The Memory Mines

She is eighteen when she leaves home. She leaves shortly after her father’s inexplicable disappearance – an event she neither understands nor accepts. She does what everyone on the cusp of adulthood does: she moves abroad to forget her past. Now, ten years later, her ageing mother is taken away. The family home is empty. The young woman returns. It is here, in her childhood home, she makes the deliberate decision to remember. Even after so many years, the house is the same. Here, her childhood memories still live, in the spaces between walls, in the cracks in the floor, in the weft of the brocade curtains. Stories are awakened with the turn of a brass handle, the swing of a glass door, the scent of sour yogurt. The memories surface of their own will, appearing suddenly, sometimes violently. She moves through the house, reliving each memory with startling lucidity. The line between her parents’ memories and her own begin to blur. She remembers things she never knew

Plasmodium falciparum Merozoite Associated Armadillo Protein (PfMAAP) Is Apically Localized in Free Merozoites and Antibodies Are Associated With Reduced Risk of Malaria.

Understanding the functional role of proteins expressed by Plasmodium falciparum is an important step toward unlocking potential targets for the development of therapeutic or diagnostic interventions. The armadillo (ARM) repeat protein superfamily is associated with varied functions across the eukaryotes. Therefore, it is important to understand the role of members of this protein family in Plasmodium biology. The Plasmodium falciparum armadillo repeats only (PfARO; Pf3D7_0414900) and P. falciparum merozoite organizing proteins (PfMOP; Pf3D7_0917000) are armadillo-repeat containing proteins previously characterized in P. falciparum. Here, we describe the characterization of another ARM repeat-containing protein in P. falciparum, which we have named the P. falciparum Merozoites-Associated Armadillo repeats protein (PfMAAP). Antibodies raised to three different synthetic peptides of PfMAAP show apical staining of free merozoites and those within the mature infected schizont. We also demonstrate that the antibodies raised to the PfMAAP peptides inhibited invasion of erythrocytes by merozoites from different parasite isolates. In addition, naturally acquired human antibodies to the N- and C- termini of PfMAAP are associated with a reduced risk of malaria in a prospective cohort analysis

"Even if the test result is negative, they should be able to tell us what is wrong with us": a qualitative study of patient expectations of rapid diagnostic tests for malaria.

BACKGROUND: The debate on rapid diagnostic tests (RDTs) for malaria has begun to shift from whether RDTs should be used, to how and under what circumstances their use can be optimized. This has increased the need for a better understanding of the complexities surrounding the role of RDTs in appropriate treatment of fever. Studies have focused on clinician practices, but few have sought to understand patient perspectives, beyond notions of acceptability. METHODS: This qualitative study aimed to explore patient and caregiver perceptions and experiences of RDTs following a trial to assess the introduction of the tests into routine clinical care at four health facilities in one district in Ghana. Six focus group discussions and one in-depth interview were carried out with those who had received an RDT with a negative test result. RESULTS: Patients had high expectations of RDTs. They welcomed the tests as aiding clinical diagnoses and as tools that could communicate their problem better than they could, verbally. However, respondents also believed the tests could identify any cause of illness, beyond malaria. Experiences of patients suggested that RDTs were adopted into an existing system where patients are both physically and intellectually removed from diagnostic processes and where clinicians retain authority that supersedes tests and their results. In this situation, patients did not feel able to articulate a demand for test-driven diagnosis. CONCLUSIONS: Improvements in communication between the health worker and patient, particularly to explain the capabilities of the test and management of RDT negative cases, may both manage patient expectations and promote patient demand for test-driven diagnoses

Potential health impacts of heavy metals on HIV-infected population in USA.

Noninfectious comorbidities such as cardiovascular diseases have become increasingly prevalent and occur earlier in life in persons with HIV infection. Despite the emerging body of literature linking environmental exposures to chronic disease outcomes in the general population, the impacts of environmental exposures have received little attention in HIV-infected population. The aim of this study is to investigate whether individuals living with HIV have elevated prevalence of heavy metals compared to non-HIV infected individuals in United States. We used the National Health and Nutrition Examination Survey (NHANES) 2003-2010 to compare exposures to heavy metals including cadmium, lead, and total mercury in HIV infected and non-HIV infected subjects. In this cross-sectional study, we found that HIV-infected individuals had higher concentrations of all heavy metals than the non-HIV infected group. In a multivariate linear regression model, HIV status was significantly associated with increased blood cadmium (p=0.03) after adjusting for age, sex, race, education, poverty income ratio, and smoking. However, HIV status was not statistically associated with lead or mercury levels after adjusting for the same covariates. Our findings suggest that HIV-infected patients might be significantly more exposed to cadmium compared to non-HIV infected individuals which could contribute to higher prevalence of chronic diseases among HIV-infected subjects. Further research is warranted to identify sources of exposure and to understand more about specific health outcomes

Comparison of quantitative real time PCR with Sequencing and ribosomal RNA-FISH for the identification of fungi in Formalin fixed, paraffin-embedded tissue specimens

Background: Identification of the causative agents of invasive fungal infections (IFI) is critical for guiding antifungal therapy. Cultures remain negative in a substantial number of IFI cases. Accordingly, species identification from formalin fixed, paraffin embedded (FFPE) tissue specimens by molecular methods such as fluorescence in situ hybridisation (FISH) and PCR provides an appealing approach to improve management of patients. Methods: We designed FISH probes targeting the 28S rRNA of Aspergillus and Candida and evaluated them with type strains. Fluorescence microscopy (FM), using FISH probes and quantitative broadrange fungal PCR targeting the rRNA gene were applied to FFPE tissue specimens from patients with proven IFI in order to explore benefits and limitations of each approach. Results: PCR followed by sequencing identified a broad spectrum of pathogenic fungi in 28 of 40 evaluable samples (70%). Hybridisation of FISH probes to fungal rRNA was documented in 19 of 40 tissue samples (47.5%), including 3 PCR negative samples with low fungal burden. The use of FISH was highly sensitive in invasive yeast infections, but less sensitive for moulds. In samples with hyphal elements, the evaluation of hybridisation was impaired due to autofluorescence of hyphae and necrotic tissue background. Conclusions: While PCR appears to be more sensitive in identifying the causative agents of IFI, some PCR negative and FISH positive samples suggest that FISH has some potential in the rapid identification of fungi from FFPE tissue samples

The socioeconomic landscape of the exposome during pregnancy

Background: While socioeconomic position (SEP) is consistently related to pregnancy and birth outcome dis-parities, relevant biological mechanisms are manifold, thus necessitating more comprehensive characterization of SEP-exposome associations during pregnancy. Objectives: We implemented an exposomic approach to systematically characterize the socioeconomic landscape of prenatal exposures in a setting where social segregation was less distinct in a hypotheses-generating manner. Methods: We described the correlation structure of 134 prenatal exogenous and endogenous sources (e.g., micronutrients, hormones, immunomodulatory metabolites, environmental pollutants) collected in a diverse, population-representative, urban, high-income longitudinal mother-offspring cohort (N = 1341; 2009-2011). We examined the associations between maternal, paternal, household, and areal level SEP indicators and 134 ex-posures using multiple regressions adjusted for precision variables, as well as potential effect measure modifi-cation by ethnicity and nativity. Finally, we generated summary SEP indices using Multiple Correspondence Analysis to further explore possible curved relationships. Results: Individual and household SEP were associated with anthropometric/adiposity measures, folate, omega-3 fatty acids, insulin-like growth factor-II, fasting glucose, and neopterin, an inflammatory marker. We observed paternal education was more strongly and consistently related to maternal exposures than maternal education. This was most apparent amongst couples discordant on education. Analyses revealed additional non-linear as-sociations between areal composite SEP and particulate matter. Environmental contaminants (e.g., per-and polyfluoroalkyl substances) and micronutrients (e.g., folate and copper) showed opposing associations by ethnicity and nativity, respectively. Discussion: SEP-exposome relationships are complex, non-linear, and context specific. Our findings reinforce the potential role of paternal contributions and context-specific modifiers of associations, such as between ethnicity and maternal diet-related exposures. Despite weak presumed areal clustering of individual exposures in our context, our approach reinforces subtle non-linearities in areal-level exposures.Peer reviewe

Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype

We have investigated the extent and pattern of immunostaining for ubiquitin protein (UBQ) in 60 patients with frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U), 37 of whom were ascertained in Manchester UK and 23 in Newcastle-Upon-Tyne, UK. There were three distinct histological patterns according to the form and distribution of the UBQ pathology. Histological type 1 was present in 19 patients (32%) and characterised by the presence of a moderate number, or numerous, UBQ immunoreactive neurites and intraneuronal cytoplasmic inclusions within layer II of the frontal and temporal cerebral cortex, and cytoplasmic inclusions within granule cells of the dentate gyrus; neuronal intranuclear inclusions (NII) of a “cat’s eye” or “lentiform” appearance were present in 17 of these patients. In histological type 2 (16 patients, 27%), UBQ neurites were predominantly, or exclusively, present with few intraneuronal cytoplasmic inclusions within layer II of the cerebral cortex, while in histological type 3 (25 patients, 42%), UBQ intraneuronal cytoplasmic inclusions either within the cortical layer II or in the granule cells of the dentate gyrus, with few or no UBQ neurites, were seen. In neither of these latter two groups were NII present. The influence of histological type on clinical phenotype was highly significant with type 1 histology being associated clinically with cases of frontotemporal dementia (FTD) or progressive non-fluent aphasia (PNFA), type 2 histology with semantic dementia (SD), and type 3 histology with FTD, or FTD and motor neurone disease (MND)

Dpr Acts as a Molecular Switch, Inhibiting Wnt Signaling when Unphosphorylated, but Promoting Wnt Signaling when Phosphorylated by Casein Kinase Iδ/ε

The Wnt pathway is a key regulator of development and tumorigenesis. Dpr (Dact/Frodo) influences Wnt signaling in part through the interaction of its PDZ-B domain with Dsh's PDZ domain. Studies have shown that XDpr1a and its close relative, Frodo, are involved in multiple steps of the Wnt pathway in either inhibitory or activating roles. We found that XDpr1a is phosphorylated by casein kinase Iδ/ε (CKIδ/ε), an activator of Wnt signaling, in the presence of XDsh. Abrogating XDpr1a's ability to bind XDsh through mutation of XDpr1a's PDZ-B domain blocks CK1δ/ε's phosphorylation of XDpr1a. Conversely, XDsh possessing a mutation in its PDZ domain that is unable to bind XDpr1a does not promote XDpr1a phosphorylation. Phosphorylation of XDpr1a and XDsh by CKIδ/ε decreases their interaction. Moreover, the phosphorylation of XDpr1a by CKIδ/ε not only abrogates XDpr1a's promotion of β-catenin degradation but blocks β-catenin degradation. Our data suggest that XDpr1a phosphorylation by CKIδ/ε is dependent on the interaction of XDpr1a's PDZ-B domain with XDsh's PDZ domain, and that the phosphorylation state of XDpr1a determines whether it inhibits or activates Wnt signaling

User Experiences of Development of Dependence on the Synthetic Cannabinoids, 5f-AKB48 and 5F-PB-22, and Subsequent Withdrawal Syndromes

Emergence of synthetic cannabinoids (SCBs) in herbal smoking mixtures is a public health concern. New SCB’s such as 5f-AKB48 and 5F-PB-22 have been detected in French seizures and in sudden death post mortems in the US. The aim was to describe development of dependence on herbal smoking mixtures containing the SCB’s, 5f-AKB48 and 5F-PB-22 and subsequent withdrawal syndromes. Dependent users of herbal smoking mixtures known to contain the SCB’s 5f-AKB48 and 5F-PB-22 with an average Severity of Dependence Score (SDS) of 13 were interviewed using a structured guide (three males/three females). Narratives were analysed using the Empirical Phenomenological Psychological (EPP) five step method. Six themes with 68 categories emerged from the analysis. Themes are illustrated as 1) Networks and Product Availability; 2) Drivers and Motives for Use; 3) Effect and Pathways toward Dependence; 4) Poly Substance Use and Comparisons to Natural Cannabis; 5) Dependence and Withdrawal and 6) Self-detoxification Attempts. Two higher levels of abstraction above these theme-levels emerged from the data, with sole use of herbal smoking mixtures containing 5f-AKB48 and 5F-PB-22 centering on the interplay between intense cravings, compulsive all-consuming seeking, use and re-dose behaviours, and fear of the psychiatric and self-harms caused when in withdrawal. This is the first study describing dependence and withdrawal experiences in users dependent on 5f-AKB48 and 5F-PB-22. Given the potential for adverse psychiatric and physical consequences of dependent use, further development of specific clinical responses and clinical research around toxicity and withdrawal severity are warranted

A Systematic Analysis of Cell Cycle Regulators in Yeast Reveals That Most Factors Act Independently of Cell Size to Control Initiation of Division

Upstream events that trigger initiation of cell division, at a point called START in yeast, determine the overall rates of cell proliferation. The identity and complete sequence of those events remain unknown. Previous studies relied mainly on cell size changes to identify systematically genes required for the timely completion of START. Here, we evaluated panels of non-essential single gene deletion strains for altered DNA content by flow cytometry. This analysis revealed that most gene deletions that altered cell cycle progression did not change cell size. Our results highlight a strong requirement for ribosomal biogenesis and protein synthesis for initiation of cell division. We also identified numerous factors that have not been previously implicated in cell cycle control mechanisms. We found that CBS, which catalyzes the synthesis of cystathionine from serine and homocysteine, advances START in two ways: by promoting cell growth, which requires CBS's catalytic activity, and by a separate function, which does not require CBS's catalytic activity. CBS defects cause disease in humans, and in animals CBS has vital, non-catalytic, unknown roles. Hence, our results may be relevant for human biology. Taken together, these findings significantly expand the range of factors required for the timely initiation of cell division. The systematic identification of non-essential regulators of cell division we describe will be a valuable resource for analysis of cell cycle progression in yeast and other organisms