Peptide toxins that adopt the inhibitory cystine knot (ICK) scaffold have very stable three-dimensional structures as a result of the conformational constraints imposed by the configuration of the three disulfide bonds that are the hallmark of this fold. Understanding the oxidative folding pathways of these complex peptides, many of which are important therapeutic leads, is important in order to devise reliable synthetic routes to correctly folded, biologically active peptides. Previous research on the ICK peptide ProTx-II has shown that in the absence of an equilibrating redox buffer, misfolded intermediates form that prevent the formation of the native disulfide bond configuration. In this paper, we used tandem mass spectrometry to examine these misfolded peptides, and identified two non-native singly bridged peptides, one with a Cys(III)-Cys(IV) linkage and one with a Cys(V)-Cys(VI) linkage. Based on these results, we propose that the C-terminus of ProTx-II has an important role in initiating the folding of this peptide. To test this hypothesis, we have also studied the folding pathways of analogs of ProTx-II containing the disulfide-bond directing group penicillamine (Pen) under the same conditions. We find that placing Pen residues at the C-terminus of the ProTx-II analogs directs the folding pathway away from the singly bridged misfolded intermediates that represent a kinetic trap for the native sequence, and allows a fully oxidized final product to be formed with three disulfide bridges. However, multiple two-disulfide peptides were also produced, indicating that further study is required to fully control the folding pathways of this modified scaffold.

Objective: To examine associations among neighbourhood food environment (NFE), household food insecurity (HFI), and child’s weight-related outcomes in a racially/ethnically diverse sample of US-born and immigrant/refugee families. Design: This cross-sectional, observational study involving individual and geographic-level data used multilevel models to estimate associations between neighbourhood food environment and child outcomes. Interactions between HFI and NFE were employed to determine whether HFI moderated the association between NFE and child outcomes, and whether the associations differed for US-born vs. immigrant/refugee groups. Setting: The sample resided in 367 census tracts in the Minneapolis/St. Paul, MN metropolitan area and the data was collected in 2016-2019 Participants: The sample was from the Family Matters study of families (n=1,296) with children from six racial/ethnic and immigrant/refugee groups (African American, Latino, Hmong, Native American, Somali/Ethiopian, and White). Results: Living in a neighbourhood with low perceived access to affordable fresh fruits and vegetables was found to be associated with lower food security (p<0.01), poorer child diet quality (p<0.01), and reduced availability of a variety of fruits (p<0.01), vegetables (p<0.05), and whole grains in the home (p<0.01). Moreover, residing in a food desert was found to be associated with a higher child BMI percentile if the child’s household was food insecure (p<0.05). No differences in associations were found for immigrant/refugee groups. Conclusions: Poor NFEs were associated with worse weight-related outcomes for children; the association with weight was more pronounced among children with HFI. Interventions aiming to improve child weight-related outcomes should consider both NFE and HFI.

The current crisis will raise existential questions for small and mid-tier institutions. Only universities with massive endowments and highly competitive admissions will escape the effects of the coming enrollment cliff. Special coronavirus relief funding from state and federal governments will improve cash flow in the short term, but they are not permanent solutions. Colleges must act now to cut unnecessary expenses while preserving core academic functions.

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