Transmitochondrial embryonic stem cells containing pathogenic mtDNA mutations are compromised in neuronal differentiation

Objectives:  Defects of the mitochondrial genome (mtDNA) cause a series of rare, mainly neurological disorders. In addition, they have been implicated in more common forms of movement disorders, dementia and the ageing process. In order to try to model neuronal dysfunction associated with mitochondrial disease, we have attempted to establish a series of transmitochondrial mouse embryonic stem cells harbouring pathogenic mtDNA mutations. Materials and methods: Transmitochondrial embryonic stem cell cybrids were generated by fusion of cytoplasts carrying a variety of mtDNA mutations, into embryonic stem cells that had been pretreated with rhodamine 6G, to prevent transmission of endogenous mtDNA. Cybrids were differentiated into neurons and assessed for efficiency of differentiation and electrophysiological function. Results:  Neuronal differentiation could occur, as indicated by expression of neuronal markers. Differentiation was impaired in embryonic stem cells carrying mtDNA mutations that caused severe biochemical deficiency. Electrophysiological tests showed evidence of synaptic activity in differentiated neurons carrying non-pathogenic mtDNA mutations or in those that caused a mild defect of respiratory activity. Again, however, neurons carrying mtDNA mutations that resulted in severe biochemical deficiency had marked reduction in post-synaptic events. Conclusions:  Differentiated neurons carrying severely pathogenic mtDNA defects can provide a useful model for understanding how such mutations can cause neuronal dysfunction

From Spectators of Public Affairs to Agents of Social Change: Engaging Students in the Basic Course through Service-Learning

Much literature bemoans the attitudes of Generation X (and their successors) toward civic participation (e.g., Putnam, 2000) and indeed education itself (e.g., Sacks, 1996). However, we have found students to be highly engaged when they have opportunities for active learning, such as those found in well designed service learning projects. We see this pedagogy as a small antidote to the sense of powerlessness that often pervades our culture. Drawing on diverse literatures, we explore theoretical reasons for using service-learning and illustrate its usefulness in speech communication basic course. Our discussion is organized around two key themes: (a) connection of self to subject matter, and (b) the connection of self to community. After discussing service learning exemplars in the basic course, we close with cautions about the use of service-learning

The statement that folate supraphysiological levels in uremic patients do not cause harm should not go unchallenged

Diversity within the major histocompatibility complex (MHC) reflects the immunological fitness of a population. MHC-linked microsatellite markers provide a simple and inexpensive method for studying MHC diversity in large scale studies. We have developed six MHC-linked microsatellite markers in the domestic cat and used these, in conjunction with five neutral microsatellites, to assess MHC diversity in domestic mixed breed (n = 129) and purebred Burmese (n = 61) cat populations in Australia. The MHC of outbred Australian cats is polymorphic (average allelic richness = 8.52) while the Burmese population has much significantly lower MHC diversity (average allelic richness = 6.81; P<0.01). The MHC-linked microsatellites along with MHC cloning and sequencing demonstrated moderate MHC diversity in cheetahs (n = 13) and extremely low diversity in Gir lions (n = 13). Our MHC-linked microsatellite markers have potential future use in diversity and disease studies in other populations and breeds of cats as well as in wild felid species

System responses to Holocene relative sea-level rise and sediment supply in a macrotidal estuary

Estuaries are at the interface of marine and terrestrial systems and as such, are subject to environmental change arising from multiple driving mechanisms, with the interplay between the dominant controls varying spatially and temporally. Relative sea-level (RSL) change and sediment supply can play a significant role in driving environmental change. This study examines the relative influence of these drivers during the Holocene. Biostratigraphic records and RSL data are presented from two locations in the inner portion and upper reaches of the macrotidal Humber Estuary, eastern England. The results provide a new terrestrial limiting point and six sea-level index points, two of which at c. 1500 cal years BP provide the youngest sea-level index points for the inner estuary. An early-mid Holocene tidal lagoon system, that lacks modern equivalent, is recorded at one site. The results indicate a shift in the dominance of RSL rise driving the early Holocene creation of wetlands, to sediment supply dominating changes in the mid-late Holocene against the backdrop of a reduced rate of RSL rise, with a submergence of wetlands evident after c. 4000 cal years BP. The persistence of fen carr evident between c. 6800 and 5500 cal years BP suggests stability and resilience of the peatland system to continuing RSL rise. As rates of contemporary RSL rise increase, combined with climate and human impacts on the landscape, the drivers of change in these type of estuary systems will shift, with the records providing analogues of potential system responses that can help inform coastal management strategies

System responses to Holocene relative sea-level rise and sediment supply in a macrotidal estuary

Estuaries are at the interface of marine and terrestrial systems and as such, are subject to environmental change arising from multiple driving mechanisms, with the interplay between the dominant controls varying spatially and temporally. Relative sea-level (RSL) change and sediment supply can play a significant role in driving environmental change. This study examines the relative influence of these drivers during the Holocene. Biostratigraphic records and RSL data are presented from two locations in the inner portion and upper reaches of the macrotidal Humber Estuary, eastern England. The results provide a new terrestrial limiting point and six sea-level index points, two of which at c. 1500 cal years BP provide the youngest sea-level index points for the inner estuary. An early-mid Holocene tidal lagoon system, that lacks modern equivalent, is recorded at one site. The results indicate a shift in the dominance of RSL rise driving the early Holocene creation of wetlands, to sediment supply dominating changes in the mid-late Holocene against the backdrop of a reduced rate of RSL rise, with a submergence of wetlands evident after c. 4000 cal years BP. The persistence of fen carr evident between c. 6800 and 5500 cal years BP suggests stability and resilience of the peatland system to continuing RSL rise. As rates of contemporary RSL rise increase, combined with climate and human impacts on the landscape, the drivers of change in these type of estuary systems will shift, with the records providing analogues of potential system responses that can help inform coastal management strategies

The social meanings of choice in living-with advanced breast cancer

Individual choice is valorised as a core social value; yet the necessity and desirability of making choices takes on new significance for people living with incurable cancer who are required to make often difficult decisions about treatment, care and family life, amidst considerable vulnerability and precariousness. There has been comparatively little exploration of how choice is negotiated and made meaningful under the spectre of incurability and a contracted future. In this paper, drawing on multiple qualitative interviews with 38 women with metastatic breast cancer, we explore how they experience and give meaning to choice in relation to their health (and beyond) in their daily lives. Our analysis highlights that while exercising choice was sometimes a concealed or silent pursuit, choice was always a socially negotiated and temporally unfolding process, nested within relational and interpersonal dynamics. Choices were also often constrained, even foreclosed, due to situational and relational dynamics. Yet even in the absence of choice, the idea of choice-as-control was discursively embraced by women. We argue that greater attention is needed to the affective, temporal and economic dimensions of choice, and how treatment decisions are asymmetrically structured when considered within the normative context of cancer

Subspace methods for electronic structure simulations on quantum computers

Quantum subspace methods (QSMs) are a class of quantum computing algorithms where the time-independent Schrodinger equation for a quantum system is projected onto a subspace of the underlying Hilbert space. This projection transforms the Schrodinger equation into an eigenvalue problem determined by measurements carried out on a quantum device. The eigenvalue problem is then solved on a classical computer, yielding approximations to ground- and excited-state energies and wavefunctions. QSMs are examples of hybrid quantum-classical methods, where a quantum device supported by classical computational resources is employed to tackle a problem. QSMs are rapidly gaining traction as a strategy to simulate electronic wavefunctions on quantum computers, and thus their design, development, and application is a key research field at the interface between quantum computation and electronic structure. In this review, we provide a self-contained introduction to QSMs, with emphasis on their application to the electronic structure of molecules. We present the theoretical foundations and applications of QSMs, and we discuss their implementation on quantum hardware, illustrating the impact of noise on their performance.Comment: 34 pages, 11 figure