Exploring the Two-Way Link between Migraines and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

BACKGROUND: The objective of this study is to utilize Mendelian randomization to scrutinize the mutual causality between migraine and venous thromboembolism (VTE) thereby addressing the heterogeneity and inconsistency that were observed in prior observational studies concerning the potential interrelation of the two conditions. METHODS: Employing a bidirectional Mendelian randomization approach, the study explored the link between migraine and VTE, incorporating participants of European descent from a large-scale meta-analysis. An inverse-variance weighted (IVW) regression model, with random-effects, leveraging single nucleotide polymorphisms (SNPs) as instrumental variables was utilized to endorse the mutual causality between migraine and VTE. SNP heterogeneity was evaluated using Cochran's Q-test and to account for multiple testing, correction was implemented using the intercept of the MR-Egger method, and a leave-one-out analysis. RESULTS: The IVW model unveiled a statistically considerable causal link between migraine and the development of VTE (odds ratio [OR] = 96.155, 95% confidence interval [CI]: 4.342-2129.458, p = 0.004), implying that migraine poses a strong risk factor for VTE development. Conversely, both IVW and simple model outcomes indicated that VTE poses as a weaker risk factor for migraine (IVW OR = 1.002, 95% CI: 1.000-1.004, p = 0.016). The MR-Egger regression analysis denoted absence of evidence for genetic pleiotropy among the SNPs while the durability of our Mendelian randomization results was vouched by the leave-one-out sensitivity analysis. CONCLUSION: The findings of this Mendelian randomization assessment provide substantiation for a reciprocal causative association between migraine and VTE within the European population.

Incidence, risk factors, and clinical outcomes of acute brain swelling associated with traumatic acute subdural hematoma: a retrospective study utilizing novel diagnostic criteria.

Background: Post-traumatic acute brain swelling (ABS) is a major cause of elevated intracranial pressure and thus mortality. The current definition of post-traumatic ABS has certain limitations, and there is limited information available regarding ABS associated with traumatic acute subdural hematoma (ASDH). Objectives: To investigate the incidence, risk factors, and clinical outcomes of ABS associated with traumatic ASDH. Design: Retrospective study. Methods: Data for 161 patients diagnosed with traumatic ASDH were retrospectively collected. Novel computed tomography-based criteria were proposed for diagnosing ABS in patients with ASDH and determining its incidence. Univariate and multivariate logistic regression analyses were performed to explore the risk factors of post-traumatic ABS. The Glasgow Outcome Scale (GOS) score, mortality, and functional prognosis of all patients at discharge and the proportion of intraoperative malignant brain bulge in surgical patients were taken as clinical outcome measures. Results: A total of 45 (28%) patients experienced post-traumatic ABS, exhibiting significantly lower Glasgow Coma Scale scores on admission (p < 0.001). The incidence of hemispheric and whole-brain swelling was 8.1% and 19.9%, respectively. Risk factors independently associated with post-traumatic ABS were: (1) age [odds ratio (OR) = 0.917, p < 0.001]; (2) platelet to white blood cell ratio (PWR) (OR = 0.887, p = 0.012); and (3) traumatic subarachnoid hemorrhage (SAH) (OR = 4.346, p = 0.005). The ABS cohort had a lower GOS score [2 (1-3) versus 4 (3-5); p < 0.001], higher mortality (46.7% versus 6.9%; p < 0.001), and higher proportion of unfavorable functional prognosis (75.6% versus 34.5%; p < 0.001) upon discharge compared to the no ABS cohort, along with higher proportion of intraoperative malignant brain bulge (43.8% versus 0%; p < 0.001). Conclusion: The incidence of ABS associated with ASDH is significantly high overall. Patients with ASDH who have young age, low PWR, and traumatic SAH are at an increased risk of developing post-traumatic ABS, and therefore of poor clinical outcomes.

A composite hydrogel loaded with the processed pyritum promotes bone repair via stimulate the osteogenic differentiation of BMSCs.

Tissue engineering shows promise in repairing extensive bone defects. The promotion of proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by biological scaffolds has a significant impact on bone regeneration outcomes. In this study we used an injectable hydrogel, known as aminated mesoporous silica gel composite hydrogel (MSNs-NH2@GelMA), loaded with a natural drug, processed pyritum (PP), to promote healing of bone defects. The mechanical properties of the composite hydrogel were significantly superior to those of the blank hydrogel. In vitro experiments revealed that the composite hydrogel stimulated the osteogenic differentiation of BMSCs, and significantly increased the expression of type I collagen (Col 1), runt-related transcription factor 2 (Runx 2), alkaline phosphatase (ALP), osteocalcin (OCN). In vivo experiments showed that the composite hydrogel promoted the generation of new bones. These findings provide evidence that the composite hydrogel pyritum-loaded holds promise as a biomaterial for bone repair.

Discrepancies in breast cancer guideline recommendations despite similar Cochrane systematic review conclusions.

AIM: This study aims to describe the citation patterns of Cochrane systematic reviews (CSR) in guidelines for managing breast cancer. METHODS: We searched for systematic reviews on breast cancer in The Cochrane Library from the date of inception to November 15, 2023, and identified guidelines that cited them. We described how systematic reviews were cited by the guidelines in each database and each year. Additionally, we presented the relationships between the conclusions of the systematic reviews and guideline recommendations and compared the consistency of the recommendations on the same topic across different guidelines. RESULTS: A total of 64 systematic reviews and 228 guidelines were included in this study. The average number of the 64 systematic reviews cited by the guidelines was 5.91. We found that the guideline recommendations were irrelevant or inconsistent with the conclusions of the systematic reviews in 56 (38.36%) cited entries. We grouped recommendations on the same topic across different guidelines into one group, of which only 5 groups (15.15%) had completely consistent recommendations, and the other 28 groups (84.85%) had inconsistent recommendations. CONCLUSION: The average number of citations for CSR on breast cancer in the guidelines was 5.91. There were also situations in which the guideline recommendations were inconsistent with the conclusions of the included systematic reviews, and recommendations on the same topic across different guidelines were inconsistent.

Study on the removal effect and mechanism of calcined pyrite powder on Cr(VI).

Pyrite exhibits considerable potential as an adsorbent in wastewater treatment. However, few pyrite adsorbents are directly obtained from natural pyrite, as most are composite materials that require a complex preparation process. To develop a pyrite-based adsorbent with a simple preparation process, pyrite was processed by calcination at 400, 600, and 800 °C for 4 h and ball-milled into a fine powder. The adsorption properties of the pyrite powder were systematically explored. The calcined pyrite powder was characterized by SEM-EDS and XRD. The results revealed that the pyrite calcined at 600 °C exhibited excellent adsorption properties and was primarily composed of Fe7S8. The optimum conditions for Cr(VI) removal were a temperature of 45 °C, an adsorbent dosage of 1 g, an equilibration time of 60 min, and an initial pH of 3. Moreover, the calcined pyrite powder exhibited excellent reusability, and the Cr(VI) removal rate exceeded 65% after three cycles. The Cr(VI) adsorption on pyrite can be well described by the Freundlich model and pseudo-second-order kinetic equation. The calcination temperature is the main factor affecting the adsorption performance of pyrite. Therefore, the calcined pyrite powder is expected to be an excellent adsorbent for Cr(VI) in the wastewater treatment industry.

Pyrite has shown promising development prospects in the field of wastewater purification. However, the preparation of most pyrite-based adsorbents is complicated. Upon high-temperature calcination, pyrite is used in traditional Chinese medicine clinics to promote the healing of fractures. The efficiency and underlying mechanism of Cr(VI) adsorption from water using calcined pyrite was investigated. The adsorbent was prepared using a simple method and exhibited excellent adsorption performance, thus allowing its application in preparing ore-based adsorbents for water pollution treatment.

Full hardware implementation of neuromorphic visual system based on multimodal optoelectronic resistive memory arrays for versatile image processing.

In-sensor and near-sensor computing are becoming the next-generation computing paradigm for high-density and low-power sensory processing. To fulfil a high-density and efficient neuromorphic visual system with fully hierarchical emulation of the retina and visual cortex, emerging multimodal neuromorphic devices for multi-stage processing and a fully hardware-implemented system with versatile image processing functions are still lacking and highly desirable. Here we demonstrate an emerging multimodal-multifunctional resistive random-access memory (RRAM) device array based on modified silk fibroin protein (MSFP), exhibiting both optoelectronic RRAM (ORRAM) mode featured by unique negative and positive photoconductance memory and electrical RRAM (ERRAM) mode featured by analogue resistive switching. A full hardware implementation of the artificial visual system with versatile image processing functions is realised for the first time, including ORRAM mode array for the in-sensor image pre-processing (contrast enhancement, background denoising, feature extraction) and ERRAM mode array for near-sensor high-level image recognition, which hugely improves the integration density, and simply the circuit design and the fabrication and integration complexity.

One-pot cascade synthesis of dibenzothiophene-based heterobiaryls from dibenzothiophene-5-oxide.

A sulfoxide directed C-H metalation/boration/B2Pin2 mediated reduction/Suzuki coupling process to synthesize 4-substituted dibenzothiophene (DBT) in one-pot from dibenzothiophene-5-oxide (DBTO) was developed. A variety of DBT-based heterobiaryls were prepared in satisfactory to good yields. A mechanism was proposed. The application of this methodology was demonstrated by synthesizing a luminescent material.

Zwitterionic Conductive Hydrogel-Based Nerve Guidance Conduit Promotes Peripheral Nerve Regeneration in Rats.

In recent years, conductive biomaterials have been widely used to enhance peripheral nerve regeneration. However, most biomaterials use electronic conductors to increase the conductivity of materials. As information carriers, electronic conductors always transmit discontinuous electrical signals, while biological systems essentially transmit continuous signals through ions. Herein, an ion-based conductive hydrogel was fabricated by simple copolymerization of the zwitterionic monomer sulfobetin methacrylate and hydroxyethyl methacrylate. Benefiting from the excellent mechanical stability, suitable electrical conductivity, and good cytocompatibility of the zwitterionic hydrogel, the Schwann cells cultured on the hydrogel could grow and proliferate better, and dorsal root ganglian had an increased neurite length. The zwitterionic hydrogel-based nerve guidance conduits were then implanted into a 10 mm sciatic nerve defect model in rats. Morphological analysis and electrophysiological data showed that the grafts achieved a regeneration effect close to that of the autologous nerve. Overall, our developed zwitterionic hydrogel facilitates efficient and efficacious peripheral nerve regeneration by mimicking the electrical and mechanical properties of the extracellular matrix and creating a suitable regeneration microenvironment, providing a new material reserve for the repair of peripheral nerve injury.

Investigation and analysis of porcine epidemic diarrhea cases and evaluation of different immunization strategies in the large-scale swine farming system.

BACKGROUND: Porcine epidemic diarrhea (PED) is a contagious intestinal disease caused by porcine epidemic diarrhea virus (PEDV) characterized by vomiting, diarrhea, anorexia, and dehydration, which has caused huge economic losses around the world. However, it is very hard to find completely valid approaches to control the transmission of PEDV. At present, vaccine immunity remains the most effective method. To better control the spread of PED and evaluate the validity of different immunization strategies, 240 PED outbreak cases from 577 swine breeding farms were collected and analyzed. The objective of the present study was to analyze the epidemic regularity of PEDV and evaluate two kinds of different immunization strategies for controlling PED. RESULTS: The results showed that the main reasons which led to the outbreak of PED were the movement of pig herds between different pig farms (41.7%) and delaying piglets from the normal production flow (15.8%). The prevalence of PEDV in the hot season (May to October) was obviously higher than that in the cold season (January to April, November to December). Results of different vaccine immunity cases showed that immunization with the highly virulent live vaccine (NH-TA2020 strain) and the commercial inactivated vaccine could significantly decrease the frequency of swine breeding farms (5.9%), the duration of PED epidemic (1.70 weeks), and the week batches of dead piglets (0.48 weeks weaned piglets), compared with immunization with commercial attenuated vaccines and inactivated vaccine of PED. Meanwhile, immunization with the highly virulent live vaccine and the commercial inactivated vaccine could bring us more cash flows of Y̶275,274 per year than immunization with commercial live attenuated vaccine and inactivated vaccine in one 3000 sow pig farm within one year. CONCLUSION: Therefore, immunization with highly virulent live vaccine and inactivated vaccine of PED is more effective and economical in the prevention and control of PED in the large-scale swine farming system.

Memristive neural network circuit implementation of associative learning with overshadowing and blocking.

In the field of second language acquisition, overshadowing and blocking by cue competition effects in classical conditioning affect the learning and expression of human cognitive associations. In this work, a memristive neural network circuit based on neurobiological mechanisms is proposed, which consists of synapse module, neuron module, and control module. In particular, the designed network introduces an inhibitory interneuron to divide memristive synapses into excitatory and inhibitory memristive synapses, so as to mimic synaptic plasticity better. In addition, the proposed circuit can implement six functions of second language acquisition conditioning, including learning, overshadowing, blocking, recovery from overshadowing, recovery from blocking, and long-term effect of overshadowing over time leading to blocking. Overshadowing, which denotes that the more salient stimulus overshadows the learning of the less salient stimulus when two stimuli differ in salience, reduces the associative strength acquired by the less salient stimulus. Blocking, which indicates that pretraining on one stimulus blocks learning about a second stimulus, inhibits the associative strength acquired by a second stimulus. Finally, the correctness and effectiveness of implementing functions mentioned above are verified by the simulation results in PSPICE. Through further research, the proposed circuit is applied to bionic devices such as social robots or educational robots, which can address language and cognitive disorders via assisted learning and training.

Atractylenolide-III alleviates osteoarthritis and chondrocyte senescence by targeting NF-κB signaling.

Atractylenolide-III (AT-III) is well known as its role in antioxidant and anti-inflammatory. Present study was aimed to figure out its effects on osteoarthritis and potential mechanisms. Rat model, human osteoarthritis cartilage explants as well as rat/human chondrocyte cultures were prepared to test AT-III's effects on osteoarthritis progression and chondrocyte senescence. Potential targeted molecules of AT-III were predicted using network pharmacology and molecular docking, assessed by Western blotting and then verified with rescue experiments. AT-III treatment alleviated osteoarthritis severity (shown by OARSI grading score and micro-CT) and chondrocyte senescence (indexed by levels of SA-ß-gal, P16, P53, MMP13, ROS and ratio of healthy/collapsed mitochondrial membrane potentials). Network pharmacology and molecular docking suggested that AT-III might play role through NF-κB pathway. Further experiments revealed that AT-III reduced phosphorylation of IKKα/ß, IκBα and P65 in NF-κB pathway. As well as nuclear translocation of p65. Both in vivo and in vitro experiments indicated that AT-III's effects on osteoarthritis and anti-senescence were reversed by an NF-κB agonist. AT-III could alleviate osteoarthritis by inhibiting chondrocyte senescence through NF-κB pathway, which indicated that AT-III is a prospective drug for osteoarthritis treatment.

The physical and structural properties of acid-Ca2+ induced casein-alginate/Ca2+ double network gels.

The design of protein or polysaccharide interpenetrating network gels according to their physicochemical properties is required to obtain the desired properties of hydrogels. In this study, a method was proposed to prepare casein-calcium alginate (CN-Alg/Ca2+) interpenetrating double-network gels by the release of calcium from a calcium retarder during acidification to form calcium-alginate (Alg/Ca2+) gel and casein (CN) acid gel. Compared with the casein-sodium alginate (CN-Alg) composite gel, the CN-Alg/Ca2+ dual gel network with an interpenetrating network gel structure has better water-holding capacity (WHC) and hardness. The rheology and microstructure results showed that the dual-network gels of CN and Alg/Ca2+ induced by gluconic acid-δ-sodium (GDL) and calcium ions were the network structure of the Alg/Ca2+ gel, which was the "first network", and the CN gel, which was the "second network". It was proven that the microstructure, texture characteristics, and WHC of the double-network gels could be regulated by changing the concentration of Alg in the double-network gels and that the 0.3 % CN-Alg/Ca2+ double gels showed the highest WHC and firmness values. The aim of this study was to provide useful information for the preparation of polysaccharide-protein mixed gels in the food industry or other fields.

Myo-Inositol Attenuates Renal Interstitial Fibrosis in Obstructive Nephropathy by Inhibiting PI3K/AKT Activation.

Emerging evidence suggests that myo-inositol (MI) has a critical role in reducing renal inflammatory processes and improving podocyte function and preventing diabetes-related renal damage. We aimed to explore the function and underlying workings of MI in renal interstitial fibrosis (RIF). Based on a mouse model, we explored the effect of MI in unilateral ureteral obstruction (UUO) and in transforming growth factor-ß1 (TGF-ß1)-treated HK-2 cells. Pathological changes of the kidney tissues were examined following staining of the tissues with hematoxylin, eosin, and Masson's trichrome. The mRNA quantities of fibrosis markers, fibronectin, α-smooth muscle actin (α-SMA), and collagen I, were analyzed by means of real-time polymerase chain reaction, whereas those of protein levels were assessed with Western blotting. We also determined the expression of collagen I by immunofluorescence, and the levels of phosphorylated phosphotidylinositol-3-kinase and protein kinase B (PI3K/AKT) by Western blot. In vivo, histopathological examination in the UUO mice revealed renal tubular epithelial cell necrosis, inflammatory cell infiltration, and RIF. UUO mice showed higher expression levels of collagen I, fibronectin, α-SMA, pPI3K, and pAKT compared with sham-operated mice. However, MI treatment diminished the pathological alterations of RIF in UUO mice and downregulated the expression of fibrosis markers and phosphorylated PI3K/AKT. In vitro, TGF-ß1 positively influenced the propagation and differentiation of HK-2 cells and upregulated the levels of α-SMA, fibronectin, collagen I, pPI3K, and pAKT, but these became significantly reversed by MI treatment. In conclusion, MI ameliorates RIF, possibly by negatively regulating TGF-ß1-induced epithelial transdifferentiation and PI3K/AKT activation.

Construction of Co3O4 anchored on Bi2MoO6 microspheres for highly efficient photocatalytic peroxymonosulfate activation towards degradation of norfloxacin.

Dissolved antibiotics have been a research subject due to their widespread presence and potential threats in drinking water treatment. To enhance the photocatalytic activity of Bi2MoO6 for the degradation of norfloxacin (NOR), the heterostructured Co3O4/Bi2MoO6 (CoBM) composites were synthesized by employing ZIF-67-derived Co3O4 on Bi2MoO6 microspheres. The as-synthesized resultant material 3-CoBM by 300 °C calcination was characterized by XRD, SEM, XPS, transient photocurrent techniques, and EIS. The photocatalytic performance was evaluated by monitoring different concentrations, NOR removal from aqueous solution. Compared with Bi2MoO6, 3-CoBM exhibited the better adsorption and elimination capacity of NOR due to the combined effect between peroxymonosulfate activation and photocatalytic reaction. The influences of catalyst dosage, PMS dosage, various interfering ions (Cl-, NO3-, HCO3-, and SO42-), pH value, and type of antibiotics for application removal were also invested. By activating PMS under visible-light irradiation, 84.95% of metronidazole (MNZ) can be degraded within 40 min, and NOR and tetracycline (TC) can be completely degraded using 3-CoBM. Degradation mechanism was elucidated by quenching tests in combination with EPR measurement, and the degree of activity of the active groups from strong to weak is h+, SO4-•, and •OH, respectively. The degradation products and conceivable degradation pathways of NOR were speculated by LC-MS. In combination of excellent peroxymonosulfate activation and highly enhanced photocatalytic performance, this newly Co3O4/Bi2MoO6 catalyst might be a promising candidate for degrading emerging antibiotic contamination in wastewater.

Safety and Efficacy Comparison of Embospheres and Gelfoam Particles in Bronchial Artery Embolization for Massive Hemoptysis.

Objective: The objective of this research study was to compare the safety and efficacy of bronchial artery embolization (BAE) using Embospheres alone versus Embospheres combined with gelfoam particles in patients with massive hemoptysis. Methods: A total of 127 patients with tuberculous massive hemoptysis who were scheduled to undergo BAE were recruited and divided into two groups: Embosphere group (E group, n = 57) and Embosphere combined with gelfoam particles group (E + G group, n = 70). Technical and clinical success were assessed after BAE surgery, and mortality, untoward reactions, and risk factors for clinical failure were recorded during follow-up. Results: The technical success rate was 92.99% in the E group and 97.14% in the E + G group (P = .272), with similar 1-year mortality rates of 1.76% and 2.86%, respectively (P = .684). However, the E group exhibited a lower clinical success rate compared to the E + G group (85.96% vs. 97.14%), and this difference was statistically significant (P = .020). The untoward reactions showed no statistically significant difference (all P > .05). Univariate analysis revealed that four factors were statistically significant: age (P = .028), presence of pulmonary cavity (P = .001), diabetes (P = .005), and a single use of Embosphere embolization (P = .020). Multivariate regression analysis demonstrated that embolization with Embosphere alone was a risk factor for clinical treatment failure (P = .025). Conclusion: The combination of Embosphere with gelfoam particles can significantly improve the hemostatic effect of BAE without increasing the incidence of adverse reactions.

Knowledge, attitude, and practice of nephrologists on the decision for renal replacement therapy.

BACKGROUND: This study aimed to investigate the Knowledge, Attitude, and Practice (KAP) of nephrologists on the decision of renal replacement therapy (RRT), including peritoneal dialysis, hemodialysis, and kidney transplantation. METHODS: This multicenter cross-sectional study was conducted on qualified nephrologists who volunteered to participate between July and August 2022 by using a self-administered questionnaire. RESULTS: Among 327 nephrologists, the total knowledge, attitude, and practice scores were 12.03 ± 2.11/16, 58.39 ± 6.62/75, and 27.15 ± 2.74/30, respectively. Multivariate logistic regression analysis showed that the attitude score (peritoneal dialysis: OR = 1.19, 95%CI: 1.13-1.25, P < 0.001; hemodialysis: OR = 1.14, 95%CI: 1.09-1.19, P < 0.001; kidney transplantation: OR = 1.12, 95%CI: 1.07-1.16, P < 0.001), 41-50 years of age (peritoneal dialysis: OR = 0.45, 95%CI: 0.21-0,98, P = 0.045; hemodialysis: OR = 0.27, 95%CI: 0.12-0.60, P = 0.001; kidney transplantation: OR = 0.45, 95%CI:0.20-0.97, P = 0.042), and > 50 years of age (peritoneal dialysis: OR = 0.27, 95%CI: 0.08-0.84, P = 0.024; hemodialysis: OR = 0.45, 95%CI: 0.20-0.97, P = 0.042; kidney transplantation: OR = 0.24, 95%CI: 0.08-0.77, P = 0.016) were independently associated with the consideration score of peritoneal dialysis, hemodialysis, and kidney transplantation. CONCLUSION: Better attitudes may lead to more consideration by nephrologists when choosing between peritoneal dialysis, hemodialysis, and kidney transplantation and relatively less consideration by senior physicians when making decisions; in addition, having good knowledge and good attitudes may lead to better practice.

Schwann cell-specific RhoA knockout accelerates peripheral nerve regeneration via promoting Schwann cell dedifferentiation.

Our previous studies indicated that RhoA knockdown or inhibition could alleviate the proliferation, migration, and differentiation of Schwann cells. However, the role of RhoA in Schwann cells during nerve injury and repair is still unknown. Herein, we developed two lines of Schwann cells conditional RhoA knockout (cKO) mice by breeding RhoAflox / flox mice with PlpCre -ERT2 or DhhCre mice. Our results indicate that RhoA cKO in Schwann cells accelerates axonal regrowth and remyelination after sciatic nerve injury, which enhances the recovery of nerve conduction and hindlimb gait, and alleviates the amyotrophy in gastrocnemius muscle. Mechanistic studies in both in vivo and in vitro models revealed that RhoA cKO could facilitate Schwann cell dedifferentiation via JNK pathway. Schwann cell dedifferentiation subsequently promotes Wallerian degeneration by enhancing phagocytosis and myelinophagy, as well as stimulating the production of neurotrophins (NT-3, NGF, BDNF, and GDNF). These findings shed light on the role of RhoA in Schwann cells during nerve injury and repair, indicating that cell type-specific RhoA targeting could serve as a promising molecular therapeutic strategy for peripheral nerve injury.

The opportunistic pathogen Pseudomonas aeruginosa exploits bacterial biotin synthesis pathway to benefit its infectivity.

Pseudomonas aeruginosa is an opportunistic pathogen that predominantly causes nosocomial and community-acquired lung infections. As a member of ESKAPE pathogens, carbapenem-resistant P. aeruginosa (CRPA) compromises the limited therapeutic options, raising an urgent demand for the development of lead compounds against previously-unrecognized drug targets. Biotin is an important cofactor, of which the de novo synthesis is an attractive antimicrobial target in certain recalcitrant infections. Here we report genetic and biochemical definition of P. aeruginosa BioH (PA0502) that functions as a gatekeeper enzyme allowing the product pimeloyl-ACP to exit from fatty acid synthesis cycle and to enter the late stage of biotin synthesis pathway. In relative to Escherichia coli, P. aeruginosa physiologically requires 3-fold higher level of cytosolic biotin, which can be attributed to the occurrence of multiple biotinylated enzymes. The BioH protein enables the in vitro reconstitution of biotin synthesis. The repertoire of biotin abundance is assigned to different mouse tissues and/or organ contents, and the plasma biotin level of mouse is around 6-fold higher than that of human. Removal of bioH renders P. aeruginosa biotin auxotrophic and impairs its intra-phagosome persistence. Based on a model of CD-1 mice mimicking the human environment, lung challenge combined with systemic infection suggested that BioH is necessary for the full virulence of P. aeruginosa. As expected, the biotin synthesis inhibitor MAC13772 is capable of dampening the viability of CRPA. Notably, MAC13772 interferes the production of pyocyanin, an important virulence factor of P. aeruginosa. Our data expands our understanding of P. aeruginosa biotin synthesis relevant to bacterial infectivity. In particular, this study represents the first example of an extracellular pathogen P. aeruginosa that exploits biotin cofactor as a fitness determinant, raising the possibility of biotin synthesis as an anti-CRPA target.

TNF-α Impairs Pericyte-Mediated Cerebral Microcirculation via the NF-κB/iNOS Axis after Experimental Traumatic Brain Injury.

Secondary structural and functional abnormalities of the neurovascular unit are important pathological mechanisms following traumatic brain injury (TBI). The neurovascular unit maintains blood-brain barrier and vascular integrity through interactions among glial cells, pericytes and endothelial cells. Trauma-induced neuroinflammation and oxidative stress may act as initiating factors for pathological damage after TBI, which in turn impairs cerebral microcirculatory function. Studies have shown that the tumor necrosis factor α (TNF-α)/nuclear factor-κB (NF-κB) pathway regulates inflammation and oxidative damage, but its role in pericyte-mediated cerebral microcirculation are currently unknown. Herein, we assessed TNF-α/NF-κB signaling and inducible nitric oxide synthase (iNOS), and the effects of the TNF-α inhibitor infliximab after TBI. Whether pericyte damage is dependent on the TNF-α/NF-κB/iNOS axis was also evaluated to explore the mechanisms underlying disturbances in the microcirculation after TBI. Microglia are activated after TBI to promote inflammatory factors and free radical release, and upregulate NF-κB and iNOS expression. After lipopolysaccharide treatment, the activity of TNF-α/NF-κB/iNOS in BV2 cells was also upregulated. Inhibition of TNF-α using infliximab reduced NF-κB phosphorylation and nuclear translocation and downregulated iNOS expression, which attenuated the inflammation and oxidative damage. Meanwhile, inhibition of TNF-α reversed pericyte marker loss, and improved pericyte function and microcirculation perfusion after TBI. In conclusion, our study suggests that microglia released TNF-α after TBI, which promoted neuroinflammation and oxidative stress by activating downstream NF-κB/iNOS signals, and this led to pericyte-mediated disturbance of the cerebral microcirculation.