Toward the total synthesis of spirastrellolide A. Part 3: Intelligence gathering and preparation of a ring-expanded analogue

Different methods for the formation of the C.25–C.26 bond of spirastrellolide A (1) are evaluated that might qualify for the end game of the projected total synthesis, with emphasis on metathetic ways to forge the macrocyclic frame

DEAD Box Protein DDX1 Regulates Cytoplasmic Localization of KSRP

mRNA decay mediated by the AU-rich elements (AREs) is one of the most studied post-transcriptional mechanisms and is modulated by ARE-binding proteins (ARE-BPs). To understand the regulation of K homology splicing regulatory protein (KSRP), a decay-promoting ARE-BP, we purified KSRP protein complexes and identified an RNA helicase, DDX1. We showed that down-regulation of DDX1 expression elevated cytoplasmic levels of KSRP and facilitated ARE-mediated mRNA decay. Association of KSRP with 14-3-3 proteins, that are predominately located in the cytoplasm, increased upon reduction of DDX1. We also demonstrated that KSRP associated with DDX1 or 14-3-3, but not both. These observations indicate that subcellular localization of KSRP is regulated by competing interactions with DDX1 or 14-3-3

Toward the Total Synthesis of Spirastrellolide A. Part 1: Strategic Considerations and Preparation of the Southern Domain

North and South: The unique biological activity of the natural product spirastrellolide A renders it an attractive lead for anticancer agents. The southern hemisphere (C1–C25) and the northern hemisphere (including the chlorinated [5,6,6]-bis-spiroacetal entity and the lateral C42–C47 chain) are prepared by concise and efficient routes. Consequently, the entire carbon framework of this potent phosphatase inhibitor, which contains 21 chiral centers, is prepared in an optically active form, and an important step toward structure determination by total synthesis is achieved

Toward the Total Synthesis of Spirastrellolide A. Part 2: Conquest of the Northern Hemisphere

North and South: The unique biological activity of the natural product spirastrellolide A renders it an attractive lead for anticancer agents. The southern hemisphere (C1–C25) and the northern hemisphere (including the chlorinated [5,6,6]-bis-spiroacetal entity and the lateral C42–C47 chain) are prepared by concise and efficient routes. Consequently, the entire carbon framework of this potent phosphatase inhibitor, which contains 21 chiral centers, is prepared in an optically active form, and an important step toward structure determination by total synthesis is achieved

Fair Loss-Tolerant Quantum Coin Flipping

Coin flipping is a cryptographic primitive in which two spatially separated players, who in principle do not trust each other, wish to establish a common random bit. If we limit ourselves to classical communication, this task requires either assumptions on the computational power of the players or it requires them to send messages to each other with sufficient simultaneity to force their complete independence. Without such assumptions, all classical protocols are so that one dishonest player has complete control over the outcome. If we use quantum communication, on the other hand, protocols have been introduced that limit the maximal bias that dishonest players can produce. However, those protocols would be very difficult to implement in practice because they are susceptible to realistic losses on the quantum channel between the players or in their quantum memory and measurement apparatus. In this paper, we introduce a novel quantum protocol and we prove that it is completely impervious to loss. The protocol is fair in the sense that either player has the same probability of success in cheating attempts at biasing the outcome of the coin flip. We also give explicit and optimal cheating strategies for both players.Comment: 12 pages, 1 figure; various minor typos corrected in version

Post-traumatic stress disorder in sexually abused children: secure attachment as a protective factor

The aim of the present study was to examine the hypothesis that attachment and CSA interacted such that school aged CSA survivors with insecure attachment to parents would be at an elevated risk of developing PTSD and trauma symptoms. Participants (n = 111, ages 7-12) comprised two groups, child CSA survivors (n = 43) and a matched comparison group of children (n = 68) recruited from the community. Children completed the Child Attachment Interview as well as the Trauma Symptom Checklist for Children (TSCC). There was a significant interaction between sexual abuse history and attachment security, such that sexually abused children with insecure attachment representations had significantly more PTSD and trauma symptoms than sexually abused children with secure attachment to parents. The findings show that using a dual lens of attachment and CSA can facilitate identification children most at risk have important implications for understanding risk and resilience processes

The Impact of Superior Labral Anterior to Posterior Lesions on Functional Status in Shoulder Instability: A Multicenter Cohort Study

BACKGROUND: Type IV superior labral anterior to posterior (SLAP) lesions, which are superior labral detachments associated with Bankart tears, are reported to occur in up to 25% of recurrent shoulder instability patients. However, the clinical implications of this finding are debatable. PURPOSE: To determine whether there are any functional differences between anterior instability patients with and without type IV SLAP lesions at the time of presentation and at short-term follow-up after surgical intervention. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A prospective, multicenter database was established to follow the clinical evolution of patients with shoulder instability. Patients were diagnosed as having a type IV SLAP lesion at the time of arthroscopic Bankart surgery (SLAP+). These patients were compared with a group of patients who simply had a Bankart lesion (SLAP-). The 2 groups had their functional outcomes (Western Ontario Shoulder Instability Index [WOSI]; Disability of the Arm, Shoulder, and Hand [QuickDASH]; and Walch-Duplay) compared prior to surgery and 1 year postoperatively. RESULTS: A total of 103 subjects were included in the study; of these, 56 (43 men, 13 women) completed 1-year follow-up. Twenty-three subjects had a type IV SLAP tear, and most had this repaired along with their Bankart lesion. At baseline, SLAP+ subjects had inferior QuickDASH scores compared with SLAP- subjects (37.8 vs 29.0) as well as poorer pain subscores on both the WOSI and QuickDASH. At 1-year follow-up, however, there were no significant differences in any of the outcome measures. CONCLUSION: A type IV SLAP lesion can be expected in 22% of patients with recurrent shoulder instability. This finding implies that at baseline, the patient will have slightly worse functional scores related to pain. However, following surgical management of the labral pathology, these patients will have equivalent functional outcomes at short-term follow-up. CLINICAL RELEVANCE: With surgical management of the superior and anteroinferior labrum, patients with type IV SLAP lesions will do as well as those with only Bankart tears. Thus, the presence of SLAP lesions should not alter the decision to provide surgical management and should not change the prognosis for a specific patient

IL-4 Signaling Drives a Unique Arginase\u3csup\u3e+\u3c/sup\u3e/IL-1β\u3csup\u3e+\u3c/sup\u3e Microglia Phenotype and Recruits Macrophages to the Inflammatory CNS: Consequences of Age-Related Deficits in IL-4Rα after Traumatic Spinal Cord Injury

Alternative activation of microglia/macrophages (M2a) by interleukin (IL)-4 is purported to support intrinsic growth and repair processes after CNS injury. Nonetheless, alternative activation of microglia is poorly understood in vivo, particularly in the context of inflammation, injury, and aging. Here, we show that aged mice (18-19 months) had reduced functional recovery after spinal cord injury (SCI) associated with impaired induction of IL-4 receptor α (IL-4Rα) on microglia. The failure to successfully promote an IL-4/IL-4Rα response in aged mice resulted in attenuated arginase (M2a associated), IL-1β, and chemokine ligand 2 (CCL2) expression, and diminished recruitment of IL-4Rα+ macrophages to the injured spinal cord. Furthermore, the link between reduced IL-4Rα expression and reduced arginase, IL-1β, and CCL2 expression was confirmed using adult IL-4Rα knock-out (IL-4RαKO) mice. To better understand IL-4Rα-mediated regulation of active microglia, a series of studies was completed in mice that were peripherally injected with lipopolysaccharide and later provided IL-4 by intracerebroventricular infusion. These immune-based studies demonstrate that inflammatory-induced IL-4Rα upregulation on microglia was required for the induction of arginase by IL-4. In addition, IL-4-mediated reprogramming of active microglia enhanced neurite growth ex vivo and increased inflammatory gene expression (i.e., IL-1β and CCL2) and the corresponding recruitment of CCR2+/IL-4Rα+/arginase+ myeloid cells in vivo. IL-4 reprogrammed active microglia to a unique and previously unreported phenotype (arginase+/IL-1β+) that augmented neurite growth and enhanced recruitment of peripheral IL-4Rα+ myeloid cells to the CNS. Moreover, this key signaling cascade was impaired with age corresponding with reduced functional recovery after SCI

Sulfur isotopes in otoliths allow discrimination of anadromous and non-anadromous ecotypes of sockeye salmon (Oncorhynchus nerka)

Oncorhynchus nerka occur both as anadromous sockeye salmon that spend most of their life in the ocean, and as non-anadromous kokanee salmon that remain in fresh water their entire lives. We assessed whether stable isotopes of sulfur (δ34S) in otoliths could be used to distinguish sockeye salmon and kokanee ecotypes that are otherwise difficult to identify when they share a common freshwater rearing environment. We also investigated the chemical link between salmon and their diet by measuring δ34S in various fish tissues (eggs, muscle, scales) and zooplankton. δ34S (mean±SE) in sockeye salmon eggs (18.7 ± 0.4‰) and marine zooplankton (20.5 ± 0.1‰) were enriched by 10–14‰ compared with kokanee eggs and freshwater zooplankton. δ34S in the otolith cores of sockeye salmon (19.2 ± 0.7‰) and kokanee salmon (5.3 ± 1.1‰) were similar to δ34S in marine and freshwater zooplankton, respectively, indicating that the core is derived from maternal yolk tissue and reflects the maternal diet. δ34S in the freshwater growth zone of otoliths did not differ significantly between sockeye (5.9 ± 1.1‰) and kokanee salmon (4.4 ± 1.2‰), and was similar to freshwater zooplankton. The mean difference between δ34S in the otolith core and first year of growth was 13.3 ± 1.4‰ for sockeye and 0.65 ± 1.3‰ for kokanee salmon. A quadratic discriminant function developed from measurements of δ34S in otoliths of known maternal origin provided perfect classification rates in cross-validation tests. Thus, sulfur isotope ratios in otoliths are effective in discriminating between anadromous and non-anadromous ecotypes of O. nerka

Fractalkine receptor (CX3CR1) deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide

<p>Abstract</p> <p>Background</p> <p>Interactions between fractalkine (CX₃CL1) and fractalkine receptor (CX₃CR1) regulate microglial activation in the CNS. Recent findings indicate that age-associated impairments in CX₃CL1 and CX₃CR1 are directly associated with exaggerated microglial activation and an impaired recovery from sickness behavior after peripheral injection of lipopolysaccharide (LPS). Therefore, the purpose of this study was to determine the extent to which an acute LPS injection causes amplified and prolonged microglial activation and behavioral deficits in CX₃CR1-deficient mice (CX₃CR1^-/-).</p> <p>Methods</p> <p>CX₃CR1^-/-mice or control heterozygote mice (CX₃CR1^+/-) were injected with LPS (0.5 mg/kg i.p.) or saline and behavior (i.e., sickness and depression-like behavior), microglial activation, and markers of tryptophan metabolism were determined. All data were analyzed using Statistical Analysis Systems General Linear Model procedures and were subjected to one-, two-, or three-way ANOVA to determine significant main effects and interactions.</p> <p>Results</p> <p>LPS injection caused a prolonged duration of social withdrawal in CX₃CR1^-/-mice compared to control mice. This extended social withdrawal was associated with enhanced mRNA expression of IL-1β, indolamine 2,3-dioxygenase (IDO) and kynurenine monooxygenase (KMO) in microglia 4 h after LPS. Moreover, elevated expression of IL-1β and CD14 was still detected in microglia of CX₃CR1^-/-mice 24 h after LPS. There was also increased turnover of tryptophan, serotonin, and dopamine in the brain 24 h after LPS, but these increases were independent of CX₃CR1 expression. When submitted to the tail suspension test 48 and 72 h after LPS, an increased duration of immobility was evident only in CX₃CR1^-/-mice. This depression-like behavior in CX₃CR1^-/-mice was associated with a persistent activated microglial phenotype in the hippocampus and prefrontal cortex.</p> <p>Conclusions</p> <p>Taken together, these data indicate that a deficiency of CX₃CR1 is permissive to protracted microglial activation and prolonged behavioral alterations in response to transient activation of the innate immune system.</p