Biology subjects

Xiong, K.

Publications and source records attributed to Xiong, K..

6 recordsLinked to original sources

bioRxiv2018

Adaptive evolution of feed-forward loops versus diamonds to filter out short spurious signals

We develop a null model of the evolution of transcriptional regulatory networks, and use it to support an adaptive origin for a canonical "motif", a 3-node feed-forward loop (FFL) hypothesized to filter out short spurious signals by integrating information from a fast and a slow pathway. Our mutational model captures the intrinsically high prevalence of weak affinity transcription factor binding sites. We also capture stochasticity and delays in gene expression that distort external signals and intrinsically generate noise. Functional FFLs evolve readily under selection for the hypothesized function, but not in negative controls. Interestingly, a 4-node "diamond" motif also emerged as a short spurious signal filter. The diamond uses expression dynamics rather than path length to provide fast and slow pathways. When there is no external spurious signal to filter out, but only internally generated noise, only the diamond and not the FFL evolves.

systems biology↗

bioRxiv2018

β-lactam Antibiotics Stimulate the Pathogenicity of Methicillin-resistant Staphylococcus aureus Via SarA-controlled Tandem Lipoprotein Expression

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of nosocomial infections worldwide. MRSA resists nearly all {beta}-lactam antibiotics that have a bactericidal activity and a signal inducer effect. However, studies have yet to clarify whether the inducer effect of empirically used {beta}-lactams stimulates MRSA pathogenicity in vivo. Here, we showed that a new cluster of tandem lipoprotein genes (tlpps) was upregulated in MRSA in response to the subinhibitory concentrations of {beta}-lactam induction. The increased Tlpps significantly altered immune responses by macrophages with high IL-6 and TNF levels. The deletion of the tlpps mutant (N315{Delta}tlpps) significantly decreased the proinflammatory cytokine levels in vitro and in vivo. The bacterial loads of N315{Delta}tlpps in the mouse kidney were also reduced compared with those of the wild type N315. The {beta}-lactam-treated MRSA exacerbated cutaneous infections with increased lesion size, extended illness, and flake-like abscess-formation compared with those of the nontreatment. The {beta}-lactam antibiotics that promoted the MRSA pathogenicity were SarA dependent, and the increasing expression of tlpps after {beta}-lactam treatment was directly controlled by the global regulator SarA. Overall, our findings suggested that {beta}-lactams should be used carefully because it might lead to a worse outcome of MRSA infection than inaction in the treatment.\n\nAuthor summary{beta}-lactams are widely used in practice to treat infectious diseases, however, {beta}-lactams worsening the outcome of a certain disease is poorly understood. In this study, we have identified a new cluster of tandem lipoprotein genes (tlpps) that is upregulated in the major clinically prevalent MRSA clones in response to the subinhibitory concentrations of {beta}-lactams induction. The major highlight in this work is that {beta}-lactams induce SarA expression, and then SarA directly binds to the tlpp cluster promoter region and upregulates the tlpp expression in MRSA. Moreover, the {beta}-lactam stimulated Tlpps are important virulence factors that enhance MRSA pathogenicity. The deletion of the tlpps mutant significantly decreases the proinflammatory cytokine levels in vitro and in vivo. The {beta}-lactam induced Tlpps enhance the host inflammatory responses by triggering the expression of IL-6 and TNF, thereby promoting bacterial colonization and abscess formation. These data elucidate that {beta}-lactams can worsen the outcome of MRSA infection through the induction of tlpps that are controlled by the global regulator SarA.

pathology↗

bioRxiv2017

Progesterone regulates hypothalamic-pituitary-thyroid axis

Progesterone is a natural steroid hormone excreted by animals and humans, which has been frequently detected in the aquatic ecosystems. The effects of the residual progesterone on fish are unclear. In this study, we aimed to examine the effects of progesterone on the hypothalamic-pituitary-thyroid (HPT) axis by detecting the gene transcriptional expression levels. Zebrafish embryos were treated with different concentrations of progesterone from 12 hours post-fertilization (hpf) to 120 hpf. Total mRNA was extracted and the transcriptional profiles of genes involved in HPT axis were examined using qPCR. The genes related to thyroid hormone metabolism and thyroid hormone synthesis were up-regulated in zebrafish exposed to progesterone. These results indicated that progesterone affected the mRNA expression of genes involved in the HPT axis, which might interrupt the endocrine system in zebrafish. Our data also suggested that zebrafish is a useful tool for evaluating the effects of chemicals on the thyroid endocrine system.

pharmacology and toxicology↗

bioRxiv2017

Effects of Progesterone on the reproductive physiology in zebrafish

Recent studies have investigated that the synthetic progestins may lead to health issues to the aquatic organisms. Progesterone is a steroidal progestin and has been used as a contraceptive drug, which is detected in the aquatic ecosystem. However, the potential effects of progesterone on the fish reproduction are largely unclear. Here, we tested the effects of progesterone on the fish reproductive and endocrine systems. Adult zebrafish were exposed to progesterone for 10 days at environmental concentrations. The production of eggs was reduced in the exposed fish, and the circulating concentrations of estradiol (E2) and testosterone (T) in female fish or 11-keto testosterone (11-KT) in male fish were significantly diminished. Our results suggested that progesterone may cause adverse health effects on fish by disrupting the endocrine system, and short-term exposure to progesterone could overt affect the fish reproduction.

pharmacology and toxicology↗

bioRxiv2017

Impairment of zebrafish reproduction upon exposure to melengestrol acetate

Synthetic progestins contamination is common in the aquatic ecosystem, which may lead to serious health problem on aquatic animals. Melengestrol acetate (MGA) has been detected in the aquatic environment; however, its potential effects on fish reproduction are largely unclear. Here, we aimed to investigate the endocrine disruption and impact of MGA on zebrafish reproduction. Six-month old reproductive zebrafish were exposed to four nominal concentrations of MGA (1,10, 100 and 200 ng/L) for 15 days. Treatment with MGA reduced the egg production with a significant decrease at 200 ng/L. The circulating concentrations of estradiol and testosterone in female zebrafish or 11-keto testosterone in male zebrafish were significantly diminished compared to the non-exposed control fish. The early embryonic development or hatching rates were unaffected during the MGA exposure. Our results indicated that MGA was a potent endocrine disruptor in fish and the fish reproduction could be impaired even during a short-term exposure to MGA.

developmental biology↗

bioRxiv2016

Quantitative Analysis of Dopamine Neuron Subtypes Generated from Mouse Embryonic Stem Cells

Dopamine (DA) neuron subtypes modulate specific physiological functions and are involved in distinct neurological disorders. Embryonic stem cell (ESC) derived DA neurons have the potential to aid in the study of disease mechanisms, drug discovery, and possibly cell replacement therapies. DA neurons can be generated from ESCs in vitro, but the subtypes of ESC-derived DA neurons have not been investigated in detail despite the diversity of DA neurons observed in vivo. Due to cell culture heterogeneity, sampling methods applied to ESC-derived cultures can be ambiguous and potentially biased. Therefore, we developed a quantification method to capture the depth of DA neuron production in vitro by estimating the error associated with systematic random sampling. Using this method, we quantified calbindin+ and calretinin+ subtypes of DA neurons generated from mouse ESCs. We found a higher production of the calbindin+ subtype (11-27%) compared to the calretinin+ subtype (2-13%) of DA neuron; in addition, DA neurons expressing neither subtype marker were also generated. We then examined whether exogenous sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF8) affected subtype generation. Our results demonstrate that exogenous SHH and FGF8 did not alter DA neuron subtype generation in vitro. These findings suggest that a deeper understanding DA neuron derivation inclusive of mechanisms that govern the in vitro subtype specification of ESC-derived DA neurons is required.\n\nNoteAll research was planned and conducted while members were at Brown University\n\nResearch fundingNIH/NCRR/NIGMS RI Hospital COBRE Center for Stem Cell Biology (8P20GM103468-04) (MZ) Brown Institute for Brain Science Pilot Grant (4-63662) (MZ/DHK)

neuroscience↗