Glideosomal GAP50 binders that inhibit invasion and restrict malaria parasite in vitro and in vivo

Malaria continues to be a killer disease even in the modern world. Vaccines and drugs have a lot to learn from the malaria parasite before they can be successful. Here, using a filter for glideosomal anchor protein PfGAP50, we have explored a plethora of small molecules to shortlist eight GAP50 binders with promising antiplasmodial activity (IC50 < 3 µM) that are also highly selective. Of these, Hayatinin, Bedaquiline, MMV688271, Curine, and Brilacidin with PfINDO IC50 ≤ 1 µM were found to stall merozoites invasion by inhibiting IMC formation besides increasing ROS levels in trophozoites. Bedaquiline loaded healthy RBCs showed prophylactic ability to prevent intraerythrocytic development of malaria parasite. Synergistic activities with ΣFIC values as low as 0.22 (Curine and Artemisinin) or 0.37 (Bedaquiline and Artemisinin) augur well for the development of drug combinations to combat malaria effectively. Interestingly, orally delivered Bedaquiline (50 mg/Kg b. wt.) showed substantial suppression of parasitemia in the mouse model of malaria.

Glideosomal GAP50 binders that inhibit invasion and restrict malaria parasite in vitro and in vivo

Malaria continues to be a killer disease even in the modern world. Vaccines and drugs have a lot to learn from the malaria parasite before they can be successful. Here, using a filter for glideosomal anchor protein PfGAP50, we have explored a plethora of small molecules to shortlist eight GAP50 binders with promising antiplasmodial activity (IC50 < 3 µM) that are also highly selective. Of these, Hayatinin, Bedaquiline, MMV688271, Curine, and Brilacidin with PfINDO IC50 ≤ 1 µM were found to stall merozoites invasion by inhibiting IMC formation besides increasing ROS levels in trophozoites. Bedaquiline loaded healthy RBCs showed prophylactic ability to prevent intraerythrocytic development of malaria parasite. Synergistic activities with ΣFIC values as low as 0.22 (Curine and Artemisinin) or 0.37 (Bedaquiline and Artemisinin) augur well for the development of drug combinations to combat malaria effectively. Interestingly, orally delivered Bedaquiline (50 mg/Kg b. wt.) showed substantial suppression of parasitemia in the mouse model of malaria.

Myogenin controls via AKAP6 non-centrosomal microtubule organizing center formation at the nuclear envelope

Non-centrosomal microtubule organizing centers (MTOC) are pivotal for the function of multiple cell types, but the processes initiating their formation are unknown. Here, we find that the transcription factor myogenin is required in murine myoblasts for the localization of MTOC proteins to the nuclear envelope. Moreover, myogenin is sufficient in fibroblasts for nuclear envelope MTOC (NE-MTOC) formation and centrosome attenuation. Bioinformatics combined with loss- and gain-of-function experiments identified induction of AKAP6 expression as one central mechanism for myogenin-mediated NE-MTOC formation. Promoter studies indicate that myogenin preferentially induces the transcription of muscle- and NE-MTOC-specific isoforms of Akap6 and Syne1, which encodes nesprin-1α, the NE-MTOC anchor protein in muscle cells. Overexpression of AKAP6β and nesprin-1α was sufficient to recruit endogenous MTOC proteins to the nuclear envelope of myoblasts in the absence of myogenin. Taken together, our results illuminate how mammals transcriptionally control the switch from a centrosomal MTOC to an NE-MTOC and identify AKAP6 as a novel NE-MTOC component in muscle cells.

Efforts to Generate a Male Contraception Just by Prevention of Sperm Motility Acquirement in Epididymis Without Influencing the Physiology of Spermatogenesis: Yet Still a Little Far Goal

In view of the world population escalating at an alarming rate anticipated population will reach 9.8 billion by 2050. In contrast to female contraceptive measures male contraceptive methods are relatively negligible. Maximum researchers have concentrated on generation of male contraceptive methods by trying to modulate hormones but had to abandon this strategy as the pharmaceutical companies were not happy in view of marked adverse actions. Maximum nonhormonal strategies in research concentrate on spermatogenesis repression or reversible physical barriers. Sperm motility represents one of the maximum significant markers of semen quality as it is necessary for sperm motion appropriately in the female reproductive tract for it to arrive intricately towards the egg as well as fertilize it. The group of Vijayraghavan S, et al. have been concentrating on generation of a male contraceptive by utilization of targeting sperm motility at epididymal level by extensively studying the regulation of flaggelar protein motion by various subunits like Protein Phosphatase 1 (PP1), Protein Phosphatase Inhibitor-2 (PPPIR2), its phosphorylation by Glycogen Synthase Kinase-3 (GSK3), A kinase anchor protein 4(AKAP4). Recently they attempted to generate a bioportide that could simulate binding of the anchor protein AKAP4 that had been earlier revealed as a PPγ2 interactor in human sperm,that are implicated in sperm motility .Unfortunately that did not abolish sperm motility completely .This seemed to be surprising as PP1/ PPPIR2crosstalk seems to be central in regulation of sperm motility. Thus Silva et al., pointed that evaluation of the probable part of PPPIR7 as well as PPPIR11 in the manipulation of sperm motility in men might be the aim of future studies that needs to be continued to get more insight in this field.

Omic markers identification for predicting risks of negative effects in children with elevated copper and nickel contents in blood

Proteomic profiling is a promising procedure for examining and substantiating molecular mechanisms of body reactions occurrence and development as a response to adverse impacts; it allows detecting and examining these reactions at early stages in their development prior to cellular damage and damage to organs. Studies aimed at increasing efficiency of adverse effects prediction are especially vital for solving tasks related to early detection and prevention of consequences associated with exposure to chemical environmental factors, first of all, ambient air. Our research goal was to identify omic-markers for predicting risks of negative effects in children with elevated copper and nickel contents in blood. We performed proteomic blood plasma examination in children and modeled cause-and-effect relations. Children with copper and nickel contents in their blood being 3.5 times higher than physiological standard had approximately 20 protein stains that were authentically different from those detected in children from the reference group. We detected correlations between an increase in relative volume of three protein stains including apolipoprotein A-I, anchor protein of A-kinase 9, vitronectin, and a decrease in relative volume of one protein strain including transthyretin and elevated copper and nickel contents in blood (R2=0.30–0.44; р=0.0001–0.008). All the above-mentioned proteins have predictive significance when it comes down to negative effects related to neuroregulation disorders and endothelial dysfunction. It was proven that there was a risk of predicted negative effects such as greater frequency of nervous and cardiovascular system diseases in case copper and nickel contents in blood were elevated (R2=0.35–0.96; р=0.0001–0.013). The established list of potential target molecules (apolipoprotein A-I, vitronectin, anchor protein of A-kinase 9, and transthyretin) and genes that coded their expression (APOA1, VTN,AKAP9,TTR) was substantiated as omic-markers indicating a possibility that negative effects might occur in the cardiovascular and nervous system.

Omic markers identification for predicting risks of negative effects in children with elevated copper and nickel contents in blood

Proteomic profiling is a promising procedure for examining and substantiating molecular mechanisms of body reactions occurrence and development as a response to adverse impacts; it allows detecting and examining these reactions at early stages in their development prior to cellular damage and damage to organs. Studies aimed at increasing efficiency of adverse effects prediction are especially vital for solving tasks related to early detection and prevention of consequences associated with exposure to chemical environmental factors, first of all, ambient air. Our research goal was to identify omic-markers for predicting risks of negative effects in children with elevated copper and nickel contents in blood. We performed proteomic blood plasma examination in children and modeled cause-and-effect relations. Children with copper and nickel contents in their blood being 3.5 times higher than physiological standard had approximately 20 protein stains that were authentically different from those detected in children from the reference group. We detected correlations between an increase in relative volume of three protein stains including apolipoprotein A-I, anchor protein of A-kinase 9, vitronectin, and a decrease in relative volume of one protein strain including transthyretin and elevated copper and nickel contents in blood (R2=0.30–0.44; р=0.0001–0.008). All the above-mentioned proteins have predictive significance when it comes down to negative effects related to neuroregulation disorders and endothelial dysfunction. It was proven that there was a risk of predicted negative effects such as greater frequency of nervous and cardiovascular system diseases in case copper and nickel contents in blood were elevated (R2=0.35–0.96; р=0.0001–0.013). The established list of potential target molecules (apolipoprotein A-I, vitronectin, anchor protein of A-kinase 9, and transthyretin) and genes that coded their expression (APOA1, VTN,AKAP9,TTR) was substantiated as omic-markers indicating a possibility that negative effects might occur in the cardiovascular and nervous system.

Myogenin controls via AKAP6 non-centrosomal microtubule organizing center formation at the nuclear envelope

Non-centrosomal microtubule organizing centers (ncMTOC) are pivotal for the function of multiple cell types, but the processes initiating their formation are unknown. Here, we find that the transcription factor myogenin is required in myoblasts for recruiting centrosomal proteins. Moreover, myogenin is sufficient in fibroblasts for ncMTOC formation and centrosome attenuation. Bioinformatics combined with loss- and gain-of-function experiments identified induction of AKAP6 expression as one central mechanism for myogenin-mediated ncMTOC formation. Promoter studies indicate that myogenin preferentially induces the transcription of muscle- and ncMTOC-specific isoforms of Akap6 and Syne1, which encodes nesprin-1α, the ncMTOC anchor protein in muscle cells. Overexpression of AKAP6β and nesprin-1α was sufficient to recruit endogenous centrosomal proteins to the nuclear envelope of myoblasts in the absence of myogenin. Taken together, our results illuminate how mammals transcriptionally control the switch from a centrosomal MTOC to an ncMTOC and identify AKAP6 as a novel ncMTOC component in muscle cells.