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Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal, autosomal recessive disease resulting from mutations in the CLN2 gene with consequent deficiency in its product tripeptidyl peptidase I (TPP-I). In the central nervous system (CNS), the deficiency of TPP-I results in the accumulation of proteins in lysosomes leading to a loss of neurons causing progressive neurological decline, and death by ages 10–12 years. To establish the feasibility of treating the CNS manifestations of LINCL by gene transfer, an adeno-associated virus 2 (AAV2) vector encoding the human CLN2 cDNA (AAV2 CU hCLN2) was assessed for its ability to establish therapeutic levels of TPP-I in the brain. In vitro studies demonstrated that AAV2 CU hCLN2 expressed CLN2 and produced biologically active TPP-I protein of which a fraction was secreted as the pro-TPP-I precursor and was taken up by nontransduced cells (ie, cross-correction). Following AAV2-mediated CLN2 delivery to the rat striatum, enzymatically active TPP-I protein was detected. By immunohistochemistry TPP-I protein was detected in striatal neurons (encompassing nearly half of the target structure) for up to 18 months. At the longer time points following striatal administration, TPP-I-positive cell bodies were also observed in the substantia nigra, frontal cerebral cortex and thalamus of the injected hemisphere, and the frontal cerebral cortex of the noninjected hemisphere. These areas of the brain contain neurons that extend axons into the striatum, suggesting that CNS circuitry may aid the distribution of the gene product. To assess the feasibility of human CNS delivery, a total of 3.6 × 10 11 particle units of AAV2 CU hCLN2 was administered to the CNS of African green monkeys in 12 distributed doses. Assessment at 5 and 13 weeks demonstrated widespread detection of TPP-I in neurons, but not glial cells, at all regions of injection. The distribution of TPP-I-positive cells was similar between the two time points at all injection sites. Together, these data support the development of direct CNS gene transfer using an AAV2 vector expressing the CLN2 cDNA for the CNS manifestations of LINCL.

This paper uses data from twenty-one online and in-person qualitative interviews to examine the meaning and use of chat rooms located on men for men (M4M) websites from the perspectives of men seeking men on the Internet. This research is inspired by recent public health and social sciences literature on gay websites and chat rooms. The data indicate that these online sites help expedite learning about sex and sexuality and, for men who are shy or geographically isolated, to interact with metropolitan gay communities. There is, however, a measure of stigma associated with use of these chat rooms, particularly by men who are older or in coupled relationships. Using these data, the paper argues that M4M chat rooms play a vital role in fostering the sexual autonomy of many men who frequent these venues and that sociologists should devote more study to the complexity of online social interaction.

Recent technological developments provide easy access to use an artificial oxygen supply (hyperoxia) during exercise training. The aim of this study was to assess the efficacy of a commercially available oxygen compressor inducing low-dose hyperoxia, on limiting factors of endurance performance. Thirteen active men (age 24 ± 3 years) performed a high-intensity interval exercise (HIIE) session (5 × 3 min at 80% of Wmax, separated by 2 min at 40% Wmax) on a cycle ergometer, both in hyperoxia (4 L∙min−1, 94% O2, HYP) or ambient conditions (21% O2, NORM) in randomized order. The primary outcome was defined as red blood cell deformability (RBC-D), while our secondary interest included changes in muscle oxygenation. RBC-D was expressed by the ratio of shear stress at half-maximal deformation (SS1/2) and maximal deformability (EImax) and muscle oxygenation of the rectus femoris muscle was assessed by near-infrared spectroscopy. No statistically significant changes occurred in SS1/2 and EImax in either condition. The ratio of SS1/2 to EImax statistically decreased in NORM (p < 0.01; Δ: −0.10; 95%CI: −0.22, 0.02) but not HYP (p > 0.05; Δ: −0.16; 95%CI: −0.23, −0.08). Muscle oxygenation remained unchanged. This study showed that low-dose hyperoxia during HIIE using a commercially available device with a flow rate of only 4 L·min−1 may not be sufficient to induce acute ergogenic effects compared to normoxic conditions.

Using customer relationship management (CRM) techniques, companies target market to their customers on an individualized basis. A variation on the CRM theme is employee relationship management (ERM), in which a company uses Web-based personalization techniques to develop a more effective relationship with its employees. This article reports some of the findings for a study sponsored by the U.S. Navy to determine how personalization can be used for a Web portal with the objective of boosting sailor morale and retention. It also discusses ways that CRM personalization techniques can be generalized to fields beyond marketing and employee relations.

Remarkable experimental advances in quantum computing are exemplified by recent announcements of impressive average gate fidelities exceeding 99.9% for single-qubit gates and 99% for two-qubit gates. Although these high numbers engender optimism that fault-tolerant quantum computing is within reach, the connection of average gate fidelity with fault-tolerance requirements is not direct. Here we use reported average gate fidelity to determine an upper bound on the quantum-gate error rate, which is the appropriate metric for assessing progress towards fault-tolerant quantum computation, and we demonstrate that this bound is asymptotically tight for general noise. Although this bound is unlikely to be saturated by experimental noise, we demonstrate using explicit examples that the bound indicates a realistic deviation between the true error rate and the reported average fidelity. We introduce the Pauli distance as a measure of this deviation, and we show that knowledge of the Pauli distance enables tighter estimates of the error rate of quantum gates.

The collection of fecal material and developments in sequencing technologies have enabled standardised and non-invasive gut microbiome profiling. Microbiome composition from several large cohorts have been cross-sectionally linked to various lifestyle factors and diseases. In spite of these advances, prospective associations between microbiome composition and health have remained uncharacterised due to the lack of sufficiently large and representative population cohorts with comprehensive follow-up data. Here, we analyse the long-term association between gut microbiome variation and mortality in a well-phenotyped and representative population cohort from Finland ( n  = 7211). We report robust taxonomic and functional microbiome signatures related to the Enterobacteriaceae family that are associated with mortality risk during a 15-year follow-up. Our results extend previous cross-sectional studies, and help to establish the basis for examining long-term associations between human gut microbiome composition, incident outcomes, and general health status. Gut microbiome composition has a role in health and disease. Here the authors show that microbiome signatures related to the Enterobacteriaceae family are associated with cause-specific mortality risk in a well phenotyped Finish population over a 15-year follow-up.

Hypersaline tidal flats (HTFs) are coastal ecosystems with freshwater deficits often occurring in arid or semi-arid regions near mangrove supratidal zones with no major fluvial contributions. Here, we estimate that organic carbon (OC), total nitrogen (TN) and total phosphorus (TP) were buried at rates averaging 21 (±6), 1.7 (±0.3) and 1.4 (±0.3) gm-2yr-1, respectively, during the previous century in three contrasting HTF systems, one in Brazil (eutrophic) and two in Australia (oligotrophic). Although these rates are lower than those from nearby mangrove, saltmarsh and seagrass systems, the importance of HTFs as sinks for OC, TN and TP may be significant given their extensive coverage. Despite the measured short-term variability between net air–saltpan CO2 influx and emission estimates found during the dry and wet season in the Brazilian HTF, the only site with seasonal CO2 flux measurements, the OC sedimentary profiles over several decades suggest efficient OC burial at all sites. Indeed, the stable isotopes of OC and TN (δ13C and δ15N) along with C:N ratios show that microphytobenthos are the major source of the buried OC in these HTFs. Our findings highlight a previously unquantified carbon as well as a nutrient sink and suggest that coastal HTF ecosystems could be included in the emerging blue carbon framework.

In this double-blind, placebo-controlled trial involving more than 84,000 Dutch adults, the 13-valent pneumococcal conjugate vaccine was found to prevent pneumococcal disease but not the overall occurrence of community-acquired pneumonia. Streptococcus pneumoniae , a major cause of community-acquired pneumonia in the elderly, results in considerable morbidity and mortality. 1 – 4 Pneumococcal community-acquired pneumonia most commonly presents as nonbacteremic disease. 3 Invasive pneumococcal disease, which involves infection of normally sterile sites, occurs in approximately 25% of cases. 3 Immunologic protection against pneumococcal disease is mediated through opsonophagocytic antibodies directed against bacterial capsular polysaccharides that define the pneumococcal serotypes and serve as virulence factors. 5 Vaccines composed of purified capsular polysaccharides, which have been available for more than 50 years, are not immunogenic in young children. 6 – 8 Although some studies have shown that purified capsular polysaccharides . . .

We introduce unitary-gate randomized benchmarking (URB) for qudit gates by extending single- and multi-qubit URB to single- and multi-qudit gates. Specifically, we develop a qudit URB procedure that exploits unitary 2-designs. Furthermore, we show that our URB procedure is not simply extracted from the multi-qubit case by equating qudit URB to URB of the symmetric multi-qubit subspace. Our qudit URB is elucidated by using pseudocode, which facilitates incorporating into benchmarking applications.

Microbial communities in the gut can be highly individual. What engenders this specificity? The gut characteristically produces gram quantities of immunoglobulin A (IgA) antibody, which is presumed to protect the gut from pathogen attack. Donaldson et al. engineered strains of Bacteroides fragilis , a common human commensal, to modify its surface capsule, which affects its ability to colonize the germ-free mouse gut. Capsule changes altered the capacity of IgA to bind to the different mutants. It seems that this commensal species exploits IgA sticking power specifically to give it a competitive edge and to promote its establishment in the gut. Science , this issue p. 795 Bacteroides fragilis modifies its surface to induce an immunoglobulin A response that promotes stable mucosal association and colonization resistance. The immune system responds vigorously to microbial infection while permitting lifelong colonization by the microbiome. Mechanisms that facilitate the establishment and stability of the gut microbiota remain poorly described. We found that a regulatory system in the prominent human commensal Bacteroides fragilis modulates its surface architecture to invite binding of immunoglobulin A (IgA) in mice. Specific immune recognition facilitated bacterial adherence to cultured intestinal epithelial cells and intimate association with the gut mucosal surface in vivo. The IgA response was required for B. fragilis (and other commensal species) to occupy a defined mucosal niche that mediates stable colonization of the gut through exclusion of exogenous competitors. Therefore, in addition to its role in pathogen clearance, we propose that IgA responses can be co-opted by the microbiome to engender robust host-microbial symbiosis.