Diverse Proteomimetic Frameworks via Rational Design of π-Stacking Peptide Tectons.

Peptide-based frameworks aim to integrate protein architecture into solid-state materials using simpler building blocks. Despite the growing number of peptide frameworks, there are few strategies to rationally engineer essential properties like pore size and shape. Designing peptide assemblies is generally hindered by the difficulty of predicting complex networks of weak intermolecular interactions. Peptides conjugated to polyaromatic groups are a unique case where assembly appears to be strongly driven by π-π interactions, suggesting that rationally adjusting the geometry of the π-stackers could create novel structures. Here, we report peptide elongation as a simple mechanism to predictably tune the angle between the π-stacking groups to produce a remarkable diversity of pore shapes and sizes, including some that are mesoporous. Notably, rapid jumps in pore size and shape can occur with just a single amino acid insertion. The geometry of the π-stacking residues also significantly influences framework structure, representing an additional dimension for tuning. Lastly, sequence identity can also indirectly modulate the π-π interactions. By correlating each of these factors with detailed crystallographic data, we find that, despite the complexity of peptide structure, the shape and polarity of the tectons are straightforward predictors of framework structure. These guidelines are expected to accelerate the development of advanced porous materials with protein-like capabilities.

Crystallography reveals metal-triggered restructuring of ß-hairpins.

Metal binding to ß-sheets occurs in many metalloproteins and is also implicated in the pathology of Alzheimer's disease. De novo designed metallo-ß-sheets have been pursued as models and mimics of these proteins. However, no crystal structures of canonical ß-sheet metallopeptides have yet been obtained, in stark contrast to many examples for ɑ-helical metallopeptides, leading to a poor understanding for their chemistry. To address this, we have engineered tryptophan zippers, stable 12-residue ß-sheet peptides, to bind Cu(II) ions and obtained crystal structures through single crystal X-ray diffraction (SC-XRD). We find that metal binding triggers several unexpected supramolecular assemblies that demonstrate the range of higher-order structures available to metallo-ß-sheets. Overall, these findings underscore the importance of crystallography in elucidating the rich structural landscape of metallo-ß-sheet peptides.

Peptide hydrogen-bonded organic frameworks.

Hydrogen-bonded porous frameworks (HPFs) are versatile porous crystalline frameworks with diverse applications. However, designing chiral assemblies or biocompatible materials poses significant challenges. Peptide-based hydrogen-bonded porous frameworks (P-HPFs) are an exciting alternative to conventional HPFs due to their intrinsic chirality, tunability, biocompatibility, and structural diversity. Flexible, ultra-short peptide-based P-HPFs (composed of 3 or fewer amino acids) exhibit adaptable porous topologies that can accommodate a variety of guest molecules and capture hazardous greenhouse gases. Longer, folded peptides present challenges and opportunities in designing P-HPFs. This review highlights recent developments in P-HPFs using ultra-short peptides, folded peptides, and foldamers, showcasing their utility for gas storage, chiral recognition, chiral separation, and medical applications. It also addresses design challenges and future directions in the field.

Pore Restructuring of Peptide Frameworks by Mutations at Distal Packing Residues.

Porous framework materials are highly useful for catalysis, adsorption, and separations. Though they are usually made from inorganic and organic building blocks, recently, folded peptides have been utilized for constructing frameworks, opening up an enormous structure-space for exploration. These peptides assemble in a metal-free fashion using π-stacking, H-bonding, dispersion forces, and the hydrophobic effect. Manipulation of pore-defining H-bonding residues is known to generate new topologies, but the impact of mutations in the hydrophobic packing region facing away from the pores is less obvious. To explore their effects, we synthesized variants of peptide frameworks with mutations in the hydrophobic packing positions and found by single-crystal X-ray crystallography (SC-XRD) that they induce significant changes to the framework pore structure. These structural changes are driven by a need to maximize van der Waals interactions of the nonpolar groups, which are achieved by various mechanisms including helix twisting, chain flipping, chain offsetting, and desymmetrization. Even subtle changes to the van der Waals interface, such as the introduction of a methyl group or isomeric replacement, result in significant pore restructuring. This study shows that the dispersion interactions upholding a peptide material are a rich area for structural engineering.

Deep Learning Provides Rapid Screen for Breast Cancer Metastasis with Sentinel Lymph Nodes.

OBJECTIVE: Deep learning has been shown to be useful in detecting breast cancer metastases by analyzing whole slide images (WSI) of sentinel lymph nodes; however, it requires extensive analysis of all the lymph node slides. Our deep learning study attempts to provide a rapid screen for metastasis by analyzing only a small set of image patches to detect changes in tumor environment. METHODS: We designed a convolutional neural network to build a diagnostic model for metastasis detection. We obtained WSIs of Hematoxylin and Eosin-stained slides from 34 cases with equal distribution in positive/negative categories. Two WSIs were selected from each case for a total of 69 WSIs. From each WSI, 40 image patches (100x100 pixels) were obtained to yield 2720 image patches, from which 2160 (79%) were used for training, 240 (9%) for validation, and 320 (12%) for testing. Interobserver variation was also examined among 3 users. RESULTS: The test results showed excellent diagnostic results: accuracy (91.15%), sensitivity (77.92%), and specificity (92.09%). No significant variation in results was observed among the 3 observers. CONCLUSION: This preliminary study provided a proof of concept for conducting a rapid screen for metastasis rather than an exhaustive search for tumors in all fields of all sentinel lymph nodes.

Rare presentation of thrombosis with bleeding in Behcet's disease.

Behcet's disease (BD) is a rare autoimmune and autoinflammatory disease characterised by recurrent oral and genital aphthous ulcers as well as gastrointestinal, ocular, neurological, articular and vascular inflammation. Patients are at risk for both thrombotic events and bleeding, so providers are often challenged in deciding whether to start patients on anticoagulation. We report a rare, complex case of a patient with BD who presented with massive gastrointestinal bleeding. This case report highlights the management of recurrent thrombosis due to protein C and S deficiency in a patient with BD who also presents with acute gastrointestinal bleeding.

The Emotional Impact of Educational Productivity Videos on YouTube: A Global, Cross-Sectional Survey.

Introduction YouTube is the most popular video-sharing website, and many students use it as a resource to find educational content. One type of video category is "productivity," in which the creator teaches viewers how to lead a more productive lifestyle by sharing ways to maximize studying, reshape daily habits, or set achievable goals. Little research has been conducted on whether these videos actually promote positive or negative feelings among viewers. Methods A survey was created through Qualtrics and shared through YouTube and Instagram. The survey asked about exposure to productivity videos and also asked individuals to share their experiences with consuming productivity-related educational content on YouTube. Survey items asked students to rate the helpfulness of these videos and share their feelings about the content. Respondents were asked to share whether YouTube videos on productivity made them feel anxious, motivated, inspired, neutral/indifferent, or inadequate. Participants were also asked to rate how helpful they found productivity videos on YouTube (1-10, with 10 being most helpful). The survey included free response sections to assess viewers' perceptions and attitudes toward productivity videos. Results The cross-sectional survey amassed 595 responses across 60 countries, with 364 responses coming from individuals within the United States. Of the respondents, 397 of the respondents were female, 177 were male, and 21 preferred not to say or identified as non-binary. The average age of participants was 22 years; 79 were in high school, 174 were in college, 223 were in medical school, and the remainder identified as "other" (graduate school, gap year, etc.). Of the 595 completed responses, 494 reported watching videos on YouTube related to improving productivity; when asked how these videos made them feel, 127 participants answered "anxious," 357 answered "motivated," 308 answered "inspired," 95 answered "neutral/indifferent," and 97 answered "inadequate." When rating how helpful they found these videos (1-10), an average score of 6.8 was recorded. Conclusion Most viewers feel motivated or inspired by productivity videos on YouTube. Based on the free responses provided by survey participants, productivity videos can be made more effective by showing more relatable routines and demonstrating what viewers should do when goals are not met.

Noncovalent Peptide Assembly Enables Crystalline, Permutable, and Reactive Thiol Frameworks.

Though thiols are exceptionally versatile, their high reactivity has also hindered the synthesis and characterization of well-defined thiol-containing porous materials. Leveraging the mild conditions of the noncovalent peptide assembly, we readily synthesized and characterized a number of frameworks with thiols displayed at many unique positions and in several permutations. Importantly, nearly all assemblies were structurally determined using single-crystal X-ray diffraction to reveal their rich sequence-structure landscape and the cooperative noncovalent interactions underlying their assembly. These observations and supporting molecular dynamics calculations enabled rational engineering by the positive and negative design of noncovalent interactions. Furthermore, the thiol-containing frameworks undergo diverse single-crystal-to-single-crystal reactions, including toxic metal ion coordination (e.g., Cd2+, Pb2+, and Hg2+), selective uptake of Hg2+ ions, and redox transformations. Notably, we find a framework that supports thiol-nitrosothiol interconversion, which is applicable for biocompatible nitric oxide delivery. The modularity, ease of synthesis, functionality, and well-defined nature of these peptide-based thiol frameworks are expected to accelerate the design of complex materials with reactive active sites.

Cognition and education benefits of increased hemoglobin and blood oxygenation in children with sickle cell disease.

BACKGROUND: Among individuals with sickle cell disease (SCD), decreased hemoglobin is associated with lower oxygen saturation (SpO2) and increased risk of stroke, both of which are associated with lower intelligence quotient (IQ) scores. Thus, increasing hemoglobin and SpO2 in individuals with SCD may increase IQ and educational attainment. METHODS: A cohort simulation model was built to determine academic performance and educational attainment based on cognitive function (measured by IQ) of a pediatric SCD cohort randomly assigned to treatment and control groups. The model contained two key stages: childhood (<10 years) and adolescence (≥10 years). In stage 1, increased hemoglobin and increased SpO2 (assigned to the treatment group) were determinants of higher IQ, prevention of IQ deterioration over time. Increased hemoglobin was also a determinant of decreased stroke risk. In stage 2, improvement in adolescent IQ as a result of treatment was a determinant of academic performance. RESULTS: In a simulated cohort of 2000 children and adolescents with SCD (52.5% female, 50% treated), stroke incidence was predicted to be 44.4% lower among the treated group than the untreated group (4.5% versus 8.1%, respectively). The average IQ among the treated group was estimated to be 91.1 compared with 82.9 in the untreated group (a 9.9% difference; P<0.001). Finally, high school (≥12 years of education) completion rates were estimated to be 64.7% higher among the treated group: 76.1% of the treated group was projected to complete high school compared with 46.2% of the untreated group. CONCLUSIONS: Our model predicts that an average improvement in hemoglobin of 1.1 g/dL (11 g/L) among individuals with SCD may be associated with improved neurocognition and educational outcomes. These improvements may also generate benefits not captured by our model, including improved quality of life, employment, and income.

Direct Remodeling of Occipital Bullet Deformity in Sagittal Synostosis Improves Two-Year Posterior Morphology After Modified Pi Procedure.

BACKGROUND: Modifications of the Pi craniectomy technique are meant to address the occipital bullet deformity of sagittal synostosis but it is not clear if they result in persistent improvement. Our purpose was to use morphometric analysis to determine if a low occipital osteotomy with verticalization results in improved occipital shape after a modified pi procedure two years after surgery. METHOD: We performed a retrospective cohort study comparing modified Pi technique with and without a low occipital osteotomy with verticalization immediately and two years after surgery relative to age-matched normal controls. We used anthropometric measures and population-level anatomical templates using multivariate template construction script from Advanced Normalization Tools for comparison between groups. A subgroup analysis was performed for severe occipital bullet deformity at presentation. RESULTS: We observed stable improvement in the angle of the inferior occiput with the occipital remodeling modification that persisted two years after surgery. This improvement was seen in the entire cohort and was greater in the severe sub-group analysis. Complications and blood transfusion volumes were not different between the two techniques. The LOOV group demonstrated improved posterior vertical height and cephalic index immediately after surgery, but these did not persist two years later. CONCLUSION: Occipital remodeling improves the bullet deformity but does not affect posterior vertical height two years after surgery. We recommend direct inferior occipital remodeling when using the Pi technique for young patients with acute occipital incline angles and occipital constriction.