Wiring Switches to Light Bulbs

Given n buttons and n bulbs so that the ith button toggles the ith bulb and at most two other bulbs, we compute the sharp lower bound on the number of bulbs that can be lit regardless of the action of the buttons.Comment: 19 pages, 14 figure

Extensive complement-dependent enhancement of HIV-1 by autologous non-neutralising antibodies at early stages of infection

Background: Non-neutralising antibodies to the envelope glycoprotein are elicited during acute HIV-1 infection and are abundant throughout the course of disease progression. Although these antibodies appear to have negligible effects on HIV-1 infection when assayed in standard neutralisation assays, they have the potential to exert either inhibitory or enhancing effects through interactions with complement and/or Fc receptors. Here we report that non-neutralising antibodies produced early in response to HIV-1 infection can enhance viral infectivity.Results: We investigated this complement-mediated antibody-dependent enhancement (C'-ADE) of early HIV infection by carrying out longitudinal studies with primary viruses and autologous sera derived sequentially from recently infected individuals, using a T cell line naturally expressing the complement receptor 2 (CR2; CD21). The C'-ADE was consistently observed and in some cases achieved infection-enhancing levels of greater than 350-fold, converting a low-level infection to a highly destructive one. C'-ADE activity declined as a neutralising response to the early virus emerged, but later virus isolates that had escaped the neutralising response demonstrated an increased capacity for enhanced infection by autologous antibodies. Moreover, sera with autologous enhancing activity were capable of C'ADE of heterologous viral isolates, suggesting the targeting of conserved epitopes on the envelope glycoprotein. Ectopic expression of CR2 on cell lines expressing HIV-1 receptors was sufficient to render them sensitive to C'ADE.Conclusions: Taken together, these results suggest that non-neutralising antibodies to the HIV-1 envelope that arise during acute infection are not 'passive', but in concert with complement and complement receptors may have consequences for HIV-1 dissemination and pathogenesis

Determinants of echolocation call frequency variation in the Formosan lesser horseshoe bat (Rhinolophus monoceros)

The origin and maintenance of intraspecific variation in vocal signals is important for population divergence and speciation. Where vocalizations are transmitted by vertical cultural inheritance, similarity will reflect co-ancestry, and thus vocal divergence should reflect genetic structure. Horseshoe bats are characterized by echolocation calls dominated by a constant frequency component that is partly determined by maternal imprinting. Although previous studies showed that constant frequency calls are also influenced by some non-genetic factors, it is not known how frequency relates to genetic structure. To test this, we related constant frequency variation to genetic and non-genetic variables in the Formosan lesser horseshoe bat (Rhinolophus monoceros). Recordings of bats from across Taiwan revealed that females called at higher frequencies than males; however, we found no effect of environmental or morphological factors on call frequency. By comparison, variation showed clear population structure, with frequencies lower in the centre and east, and higher in the north and south. Within these regions, frequency divergence was directional and correlated with geographical distance, suggesting that call frequencies are subject to cultural drift. However, microsatellite clustering analysis showed that broad differences in constant frequency among populations corresponded to discontinuities in allele frequencies resulting from vicariant events. Our results provide evidence that the processes shaping genetic subdivision have concomitant consequences for divergence in echolocation call frequency

Using Medical Students to Enhance Curricular Integration of Cross-Cultural Content

We hypothesized that an interested medical student group would be helpful in reviewing tutorial cases and giving relevant feedback on the curricular integration of cross-cultural content using case triggers in a preclinical gastrointestinal pathophysiology course. Self-selected student leaders (n = 9) reviewed pre-existing problem-based learning tutorial cases (n = 3) with cross-cultural triggers, and provided narrative feedback to course faculty. The cases were modified and used for the entire class in the following 2 years. Participating course students' comments and teaching faculty feedback were also noted. Outcomes were a change in case content, student global evaluations of the course, and self-reported faculty comfort with teaching the cases. All three tutorial cases were reviewed by a separate group of 2–3 students. Major and minor revisions were made to each case based on the student feedback. These cases were used in 2007 and 2008 and were the major change to the course during that time. Overall course evaluation scores improved significantly from 2006 to 2008 (p = 0.000). Tutors (n = 22 in 2007; n = 23 in 2008) expressed relief during tutor meetings that students had reviewed the cases. A general framework for eliciting student feedback on problem-based cases was developed. Student feedback, consisting of self-selected students' case reviews and solicited course and tutor comments, added value to a curricular reform to improve the integration of cross-cultural content into a problem-based learning curriculum. Our study underscores the fundamental link between teachers and students as partners in curricular development

In vivo emergence of HIV-1 highly sensitive to neutralizing antibodies.

BACKGROUND: The rapid and continual viral escape from neutralizing antibodies is well documented in HIV-1 infection. Here we report in vivo emergence of viruses with heightened sensitivity to neutralizing antibodies, sometimes paralleling the development of neutralization escape. METHODOLOGY/PRINCIPAL FINDINGS: Sequential viral envs were amplified from seven HIV-1 infected men monitored from seroconversion up to 5 years after infection. Env-recombinant infectious molecular clones were generated and tested for coreceptor use, macrophage tropism and neutralization sensitivity to homologous and heterologous serum, soluble CD4 and monoclonal antibodies IgG1b12, 2G12 and 17b. We found that HIV-1 evolves sensitivity to contemporaneous neutralizing antibodies during infection. Neutralization sensitive viruses grow out even when potent autologous neutralizing antibodies are present in patient serum. Increased sensitivity to neutralization was associated with susceptibility of the CD4 binding site or epitopes induced after CD4 binding, and mediated by complex envelope determinants including V3 and V4 residues. The development of neutralization sensitive viruses occurred without clinical progression, coreceptor switch or change in tropism for primary macrophages. CONCLUSIONS: We propose that an interplay of selective forces for greater virus replication efficiency without the need to resist neutralizing antibodies in a compartment protected from immune surveillance may explain the temporal course described here for the in vivo emergence of HIV-1 isolates with high sensitivity to neutralizing antibodies

Toxoplasma gondii-Induced Activation of EGFR Prevents Autophagy Protein-Mediated Killing of the Parasite

Toxoplasma gondii resides in an intracellular compartment (parasitophorous vacuole) that excludes transmembrane molecules required for endosome-lysosome recruitment. Thus, the parasite survives by avoiding lysosomal degradation. However, autophagy can re-route the parasitophorous vacuole to the lysosomes and cause parasite killing. This raises the possibility that T. gondii may deploy a strategy to prevent autophagic targeting to maintain the non-fusogenic nature of the vacuole. We report that T. gondii activated EGFR in endothelial cells, retinal pigment epithelial cells and microglia. Blockade of EGFR or its downstream molecule, Akt, caused targeting of the parasite by LC3(+) structures, vacuole-lysosomal fusion, lysosomal degradation and killing of the parasite that were dependent on the autophagy proteins Atg7 and Beclin 1. Disassembly of GPCR or inhibition of metalloproteinases did not prevent EGFR-Akt activation. T. gondii micronemal proteins (MICs) containing EGF domains (EGF-MICs; MIC3 and MIC6) appeared to promote EGFR activation. Parasites defective in EGF-MICs (MIC1 ko, deficient in MIC1 and secretion of MIC6; MIC3 ko, deficient in MIC3; and MIC1-3 ko, deficient in MIC1, MIC3 and secretion of MIC6) caused impaired EGFR-Akt activation and recombinant EGF-MICs (MIC3 and MIC6) caused EGFR-Akt activation. In cells treated with autophagy stimulators (CD154, rapamycin) EGFR signaling inhibited LC3 accumulation around the parasite. Moreover, increased LC3 accumulation and parasite killing were noted in CD154-activated cells infected with MIC1-3 ko parasites. Finally, recombinant MIC3 and MIC6 inhibited parasite killing triggered by CD154 particularly against MIC1-3 ko parasites. Thus, our findings identified EGFR activation as a strategy used by T. gondii to maintain the non-fusogenic nature of the parasitophorous vacuole and suggest that EGF-MICs have a novel role in affecting signaling in host cells to promote parasite survival

Smoking and mental illness: results from population surveys in Australia and the United States

<p>Abstract</p> <p>Background</p> <p>Smoking has been associated with a range of mental disorders including schizophrenia, anxiety disorders and depression. People with mental illness have high rates of morbidity and mortality from smoking related illnesses such as cardiovascular disease, respiratory diseases and cancer. As many people who meet diagnostic criteria for mental disorders do not seek treatment for these conditions, we sought to investigate the relationship between mental illness and smoking in recent population-wide surveys.</p> <p>Methods</p> <p>Survey data from the US National Comorbidity Survey-Replication conducted in 2001–2003, the 2007 Australian Survey of Mental Health and Wellbeing, and the 2007 US National Health Interview Survey were used to investigate the relationship between current smoking, ICD-10 mental disorders and non-specific psychological distress. Population weighted estimates of smoking rates by disorder, and mental disorder rates by smoking status were calculated.</p> <p>Results</p> <p>In both the US and Australia, adults who met ICD-10 criteria for mental disorders in the 12 months prior to the survey smoked at almost twice the rate of adults without mental disorders. While approximately 20% of the adult population had 12-month mental disorders, among adult smokers approximately one-third had a 12-month mental disorder – 31.7% in the US (95% CI: 29.5%–33.8%) and 32.4% in Australia (95% CI: 29.5%–35.3%). Female smokers had higher rates of mental disorders than male smokers, and younger smokers had considerably higher rates than older smokers. The majority of mentally ill smokers were not in contact with mental health services, but their rate of smoking was not different from that of mentally ill smokers who had accessed services for their mental health problem. Smokers with high levels of psychological distress smoked a higher average number of cigarettes per day.</p> <p>Conclusion</p> <p>Mental illness is associated with both higher rates of smoking and higher levels of smoking among smokers. Further, a significant proportion of smokers have mental illness. Strategies that address smoking in mental illness, and mental illness among smokers would seem to be important directions for tobacco control. As the majority of smokers with mental illness are not in contact with mental health services for their condition, strategies to address mental illness should be included as part of population health-based mental health and tobacco control efforts.</p

Data for EuCAP2018 Conference Paper: A low-complexity array of directly phase modulating antennas

This dataset accompanies the paper "A low-complexity array of directly phase modulating antennas", presented at the European Conference on Antennas and Propagation, April 2018, London.<br