Systematic population screening, using biomarkers and genetic testing, identifies 2.5% of the U.K. pediatric diabetes population with monogenic diabetes

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.OBJECTIVE: Monogenic diabetes is rare but is an important diagnosis in pediatric diabetes clinics. These patients are often not identified as this relies on the recognition of key clinical features by an alert clinician. Biomarkers (islet autoantibodies and C-peptide) can assist in the exclusion of patients with type 1 diabetes and allow systematic testing that does not rely on clinical recognition. Our study aimed to establish the prevalence of monogenic diabetes in U.K. pediatric clinics using a systematic approach of biomarker screening and targeted genetic testing. RESEARCH DESIGN AND METHODS: We studied 808 patients (79.5% of the eligible population) <20 years of age with diabetes who were attending six pediatric clinics in South West England and Tayside, Scotland. Endogenous insulin production was measured using the urinary C-peptide creatinine ratio (UCPCR). C-peptide-positive patients (UCPCR ≥0.2 nmol/mmol) underwent islet autoantibody (GAD and IA2) testing, with patients who were autoantibody negative undergoing genetic testing for all 29 identified causes of monogenic diabetes. RESULTS: A total of 2.5% of patients (20 of 808 patients) (95% CI 1.6-3.9%) had monogenic diabetes (8 GCK, 5 HNF1A, 4 HNF4A, 1 HNF1B, 1 ABCC8, 1 INSR). The majority (17 of 20 patients) were managed without insulin treatment. A similar proportion of the population had type 2 diabetes (3.3%, 27 of 808 patients). CONCLUSIONS: This large systematic study confirms a prevalence of 2.5% of patients with monogenic diabetes who were <20 years of age in six U.K. clinics. This figure suggests that ∼50% of the estimated 875 U.K. pediatric patients with monogenic diabetes have still not received a genetic diagnosis. This biomarker screening pathway is a practical approach that can be used to identify pediatric patients who are most appropriate for genetic testing.This work presents independent research commissioned by the Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the Department of Health (grant HICF-1009-041); and was supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility and the South West Peninsula Diabetes Research Network. M.S. is supported by the NIHR Exeter Clinical Research Facility. T.J.M. is funded by an NIHR CSO Fellowship. S.E. and A.T.H. are both Wellcome Trust Senior Investigators. E.R.P. is a Wellcome Trust New Investigator. A.T.H. is an NIHR Senior Investigator

Knotted vs. Unknotted Proteins: Evidence of Knot-Promoting Loops

Knotted proteins, because of their ability to fold reversibly in the same topologically entangled conformation, are the object of an increasing number of experimental and theoretical studies. The aim of the present investigation is to assess, on the basis of presently available structural data, the extent to which knotted proteins are isolated instances in sequence or structure space, and to use comparative schemes to understand whether specific protein segments can be associated to the occurrence of a knot in the native state. A significant sequence homology is found among a sizeable group of knotted and unknotted proteins. In this family, knotted members occupy a primary sub-branch of the phylogenetic tree and differ from unknotted ones only by additional loop segments. These "knot-promoting" loops, whose virtual bridging eliminates the knot, are found in various types of knotted proteins. Valuable insight into how knots form, or are encoded, in proteins could be obtained by targeting these regions in future computational studies or excision experiments

Value migration: digitalization of shipping as a mechanism of industry dethronement

In this conceptual paper, we review latest developments related to unmanned vessels and sketch potential scenarios that implicate with the existing maritime industry structure. On the one hand, we isolate a range of challenges that make the imminent realization of unmanned vessels seem like a rather utopian pursuit. On the other hand, we explain the reasons that may catalyse their emergence. Inspired by these opposing tensions, we highlight that the digital transformation of the shipping industry has the potential to enhance value within the industry’s ecosystem. However, we also contend that unmanned vessels -if realized- pose a very particular threat to the identity of the shipping industry as we know it. In particular, we build upon the concept of value migration and we highlight the drastic existential changes that may likely stem from a shift to non-seafarer-centric shipping. We conclude with questions that matter for industry dethronement purposes i.e., the possibility that existing industry structures may be substantially reconfigured following a removal of the seafarer as the nucleus of value creation in shipping

Mechanical Bonds and Topological Effects in Radical Dimer Stabilization

While mechanical bonding stabilizes tetrathiafulvalene (TTF) radical dimers, the question arises: what role does topology play in catenanes containing TTF units? Here, we report how topology, together with mechanical bonding, in isomeric [3]- and doubly interlocked [2]catenanes controls the formation of TTF radical dimers within their structural frameworks, including a ring-in-ring complex (formed between an organoplatinum square and a {2+2} macrocyclic polyether containing two 1,5-dioxynaphthalene (DNP) and two TTF units) that is topologically isomeric with the doubly interlocked [2]catenane. The separate TTF units in the two {1+1} macrocycles (each containing also one DNP unit) of the isomeric [3]catenane exhibit slightly different redox properties compared with those in the {2+2} macrocycle present in the [2]catenane, while comparison with its topological isomer reveals substantially different redox behavior. Although the stabilities of the mixed-valence (TTF2)^(•+) dimers are similar in the two catenanes, the radical cationic (TTF^(•+))_2 dimer in the [2]catenane occurs only fleetingly compared with its prominent existence in the [3]catenane, while both dimers are absent altogether in the ring-in-ring complex. The electrochemical behavior of these three radically configurable isomers demonstrates that a fundamental relationship exists between topology and redox properties

Maritime education and training in the COVID-19 era and beyond

The rapid global spread of COVID–19 has created numerous challenges for educational organizations of all levels around the world. Maritime Education and Training (MET) institutions are no exception and have faced major disruptions from the pandemic. Differing technological and organizational solutions have had to be quickly adapted in short timeframes in order to fill gaps and ensure continued teaching and learning. Although online education is nothing new, COVID-19 has accelerated the necessity for distributed learning, digital tools and infrastructure needed to not only cope, but excel in the restructuring of MET. In this article we present our experiences from the blended course offered to maritime bachelor students at our university in Norway through a case study. The findings from the study have revealed that although blended learning has helped continued education during the pandemic, it still has to overcome general as well as MET specific challenges to be successful in future. Considering the impact and challenges of the COVID-19 pandemic on MET, we further discuss the short-term responses and possible long-term solutions that can contribute to uninterrupted, high-quality learning for future MET. The use of emerging technologies for education, such as virtual reality (VR) and web-based training simulators, are likely to play an essential role in the future direction of MET

Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro

AbstractBone marrow-derived mesenchymal stem cells (MSCs) are of therapeutic interest in a variety of neurological diseases. In this study, we wished to determine whether human MSCs secrete factors which protect cultured rodent cortical neurons from death by trophic factor withdrawal or nitric oxide (NO) exposure. Medium conditioned by MSCs attenuated neuronal death under these conditions, a process which was dependent on intact PI3kinase/Akt pathway signaling. Trophic withdrawal and NO exposure in cultured cortical neurons led to reduction in Akt signaling pathways, whereas NO administration activated p38 MAPkinase in neuronal cultures. Addition of MSC-conditioned medium significantly activated the PI3kinase/Akt pathway and in neurons exposed to NO, MSC-conditioned medium reduced p38 signaling. We show that MSCs secrete brain-derived neurotrophic factor (BDNF) and addition of anti-BDNF neutralising antibodies to MSC-conditioned medium attenuated its neuroprotective effect. Exposure of neurons to BDNF increased activation of Akt pathways and protected neurons from trophic factor withdrawal. These observations determine the mechanisms of neuroprotection offered by MSC-derived factors and suggest an important role for BDNF in neuronal protection