A single-chain class II MHC-IgG3 fusion protein inhibits autoimmune arthritis by induction of antigen-specific hyporesponsiveness

T cells play a central role in many autoimmune diseases. A method to specifically target the function of autoreactive T cell clones would avoid the global immunosuppression associated with current therapies. To develop a molecule capable of inhibiting autoreactive T cell responses in vivo, single-chain peptide-I-A-IgG3 fusion proteins were constructed and expressed in both mammalian and insect cells. The fusion proteins were designed with an IgG3 Fc moiety to make them divalent, allowing TCR cross-linking, while lacking FcR binding and costimulation. The fusion proteins stimulated T cell hybridomas in vitro in a peptide-specific, MHC-restricted manner but failed to do so in soluble form. In vivo administration of an I-A(q) fusion protein, containing an immunodominant collagen II peptide, significantly delayed the onset and reduced the severity of collagen-induced arthritis in DBA/1 mice by induction of Ag-specific hyporesponsiveness. Such fusion proteins may be useful to study novel therapeutic approaches for T cell-mediated autoimmune diseases.     

Detecting single molecules launched from liquid surfaces in a time-of-flight mass spectrometer using ultraviolet and infrared lasers

The launch of molecules from liquid surfaces in a time of flight mass spectrometer has been investigated using different sample preparation techniques, and by exposing the liquid samples to two different laser wavelengths, 337 nm from a N2 ultraviolet laser and 10.6 microm from a CO2 infrared laser. The molecules were detected with cryodetectors measuring the energy of the individual molecules. We present insulin and lysozyme results from samples introduced into the vacuum through a micromachined silicon injector, and from samples consisting of a glycerol droplet deposited directly on the sample holder at the high voltage stage of the ion optics.     

A new species of Sanicula L. (Umbelliferae/Apiaceae) endemic to Baja California, Mexico

A new species of the genusSanicula (sect.Sanicoria) endemic to the southern Sierra Juárez of Baja California, Mexico, is described and illustrated.Sanicula moranii resemblesS. deserticola andS. bipinnatifida, but has thicker basal leaves, with broader petioles and rachises, and shorter fruit prickles that are confined to the apical part of the mericarps. The taxonomic relationships of these species are discussed, along with aspects of their distribution and habitat.

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Resumen  Una neuva especie del géneroSanicula (secciónSanicoria) endémica de la Sierra Juárez de Baja California, México, es descrita e ilustrada.Sanicula moranii presenta similitud conS. deserticola yS. bipinnatifida, no obstante tiene gruesas hojas basales con pecíolos y raquis anchos, y espínulas del fruto más cortas que se distribuyen únicamente en la parte apical de los mericarpos. Además, se comentan las relaciones taxonómicas de las tres especies, así como algunos aspectos de sus distribuciones y hábitats.

     

Annexin A1 Preferentially Predicts Poor Prognosis of Basal-Like Breast Cancer Patients by Activating mTOR-S6 Signaling

IntroductionAnnexin A1 (ANXA1) is an anti-inflammatory protein reported to play a role in cell proliferation and apoptosis, and to be deregulated in breast cancer. The exact role of annexin A1 in the biology of breast cancer remains unclear. We hypothesized that the annexin A1 plays an oncogenic role in basal subtype of breast cancer by modulating key growth pathway(s).MethodsBy mining the Cancer Genome Atlas (TCGA)-Breast Cancer dataset and manipulating annexin A1 levels in breast cancer cell lines, we studied the role of annexin A1 in breast cancer and underlying signaling pathways.ResultsOur in-silico analysis of TCGA-breast cancer dataset demonstrated that annexin A1 mRNA expression is higher in basal subtype compared to luminal and HER2 subtypes. Within the basal subtype, patients show significantly poorer overall survival associated with higher expression of annexin A1. In both TCGA patient samples and cell lines, annexin A1 levels were significantly higher in basal-like breast cancer than luminal and Her2/neu-positive breast cancer. Stable annexin A1 knockdown in TNBC cell lines suppressed the mTOR-S6 pathway likely through activation of AMPK but had no impact on the MAPK, c-Met, and EGFR pathways. In a cell migration assay, annexin A1-depleted TNBC cells showed delayed migration as compared to wild-type cells, which could be responsible for poor patient prognosis in basal like breast cancers that are known to express higher annexin A1.ConclusionsOur data suggest that annexin A1 is prognostic only in patients with basal like breast cancer. This appears to be in part due to the role of annexin A1 in activating mTOR-pS6 pathway.     

Hippocampus Is Place of Interaction between Unconscious and Conscious Memories

Recent evidence suggests that humans can form and later retrieve new semantic relations unconsciously by way of hippocampus—the key structure also recruited for conscious relational (episodic) memory. If the hippocampus subserves both conscious and unconscious relational encoding/retrieval, one would expect the hippocampus to be place of unconscious-conscious interactions during memory retrieval. We tested this hypothesis in an fMRI experiment probing the interaction between the unconscious and conscious retrieval of face-associated information. For the establishment of unconscious relational memories, we presented subliminal (masked) combinations of unfamiliar faces and written occupations (“actor” or “politician”). At test, we presented the former subliminal faces, but now supraliminally, as cues for the reactivation of the unconsciously associated occupations. We hypothesized that unconscious reactivation of the associated occupation—actor or politician—would facilitate or inhibit the subsequent conscious retrieval of a celebrity’s occupation, which was also actor or politician. Depending on whether the reactivated unconscious occupation was congruent or incongruent to the celebrity’s occupation, we expected either quicker or delayed conscious retrieval process. Conscious retrieval was quicker in the congruent relative to a neutral baseline condition but not delayed in the incongruent condition. fMRI data collected during subliminal face-occupation encoding confirmed previous evidence that the hippocampus was interacting with neocortical storage sites of semantic knowledge to support relational encoding. fMRI data collected at test revealed that the facilitated conscious retrieval was paralleled by deactivations in the hippocampus and neocortical storage sites of semantic knowledge. We assume that the unconscious reactivation has pre-activated overlapping relational representations in the hippocampus reducing the neural effort for conscious retrieval. This finding supports the notion of synergistic interactions between conscious and unconscious relational memories in a common, cohesive hippocampal-neocortical memory space.     

Streptococcus suis Meningitis: A Systematic Review and Meta-analysis

Background

Streptococcus suis is the most common cause of meningitis in pork consuming and pig rearing countries in South-East Asia. We performed a systematic review of studies on S. suis meningitis to define the clinical characteristics, predisposing factors and outcome.

Methodology

Studies published between January 1, 1980 and August 1, 2015 were identified from main literature databases and reference lists. Studies were included if they were written in West-European languages and described at least 5 adult patients with S. suis meningitis in whom at least one clinical characteristic was described.

Findings

We identified 913 patients with S. suis meningitis included in 24 studies between 1980 and 2015. The mean age was 49 years and 581 of 711 patients were male (82%). Exposure to pigs or pork was present in 395 of 648 patients (61%) while other predisposing factors were less common. 514 of 528 patients presented with fever (97%), 429 of 451 with headache (95%), 462 of 496 with neck stiffness (93%) and 78 of 384 patients (20%) had a skin injury in the presence of pig/pork contact. The case fatality rate was 2.9% and hearing loss was a common sequel occurring in 259 of 489 patients (53%). Treatment included dexamethasone in 157 of 300 (52%) of patients and was associated with reduced hearing loss in S. suis meningitis patients included in a randomized controlled trial.

Conclusion

S. suis meningitis has a clear association with pig and pork contact. Mortality is low, but hearing loss occurs frequently. Dexamethasone was shown to reduce hearing loss.     

An In Vitro Model for Measuring Immune Responses to Malaria in the Context of HIV Co-infection

Malaria and HIV co-infection is a growing health priority. However, most research on malaria or HIV currently focuses on each infection individually. Although understanding the disease dynamics for each of these pathogens independently is vital, it is also important that the interactions between these pathogens are investigated and understood. We have developed a versatile in vitro model of HIV-malaria co-infection to study host immune responses to malaria in the context of HIV infection. Our model allows the study of secreted factors in cellular supernatants, cell surface and intracellular protein markers, as well as RNA expression levels. The experimental design and methods used limit variability and promote data reliability and reproducibility. All pathogens used in this model are natural human pathogens (Plasmodium falciparum and HIV-1), and all infected cells are naturally infected and used fresh. We use human erythrocytes parasitized with P. falciparum and maintained in continuous in vitro culture. We obtain freshly isolated peripheral blood mononuclear cells from chronically HIV-infected volunteers. Every condition used has an appropriate control (P. falciparum parasitized vs. normal erythrocytes), and every HIV-infected donor has an HIV uninfected control, from which cells are harvested on the same day. This model provides a realistic environment to study the interactions between malaria parasites and human immune cells in the context of HIV infection.     

Improving Maternal Care through a State-Wide Health Insurance Program: A Cost and Cost-Effectiveness Study in Rural Nigeria

Background

While the Nigerian government has made progress towards the Millennium Development Goals, further investments are needed to achieve the targets of post-2015 Sustainable Development Goals, including Universal Health Coverage. Economic evaluations of innovative interventions can help inform investment decisions in resource-constrained settings. We aim to assess the cost and cost-effectiveness of maternal care provided within the new Kwara State Health Insurance program (KSHI) in rural Nigeria.

Methods and Findings

We used a decision analytic model to simulate a cohort of pregnant women. The primary outcome is the incremental cost effectiveness ratio (ICER) of the KSHI scenario compared to the current standard of care. Intervention cost from a healthcare provider perspective included service delivery costs and above-service level costs; these were evaluated in a participating hospital and using financial records from the managing organisations, respectively. Standard of care costs from a provider perspective were derived from the literature using an ingredient approach. We generated 95% credibility intervals around the primary outcome through probabilistic sensitivity analysis (PSA) based on a Monte Carlo simulation. We conducted one-way sensitivity analyses across key model parameters and assessed the sensitivity of our results to the performance of the base case separately through a scenario analysis. Finally, we assessed the sustainability and feasibility of this program’s scale up within the State’s healthcare financing structure through a budget impact analysis. The KSHI scenario results in a health benefit to patients at a higher cost compared to the base case. The mean ICER (US$46.4/disability-adjusted life year averted) is considered very cost-effective compared to a willingness-to-pay threshold of one gross domestic product per capita (Nigeria, US$ 2012, 2,730). Our conclusion was robust to uncertainty in parameters estimates (PSA: median US$49.1, 95% credible interval 21.9–152.3), during one-way sensitivity analyses, and when cost, quality, cost and utilization parameters of the base case scenario were changed. The sustainability of this program’s scale up by the State is dependent on further investments in healthcare.

Conclusions

This study provides evidence that the investment made by the KSHI program in rural Nigeria is likely to have been cost-effective; however, further healthcare investments are needed for this program to be successfully expanded within Kwara State. Policy makers should consider supporting financial initiatives to reduce maternal mortality tackling both supply and demand issues in the access to care.     

Phylogeny Poorly Predicts the Utility of a Challenging Horizontally Transferred Gene in Methylobacterium Strains

Horizontal gene transfer plays a crucial role in microbial evolution. While much is known about the mechanisms that determine whether physical DNA can be transferred into a new host, the factors determining the utility of the transferred genes are less clear. We have explored this issue using dichloromethane consumption in Methylobacterium strains. Methylobacterium extorquens DM4 expresses a dichloromethane dehalogenase (DcmA) that has been acquired through horizontal gene transfer and allows the strain to grow on dichloromethane as the sole carbon and energy source. We transferred the dcmA gene into six Methylobacterium strains that include both close and distant evolutionary relatives. The transconjugants varied in their ability to grow on dichloromethane, but their fitness on dichloromethane did not correlate with the phylogeny of the parental strains or with any single tested physiological factor. This work highlights an important limiting factor in horizontal gene transfer, namely, the capacity of the recipient strain to accommodate the stress and metabolic disruption resulting from the acquisition of a new enzyme or pathway. Understanding these limitations may help to rationalize historical examples of horizontal transfer and aid deliberate genetic transfers in biotechnology for metabolic engineering.