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BACKGROUND. Cryptococcal meningitis (CM) causes an estimated 180,000 deaths annually, predominantly in sub-Saharan Africa, where most patients receive fluconazole (FLC) monotherapy. While relapse after FLC monotherapy with resistant strains is frequently observed, the mechanisms and impact of emergence of FLC resistance in human CM are poorly understood. Heteroresistance (HetR)--a resistant subpopulation within a susceptible strain-- is a recently described phenomenon in Cryptococcusneoformans (Cn) and Cryptococcusgattii (Cg), the significance of which has not previously been studied in humans. METHODS. A cohort of 20 patients with HIV-associated CM in Tanzania was prospectively observed during therapy with either FLC monotherapy or in combination with flucytosine (5FC). Total and resistant subpopulations of Cryptococcus spp. were quantified directly from patient cerebrospinal fluid (CSF). Stored isolates underwent whole genome sequencing and phenotypic characterization. RESULTS. Heteroresistance was detectable in Cryptococcus spp. in the CSF of all patients at baseline (i.e., prior to initiation of therapy). During FLC monotherapy, the proportion of resistant colonies in the CSF increased during the first 2 weeks of treatment. In contrast, no resistant subpopulation was detectable in CSF by day 14 in those receiving a combination of FLC and 5FC. Genomic analysis revealed high rates of aneuploidy in heteroresistant colonies as well as in relapse isolates, with chromosome 1 (Chr1) disomy predominating. This is apparently due to the presence on Chr1 of ERG11, which is the FLC drug target, and AFR1, which encodes a drug efflux pump. In vitro efflux levels positively correlated with the level of heteroresistance. CONCLUSION. Our findings demonstrate for what we believe is the first time the presence and emergence of aneuploidy-driven FLC heteroresistance in human CM, association of efflux levels with heteroresistance, and the successful suppression of heteroresistance with 5FC/FLC combination therapy. FUNDING. This work was supported by the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z and the Daniel Turnberg Travel Fellowship., Introduction Cryptococcal meningitis (CM) is a common and severe opportunistic infection primarily affecting patients with advanced HIV/AIDS caused by the basidiomycete yeasts Cryptococcus neoformans (Cn) or less frequently Cryptococcus gattii [...]

Scribal Correction and Literary Craft: English Manuscripts 1375-1510. By Daniel Wakelin. Cambridge Studies in Medieval Literature. Cambridge: Cambridge University Press, 2014. Pp. xviii + 345; 6 b/w illustrations. $99. Scribal [...]

Background. Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality globally. High fungal burden in cerebrospinal fluid (CSF) at diagnosis and poor fungal clearance during treatment are recognized adverse prognostic markers; however, the underlying pathogenic factors that drive these clinical manifestations are incompletely understood. We profiled a large set of clinical isolates for established cryptococcal virulence traits to evaluate the contribution of C. neoformans phenotypic diversity to clinical presentation and outcome in human cryptococcosis. Methods. Sixty-five C. neoformans isolates from clinical trial patients with matched clinical data were assayed in vitro to determine murine macrophage uptake, intracellular proliferation rate (IPR), capsule induction, and laccase activity. Analysis of the correlation between prognostic clinical and host immune parameters and fungal phenotypes was performed using Spearman's r, while the fungal-dependent impact on long-term survival was determined by Cox regression analysis. Results. High levels of fungal uptake by macrophages in vitro, but not the IPR, were associated with CSF fungal burden (r = 0.38, P = 0.002) and long-term patient survival (hazard ratio [HR] 2.6, 95% CI 1.2-5.5, P = 0.012). High-uptake strains were hypocapsular (r = -0.28, P = 0.05) and exhibited enhanced laccase activity (r = 0.36, P = 0.003). Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF (r = 0.49, P < 0.0001) and resistance to clearance following patient antifungal treatment (r = 0.39, P = 0.003). Conclusion. These findings underscore the contribution of cryptococcal-phagocyte interactions and laccase-dependent melanin pathways to human clinical presentation and outcome. Furthermore, characterization of fungal-specific pathways that drive clinical manifestation provide potential targets for the development of therapeutics and the management of CM. Funding. This work was made possible by funding from the Wellcome Trust (WT088148MF), the Medical Research Council (MR/J008176/1), the NIHR Surgical Reconstruction and Microbiology Research Centre and the Lister Institute for Preventive Medicine (to R.C. May), and a Wellcome Trust Intermediate fellowship (089966, to T. Bicanic). The C. neoformans isolates were collected within clinical trials funded by the British Infection Society (fellowship to T. Bicanic), the Wellcome Trust (research training fellowships WT069991, to A.E. Brouwer and WT081794, to J.N. Jarvis), and the Medical Research Council, United Kingdom (76201). The funding sources had no role in the design or conduct of this study, nor in preparation of the manuscript., Introduction Cryptococcal meningoencephalitis (CM), caused by the fungus C. neoformans, is a leading cause of mortality in HIV-infected individuals globally (1). Sub-Saharan Africa, with the highest HIV burden, is the [...]

Developing a theoretical framework for conducting electronic fluids qualitatively distinct from those described by Landau's Fermi-liquid theory is of central importance to many outstanding problems in condensed matter physics. One such problem is that, above the transition temperature and near optimal doping, high-transition-temperature copper-oxide superconductors exhibit 'strange metal' behaviour that is inconsistent with being a traditional Landau Fermi liquid. Indeed, a microscopic theory of a strange-metal quantum phase could shed new light on the interesting low-temperature behaviour in the pseudogap regime and on the d-wave superconductor itself. Here we present a theory for a specific example of a strange metal--the 'd-wave metal'. Using variational wavefunctions, gauge theoretic arguments, and ultimately large-scale density matrix renormalization group calculations, we show that this remarkable quantum phase is the ground state of a reasonable microscopic Hamiltonian--the usual t-J model with electron kinetic energy t and two-spin exchange J supplemented with a frustrated electron 'ring-exchange' term, which we here examine extensively on the square lattice two-leg ladder. These findings constitute an explicit theoretical example of a genuine non-Fermi-liquid metal existing as the ground state of a realistic model., Over the past several decades, experiments on strongly correlated materials have routinely revealed, in certain parts of the phase diagram, conducting liquids with physical properties that are qualitatively inconsistent with [...]

The past two decades have seen an increasing number of virulent infectious diseases in natural populations and managed landscapes. In both animals and plants, an unprecedented number of fungal and fungal-like diseases have recently caused some of the most severe die-offs and extinctions ever witnessed in wild species, and are jeopardizing food security. Human activity is intensifying fungal disease dispersal by modifying natural environments and thus creating new opportunities for evolution. We argue that nascent fungal infections will cause increasing attrition of biodiversity, with wider implications for human and ecosystem health, unless steps are taken to tighten biosecurity worldwide., Emerging infectious diseases (EIDs) caused by fungi are increasingly recognized as presenting a worldwide threat to food security (1,2) (Table 1 and Supplementary Table 1). This is not a new [...]

Vascular-disrupting agents (VDAs) such as combretastatin A4 phosphate (CA4P) selectively disrupt blood vessels in tumors and induce tumor necrosis. However, tumors rapidly repopulate after treatment with such compounds. Here, we [...]

Penicillium marneffei is the only pathogenic species of A Penicillium within this grouping of >270 species. This unique feature is due to the ability of P. marneffei to exhibit temperature-dependent [...]

Invasive aspergillosis in immunosuppressed patients is difficult to diagnose, is problematic to treat, and results in a high mortality rate (1). Chronic and allergic pulmonary and sinus aspergillosis are increasingly [...]

The dispersive characteristic of an electronically tunable optical filter is presented with application toward delaying high-speed digital and analog signals. It is shown that for 2-GHz square waves, dispersion is not a limiting factor and the filter can be operated over the full range of delays.

The theory of second-order phase transitions is one of the foundations of modern statistical mechanics and condensed-matter theory. A central concept is the observable order parameter, whose nonzero average value characterizes one or more phases. At large distances and long times, fluctuations of the order parameter(s) are described by a continuum field theory, and these dominate the physics near such phase transitions. We show that near second-order quantum phase transitions, subtle quantum interference effects can invalidate this paradigm, and we present a theory of quantum critical points in a variety of experimentally relevant two-dimensional antiferromagnets. The critical points separate phases characterized by conventional 'confining' order parameters. Nevertheless, the critical theory contains an emergent gauge field and 'deconfined' degrees of freedom associated with fractionalization of the order parameters. We propose that this paradigm for quantum criticality may be the key to resolving a number of experimental puzzles in correlated electron systems and offer a new perspective on the properties of complex materials., Much recent research in condensed-matter physics has focused on the behavior of matter near zero-temperature 'quantum' phase transitions that are seen in several strongly correlated many-particle systems (1). Indeed, a [...]

Molecular surveillance of pathogenic microbes works by genotyping isolates with DNA fingerprinting techniques and then using these genotypes to assign individuals to populations. Clonality is assumed in many fingerprinting studies, although this assumption has been shown to be false for many organisms. To accommodate recombining organisms into surveillance programs, methods using population allele frequencies in combination with individual multilocus genotypes are necessary. Here, we develop a statistical method appropriate for haploid recombining microbes that allows individuals to be assigned to populations. We illustrate the usefulness of this technique by inferring the source populations for Coccidioides isolates recovered from patients treated outside the endemic area of Coccidioides sp., the etiological agents of human coccidioidomycosis, but with a travel history including visits to one or more endemic areas.

The American Chemical Society held a symposia for college chemistry teachers to focus on changes in chemistry education in the 21st century. Seven symposiums were held, each focusing on a particular area of chemical education. A listing of the papers for each symposium is included.

Low-temperature type II superconductors lose electrical resistance far less readily in cooling temperatures than do the copper oxide high-temperature superconductors. This difference in properties indicates that the type II superconductors' resistivity is zero when the temperature drop occurs in a magnetic field. However, experimental and theoretical data show that the colder temperatures cause the type II material to exhibit a sharp phase transition to a bona fide superconducting, impurity-containing phase marked by a chaotic, frozen magnetic flux vortices.

To the Editor: Amphibian species are declining at an alarming rate on a global scale (1). One of the major reasons for these declines is chytridiomycosis, caused by the chytridiomycete [...]

Long-distance population dispersal leaves its characteristic signature in genomes, namely, reduced diversity and increased linkage between genetic markers. This signature enables historical patterns of range expansion to be traced. Herein, we use microsatellite loci from the human pathogen Coccidioides immitis to show that genetic diversity in this fungus is geographically partitioned throughout North America. In contrast, analyses of South American C. immitis show that this population is genetically depauperate and was founded from a single North American population centered in Texas. Variances of allele distributions show that South American C. immitis have undergone rapid population growth, consistent with an epidemic increase in postcolonization population size. Herein, we estimate the introduction into South America to have occurred within the last 9,000-140,000 years. This range increase parallels that of Homo sapiens. Because of known associations between Amerindians and this fungus, we suggest that the colonization of South America by C. immitis represents a relatively recent and rapid codispersal of a host and its pathogen.

Scientific research shows that quasiparticles of the fractional quantum Hall effect have a fractional charge. Experiments used a quantum point contact, achieved through pinching together the ends of an electron gas, to create a week tunnelling current. The paths of flowing currents at quantum points are shown. External circuitry noise was filtered out.

50 women and 50 men first- and third-year students were asked how they would like to be remembered after graduation. First-year women were more concerned about being remembered as brilliant students than being popular, whilst the order was reversed for their third-year peers. Men in both years did not differ significantly on how they would like to be remembered. None wished to be remembered as athletic stars.

In his preface, John Herdman acknowledges that the concept of the literary double--or Doppelganger--has received more than a fair amount of critical attention. Thus the context for Herdman's study is [...]