MAPKs trigger antiviral immunity by directly phosphorylating a rhabdovirus nucleoprotein in plants and insect vectors.

Signaling by the evolutionarily conserved mitogen-activated protein kinase or extracellular signal-regulated kinase (MAPK/ERK) plays critical roles in converting extracellular stimuli into immune responses. However, whether MAPK/ERK signaling induces virus immunity by directly phosphorylating viral effectors remains largely unknown. Barley yellow striate mosaic virus (BYSMV) is an economically important plant cytorhabdovirus that is transmitted by the small brown planthopper (SBPH, Laodelphax striatellus) in a propagative manner. Here, we found that the barley (Hordeum vulgare) MAPK MPK3 (HvMPK3) and the planthopper ERK (LsERK) proteins interact with the BYSMV nucleoprotein (N) and directly phosphorylate N protein primarily on serine 290. The overexpression of HvMPK3 inhibited BYSMV infection, whereas barley plants treated with the MAPK pathway inhibitor U0126 displayed greater susceptibility to BYSMV. Moreover, knockdown of LsERK promoted virus infection in SBPHs. A phosphomimetic mutant of the N Ser290 (S290D) completely abolished virus infection because of impaired self-interaction of BYSMV N and formation of unstable N-RNA complexes. Altogether, our results demonstrate that the conserved MAPK and ERK directly phosphorylate the viral nucleoprotein to trigger immunity against cross-kingdom infection of BYSMV in host plants and its insect vectors.

Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation.

Testicular nuclear receptor 4 (TR4) modulates the transcriptional activation of genes and plays important roles in many diseases. The regulation of TR4 on target genes involves direct interactions with DNA molecules via the DNA-binding domain (DBD) and recruitment of coregulators by the ligand-binding domain (LBD). However, their regulatory mechanisms are unclear. Here, we report high-resolution crystal structures of TR4DBD, TR4DBD-DNA complexes and the TR4LBD-JAZF1 complex. For DNA recognition, multiple factors come into play, and a specific mutual selectivity between TR4 and target genes is found. The coactivators SRC-1 and CREBBP can bind at the interface of TR4 originally occupied by the TR4 activation function region 2 (AF-2); however, JAZF1 suppresses the binding through a novel mechanism. JAZF1 binds to an unidentified surface of TR4 and stabilizes an α13 helix never reported in the nuclear receptor family. Moreover, the cancer-associated mutations affect the interactions and the transcriptional activation of TR4 in vitro and in vivo, respectively. Overall, our results highlight the crucial role of DNA recognition and a novel mechanism of how JAZF1 reinforces the autorepressed conformation and influences the transcriptional activation of TR4, laying out important structural bases for drug design for a variety of diseases, including diabetes and cancers.

An Octacarboxylate-Linked Sodium Metal-Organic Framework with High Porosity.

Alkali metal-based metal-organic frameworks (MOFs) with permanent porosity are scarce because of their high tendency to coordinate with solvents such as water. However, these MOFs are lightweight and bear gravimetric benefits for gas adsorption related applications. In this study, we present the successful construction of a microporous MOF, designated as HIAM-111, built solely on sodium ions by using an octacarboxylate linker. The structure of HIAM-111 is based on 8-connected Na4 clusters and exhibits a novel topology with an underlying 32,42,8-c net. Remarkably, HAM-111 possesses a robust and highly porous framework with a BET surface area of 1561 m2/g, significantly surpassing that of the previously reported Na-MOFs. Further investigations demonstrate that HIAM-111 is capable of separating C2H2/CO2 and purifying C2H4 directly from C2H4/C2H2/C2H6 with high adsorption capacities. The current work may shed light on the rational design of robust and porous MOFs based on alkali metals.

Structural Basis of Nucleic Acid Recognition and 6mA Demethylation by Caenorhabditis elegans NMAD-1A.

N6-methyladenine (6mA) of DNA is an emerging epigenetic mark in the genomes of Chlamydomonas, Caenorhabditis elegans, and mammals recently. Levels of 6mA undergo drastic fluctuation and thus affect fertility during meiosis and early embryogenesis. Here, we showed three complex structures of 6mA demethylase C. elegans NMAD-1A, a canonical isoform of NMAD-1 (F09F7.7). Biochemical results revealed that NMAD-1A prefers 6mA Bubble or Bulge DNAs. Structural studies of NMAD-1A revealed an unexpected "stretch-out" conformation of its Flip2 region, a conserved element that is usually bent over the catalytic center to facilitate substrate base flipping in other DNA demethylases. Moreover, the wide channel between the Flip1 and Flip2 of the NMAD-1A explained the observed preference of NMAD-1A for unpairing substrates, of which the flipped 6mA was primed for catalysis. Structural analysis and mutagenesis studies confirmed that key elements such as carboxy-terminal domain (CTD) and hypothetical zinc finger domain (ZFD) critically contributed to structural integrity, catalytic activity, and nucleosome binding. Collectively, our biochemical and structural studies suggest that NMAD-1A prefers to regulate 6mA in the unpairing regions and is thus possibly associated with dynamic chromosome regulation and meiosis regulation.

Study on the effect of enzymolysis combined fermentation on reducing the off-flavor of egg white powder.

BACKGROUND: The application of egg white powder (EWP) was subject to its off-flavor. In the present study, flavourzyme and lactic acid bacteria were used to treat egg white powder (EWP) and the mechanism effects of enzymolysis-fermentation were explored. RESULTS: Compared with the control group, enzymolysis combined with fermentation treatment group (EW-EF) reduced the four-representative off-flavor compounds (geranyl acetone, 1-octen-3-ol, octanal and nonanal) by more than 62.66%. Fermentation produced esters with good flavor, and enzymolysis produced fresh amino acids. Characterization of protein structure indicated that fermentation decreased both fluorescence intensity and surface negative charges, accelerating the aggregation of proteins; enzymolysis promoted aggregation and degradation, improving the stability of the egg white proteins. Meanwhile, enzymolysis broke down the hydrophobic cavities bound to off-flavor compounds, releasing protein-bound off-flavor compounds and removing them through fermentation. CONCLUSION: EW-EF had the best effect of off-flavor removal on EWP. The results of the present study could provide a green and effective method for improving the flavor of EWP. © 2024 Society of Chemical Industry.

Structural insights into the interactions and epigenetic functions of human nucleic acid repair protein ALKBH6.

Human AlkB homolog 6, ALKBH6, plays key roles in nucleic acid damage repair and tumor therapy. However, no precise structural and functional information are available for this protein. In this study, we determined atomic resolution crystal structures of human holo-ALKBH6 and its complex with ligands. AlkB members bind nucleic acids by NRLs (nucleotide recognition lids, also called Flips), which can recognize DNA/RNA and flip methylated lesions. We found that ALKBH6 has unusual Flip1 and Flip2 domains, distinct from other AlkB family members both in sequence and conformation. Moreover, we show that its unique Flip3 domain has multiple unreported functions, such as discriminating against double-stranded nucleic acids, blocking the active center, binding other proteins, and in suppressing tumor growth. Structural analyses and substrate screening reveal how ALKBH6 discriminates between different types of nucleic acids and may also function as a nucleic acid demethylase. Structure-based interacting partner screening not only uncovered an unidentified interaction of transcription repressor ZMYND11 and ALKBH6 in tumor suppression but also revealed cross talk between histone modification and nucleic acid modification in epigenetic regulation. Taken together, these results shed light on the molecular mechanism underlying ALKBH6-associated nucleic acid damage repair and tumor therapy.

Temporal trends and geographic variations in perioperative red blood cell transfusion in major surgical procedures from 2013 to 2018 in China.

BACKGROUND AND OBJECTIVES: Transfusion-related guidelines promote restrictive blood transfusion. However, whether these guidelines have been successfully translated into clinical practice in China is unknown. This study aimed to provide updated information about the temporal trends in the prevalence of perioperative red blood cell (RBC) transfusion in China. MATERIALS AND METHODS: We analysed data from the Hospital Quality Monitoring System database (2013-2018) to investigate the prevalence of perioperative RBC transfusion in patients undergoing craniotomy for cerebral aneurysms or arteriovenous malformations, sternotomy for mitral valve replacement, open thoracotomy lobectomy, open gastrectomy and hip arthroplasty. Mixed-effects logistic regression models quantified the likelihood of RBC transfusions. RESULTS: The study included 438,183 patients, with 44,697 (10.20%) receiving perioperative RBC transfusions. Introducing transfusion-related guidelines in China markedly decreased the prevalence of RBC transfusion among patients who underwent major surgical procedures in the following years. The prevalence of RBC transfusion for hip arthroplasty was 17.34% in 2013 and 7.03% in 2018. After adjusting for patient risk factors, the odds ratio of RBC transfusion for hip arthroplasty was significantly lower in 2018 (0.74, 95% confidence intervals [CI] 0.53-1.02) than in 2013 (1.84, 95% CI 1.37-2.48). CONCLUSION: The prevalence of perioperative RBC transfusion decreased from 2013 to 2018 in China, supporting the potential beneficial effects of transfusion-related guidelines. Considering the geographic variations in RBC transfusion, reducing heterogeneity may impact public health by improving surgical outcomes.

Separation of C2H2/C2H4/C2H6 and C2H2/CO2 in a Nitrogen-Rich Copper-Based Microporous Metal-Organic Framework.

The purification of industrially valuable C2H2 and C2H4 from multicomponent mixtures represents a crucial process in the chemical industry. In this study, we present a copper-based metal-organic framework (L-py-Cu) built on a nitrogen-rich organic linker that is capable of separating C2H2/C2H4/C2H6 and C2H2/CO2 mixtures, therefore producing highly pure C2H4 and C2H2, respectively. L-py-Cu exhibits favorable adsorption of C2H2 and C2H6 over C2H4 and thus achieves one-step C2H4 purification from C2H2/C2H4/C2H6 ternary mixtures, as verified by multicomponent breakthrough measurements. In addition, it can also extract C2H2 from C2H2/CO2 binary mixtures.

Isolated unilateral oculomotor palsy caused by pure midbrain infarction: a case report.

Purpose: Multiple etiologies may cause oculomotor nerve palsies. Identification of different etiologies is very important for subsequent treatment. Midbrain infarction is a rare cause of oculomotor nerve palsy. Materials and methods: We herein present a case of isolated unilateral oculomotor paresis caused by pure midbrain infarction. Results: Her pupillary sphincter and inferior rectus muscles were selectively spared. The symptoms were completely relieved after two months of antiplatelet therapy. We proposed that fibers from Edinger-Westphal nucleus and inferior rectus nucleus do not course through the paramedian area of the midbrain. Conclusions: Our report adds to the understanding of fascicles arrangement in the midbrain.

Structures of MPND Reveal the Molecular Recognition of Nucleosomes.

Adenine N6 methylation in DNA (6mA) is a well-known epigenetic modification in bacteria, phages, and eukaryotes. Recent research has identified the Mpr1/Pad1 N-terminal (MPN) domain-containing protein (MPND) as a sensor protein that may recognize DNA 6mA modification in eukaryotes. However, the structural details of MPND and the molecular mechanism of their interaction remain unknown. Herein, we report the first crystal structures of the apo-MPND and MPND-DNA complex at resolutions of 2.06 Å and 2.47 Å, respectively. In solution, the assemblies of both apo-MPND and MPND-DNA are dynamic. In addition, MPND was found to possess the ability to bind directly to histones, no matter the N-terminal restriction enzyme-adenine methylase-associated domain or the C-terminal MPN domain. Moreover, the DNA and the two acidic regions of MPND synergistically enhance the interaction between MPND and histones. Therefore, our findings provide the first structural information regarding the MPND-DNA complex and also provide evidence of MPND-nucleosome interactions, thereby laying the foundation for further studies on gene control and transcriptional regulation.

A critical review of on-site inorganic arsenic screening methods.

Approximately 94 to 220 million people worldwide are at risk of drinking well water containing arsenic > 10 µg/L, the WHO guideline value. To identify non-compliant domestic wells, assess health risks and reduce exposure, accurate and rapid on-site inorganic arsenic screening methods are desirable because all domestic wells worldwide need to be tested. Here, the principles, advantages and limitations of commonly used colorimetry, electrochemistry, and biosensing methods are critically reviewed, with the performance compared with laboratory-based benchmark methods. Most commercial kits are based on the classic Gutzeit reaction. Despite being semi-quantitative, the more recent and more expensive products display improved and acceptable accuracy and shorter testing time (∼10 min). Carried out by trained professionals, electrochemical methods are also feasible for on-site analysis, although miniaturization is desirable yet challenging. Biosensing using whole bacterial cells or bio-engineered materials such as aptamers is promising, if incorporated with function specific nanomaterials and biomaterials. Since arsenic is frequently found as arsenite in reducing groundwater and subject to oxidation during sampling, transportation and storage, on-site separation and sample preservation are feasible but the specific methods should be chosen based on sample matrix and tested before use. To eliminate arsenic exposure among hundreds of millions of mostly rural residents worldwide, we call for concerted efforts in research community and regulatory authority to develop accurate, rapid, and affordable tests for on-site screening and monitoring of arsenic in drinking water. Access to affordable testing will benefit people who are socioeconomically disadvantaged.

Astrocyte-microglia interaction through C3/C3aR pathway modulates neuropathic pain in rats model of chronic constriction injury.

Neuropathic pain (NP) is the cardinal symptom of neural injury, and its underlying molecular mechanism needs further investigation. Complements, especially complement 3 (C3), are involved in the pathophysiology of many neurological disorders, while the specific role of C3 in NP is still obscure. In this study, we found that both C3 and its receptor C3aR were upregulated in the spinal dorsal horn in a rat chronic constriction injury (CCI) model. In addition, C3 was mainly detected in astrocytes, while C3aR was expressed in microglia and neuron. Intrathecal injection of C3 antibody and C3aR antagonist alleviated NP in CCI model together with reduced M1 polarization of microglia. Our finding suggested that blockade of the C3/C3aR pathway might be a novel strategy for NP.

Lanthanide-Organic Frameworks with Uncoordinated Lewis Base Sites: Tunable Luminescence, Antibiotic Detection, and Anticounterfeiting.

Several new isostructural lanthanide metal-organic frameworks (Ln-MOFs), {[Ln2(L)3DMA4]·2DMA}n (1-Ln, where Ln = Eu, Tb, or EuxTb1-x), were first constructed via the solvothermal reactions of 4,6-di(4-carboxyphenyl)pyrimidine and Ln3+ ions. 1-Ln exhibits a 4-connected two-dimensional framework endowed with uncoordinated Lewis base sites. An exploration of luminescence sensing demonstrated 1-Eu can be used for the selectivity detection of dimetridazole and metronidazole antibiotics in other antibiotics, blood plasma, and urine, acting as an exceptional recyclable luminescent probe. More importantly, the luminescent inks of 1-Ln are invisible, color adjustable, and stabilized, which may greatly improve their anticounterfeiting applications.

Risk factors of postoperative pulmonary complications after primary posterior fusion and hemivertebra resection in congenital scoliosis patients younger than 10 years old: a retrospective study.

BACKGROUND: Postoperative pulmonary complications are common and associated with morbidity and mortality. Congenital scoliosis is a failure of vertebral formation and/or segmentation arising from abnormal vertebral development. Posterior fusion and osteotomy are necessary for these patients to prevent deterioration of spine deformity. The incidence of postoperative pulmonary complications in this specific group of patients, especially young children were unknown. METHODS: A retrospective study was conducted and electronic medical records of early-onset scoliosis patients who had primary posterior fusion and hemivertebra resection at our institution from January 2014 to September 2019 were reviewed. The demographic characteristics, the intraoperative and postoperative parameters were collected to identify the predictors of postoperative pulmonary complications. RESULTS: A total of 174 patients (57.5% boys) with a median age of 3 years old were included for analysis. Eighteen patients (10.3%) developed perioperative pulmonary complications and pneumonia (n=13) was the most common. History of recent upper respiratory infection was not related to postoperative pulmonary complications. Multifactorial regression analysis showed thoracoplasty was the only predictive risk factor of postoperative pulmonary complications. CONCLUSIONS: For congenital scoliosis patients younger than 10 years old, thoracoplasty determine the occurrence of postoperative pulmonary complications. Both surgeons and anesthesiologists should pay attention to patients undergoing thoracoplasty and preventive measures are necessary.

Obesity paradox among patients undergoing total knee arthroplasty: a retrospective cohort study.

BACKGROUND: Obesity has been recognized as the risk factor for postoperative complication for surgical patients. However, recent studies have showed protective effect of obesity in surgical and non-surgical patients. Our study is to examine the association of body mass index(BMI) with early postoperative complications in patients undergoing total knee arthroplasty. MATERIALS AND METHODS: All patients who had primary total knee arthroplasty between January 2014 and December 2019 were included. Medical records were retrospectively reviewed and BMI was categorized as underweight(BMI < 18.5), normal weight(18.5 < BMI < 24.9), overweight I(25 < BMI < 27.4), overweight II(27.5 < BMI < 29.9), obese I(30 < BMI < 34.9) and obese II(BMI ≥ 35). The association between BMI and occurrence of early postoperative complications was examined and logistic regression was used to calculate relationship between BMI and early postoperative complications. RESULTS: A total of 2969 patients were included in our analysis. The overall complication rate in patients undergoing total knee arthroplasty was 14.8%, with the highest complication being 22.2% in the underweight group, the second highest in the normal weight group(17.5%), the lowest in the overweight I(13.8%) and obese I(12.0%) group and then higher again in obese II group(16.7%). In multivariable analyses, overweight I (OR 0.737, 95% CI 0.559-0.972, P = 0.031) and obese I (OR 0.631, 95% CI 0.449-0.885, P = 0.008) were associated with lower risk of early postoperative complications after total knee arthroplasty. CONCLUSION: In this retrospective study, overweight and obese patients had a lower risk of early postoperative complications after total knee arthroplasty. Further studies are necessary to confirm and investigate the mechanism of obesity paradox in this surgical population. TRIAL REGISTRATION: This study had been registrated in www.chictr.org.cn on 25/10/2021 and the registration ID was ChiCTR2100052408.

Quantitative Analysis and Stability Study on Iridoid Glycosides from Seed Meal of Eucommia ulmoides Oliver.

As a traditional Chinese medicine, Eucommia ulmoides Oliver (E. ulmoides Oliv.) is an important medicinal plant, and its barks, male flowers, leaves, and fruits have high value of utilization. The seed meal of E. ulmoides Oliv. is the waste residue produced after oil extraction from seeds of E. ulmoides Oliv. Though the seed meal of E. ulmoides Oliv. is an ideal feed additive, its medicinal value is far from being developed and utilized. We identified six natural iridoid compounds from the seed meal of E. ulmoides Oliv., namely geniposidic acid (GPA), scyphiphin D (SD), ulmoidoside A (UA), ulmoidoside B (UB), ulmoidoside C (UC), and ulmoidoside D (UD). Six natural iridoid compounds were validated to have anti-inflammatory activities. Hence, six compounds were quantified at the optimum extracting conditions in the seed meal of E. ulmoides Oliv. by an established ultra-performance liquid chromatography (UPLC) method. Some interesting conversion phenomena of six tested compounds were uncovered by a systematic study of stability performed under different temperatures and pH levels. GPA was certified to be stable. SD, UA, and UC were only hydrolyzed under strong alkaline solution. UB and UD were affected by high temperature, alkaline, and strong acid conditions. Our findings reveal the active compounds and explore the quantitative analysis of the tested compounds, contributing to rational utilization for the seeds residues of E. ulmoides Oliv.

Possible Risk Factors for Severe Complications Occurring after Primary Total Knee Arthroplasty.

Objective Total knee arthroplasty is one of the most common orthopedic surgeries. Readmission due to severe complications after total knee arthroplasty is a grave concern to surgeons. In this study, we evaluated the risk factors for severe complications after primary total knee arthroplasty. Methods We retrospectively collected clinical data of 2,974 patients who underwent primary total knee arthroplasty from July 2013 to June 2019 in our hospital. Postoperative complication ≥ grade Ⅲ was defined as severe complication according to Clavien-Dindo classification system. Binary logistic regression was used to identify the predictive risk factors for severe complications. Results The complication rate after primary total knee arthroplasty was 6.8% and severe complication rate was 2.5%. Male (OR = 2.178, 95%CI: 1.324-3.585, P= 0.002), individuals above 75 years old (OR = 1.936, 95%CI: 1.155-3.244, P= 0.012), arrhythmia (OR = 2.913, 95%CI: 1.350-6.285, P= 0.006) and cerebrovascular disease (OR = 2.804, 95%CI: 1.432-5.489, P= 0.003) were predictive risk factors for severe complications after primary total knee arthroplasty. Conclusion Advanced age, male, arrhythmia, and cerebrovascular disease might be patients-related risk factors for postoperative severe complications after primary total knee arthroplasty. Special attention should be paid to patients with risk factors.

Suppression of TLR4-MyD88 signaling pathway attenuated chronic mechanical pain in a rat model of endometriosis.

BACKGROUND: As a classic innate immunity pathway, Toll-like receptor 4 (TLR4) signaling has been intensively investigated for its function of pathogen recognition. The receptor is located not only on immune cells but also on sensory neurons and spinal glia. Recent studies revealed the involvement of neuronal TLR4 in different types of pain. However, the specific role of TLR4 signaling in the pain symptom of endometriosis (EM) remains obscure. METHODS: The rat endometriosis model was established by transplanting uterine horn tissue into gastrocnemius. Western blotting and/or immunofluorescent staining were applied to detect high mobility group box 1 (HMGB1), TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) and MyD88 homodimerization inhibitory peptide (MIP) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on endometriosis-related pain. RESULTS: Mechanical hyperalgesia was observed at the graft site, while HMGB1 was upregulated in the implanted uterine tissue, dorsal root ganglion (DRG), and spinal dorsal horn (SDH). Compared with sham group, upregulated TLR4, MyD88, and phosphorylated NF-κB-p65 were detected in the DRG and SDH in EM rats. The activation of astrocytes and microglia in the SDH was also confirmed in EM rats. Intrathecal application of LRU and MIP alleviated mechanical pain on the graft site of EM rats, with decreased phosphorylation of NF-κB-p65 in the DRG and reduced activation of glia in the SDH. CONCLUSIONS: HMGB1-TLR4-MyD88 signaling pathway in the DRG and SDH may involve in endometriosis-related hyperpathia. Blockade of TLR4 and MyD88 might serve as a potential treatment for pain in endometriosis.

Determination of stress components in a complex stress condition using micro-Raman spectroscopy.

In this study, an iterative method using polarized Raman spectroscopy to quantitatively determine all the in-plane components of the stress tensor in semiconductor structures is presented. Raman experiments were conducted on silicon at different stress states. The results obtained by the proposed method were in good agreement with the given stress state. In addition, the effect of random errors of Raman shifts on the stress component calculation is discussed. In contrast to the conventional analytical solution, our iterative method can significantly reduce the random errors.

Coronavirus Disease-2019 (COVID-19) and Cardiovascular Complications.

The coronavirus disease-2019 (COVID-19) has become a global pandemic. It has spread to more than 100 countries, and more than 1 million cases have been confirmed. Although coronavirus causes severe respiratory infections in humans, accumulating data have demonstrated cardiac complications and poor outcome in patients with COVID-19. A large percent of patients have underlying cardiovascular disease, and they are at a high risk of developing cardiac complications. The basics of the virus, the clinical manifestations, and the possible mechanisms of cardiac complications in patients with COVID-19 are reviewed. Before an effective vaccine or medicine is available, supportive therapy and identifying patients who are at high risk of cardiac complications are important.