Toxoplasma gondii commonly infects humans and while most infections are controlled by the immune response, currently approved drugs are not capable of clearing chronic infection in humans. Hence, approximately one third of the world’s human population is at risk of reactivation, potentially leading to severe sequelae. To identify new candidates for treating chronic infection, we investigated a series of compounds derived from diversity-oriented synthesis. Bicyclic azetidines are potent low nanomolar inhibitors of phenylalanine tRNA synthetase (PheRS) in T. gondii, with excellent selectivity. Biochemical and genetic studies validate PheRS as the primary target of bicyclic azetidines in T. gondii, providing a structural basis for rational design of improved analogs. Favorable pharmacokinetic properties of a lead compound provide excellent protection from acute infection and partial protection from chronic infection in an immunocompromised mouse model of toxoplasmosis. Collectively, PheRS inhibitors of the bicyclic azetidine series offer promise for treatment of chronic toxoplasmosis.

Fasciotomy incisions lead to large, unsightly, chronic wounds after surgical intervention. Classic management was to use split-thickness skin grafts, but this leads to insensate skin with reports that as many as 23% of patients are dissatisfied by the appearance of the wound. Since no skin loss has occurred with the fasciotomy incision, utilizing the dermal properties of creep, stress relaxation and load cycling, closure can be achieved in a better way. We describe using dermotaxis for skin edge approximation that is done using inexpensive equipment available readily in any standard operating room. Twenty-five patients had fasciotomy wounds closed either by dermotaxis or a loop suture technique with the inclusion criteria being closed fractures, no concomitant skin loss, fracture-related compartment syndrome and fasciotomy performed within 36 h. The fasciotomy incision was closed in a single stage by loop suture technique or gradually by dermotaxis once the oedema had settled between 3 and 5 days. Results were graded as excellent if approximation could be achieved, good if sutures had to be applied for protective care and poor if wounds needed to be skin-grafted. In the dermotaxis group, results were excellent in 15, good in 8 and poor in 2 cases. In the loop suture technique group, results were excellent in 20, good in 4 and poor in 1 case. Dermal apposition using inexpensive, readily available equipment is an alternative method for closure of fasciotomy wounds. If limb oedema has settled sufficiently, closure using a loop suture can be done in a single stage. If the limb remains oedematous, gradual closure can be done using dermotaxis.

Plasmodium vivax ( Pv ) malaria continues to be geographically widespread with approximately 15 million worldwide cases annually. Along with other proteins, Duffy-binding proteins (DBPs) are used by plasmodium for RBC invasion and the parasite-encoded receptor binding regions lie in their Duffy-binding-like (DBL) domains—thus making it a prime vaccine candidate. This study explores the sequence diversity in Pv DBL globally, with an emphasis on India as it remains a major contributor to the global Pv malaria burden. Based on 1358 Pv DBL protein sequences available in NCBI, we identified 140 polymorphic sites within 315 residues of Pv DBL. Alarmingly, country-wise mapping of SAAPs from field isolates revealed varied and distinct polymorphic profiles for different nations. We report here 31 polymorphic residue positions in the global SAAP profile, most of which map to the Pv DBL subdomain 2 ( α 1– α 6). A distinct clustering of SAAPs distal to the DARC-binding sites is indicative of immune evasive strategies by the parasite. Analyses of Pv DBL-neutralizing antibody complexes revealed that between 24% and 54% of interface residues are polymorphic. This work provides a framework to recce and expand the polymorphic space coverage in Pv DBLs as this has direct implications for vaccine development studies. It also emphasizes the significance of surveying global SAAP distributions before or alongside the identification of vaccine candidates.