Neonatal IL-4 Over-Exposure is Accompanied by Macrophage Accumulation in Dura Mater After Instant Anti-inflammatory Cytokine Response in CSF.

Multiple studies have shown that clinical events resulting into neonatal IL-4 over-exposure, such as asthma in early life and food allergy, were associated with brain damage and that the neuroinflammation induced by them might lead to cognitive impairments, anxiety-/depressive-like behaviors. IL-4 is the most major elevated cytokine in periphery when these clinical events occur and peripheral IL-4 level positively correlates with the severity of those events. Our previous studies have verified that neonatal IL-4 over-exposure induced a delayed neuroinflammatory damage in rodents, which might have adverse implications for brain development and cognition. Neuroinflammation in brain parenchyma is often accompanied by changes in CSF cytokines levels. However, whether the cytokines levels in CSF change after neonatal IL-4 over-exposure is unknown. Here, we found a delayed pro-inflammatory cytokines response (higher IL-6, IL-1ß and, TNF levels) in both hippocampus and CSF after an instant anti-inflammatory cytokine response in IL-4 over-exposed rats. Moreover, the pro-inflammatory cytokines response appeared earlier in CSF than in hippocampus. The level of each of the pro-inflammatory cytokines in CSF positively correlated with that in hippocampus at the age of postnatal day 42. More microglia numbers/activation and higher M-CSF level in the hippocampus in IL-4 over-exposed rats were also observed. Furthermore, there were more macrophages with inflammatory activation in dural mater of IL-4 over-exposed rats. In sum, neonatal IL-4 over-exposure in rats induces delayed inflammation in CSF, suggesting CSF examination may serve as a potential method in predicting delayed neuroinflammation in brain following neonatal IL-4 over-exposure.

Analysis of minimal levator ani hiatus area based on MRI in female adults without pelvic floor dysfunction at different age groups.

PURPOSE: To investigate the association of minimal levator ani hiatus area with age in female adults without pelvic floor dysfunction. METHODS: 532 female subjects aged 18 ~ 90 years without pelvic floor dysfunction, divided into four groups (Group A, 18 ~ 29 years old; Group B, 30 ~ 39 years old; Group C, 40 ~ 49 years old; Group D, ≥ 50 years old) based on age, underwent traditional pelvic two-dimensional (2D) T2-weighted imaging (T2WI) axial to the body (AxB) for measuring the minimal levator ani hiatus area. 39 female volunteers were re-recruited to undergo both traditional pelvic 2D T2WI AxB and three-dimensional (3D) T2WI. An axial plane parallel to the direction of the puborectalis muscle (AxPRM) was acquired based on 3D T2WI. The difference of levator ani hiatus area measured on AxB and AxPRM images in 39 female volunteers was compared by one-sample t test, to verify if minimal levator ani hiatus area can be acquired on the traditional pelvic 2D T2WI AxB images. Spearman analysis evaluated the association of minimal levator ani hiatus area with age and the rank-sum test analyzed the area differences among four age groups. RESULTS: Female age was positively correlated with minimal levator ani hiatus area (r = 0.23; p < 0.001). The minimal levator ani hiatus areas of 532 subjects were: 15.17 ± 1.77 cm2 in Group A, 15.52 ± 2.21 cm2 in Group B, 16.03 ± 2.16 cm2 in Group C, and 16.40 ± 2.10 cm2 in Group D. ANOVA showed significant statistical differences among four age groups (F = 7.519, p < 0.0001). Significant differences in minimal levator ani hiatus areas were found between Group A and Group C (p = 0.0491), Group A and Group D (p = 0.0007), and Group B and Group D (p < 0.001). There was no statistical difference in minimal levator ani hiatus areas measured on AxB and AxPRM images in 39 female volunteers (p = 0.1000). There were no statistical difference in minimal levator ani hiatus areas between nulliparous and multiparous group for each age group (all p > 0.05). CONCLUSIONS: Based on a large sample, this study summarized the minimum levator ani hiatus area of female adults without pelvic floor dysfunction in different age groups. We found significant differences among different age groups. In addition, a positive correlation was found between age and the minimum levator ani hiatus area. These findings can provide reference criteria for diagnosing pelvic organ prolapse in female adults of different age groups.

Serodiagnosis of Abdominal Abscess Caused by Burkholderia pseudomallei: Case Report and Literature Review.

Burkholderia pseudomallei, the causative agent of melioidosis can be responsible for a wide spectrum of clinical manifestations and heterogeneous prognoses, with a high mortality in the acute onset. We report a case of a deep abdominal abscess with sepsis secondary to melioidosis in a young farmer from a non-high-risk population. Emergency medical treatment was administered according to the detection of serum antibodies against Hcp1, the results of which provided etiological evidence of B. pseudomallei infection for the timely and properly antimicrobial therapy in the absence of direct evidence of melioidosis. To our knowledge, this is the first reported case of serodiagnosis of acute exacerbation of melioidosis in China.

Oral exposure to an acceptable daily intake dose of aspartame induced a delayed proinflammatory cytokine response in the cerebrospinal fluid of rats.

This study aimed to investigate the effect of exposure to aspartame (ASP) at safe levels on proinflammatory cytokines in the cerebrospinal fluid (CSF) of rats. Sprague Dawley rats were sacrificed after 1, 2, 4 or 8 week(s) of continuous exposure to ASP (40 mg/kg body weight). Serum, CSF and brain tissue samples were prepared, and the levels of the IL-1ß, IL-6 and TNF-α were analyzed by ELISA. In serum, the levels of all three cytokines showed a two-phase alteration, a decrease followed by an increase in the ASP group. In the brain, their levels increased from the second or fourth week compared with the control group. In CSF, the levels of these cytokines showed a similar change to that in brain tissue, but the increase appeared at a later time point. For each cytokine, there was a significant positive correlation between its levels in serum, brain tissue and CSF. This is the first discovery that ASP exposure increased the levels of proinflammatory cytokines in CSF in rats, which emerged later than in blood and brain tissue. This study suggests the necessity of conducting related clinical studies to evaluate potential neuroinflammatory effects induced by chronic ASP exposure through CSF analysis.

Blocking coprophagy increases the levels of inflammation and depression in healthy mice as well as mice receiving fecal microbiota transplantation from disease model mice donors.

Rodents have been extensively used as animal models in microbiome studies. However, all rodents have a habitual nature called coprophagy, a phenomenon that they self-reinoculate feces into their gastrointestinal tract. Recent studies have shown that blocking coprophagy can alter rodents' diversity of gut microbiota, metabolism, neurochemistry, and cognitive behavior. However, whether rodents' coprophagy behavior affects the levels of inflammation and depression is unclear. In order to address this problem, we first blocked coprophagy in healthy mice. It displayed an increase in the levels of depression, verified by depressive-like behaviors and mood-related indicators, and inflammation, verified by the increased levels of the pro-inflammatory cytokine, in coprophagy-blocked mice. Furthermore, we transplanted fecal microbiota from chronic restraint stress (CRS) depression model mice and lipopolysaccharide (LPS) inflammation model mice to healthy recipient mice, respectively. It showed that the disease-like phenotypes in the coprophagy-blocked group were worse than those in the coprophagy-unblocked group, including severer depressive symptoms and higher levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α and IFN-γ) in serum, prefrontal cortex (PFC), and hippocampus (HIP). These findings showed that blocking coprophagy in mice not only increased the levels of inflammation and depression in healthy mice but also aggravated inflammation and depression induced by fecal microbiota from disease donors. The discovery may provide a vital reference for future research involving FMT in rodents.

MicroRNA-31 induced by Fusobacterium nucleatum infection promotes colorectal cancer tumorigenesis.

Persistent Fusobacterium nucleatum infection is associated with the development of human colorectal cancer (CRC) and promotes tumorigenicity, but the underlying mechanisms remain unclear. Here, we reported that F. nucleatum promoted the tumorigenicity of CRC, which was associated with F. nucleatum-induced microRNA-31 (miR-31) expression in CRC tissues and cells. F. nucleatum infection inhibited autophagic flux by miR-31 through inhibiting syntaxin-12 (STX12) and was associated with the increased intracellular survival of F. nucleatum. Overexpression of miR-31 in CRC cells promoted their tumorigenicity by targeting eukaryotic initiation factor 4F-binding protein 1/2 (eIF4EBP1/2), whereas miR-31 knockout mice were resistant to the formation of colorectal tumors. In conclusion, F. nucleatum, miR-31, and STX12 form a closed loop in the autophagy pathway, and continuous F. nucleatum-induced miR-31 expression promotes the tumorigenicity of CRC cells by targeting eIF4EBP1/2. These findings reveal miR-31 as a potential diagnostic biomarker and therapeutic target in CRC patients with F. nucleatum infection.

Single-cell sequencing of immune cells after marathon and symptom-limited cardiopulmonary exercise.

Vigorous-intensity leisure-time physical activity, such as marathon, has become increasingly popular, but its effect on immune functions and health is poorly understood. Here, we performed scRNA-seq analysis of peripheral blood mononuclear cells (PBMCs) after a bout of symptom-limited cardiopulmonary exercise (CPX) test or marathon. Time-series single-cell analysis revealed the detailed series of landscapes of immune cells in response to short and long vigorous-intensity activities. Reduction of effective T cells was observed with the cell migration and motility pathways enriched in circulation following marathon. Baseline values of PBMCs abundance were reached around 1 h after CPX and 24 h following marathon, but longer time was required for expression recovery of cytotoxicity genes. The ratio of effector/naive T cells was found to change uniformly among the participants and could serve as a better indicator for exercise intensity than the CD4+/CD8+ T cell ratio. Moreover, we identified time-dependent monocyte state transitions after marathon.

A Model of Long-Term Ventricular Fibrillation in Isolated Rat Hearts.

Ventricular fibrillation (VF) is a fatal arrhythmia with a high incidence in cardiac patients, but VF arrest under perfusion is a neglected method of intraoperative arrest in the field of cardiac surgery. With recent advances in cardiac surgery, the demand for prolonged VF studies under perfusion has increased. However, the field lacks simple, reliable, and reproducible animal models of chronic ventricular fibrillation. This protocol induces long-term VF through alternating current (AC) electrical stimulation of the epicardium. Different conditions were used to induce VF, including continuous stimulation with a low or high voltage to induce long-term VF and stimulation for 5 min with a low or high voltage to induce spontaneous long-term VF. The success rates of the different conditions, as well as the rates of myocardial injury and recovery of cardiac function, were compared. The results showed that continuous low-voltage stimulation induced long-term VF and that 5 min of low-voltage stimulation induced spontaneous long-term VF with mild myocardial injury and a high rate of recovery of cardiac function. However, the low-voltage, continuously stimulated long-term VF model had a higher success rate. High-voltage stimulation provided a higher rate of VF induction but showed a low defibrillation success rate, poor recovery of cardiac function, and severe myocardial injury. On the basis of these results, continuous low-voltage epicardial AC stimulation is recommended for its high success rate, stability, reliability, reproducibility, low impact on cardiac function, and mild myocardial injury.

One-pot RPA-Cas12a assay for instant and visual detection of Burkholderia pseudomallei.

Burkholderia pseudomallei is the causative agent of melioidosis, a potentially life-threatening infectious disease, and poses public health risks in endemic areas. Due to the high mortality, intrinsic antibiotic resistance, and atypical manifestations, establishing a rapid, accurate, and sensitive identification of B. pseudomallei enables earlier diagnosis, proper treatments, and better outcomes of melioidosis. Herein, we present a One-Pot CRISPR-integrated assay for Instant and Visual Detection (termed OPC-IVD) of B. pseudomallei. The integration of recombinase polymerase amplification and CRISPR-Cas12a recognition-activated trans-cleavage, achieved a true all-in-one single-tube reaction system, initiating the amplification and cleavage simultaneously, which realized a facile sample-to-answer assay. This approach could be performed with simplified DNA extraction and completed around 30 min by holding the reaction tube in the hand. The detection limit of our OPC-IVD was determined to be 2.19 copy/uL of plasmid DNA, 12.5 CFU/mL of B. pseudomallei, and 61.5 CFU/mL of bacteria in spiked blood samples, respectively. Furthermore, the introduction of internal amplification control effectively reduced the occurrence of false negatives, which was incorporated in the reaction system, and amplified simultaneously with the target and read by naked eyes. The assay exhibited 100% accuracy when evaluated in clinical isolates and samples. The streamlined workflow of our OPC-IVD of B. pseudomallei enables a field-deployable, instrument-free, and ultra-fast approach that can be utilized by non-expert personnel in the field of molecular diagnosis of melioidosis especially in under-resourced setting.

Activated partial thromboplastin time as a potential biomarker for the diagnosis of tuberculous pleural effusion.

BACKGROUND: The aim of this study was to explore the difference in activated partial thromboplastin time (APTT) levels in patients with tuberculous and non-tuberculous pleural effusion (TPE and non-TPE) and its possible mechanism to provide a new direction for the diagnosis of pleural effusion (PE). METHODS: A total of 61 patients diagnosed with tuberculous pleurisy with pleural effusion at Shunde Hospital of Southern Medical University from July 2013 to September 2020 were selected as the observation group (tuberculosis group). Another 89 patients (45 with malignant pleural effusion (MPE) and 44 with parapneumonic pleural effusion (PPE) composed the control group. The adenosine deaminase (ADA) level in pleural fluid and plasma APTT level were measured in the two groups. RESULTS: The levels of APTT and ADA in the TPE group were significantly higher than the control group, and were 40.03 (37.00, 42.60) (s) and 55.00 (47.00, 69.25) (U/L) for TPE, 29.50 (25.45, 34.20) (s) and 11.90 (9.15, 19.05) (U/L) for malignant pleural effusion (MPE) and 31.35 (27.43, 35.76) (s) and 15.15 (7.40, 35.00) (U/L) for parapneumonic pleural effusion (PPE), respectively. CONCLUSIONS: The level of plasma APTT has certain significance in differentiating tuberculous pleural effusion from nontuberculous pleural effusion.

A dish-like molecular architecture for dynamic ultralong room-temperature phosphorescence through reversible guest accommodation.

Developing dynamic organic ultralong room-temperature phosphorescent (URTP) materials is of practical importance in various applications but remains a challenge due to the difficulty in manipulating aggregate structures. Herein, we report a dish-like molecular architecture via a bottom-up way, featuring guest-responsive dynamic URTP. Through controlling local fragment motions in the molecular architecture, fascinating dynamic URTP performances can be achieved in response to reversible accommodation of various guests, including solvents, alkyl bromides and even carbon dioxide. Large-scale regulations of phosphorescence lifetime (100-fold) and intensity (10-fold) can be realized, presenting a maximum phosphorescence efficiency and lifetime of 78.8% and 483.1 ms, respectively. Moreover, such a dish-like molecular architecture is employed for temperature-dependent multiple information encryption and visual identification of linear alkyl bromides. This work can not only deepen our understanding to construct multifunctional organic aggregates, but also facilitate the design of high-performance dynamic URTP materials and enrich their practical applications.

Fusobacterium nucleatum induces excess methyltransferase-like 3-mediated microRNA-4717-3p maturation to promote colorectal cancer cell proliferation.

Fusobacterium nucleatum infection plays vital roles in colorectal cancer (CRC) progression. Overexpression of microRNA-4717-3p (miR-4717) was reported to be upregulated in F. nucleatum positive CRC tissues, however, the underlying mechanism is unknown. In this study, we found that miR-4717 promoted CRC cell proliferation in vitro and growth of CRC in vivo following F. nucleatum infection. MicroRNA-4717 suppressed the expression of mitogen-activated protein kinase kinase 4 (MAP2K4), a tumor suppressor, by directly targeting its 3'-UTR. Furthermore, we confirmed that methyltransferase-like 3 (METTL3)-dependent m6 A methylation could methylate primary (pri)-miR-4717, which further promoted the maturation of pri-miR-4717, and METTL3 positively regulated CRC cell proliferation through miR-4717/MAP2K4 pathways. In conclusion, F. nucleatum-induced miR-4717 excessive maturation through METTL3-dependent m6 A modification promotes CRC cell proliferation, which provides a potential therapeutic target and diagnostic biomarker for CRC.

Latitudinal and longitudinal regulation of tissue macrophages in inflammatory diseases.

Macrophages are dominant innate immune cells. They demonstrate remarkable heterogeneity and plasticity that are essential for homeostasis and host defense. The heterogeneity of tissue macrophages is shaped by the ontogeny, tissue factors, and environmental signals, a pattern in a tissue-associated latitudinal manner. At the same time, macrophages have long been considered as mainly plastic cells. These cells respond to stimulation quickly and in a stimulus-specific way by utilizing a longitudinal cascaded activation, including coordination of signal transducer, epigenetic elements, and transcription factors, conclusively determine the macrophage phenotypes and functions. With the development of cutting-edge technologies, such as fate-mapping, single-cell transcriptomics, ipsc platform, nanotherapeutic materials, etc., our understanding of macrophage biology and the roles in the pathogenesis of diseases is much advanced. This review summarizes recent progress on the latitudinal and longitudinal regulation of tissue macrophages in inflammatory diseases. The latitudinal regulation covers the tissue macrophage origins, tissue factors, and environmental signals, reflecting the macrophage heterogeneity. The longitudinal regulation focuses on how multiple factors shape the phenotypes and functions of macrophage subsets to gain plasticity in inflammatory diseases (i.e., inflammatory bowel disease). In addition, how to target macrophages as a potential therapeutic approach and cutting edge-technologies for tissue macrophage study are also discussed in this review.

The Diagnostic Value of the Combined 3D Pseudo-Continuous Arterial Spin Labeling and Diffusion Kurtosis Imaging in Patients With Binswanger's Disease.

Background and Purpose: The clinical diagnosis of Binswanger's disease (BD), a chronic progressive form of subcortical vascular dementia, remains challenging. 3D pseudo-continuous arterial-spin-labeling (pcASL) and diffusion kurtosis imaging (DKI) can quantitatively reveal the microcirculation changes and heterogeneity of white matter (WM), respectively. We thus aimed to determine the diagnostic value of the combined 3D-pcASL and DKI in BD. Materials and Methods: A total of 35 patients with BD and 33 healthy controls underwent 3D-ASL and DKI experiments. The perfusion parameter of cerebral blood flow (CBF), diffusion parameters of fractional anisotropy (FA), mean/axial/radial diffusivity (MD/Da/Dr), and kurtosis parameters of anisotropy fraction of kurtosis (FAk) and mean/axial/radial kurtosis MK/Ka/Kr were obtained to quantitatively measure the parametric distributions of functional brain subregions. One-way analysis of variance and post hoc t-test were applied to explore the different distributions of DKI/ASL-derived parameters among brain subregions of BD. In addition, all region-specific DKI/ASL parameters were separately analyzed in Pearson correlation analysis to investigate the relationship with Mini-Mental State Examination (MMSE), a typical clinical scale for cognitive function assessment in patients with BD. Results: FA/FAk/MK/Ka/Kr was significantly declined in all WM hyperintensities (WMHs) of BD compared with healthy controls, while the corresponding MD/Da/Dr was significantly increased (all p < 0.005). In addition, significant changes, similar to the WMHs of patients with BD, were also observed in almost all DKI parameters in WM normal areas and genu/splenium of the corpus callosum (GCC/SCC) in BD (p < 0.005). Finally, CBF was significantly reduced in all of the above regions we measured in patients with BD (p < 0.005). For patients with BD, MMSE showed a negative correlation with MD/Da in thalamus (r = -0.42/-0.58; p < 0.05), and a positive correlation with CBF in PWM/TWM (r = 0.49/0.39; p < 0.05). Using receiver operating characteristic (ROC) analysis, FA/FAk/Kr in GCC, CBF/FA/Dr/FAk in SCC, MD/Da/Ka in thalamus, and the combined FA/MD/Dr/CBF in TWM showed high accuracy [area under the curves (AUCs) 0.957/0.946/0.942/0.986] in distinguishing patients with BD from healthy controls. Conclusion: We found that combined DKI and 3D-ASL are helpful in diagnosing patients with BD, especially with FA, MD, Dr, and CBF in the temporal WM region. Additionally, the kurtosis parameters of DKI can sensitively monitor the potentially damaged WM areas in patients with BD patients, adding complementary clinical value.

Long non-coding RNA EVADR induced by Fusobacterium nucleatum infection promotes colorectal cancer metastasis.

Both Fusobacterium nucleatum (F. nucleatum) and long non-coding RNA (lncRNA) EVADR are associated with colorectal cancer (CRC), but their relationship with CRC metastasis and the mechanisms by which EVADR promotes CRC metastasis are poorly understood. Here, we report that F. nucleatum promotes colorectal cancer cell metastasis to the liver and lung and that it can be detected in CRC-metastasis colonization in mouse models. Furthermore, F. nucleatum upregulates the expression of EVADR, which can increase the metastatic ability of CRC cells in vivo and in vitro. Mechanistically, elevated EVADR serves as a modular scaffold for the Y-box binding protein 1 (YBX1) to directly enhance the translation of epithelial-mesenchymal transition (EMT)-related factors, such as Snail, Slug, and Zeb1. These findings suggest that EVADR induced by F. nucleatum promotes colorectal cancer metastasis through YBX1-dependent translation. The EVADR-YBX1 axis may be useful for the prevention and treatment of patients with F. nucleatum-associated CRC metastasis.

Development of machine learning models for mortality risk prediction after cardiac surgery.

Background: We developed machine learning models that combine preoperative and intraoperative risk factors to predict mortality after cardiac surgery. Methods: Machine learning involving random forest, neural network, support vector machine, and gradient boosting machine was developed and compared with the risk scores of EuroSCORE I and II, Society of Thoracic Surgeons (STS), as well as a logistic regression model. Clinical data were collected from patients undergoing adult cardiac surgery at the First Medical Centre of Chinese PLA General Hospital between December 2008 and December 2017. The primary outcome was post-operative mortality. Model performance was estimated using several metrics, including sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC). The visualization algorithm was implemented using Shapley's additive explanations. Results: A total of 5,443 patients were enrolled during the study period. The mean EuroSCORE II score was 3.7%, and the actual in-hospital mortality rate was 2.7%. For predicting operative mortality after cardiac surgery, the AUC scores were 0.87, 0.79, 0.81, and 0.82 for random forest, neural network, support vector machine, and gradient boosting machine, compared with 0.70, 0.73, 0.71, and 0.74 for EuroSCORE I and II, STS, and logistic regression model. Shapley's additive explanations analysis of random forest yielded the top-20 predictors and individual-level explanations for each prediction. Conclusions: Machine learning models based on available clinical data may be superior to clinical scoring tools in predicting postoperative mortality in patients following cardiac surgery. Explanatory models show the potential to provide personalized risk profiles for individuals by accounting for the contribution of influencing factors. Additional prospective multicenter studies are warranted to confirm the clinical benefit of these machine learning-driven models.

Prognostic nutritional index and systemic immune-inflammation index are prognostic biomarkers for non-small-cell lung cancer brain metastases.

Aim: This research aimed to elucidate the prognosis values of prognostic nutritional index (PNI) and systemic immune-inflammation index (SII) and clinical characteristics in NSCLC patients with brain metastases (BM) underwent radiotherapy. Materials & methods: Cut-off points of hematological indicators were determined by receiver operating characteristic curve. Overall survival was evaluated by Kaplan-Meier method and Cox proportional hazards model. Results: We retrospectively analyzed 214 patients from January 2009 to December 2018. The result demonstrated the independent prognostic values of PNI (hazard ratio: 0.600; p = 0.004) and SII (hazard ratio: 1.486; p = 0.019). The remaining clinicopathologic factors, including brain radiotherapy modality, smoking history, numbers of brain metastases, intracranial symptoms and Radiation Therapy Oncology Group - recursive partitioning analysis, were independently related to survival (p < 0.05). Conclusion: PNI and SII could be critical prognostic indicators for NSCLC patients with BM.

Life Cycle Greenhouse Gas Emissions for Last-Mile Parcel Delivery by Automated Vehicles and Robots.

Increased E-commerce and demand for contactless delivery during the COVID-19 pandemic have fueled interest in robotic package delivery. We evaluate life cycle greenhouse gas (GHG) emissions for automated suburban ground delivery systems consisting of a vehicle (last-mile) and a robot (final-50-feet). Small and large cargo vans (125 and 350 cubic feet; V125 and V350) with an internal combustion engine (ICEV) and battery electric (BEV) powertrains were assessed for three delivery scenarios: (i) conventional, human-driven vehicle with human delivery; (ii) partially automated, human-driven vehicle with robot delivery; and (iii) fully automated, connected automated vehicle (CAV) with robot delivery. The robot's contribution to life cycle GHG emissions is small (2-6%). Compared to the conventional scenario, full automation results in similar GHG emissions for the V350-ICEV but 10% higher for the V125-BEV. Conventional delivery with a V125-BEV provides the lowest GHG emissions, 167 g CO2e/package, while partially automated delivery with a V350-ICEV generates the most at 486 g CO2e/package. Fuel economy and delivery density are key parameters, and electrification of the vehicle and carbon intensity of the electricity have a large impact. CAV power requirements and efficiency benefits largely offset each other, and automation has a moderate impact on life cycle GHG emissions.

Tauroursodeoxycholic acid prevents Burkholderia pseudomallei-induced endoplasmic reticulum stress and is protective during melioidosis in mice.

BACKGROUND: Burkholderia pseudomallei, a facultative intracellular bacterium, is the aetiological agent of melioidosis that is responsible for up to 40% sepsis-related mortality in epidemic areas. However, no effective vaccine is available currently, and the drug resistance is also a major problem in the treatment of melioidosis. Therefore, finding new clinical treatment strategies in melioidosis is extremely urgent. RESULTS: We demonstrated that tauroursodeoxycholic acid (TUDCA), a clinically available endoplasmic reticulum (ER) stress inhibitor, can promote B. pseudomallei clearance both in vivo and in vitro. In this study, we investigated the effects of TUDCA on the survival of melioidosis mice, and found that treatment with TUDCA significantly decreased intracellular survival of B. pseudomallei. Mechanistically, we found that B. pseudomallei induced apoptosis and activated IRE1 and PERK signaling ways of ER stress in RAW264.7 macrophages. TUDCA treatment could reduce B. pseudomallei-induced ER stress in vitro, and TUDCA is protective in vivo. CONCLUSION: Taken together, our study has demonstrated that B. pseudomallei infection results in ER stress-induced apoptosis, and TUDCA enhances the clearance of B. pseudomallei by inhibiting ER stress-induced apoptosis both in vivo and in vitro, suggesting that TUDCA could be used as a potentially alternative treatment for melioidosis.

Endophytic fungus Mucor circinelloides DF20 promote tanshinone biosynthesis and accumulation in Salvia miltiorrhiza root.

As a traditional Chinese medicine, Salvia miltiorrhiza rhizome is mainly used to treat cardiovascular diseases. Symbiosis of endophytic fungi with their host plants, is an effectively regulatory means to promote the growth and secondary metabolism of medicinal plants. Here, an endophytic fungus Mucor circinelloides DF20 was co-cultivated with the sterile seedlings of S. miltiorrhiza, to clarify the promoting mechanism on tanshinone biosynthesis and accumulation in S. miltiorrhiza root. The assay of promoting-growth activities in vitro showed that DF20 have the ability to produce IAA and siderophores. DF20 could significantly promote the biosynthesis and accumulation of tanshinones in the root of S. miltiorrhiza, especially the content of tanshinone ⅡA, reaching 4.630 ± 0.342 mg/g after 56 days of DF20 treatment, which is 22-fold of the control group. The result also showed that the hyphae of M. circunelloides DF20 mainly colonized in the root tissue interspace of S. miltiorrhiza, and a small amount of hyphae were located inside the cells. The results of florescent real-time quantitative RT-PCR showed that DF20 colonization significantly increase the expression level of some key enzyme genes (DXS, DXR, HMGR, GGPPS) in tanshinone biosynthesis pathway, but the regulatory effect mainly occurred in the early stage of co-culture, while the expression level decreased in different degrees in the later stage. In conclusion, the endophytic fungus M. circunelloides DF20 can form an interaction relationship with its host, then to promote the biosynthesis and accumulation of tanshinones in root by upregulating the key enzyme genes expression levels of the biosynthesis pathway.