Comparing research investment to United Kingdom institutions and published outputs for tuberculosis, HIV and malaria: A systematic analysis across 1997-2013

Background: The "Unfinished Agenda" of infectious diseases is of great importance to policymakers and research funding agencies that require ongoing research evidence on their effective management. Journal publications help effectively share and disseminate research results to inform policy and practice. We assess research investments to United Kingdom institutions in HIV, tuberculosis and malaria, and analyse these by numbers of publications and citations and by disease and type of science. Methods: Information on infection-related research investments awarded to United Kingdom institutions across 1997-2010 were sourced from funding agencies and individually categorised by disease and type of science. Publications were sourced from the Scopus database via keyword searches and filtered to include only publications relating to human disease and containing a United Kingdom-based first and/or last author. Data were matched by disease and type of science categories. Investment (United Kingdom pounds) and publications were compared to generate an 'investment per publication' metric; similarly, an 'investment per citation' metric was also developed as a measure of the usefulness of research. Results: Total research investment for all three diseases was £1.4 billion, and was greatest for HIV (£651.4 million), followed by malaria (£518.7 million) and tuberculosis (£239.1 million). There were 17,271 included publications, with 9,322 for HIV, 4,451 for malaria, and 3,498 for tuberculosis. HIV publications received the most citations (254,949), followed by malaria (148,559) and tuberculosis (100,244). According to UK pound per publication, tuberculosis (£50,691) appeared the most productive for investment, compared to HIV (£61,971) and malaria (£94,483). By type of science, public health research was most productive for HIV (£27,296) and tuberculosis (£22,273), while phase I-III trials were most productive for malaria (£60,491). According to UK pound per citation, tuberculosis (£1,797) was the most productive area for investment, compared to HIV (£2,265) and malaria (£2,834). Public health research was the most productive type of science for HIV (£2,265) and tuberculosis (£1,797), whereas phase I-III trials were most productive for malaria (£1,713). Conclusions: When comparing total publications and citations with research investment to United Kingdom institutions, tuberculosis research appears to perform best in terms of efficiency. There were more public health-related publications and citations for HIV and tuberculosis than other types of science. These findings demonstrate the diversity of research funding and outputs, and provide new evidence to inform research investment strategies for policymakers, funders, academic institutions, and healthcare organizations.Infectious Disease Research Networ

Punica granatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide

BACKGROUND: For ≈ 24 years the AIDS pandemic has claimed ≈ 30 million lives, causing ≈ 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be: acceptable; accessible; affordable; and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option. METHODS: Fruit juices were screened for inhibitory activity against HIV-1 IIIB using CD4 and CXCR4 as cell receptors. The best juice was tested for inhibition of: (1) infection by HIV-1 BaL, utilizing CCR5 as the cellular coreceptor; and (2) binding of gp120 IIIB and gp120 BaL, respectively, to CXCR4 and CCR5. To remove most colored juice components, the adsorption of the effective ingredient(s) to dispersible excipients and other foods was investigated. A selected complex was assayed for inhibition of infection by primary HIV-1 isolates. RESULTS: HIV-1 entry inhibitors from pomegranate juice adsorb onto corn starch. The resulting complex blocks virus binding to CD4 and CXCR4/CCR5 and inhibits infection by primary virus clades A to G and group O. CONCLUSION: These results suggest the possibility of producing an anti-HIV-1 microbicide from inexpensive, widely available sources, whose safety has been established throughout centuries, provided that its quality is adequately standardized and monitored

BDNF Facilitates L-LTP Maintenance in the Absence of Protein Synthesis through PKMζ

Late-phase long term potentiation (L-LTP) is thought to be the cellular basis for long-term memory (LTM). While LTM as well as L-LTP is known to depend on transcription and translation, it is unclear why brain-derived neurotrophic factor (BDNF) could sustain L-LTP when protein synthesis is inhibited. The persistently active protein kinase ζ (PKMζ) is the only molecule implicated in perpetuating L-LTP maintenance. Here, in mouse acute brain slices, we show that inhibition of PKMζ reversed BDNF-dependent form of L-LTP. While BDNF did not alter the steady-state level of PKMζ, BDNF together with the L-LTP inducing theta-burst stimulation (TBS) increased PKMζ level even without protein synthesis. Finally, in the absence of de novo protein synthesis, BDNF maintained TBS-induced PKMζ at a sufficient level. These results suggest that BDNF sustains L-LTP through PKMζ in a protein synthesis-independent manner, revealing an unexpected link between BDNF and PKMζ

Austro-Asiatic Tribes of Northeast India Provide Hitherto Missing Genetic Link between South and Southeast Asia

Northeast India, the only region which currently forms a land bridge between the Indian subcontinent and Southeast Asia, has been proposed as an important corridor for the initial peopling of East Asia. Given that the Austro-Asiatic linguistic family is considered to be the oldest and spoken by certain tribes in India, Northeast India and entire Southeast Asia, we expect that populations of this family from Northeast India should provide the signatures of genetic link between Indian and Southeast Asian populations. In order to test this hypothesis, we analyzed mtDNA and Y-Chromosome SNP and STR data of the eight groups of the Austro-Asiatic Khasi from Northeast India and the neighboring Garo and compared with that of other relevant Asian populations. The results suggest that the Austro-Asiatic Khasi tribes of Northeast India represent a genetic continuity between the populations of South and Southeast Asia, thereby advocating that northeast India could have been a major corridor for the movement of populations from India to East/Southeast Asia

Experimental measurement-based quantum computing beyond the cluster-state model

The paradigm of measurement-based quantum computation opens new experimental avenues to realize a quantum computer and deepens our understanding of quantum physics. Measurement-based quantum computation starts from a highly entangled universal resource state. For years, clusters states have been the only known universal resources. Surprisingly, a novel framework namely quantum computation in correlation space has opened new routes to implement measurement-based quantum computation based on quantum states possessing entanglement properties different from cluster states. Here we report an experimental demonstration of every building block of such a model. With a four-qubit and a six-qubit state as distinct from cluster states, we have realized a universal set of single-qubit rotations, two-qubit entangling gates and further Deutsch's algorithm. Besides being of fundamental interest, our experiment proves in-principle the feasibility of universal measurement-based quantum computation without using cluster states, which represents a new approach towards the realization of a quantum computer.Comment: 26 pages, final version, comments welcom

Structure and mechanism of human DNA polymerase η

The variant form of the human syndrome xeroderma pigmentosum (XPV) is caused by a deficiency in DNA polymerase eta (Pol eta), a DNA polymerase that enables replication through ultraviolet-induced pyrimidine dimers. Here we report high-resolution crystal structures of human Pol eta at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Pol eta acts like a 'molecular splint' to stabilize damaged DNA in a normal B-form conformation. An enlarged active site accommodates the thymine dimer with excellent stereochemistry for two-metal ion catalysis. Two residues conserved among Pol eta orthologues form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. On the basis of the structures, eight Pol eta missense mutations causing XPV can be rationalized as undermining the molecular splint or perturbing the active-site alignment. The structures also provide an insight into the role of Pol eta in replicating through D loop and DNA fragile sites

Mitochondrial echoes of first settlement and genetic continuity in El Salvador

Background: From Paleo-Indian times to recent historical episodes, the Mesoamerican isthmus played an important role in the distribution and patterns of variability all around the double American continent. However, the amount of genetic information currently available on Central American continental populations is very scarce. In order to shed light on the role of Mesoamerica in the peopling of the New World, the present study focuses on the analysis of the mtDNA variation in a population sample from El Salvador. Methodology/Principal Findings: We have carried out DNA sequencing of the entire control region of the mitochondrial DNA (mtDNA) genome in 90 individuals from El Salvador. We have also compiled more than 3,985 control region profiles from the public domain and the literature in order to carry out inter-population comparisons. The results reveal a predominant Native American component in this region: by far, the most prevalent mtDNA haplogroup in this country (at ~90%) is A2, in contrast with other North, Meso- and South American populations. Haplogroup A2 shows a star-like phylogeny and is very diverse with a substantial proportion of mtDNAs (45%; sequence range 16090–16365) still unobserved in other American populations. Two different Bayesian approaches used to estimate admixture proportions in El Salvador shows that the majority of the mtDNAs observed come from North America. A preliminary founder analysis indicates that the settlement of El Salvador occurred about 13,400±5,200 Y.B.P.. The founder age of A2 in El Salvador is close to the overall age of A2 in America, which suggests that the colonization of this region occurred within a few thousand years of the initial expansion into the Americas. Conclusions/Significance: As a whole, the results are compatible with the hypothesis that today's A2 variability in El Salvador represents to a large extent the indigenous component of the region. Concordant with this hypothesis is also the observation of a very limited contribution from European and African women (~5%). This implies that the Atlantic slave trade had a very small demographic impact in El Salvador in contrast to its transformation of the gene pool in neighbouring populations from the Caribbean facade

Paradox of low field enhancement factor for field emission nanodiodes in relation to quantum screening effects

We put forward the quantum screening effect in field emission [FE] nanodiodes, explaining relatively low field enhancement factors due to the increased potential barrier that impedes the electron Fowler-Nordheim tunneling, which is usually observed in nanoscale FE experiments. We illustratively show this effect from the energy band diagram and experimentally verify it by performing the nanomanipulation FE measurement for a single P-silicon nanotip emitter (Φ = 4.94eV), with a scanning tungsten-probe anode (work function, Φ = 4.5eV) that constitutes a 75-nm vacuum nanogap. A macroscopic FE measurement for the arrays of emitters with a 17-μm vacuum microgap was also performed for a fair comparison

In vitro hypoxia-conditioned colon cancer cell lines derived from HCT116 and HT29 exhibit altered apoptosis susceptibility and a more angiogenic profile in vivo

Hypoxia is an important selective force in the clonal evolution of tumours. Through HIF-1 and other transcription factors combined with tumour-specific genetic alterations, hypoxia is a dominant factor in the angiogenic phenotype. Cellular adaptation to hypoxia is an important requirement of tumour progression independent of angiogenesis. The adaptive changes, insofar as they alter hypoxia-induced apoptosis, are likely to determine responsiveness to antiangiogenic strategies. To investigate this adaptation of tumour cells to hypoxia, we recreated in vitro the in vivo situation of chronic intermittent exposure to low-oxygen levels. The colon carcinoma cell lines HT29 and HCT116 were subjected to 40 episodes of sublethal hypoxia (4 h) three times a week. The resulting two hypoxia-conditioned cell lines have been maintained in culture for more than 2 years. In both cell lines changes in doubling times occurred: in HT29 an increase, and in HCT116 a decrease. Cell survival in response to hypoxia and to DNA damage differed strikingly in the two cell lines. The HT29 hypoxia-conditioned cells were more resistant than the parental line to a 24 h hypoxic challenge, while those from HCT116 surprisingly were more sensitive. Sensitivity to cisplatin in vitro was also significantly different for the hypoxia-conditioned compared with the parental lines, suggesting a change in pathways leading to apoptosis following DNA damage signaling. The growth of both conditioned cell lines in vivo as xenografts in immunodeficient (SCID) mice was more rapid than their parental lines, and was accompanied in each by evidence of enhanced vascular proliferation as a consequence of the hypoxia-conditioning. Thus the changes in apoptotic susceptibility were independent of altered angiogenesis. The derivation of these lines provides a model for events within hypoxic regions of colon cancers, and for the acquisition of resistance and sensitivity characteristics that may have therapeutic implications for the use of antiangiogenesis drugs