Transferrin receptor targeting by de novo sheet extension.

The de novo design of polar protein-protein interactions is challenging because of the thermodynamic cost of stripping water away from the polar groups. Here, we describe a general approach for designing proteins which complement exposed polar backbone groups at the edge of beta sheets with geometrically matched beta strands. We used this approach to computationally design small proteins that bind to an exposed beta sheet on the human transferrin receptor (hTfR), which shuttles interacting proteins across the blood-brain barrier (BBB), opening up avenues for drug delivery into the brain. We describe a design which binds hTfR with a 20 nM Kd, is hyperstable, and crosses an in vitro microfluidic organ-on-a-chip model of the human BBB. Our design approach provides a general strategy for creating binders to protein targets with exposed surface beta edge strands.

Reconfigurable asymmetric protein assemblies through implicit negative design.

Asymmetric multiprotein complexes that undergo subunit exchange play central roles in biology but present a challenge for design because the components must not only contain interfaces that enable reversible association but also be stable and well behaved in isolation. We use implicit negative design to generate ß sheet-mediated heterodimers that can be assembled into a wide variety of complexes. The designs are stable, folded, and soluble in isolation and rapidly assemble upon mixing, and crystal structures are close to the computational models. We construct linearly arranged hetero-oligomers with up to six different components, branched hetero-oligomers, closed C4-symmetric two-component rings, and hetero-oligomers assembled on a cyclic homo-oligomeric central hub and demonstrate that such complexes can readily reconfigure through subunit exchange. Our approach provides a general route to designing asymmetric reconfigurable protein systems.

Smoking cessation methods among homeless youth in a Midwestern city.

INTRODUCTION: Nearly three times as many homeless youth smoke cigarettes in the United States (US) compared to the general population of youth. Few studies have focused on how to help homeless youth quit smoking. As part of a series of studies to develop a smoking cessation intervention for homeless youth, this study aimed to describe methods used in past quit attempts by homeless youth. METHODS:  Recruited from a drop-in center in the Midwestern US, the analytic sample was comprised of 32 unaccompanied homeless youth aged 14-24 who smoked combustible tobacco at some point in the past week. In-person qualitative interviews were conducted to understand prior quit attempt experiences of homeless youth. RESULTS: Twenty-two youth (69%) were willing to quit smoking in the next 30 days. Most previous quit attempts were unassisted (78%). Participants frequently reported engaging in distracting behaviors (e.g., video games) or thoughts (e.g., remaining positive). Nicotine replacement therapy (NRT) was another popular method (38%), but with mostly negative reactions. While less common, vaping and use of cannabis to substitute cigarettes was reported in a notable faction of youth (28%), primarily 18-24 years of age. CONCLUSIONS: Youth are primarily engaging in non-evidence-based strategies to quit smoking. Existing evidence-based treatments are often underutilized or not used according to instructions, and youth who do use evidence-based treatments do not find them useful. Future research should explore effective cessation treatment among homeless youth that can ideally be provided at shelters and drop-in centers. IMPLICATIONS: Existing evidence-based treatments are underutilized by homeless youth in this study. Most homeless youth are willing to quit in the next month and are interested in trying behavioral counseling and monitored use of NRT. Drop-in centers may be an effective location from which to develop and offer targeted smoking cessation interventions for homeless youth.

Who Stays in Treatment? Child and Family Predictors of Youth Client Retention in a Public Mental Health Agency.

The present study examined possible predictors of youth client retention in therapy in a large community-based sample. We used several conceptualizations of retention, including (a) "intake retention" (i.e., returned to treatment after intake session); (b) "mutual termination" (i.e., termination agreed upon by family and therapist), (c) "mean treatment duration" (i.e., completing the mean number of sessions in the agency), and (d) "total treatment duration" (i.e., total number of sessions). Archival data from over 400 children and adolescents who sought treatment at a large public mental health clinic were analyzed using regression analyses. Although different predictors were identified across the various conceptualizations, a few robust predictors emerged including ethnicity and client symptom severity. Clinical implications and future research directions are discussed.

Are children with anxiety disorders privately referred to a university clinic like those referred from the public mental health system?

Compared two groups of children with anxiety disorders served at a single mental health clinic whose referral source differed: private referrals (i.e., parent/legal guardian initiated) and public referrals (e.g., via state contracts--Departments of Health and Education, juvenile justice system). Comparisons were made across three domains of variables: (a) symptoms/diagnoses, (b) functioning, and (c) environments. Few symptom differences emerged. However, large differences were evident for contextual variables like family income and life stressors. Overall, the pattern of differences point to possible directions for adaptation of treatments for use with children with anxiety disorders served in public mental health systems.