Time in a Bottle: The Evolutionary Fate of Species Discrimination in Sibling Drosophila Species

Disadvantageous hybridization favors the evolution of prezygotic isolating behaviors, generating a geographic pattern of interspecific mate discrimination where members of different species drawn from sympatric populations exhibit stronger preference for members of their own species than do individuals drawn from allopatric populations. Geographic shifts in species' boundaries can relax local selection against hybridization; under such scenarios the fate of enhanced species preference is unknown. Lineages established from populations in the region of sympatry that have been maintained as single-species laboratory cultures represent cases where allopatry has been produced experimentally. Using such cultures dating from the 1950s, we assess how Drosophila pseudoobscura and D. persimilis mate preferences respond to relaxed natural selection against hybridization. We found that the propensity to hybridize generally declines with increasing time in experimental allopatry, suggesting that maintaining enhanced preference for conspecifics may be costly. However, our data also suggest a strong role for drift in determining mating preferences once secondary allopatry has been established. Finally, we discuss the interplay between populations in establishing the presence or absence of patterns consistent with reinforcement

Elevation of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline: a blood pressure-independent beneficial effect of angiotensin I-converting enzyme inhibitors

Blockade of the renin-angiotensin system (RAS) is well recognized as an essential therapy in hypertensive, heart, and kidney diseases. There are several classes of drugs that block the RAS; these drugs are known to exhibit antifibrotic action. An analysis of the molecular mechanisms of action for these drugs can reveal potential differences in their antifibrotic roles. In this review, we discuss the antifibrotic action of RAS blockade with an emphasis on the potential importance of angiotensin I-converting enzyme (ACE) inhibition associated with the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP)

Identification and characterization of antibacterial compound(s) of cockroaches (Periplaneta americana)

Infectious diseases remain a significant threat to human health, contributing to more than 17 million deaths, annually. With the worsening trends of drug resistance, there is a need for newer and more powerful antimicrobial agents. We hypothesized that animals living in polluted environments are potential source of antimicrobials. Under polluted milieus, organisms such as cockroaches encounter different types of microbes, including superbugs. Such creatures survive the onslaught of superbugs and are able to ward off disease by producing antimicrobial substances. Here, we characterized antibacterial properties in extracts of various body organs of cockroaches (Periplaneta americana) and showed potent antibacterial activity in crude brain extract against methicillin-resistant Staphylococcus aureus and neuropathogenic E. coli K1. The size-exclusion spin columns revealed that the active compound(s) are less than 10 kDa in molecular mass. Using cytotoxicity assays, it was observed that pre-treatment of bacteria with lysates inhibited bacteria-mediated host cell cytotoxicity. Using spectra obtained with LC-MS on Agilent 1290 infinity liquid chromatograph, coupled with an Agilent 6460 triple quadruple mass spectrometer, tissues lysates were analyzed. Among hundreds of compounds, only a few homologous compounds were identified that contained isoquinoline group, chromene derivatives, thiazine groups, imidazoles, pyrrole containing analogs, sulfonamides, furanones, flavanones, and known to possess broad-spectrum antimicrobial properties, and possess anti-inflammatory, anti-tumour, and analgesic properties. Further identification, characterization and functional studies using individual compounds can act as a breakthrough in developing novel therapeutics against various pathogens including superbugs

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

N-3 PUFA supplementation benefits microglial responses to myelin pathology

Microglia represent rational but challenging targets for improving white matter integrity because of their dualistic protective and toxic roles. The present study examines the effect of Omega-3 polyunsaturated fatty acids (n-3 PUFAs) on microglial responses to myelin pathology in primary cultures and in the cuprizone mouse model of multiple sclerosis (MS), a devastating demyelination disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the two main forms of n-3 PUFAs in the brain, inhibited the release of nitric oxide and tumor necrosis factor- αfrom primary microglia upon IFN-γ and myelin stimulation. DHA and EPA also enhanced myelin phagocytosis in vitro. Therefore, n-3 PUFAs can inhibit inflammation while at the same time enhancing beneficial immune responses such as microglial phagocytosis. In vivo studies demonstrated that n-3 PUFA supplementation reduced cuprizone-induced demyelination and improved motor and cognitive function. The positive effects of n-3 PUFAs were accompanied by a shift in microglial polarization toward the beneficial M2 phenotype both in vitro and in vivo. These results suggest that n-3 PUFAs may be clinically useful as immunomodulatory agents for demyelinating diseases through a novel mechanism involving microglial phenotype switching

Neurobiology of microglial action in CNS injuries: Receptor-mediated signaling mechanisms and functional roles

Microglia are the first line of immune defense against central nervous system (CNS) injuries and disorders. These highly plastic cells play dualistic roles in neuronal injury and recovery and are known for their ability to assume diverse phenotypes. A broad range of surface receptors are expressed on microglia and mediate microglial \u27On\u27 or \u27Off\u27 responses to signals from other host cells as well as invading microorganisms. The integrated actions of these receptors result in tightly regulated biological functions, including cell mobility, phagocytosis, the induction of acquired immunity, and trophic factor/inflammatory mediator release. Over the last few years, significant advances have been made toward deciphering the signaling mechanisms related to these receptors and their specific cellular functions. In this review, we describe the current state of knowledge of the surface receptors involved in microglial activation, with an emphasis on their engagement of distinct functional programs and their roles in CNS injuries. It will become evident from this review that microglial homeostasis is carefully maintained by multiple counterbalanced strategies, including, but not limited to, \u27On\u27 and \u27Off\u27 receptor signaling. Specific regulation of theses microglial receptors may be a promising therapeutic strategy against CNS injuries. © 2014 Elsevier Ltd

Galectin-1-secreting neural stem cells elicit long-term neuroprotection against ischemic brain injury

Galectin-1 (gal-1), a special lectin with high affinity to β-galactosides, is implicated in protection against ischemic brain injury. The present study investigated transplantation of gal-1-secreting neural stem cell (s-NSC) into ischemic brains and identified the mechanisms underlying protection. To accomplish this goal, secretory gal-1 was stably overexpressed in NE-4C neural stem cells. Transient cerebral ischemia was induced in mice by middle cerebral artery occlusion for 60 minutes and s-NSCs were injected into the striatum and cortex within 2 hours post-ischemia. Brain infarct volume and neurological performance were assessed up to 28 days post-ischemia. s-NSC transplantation reduced infarct volume, improved sensorimotor and cognitive functions, and provided more robust neuroprotection than non-engineered NSCs or gal-1-overexpressing (but non-secreting) NSCs. White matter injury was also ameliorated in s-NSC-treated stroke mice. Gal-1 modulated microglial function in vitro, by attenuating secretion of pro-inflammatory cytokines (TNF-α and nitric oxide) in response to LPS stimulation and enhancing production of anti-inflammatory cytokines (IL-10 and TGF-β). Gal-1 also shifted microglia/macrophage polarization toward the beneficial M2 phenotype in vivo by reducing CD16 expression and increasing CD206 expression. In sum, s-NSC transplantation confers robust neuroprotection against cerebral ischemia, probably by alleviating white matter injury and modulating microglial/macrophage function

Implantation of brain-derived extracellular matrix enhances neurological recovery after traumatic brain injury

Scaffolds composed of extracellular matrix (ECM) are being investigated for their ability to facilitate brain tissue remodeling and repair following injury. The present study tested the hypothesis that the implantation of brain-derived ECM would attenuate experimental traumatic brain injury (TBI) and explored potential underlying mechanisms. TBI was induced in mice by a controlled cortical impact (CCI). ECM was isolated from normal porcine brain tissue by decellularization methods, prepared as a hydrogel, and injected into the ipsilesional corpus callosum and striatum 1 h after CCI. Lesion volume and neurological function were evaluated up to 35 d after TBI. Immunohistochemistry was performed to assess post-TBI white matter integrity, reactive astrogliosis, and microglial activation. We found that ECM treatment reduced lesion volume and improved neurobehavioral function. ECM-treated mice showed less post-TBI neurodegeneration in the hippocampus and less white matter injury than control, vehicle-treated mice. Furthermore, ECM ameliorated TBI-induced gliosis and microglial pro-inflammatory responses, thereby providing a favorable microenvironment for tissue repair. Our study indicates that brain ECM hydrogel implantation improved the brain microenvironment that facilitates post-TBI tissue recovery. Brain ECM offers excellent biocompatibility and holds potential as a therapeutic agent for TBI, alone or in combination with other treatments