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1.
BMC Genomics ; 21(1): 204, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131728

RESUMO

BACKGROUND: In response to ecological niche of domestication, domesticated mammals and birds developed adaptively phenotypic homoplasy in behavior modifications like fearlessness, altered sociability, exploration and cognition, which partly or indirectly result in consequences for economic productivity. Such independent adaptations provide an excellent model to investigate molecular mechanisms and patterns of evolutionary convergence driven by artificial selection. RESULTS: First performing population genomic and brain transcriptional comparisons in 68 wild and domesticated chickens, we revealed evolutionary trajectories, genetic architectures and physiologic bases of adaptively behavioral alterations. To extensively decipher molecular convergence on behavioral changes thanks to domestication, we investigated selection signatures in hundreds of genomes and brain transcriptomes across chicken and 6 other domesticated mammals. Although no shared substitution was detected, a common enrichment of the adaptive mutations in regulatory sequences was observed, presenting significance to drive adaptations. Strong convergent pattern emerged at levels of gene, gene family, pathway and network. Genes implicated in neurotransmission, semaphorin, tectonic protein and modules regulating neuroplasticity were central focus of selection, supporting molecular repeatability of homoplastic behavior reshapes. Genes at nodal positions in trans-regulatory networks were preferably targeted. Consistent down-regulation of majority brain genes may be correlated with reduced brain size during domestication. Up-regulation of splicesome genes in chicken rather mammals highlights splicing as an efficient way to evolve since avian-specific genomic contraction of introns and intergenics. Genetic burden of domestication elicits a general hallmark. The commonly selected genes were relatively evolutionary conserved and associated with analogous neuropsychiatric disorders in human, revealing trade-off between adaption to life with human at the cost of neural changes affecting fitness in wild. CONCLUSIONS: After a comprehensive investigation on genomic diversity and evolutionary trajectories in chickens, we revealed basis, pattern and evolutionary significance of molecular convergence in domesticated bird and mammals, highlighted the genetic basis of a compromise on utmost adaptation to the lives with human at the cost of high risk of neurophysiological changes affecting animals' fitness in wild.

2.
Soft Matter ; 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32215386

RESUMO

The cell membranes of different cells deviate significantly in lipid compositions and thus provide varying biological environments to modulate the diffusion, organization and the resultant function of biomacromolecules. However, the detailed modulation mechanism remains elusive especially in consideration of the current overuse of the simplified membrane models such as the pure phosphatidylcholine (PC) membrane. In this work, with the typical membrane-active peptide melittin, we demonstrated that a more complicated membrane environment, such as the bacterial (IME) or plasma membrane (PM), would significantly change the organization and dynamics of melittin, by using molecular dynamics simulations as a "computational microscope". It was found that in these membrane systems, adding melittin would cause a varying degree of reduction in the lateral diffusion of lipids due to the different assembly states of peptides. Melittin tended to aggregate to oligomers in the pure PC membrane, mostly as a tetramer or trimer, while in IME or PM, its degree of oligomerization was significantly reduced. More surprisingly, melittin displayed a strong affinity with ganglioside GM3 in PM, leading to the formation of melittin-GM3 nanoclusters, which hindered its diffusion and further oligomerization. Additionally, small changes in the residue sequence of melittin could modulate the degree or structure of the peptide oligomer. Our work provides a typical example of a study on the organization and dynamics of pore-forming peptides in specific membrane environments and has great significance on the optimization of peptide sequences and the design of helix bundles in the membrane for target biological function.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32205176

RESUMO

Uncovering the functionally essential variations related to tumorigenesis and tumor progression from cancer genomics data is still challenging due to the genetic diversity among patients, and extensive inter- and intra-tumoral heterogeneity at different levels of gene expression regulation, including but not limited to the genomic, epigenomic, and transcriptional levels. To minimize the impact of germline genetic heterogeneities, in this study, we establish multiple primary cultures from the primary and recurrent tumors of a single patient with hepatocellular carcinoma (HCC). Multi-omics sequencing was performed for these cultures that encompass the diversity of tumor cells from the same patient. Variations in the genome sequence, epigenetic modification, and gene expression are used to infer the phylogenetic relationships of these cell cultures. We find the discrepancy among the relationships revealed by single nucleotide variations (SNVs) and transcriptional/epigenomic profiles from the cell cultures. We fail to find overlap between sample-specific mutated genes and differentially expressed genes (DEGs), suggesting that most of the heterogeneous SNVs among tumor stages or lineages of the patient are functionally insignificant. Moreover, copy number alterations (CNAs) and DNA methylation variation within gene bodies, rather than promoters, are significantly correlated with gene expression variability among these cell cultures. Pathway analysis of CNA/DNA methylation-related genes indicates that a single cell clone from the recurrent tumor exhibits distinct cellular characteristics and tumorigenicity, and such an observation is further confirmed by cellular experiments both in vitro and in vivo. Our systematic analysis reveals that CNAs and epigenomic changes, rather than SNVs, are more likely to contribute to the phenotypic diversity among subpopulations in the tumor. These findings suggest that new therapeutic strategies targeting gene dosage and epigenetic modification should be considered in personalized cancer medicine. This culture model may be applied to the further identification of plausible determinants of cancer metastasis and relapse.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32033954

RESUMO

Cytophaga hutchinsonii cells can bind to the surface of insoluble cellulose and degrade it utilizing a novel cell-contact dependent mechanism, in which the outer membrane proteins may play important roles. In this study, the deletion of a gene locus chu_1165, which encodes a hypothetical protein with a 32% identity with TlpB, a disulfide oxidoreductase in Flavobacterium psychrophilum, caused a complete cellulolytic defect in C. hutchinsonii Further study showed that the cells of Δ1165 could not bind to cellulose and many outer membrane proteins that can bind to cellulose were significantly decreased. The N-terminal region of CHU_1165 is anchored to the cytoplasmic membrane with five predicted transmembrane helices, and the C-terminal region is predicted to stretch to the periplasm and has a similar Trx-fold containing a Cys-X-X-Cys motif which is conserved in disulfide oxidoreductases. Recombinant CHU_1165His containing the Cys-X-X-Cys motif was able to reduce the disulfide bonds of insulin in vitro Site directed mutation showed that the cysteines in the Cys-X-X-Cys motif and at residues 106, 108 were indispensable for the function of CHU_1165. Western blot showed that CHU_1165 was in an oxidized state in vivo, suggesting that it may act as an oxidase to catalyze disulfide bond formation. However, many of the decreased outer membrane proteins that were essential for cellulose degradation contained no or one cysteine and the mutation of the cysteine in them did not affect cellulose degradation, indicating that CHU_1165 may have an indirect or pleiotropic effect on the function of these outer membrane proteins.IMPORTANCE Cytophaga hutchinsonii could rapidly digest cellulose in a contact-dependent manner, in which the outer membrane proteins may play important roles. In this study, a hypothetical protein, CHU_1165, characterized as a disulfide oxidoreductase, is essential for cellulose degradation through affecting the cellulose binding ability of many outer membrane proteins in C. hutchinsonii Disulfide oxidoreductases are involved in disulfide bond formation. However, our studies showed that many of the decreased outer membrane proteins that were essential for cellulose degradation contained no or one cysteine, and the mutation of cysteine did not affect their function, indicating that CHU_1165 did not facilitate these proteins in the formation of a disulfide bond. It may have an indirect or pleiotropic effect on the function of these outer membrane proteins. Our study provides an orientation for exploring the proteins that assist the appropriate conformation of many outer membrane proteins essential for cellulose degradation, which is important for exploring the novel mechanism of cellulose degradation in C. hutchinsonii.

5.
J Cell Physiol ; 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32083315

RESUMO

Oxidative stress is a major pathogenesis of some ocular surface diseases. Our previous study demonstrated that epidermal growth factor (EGF)-activated reactive oxygen species (ROS) could protect against human corneal epithelial cell (HCE) injury. In the present study, we aimed to explore the role and mechanisms of oxidative stress and mitochondrial autophagy in HCE cells subjected to scratch injury. CCK-8 assays, EdU assays, Western blot analysis, wound-healing assays, and flow cytometry were conducted to determine cell viability, proliferation, protein expression, cell apoptosis, and intracellular ROS levels, respectively. The results showed that EGF could promote damage repair and inhibit cell apoptosis in scratch injured HCE cells by upregulating ROS (**p < .01, ***p < .001). EGF also induced mitochondrial autophagy and alleviated mitochondrial damage. Interestingly, the combination of the mitochondrial autophagy inhibitor and mitochondrial division inhibitor 1 (MDIVI-1) with EGF could reduce cell proliferation, viability, and the ROS level (*p < .05, **p < .01, ***p < .001). Treatment using the ROS inhibitor N-acetyl- l-cysteine abrogated the increase in mitochondrial membrane potential after EGF treatment. (*p < .05). Taken together, these findings indicated that EGF plays an important role in HCE damage repair and could activate ROS to protect against HCE injury by inducing mitochondrial autophagy via activation of TRPM2.

6.
Spectrochim Acta A Mol Biomol Spectrosc ; 227: 117687, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31676150

RESUMO

Graphite phase carbon nitride (g-C3N4) with triazine ring structures is a polymeric metal-free semiconductor with a medium bandgap and two-dimensional layered structure. g-C3N4 has attracted attention because of its photocatalytic applications, such as the photodegradation of pollution and hydrogen production via water splitting. Defective elements and sites are two essential factors in rationally designing highly-efficient photocatalysts based on g-C3N4 at the nanoscale. When the molecule absorbs energy and enters an excited state, electrons migrate and the charge distribution changes accordingly. The properties of the excited states of g-C3N4 are related to its defect elements and sites. Therefore, it is necessary to understand the effects of defects on excited states in the design of g-C3N4 catalysts. In this paper, the excited-state characteristics of intrinsic g-C3N4 and g-C3N4 with C- and N-atom defects are analyzed by density functional theory. We apply quantum chemistry and wave function analysis to determine the hole-electron distributions and charge transfer directions. To measure and discuss the characteristics of electron excitation using quantitative numerical methods, the D, Sr, H, and t indices are calculated. Our results promote a deeper understanding of the roles of defective elements and sites in photocatalysis by g-C3N4.

7.
Cell Death Dis ; 10(12): 922, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801953

RESUMO

Acquired resistance to chemotherapy is a major obstacle in breast cancer (BC) treatment. Accumulated evidence has uncovered that microRNAs (miRNAs) are vital regulators of chemoresistance in cancer. Growing studies reveal that miR-137 acts as a suppressor in tumor progression. However, it remains obscure the role of miR-137 in modulating the sensitivity of BC cells to doxorubicin (DOX). In this study, we demonstrate that miR-137 exerts a significant effect on repressing the development of chemoresistance of BC cells in response to DOX via attenuating epithelial-mesenchymal transition (EMT) of tumor cells in vitro and in vivo. MiR-137 overexpression dramatically elevated the sensitivity of BC cells to DOX as well as impaired the DOX-promoted EMT of tumor cells. Mechanistically, miR-137 directly targeted dual-specificity phosphatase 4 (DUSP4) to impact on the EMT and chemoresistance of BC cells upon DOX treatment. Consistently, decreased DUSP4 efficiently enhanced the sensitivity of BC cells to DOX while overexpressed DUSP4 significantly diminished the beneficial effect of miR-137 on BC cells chemoresistance. Moreover, the increased miR-137 heightened the sensitivity of BC cells-derived tumors to DOX through targeting DUSP4 in vivo. Together, our results provide a novel insight into the DOX resistance of BC cells and miR-137 may serve as a new promising therapeutic target for overcoming chemoresistance in BC.

8.
Huan Jing Ke Xue ; 40(6): 2493-2500, 2019 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854638

RESUMO

To characterize the dry and wet deposition of atmospheric trace elements in urban Beijing, both active and passive samplers were used to collect bulk and wet sedimentation samples between May 2014 and April 2015.The concentrations of 19 trace elements (Na, Mg, Al, K, Ca, V, Cr, Mn, Fe, Cu, Zn, As, Se, Mo, Cd, Sb, Tl, Th, and U) in the samples were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). The results show that the concentrations of metals in bulk deposition samples[7160.68 µg·L-1 (Ca)-0.02 µg·L-1 (Th)] were generally higher than those in wet deposition samples[4237.74 µg·L-1 (Ca)-0.01 µg·L-1 (Th)], but the enrichment factors of each metal in the two kinds of samples were less different. Of note, the enrichment factors of Cu, As, Tl, Zn, Cd, Se, and Sb were all larger than 100, thus indicating that these heavy metals were mainly from anthropogenic sources. The statistical analysis of the air mass trajectory shows that the precipitation chemistry in urban Beijing is mainly affected by southward air flows. The air mass originating from the southwest region always had higher concentrations of Ca, Mg, Fe, Al, Cu, Mo, U, and Th, whereas the air mass from the south had higher concentrations of K, Zn, Mn, Sb, Cd, and Tl. During the observation period, the bulk deposition fluxes of metals varied from 3591.35 mg·(m2·a)-1 (Ca)-0.01 mg·(m2·a)-1 (Th), and wet deposition fluxes varied from 1847.78 mg·(m2·a)-1 (Ca)-0.01 mg·(m2·a)-1 (Th). The dry deposition fluxes of the 19 metals varied from 1743.57 mg·(m2·a)-1 (Ca)-0.01 mg·(m2·a)-1 (Th). The particle size has important implications in the evaluation of the relative importance of dry deposition versus wet deposition during the scavenging of trace elements in air.

9.
Epigenetics Chromatin ; 12(1): 66, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31711526

RESUMO

BACKGROUND: Numerous cell types can be identified within plant tissues and animal organs, and the epigenetic modifications underlying such enormous cellular heterogeneity are just beginning to be understood. It remains a challenge to infer cellular composition using DNA methylomes generated for mixed cell populations. Here, we propose a semi-reference-free procedure to perform virtual methylome dissection using the nonnegative matrix factorization (NMF) algorithm. RESULTS: In the pipeline that we implemented to predict cell-subtype percentages, putative cell-type-specific methylated (pCSM) loci were first determined according to their DNA methylation patterns in bulk methylomes and clustered into groups based on their correlations in methylation profiles. A representative set of pCSM loci was then chosen to decompose target methylomes into multiple latent DNA methylation components (LMCs). To test the performance of this pipeline, we made use of single-cell brain methylomes to create synthetic methylomes of known cell composition. Compared with highly variable CpG sites, pCSM loci achieved a higher prediction accuracy in the virtual methylome dissection of synthetic methylomes. In addition, pCSM loci were shown to be good predictors of the cell type of the sorted brain cells. The software package developed in this study is available in the GitHub repository (https://github.com/Gavin-Yinld). CONCLUSIONS: We anticipate that the pipeline implemented in this study will be an innovative and valuable tool for the decoding of cellular heterogeneity.

10.
Nat Commun ; 10(1): 4815, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645571

RESUMO

Nanoconfinement could dramatically change molecular transport and reaction kinetics in heterogeneous catalysis. Here we specifically design a core-shell nanocatalyst with aligned linear nanopores for single-molecule studies of the nanoconfinement effects. The quantitative single-molecule measurements reveal unusual lower adsorption strength and higher catalytic activity on the confined metal reaction centres within the nanoporous structure. More surprisingly, the nanoconfinement effects on enhanced catalytic activity are larger for catalysts with longer and narrower nanopores. Experimental evidences, including molecular orientation, activation energy, and intermediate reactive species, have been gathered to provide a molecular level explanation on how the nanoconfinement effects enhance the catalyst activity, which is essential for the rational design of highly-efficient catalysts.

11.
Aging Clin Exp Res ; 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31267378

RESUMO

BACKGROUND: Little is known about muscle strength and physical performance in Chinese. AIM: This study aimed to assess the age- and sex-related differences in muscle strength and physical performance in older Chinese. METHODS: Three hundred and eight healthy participants (110 males and 198 females) age 68.3 ± 6.1 (mean ± SD) years were enrolled in this cross-sectional study. The handgrip muscle strength (HGS) of the dominant hand was measured using a Jamar dynamometer. Physical performance was assessed by the Timed Up and Go test (TUG). The EuroQol five-dimension questionnaire (EQ-5D) was used to evaluate participants' health status. RESULTS: Men showed higher levels of HGS with a smaller percentage having low muscle strength compared with women. No differences were observed in TUG between sexes. No significant association of TUG and age was observed in males. However, older females had increased TUG and hence poorer performance. Good health status was associated with better physical performance but was not related to muscle strength in either sex. DISCUSSION: In men, there was no correlation between age and TUG, although a negative association with handgrip muscle strength was observed. For women, both muscle strength and physical performance declined with age. The sex-related differences in aging effects on physical performance in our study could partly explain why women have a higher incidence of hip fracture than men. CONCLUSION: Chinese women may be more vulnerable to severe sarcopenia in old age than men.

12.
J Ind Microbiol Biotechnol ; 46(11): 1479-1490, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31321576

RESUMO

The crystalline region of cellulose is the main barrier to the utilization of crystalline cellulose. Cytophaga hutchinsonii actively digests the crystalline region of cellulose by an unknown mechanism. Transposon mutagenesis was done to identify a novel gene locus chu_1557, which is required for efficient disruption of the crystalline region of cellulose, and the absence of CHU_1557 resulted in decreased glucose assimilation efficiency. The defect of the mutant in the disruption of the crystalline region of cellulose was partially retained by additional glucose or pre-culturing the mutant in a low glucose concentration medium which could improve its glucose absorption efficiency. These results suggested that extracellular glucose has important roles in the disruption of crystalline cellulose by C. hutchinsonii. Further study showed that the expression of an outer membrane protein CHU_3732 was downregulated by the absence of CHU_1557 in a low glucose concentration medium. CHU_3732 was involved in uptake of glucose and its expression was induced by a low concentration of glucose. CHU_3732 was predicted to be a porin, so we inferred that it may work as a glucose transport channel in the outer membrane. Based on these results, we deduced that CHU_1557 played a role in the process of glucose assimilation and its disruption affected the expression of other proteins related to glucose transportation such as CHU_3732, and then affected the cell growth in a low glucose concentration medium and disruption of the crystalline region of cellulose.


Assuntos
Celulose/metabolismo , Cytophaga/metabolismo , Glucose/metabolismo , Proteínas de Membrana/metabolismo , Cytophaga/genética , Proteínas de Membrana/genética , Mutagênese
13.
Molecules ; 24(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067828

RESUMO

Antimicrobial peptides (AMPs), as a key component of the immune defense systems of organisms, are a promising solution to the serious threat of drug-resistant bacteria to public health. As one of the most representative and extensively studied AMPs, melittin has exceptional broad-spectrum activities against microorganisms, including both Gram-positive and Gram-negative bacteria. Unfortunately, the action mechanism of melittin with bacterial membranes, especially the underlying physics of peptide-induced membrane poration behaviors, is still poorly understood, which hampers efforts to develop melittin-based drugs or agents for clinical applications. In this mini-review, we focus on recent advances with respect to the membrane insertion behavior of melittin mostly from a computational aspect. Membrane insertion is a prerequisite and key step for forming transmembrane pores and bacterial killing by melittin, whose occurrence is based on overcoming a high free-energy barrier during the transition of melittin molecules from a membrane surface-binding state to a transmembrane-inserting state. Here, intriguing simulation results on such transition are highlighted from both kinetic and thermodynamic aspects. The conformational changes and inter-peptide cooperation of melittin molecules, as well as melittin-induced disturbances to membrane structure, such as deformation and lipid extraction, are regarded as key factors influencing the insertion of peptides into membranes. The associated intermediate states in peptide conformations, lipid arrangements, membrane structure, and mechanical properties during this process are specifically discussed. Finally, potential strategies for enhancing the poration ability and improving the antimicrobial performance of AMPs are included as well.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Membrana Celular/química , Meliteno/química , Conformação Proteica , Peptídeos Catiônicos Antimicrobianos/genética , Membrana Celular/genética , Biologia Computacional , Bactérias Gram-Negativas/química , Bactérias Gram-Negativas/patogenicidade , Bactérias Gram-Positivas/química , Bactérias Gram-Positivas/patogenicidade , Cinética , Lipídeos de Membrana/química , Lipídeos de Membrana/genética , Termodinâmica
14.
Spectrochim Acta A Mol Biomol Spectrosc ; 220: 117145, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31141784

RESUMO

The rates of charge separation and charge recombination of the cyanine dye/C60 heterojunction solar cell in an external electric field were provided using the Marcus and Marcus-Levich-Jortner formalisms. The vibrational mode as another influencing factor was also introduced into the rate expression for the planar heterojunction solar cell. Detailed theoretical analysis of the excited-state of the Cy3/C60 blend was achieved using density functional theory and time-dependent density functional theory. The Gibbs free energy was regulated by an external electric field, while the reorganisation energy presented the opposite conclusion. Frequency analysis was utilised to demonstrate the energy stability of the obtained structures. The rate calculated using the Marcus formalism was greater than that obtained by the Marcus-Levich-Jortner formalism. Consideration of the calculated rates in all vibration modes and at different external electric field strengths indicated that vibrational mode and external electric field played important roles in determining the rates of charge separate and charge recombination, which could provide a more accurate theoretical rate for organic photovoltaic devices.

15.
Front Microbiol ; 10: 522, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930887

RESUMO

Salmonella typhimurium, a Gram-negative food-borne pathogen, induces impairment in intestinal mucosal barrier function frequently. The injury is related to many factors such as inflammation, oxidative stress, tight junctions and flora changes in the host intestine. Musca domestica cecropin (Mdc), a novel antimicrobial peptide containing 40 amino acids, has potential antibacterial, anti-inflammatory, and immunological functions. It remains unclear exactly whether and how Mdc reduces colonic mucosal barrier damage caused by S. typhimurium. Twenty four 6-week-old male mice were divided into four groups: normal group, control group (S. typhimurium-challenged), Mdc group, and ceftriaxone sodium group (Cs group). HE staining and transmission electron microscopy (TEM) were performed to observe the morphology of the colon tissues. Bacterial load of S. typhimurium in colon, liver and spleen were determined by bacterial plate counting. Inflammatory factors were detected by enzyme linked immunosorbent assay (ELISA). Oxidative stress levels in the colon tissues were also analyzed. Immunofluorescence analysis, RT-PCR, and Western blot were carried out to examine the levels of tight junction and inflammatory proteins. The intestinal microbiota composition was assessed via 16s rDNA sequencing. We successfully built and evaluated an S. typhimurium-infection model in mice. Morphology and microcosmic change of the colon tissues confirmed the protective qualities of Mdc. Mdc could inhibit colonic inflammation and oxidative stress. Tight junctions were improved significantly after Mdc administration. Interestingly, Mdc ameliorated intestinal flora imbalance, which may be related to the improvement of tight junction. Our results shed a new light on protective effects and mechanism of the antimicrobial peptide Mdc on colonic mucosal barrier damage caused by S. typhimurium infection. Mdc is expected to be an important candidate for S. typhimurium infection treatment.

16.
Adv Healthc Mater ; 8(9): e1801521, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30866165

RESUMO

Antimicrobial peptides (AMPs) promise a fundamental solution to the devastating threat of drug-resistant bacteria. However, drawbacks of AMPs (e.g., poor cell membrane penetration efficiency) seriously block their clinical use. In this work, rational design of a hybrid complex of melittin (as a representative AMP) and graphene or graphene oxide (Gra or GO) nanosheets for enhanced antibacterial ability is achieved, via combining in-silico prediction and in-tube test. In comparison to pristine melittin, the specifically designed AMP-Gra (/GO) complex exhibits remarkable efficiency in transmembrane perforation with an over tenfold decrease in the threshold working concentration of peptide; moreover, it has an up to 20-fold enhancement in antibacterial activity against both Gram-negative and Gram-positive bacteria. Such improvement is ascribed to the synergetic insertion of nanosheets and melittin due to similarity in antibacterial mechanism between them and is further regulated by the structural factors of the complex, including the intersheet spacing and surface functionalization of the Gra/GO sheets, etc. These results provide practical guidelines to engineer AMPs with nanotechnology for improved antimicrobial performances, especially based on targeted functionalization of the Gra/GO nanosheets.

17.
PLoS One ; 14(2): e0211581, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30721267

RESUMO

Heterogeneity is prevalent in cancer both between and within individuals. Although a few studies have identified several circulating microRNAs (miRNAs) for cancer diagnosis, the complete plasma miRNA profile for hepatocellular carcinoma (HCC) remains undefined, and whether the plasma miRNA profiles are heterogeneous is unknown. Here, we obtained individualized plasma miRNA profiles of both healthy subjects and HCC patients via genome-wide deep sequencing. Compared with the highly stable miRNA profile of the healthy subjects, the profile of the HCC patients was highly variable. Seven miRNAs were optimized as potential plasma-based biomarkers for HCC diagnosis. Combined with the clinical data of The Cancer Genome Atlas (TCGA) cohort, three out of the seven miRNAs were correlated with the survival of the HCC patients. To investigate the effect of cancer cells on the plasma miRNAs profile, we compared the most differentially expressed miRNAs between plasma and tissues. Furthermore, miRNAseq data of HCC patients from TCGA were recruited for comparisons. We found that the differences between plasma and tissue were inconsistent, suggesting that other cells in addition to cancer cells also contribute to plasma miRNAs. Using two HCC cancer cell lines, we examined the levels of seven differentially expressed miRNAs. The reverse direction of certain miRNAs alterations between cancer cells and media further confirmed that miRNAs may be selectively pump out by cancer cells.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/química , Linhagem Celular Tumoral , MicroRNA Circulante/sangue , MicroRNA Circulante/química , Humanos , Masculino , MicroRNAs/metabolismo
18.
Mol Biol Evol ; 36(3): 541-552, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649444

RESUMO

Large genomes with elevated mutation rates are prone to accumulating deleterious mutations more rapidly than natural selection can purge (Muller's ratchet). As a consequence, it may lead to the extinction of small populations. Relative to most unicellular organisms, cancer cells, with large and nonrecombining genome and high mutation rate, could be particularly susceptible to such "mutational meltdown." However, the most common type of mutation in organismal evolution, namely, deleterious mutation, has received relatively little attention in the cancer biology literature. Here, by monitoring single-cell clones from HeLa cell lines, we characterize deleterious mutations that retard the rate of cell proliferation. The main mutation events are copy number variations (CNVs), which, estimated from fitness data, happen at a rate of 0.29 event per cell division on average. The mean fitness reduction, estimated reaching 18% per mutation, is very high. HeLa cell populations therefore have very substantial genetic load and, at this level, natural population would likely face mutational meltdown. We suspect that HeLa cell populations may avoid extinction only after the population size becomes large enough. Because CNVs are common in most cell lines and tumor tissues, the observations hint at cancer cells' vulnerability, which could be exploited by therapeutic strategies.


Assuntos
Proliferação de Células/genética , Variações do Número de Cópias de DNA , Carga Genética , Células HeLa/fisiologia , Acúmulo de Mutações , Humanos , Modelos Biológicos , Mutação , Células PC-3
19.
Genome Biol Evol ; 11(2): 486-496, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30689862

RESUMO

Segmental duplications are an important class of mutations. Because a large proportion of segmental duplications may often be strongly deleterious, high frequency or fixed segmental duplications may represent only a tiny fraction of the mutational input. To understand the emergence and elimination of segmental duplications, we survey polymorphic duplications, including tandem and interspersed duplications, in natural populations of Drosophila by haploid embryo genomes. As haploid embryos are not expected to be heterozygous, the genome, sites of heterozygosity (referred to as pseudoheterozygous sites [PHS]), may likely represent recent duplications that have acquired new mutations. Among the 29 genomes of Drosophila melanogaster, we identify 2,282 polymorphic PHS duplications (linked PHS regions) in total or 154 PHS duplications per genome. Most PHS duplications are small (83.4% < 500 bp), Drosophila melanogaster lineage specific, and strain specific (72.6% singletons). The excess of the observed singleton PHS duplications deviates significantly from the neutral expectation, suggesting that most PHS duplications are strongly deleterious. In addition, these small segmental duplications are not evenly distributed in genomic regions and less common in noncoding functional element regions. The underrepresentation in RNA polymerase II binding sites and regions with active histone modifications is correlated with ages of duplications. In conclusion, small segmental duplications occur frequently in Drosophila but rapidly eliminated by natural selection.


Assuntos
Drosophila melanogaster/genética , Duplicação Gênica , Animais , Genoma de Inseto , Seleção Genética
20.
Mol Genet Genomics ; 294(1): 121-133, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30238319

RESUMO

Gene duplication and amino acid substitution are two types of genetic innovations of antiviral genes in inhibiting the emerging pathogens in different species. Mx proteins are well known for inhibiting negative-stranded RNA viruses and have evolved a number of paralogs or orthologs, showing distinct antiviral activities or capacities within or between species. The presence of upstream genes in the signaling pathway(s) that activates Mx genes (upstream regulators of Mx gene) also exhibits variety across species. The association between the evolution of Mx gene and their upstream regulators and the various antiviral capacities in host species has not been investigated. Herein, we traced the evolution of Mx gene and profiled the gene birth/death events on each branch of the 64 chordate species. We provided additional support that the diversity in gene member and amino acid changes in the different clades is correlated to their various antiviral activities of the species. We identified amino acid substitutions that may lead to the functional divergence between Mx paralogs in rodents. Although the copy number of the Mx gene is conserved in birds, infection by influenza A virus (IAV) results in diverse morbidity rates in different avian species. The evidences of gene interaction in the IAV-induced pathway and the genome analysis performed in this study indicated that the existence of the upstream regulators of Mx gene exhibits variation among different species, particularly in birds. The variation is related to the differences in the expression of Mx genes, resulting in the antiviral specificity and morbidity rates in avian species. We conclude that the antiviral capacity in host species is associated with the variations in the gene number of the Mx gene family and the existence of upstream regulators of Mx gene as well.


Assuntos
Aves/virologia , Dosagem de Genes , Vírus da Influenza A/patogenicidade , Influenza Aviária/mortalidade , Proteínas de Resistência a Myxovirus/genética , Substituição de Aminoácidos , Animais , Proteínas Aviárias/genética , Aves/genética , Evolução Molecular , Duplicação Gênica , Regulação da Expressão Gênica , Variação Genética , Influenza Aviária/genética , Transdução de Sinais
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