lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy.

Cryptosporidiosis is a diarrheal disease caused by infection with spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population.

Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism.

A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily ("8HUM") can circumvent these problems.

Integrating Treatment for Maternal Depression and Young Children's Behavior Problems.

It is important to consider reciprocal associations between maternal and offspring mental health problems during early childhood. Existing interventions often focus narrowly on either adult or child mental health, missing the opportunity for holistic care. We describe the rationale and development of a pilot randomized clinical trial that explores their integration, combining an evidence-based parenting intervention with depression treatment to improve both maternal and child outcomes.

Structure-Guided Design and Synthesis of a Pyridazinone Series of Proteasome Inhibitors.

There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the proteasome. A related analogue, active against , showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated.

A Caregiver-Child Intervention for Mitigating Toxic Stress ("The Resiliency Clinic"): A Pilot Study.

Introduction: Primary care-based interventions that promote nurturing caregiving relationships and early relational health may help mitigate toxic stress and promote resilience in children. This pilot study aims to: (1) describe a novel group-based, psychoeducational primary care intervention for children experiencing adverse childhood experiences (ACEs) ("The Resiliency Clinic"), (2) assess program feasibility and acceptability, and (3) explore effects on child/caregiver behavioral health.

Methods: Intervention design centered on promoting supportive caregiving, caregiver/child self-regulation and co-regulation and teaching evidence-based stress management tools.

Development of a label-free Raman imaging technique for differentiation of malaria parasite infected from non-infected tissue.

During malarial infection, the host uses the spleen to clear the malaria parasites, however, the parasites have evolved the ability to bind to endothelial receptors in blood vessels of tissues to avoid removal, known as sequestration, and this is largely responsible for the symptoms and severity of infection. So a technique which could non-invasively diagnose tissue burden could be utilised as an aid for localised malaria diagnosis within tissue. Raman spectroscopy is a label-free imaging technique and can provide unique and chemically specific Raman 'fingerprint' spectrum of biological samples such as tissue.

Marriage education for clinicians.

The field of marriage education has come to be dominated by nonprofessionals with no clinical training because clinicians interested in relationships typically provide marital therapy to couples in distress rather than marriage education to healthy couples. In this paper, we encourage clinicians to participate in the development of marriage education programs, such as that described by our Supporting Healthy Marriage program, which serves a large number of low-income couples, and propose a psychological conceptual framework for delivering marriage education services. It makes sense for clinicians to consider using this novel approach given the opportunity to impact such a large segment of society that might not receive psychological services.

Reasonable efforts? Implementation of the reunification bypass provision of ASFA.

The Adoption and Safe Families Act (ASFA) of 1997 includes provisions to deny reunification services under specified conditions and gives states latitude to develop any number of additional "aggravated circumstances" in which parents need not be offered services. California legislators have developed a relatively large number of conditions enabling agencies to bypass reunification services. Based upon a case record review involving 1,055 parents, this study attempts to identify the proportion of parents eligible for a reunification bypass, the proportion recommended to the courts, and the proportion of parents who were denied reunification services, and examines the characteristics of parents associated with reunification bypass recommendations.

Larval feeding duration affects ecdysteroid levels and nutritional reserves regulating pupal commitment in the yellow fever mosquito Aedes aegypti (Diptera: Culicidae).

What little is known about the endocrine regulation of mosquito development suggests that models based on Lepidoptera and Drosophila may not apply. We report on basic parameters of larval development and the commitment to metamorphosis in the yellow fever mosquito Aedes aegypti that are affected by varying the length of feeding time for last instar larvae. A critical mass for pupal commitment was achieved after 24 h of feeding by last instars, also the age at which tissue production and hemolymph titers of ecdysteroids are increasing.