Novel <em>GFM2</em> variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits

Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.569G&gt;A, p.(Arg190Gln); c.636delA, p.(Glu213Argfs*3)) and homozygous (c.275A&gt;C, p.(Tyr92Ser)) recessive variants in GFM2 identified by whole exome sequencing (WES) together with histochemical and biochemical findings to support the diagnoses of pathological GFM2 variants in each case. Both patients presented similarly in early childhood with global developmental delay, raised CSF lactate and abnormalities on cranial MRI. Sanger sequencing of familial samples confirmed the segregation of bi-allelic GFM2 variants with disease, while investigations into steady-state mitochondrial protein levels revealed respiratory chain subunit defects and loss of mtEFG2 protein in muscle. These data demonstrate the effects of defective mtEFG2 function, caused by previously unreported variants, confirming pathogenicity and expanding the clinical phenotypes associated with GFM2 variants

The effective action of D6-branes in N=1 type IIA orientifolds

We use a Kaluza-Klein reduction to compute the low-energy effective action for the massless modes of a spacetime-filling D6-brane wrapped on a special Lagrangian 3-cycle of a type IIA Calabi-Yau orientifold. The modifications to the characteristic data of the N=1 bulk orientifold theory in the presence of a D6-brane are analysed by studying the underlying Type IIA supergravity coupled to the brane worldvolume in the democratic formulation and performing a detailed dualisation procedure. The N=1 chiral coordinates are found to be in agreement with expectations from mirror symmetry. We work out the Kahler potential for the chiral superfields as well as the gauge kinetic functions for the bulk and the brane gauge multiplets including the kinetic mixing between the two. The scalar potential resulting from the dualisation procedure can be formally interpreted in terms of a superpotential. Finally, the gauging of the Peccei-Quinn shift symmetries of the complex structure multiplets reproduces the D-term potential enforcing the calibration condition for special Lagrangian 3-cycles.Comment: 48 pages, v2: typos corrected, references adde

Physiological and autonomic stress responses after prolonged sleep restriction and subsequent recovery sleep in healthy young men

Purpose Sleep restriction is increasingly common and associated with the development of health problems. We investigated how the neuroendocrine stress systems respond to prolonged sleep restriction and subsequent recovery sleep in healthy young men. Methods After two baseline (BL) nights of 8 h time in bed (TIB), TIB was restricted to 4 h per night for five nights (sleep restriction, SR, n = 15), followed by three recovery nights (REC) of 8 h TIB, representing a busy workweek and a recovery weekend. The control group (n = 8) had 8 h TIB throughout the experiment. A variety of autonomic cardiovascular parameters, together with salivary neuropeptide Y (NPY) and cortisol levels, were assessed. Results In the control group, none of the parameters changed. In the experimental group, heart rate increased from 60 +/- 1.8 beats per minute (bpm) at BL, to 63 +/- 1.1 bpm after SR and further to 65 +/- 1.8 bpm after REC. In addition, whole day low-frequency to-high frequency (LF/HF) power ratio of heart rate variability increased from 4.6 +/- 0.4 at BL to 6.0 +/- 0.6 after SR. Other parameters, including salivary NPY and cortisol levels, remained unaffected. Conclusions Increased heart rate and LF/HF power ratio are early signs of an increased sympathetic activity after prolonged sleep restriction. To reliably interpret the clinical significance of these early signs of physiological stress, a follow-up study would be needed to evaluate if the stress responses escalate and lead to more unfavourable reactions, such as elevated blood pressure and a subsequent elevated risk for cardiovascular health problems.Peer reviewe

The IceCube Neutrino Observatory - Contributions to ICRC 2017 Part VI: IceCube-Gen2, the Next Generation Neutrino Observatory

Papers on research & development towards IceCube-Gen2, the next generation neutrino observatory at South Pole, submitted to the 35th International Cosmic Ray Conference (ICRC 2017, Busan, South Korea) by the IceCube-Gen2 Collaboration

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Towards an appreciation of ethics in social enterprise business models

How can a critical analysis of entrepreneurial intention inform an appreciation of ethics in social enterprise business models? In answering this question, we consider the ethical commitments that inform entrepreneurial action (inputs) and the hybrid organisations that emerge out of these commitments and actions (outputs). Ethical theory can be a useful way to re-orient the field of social enterprise so that it is more critical of bureaucratic (charitable) and market-driven (business) enterprises connected to neo-liberal doctrine. Social enterprise hybrid business models are therefore reframed as outcomes of both ethical and entrepreneurial intentions. We challenge the dominant conceptualisation of social enterprise as a hybrid blend of mission and market (purpose-versus-resource) by reframing hybridity in terms of the moral choice of economic system (redistribution, reciprocity and market) and social value orientation (personal, mutual or public benefit). We deconstruct the political foundations of charitable trading activities (CTAs), co-operative and mutual enterprises (CMEs) and socially responsible businesses (SRBs) by examining the rationalities (formal, social and substantive) and ethical commitments (utilitarian, communitarian, pragmatic) that underpin them. Whilst conceptual modelling of social enterprise is not new, this paper contributes to knowledge by developing a theory of social enterprise ethics based on the moral/political choices that are made by entrepreneurs (knowingly and unknowingly) when choosing between systems of economic exchange and social value orientation, then expressing it through a legal form

Dry Truth and Real Knowledge : Epistemologies of Metaphors and Metaphors of Epistemology

Locke is eloquent in defence of plain speech. In a famous, or notorious, passage at close of chapter X of Book III of the Essay: “Of the Abuse of Words,” though he admits that “since wit and fancy find easier entertainment than dry truth and real knowledge, figurative speeches and allusions in language will hardly be admitted as an imperfection of it,” Locke insists that nevertheless, if we would speak of things as they are, we must allow that all the art of rhetoric, besides order and clearness; all the artificial and figurative applications of words eloquence hath invented, are for nothing else than to insinuate wrong ideas, move the passions, and thereby mislead the judgement; and so indeed are perfect cheats