed and at 48 after blood feeding showed a pH optimum of 4-5 with a broad shoulder of activity from pH 6 to 10. Dot blot analyses show that the enzyme's transcript is downregulated after females take a blood meal and upregulated at 48 h after the blood meal. A Chymotrypsin II transcript was also detected in the larval gut during different times of larval developmental stages, indication that Ae. aegypti chymotrypsin II is synthesized by adults and larval guts. The possibility that JH III and 20HE play an active role in the regulation is discussed.

The endocrine disruptor, fenoxycarb modulates gut immunity and gut bacteria titer in the cotton bollworm, Helicoverpa armigera.

The endocrine system modulates several physiological functions such as development and metamorphosis in insects. The normal growth and development of insects is interfered with insect growth regulators (IGRs), which act as mimics of insect hormones like juvenile hormone (JH) and ecdysone hormone. The effects of JH and its analogs on systemic immunity have been identified. However the effect of these compounds on local gut immunity is largely unknown. In this study, the effects of JH analog fenoxycarb on the local gut immunity of Helicoverpa armigera, gut bacteria population, and their role in the pathogenicity of Bacillus thuringiensis (Bt) were analyzed. The results showed that feeding fenoxycarb causes a decrease in the transcription level of IMD (Relish and PGPR-LC), ROS (DUOX and SOD) related genes and antimicrobial peptides (AMPs), followed by an overpopulation of gut bacteria. The fenoxycarb-treated larvae showed higher susceptibility to Bt compared to the control larvae. Overall, these findings collectively suggest that JH analog affects local gut immunity and gut bacteria titer.