Biology subjects

Feng, J.

Publications and source records attributed to Feng, J..

25 records · Page 2Linked to original sources

bioRxiv2017

High Activity Of Selective Essential Oils Against Stationary Phase Borrelia burgdorferi As A Persister Model

Although the majority of patients with Lyme disease can be cured with the standard 2-4 week antibiotic treatment, about 10-20% of patients continue to suffer from post-treatment Lyme disease syndrome (PTLDS). While the cause for this is debated, one possibility is due to persisters not killed by the current Lyme antibiotics. It has been reported that essential oils have antimicrobial activities and some have been used by patients with persisting Lyme disease symptoms. However, the activity of essential oils against the causative agent Borrelia burgdorferi (B. burgdorferi) has not been carefully studied. Here, we evaluated the activity of 34 essential oils against B. burgdorferi stationary phase culture as a model for persisters. We found that many essential oils had varying degrees of activity against B. burgdorferi, with top 5 essential oils (oregano, cinnamon bark, clove bud, citronella, and wintergreen) at a low concentration of 0.25% showing more activity than the persister drug daptomycin. Interestingly, some highly active essential oils were found to have excellent anti-biofilm ability as shown by their ability to dissolve the aggregated biofilm-like structures. The top 3 hits, oregano, cinnamon bark and clove bud, completely eradicated all viable cells without regrowth in subculture. Carvacrol was found to be the most active ingredient of oregano oil showing excellent activity against B. burgdorferi stationary phase cells, while p-cymene and -terpinene had no apparent activity. Future studies are needed to characterize and optimize the active essential oils in drug combinations in vitro and in vivo for improved treatment of persistent Lyme disease.\n\nIMPORTANCEThere is a huge need for effective treatment of patients with Lyme disease who suffer from PTLDS. Recent in vitro and in vivo studies suggest that B. burgdorferi develops persisters that are not killed by the current Lyme antibiotics as a possible contributor to this condition. Although essential oils are used by patients with Lyme disease with variable improvement in symptoms, their anti-borrelia activity has not been carefully studied. Here we found that not all essential oils have adequate anti-borrelia activity and identified some highly potent essential oils (oregano, cinnamon bark, clove bud) that have even higher anti-persister and anti-biofilm activity than the persister drug daptomycin. Carvacrol was found to be the most active ingredient of oregano oil and have the potential to serve as a promising oral persister drug. Our findings may have implications for developing improved treatment of persisting Lyme disease.

microbiology↗

bioRxiv2017

Identification of a Novel Gene argJ involved in Arginine Biosynthesis Critical for Persister Formation in Staphylococcus aureus

Staphylococcus aureus can cause both acute and recurrent persistent infections such as peritonitis, endocarditis, abscess, osteomyelitis, and chronic wound infections. An effective treatment to eradicate the persistent disease is still lacking as the mechanisms of S. aureus persistence are poorly understood. In this study, we performed a comprehensive and unbiased high-throughput mutant screen using S. aureus USA300 and identified argJ, encoding an acetyltransferase in the arginine biosynthesis pathway, whose mutation produced a significant defect in persister formation in multiple drugs and stresses. Genetic complementation and arginine supplementation restored persistence in the ArgJ mutant. Quantitative real-time PCR analysis showed that the arg genes were over-expressed under drug stressed conditions and in stationary phase cultures. In addition, the ArgJ mutant had attenuated virulence in both C. elegans and mouse models of infection. Our studies identify a novel mechanism of persistence mediated by arginine metabolism in S. aureus. These findings will not only provide new insights about the mechanisms of S. aureus persistence but also offer novel therapeutic targets that may help to develop more effective treatment of persistent S. aureus infections.

microbiology↗

bioRxiv2017

Varying Effects of Common Tuberculosis Drugs on Enhancing Clofazimine Activity in vitro

Clofazimine (CFZ), originally developed as an anti-tuberculosis (TB) drug in the 1950s 1, is commonly used to treat leprosy and also nontuberculous mycobacterial (NTM) infections. 2 Although CFZ has good activity against Mycobacterium tuberculosis, it was not used in the treatment of pulmonary TB mainly because it had the side effect of skin discoloration and there were other more effective drugs like isoniazid (INH), rifampin (RIF) and pyrazinamide (PZA) already available for the treatment of TB. 2 However, the increasing emergence of multi-drug-resistant TB (MDR-TB) has revived interest in the use of CFZ to treat MDR-TB. 2,3\n\nAlthough resistance to CFZ has been shown to be mediated by mutations in Rv0678,4,5 Rv1979c, or Rv2535c (PepQ),5 the mode of action of CFZ has remained poorly understood. CFZ appears to hav ...

microbiology↗

bioRxiv2017

Identification of drug candidates that enhance pyrazinamide activity from a clinical drug library

Tuberculosis (TB) remains a leading cause of morbidity and mortality globally despite the availability of the TB therapy. 1 The current TB therapy is lengthy and suboptimal, requiring a treatment time of at least 6 months for drug susceptible TB and 9-12 months (shorter Bangladesh regimen) or 18-24 months (regular regimen) for multi-drug-resistant tuberculosis (MDR-TB). 1 The lengthy therapy makes patient compliance difficult, which frequently leads to emergence of drug-resistant strains. The requirement for the prolonged treatment is thought to be due to dormant persister bacteria which are not effectively killed by the current TB drugs, except rifampin and pyrazinamide (PZA) which have higher activity against persisters. 2, 3 Therefore new therapies should address the problem of insufficient efficacy against M. tuberculosis persisters, which could cause relapse of clinical disease. 4 PZA is a critical frontline TB drug that kills persister bacteria 5 and shortens the TB treatment from 9-12 months to 6 months. 6, 7 Although several new TB drugs are showing promise in clinical studies, none can replace PZA as they all have to be used together with PZA. 7 Because of the essentiality of PZA and the high cost of developing new drugs, in this study, we explored the idea of identifying drugs that enhance the anti-persister activity of PZA as an economic alternative approach to developing new drugs for improved treatment by screening an clinical drug library against old M. tuberculosis cultures enriched with persisters.

microbiology↗

bioRxiv2017

Activity of Sulfa Drugs and Their Combinations against Stationary Phase B. burgdorferi in vitro

Lyme disease is a most common vector borne disease in the US. Although the majority of Lyme patients can be cured with the standard 2-4 week antibiotic treatment, at least 10-20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, one possibility is that persisting organisms are not killed by current Lyme antibiotics. In our previous studies, we screened an FDA drug library and an NCI compound library on B. burgdorferi and found some drug hits including sulfa drugs as having good activity against B. burgdorferi stationary phase cells. In this study, we evaluated the relative activity of three commonly used sulfa drugs sulfamethoxazole (Smx), dapsone (Dps), sulfachlorpyridazine (Scp), and also trimethoprim (Tmp), and assessed their combinations with the commonly prescribed Lyme antibiotics for activities against B. burgdorferi stationary phase cells. Using the same molarity concentration, dapsone, sulfachlorpyridazine and trimethoprim showed very similar activity against stationary phase B. burgdorferi enriched in persisters, however, sulfamethoxazole was the least active drug among the three sulfa drugs tested. Interestingly, contrary to other bacterial systems, Tmp did not show synergy in drug combinations with the three sulfa drugs at their clinically relevant serum concentrations against B. burgdorferi. We found that sulfa drugs combined with other antibiotics were more active than their respective single drugs and that four-drug combinations were more active than three-drug combinations. Four drug combinations dapsone+minocycline+cefuroxime+azithromycin and dapsone+minocycline+cefuroxime+rifampin showed best activity against stationary phase B. burgdorferi in these sulfa drug combinations. However, these 4-sulfa drug containing combinations still had considerably less activity against B. burgdorferi stationary phase cells than the daptomycin+cefuroxime+doxycycline used as a positive control which completely eradicated B. burgdorferi stationary phase cells. Future studies are needed to evaluate and optimize the sulfa drug combinations in vitro and also in animal models.

microbiology↗

bioRxiv2017

BMP signaling orchestrates a transcriptional network to control the fate of mesenchymal stem cells (MSCs)

Signaling pathways are used reiteratively in different developmental processes yet produce distinct cell fates through activating specific downstream transcription factors. In this study, we used tooth root development as a model to investigate how the BMP signaling pathway regulates specific downstream transcriptional complexes to direct the fate determination of multipotent mesenchymal stem cells (MSCs). We first identified the MSC population supporting mouse molar root growth as Gli1+ cells. Using a Gli1-mediated transgenic animal model, our results provide the first in vivo evidence that BMP signaling activity is required for the odontogenic differentiation of MSCs. Specifically, we identified transcription factors that are downstream of BMP signaling and are expressed in a spatially restricted pattern consistent with their potential involvement in determining distinct cellular identities within the dental mesenchyme. Finally, we found that overactivation of one key transcription factor, Klf4, associated with the odontogenic region, promotes odontogenic differentiation of MSCs. Collectively, our results demonstrate the functional significance of BMP signaling in regulating the fate of MSCs during root development and shed light on how BMP signaling can achieve functional specificity in regulating diverse organ development.\n\nSummary StatementBMP signaling activity is required for the lineage commitment of MSCs and transcription factors downstream of BMP signaling may determine distinct cellular identities within the dental mesenchyme.

developmental biology↗

bioRxiv2016

Statistical testing and power analysis for brain-wide association study

The identification of connexel-wise associations, which involves examining functional connectivities between pairwise voxels across the whole brain, is both statistically and computationally challenging. Although such a connexel-wise methodology has recently been adopted by brain-wide association studies (BWAS) to identify connectivity changes in several mental disorders, such as schizophrenia, autism and depression [Cheng et al., 2015a,b, 2016], the multiple correction and power analysis methods designed specifically for connexel-wise analysis are still lacking. Therefore, we herein report the development of a rigorous statistical framework for connexel-wise significance testing based on the Gaussian random field theory. It includes controlling the family-wise error rate (FWER) of multiple hypothesis testings using topological inference methods, and calculating power and sample size for a connexel-wise study. Our theoretical framework can control the false-positive rate accurately, as validated empirically using two resting-state fMRI datasets. Compared with Bonferroni correction and false discovery rate (FDR), it can reduce false-positive rate and increase statistical power by appropriately utilizing the spatial information of fMRI data. Importantly, our method considerably reduces the computational complexity of a permutation-or simulation-based approach, thus, it can efficiently tackle large datasets with ultra-high resolution images. The utility of our method is shown in a case-control study. Our approach can identify altered functional connectivities in a major depression disorder dataset, whereas existing methods failed. A software package is available at https://github.com/weikanggong/BWAS.

neuroscience↗