Efforts toward rapid construction of the cortistatin A carbocyclic core via enyne-ene metathesis

Our efforts toward the construction of the carbocylic core of cortistatin A via an enyne-ene metathesis are disclosed. Interestingly, an attempted S_N2 inversion of a secondary mesylate in our five-membered D-ring piece gave a product with retention of stereochemistry

Catalytic Enantioselective Stereoablative Alkylation of 3-Halooxindoles: Facile Access to Oxindoles with C3 All-Carbon Quaternary Stereocenters

From 2 to 1! Racemic tertiary halooxindoles proceed to enantioenriched oxindoles bearing all-carbon quaternary stereocenters as a result of a catalytic enantioselective stereoablative process (see scheme). The application of this procedure allows for the rapid asymmetric construction of biologically significant alkaloid core motifs

Inverse seesaw and dark matter in models with exotic lepton triplets

We show that models with exotic leptons transforming as E ~ (1,3,-1) under the standard model gauge symmetry are well suited for generating neutrino mass via a radiative inverse seesaw. This approach realizes natural neutrino masses and allows multiple new states to appear at the TeV scale. The exotic leptons are therefore good candidates for new physics that can be probed at the LHC. Furthermore, remnant low-energy symmetries ensure a stable dark matter candidate, providing a link between dark matter and the origins of neutrino mass.Comment: 6 pages, 3 figures (revtex4.1, two-columns

Striatal and thalamic GABA level concentrations play differential roles for the modulation of response selection processes by proprioceptive information.

The selection of appropriate responses is a complex endeavor requiring the integration of many different sources of information in fronto-striatal-thalamic circuits. An often neglected but relevant piece of information is provided by proprioceptive inputs about the current position of our limbs. This study examines the importance of striatal and thalamic GABA levels in these processes using GABA-edited magnetic resonance spectroscopy (GABAMRS) and a Simon task featuring proprioception-induced interference in healthy subjects. As a possible model of deficits in the processing of proprioceptive information, we also included Parkinson's disease (PD) patients in this study.The results show that proprioceptive information about unusual postures complicates response selection processes in controls, but not in PD patients. The well-known deficits of PD patients in processing proprioceptive information can turn into a benefit when altered proprioceptive information would normally complicate response selection processes. Striatal and thalamic GABA levels play dissociable roles in the modulation of response selection processes by proprioceptive information: Striatal GABA levels seem to be important for the general speed of responding, most likely because striatal GABA promotes response selection. In contrast, the modulation of response conflict by proprioceptive information is closely related to thalamic GABA concentrations with higher concentration being related to a smaller response conflict effect. The most likely explanation for this finding is that the thalamus is involved in the integration of sensorimotor, attentional, and cognitive information for the purpose of response formation. Yet, this effect in the thalamus vanishes when controls and PD patients were analyzed separately

Thalamic GABA levels and Occupational Manganese Neurotoxicity: Association with Exposure Levels and Brain MRI

Excessive occupational exposure to Manganese (Mn) has been associated with clinical symptoms resembling idiopathic Parkinson’s disease (IPD), impairing cognitive and motor functions. Several studies point towards an involvement of the brain neurotransmitter system in Mn intoxication, which is hypothesized to be disturbed prior to onset of symptoms. Edited Magnetic Resonance Spectroscopy (MRS) offers the unique possibility to measure γ-amminobutyric acid (GABA) and other neurometabolites in vivo non-invasively in workers exposed to Mn. In addition, the property of Mn as Magnetic Resonance Imaging (MRI) contrast agent may be used to study Mn deposition in the human brain. In this study, using MRI, MRS, personal air sampling at the working place, work history questionnaires, and neurological assessment (UPDRS-III), the effects of chronic Mn exposure on the thalamic GABAergic system was studied in a group of welders (N = 39) with exposure to Mn fumes in a typical occupational setting. Two subgroups of welders with different exposure levels (Low: N = 26; mean air Mn = 0.13 ± 0.1 mg/m3; High: N = 13; mean air Mn = 0.23 ± 0.18 mg/m3), as well as unexposed control workers (N = 22, mean air Mn = 0.002 ± 0.001 mg/m3) were recruited. The group of welders with higher exposure showed a significant increase of thalamic GABA levels by 45% (p < 0.01, F(1,33) = 9.55), as well as significantly worse performance in general motor function (p < 0.01, F(1,33) = 11.35). However, welders with lower exposure did not differ from the controls in GABA levels or motor performance. Further, in welders the thalamic GABA levels were best predicted by past-12-months exposure levels and were influenced by the Mn deposition in the substantia nigra and globus pallidus. Importantly, both thalamic GABA levels and motor function displayed a non-linear pattern of response to Mn exposure, suggesting a threshold effect

The Inner-Sphere Process in the Enantioselective Tsuji Allylation Reaction with (S)-t-Bu-phosphinooxazoline Ligands

We propose an inner-sphere mechanism explaining the unique performance of the Tsuji asymmetrical allylation reaction using hard prochiral enolate nucleophiles and non-prochiral allyl groups. Using first principles quantum mechanics (B3LYP density functional theory), we find that the pathway for this reaction involves nucleophilic attack followed by interconversion from a five-coordinate Pd complex to a four-coordinate complex. This intermediate is trapped in a potential well and escapes via reductive elimination that proceeds through a seven-membered transition state to generate the product and a Pd^0 complex. This seven-membered transition state contrasts dramatically from the usual three-centered C−C reductive elimination paradigm generally associated with C−C coupling reactions. This inner-sphere asymmetric allylation pathway involving hard enolates is energetically more favorable than outer-sphere nucleophilic attack, a process understood to occur in asymmetric allylic alkylations with soft enolates

Substrate Suppression of Thermal Roughness in Stacked Supported Bilayers

We have fabricated a stack of five 1,2-dipalmitoyl-sn-3-phosphatidylethanolamine (DPPE) bilayers supported on a polished silicon substrate in excess water. The density profile of these stacks normal to the substrate was obtained through analysis of x-ray reflectivity. Near the substrate, we find the layer roughness and repeat spacing are both significantly smaller than values found in bulk multilayer systems. The reduced spacing and roughness result from suppression of lateral fluctuations due to the flat substrate boundary. The layer spacing decrease then occurs due to reduced Helfrich repulsion.This work was partially supported by NSF Grants No. DMR-0706369 and No. DMR-0706665. Use of the Advanced Photon Sourcewas supported by theUSDepartment of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. SKS and ANP wish to acknowledge support from the Office of Basic Energy Sciences, US Department of Energy, via Grant No. DE-FG02- 04ER46173. We would also like to thank Suresh Narayanan for his support of the experimental work at Sector 8-ID

Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon

To profile the messenger RNA (mRNA) expression for the 23 known genes of matrix metalloproteinases (MMPs), 19 genes of ADAMTS, 4 genes of tissue inhibitors of metalloproteinases (TIMPs), and ADAM genes 8, 10, 12, and 17 in normal, painful, and ruptured Achilles tendons. Tendon samples were obtained from cadavers or from patients undergoing surgical procedures to treat chronic painful tendinopathy or ruptured tendon. Total RNA was extracted and mRNA expression was analyzed by quantitative real-time reverse transcription–polymerase chain reaction, normalized to 18S ribosomal RNA. In comparing expression of all genes, the normal, painful, and ruptured Achilles tendon groups each had a distinct mRNA expression signature. Three mRNA were not detected and 14 showed no significant difference in expression levels between the groups. Statistically significant (P < 0.05) differences in mRNA expression, when adjusted for age, included lower levels of MMPs 3 and 10 and TIMP-3 and higher levels of ADAM-12 and MMP-23 in painful compared with normal tendons, and lower levels of MMPs 3 and 7 and TIMPs 2, 3, and 4 and higher levels of ADAMs 8 and 12, MMPs 1, 9, 19, and 25, and TIMP-1 in ruptured compared with normal tendons. The distinct mRNA profile of each tendon group suggests differences in extracellular proteolytic activity, which would affect the production and remodeling of the tendon extracellular matrix. Some proteolytic activities are implicated in the maintenance of normal tendon, while chronically painful tendons and ruptured tendons are shown to be distinct groups. These data will provide a foundation for further study of the role and activity of many of these enzymes that underlie the pathologic processes in the tendon

Palladium-catalyzed decarboxylative allylic alkylation of diastereomeric β-ketoesters

The palladium-catalyzed decarboxylative allylic alkylation of diastereomeric β-ketoesters derived from 4-tert-butylcyclohexanone is described. These experiments were performed to elucidate our understanding of stereoablative enantioconvergent catalysis. A detailed analysis of the product distribution, including stereochemical outcome of the products, is included. These studies also reveal an interesting example of selectivity that is governed by competing modes of substrate and catalyst control

Multimodal Modeling For Spoken Language Identification

Spoken language identification refers to the task of automatically predicting the spoken language in a given utterance. Conventionally, it is modeled as a speech-based language identification task. Prior techniques have been constrained to a single modality; however in the case of video data there is a wealth of other metadata that may be beneficial for this task. In this work, we propose MuSeLI, a Multimodal Spoken Language Identification method, which delves into the use of various metadata sources to enhance language identification. Our study reveals that metadata such as video title, description and geographic location provide substantial information to identify the spoken language of the multimedia recording. We conduct experiments using two diverse public datasets of YouTube videos, and obtain state-of-the-art results on the language identification task. We additionally conduct an ablation study that describes the distinct contribution of each modality for language recognition