To bnAb or Not to bnAb: Defining Broadly Neutralising Antibodies Against HIV-1

Since their discovery, antibodies capable of broad neutralisation have been at the forefront of HIV-1 research and are of particular interest due to in vivo passive transfer studies demonstrating their potential to provide protection. Currently an exact definition of what is required for a monoclonal antibody to be classed as a broadly neutralising antibody (bnAb) has not yet been established. This has led to hundreds of antibodies with varying neutralisation breadth being studied and has given insight into antibody maturation pathways and epitopes targeted. However, even with this knowledge, immunisation studies and vaccination trials to date have had limited success in eliciting antibodies with neutralisation breadth. For this reason there is a growing need to identify factors specifically associated with bnAb development, yet to do this a set of criteria is necessary to distinguish bnAbs from non-bnAbs. This review aims to define what it means to be a HIV-1 bnAb by comparing neutralisation breadth, genetic features and epitopes of bnAbs, and in the process highlights the challenges of comparing the array of antibodies that have been isolated over the years

Spatial weights : constructing weight-compatible exchange matrices from proximity matrices

Exchange matrices represent spatial weights as symmetric probability distributions on pairs of regions, whose margins yield regional weights, generally well-specified and known in most contexts. This contribution proposes a mechanism for constructing exchange matrices, derived from quite general symmetric proximity matrices, in such a way that the margin of the exchange matrix coincides with the regional weights. Exchange matrices generate in turn diffusive squared Euclidean dissimilarities, measuring spatial remoteness between pairs of regions. Unweighted and weighted spatial frameworks are reviewed and compared, regarding in particular their impact on permutation and normal tests of spatial autocorrelation. Applications include tests of spatial autocorrelation with diagonal weights, factorial visualization of the network of regions, multivariate generalizations of Moran's I, as well as "landscape clustering", aimed at creating regional aggregates both spatially contiguous and endowed with similar features

Occurrence of nontuberculous mycobacteria in aquatic sources of Sri Lanka

AbstractNontuberculous mycobacteria (NTM) have been reported to cause opportunistic infections with increasing frequency, especially in immunocompromised patients. Water plays a major role in the epidemiology of nontuberculous mycobacterial infection in humans, as it is one of the natural sources for transmission of this group of organisms. The current study focused on determining the occurrence of NTM in different aquatic sources of Sri Lanka by using phenotypic tests and polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) analysis of the rpoβ gene. Of 290 water samples, 45 (15%) were positive for NTM on culture. The percentage of mycobacteria identified at species level by phenotypic tests and PCR–RFLP analysis were 44% (20/45) and 73% (33/45), respectively. The frequency of isolation of mycobacteria from aquarium water, surface water, ground water and chlorinated water were 29% (20/70), 26% (20/76), 5% (4/76) and 1% (1/68), respectively. Eleven different NTM species were identified by PCR–RFLP analysis. M. fortuitum type I was the most frequently isolated species from all the four water sources. The current study suggests that water is an environmental source harboring NTM, a potential public health hazard especially for those with immunodeficiency

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Immune Dysregulation and Pathobiology Working Group Report

Immune reconstitution after hematopoietic stem cell transplantation (HCT) beyond 1 year is not completely understood. Many transplant recipients who are free of graft-versus-host disease (GVHD) and not receiving any immunosuppression more than 1 year after transplantation seem to be able to mount appropriate immune responses to common pathogens and respond adequately to immunizations. However, 2 large registry studies over the last 2 decades seem to indicate that infection is a significant cause of late mortality in some patients, even in the absence of concomitant GVHD. Research on this topic is particularly challenging for several reasons. First, there are not enough long-term follow-up clinics able to measure even basic immune parameters late after HCT. Second, the correlation between laboratory measurements of immune function and infections is not well known. Third, accurate documentation of infectious episodes is notoriously difficult. Finally, it is unclear what measures can be implemented to improve the immune response in a clinically relevant way. A combination of long-term multicenter prospective studies that collect detailed infectious data and store samples as well as a national or multinational registry of clinically significant infections (eg, vaccine-preventable severe infections, opportunistic infections) could begin to address our knowledge gaps. Obtaining samples for laboratory evaluation of the immune system should be both calendar and eventdriven. Attention to detail and standardization of practices regarding prophylaxis, diagnosis, and definitions of infections would be of paramount importance to obtain clean reliable data. Laboratory studies should specifically address the neogenesis, maturation, and exhaustion of the adaptive immune system and, in particular, how these are influenced by persistent alloreactivity, inflammation, and viral infection. Ideally, some of these long-term prospective studies would collect information on long-term changes in the gut microbiome and their influence on immunity. Regarding enhancement of immune function, prospective measurement of the response to vaccines late after HCT in a variety of clinical settings should be undertaken to better understand the benefits as well as the limitations of immunizations. The role of intravenous immunoglobulin is still not well defined, and studies to address it should be encouraged

Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

Background: The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method: 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results: Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n=4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8+/-5.9 vs 59+/-2.0 mmHg), increased cardiac output (7.26+/-1.86 vs 3.30+/-0.40 l/min) and decreased systemic vascular resistance (8.48+/-2.75 vs 16.2+/-1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636+/-95 vs 301+/-26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23+/-0.05 vs 7.45+/-0.02) and prothrombin time (36+/-2 vs 8.9+/-0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5+/-210 vs 42+/-8.14) coincided with a marked reduction in serum albumin (11.5+/-1.71 vs 25+/-1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2+/-36.5 vs 131.6+/-9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. Conclusion: We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems

A deep search for 21cm absorption in high redshift damped Lyman-α\alpha systems

We present deep GMRT 21cm absorption spectra of 10 damped Lyman-$\alpha$ systems (DLAs), of which 8 are at redshifts z \ga 1.3. HI absorption was detected in only one DLA, the $z = 0.5318$ absorber toward PKS 1629+12, which has been identified with a luminous spiral galaxy; the spin temperature limit ($T_s \le 310$ K) derived from our observations continues the trend of DLAs associated with bright spirals having low spin temperatures. In 7 of the remaining 9 systems, the observations place strong lower limits on the spin temperature of the HI gas. The sample of DLAs searched for 21cm absorption now consists of 31 systems, with $T_s$ estimates available in 24 cases; of these, 16 are at $z < 2$ and 8 at $z > 2$, with 11 (all at $z < 1$) having optical IDs. For the latter 11 systems, we find that all low $T_s$ DLAs have been identified with luminous galaxies, while all high $T_s$ (T_s \ga 1000 K) DLAs have been identified with either LSBs or dwarfs. DLA spin temperatures thus appear to correlate with galaxy type, with no correlation seen between $T_s$ and impact parameter. The trend that low $z$ DLAs exhibit both high and low $T_s$ values while high redshift (z \ga 3) DLAs only show high spin temperatures is present in this expanded data set. Based on this difference in spin temperatures, the Gehan test rules out the hypothesis that DLAs at $z > 2$ and DLAs at $z < 2$ are drawn from the same parent population at ~ 99 % confidence level. Finally, we estimate upper limits on the fraction of cold HI, $f_{CNM}$, in the z \ga 3 DLAs. In local spirals, $f_{CNM} \sim 0.5$; in contrast, we find that $f_{CNM} < 0.3$ in all 7 high $z$ DLAs, with $f_{CNM} < 0.1$ in 5 of the 7 cases. (abridged)Comment: 13 pages, 5 figures. Accepted for publication in Astronomy & Astrophysic

NOX Enzymes and Pulmonary Disease

Abstract The primary function of the lung is to facilitate the transfer of molecular oxygen (O2; dioxygen) from the atmosphere to the systemic circulation. In addition to its essential role in aerobic metabolism, O2 serves as the physiologic terminal acceptor of electron transfer catalyzed by the NADPH oxidase (NOX) family of oxidoreductases. The evolution of the lungs and circulatory systems in vertebrates was accompanied by increasing diversification of NOX family enzymes, suggesting adaptive roles for NOX-derived reactive oxygen species in normal physiology. However, this adaptation may paradoxically carry detrimental consequences in the setting of overwhelming/persistent environmental stressors, both infectious and noninfectious, and during the process of aging. Here, we review current understanding of NOX enzymes in normal lung physiology and their pathophysiologic roles in a number of pulmonary diseases, including lung infections, acute lung injury, pulmonary arterial hypertension, obstructive lung disorders, fibrotic lung disease, and lung cancer. Antioxid. Redox Signal. 11, 2505-2516.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78108/1/ars.2009.2599.pd

Yukawa Textures From Heterotic Stability Walls

A holomorphic vector bundle on a Calabi-Yau threefold, X, with h^{1,1}(X)>1 can have regions of its Kahler cone where it is slope-stable, that is, where the four-dimensional theory is N=1 supersymmetric, bounded by "walls of stability". On these walls the bundle becomes poly-stable, decomposing into a direct sum, and the low energy gauge group is enhanced by at least one anomalous U(1) gauge factor. In this paper, we show that these additional symmetries can strongly constrain the superpotential in the stable region, leading to non-trivial textures of Yukawa interactions and restrictions on allowed masses for vector-like pairs of matter multiplets. The Yukawa textures exhibit a hierarchy; large couplings arise on the stability wall and some suppressed interactions "grow back" off the wall, where the extended U(1) symmetries are spontaneously broken. A number of explicit examples are presented involving both one and two stability walls, with different decompositions of the bundle structure group. A three family standard-like model with no vector-like pairs is given as an example of a class of SU(4) bundles that has a naturally heavy third quark/lepton family. Finally, we present the complete set of Yukawa textures that can arise for any holomorphic bundle with one stability wall where the structure group breaks into two factors.Comment: 53 pages, 4 figures and 13 table

Plasmodium falciparum Malaria and Atovaquone-Proguanil Treatment Failure

We noticed overrepresentation of atovaquone-proguanil therapeutic failures among Plasmodium falciparum–infected travelers weighing >100 kg. We report here 1 of these cases, which was not due to resistant parasites or impaired drug bioavailability. The follow-up of such patients should be strengthened