Enantioselective Aziridination of Unactivated Terminal Alkenes Using a Planar Chiral Rh(III) Indenyl Catalyst.

Chiral aziridines are important structural motifs found in natural products and various target molecules. They serve as versatile building blocks for the synthesis of chiral amines. While advances in catalyst design have enabled robust methods for enantioselective aziridination of activated olefins, simple and abundant alkyl-substituted olefins pose a significant challenge. In this work, we introduce a novel approach utilizing a planar chiral rhodium indenyl catalyst to facilitate the enantioselective aziridination of unactivated alkenes. This transformation exhibits a remarkable degree of functional group tolerance and displays excellent chemoselectivity favoring unactivated alkenes over their activated counterparts, delivering a wide range of enantioenriched high-value chiral aziridines. Computational studies unveil a stepwise aziridination mechanism in which alkene migratory insertion plays a central role. This process results in the formation of a strained four-membered metallacycle and serves as both the enantio- and rate-determining steps in the overall reaction.

Synthesis, stereochemical assignment, and enantioselective catalytic activity of late transition metal planar chiral complexes.

Planar chirality is an important form of molecular chirality that can be utilized to induce enantioselectivity when incorporated into transition metal catalysts. However, due to synthetic constraints, the use of late transition metal planar chiral complexes to conduct enantioselective transformations has been limited. Additionally, the published methods surrounding the stereochemical assignment of planar chiral compounds are sometimes conflicting, making proper assignment difficult. This review aims to provide clarity on the methods available to assign planar chirality and provide an overview on the synthesis and use of late transition metal planar chiral complexes as enantioselective catalysts.

Synthesis of Ribosomally Synthesized and Post-Translationally Modified Peptides Containing C-C Cross-Links.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are known for their macrocyclic structures, which impart unique biological activity. One rapidly emerging subclass of RiPP natural products contains macrocyclic C-C cross-links between two amino acid side chains. These linkages, often biosynthetically formed by a single rSAM or P450 enzyme, introduce significant structural and synthetic complexity to the molecules. While nature utilizes elegant mechanisms to produce C-C cross-linked RiPPs, synthetic tools are only able to access a portion of these biologically relevant natural products. This review provides an overview of the structures in this subclass as well as a discussion on their chemical syntheses.

From research to practice: results of 7300 mortality retrospective case record reviews in four acute hospitals in the North-East of England.

INTRODUCTION: Monitoring hospital mortality using retrospective case record review (RCRR) is being adopted throughout the National Health Service (NHS) in England with publication of estimates of avoidable mortality beginning in 2017. We describe our experience of reviewing the care records of inpatients who died following admission to hospital in four acute hospital NHS Foundation Trusts in the North-East of England. METHODS: RCRR of 7370 patients who died between January 2012 and December 2015. Cases were reviewed by consultant reviewers with support from other disciplines and graded in terms of quality of care and preventability of deaths. Results were compared with the estimates published in the Preventable Incidents, Survival and Mortality (PRISM) studies, which established the original method. RESULTS: 34 patients (0.5%, 95% CI 0.3% to 0.6%) were judged to have a greater than 50% probability of death being preventable. 1680 patients (22.3%, 95% CI 22.4% to 23.3%) were judged to have room for improvement in clinical, organisational (or both) aspects of care or less than satisfactory care. CONCLUSIONS: Reviews using clinicians within trusts produce lower estimates of preventable deaths than published results using external clinicians. More research is needed to understand the reasons for this, but as the requirement for NHS Trusts to publish estimates of preventable mortality is based on reviews by consultants working for those trusts, lower estimates of preventable mortality can be expected. Room for improvement in the quality of care is more common than preventability of death and so mortality reviews contribute to improvement activity although the outcome of care cannot be changed. RCRR conducted internally is a feasible mechanism for delivering quantitative analysis and in the future can provide qualitative insights relating to inhospital deaths.

Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhäuser syndrome and central corneal thickness.

We describe novel CHRDL1 mutations in ten families with X-linked megalocornea (MGC1). Our mutation-positive cohort enabled us to establish ultrasonography as a reliable clinical diagnostic tool to distinguish between MGC1 and primary congenital glaucoma (PCG). Megalocornea is also a feature of Neuhäuser or megalocornea-mental retardation (MMR) syndrome, a rare condition of unknown etiology. In a male patient diagnosed with MMR, we performed targeted and whole exome sequencing (WES) and identified a novel missense mutation in CHRDL1 that accounts for his MGC1 phenotype but not his non-ocular features. This finding suggests that MMR syndrome, in some cases, may be di- or multigenic. MGC1 patients have reduced central corneal thickness (CCT); however no X-linked loci have been associated with CCT, possibly because the majority of genome-wide association studies (GWAS) overlook the X-chromosome. We therefore explored whether variants on the X-chromosome are associated with CCT. We found rs149956316, in intron 6 of CHRDL1, to be the most significantly associated single nucleotide polymorphism (SNP) (p = 6.81×10(-6)) on the X-chromosome. However, this association was not replicated in a smaller subset of whole genome sequenced samples. This study highlights the importance of including X-chromosome SNP data in GWAS to identify potential loci associated with quantitative traits or disease risk.

Evisceration for the management of ocular trauma.

Despite the eye being surrounded by orbital bones and protective mechanisms such as the blink reflex, it is vulnerable to trauma. The two key issues to consider when presented with a case of ocular trauma are the visual potential of the eye and the risk of sympathetic ophthalmia. The Ocular Trauma Score can be used to assess the visual potential of the injured eye. Surgical management may be either repair or removal of the eye (evisceration or enucleation). Herein we describe a case of ocular trauma and the decision-making process in the management of the injury.

Ramos-Arroyo syndrome: confirmation of an entity.

In 1987, Ramos-Arroyo et al. described a family with a previously unreported combination of features, which included corneal anesthesia, short stature, sensorineural deafness, learning difficulties, and a characteristic facial appearance. The family was reviewed in 2008 and additional features were noted. The name Ramos-Arroyo syndrome was proposed. The condition can be delineated by corneal anesthesia, absence of the peripapillary choriocapillaris and retinal pigment epithelium, bilateral sensorineural hearing loss, unusual facial appearance, persistent ductus arteriosus, Hirschprung disease, short stature, and intellectual disability. No other patient has been described since. Here, we report on a 5-year-old girl with features consistent with Ramos-Arroyo syndrome. We propose an overlap of this condition with dysautonomia syndromes.

Sympathetic ophthalmia secondary to cyclodiode laser in a 10-year-old boy.

A 10-year-old boy with tuberous sclerosis was treated with cyclodiode laser for right rubeotic glaucoma. Five months after treatment, he developed a bilateral granulomatous uveitis. Enucleation of the exciting eye demonstrated sympathetic ophthalmia.

Postoperative surface deposits on intraocular lenses in children.

PURPOSE: To report the clinicopathologic features of 4 intraocular lenses (IOLs) composed of 3 different hydrophilic biomaterials explanted from children who had postoperative opacification of the IOL optic. SETTING: David J Apple, MD, Laboratories for Ophthalmic Devices Research, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, USA. METHODS: The IOLs were explanted 20, 11, 22, and 25 months postoperatively from children aged 10, 3, 36, and 20 months old, respectively, at IOL implantation. Clinical data were obtained to correlate the findings with possible associated risk factors. The explanted IOLs were examined by gross and light microscopy. They were further analyzed with a stain for calcium, alizarin red 1%. Scanning electron microscopy and energy dispersive X-ray spectroscopy (EDS) were also performed. RESULTS: The primary reason for cataract surgery in Case 1 and Case 2 was persistent hyperplastic primary vitreous (PHPV); 1 patient received a B-Lens IOL (Hanita) and the other a Centerflex IOL (Rayner). The primary reason in Case 3 was familial bilateral congenital cataract and in Case 4, rubella cataract; both patients received a Hydroview IOL (Bausch & Lomb). All 4 IOLs had surface deposits on the optic, but the morphology of the deposits on the B-Lens and Centerflex IOLs was different than that in previously reported cases. The deposits in all four cases stained positive with alizarin red and consisted of calcium and phosphorus when imaged with EDS. CONCLUSIONS: Calcified deposits on 2 Hydroview IOLs explanted from children were similar to those seen in adults with the same IOL. The deposits on the B-Lens and Centerflex IOLs were probably secondary to a breakdown of the blood-aqueous barrier caused by preexisting PHPV.

Stimulation and inhibition of uveal melanoma invasion by HGF, GRO, IL-1alpha and TGF-beta.

PURPOSE: To investigate potential factors involved in uveal melanoma migration and invasion in vitro. METHODS: Using a microchemotaxis chamber, the effects were studied of a range of stimulators and inhibitors on a series of 10 primary uveal melanomas and 2 uveal melanoma cell lines, by assessing invasion through an 8- micro m pore membrane, precoated with an extracellular matrix solution. In addition, invasion in response to the effect of cells and conditioned media derived from the liver and other tissues was studied for one uveal melanoma culture, by using double-chambered wells, and invasion was assessed through an 8- micro m pore membrane, precoated with synthetic extracellular matrix. In all instances, invading cells were counted under x400 magnification on the lower surface of the membrane. Levels of invasion were correlated with histopathologic markers of prognosis. RESULTS: Conditioned media and cells derived from other tissues, including the liver, increased cellular invasion of the uveal melanoma cell line studied. For specific regulators, maximum stimulation of invasion was induced by hepatic growth factor (HGF), growth-related oncogene (GRO), and macrophage inflammatory protein (MIP)-1beta, whereas significant inhibition was induced by IL-1alpha, TGF-beta1, and TGF-beta2. CONCLUSIONS: The primary site of metastasis in patients with uveal melanoma is the liver. For the degree of site specificity commonly seen, regulators involved in the process may be expressed at the secondary sites, promoting adhesion, migration, invasion, and proliferation of tumor cells. HGF, GRO, MIP-1beta, IL-1alpha, TGF-beta1, and TGF-beta2 may play a significant role in regulating invasion of uveal melanoma cells.

Solid-state NMR spectroscopic methods in chemistry.

Over the last decades, NMR spectroscopy has grown into an indispensable tool for chemical analysis, structure determination, and the study of dynamics in organic, inorganic, and biological systems. It is commonly used for a wide range of applications from the characterization of synthetic products to the study of molecular structures of systems such as catalysts, polymers, and proteins. Although most NMR experiments are performed on liquid-state samples, solid-state NMR is rapidly emerging as a powerful method for the study of solid samples and materials. This Review outlines some of the developments of solid-state NMR spectroscopy, including techniques such as cross-polarization, magic-angle spinning, multiple-pulse sequences, homo- and heteronuclear decoupling and recoupling techniques, multiple-quantum spectroscopy, and dynamic angle spinning, as well as their applications to structure determination. Modern solid-state NMR spectroscopic techniques not only produce spectra with a resolution close to that of liquid-state spectra, but also capitalize on anisotropic interactions, which are often unavailable for liquid samples. With this background, the future of solid-state NMR spectroscopy in chemistry appears to be promising, indeed.