PLOS Biology (new articles)

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Treadmilling analysis reveals new insights into dynamic FtsZ ring architecture

пт, 2018-05-18 23:00

by Diego A. Ramirez-Diaz, Daniela A. García-Soriano, Ana Raso, Jonas Mücksch, Mario Feingold, Germán Rivas, Petra Schwille

FtsZ, the primary protein of the bacterial Z ring guiding cell division, has been recently shown to engage in intriguing treadmilling dynamics along the circumference of the division plane. When coreconstituted in vitro with FtsA, one of its natural membrane anchors, on flat supported membranes, these proteins assemble into dynamic chiral vortices compatible with treadmilling of curved polar filaments. Replacing FtsA by a membrane-targeting sequence (mts) to FtsZ, we have discovered conditions for the formation of dynamic rings, showing that the phenomenon is intrinsic to FtsZ. Ring formation is only observed for a narrow range of protein concentrations at the bilayer, which is highly modulated by free Mg2+ and depends upon guanosine triphosphate (GTP) hydrolysis. Interestingly, the direction of rotation can be reversed by switching the mts from the C-terminus to the N-terminus of the protein, implying that the filament attachment must have a perpendicular component to both curvature and polarity. Remarkably, this chirality switch concurs with previously shown inward or outward membrane deformations by the respective FtsZ mutants. Our results lead us to suggest an intrinsic helicity of FtsZ filaments with more than one direction of curvature, supporting earlier hypotheses and experimental evidence.
Категории: Biology, Journals

Receptors of intermediates of carbohydrate metabolism, GPR91 and GPR99, mediate axon growth

чт, 2018-05-17 23:00

by Hosni Cherif, François Duhamel, Bruno Cécyre, Alex Bouchard, Ariane Quintal, Sylvain Chemtob, Jean-François Bouchard

During the development of the visual system, high levels of energy are expended propelling axons from the retina to the brain. However, the role of intermediates of carbohydrate metabolism in the development of the visual system has been overlooked. Here, we report that the carbohydrate metabolites succinate and α-ketoglutarate (α-KG) and their respective receptor—GPR91 and GPR99—are involved in modulating retinal ganglion cell (RGC) projections toward the thalamus during visual system development. Using ex vivo and in vivo approaches, combined with pharmacological and genetic analyses, we revealed that GPR91 and GPR99 are expressed on axons of developing RGCs and have complementary roles during RGC axon growth in an extracellular signal–regulated kinases 1 and 2 (ERK1/2)-dependent manner. However, they have no effects on axon guidance. These findings suggest an important role for these receptors during the establishment of the visual system and provide a foundational link between carbohydrate metabolism and axon growth.
Категории: Biology, Journals

Do plants have a segregated germline?

ср, 2018-05-16 23:00

by Robert Lanfear

For the last 100 years, it has been uncontroversial to state that the plant germline is set aside late in development, but there is surprisingly little evidence to support this view. In contrast, much evolutionary theory and several recent empirical studies seem to suggest the opposite—that the germlines of some and perhaps most plants may be set aside early in development. But is this really the case? How much does it matter? How can we reconcile the new evidence with existing knowledge of plant development? And is there a way to reliably establish the timing of germline segregation in both model and nonmodel plants? Answering these questions is vital to understanding one of the most fundamental aspects of plant development and evolution.
Категории: Biology, Journals

High-dimensional single-cell phenotyping reveals extensive haploinsufficiency

ср, 2018-05-16 23:00

by Shinsuke Ohnuki, Yoshikazu Ohya

Haploinsufficiency, a dominant phenotype caused by a heterozygous loss-of-function mutation, has been rarely observed. However, high-dimensional single-cell phenotyping of yeast morphological characteristics revealed haploinsufficiency phenotypes for more than half of 1,112 essential genes under optimal growth conditions. Additionally, 40% of the essential genes with no obvious phenotype under optimal growth conditions displayed haploinsufficiency under severe growth conditions. Haploinsufficiency was detected more frequently in essential genes than in nonessential genes. Similar haploinsufficiency phenotypes were observed mostly in mutants with heterozygous deletion of functionally related genes, suggesting that haploinsufficiency phenotypes were caused by functional defects of the genes. A global view of the gene network was presented based on the similarities of the haploinsufficiency phenotypes. Our dataset contains rich information regarding essential gene functions, providing evidence that single-cell phenotyping is a powerful approach, even in the heterozygous condition, for analyzing complex biological systems.
Категории: Biology, Journals

Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

ср, 2018-05-16 23:00

by Françoise Helmbacher

Muscle morphogenesis is tightly coupled with that of motor neurons (MNs). Both MNs and muscle progenitors simultaneously explore the surrounding tissues while exchanging reciprocal signals to tune their behaviors. We previously identified the Fat1 cadherin as a regulator of muscle morphogenesis and showed that it is required in the myogenic lineage to control the polarity of progenitor migration. To expand our knowledge on how Fat1 exerts its tissue-morphogenesis regulator activity, we dissected its functions by tissue-specific genetic ablation. An emblematic example of muscle under such morphogenetic control is the cutaneous maximus (CM) muscle, a flat subcutaneous muscle in which progenitor migration is physically separated from the process of myogenic differentiation but tightly associated with elongating axons of its partner MNs. Here, we show that constitutive Fat1 disruption interferes with expansion and differentiation of the CM muscle, with its motor innervation and with specification of its associated MN pool. Fat1 is expressed in muscle progenitors, in associated mesenchymal cells, and in MN subsets, including the CM-innervating pool. We identify mesenchyme-derived connective tissue (CT) as a cell type in which Fat1 activity is required for the non–cell-autonomous control of CM muscle progenitor spreading, myogenic differentiation, motor innervation, and for motor pool specification. In parallel, Fat1 is required in MNs to promote their axonal growth and specification, indirectly influencing muscle progenitor progression. These results illustrate how Fat1 coordinates the coupling of muscular and neuronal morphogenesis by playing distinct but complementary actions in several cell types.
Категории: Biology, Journals

Death and population dynamics affect mutation rate estimates and evolvability under stress in bacteria

пт, 2018-05-11 23:00

by Antoine Frenoy, Sebastian Bonhoeffer

The stress-induced mutagenesis hypothesis postulates that in response to stress, bacteria increase their genome-wide mutation rate, in turn increasing the chances that a descendant is able to better withstand the stress. This has implications for antibiotic treatment: exposure to subinhibitory doses of antibiotics has been reported to increase bacterial mutation rates and thus probably the rate at which resistance mutations appear and lead to treatment failure. More generally, the hypothesis posits that stress increases evolvability (the ability of a population to generate adaptive genetic diversity) and thus accelerates evolution. Measuring mutation rates under stress, however, is problematic, because existing methods assume there is no death. Yet subinhibitory stress levels may induce a substantial death rate. Death events need to be compensated by extra replication to reach a given population size, thus providing more opportunities to acquire mutations. We show that ignoring death leads to a systematic overestimation of mutation rates under stress. We developed a system based on plasmid segregation that allows us to measure death and division rates simultaneously in bacterial populations. Using this system, we found that a substantial death rate occurs at the tested subinhibitory concentrations previously reported to increase mutation rate. Taking this death rate into account lowers and sometimes removes the signal for stress-induced mutagenesis. Moreover, even when antibiotics increase mutation rate, we show that subinhibitory treatments do not increase genetic diversity and evolvability, again because of effects of the antibiotics on population dynamics. We conclude that antibiotic-induced mutagenesis is overestimated because of death and that understanding evolvability under stress requires accounting for the effects of stress on population dynamics as much as on mutation rate. Our goal here is dual: we show that population dynamics and, in particular, the numbers of cell division are crucial but neglected parameters in the evolvability of a population, and we provide experimental and computational tools and methods to study evolvability under stress, leading to a reassessment of the magnitude and significance of the stress-induced mutagenesis paradigm.
Категории: Biology, Journals

Tumor-associated neutrophils suppress pro-tumoral IL-17+ γδ T cells through induction of oxidative stress

пт, 2018-05-11 23:00

by Sofia Mensurado, Margarida Rei, Telma Lança, Marianna Ioannou, Natacha Gonçalves-Sousa, Hiroshi Kubo, Marie Malissen, Venizelos Papayannopoulos, Karine Serre, Bruno Silva-Santos

Interleukin 17 (IL-17)–producing γδ T cells (γδ17 T cells) have been recently found to promote tumor growth and metastasis formation. How such γδ17 T-cell responses may be regulated in the tumor microenvironment remains, however, largely unknown. Here, we report that tumor-associated neutrophils can display an overt antitumor role by strongly suppressing γδ17 T cells. Tumor-associated neutrophils inhibited the proliferation of murine CD27− Vγ6+ γδ17 T cells via induction of oxidative stress, thereby preventing them from constituting the major source of pro-tumoral IL-17 in the tumor microenvironment. Mechanistically, we found that low expression of the antioxidant glutathione in CD27− γδ17 T cells renders them particularly susceptible to neutrophil-derived reactive oxygen species (ROS). Consistently, superoxide deficiency, or the administration of a glutathione precursor, rescued CD27− Vγ6+ γδ17 T-cell proliferation in vivo. Moreover, human Vδ1+ γδ T cells, which contain most γδ17 T cells found in cancer patients, also displayed low glutathione levels and were potently inhibited by ROS. This work thus identifies an unanticipated, immunosuppressive yet antitumoral, neutrophil/ROS/γδ17 T-cell axis in the tumor microenvironment.
Категории: Biology, Journals

Metabolic benefits of inhibition of p38α in white adipose tissue in obesity

пт, 2018-05-11 23:00

by Shengjie Zhang, Hongchao Cao, Yan Li, Yanyan Jing, Shengnan Liu, Cheng Ye, Hui Wang, Shuxian Yu, Chengyuan Peng, Lijian Hui, Yu-cheng Wang, Haibing Zhang, Feifan Guo, Qiwei Zhai, Hui Wang, Ruimin Huang, Ling Zhang, Jingjing Jiang, Wei Liu, Hao Ying

p38 has long been known as a central mediator of protein kinase A (PKA) signaling in brown adipocytes, which positively regulate the transcription of uncoupling protein 1 (UCP-1). However, the physiological role of p38 in adipose tissues, especially the white adipose tissue (WAT), is largely unknown. Here, we show that mice lacking p38α in adipose tissues display a lean phenotype, improved metabolism, and resistance to diet-induced obesity. Surprisingly, ablation of p38α causes minimal effects on brown adipose tissue (BAT) in adult mice, as evident from undetectable changes in UCP-1 expression, mitochondrial function, body temperature (BT), and energy expenditure. In contrast, genetic ablation of p38α in adipose tissues not only markedly facilitates the browning in WAT upon cold stress but also prevents diet-induced obesity. Consistently, pharmaceutical inhibition of p38α remarkably enhances the browning of WAT and has metabolic benefits. Furthermore, our data suggest that p38α deficiency promotes white-to-beige adipocyte reprogramming in a cell-autonomous manner. Mechanistically, inhibition of p38α stimulates the UCP-1 transcription through PKA and its downstream cAMP-response element binding protein (CREB), which form a positive feedback loop that functions to reinforce the white-to-beige phenotypic switch during cold exposure. Together, our study reveals that inhibition of p38α is able to promote WAT browning and confer metabolic benefits. Our study also indicates that p38α in WAT represents an exciting pharmacological target to combat obesity and metabolic diseases.
Категории: Biology, Journals

Hey1- and p53-dependent TrkC proapoptotic activity controls neuroblastoma growth

пт, 2018-05-11 23:00

by Marie Ménard, Clélia Costechareyre, Gabriel Ichim, Jonathan Blachier, David Neves, Loraine Jarrosson-Wuilleme, Reinhard Depping, Jan Koster, Pierre Saintigny, Patrick Mehlen, Servane Tauszig-Delamasure

The neurotrophin-3 (NT-3) receptor tropomyosin receptor kinase C (TrkC/NTRK3) has been described as a dependence receptor and, as such, triggers apoptosis in the absence of its ligand NT-3. This proapoptotic activity has been proposed to confer a tumor suppressor activity to this classic tyrosine kinase receptor (RTK). By investigating interacting partners that might facilitate TrkC-induced cell death, we have identified the basic helix-loop-helix (bHLH) transcription factor Hey1 and importin-α3 (karyopherin alpha 4 [KPNA4]) as direct interactors of TrkC intracellular domain, and we show that Hey1 is required for TrkC-induced apoptosis. We propose here that the cleaved proapoptotic portion of TrkC intracellular domain (called TrkC killer-fragment [TrkC-KF]) is translocated to the nucleus by importins and interacts there with Hey1. We also demonstrate that Hey1 and TrkC-KF transcriptionally silence mouse double minute 2 homolog (MDM2), thus contributing to p53 stabilization. p53 transcriptionally regulates the expression of TrkC-KF cytoplasmic and mitochondrial interactors cofactor of breast cancer 1 (COBRA1) and B cell lymphoma 2–associated X (BAX), which will subsequently trigger the intrinsic pathway of apoptosis. Of interest, TrkC was proposed to constrain tumor progression in neuroblastoma (NB), and we demonstrate in an avian model that TrkC tumor suppressor activity requires Hey1 and p53.
Категории: Biology, Journals

Rif1 prolongs the embryonic S phase at the <i>Drosophila</i> mid-blastula transition

чт, 2018-05-10 23:00

by Charles A. Seller, Patrick H. O’Farrell

In preparation for dramatic morphogenetic events of gastrulation, rapid embryonic cell cycles slow at the mid-blastula transition (MBT). In Drosophila melanogaster embryos, down-regulation of cyclin-dependent kinase 1 (Cdk1) activity initiates this slowing by delaying replication of heterochromatic satellite sequences and extending S phase. We found that Cdk1 activity inhibited the chromatin association of Rap1 interacting factor 1 (Rif1), a candidate repressor of replication. Furthermore, Rif1 bound selectively to satellite sequences following Cdk1 down-regulation at the MBT. In the next S phase, Rif1 dissociated from different satellites in an orderly schedule that anticipated their replication. Rif1 lacking potential phosphorylation sites failed to dissociate and dominantly prevented completion of replication. Loss of Rif1 in mutant embryos shortened the post-MBT S phase and rescued embryonic cell cycles disrupted by depletion of the S phase–promoting kinase, cell division cycle 7 (Cdc7). Our work shows that Rif1 and S phase kinases compose a replication timer controlling first the developmental onset of late replication and then the precise schedule of replication within S phase. In addition, we describe how onset of late replication fits into the progressive maturation of heterochromatin during development.
Категории: Biology, Journals

The Cybathlon BCI race: Successful longitudinal mutual learning with two tetraplegic users

чт, 2018-05-10 23:00

by Serafeim Perdikis, Luca Tonin, Sareh Saeedi, Christoph Schneider, José del R. Millán

This work aims at corroborating the importance and efficacy of mutual learning in motor imagery (MI) brain–computer interface (BCI) by leveraging the insights obtained through our participation in the BCI race of the Cybathlon event. We hypothesized that, contrary to the popular trend of focusing mostly on the machine learning aspects of MI BCI training, a comprehensive mutual learning methodology that reinstates the three learning pillars (at the machine, subject, and application level) as equally significant could lead to a BCI–user symbiotic system able to succeed in real-world scenarios such as the Cybathlon event. Two severely impaired participants with chronic spinal cord injury (SCI), were trained following our mutual learning approach to control their avatar in a virtual BCI race game. The competition outcomes substantiate the effectiveness of this type of training. Most importantly, the present study is one among very few to provide multifaceted evidence on the efficacy of subject learning during BCI training. Learning correlates could be derived at all levels of the interface—application, BCI output, and electroencephalography (EEG) neuroimaging—with two end-users, sufficiently longitudinal evaluation, and, importantly, under real-world and even adverse conditions.
Категории: Biology, Journals

Identifying novel strategies for treating human hair loss disorders: Cyclosporine A suppresses the Wnt inhibitor, SFRP1, in the dermal papilla of human scalp hair follicles

вт, 2018-05-08 23:00

by Nathan J. Hawkshaw, Jonathan A. Hardman, Iain S. Haslam, Asim Shahmalak, Amos Gilhar, Xinhong Lim, Ralf Paus

Hair growth disorders often carry a major psychological burden. Therefore, more effective human hair growth–modulatory agents urgently need to be developed. Here, we used the hypertrichosis-inducing immunosuppressant, Cyclosporine A (CsA), as a lead compound to identify new hair growth–promoting molecular targets. Through microarray analysis we identified the Wnt inhibitor, secreted frizzled related protein 1 (SFRP1), as being down-regulated in the dermal papilla (DP) of CsA-treated human scalp hair follicles (HFs) ex vivo. Therefore, we further investigated the function of SFRP1 using a pharmacological approach and found that SFRP1 regulates intrafollicular canonical Wnt/β-catenin activity through inhibition of Wnt ligands in the human hair bulb. Conversely, inhibiting SFRP1 activity through the SFRP1 antagonist, WAY-316606, enhanced hair shaft production, hair shaft keratin expression, and inhibited spontaneous HF regression (catagen) ex vivo. Collectively, these data (a) identify Wnt signalling as a novel, non–immune-inhibitory CsA target; (b) introduce SFRP1 as a physiologically important regulator of canonical β-catenin activity in a human (mini-)organ; and (c) demonstrate WAY-316606 to be a promising new promoter of human hair growth. Since inhibiting SFRP1 only facilitates Wnt signalling through ligands that are already present, this ‘ligand-limited’ therapeutic strategy for promoting human hair growth may circumvent potential oncological risks associated with chronic Wnt over-activation.
Категории: Biology, Journals

POMC neurons in heat: A link between warm temperatures and appetite suppression

пн, 2018-05-07 23:00

by Maria A. Vicent, Conor L. Mook, Matthew E. Carter

When core body temperature increases, appetite and food consumption decline. A higher core body temperature can occur during exercise, during exposure to warm environmental temperatures, or during a fever, yet the mechanisms that link relatively warm temperatures to appetite suppression are unknown. A recent study in PLOS Biology demonstrates that neurons in the mouse hypothalamus that express pro-opiomelanocortin (POMC), a neural population well known to suppress food intake, also express a temperature-sensitive ion channel, transient receptor potential vanilloid 1 (TRPV1). Slight increases in body temperature cause a TRPV1-dependent increase in activity in POMC neurons, which suppresses feeding in mice. Taken together, this study suggests a novel mechanism linking body temperature and food-seeking behavior.
Категории: Biology, Journals

Structural basis for overhang excision and terminal unwinding of DNA duplexes by TREX1

пн, 2018-05-07 23:00

by Kuan-Wei Huang, Tung-Chang Liu, Ruei-Yue Liang, Lee-Ya Chu, Hiu-Lo Cheng, Jhih-Wei Chu, Yu-Yuan Hsiao

Three prime repair exonuclease 1 (TREX1) is an essential exonuclease in mammalian cells, and numerous in vivo and in vitro data evidenced its participation in immunity regulation and in genotoxicity remediation. In these very complicated cellular functions, the molecular mechanisms by which duplex DNA substrates are processed are mostly elusive because of the lack of structure information. Here, we report multiple crystal structures of TREX1 complexed with various substrates to provide the structure basis for overhang excision and terminal unwinding of DNA duplexes. The substrates were designed to mimic the intermediate structural DNAs involved in various repair pathways. The results showed that the Leu24-Pro25-Ser26 cluster of TREX1 served to cap the nonscissile 5′-end of the DNA for precise removal of the short 3′-overhang in L- and Y-structural DNA or to wedge into the double-stranded region for further digestion along the duplex. Biochemical assays were also conducted to demonstrate that TREX1 can indeed degrade double-stranded DNA (dsDNA) to a full extent. Overall, this study provided unprecedented knowledge at the molecular level on the enzymatic substrate processing involved in prevention of immune activation and in responses to genotoxic stresses. For example, Arg128, whose mutation in TREX1 was linked to a disease state, were shown to exhibit consistent interaction patterns with the nonscissile strand in all of the structures we solved. Such structure basis is expected to play an indispensable role in elucidating the functional activities of TREX1 at the cellular level and in vivo.
Категории: Biology, Journals

Correction: Nucleic acid purification from plants, animals and microbes in under 30 seconds

пн, 2018-05-07 23:00

by Yiping Zou, Michael Glenn Mason, Yuling Wang, Eugene Wee, Conny Turni, Patrick J. Blackall, Matt Trau, Jose Ramon Botella

Категории: Biology, Journals

Robust stochastic Turing patterns in the development of a one-dimensional cyanobacterial organism

пт, 2018-05-04 23:00

by Francesca Di Patti, Laura Lavacchi, Rinat Arbel-Goren, Leora Schein-Lubomirsky, Duccio Fanelli, Joel Stavans

Under nitrogen deprivation, the one-dimensional cyanobacterial organism Anabaena sp. PCC 7120 develops patterns of single, nitrogen-fixing cells separated by nearly regular intervals of photosynthetic vegetative cells. We study a minimal, stochastic model of developmental patterns in Anabaena that includes a nondiffusing activator, two diffusing inhibitor morphogens, demographic fluctuations in the number of morphogen molecules, and filament growth. By tracking developing filaments, we provide experimental evidence for different spatiotemporal roles of the two inhibitors during pattern maintenance and for small molecular copy numbers, justifying a stochastic approach. In the deterministic limit, the model yields Turing patterns within a region of parameter space that shrinks markedly as the inhibitor diffusivities become equal. Transient, noise-driven, stochastic Turing patterns are produced outside this region, which can then be fixed by downstream genetic commitment pathways, dramatically enhancing the robustness of pattern formation, also in the biologically relevant situation in which the inhibitors' diffusivities may be comparable.
Категории: Biology, Journals

Morphological changes of plasma membrane and protein assembly during clathrin-mediated endocytosis

чт, 2018-05-03 23:00

by Aiko Yoshida, Nobuaki Sakai, Yoshitsugu Uekusa, Yuka Imaoka, Yoshitsuna Itagaki, Yuki Suzuki, Shige H. Yoshimura

Clathrin-mediated endocytosis (CME) proceeds through a series of morphological changes of the plasma membrane induced by a number of protein components. Although the spatiotemporal assembly of these proteins has been elucidated by fluorescence-based techniques, the protein-induced morphological changes of the plasma membrane have not been fully clarified in living cells. Here, we visualize membrane morphology together with protein localizations during CME by utilizing high-speed atomic force microscopy (HS-AFM) combined with a confocal laser scanning unit. The plasma membrane starts to invaginate approximately 30 s after clathrin starts to assemble, and the aperture diameter increases as clathrin accumulates. Actin rapidly accumulates around the pit and induces a small membrane swelling, which, within 30 s, rapidly covers the pit irreversibly. Inhibition of actin turnover abolishes the swelling and induces a reversible open–close motion of the pit, indicating that actin dynamics are necessary for efficient and irreversible pit closure at the end of CME.
Категории: Biology, Journals

Active photosynthetic inhibition mediated by MPK3/MPK6 is critical to effector-triggered immunity

чт, 2018-05-03 23:00

by Jianbin Su, Liuyi Yang, Qiankun Zhu, Hongjiao Wu, Yi He, Yidong Liu, Juan Xu, Dean Jiang, Shuqun Zhang

Extensive research revealed tremendous details about how plants sense pathogen effectors during effector-triggered immunity (ETI). However, less is known about downstream signaling events. In this report, we demonstrate that prolonged activation of MPK3 and MPK6, two Arabidopsis pathogen-responsive mitogen-activated protein kinases (MPKs), is essential to ETI mediated by both coiled coil-nucleotide binding site-leucine rich repeats (CNLs) and toll/interleukin-1 receptor nucleotide binding site-leucine rich repeats (TNLs) types of R proteins. MPK3/MPK6 activation rapidly alters the expression of photosynthesis-related genes and inhibits photosynthesis, which promotes the accumulation of superoxide (O2•−) and hydrogen peroxide (H2O2), two major reactive oxygen species (ROS), in chloroplasts under light. In the chemical-genetically rescued mpk3 mpk6 double mutants, ETI-induced photosynthetic inhibition and chloroplastic ROS accumulation are compromised, which correlates with delayed hypersensitive response (HR) cell death and compromised resistance. Furthermore, protection of chloroplasts by expressing a plastid-targeted cyanobacterial flavodoxin (pFLD) delays photosynthetic inhibition and compromises ETI. Collectively, this study highlights a critical role of MPK3/MPK6 in manipulating plant photosynthetic activities to promote ROS accumulation in chloroplasts and HR cell death, which contributes to the robustness of ETI. Furthermore, the dual functionality of MPK3/MPK6 cascade in promoting defense and inhibiting photosynthesis potentially allow it to orchestrate the trade-off between plant growth and defense in plant immunity.
Категории: Biology, Journals

A direct link between MITF, innate immunity, and hair graying

чт, 2018-05-03 23:00

by Melissa L. Harris, Temesgen D. Fufa, Joseph W. Palmer, Sandeep S. Joshi, Denise M. Larson, Arturo Incao, Derek E. Gildea, Niraj S. Trivedi, Autumne N. Lee, Chi-Ping Day, Helen T. Michael, Thomas J. Hornyak, Glenn Merlino, NISC Comparative Sequencing Program , William J. Pavan

Melanocyte stem cells (McSCs) and mouse models of hair graying serve as useful systems to uncover mechanisms involved in stem cell self-renewal and the maintenance of regenerating tissues. Interested in assessing genetic variants that influence McSC maintenance, we found previously that heterozygosity for the melanogenesis associated transcription factor, Mitf, exacerbates McSC differentiation and hair graying in mice that are predisposed for this phenotype. Based on transcriptome and molecular analyses of Mitfmi-vga9/+ mice, we report a novel role for MITF in the regulation of systemic innate immune gene expression. We also demonstrate that the viral mimic poly(I:C) is sufficient to expose genetic susceptibility to hair graying. These observations point to a critical suppressor of innate immunity, the consequences of innate immune dysregulation on pigmentation, both of which may have implications in the autoimmune, depigmenting disease, vitiligo.
Категории: Biology, Journals

Antibiotic combination efficacy (ACE) networks for a <i>Pseudomonas aeruginosa</i> model

пн, 2018-04-30 23:00

by Camilo Barbosa, Robert Beardmore, Hinrich Schulenburg, Gunther Jansen

The spread of antibiotic resistance is always a consequence of evolutionary processes. The consideration of evolution is thus key to the development of sustainable therapy. Two main factors were recently proposed to enhance long-term effectiveness of drug combinations: evolved collateral sensitivities between the drugs in a pair and antagonistic drug interactions. We systematically assessed these factors by performing over 1,600 evolution experiments with the opportunistic nosocomial pathogen Pseudomonas aeruginosa in single- and multidrug environments. Based on the growth dynamics during these experiments, we reconstructed antibiotic combination efficacy (ACE) networks as a new tool for characterizing the ability of the tested drug combinations to constrain bacterial survival as well as drug resistance evolution across time. Subsequent statistical analysis of the influence of the factors on ACE network characteristics revealed that (i) synergistic drug interactions increased the likelihood of bacterial population extinction—irrespective of whether combinations were compared at the same level of inhibition or not—while (ii) the potential for evolved collateral sensitivities between 2 drugs accounted for a reduction in bacterial adaptation rates. In sum, our systematic experimental analysis allowed us to pinpoint 2 complementary determinants of combination efficacy and to identify specific drug pairs with high ACE scores. Our findings can guide attempts to further improve the sustainability of antibiotic therapy by simultaneously reducing pathogen load and resistance evolution.
Категории: Biology, Journals