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Stimuli-responsive molecular junctions, where the conductance can be altered by an external perturbation, are an important class of nanoelectronic devices. These have recently attracted interest as large effects can be introduced through exploitation of quantum phenomena. We show here that significant changes in conductance can be attained as a molecule is repeatedly compressed and relaxed, resulting in molecular folding along a flexible fragment and cycling between an anti and a syn conformation. Power spectral density analysis and DFT transport calculations show that through-space tunneling between two phenyl fragments is responsible for the conductance increase as the molecule is mechanically folded to the syn conformation. This phenomenon represents a novel class of mechanoresistive molecular devices, where the functional moiety is embedded in the conductive backbone and exploits intramolecular nonbonding interactions, in contrast to most studies where mechanoresistivity arises from changes in the molecule–electrode interface.

Noninvasive bioimaging techniques are critical for assessing the biodistribution of cellular therapies longitudinally. Among them, photoacoustic imaging (PAI) can generate high-resolution images with a tissue penetration depth of ∼4 cm. However, it is essential and still highly challenging to develop stable and efficient near-infrared (NIR) probes with low toxicity for PAI. We report here the preparation and use of perylene diimide derivative (PDI) with NIR absorbance (around 700 nm) as nanoprobes for tracking mesenchymal stromal cells (MSCs) in mice. Employing an in-house synthesized star hyperbranched polymer as a stabilizer is the key to the formation of stable PDI nanoparticles with low toxicity and high uptake by the MSCs. The PDI nanoparticles remain within the MSCs as demonstrated by in vitro and in vivo assessments. The PDI-labeled MSCs injected subcutaneously on the flanks of the mice are clearly visualized with PAI up to 11 days postadministration. Furthermore, bioluminescence imaging of PDI-labeled luciferase-expressing MSCs confirms that the administered cells remain viable for the duration of the experiment. These PDI nanoprobes thus have good potential for tracking administered cells in vivo using PAI.

Stimuli-responsive molecular junctions, where the conductance can be altered by an external perturbation, are an important class of nanoelectronic devices. These have recently attracted interest as large effects can be introduced through exploitation of quantum phenomena. We show here that significant changes in conductance can be attained as a molecule is repeatedly compressed and relaxed, resulting in molecular folding along a flexible fragment and cycling between an anti and a syn conformation. Power spectral density analysis and DFT transport calculations show that through-space tunnelling between two phenyl fragments is responsible for the conductance increase as the molecule is mechanically folded to the syn conformation. This phenomenon represents a novel class of mechanoresistive molecular devices, where the functional moiety is embedded in the conductive backbone and exploits intramolecular nonbonding interactions, in contrast to most studies where mechanoresistivity arises from changes in the molecule-electrode interface.

Introduction: Guidelines are available to assist providers in identifying patients with renal cell carcinoma (RCC) that may benefit from genetic counselling, however, the evidence for these recommendations lacks support from the literature and controversy remains as to who should be referred. We aimed to delineate risk factors associated with a positive genetic test in a real-life cohort of patients with RCC referred to a regional medical genetics unit for evaluation of a hereditary kidney cancer syndrome. Methods: Patients with a diagnosis of RCC referred to Maritime Medical Genetics Service (Nova Scotia, Canada) from 2006–2017 were reviewed using retrospective data. The primary outcome was identification of clinical features that were associated with a positive test result. Logistic regression models were used for analysis. Results: A total of 135 patients were referred to medical genetics for evaluation; 102 patients were evaluated, 75 underwent testing, and 74 were included in the final analysis. Five patients tested positive: three Birt Hogg Dube, one Cowden syndrome, and one Von Hippel Lindau. Presence of dermatological lesions (specifically fibrofolliculomas) and more than two high-risk features were the only predictors of a positive test result. Conclusions: The presence of dermatological lesions and more than two high-risk features are the only predictors of a positive test result in patients with a suspected hereditary kidney cancer syndrome. These findings are not reflected in current guidelines, and the clinical implementation of our results may improve the identification of high-risk patients for genetic counselling.

Newborns with hemophilia are at risk of intracranial hemorrhage, extracranial hemorrhage, and other bleeding complications. The safe delivery of a healthy newborn with hemophilia is a complex process that can begin even before conception, and continues throughout pregnancy, birth, and the newborn period. This process involves the expectant parents and a wide variety of health-care professionals: genetic counselors, obstetricians, neonatologists, pediatricians, radiologists, adult and pediatric hematologists, and nurses with expertise in hemophilia. Because of this multidisciplinary complexity, the relative rarity of births of newborns with hemophilia, and the lack of high-quality evidence to inform decisions, there is considerable variation in practice in this area. We present a comprehensive multidisciplinary approach, from preconception counseling to discharge planning after birth, and describe available options for management decisions. We highlight a number of areas of important uncertainty and controversy, including the preferred mode of delivery, the appropriate use and timing of neuroimaging tests, and the appropriate use of clotting factor concentrates in the newborn period. While the approach presented here will aid clinicians in planning and providing care, further research is required to optimize the care of newborns with hemophilia.

Meier-Gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. Using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome. In two such individuals that were negative for mutations in ORC4, we found potential mutations in ORC1 and CDT1, two other genes involved in origin recognition. ORC4 is well conserved in eukaryotes, and the yeast equivalent of the human ORC4 missense mutation was shown to be pathogenic in functional assays of cell growth. This is the first report, to our knowledge, of a germline mutation in any gene of the origin recognition complex in a vertebrate organism.

Retinal detachment with avascularity of the peripheral retina, typically associated with familial exudative vitreoretinopathy (FEVR), can result from mutations in KIF11, a gene recently identified to cause microcephaly, lymphedema, and chorioretinal dysplasia (MLCRD) as well as chorioretinal dysplasia, microcephaly, and mental retardation (CDMMR). Ophthalmologists should be aware of the range of presentations for mutations in KIF11 because the phenotypic distinction between FEVR and MLCRD/CDMMR portends management implications in patients with these conditions.To identify gene mutations in patients who present with a FEVR phenotype and explore the spectrum of ocular and systemic abnormalities caused by KIF11 mutations in a cohort of patients with FEVR or microcephaly in conjunction with chorioretinopathy or FEVR.Clinical data and DNA were collected from each participant between 1998 and 2013 from the clinical practices of ophthalmologists and clinical geneticists internationally. Twenty-eight FEVR probands with diagnoses made by the referring physician and without a known FEVR gene mutation, and 3 with microcephaly and chorioretinopathy, were included. At least 1 patient in each pedigree manifested 1 or more of the following: macular dragging, partial retinal detachment, falciform folds, or total retinal detachment.Whole-exome sequencing was conducted on affected members in multiplex pedigrees, and Sanger sequencing of the 22 exons of the KIF11 gene was performed on singletons. Clinical data and history were collected and reviewed.Identification of mutations in KIF11.Four novel heterozygous KIF11 mutations and 1 previously published mutation were identified in probands with FEVR: p.A218Gfs*15, p.E470X, p.R221G, c.790-1GT, and the previously described heterozygous p.R47X. Documentation of peripheral avascular areas on intravenous fluorescein angiography was possible in 2 probands with fibrovascular proliferation demonstrating phenotypic overlap with FEVR.Mutations in KIF11 cause a broader spectrum of ocular disease than previously reported, including retinal detachment. The KIF11 gene likely plays a role in retinal vascular development and mutations in this gene can lead to clinical overlap with FEVR. Cases of FEVR should be carefully inspected for the presence of microcephaly as a marker for KIF11-related disease to enhance the accuracy of the prognosis and genetic counseling.

There is little published information regarding the clinical presentation of Sotos syndrome in pregnancy. In this report, we describe the antenatal presentation of a child subsequently diagnosed with Sotos syndrome by molecular analysis. The pregnancy was complicated by a positive maternal serum screen and abnormal ultrasound findings including macrocephaly, polyhydramnios and decreased fetal movements. This is the first report of an elevated Down syndrome risk in a pregnancy with confirmed Sotos syndrome. Sotos syndrome should be included in the differential diagnosis of newborns with a normal karyotype where the pregnancy has demonstrated an increased risk for Down syndrome by maternal serum screening, especially in the presence of supportive ultrasound findings.

Primary microcephaly is a rare condition in which brain size is substantially diminished without other syndromic abnormalities. Seven autosomal loci have been genetically mapped, and the underlying causal genes have been identified for MCPH1, MCPH3, MCPH5, MCPH6, and MCPH7 but not for MCPH2 or MCPH4. The known genes play roles in mitosis and cell division. We ascertained three families from an Eastern Canadian subpopulation, each with one microcephalic child. Homozygosity analysis in two families using genome-wide dense SNP genotyping supported linkage to the published MCPH4 locus on chromosome 15q21.1. Sequencing of coding exons of candidate genes in the interval identified a nonconservative amino acid change in a highly conserved residue of the centrosomal protein CEP152. The affected children in these two families were both homozygous for this missense variant. The third affected child was compound heterozygous for the missense mutation plus a second, premature-termination mutation truncating a third of the protein and preventing its localization to centrosomes in transfected cells. CEP152 is the putative mammalian ortholog of Drosphila asterless, mutations in which affect mitosis in the fly. Published data from zebrafish are also consistent with a role of CEP152 in centrosome function. By RT-PCR, CEP152 is expressed in the embryonic mouse brain, similar to other MCPH genes. Like some other MCPH genes, CEP152 shows signatures of positive selection in the human lineage. CEP152 is a strong candidate for the causal gene underlying MCPH4 and may be an important gene in the evolution of human brain size.

Spatial interfaces provide the conditions that facilitate or constrain unplanned social interaction. Emergent strategy work is constituted by unintentional social interaction. This paper draws on two disparate literatures, strategy process and architecture, to argue that a possible relationship between spatial configuration and emergent strategy should be taken seriously. Strategy process research has shown that emergent strategy making is important to an organisation’s ability to innovate and adapt in dynamic environments, these abilities are associated with the frequency, diversity, duration and distribution of non-deliberate strategic interactions. Architecture research has shown that spatial configuration has a powerful affect on unplanned social interaction. Strategy-as-Practice, with its focus on social interaction, is proposed as the ideal perspective with which to investigate this possible relationship further. The research uses quantitative methods to explore the extent of the relationship between spatial configuration and the unplanned interactions that constitute emergent strategy making. The results suggest a strong relationship which when compared across four organisations imply very different opportunities for emergent strategy work in each and concludes that emergent strategy needs to be thought of as a material, spatial phenomenon and not just a conceptual one.