The Antimicrobial, Hemostatic, and Anti-Adhesion Effects of a Peptide Hydrogel Constructed by the All-d-Enantiomer of Antimicrobial Peptide Jelleine-1.

Peptide hydrogels are believed to be potential biomaterials with wide application in the biomedical field because of their good biocompatibility, injectability, and 3D printability. Most of the previously reported polypeptide hydrogels are composed of l-peptides, while the hydrogels formed by self-assembly of d-peptides are rarely reported. Herein, a peptide hydrogel constructed by D-J-1, which is the all-d-enantiomer of antimicrobial peptide Jelleine-1 (J-1) is reported. Field emission scanning electron microscope (FE-SEM) and rheologic study are performed to characterize the hydrogel. Antimicrobial, hemostatic, and anti-adhesion studies are carried out to evaluate its biofunction. The results show that D-J-1 hydrogel is formed by self-assembly and cross-linking driven by hydrogen bonding, hydrophobic interaction, and π-π stacking force of aromatic ring in the structure of D-J-1. It exhibits promising antimicrobial activity, hemostatic activity, and anti-adhesion efficiency in a rat sidewall defect-cecum abrasion model. In addition, it also exhibits good biocompatibility. Notably, D-J-1 hydrogel shows improved in vitro and in vivo stability when compared with its l-enantiomer J-1 hydrogel. Therefore, the present study will provide new insight into the application of d-peptide hydrogel, and provides a new peptide hydrogel with antibacterial, hemostatic, and anti-adhesion efficacy for clinical use.

DANCR Induces Cisplatin Resistance of Triple-Negative Breast Cancer by KLF5/p27 Signaling.

An increasing body of evidence suggests that long noncoding RNAs play critical roles in human cancer. Breast cancer is a heterogeneous disease and the potential involvement of long noncoding RNAs in breast cancer remains poorly understood. Herein, the study identified a long noncoding RNA, DANCR, which promotes cisplatin chemoresistance in triple-negative breast cancer (TNBC) cells. Mechanistically, binding of DANCR to Krüppel-like factor 5 (KLF5) induced acetylation of KLF5 at lysine 369 (K369), and DANCR knockdown resulted in down-regulation of KLF5 protein levels. Furthermore, DANCR/KLF5 signaling pathway induced hypersensitivity to cisplatin in chemoresistant patients by inhibiting p27 transcription. In summary, this study reinforced the potential presence of a growth regulatory network in TNBC cells, and documented a DANCR/KLF5/p27 signaling pathway mediating cisplatin chemoresistance in TNBC.

A carrier-free, dual-functional hydrogel constructed of antimicrobial peptide Jelleine-1 and 8Br-cAMP for MRSA infected diabetic wound healing.

Bacterial infection and local growth factor deficiency are two of the major causes of the nonunion of diabetic wounds. Antimicrobial peptides (AMPs) are believed to be alternatives to antibiotics against drug-resistant bacterial infections. 8-Bromoadenosine-3', 5'-cyclic monophosphate (8Br-cAMP) can promote cells to secrete growth factors and accelerate cell proliferation. In the present study, we constructed a hydrogel with antimicrobial peptide Jelleine-1 (J-1) and 8Br-cAMP without any other gelators or chemical crosslinking agents. The hydrogel was proved to promote the secretion of transforming growth factor-ß (TGF-ß) and vascular endothelial growth factor-A (VEGFA) in vitro and in vivo. Notably, it exhibited potent potential for wound healing in methicillin-resistant Staphylococcus aureus (MRSA) infected diabetic wounds. This would be attributed to the retention of AMPs and 8Br-cAMP on the wound site by the hydrogel system. In addition, the hydrogel also showed good biodegradability, proper stability, and good biocompatibility. This study would shed light on the development of carrier-free and multifunctional hydrogel for wound healing. STATEMENT OF SIGNIFICANCE: Bacterial infection and local growth factor deficiency are two of the major causes for the nonunion of refractory wounds. In the present study, an injectable carrier-free hydrogel was constructed of a natural antimicrobial peptide J-1 and 8Br-cAMP by eco-friendly physical crosslinking without any other gelators or chemical crosslinking agents. The hydrogel exhibited excellent antimicrobial activity and was proved to promote the secretion of TGF-ß and VEGFA in vitro and in vivo. Correspondingly, the hydrogel showed exceptionally wound healing effects in the wound model of MRSA infected diabetic rats. This study would provide an alternative strategy or a potential hydrogel dressing for the treatment of chronic or refractory wounds.

An Injectable Peptide Hydrogel Constructed of Natural Antimicrobial Peptide J-1 and ADP Shows Anti-Infection, Hemostasis, and Antiadhesion Efficacy.

Postoperative adhesion is a common complication of abdominal surgery, which always has many adverse effects in patients. At present, there is still a lack of effective treatment measures and materials to prevent adhesion in the clinics. Herein, we report the potential use of J-1-ADP hydrogel formed by natural antimicrobial peptide jelleine-1 (J-1) self-assembling in adenosine diphosphate (ADP) sodium solution to prevent postsurgery adhesion formation. J-1-ADP hydrogel was found to have good antimicrobial activity against the bacteria and fungi tested and can be used to prevent tissue infection, which was thought to be one of the incitements of adhesion. Due to ADP being a platelet-activating factor, J-1-ADP hydrogel showed significant hemostatic activity in vitro verified by whole blood coagulation, plasma coagulation, platelet activation, and platelet adhesion assays. Further, it showed potent hemostatic activity in a mouse liver hemorrhage model. Bleeding was believed to be a cause of the formation of postsurgery adhesion. J-1-ADP hydrogel had a significant antiadhesion effect in a rat side wall defect-cecum abrasion model. In addition, it had good biocompatibility and degradation properties. So the present study may provide an alternative strategy for designing antimicrobial peptide hydrogel material to prevent postoperative adhesion formation in the clinic.

The effects of incorporation of the counterparts and mimics of L-lysine on the antimicrobial activity, hemolytic activity, cytotoxicity and tryptic stability of antimicrobial peptide polybia-MPII.

Due to the limited effects of conventional antibiotics on the increasing emergence of drug-resistant bacteria and fungi, novel antimicrobial agents were urgently needed to alleviate this phenomenon. Nowadays, antimicrobial peptides are believed to be a promising candidate for a new generation of antimicrobial drugs. Antimicrobial peptide polybia-MPII (MPII) was first isolated from the venom of the social wasp Polybia paulista with a broad spectrum of antimicrobial activity. In the present study, the counterparts and mimics of cationic amino acids of Lys, such as Arg, His, Orn, Dab and Dap were employed to substitute Lys in the sequence of MPII. The effects of the incorporation of these amino acids on its antimicrobial activity, hemolytic activity, cytotoxicity, enzyme stability and therapeutic potential were explored. Our results showed that although the incorporation of Arg could improve its antimicrobial activity, there is no improvement in enzyme stability. The incorporation of His makes MPII exert its antimicrobial activity in a pH-dependent manner. Notably, incorporating Dap could effectively decrease its hemolytic activity and cytotoxicity and enhance its enzyme stability against trypsin. In conclusion, this study would provide an effective strategy to improve the bioavailability and metabolic stability of AMPs while decrease their hemolytic activity and cytotoxicity.

An optimized analog of antimicrobial peptide Jelleine-1 shows enhanced antimicrobial activity against multidrug resistant P. aeruginosa and negligible toxicity in vitro and in vivo.

Due to the threat of escalating multi-drug resistant gram-negative bacteria to human health and life, novel antimicrobial agents against gram-negative pathogens are urgently needed. As antimicrobial peptides are not prone to induce bacteria resistance, they are believed to be one kind of promising class of potential antimicrobial agent candidates to combat multi-drug resistant bacteria for long-term use. Jelleine-1, first isolated from the royal jelly of honeybees, is a typical amphiphilic antimicrobial peptide and shows broad antimicrobial spectrum and negligible toxicity. To promote its antimicrobial activity and extend its potential of clinical use against multi-drug resistant gram-negative bacteria, novel analogs of jelleine-1 were designed, synthesized and their antimicrobial functions and toxicity were examined in this study. Our results showed that fine tuning of the cationic charge, polarity, and basicity of the sequence through amino acids substitution at position 3, 5, 7 and maintaining position 1, 4, 6, 8 unchanged could improve the bioactivity of jelleine-1 significantly. Meanwhile, we also found that the substitution of phenylalanine by tryptophan also could improve the antimicrobial activity of jelleine-1. Among all the analogs, analog 15, which is enriched in arginine and leucine, showed the most potent antimicrobial activity against both gram-negative and gram-positive bacteria, especially to multi-drug resistant Pseudomonas aeruginosa in vivo and in vitro. In addition, analog 15 also showed potent inhibition of the formation of multi-drug resistant P. aeruginosa biofilm and negligible toxicity, which was certified by MTT, hemolysis, blood assay, and biochemical analysis.

The impact of training methodology and representation on rule-based categorization: An fMRI study.

Hélie, Shamloo, & Ell (2017) showed that regular classification learning instructions (A/B) promote between-category knowledge in rule-based categorization whereas conceptual learning instructions (YES/NO) promote learning within-category knowledge with the same categories. Here we explore how these tasks affect brain activity using fMRI. Participants learned two sets of two categories. Computational models were fit to the behavioral data to determine the type of knowledge learned by each participant. fMRI contrasts were computed to compare BOLD signal between the tasks and between the types of knowledge. The results show that participants in the YES/NO task had more activity in the pre-supplementary motor area, prefrontal cortex, and the angular/supramarginal gyrus. These brain areas are related to working memory and part of the dorsal attention network, which showed increased task-based functional connectivity with the medial temporal lobes. In contrast, participants in the A/B task had more activity in the thalamus and caudate. These results suggest that participants in the YES/NO task used bivalent rules and may have treated each contextual question as a separate task, switching task each time the question changed. Activity in the A/B condition was more consistent with participants applying direct Stimulus → Response rules. With regards to knowledge representation, there was a large shared network of brain areas, but participants learning between-category information showed additional posterior parietal activity, which may be related to the inhibition of incorrect motor programs.

Residential mobility during pregnancy in Urban Gansu, China.

BACKGROUND: Studies on environmental exposures during pregnancy commonly use maternal residence at time of delivery, which may result in exposure misclassification and biased estimates of exposure and disease association. Studies on residential mobility during pregnancy are needed in various populations to aid studies of the environmental exposure and birth outcomes. However, there is still a lack of studies investigating residential mobility patterns in Asian populations. METHODS: We analyzed data from 10,542 pregnant women enrolled in a birth cohort study in Lanzhou, China (2010-2012), a major industrial city. Multivariate logistic regression was used to evaluate residential mobility patterns in relation to maternal complications and birth outcomes. RESULTS: Of the participants, 546 (5.2%) moved during pregnancy; among those who moved, 40.5%, 34.8%, and 24.7% moved during the first, second, and third trimester, respectively. Most movers (97.3%) moved once with a mean distance of 3.75 km (range: 1-109 km). More than half (66.1%) of the movers moved within 3 km, 13.9% moved 3-10 km, and 20.0% moved > 10 km. Pregnant women who were > 30 years or multiparous, or who had maternal complications were less likely to have moved during pregnancy. In addition, movers were less likely to deliver infants with birth defects, preterm births, and low birth weight. CONCLUSIONS: Residential mobility was significantly associated with several maternal characteristics and complications during pregnancy. The study also showed a lower likelihood of adverse birth outcomes among movers than non-movers, suggesting that moving might be related to reduce exposure to environmental hazards. These results confirm the hypothesis that residential mobility may be important with respect to exposure misclassification and that this misclassification may vary by subpopulations.

Folic acid supplementation, dietary folate intake and risk of preterm birth in China.

PURPOSE: Folic acid supplementation has been suggested to reduce the risk of preterm birth. However, results from previous epidemiologic studies have been inconclusive. We investigated the hypothesis that folic acid supplementation and dietary folate intake during pre- and post-conception reduces the risk of preterm birth. METHODS: We analyzed data from a birth cohort study conducted between 2010 and 2012 in Lanzhou, China, including 10,179 pregnant women with live singleton births. RESULTS: Compared to non-users, folic acid supplement users with >12-week duration had a reduced risk of preterm birth (OR 0.67, 95 % CI 0.55-0.83) with a significant dose-response relationship (P for trend = 0.01). A similar pattern was observed for spontaneous preterm birth. Stronger associations were seen for ever use of folic acid supplement and very preterm birth (OR 0.50, 95 % CI 0.36-0.69) and spontaneous very preterm birth (OR 0.42, 95 % CI 0.29-0.63). Dietary folate intake during preconception and pregnancy were also associated with reduced risk of preterm birth (OR 0.68, 95 % CI 0.56-0.83, OR 0.57, 95 % CI 0.47-0.70 for the highest quartiles, respectively), particularly for spontaneous very preterm (OR 0.41, 95 % CI 0.24-0.72, OR 0.26, 95 % CI 0.15-0.47 for the highest quartiles, respectively). There were also decreased risks of preterm birth observed per 10-µg increase in dietary folate intake, and similar associations were found after stratification by folic acid supplementation status. CONCLUSIONS: Our results suggest that folic acid supplementation and higher dietary folate intake during preconception and pregnancy reduces the risk of preterm birth, and the protective effect varies by preterm subtypes.

Exposure to cooking fuels and birth weight in Lanzhou, China: a birth cohort study.

BACKGROUND: Early studies have suggested that biomass cooking fuels were associated with increased risk of low birth weight (LBW). However it is unclear if this reduced birth weight was due to prematurity or intrauterine growth restriction (IUGR). METHODS: In order to understand the relationship between various cooking fuels and risk of LBW and small for gestational age (SGA), we analyzed data from a birth cohort study conducted in Lanzhou, China which included 9,895 singleton live births. RESULTS: Compared to mothers using gas as cooking fuel, significant reductions in birth weight were observed for mothers using coal (weight difference = 73.31 g, 95 % CI: 26.86, 119.77) and biomass (weight difference = 87.84 g, 95 % CI: 10.76, 164.46). Using biomass as cooking fuel was associated with more than two-fold increased risk of LBW (OR = 2.51, 95 % CI: 1.26, 5.01), and the risk was mainly seen among preterm births (OR = 3.43, 95 % CI: 1.21, 9.74). No significant associations with LBW were observed among mothers using coal or electromagnetic stoves for cooking. CONCLUSIONS: These findings suggest that exposure to biomass during pregnancy is associated with risk of LBW, and the effect of biomass on LBW may be primarily due to prematurity rather than IUGR.

Ambient air pollutant PM10 and risk of preterm birth in Lanzhou, China.

IMPORTANCE: Exposure to ambient particulate matter during pregnancy has been suggested as a risk factor for preterm birth. However results from limited epidemiologic studies have been inconclusive. Very few studies have been conducted in areas with high air pollution levels. OBJECTIVE: We investigated the hypothesis that high level exposure to particulate matter with aerodynamic diameter no larger than 10µm (PM10) during pregnancy increases the risk of preterm birth. METHODS: A birth cohort study was carried out between 2010 and 2012 in Lanzhou, China, including 8969 singleton live births with available information on daily PM10 levels from four monitoring stations, individual exposures during pregnancy were calculated using inverse-distance weighting based on both home and work addresses. Unconditional logistic regression modeling was used to examine the associations between PM10 exposure and risk of preterm birth and its clinical subtypes. RESULTS: Increased risk of very preterm birth was associated with exposure to PM10 during the last two months of pregnancy (OR, 1.07; 95%CI, 1.02-1.13 per 10µg/m(3) increase for last four weeks before delivery; 1.09; 1.02-1.15 for last six weeks before delivery; 1.10; 1.03-1.17 for last eight weeks before delivery). Compared to the U.S. National Ambient Air Quality Standard (150µg/m(3)), higher exposure level (≥150µg/m(3)) of PM10 during entire pregnancy was associated with an increased risk of preterm birth (1.48; 1.22-1.81) and the association was higher for medically indicated preterm birth (1.80, 1.24-2.62) during entire pregnancy and for very preterm during last 6weeks before delivery (2.03, 1.11-3.72). CONCLUSIONS AND RELEVANCE: Our study supports the hypothesis that exposure to high levels of ambient PM10 increases the risk of preterm birth. Our study also suggests that the risk may vary by clinical subtypes of preterm birth and exposure time windows. Our findings are relevant for health policy makers from China and other regions with high levels of air pollution to facilitate the efforts of reducing air pollution level in order to protect public health.

Passive smoking and preterm birth in urban China.

Studies investigating the relationship between maternal passive smoking and the risk of preterm birth have reached inconsistent conclusions. A birth cohort study that included 10,095 nonsmoking women who delivered a singleton live birth was carried out in Lanzhou, China, between 2010 and 2012. Exposure to passive smoking during pregnancy was associated with an increased risk of very preterm birth (<32 completed weeks of gestation; odds ratio = 1.98, 95% confidence interval: 1.41, 2.76) but not moderate preterm birth (32-36 completed weeks of gestation; odds ratio = 0.98, 95% confidence interval: 0.81, 1.19). Risk of very preterm birth increased with the duration of exposure (P for trend = 0.0014). There was no variability in exposures by trimester. The associations were consistent for both medically indicated and spontaneous preterm births. Overall, our findings support a positive association between passive smoking and the risk of very preterm birth.

A wireless magnetic resonance energy transfer system for micro implantable medical sensors.

Based on the magnetic resonance coupling principle, in this paper a wireless energy transfer system is designed and implemented for the power supply of micro-implantable medical sensors. The entire system is composed of the in vitro part, including the energy transmitting circuit and resonant transmitter coils, and in vivo part, including the micro resonant receiver coils and signal shaping chip which includes the rectifier module and LDO voltage regulator module. Transmitter and receiver coils are wound by Litz wire, and the diameter of the receiver coils is just 1.9 cm. The energy transfer efficiency of the four-coil system is greatly improved compared to the conventional two-coil system. When the distance between the transmitter coils and the receiver coils is 1.5 cm, the transfer efficiency is 85% at the frequency of 742 kHz. The power transfer efficiency can be optimized by adding magnetic enhanced resonators. The receiving voltage signal is converted to a stable output voltage of 3.3 V and a current of 10 mA at the distance of 2 cm. In addition, the output current varies with changes in the distance. The whole implanted part is packaged with PDMS of excellent biocompatibility and the volume of it is about 1 cm(3).