Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans

The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans

Education and training of healthcare staff in the knowledge, attitudes and skills needed to work effectively with breastfeeding women:a systematic review

BACKGROUND: Current evidence suggests that women need effective support to breastfeed, but many healthcare staff lack the necessary knowledge, attitudes and skills. There is therefore a need for breastfeeding education and training for healthcare staff. The primary aim of this review is to determine whether education and training programs for healthcare staff have an effect on their knowledge and attitudes about supporting breastfeeding women. The secondary aim of this review was to identify whether any differences in type of training or discipline of staff mattered. METHODS: A systematic search of the literature was conducted using the Cochrane Pregnancy and Childbirth Group’s trial register. Randomised controlled trials comparing breastfeeding education and training for healthcare staff with no or usual training and education were included if they measured the impact on staff knowledge, attitudes or compliance with the Baby Friendly Hospital Initiative (BFHI). RESULTS: From the 1192 reports identified, four distinct studies were included. Three studies were two-arm cluster-randomised trials and one was a two-arm individual randomised trial. Of these, three contributed quantitative data from a total of 250 participants. Due to heterogeneity of outcome measures meta-analysis was not possible. Knowledge was included as an outcome in two studies and demonstrated small but significant positive effects. Attitudes towards breastfeeding was included as an outcome in two studies, however, results were inconsistent both in terms of how they were measured and the intervention effects. One study reported a small but significant positive effect on BFHI compliance. Study quality was generally deemed low with the majority of domains being judged as high or unclear risk of bias. CONCLUSIONS: This review identified a lack of good evidence on breastfeeding education and training for healthcare staff. There is therefore a critical need for research to address breastfeeding education and training needs of multidisciplinary healthcare staff in different contexts through large, well-conducted RCTs

Ecological influences on the behaviour and fertility of malaria parasites

BACKGROUND: Sexual reproduction in the mosquito is essential for the transmission of malaria parasites and a major target for transmission-blocking interventions. Male gametes need to locate and fertilize females in the challenging environment of the mosquito blood meal, but remarkably little is known about the ecology and behaviour of male gametes. METHODS: Here, a series of experiments explores how some aspects of the chemical and physical environment experienced during mating impacts upon the production, motility, and fertility of male gametes. RESULTS AND CONCLUSIONS: Specifically, the data confirm that: (a) rates of male gametogenesis vary when induced by the family of compounds (tryptophan metabolites) thought to trigger gamete differentiation in nature; and (b) complex relationships between gametogenesis and mating success exist across parasite species. In addition, the data reveal that (c) microparticles of the same size as red blood cells negatively affect mating success; and (d) instead of swimming in random directions, male gametes may be attracted by female gametes. Understanding the mating ecology of malaria parasites, may offer novel approaches for blocking transmission and explain adaptation to different species of mosquito vectors

Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.

The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening.This work was funded by ERC starting grant Relieve IMDs (L.V., N.H.), the Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V., N.H., F.S.), the Evelyn trust (N.H.) and the EU Fp7 grant TissuGEN (M.CDB.). FS has been supported by an Addenbrooke’s Charitable Trust Clinical Research Training Fellowship and a joint MRC-Sparks Clinical Research Training Fellowship.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nbt.327

Social density processes regulate the functioning and performance of foraging human teams

Social density processes impact the activity and order of collective behaviours in a variety of biological systems. Much effort has been devoted to understanding how density of people affects collective human motion in the context of pedestrian flows. However, there is a distinct lack of empirical data investigating the effects of social density on human behaviour in cooperative contexts. Here, we examine the functioning and performance of human teams in a central-place foraging arena using high-resolution GPS data. We show that team functioning (level of coordination) is greatest at intermediate social densities, but contrary to our expectations, increased coordination at intermediate densities did not translate into improved collective foraging performance, and foraging accuracy was equivalent across our density treatments. We suggest that this is likely a consequence of foragers relying upon visual channels (local information) to achieve coordination but relying upon auditory channels (global information) to maximise foraging returns. These findings provide new insights for the development of more sophisticated models of human collective behaviour that consider different networks for communication (e.g. visual and vocal) that have the potential to operate simultaneously in cooperative contexts

Alterations in voltage-sensing of the mitochondrial permeability transition pore in ANT1-deficient cells

The probability of mitochondrial permeability transition (mPT) pore opening is inversely related to the magnitude of the proton electrochemical gradient. The module conferring sensitivity of the pore to this gradient has not been identified. We investigated mPT's voltage-sensing properties elicited by calcimycin or H2O2 in human fibroblasts exhibiting partial or complete lack of ANT1 and in C2C12 myotubes with knocked-down ANT1 expression. mPT onset was assessed by measuring in situ mitochondrial volume using the 'thinness ratio' and the 'cobalt-calcein' technique. De-energization hastened calcimycin-induced swelling in control and partially-expressing ANT1 fibroblasts, but not in cells lacking ANT1, despite greater losses of mitochondrial membrane potential. Matrix Ca(2+) levels measured by X-rhod-1 or mitochondrially-targeted ratiometric biosensor 4mtD3cpv, or ADP-ATP exchange rates did not differ among cell types. ANT1-null fibroblasts were also resistant to H2O2-induced mitochondrial swelling. Permeabilized C2C12 myotubes with knocked-down ANT1 exhibited higher calcium uptake capacity and voltage-thresholds of mPT opening inferred from cytochrome c release, but intact cells showed no differences in calcimycin-induced onset of mPT, irrespective of energization and ANT1 expression, albeit the number of cells undergoing mPT increased less significantly upon chemically-induced hypoxia than control cells. We conclude that ANT1 confers sensitivity of the pore to the electrochemical gradient

Alterations in voltage-sensing of the mitochondrial permeability transition pore in ANT1-deficient cells

The probability of mitochondrial permeability transition (mPT) pore opening is inversely related to the magnitude of the proton electrochemical gradient. The module conferring sensitivity of the pore to this gradient has not been identified. We investigated mPT's voltage-sensing properties elicited by calcimycin or H2O2 in human fibroblasts exhibiting partial or complete lack of ANT1 and in C2C12 myotubes with knocked-down ANT1 expression. mPT onset was assessed by measuring in situ mitochondrial volume using the 'thinness ratio' and the 'cobalt-calcein' technique. De-energization hastened calcimycin-induced swelling in control and partially-expressing ANT1 fibroblasts, but not in cells lacking ANT1, despite greater losses of mitochondrial membrane potential. Matrix Ca(2+) levels measured by X-rhod-1 or mitochondrially-targeted ratiometric biosensor 4mtD3cpv, or ADP-ATP exchange rates did not differ among cell types. ANT1-null fibroblasts were also resistant to H2O2-induced mitochondrial swelling. Permeabilized C2C12 myotubes with knocked-down ANT1 exhibited higher calcium uptake capacity and voltage-thresholds of mPT opening inferred from cytochrome c release, but intact cells showed no differences in calcimycin-induced onset of mPT, irrespective of energization and ANT1 expression, albeit the number of cells undergoing mPT increased less significantly upon chemically-induced hypoxia than control cells. We conclude that ANT1 confers sensitivity of the pore to the electrochemical gradient

Expression profile of human Fc receptors in mucosal tissue: implications for antibody-dependent cellular effector functions targeting HIV-1 transmission

The majority of new Human Immunodeficiency Virus (HIV)-1 infections are acquired via sexual transmission at mucosal surfaces. Partial efficacy (31.2%) of the Thai RV144 HIV-1 vaccine trial has been correlated with Antibody-dependent Cellular Cytotoxicity (ADCC) mediated by non-neutralizing antibodies targeting the V1V2 region of the HIV-1 envelope. This has led to speculation that ADCC and other antibody-dependent cellular effector functions might provide an important defense against mucosal acquisition of HIV-1 infection. However, the ability of antibody-dependent cellular effector mechanisms to impact on early mucosal transmission events will depend on a variety of parameters including effector cell type, frequency, the class of Fc-Receptor (FcR) expressed, the number of FcR per cell and the glycoslyation pattern of the induced antibodies. In this study, we characterize and compare the frequency and phenotype of IgG (CD16 [FcγRIII], CD32 [FcγRII] and CD64 [FcγRI]) and IgA (CD89 [FcαR]) receptor expression on effector cells within male and female genital mucosal tissue, colorectal tissue and red blood cell-lysed whole blood. The frequency of FcR expression on CD14+ monocytic cells, myeloid dendritic cells and natural killer cells were similar across the three mucosal tissue compartments, but significantly lower when compared to the FcR expression profile of effector cells isolated from whole blood, with many cells negative for all FcRs. Of the three tissues tested, penile tissue had the highest percentage of FcR positive effector cells. Immunofluorescent staining was used to determine the location of CD14+, CD11c+ and CD56+ cells within the three mucosal tissues. We show that the majority of effector cells across the different mucosal locations reside within the subepithelial lamina propria. The potential implication of the observed FcR expression patterns on the effectiveness of FcR-dependent cellular effector functions to impact on the initial events in mucosal transmission and dissemination warrants further mechanistic studies

The Anatomy of the bill Tip of Kiwi and Associated Somatosensory Regions of the Brain: Comparisons with Shorebirds

Three families of probe-foraging birds, Scolopacidae (sandpipers and snipes), Apterygidae (kiwi), and Threskiornithidae (ibises, including spoonbills) have independently evolved long, narrow bills containing clusters of vibration-sensitive mechanoreceptors (Herbst corpuscles) within pits in the bill-tip. These ‘bill-tip organs’ allow birds to detect buried or submerged prey via substrate-borne vibrations and/or interstitial pressure gradients. Shorebirds, kiwi and ibises are only distantly related, with the phylogenetic divide between kiwi and the other two taxa being particularly deep. We compared the bill-tip structure and associated somatosensory regions in the brains of kiwi and shorebirds to understand the degree of convergence of these systems between the two taxa. For comparison, we also included data from other taxa including waterfowl (Anatidae) and parrots (Psittaculidae and Cacatuidae), non-apterygid ratites, and other probe-foraging and non probe-foraging birds including non-scolopacid shorebirds (Charadriidae, Haematopodidae, Recurvirostridae and Sternidae). We show that the bill-tip organ structure was broadly similar between the Apterygidae and Scolopacidae, however some inter-specific variation was found in the number, shape and orientation of sensory pits between the two groups. Kiwi, scolopacid shorebirds, waterfowl and parrots all shared hypertrophy or near-hypertrophy of the principal sensory trigeminal nucleus. Hypertrophy of the nucleus basorostralis, however, occurred only in waterfowl, kiwi, three of the scolopacid species examined and a species of oystercatcher (Charadriiformes: Haematopodidae). Hypertrophy of the principal sensory trigeminal nucleus in kiwi, Scolopacidae, and other tactile specialists appears to have co-evolved alongside bill-tip specializations, whereas hypertrophy of nucleus basorostralis may be influenced to a greater extent by other sensory inputs. We suggest that similarities between kiwi and scolopacid bill-tip organs and associated somatosensory brain regions are likely a result of similar ecological selective pressures, with inter-specific variations reflecting finer-scale niche differentiation