Transition metal-mediated formation of C–N bonds is an essential synthetic methodology. The discovery of the Chan–Lam amination provided a C–N bond forming process that was mild, convenient, and ...inexpensive, offering an alternative to complementary methods using other transition metals (TMs). Over the past 20 years, this reaction has seen considerable development in its scope of application, uptake into industry, and understanding of its mechanism. This review provides an account of the development of the Chan–Lam amination, highlighting progress and notable examples of application since 2011. Focus is given to evolution in mechanistic understanding and selected applications of the methodology within medicinal and process chemistry.
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Many global environmental agendas, including halting biodiversity loss, reversing land degradation, and limiting climate change, depend upon retaining forests with high ecological integrity, yet the ...scale and degree of forest modification remain poorly quantified and mapped. By integrating data on observed and inferred human pressures and an index of lost connectivity, we generate a globally consistent, continuous index of forest condition as determined by the degree of anthropogenic modification. Globally, only 17.4 million km
of forest (40.5%) has high landscape-level integrity (mostly found in Canada, Russia, the Amazon, Central Africa, and New Guinea) and only 27% of this area is found in nationally designated protected areas. Of the forest inside protected areas, only 56% has high landscape-level integrity. Ambitious policies that prioritize the retention of forest integrity, especially in the most intact areas, are now urgently needed alongside current efforts aimed at halting deforestation and restoring the integrity of forests globally.
Anorexia nervosa is a potentially deadly psychiatric illness that develops predominantly in females around puberty but is increasingly being recognized as also affecting boys and men and women across ...the lifespan. The aim of this environmental scan is to provide an overview of best practices in anorexia nervosa treatment across the age spectrum.
A triangulation approach was used. First, a detailed review of randomized controlled trials (RCTs) for anorexia nervosa published between 1980 and 2011 was conducted; second, clinical practice guidelines were consulted and reviewed; third, information about RCTs currently underway was sourced. This approach facilitated a comprehensive overview, which addressed the extant evidence base, recent advances in evidence and improvements in treatment, and future directions.
The evidence base for the treatment of anorexia nervosa is advancing, albeit unevenly. Evidence points to the benefit of family-based treatment for youth. For adults no specific approach has shown superiority and, presently, a combination of renourishment and psychotherapy such as specialist supportive clinical management, cognitive behavioral therapy, or interpersonal psychotherapy is recommended. RCTs have neither sufficiently addressed the more complex treatment approaches seen in routine practice settings, such as multidisciplinary treatment or level of care, nor specifically investigated treatment in ethnically diverse populations. Methodological challenges that hinder progress in controlled research for anorexia nervosa are explained.
The review highlights evidence-based and promising treatment modalities for anorexia nervosa and presents a triangulated analysis including controlled research, practice guidelines, and emerging treatments to inform and support clinical decision making.
We report an investigation of the Chan–Lam amination reaction. A combination of spectroscopy, computational modeling, and crystallography has identified the structures of key intermediates and ...allowed a complete mechanistic description to be presented, including off-cycle inhibitory processes, the source of amine and organoboron reactivity issues, and the origin of competing oxidation/protodeboronation side reactions. Identification of key mechanistic events has allowed the development of a simple solution to these issues: manipulating Cu(I) → Cu(II) oxidation and exploiting three synergistic roles of boric acid has allowed the development of a general catalytic Chan–Lam amination, overcoming long-standing and unsolved amine and organoboron limitations of this valuable transformation.
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The Give and Take of Alcohol Activation Watson, Andrew J. A.; Williams, Jonathan M. J.
Science (American Association for the Advancement of Science),
08/2010, Volume:
329, Issue:
5992
Journal Article
Peer reviewed
Catalysts make alcohols more reactive by taking away hydrogen to create carbonyl compounds and then returning the hydrogen to the final products.
Alcohols are relatively common starting materials for ...chemical reactions, even though they are quite unreactive. For example, reactions that would substitute another functional group (a nucleophile) for OH often fail because the hydroxide group (HO
−
) is difficult to displace—it is a poor leaving group. Alcohols are usually activated by turning the hydroxide into a better leaving group, either by protonating the alcohol or by converting it into a sulfonate or halide. However, both of these activation methods have some disadvantages (
1
). The acidic environment required for protonating the alcohol also protonates and deactivates the incoming nucleophile, especially amines. Conversion of the alcohol into a sulfonate or halide can lead to toxicity problems; many alkyl halides and alkyl sulfonates are mutagenic.
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Class I histone deacetylases (HDAC1, HDAC2, and HDAC3) are recruited by cognate corepressor proteins into specific transcriptional repression complexes that target HDAC activity to chromatin ...resulting in chromatin condensation and transcriptional silencing. We previously reported the structure of HDAC3 in complex with the SMRT corepressor. This structure revealed the presence of inositol-tetraphosphate Ins(1,4,5,6)P4 at the interface of the two proteins. It was previously unclear whether the role of Ins(1,4,5,6)P4 is to act as a structural cofactor or a regulator of HDAC3 activity. Here we report the structure of HDAC1 in complex with MTA1 from the NuRD complex. The ELM2-SANT domains from MTA1 wrap completely around HDAC1 occupying both sides of the active site such that the adjacent BAH domain is ideally positioned to recruit nucleosomes to the active site of the enzyme. Functional assays of both the HDAC1 and HDAC3 complexes reveal that Ins(1,4,5,6)P4 is a bona fide conserved regulator of class I HDAC complexes.
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•Inositol phosphates are bona fide regulators of class I HDAC corepressor complexes•The ELM2-SANT motif is a conserved HDAC corepressor assembly module•MTA1 is a dimer that recruits two HDACs into the NuRD complex•The MTA1-BAH domain is positioned to recruit chromatin to the HDAC active site
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neuroimaging studies of patients with chronic pain have shown that neurotransmitter abnormalities, including increases in glutamate and decreases in GABA, could be responsible for the cortical ...hyperactivity and hyperalgesia/allodynia observed in some pain conditions. These finding are particularly evident in the insula, a brain region known to play a role in both the sensory-discriminative and the affective-motivational aspects of pain processing. However, clinical studies are not entirely able to determine the directionality of these findings, nor whether they are causal or epiphenomenon. Thus, a set of animal studies was performed to determine whether alterations in glutamate and GABA are the result of injury, the cause of augmented pain processing, or both. Compared with controls, the excitatory neurotransmitters glutamate and aspartate are significantly higher in the rat insula after chronic constriction injury of the sciatic nerve (CCI). The CCI also produced significant increases in allodynia (mechanical and cold), thermal hyperalgesia, and nociceptive aversiveness. Unilateral microinjection of ionotropic glutamate receptor antagonists restored these nociceptive behaviors to preinjury values. Increasing endogenous levels of GABA or enhancing signaling at inhibitory glycinergic receptors had similar effects as the glutamate receptor antagonists. In naive rats, increasing endogenous levels of glutamate, decreasing endogenous levels of GABA, or blocking strychnine-sensitive glycine receptors in the insula significantly increased thermal hyperalgesia and mechanical allodynia. These data support the hypothesis that an altered balance of excitatory and inhibitory neurotransmitters in brain regions such as the insula occurs in chronic pain states and leads to augmented central pain processing and increased pain sensitivity.
A cardinal symptom of major depressive disorder (MDD) is the disruption of circadian patterns. However, to date, there is no direct evidence of circadian clock dysregulation in the brains of patients ...who have MDD. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain were difficult to characterize. Here, we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-h cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses (“controls”) and 34 patients with MDD. Our dataset covered ∼12,000 transcripts in the dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum. Several hundred transcripts in each region showed 24-h cyclic patterns in controls, and >100 transcripts exhibited consistent rhythmicity and phase synchrony across regions. Among the top-ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1(REV-ERBa), DBP, BHLHE40 (DEC1) , and BHLHE41(DEC2) . The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in the brains of patients with MDD due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This transcriptome-wide analysis of the human brain demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggests potentially important molecular targets for treatment of mood disorders.
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There is a significant burden of disease associated with bone defects, and their management is challenging. These injuries have a profound clinical and economic impact, and outcomes are limited by ...high rates of complication and reoperation, as well as poor functional outcomes. There remains a lack of consensus around definitions, reliable models, and best practices for the surgical management of bone defects. The current state of the literature on bone defects is reviewed here, with a focus on defining critical-size bone defect, the use of the induced membrane technique, the role of biologics, and the management of infected bone defects.
We show that gecko microspinules (hairs) and their equivalent replicas, bearing nanoscale tips, can kill or impair surface associating oral pathogenic bacteria with high efficiency even after 7 days ...of repeated attacks. Scanning Electron Microscopy suggests that there is more than one mechanism contributing to cell death which appears to be related to the scaling of the bacteria type with the hair arrays and accessibility to the underlying nano-topography of the hierarchical surfaces.
We show that gecko microspinules (hairs) and their equivalent replicas, bearing nanoscale tips, can kill or impair surface associating oral pathogenic bacteria with high efficiency even after 7 days of repeated attacks.
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