Promising response of dabrafenib, trametinib, and osimertinib combination therapy for concomitant BRAF and EGFR-TKI resistance mutations.

Despite the initial promise of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in effectively combating tumor growth, the majority of patients with advanced non-small cell lung cancers (NSCLCs) inevitably develop resistance to these treatments. An infrequent genetic mutation known as BRAFV600E has been identified as a contributing factor to the emergence of acquired resistance to EGFR-TKIs. Genetic alterations in BRAF, particularly V600E, contribute to resistance to osimertinib. However, a combination therapy involving osimertinib, dabrafenib (a BRAF inhibitor), and trametinib has shown effectiveness in overcoming BRAF V600E-mediated resistance in advanced lung adenocarcinoma. This treatment regimen holds promise for similar cases. In our case report, the combination of osimertinib, dabrafenib, and trametinib effectively overcame osimertinib resistance and resulted in sustained partial remission.

[Acute heart failure in a neonate]. / æ–°ç”Ÿå„¿æ€¥æ€§å¿ƒåŠŸèƒ½ä¸å ¨1例.

The male patient, one day old, was admitted to the hospital due to hypoglycemia accompanied by apnea appearing six hours after birth. The patient had transient hypoglycemia early after birth, and acute heart failure suddenly occurred on the eighth day after birth. Laboratory tests showed significantly reduced levels of adrenocorticotropic hormone and cortisol, and pituitary magnetic resonance imaging was normal. Genetic testing results showed that the patient had probably pathogenic compound heterozygous mutations of the TBX19 gene (c.917-2A>G+c.608C>T), inherited respectively from the parents. The patient was conclusively diagnosed with congenital isolated adrenocorticotropic hormone deficiency caused by mutation of the TBX19 gene. Upon initiating hydrocortisone replacement therapy, cardiac function rapidly returned to normal. After being discharged, the patient continued with the hydrocortisone replacement therapy. By the 18-month follow-up, the patient was growing and developing well. In neonates, unexplained acute heart failure requires caution for possible endocrine hereditary metabolic diseases, and timely cortisol testing and genetic testing should be conducted.

Comparative study of the gut microbiota in three captive Rhinopithecus species.

BACKGROUND: Snub-nosed monkeys are highly endangered primates and their population continues to decline with the habitat fragmentation. Artificial feeding and breeding is an important auxiliary conservation strategy. Studies have shown that changes and imbalances in the gut microbiota often cause gastrointestinal problems in captive snub-nosed monkeys. Here, we compare the gut microbiota composition, diversity, and predicted metabolic function of three endangered species of snub-nosed monkeys (Rhinopithecus bieti, R. brelichi, and R. roxellana) under the same captive conditions to further our understanding of the microbiota of these endangered primates and inform captive conservation strategies. 16 S rRNA gene sequencing was performed on fecal samples from 15 individuals (R. bieti N = 5, R. brelichi N = 5, R. roxellana N = 5). RESULTS: The results showed that the three Rhinopithecus species shared 24.70% of their amplicon sequence variants (ASVs), indicating that the composition of the gut microbiota varied among the three Rhinopithecus species. The phyla Firmicutes and Bacteroidetes represented 69.74% and 18.45% of the core microbiota. In particular, analysis of microbiota diversity and predicted metabolic function revealed a profound impact of host species on the gut microbiota. At the genus level, significant enrichment of cellulolytic genera including Rikenellaceae RC9 gut group, Ruminococcus, Christensenellaceae R7 group, UCG 004 from Erysipelatoclostridiaceae, and UCG 002 and UCG 005 from Oscillospiraceae, and carbohydrate metabolism including propionate and butyrate metabolic pathways in the gut of R. bieti indicated that R. bieti potentially has a stronger ability to use plant fibers as energy substances. Bacteroides, unclassified Muribaculaceae, Treponema, and unclassified Eubacterium coprostanoligenes group were significantly enriched in R. brelichi. Prevotella 9, unclassified Lachnospiraceae, and unclassified UCG 010 from Oscillospirales UCG 010 were significantly enriched in R. roxellana. Among the predicted secondary metabolic pathways, the glycan biosynthesis and metabolism had significantly higher relative abundance in the gut of R. brelichi and R. roxellana than in the gut of R. bieti. The above results suggest that different Rhinopithecus species may have different strategies for carbohydrate metabolism. The Principal coordinate analysis (PCoA) and Unweighted pair-group method with arithmetic mean (UPGMA) clustering tree revealed fewer differences between the gut microbiota of R. brelichi and R. roxellana. Correspondingly, no differences were detected in the relative abundances of functional genes between the two Rhinopithecus species. CONCLUSION: Taken together, the study highlights that host species have an effect on the composition and function of the gut microbiota of snub-nosed monkeys. Therefore, the host species should be considered when developing nutritional strategies and investigating the effects of niche on the gut microbiota of snub-nosed monkeys.

Autophagy benefits the in vitro and in vivo clearance of Talaromyces marneffei.

Talaromycosis, namely Talaromyces marneffei infection, is increasing gradually and has a high mortality rate even under antifungal therapy. Although autophagy acts differently on different pathogens, it is a promising therapeutic strategy. However, information on autophagy in macrophages and animals upon infection by T. marneffei is still limited. Therefore, several models were employed here to investigate the role of autophagy in host defense against T. marneffei, including RAW264.7 macrophages as in vitro models, different types of Caenorhabditis elegans and BALB/c mice as in vivo models. We applied the clinical T. marneffei isolate SUMS0152 in this study. T. marneffei-infected macrophages exhibit increased formation of autophagosomes. Further, macrophage autophagy promoted by rapamycin or Earle's balanced salt solution (EBSS) inhibited the viability of intracellular T. marneffei. In vivo, compared with uninfected Caenorhabditis elegans, the wild-type nematodes upregulated the expression of the autophagy-related gene lgg-1 and atg-18, and nematodes carrying GFP reporter were induced to form autophagosomes (GFP::LGG-1) after T. marneffei infection. Furthermore, the knockdown of lgg-1 significantly reduced the survival rate of T. marneffei-infected nematodes. Likewise, the autophagy activator rapamycin reduced the fungal burden and suppressed lung inflammation in a mouse model of infection. In conclusion, autophagy is essential for host defense against T. marneffei in vitro and in vivo. Therefore, autophagy may be an attractive target for developing new therapeutics to treat talaromycosis.

Two Chiral YbIII Enantiomeric Pairs with Distinct Enantiomerically Pure N-Donor Ligands Presenting Significant Differences in Photoluminescence, Circularly Polarized Luminescence, and Second-Harmonic Generation.

Using enantiomerically pure bidentate and tridentate N-donor ligands (1LR/1LS and 2LR/2LS) to replace two coordinated H2O molecules of Yb(tta)3(H2O)2, respectively, two eight- and nine-coordinated YbIII enantiomeric pairs, namely, Yb(tta)31LR/Yb(tta)31LS (Yb-R-1/Yb-S-1) and [Yb(tta)32LR]·CH3CN/[Yb(tta)32LS]·CH3CN (Yb-R-2/Yb-S-2), were isolated, in which Htta = 2-thenoyltrifluoroacetone, 1LR/1LS = (-)/(+)-4,5-pinene-2,2'-bipyridine, and 2LR/2LS = (-)/(+)-2,6-bis(4',5'-pinene-2'-pyridyl)pyridine. Interestingly, they not only present distinct degrees of chirality but also show large differences in near-infrared (NIR) photoluminescence (PL), circularly polarized luminescence (CPL), and second-harmonic generation (SHG). Eight-coordinated Yb-R-1 with an asymmetric bidentate 1LR ligand has a high NIR-PL quantum yield (1.26%) and a long decay lifetime (20 µs) at room temperature, being more than two times those (0.48%, 8 µs) of nine-coordinated Yb-R-2 with a C2-symmetric tridentate 2LR ligand. In addition, Yb-R-1 displays an efficient CPL with a luminescence dissymmetry factor glum = 0.077, being 4 × Yb-R-2 (0.018). In particular, Yb-R-1 presents a strong SHG response (0.8 × KDP), which is 8 × Yb-R-2 (0.1 × KDP). More remarkably, the precursor Yb(tta)3(H2O)2 exhibits a strong third-harmonic generation (THG) response (41 × α-SiO2), while the introduction of chiral N-donors results in the switching of THG to SHG. Our interesting findings provide new insights into both the functional regulation and switching in multifunctional lanthanide molecular materials.

Correlation between frailty and cardiac structure and function in echocardiography in elderly patients with normal ejection fraction.

OBJECTIVE: This study aims to accurately evaluate the cardiac structure and function of the frail population in elderly patients with normal ejection fraction (EF) using the 3D volume quantification and speckle tracking of echocardiography, to explore the correlation between frailty and cardiac structure and function. METHODS: A total of 350 elderly aged 65 and above in-patients, excluding those with congenital heart disease, cardiomyopathy, and severe valvular heart disease, were included in the study. Patients were divided into non-frail, pre-frail, and frail group. Echocardiography techniques including speckle tracking and 3D volume quantification, were used to analyze the cardiac structure and function of the study subjects. Comparative analysis was statistically significant if P < 0.05. RESULTS: The cardiac structure of the frail group was different compared with non-frail patients, the frail group demonstrated increased left ventricular myocardial mass index (LVMI), but decreased stroke volume. Cardiac function was also impaired in the frail group: reservoir strain and conduit strain of left atrium, strain of right ventricular (RV) free wall, strain of RV septum, 3D EF of RV, and global longitudinal strain of LV were significantly decreased. Frailty was significantly and independently associated with LV hypertrophy (OR 1.889; 95% CI 1.240,2.880; P = 0.003), LV diastolic dysfunction (OR 1.496; 95% CI 1.016,2.203; P = 0.041), left ventricular global longitudinal strain (LVGLS) reduction (OR 1.697; 95% CI 1.192, 2.416; P = 0.003), and reduced RV systolic function (OR 2.200; 95% CI 1.017, 4.759; P = 0.045). CONCLUSION: Frailty is closely associated with several heart structural and functional alterations, which not only manifested as LV hypertrophy and reduced LV systolic function, but also decreased LV diastolic function, RV systolic function, and left atrial systolic function. Frailty is an independent risk factor for LV hypertrophy, LV diastolic dysfunction, LVGLS reduction, and reduced RV systolic function. TRIAL REGISTRATION NUMBER: ChiCTR2000033419. Date of registration: May 31, 2020.

Concentrations, seasonal trends, sources, health risk and subchronic toxicity to the respiratory and immune system of PAHs in PM2.5 in Xi'an.

PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) have been proved to be hazardous to health. Previous studies have focused on the distribution and sources of PAHs, whereas there is little knowledge of the damage to organs. Here we sought to investigate the pollution level and seasonal variation characteristics of PAHs in PM2.5 in Xi'an and assess the health risk, to establish a PAHs exposure model, and investigate the toxicological effects of PAHs on the respiratory and immune functions. A sub-chronic exposure model of PAHs was established by inhalation. The pathological changes of lung tissues were observed with a light microscope. Inflammatory reactions in alveolar lavage fluid were determined using the corresponding kit. The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) were detected with enzyme linked immunosorbent assay (ELISA) kit; the proliferation of lymphocytes in spleen was detected with methyl tetrazolium (MTT); DNA immune damage was determined with DNA gel electrophoresis. The results showed that (1) the total concentration of 16 PAHs ranged from 41.1 to 387 ng/m3, with a mean value of 170 ng/m3, and the concentration of PAHs in PM2.5 was higher in winter than in other seasons. (2) The sources of PAHs in the atmosphere of Xi'an urban area were mainly coal combustion, and the equivalent carcinogenic concentration of PAHs in PM2.5 was 3.9 ng/m3. (3) Foreign body granuloma formation and inflammatory cell damage were observed in the lungs of rats infected with toxin; the levels of reactive oxygen species (ROS) and mobile device assistant (MDA) increased while nitric oxide synthase (NOS) decreased with the increase of dose; the expression levels of IL-6 and IL-8 elevated with the increase of toxin dose, showing an obvious dose-effect relationship; the level of PAHs damage to cells showed a dose-effect relationship. Sub-chronic exposure to PAHs could cause sustained inflammatory injury to the organism. Measures should be taken to counter the problems of PAHs in PM2.5 in Xi'an and relevant health promotion strategies should be developed.

Functional insights into Brucella transcriptional regulator ArsR.

ArsR-family transcriptional factors regulates diverse physiological functions necessary for Brucella adaptation to environmental changes. However, whether the ArsR-family transcriptional regulator are related to virulence, and the precise determination of ArsR direct targets in Brucella are still unknown. Therefore, we created a 2308ΔArsR6 mutant of B. abortus 2308 (S2308). Virulence assay was performed using a murine macrophage cell line (RAW 264.7). We performed chromatin immunoprecipitation of ArsR6 followed by next-generation sequencing (ChIP-seq). We also selected the target gene pobA (BAB2_0600), and created the mutant (2308ΔpobA). The survival capability of 2308ΔpobA strain in RAW 264.7 was detected and the levels of tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), interleukin-12 (IL-12) and interleukin-18 (IL-18) were also measured. The results showed that 2308ΔArsR6 reduced survival capability in RAW 264.7. We detected 40 intergenic ChIP-seq peaks of ArsR6 binding distributed across the Brucella genome. 2308ΔpobA was significantly reduced survival capability in RAW 264.7. After the macrophages were infected with 2308ΔpobA, the levels of TNF-α, IFN-γ, IL-12 and IL-18 were decreased and were significantly lower than that for the S2308-infected group, indicating that the 2308ΔpobA could reduce the secretion of inflammatory cytokines. Taken together, the research provided new insights into the functionality of ArsR6 and great significance to clarify the function of ArsR6.

Clinical severity prediction in children with osteogenesis imperfecta caused by COL1A1/2 defects.

Osteogenesis imperfecta (OI) is a genetic disease with an estimated prevalence of 1 in 13,500 and 1 in 9700. The classification into subtypes of OI is important for prognosis and management. In this study, we established a clinical severity prediction model depending on multiple features of variants in COL1A1/2 genes. INTRODUCTION: Ninety percent of OI cases are caused by pathogenic variants in the COL1A1/COL1A2 gene. The Sillence classification describes four OI types with variable clinical features ranging from mild symptoms to lethal and progressively deforming symptoms. METHODS: We established a prediction model of the clinical severity of OI based on the random forest model with a training set obtained from the Human Gene Mutation Database, including 790 records of the COL1A1/COL1A2 genes. The features used in the prediction model were respectively based on variant-type features only, and the optimized features. RESULTS: With the training set, the prediction results showed that the area under the receiver operating characteristic curve (AUC) for predicting lethal to severe OI or mild/moderate OI was 0.767 and 0.902, respectively, when using variant-type features only and optimized features for COL1A1 defects, 0.545 and 0.731, respectively, for COL1A2 defects. For the 17 patients from our hospital, prediction accuracy for the patient with the COL1A1 and COL1A2 defects was 76.5% (95% CI: 50.1-93.2%) and 88.2% (95% CI: 63.6-98.5%), respectively. CONCLUSION: We established an OI severity prediction model depending on multiple features of the specific variants in COL1A1/2 genes, with a prediction accuracy of 76-88%. This prediction algorithm is a promising alternative that could prove to be valuable in clinical practice.

Effects of Counterions, Coordination Anions, and Coordination Solvent Molecules on Single-Molecule Magnetic Behaviors and Nonlinear Optical Properties of Chiral Zn2Dy Schiff Base Complexes.

By changing the counterions (ClO4- and CF3SO3-) and the coordination anions (Cl- and Br-), we investigated their influences on the structures and performances of a class of Zn2Dy chiral single-molecule magnets (SMMs), which are based on a pair of chiral Schiff bases R,R-H2LSchiff and S,S-H2LSchiff {R,R-H2LSchiff = 2-((E)-((1R,2R)-2-((E)-2-hydroxy-3-methoxybenzylideneamino)cyclohexylimino)methyl)-6-methoxyphenol and S,S-H2LSchiff = 2-((E)-((1S,2S)-2-((E)-2-hydroxy-3-methoxybenzylideneamino)cyclohexylimino)methyl)-6-methoxyphenol}. Three pairs of chiral Zn2Dy Schiff base complexes were obtained by directed synthesis, which are [DyZn2(R,R-LSchiff)Cl2(H2O)](ClO4)·0.5MeOH·0.25H2O (R-1) and [DyZn2(S,S-LSchiff)Cl2(H2O)][DyZn2(S,S-LSchiff)Cl2(MeOH)](ClO4)2·MeOH·0.5H2O (S-1), [DyZn2(R,R-LSchiff)Cl2(H2O)](CF3SO3)·0.5MeOH (R-2) and [DyZn2(S,S-LSchiff)Cl2(H2O)][DyZn2(S,S-LSchiff)Cl2(MeOH)](CF3SO3)2·MeOH (S-2), and [DyZn2(R,R-LSchiff)Br2(H2O)](CF3SO3)·0.25MeOH (R-3) and [DyZn2(S,S-LSchiff)Br2(H2O)][DyZn2(S,S-LSchiff)Br2(MeOH)](CF3SO3)2 (S-3). They all exhibit good SMM behaviors, and their magnet relaxation is regulated by not only the counterions (ClO4- and CF3SO3-) but also the coordination anions (Cl- and Br-); these anions also have important effects on the second-harmonic generation (SHG) and third harmonic generation (THG) nonlinear optical properties. Interestingly, in the S-configuration complexes, the coordination solvent molecule of the Dy3+ ion on half of the molecules is the methanol molecule instead of the water molecule. This change in the coordinating solvent molecule can also significantly affect the SMM behaviors and the SHG and THG nonlinear optical properties. Moreover, ab initio calculations were applied to rationally explain the SMM properties.

Modulating Two Pairs of Chiral DyIII Enantiomers by Distinct ß-Diketone Ligands to Show Giant Differences in Single-Ion Magnet Performance and Nonlinear Optical Response.

Using Dy(dbm)3(H2O) and Dy(btfa)3(H2O)2 to react with enantiopure N-donors, (-)/(+)-4,5-pinenepyridyl-2-pyrazine (LR/LS), respectively, two pairs of chiral DyIII enantiomers, Dy(dbm)3LR/Dy(dbm)3LS (R-1-Dy/S-1-Dy) and Dy(btfa)3LR/Dy(btfa)3LS (R-2-Dy/S-2-Dy) were obtained, wherein one of the benzene rings of dbm- (dibenzoylmethanate) in R-1-Dy/S-1-Dy is displaced by the -CF3 group of btfa- (4,4,4-trifluoro-1-phenyl-1,3-butanedionate) in R-2-Dy/S-2-Dy. Interestingly, this substitution results not only in giant differences in their single-ion magnetic (SIM) performances but also in their completely different nonlinear optical (NLO) responses. R-1-Dy presents a large effective energy barrier (Ueff = 265.47 K) under zero applied field, being more than 4 × R-2-Dy (61.40 K). The discrepancy on their magnetic performances has been further elucidated by ab initio calculations. Meanwhile, R-1-Dy/S-1-Dy display the strongest third-harmonic generation responses (35/33 × α-SiO2) among the known lanthanide NLO-active coordination compounds (CCs). On the contrary, R-2-Dy/S-2-Dy exhibit moderate second-harmonic generation responses (0.65/0.70 × KDP). These results not only give the first example of the CCs with both SMM/SIM behavior and a THG response but also provide an efficient strategy for achieving the function regulation and switch in multifunctional CCs.

L-Cysteine attenuates osteopontin-mediated neuroinflammation following hypoxia-ischemia insult in neonatal mice by inducing S-sulfhydration of Stat3.

We previously show that L-Cysteine administration significantly suppresses hypoxia-ischemia (HI)-induced neuroinflammation in neonatal mice through releasing H2S. In this study we conducted proteomics analysis to explore the potential biomarkers or molecular therapeutic targets associated with anti-inflammatory effect of L-Cysteine in neonatal mice following HI insult. HI brain injury was induced in postnatal day 7 (P7) neonatal mice. The pups were administered L-Cysteine (5 mg/kg) at 24, 48, and 72 h post-HI. By conducting TMT-based proteomics analysis, we confirmed that osteopontin (OPN) was the most upregulated protein in ipsilateral cortex 72 h following HI insult. Moreover, OPN was expressed in CD11b+/CD45low cells and infiltrating CD11b+/CD45high cells after HI exposure. Intracerebroventricular injection of OPN antibody blocked OPN expression, significantly attenuated brain damage, reduced pro-inflammatory cytokine levels and suppressed cerebral recruitment of CD11b+/CD45high immune cells following HI insult. L-Cysteine administration reduced OPN expression in CD11b+/CD45high immune cells, concomitant with improving the behavior in Y-maze test and suppressing cerebral recruitment of CD11b+/CD45high immune cells post-HI insult. Moreover, L-Cysteine administration suppressed the Stat3 activation by inducing S-sulfhydration of Stat3. Intracerebroventricular injection of Stat3 siRNA not only decreased OPN expression, but also reversed HI brain damage. Our data demonstrate that L-Cysteine administration effectively attenuates the OPN-mediated neuroinflammation by inducing S-sulfhydration of Stat3, which contributes to its anti-inflammatory effect following HI insult in neonatal mice. Blocking OPN expression may serve as a new target for therapeutic intervention for perinatal HI brain injury.

Microbiome analysis reveals the significant changes in gut microbiota of diarrheic Baer's Pochards (Aythya baeri).

Gut microbiota has been demonstrated to play multiple crucial roles in immunity, physiology, metabolism, and health maintenance. Diarrhea was closely related to the gut microbiota, but information regarding the alterations in gut microbial composition and structure in Baer's Pochard (Aythya baeri) with diarrhea remains scarce. Here, 16S rDNA amplicon sequencing was performed to investigate the gut microbial variability between diarrheic and healthy Baer's Pochard. Results indicated that the gut bacterial community of diarrheic Baer's Pochard showed a distinct decrease in alpha diversity, accompanied by evident changes in taxonomic compositions. Microbial taxonomic analysis revealed that Firmicutes, Proteobacteria and Bacteroidetes were the most dominant phyla in all the fecal samples regardless of health status. At the genus level, the differences in gut bacterial abundance between healthy and diarrheic populations were gradually observed. Specifically, the proportion of Elusimicrobia in the diarrheic Baer's Pochard was increased in comparison with healthy populations, while Acidobacteria, Rokubacteria, Cyanobacteria and Patescibacteria were dramatically decreased. Additionally, the relative proportion of 23 bacterial genera significantly decreased in diarrheic Baer's Pochard, whereas the relative percentage of 4 bacterial genera (Alkanindiges, Elusimicrobium, Spirosoma and Exiguobacterium) observably increased as compared to healthy populations. Taken together, the present study revealed that there were distinct differences in the gut microbial composition and diversity between the healthy and diarrheic Baer's Pochard. Remarkably, this is the first report on the differences in the gut microbiota of Baer's Pochard under different health states and may contribute to provide better insight into gut microbial composition and diversity of Baer's Pochard.

Multifunctional DyIII Enantiomeric Pairs Showing Enhanced Photoluminescences and Third-Harmonic Generation Responses through the Coordination Role of Homochiral Tridentate N,N,N-Pincer Ligands.

By utilizing Dy(hfac)3(H2O)2 to react with enantiomerically pure tridentate N,N,N-pincer ligands, namely (-)/(+)-2,6-bis(4',5'-pinene-2'-pyridyl)pyridine (LR and LS), respectively, homochiral DyIII enantiomeric pairs formulated as Dy(hfac)3LR/Dy(hfac)3LS (R-1/S-1) (hfac- = hexafluoroacetylacetonate) were achieved and structurally characterized. Meanwhile, their magnetic, photoluminescent (PL), and chiroptical properties were probed. The PL test results indicate that the precursor Dy(hfac)3(H2O)2 only shows very weak emission, while R-1 exhibits characteristic DyIII f-f transition emission bands at room temperature. Furthermore, the nonlinear optical responses of Dy(hfac)3(H2O)2, LR/LS, and R-1/S-1 were investigated in detail based on crystalline samples. The results reveal that LR and LS present the coexistence of second- and third-harmonic generation (SHG and THG) responses with more intense signals for SHG responses; and Dy(hfac)3(H2O)2 merely displays weak THG responses, while R-1 and S-1 also only exhibit THG responses. However, the THG intensities of R-1 and S-1 are more than six times larger than that of Dy(hfac)3(H2O)2 under the identical measurement conditions. These results demonstrate that introducing homochiral N,N,N-pincer ligands to replace two H2O molecules of Dy(hfac)3(H2O)2 results in significant improvements of both PL performances and THG responses of resultant R-1/S-1 enantiomers. R-1 and S-1 integrate PL, THG, and chiral optical activity in one molecule, suggesting their multifunctional merits. In particular, a convenient method is introduced to simultaneously test THG and SHG responses of molecular materials based on crystalline samples in this work.

Clinical risk score for central precocious puberty among girls with precocious pubertal development: a cross sectional study.

BACKGROUND: The gold standard for the diagnosis of central precocious puberty (CPP) is gonadotropin-releasing hormone (GnRH) or GnRH analogs (GnRHa) stimulation test. But the stimulation test is time-consuming and costly. Our objective was to develop a risk score model readily adoptable by clinicians and patients. METHODS: A cross-sectional study based on the electronic medical record system was conducted in the Children's Hospital, Fudan University, Shanghai, China from January 2010 to August 2016. Patients with precocious puberty were randomly split into the training (n = 314) and validation (n = 313) sample. In the training sample, variables associated with CPP (P < 0.2) in univariate analyses were introduced in a multivariable logistic regression model. Prediction model was selected using a forward stepwise analysis. A risk score model was built with the scaled coefficients of the model and tested in the validation sample. RESULTS: CPP was diagnosed in 54.8% (172/314) and 55.0% (172/313) of patients in the training and validation sample, respectively. The CPP risk score model included age at the onset of puberty, basal luteinizing hormone (LH) concentration, largest ovarian volume, and uterine volume. The C-index was 0.85 (95% CI: 0.81-0.89) and 0.86 (95% CI: 0.82-0.90) in the training and the validation sample, respectively. Two cut-off points were selected to delimitate a low- (< 10 points), median- (10-19 points), and high-risk (≥ 20 points) group. CONCLUSIONS: A risk score model for the risk of CPP had a moderate predictive performance, which offers the advantage of helping evaluate the requirement for further diagnostic tests (GnRH or GnRHa stimulation test).

Two single mutations in carboxylesterase 001C improve fenvalerate hydrolase activity in Helicoverpa armigera.

Carboxylesterases (CarEs) usually play critical roles in the detoxification of toxic chemicals and therefore may be involved in insecticide resistance in agricultural pests. Previous work has shown that CarE 001C from Helicoverpa armigera was able to metabolize the isomers of cypermethrin and fenvalerate. In this study, seven mutants of CarE 001C with single amino acid substitution were produced and expressed in the Escherichia coli. Enzyme kinetic analysis indicated that all seven mutations dramatically reduced enzymatic activities toward the generic substrate α-naphthyl acetate, but in vitro metabolism assay showed that two of the mutations, H423I and R322L, significantly improved hydrolase activities toward fenvalerate, with their recorded specific activities being 3.5 and 5.1 nM·s-1·mg -1 proteins, respectively. Further, thermostability assay showed that the stability of one mutant enzyme was enhanced. This study will help us better understand the potential of CarEs in insecticide detoxification and resistance in H. armigera.

[Research progress of correlation between multidrug resistance and transporters and traditional Chinese medicine intervention].

With the emergence of drug resistance in Western medicine, the repeated administration of clinical first-line drugs becomes more severe. There are many factors leading to multidrug resistance(MDR), so it is very difficult to solve the problem. Since traditional Chinese medicine(TCM) has been used in the field of MDR in recent years, the research on the transporter-associated drug resistance and intervention of TCM has gradually become a hot spot. Therefore, in order to further explore the relationships among drug resistance, transporters, and TCM intervention, we review the relevant research progress in recent years and comb the achievements and limitations of this research at present. In the end, we put forward the research direction of changing body's ADME through the host's transporters and gastrointestinal flora, which provides new ideas for future research.

Pseudomonas phragmitis sp. nov., isolated from petroleum polluted river sediment.

A Gram-stain-negative, rod-shaped bacterium, motile by means of a single polar flagellum, designated S-6-2T, was isolated from petroleum polluted river sediment in Huangdao, Shandong Province, PR China. The 16S rRNA gene sequence analysis revealed that S-6-2T represented a member of the genus Pseudomonas, sharing the highest sequence similarities with Pseudomonas parafulva (97.5 %) and Pseudomonas fulva (97.5 %). Phylogenetic analysis based on 16S rRNA gene, concatenated 16S rRNA, gyrB, rpoB and rpoD genes and genome core-genes indicated that S-6-2T was affiliated with the members of the Pseudomonas pertucinogena group. The average nucleotide identity (ANI) and genome-to-genome distance between the whole genome sequences of S-6-2T and closely related species of the genus Pseudomonas within the P. pertucinogena group were less than 77.94 % and 20.5 %, respectively. Differences in phenotypic characteristics were also found between S-6-2T and the closely related species. The major cellular fatty acids (>10 %) were summed feature 8 (C18 : 1ω7c/ C18  : 1ω6c), C16 : 0, C17 : 0cyclo and C12 : 0. The predominant respiratory quinone was ubiquinone 9. The major polar lipids were diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), one unidentified lipid (L1), two unidentified phospholipids (PL1 and PL2) and an aminophospholipid (APL). The DNA G+C content of the genome of S-6-2T was 60.1 mol%. On the basis of the evidence from the polyphasic taxonomic study, strain S-6-2T can be classified as representative of a novel species of the genus Pseudomonas, for which the name Pseudomonas phragmitis sp. nov. is proposed. The type strain is S-6-2T (=CGMCC 1.15798T=KCTC 52539T).

Design, synthesis, and fungicidal evaluation of novel oxysterol binding protein inhibitors for combatting resistance associated with oxathiapiprolin.

Oxathiapiprolin, the first successful oxysterol binding protein (OSBP) inhibitor for oomycete control, is regarded as an important milestone in the history of fungicide discovery. However, its interaction with OSBP remain unclear. Moreover, some plant pathogenic oomycetes have developed medium to high resistance to oxathiapiprolin. In this paper, the three-dimensional (3D) structure of OSBP from Phytophthora capsici (pcOSBP) was built, and its interaction with oxathiapiprolin was systematically investigated by integrating molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. The computational results showed that oxathiapiprolin bound to pcOSBP forms H-bonds with Leu73, Lys74, Ser69, and water molecules. Then, based on its interaction with pcOSBP, oxathiapiprolin was structurally modified to discover new analogs with high fungicidal activity and a low risk of resistance. Fortunately, compound 1e was successfully designed and synthesized as the most potent candidate, and it showed a much lower resistance risk (RF < 1) against LP3-M and LP3-H in P. capsici. The present work indicated that the piperidinyl-thiazole-isoxazoline moiety is useful for further optimization. Furthermore, compound 1e could be used as a lead compound for the discovery of new OSBP inhibitors.

ChIP-seq analysis of Brucella reveals transcriptional regulation of GntR.

Transcriptional regulator GntR controls diverse physiological functions necessary for Brucella survival. In the intracellular pathogen Brucella, GntR has been shown to regulate the expression of genes related to virulence. However, the precise determination of GntR direct targets has so far proved elusive. Therefore, we performed chromatin immunoprecipitation of GntR10 followed by next-generation sequencing (ChIP-seq). We selected target gene BAB1_1163 directly regulated by GntR10 and created the mutant (2308Δ1163) from virulent Brucella abortus 2308 (S2308). 2308Δ1163 strain survival capability in murine macrophages (RAW 264.7) was detected and the levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were also measured. We detected 88 intergenic ChIP-seq peaks of GntR10 binding distributed across the Brucella genome and determined a markedly asymmetric binding consensus motif with 12 bp length. 2308Δ1163 showed reduced survival capability in RAW 264.7. After the macrophages were infected with 2308Δ1163, the levels of TNF-α and IL-1ß were decreased and were significantly lower than that for the S2308-infected group, indicating that the 2308Δ1163 mutant could inhibit the secretion of inflammatory cytokines. Taken together, the research has recorded valuable data about GntR10 and provided new insights into the functionality of GntR10.