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The Patented Naoxueshuan formula is an empirical formula for treating cerebral thrombosis, which has been proven to have significant and stable therapeutic effects through long-term clinical application. The Naoxueshuan formula has rich chemical components and diverse structures. In this study, chemical compositions of the Patent Naoxueshuan formula were analyzed by using ultra-performance liquid chromatography-time of flight mass spectrometry (UPLC-Q-TOF MS) and gas chromatography-mass spectrometry (GC-MS). For UPLC-Q-TOF MS analysis, the decoction of Naoxueshuan formula was separated using a Waters BEH C18 column (100 mm×2.1 mm, 1.7 μm). The mobile phase was comprised of 0.1% formic acid solution and acetonitrile with the flow rate of 0.3 mL/min. MS data was collected under positive and negative ion modes. For GC-MS analysis, the Agilent DB-5MS capillary column (30 m×0.25 mm, 0.25 μm) was employed to analyze the volatile components of the decoction of Naoxueshuan formula. The GC-MS analysis was performed under programmed heating conditions with electron ionization (EI) as the ion source and a scanning mass range of m/z 50-550. The main chromatographic peaks in both liquid and gas chromatograms were identified and analyzed according to the secondary mass spectrum information, NIST standard spectrum library and literatures. A total of 61 non-volatile components are identified in the Naoxueshuan decoction, including 14 flavonoids, 13 terpenoids, 9 glycosides, 5 organic acids, and 10 other types of compounds. A total of 29 volatile components are identified in the Naoxueshuan decoction, including 17 hydrocarbons, 3 alcohols, 1 aldehydes, 1 esters, 3 phenols, 2 terpenes and 2 other types of compounds. Among them, the organic acids are mainly from Salvia miltiorrhiza Bunge, the flavonoids are mainly from Pueraria lobata, Astragalus membranaceus (Fisch.) Bunge and Carthamus tinctorius L., the terpenoids are mainly from Salvia miltiorrhiza Bunge and Cornus officinalis Sieb. et Zucc. The volatile components are mainly from Ligusticum sinense, Fructus Amomi, Alpinia katsumadai Hayata, and Semen Alpiniae Katsumadai. This study provides an effective and comprehensive method for qualitative analysis of the chemical components in the Patented Naoxueshuan formula, and also provides data support for clarifying effective substances and establishing a quality evaluation system.

BackgroundThe COVID-19 pandemic prompted social distancing policies and caused misinformation that hindered in-person HIV screening for high-risk groups. Social media platforms provide additional options for voluntary counseling and testing (VCT) for HIV, overcoming these limitations. However, there is a lack of data on HIV testing recruitment through social media platforms and its outcomes during the pandemic. ObjectiveThis study aimed to measure the rate of face-to-face mobile and video VCT conducted after recruitment through social media platforms and friend referrals during the pandemic and compare the geographic distribution, risk feature targeting, testing outcome, and cost between the 2 models. MethodsData were collected from March 3 to December 31, 2021, during the COVID-19 outbreak in Taiwan. Participants engaging in unprotected sex were recruited. After one-on-one message discussions through the platforms, the well-trained research assistants provided mobile or video VCT based on the participants’ availability. Primary outcomes were completion rate, testing results, and CD4 count. Secondary outcomes included demographic and HIV risk-taking and protective features from a questionnaire. Selection bias was controlled by adjusting for the testing site (Taipei vs non-Taipei) using univariable multinomial logistic regression. ResultsThis study gathered 5142 responses on the social media platforms, recruiting 1187 participants. Video VCT had a completion rate of 31.8% (207/651), higher than mobile VCT’s 21.8% (980/4491). Both rates were higher than those before the COVID-19 pandemic. Recruitment through friend referrals, instant messaging apps (eg, Line [LY Corporation]), and geosocial dating apps (eg, Hornet [Queer Networks Inc], Grindr [Grindr LLC], and Gsland [Tien-Hao Tsai]) resulted in higher acceptance and completion rates than social networks (eg, Facebook [Meta], X [formerly Twitter], and Instagram [Meta]). Mobile VCT had higher recruitment among urban residents and screening density, while video VCT reached a broader geographic area. The mobile group was more likely to have had more than 10 sexual partners (odds ratio [OR] 1.92, 95% CI 1.05-3.50; P=.03), history of sex work (OR 4.19, 95% CI 1.68-10.43; P=.002), and sexually transmitted diseases (OR 2.23, 95% CI 1.18-4.23; P=.01) within the past 3 months. The video group was more likely to meet sexual partners through social media. The HIV-positive rate in the mobile group was 0.7% (7/973) with an average CD4 count of 460/μL, while in the video group, it was 1% (2/205) with an average CD4 count of 347/μL, indicating a later diagnosis. Both positivity rates were higher than those before the COVID-19 pandemic, with no significant difference between the groups. The video group cost US $54.68 per participant, slightly higher than the US $50.36 for the mobile group. ConclusionsRecruiting through social media platforms that facilitate one-on-one message discussions can effectively target high-risk groups for mobile and video VCT. This approach should be integrated into the current screening model to enhance HIV case finding.

Abstract Background Self-sampling HPV test and thermal ablation are effective tools to increase screening coverage and treatment compliance for accelerating cervical cancer elimination. We assessed the cost-effectiveness of their combined strategies to inform accessible, affordable, and acceptable cervical cancer prevention strategies. Methods We developed a hybrid model to evaluate costs, health outcomes, and incremental cost-effectiveness ratios (ICER) of six screen-and-treat strategies combining HPV testing (self-sampling or physician-sampling), triage modalities (HPV genotyping, colposcopy or none) and thermal ablation, from a societal perspective. A designated initial cohort of 100,000 females born in 2015 was considered. Strategies with an ICER less than the Chinese gross domestic product (GDP) per capita ($10,350) were considered highly cost-effective. Results Compared with current strategies in China (physician-HPV with genotype or cytology triage), all screen-and-treat strategies are cost-effective and self-HPV without triage is optimal with the most incremental quality-adjusted life-years (QALYs) gained (220 to 440) in rural and urban China. Each screen-and-treat strategy based on self-collected samples is cost-saving compared with current strategies (−$818,430 to −$3540) whereas more costs are incurred using physician-collected samples compared with current physician-HPV with genotype triage (+$20,840 to +$182,840). For screen-and-treat strategies without triage, more costs (+$9404 to +$380,217) would be invested in the screening and treatment of precancerous lesions rather than the cancer treatment compared with the current screening strategies. Notably, however, more than 81.6% of HPV-positive women would be overtreated. If triaged with HPV 7 types or HPV16/18 genotypes, 79.1% or 67.2% (respectively) of HPV-positive women would be overtreated with fewer cancer cases avoided (19 cases or 69 cases). Conclusions Screen-and-treat strategy using self-sampling HPV test linked to thermal ablation could be the most cost-effective for cervical cancer prevention in China. Additional triage with quality-assured performance could reduce overtreatment and remains highly cost-effective compared with current strategies.

ATP-binding cassette (ABC) transporters are involved in transporting multiple substrates, such as toxins, and may be important for the survival of Trichoderma when encountering biotic toxins. In this study, genome searching revealed that there are 44 ABC transporters encoded in the genome of Trichoderma asperellum. These ABC transporters were divided into six types based on three-dimensional (3D) structure prediction, of which four, represented by 39 ABCs, are involved in transport and the remaining two, represented by 5 ABCs, are involved in regulating translation. The characteristics of nucleotide-binding domain (NBD) are important in the identification of ABC proteins. Even though the 3D structures of the 79 NBDs in the 44 ABCs are similar, multiple sequence alignment showed they can be divided into three classes. In total, 794 motifs were found in the promoter regions of the 44 ABC genes, of which 541 were cis-regulators related to stress responses. To characterize how their ABCs respond when T. asperellum interact with fungi or plants, T. asperellum was cultivated in either minimal media (MM) control, C-hungry, N-hungry, or poplar medium (PdPap) to simulate normal conditions, competition with pathogens, interaction with pathogens, and interaction with plants, respectively. The results show that 17 of 39 transport ABCs are highly expressed in at least one condition, whereas four of the five translation-regulating ABCs are highly expressed in at least one condition. Of these 21 highly expressed ABCs, 6 were chosen for RT-qPCR expression under the toxin stress of phytopathogen Alternaria alternata, and the results show ABC01, ABC04, ABC05, and ABC31 were highly expressed and may be involved in pathogen interaction and detoxifying toxins from A. alternata.

The current animal models of stroke primarily model a single intracerebral hemorrhage (ICH) attack, and there is a lack of a reliable model of recurrent ICH. In this study, we established 16-month-old C57BL/6 male mouse models of ICH by injecting collagenase VII-S into the left striatum. Twenty-one days later, we injected collagenase VII-S into the right striatum to simulate recurrent ICH. Our results showed that mice subjected to bilateral striatal hemorrhage had poorer neurological function at the early stage of hemorrhage, delayed recovery in locomotor function, motor coordination, and movement speed, and more obvious emotional and cognitive dysfunction than mice subjected to unilateral striatal hemorrhage. These findings indicate that mouse models of bilateral striatal hemorrhage can well simulate clinically common recurrent ICH. These models should be used as a novel tool for investigating the pathogenesis and treatment targets of recurrent ICH.

White birch (Betula platyphylla Suk.) is a typical pioneer tree species that is important in forest restoration in northern China, Japan, and Korea. In the present study, 37 isolates were obtained from B. platyphylla rhizosphere soils in Heilongjiang Province; they were identified as T. pleuroticola (3 isolates), T. virens (2 isolates), T. hamatum (8 isolates), T. atroviride (21 isolates, dominant species) and T. asperelloides (3 isolates). Stress tolerance tests (salt, alkali, and nutritional stress that simulated saline alkali or barren soil) and confrontation assays (with four pathogens) were performed to determine which isolates had good biocontrol ability in barren soil; the results show that T. atroviride was outstanding. Then, in order to determine the effect of T. atroviride on plants and soil, Gynura cusimbua seeds were sown and treated with a T. atroviride spore suspension, as was unsown soil. The seedlings treated using T. atroviride had significantly greater height, stem diameter, soluble protein content, soluble sugar content, and malonaldehyde (MDA) content and their catalase (CAT) activity was also significantly increased. In addition, when the plants were inoculated with Alternaria alternata, the plants treated using T. atroviride had stronger CAT activity, significantly higher soluble protein content and soluble sugar content, and significantly lower MDA content, which indicates stronger resistance and less injury caused by the pathogen. In addition, T. atroviride not only increased the content of available nitrogen and available phosphorus in the soil, but also promoted G. cusimbua seedlings’ absorption of available nitrogen and available phosphorus. Thus, the characteristics of T. atroviride may make it the main factor that helps B. platyphylla colonise cut-over lands. T. atroviride, a promising biocontrol candidate, can be used in agriculture and forestry.

Bisphenol A (BPA), a well-known environmental endocrine disruptor, has been implicated in anxiety-like behavior. But the neural mechanism remains elusive. Herein, we found that mice exposed to 0.5 mg/kg/day BPA chronically from postnatal days (PND) 21 to PND 80 exhibited depression- and anxiety-like behavior. Further study showed that medial prefrontal cortex (mPFC), was associated with BPA-induced depression- and anxiety-like behavior, as evidenced by decreased c-fos expression in mPFC of BPA-exposed mice. Both the morphology and function of glutamatergic neurons (also called pyramidal neurons) in mPFC of mice were impaired following BPA exposure, characterized by reduced primary branches, weakened calcium signal, and decreased mEPSC frequency. Importantly, optogenetic activation of the pyramidal neurons in mPFC greatly reversed BPA-induced depression- and anxiety-like behavior in mice. Furthermore, we reported that microglial activation in mPFC of mice may also have a role in BPA-induced depression- and anxiety-like behavior. Taken together, the results indicated that mPFC is the brain region that is greatly damaged by BPA exposure and is associated with BPA-induced depression- and anxiety-like behavior. The study thus provides new insights into BPA-induced neurotoxicity and behavioral changes.

BackgroundThe present study aimed to evaluate the association between the cumulative dose of glucocorticoids (GCs) and case fatality in hospitalized patients who developed pneumonia while receiving glucocorticoid therapy.MethodsThis retrospective cohort study included 625 patients receiving long-term GC treatment who were hospitalized with pneumonia (322 male and 303 female). Data were obtained from the Dryad Digital Repository and were used to perform secondary analysis. Multivariable Cox proportional hazard regression model and restricted cubic splines (RCS) were used to evaluate the association between the cumulative dose of GCs and case fatality. Sensitivity analyses and subgroup analyses were performed.ResultsThe 30-day and 90-day death rates were 22.9 and 26.2%, respectively. After adjusting for potential confounders, compared with those in the lowest quintile (≤ 1.5 g), the Cox proportional hazard regression model analysis showed that patients with different cumulative doses of GCs (1.5 to 2.95, 2.95 to 5, 5 to 11.5, and > 11.5 g) had lower risks for 30-day death, with respective hazard ratios of 0.86 (95% CI, 0.52 to 1.42), 0.81 (0.49 to 1.33), 0.29 (0.15 to 0.55), and 0.42 (0.22 to 0.79). The multivariable-adjusted RCS analysis suggested a statistically significant N-shaped association between the cumulative dose of GCs and 30-day death. A higher cumulative dose of GC tended to first lead to an increase in 30-day death within 1.8 g, then to a statistically significant decrease until around 8 g [HR for 1 g = 0.82 (0.69 to 0.97)], and again to an increase afterward. Similar results were found in the subgroup analyses and sensitivity analyses.ConclusionN-shaped association between the cumulative dose of GCs and case fatality was observed in patients receiving long-term GC treatment who were hospitalized with pneumonia. Our findings may help physicians manage these patients.

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants with major risks to human health. Biological degradation is environmentally friendly and the most appealing remediation method for a wide range of persistent pollutants. Meanwhile, due to the large microbial strain collection and multiple metabolic pathways, PAH degradation via an artificial mixed microbial system (MMS) has emerged and is regarded as a promising bioremediation approach. The artificial MMS construction by simplifying the community structure, clarifying the labor division, and streamlining the metabolic flux has shown tremendous efficiency. This review describes the construction principles, influencing factors, and enhancement strategies of artificial MMS for PAH degradation. In addition, we identify the challenges and future opportunities for the development of MMS toward new or upgraded high-performance applications.

Abstract Scopoletin is a typical example of coumarins, which can be produced in plants. Scopoletin acts as a precursor for pharmaceutical and health care products, and also possesses promising biological properties, including antibacterial, anti-tubercular, anti-hypertensive, anti-inflammatory, anti-diabetic, and anti-hyperuricemic activity. Despite the potential benefits, the production of scopoletin using traditional extraction processes from plants is unsatisfactory. In recent years, synthetic biology has developed rapidly and enabled the effective construction of microbial cell factories for production of high value-added chemicals. Herein, this review summarizes the progress of scopoletin biosynthesis in artificial microbial cell factories. The two main pathways of scopoletin biosynthesis are summarized firstly. Then, synthetic microbial cell factories are reviewed as an attractive improvement strategy for biosynthesis. Emerging techniques in synthetic biology and metabolic engineering are introduced as innovative tools for the efficient synthesis of scopoletin. This review showcases the potential of biosynthesis of scopoletin in artificial microbial cell factories.

Abstract Background As the second most abundant polysaccharide in nature, hemicellulose can be degraded to xylose as the feedstock for bioconversion to fuels and chemicals. To enhance xylose conversion, the engineered Saccharomyces cerevisiae with xylose metabolic pathway is usually adapted with xylose as the carbon source in the laboratory. However, the mechanism under the adaptation phenomena of the engineered strain is still unclear. Results In this study, xylose-utilizing S. cerevisiae was constructed and used for the adaptation study. It was found that xylose consumption rate increased 1.24-fold in the second incubation of the yYST12 strain in synthetic complete-xylose medium compared with the first incubation. The study figured out that it was observed at the single-cell level that the stagnation time for xylose utilization was reduced after adaptation with xylose medium in the microfluidic device. Such transient memory of xylose metabolism after adaptation with xylose medium, named “xylose consumption memory”, was observed in the strains with both xylose isomerase pathway and xylose reductase and xylitol dehydrogenase pathways. In further, the proteomic acetylation of the strains before and after adaptation was investigated, and it was revealed that H4K5 was one of the most differential acetylation sites related to xylose consumption memory of engineered S. cerevisiae. We tested 8 genes encoding acetylase or deacetylase, and it was found that the knockout of the GCN5 and HPA2 encoding acetylases enhanced the xylose consumption memory. Conclusions The behavior of xylose consumption memory in engineered S. cerevisiae can be successfully induced with xylose in the adaptation. H4K5Ac and two genes of GCN5 and HPA2 are related to xylose consumption memory of engineered S. cerevisiae during adaptation. This study provides valuable insights into the xylose adaptation of engineered S. cerevisiae.

Relative weakness in sensitivity and contribution integration, especially lack of specific indicators at spatial and temporal scales, may hinder the formation of systematic knowledge for climate change impact on vegetation activity. Considering the interannual variability and periods difference, we investigated the ecosystem sensitivity to hydrothermal conditions and the contribution of individual climatic factors to vegetation activity on spatiotemporal scales during the period of 1980s–2013 in China. We ran simulations of the Common Land Model (CoLM) to obtain the photosynthetic rate, and used the satellite-derived Normalized Difference Vegetation Index (NDVI), to which we applied a temporal sensitivity analysis, the slope change ratio of accumulative quantity (SCRAQ), and geographical detectors. We show that the discrepancy between warming and precipitation variation contributed to vegetation activity was more notable than the ecosystem sensitivity to hydrothermal conditions, regardless of which temporal and spatial scale was considered. The sensitivity of vegetation activity to hydrothermal variation in most parts of northeastern and western China was higher than elsewhere, and the contribution of warming to vegetation dynamics was relatively high in the Inner Mongolian Plateau and Tibetan Plateau (>60%), where the contribution of warming to the vegetation distribution was also greater than elsewhere in China. Conversely, the contribution of precipitation variation to vegetation dynamics was comparatively greater in northwestern China and subtropical and tropical regions (>55%). The spatiotemporal contribution of precipitation variation to vegetation activity differed between regions, especially on the Tibetan Plateau and in subtropical and tropical regions. Moreover, both the temporal and spatial sensitivities to climate change were weak in the subtropical and tropical regions, where the contribution of climatic factors to vegetation distribution was also small. Overall, temperature sensitivity and its contribution to vegetation activity were positively associated in most regions. However, the regions where precipitation contributed substantially to vegetation activity were not necessarily also highly sensitive to changes in precipitation within the range of variation explored.

The current biorefineries yield lignin with inadequate fractionation for bioconversion, yet substantial changes of these biorefinery designs could jeopardize carbohydrate efficiency and increase capital costs. Here the authors resolve the dilemma by designing ‘plug-in processes of lignin’ to enable economic waste valorization.

Abstract A significant proportion of the land area of Heilongjiang Province, China, is composed of saline–alkaline soil, which severely inhibits maize growth. Although Trichoderma treatment is widely regarded as a promising strategy for improving the soil environment and promoting plant growth, the mechanism through which Trichoderma asperellum enhances maize resistance to saline–alkaline stress is not clear. In this study, we explored the effect of T. asperellum application at different concentrations to soil saline–alkaline environment on the seedlings of two maize cultivars, assessing the biochemical parameters related to oxidation resistance. Increasing spore densities of T. asperellum suspension effectively regulated the soil ion balance in the rhizosphere of maize seedlings, reduced the soil pH by 2.15–5.76% and sodium adsorption ratios by 22.70–54.13%, increased soil nutrient content and enzyme activity, and improved the soil environment for seedling growth. Additionally, T. asperellum treatment increased the maize seedling content of osmo-regulating substances and rate of glutathione:oxidised glutathione (43.86–88.25%) and ascorbate:oxidised ascorbate (25.26–222.32%) by affecting the antioxidant enzyme activity in the roots, increasing reactive oxygen species scavenging, and maintaining the osmotic balance and metabolic homeostasis under saline–alkaline stress. T. asperellum also improved the saline–alkaline tolerance of maize seedlings by improving the root growth characteristics. Moreover, results showed that Trichoderma applied at high concentration had the greatest effect. In conclusion, improvement in the saline–alkaline tolerance of maize seedlings by T. asperellum under saline–alkaline soil conditions may be achieved through diverse effects that vary among maize cultivars.

BackgroundNeuraxial analgesia is widely used to relieve labor pain; its effects on long-term neurodevelopment of offspring remain unclear. This study was designed to investigate the influence of maternal neuraxial labor analgesia on offspring mental development.MethodsThis was a predefined secondary analysis of a 2-year prospective longitudinal study. Nulliparous women with single-term cephalic pregnancy preparing for vaginal delivery self-selected neuraxial analgesia or not during labor. Mothers and their offspring were followed up 2 years later. children's mental development was assessed with the bayley scales of infant development. A multivariable logistic model was used to identify factors associated with below-average mental development (Mental Development Index

Abstract Background Cornell assessment of pediatric delirium (CAPD) showed advantage in diagnosis of pediatric delirium in Chinese critically ill patients. But its performance in surgical patients is still unclear. The present study was designed to validate the diagnostic performance of CAPD in surgical pediatric patients. Methods This is a prospective validation study. Pediatric patients who underwent selective surgery and general anesthesia were enrolled. Primary outcome was the incidence of delirium within postoperative three days. CAPD Chinese version was used to evaluate if the patient had delirium one time per day. At the meantime, a psychiatrist employed Diagnostic and Statistical Manual of Mental Disorders fifth edition to diagnose delirium, which was the “gold standard”, and the result was considered as reference standard. Sensitivity, specificity and area under receiver operating characteristic (ROC) curve were calculated to investigate the performance of CAPD. Results A total of 170 patients were enrolled. Median age was 4 years old. As diagnosed by psychiatrist, 23 (13.5 %) patients experienced at least one episode of delirium during the follow-up period. When diagnostic threshold was set at 9, CAPD showed the optimal sensitivity (87.0 %, 95 %CI 65.3 %-96.6 %) and specificity (98.0 %, 95 %CI 93.7 %-99.5 %) in comparison with other diagnostic thresholds. ROC analysis showed that CAPD was a good delirium assessment instrument with area under curve of 0.911 (95 % CI 0.812 to 1.000, P

Abstract. This review summarizes recent evidences regarding the potential influences of epidural labor analgesia (ELA) on the outcomes of neonates and children. Terms and relevant words including “ELA,” “ELA and neonatal outcomes,” “ELA and children's development,” and “ELA and children's neurocognitive development” were used to search articles published in PubMed database up to October 2019. Original articles and reviews regarding potential influences of ELA on neonates and children were identified. Relevant references of the selected articles were also screened. The anesthetics used during ELA can be absorbed, enter the fetus, and produce neonatal depression; however, these effects are less severe than those during systematic opioid analgesia. The impact of anesthetic exposure during ELA on children's neurodevelopment has not been fully studied, but would be mild if any. ELA increases the risk of intrapartum maternal fever; the latter may be harmful to neonatal outcomes. The use of ELA may increase birth injury by increasing instrumental delivery, although long-term adverse events are rare. On the other hand, ELA may reduce maternal depression and, thus, produce favorable effects on neurocognitive development in childhood; but evidences are still lacking in this aspect. ELA may produce both favorable and unfavorable effects on neonates and children. These effects should be discussed with parturient women before making decisions. The potential harmful effects should be carefully managed. The overall impacts of ELA on neonatal and children's outcomes need to be studied further.

Auxin regulates cell division and elongation of the primordial cells through its concentration and then shaped the plant architecture. Cell division and elongation form the internode of soybean and result in different plant heights and lodging resistance. Yet the mechanisms behind are unclear in soybean. To elucidate the mechanism of the concentration difference of auxin related to stem development in soybean, samples of apical shoot, elongation zone, and mature zone from the developing stems of soybean seedlings, Charleston, were harvested and measured for auxin concentration distributions and metabolites to identify the common underlying mechanisms responsible for concentration difference of auxin. Distribution of indole-3-acetic acid (IAA), indole-3-butyric acid (IBA), and methylindole-3-acetic acid (Me-IAA) were determined and auxin concentration distributions were found to have a complex regulation mechanism. The concentrations of IAA and Me-IAA in apical shoot were significantly different between elongation zone and mature zone resulting in an IAA gradient. Tryptophan dependent pathway from tryptamine directly to IAA or through indole-3-acetonitrile to IAA and from indole-3-propionic acid (IPA) to IAA were three primary IAA synthesis pathways. Moreover, some plant metabolites from flavonoid and phenylpropanoid synthesis pathways showed similar or reverse gradient and should involve in auxin homeostasis and concentration difference. All the data give the first insight in the concentration difference and homeostasis of auxin in soybean seedlings and facilitate a deeper understanding of the molecular mechanism of stem development and growth. The gathered information also helps to elucidate how plant height is formed in soybean and what strategy should be adopted to regulate the lodging resistance in soybean.

Abstract Background For bioethanol production from lignocellulosic biomass, phenolics derived from pretreatment have been generally considered as highly inhibitory towards enzymatic hydrolysis and fermentation. As phenolics are produced from lignin degradation during pretreatment, it is likely that the pretreatment will exert a strong impact on the structure of phenolics, resulting in varied levels of inhibition of the bioconversion process. Despite the extensive studies on pretreatment, it remains unclear how pretreatment process affects the properties of generated phenolics and how the inhibitory effect of phenolics from different pretreatment varies on enzymatic hydrolysis and fermentation. Results In this study, the structural properties of phenolic compounds derived from four typical pretreatment [dilute acid (DA), liquid hot water pretreatment (LHW), ammonia fiber expansion (AFEX) and alkaline pretreatment (AL)] were characterized, and their effect on both enzymatic hydrolysis and fermentation were evaluated. The inhibitory effect of phenolics on enzymatic hydrolysis followed the order: AFEX > LHW > DA > AL, while the inhibitory effect of phenolics on Zymomonas mobilis 8b strain fermentation followed the order: AL > LHW > DA > AFEX. Interestingly, this study revealed that phenolics derived from AFEX showed more severe inhibitory effect on enzymatic hydrolysis than those from the other pretreatments at the same phenolics concentrations (note: AFEX produced much less amount of phenolics compared to AL and DA), while they exhibited the lowest inhibitory effect on fermentation. The composition of phenolics from different pretreatments was analyzed and model phenolics were applied to explore the reason for this difference. The results suggested that the amide group in phenolics might account for this difference. Conclusions Pretreatment process greatly affects the properties of generated phenolics and the inhibitory effects of phenolics on enzymatic hydrolysis and fermentation. This study provides new insight for further pretreatment modification and hydrolysate detoxification to minimize phenolics-caused inhibition and enhance the efficiency of enzymatic hydrolysis and fermentation.

As the most abundant natural aromatic resource, lignin valorization will contribute to a feasible biobased economy. Recently, biological lignin valorization has been advocated since ligninolytic microbes possess proficient funneling pathways of lignin to valuable products. In the present study, the potential to convert an actual lignin stream into polyhydroxyalkanoates (PHAs) had been evaluated using ligninolytic genome-reduced Pseudomonas putida. The results showed that the genome-reduced P. putida can grow well on an actual lignin stream to successfully yield a high PHA content and titer. The designed fermentation strategy almost eliminated the substrate effects of lignin on PHA accumulation. Employing a fed-batch strategy produced the comparable PHA contents and titers of 0.35 g/g dried cells and 1.4 g/L, respectively. The molecular mechanism analysis unveiled that P. putida consumed more small and hydrophilic lignin molecules to stimulate cell growth and PHA accumulation. Overall, the genome-reduced P. putida exhibited a superior capacity of lignin bioconversion and promote PHA accumulation, providing a promising route for sustainable lignin valorization.

Microbial cell factories have been widely used in the production of various chemicals. Although synthetic biology is useful in improving the cell factories, adaptation is still widely applied to enhance its complex properties. Adaptation is an important strategy for enhancing stress tolerance in microbial cell factories. Adaptation involves gradual modifications of microorganisms in a stressful environment to enhance their tolerance. During adaptation, microorganisms use different mechanisms to enhance non-preferred substrate utilization and stress tolerance, thereby improving their ability to adapt for growth and survival. In this paper, the progress on the effects of adaptation on microbial substrate utilization capacity and environmental stress tolerance are reviewed, and the mechanisms involved in enhancing microbial adaptive capacity are discussed.

The sustainability and economic feasibility of modern biorefinery depend on the efficient processing of both carbohydrate and lignin fractions for value-added products. By mimicking the biomass degradation process in white-rote fungi, a tailored two-step fractionation process was developed to maximize the sugar release from switchgrass biomass and to optimize the lignin processability for bioconversion. Biomimicking biomass processing using Formic Acid: Fenton: Organosolv (F2O) and achieved high processability for both carbohydrate and lignin. Specifically, switchgrass pretreated by the F2O process had 99.6% of the theoretical yield for glucose release. The fractionated lignin was also readily processable by fermentation via Rhodococcus opacus PD630 with a lipid yield of 1.16 g/L. Scanning electron microscope analysis confirmed the fragmentation of switchgrass fiber and the cell wall deconstruction by the F2O process. 2D-HSQC NMR further revealed the cleavage of aryl ether linkages (β-O-4) in lignin components. These results revealed the mechanisms for efficient sugar release and lignin bioconversion. The F2O process demonstrated effective mimicking of natural biomass utilization system and paved a new path for improving the lignin and carbohydrate processability in next generation lignocellulosic biorefinery.

Black soybean seed coat extract (BSSCE) is a rich source of anthocyanins. This study was aimed at investigating the effects of BSSCE on Lead (Pb) toxicity. Here using Drosophila melanogaster, we show that defects caused by Pb was significantly ameliorated by BSSCE supplementation. Further studies showed that BSSCE attenuated Pb-induced systemic iron deficiency by modulating genes involved in iron absorption in the midgut. Additionally, BSSCE eliminated the reactive oxygen species (ROS) generated by Pb in the midgut through improving the antioxidant defense system. The protection of BSSCE against Pb was suppressed when dietary iron was restricted. These results suggest that promotion of iron absorption plays a dominant role in protective effects of BSSCE against Pb. The findings indicated that black soybean might be a promising functional food for preventing Pb toxicity or other iron deficiency related diseases, providing novel insight into mechanisms of antioxidants in protecting against heavy metal induced impairment.

Background: How the oncoprotein epidermal growth factor receptor (EGFR) evades proteolytic degradation and accumulates in non-small cell lung cancer (NSCLC) remains unclear, and ubiquitin pathway genes (UPGs) that are critical to NSCLC needs to be systematically identified. Methods: A total of 696 UPGs (including E1, E2, E3, and deubiquitinases) were silenced by small interfering RNA (siRNA) library in NSCLC cells, the candidates were verified, and their significance was evaluated in patients with NSCLC. The effects of a candidate gene on EGFR were investigated in vitro and in vivo. Findings: We report 31 candidates that are required for cell proliferation, with the E2 ubiquitin conjugase CDC34 as the most significant one. CDC34 is elevated in tumor tissues in 76 of 114 (66.7%) NSCLCs and inversely associated with prognosis, is higher in smoker patients than nonsmoker patients, and is induced by tobacco carcinogens in normal human lung epithelial cells. Forced expression of CDC34 promotes, whereas knockdown of CDC34 inhibits, NSCLC cell proliferation in vitro and in vivo. CDC34 competes with c-Cbl to bind Y1045 to inhibit polyubiquitination and degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del (exon 19)-driven lung tumor growth in mouse models, knockdown of CDC34 significantly inhibits tumor formation. Interpretation: These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to stabilize substrates, and CDC34 represents an attractive therapeutic target for NSCLCs. Funding: National Key Research and Development Program of China, National Natural Science Foundation of China, and the CAMS Innovation Fund for Medical Sciences. Keywords: Lung cancer, Ubiquitin pathway genes, CDC34, EGFR, c-Cbl

The increasing incidence of multidrug resistant bacterial infection renders an urgent need for the development of new antibiotics. To develop small molecules disturbing FtsZ activity has been recognized as promising approach to search for antibacterial of high potency systematically. Herein, a series of novel quinolinium derivatives were synthesized and their antibacterial activities were investigated. The compounds show strong antibacterial activities against different bacteria strains including MRSA, VRE and NDM-1 Escherichia coli. Among these derivatives, a compound bearing a 4-fluorophenyl group (A2) exhibited a superior antibacterial activity and its MICs to the drug-resistant strains are found lower than those of methicillin and vancomycin. The biological results suggest that these quinolinium derivatives can disrupt the GTPase activity and dynamic assembly of FtsZ, and thus inhibit bacterial cell division and then cause bacterial cell death. These compounds deserve further evaluation for the development of new antibacterial agents targeting FtsZ.

Abstract Background Lignin valorization has recently been considered to be an essential process for sustainable and cost-effective biorefineries. Lignin represents a potential new feedstock for value-added products. Oleaginous bacteria such as Rhodococcus opacus can produce intracellular lipids from biodegradation of aromatic substrates. These lipids can be used for biofuel production, which can potentially replace petroleum-derived chemicals. However, the low reactivity of lignin produced from pretreatment and the underdeveloped fermentation technology hindered lignin bioconversion to lipids. In this study, combinatorial pretreatment with an optimized fermentation strategy was evaluated to improve lignin valorization into lipids using R. opacus PD630. Results As opposed to single pretreatment, combinatorial pretreatment produced a 12.8–75.6% higher lipid concentration in fermentation using lignin as the carbon source. Gas chromatography–mass spectrometry analysis showed that combinatorial pretreatment released more aromatic monomers, which could be more readily utilized by lignin-degrading strains. Three detoxification strategies were used to remove potential inhibitors produced from pretreatment. After heating detoxification of the lignin stream, the lipid concentration further increased by 2.9–9.7%. Different fermentation strategies were evaluated in scale-up lipid fermentation using a 2.0-l fermenter. With laccase treatment of the lignin stream produced from combinatorial pretreatment, the highest cell dry weight and lipid concentration were 10.1 and 1.83 g/l, respectively, in fed-batch fermentation, with a total soluble substrate concentration of 40 g/l. The improvement of the lipid fermentation performance may have resulted from lignin depolymerization by the combinatorial pretreatment and laccase treatment, reduced inhibition effects by fed-batch fermentation, adequate oxygen supply, and an accurate pH control in the fermenter. Conclusions Overall, these results demonstrate that combinatorial pretreatment, together with fermentation optimization, favorably improves lipid production using lignin as the carbon source. Combinatorial pretreatment integrated with fed-batch fermentation was an effective strategy to improve the bioconversion of lignin into lipids, thus facilitating lignin valorization in biorefineries.

New generation of antibacterial agents are urgently needed in order to fight the emergence of multidrug-resistant bacteria. FtsZ is currently identified as a promising target for new types of antimicrobial compounds development because of its conservative characteristics and its essential role played in bacterial cell division. In the present study, the antibacterial activity of a series of benzofuroquinolinium derivatives was investigated. The results show that the compounds possess potent antibacterial activity against drug resistant pathogens including MRSA, VREF and NDM-1 Escherichia coli. Biological studies reveal that the compound is an effective inhibitor that is able to suppress FtsZ polymerization and GTPase activity and thus stopping the cell division and causing cell death. More importantly, this series of compounds shows low cytotoxicity on mammalian cells and therefore they could be new chemotypes for the development of new antibacterial agents targeting the cell-division protein FtsZ.

Acids and alkalis are considered important catalysts in biomass pretreatment, which is essential to overcome the recalcitrance of lignocellulose for sugar release. In this study, the effects of various chemicals and temperatures on the pretreatment and subsequent enzymatic hydrolysis of wheat straw were investigated. The conversions of glucan and xylan during pretreatment and enzymatic hydrolysis were examined. The temperature and different ions in pretreatment govern the dissociation constant and hydrogen ion concentration. Due to higher dissociation at higher temperature, weak acids and weak alkalis can produce high glucose yields, similar to strong acids and alkalis. The concept of modified combined severity for weak acid pretreatment was explored. The pH value and real combined severity of weak acids at reaction temperatures were estimated according to xylan recovery during pretreatment. Glucose yield in enzymatic hydrolysis is mainly decided by xylan recovery for acidic pretreatment and by total content of xylan and acid-insoluble-lignin in solids for alkaline pretreatment.

Lectin-like oxidized low-density lipoprotein-1 (LOX-1) is the major receptor for oxidized low density lipoprotein (ox-LDL) uptake in human umbilical vein endothelial cells (HUVECs). Previously, we found that rapamycin inhibited ox-LDL accumulation in HUVECs, and this effect was related to its role in increasing the activity of autophagy-lysosome pathway. In this study, we determined whether rapamycin could also reduce ox-LDL uptake in HUVECs and investigated the underlying signaling mechanisms.Flow cytometry and live cell imaging showed that rapamycin reduced Dil-ox-LDL accumulation in HUVECs. Furthermore, rapamycin reduced the ox-LDL-induced increase in LOX-1 mRNA and protein levels. Western blotting showed that rapamycin inhibited mechanistic target of rapamycin (mTOR), p70s6k and IκBα phosphorylation triggered by ox-LDL. Flow cytometry implied that mTOR, NF-κB knockdown and NF-κB inhibitors significantly reduced Dil-ox-LDL uptake. Moreover, immunofluorescent staining showed that rapamycin reduced the accumulation of p65 in the nucleus after ox-LDL treatment for 30 h. mTOR knockdown decreased LOX-1 protein production and IκBα phosphorylation induced by ox-LDL. NF-κB knockdown and NF-κB inhibitors reduced LOX-1 protein production, but did not inhibit mTOR phosphorylation stimulated by ox-LDL.These findings demonstrate that rapamycin reduce mTOR phosphorylation and subsequently inhibit NF-κB activation and suppresses LOX-1, resulting in a reduction in ox-LDL uptake in HUVECs.

Lead (Pb) exposure has been implicated in the impairment of synaptic plasticity in the developing hippocampus, but the mechanism remains unclear. Here, we investigated whether developmental lead exposure affects the dendritic spine formation through Wnt signaling pathway in vivo and in vitro. Sprague-Dawley rats were exposed to lead throughout the lactation period and Golgi-Cox staining method was used to examine the spine density of pyramidal neurons in the hippocampal CA1 area of rats. We found that lead exposure significantly decreased the spine density in both 14 and 21 days-old pups, accompanied by a significant age-dependent decline of the Wnt7a expression and stability of its downstream protein (β-catenin). Furthermore, in cultured hippocampal neurons, lead (0.1 and 1 µM lead acetate) significantly decreased the spine density in a dose-dependent manner. Exogenous Wnt7a application attenuated the decrease of spine density and increased the stability of the downstream molecules in Wnt signaling pathway. Together, our results suggest that lead has a negative impact on spine outgrowth in the developing hippocampus through altering the canonical Wnt pathway.

In the title complex, [Mn(N3)2(C8H8N6)2], the complete molecule is generated by the application of twofold symmetry, and is in a distorted octahedral environment, coordinated by four N atoms of two bidentate 6-(pyridin-2-yl)-1,3,5-triazine-2,4-diamine ligands and two N atoms from two azide anions. The two chelated 6-(pyridin-2-yl)-1,3,5-triazine-2,4-diamine ligands form a dihedral angle 74.75 (5)°. The mononuclear molecules are alternatively linked into layers parallel to the ac plane via N—H...N hydrogen bonds. Adjacent layers are connected into a three-dimensional supramolecular framework by futher N—H...N hydrogen-bonding interactions.

In the title complex, {[Cd(C9H8NO4)2(H2O)2]·4H2O}n, the CdII atom (site symmetry 2) is coordinated by six O atoms from four crystallographically related 1-(1,2-dicarboxylate)pyridin-1-ium ligands (L) and from two water molecules in a distorted octahedral geometry. Paired L ligands connect CdII atoms into a chain motif parallel to [001], which is further interlinked by O—H...O hydrogen bonds into a three-dimensional supramolecular net.

A sustainable lignin bioconversion depends on the exploitation of the inherent aromaticity of lignin for high-value aromatic products. However, the microbial valorization of lignin is hindered by the lack of established bioconversion routes or the inefficient heterologous expression of key enzymes. Here, an efficient biological lignin conversion route was constructed in a microbial cell factory by tapping the inherent aromaticity of lignin to produce aromatic natural compounds such as homoeriodictyol. The heterologous biosynthesis pathways were successfully constructed to convert lignin-derived monomers to homoeriodictyol in Saccharomyces cerevisiae. The implementation of combinatorial regulating strategies resulted in enhanced CoA supply, suppression of branch pathways, and upregulation of the rate-liming enzymes, which increased the titer of homoeriodictyol by a remarkable 22.5-fold. After that, engineering cofactor supply and recycling led to a substantial 95% increase in homoeriodictyol production. The rational design and modification of the heterologous rate-limiting enzymes helped achieve substantial improvement in the homoeriodictyol yield. All these strategies together enabled the record homoeriodictyol titer of 3.2 mmol l-1 from lignin derivatives by S. cerevisiae. Overall, such an innovative conversion route meets the atom-economy concept by converting lignin derivatives into valuable flavonoids, paving a green, sustainable way for both the valorization of lignin and the production of aromatic natural products. [ABSTRACT FROM AUTHOR]