Lewis Base Catalysis Promoted Nucleophilic Substitutions - Recent Advances and Future Directions

Nucleophilic substitutions (SN) account for the most essential and frequently applied chemical transformations. SN‐reactions allow forging C–C, C–O, C–N and C–Cl bonds, for example, from natural abundant starting materials such as alcohols and carboxylic acids. Products of SN‐reactions are ubiquitous and find inter alia applications as pharmaceuticals, plant protection agents and polymers. However, conventional SN‐type approaches are restricted frequently by the necessity of hazardous reagents and by‐products, a poor waste‐balance and therefore sustainability and high levels of costs, which especially impedes application in large scale synthesis. In order to provide solutions to these limitations, the development of novel catalytic methods for SN‐transformations has evolved into a flourishing and reviving area of research. The current review enables an overview of modern strategies for catalytic nucleophilic substitutions, presents as main topic the state‐of‐the‐art with respect to SN‐methods that are promoted by Lewis bases and points out potential future directions for further innovations

The Morphological Spectrum of Papillary Renal Cell Carcinoma and Prevalence of Provisional/Emerging Renal Tumor Entities with Papillary Growth

Renal cell carcinoma (RCC) represents a heterogeneous disease, encompassing an increasing number of tumor subtypes. Post-2016, the World Health Organization (WHO) classification recognized that the spectrum of papillary renal cell carcinoma is evolving and has long surpassed the dichotomic simplistic "type 1 versus type 2" classification. The differential diagnosis of pRCC includes several new provisional/emerging entities with papillary growth. Type 2 tumors have been cleared out of several confounding entities, now regarded as independent tumors with specific clinical and molecular backgrounds. In this work we describe the prevalence and characteristics of emerging papillary tumor entities in two renal tumor cohorts (one consisting of consecutive papillary tumors from a single institute, the other consisting of consultation cases from several centers). After a review of 154 consecutive pRCC cases, 58% remained type 1 pRCC, and 34% type 2 pRCC. Papillary renal neoplasm with reversed polarity (1.3%), biphasic hyalinizing psammomatous RCC (1.3%), and biphasic squamoid/alveolar RCC (4.5%) were rare. Among 281 consultation cases, 121 (43%) tumors had a dominant papillary growth (most frequently MiT family translocation RCCs, mucinous tubular and spindle cell carcinoma and clear cell papillary RCC). Our data confirm that the spectrum of RCCs with papillary growth represents a major diagnostical challenge, frequently requiring a second expert opinion. Papillary renal neoplasm with reversed polarity, biphasic hyalinizing psammomatous RCC, and biphasic squamoid/alveolar RCC are rarely sent out for a second opinion, but correct classification and knowledge of these variants will improve our understanding of the clinical behavior of renal tumors with papillary growth

Vestibular Perception following Acute Unilateral Vestibular Lesions.

Little is known about the vestibulo-perceptual (VP) system, particularly after a unilateral vestibular lesion. We investigated vestibulo-ocular (VO) and VP function in 25 patients with vestibular neuritis (VN) acutely (2 days after onset) and after compensation (recovery phase, 10 weeks). Since the effect of VN on reflex and perceptual function may differ at threshold and supra-threshold acceleration levels, we used two stimulus intensities, acceleration steps of 0.5°/s(2) and velocity steps of 90°/s (acceleration 180°/s(2)). We hypothesised that the vestibular lesion or the compensatory processes could dissociate VO and VP function, particularly if the acute vertiginous sensation interferes with the perceptual tasks. Both in acute and recovery phases, VO and VP thresholds increased, particularly during ipsilesional rotations. In signal detection theory this indicates that signals from the healthy and affected side are still fused, but result in asymmetric thresholds due to a lesion-induced bias. The normal pattern whereby VP thresholds are higher than VO thresholds was preserved, indicating that any 'perceptual noise' added by the vertigo does not disrupt the cognitive decision-making processes inherent to the perceptual task. Overall, the parallel findings in VO and VP thresholds imply little or no additional cortical processing and suggest that vestibular thresholds essentially reflect the sensitivity of the fused peripheral receptors. In contrast, a significant VO-VP dissociation for supra-threshold stimuli was found. Acutely, time constants and duration of the VO and VP responses were reduced - asymmetrically for VO, as expected, but surprisingly symmetrical for perception. At recovery, VP responses normalised but VO responses remained shortened and asymmetric. Thus, unlike threshold data, supra-threshold responses show considerable VO-VP dissociation indicative of additional, higher-order processing of vestibular signals. We provide evidence of perceptual processes (ultimately cortical) participating in vestibular compensation, suppressing asymmetry acutely in unilateral vestibular lesions

Racial Disparities in Emergency General Surgery: Do Differences in Outcomes Persist Among Universally Insured Military Patients?

Research Objective: Described as one of the most serious health problems affecting the nation, racial disparities are estimated to account for \u3e83,000 deaths, \u3e$57 billion per year. They have been identified in multiple surgical settings, including differences in outcomes by race among emergency general surgery(EGS) patients. As many minority patients are uninsured, increasing access to care is thought to be a viable solution to mitigate inequities. The objectives of this study were to determine whether racial disparities in 30/90/180day outcomes exist within a universally-insured population of military/civilian-dependent EGS patients and whether differences in outcomes differentially persist in care received at military-vs-civilian hospitals and among sponsors who are enlisted-service members-vs-officers. It also considered longer-term outcomes of care. Study Design: Risk-adjusted survival analyses using Cox proportional-hazards models assessed race-based differences in mortality, major morbidity, and readmission from index-hospital admission (discharge for readmission) through 30/90/180days. Models accounted for hospital clustering and possible biases associated with missing race (reweighted-estimating equations). Sub-analyses considered effects restricted to operative interventions, stratified by 24 EGS-diagnostic categories defined by the American Association for the Surgery of Trauma(AAST), and effect modification related to rank (SES-proxy: officers-vs-enlisted-sponsors) and military-vs-civilian-hospital care. Population Studied: Five years of national TRICARE Prime/Prime-plus data, which provides insurance to active/reserve/retired members of the US Armed Services and dependents, were queried for adults (≥18y) with primary EGS conditions, defined by the AAST. Patients who did not have an index admission between 01/01/2006-01/07/2010 (minimum 180days follow-up) or who were not continuously enrolled in TRICARE for 180days were excluded. Non-surviving patients were retained while they survived. Principal Findings: A total of 101,011 patients were included: 73.5% White, 14.5% Black, 4.4% Asian, 7.7% other. Risk-adjusted analyses reported equivalent-or-better mortality and readmission outcomes among minority patients at 30/90/180days—even when restricted to civilian hospitals where studies suggest that EGS disparities are found. Readmissions within military hospitals were lower among minority patients. Major morbidity was higher among Black versus White patients (HR[95%CI]): 30day-1.23[1.13-1.35], 90day-1.18[1.09-1.28], 180day-1.15[1.07-1.24]—a finding driven by appendiceal disorders (HR:1.69-1.70). No other diagnostic category-based HR was significant. When considered by rank, significant effects were isolated to enlisted-service members. However, given the relatively small number of patients who were (dependents of) officers, it is difficult to determine whether rank-based findings are a result of social determinants or influenced by the limited number of minority patients. Conclusions: The first of its kind to examine racial disparities in longer-term outcomes of EGS care, this longitudinal analysis of military patients demonstrated apparent mitigation of racial disparities within a universally-insured health system when compared to the overall US health system. Efforts to explain findings based on consideration of care provided in military-vs-civilian hospitals, among specific EGS-diagnostic categories, and based on sponsor rank revealed modification of the association between race and outcomes to some extent for all three. Implications for Policy or Practice: The contrast between results for universally-insured military/civilian-dependent patients and reported disparities among all US civilian patients merits consideration. The data speak to the importance of insurance-coverage in the development of disparities interventions nationwide and will help to inform policy within the DoD

Psychiatry during the Nazi era: ethical lessons for the modern professional

For the first time in history, psychiatrists during the Nazi era sought to systematically exterminate their patients. However, little has been published from this dark period analyzing what may be learned for clinical and research psychiatry. At each stage in the murderous process lay a series of unethical and heinous practices, with many psychiatrists demonstrating a profound commitment to the atrocities, playing central, pivotal roles critical to the success of Nazi policy. Several misconceptions led to this misconduct, including allowing philosophical constructs to define clinical practice, focusing exclusively on preventative medicine, allowing political pressures to influence practice, blurring the roles of clinicians and researchers, and falsely believing that good science and good ethics always co-exist. Psychiatry during this period provides a most horrifying example of how science may be perverted by external forces. It thus becomes crucial to include the Nazi era psychiatry experience in ethics training as an example of proper practice gone awry

High Speed Two-Photon Imaging of Calcium Dynamics in Dendritic Spines: Consequences for Spine Calcium Kinetics and Buffer Capacity

Rapid calcium concentration changes in postsynaptic structures are crucial for synaptic plasticity. Thus far, the determinants of postsynaptic calcium dynamics have been studied predominantly based on the decay kinetics of calcium transients. Calcium rise times in spines in response to single action potentials (AP) are almost never measured due to technical limitations, but they could be crucial for synaptic plasticity. With high-speed, precisely-targeted, two-photon point imaging we measured both calcium rise and decay kinetics in spines and secondary dendrites in neocortical pyramidal neurons. We found that both rise and decay kinetics of changes in calcium-indicator fluorescence are about twice as fast in spines. During AP trains, spine calcium changes follow each AP, but not in dendrites. Apart from the higher surface-to-volume ratio (SVR), we observed that neocortical dendritic spines have a markedly smaller endogenous buffer capacity with respect to their parental dendrites. Calcium influx time course and calcium extrusion rate were both in the same range for spines and dendrites when fitted with a dynamic multi-compartment model that included calcium binding kinetics and diffusion. In a subsequent analysis we used this model to investigate which parameters are critical determinants in spine calcium dynamics. The model confirmed the experimental findings: a higher SVR is not sufficient by itself to explain the faster rise time kinetics in spines, but only when paired with a lower buffer capacity in spines. Simulations at zero calcium-dye conditions show that calmodulin is more efficiently activated in spines, which indicates that spine morphology and buffering conditions in neocortical spines favor synaptic plasticity

A Mathematical model for Astrocytes mediated LTP at Single Hippocampal Synapses

Many contemporary studies have shown that astrocytes play a significant role in modulating both short and long form of synaptic plasticity. There are very few experimental models which elucidate the role of astrocyte over Long-term Potentiation (LTP). Recently, Perea & Araque (2007) demonstrated a role of astrocytes in induction of LTP at single hippocampal synapses. They suggested a purely pre-synaptic basis for induction of this N-methyl-D- Aspartate (NMDA) Receptor-independent LTP. Also, the mechanisms underlying this pre-synaptic induction were not investigated. Here, in this article, we propose a mathematical model for astrocyte modulated LTP which successfully emulates the experimental findings of Perea & Araque (2007). Our study suggests the role of retrograde messengers, possibly Nitric Oxide (NO), for this pre-synaptically modulated LTP.Comment: 51 pages, 15 figures, Journal of Computational Neuroscience (to appear

The total synthesis of (-)-cyanthiwigin F by means of double catalytic enantioselective alkylation

Double catalytic enantioselective transformations are powerful synthetic methods that can facilitate the construction of stereochemically complex molecules in a single operation. In addition to generating two or more stereocentres in a single reaction, multiple asymmetric reactions also impart increased enantiomeric excess to the final product in comparison with the analogous single transformation. Furthermore, multiple asymmetric operations have the potential to independently construct several stereocentres at remote points within the same molecular scaffold, rather than relying on pre-existing chiral centres that are proximal to the reactive site. Despite the inherent benefits of multiple catalytic enantioselective reactions, their application to natural product total synthesis remains largely underutilized. Here we report the use of a double stereoablative enantioselective alkylation reaction in a concise synthesis of the marine diterpenoid (-)-cyanthiwigin F (ref. 8). By employing a technique for independent, selective formation of two stereocentres in a single stereoconvergent operation, we demonstrate that a complicated mixture of racemic and meso diastereomers may be smoothly converted to a synthetically useful intermediate with exceptional enantiomeric excess. The stereochemical information generated by means of this catalytic transformation facilitates the easy and rapid completion of the total synthesis of this marine natural product