Studying the effect of chloroquine on sporozoite-induced protection and immune responses in Plasmodium berghei malaria

BACKGROUND Sporozoite immunization of animals and humans under a chemo-prophylactic cover of chloroquine (CPS-CQ) efficiently induces sterile protection against malaria. In humans, CPS-CQ is strikingly more efficient than immunization with radiation attenuated sporozoites (RAS), raising the hypothesis that this might be partially due to CQ. Chloroquine, an established anti-malarial drug, is also well known for its immune modulating properties including improvement of cross-presentation. The aim of this study was to investigate whether co-administration of CQ during sporozoite immunization improves cellular responses and protective efficacy in Plasmodium berghei models. METHODS A number of experiments in selected complimentary P. berghei murine models in Balb/cByJ and C57BL/6j mice was performed. First, the effect of CQ administration on the induction of protection and immune responses by RAS immunization was studied. Next, the effect of CQ on the induction of circumsporozoite (CS) protein-specific CD8(+) T cells by immunization with P. berghei parasites expressing a mutant CS protein was investigated. Finally, a direct comparison of CPS-CQ to CPS with mefloquine (MQ), an anti-malarial with little known immune modulating effects, was performed. RESULTS When CQ was co-administered during immunization with graded numbers of RAS, this did not lead to an increase in frequencies of total memory CD8(+) T cells or CS protein-specific CD8(+) T cells. Also parasite-specific cytokine production and protection remained unaltered. Replacement of CQ by MQ for CPS immunization resulted in significantly reduced percentages of IFNγ producing memory T cells in the liver (p = 0.01), but similar protection. CONCLUSIONS This study does not provide evidence for a direct beneficial effect of CQ on the induction of sporozoite-induced immune responses and protection in P. berghei malaria models. Alternatively, the higher efficiency of CPS compared to RAS might be explained by an indirect effect of CQ through limiting blood-stage exposure after immunization or to increased antigen exposure and, therefore, improved breadth of the immune response.EMB was supported by Top Institute Pharma (grant T4-102) and KN was supported by the NWO Mozaiek (grant no. 017.005.011)

J Regularization Improves Imbalanced Multiclass Segmentation

We propose a new loss formulation to further advance the multiclass segmentation of cluttered cells under weakly supervised conditions. When adding a Youden's J statistic regularization term to the cross entropy loss we improve the separation of touching and immediate cells, obtaining sharp segmentation boundaries with high adequacy. This regularization intrinsically supports class imbalance thus eliminating the necessity of explicitly using weights to balance training. Simulations demonstrate this capability and show how the regularization leads to correct results by helping advancing the optimization when cross entropy stagnates. We build upon our previous work on multiclass segmentation by adding yet another training class representing gaps between adjacent cells. This addition helps the classifier identify narrow gaps as background and no longer as touching regions. We present results of our methods for 2D and 3D images, from bright field images to confocal stacks containing different types of cells, and we show that they accurately segment individual cells after training with a limited number of images, some of which are poorly annotated

Extended depth of focus intraocular lens: Chromatic performance

We describe a first-and-second-diffractive-order intraocular lens ((1st,2nd)DIOL) within the class of hybrid refractive-diffractive designs for intraocular lenses (IOLs) and analyse its properties of focus extension and compensation of longitudinal chromatic aberration (LCA), particularly for lenses with low addition. Power, energy efficiency and their wavelength dependence are extended from monofocal IOL and conventional bifocal zeroth-and-first-diffractive-order IOL ((0th,1st)DIOL) to (1st,2nd)DIOL of low addition. Compensation of LCA is experimentally assessed in optical bench through the through-focus energy efficiency of three Tecnis IOLs with red, green and blue illuminations: ZA9003 (monofocal), ZKB00 (bifocal (0th,1st)DIOL with + 2.75 D add) and Symfony ZXR00. We prove Tecnis Symfony ZXR00 IOL can be considered an example of (1st,2nd)DIOL design of low addition, with LCA compensation in both the distance and intermediate foci, whereas the bifocal (0th,1st)DIOL does not compensate in the distance focus. However, the energy efficiency of (1st,2nd)DIOL for wavelengths other than the design wavelength is markedly more asymmetric.Postprint (published version

Pemanfaatan Program Pemerintah Bantuan Langsung Tunai Di Desa Tambelang Kecamatan Maesaan Kabupaten Minahasa Selatan

This study aims to determine the direct cash assistance (BLT) program is right on target in terms of accuracy of recipient recruitment, disbursement time, supervision and to determine community utilization of the BLT Program in Tambelang Village, Maesaan District. The research was carried out from January to February 2022. The data collected in the study were primary data obtained from direct interviews with BLT recipient communities using a questionnaire. Secondary data were obtained from the Tambelang Village Office, as well as data related to research taken from the internet. The number of BLT recipients was 130 respondents who received BLT phase I in 2021 and phase II in 2021. The sample selected by Purposive Sampling was 60 respondents. The results showed that the use of the government's direct cash assistance program in Tambelang Village was appropriate, the recipients of the assistance had fulfilled the correct recruitment process in accordance with the implementation instructions, on time in disbursing funds, officers disbursed aid funds according to the specified schedule. The Government's Cash Direct Assistance Program is used by the community to meet their daily basic needs, namely buying rice, eggs, meat, transportation and for emergency funds, namely buying medicine and children's school needs

Students’ exploring and refining their equity ethic within the access network

The Access Network is an organization that supports vibrant interactions among students and faculty who advocate for equity work in the physical sciences. This paper uses McGee and Bentley’s framework of “equity ethic” (EE) to understand how Access student leaders adopt and refine a commitment to equity and social justice work within the physical sciences. In McGee and Bentley’s study of STEM students of color, they define EE as students’ sense of altruism and collectivism within and outside of their communities. Through interviews with student leaders, we model components of students’ EEs and how their EEs are influenced by their participation in Access. Student accounts illustrate that they are invested in improving equity within their disciplinary communities and see progress toward these goals as an important measure of success. Our findings highlight how students are already infusing an EE into their professional physics activities. This research suggests that student leaders benefit from having opportunities to articulate and refine critiques of disciplinary culture, and connect their EE to their professional practices. These accounts suggest that this work occurs in conversation with other equity leaders around issues of social justice

Seeking theta's desperately: Estimating the distribution of consumers under increasing block rates

This paper shows that the distribution of observed consumption is not a good proxy for the distribution of heterogeneous consumers when the current tariff is an increasing block tariff. We use a two step method to recover the "true" distribution of consumers. First, we estimate the demand function induced by the current tariff. Second, using the demand system, we specify the distribution of consumers as a function of observed consumption to recover the true distribution. Finally, we design a new two-part tariff which allows us to evaluate the equity of the existence of an increasing block tariff.Heterogeneous demand, nonlinear pricing

Borehole climatology: a discussion based on contributions from climate modeling

Progress in understanding climate variability through the last millennium leans on simulation and reconstruction efforts. Exercises blending both approaches present a great potential for answering questions relevant both for the simulation and reconstruction of past climate, and depend on the specific peculiarities of proxies and methods involved in climate reconstructions, as well as on the realism and limitations of model simulations. This paper explores research specifically related to paleoclimate modeling and borehole climatology as a branch of climate reconstruction that has contributed significantly to our knowledge of the low frequency climate evolution during the last five centuries. The text flows around three main issues that group most of the interaction between model and geothermal efforts: the use of models as a validation tool for borehole climate reconstructions; comparison of geothermal information and model simulations as a means of either model validation or inference about past climate; and implications of the degree of realism on simulating subsurface climate on estimations of future climate change. The use of multi-centennial simulations as a surrogate reality for past climate suggests that within the simplified reality of climate models, methods and assumptions in borehole reconstructions deliver a consistent picture of past climate evolution at long time scales. Comparison of model simulations and borehole profiles indicate that borehole temperatures are responding to past external forcing and that more realism in the development of the soil model components in climate models is desirable. Such an improved degree of realism is important for the simulation of subsurface climate and air-ground interaction; results indicate it could also be crucial for simulating the adequate energy balance within climate change scenario experiments