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A new class of conformal invariants for a given spacetime $M$ is introduced exploiting the conformal geometry of any light ray $\Gamma$. Each congruence of light rays passing through a given point $p$ defines the sky $S(p)$ of such point. The new conformal invariants are defined on the bundle of skies of the spacetime $M$, being called sky invariants accordingly. The natural conformal covariant derivative defined on a light ray and its associated covariant calculus allows us show the existence of a natural conformal invariant differential of arc that, together with the restriction of the curvature of the conformal covariant derivative, can be used to construct a sky invariant that will be called the sky curvature. An algorithm, that can be implemented on any symbolic manipulation software system, to compute the sky curvature will be discussed and the main ideas and the explicit computation of the sky curvature are illustrated in Schwarzschild spacetime., Comment: 20 pages, 2 figures, accepted for publication in International Journal of Geometric Methods in Modern Physics

The notion of L-boundary, a new causal boundary proposed by R. Low based on constructing a `sky at infinity' for any light ray, is discussed in detail. The analysis of the notion of L-boundary will be done in the 3-dimensional situation for the ease of presentation. The proposed notion of causal boundary is intrinsically conformal and, as it will be proved in the paper, under natural conditions provides a natural extension $\bar{M}$ of the given spacetime $M$ with smooth boundary $\partial M = \bar{M} \backslash M$. The extensions $\bar{M}$ of any conformal manifold $M$ constructed in this way are characterised exclusively in terms of local properties at the boundary points. Such extensions are called L-extensions and it is proved that, if they exist, they are essentially unique. Finally it is shown that in the 3-dimensional case, any L-extension is equivalent to the canonical extension obtained by using the L-boundary of the manifold., 39 pages, 6 figures

The space of light rays $\mathcal{N}$ of a conformal Lorentz manifold $(M,\mathcal{C})$ is, under some topological conditions, a manifold whose basic elements are unparametrized null geodesics. This manifold $\mathcal{N}$, strongly inspired on R. Penrose's twistor theory, keeps all information of $M$ and it could be used as a space complementing the spacetime model. In the present review, the geometry and related structures of $\mathcal{N}$, such as the space of skies $\Sigma$ and the contact structure $\mathcal{H}$, are introduced. The causal structure of $M$ is characterized as part of the geometry of $\mathcal{N}$. A new causal boundary for spacetimes $M$ prompted by R. Low, the $L$-boundary, is constructed in the case of $3$-dimensional manifolds $M$ and proposed as a model of its construction for general dimension. Its definition only depends on the geometry of $\mathcal{N}$ and not on the geometry of the spacetime $M$. The properties satisfied by the $L$-boundary $\partial M$ permit to characterize the obtained extension $\overline{M}=M\cup \partial M$ and this characterization is also proposed for general dimension., Comment: 57 pages, 15 figures, accepted for publication in the topical collection of General Relativity and Gravitation dedicated to the meeting Singularity theorems, causality, and all that (SCRI21) in honor of Roger Penrose

Altres ajuts: acords transformatius de la UAB Glycerol can be converted to ethanol, 1,3-propanediol, formate, acetate, propionate, and inorganic carbon under anaerobic conditions through oxidative and reductive pathways in the absence and presence of sulfate. A structured mathematical model considering multiple pathways of glycerol fermentation combined with sulfate reduction was set up in this work, where three mechanisms were proposed and verified by modeling. Finally a mechanism properly predicting both glycerol fermenting and sulfate-reducing processes was chosen. Concentrations of multiple intermediates measured in batch activity tests were satisfactorily described by the model. The intermediate products of glycerol fermentation included formate, propionate, ethanol, 1,3-propanediol, and 3-hydroxypropionate (3HP). The main pathways of glycerol fermentation were the oxidative pathway to produce ethanol and the reductive pathway to produce 1,3-propanediol. The former accounted for 40.6% of the total glycerol converted whereas the latter accounted for 42.6%. 1,3-propanediol was converted to 3HP coupled to sulfate reduction. 3HP was mainly further oxidized to acetate. The kinetic parameters of maximum specific uptake rates of substrate were calibrated and then, the sulfate reduction process was validated. The confidence intervals of estimated parameters were assessed according to the Fisher information matrix (FIM) method. The low confidence intervals obtained indicated that the experimental behavior was satisfactorily described with the proposed kinetic model.

The Andalusian medieval citadels are walled enclosures that, strategically placed on hills, still continue showing their defensive function inside the city and the surrounding territory. There are still good examples in the south of Spain, especially concentrated in the last territories of Al-Andalus. To the north of the old Nasrid kingdom of Granada, the city of Baza, with a brilliant Iberian and Roman past, also preserves some remains of its medieval past in its urban fabric. However, the Alcazaba of Baza, which was its main medieval architectural landmark, has suffered during the last century a lamentable process of abandonment and destruction that has almost made it disappear. Today its limits are unrecognizable and there are hardly visible parts of its walls or its towers. Anyone that visits it for the first time only recognizes a central empty space in the urban fabric. It has been mistreated by sporadic inappropriate uses, most of the time in disuse and converted into residual space of the city, a focus of marginality where it is not convenient to go. Despite its poor state of preservation, the fact of being an old military structure makes it a Historical Place of Interest (Bien de Interés Cultural–BIC-), the highest level of protection granted by the Law of Spanish Historical Heritage (1985). Since then, with greater or lesser fortune, the urban planning of Baza has recognized its values, although it has allowed lamentable interventions inside

The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (

Malaria remains a major global health problem, with more than half of the world population at risk of contracting the disease and nearly a million deaths each year. Here, we report the discovery of inhibitors that target multiple stages of malaria parasite growth. To identify these inhibitors, we took advantage of the Tres Cantos Antimalarial Compound Set (TCAMS) small-molecule library, which is comprised of diverse and potent chemical scaffolds with activities against the blood stage of the malaria parasite, and investigated their effects against the elusive liver stage of the malaria parasite using a forward chemical screen. From a screen of nearly 14,000 compounds, we identified and confirmed 103 compounds as dual-stage malaria inhibitors. Interestingly, these compounds show preferential inhibition of parasite growth in liver- versus blood-stage malaria parasite assays, highlighting the drug susceptibility of this parasite form. Mode-of-action studies were completed using genetically modified and drug-resistant Plasmodium parasite strains. While we identified some compound targets as classical antimalarial pathways, such as the mitochondrial electron transport chain through cytochrome bc 1 complex inhibition or the folate biosynthesis pathway, most compounds induced parasite death through as yet unknown mechanisms of action. Importantly, the identification of new chemotypes with different modes of action in killing Plasmodium parasites represents a promising opportunity for probing essential and novel molecular processes that remain to be discovered. The chemical scaffolds identified with activity against drug-resistant Plasmodium parasites represent starting points for dual-stage antimalarial development to surmount the threat of malaria parasite drug resistance.

Plasmodium parasites undergo a clinically silent and obligatory developmental phase in the host's liver cells before they are able to infect erythrocytes and cause malaria symptoms. To overcome the scarcity of compounds targeting the liver stage of malaria, we screened a library of 1037 existing drugs for their ability to inhibit Plasmodium hepatic development. Decoquinate emerged as the strongest inhibitor of Plasmodium liver stages, both in vitro and in vivo. Furthermore, decoquinate kills the parasite's replicative blood stages and is active against developing gametocytes, the forms responsible for transmission. The drug acts by selectively and specifically inhibiting the parasite's mitochondrial bc(1) complex, with little cross-resistance with the antimalarial drug atovaquone. Oral administration of a single dose of decoquinate effectively prevents the appearance of disease, warranting its exploitation as a potent antimalarial compound.

A new causal boundary, which we will term the $l$-boundary, inspired by the geometry of the space of light rays and invariant by conformal diffeomorphisms for space-times of any dimension $m\geq 3$, proposed by one of the authors (R.J. Low, The space of null geodesics (and a new causal boundary), Lecture Notes in Physics, 692, Springer, 2006, 35--50) is analyzed in detail for space-times of dimension 3. Under some natural assumptions it is shown that the completed space-time becomes a smooth manifold with boundary and its relation with Geroch-Kronheimer-Penrose causal boundary is discussed. A number of examples illustrating the properties of this new causal boundary as well as a discussion on the obtained results will be provided., 28 pages, 5 figures

Going one step further in the use and impact measurement of new strategies to improve the teaching-learning process during lecturing General Physics courses, the current contribution reports the last results/observations obtained by the authors on the combination of simple classroom experiments with active methodologies and new technologies (media). Cross-checking the answers in multiple choice questions done online during the lectures and in exams at the end of the term shows that this strategy has, at least partly, a positive effect on clarifying misconceptions. The overall opinion of the students was assessed and it showed that this lecturing approach is useful and motivating, making the lectures more attractive and stimulating eagerness to understand Physics.

Drug resistance emerges in an ecological context where fitness costs restrict the diversity of escape pathways. These pathways are targets for drug discovery, and here we demonstrate that we can identify small-molecule inhibitors that differentially target resistant parasites. Combining wild-type and mutant-type inhibitors may prevent the emergence of competitively viable resistance. We tested this hypothesis with a clinically derived chloroquine-resistant (CQ(r)) malaria parasite and with parasites derived by in vitro selection with Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. We screened a chemical library against CQ(s) and CQ(r) lines and discovered a drug-like compound (IDI-3783) that was potent only in the CQ(r) line. Surprisingly, in vitro selection of Plasmodium falciparum resistant to IDI-3783 restored CQ sensitivity, thereby indicating that CQ might once again be useful as a malaria therapy. In parallel experiments, we selected P. falciparum lines resistant to structurally unrelated PfDHODH inhibitors (Genz-666136 and DSM74). Both selections yielded resistant lines with the same point mutation in PfDHODH:E182D. We discovered a compound (IDI-6273) more potent against E182D than wild-type parasites. Selection of the E182D mutant with IDI-6273 yielded a reversion to the wild-type protein sequence and phenotype although the nucleotide sequence was different. Importantly, selection with a combination of Genz-669178, a wild-type PfDHODH inhibitor, and IDI-6273, a mutant-selective PfDHODH inhibitor, did not yield resistant parasites. These two examples demonstrate that the compromise between resistance and evolutionary fitness can be exploited to design therapies that prevent the emergence and spread of resistant organisms.

Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.

Consider a smooth manifold with a smooth metric which changes bilinear type on a hypersurface Σ and whose radical line field is everywhere tangent to Σ. We describe two natural tensors on Σ and use them to describe “integrability conditions” which are similar to the Gauss–Codazzi conditions. We show that these forms control the smooth extendibility to Σ of ambient curvatures.

Programmed cell death (pcd) may take the form of apoptotic or nonapoptotic pcd. Whereas cysteine aspartyl-specific proteases (caspases) mediate apoptosis, the mediators of nonapoptotic cell death programs are much less well characterized. Here, we report that paraptosis, an alternative, nonapoptotic cell death program that may be induced by the insulin-like growth factor I receptor (among other inducers), is mediated by mitogen-activated protein kinases (MAPKs) and inhibited by AIP-1/Alix. The inhibition by AIP-1/Alix is specific for paraptosis since apoptosis was not inhibited. Caspases were not activated in this paradigm, nor were caspase inhibitors effective in blocking cell death. However, insulin-like growth factor I receptor (IGFIR)-induced paraptosis was inhibited by MEK-2-specific inhibitors and by antisense oligonucleotides directed against c-jun N-terminal kinase-1 (JNK-1). These results suggest that IGFIR-induced paraptosis is mediated by MAPKs, and inhibited by AIP-1/Alix.

OBJECTIVE: To examine the relationship of overweight and obesity with subjective health and use of health-care services among women in Spain. METHODS: Data were drawn from the 1993 Spanish National Health Survey, covering a 13 244-woman sample representative of the non-institutionalised Spanish population aged 16 y and over. Information was collected through home-based interviews. Multiple logistic regression models were used to calculate odds ratios for suboptimal health (fair, poor or very poor) and utilisation of health-care services by women with normal weight (BMI 18.5–24.9 kg/m2), overweight (BMI 25.0–29.9 kg/m2) and obesity (BMI≥30 kg/m2). Analyses were adjusted for age, education level, occupation, civil status, social support, tobacco use, alcohol consumption, physical activity at work and during leisure time, job status and town of residence. RESULTS: Frequency of suboptimal health was higher in women with overweight (OR 1.7; 95% CI 1.5–1.9) and obesity (OR 2.1; 95% CI 1.8–2.5) than in those with normal weight. Overweight and obese women visited the physician, used hospital emergency services and took medication with greater frequency than did women of normal weight. There was a positive dose–response relationship (P

Background: Inhibiting PfDHODH kills malaria parasites, but the potential for drug resistance is unknown. Results: Selections gave several categories of resistance mutations. Several mutants were hypersensitive to other drugs. Conclusion: Resistance to PfDHODH inhibitors is largely though mutations in or amplification of the target gene, PfDHODH. Significance: Resistance to PfDHODH inhibitors is possible but often increases sensitivity to other compounds., Malaria is a preventable and treatable disease; yet half of the world's population lives at risk of infection, and an estimated 660,000 people die of malaria-related causes every year. Rising drug resistance threatens to make malaria untreatable, necessitating both the discovery of new antimalarial agents and the development of strategies to identify and suppress the emergence and spread of drug resistance. We focused on in-development dihydroorotate dehydrogenase (DHODH) inhibitors. Characterizing resistance pathways for antimalarial agents not yet in clinical use will increase our understanding of the potential for resistance. We identified resistance mechanisms of Plasmodium falciparum (Pf) DHODH inhibitors via in vitro resistance selections. We found 11 point mutations in the PfDHODH target. Target gene amplification and unknown mechanisms also contributed to resistance, albeit to a lesser extent. These mutant parasites were often hypersensitive to other PfDHODH inhibitors, which immediately suggested a novel combination therapy approach to preventing resistance. Indeed, a combination of wild-type and mutant-type selective inhibitors led to resistance far less often than either drug alone. The effects of point mutations in PfDHODH were corroborated with purified recombinant wild-type and mutant-type PfDHODH proteins, which showed the same trends in drug response as the cognate cell lines. Comparative growth assays demonstrated that two mutant parasites grew less robustly than their wild-type parent, and the purified protein of those mutants showed a decrease in catalytic efficiency, thereby suggesting a reason for the diminished growth rate. Co-crystallography of PfDHODH with three inhibitors suggested that hydrophobic interactions are important for drug binding and selectivity.

It is shown that if $M$ is a strongly causal free of naked singularities space-time, then its causal structure is completely characterized by a partial order in the space of skies defined by means of a class non-negative Legendrian isotopies. It is also proved that such partial order is determined by the class of future causal celestial curves, that is, curves in the space of light rays which are tangent to skies and such that they determine non-negative sky-Legendrian isotopies. It will also be proved that the space of skies $\Sigma$ equipped with Low's (or reconstructive) topology is homeomorphic and diffeomorphic to $M$ under the only additional assumption that $M$ separates skies, that is, that different points determine different skies. The sky-separating property of $M$ being weaker than the "non-refocussing" property encountered in the previous literature is sharp and the previous result provides the answer to the question of what is the class of space-times whose causal structure, topology and differentiable structure can be reconstructed from their spaces of light rays and skies. Finally, the previous results allow a formulation of Malament-Hawking theorem in terms of the partial order defined on the space of skies.

The influence of the drop size of oleic acid on extracellular lipase production by Candida rugosa was studied. The specific interfacial area was determined under different experimental conditions and the drop populations obtained were compared on the basis of the Kruskal-Wallis statistical test. Lipase production was found to increase with increasing drop size of the disperse phase, i.e. when the microorganism grew at a low stirring rate (300 rpm). Enzyme production in two bioreactors of different volume, viz. Biostat E (5 l) and Bioflo III (1 l), was also compared. The two bioreactors were found to yield similar enzyme activities provided the same initial oleic acid drop size was used. This allows the establishment of a specific criterion for adaptation to a different scale or bioreactor, and for the mathematical modelling of the process

In this paper we get an effective algorithm to compute all odd orders and ramification indices of homeomorphisms acting on compact surfaces, orientable or not.

Oleic acid has been reported as a good inducer of lipase production by Candida rugosa. In order to know if this enzyme is induced by oleic acid itself or by a metabolite, different short chain fatty acids were tested. Butyric acid was the best carbon source to growth microorganism but it did not induce lipase production. Although caprylic and capric acid were the best inducers of lipase production, at concentrations up 1 g/l they have toxic effect in Candida rugosa growth. Thus, from the point of view of industrial production oleic acid could be considered as the best substrate tested.

Physical reasons suggested in [J.B. Hartle, S.W. Hawking, Wave function of the universe, Phys. Rev. D41 (1990) 1815-1834] for the Quantum Gravity Problem lead us to study type-changing metrics on a manifold. The most interesting cases are Transverse Rieniann-Lorentz Manifolds. Here we study the conformal geometry of such manifolds.

Objectives: To evaluate the results of treatment of patients with a ruptured intracranial aneurysm treated by a single experienced vascular neurosurgeon in the period prior to the introduction of endovascular coiling. Methods: Over a mean (SD) period of 9 (2) years, between January 1990 and June 1999, 245 consecutive patients with ruptured intracranial aneurysms were treated. Patients’ details were obtained from a database that had been constructed prospectively. The patients consisted of all those patients treated by the senior author (Mr Maurice-Williams) over this period—that is, every third day on call at his unit. During this period, all patients under the age of 75 years with a diagnosis of subarachnoid haemorrhage were admitted to the neurosurgical unit as soon as was practicable regardless of clinical grade. Results: Of 245 patients, 190 (77.6%) underwent treatment by open surgery using standard microsurgical techniques. At 1 year, the mortality of the operated patients was 2.6%, while 89.5% of the patients had a Glasgow Outcome Score (GOS) of 4 and 5. The overall management outcome (all patients treated, including operated and non-operated cases) at 1 year was: 17.1 % dead while 74.3% had GOS 4 and 5. Of the 190 patients who underwent surgery, 38 (20%) required additional operations, totalling 72 operations in all. Of these, 32 were for hydrocephalus and 17 for the evacuation of intracranial haematomas/collections. Complications of surgery occurred in 56 patients (29.5%). Conclusion: Open surgery, despite good eventual results, is associated with a significant rate of re-operations and complications that would probably be largely avoided with endovascular treatment. Nevertheless, although endovascular coiling has these immediate advantages over surgery it is still not certain that the long term results will be superior to surgery which leads to permanent obliteration of the aneurysm. There may still be a need for open surgery in the future.

The history of intracranial surgery for aneurysms is not a long one. The first direct operation on an intracranial aneurysm was performed by Norman Dott, who wrapped a ruptured aneurysm in 1933,1 and the first obliterative clipping of an aneurysm was performed by Walter Dandy in 1938.2 The results of surgery improved dramatically when the operating microscope was introduced in the 1960s3 and a subsequent improvement followed the use of the calcium antagonist nimodipine and the maintenance of a high fluid intake to lessen the risk of delayed cerebral ischaemia.4 For many years clipping of a ruptured aneurysm was regarded as the definitive mode of treatment, but the development of the GDC coil in 1990 allowed an alternative approach that avoided the hazards of open surgery. In the latter half of the 1990s, as experience of endovascular techniques spread, this form of treatment began to displace open surgery and the International Subarachnoid Aneurysm Trial (ISAT) was set up to compare the efficacy of the two forms of treatment. Early in 2002 the trial was interrupted by the steering committee when an intermediate analysis of the results revealed that, in the short term at any rate, the results of endovascular coiling were superior to those of clipping, in that the chances of survival free of disability at one year were significantly better for coiling. Furthermore, the risk of rebleeding from a successfully coiled aneurysm at one year was only 0.16%.5 Although this still leaves open the long-term risks of aneurysm re-formation and rebleeding after coiling (a risk which is negligible after successful clipping), we believe that the results of ISAT must spell the end of aneurysm surgery—though no doubt there will be a transitional period of some years before surgery finally disappears. As things stand, it is difficult to advise surgery in those cases where coiling is practicable, and publication of the ISAT probably led to an immediate shift towards coiling in most units in the UK. The current margin in favour of endovascular treatment is likely to increase in the future, for the following reasons. Endovascular as opposed to surgical treatment is an evolving technique. Not only is the microtechnology constantly improving but also more and more neuroradiologists are acquiring and honing their skills in this field. As this happens, increasing proportions of aneurysms are proving amenable to endovascular treatment. By contrast, the technology of surgery has been static for many years and, after the quantum leap in results provided by the introduction of the operating microscope and associated microinstrumentation, it is difficult to see how the techniques of open surgery could be further improved. Furthermore, as the use of endovascular techniques extends, so the surgical expertise will be lost. Already the pool of very experienced surgeons is draining away as a result of death and retirement, and as these surgeons disappear the advantages of endovascular treatment will become greater still. The number of cases unsuitable for endovascular treatment will shrink to the point where there will be a residue of difficult and complex cases for which only surgery is available. However, it is by no means certain that surgery would be justified in such cases. These are likely to be patients with, for example, giant and complex aneurysms in inaccessible situations where even at present surgical as opposed to conservative treatment may be difficult to justify. This will be still more true when the surgical skills honed upon hundreds of more straightforward cases have been lost. For these reasons, any review of aneurysm surgery must be largely of historical interest. However, we think it of value to touch on some topics that have concerned the senior author in the course of 30 years of aneurysm surgery during which time he has treated almost a thousand cases. Over this period he had prepared prospective datasheets for every patient treated under his care. These datasheets have provided much information on the clinical course of the patients treated, the technical difficulties encountered at surgery and the postoperative problems that arose.

Aims: To assess the effectiveness of a smoking cessation intervention at the workplace. The intervention was adapted to smokers’ tobacco dependence, and included minimal structured counselling at the first visit (5‐8 minutes), nicotine patches for three months, and three sessions of counselling for reinforcement of abstinence (2‐3 minutes) over a three month period. Methods: Open randomised trial with two groups: the intervention group, and the control group which was subjected to standard clinical practice, consisting of short (30 seconds to one minute) sporadic sessions of unstructured medical antismoking advice. The trial was carried out among 217 smokers of both sexes, aged 20‐63 years, motivated to quit smoking and without contraindications for nicotine patches, who were employees at a public transport company and at two worksites of an electric company. The main outcome measure was self reported tobacco abstinence confirmed by carbon monoxide in expired air

Malaria is a preventable and treatable disease, yet annually there are still hundreds of thousands of malaria-related deaths. The disease is caused by infection with mosquito-borne Plasmodium parasites. With hundreds of millions of cases each year there is a very high potential for drug resistance and this has compromised many existing therapies. One target under investigation is the enzyme dihydroorotate dehydrogenase (DHODH) which catalyses the rate-limiting step of pyrimidine biosynthesis and is an essential enzyme in the malaria parasite. There are currently several Plasmodium-selective DHODH inhibitors under development. To investigate the potential for drug resistance against DHODH inhibitors in vitro resistance selections were carried out using known inhibitors from different structural classes [1]. These studies identified point mutations in the drug binding site which lead to reduced sensitivity to the inhibitors, and in some cases increased sensitivity to a different inhibitor, suggesting a novel combination therapy approach to combat resistance. To help understand the significance of the inhibitor binding site mutations we determined the crystal structures of P. falciparum DHODH in complex with the inhibitors Genz-669178, IDI-6253 and IDI-6273. Co-crystallisation experiments led to a new crystal form in each case. Here we describe the crystal structures, the binding modes of the inhibitors and the great flexibility of the binding site, which is able to adjust to accommodate different inhibitor series. The structural role of the resistance mutations is also discussed.

A reconstruction theorem in terms of the topology and geometrical structures on the spaces of light rays and skies of a given space-time is discussed. This result can be seen as part of Penrose and Low's programme intending to describe the causal structure of a space-time $M$ in terms of the topological and geometrical properties of the space of light rays, i.e., unparametrized time-oriented null geodesics, $\mathcal{N}$. In the analysis of the reconstruction problem it becomes instrumental the structure of the space of skies, i.e., of congruences of light rays. It will be shown that the space of skies $\Sigma$ of a strongly causal skies distinguishing space-time $M$ carries a canonical differentiable structure diffeomorphic to the original manifold $M$. Celestial curves, this is, curves in $\mathcal{N}$ which are everywhere tangent to skies, play a fundamental role in the analysis of the geometry of the space of light rays. It will be shown that a celestial curve is induced by a past causal curve of events iff the legendrian isotopy defined by it is non-negative. This result extends in a nontrivial way some recent results by Chernov \emph{et al} on Low's Legendrian conjecture. Finally, it will be shown that a celestial causal map between the space of light rays of two strongly causal spaces (provided that the target space is null non-conjugate) is necessarily induced from a conformal immersion and conversely. These results make explicit the fundamental role played by the collection of skies, a collection of legendrian spheres with respect to the canonical contact structure on $\mathcal{N}$, in characterizing the causal structure of space-times.

The huntingtin-associated protein (HAP-1) interacts with the Huntington disease gene product, huntingtin. It is predominantly expressed in the brain and shows an increased affinity for mutant huntingtin. We have sequenced an 18,656 bp genomic region encompassing the entire human HAP-1 gene and determined its genomic organisation, with 11 exons spanning 12.1 kb. We have also found an intragenic polymorphism within intron 6 of HAP-1. We have recently shown that HAP-1 maps to a region of the genome which has been implicated in a variety of neurological conditions, including progressive supranuclear palsy (PSP), a late-onset atypical parkinsonian disorder. The detailed characterisation of the genomic organisation of HAP-1 and the presence of an intragenic polymorphism will be helpful in evaluating its role in different disorders, using candidate gene approaches.

BackgroundA minority of hospitals in the UK have a high-dependency unit (HDU). One reason for this is a lack of evidence supporting its benefit. This study sought to compare the outcomes of patients undergoing major abdominal surgery with regard to HDU utilization.MethodsData were collected prospectively from two groups of patients over 10 months. Patients in the no-HDU group underwent major abdominal surgery in a hospital without an HDU and returned to a general surgical ward. The other group was managed initially in an HDU. Data collected included Physiological and Operative Severity Score for enUmeration of Mortality and morbidity (POSSUM) scores, complications, deaths and length of stay.ResultsPhysiological and operative scores as calculated on the RAJIS POSSUM software were similar in both groups. The HDU group comprised 121 patients. Sixty-four developed a complication whereas 58·81 were expected to, giving an observed: expected (O: E) ratio of 1·09. Sixteen deaths occurred and 14·54 were expected (O: E ratio 1·10). Some 50 per cent stayed in hospital longer than was predicted. The no-HDU group comprised 71 patients. Fifty-nine developed a complication compared with 33·82 expected (O: E ratio 1·74). Ten deaths occurred, whereas 8·88 were expected, giving an O: E ratio of 1·13. Some 63 per cent stayed longer than predicted. The O: E ratios for morbidity were significantly different (P < 0·0005). The complications that occurred more frequently in the absence of an HDU were chest infection, arrhythmias and hypotension.ConclusionPostoperative management on an HDU was associated with fewer cardiorespiratory complications. There was no difference in mortality rate but there was a trend towards shorter hospital stay.

Colorectal cancer (CRC) occurring in the proximal colon and among women may represent a distinct subtype of the disease. In the present study of 120 sporadic CRCs, we used methylation-specific PCR to test whether methylation of the CpG island in the 5' region of the p16INK4a tumor suppressor gene was associated with anatomical location, gender, or other clinicopathological characteristics. Overall, 18.3% of the tumors had detectable p16INK4a methylation. A marked preponderance of methylated tumors occurred within the proximal colon; cancers occurring proximal to the sigmoid colon were 13.1 times more likely to contain methylated p16INK4a compared with distal tumors. In addition, female patients were 8.8 times more likely than males to have methylation-positive cancers, and p16INK4a methylation was also associated with poorly differentiated tumors. The localization of tumors with p16INK4a methylation within the proximal colon and among female patients specifically adds to a growing database of molecular alterations that define important subtypes of sporadic CRC. The potentially reversible nature of CpG methylation may provide novel therapeutic opportunities for this increasing subtype of the disease, which, due to anatomical location, presents a great challenge for early detection.

The first reported Spanish family with autosomal dominant endosteal hyperostosis is presented and two members in two different generations studied. Neurological involvement with sensorineural hearing loss, chronic intracranial hypertension, and mild corticospinal tract abnormalities were found in one case with radiological evidence of progressive bone disease at follow-up. In addition to mild hydrocephalus, CT-scan of the head documented a reduction in size of the posterior fossa and encroachment of the foramen magnum. A pattern of selective increase in the bone fraction of serum alkaline phosphatase was also recorded. This family supports the view that severe forms of endosteal hyperostosis are not confined to the autosomal recessive variant, as individuals with the autosomal dominant form may also show relentless progression to neurological involvement during adulthood.

Sparing of sensation in sacral dermatomes and of sphincter control was found in eight out of fourteen cases of severe cauda equina compression from massive central lumbar disc prolapse. Although the triangular shape of the lumbar spinal canal may be one factor for this it was found from a necropsy model that the increase in linear strain on the stretched roots of the cauda equina is least in the more centrally placed lower sacral roots. It is argued that the lower tension in these roots is determined by Young's Modulus.

This work aims to develop a new software tool for the monitoring, control and mitigation of the carbon footprint of WWTPs, called C-FOOT-CTRL. GHG emissions are emitted from various stages of treatment in a WWTP. Currently, in developed countries the energy required for wastewater treatment accounts for approximately 3% of the total electricity load. Also, WWTPs are the biggest single energy consumers of municipalities with a share of 20% of the total energy consumption. Various GHG emissions are associated with the construction and operation of WWTPs. These include carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O). The development of a tool that will be able to accurately record and predict the various GHG emissions in the different treatment processes of WWTPs is important in order to (i) track the emissions (ii) apply measures to reduce GHG contaminants and to (iii) link the GHG emission with a particular activity in the plant. The tool will be an innovative, low cost and flexible system that will constitute of a database for the storing and recording of data, a model for the estimation of direct and indirect GHG emissions and online sensors for recording GHG emissions in WWTPs.

This work aims to develop a new software tool for the monitoring, control and mitigation of the carbon footprint of WWTPs, called C-FOOT-CTRL. GHG emissions are emitted from various stages of treatment in a WWTP. Currently, in developed countries the energy required for wastewater treatment accounts for approximately 3% of the total electricity load. Also, WWTPs are the biggest single energy consumers of municipalities with a share of 20% of the total energy consumption. Various GHG emissions are associated with the construction and operation of WWTPs. These include carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O). The development of a tool that will be able to accurately record and predict the various GHG emissions in the different treatment processes of WWTPs is important in order to (i) track the emissions (ii) apply measures to reduce GHG contaminants and to (iii) link the GHG emission with a particular activity in the plant. The tool will be an innovative, low cost and flexible system that will constitute of a database for the storing and recording of data, a model for the estimation of direct and indirect GHG emissions and online sensors for recording GHG emissions in WWTPs.

This work aims to develop a new software tool for the monitoring, control and mitigation of the carbon footprint of WWTPs, called C-FOOT-CTRL. GHG emissions are emitted from various stages of treatment in a WWTP. Currently, in developed countries the energy required for wastewater treatment accounts for approximately 3% of the total electricity load. Also, WWTPs are the biggest single energy consumers of municipalities with a share of 20% of the total energy consumption. Various GHG emissions are associated with the construction and operation of WWTPs. These include carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O). The development of a tool that will be able to accurately record and predict the various GHG emissions in the different treatment processes of WWTPs is important in order to (i) track the emissions (ii) apply measures to reduce GHG contaminants and to (iii) link the GHG emission with a particular activity in the plant. The tool will be an innovative, low cost and flexible system that will constitute of a database for the storing and recording of data, a model for the estimation of direct and indirect GHG emissions and online sensors for recording GHG emissions in WWTPs.

The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work., Starting from hits identified by a pharmaceutical company, new antimalarials have been discovered using an “open source” approach that discloses data in real time and eschews secrecy.