Infant cortex responds to other humans from shortly after birth

A significant feature of the adult human brain is its ability to selectively process information about conspecifics. Much debate has centred on whether this specialization is primarily a result of phylogenetic adaptation, or whether the brain acquires expertise in processing social stimuli as a result of its being born into an intensely social environment. Here we study the haemodynamic response in cortical areas of newborns (1–5 days old) while they passively viewed dynamic human or mechanical action videos. We observed activation selective to a dynamic face stimulus over bilateral posterior temporal cortex, but no activation in response to a moving human arm. This selective activation to the social stimulus correlated with age in hours over the first few days post partum. Thus, even very limited experience of face-to-face interaction with other humans may be sufficient to elicit social stimulus activation of relevant cortical regions

Simple, Fast and Accurate Implementation of the Diffusion Approximation Algorithm for Stochastic Ion Channels with Multiple States

The phenomena that emerge from the interaction of the stochastic opening and closing of ion channels (channel noise) with the non-linear neural dynamics are essential to our understanding of the operation of the nervous system. The effects that channel noise can have on neural dynamics are generally studied using numerical simulations of stochastic models. Algorithms based on discrete Markov Chains (MC) seem to be the most reliable and trustworthy, but even optimized algorithms come with a non-negligible computational cost. Diffusion Approximation (DA) methods use Stochastic Differential Equations (SDE) to approximate the behavior of a number of MCs, considerably speeding up simulation times. However, model comparisons have suggested that DA methods did not lead to the same results as in MC modeling in terms of channel noise statistics and effects on excitability. Recently, it was shown that the difference arose because MCs were modeled with coupled activation subunits, while the DA was modeled using uncoupled activation subunits. Implementations of DA with coupled subunits, in the context of a specific kinetic scheme, yielded similar results to MC. However, it remained unclear how to generalize these implementations to different kinetic schemes, or whether they were faster than MC algorithms. Additionally, a steady state approximation was used for the stochastic terms, which, as we show here, can introduce significant inaccuracies. We derived the SDE explicitly for any given ion channel kinetic scheme. The resulting generic equations were surprisingly simple and interpretable - allowing an easy and efficient DA implementation. The algorithm was tested in a voltage clamp simulation and in two different current clamp simulations, yielding the same results as MC modeling. Also, the simulation efficiency of this DA method demonstrated considerable superiority over MC methods.Comment: 32 text pages, 10 figures, 1 supplementary text + figur

Issues potentially affecting quality of life arising from long-term medicines use: a qualitative study

Background Polypharmacy is increasing and managing large number of medicines may create a burden for patients. Many patients have negative views of medicines and their use can adversely affect quality of life. No studies have specifically explored the impact of general long-term medicines use on quality of life. Objective To determine the issues which patients taking long-term medicines consider affect their day-to-day lives, including quality of life. Setting Four primary care general practices in North West England Methods Face-to-face interviews with adults living at home, prescribed four or more regular medicines for at least 1 year. Interviewees were identified from primary care medical records and purposively selected to ensure different types of medicines use. Interviews were recorded, transcribed and analysed thematically. Results Twenty-one interviews were conducted and analysed. Patients used an average of 7.8 medicines, 51 % were preventive, 40 % for symptom relief and 9 % treatment. Eight themes emerged: relationships with health professionals, practicalities, information, efficacy, side effects, attitudes, impact and control. Ability to discuss medicines with health professionals varied and many views were coloured by negative experiences, mainly with doctors. All interviewees had developed routines for using multiple medicines, some requiring considerable effort. Few felt able to exert control over medicines routines specified by health professionals. Over half sought additional information about medicines whereas others avoided this, trusting in doctors to guide their medicines use. Patients recognised their inability to assess efficacy for many medicines, notably those used for prophylaxis. All were concerned about possible side effects and some had poor experiences of discussing concerns with doctors. Medicines led to restrictions on social activities and personal life to the extent that, for some, life can revolve around medicines. Conclusion There is a multiplicity and complexity of issues surrounding medicines use, which impact on day-to-day lives for patients with long-term conditions. While most patients adapt to long-term medicines use, others did so at some cost to their quality of life

Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial

BACKGROUND: Standard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options. METHODS: In this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per μL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patient's virus was deemed sensitive at trial entry (assessed at 3 years; non-inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074. FINDINGS: Between Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (-0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI -1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events. INTERPRETATION: Protease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection. FUNDING: National Institute for Health Research

Purification and functional characterisation of rhiminopeptidase A, a novel aminopeptidase from the venom of Bitis gabonica rhinoceros

This study describes the discovery and characterisation of a novel aminopeptidase A from the venom of B. g. rhinoceros and highlights its potential biological importance. Similar to mammalian aminopeptidases, rhiminopeptidase A might be capable of playing roles in altering the blood pressure and brain function of victims. Furthermore, it could have additional effects on the biological functions of other host proteins by cleaving their N-terminal amino acids. This study points towards the importance of complete analysis of individual components of snake venom in order to develop effective therapies for snake bites

Numerical Integration of the Master Equation in Some Models of Stochastic Epidemiology

The processes by which disease spreads in a population of individuals are inherently stochastic. The master equation has proven to be a useful tool for modeling such processes. Unfortunately, solving the master equation analytically is possible only in limited cases (e.g., when the model is linear), and thus numerical procedures or approximation methods must be employed. Available approximation methods, such as the system size expansion method of van Kampen, may fail to provide reliable solutions, whereas current numerical approaches can induce appreciable computational cost. In this paper, we propose a new numerical technique for solving the master equation. Our method is based on a more informative stochastic process than the population process commonly used in the literature. By exploiting the structure of the master equation governing this process, we develop a novel technique for calculating the exact solution of the master equation – up to a desired precision – in certain models of stochastic epidemiology. We demonstrate the potential of our method by solving the master equation associated with the stochastic SIR epidemic model. MATLAB software that implements the methods discussed in this paper is freely available as Supporting Information S1

Holographic GB gravity in arbitrary dimensions

We study the properties of the holographic CFT dual to Gauss-Bonnet gravity in general $D \ge 5$ dimensions. We establish the AdS/CFT dictionary and in particular relate the couplings of the gravitational theory to the universal couplings arising in correlators of the stress tensor of the dual CFT. This allows us to examine constraints on the gravitational couplings by demanding consistency of the CFT. In particular, one can demand positive energy fluxes in scattering processes or the causal propagation of fluctuations. We also examine the holographic hydrodynamics, commenting on the shear viscosity as well as the relaxation time. The latter allows us to consider causality constraints arising from the second-order truncated theory of hydrodynamics.Comment: 48 pages, 9 figures. v2: New discussion on free fields in subsection 3.3 and new appendix B on conformal tensor fields. Added comments on the relation between the central charge appearing in the two-point function and the "central charge" characterizing the entropy density in the discussion. References adde

Closing in on Asymmetric Dark Matter I: Model independent limits for interactions with quarks

It is argued that experimental constraints on theories of asymmetric dark matter (ADM) almost certainly require that the DM be part of a richer hidden sector of interacting states of comparable mass or lighter. A general requisite of models of ADM is that the vast majority of the symmetric component of the DM number density must be removed in order to explain the observed relationship $\Omega_B\sim\Omega_{DM}$ via the DM asymmetry. Demanding the efficient annihilation of the symmetric component leads to a tension with experimental limits if the annihilation is directly to Standard Model (SM) degrees of freedom. A comprehensive effective operator analysis of the model independent constraints on ADM from direct detection experiments and LHC monojet searches is presented. Notably, the limits obtained essentially exclude models of ADM with mass 1GeV$\lesssim m_{DM} \lesssim$ 100GeV annihilating to SM quarks via heavy mediator states. This motivates the study of portal interactions between the dark and SM sectors mediated by light states. Resonances and threshold effects involving the new light states are shown to be important for determining the exclusion limits.Comment: 18+6 pages, 18 figures. v2: version accepted for publicatio

Holographic studies of quasi-topological gravity

Quasi-topological gravity is a new gravitational theory including curvature-cubed interactions and for which exact black hole solutions were constructed. In a holographic framework, classical quasi-topological gravity can be thought to be dual to the large $N_c$ limit of some non-supersymmetric but conformal gauge theory. We establish various elements of the AdS/CFT dictionary for this duality. This allows us to infer physical constraints on the couplings in the gravitational theory. Further we use holography to investigate hydrodynamic aspects of the dual gauge theory. In particular, we find that the minimum value of the shear-viscosity-to-entropy-density ratio for this model is $\eta/s \simeq 0.4140/(4\pi)$.Comment: 45 pages, 6 figures. v2: References adde

The what and where of adding channel noise to the Hodgkin-Huxley equations

One of the most celebrated successes in computational biology is the Hodgkin-Huxley framework for modeling electrically active cells. This framework, expressed through a set of differential equations, synthesizes the impact of ionic currents on a cell's voltage -- and the highly nonlinear impact of that voltage back on the currents themselves -- into the rapid push and pull of the action potential. Latter studies confirmed that these cellular dynamics are orchestrated by individual ion channels, whose conformational changes regulate the conductance of each ionic current. Thus, kinetic equations familiar from physical chemistry are the natural setting for describing conductances; for small-to-moderate numbers of channels, these will predict fluctuations in conductances and stochasticity in the resulting action potentials. At first glance, the kinetic equations provide a far more complex (and higher-dimensional) description than the original Hodgkin-Huxley equations. This has prompted more than a decade of efforts to capture channel fluctuations with noise terms added to the Hodgkin-Huxley equations. Many of these approaches, while intuitively appealing, produce quantitative errors when compared to kinetic equations; others, as only very recently demonstrated, are both accurate and relatively simple. We review what works, what doesn't, and why, seeking to build a bridge to well-established results for the deterministic Hodgkin-Huxley equations. As such, we hope that this review will speed emerging studies of how channel noise modulates electrophysiological dynamics and function. We supply user-friendly Matlab simulation code of these stochastic versions of the Hodgkin-Huxley equations on the ModelDB website (accession number 138950) and http://www.amath.washington.edu/~etsb/tutorials.html.Comment: 14 pages, 3 figures, review articl