The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia

Anonychia and hyponychia congenita (OMIM 206800) are rare autosomal recessive conditions in which the only presenting phenotype is the absence or severe hypoplasia of all fingernails and toenails. After determining linkage to chromosome 20p13, we identified homozygous or compound heterozygous mutations in the gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, in eight affected families. Rspo4 expression was specifically localized to developing mouse nail mesenchyme at embryonic day 15.5, suggesting a crucial role in nail morphogenesis.     

Revisiting Galison’s ‘Aufbau/Bauhaus’ in light of Neurath’s philosophical projects

In his article entitled ‘Aufbau/Bauhaus’ and related work, Peter Galison explores the connections between the Vienna Circle and the Dessau Bauhaus. Historically, these groups were related, with members of each group familiar with the ideas of the other. Galison argues that their projects are related as well, through shared political views and methodological approach. The two main figures that connect the Vienna Circle to the Bauhaus—and the figures upon which Galison focuses—are Rudolf Carnap and Otto Neurath. Yet, in our view, the connections that Galison develops do not properly capture the common themes between the Bauhaus and Neurath’s philosophical projects. In this paper, we will examine a few of the historical connections between the Dessau Bauhaus and the Vienna Circle, as well as the philosophical connections that Galison draws between these two groups. By examining in greater depth Neurath’s philosophical commitments, we aim to demonstrate that some of these philosophical connections fail to resonate with Neurath’s projects. And, finally, we develop different connections between Neurath’s projects and the Bauhaus. In our view, these new connections between Neurath and the Dessau Bauhaus are both substantive and philosophically interesting.     

Towards an Holistic Framework for Environmental Change: The Role of Normative Behaviour and Informal Networking to Enhance Sustainable Business Practices

The term ‘Sustainable Development’ is brandished by modern businesses as a marketing ploy used to suggest evidence of ethical conduct, innovative thinking and moral superiority. However, when analysing an organisations’ adoption of sustainable practices, it is often clear—within the UK—that there are few activities that have been undertaken as an ethical stance instead of legal obligation (McCormick in Environmental politics and policy in industrialized countries, MIT, London, 2002). Our hypothesis is that most methodologies and practices for environmental management do not adopt a holistic perspective, causing significant problems in implementation from inadequate structures and communication channels (Espinosa et al. in Eur J Oper Res, 187:636–651, 2008). In particular we consider that most organisations are currently stifled with management hierarchies that prevent informal/social networking, which may be one of the most powerful natural forms for self-organisation. It is proposed that sustainable development requires more efficient communication channels that foster self-organisation and self-regulation as a method for more productive change processes. In this paper, we explain the reasons why meta-systemic principles of self-organisation and distributed network management offer clear criteria to design an environmental management system that operates on the basis of self-controlled individuals and communities.     

Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys

Preclinical studies of human immunodeficiency virus type 1 (HIV-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges. Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant simian immunodeficiency virus (SIV) challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus-vector-based vaccines expressing SIV(SME543) Gag, Pol and Env antigens resulted in an 80% or greater reduction in the per-exposure probability of infection against repetitive, intrarectal SIV(MAC251) challenges in rhesus monkeys. Protection against acquisition of infection showed distinct immunological correlates compared with post-infection virological control and required the inclusion of Env in the vaccine regimen. These data demonstrate the proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys.     

The cells and logic for mammalian sour taste detection

Mammals taste many compounds yet use a sensory palette consisting of only five basic taste modalities: sweet, bitter, sour, salty and umami (the taste of monosodium glutamate). Although this repertoire may seem modest, it provides animals with critical information about the nature and quality of food. Sour taste detection functions as an important sensory input to warn against the ingestion of acidic (for example, spoiled or unripe) food sources. We have used a combination of bioinformatics, genetic and functional studies to identify PKD2L1, a polycystic-kidney-disease-like ion channel, as a candidate mammalian sour taste sensor. In the tongue, PKD2L1 is expressed in a subset of taste receptor cells distinct from those responsible for sweet, bitter and umami taste. To examine the role of PKD2L1-expressing taste cells in vivo, we engineered mice with targeted genetic ablations of selected populations of taste receptor cells. Animals lacking PKD2L1-expressing cells are completely devoid of taste responses to sour stimuli. Notably, responses to all other tastants remained unaffected, proving that the segregation of taste qualities even extends to ionic stimuli. Our results now establish independent cellular substrates for four of the five basic taste modalities, and support a comprehensive labelled-line mode of taste coding at the periphery. Notably, PKD2L1 is also expressed in specific neurons surrounding the central canal of the spinal cord. Here we demonstrate that these PKD2L1-expressing neurons send projections to the central canal, and selectively trigger action potentials in response to decreases in extracellular pH. We propose that these cells correspond to the long-sought components of the cerebrospinal fluid chemosensory system. Taken together, our results suggest a common basis for acid sensing in disparate physiological settings.     

Complex social behaviour derived from maternal reproductive traits

A fundamental goal of sociobiology is to explain how complex social behaviour evolves, especially in social insects, the exemplars of social living. Although still the subject of much controversy, recent theoretical explanations have focused on the evolutionary origins of worker behaviour (assistance from daughters that remain in the nest and help their mother to reproduce) through expression of maternal care behaviour towards siblings. A key prediction of this evolutionary model is that traits involved in maternal care have been co-opted through heterochronous expression of maternal genes to result in sib-care, the hallmark of highly evolved social life in insects. A coupling of maternal behaviour to reproductive status evolved in solitary insects, and was a ready substrate for the evolution of worker-containing societies. Here we show that division of foraging labour among worker honey bees (Apis mellifera) is linked to the reproductive status of facultatively sterile females. We thereby identify the evolutionary origin of a widely expressed social-insect behavioural syndrome, and provide a direct demonstration of how variation in maternal reproductive traits gives rise to complex social behaviour in non-reproductive helpers.     

Platensimycin is a selective FabF inhibitor with potent antibiotic properties

Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of beta-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.     

基于流量恢复法的黄河下游鱼类生态需水研究

运用流量恢复(the flow restoration methodology)方法研究黄河下游鱼类生态需水,其基本思路是:首先获得所保护鱼类生态习性相关的流量信息,包括水深、流速、水量等.然后建立概念性模型,确定鱼类和特定流量组分之间的联系.在此基础上,确定流量目标,每一个流量目标被赋予一些水力指标,作为获得满足这个目标的环境流量计算的依据.运用水文学、水力学模型确定满足这些流量目标需要的水流条件,包括数量、持续时间、频率和发生时间,给出满足鱼类生长需要的生态流量.最后给出不同水资源管理情景下可接受的鱼类生态需水.     

Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2

Familial glucocorticoid deficiency (FGD), or hereditary unresponsiveness to adrenocorticotropin (ACTH; OMIM 202200), is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex, which stimulates glucocorticoid production. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia or overwhelming infection in infancy or childhood. Mutations of the ACTH receptor (melanocortin 2 receptor, MC2R) account for approximately 25% of cases of FGD. FGD without mutations of MC2R is called FGD type 2. Using SNP array genotyping, we mapped a locus involved in FGD type 2 to chromosome 21q22.1. We identified mutations in a gene encoding a 19-kDa single-transmembrane domain protein, now known as melanocortin 2 receptor accessory protein (MRAP). We show that MRAP interacts with MC2R and may have a role in the trafficking of MC2R from the endoplasmic reticulum to the cell surface.