A bedaquiline, pyrazinamide, levofloxacin, linezolid, clofazimine second line regimen for tuberculosis displays similar early bactericidal activity as the standard rifampin based first line regimen.

BACKGROUND: In 2018 the World Health Organization (WHO) recommended a switch to an all oral bedaquiline based second line regimen for treatment of drug resistant (DR) tuberculosis (TB). How these new second line regimens fare in comparison to first line regimens for treatment of drug sensitive (DS) tuberculosis is not well known. METHODS: In this study, we contemporaneously enrolled subjects with DS (n = 31) and DR (n = 23) TB and assessed their response to therapy with first-line (rifampin, isoniazid, ethambutol, pyrazinamide) or second-line (bedaquiline, pyrazinamide, levofloxacin, linezolid, clofazimine) regimens, respectively. RESULTS: We found that the early bactericidal activity of first and second line regimens was similar during the first two weeks of therapy as determined by BACTEC MGIT, colony forming units (CFU), and a liquid limiting dilution (LD) assays capable of detecting differentially detectable/culturable Mtb (DD Mtb). Further, an identical percentage (77.8%) of subjects from the DS and DR cohorts converted to culture negative after two months of therapy. CONCLUSIONS: Despite presenting with more advanced disease at time of treatment, subjects with DR TB receiving an all oral bedaquiline based second line treatment regimen displayed a similar microbiological response to therapy as subjects with DS TB receiving a first-line treatment regimen.

Genetic and environmental effects on processing productivity and food product yield: drudgery of women's work.

BACKGROUND: Cassava processing is a crucial source of livelihood for rural farmers and processors in Nigeria and Cameroon. This study investigated the varietal effect on the processing productivity of women farmer processors within their working environment and compared this with the food product quality as evaluated by the processors and the field yield. Field trials were established in Nigeria (Benue and Osun state) and Cameroon (Littoral region). Eight cassava genotypes were evaluated. These eight varieties included newly bred genotypes, commercial checks and varieties provided and preferred by the processors. The roots of these genotypes were harvested and processed into gari and eba by processors. The time of each processing step was recorded. Processors assessed the quality of the roots and food products using pairwise ranking. RESULTS: In the field trials in Cameroon and Nigeria (Benue state), the newly bred genotypes showed superior performance in terms of dry matter content and fresh and dry yield. During processing, genotypes showed significant variation for most assessed parameters in both countries. Some newly bred varieties exhibited lower productivity that can make them more prone to drudgery than the local commercial checks and the varieties provided and preferred by the processors. Newly bred varieties were mostly ranked higher or equal to processors' preferred varieties concerning fresh root and food product quality. In the Cameroon location there were significant varietal differences in processing productivity and drudgery index which suggest that the particular processing methods there - such as pressing methods and fermentation time - cause these varietal differences to matter more. CONCLUSIONS: The varieties that were tested were observed to differ in yield, product quality, processing productivity, and potential drudgery levels. Some breeders' germplasms displayed a combination of increased yields and good product quality and good processor productivity. Those varieties that showed low processor productivity should be avoided during selection to avoid increased labour burden and associated drudgery of women processors. Further research is recommended to enhance food product color, latent culinary qualities, and processing productivity of newly bred varieties to improve acceptability and reduce processing drudgery for women. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Drivers of consumer acceptability of cassava gari-eba food products across cultural and environmental settings using the triadic comparison of technologies approach (tricot).

BACKGROUND: Nigeria and Cameroon are multi-ethnic countries with diverse preferences for food characteristics. The present study aimed to inform cassava breeders on consumer-prioritized eba quality traits. Consumer testing was carried out using the triadic comparison of technologies (tricot). Diverse consumers in villages, towns and cities evaluated the overall acceptability of eba made from different cassava genotypes. Data from both countries were combined and linked to laboratory analyses of eba and the gari used to make it. RESULTS: There is a strong preference for eba with higher cohesiveness and eba from gari with higher brightness and especially in Cameroon, with lower redness and yellowness. Relatively higher eba hardness and springiness values are preferred in the Nigerian locations, whereas lower values are preferred in Cameroon. Trends for solubility and swelling power of the gari differ between the two countries. The study also reveals that the older improved cassava genotype TMS30572 is a benchmark genotype with superior eba characteristics across different regions in Nigeria, whereas the recently released variety Game changer performs very well in Cameroon. In both locations, the recently released genotypes Obansanjo-2 and improved variety TM14F1278P0003 have good stability and overall acceptability for eba characteristics. CONCLUSION: The wide acceptance of a single genotype across diverse geographical and cultural conditions in Nigeria, as well as three acceptable new improved varieties in both locations, indicates that consumers' preferences are surprisingly homogeneous for eba. This would enhance breeding efforts to develop varieties with wider acceptability and expand potential target areas for released varieties. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Local Society Perception on Ecosystem Services as an Adaptation Strategy in Urban Stream Recovery Programs in the City of São Paulo, Brazil.

Recent public policies in developing countries have emerged to address challenges of delivering water-related ecosystem services in urban areas. Some initiatives, such as the Brazilian Plan for Adaptation to Climate Change (BPACC) highlights sustainable urban drainage as a key strategy for promoting sustainable cities, including ecosystem-based adaptation (EbA) measures. Despite the importance of these national guidelines, little is known about how the recommendations are incorporated and the provision of ecosystem services are perceived in local initiatives. We aim to explore stakeholders' perception of ecosystem services in relation to public urban programs for improving the local environment through EbA measures. For this, we studied a stream revitalization project in the city of São Paulo, Brazil, as an emblematic case by integrating three public programs: re-urbanization of irregular settlements, implementation of linear parks and cleansing of urban streams. Our methods involved literature review, documentary data, field surveys and semi-structured interviews with local populations, public agents, and NGOs. Despite some positive results of supplying ecosystem services, we recommend that local programs expand the scope of EbA measures based on BPACC guidelines, strengthen the specific objectives of the three individual public programs and better manage public resources, especially in the context of promoting resilient cities in developing countries. At the same time, local programs can teach lessons and show opportunities for improving national guidelines on climate change adaptation.

Dyadic interaction processing in the posterior temporal cortex.

Recent behavioural evidence shows that visual displays of two individuals interacting are not simply encoded as separate individuals, but as an interactive unit that is 'more than the sum of its parts'. Recent functional magnetic resonance imaging (fMRI) evidence shows the importance of the posterior superior temporal sulcus (pSTS) in processing human social interactions, and suggests that it may represent human-object interactions as qualitatively 'greater' than the average of their constituent parts. The current study aimed to investigate whether the pSTS or other posterior temporal lobe region(s): 1) Demonstrated evidence of a dyadic information effect - that is, qualitatively different responses to an interacting dyad than to averaged responses of the same two interactors, presented in isolation, and; 2) Significantly differentiated between different types of social interactions. Multivoxel pattern analysis was performed in which a classifier was trained to differentiate between qualitatively different types of dyadic interactions. Above-chance classification of interactions was observed in 'interaction selective' pSTS-I and extrastriate body area (EBA), but not in other regions of interest (i.e. face-selective STS and mentalizing-selective temporo-parietal junction). A dyadic information effect was not observed in the pSTS-I, but instead was shown in the EBA; that is, classification of dyadic interactions did not fully generalise to averaged responses to the isolated interactors, indicating that dyadic representations in the EBA contain unique information that cannot be recovered from the interactors presented in isolation. These findings complement previous observations for congruent grouping of human bodies and objects in the broader lateral occipital temporal cortex area.

Decoding subcategories of human bodies from both body- and face-responsive cortical regions.

Our visual system can easily categorize objects (e.g. faces vs. bodies) and further differentiate them into subcategories (e.g. male vs. female). This ability is particularly important for objects of social significance, such as human faces and bodies. While many studies have demonstrated category selectivity to faces and bodies in the brain, how subcategories of faces and bodies are represented remains unclear. Here, we investigated how the brain encodes two prominent subcategories shared by both faces and bodies, sex and weight, and whether neural responses to these subcategories rely on low-level visual, high-level visual or semantic similarity. We recorded brain activity with fMRI while participants viewed faces and bodies that varied in sex, weight, and image size. The results showed that the sex of bodies can be decoded from both body- and face-responsive brain areas, with the former exhibiting more consistent size-invariant decoding than the latter. Body weight could also be decoded in face-responsive areas and in distributed body-responsive areas, and this decoding was also invariant to image size. The weight of faces could be decoded from the fusiform body area (FBA), and weight could be decoded across face and body stimuli in the extrastriate body area (EBA) and a distributed body-responsive area. The sex of well-controlled faces (e.g. excluding hairstyles) could not be decoded from face- or body-responsive regions. These results demonstrate that both face- and body-responsive brain regions encode information that can distinguish the sex and weight of bodies. Moreover, the neural patterns corresponding to sex and weight were invariant to image size and could sometimes generalize across face and body stimuli, suggesting that such subcategorical information is encoded with a high-level visual or semantic code.

First-Time-in-Human Study and Prediction of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis Treatment.

This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC0-τ) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged GSK3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA0-14) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at ClinicalTrials.gov under identifier NCT03075410.).

Erythrocyte binding ligand region VI specific IgA confers tissue protection in malaria infection.

A direct role for IgA either for elimination of malaria parasite or for improvement in tissue pathology has not been investigated in case of Malaria infection while IgG, IgE and IgM were all implicated in the adverse pathology. In this communication, we delineate further that Malaria specific IgA appears to be significant among individuals who had multiple episodes of infection. Interestingly, the IgA elicited by immunization of the homologous peptides derived from Plasmodium berghei ANKA have also resulted in protection of host from adverse lung pathology, while the parasite load is unaffected. The PfrVI immunized mice and mice infected with repeated cycles of 'infection and recovery', simulating an endemic like situation, have resulted in development of B cell population that secretes the IgA specific to this region VI. Summarily, our results suggest that the IgA specific to the malarial antigen can confer significant advantage to hosts in protecting the overall tissue pathology.

Ventral aspect of the visual form pathway is not critical for the perception of biological motion.

Identifying the movements of those around us is fundamental for many daily activities, such as recognizing actions, detecting predators, and interacting with others socially. A key question concerns the neurobiological substrates underlying biological motion perception. Although the ventral "form" visual cortex is standardly activated by biologically moving stimuli, whether these activations are functionally critical for biological motion perception or are epiphenomenal remains unknown. To address this question, we examined whether focal damage to regions of the ventral visual cortex, resulting in significant deficits in form perception, adversely affects biological motion perception. Six patients with damage to the ventral cortex were tested with sensitive point-light display paradigms. All patients were able to recognize unmasked point-light displays and their perceptual thresholds were not significantly different from those of three different control groups, one of which comprised brain-damaged patients with spared ventral cortex (n > 50). Importantly, these six patients performed significantly better than patients with damage to regions critical for biological motion perception. To assess the necessary contribution of different regions in the ventral pathway to biological motion perception, we complement the behavioral findings with a fine-grained comparison between the lesion location and extent, and the cortical regions standardly implicated in biological motion processing. This analysis revealed that the ventral aspects of the form pathway (e.g., fusiform regions, ventral extrastriate body area) are not critical for biological motion perception. We hypothesize that the role of these ventral regions is to provide enhanced multiview/posture representations of the moving person rather than to represent biological motion perception per se.

ATYPICAL CHLAMYDIACEAE IN WILD POPULATIONS OF HAWKS ( BUTEO SPP.) IN CALIFORNIA.

Chlamydiaceae bacteria infect many vertebrate hosts, and previous reports based on polymerase chain reaction (PCR) assays and serologic assays that are prone to cross-reaction among chlamydial organisms have been used to describe the prevalence of either DNA fragments or antibodies to Chlamydia spp. in wild raptorial populations. This study reports the PCR-based prevalence of Chlamydiaceae DNA that does not 100% match any avian or mammalian Chlamydiaceae in wild populations of hawks in California Buteo species. In this study, multimucosal swab samples ( n = 291) for quantitative PCR (qPCR) and plasma ( n = 78) for serology were collected from wild hawks. All available plasma samples were negative for antibodies using a C. psittaci-specific elementary body agglutination test (EBA; n = 78). For IgY antibodies all 51 available samples were negative using the indirect immunofluorescent assay. The overall prevalence of Chlamydiaceae DNA detection in wild Buteo species sampled was 1.37% (4/291) via qPCR-based analysis. Two fledgling Swainson's hawks ( Buteo swainsoni) and two juvenile red-tailed hawks ( Buteo jamaicensis) were positive by qPCR-based assay for an atypical chlamydial sequence that did not 100% match any known C. psittaci genotype. Positive swab samples from these four birds were sequenced based on the ompA gene and compared by high-resolution melt analysis with all known avian and mammalian Chlamydiaceae. The amplicon sequence did not 100% match any known avian chlamydial sequence; however, it was most similar (98.6%) to C. psittaci M56, a genotype that is typically found in muskrats and hares. Culture and full genome sequence analysis of Chlamydia spp. isolated from diseased hawks will be necessary to classify this organism and to better understand its epizootiology and potential health impact on wild Buteo populations in California.

Constructing Visual Perception of Body Movement with the Motor Cortex.

The human brain readily perceives fluent movement from static input. Using functional magnetic resonance imaging, we investigated brain mechanisms that mediate fluent apparent biological motion (ABM) perception from sequences of body postures. We presented body and nonbody stimuli varying in objective sequence duration and fluency of apparent movement. Three body postures were ordered to produce a fluent (ABC) or a nonfluent (ACB) apparent movement. This enabled us to identify brain areas involved in the perceptual reconstruction of body movement from identical lower-level static input. Participants judged the duration of a rectangle containing body/nonbody sequences, as an implicit measure of movement fluency. For body stimuli, fluent apparent motion sequences produced subjectively longer durations than nonfluent sequences of the same objective duration. This difference was reduced for nonbody stimuli. This body-specific bias in duration perception was associated with increased blood oxygen level-dependent responses in the primary (M1) and supplementary motor areas. Moreover, fluent ABM was associated with increased functional connectivity between M1/SMA and right fusiform body area. We show that perceptual reconstruction of fluent movement from static body postures does not merely enlist areas traditionally associated with visual body processing, but involves cooperative recruitment of motor areas, consistent with a "motor way of seeing".

Assessment of stormwater runoff management practices and BMPs under soil sealing: A study case in a peri-urban watershed of the metropolitan area of Rome (Italy).

By 2006, almost 100,000 km2 of EU soil (2.3% of the whole territory) had been sealed, with a per capita quota of 200 m2 of sealed surface for each EU citizen. Italy, in 2016, recorded a soil sealing rate of 2.8% of the entire territory. In this context, the urban expansion which occurred in past decades is considered one of the main causes of the increase in flood frequency and intensity in small catchments, causing both social and financial damage. In the present paper, the positive impact of introducing Best Management Practices (BMPs) at urban scale is assessed, with particular regard to the decreasing of flood prone areas. A suburban watershed of the metropolitan area of Rome has been selected for a study case, as its soil sealing rate can be considered paradigmatic at this scale. Starting from the analysis of rainfall events occurring between 2008 and 2011 which caused millions of euros worth of damage, and using a high resolution data set in a GIS environment, two scenarios, with and without BMP introduction, are evaluated applying a rainfall-runoff model and a bidimensional hydraulic model. From a comparison of the flood maps with and without the introduction of BMPs, it was determined that in 90% of the circumstances the employment of the BMPs would completely remove the hydraulic risk, while in the remaining 10% the BMP would at least reduce the areas subjected to flooding.

An evolutionary approach to identify potentially protective B cell epitopes involved in naturally acquired immunity to malaria and the role of EBA-175 in protection amongst denizens of Bolifamba, Cameroon.

BACKGROUND: The search for a vaccine against malaria caused by Plasmodium falciparum has lasted for more than 100 years, with considerable progress in the identification of a number of vaccine candidates. The post-genomic era offers new opportunities for an expedited search using rational vaccine design and prioritization of key B-cell epitopes involved in natural acquired immunity. METHODS: Malaria vaccine candidate genes that have reached clinical trial were searched on an evolutionary relationship tree, to determine their level of lineage-specificity. Ten other genes with similar protein features and level of lineage specificity to the vaccine candidates were randomly selected, and computationally evaluated for the presence of B-cell epitopes. The protein fragment with maximum probability of putative epitopes were synthesized and used in an ELISA experiment to determine the presence of antibodies to these peptides, in the serum of malaria patients and healthy malaria uninfected inhabitants from a malaria endemic region (Bolifamba), alongside with a vaccine candidate EBA-175. RESULTS: Two peptide fragments of 25 and 30 amino acid length from PF3D7_1233400 and PF3D7_1437500 respectively, coded as PF4-123 and PF4-143 were shown to contain B-cell epitope(s). Total IgG antibodies to these peptides were not significantly different between sick and healthy participants, but cytophilic antibodies to these peptides were significantly higher in healthy participants (p < 0.03). Total IgG to the vaccine candidate EBA-175 was significantly higher in sick participants than in healthy participants, likewise cytophilic antibodies (p < 0.04). Antibodies to the peptides PF4-123 and PF4-143 correlated negatively (p = 0.025 and 0.008 and r = -0.291 and -0.345, respectively) to parasite load. Total IgG antibodies to EBA-175 showed a negative correlation to parasite load (r = -0.144), which was not significant (p = 0.276). Duration of stay in Bolifamba also negatively correlated with parasite load (p = 0.026, r = -0.419) and total IgG to PF4-143 was significantly associated with prolonged duration of stay in the locality of Bolifamba, Cameroon (p = 0.006, r = 0.361). CONCLUSIONS: The present study has identified two genes PF3D7_1233400 and PF3D7_1437500 containing peptide fragment (PF4-123 and PF4-143) with B-cell epitopes that are correlated with naturally acquired immunity to malaria. A pipeline has been developed for rapid identification of other B-cell epitopes involved in naturally acquired immunity.

Hierarchy of Gambling Choices: A Framework for Examining EGM Gambling Environment Preferences.

This paper presents the Hierarchy of Gambling Choices (HGC), which is a consumer-oriented framework for understanding the key environmental and contextual features that influence peoples' selections of online and venue-based electronic gaming machines (EGMs). The HGC framework proposes that EGM gamblers make choices in selection of EGM gambling experiences utilising Tversky's (Psychol Rev 79(4):281-299, 1972). Elimination-by-Aspects model, and organise their choice in a hierarchical manner by virtue of EGMs being an "experience good" (Nelson in J Polit Econ 78(2):311-329, 1970). EGM features are divided into three levels: the platform-including, online, mobile or land-based; the provider or specific venue in which the gambling occurs; and the game or machine characteristics, such as graphical themes and bonus features. This framework will contribute to the gambling field by providing a manner in which to systematically explore the environment surrounding EGM gambling and how it affects behaviour.

The brain network underlying the recognition of hand gestures in the blind: the supramodal role of the extrastriate body area.

The visual perception of others' body parts is critical for understanding and imitating their behavior. The visual cortex in humans includes the extrastriate body area (EBA), which is a large portion of the occipitotemporal cortex that is selectively responsive to visually perceived body parts. Previous neuroimaging studies showed that the EBA not only receives sensory inputs regarding others' body information but also receives kinesthetic feedback regarding one's own actions. This finding raised the possibility that the EBA could be formed via nonvisual sensory modalities. However, the effect of visual deprivation on the formation of the EBA has remained largely unknown. Here, we used fMRI to investigate the effect of vision loss on the development of the EBA. Blind and sighted human subjects performed equally well in a haptic-identification task involving three categories of objects (hand shapes, toy cars, and teapots). The superior part (i.e., the middle temporal gyrus and angular gyrus) of the EBA and the supramarginal gyrus showed greater sensitivity to recognized hand shapes than to inanimate objects, regardless of the sensory modality and visual experience. Unlike the superior part of the EBA, the sensitivity of the inferior part (i.e., the inferior temporal sulcus and middle occipital gyrus) depended on visual experience. However, this vision-dependent sensitivity explained minor individual differences in hand-recognition performance. These results indicate that nonvisual modalities drive the development of the cortical network underlying the recognition of hand gestures with a node in the visual cortex.

The structures of glycophorin C N-glycans, a putative component of the GPC receptor site for Plasmodium falciparum EBA-140 ligand.

Glycophorins C and D are highly glycosylated integral sialoglycoproteins of human red blood cell membranes carrying the Gerbich blood group antigens. The O- and N-glycosidic chains of the major erythrocyte glycoprotein (Lisowska E. 2001, Antigenic properties of human glycophorins - an update. Adv Exp Med Biol, 491:155-169; Tomita M and Marchesi VT. 1975, Amino-acid sequence and oligosaccharide attachment sites of human erythrocyte glycophorin. Proc Natl Acad Sci USA, 72:2964-2968.) are well characterized but the structure of GPC N-glycans has remained unknown. This problem became important since it was reported that GPC N-glycans play an essential role in the interaction with Plasmodium falciparum EBA-140 merozoite ligand. The elucidation of these structures seems essential for full characterization of the GPC binding site for the EBA-140 ligand. We have employed detailed structural analysis using sequential mass spectrometry to show that many GPC N-glycans contain H2 antigen structures and several contain polylactosamine structures capped with fucose. The results obtained indicate structural heterogeneity of the GPC N-glycans and show the existence of structural elements not found in glycophorin A N-glycans. Our results also open a possibility of new interpretation of the data concerning the binding of P. falciparum EBA-140 ligand to GPC. We hypothesize that preferable terminal fucosylation of N-glycosidic chains containing repeating lactosamine units of the GPC Gerbich variant could be an explanation for why the EBA-140 ligand does not react with GPC Gerbich and an indication that the EBA-140 interaction with GPC is distinctly dependent on the GPC N-glycan structure.

Acquisition of Functional Antibodies That Block the Binding of Erythrocyte-Binding Antigen 175 and Protection Against Plasmodium falciparum Malaria in Children.

BACKGROUND: The targets and mechanisms of human immunity to malaria are poorly understood, which poses a major barrier to malaria vaccine development. Antibodies play a key role in human immunity and may act by inhibiting receptor-binding functions of key merozoite invasion ligands. Antibodies to the major invasion ligand and vaccine candidate, erythrocyte-binding antigen 175 (EBA-175), have been linked with protection, but how these antibodies function has not been established. METHODS: We developed 2 new assays that quantify the ability of antibodies to inhibit binding of EBA-175 to its erythrocyte receptor, glycophorin A, using either native or recombinant EBA-175. Binding-inhibitory antibodies were evaluated in a longitudinal cohort study of Papua New Guinean children and related to risk of malaria, age, infection status, and markers of parasite exposure. RESULTS: Binding-inhibition assays (BIAs) were reproducible, and the 2 assays had a high level of agreement. Inhibitory antibodies were common among children, acquired in association with markers of increasing parasite exposure, and high in those children with active infection. Inhibitory antibodies correlated with total immunoglobulin G levels to the EBA-175 binding domain (region II). Importantly, binding-inhibitory antibodies were significantly associated with protection from symptomatic malaria when measured using either BIA. CONCLUSIONS: Findings suggest that naturally acquired binding-inhibitory antibodies are an important functional mechanism that contributes to protection against malaria and further supports the potential of EBA-175 as a vaccine candidate. Identifying vaccines and approaches that induce potent binding-inhibitory antibodies may be a valuable strategy in the development of highly efficacious malaria vaccines.

A Bayesian Nonlinear Mixed-Effects Regression Model for the Characterization of Early Bactericidal Activity of Tuberculosis Drugs.

Trials of the early bactericidal activity (EBA) of tuberculosis (TB) treatments assess the decline, during the first few days to weeks of treatment, in colony forming unit (CFU) count of Mycobacterium tuberculosis in the sputum of patients with smear-microscopy-positive pulmonary TB. Profiles over time of CFU data have conventionally been modeled using linear, bilinear, or bi-exponential regression. We propose a new biphasic nonlinear regression model for CFU data that comprises linear and bilinear regression models as special cases and is more flexible than bi-exponential regression models. A Bayesian nonlinear mixed-effects (NLME) regression model is fitted jointly to the data of all patients from a trial, and statistical inference about the mean EBA of TB treatments is based on the Bayesian NLME regression model. The posterior predictive distribution of relevant slope parameters of the Bayesian NLME regression model provides insight into the nature of the EBA of TB treatments; specifically, the posterior predictive distribution allows one to judge whether treatments are associated with monolinear or bilinear decline of log(CFU) count, and whether CFU count initially decreases fast, followed by a slower rate of decrease, or vice versa.

Sealing ability of root-end filling materials.

BACKGROUND: The aim of this research was to compare the apical sealing ability of different root-end filling materials (SuperEBA(®), ProRoot MTA(®), thermoplasticized gutta-percha + AH-Plus(®), thermoplasticized RealSeal(®)), by means of microbial indicators. MATERIALS AND METHODS: Thus, 50 human single-rooted teeth were employed, which were shaped until size 5 0, retro - prepared with ultrasonic tips and assigned to 4 groups, retro-filled with each material or controls. A platform was employed, which was split in two halves: upper chamber-where the microbial suspension containing the biological indicators was introduced (E. faecalis + S. aureus + P. aeruginosa + B. subtilis + C. albicans); and a lower chamber containing the culture medium brain, heart influsion, where 3 mm of the apical region of teeth were kept immersed. Lectures were made daily for 60 days, using the turbidity of the culture medium as indicative of microbial contamination. Statistical analyses were carried out at 5% level of significance. RESULTS: The results showed microbial leakage at least in some specimens in all of the groups. RealSeal(®) has more microbial leakage, statistically significant, compared to ProRoot(®) MTA and SuperEBA(®). No significant differences were observed when compared ProRoot(®) MTA and SuperEBA(®). The gutta-percha + AH Plus results showed no statistically significant differences when compared with the other groups. CONCLUSIONS: All the tested materials showed microbial leakage. Root-end fillings with Super-EBA or MTA had the lowest bacterial filtration and RealSeal shows highest bacterial filtration.

Reduced glycerol incorporation into phospholipids contributes to impaired intra-erythrocytic growth of glycerol kinase knockout Plasmodium falciparum parasites.

BACKGROUND: Malaria is a devastating disease and Plasmodium falciparum is the most lethal parasite infecting humans. Understanding the biology of this parasite is vital in identifying potential novel drug targets. During every 48-hour intra-erythrocytic asexual replication cycle, a single parasite can produce up to 32 progeny. This extensive proliferation implies that parasites require substantial amounts of lipid precursors for membrane biogenesis. Glycerol kinase is a highly conserved enzyme that functions at the interface of lipid synthesis and carbohydrate metabolism. P. falciparum glycerol kinase catalyzes the ATP-dependent phosphorylation of glycerol to glycerol-3-phosphate, a major phospholipid precursor. METHODS: The P. falciparum glycerol kinase gene was disrupted using double crossover homologous DNA recombination to generate a knockout parasite line. Southern hybridization and mRNA analysis were used to verify gene disruption. Parasite growth rates were monitored by flow cytometry. Radiolabelling studies were used to assess incorporation of glycerol into parasite phospholipids. RESULTS: Disruption of the P. falciparum glycerol kinase gene produced viable parasites, but their growth was significantly reduced to 56.5±1.8% when compared to wild type parasites. (14)C-glycerol incorporation into the major phospholipids of the parasite membrane, phosphatidylcholine and phosphatidylethanolamine, was 48.4±10.8% and 53.1±5.7% relative to an equivalent number of wild type parasites. CONCLUSIONS: P. falciparum glycerol kinase is required for optimal intra-erythrocytic asexual parasite development. Exogenous glycerol may be used as an alternative carbon source for P. falciparum phospholipid biogenesis, despite the lack of glycerol kinase to generate glycerol-3-phosphate. GENERAL SIGNIFICANCE: These studies provide new insight into glycerolipid metabolism in P. falciparum.