Review of pyronaridine anti-malarial properties and product characteristics.

Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure

Raman Fingerprints of Graphene Produced by Anodic Electrochemical Exfoliation

Electrochemical exfoliation is one of the most promising methods for scalable production of graphene. However, limited understanding of its Raman spectrum as well as lack of measurement standards for graphene strongly limit its industrial applications. In this work we show a systematic study of the Raman spectrum of electrochemically exfoliated graphene, produced using different electrolytes and different types of solvents in varying amounts. We demonstrate that no information on the thickness can be extracted from the shape of the 2D peak as this type of graphene is defective. Furthermore, the number of defects and the uniformity of the samples strongly depend on the experimental conditions, including post-processing. Under specific conditions, formation of short conductive trans-polyacetylene chains has been observed. Our Raman analysis provides guidance for the community on how to get information on defects coming from electrolyte, temperature and other experimental conditions, by making Raman spectroscopy a powerful metrology tool.Comment: This document is the unedited Author's version of a Submitted Work that was subsequently accepted for publication in Nano Letters, American Chemical Society after peer review. To access the final edited and published work, included the SI, see DOI: 10.1021/acs.nanolett.0c0033

Vimentin intermediate filaments and filamentous actin form unexpected interpenetrating networks that redefine the cell cortex

The cytoskeleton of eukaryotic cells is primarily composed of networks of filamentous proteins, F-actin, microtubules, and intermediate filaments. Interactions among the cytoskeletal components are important in determining cell structure and in regulating cell functions. For example, F-actin and microtubules work together to control cell shape and polarity, while the subcellular organization and transport of vimentin intermediate filament (VIF) networks depend on their interactions with microtubules. However, it is generally thought that F-actin and VIFs form two coexisting but separate networks that are independent due to observed differences in their spatial distribution and functions. In this paper, we present a closer investigation of both the structural and functional interplay between the F-actin and VIF cytoskeletal networks. We characterize the structure of VIFs and F-actin networks within the cell cortex using structured illumination microscopy and cryo-electron tomography. We find that VIFs and F-actin form an interpenetrating network (IPN) with interactions at multiple length scales, and VIFs are integral components of F-actin stress fibers. From measurements of recovery of cell contractility after transient stretching, we find that the IPN structure results in enhanced contractile forces and contributes to cell resilience. Studies of reconstituted networks and dynamic measurements in cells suggest direct and specific associations between VIFs and F-actin. From these results, we conclude that VIFs and F-actin work synergistically, both in their structure and in their function. These results profoundly alter our understanding of the contributions of the components of the cytoskeleton, particularly the interactions between intermediate filaments and F-actin

Inhibition of Geranylgeranyl Diphosphate Synthase is a Novel Therapeutic Strategy for Pancreatic Ductal Adenocarcinoma

Rab proteins play an essential role in regulating intracellular membrane trafficking processes. Rab activity is dependent upon geranylgeranylation, a post-translational modification that involves the addition of 20-carbon isoprenoid chains via the enzyme geranylgeranyl transferase (GGTase) II. We have focused on the development of inhibitors against geranylgeranyl diphosphate synthase (GGDPS), which generates the isoprenoid donor (GGPP), as anti-Rab agents. Pancreatic ductal adenocarcinoma (PDAC) is characterized by abnormal mucin production and these mucins play important roles in tumor development, metastasis and chemo-resistance. We hypothesized that GGDPS inhibitor (GGDPSi) treatment would induce PDAC cell death by disrupting mucin trafficking, thereby inducing the unfolded protein response pathway (UPR) and apoptosis. To this end, we evaluated the effects of RAM2061, a potent GGDPSi, against PDAC. Our studies revealed that GGDPSi treatment activates the UPR and triggers apoptosis in a variety of human and mouse PDAC cell lines. Furthermore, GGDPSi treatment was found to disrupt the intracellular trafficking of key mucins such as MUC1. These effects could be recapitulated by incubation with a specific GGTase II inhibitor, but not a GGTase I inhibitor, consistent with the effect being dependent on disruption of Rab-mediated activities. In addition, siRNA-mediated knockdown of GGDPS induces upregulation of UPR markers and disrupts MUC1 trafficking in PDAC cells. Experiments in two mouse models of PDAC demonstrated that GGDPSi treatment significantly slows tumor growth. Collectively, these data support further development of GGDPSi therapy as a novel strategy for the treatment of PDAC

Cost of community-based human papillomavirus self-sampling in Peru : A micro-costing study

Declaration of Interest The authors declare no conflict of interest. Thomas Francis Jr. Fellowship provided funding for data collection. The Hope Project was funded by grants from Grand Challenges Canada (TTS-1812-21131), Uniting for Health Innovation, Global Initiative Against HPV and Cervical Cancer, University of Manitoba, and the John E. Fogarty International Center (5D43TW009375-05). None of the funders had any role in the study design, implementation, the process of data collection, data analysis, interpretation, or writing of the manuscript or the decision to submit it for publication. No authors have been paid to write this article by a pharmaceutical company or other agency. The authors were not precluded from accessing data in the study, and they accept responsibility to submit for publication. Publisher Copyright: © 2021 The Author(s)Background: Cost data of human papillomavirus (HPV) self-sampling programs from low-and-middle-income countries is limited. We estimated the total and unit costs associated with the Hope Project, a community-based HPV self-sampling social entrepreneurship in Peru. Methods: We conducted a micro-costing analysis from the program perspective to determine the unit costs of (1) recruitment/training of community women (Hope Ladies); (2) Hope Ladies distributing HPV self-sampling kits in their communities and the laboratory testing; and (3) Hope Ladies linking screened women with follow-up care. A procedural manual was used to identify the program's activities. A structured questionnaire and in-depth interviews were conducted with administrators to estimate the resource/time associated with activities. We obtained unit costs for each input previously identified from budgets and expenditure reports. Findings: From November 2018 to March 2020, the program recruited and trained 62 Hope Ladies who distributed 4,882 HPV self-sampling kits in their communities. Of the screened women, 586 (12%) tested HPV positive. The annual cost per Hope Lady recruited/trained was $147·51 (2018 USD). The cost per HPV self-sampling kit distributed/tested was$45·39, the cost per woman followed up with results was $55·64, and the cost per HPV-positive woman identified was$378·14. Personnel and laboratory costs represented 56·1% and 24·7% of the total programmatic cost, respectively. Interpretation: Our findings indicate that implementation of a community-based HPV self-sampling has competitive prices, which increases its likelihood to be feasible in Peru. Further economic evaluation is needed to quantify the incremental benefits of HPV self-sampling compared to more established options such as Pap tests. Funding: Thomas Francis Jr. Fellowship provided funding for data collection. The Hope Project was funded by grants from Grand Challenges Canada (TTS-1812-21131), Uniting for Health Innovation, Global Initiative Against HPV and Cervical Cancer, University of Manitoba, and the John E. Fogarty International Center (5D43TW009375-05).Peer reviewe

Cross-continental comparison of national food consumption survey methods—A narrative review

Food consumption surveys are performed in many countries. Comparison of results from those surveys across nations is difficult because of differences in methodological approaches. While consensus about the preferred methodology associated with national food consumption surveys is increasing, no inventory of methodological aspects across continents is available. The aims of the present review are (1) to develop a framework of key methodological elements related to national food consumption surveys, (2) to create an inventory of these properties of surveys performed in the continents North- America, South-America, Asia and Australasia, and (3) to discuss and compare these methodological properties cross-continentally. A literature search was performed using a fixed set of search terms in different databases. The inventory was completed with all accessible information from all retrieved publications and corresponding authors were requested to provide additional information where missing. Surveys from ten individual countries, originating from four continents are listed in the inventory. The results are presented according to six major aspects of food consumption surveys. The most common dietary intake assessment method used in food consumption surveys worldwide is the 24-HDR (24 h dietary recall), occasionally administered repeatedly, mostly using interview software. Only three countries have incorporated their national food consumption surveys into continuous national health and nutrition examination surveys

The characteristics of solar x-class flares and CMEs: a paradigm for stellar superflares and eruptions?

This paper explores the characteristics of 42 solar X-class flares that were observed between February 2011 and November 2014, with data from the Solar Dynamics Observatory (SDO) and other sources. This flare list includes nine X-class flares that had no associated CMEs. In particular our aim was to determine whether a clear signature could be identified to differentiate powerful flares that have coronal mass ejections (CMEs) from those that do not. Part of the motivation for this study is the characterization of the solar paradigm for flare/CME occurrence as a possible guide to the stellar observations; hence we emphasize spectroscopic signatures. To do this we ask the following questions: Do all eruptive flares have long durations? Do CME-related flares stand out in terms of active-region size vs. flare duration? Do flare magnitudes correlate with sunspot areas, and, if so, are eruptive events distinguished? Is the occurrence of CMEs related to the fraction of the active-region area involved? Do X-class flares with no eruptions have weaker non-thermal signatures? Is the temperature dependence of evaporation different in eruptive and non-eruptive flares? Is EUV dimming only seen in eruptive flares? We find only one feature consistently associated with CME-related flares specifically: coronal dimming in lines characteristic of the quiet-Sun corona, i.e. 1 – 2 MK. We do not find a correlation between flare magnitude and sunspot areas. Although challenging, it will be of importance to model dimming for stellar cases and make suitable future plans for observations in the appropriate wavelength range in order to identify stellar CMEs consistently

Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine

Testicular germ cell tumors (TGCTs) are the most common cancers of young males. A substantial portion of TGCT patients are refractory to cisplatin. There are no effective therapies for these patients, many of whom die from progressive disease. Embryonal carcinoma (EC) are the stem cells of TGCTs. In prior in vitro studies we found that EC cells were highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). Here, as an initial step in bringing demethylation therapy to the clinic for TGCT patients, we evaluated the effects of the clinically optimized, second generation demethylating agent guadecitabine (SGI-110) on EC cells in an animal model of cisplatin refractory testicular cancer. EC cells were exquisitely sensitive to guadecitabine and the hypersensitivity was dependent on high levels of DNA methyltransferase 3B. Guadecitabine mediated transcriptional reprogramming of EC cells included induction of p53 targets and repression of pluripotency genes. As a single agent, guadecitabine completely abolished progression and induced complete regression of cisplatin resistant EC xenografts even at doses well below those required to impact somatic solid tumors. Low dose guadecitabine also sensitized refractory EC cells to cisplatin in vivo. Genome-wide analysis indicated that in vivo antitumor activity was associated with activation of p53 and immune-related pathways and the antitumor effects of guadecitabine were dependent on p53, a gene rarely mutated in TGCTs. These preclinical findings suggest that guadecitabine alone or in combination with cisplatin is a promising strategy to treat refractory TGCT patients

Evaluation of Women's Empowerment in a Community-Based Human Papillomavirus Self-Sampling Social Entrepreneurship Program (Hope Project) in Peru : A Mixed-Method Study

Funding Information: This work was supported by the University of Washington: School of Nursing, the United States Agency for International Development (USAID-DIV 7200AA19FA00001), Duke Universities Bass Connections project titled Analysis of Bringing Elements of Referral Services to Community Care, and GMaP Region 5 program of the Fred Hutch/University of Washington Cancer Consortium 3P30CA015704-46S5. Publisher Copyright: Copyright © 2022 Shin, Garcia, Dotson, Valderrama, Chiappe, Ramanujam, Krieger, Ásbjörnsdóttir, Barnabas, Iribarren and Gimbel.Introduction: Understanding community women's relational and financial empowerment in social entrepreneurship could be the key to scaling up community-based human papillomavirus (HPV) self-sampling programs in low- and middle-income countries. The Hope Project, social entrepreneurship in Peru, trains women (Hope Ladies) to promote HPV self-sampling among other women in their communities. This study aims to evaluate the Hope Ladies' relational and financial empowerment after participating in the program. Materials and Methods: We evaluated the Hope Ladies' experiences of empowerment in social entrepreneurship using a parallel convergent mixed methods design. The Hope Ladies participated in semi-structured in-depth interviews (n = 20) and an eight-questions five-point Likert scale survey that evaluated their relational (n = 19)/financial (n = 17) empowerment. The interview and the survey questions were developed using three empowerment frameworks: Kabeer's conceptual framework, International Center for Research on Women's economic empowerment indicators, and the Relational Leadership Theory. Deductive content analysis was used to evaluate the interviews with pre-determined codes and categories of empowerment. Descriptive statistics were used to analyze the survey results. Qualitative and quantitative data were integrated through a cross-case comparison of emergent themes and corresponding survey responses during the results interpretation. Results: All Hope Ladies reported experiencing increased empowerment in social entrepreneurship. Interviews: The women reported challenges and improvement in three categories of empowerment: (1) resources (balancing between household and Hope Lady roles, recognition from the community as a resource, camaraderie with other Hope Ladies); (2) agency (increased knowledge about reproductive health, improved confidence to express themselves, and ability to speak out against male-dominant culture); and (3) achievement (increased economic assets, improved ability to make financial decisions, and widened social network and capital, and technology skills development). Survey: All (100%) agreed/totally agreed an increase in social contacts, increased unaccompanied visits to a healthcare provider (86%), improved confidence in discussing reproductive topics (100%), improved ability to make household decisions about money (57% pre-intervention vs. 92% post-intervention). Conclusions: The Hope Ladies reported improved relational and financial empowerment through participating in community-based social entrepreneurship. Future studies are needed to elucidate the relationship between empowerment and worker retention/performance to inform the scale-up of HPV self-sampling social entrepreneurship programs.Peer reviewe

Exploring the utility of alcohol flushing as an instrumental variable for alcohol intake in Koreans

Abstract Previous studies have indicated an association of higher alcohol intake with cardiovascular disease and related traits, but causation has not been definitively established. In this study, the causal effect of alcohol intake on hypertension in 2,011 men and women from the Ansan-Ansung cohort was estimated using an instrumental variable (IV) approach, with both a phenotypic and genotypic instrument for alcohol intake: alcohol flushing and the rs671 genotype (in the alcohol dehydrogenase 2 [ALDH2] gene), respectively. Both alcohol flushing and the rs671 genotype were associated with alcohol intake (difference in alcohol intake with alcohol flushers vs. non-flushers: −9.07 g/day; 95% confidence interval [CI]: −11.12, −7.02; P-value: 8.3 × 10−18 and with the rs671 GA + AA vs. GG genotype: −7.94 g/day; 95% CI: −10.20, −5.69; P-value: 6.1 × 10−12). An increase in alcohol intake, as predicted by both the absence of alcohol flushing and the presence of the rs671 GG genotype in the IV analyses, was associated with an increase in blood pressure in men from this Korean population. In conclusion, this study supports a causal effect of alcohol intake on hypertension and indicated that alcohol flushing may be a valid proxy for the ALDH2 rs671 polymorphism, which influences alcohol intake in this Korean population