Molecular modelling of dendrimers for nanoscale applications

Dendrimers are well defined, highly branched macromolecules that radiate from a central core and are synthesized through a stepwise, repetitive reaction sequence that guarantees complete shells for each generation, leading to polymers that are monodisperse. The synthetic procedures developed for dendrimer preparation permit nearly complete control over the critical molecular design parameters, such as size, shape, surface/interior chemistry, flexibility, and topology. Recent results suggest that dendritic polymers may provide the key to developing a reliable and economical fabrication and manufacturing route to functional nanoscale materials that would have unique properties (electronic, optical, opto-electronic, magnetic, chemical, or biological). In turn, these could be used in designing new nanoscale devices. In this paper, we determine the 3D molecular structure of various dendrimers with continuous configurational Boltzmann biased direct Monte Carlo method and study their energetic and structural properties using molecular dynamics after annealing these molecular representations

Stress-induced reinstatement of nicotine preference requires dynorphin/kappa opioid activity in the basolateral amygdala

UNLABELLED: The dynorphin (DYN)/kappa-opioid receptor (KOR) system plays a conserved role in stress-induced reinstatement of drug seeking for prototypical substances of abuse. Due to nicotine\u27s high propensity for stress-induced relapse, we hypothesized that stress would induce reinstatement of nicotine seeking-like behavior in a KOR-dependent manner. Using a conditioned place preference (CPP) reinstatement procedure in mice, we show that both foot-shock stress and the pharmacological stressor yohimbine (2 mg/kg, i.p.) induce reinstatement of nicotine CPP in a norbinaltorphimine (norBNI, a KOR antagonist)-sensitive manner, indicating that KOR activity is necessary for stress-induced nicotine CPP reinstatement. After reinstatement testing, we visualized robust c-fos expression in the basolateral amygdala (BLA), which was reduced in mice pretreated with norBNI. We then used several distinct but complementary approaches of locally disrupting BLA KOR activity to assess the role of KORs and KOR-coupled intracellular signaling cascades on reinstatement of nicotine CPP. norBNI injected locally into the BLA prevented yohimbine-induced nicotine CPP reinstatement without affecting CPP acquisition. Similarly, selective deletion of BLA KORs in KOR conditional knock-out mice prevented foot-shock-induced CPP reinstatement. Together, these findings strongly implicate BLA KORs in stress-induced nicotine seeking-like behavior. In addition, we found that chemogenetic activation of Gαi signaling within CaMKIIα BLA neurons was sufficient to induce nicotine CPP reinstatement, identifying an anatomically specific intracellular mechanism by which stress leads to reinstatement. Considered together, our findings suggest that activation of the DYN/KOR system and Gαi signaling within the BLA is both necessary and sufficient to produce reinstatement of nicotine preference. SIGNIFICANCE STATEMENT: Considering the major impact of nicotine use on human health, understanding the mechanisms by which stress triggers reinstatement of drug-seeking behaviors is particularly pertinent to nicotine. The dynorphin (DYN)/kappa-opioid receptor (KOR) system has been implicated in stress-induced reinstatement of drug seeking for other commonly abused drugs. However, the specific role, brain region, and mechanisms that this system plays in reinstatement of nicotine seeking has not been characterized. Here, we report region-specific engagement of the DYN/KOR system and subsequent activation of inhibitory (Gi-linked) intracellular signaling pathways within the basolateral amygdala during stress-induced reinstatement of nicotine preference. We show that the DYN/KOR system is necessary to produce this behavioral state. This work may provide novel insight for the development of therapeutic approaches to prevent stress-related nicotine relapse

What does a binary black hole merger look like?

We present a method of calculating the strong-field gravitational lensing caused by many analytic and numerical spacetimes. We use this procedure to calculate the distortion caused by isolated black holes and by numerically evolved black hole binaries. We produce both demonstrative images illustrating details of the spatial distortion and realistic images of collections of stars taking both lensing amplification and redshift into account. On large scales the lensing from inspiraling binaries resembles that of single black holes, but on small scales the resulting images show complex and in some cases self-similar structure across different angular scales.Comment: 10 pages, 12 figures. Supplementary images and movies can be found at http://www.black-holes.org/the-science-numerical-relativity/numerical-relativity/gravitational-lensin

Scientific Integrity in the Forensic Sciences: Consumerism, Conflicts of Interest, and Transparency

The goal of this paper is to discuss scientific integrity, consumerism, conflicts of interest, and transparency within the context of forensic science. Forensic scientists play crucial roles within the legal system and are constantly under various pressures when performing analytical work, generating reports based on their analyses, or testifying to the content of these reports. Maintaining the scientific integrity of these actions is paramount to supporting a functional legal system and the practice of good science. Our goal is to discuss the importance of scientific integrity as well as the factors it may compromise, so that forensic practitioners may be better equipped to recognize and avoid conflicts of interest when they arise. In this discussion we define terms, concepts, and professional relationships as well as present three case studies to contextualize these ideas

Role of Mycobacterium tuberculosis pknD in the Pathogenesis of central nervous system tuberculosis

<p>Abstract</p> <p>Background</p> <p>Central nervous system disease is the most serious form of tuberculosis, and is associated with high mortality and severe neurological sequelae. Though recent clinical reports suggest an association of distinct <it>Mycobacterium tuberculosis </it>strains with central nervous system disease, the microbial virulence factors required have not been described previously.</p> <p>Results</p> <p>We screened 398 unique <it>M. tuberculosis </it>mutants in guinea pigs to identify genes required for central nervous system tuberculosis. We found <it>M. tuberculosis pknD </it>(<it>Rv0931c</it>) to be required for central nervous system disease. These findings were central nervous system tissue-specific and were not observed in lung tissues. We demonstrated that <it>pknD </it>is required for invasion of brain endothelia (primary components of the blood-brain barrier protecting the central nervous system), but not macrophages, lung epithelia, or other endothelia. <it>M. tuberculosis pknD </it>encodes a "eukaryotic-like" serine-threonine protein kinase, with a predicted intracellular kinase and an extracellular (sensor) domain. Using confocal microscopy and flow cytometry we demonstrated that the <it>M. tuberculosis </it>PknD sensor is sufficient to trigger invasion of brain endothelia, a process which was neutralized by specific antiserum.</p> <p>Conclusions</p> <p>Our findings demonstrate a novel <it>in vivo </it>role for <it>M. tuberculosis pknD </it>and represent an important mechanism for bacterial invasion and virulence in central nervous system tuberculosis, a devastating and understudied disease primarily affecting young children.</p