Carbon Atom Insertion into Pyrroles and Indoles Promoted by Chlorodiazirines

Herein, we report a reaction that selectively generates 3-arylpyridine and quinoline motifs by inserting aryl carbynyl cation equivalents into pyrrole and indole cores, respectively. By employing α-chlorodiazirines as thermal precursors to the corresponding chlorocarbenes, the traditional haloform-based protocol central to the parent Ciamician-Dennstedt rearrangement can be modified to directly afford 3-(hetero)arylpyridines and quinolines. Chlorodiazirines are conveniently prepared in a single step by oxidation of commercially available amidinium salts. Selectivity as a function of pyrrole substitution pattern was examined, and a predictive model based on steric effects is put forward, with DFT calculations supporting a selectivity-determining cyclopropanation step. Computations surprisingly indicate that the stereochemistry of cyclopropanation is of little consequence to the subsequent electrocyclic ring opening that forges the pyridine core, due to a compensatory homoaromatic stabilization that counterbalances orbital-controlled torquoselectivity effects. The utility of this skeletal transform is further demonstrated through the preparation of quinolinophanes and the skeletal editing of pharmaceutically relevant pyrroles

Simulating the global distribution of nitrogen isotopes in the ocean

We present a new nitrogen isotope model incorporated into the three-dimensional ocean component of a global Earth system climate model designed for millennial timescale simulations. The model includes prognostic tracers for the two stable nitrogen isotopes, 14N and 15N, in the nitrate (NO3−), phytoplankton, zooplankton, and detritus variables of the marine ecosystem model. The isotope effects of algal NO3− uptake, nitrogen fixation, water column denitrification, and zooplankton excretion are considered as well as the removal of NO3− by sedimentary denitrification. A global database of δ15NO3− observations is compiled from previous studies and compared to the model results on a regional basis where sufficient observations exist. The model is able to qualitatively and quantitatively reproduce many of the observed patterns such as high subsurface values in water column denitrification zones and the meridional and vertical gradients in the Southern Ocean. The observed pronounced subsurface minimum in the Atlantic is underestimated by the model presumably owing to too little simulated nitrogen fixation there. Sensitivity experiments reveal that algal NO3− uptake, nitrogen fixation, and water column denitrification have the strongest effects on the simulated distribution of nitrogen isotopes, whereas the effect from zooplankton excretion is weaker. Both water column and sedimentary denitrification also have important indirect effects on the nitrogen isotope distribution by reducing the fixed nitrogen inventory, which creates an ecological niche for nitrogen fixers and, thus, stimulates additional N2 fixation in the model. Important model deficiencies are identified, and strategies for future improvement and possibilities for model application are outlined

Bodily Expression of Social Initiation Behaviors in ASC and non-ASC children: Mixed Reality vs. LEGO Game Play

This study is part of a larger project that showed the potential of our mixed reality (MR) system in fostering social initiation behaviors in children with Autism Spectrum Condition (ASC). We compared it to a typical social intervention strategy based on construction tools, where both mediated a face-to-face dyadic play session between an ASC child and a non-ASC child. In this study, our first goal is to show that an MR platform can be utilized to alter the nonverbal body behavior between ASC and non-ASC during social interaction as much as a traditional therapy setting (LEGO). A second goal is to show how these body cues differ between ASC and non-ASC children during social initiation in these two platforms. We present our first analysis of the body cues generated under two conditions in a repeated-measures design. Body cue measurements were obtained through skeleton information and characterized in the form of spatio-temporal features from both subjects individually (e.g. distances between joints and velocities of joints), and interpersonally (e.g. proximity and visual focus of attention). We used machine learning techniques to analyze the visual data of eighteen trials of ASC and non-ASC dyads. Our experiments showed that: (i) there were differences between ASC and non-ASC bodily expressions, both at individual and interpersonal level, in LEGO and in the MR system during social initiation; (ii) the number of features indicating differences between ASC and non-ASC in terms of nonverbal behavior during initiation were higher in the MR system as compared to LEGO; and (iii) computational models evaluated with combination of these different features enabled the recognition of social initiation type (ASC or non-ASC) from body features in LEGO and in MR settings. We did not observe significant differences between the evaluated models in terms of performance for LEGO and MR environments. This might be interpreted as the MR system encouraging similar nonverbal behaviors in children, perhaps more similar than the LEGO environment, as the performance scores in the MR setting are lower as compared to the LEGO setting. These results demonstrate the potential benefits of full body interaction and MR settings for children with ASC.EPSR

Developmental pathways to autism: a review of prospective studies of infants at risk

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterized by impairments in social interaction and communication, and the presence of restrictive and repetitive behaviors. Symptoms of ASD likely emerge from a complex interaction between pre-existing neurodevelopmental vulnerabilities and the child's environment, modified by compensatory skills and protective factors. Prospective studies of infants at high familial risk for ASD (who have an older sibling with a diagnosis) are beginning to characterize these developmental pathways to the emergence of clinical symptoms. Here, we review the range of behavioral and neurocognitive markers for later ASD that have been identified in high-risk infants in the first years of life. We discuss theoretical implications of emerging patterns, and identify key directions for future work, including potential resolutions to several methodological challenges for the field. Mapping how ASD unfolds from birth is critical to our understanding of the developmental mechanisms underlying this disorder. A more nuanced understanding of developmental pathways to ASD will help us not only to identify children who need early intervention, but also to improve the range of interventions available to them

A review of nitrogen isotopic alteration in marine sediments

Key Points: Use of sedimentary nitrogen isotopes is examined; On average, sediment 15N/14N increases approx. 2 per mil during early burial; Isotopic alteration scales with water depth Abstract: Nitrogen isotopes are an important tool for evaluating past biogeochemical cycling from the paleoceanographic record. However, bulk sedimentary nitrogen isotope ratios, which can be determined routinely and at minimal cost, may be altered during burial and early sedimentary diagenesis, particularly outside of continental margin settings. The causes and detailed mechanisms of isotopic alteration are still under investigation. Case studies of the Mediterranean and South China Seas underscore the complexities of investigating isotopic alteration. In an effort to evaluate the evidence for alteration of the sedimentary N isotopic signal and try to quantify the net effect, we have compiled and compared data demonstrating alteration from the published literature. A >100 point comparison of sediment trap and surface sedimentary nitrogen isotope values demonstrates that, at sites located off of the continental margins, an increase in sediment 15N/14N occurs during early burial, likely at the seafloor. The extent of isotopic alteration appears to be a function of water depth. Depth-related differences in oxygen exposure time at the seafloor are likely the dominant control on the extent of N isotopic alteration. Moreover, the compiled data suggest that the degree of alteration is likely to be uniform through time at most sites so that bulk sedimentary isotope records likely provide a good means for evaluating relative changes in the global N cycle

Endangered right whales enhance primary productivity in the bay of fundy

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Marine mammals have recently been documented as important facilitators of rapid and efficient nutrient recycling in coastal and offshore waters. Whales enhance phytoplankton nutrition by releasing fecal plumes near the surface after feeding and by migrating from highly productive, high-latitude feeding areas to low-latitude nutrient-poor calving areas. In this study, we measured NH4 + and PO4 3- release rates from the feces of North Atlantic right whales (Eubalaena glacialis), a highly endangered baleen whale. Samples for this species were primarily collected by locating aggregations of whales in surface- Active groups (SAGs), which typically consist of a central female surrounded by males competing for sexual activity. When freshly collected feces were incubated in seawater, high initial rates of N release were generally observed, which decreased to near zero within 24 hours of sampling, a pattern that is consistent with the active role of gut microflora on fecal particles. We estimate that at least 10% of particulate N in whale feces becomes available as NH4 + within 24 hours of defecation. Phosphorous was also abundant in fecal samples: Initial release rates of PO4 3- were higher than for NH4 +, yielding low N/P nutrient ratios over the course of our experiments. The rate of PO4 3- release was thus more than sufficient to preclude the possibility that nitrogenous nutrients supplied by whales would lead to phytoplankton production limited by P availability. Phytoplankton growth experiments indicated that NH4 + released from whale feces enhance productivity, as would be expected, with no evidence that fecal metabolites suppress growth. Although North Atlantic right whales are currently rare (approximately 450 individuals), they once numbered about 14,000 and likely played a substantial role in recycling nutrients in areas where they gathered to feed and mate. Even though the NH4 + released from fresh whale fecal material is a small fraction of total whale fecal nitrogen, and recognizing the fact that the additional nitrogen released in whale urine would be difficult to measure in a field study, the results of this study support the idea that the distinctive isotopic signature of the released NH4 + could be used to provide a conservative estimate of the contribution of the whale pump to primary productivity in coastal regions where whales congregate

The influence of light on nitrogen cycling and the primary nitrite maximum in a seasonally stratified sea

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Progress In Oceanography 91 (2011): 545–560, doi:10.1016/j.pocean.2011.09.001.In the seasonally stratified Gulf of Aqaba Red Sea, both NO2- release by phytoplankton and NH4+ oxidation by nitrifying microbes contributed to the formation of a primary nitrite maximum (PNM) over different seasons and depths in the water column. In the winter and during the days immediately following spring stratification, NO2- formation was strongly correlated (R2=0.99) with decreasing irradiance and chlorophyll, suggesting that incomplete NO3- reduction by light limited phytoplankton was a major source of NO2-. However, as stratification progressed, NO2- continued to be generated below the euphotic depth by microbial NH4+ oxidation, likely due to differential photoinhibition of NH4+ and NO2- oxidizing populations. Natural abundance stable nitrogen isotope analyses revealed a decoupling of the δ15N and δ18O in the combined NO3- and NO2- pool, suggesting that assimilation and nitrification were co-occurring in surface waters. As stratification progressed, the δ15N of particulate N below the euphotic depth increased from -5‰ to up to +20‰. N uptake rates were also influenced by light; based on 15N tracer experiments, assimilation of NO3-, NO2-, and urea was more rapid in the light (434±24, 94±17, and 1194±48 nmol N L-1 day-1 respectively) than in the dark (58±14, 29±14, and 476±31 nmol N L-1 day-1 respectively). Dark NH4+ assimilation was 314±31 nmol N L-1 day-1, while light NH4+ assimilation was much faster, resulting in complete consumption of the 15N spike in less than 7 hour from spike addition. The overall rate of coupled urea mineralization and NH¬4+ oxidation (14.1±7.6 nmol N L-1 day-1) was similar to that of NH¬4+ oxidation alone (16.4±8.1 nmol N L-1 day-1), suggesting that for labile dissolved organic N compounds like urea, mineralization was not a rate limiting step for nitrification. Our results suggest that assimilation and nitrification compete for NH4+ and that N transformation rates throughout the water column are influenced by light over diel and seasonal cycles, allowing phytoplankton and nitrifying microbes to contribute jointly to PNM formation. We identify important factors that influence the N cycle throughout the year, including light intensity, substrate availability, and microbial community structure. These processes could be relevant to other regions worldwide where seasonal variability in mixing depth and stratification influence the contributions of phytoplankton and non-photosynthetic microbes to the N cycle.This research was supported under the North Atlantic Treaty Organization (NATO) Science for Peace Grant SfP 982161 to AP and AFP, a grant from the Koret Foundation to AP, a National Science Foundation Biological Oceanography grant to AP, the Israel Science Foundation grant 135/05 to AFP, and research grant 8330-06 from the Geological Society of America to KRMM

Minimal residual disease in Myeloma: Application for clinical care and new drug registration

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow–based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy–based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid–based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes

An extended multisensory temporal binding window in autism spectrum disorders

Autism spectrum disorders (ASD) form a continuum of neurodevelopmental disorders, characterized by deficits in communication and reciprocal social interaction, as well as by repetitive behaviors and restricted interests. Sensory disturbances are also frequently reported in clinical and autobiographical accounts. However, surprisingly few empirical studies have characterized the fundamental features of sensory and multisensory processing in ASD. The current study is structured to test for potential differences in multisensory temporal function in ASD by making use of a temporally dependent, low-level multisensory illusion. In this illusion, the presentation of a single flash of light accompanied by multiple sounds often results in the illusory perception of multiple flashes. By systematically varying the temporal structure of the audiovisual stimuli, a “temporal window” within which these stimuli are likely to be bound into a single perceptual entity can be defined. The results of this study revealed that children with ASD report the flash-beep illusion over an extended range of stimulus onset asynchronies relative to children with typical development, suggesting that children with ASD have altered multisensory temporal function. These findings provide valuable new insights into our understanding of sensory processing in ASD and may hold promise for the development of more sensitive diagnostic measures and improved remediation strategies