Mechanical Activation of Al-Oxyhydroxide Minerals – Physicochemical Changes, Reactivity and Relevance to Bayer Process

Overview of our research on ‘structure and reactivity’ of gibbsite and boehmite under varied conditions of mechanical activation, e.g. milling energy and presence of a second phase is presented. Bulk and surface changes induced in the solids by milling are characterized in terms of morphology, particle size distribution, specific surface area and nature of porosity, crystallite size and zeta potential. Results on enhanced amorphisation of gibbsite in presence of a second phase (quartz, hematite etc), changes in zeta potential of gibbsite due to loss of texture during milling and anomalous decrease in surface area of boehmite during milling are reported. Reactivity of the activated solids in sodium hydroxide and variation in thermal transformation temperatures is correlated with physicochemical characteristics of the samples and plausible explanation for the observed correlations presented. Significance of the results with specific reference to bauxite and alumina processing in Bayer process is highlighted

CD161 contributes to prenatal immune suppression of IFNγ-producing PLZF^{+} T cells

BACKGROUND: While the human fetal immune system defaults to a program of tolerance, there is a concurrent need for protective immunity to meet the antigenic challenges encountered after birth. Activation of T cells in utero is associated with the fetal inflammatory response, with broad implications for the health of the fetus and of the pregnancy. However, the characteristics of the fetal effector T cells that contribute to this process are largely unknown. METHODS: We analyzed primary human fetal lymphoid and mucosal tissues and performed phenotypic, functional, and transcriptional analysis to identify T cells with proinflammatory potential. The frequency and function of fetal-specific effector T cells was assessed in the cord blood of infants with localized and systemic inflammatory pathologies and compared with that of healthy term controls. RESULTS: We identified a transcriptionally distinct population of CD4^{+} T cells characterized by expression of the transcription factor promyelocytic leukemia zinc finger (PLZF). PLZF^{+}CD4^{+} T cells were specifically enriched in the fetal intestine, possessed an effector memory phenotype, and rapidly produced proinflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFN-γ in a fetal-specific manner. IFN-γ–producing PLZF^{+}CD4^{+} T cells were enriched in the cord blood of infants with gastroschisis, a natural model of chronic inflammation originating from the intestine, as well as in preterm birth, suggesting these cells contribute to fetal systemic immune activation. CONCLUSION: Our work reveals a fetal-specific program of protective immunity whose dysregulation is associated with fetal and neonatal inflammatory pathologies. FUNDING: This work was supported by the UCSF Clinical and Translational Science Institute (CTSI) Pilot Award for Basic and Translational Investigators (2014908), UCSF (K12HD072222), the NIAID (K08 AI128007 and 1F31AI136336-01), a National Science Foundation (NSF) Graduate Research Fellowship (1650113 ), and an Academy for Medical Sciences Clinical Lecturer grant (535274)

Could Seals Prevent Cod Recovery in the Baltic Sea?

Fish populations are increasingly affected by multiple human and natural impacts including exploitation, eutrophication, habitat alteration and climate change. As a result many collapsed populations may have to recover in ecosystems whose structure and functioning differ from those in which they were formerly productive and supported sustainable fisheries. Here we investigate how a cod (Gadus morhua) population in the Baltic Sea whose biomass was reduced due to a combination of high exploitation and deteriorating environmental conditions might recover and develop in the 21st century in an ecosystem that likely will change due to both the already started recovery of a cod predator, the grey seal Halichoerus grypus, and projected climate impacts. Simulation modelling, assuming increased seal predation, fishing levels consistent with management plan targets and stable salinity, shows that the cod population could reach high levels well above the long-term average. Scenarios with similar seal and fishing levels but with 15% lower salinity suggest that the Baltic will still be able to support a cod population which can sustain a fishery, but biomass and yields will be lower. At present knowledge of cod and seal interactions, seal predation was found to have much lower impact on cod recovery, compared to the effects of exploitation and salinity. These results suggest that dual management objectives (recovery of both seal and cod populations) are realistic but success in achieving these goals will also depend on how climate change affects cod recruitment

The long-term prediction of return to work following serious accidental injuries: A follow up study

Background Considerable indirect costs are incurred by time taken off work following accidental injuries. The aim of this study was to predict return to work following serious accidental injuries. Method 121 severely injured patients were included in the study. Complete follow-up data were available for 85 patients. Two weeks post trauma (T1), patients rated their appraisal of the injury severity and their ability to cope with the injury and its job-related consequences. Time off work was assessed at one (T2) and three years (T3) post accident. The main outcome was the number of days of sick leave taken due to the accidental injury. Results The patients' appraisals a) of the injury severity and b) of their coping abilities regarding the accidental injury and its job-related consequences were significant predictors of the number of sick-leave days taken. Injury severity (ISS), type of accident, age and gender did not contribute significantly to the prediction. Conclusions Return to work in the long term is best predicted by the patients' own appraisal of both their injury severity and the ability to cope with the accidental injury

Effects of the search technique on the measurement of the change in quality of randomized controlled trials over time in the field of brain injury

BACKGROUND: To determine if the search technique that is used to sample randomized controlled trial (RCT) manuscripts from a field of medical science can influence the measurement of the change in quality over time in that field. METHODS: RCT manuscripts in the field of brain injury were identified using two readily-available search techniques: (1) a PubMed MEDLINE search, and (2) the Cochrane Injuries Group (CIG) trials registry. Seven criteria of quality were assessed in each manuscript and related to the year-of-publication of the RCT manuscripts by regression analysis. RESULTS: No change in the frequency of reporting of any individual quality criterion was found in the sample of RCT manuscripts identified by the PubMed MEDLINE search. In the RCT manuscripts of the CIG trials registry, three of the seven criteria showed significant or near-significant increases over time. CONCLUSIONS: We demonstrated that measuring the change in quality over time of a sample of RCT manuscripts from the field of brain injury can be greatly affected by the search technique. This poorly recognized factor may make measurements of the change in RCT quality over time within a given field of medical science unreliable

Stable isotope evidence for late medieval (14th-15th C) origins of the eastern Baltic cod (Gadus morhua) fishery

Although recent historical ecology studies have extended quantitative knowledge of eastern Baltic cod (Gadus morhua) exploitation back as far as the 16th century, the historical origin of the modern fishery remains obscure. Widespread archaeological evidence for cod consumption around the eastern Baltic littoral emerges around the 13th century, three centuries before systematic documentation, but it is not clear whether this represents (1) development of a substantial eastern Baltic cod fishery, or (2) large-scale importation of preserved cod from elsewhere. To distinguish between these hypotheses we use stable carbon and nitrogen isotope analysis to determine likely catch regions of 74 cod vertebrae and cleithra from 19 Baltic archaeological sites dated from the 8th to the 16th centuries. δ¹³C and δ¹⁵N signatures for six possible catch regions were established using a larger sample of archaeological cod cranial bones (n = 249). The data strongly support the second hypothesis, revealing widespread importation of cod during the 13th to 14th centuries, most of it probably from Arctic Norway. By the 15th century, however, eastern Baltic cod dominate within our sample, indicating the development of a substantial late medieval fishery. Potential human impact on cod stocks in the eastern Baltic must thus be taken into account for at least the last 600 years.The research was funded by the Leverhulme Trust (grant no. F/00 224/S), the History of Marine Animal Populations project (supported by the Alfred P. Sloan Foundation) and the McDonald Institute for Archaeological Research

Purine Nucleoside Phosphorylase mediated molecular chemotherapy and conventional chemotherapy: A tangible union against chemoresistant cancer

Background Late stage Ovarian Cancer is essentially incurable primarily due to late diagnosis and its inherent heterogeneity. Single agent treatments are inadequate and generally lead to severe side effects at therapeutic doses. It is crucial to develop clinically relevant novel combination regimens involving synergistic modalities that target a wider repertoire of cells and lead to lowered individual doses. Stemming from this premise, this is the first report of two- and three-way synergies between Adenovirus-mediated Purine Nucleoside Phosphorylase based gene directed enzyme prodrug therapy (PNP-GDEPT), docetaxel and/or carboplatin in multidrug-resistant ovarian cancer cells. Methods The effects of PNP-GDEPT on different cellular processes were determined using Shotgun Proteomics analyses. The in vitro cell growth inhibition in differentially treated drug resistant human ovarian cancer cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The involvement of apoptosis and implicated proteins in effects of different treatments was established using flow cytometry based detection of M30 (an early marker of apoptosis), cell cycle analyses and finally western blot based analyses. Results Efficacy of the trimodal treatment was significantly greater than that achieved with bimodal- or individual treatments with potential for 10-50 fold dose reduction compared to that required for individual treatments. Of note was the marked enhancement in apoptosis that specifically accompanied the combinations that included PNP-GDEPT and accordingly correlated with a shift in the expression of anti- and pro-apoptotic proteins. PNP-GDEPT mediated enhancement of apoptosis was reinforced by cell cycle analyses. Proteomic analyses of PNP-GDEPT treated cells indicated a dowregulation of proteins involved in oncogenesis or cancer drug resistance in treated cells with accompanying upregulation of apoptotic- and tumour- suppressor proteins. Conclusion Inclusion of PNP-GDEPT in regular chemotherapy regimens can lead to significant enhancement of the cancer cell susceptibility to the combined treatment. Overall, these data will underpin the development of regimens that can benefit patients with late stage ovarian cancer leading to significantly improved efficacy and increased quality of life

Ivermectin treatment of Loa loa hyper-microfilaraemic baboons (Papio anubis): Assessment of microfilarial loads, haematological and biochemical parameters and histopathological changes following treatment.

Individuals with high intensity of Loa loa are at risk of developing serious adverse events (SAEs) post treatment with ivermectin. These SAEs have remained unclear and a programmatic impediment to the advancement of community directed treatment with ivermectin. The pathogenesis of these SAEs following ivermectin has never been investigated experimentally. The Loa/baboon (Papio anubis) model can be used to investigate the pathogenesis of Loa-associated encephalopathy following ivermectin treatment in humans. 12 baboons with microfilarial loads > 8,000mf/mL of blood were randomised into four groups: Group 1 (control group receiving no drug), Group 2 receiving ivermectin (IVM) alone, Group 3 receiving ivermectin plus aspirin (IVM + ASA), and Group 4 receiving ivermectin plus prednisone (IVM + PSE). Blood samples collected before treatment and at Day 5, 7 or 10 post treatment, were analysed for parasitological, hematological and biochemical parameters using standard techniques. Clinical monitoring of animals for side effects took place every 6 hours post treatment until autopsy. At autopsy free fluids and a large number of standard organs were collected, examined and tissues fixed in 10% buffered formalin and processed for standard haematoxylin-eosin staining and specific immunocytochemical staining. Mf counts dropped significantly (p0.05). All animals became withdrawn 48 hours after IVM administration. All treated animals recorded clinical manifestations including rashes, itching, diarrhoea, conjunctival haemorrhages, lymph node enlargement, pinkish ears, swollen face and restlessness; one animal died 5 hours after IVM administration. Macroscopic changes in post-mortem tissues observed comprised haemorrhages in the brain, lungs, heart, which seen in all groups given ivermectin but not in the untreated animals. Microscopically, the major cellular changes seen, which were present in all the ivermectin treated animals included microfilariae in varying degrees of degeneration in small vessels. These were frequently associated with fibrin deposition, endothelial changes including damage to the integrity of the blood vessel and the presence of extravascular erythrocytes (haemorrhages). There was an increased presence of eosinophils and other chronic inflammatory types in certain tissues and organs, often in large numbers and associated with microfilarial destruction. Highly vascularized organs like the brain, heart, lungs and kidneys were observed to have more microfilariae in tissue sections. The number of mf seen in the brain and kidneys of animals administered IVM alone tripled that of control animals. Co-administration of IVM + PSE caused a greater increase in mf in the brain and kidneys while the reverse was noticed with the co-administration of IVM + ASA. The treatment of Loa hyper-microfilaraemic individuals with ivermectin produces a clinical spectrum that parallels that seen in Loa hyper-microfilaraemic humans treated with ivermectin. The utilization of this experimental model can contribute to the improved management of the adverse responses in humans

A Dynamic Landscape for Antibody Binding Modulates Antibody-Mediated Neutralization of West Nile Virus

Neutralizing antibodies are a significant component of the host's protective response against flavivirus infection. Neutralization of flaviviruses occurs when individual virions are engaged by antibodies with a stoichiometry that exceeds a required threshold. From this “multiple-hit” perspective, the neutralizing activity of antibodies is governed by the affinity with which it binds its epitope and the number of times this determinant is displayed on the surface of the virion. In this study, we investigated time-dependent changes in the fate of West Nile virus (WNV) decorated with antibody in solution. Experiments with the well-characterized neutralizing monoclonal antibody (MAb) E16 revealed a significant increase in neutralization activity over time that could not be explained by the kinetics of antibody binding, virion aggregation, or the action of complement. Additional kinetic experiments using the fusion-loop specific MAb E53, which has limited neutralizing activity because it recognizes a relatively inaccessible epitope on mature virions, identified a role of virus “breathing” in regulating neutralization activity. Remarkably, MAb E53 neutralized mature WNV in a time- and temperature-dependent manner. This phenomenon was confirmed in studies with a large panel of MAbs specific for epitopes in each domain of the WNV envelope protein, with sera from recipients of a live attenuated WNV vaccine, and in experiments with dengue virus. Given enough time, significant inhibition of infection was observed even for antibodies with very limited, or no neutralizing activity in standard neutralization assays. Together, our data suggests that the structural dynamics of flaviviruses impacts antibody-mediated neutralization via exposure of otherwise inaccessible epitopes, allowing for antibodies to dock on the virion with a stoichiometry sufficient for neutralization