Artemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation.

The potency of frontline antimalarial drug artemisinin (ART) derivatives is triggered by heme-induced cleavage of the endoperoxide bond to form reactive heme-ART alkoxy radicals and covalent heme-ART adducts, which are highly toxic to the parasite. ART-resistant (ART-R) parasites with mutations in the Plasmodium falciparum Kelch-containing protein Kelch13 (PfKekch13) exhibit impaired hemoglobin uptake, reduced yield of hemoglobin-derived heme, and thus decreased ART activation. However, any direct involvement of PfKelch13 in heme-mediated ART activation has not been reported.

Bangladesh should engage the private sector for malaria elimination by 2030.

Bangladesh reduced malaria incidence by 93% from 2008 to 2020 through the action of governmental and non-governmental organizations. The Bangladesh context is unique to South Asia because its successful public sector malaria control programs have historically not engaged corporate partners (as undertaken in Sri Lanka and proposed in India). However, ∼18 million people continue to live at risk of infection in Bangladesh and for-profit private healthcare providers, catalytic for malaria elimination in many countries, are expected to benefit the national program.

Long-range action of an HDAC inhibitor treats chronic pain in a spared nerve injury rat model.

Histone deacetylase inhibitors (HDACi) that modulate epigenetic regulation and are approved for treating rare cancers have, in disease models, also been shown to mitigate neurological conditions, including chronic pain. They are of interest as non-opioid treatments, but achieving long-term efficacy with limited dosing has remained elusive. Here we utilize a triple combination formulation (TCF) comprised of a pan-HDACi vorinostat (Vo at its FDA-approved daily dose of 50mg/Kg), the caging agent 2-hydroxypropyl-β-cyclodextrin (HPBCD) and polyethylene glycol (PEG) known to boost plasma and brain exposure and efficacy of Vo in mice and rats, of various ages, spared nerve injury (SNI) model of chronic neuropathic pain.

Bangladesh in the era of malaria elimination.

Bangladesh has dramatically reduced malaria by 93% from 2008 to 2020. The strategy has been district-wise, phased elimination; however, the last districts targeted for elimination include remote, forested regions which present several challenges for prevention, detection, and treatment of malaria. These districts border Myanmar which harbors Plasmodium falciparum malaria parasites resistant to artemisinins, key drugs used in artemisinin-based combination therapies (ACTs) that have been vital for control programs.

Simultaneous adjunctive treatment of malaria and its coevolved genetic disorder sickle cell anemia.

Effective treatments for genetic disorders that coevolved with pathogens require simultaneous betterment of both conditions. Hydroxyurea (HU) offers safe and efficacious treatment for sickle cell anemia (SCA) by reducing clinical complications, transfusions, and death rates. Despite concerns that the HU treatment for SCA would increase infection risk by the human malaria Plasmodium falciparum, (the genetic driver of the sickle mutation), HU instead reduced clinical malaria.

Generation of three induced pluripotent stem cell lines from a patient with Kabuki syndrome carrying the KMT2D p.R4198X mutation.

Kabuki syndrome (KS) is a rare genetic disorder typically characterized by facial abnormalities, developmental delay, cognitive dysfunction, and organ impairment. In this report, fibroblast cells obtained from a KS patient containing a heterozygous KMT2D c.12592 C>T mutation (p.

Assessment of Plasmodium falciparum Artemisinin Resistance Independent of Polymorphisms and with Escalating Malaria in Bangladesh.

Emerging resistance to artemisinin drugs threatens the elimination of malaria. Resistance is widespread in South East Asia (SEA) and Myanmar. Neighboring Bangladesh, where 90% of infections occur in the Chittagong Hill Tracts (CHTs), lacks recent assessment.

Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease.

Hundreds of mutations in a single gene result in rare diseases, but why mutations induce severe or attenuated states remains poorly understood. Defect in glycine decarboxylase (GLDC) causes Non-ketotic Hyperglycinemia (NKH), a neurological disease associated with elevation of plasma glycine. We unified a human multiparametric NKH mutation scale that separates severe from attenuated neurological disease with new in silico tools for murine and human genome level-analyses, gathered in vivo evidence from mice engineered with top-ranking attenuated and a highly pathogenic mutation, and integrated the data in a model of pre- and post-natal disease outcomes, relevant for over a hundred major and minor neurogenic mutations.

Identification of tyrosine kinase inhibitors that halt Plasmodium falciparum parasitemia.

Although current malaria therapies inhibit pathways encoded in the parasite's genome, we have looked for anti-malaria drugs that can target an erythrocyte component because development of drug resistance might be suppressed if the parasite cannot mutate the drug's target. In search for such erythrocyte targets, we noted that human erythrocytes express tyrosine kinases, whereas the Plasmodium falciparum genome encodes no obvious tyrosine kinases. We therefore screened a library of tyrosine kinase inhibitors from Eli Lilly and Co.

Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein.

Von Hippel-Lindau disease (VHL) is an autosomal dominant rare disease that causes the formation of angiogenic tumors. When functional, pVHL acts as an E3 ubiquitin ligase that negatively regulates hypoxia inducible factor (HIF). Genetic mutations that perturb the structure of pVHL result in dysregulation of HIF, causing a wide array of tumor pathologies including retinal angioma, pheochromocytoma, central nervous system hemangioblastoma, and clear cell renal carcinoma.

Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity.

Monogenetic diseases provide unique opportunity for studying complex, clinical states that underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH is a neuro-metabolic disorder lacking quantitative predictors of disease states.

Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing.

Background: von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations. Synonymous mutations are expected to be phenotypically silent and their role in VHL disease remains poorly understood.

Complications of Insufficient Dura and Blood Loss During Surgical Intervention in Shprintzen-Goldberg Syndrome: A Case Report.

BACKGROUND Shprintzen-Goldberg syndrome (SGS) is an extremely rare collagenopathy, most often caused by autosomal-dominant mutations in the SKI proto-oncogene, which is a component of the transforming growth factor beta (TGF-ß) signaling pathway. Approximately 50-60 cases of SGS have been recorded in the literature worldwide since its discovery in 1982. This collagen disorder affects bone and vascular development throughout the body, resulting in craniosynostosis, scoliosis, chest deformities, and aortic root dilation.

Mechanisms of artemisinin resistance in Plasmodium falciparum malaria.

Artemisinin-based combination therapies (ACTs) have substantially reduced worldwide malaria burden and deaths. But malaria parasites have become resistant to artemisinins. Prior studies suggested two different molecular pathways of artemisinin-resistance.

Tolerance of chronic HDACi treatment for neurological, visceral and lung Niemann-Pick Type C disease in mice.

Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use to treat neurological disorders has raised concern because HDACs are required for brain function. We have previously shown that a triple combination formulation (TCF) of the pan HDACi vorinostat (Vo), 2-hydroxypropyl-beta-cyclodextrin (HPBCD) and polyethylene glycol (PEG) 400 improves pharmacokinetic exposure and entry of Vo into the brain.

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 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 Kelch13 (K13), the marker of artemisinin resistance.

Drug resistance in Plasmodium.

A marked decrease in malaria-related deaths worldwide has been attributed to the administration of effective antimalarials against Plasmodium falciparum, in particular, artemisinin-based combination therapies (ACTs). Increasingly, ACTs are also used to treat Plasmodium vivax, the second major human malaria parasite. However, resistance to frontline artemisinins and partner drugs is now causing the failure of P.

Pluronic based β-cyclodextrin polyrotaxanes for treatment of Niemann-Pick Type C disease.

Niemann-Pick Type C disease (NPC) is a rare metabolic disorder characterized by disruption of normal cholesterol trafficking within the cells of the body. There are no FDA approved treatments available for NPC patients. Recently, the cycloheptaglucoside 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) has shown efficacy as a potential NPC therapeutic by extending lifetime in NPC mice, delaying neurodegeneration, and decreasing visceral and neurological cholesterol burden.

Protein trafficking in apicomplexan parasites: crossing the vacuolar Rubicon.

Although apicomplexans like the blood stages of Plasmodium and the actively replicating 'tachyzoite' stage of Toxoplasma infect very dissimilar host cells, recent studies suggest they share molecular commonalities amongst differences at the parasitophorous vacuolar membrane (PVM) surrounding these intracellular parasites. A protein translocation export (PTEX) complex in the PVM of Plasmodium, is functionally informed by findings in Toxoplasma. Lipids play a role in trafficking to and across the PVM.

Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model.

Histone deacetylase inhibitors (HDACi) are approved for treating rare cancers and are of interest as potential therapies for neurodegenerative disorders. We evaluated a triple combination formulation (TCF) comprising the pan-HDACi vorinostat, the caging agent 2-hydroxypropyl-β-cyclodextrin (HPBCD), and polyethylene glycol (PEG) for treating a mouse model (the Npc1(nmf164) mouse) of Niemann-Pick type C (NPC) disease, a difficult-to-treat cerebellar disorder. Vorinostat alone showed activity in cultured primary cells derived from Npc1(nmf164) mice but did not improve animal survival.