The Influence of the French Revolution on Mathematics

A study of the early volumes of the Journal de L\u27École Polytechnique for the light they throw upon the relationship between the history of the times and the rapid development of French mathematics

The Leishmania major BBSome subunit BBS1 is essential for parasite virulence in the mammalian host

Bardet–Biedl syndrome (BBS) is a human genetic disorder with a spectrum of symptoms caused by primary cilium dysfunction. The disease is caused by mutations in one of at least 17 identified genes, of which seven encode subunits of the BBSome, a protein complex required for specific trafficking events to and from the primary cilium. The molecular mechanisms associated with BBSome function remain to be fully elucidated. Here, we generated null and complemented mutants of the BBSome subunit BBS1 in the protozoan parasite, Leishmania. In the absence of BBS1, extracellular parasites have no apparent defects in growth, flagellum assembly, motility or differentiation in vitro but there is accumulation of vacuole-like structures close to the flagellar pocket. Infectivity of these parasites for macrophages in vitro is reduced compared with wild-type controls but the null parasites retain the ability to differentiate to the intracellular amastigote stage. However, infectivity of BBS1 null parasites is severely compromised in a BALB/c mouse footpad model. We hypothesize that the absence of BBS1 in Leishmania leads to defects in specific trafficking events that affect parasite persistence in the host. This is the first report of an association between the BBSome complex and pathogen infectivity

Using hormones to manage dairy cow fertility: the clinical and ethical beliefs of veterinary practitioners

In the face of a steady decline in dairy cow fertility over several decades, using hormones to assist reproduction has become common. In the European Union, hormones are prescription-only medicines, giving veterinary practitioners a central role in their deployment. This study explored the clinical and ethical beliefs of practitioners, and provides data on their current prescribing practices. During 2011, 93 practitioners working in England completed a questionnaire (95% response rate). Of the 714 non-organic farms they attended, only 4 farms (0.6%) never used hormones to assist the insemination of lactating dairy cows. Practitioners agreed (.80%) that hormones improve fertility and farm businesses profitability. They also agreed(.80%) that if farmers are able to tackle management issues contributing to poor oestrus expression, then over a five year period these outcomes would both improve, relative to using hormones instead. If management issues are addressed instead of prescribing hormones, practitioners envisaged a less favourable outcome for veterinary practices profitability (p,0.01), but an improvement in genetic selection for fertility (p,0.01) and overall cow welfare (p,0.01). On farms making no efforts to address underlying management problems, long-term routine use at the start of breeding for timing artificial insemination or inducing oestrus was judged ‘‘unacceptable’’ by 69% and 48% of practitioners, respectively. In contrast, practitioners agreed ($90%) that both these types of use are acceptable, provided a period of time has been allowed to elapse during which the cow is observed for natural oestrus. Issues discussed include: weighing quality versus length of cow life, fiscal factors, legal obligations, and balancing the interests of all stakeholders, including the increasing societal demand for food. This research fosters debate and critical appraisal, contributes to veterinary ethics, and encourages the pro-active development of professional codes of conduct

Hsc70-induced changes in clathrin-auxilin cage structure suggest a role for clathrin light chains in cage disassembly

The molecular chaperone, Hsc70, together with its co-factor, auxilin, facilitates the ATP-dependent removal of clathrin during clathrin-mediated endocytosis in cells. We have used cryo-electron microscopy to determine the 3D structure of a complex of clathrin, auxilin401-910 and Hsc70 at pH 6 in the presence of ATP, frozen within 20 seconds of adding Hsc70 in order to visualize events that follow the binding of Hsc70 to clathrin and auxilin before clathrin disassembly. In this map, we observe density beneath the vertex of the cage that we attribute to bound Hsc70. This density emerges asymmetrically from the clathrin vertex, suggesting preferential binding by Hsc70 for one of the three possible sites at the vertex. Statistical comparison with a map of whole auxilin and clathrin previously published by us reveals the location of statistically significant differences which implicate involvement of clathrin light chains in structural rearrangements which occur after Hsc70 is recruited. Clathrin disassembly assays using light scattering suggest that loss of clathrin light chains reduces the efficiency with which auxilin facilitates this reaction. These data support a regulatory role for clathrin light chains in clathrin disassembly in addition to their established role in regulating clathrin assembly

An empirical thermal history of the Earth's upper mantle

We have compiled petrological and geochemical data from 71 ophiolite suites and greenstone belts, which range in age from 15 to 3760 Ma. We have selected those rocks whose compositions indicate that they are either normal mid-ocean ridge basalts (MORBs) or hotspot-type MORBs. Then we used the data base to calculate the most primitive liquidus temperature for each rock suite. The results show that the liquidus temperature of the Phanerozoic ophiolites ranges from a low of 1212°C to a high of 1417°C. Using these data and two exponential curves bracketing the maximum and minimum temperatures versus time, we infer that the Phanerozoic suites had a mean liquidus temperature of 1272±7°C and a mean temperature range of 1218° to 1425°C. The liquidus temperatures of Archean MORBlike greenstones range from 1305° to 1576°C. Using these data and two exponential curves bracketing the maximum and minimum temperatures versus time, we infer that Archean melts at 2.8 Ga had a mean liquidus temperature of 1399±13°C and a temperature range from 1301° to 1533°C. Using two different methods, we show that the change in the mean liquidus temperature since the late Archean is from 96±13°C (from temperature ranges) to 127±20°C (from temperature means). When we convert these liquidus temperatures to potential temperature of the mantle, we find that the change in the mean upper mantle potential temperature since the late Archean is from 137±8°C (from temperature ranges) to 187±42°C (from temperature means). This change is less than that which was previously thought to have occurred. We compared the liquidus temperatures calculated from our data set with an independent data set from the modern day Pacific plate. The resulting histograms have the same shape and the same temperature range, showing that our method for calculating mantle temperatures from MORBlike rocks in ophiolite suites is valid. When our calculated liquidus temperatures for all time intervals are plotted in histograms, the resulting distributions are not bimodal, but skewed unimodal. That is, the distributions show a high-T tail which results from the presence of hotspot magmas in the data set. The Archean temperature distribution is also skewed unimodal, and the high-temperature Archean rocks, such as komatiites, plot in the hotspot area of the distribution. This strongly supports the contention that komatiites do not represent “normal” Archean mantle but rather were probably erupted by hotspots. Our data suggest that the relative proportion of hotspot magmas in oceanic lithosphere has remained nearly constant over geologic time

Global Profiling and Inhibition of Protein Lipidation in Vector and Host Stages of the Sleeping Sickness Parasite Trypanosoma brucei

The enzyme N-myristoyltransferase (NMT) catalyzes the essential fatty acylation of substrate proteins with myristic acid in eukaryotes and is a validated drug target in the parasite Trypanosoma brucei, the causative agent of African trypanosomiasis (sleeping sickness). N-Myristoylation typically mediates membrane localization of proteins and is essential to the function of many. However, only a handful of proteins are experimentally validated as N-myristoylated in T. brucei. Here, we perform metabolic labeling with an alkyne-tagged myristic acid analogue, enabling the capture of lipidated proteins in insect and host life stages of T. brucei. We further compare this with a longer chain palmitate analogue to explore the chain length-specific incorporation of fatty acids into proteins. Finally, we combine the alkynyl-myristate analogue with NMT inhibitors and quantitative chemical proteomics to globally define N-myristoylated proteins in the clinically relevant bloodstream form parasites. This analysis reveals five ARF family small GTPases, calpain-like proteins, phosphatases, and many uncharacterized proteins as substrates of NMT in the parasite, providing a global view of the scope of this important protein modification and further evidence for the crucial and pleiotropic role of NMT in the cell

Racial Differences in the Human Endogenous Circadian Period

The length of the endogenous period of the human circadian clock (tau) is slightly greater than 24 hours. There are individual differences in tau, which influence the phase angle of entrainment to the light/dark (LD) cycle, and in doing so contribute to morningness-eveningness. We have recently reported that tau measured in subjects living on an ultradian LD cycle averaged 24.2 hours, and is similar to tau measured using different experimental methods. Here we report racial differences in tau. Subjects lived on an ultradian LD cycle (1.5 hours sleep, 2.5 hours wake) for 3 days. Circadian phase assessments were conducted before and after the ultradian days to determine the change in circadian phase, which was attributed to tau. African American subjects had a significantly shorter tau than subjects of other races. We also tested for racial differences in our previous circadian phase advancing and phase delaying studies. In the phase advancing study, subjects underwent 4 days of a gradually advancing sleep schedule combined with a bright light pulse upon awakening each morning. In the phase delaying study, subjects underwent 4 days of a gradually delaying sleep schedule combined with evening light pulses before bedtime. African American subjects had larger phase advances and smaller phase delays, relative to Caucasian subjects. The racial differences in tau and circadian phase shifting have important implications for understanding normal phase differences between individuals, for developing solutions to the problems of jet lag and shift work, and for the diagnosis and treatment of circadian rhythm based sleep disorders such as advanced and delayed sleep phase disorder

Firm heterogeneity in biotech: absorptive capacity, strategies, and local-regional connections

This paper focuses on the characteristics of biotech firms with various levels of research and development (R&D) activity. It is done by exploring the relationship between R&D intensity, alliances and the extent of regionalization of firms' activities using evidence from a survey of US-based biotechnology firms. We profile two firm prototypes: research-oriented firms and product-oriented firms, focusing on their characteristics, strategies and operations. These include activities devoted to exploration and exploitation through alliances with universities (more exploration) and with pharmaceutical companies (exploration and exploitation), and locational needs which facilitate both exploration and exploitation

Genetic validation of Leishmania genes essential for amastigote survival in vivo using N-myristoyltransferase as a model

BACKGROUND: Proving that specific genes are essential for the intracellular viability of Leishmania parasites within macrophages remains a challenge for the identification of suitable targets for drug development. This is especially evident in the absence of a robust inducible expression system or functioning RNAi machinery that works in all Leishmania species. Currently, if a target gene of interest in extracellular parasites can only be deleted from its genomic locus in the presence of ectopic expression from a wild type copy, it is assumed that this gene will also be essential for viability in disease-promoting intracellular parasites. However, functional essentiality must be proven independently in both life-cycle stages for robust validation of the gene of interest as a putative target for chemical intervention. METHODS: Here, we have used plasmid shuffle methods in vivo to provide supportive genetic evidence that N-myristoyltransferase (NMT) is essential for Leishmania viability throughout the parasite life-cycle. Following confirmation of NMT essentiality in vector-transmitted promastigotes, a range of mutant parasites were used to infect mice prior to negative selection pressure to test the hypothesis that NMT is also essential for parasite viability in an established infection. RESULTS: Ectopically-expressed NMT was only dispensable under negative selection in the presence of another copy. Total parasite burdens in animals subjected to negative selection were comparable to control groups only if an additional NMT copy, not affected by the negative selection, was expressed. CONCLUSIONS: NMT is an essential gene in all parasite life-cycle stages, confirming its role as a genetically-validated target for drug development