EGR1 modulates EPHB4-induced trophoblast dysfunction in recurrent spontaneous abortion†.

Recurrent spontaneous abortion, defined as at least three unexplained abortions occurring before the 20-24 week of pregnancy, has a great impact on women's quality of life. Ephrin receptor B4 has been associated with trophoblast function in preeclampsia. The present study aimed to verify the hypothesis that ephrin receptor B4 regulates the biological functions of trophoblasts in recurrent spontaneous abortion and to explore the upstream mechanism. Ephrin receptor B4 was overexpressed in mice with recurrent spontaneous abortion. Moreover, ephrin receptor B4 inhibited trophoblast proliferation, migration, and invasion while promoting apoptosis. Downregulation of early growth response protein 1 expression in mice with recurrent spontaneous abortion led to ephrin receptor B4 overexpression. Poor expression of WT1-associated protein in mice with recurrent spontaneous abortion reduced the modification of early growth response protein 1 mRNA methylation, resulting in decreased early growth response protein 1 mRNA stability and expression. Overexpression of WT1-associated protein reduced the incidence of recurrent spontaneous abortion in mice by controlling the phenotype of trophoblasts, which was reversed by early growth response protein 1 knockdown. All in all, our findings demonstrate that dysregulation of WT1-associated protein contributes to the instability of early growth response protein 1, thereby activating ephrin receptor B4-induced trophoblast dysfunction in recurrent spontaneous abortion. Our study provides novel insights into understanding the molecular pathogenesis of recurrent spontaneous abortion.

Desertivirga arenae gen. nov., sp. nov. and Desertivirga brevis sp. nov., isolated from desert soil, and reclassification of Pedobacter xinjiangensis as Desertivirga xinjiangensis comb. nov. and Pedobacter mongoliensis as Paradesertivirga mongoliensis gen.nov., comb. nov.

Two novel bacterial strains, designated as SYSU D00823T and SYSU D00873T, were isolated from sandy soil of the Gurbantunggut Desert in Xinjiang, north-west China. SYSU D00823T and SYSU D00873T shared 99.0 % 16S rRNA gene sequence identity, and were both most closely related to Pedobacter xinjiangensis 12157T with 96.1 % and 96.0 % similarities, respectively. Phylogenetic and phylogenomic analyses revealed that the two isolates and P. xinjiangensis 12157T formed a separate distinct cluster in a stable subclade with the nearby species Pedobacter mongoliensis 1-32T, as well as the genera Pararcticibacter and Arcticibacter. Furthermore, P. mongoliensis 1-32T formed a separate deep-branching lineage and did not form a cluster with members of the genus Pedobacter. The average nucleotide identity and digital DNA-DNA hybridization values between SYSU D00823T and SYSU D00873T and related species were well below the thresholds for species delineation (<81.0 % and <24.0 %, respectively). The genomes of SYSU D00823T and SYSU D00873T were 6.19 and 6.43 Mbp in size with 40.4 % and 40.5 % DNA G+C contents, respectively. The predominant fatty acids (>10 %) of SYSU D00823T and SYSU D00873T were iso-C15 : 0, iso-C17 : 0 3-OH and summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c). Menaquinone-7 was the only respiratory quinone. The major polar lipids were phosphatidylethanolamine, glycosphingolipid, aminoglycolipid/glycolipid, aminophospholipid and three or four unidentified polar lipids. These data indicated that strains SYSU D00823T and SYSU D00873T should be assigned to two novel species of a new genus within the family Sphingobacteriaceae, for which the names Desertivirga arenae gen. nov., sp. nov. and Desertivirga brevis sp. nov. are proposed. The type strains are SYSU D00823T (=CGMCC 1.18630T=MCCC 1K04973T=KCTC 82278T) and SYSU D00873T (=CGMCC 1.18629T=MCCC 1K04974T=KCTC 82281T), respectively. Accordingly, the reclassification of P. xinjiangensis as Desertivirga xinjiangensis comb. nov., and P. mongoliensis as Paradesertivirga mongoliensis gen. nov., comb. nov. are also proposed.

Insight into Multiphase Interlayer Molecular Packing and Stepwise Phase Transition in 4-(Phenylazo)benzoate Anion-Intercalated Layered Zinc Hydroxide.

The properties of layered intercalation hybrids are closely related to interlayer molecular packing. To develop functional intercalation hybrids, it is essential to gain deep insights into interlayer molecular packing. This work reports a new comprehensive insight into the controllable multiphase interlayer molecular packing in 4-(phenylazo)benzoate anion-intercalated layered zinc hydroxide (LZH-4-PAB intercalation hybrids). The new insight breaks up the general understanding that the interlayer molecular packing of anions is usually single-phase, lacking diversity and controllability. Furthermore, it uncovers an interesting stepwise rather than the generally expected continuous phase transition of the interlayer molecular packing. The intercalated 4-PAB anions initially organize into the horizontal monolayer packing (θ = 0°, Phase I), which stepwise transforms to the tilted interdigitated antiparallel bilayer packing (θ ≈ 50°, Phase II) along with an increased intercalation loading and eventually to the vertical interdigitated antiparallel bilayer packing (θ = 90°, Phase III). The LZH-4-PAB hybrids exhibited a greatly enhanced interlayer molecular packing-dependent UV-vis absorption. This study provides helpful guidance for developing property-tailored intercalation hybrids. It may attract new interest in more layered intercalation hybrids. New and rich intercalation chemistry might be discovered in more functional intercalation hybrids beyond the 4-PAB anion-intercalated layered zinc hydroxide.

Iodine Adsorption-Desorption-Induced Structural Transformation and Improved Ag+ Turn-On Luminescent Sensing Performance of a Nonporous Eu(III) Metal-Organic Framework.

Posttreatment of pristine metal-organic frameworks (MOFs) with suitable vapor may be an effective way to regulate their structures and properties but has been less explored. Herein, we report an interesting example in which a crystalline nonporous Eu(III)-MOF was transferred to a porous amorphous MOF (aMOF) via iodine vapor adsorption-desorption posttreatment, and the resulting aMOF showed improved turn-on sensing properties with respect to Ag+ ions. The crystalline Eu-MOF, namely, Eu-IPDA, was assembled from Eu(III) and 4,4'-{4-[4-(1H-imidazol-1-yl)phenyl]pyridine-2,6-diyl}dibenzoic acid (H2IPDA) and exhibited a two-dimensional (2D) coordination network based on one-dimensional secondary building blocks. The close packing of the 2D networks gives rise to a three-dimensional supramolecular framework without any significant pores. Interestingly, the nonporous Eu-IPDA could absorb iodine molecules when Eu-IPDA crystals were placed in iodine vapor at 85 °C, and the adsorption capacity was 1.90 g/g, which is comparable to those of many MOFs with large BET surfaces. The adsorption of iodine is attributed to the strong interactions among the iodine molecule, the carboxy group, and the N-containing group and leads to the amorphization of the framework. After immersion of the iodine-loaded Eu-IPDA in EtOH, approximately 89.7% of the iodine was removed, resulting in a porous amorphous MOF, denoted as a-Eu-IPDA. In addition, the remaining iodine in the a-Eu-IPDA framework causes strong luminescent quenching in the fluorescence emission region of the Eu(III) center when compared with that in Eu-IPDA. The luminescence intensity of a-Eu-IPDA in water suspensions was significantly enhanced when Ag+ ions were added, with a detection limit of 4.76 × 10-6 M, which is 1000 times that of pristine Eu-IPDA. It also showed strong anti-interference ability over many common competitive metal ions and has the potential to sense Ag+ in natural water bodies and traditional Chinese medicine preparations. A mechanistic study showed that the interactions between Ag+ and the absorbed iodine, the carboxylate group, and the N atoms all contribute to the sensing performance of a-Eu-IPDA.

Pedobacter deserti sp. nov., a novel species isolated from desert soil.

An aerobic, Gram-stain-negative bacterium, designated as SYSU D00382T, was sourced from soil of Gurbantunggut Desert, PR China. The strain was short-rod-shaped, oxidase-positive and catalase-negative, with yellow-colored, convex, round, and smooth colonies on TSA plate. Growth and proliferation occurred at 4-37 °C (optimal: 28-30 °C), pH 5.0-8.0 (optimal: pH 6.0-7.0) and NaCl concentration of 0-2.5% (optimal: 0-0.5%). The 16S rRNA gene based phylogenetic assessment showed that SYSU D00382T belonged to the genus Pedobacter, and was most closely related to Pedobacter ginsengisoli Gsoil 104T with similarity of 97.7%. The genomic DNA G+C content of SYSU D00382T was 46.4%. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between SYSU D00382T and P. ginsengisoli Gsoil 104T were 75.7% and 17.5%, respectively. The main polar lipid was phosphatidylethanolamine. The major fatty acids (> 5%) were iso-C15:0, iso-C17:0 3-OH, summed features 3 and 9. The sole respiratory quinone identified was MK-7. The phylogeny based on 16S rRNA gene and whole-genome sequences revealed that SYSU D00382T formed a robust lineage with P. ginsengisoli Gsoil 104T. Based on phenotypic, phylogenetic and genotypic data, a novel specie named Pedobacter deserti sp. nov. is proposed. The type strain is SYSU D00382T (= CGMCC 1.18627T = MCCC 1K04972T = KCTC 82279T).

Characterization and Effect of a Nematophagous Fungus Talaromyces cystophila sp. nov. for the Biological Control of Corn Cyst Nematode.

The dynamic of plant-parasitic nematode populations in soil is closely related to soil microorganisms. Fungi from Heterodera zeae cysts were isolated to explore the phenomenon of decline in the H. zeae population in the soil. Phylogenetic study of partial ITS, BenA, CaM, and RPB2 gene sequences, in addition to morphological investigations, was utilized to identify a nematode-destroying fungus. The nematicidal activity of a novel strain GX1 against H. zeae was assessed in vitro and in the greenhouse. Our findings revealed that strain GX1 is a new species of Talaromyces, named Talaromyces cystophila. It has a strong parasitic and lethal effect on H. zeae cysts, with 91.11% parasitism on cysts at 3 days after treatment. The contents of second-stage juveniles (J2s) and eggs inside the cysts were degraded and formed dense vacuoles, and the damaged eggs could not hatch normally. The spore suspension exhibited high nematophagous activity against nematodes, and fermentation filtrate exhibited marked inhibition of egg hatching and nematicidal activities on J2s. The hatching inhibition rates of eggs exposed to 1 × 108 CFU/ml spore suspensions or 20% 1-week fermentation filtrate (1-WF) for 15 days were 98.56 and 100%, respectively. The mortality of J2s exposed to 1 × 108 CFU/ml spore suspension reached 100% at 24 h; exposure to 50% 2-WF was 98.65 and 100% at 24 and 48 h, respectively. Greenhouse experiments revealed that the spore suspension and fermentation broth considerably decreased H. zeae reproduction by 56.17 to 78.76%. T. cystophila is a potential biocontrol strain with nematophagous and nematicidal activity that deserves attention and application.

Resistance of the Ginseng Gray Mold Pathogen, Botrytis cinerea, to Boscalid and Pyraclostrobin Fungicides in China.

Gray mold caused by Botrytis cinerea severely threatens the yield of ginseng (Panax ginseng). Various categories of fungicides have been utilized to control gray mold on this crop. In this study, the resistance of 102 isolates of B. cinerea from 11 commercial ginseng-growing regions in China to fungicides was examined. A total of 32.4% were resistant to boscalid, with EC50 values that ranged from 12.26 to 235.87 µg/ml, and 94.1% were resistant to pyraclostrobin, with EC50 values that ranged from 5.88 to 487.72 µg/ml. Except for sdhA and sdhD, the amino acid substitutions of P225F, P225L, N230I, H272Y, and H272R in the sdhB subunit from 24 (4 sensitive [S] and 20 resistant [R]), 5 (1 S and 4 R), 1 (S), 1 (R), and 8 (4 S and 4 R) strains, respectively, and the concurrent amino acid substitutions of G85A + I93V + M158V + V168I in the sdhC subunit from 5 (4 S and 1 R) strains were identified. A G143A substitution in cytochrome b was identified in 96 isolates that were resistant to pyraclostrobin and three that were sensitive to it. The Bcbi-143/144 intron was identified in the other three isolates sensitive to pyraclostrobin, but it was absent in the isolates that harbored the G143A mutation. The results showed that the populations of B. cinerea on ginseng have developed strong resistance to pyraclostrobin. Therefore, it is not recommended to continue using this fungicide to control gray mold on P. ginseng. Boscalid is still effective against most isolates. However, to prevent fungicide resistance, it is recommended to use a mixture of boscalid with other categories of fungicides.

Bibliometrics analysis of hotspots research on infertility syndromes and polystyrene.

Polystyrene plastic pollution poses a pressing environmental concern and represents a significant risk factor for infertility. Despite this, a comprehensive overview of the field remains scarce, with future trends largely unknown. Bibliometrics, an applied mathematical and statistical method, offers a means to analyze textual information across various levels, facilitating quantitative assessments of all knowledge carriers and unveiling the nature and developmental trajectories of a discipline. This study aimed to employ bibliometric methods to scrutinize the current status and research hotspots within the realm of polystyrene and infertility. Literature spanning from 1980 to 2023 pertaining to polystyrene and infertility was retrieved from the core database of Web of Science. Quantitative analyses were conducted utilizing CiteSpace (version 5.7.R7), VOSviewer (version 1.6.18.0), and an online literature analysis website (https://bibliometric.com/). The analysis visually represented countries, institutions, authors, journals, and keywords within the field. This study delved into the development history, knowledge structure, research hotspots, and potential trends in the field, furnishing a macro perspective for researchers. The investigation encompassed 267 articles published across 120 journals by 1,352 authors affiliated with 417 institutions in 51 countries, with these articles garnering 10,310 citations across 2,811 journals. The top three countries contributing the most articles were China, the United States, and Germany. In essence, the research hotspots primarily revolved around metabolism, endocrinology, and immunity. Despite China's relatively recent entry into this field, its rapid development is evident. However, the low citation frequency suggests a need for improved article quality.

Research on the dentification of Panax ginseng and Panax quinquefolium using catalysed hairpin assembly technology.

INTRODUCTION: Panax ginseng and Panax quinquefolium are traditional Chinese herb medicines and similar in morphology and some chemical components but differ in drug properties, so they cannot be mixed. However, the processed products of them are often sold in the form of slices, powder, and capsules, which are difficult to identify by traditional morphological methods. Furthermore, an accurate evaluation of P. ginseng, P. quinquefolium and the processed products have not been conducted. OBJECTIVE: This study aimed to establish a catalysed hairpin assembly (CHA) identification method for authenticating products made from P. ginseng and P. quinquefolium based on single nucleotide polymorphism (SNP) differences. METHOD: By analysing the differences of SNP in internal transcribed spacer 2 (ITS2) in P. ginseng and P. quinquefolium to design CHA-specific hairpins. Establish a sensitive and efficient CHA method that can identify P. ginseng and P. quinquefolium, use the sequencing technology to verify the accuracy of this method in identifying Panax products, and compare this method with high-resolution melting (HRM). RESULTS: The reaction conditions of CHA were as follows: the ratio of forward and reverse primers, 20:1; hairpin concentration, 5 ng/µL. Compared with capillary electrophoresis, this method had good specificity and the limit of detection was 0.5 ng/µL. The result of Panax product identification with CHA method were coincidence with that of the sequencing method; the positive rate of CHA reaction was 100%. CONCLUSION: This research presents an effective identification method for authenticating P. ginseng and P. quinquefolium products, which is helpful to improve the quality of Panax products.

Leptin Receptor Gln223Arg Polymorphism of Human Spermatozoa Associated with Male Infertility in a Chinese Population.

Background: Leptin (LEP) is believed to play a crucial role in male reproduction, while the molecular mechanisms through which LEP affects the male reproductive system are unclear. LEP acts by binding to a leptin receptor (LEPR) which mediates its physiological action, but there are only limited studies on the function of LEPR in human sperm. Purpose: This study aimed to determine the Gln223Arg polymorphisms of the LEPR gene in human spermatozoa and evaluate their possible relationship with semen variables. Methods: The study was performed on Chinese men: 115 healthy subjects and 108 patients with primary and 98 with secondary infertility. Semen samples were obtained from all patients, and semen variables were analyzed. The genotypic and allelic frequencies of Gln223Arg polymorphism in spermatozoa were determined by PCR and restriction fragment length polymorphism (RFLP) analyses. Statistical analyses were performed using the chi-square test, the Kruskal-Wallis test, and the Mann-Whitney test. Results: There were no significant differences in genotypic or allelic frequency distributions of Gln223Arg polymorphism among men with primary infertility, secondary infertility, and controls. Similarly, semen volume and sperm concentration did not differ with the different genotypes in all groups of men. The percentages of motile sperm for AA + AG genotypes in men with primary infertility (31.98%) were significantly lower than those in secondary infertility, and control men with GG genotypes were 34.41% and 59.36%, respectively. At the same time, the percentages of normal morphology sperm for AA + AG genotypes in men with primary infertility (2.93%) were significantly lower than those in secondary infertility and control men with GG genotypes 3.71% and 6.54%, respectively. Conclusion: This study reveals a possible association between the Gln223Arg polymorphism of the LEPR gene in spermatozoa affecting spermatozoal membrane integrity and having a direct role in sperm motility.

Engineering Trichoderma reesei for the hyperproduction of cellulose induced protein 1 (Cip1) on a sophorose-containing inducer to efficiently saccharify alkali-pretreated corn stover.

Trichoderma reesei was induced to produce cellulase by a combination of glucose and ß-disaccharide; however, lower levels of auxiliary proteins for degrading lignocellulosic biomass were detected by iTRAQ analysis compared with cellulose as an inducer, especially cellulose induced protein 1 (CIP1). In this study, A pdc1 promoter-driven overexpression of the endogenous Trcip1 gene was observed in T. reesei Rut C30, and the Trcip1 transcription levels of the two transformants, T. reesei OE-cip1-1 and OE-cip1-2, demonstrated 31.2- and 164.6-fold increases, respectively, but there was no significant change in cellobiohydrolase, endoglucanase and filter paper activity at 48 h. The crude enzyme was then used to hydrolyze corn stover. For T. reesei OE-cip1-1 and OE-cip1-2, the hydrolysis efficiency increased by 25.0 and 28.6% with a solid loading of 5% at 2 h, respectively. Simultaneously, 85.5 and 85.2 g/L glucose were released using a cellulase cocktail at high solid loading (20%), and these glucose release rates were significantly greater than that of T. reesei Rut C30 cellulase (77.4 g/L) at 120 h. Furthermore, scanning electron microscopy (SEM) and X-ray diffraction (XRD) showed that the enhanced hydrolysis efficiency was primarily triggered by the decrease in the crystallinity of lignocellulose, and the fiber structure had varying degrees of loosening and disintegration.

[Sensitivity baseline establishment and resistance risk assessment of Botrytis cinerea from Panax ginseng to prochloraz].

This study aimed to establish the baseline sensitivity of Botrytis cinerea from Panax ginseng to prochloraz, and ensure the fitness of prochloraz-resistant mutants and the cross-resistance of B. cinerea to prochloraz and commonly used fungicides for the prevention and control of gray mold including boscalid, pyraclostrobin, iprodione, and pyrimethanil. The sensitivity of B. cinerea from P. ginseng to fungicides was determined by the mycelial growth rate method. The prochloraz-resistant mutants were screened out through fungicide domestication and ultraviolet(UV) induction. The fitness of resistant mutants was determined through the stability of subculture, mycelial growth rate, and pathogenicity test. The cross-resistance between prochloraz and the four fungicides was determined by Person correlation analysis. The results showed that all B. cinerea strains tested were sensitive to prochloraz, and the EC_(50) value ranged from 0.004 8 to 0.062 9 µg·mL~(-1), with an average of 0.022 µg·mL~(-1). The sensitivity frequency distribution diagram showed that 89 B. cinerea strains were located within the main peak with a continuous single peak curve, and the average EC_(50) value of 0.018 µg·mL~(-1) was taken as the baseline sensitivity of B. cinerea to prochloraz. The fungicide domestication and UV induction obtained 6 resistant mutants, among which 2 strains were unstable and the other 2 strains showed decreased resistance after multiple generations of culture. Furthermore, the mycelial growth rate and spore yield of all resistant mutants were lower than those of their parents, and the pathogenicity of most mutants was lower than that of their parents. In addition, prochloraz had no obvious cross-resistance with boscalid, pyraclostrobin, iprodione, and pyrimethanil. In conclusion, prochloraz has great potential for controlling gray mold in P. ginseng, and the resistance risk of B. cinerea to prochloraz is low.

Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease.

BACKGROUND: Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aß). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS: The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.).

Prevalence and diagnostic agreement of sarcopenic obesity with different definitions among Chinese community-dwelling older adults.

OBJECTIVE: this retrospective study aims to compare the prevalence and diagnostic agreement of sarcopenic obesity (SO) using different obesity diagnostic methods among Chinese community-dwelling older adults. METHODS: SO was diagnosed with sarcopenia and obesity diagnostic methods. Sarcopenia was defined using the Asian Working Group for Sarcopenia criteria 2019 (AWGS2019). Four widely used indicators were used to define obesity: body mass index (BMI), waist circumference (WC), percent of body fat (PBF) and visceral fat area (VFA). Cohen's kappa was used to analyse the diagnosis agreement of SO between different diagnostic methods. RESULTS: a total of 1,050 participants were included, including 347 men (71.3 ± 7.4 years) and 703 women (69.9 ± 7.5 years). The prevalence of sarcopenia was 25% in total participants, there was no difference between men (24.2%) and women (25.5%), (P = 0.705). With different obesity diagnostic methods, the obesity prevalence ranged from 4.1 to 42.2%, the SO prevalence was 0.1-7.9%. The diagnosis agreement of SO was poor-to-moderate (κ ranged from -0.002 to 0.682). Among the four diagnostic methods, AWGS combined with BMI had the poorest agreement (κ = -0.002 with other methods), AWGS combined with VFA had the best agreement (κ = 0.641 and 0.682 with AWGS combined with PBF and with AWGS combined with WC, respectively). CONCLUSION: the prevalence of SO vary considerably and the diagnostic agreement is poor-to-moderate with non-uniform diagnostic methods. BMI has the lowest sensitivity, whereas VFA has the highest sensitivity in diagnosis of SO, and VFA has a relatively good diagnostic agreement with other diagnostic methods.

Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is characterized by the deposition of amyloid-beta (Aß) plaques in the brain. Aß is produced from the sequential cleavage of amyloid precursor protein by ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aß level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS: A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer's disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).

Decoding brain encoded by genome.

Human brain is the most complicated living organ in nature. How the human genome encodes the structure and function of brain is a fundamental question to understand the essence of mind. Currently, it is still an unsolved scientific problem requiring the further breakthrough of comprehensive technologies. Here, we summarize the recent advances in brain development/function OMICS studies, and discuss the huge challenges and prospects in understanding how brain is encoded by genome.

On-Surface Growth of Single-Layered Homochiral 2D Covalent Organic Frameworks by Steric Hindrance Strategy.

Investigation of chirality in on-surface synthesis is of significance not only for fabricating atomically precise covalently bonded chiral species but also for unveiling chiral phenomena involving chemical reactions. In this contribution, we present the growth of single-layered homochiral 2D covalent organic frameworks (COFs) on surfaces based on a steric hindrance strategy, by which both the chiral expression of the prochiral precursor and the newly formed C═N bonds are successfully steered. When coupling a tritopic monomer with the prochiral ditopic molecule with phenyl substituents, two enantiomers of the precursor are randomly integrated in the product via variable C═N linkages, resulting in distorted hexagonal frameworks without chiral expression. After equipping the prochiral precursor with more hindered bulky substituents, highly regular homochiral 2D COFs are fabricated, in which only one of the enantiomers of the prochiral precursor is integrated, and all C═N linkages possess the same configuration. Structural analysis based on high resolution scanning tunneling microscopy images and theoretical simulations indicate that the homochiral 2D COFs are generated through an enantioselective on-surface polymerization driven by the steric hindrance effect. This result not only benefits understanding and controlling chirality in on-surface synthesis but also provides a new approach for the growth of highly regular COFs on surfaces.

Characterization and application of a gall midge resistance gene (Gm6) from Oryza sativa 'Kangwenqingzhan'.

KEY MESSAGE: The resistance gene Gm6 was mapped and characterized using near-isogenic and pyramided lines, followed by marker-assisted selection to develop lines with resistance to both gall midge and brown planthopper. The Asian rice gall midge (GM; Orseolia oryzae; Diptera: Cecidomyiidae) is a major destructive pest affecting rice cultivation regions. The characterization of GM-resistance genes and the breeding of resistant varieties are together considered the most efficient strategy for managing this insect. Here, the Gm6 resistance gene derived from the Kangwenqingzhan (KW) variety was found to be located on the long arm of chromosome 4 using the F2 population of 9311/KW. The region was narrowed to a 90-kb segment flanked by the markers YW91 and YW3-4 using backcrossing populations. Based on no-choice feeding and host choice tests, GM development and growth in near-isogenic lines (NILs) were severely restricted compared to that in the 9311 control. On day 8, the average GM body length was 0.69 mm and 0.56 mm on NILs and 9311, respectively, and the differences were more significant at later time points. However, GM insects exhibited no host preference between NILs and 9311, and there was normal egg hatching on the resistant plants. We developed pyramided lines carrying BPH27, BPH36, and Gm6 by crossing and backcrossing with marker-assisted selection. These lines were similar to the KW parent in terms of agronomic traits while also exhibiting high resistance to brown planthopper (BPH) and GM. The present mapping and characterization of Gm6 will facilitate map-based cloning of this important resistance gene and its application in the breeding of insect-resistant rice varieties.

Genetic analysis and fine mapping of the gall midge resistance gene Gm5 in rice (Oryza sativa L.).

KEY MESSAGE: The rice gall midge resistance gene, Gm5, confers remarkable antibiosis and is located in the same region on chromosome 12 in three different rice varieties. Fine mapping narrowed this region to a 49-kb segment and identified two candidate genes showing remarkable response to GM infestation. The Asian rice gall midge (GM; Orseolia oryzae; Diptera: Cecidomyiidae) invades rice shoots and forms galls, adversely affecting plant growth and yield production. Thus, the development of resistant varieties through the identification, mapping, and application of GM resistance genes is considered the most efficient strategy for managing this insect. Here, a GM resistance survey of F2 populations derived from intercrosses between resistant rice varieties 'ARC5984,' '570011,' and 'ARC5833' indicated that the resistance gene Gm5 was located on the same chromosomal region in the three varieties. For the initial mapping, three independent F2 mapping populations were developed for the three resistant varieties, and the Gm5 gene was consistently mapped to the same chromosomal region near marker 12M22.6. Fine mapping, which was conducted using the BC1F2 and BC2F2 populations derived from the 9311/ARC5984 cross, narrowed the Gm5 gene region to a 49-kb segment flanked by the markers Z57 and Z64. In the final mapped region, we detected 10 candidate genes, of which six were analyzed for their relative expression. Consequently, two of these genes, Os12g36830 and Os12g36880, showed significantly higher expression in GM-resistant plants than in GM-susceptible plants at 24 and 72 h after GM infestation. Finally, the PCR amplification of markers 12M22.5 and 12M22.6 yielded clear single bands, and these markers were effectively applied for the marker-assisted selection (MAS) of the Gm5 gene. With the developed MAS markers, the fine mapping of this resistance gene will facilitate its map-based cloning and incorporation into insect-resistant rice varieties through breeding.

Interfacial Debonding Detection for Rectangular CFST Using the MASW Method and Its Physical Mechanism Analysis at the Meso-Level.

In this study, the transient multichannel analysis of surface waves (MASW) is proposed to detect the existence, the location and the length of interface debonding defects in rectangular concrete-filled steel tubes (CFST). Mesoscale numerical analysis is performed to validate the feasibility of MASW-based interfacial debonding detection. Research findings indicate that the coaxial characteristics in the Rayleigh wave disperse at the starting point of the debonding area and gradually restores at the end of the defect. For healthy specimens, the surface wave mode in CFST is closer to the Rayleigh wave. However, it can be treated as a Lamb wave since the steel plate is boundary-free on both sides in the debonding area. The displacement curves are further investigated with forward analysis to obtain the dispersion curves. The mesoscale numerical simulation results indicate that the propagation characteristic of the surface wave is dominated by the debonding defect. The detectability of interfacial debonding detection for rectangular CFST using the MASW approach is numerically verified in this study. The proposed MASW-based nondestructive testing technique can achieve bond-slip detection by comparing the variation trend of the coaxial characteristics in the time-history output signals and the dispersion curves obtained from the forward analysis, for avoiding misjudgment of the experimental observations.