Subconjunctival and Orbital (Twin) Cysticercosis in a Child

This article is a Photo Essay and does not include an Abstract

Opinion Detection, Sentiment Analysis and User Attribute Detection from Online Text Data

With the growing increase in the use of the internet in most parts of the world today, users generate significant amounts of online text on different platforms such as online social networks, product review websites, travel blogs, to name just a few. The variety of content on these platforms has made them an important resource for researchers to gauge user activity, determine their opinions and analyze their behavior, without having to perform monetarily and temporally expensive surveys. Gaining insights into user behavior enables us to better understand their likes and dislikes, which in turn is helpful for economic purposes such as marketing, advertising and recommendations. Further, owing to the fact that online social networks have recently been instrumental in socio-political revolutions such as the Arab Spring, and for awareness-generation campaigns by MoveOn.org and Avaaz.org, analysis of online data can uncover user preferences. The overarching goal of this Ph.D. thesis is to pose some research questions and propose solutions, mostly pertaining to user opinions and attributes, keeping in mind the large quantities of noise present in online textual data. This thesis illustrates that with the extraction of informative textual features and the use of robust NLP and machine learning techniques, it is possible to perform efficient signal extraction from online text data, and use it to better understand user behavior. The first research problem addressed is that of opinion detection and sentiment analysis of users on a given topic, from their self-generated tweets. The key idea is to select relevant hashtags and n-grams using an $l_1$-regularized logistic regression model for opinion detection. The second research problem deals with temporal opinion detection from tweets, i.e., detecting user opinions on a topic in which the conversation evolves over time. For instance, on the widely-discussed topic of Obamacare (the Affordable Care Act in the U.S.), various issues became the focal points of discussion among users over time, as corresponding socio-political events and occurrences took place in real-time. We propose a machine-learning model based on seminal work from the sociological literature that is based on the premise that most opinion changes occur slowly over time. Our model is able to successfully capture opinions over time using publicly available tweets, as well as to uncover the key points of discussion as time progresses. In the third research problem, we utilize distributed representation of words in a method that determines, from user reviews, aspects of products and services that users like and dislike. We harness the contextual similarity between words and effectively build meta-features that capture user sentiment at a granular level. Finally in the fourth research problem, we propose a method to detect the age of users from their publicly available tweets. Using a method based on distributed representation of words and clustering, we are able to achieve high accuracies in age detection, as well as to simultaneously discover topics of conversation in which users of different age groups engage

DOCTOR OF MEDICINE AND DIPLOMATE OF NATIONAL BOARD COURSES IN INDIA–ISSUES AND EQUIVALENCE: A COMPARATIVE ANALYSIS

India is the only country in the world running two different doctoral courses for doctors, i.e., Doctor of Medicine (MD) and Diplomate of National Board (DNB). DNB course was introduced in 1975 to overcome shortage of specialist doctors and medical teachers. Both courses have centralized entry examination, similar tenure period, academic and clinical activities, and research exposure and exit examination (in the host institute in MD examination and in designated exit exam centre in institute other than poarent institute in case of DNB examination). Initially, the Ministry of Health and Family Welfare and Medical Council of India (MCI) established the equivalence between two. Discrimination started since October 2012 through MCI gazette notification for DNB trainees from non-MCI recognized institutes with regards to teacher appointment. DNB doctors were united to raise their voice against this. While the Government of India (GOI) is in favor of equivalence between two, MCI is against the same. Recently, MCI is dissolved and is going to be replaced by the National Medical Commission and positive outcome is expected for the DNB side. A recent notification is issued toward equivalence of two courses provided candidate completed DNB course from hospitals with minimum 500 beds. Evaluating quality of education on the basis of number of beds seems unjustifiable as there are many better indicators of quality of medical education. The NMC act also retained the same 500 bed criteria. Taking into account the view point of benefit of population and improvement in medical education in India, it is desirable to reconsider the issue by the Government of India (GOI) and to act accordingly. To enhance the standard of current medical education, higher standards should be imposed in curriculum and centralized exit examination to be made compulsory for both the courses

Endoplasmic Reticulum PI(3)P Lipid Binding Targets Malaria Proteins to the Host Cell

SummaryHundreds of effector proteins of the human malaria parasite Plasmodium falciparum constitute a “secretome” carrying a host-targeting (HT) signal, which predicts their export from the intracellular pathogen into the surrounding erythrocyte. Cleavage of the HT signal by a parasite endoplasmic reticulum (ER) protease, plasmepsin V, is the proposed export mechanism. Here, we show that the HT signal facilitates export by recognition of the lipid phosphatidylinositol-3-phosphate (PI(3)P) in the ER, prior to and independent of protease action. Secretome HT signals, including those of major virulence determinants, bind PI(3)P with nanomolar affinity and amino acid specificities displayed by HT-mediated export. PI(3)P-enriched regions are detected within the parasite's ER and colocalize with endogenous HT signal on ER precursors, which also display high-affinity binding to PI(3)P. A related pathogenic oomycete's HT signal export is dependent on PI(3)P binding, without cleavage by plasmepsin V. Thus, PI(3)P in the ER functions in mechanisms of secretion and pathogenesis

The Malarial Host-Targeting Signal Is Conserved in the Irish Potato Famine Pathogen

Animal and plant eukaryotic pathogens, such as the human malaria parasite Plasmodium falciparum and the potato late blight agent Phytophthora infestans, are widely divergent eukaryotic microbes. Yet they both produce secretory virulence and pathogenic proteins that alter host cell functions. In P. falciparum, export of parasite proteins to the host erythrocyte is mediated by leader sequences shown to contain a host-targeting (HT) motif centered on an RxLx (E, D, or Q) core: this motif appears to signify a major pathogenic export pathway with hundreds of putative effectors. Here we show that a secretory protein of P. infestans, which is perceived by plant disease resistance proteins and induces hypersensitive plant cell death, contains a leader sequence that is equivalent to the Plasmodium HT-leader in its ability to export fusion of green fluorescent protein (GFP) from the P. falciparum parasite to the host erythrocyte. This export is dependent on an RxLR sequence conserved in P. infestans leaders, as well as in leaders of all ten secretory oomycete proteins shown to function inside plant cells. The RxLR motif is also detected in hundreds of secretory proteins of P. infestans, Phytophthora sojae, and Phytophthora ramorum and has high value in predicting host-targeted leaders. A consensus motif further reveals E/D residues enriched within ~25 amino acids downstream of the RxLR, which are also needed for export. Together the data suggest that in these plant pathogenic oomycetes, a consensus HT motif may reside in an extended sequence of ~25–30 amino acids, rather than in a short linear sequence. Evidence is presented that although the consensus is much shorter in P. falciparum, information sufficient for vacuolar export is contained in a region of ~30 amino acids, which includes sequences flanking the HT core. Finally, positional conservation between Phytophthora RxLR and P. falciparum RxLx (E, D, Q) is consistent with the idea that the context of their presentation is constrained. These studies provide the first evidence to our knowledge that eukaryotic microbes share equivalent pathogenic HT signals and thus conserved mechanisms to access host cells across plant and animal kingdoms that may present unique targets for prophylaxis across divergent pathogens

Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance

Artemisinin resistance threatens worldwide malaria control and elimination. Elevation of phosphatidylinositol-3-phosphate (PI3P) can induce resistance in blood stages of Plasmodium falciparum The parasite unfolded protein response (UPR) has also been implicated as a proteostatic mechanism that may diminish artemisinin-induced toxic proteopathy. How PI3P acts and its connection to the UPR remain unknown, although both are conferred by mutation in P falciparum Kelch13 (K13), the marker of artemisinin resistance. Here we used cryoimmunoelectron microscopy to show that K13 concentrates at PI3P tubules/vesicles of the parasite's endoplasmic reticulum (ER) in infected red cells. K13 colocalizes and copurifies with the major virulence adhesin PfEMP1. The PfEMP1-K13 proteome is comprehensively enriched in multiple proteostasis systems of protein export, quality control, and folding in the ER and cytoplasm and UPR. Synthetic elevation of PI3P that induces resistance in absence of K13 mutation also yields signatures of proteostasis and clinical resistance. These findings imply a key role for PI3P-vesicle amplification as a mechanism of resistance of infected red cells. As validation, the major resistance mutation K13C580Y quantitatively increased PI3P tubules/vesicles, exporting them throughout the parasite and the red cell. Chemical inhibitors and fluorescence microscopy showed that alterations in PfEMP1 export to the red cell and cytoadherence of infected cells to a host endothelial receptor are features of multiple K13 mutants. Together these data suggest that amplified PI3P vesicles disseminate widespread proteostatic capacity that may neutralize artemisinins toxic proteopathy and implicate a role for the host red cell in artemisinin resistance. The mechanistic insights generated will have an impact on malaria drug development

A Plasmodium falciparum Host-Targeting Motif Functions in Export during Blood Stage Infection of the Rodent Malarial Parasite Plasmodium berghei

Plasmodium falciparum (P. falciparum) secretes hundreds of proteins—including major virulence proteins—into the host erythrocyte. In order to reach the host cytoplasm, most P. falciparum proteins contain an N terminal host-targeting (HT) motif composed of 11 amino acids. In silico analyses have suggested that the HT motif is conserved throughout the Plasmodium species but experimental evidence only exists for P. falciparum. Here, we show that in the rodent malaria parasite Plasmodium berghei (P. berghei) a reporter-like green fluorescent protein expressed by the parasite can be exported to the erythrocyte cytoplasm in a HT-specific manner. This provides the first experimental proof that the HT motif can function as a signal for protein delivery to the erythrocyte across Plasmodium species. Further, it suggests that P. berghei may serve as a model for validation of P. falciparum secretome proteins. We also show that tubovesicular membranes extend from the vacuolar parasite into the erythrocyte cytoplasm and speculate that these structures may facilitate protein export to the erythrocyte

A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria

Artemisinins are the cornerstone of anti-malarial drugs. Emergence and spread of resistance to them raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination