Natural products chemistry has historically been the prime arena for the discovery of new chemical transformations and the fountain of insights into key biological processes. It remains a fervent ...incubator of progress in the fields of chemistry and biology and an exchange mediating the flow of ideas between these allied fields of science. It is with this ethos that our group has taken an interest in and pursued the synthesis of a complex family of natural products termed the dimeric epipolythiodiketopiperazine (ETP) alkaloids. We present here an Account of the highly complex target molecules to which we pegged our ambitions, our systematic and relentless efforts toward those goals, the chemistry we developed in their pursuit, and the insight we have gained for their translational potential as potent anticancer molecules. The dimeric ETP alkaloids are fungal metabolites that feature a highly complex molecular architecture comprising a densely functionalized core structure with many stereogenic centers, six of which are fully substituted, and a pair of vicinal quaternary carbon stereocenters, decorated on polycyclic architectures in addition to the unique ETP motif that has been recognized as acid-, base-, and redox-sensitive. A cyclo-dipeptide consisting of an essential tryptophan residue and a highly variable ancillary amino acid lies at the core of these structures; investigation of the transformations that take this simplistic core to the complex alkaloids lies at the heart of our research program. The dimeric epidithiodiketopiperazine alkaloids have largely resisted synthesis on account of their complexity since the 1970s when the founding members of this class, chaetocin A ( Hauser D. et al. Helv. Chim. Acta 1970, 53, 1061 ) and verticillin A ( Katagiri K. et al. J. Antibiot. 1970, 23, 420 ), were first isolated. This was despite their potent cytotoxic and bacteriostatic activities, which were well appreciated at the time of their discovery. In the past decade, an increasing number of studies have uncovered powerful new biological processes that these molecules can uniquely effect, such as the inhibition of histone methyltransferases by chaetocin A ( Greiner D. et al. Nat. Chem. Biol. 2005, 1, 143 ). In fact, the complete collection of hexahydropyrroloindoline alkaloids features a diverse range of potent biological properties including cytotoxic, antitumor, antileukemic, antiviral, antibiotic, and antinematodal activities ( Jiang C.-S. ; Guo Y.-W. Mini-Rev. Med. Chem. 2011, 11, 728 ). This mélange of activities is reflective of their structural diversity. Under the precepts of retrobiosynthetic analysis, we have accomplished the syntheses of more than a dozen natural products, including members of the bionectin, calycanthaceous, chaetocin, gliocladin, naseseazine, and verticillin alkaloids. More importantly, these molecules have acted as venerable venues for the development of new strategies to address structural challenges including, but not limited to, C3–C3′ vicinal quaternary centers, heterodimeric linkages, C3–Csp2 linkages, diketopiperazine oxidation, stereoselective thiolation, homologue-specific polysulfidation, and C12-hydroxyl incorporation. Synthesis of these natural products has resulted in the structural confirmation, and sometimes revision such as the case of (+)-naseseazines A and B, as well as access to many plausible biogenetically relevant intermediates and new synthetic ETP derivatives. Furthermore, our studies have paved the way for the formulation of a comprehensive SAR profile and the identification of lead compounds with in vitro subnanomolar IC50’s against a broad range of cancer types.
We write in response to an article published in this journal by Andrew Ortony titled “Are All ‘Basic Emotions’ Emotions? A Problem for the (Basic) Emotions Construct.” The author claimed that “for ...all its elevated status as a basic emotion, surprise fails to satisfy the minimal requirements that he proposed for something to be an emotion, and if it is not an emotion, it cannot possibly be a basic emotion.” Although we acknowledge the concerns brought forth by Ortony, we respectfully disagree with his conclusion about surprise. To make a case against the assertion that surprise is valence-free, we summarize an extensive body of work showing that surprise is indeed valenced—in a specific manner (i.e., ambiguously valenced)—and that it meets all of Ortony’s criteria for an emotion. In other words, rather than being described as neither positive nor negative, this emotion is either positive or negative. We consider the data with respect to surprise as a basic emotion, and we dispute the definitions of basic emotions as “widely divergent.” Future work is needed to continue defining an emotion, and a basic emotion, but we believe this is a worthy effort toward shaping a still evolving field.
Generalized anxiety disorder (GAD) is marked by uncontrollable, persistent worry and exaggerated response to uncertainty. Here, we review and summarize the findings from the GAD literature that ...employs functional neuroimaging methods. In particular, the present review focuses on task-based blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. We find that select brain regions often regarded as a part of a corticolimbic circuit (e.g., amygdala, anterior cingulate cortex, prefrontal cortex) are consistently targeted for a priori hypothesis-driven analyses, which, in turn, shows varying degrees of abnormal BOLD responsivity in GAD. Data-driven whole-brain analyses show the insula and the hippocampus, among other regions, to be affected by GAD, depending on the task used in each individual study. Overall, while the heterogeneity of the tasks and sample size limits the generalizability of the findings thus far, some promising convergence can be observed in the form of the altered BOLD responsivity of the corticolimbic circuitry in GAD.
► Amygdala is extensively interconnected with the medial prefrontal cortex ► Amygdala-prefrontal circuitry is critical in top-down and bottom-up processes ► Stronger amygdala-prefrontal connectivity ...predicts lower levels of anxiety ► Stronger amygdala-prefrontal connectivity predicts effective emotion regulation.
The dynamic interactions between the amygdala and the medial prefrontal cortex (mPFC) are usefully conceptualized as a circuit that both allows us to react automatically to biologically relevant predictive stimuli as well as regulate these reactions when the situation calls for it. In this review, we will begin by discussing the role of this amygdala–mPFC circuitry in the conditioning and extinction of aversive learning in animals. We will then relate these data to emotional regulation paradigms in humans. Finally, we will consider how these processes are compromised in normal and pathological anxiety. We conclude that the capacity for efficient crosstalk between the amygdala and the mPFC, which is represented as the strength of the amygdala–mPFC circuitry, is crucial to beneficial outcomes in terms of reported anxiety.
Micro-LEDs (µLEDs) have been explored for augmented and virtual reality display applications that require extremely high pixels per inch and luminance
. However, conventional manufacturing processes ...based on the lateral assembly of red, green and blue (RGB) µLEDs have limitations in enhancing pixel density
. Recent demonstrations of vertical µLED displays have attempted to address this issue by stacking freestanding RGB LED membranes and fabricating top-down
, but minimization of the lateral dimensions of stacked µLEDs has been difficult. Here we report full-colour, vertically stacked µLEDs that achieve, to our knowledge, the highest array density (5,100 pixels per inch) and the smallest size (4 µm) reported to date. This is enabled by a two-dimensional materials-based layer transfer technique
that allows the growth of RGB LEDs of near-submicron thickness on two-dimensional material-coated substrates via remote or van der Waals epitaxy, mechanical release and stacking of LEDs, followed by top-down fabrication. The smallest-ever stack height of around 9 µm is the key enabler for record high µLED array density. We also demonstrate vertical integration of blue µLEDs with silicon membrane transistors for active matrix operation. These results establish routes to creating full-colour µLED displays for augmented and virtual reality, while also offering a generalizable platform for broader classes of three-dimensional integrated devices.
Concise and enantioselective total syntheses of (+)-naseseazines A and B are described. Our regioselective and directed dimerization of diketopiperazines provides their critical C3–Csp2 linkages, an ...assembly with plausible biogenetic relevance. We revise the absolute stereochemistry of (+)-naseseazines A and B.
Here, we used diffusion tensor imaging (DTI) and showed that the strength of an axonal pathway identified between the amygdala and prefrontal cortex predicted individual differences in trait anxiety. ...A functional magnetic resonance imaging (fMRI) functional localizer that has been shown to produce reliable amygdala activation was collected in 20 psychiatrically healthy subjects. Voxelwise regression analyses using this fMRI amygdala reactivity as a regressor were performed on fractional anisotropy images derived from DTI. This analysis identified a white matter pathway between the amygdala and ventromedial prefrontal cortex. Individual differences in the structural integrity of this putative amygdala-prefrontal pathway were inversely correlated with trait anxiety levels (i.e., higher pathway strength predicted lower anxiety). More generally, this study illustrates a strategy for combining fMRI and DTI to identify individual differences in structural pathways that predict behavioral outcomes.
A highly stereoselective and systematic strategy for the introduction of polysulfides in the synthesis of epipolythiodiketopiperazines is described. We report the first total synthesis of dimeric ...epitri- and epitetrathiodiketopiperazines.
Generalized anxiety disorder (GAD) is a common condition characterized by excessive and uncontrollable worry, along with its high comorbidity rates. Despite increasing efforts to identify the neural ...underpinnings of GAD, neuroimaging research using cortical thickness have yielded largely inconsistent results. To address this, we adopted an inter-subject representational similarity analysis framework to explore a potential nonlinear relationship between vertex-wise cortical thickness and generalized anxiety symptom severity. We utilized a sample of 120 adolescents (13–18 years of age) from the Healthy Brain Network dataset. Here, we found greater topographical resemblance among participants with heightened generalized anxiety symptoms in the left caudal anterior cingulate and pericalcarine cortex. These results were not driven by the effects of age, sex, ADHD diagnosis, and GAD diagnosis. Such associations were not observed when including a group of younger participants (11–12 years of age) for analyses, highlighting the importance of age range selection when considering the link between cortical thickness and anxiety. Our findings reveal a novel cortical thickness topography that represents generalized anxiety in adolescents, which is embedded within the shared geometries between generalized anxiety symptoms and cortical thickness.
•Cortical thickness topography represents generalized anxiety (GA) in adolescents.•Topographical resemblance of ACC/pericalcarine cortex correlated with GA symptoms.•Such associations were no longer observed when including data from a younger sample.•Cortical thickness topography may serve as a potential neuroimaging-based biomarker.
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