86 research outputs found
Southern Thailand: from conflict to negotiations?
Summary: In this Analysis, University of Leeds professor Duncan McCargo argues that the recent Malaysian-backed Southern Thai peace initiative has now run into some serious problems. He argues that despite its various shortcomings the initiative is still worthy of support, since it has gained far more traction that any previous attempts to address the decade-long insurgency. Thailand needs to maintain focus on the southern conflict despite its current preoccupation with a national-level political crisis that threatens to topple the government of Yingluck Shinawatra.
Key findings
The conflict in Southern Thailand is one of Asia’s most serious insurgencies, with over 6,000 dead over the last 10 years.
The Malaysian government sponsored negotiations represents the best hope for reaching a political settlement and bringing peace to the region.
However, both sides need to show greater commitment to the negotiations, introducing new structures and procedures
From-omics to personalized medicine in nephrology: Integration is the key
Large-scale gene, protein and metabolite measurements ('omics') have driven the resolution of biology to an unprecedented high definition. Passing from reductionism to a system-oriented perspective, medical research will take advantage of these high-throughput technologies unveiling their full potential. Integration is the key to decoding the underlying principles that govern the complex functions of living systems. Extensive computational support and statistical modelling is needed to manage and connect the-omic data sets but this, in turn, is speeding up the hypothesis generation in biology enormously and yielding a deep insight into the pathophysiology. This systems biology approach will transform diagnostic and therapeutic strategies with the discovery of novel biomarkers that will enable a predictive and preventive medicine leading to personalized medicine. © 2013 The Author
Screening of different genotypes/cultivars of black gram against stem fly, Melanagromyza sojae (Zehntner) in Kharif season
Total thirteen black gram genotypes/cultivars (SKNU-13-02, SKNU-13-03, SKNU-13-05, SKNU-11-11, SKNU-12-04, SKNU-12-07, SKNU-12-08, SKNU-15-01, SKNU-15-02, SKNU-15-03, T9, GU 1 and Rajasthan local) were screened for their relative susceptibility against stem fly, Melanagromyza sojae during summer (2017) at Entomological farm, B. A. College of Agriculture, Anand Agricultural University, Anand.SKNU-15-01 (17.99%), SKNU-15-02 (18.81%) and SKNU-12-07 (19.48%) registered less infestation of stem fly and emerged as resistant genotypes. The genotypes/cultivars SKNU-13-05 (35.43%), SKNU-12-08 (35.83%) and Rajasthan local (38.26%) proved to be moderately resistant. GU 1 (51.43%), T9 (55.00%), SKNU-13-02 (55.05%), SKNU-12-04 (55.05%), SKNU-15-03 (58.03%) and SKNU-13-03 (59.25%) categorized as moderately susceptible. At the same time, SKNU-11-11 (60.36%) proved to be susceptible against stem fly. Maximum seed yield was harvested from the genotype SKNU-15-02 (833 kg/ha) during Kharif, 2017 followed by SKNU-12-07 (786 kg/ha)
Th1/Th17 cell induction and corresponding reduction in ATP consumption following vaccination with the novel Mycobacterium tuberculosis vaccine MVA85A.
Vaccination with Bacille Calmette-Guérin (BCG) has traditionally been used for protection against disease caused by the bacterium Mycobacterium tuberculosis (M.tb). The efficacy of BCG, especially against pulmonary tuberculosis (TB) is variable. The best protection is conferred in temperate climates and there is close to zero protection in many tropical areas with a high prevalence of both tuberculous and non-tuberculous mycobacterial species. Although interferon (IFN)-γ is known to be important in protection against TB disease, data is emerging on a possible role for interleukin (IL)-17 as a key cytokine in both murine and bovine TB vaccine studies, as well as in humans. Modified Vaccinia virus Ankara expressing Antigen 85A (MVA85A) is a novel TB vaccine designed to enhance responses induced by BCG. Antigen-specific IFN-γ production has already been shown to peak one week post-MVA85A vaccination, and an inverse relationship between IL-17-producing cells and regulatory T cells expressing the ectonucleosidease CD39, which metabolises pro-inflammatory extracellular ATP has previously been described. This paper explores this relationship and finds that consumption of extracellular ATP by peripheral blood mononuclear cells from MVA85A-vaccinated subjects drops two weeks post-vaccination, corresponding to a drop in the percentage of a regulatory T cell subset expressing the ectonucleosidase CD39. Also at this time point, we report a peak in co-production of IL-17 and IFN-γ by CD4(+) T cells. These results suggest a relationship between extracellular ATP and effector responses and unveil a possible pathway that could be targeted during vaccine design
Expansion of anti-AFP Th1 and Tc1 responses in hepatocellular carcinoma occur in different stages of disease
Copyright @ 2010 Cancer Research UK. This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.
To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.Background: α-Fetoprotein (AFP) is a tumour-associated antigen in hepatocellular carcinoma (HCC) and is a target for immunotherapy. However, there is little information on the pattern of CD4 (Th1) and CD8 (Tc1) T-cell response to AFP in patients with HCC and their association with the clinical characteristics of patients.
Methods: We therefore analysed CD4 and CD8 T-cell responses to a panel of AFP-derived peptides in a total of 31 HCC patients and 14 controls, using an intracellular cytokine assay for IFN-γ.
Results: Anti-AFP Tc1 responses were detected in 28.5% of controls, as well as in 25% of HCC patients with Okuda I (early tumour stage) and in 31.6% of HCC patients with stage II or III (late tumour stages). An anti-AFP Th1 response was detected only in HCC patients (58.3% with Okuda stage I tumours and 15.8% with Okuda stage II or III tumours). Anti-AFP Th1 response was mainly detected in HCC patients who had normal or mildly elevated serum AFP concentrations (P=0.00188), whereas there was no significant difference between serum AFP concentrations in these patients and the presence of an anti-AFP Tc1 response. A Th1 response was detected in 44% of HCC patients with a Child–Pugh A score (early stage of cirrhosis), whereas this was detected in only 15% with a B or C score (late-stage cirrhosis). In contrast, a Tc1 response was detected in 17% of HCC patients with a Child–Pugh A score and in 46% with a B or C score.
Conclusion: These results suggest that anti-AFP Th1 responses are more likely to be present in patients who are in an early stage of disease (for both tumour stage and liver cirrhosis), whereas anti-AFP Tc1 responses are more likely to be present in patients with late-stage liver cirrhosis. Therefore, these data provide valuable information for the design of vaccination strategies against HCC.Association for International Cancer Research and Polkemmet Fund, London
Clinic
From-omics to personalized medicine in nephrology: Integration is the key
Large-scale gene, protein and metabolite measurements ('omics') have driven the resolution of biology to an unprecedented high definition. Passing from reductionism to a system-oriented perspective, medical research will take advantage of these high-throughput technologies unveiling their full potential. Integration is the key to decoding the underlying principles that govern the complex functions of living systems. Extensive computational support and statistical modelling is needed to manage and connect the-omic data sets but this, in turn, is speeding up the hypothesis generation in biology enormously and yielding a deep insight into the pathophysiology. This systems biology approach will transform diagnostic and therapeutic strategies with the discovery of novel biomarkers that will enable a predictive and preventive medicine leading to personalized medicine. © 2013 The Author
Molecular docking and molecular dynamics studies of natural products unravel potential inhibitors against OmpA of <i>Acinetobacter baumannii</i>
Emerging antimicrobial resistance has highlighted the need to design more effective antibiotics to treat deadly bacterial infections. Acinetobacter baumannii’s outer membrane protein A (OmpA) is a critical virulence component involved in biofilm formation, immunomodulation, and antibiotic resistance, which characterizes it as a potential therapeutic target. The present study aimed to screen the natural product database (>1,00,000) to identify the potential inhibitor against OmpA. Molecular docking studies revealed that 10 compounds had good docking scores (≤ −7 kcal/mol) compared to the reported inhibitor epiestriol (-3.079). Further, these 10 compounds were subjected to ADME analysis and MMGBSA analysis. Based on MMGBSA results, we selected 5 compounds [NP-1 (MolPort-039-337-117), NP-5(MolPort-019-932-973), NP-6 (MolPort-005-948-336), NP-8(MolPort-042-673-978) and NP-9(MolPort-042-673-766)] with high binding affinity. Molecular dynamics simulation found that NP-5, NP-8, and NP-9 were stable after analysing their RMSD, RMSF, the radius of gyration, and hydrogen interactions of complexes. Our study revealed that NP-5, NP-8, and NP-9 bind perfectly with OmpA and can act as its potential inhibitors. The results of this study imply that the identified inhibitors have the potential for further investigation. Communicated by Ramaswamy H. Sarma</p
Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in mycobacterium tuberculosis–infected individuals
Copyright © 2009 by the American Thoracic Society.Rationale: An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care.
Objectives: To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI.
Methods: An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNγ and IL-2 ELISpot assays and FACS.
Measurements and Main Results: MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-γ and IL-2 response that was durable for 52 weeks. The magnitude of IFN-γ response was comparable to previous trials of MVA85A in bacillus Calmette-Guérin–vaccinated individuals. Antigen 85A–specific polyfunctional CD4+ T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination.
Conclusions: MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas.Oxford Biomedical Research Centre, Wellcome Trust, and AFTBVAC
Eurydice mohani Anil & Jayaraj 2023, sp. nov.
<i>Eurydice mohani</i> sp. nov. <p>(Figures 6–9)</p> <p> <i>Material examined</i></p> <p> <i>Holotype.</i> Male (3.5 mm), sta. Corbyns Cove (low-tide zone), 11.37′483°N, 92.45′140°E, South Andaman, Andaman Islands, intertidal sand, coll. Pathan Anil, 18 November 2016 (Reg. no. PUMB 3585).</p> <p> <i>Paratypes.</i> 1 male (3.4 mm), 3 females (3.3, 3.4, 3.4 mm), same data as holotype (Reg. no. PUMB 3586). 1 male (3.4 mm), 2 females (3.3, 3.4 mm): sta Marina Park (low-tide zone), 11.40′18°N, 092.44′58°E, South Andaman, Andaman Islands, intertidal sand, coll. Pathan Anil, 9 December 2016 (Reg. no. PUMB 3587; Reg. no. BAKRZRL 2704, 2705).</p> <p> <i>Description of male holotype.</i> Body about 2.3 times as long as greatest width; maximum width at pereonites 4 and 6. Cephalon anterior median margin weakly produced, with minute rostral point. Eyes prominent. Coxae 2–3 posteriorly sub-acute with minute setae, posterolateral angles of coxae 6–7 acute with minute setae, not produced. Pleonite 1 concealed by pereonite 7, ventral margins of pleonites 2–4 produced with acute points. Pleotelson about 82% as long as pleon in lateral view; lateral distal margins are sinuate; pleotelson posterior margin 20% of pleotelson anterior width, convex, subtruncate with 6 PMS and 4 RS, dorsally with minute thin setae; anterodorsal surface without distinct depression.</p> <p>Antennula peduncle article 1 anteriorly with 1 simple, 1 pappose setae; article 2 slightly shorter (0.83 times) than 3; article 2 posterodistal angle with 2 simple, 1 pappose setae, anterodistal angle with 1 simple seta; article 3 anterodistal angle with 4 simple short setae; flagellum about 0.8 times as long as peduncle, with 5 articles, article 1 of which is longest, about 1.7 times as long as article 2; flagellum extending to anterior of pereonite 1. Antenna peduncle article 1 dorsal posterior margin with 1 seta, article 2 anterodistal angle with 2 slender simple setae; article 3 short and wide, about 0.9 times as long as wide and about 1.5 times as long as article 2, anterior margin with 8 simple long setae, posterior distal margin with 1 simple long seta; article 4 longest about 2.3 times as long as 3, anterior margin with 4 clusters of 2, 2, 2 and 2 simple long setae, posterior margin with 3 long simple setae and 1 brush-tipped seta; flagellum extending to mid-pereonite 5, composed of about 12 articles.</p> <p>Frontal lamina distinct; clypeus blade prominent. Mandible spine row with 7 spines; molar process anterior margin with about 21 teeth; article 2 with 4 simple long setae; article 3 apically with 3 simple long setae. Maxillule lateral lobe with 12 RS, medial lobe with 3 CPS and 1 simple seta. Maxilla lateral lobe with 3 stiff simple setae, middle lobe with 5 weakly serrate setae, medial lobe with 5 simple setae and 3 CPS. Maxilliped article 2 medial distal margin with 5 long setae, lateral margin with 1 long seta; article 3 medial distal margin with 4 long setae, lateral margin with 1 long seta; article 4 medial distal margin with 4 long setae, lateral margin with 1 long seta; article 5 apically 6 long setae; endite with 1 CPS and 3 simple setae.</p> <p>Pereopod 1 basis 3.3 times as long as greatest width, superior proximal margin with 3 small sensory palmate setae, distal margin with 3 long setae, inferior margin with 10 long setae; ischium 0.7 times as long as basis, superior distal margin with 8 long setae, dorsal posterior margin with 3 long setae, inferior margin with 8 long setae; merus inferior margin with 3 RS and 7 long setae, dorsal medial margin with 2 simple long setae and 1 short RS, superior distal margin with 6 long setae; carpus inferior margin with 1 RS and 6 simple long setae; propodus 3.8 times as long as width, inferior margin with 3 RS and 9 long setae; dactylus about half as long as propodus, robust seta opposing dactylus extending to accessory unguis; accessory unguis slender, 0.8 times length of unguis.</p> <p>Pereopod 2 basis about 3.9 times as long as wide, superior margin with 3 small sensory palmate setae, inferior distal angle with 18 long setae; ischium 2.2 times as long as basis, inferior margin with 2 RS and 11 long setae,dorsal posterior margin with 4 long setae,superior distal margin with 8 long setae; merus inferior margin with 5 RS and 9 long setae, superior distal angle with 8 long setae; carpus inferior distal angle with 2 RS and 5 long setae;propodus 4.1 times as long as width, inferior margin with 3 RS and 8 long setae, dorsal posterior margin with 1 short RS; dactylus about half as long as propodus; robust seta opposing dactylus extending to accessory unguis; accessory unguis 0.9 times length of unguis.</p> <p>Pereopod 3 basis superior margin with 3 small sensory palmate setae, inferior margin with 13 long setae; ischium inferior margin with 2 RS and 12 long setae, dorsal medial margin with 5 long setae, superior distal angle with 9 long setae; merus inferior margin with 6 RS and 9 long setae, superior distal angle with 7 long setae; carpus inferior distal angle with 2 RS and 5 long setae; propodus inferior margin with 3 RS and 10 long setae; dactylus less than half as long as propodus; robust seta opposing dactylus extending near to accessory unguis. Pereopods 5–7 similar to each other.</p> <p>Pereopod 6 basis 5.6 times as long as wide, superior margin with 2 small sensory palmate setae and 6 long setae, inferior margin with 13 long setae; ischium 0.8 times as long as basis, inferior margin with 15 RS and 11 long setae, superior margin with 4 RS and 11 long setae; merus 0.5 times as long as ischium, 1.8 times as long as wide, inferior margin with 5 RS and 2 long setae, superior margin with 4 RS and 7 long setae; carpus 0.9 times as long as ischium, 2.5 times as long as wide, inferior margin with 6 RS, 1 uni-serrate seta and 1 long seta, superior margin with 5 RS, 1 uni-serrate seta and 4 simple long setae; propodus 0.6 times as long as ischium, 4.9 times as long as wide, inferior margin with 10 RS and 2 long setae, superior margin with 5 RS and 4 long setae; dactylus 0.6 times as long as propodus.</p> <p>Pereopod 7 basis 5.8 times as long as wide, superior margin with 4 small sensory palmate setae and 3 long setae, inferior margin with 10 long setae and 1 long uni-serrate seta; ischium 0.9 times as long as basis, inferior margin with 7 RS and 11 long setae, superior margin with 3 RS and 9 long setae; merus 0.7 times as long as ischium, 1.9 times as long as wide, inferior margin with 4 RS, 3 bi-serrate setae and 3 long setae, superior margin with 2 bi-serrate setae, 1 RS and 5 long setae; carpus 0.9 times as long as ischium, 2.7 times as long as wide, inferior margin with 6 RS, 1 bi-serrate seta and 6 long setae, superior margin with 7 RS, 1 uni-serrate seta and 4 long setae; propodus 0.8 times as long as ischium, 5.1 times as long as wide, inferior margin with 14 RS and 1 bi-serrate seta, superior margin with 10 RS and 8 long setae.</p> <p>Penes 1.6 times as long as basal width, distal margin rounded.</p> <p>Pleopod 1 exopod 1.6 times as long as wide, lateral margin weakly convex, distally narrowly rounded with oblique medial margin, mesial margin strongly convex, with PMS from distal one-fourth, with 20 PMS; endopod 2.2 times as long as wide, distally narrowly rounded, lateral margin weakly convex, with PMS from distal one-third, mesial margin with PMS from distal one-sixth, endopod with 10 PMS; peduncle 0.8 times as wide as long, mesial margin with 4 coupling setae, 2 plumose setae and 1 short setae. Pleopod 2 exopod with 20 PMS, endopod with 9 PMS; appendix masculina arises from medial margin of the endopod, lateral margin with a sinuate notch and apex is rounded, appendix masculina 0.4 times as long as endopod, projecting beyond mid-region of endopod by 0.02 of its length. Pleopod 3 exopod with 20 PMS, endopod with 9 PMS. Pleopod 4 exopod with 24 PMS, endopod with 8 PMS. Pleopod 5 exopod with 22 PMS. Pleopods 3–5 exopods with complete sutures.</p> <p>Uropod peduncle lateral margin with 5 stiff PMS and 1 RS; exopod rounded, about 0.9 times as long as length of endopod lateral margin, medial margin with about 12 PMS and 3 RS; endopod lateral margin straight, with 2 setae, medial margin obliquely truncate, with 2 small RS and 20 PMS.</p> <p> <i>Female.</i> As for male but body slightly broader, about 1.5 times as long as greatest width; antennulae shorter reaching mid-region of the eye; antennae shorter, reaching posterior margin of pereonite 4; pleotelson about 80% as long as pleon in lateral view.</p> <p> <i>Colour.</i> Body white; black chromatophores occur densely on the dorsal surface of the pereion, pleon and pleotelson.</p> <p> <i>Remarks.</i> <i>Eurydice mohani</i> sp. nov. can be identified by the pleotelson posterior margin being 20% of pleotelson anterior width, with 6 plumose marginal setae, anterodorsal surface without distinct depression; appendix masculina 0.4 times as long as endopod, projecting beyond mid-region of endopod by 0.02 of its length, lateral margin with a sinuate notch and apex is rounded; the antennal flagellum is relatively short, extending to mid-length of pereonite 5.</p> <p> <i>Eurydice mohani</i> sp. nov. is separated from <i>Eurydice andamanensis</i> sp. nov. by the antennula flagellum extending to anterior of pereonite 1 (vs posterior of pereonite 1), posterior margin of pleotelson one-fifth of pleotelson anterior width, with 6 plumose marginal setae (vs one-fourth and 11 plumose marginal setae), pleotelson anterodorsal surface without distinct depression (vs distinct depression), appendix masculina lateral margin with a sinuate notch (vs lacking), appendix masculina 0.4 times as long as endopod, projecting beyond mid-region of endopod by 0.02 of its length (vs 0.8 long as endopod, projecting slightly beyond by one-third of its length), uropodal exopod medial margin rounded (vs obliquely subtruncate).</p> <p> <i>Eurydice mohani</i> sp. nov. is similar to <i>Eurydice barnardi</i> Bruce and Soares, 1996, which was described from the Atlantic coast of South Africa and shares some characters such as cephalon anterior median margin with minute rostral point, coxae 2–3 posteriorly sub-acute, posterolateral angles of coxae 6–7 acute, not produced, and pleotelson anterodorsal surface without depression, but <i>E. mohani</i> sp. nov. differs from <i>E. barnardi</i> in the pleotelson posterior margin 20% of width (vs 5% of width), pleotelson posterior margin with 4 robust setae and 6 plumose marginal setae (vs 2 robust setae and 3 plumose marginal setae), appendix masculina lateral margin with sinuate notch (vs lacking).</p> <p> <i>Eurydice mohani</i> sp. nov. can be separated from <i>Eurydice indicis</i> by convex pleotelson posterior margin, with 6 plumose marginal setae (vs straight with 8 plumose marginal setae), pleotelson anterodorsal surface without distinct depression (vs distinct depression), appendix masculina lateral margin with sinuate notch (vs lacking notch).</p> <p> <i>Eurydice mohani</i> sp. nov. also differs from <i>Eurydice peraticis</i> in pleotelson posterior margin convex with 6 plumose marginal setae (vs almost straight with 13 plumose marginal setae), appendix masculina lateral margin with sinuate notch (vs lacking notch).</p> <p> <i>Distribution.</i> Known only from the type locality: South Andaman, Andaman Islands.</p> <p> <i>Etymology.</i> This species is named in honour of Dr P.M. Mohan, Professor, Department of Ocean Studies and Marine Biology, Pondicherry Central University, the DC member of the first author (Pathan Anil) and a well-known benthologist, taxonomist and ecologist in India.</p>Published as part of <i>Anil, Pathan & Jayaraj, K. A., 2023, Two new species of Eurydice Leach, 1815 (Crustacea: Isopoda: Cirolanidae) from the Andaman Islands, northern Indian Ocean, pp. 976-995 in Journal of Natural History 57 (13 - 16)</i> on pages 986-993, DOI: 10.1080/00222933.2021.2017046, <a href="http://zenodo.org/record/8221408">http://zenodo.org/record/8221408</a>
Roles for Treg expansion and HMGB1 signaling through the TLR1-2-6 axis in determining the magnitude of the antigen-specific immune response to MVA85A
© 2013 Matsumiya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedA better understanding of the relationships between vaccine, immunogenicity and protection from disease would greatly facilitate vaccine development. Modified vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel tuberculosis vaccine candidate designed to enhance responses induced by BCG. Antigen-specific interferon-γ (IFN-γ) production is greatly enhanced by MVA85A, however the variability between healthy individuals is extensive. In this study we have sought to characterize the early changes in gene expression in humans following vaccination with MVA85A and relate these to long-term immunogenicity. Two days post-vaccination, MVA85A induces a strong interferon and inflammatory response. Separating volunteers into high and low responders on the basis of T cell responses to 85A peptides measured during the trial, an expansion of circulating CD4+ CD25+ Foxp3+ cells is seen in low but not high responders. Additionally, high levels of Toll-like Receptor (TLR) 1 on day of vaccination are associated with an increased response to antigen 85A. In a classification model, combined expression levels of TLR1, TICAM2 and CD14 on day of vaccination and CTLA4 and IL2Rα two days post-vaccination can classify high and low responders with over 80% accuracy. Furthermore, administering MVA85A in mice with anti-TLR2 antibodies may abrogate high responses, and neutralising antibodies to TLRs 1, 2 or 6 or HMGB1 decrease CXCL2 production during in vitro stimulation with MVA85A. HMGB1 is released into the supernatant following atimulation with MVA85A and we propose this signal may be the trigger activating the TLR pathway. This study suggests an important role for an endogenous ligand in innate sensing of MVA and demonstrates the importance of pattern recognition receptors and regulatory T cell responses in determining the magnitude of the antigen specific immune response to vaccination with MVA85A in humans.This work was funded by the Wellcome Trust. MM has a Wellcome Trust PhD studentship and HM is a Wellcome Trust Senior Fello
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