A modified Agrobacterium-mediated transformation for two oomycete pathogens.

Oomycetes are a group of filamentous microorganisms that include some of the biggest threats to food security and natural ecosystems. However, much of the molecular basis of the pathogenesis and the development in these organisms remains to be learned, largely due to shortage of efficient genetic manipulation methods. In this study, we developed modified transformation methods for two important oomycete species, Phytophthora infestans and Plasmopara viticola, that bring destructive damage in agricultural production. As part of the study, we established an improved Agrobacterium-mediated transformation (AMT) method by prokaryotic expression in Agrobacterium tumefaciens of AtVIP1 (VirE2-interacting protein 1), an Arabidopsis bZIP gene required for AMT but absent in oomycetes genomes. Using the new method, we achieved an increment in transformation efficiency in two P. infestans strains. We further obtained a positive GFP transformant of P. viticola using the modified AMT method. By combining this method with the CRISPR/Cas12a genome editing system, we successfully performed targeted mutagenesis and generated loss-of-function mutations in two P. infestans genes. We edited a MADS-box transcription factor-encoding gene and found that a homozygous mutation in MADS-box results in poor sporulation and significantly reduced virulence. Meanwhile, a single-copy avirulence effector-encoding gene Avr8 in P. infestans was targeted and the edited transformants were virulent on potato carrying the cognate resistance gene R8, suggesting that loss of Avr8 led to successful evasion of the host immune response by the pathogen. In summary, this study reports on a modified genetic transformation and genome editing system, providing a potential tool for accelerating molecular genetic studies not only in oomycetes, but also other microorganisms.

Field-work reveals a novel function for MAX2 in a native tobacco's high-light adaptions.

Laboratory studies have revealed that strigolatone (SL) and karrikin (KAR) signalling mediate responses to abiotic and biotic stresses, and reshape branching architecture that could increase reproductive performance and crop yields. To understand the ecological function of SL and KAR signalling, transgenic lines of wild tobacco Nicotiana attenuata, silenced in SL/KAR biosynthesis/signalling were grown in the glasshouse and in two field plots in the Great Basin Desert in Utah over four field seasons. Of the lines silenced in SL and KAR signalling components (irMAX2, irD14, irKAI2 and irD14 × irKAI2 plants), which exhibited the expected increases in shoot branching, only irMAX2 plants showed a strong leaf-bleaching phenotype when grown in the field. In the field, irMAX2 plants had lower sugar and higher leaf amino acid contents, lower lifetime fitness and were more susceptible to herbivore attack compared to wild-type plants. These irMAX2 phenotypes were not observed in glasshouse-grown plants. Transcriptomic analysis revealed dramatic responses to high-light intensity in irMAX2 leaves in the field: lutein contents decreased, and transcriptional responses to high-intensity light, singlet oxygen and hydrogen peroxide increased. PAR and UV-B manipulations in the field revealed that the irMAX2 bleaching phenotype is reversed by decreasing PAR, but not UV-B fluence. We propose that NaMAX2 functions in high-light adaptation and fitness optimisation by regulating high-light responses independently of its roles in the SL and KAR signalling pathways. The work provides another example of the value of studying the function of genes in the complex environments in which plants evolved, namely nature.

Type 1 diabetes, its complications, and non-ischemic cardiomyopathy: a mendelian randomization study of European ancestry.

BACKGROUND: Type 1 diabetes (T1D) is a significant risk factor for a range of cardiovascular diseases. Nonetheless, the causal relationship between T1D and non-ischemic cardiomyopathy (NICM) remains to be elucidated. Furthermore, the mechanisms responsible for the progression from T1D to NICM have not been definitively characterized. OBJECTIVE: The aim of this study was to conduct a Mendelian randomization (MR) study to investigate the causal effects of T1D and its complications on the development of NICM. Additionally, this study aimed to conduct a mediation analysis to identify potential mediators within this correlation. METHODS: Genetic variants were used as instrumental variables for T1D. The summary data for T1D were obtained from two genome-wide association study datasets. The summary data for T1D with complications and NICM were obtained from the Finnish database. Two-sample MR, multivariable MR and mediation MR were conducted in this study. RESULTS: The study revealed a causal association between T1D, T1D with complications, and NICM (with odds ratios of 1.02, 95% CI 1.01-1.04, p = 1.17e-04 and 1.03, 95% CI 1.01-1.05, p = 3.15e-3). Even after adjusting for confounding factors such as body mass index and hypertension, T1D remained statistically significant (with odds ratio of 1.02, 95% CI 1.01-1.04, p = 1.35e-4). Mediation analysis indicated that monokine induced by gamma interferon may play a mediating role in the pathogenesis of T1D-NICM (mediation effect indicated by odds ratio of 1.005, 95% CI 1.001-1.01, p = 4.9e-2). CONCLUSION: The study demonstrates a causal relationship between T1D, its complications, and NICM. Additionally, monokine induced by gamma interferon may act as a potential mediator in the pathogenesis of T1D-NICM.

Effects of adipose tissues on the relationship between type 2 diabetes mellitus and reduced heart rate variability: mediation analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with decreased heart rate variability (HRV) with an unclear intermediate mechanism. This study aimed to conduct mediation analysis to explore the impact of various adipose tissues on the relationship between T2DM and HRV. METHODS: A total of 380 participants were enrolled for analysis, including 249 patients with T2DM and 131 non-diabetic controls. The thicknesses of four adipose tissues (subcutaneous, extraperitoneal, intraperitoneal, and epicardial) were measured by abdominal ultrasound or echocardiography respectively. HRV was assessed by 24-hour Holter for monitoring both frequency domain indices (LF, HF, and LF/HF) and time domain indices (SDNN, SDANN, SDNN index, rMSSD and pNN50). Mediation analysis was used toexamine whether adipose tissues mediated the relationship between T2DM and each index of HRV. Then, a latent variable - HRV burden - was constructed by structural equation model with selected HRV indices to comprehensively assess the whole HRV. RESULTS: Compared to non-diabetic controls, patients with T2DM exhibited a significant reduction in indices of HRV, and a remarkable increase in the thicknesses of extraperitoneal, intraperitoneal, and epicardial adipose tissues. Mediation analysis found significant indirect effects of T2DM on six indices of HRV, including HF, SDNN, SDANN, SDNN index, rMSSD, and pNN50, which was mediated by epicardial adipose tissue rather than other adipose tissues, with the mediation proportions of 64.21%, 16.38%, 68.33%, 24.34%, 24.10% and 30.51%, respectively. Additionally, epicardial adipose tissue partially mediated the relationship between T2DM and reduced HRV burden (24.26%), which composed by SDNN, SDNN index, rMSSD, and pNN50. CONCLUSION: Epicardial adipose tissue partially mediated the relationship between T2DM and reduced HRV, which reinforces the value of targeting heart-specific visceral fat to prevent cardiac autonomic neuropathy in diabetes.

Interaction Between Hypoxia-Inducible Factor 1-alpha Gene Polymorphism and Helicobacter pylori Infection on Gastric Cancer in a Chinese Tibetan Population.

To investigate the impact of four single nucleotide polymorphisms (SNPs) of the HIF1α gene and its interaction with Helicobacter pylori (H. pylori) infection on susceptibility to gastric cancer (GC).Logistic regression was used to test the relationship between four SNPs of HIF1α gene and the susceptibility of GC. A generalized multifactor dimensionality reduction (GMDR) model was used to assess the HIF1α gene-H. pylori infection interaction.Logistic regression analysis indicated that both the rs11549465-CT genotype and the T allele were associated with an increased risk of GC, adjusted OR (95% CI) were 1.63 (1.09-2.20) (CT vs. CC) and 1.70 (1.13-2.36) (T vs. C), respectively. We also found that both the rs11549467-A allele and rs11549467-GA genotype were associated with an increased risk of GC, and adjusted OR (95% CI) were 2.21 (1.61-2.86) (GA vs. GG), 2.13 (1.65-2.65) (A vs. G), respectively. However, no statistically significant impact of rs2057482 or rs1957757 on risk of GC was found. The GMDR model indicated a statistically significant two-dimensional model combination (including rs11549467 and H. pylori infection). The selected model had testing balanced accuracy of 0.60 and the best cross-validation consistencies of 10/10 (p = 0.0107). Compared with H. pylori infection negative participants with rs11549467-GG genotype, H. pylori positive participants with the rs11549467-GA genotype had the highest GC risk, the OR (95% CI) was 3.04 (1.98-4.12).The rs11549467-A allele and rs11549467-GA genotype was associated with increased GC risk. Additionally, the gene-environment interaction between HIF-1α-rs11549467 and H. pylori infection was also correlated with an increased risk of GC.

ADAM17 is an essential attachment factor for classical swine fever virus.

Classical swine fever virus (CSFV) is an important pathogen in the swine industry. Virion attachment is mediated by envelope proteins Erns and E2, and E2 is indispensable. Using a pull-down assay with soluble E2 as the bait, we demonstrated that ADAM17, a disintegrin and metalloproteinase 17, is essential for CSFV entry. Loss of ADAM17 in a permissive cell line eliminated E2 binding and viral entry, but compensation with pig ADAM17 cDNA completely rescued these phenotypes. Similarly, ADAM17 silencing in primary porcine fibroblasts significantly impaired virus infection. In addition, human and mouse ADAM17, which is highly homologous to pig ADAM17, also mediated CSFV entry. The metalloproteinase domain of ADAM17 bound directly to E2 protein in a zinc-dependent manner. A surface exposed region within this domain was mapped and shown to be critical for CSFV entry. These findings clearly demonstrate that ADAM17 serves as an essential attachment factor for CSFV.

Sodium-glucose cotransporter 2 inhibitor may not prevent atrial fibrillation in patients with heart failure: a systematic review.

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) frequently coexist because of their similar pathological basis. However, whether sodium-glucose cotransporter 2 inhibitor (SGLT2i), a novel class of anti-HF medication, decreases the risk of AF in HF patients remains unclear. OBJECTIVES: The aim of this study was to assess the relationship between SGLT2i and AF in HF patients. METHODS: A meta-analysis of randomized controlled trails evaluating the effects of SGLT2i on AF in HF patients was performed. PubMed and ClinicalTrails.gov were searched for eligible studies until 27 November 2022. The risk of bias and quality of evidence were assessed through the Cochrane tool. Pooled risk ratio of AF for SGLT2i versus placebo in eligible studies was calculated. RESULTS: A total of 10 eligible RCTs examining 16,579 patients were included in the analysis. AF events occurred in 4.20% (348/8292) patients treated with SGLT2i, and in 4.57% (379/8287) patients treated with placebo. Meta-analysis showed that SGLT2i did not significantly reduce the risk of AF (RR 0.92; 95% CI 0.80-1.06; p = 0.23) in HF patients when compared to placebo. Similar results remained in the subgroup analyses, regardless of the type of SGLT2i, the type of HF, and the duration of follow-up. CONCLUSIONS: Current evidences showed that SGLT2i may have no preventive effects on the risk of AF in patients with HF. TRANSLATIONAL PERSPECTIVE: Despite HF being one of the most common heart diseases and conferring increased risk for AF, affective prevention of AF in HF patients is still unresolved. The present meta-analysis demonstrated that SGLT2i may have no preventive effects on reducing AF in patients with HF. How to effectively prevent and early detect the occurrence of AF is worth discussing.

Strigolactone signaling regulates specialized metabolism in tobacco stems and interactions with stem-feeding herbivores.

Plants are attacked by herbivores, which often specialize on different tissues, and in response, have evolved sophisticated resistance strategies that involve different types of chemical defenses frequently targeted to different tissues. Most known phytohormones have been implicated in regulating these defenses, with jasmonates (JAs) playing a pivotal role in complex regulatory networks of signaling interactions, often generically referred to as "cross talk." The newly identified class of phytohormones, strigolactones (SLs), known to regulate the shoot architecture, remain unstudied with regard to plant-herbivore interactions. We explored the role of SL signaling in resistance to a specialist weevil (Trichobaris mucorea) herbivore of the native tobacco, Nicotiana attenuata, that attacks the root-shoot junction (RSJ), the part of the plant most strongly influenced by alterations in SL signaling (increased branching). As SL signaling shares molecular components, such as the core F-box protein MORE AXILLARY GROWTH 2 (MAX2), with another new class of phytohormones, the karrikins (KARs), which promote seed germination and seedling growth, we generated transformed lines, individually silenced in the expression of NaMAX2, DWARF 14 (NaD14: the receptor for SL) and CAROTENOID CLEAVAGE DIOXYGENASE 7 (NaCCD7: a key enzyme in SL biosynthesis), and KARRIKIN INSENSITIVE 2 (NaKAI2: the KAR receptor). The mature stems of all transgenic lines impaired in the SL, but not the KAR signaling pathway, overaccumulated anthocyanins, as did the stems of plants attacked by the larvae of weevil, which burrow into the RSJs to feed on the pith of N. attenuata stems. T. mucorea larvae grew larger in the plants silenced in the SL pathway, but again, not in the KAI2-silenced plants. These phenotypes were associated with elevated JA and auxin (indole-3-acetic acid [IAA]) levels and significant changes in the accumulation of defensive compounds, including phenolamides and nicotine. The overaccumulation of phenolamides and anthocyanins in the SL pathway-silenced plants likely resulted from antagonism between the SL and JA pathway in N. attenuata. We show that the repressors of SL signaling, suppressor of max2-like (NaSMXL6/7), and JA signaling, jasmonate zim-domain (NaJAZs), physically interact, promoting NaJAZb degradation and releasing JASMONATE INSENSITIVE 1 (JIN1/MYC2) (NaMYC2), a critical transcription factor promoting JA responses. However, the increased performance of T. mucorea larvae resulted from lower pith nicotine levels, which were inhibited by increased IAA levels in SL pathway-silenced plants. This inference was confirmed by decapitation and auxin transport inhibitor treatments that decreased pith IAA and increased nicotine levels. In summary, SL signaling tunes specific sectors of specialized metabolism in stems, such as phenylpropanoid and nicotine biosynthesis, by tailoring the cross talk among phytohormones, including JA and IAA, to mediate herbivore resistance of stems. The metabolic consequences of the interplay of SL, JA, and IAA signaling revealed here could provide a mechanism for the commonly observed pattern of herbivore tolerance/resistance trade-offs.

Pyridine N-Oxide-Promoted Cobalt-Catalyzed Dioxygen-Mediated Methane Oxidation.

The partial oxidation of methane with O2 is significant due to its potential of providing abundant chemical feedstock. Only a few examples realized this type of reaction in homogeneous solvent systems, most of which are in low efficiency. Herein, we present a pyridine N-oxide-promoted cobalt-catalyzed O2-mediated methane oxidation to produce methylene bis(trifluoroacetate) with productivity over 500 molester molmetal-1 h-1.

The expression and clinical value of LRP11, FUBP1 and TET1 in cervical cancer.

Cervical cancer is the second leading cause of cancer death among women worldwide. Identification of effective genes along with biological markers as targeting agents is very necessary for the diagnosis and treatment of this disease. Bioinformatics techniques along with genetic and molecular investigations have provided the possibility of studying different levels of information such as the genome, transcriptome, proteome, and metabolize with high depth and accuracy. The collection of these data provides comprehensive and valuable information about the investigated phenotypes, including complex diseases such as cancer. In this study, we examined three genes LRP11, FUBP1, and TET1 related to cervical cancer. The results of this study showed that the level of expression of these genes is high in lymph nodes and the thyroid and is less in the pancreas and liver. Also, the expression level of the FUBP1 gene is higher than that of LRP11, and the expression level of the LRP11 gene is higher than that of TET1. Regarding the structure and proteomics of the studied genes, it can be seen that due to the presence of more domains in the LRP11 and FUBP1 genes, these genes probably independently participate in various functions and have a wider range of activity than the TET1 gene. Also, the analysis of the stability of the examined genes showed that the stability of the FUBP1 gene is relatively higher than that of the TET1 gene, and this gene is also more stable than the LRP11 gene. Considering that these genes are effective key genes for the early detection of cervical cancer, it is hoped that they will be used as markers in the diagnosis and treatment of cervical cancer.

Strigolactone mimic 2-nitrodebranone is highly active in Arabidopsis growth and development.

Strigolactones play crucial roles in regulating plant architecture and development, as endogenous hormones, and orchestrating symbiotic interactions with fungi and parasitic plants, as components of root exudates. rac-GR24 is currently the most widely used strigolactone analog and serves as a reference compound in investigating the action of strigolactones. In this study, we evaluated a suite of debranones and found that 2-nitrodebranone (2NOD) exhibited higher biological activity than rac-GR24 in various aspects of plant growth and development in Arabidopsis, including hypocotyl elongation inhibition, root hair promotion and senescence acceleration. The enhanced activity of 2NOD in promoting AtD14-SMXL7 and AtD14-MAX2 interactions indicates that the molecular structure of 2NOD is a better match for the ligand perception site pocket of D14. Moreover, 2NOD showed lower activity than rac-GR24 in promoting Orobanche cumana seed germination, suggesting its higher ability to control plant architecture than parasitic interactions. In combination with the improved stability of 2NOD, these results demonstrate that 2NOD is a strigolactone analog that can specifically mimic the activity of strigolactones and that 2NOD exhibits strong potential as a tool for studying the strigolactone signaling pathway in plants.

The jasmonic acid-amino acid conjugates JA-Val and JA-Leu are involved in rice resistance to herbivores.

The phytohormone jasmonic acid (JA) plays a core role in plant defence against herbivores. When attacked by herbivores, JA and its bioactive derivatives are accumulated at the damage site, and subsequently perceived by the jasmonate co-receptors COI1 and JAZ proteins. The (+)-7-iso-jasmonoyl-L-isoleucine (JA-Ile) is known to be the main active JA derivative controlling vascular plant responses to herbivores as well as other JA-regulated processes. However, whether other endogenous JA-amino acid conjugates (JA-AAs) are involved in herbivore-induced defence responses remain unknown. Here, we investigated the role of herbivore-elicited JA-AAs in the crop plant rice. The levels of five JA-AAs were significantly increased under the armyworm, leaf folder and brown planthopper attack. Of the elicited JA derivatives, JA-Ile, JA-Val and JA-Leu could serve as ligands to promote the interaction between rice COI1 and JAZs, inducing OsJAZ4 degradation in vivo. JA-Val or JA-Leu treatment increased the expression of JA- and defence-related pathway genes but not JA-Ile levels, suggesting that these JA-AAs may directly function in JA signalling. Furthermore, the application of JA-Val or JA-Leu resulted in JA-mediated plant growth inhibition, while enhancing plant resistance to herbivore attack. This study uncovers that JA-Val and JA-Leu also play a role in rice defence against herbivores.

Genetic polymorphism of circumsporozoite protein of Plasmodium falciparum among Chinese migrant workers returning from Africa to Henan Province.

BACKGROUND: Plasmodium falciparum malaria is recognized as a major global public health problem. The malaria vaccine was important because the case fatality rate of falciparum malaria was high. Plasmodium falciparum circumsporozoite protein (PfCSP) is one of the potential vaccine candidates, but the genetic polymorphism of PfCSP raises concerns regarding the efficacy of the vaccine. This study aimed to investigate the genetic polymorphism of PfCSP and provide data for the improvement of PfCSP-based vaccine (RTS,S malaria vaccine). METHODS: Blood samples were collected from 287 Chinese migrant workers who were infected with P. falciparum and returning from Africa to Henan Province during 2016-2018. The Pfcsp genes were analysed to estimate the genetic diversity of this parasite. RESULTS: The results showed that there were two mutations at the N-terminus of imported Pfcsp in Henan Province, including insertion amino acids (58.71%, 118/201) and A → G (38.81%, 78/201). The number of repeats of tetrapeptide motifs (NANP/NVDP/NPNP/NVDA) in the central repeat region ranged mainly from 39 to 42 (97.51%, 196/201). A total of 14 nonsynonymous amino acid changes were found at the C-terminus. The average nucleotide difference (K) of imported Pfcsp in Henan Province was 5.719, and the haplotype diversity (Hd) was 0.964 ± 0.004. The estimated value of dN-dS was 0.047, indicating that the region may be affected by positive natural selection. The minimum number of recombination events (Rm) of imported Pfcsp in Henan Province was close to that in Africa. The analysis of genetic differentiation showed that there may be moderate differentiation between East Africa and North Africa (Fst = 0.06484), and the levels of differentiation in the other regions were very small (Fst < 0.05). CONCLUSIONS: The N-terminus of Pfcsp was relatively conserved, and the central repeat region and the Th2R and Th3R regions of the C-terminus were highly polymorphic. The gene polymorphism pattern among Chinese migrant workers returning from Africa to Henan Province was consistent with that in Africa. The geographical pattern of population differentiation and the evidence of natural selection and gene recombination suggested that the effect of polymorphism on the efficacy of PfCSP-based vaccines should be considered.

DWARF14 is a non-canonical hormone receptor for strigolactone.

Classical hormone receptors reversibly and non-covalently bind active hormone molecules, which are generated by biosynthetic enzymes, to trigger signal transduction. The α/ß hydrolase DWARF14 (D14), which hydrolyses the plant branching hormone strigolactone and interacts with the F-box protein D3/MAX2, is probably involved in strigolactone detection. However, the active form of strigolactone has yet to be identified and it is unclear which protein directly binds the active form of strigolactone, and in which manner, to act as the genuine strigolactone receptor. Here we report the crystal structure of the strigolactone-induced AtD14-D3-ASK1 complex, reveal that Arabidopsis thaliana (At)D14 undergoes an open-to-closed state transition to trigger strigolactone signalling, and demonstrate that strigolactone is hydrolysed into a covalently linked intermediate molecule (CLIM) to initiate a conformational change of AtD14 to facilitate interaction with D3. Notably, analyses of a highly branched Arabidopsis mutant d14-5 show that the AtD14(G158E) mutant maintains enzyme activity to hydrolyse strigolactone, but fails to efficiently interact with D3/MAX2 and loses the ability to act as a receptor that triggers strigolactone signalling in planta. These findings uncover a mechanism underlying the allosteric activation of AtD14 by strigolactone hydrolysis into CLIM, and define AtD14 as a non-canonical hormone receptor with dual functions to generate and sense the active form of strigolactone.

Monocyte to High-Density Lipoprotein Cholesterol Ratio Is Associated with Subclinical Left Cardiac Remodeling and Dysfunction in Type 2 Diabetes Mellitus.

Chronic inflammation is involved in the development of heart failure (HF) in type 2 diabetes mellitus (T2DM). However, reliable and easily accessible biomarker of subclinical left cardiac remodeling and dysfunction remains a challenge.Overall, 1020 patients with T2DM without overt HF were enrolled from May 2019 to April 2020. Monocyte to high-density lipoprotein ratio (MHR) was calculated by blood monocyte count divided by high-density lipoprotein cholesterol. Left cardiac structure and function were assessed using transthoracic echocardiography. Univariate and multivariate linear regression analyses were used to estimate the association of MHR (Lg transferred) with echocardiographic parameters. We found that septal wall thickness (SWT), left ventricular internal end-diastole dimension (LVIDd), and left ventricular mass index (LVMI) raised with increasing MHR (P = 0.002 for SWT, P < 0.001 for LVIDd, and P = 0.001 for LVMI). Declined trends were shown in ejection fraction (EF) (P = 0.016), E velocity (P = 0.037), E/A ratio (P = 0.009), and tissue Doppler e' (P < 0.001), and elevating trend was observed in E/e' (P < 0.001). In multivariate regression analysis, MHR (Lg transferred) was positively associated with LVIDd (ß = 0.031; P = 0.016), LVMI (ß = 0.073; P = 0.014), and E/e' (ß = 0.331; P < 0.001), whereas it was negatively associated with EF (ß = -0.086; P = 0.007), E/A (ß = -0.072; P = 0.009), and e' (ß = -0.332; P < 0.001).MHR could be a practical biomarker for indicating subclinical cardiac remodeling and dysfunction in T2DM, due to low cost and easy availability.

Ligand-enabled meta-C-H activation using a transient mediator.

Achieving site selectivity in C-H functionalization reactions is a significant challenge, especially when the target C-H bond is distant from existing functional groups. Coordination of a functional group to a metal is often a key driving force and control element in many important reactions including asymmetric hydrogenation, epoxidation and lithiation. Exploitation of this effect has led to the development of a broad range of directed C-H activation reactions. However, these C-H activation methods are limited to proximal C-H bonds, which are spatially and geometrically accessible from the directing functional group. The development of meta-selective C-H functionalizations remains a significant challenge. We recently developed a U-shaped template that can be used to overcome this constraint and have shown that it can be used to selectively activate remote meta-C-H bonds. Although this approach has proved to be applicable to various substrates and catalytic transformations, the need for a covalently attached, complex template is a substantial drawback for synthetic applications. Here we report an alternative approach employing norbornene as a transient mediator to achieve meta-selective C-H activation with a simple and common ortho-directing group. The use of a newly developed pyridine-based ligand is crucial for relaying the palladium catalyst to the meta position by norbornene after initial ortho-C-H activation. This catalytic reaction demonstrates the feasibility of switching ortho-selectivity to meta-selectivity in C-H activation of the same substrate by catalyst control.

Inhaled Beta2-Agonists Increase In-Hospital Mortality in ICU Patients with Heart Failure.

The impact of beta2-agonists (B2As) on heart failure (HF) remains controversial. This study aimed to investigate whether inhaled B2As increased in-hospital mortality in ICU patients with HF.The Multiparameter Intelligent Monitoring in Intensive Care III database was initially searched to identify adult patients (≥ 18 years old) with HF in ICU. Then, patients using or not using inhaled B2As were matched using propensity score matching on a 1:1 basis to control for baseline confounders. In-hospital mortality was compared between the two groups, and logistic regression analysis was performed to assess the association between B2As and in-hospital mortality.The initial search retrieved 2345 eligible patients with HF from the database. After propensity score matching, 705 pairs of patients were included in the final analysis. Patients using B2As had markedly higher in-hospital mortality than those not using B2As (4.68% versus 2.27%; P = 0.013). In the multivariate logistic regression analysis, B2A use (odd ratios (OR), 2.471; 95% confidence interval (CI), 1.289-4.734; P = 0.006), stroke (OR, 4.581; 95% CI, 1.621-12.948; P = 0.004), and simplified acute physiology score II (SAPS-II) scores (OR, 1.090; 95% CI, 1.064-1.116; P < 0.001) were significantly associated with increased risk of in-hospital mortality, whereas renin angiotensin system inhibitor use (OR, 0.396; 95% CI, 0.202-0.778; P = 0.007) was significantly associated with decreased risk of in-hospital mortality. Subgroup analysis further indicated that the association between B2A use and mortality was significant only in patients with HF without chronic pulmonary disease (OR, 2.427; 95% CI, 1.351-4.362; P = 0.003), but not in those with chronic pulmonary disease (OR, 2.094; 95% CI, 0.582-7.537; P = 0.258).In ICU patients with HF but without chronic pulmonary disease, the use of inhaled B2As is associated with increased in-hospital mortality.

Impact of long-term glucose variability on coronary atherosclerosis progression in patients with type 2 diabetes: a 2.3 year follow-up study.

BACKGROUND: Glycemic variability (GV) confers a risk of cardiovascular events. In this study, we aimed to investigate whether long-term GV has an impact on coronary atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 396 patients with T2DM who had coronary computed tomography angiography and laboratory data available at baseline and for follow-up evaluations [median 2.3 (1.8-3.1) years] were included. Fasting plasma glucose (FPG) was measured every 1-3 months, and HbA1c was measured quarterly. The coefficient of variation (CV) of HbA1c and FPG were calculated as measures of GV. Quantitative assessment of coronary plaques was performed by measuring the annual change and progression rate of total plaque volume (TPV). Significant progression was defined as annual TPV progression ≥ 15%. Multivariable regression analyses were used to assess the effects of GV on atherosclerosis progression. RESULTS: In the 396 patients, the annual change in TPV was 12.35 ± 14.23 mm3, and annual progression rate was 13.36 ± 12.69%. There were 143 (36.11%) patients with significant progression, and they had a significantly higher CV-HbA1c (P < 0.001) and CV-FPG (P < 0.001) than those without significant progression. In multivariable regression analyses, both CV-HbA1c and CV-FPG were independent predictors of annual change in TPV [CV-HbA1c: ß = 0.241 (0.019-0.462), P = 0.034; CV-FPG: ß = 0.265 (0.060-0.465), P = 0.012], annual TPV progression [CV-HbA1c: ß = 0.214 (0.023-0.405), P = 0.029; CV-FPG: ß = 0.218 (0.037-0.399), P = 0.019], and significant atherosclerosis progression [CV-HbA1c: odds ratio [OR] = 1.367 (1.149-1.650), P = 0.010; CV-FPG: OR = 1.321 (1.127-1.634), P = 0.013]. CONCLUSIONS: Long-term GV is associated with accelerated progression of coronary atherosclerosis independent of conventional risk factors in patients with T2DM. Trial registration ClinicalTrials.gov (NCT02587741), October 27, 2015; retrospectively registered.

Renin-Angiotensin System Inhibitors for the Prevention of Atrial Fibrillation Recurrence After Ablation　- A Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) recurrence remains a tricky problem in patients undergoing ablation. This meta-analysis aimed to summarize the current literature to clarify whether renin-angiotensin system inhibitors (RASIs) prevent AF recurrence after ablation.Methods and Results:Relevant studies were searched on Pubmed and EMBASE through December 2019. Pooled relative risk (RR) of AF recurrence was calculated. Subgroup analyses according to study design, race, and follow-up duration were further performed. A total of 15 studies examining 4,300 patients were included, with 3 randomized controlled trials and 12 cohort studies. Overall analysis showed that RASIs significantly reduced AF recurrence after ablation (RR=0.83; 95% confidence interval (CI) 0.70-0.98, P=0.028; I2=68.9%). Subgroup analysis further indicated that positive results were found in randomized controlled trials (RR=0.51, 95% CI 0.37-0.70, P<0.001; I2=4%), studies conducted in Asia (RR=0.59, 95% CI 0.46-0.76, P<0.001; I2=30.7%), and studies with follow-up duration ≥1 year (RR=0.82, 95% CI 0.70-0.95, P=0.01; I2=59.1%); negative results were found in cohort studies, studies conducted in Europe or the USA, and studies with follow-up duration <1 year. CONCLUSIONS: RASIs can potentially prevent AF recurrence after ablation under selected conditions. However, more studies are required to confirm this finding due to the variation in current evidence.

Predictive value of P wave terminal force in lead V1 for atrial fibrillation: A meta-analysis.

BACKGROUND: Several studies have explored the association between P wave terminal force in lead V1 (PTFV1) and risk of atrial fibrillation (AF) occurrence, but the results were controversial. This meta-analysis aimed to examine whether abnormal PTFV1 could predict AF occurrence. METHODS: We searched PubMed, Embase, and Cochrane Library databases for articles published before August 25, 2018. Pooled odds ratios (ORs) of AF occurrence were calculated using random-effects models to explore the significance of PTFV1. RESULTS: A total of 12 studies examining 51,372 participants were included, with 9 studies analyzing PTFV1 as a categorical variable and 4 studies analyzing PTFV1 as a continuous variable. As a categorical variable, abnormal PTFV1 (>0.04 mm s) was significantly associated with AF occurrence with a pooled OR of 1.39 (95% confidence interval [CI] 1.08-1.79, p = .01). Subgroup analysis found that ORs of studies in hemodialysis patients (OR = 4.89, 95% CI 2.54-9.90, p < .001) and acute ischemic stroke patients (OR = 1.60, 95% CI 1.14-2.25, p = .007) were higher than general population (OR = 1.15, 95% CI 1.03-1.29, p = .01). Studies from Europe (OR = 1.05, 95% CI 0.91-1.20, p = .51) yielded lower OR of endpoints compared with Asia (OR = 1.89, 95% CI 1.38-2.60, p < .001) and United States (OR = 1.43, 95% CI 1.19-1.72, p < .001). As a continuous variable, PTFV1 was also significantly associated with AF occurrence with a polled OR per 1 standard deviation (SD) change of 1.27 (95% CI 1.02-1.59, p = .03). CONCLUSIONS: PTFV1 was significantly associated with the risk of AF and was considered to be a good predictor of AF occurrence in population with or without cardiovascular diseases.