We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral bioavailability. We designed ...184 6–12 residue macrocycles with a wide range of predicted structures containing noncanonical backbone modifications and experimentally determined structures of 35; 29 are very close to the computational models. With such control, we show that membrane permeability can be systematically achieved by ensuring all amide (NH) groups are engaged in internal hydrogen bonding interactions. 84 designs over the 6–12 residue size range cross membranes with an apparent permeability greater than 1 × 10−6 cm/s. Designs with exposed NH groups can be made membrane permeable through the design of an alternative isoenergetic fully hydrogen-bonded state favored in the lipid membrane. The ability to robustly design membrane-permeable and orally bioavailable peptides with high structural accuracy should contribute to the next generation of designed macrocycle therapeutics.
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•Computational design of diverse permeable macrocycles beyond the “rule-of-five” space•X-ray and NMR structures of designed macrocycles match their computational models•Designed macrocycles are permeable in vitro and orally bioavailable in vivo•Designed chameleonic peptides show solvent-dependent conformational switching
An investigation of the design principles of macrocyclic peptide membrane permeability and oral bioavailability enables the generation of synthetic macrocycles that fold into the predicted conformation, can cross membranes, and even adopt different conformations depending on polar versus nonpolar contexts.
Undergraduate research experiences can improve student success in graduate education and STEM careers. During the COVID-19 pandemic, undergraduate researchers at our institution and many others lost ...their work–study research positions due to interruption of in-person research activities. This imposed a financial burden on the students and eliminated an important learning opportunity. To address these challenges, we created a paid, fully remote, cohort-based research curriculum in computational protein design. Our curriculum used existing protein design methods as a platform to first educate and train undergraduate students and then to test research hypotheses. In the first phase, students learned computational methods to assess the stability of designed protein assemblies. In the second phase, students used a larger data set to identify factors that could improve the accuracy of current protein design algorithms. This cohort-based program created valuable new research opportunities for undergraduates at our institute and enhanced the undergraduates’ feeling of connection with the lab. Students learned transferable and useful skills such as literature review, programming basics, data analysis, hypothesis testing, and scientific communication. Our program provides a model of structured computational research training opportunities for undergraduate researchers in any field for organizations looking to expand educational access.
Increasing access, representation, and retention of underrepresented groups is essential across academia. Invited speaker seminars are common practice in academic science departments and serve to ...disseminate research, establish connections and collaborations, advance faculty careers, and connect trainees to mentors outside of departmental faculty. Thus, lack of representation among seminar speakers can affect both faculty and trainee professional development. This study characterizes gender demographics of seminar speakers across science departments at an R1 institution for the years 2015–2019, using pronoun usage as a proxy for gender identity. We found that most faculty and invited speakers were male, and few were female or nonbinary. The percentage of female and nonbinary invited speakers increased from 2015–2019 along with the percentage of female and nonbinary host faculty. Overall, male faculty hosted fewer female and nonbinary speakers than their female and nonbinary faculty colleagues. This study provides evidence for a correlation between faculty identity and the scientists they host at their department and motivates further studies investigating this relationship at other R1 institutions and institution types.
Inactivity‐related diseases such as cardiovascular disease (CVD) involve a complex interplay among endothelial cells, leukocytes and activated platelets in response to vascular injury. Activated ...platelets are involved in atherogenesis and can promote an inflammatory phenotype of both the vasculature and leukocytes, particularly monocytes. Platelet‐monocyte complexes (PMCs) are markers of in vivo platelet activation and may be early indicators of subclinical inflammation.
PURPOSE
To examine the influence of combined aerobic and resistance exercise training on platelet activation, as measured by PMCs, and to characterize the acute exercise‐induced response of PMCs in a population at risk for CVD.
METHODS
Thirty‐eight overweight‐obese (BMI: 32.8 ± 4.6 kg×m−2, age: 64 ± 5.1 years) post‐menopausal women were randomly assigned to either an exercise (EX, n=20) or education control (ED, n=18) group. EX performed 2 sets of 8 resistance exercises and 25 minutes of treadmill walking three times a week for 12 weeks while ED attended education classes (CPR certification, invited authors, health‐related talks) twice weekly for the same duration. Before (BT) and after (AT) the intervention, EX performed a single exercise bout during which blood was obtained pre‐exercise, immediately post‐exercise, 1‐hour and 2 hours post‐exercise. Blood was obtained at the same time points in resting ED. PMCs were identified via flow cytometry and analyzed in each monocyte phenotype. Monocyte phenotypes were defined as: Mon1 (CD14++CD16−), Mon2 (CD14++CD16+), and Mon3 (CD14loCD16++). All events positive for both CD14 and CD42a (marker for platelets) were considered PMCs.
RESULTS
Exercise training resulted in a significant increase in VO2max (BT: 21.1 ± 0.85, AT: 23.7 ± 0.90 ml×kg−1×min−1, p < 0.001) and leg press strength (BT: 70 ± 4.1, AT: 99 ± 5.9 kg, p < 0.001), while no changes in fitness were observed in ED. Exercise training (EX: BT = 27.6 ± 2.7, AT = 23.7 ± 2.9 %) prevented the observed increase in percent PMC in ED (ED: BT = 20.9 ± 2.9, AT = 26.4 ± 3.2 %, p = 0.029). We observed a group x training interaction where exercise training reduced mean PMC percentage across all time points (EX: BT = 27.6 ± 2.4, AT = 22.1 ± 2.8 %, p = 0.034) while ED did not change (ED: BT = 20.2 ± 2.5, AT = 23.6 ± 2.9 %). PMCs formed with Mon1 monocytes followed a similar response (p = 0.031), but no significant changes were observed with PMCs formed in Mon2 or Mon3. A single exercise bout did not influence PMCs in any phenotype.
CONCLUSION
Our results indicate that 12 weeks of combined exercise training reduces PMC formation in obese, postmenopausal women; however, a single bout of exercise did not significantly change percent PMC. The increase in PMCs in ED after the intervention is difficult to explain, but may be related to the time of year of the BT and AT experimental trials. These data may provide evidence that exercise training reduces CVD risk via reductions in platelet activation.
Support or Funding Information
TCU Invests in Scholarship Grant; TCU Research and Creative Activities Fund
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
Cyclic peptides fill an intermediate niche between traditional small molecule therapeutics and larger biologics. In ideal cases they combine the passive permeability and oral availability of small ...molecules with the binding specificity of larger biologics. However, achieving both of these features in a single designed cyclic peptide has remained elusive, with the majority of clinically approved cyclic peptides being derived from natural products. In order to address this problem my doctoral research focuses on developing new methods for the de novo computational design of cyclic peptides to have improved permeability and binding properties. Collaborators and I designed over 70 cyclic peptides that have apparent passive membrane permeabilities > 1*10^-6 cm/s that are of a broader size and conformational range than have been previously reported. I also worked to expand computational methods for the incorporation of noncanonical amino acids at cyclic peptide binder interfaces to increase predicted binding affinity.
Recently,single nucleotide polymorphisms,in the vicinity of the interferon lambda 3(IFNL3)gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of ...hepatitis C virus(HCV)infection.Since then,increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype effect.Dendritic cells(DCs)are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is emerging.Reports have identified subclasses of DCs,particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV infection.Given the complexities of dendritic cell biology and the conflicting current available data,this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to placeit into context of what is know about lambda interferons and dendritic cells in general.
Ferroptosis is a form of regulated cell death that can be induced by inhibition of the cystine-glutamate antiporter, system x
. Among the existing system x
inhibitors, imidazole ketone erastin (IKE) ...is a potent, metabolically stable inhibitor of system x
and inducer of ferroptosis potentially suitable for in vivo applications. We investigated the pharmacokinetic and pharmacodynamic features of IKE in a diffuse large B cell lymphoma (DLBCL) xenograft model and demonstrated that IKE exerted an antitumor effect by inhibiting system x
, leading to glutathione depletion, lipid peroxidation, and the induction of ferroptosis biomarkers both in vitro and in vivo. Using untargeted lipidomics and qPCR, we identified distinct features of lipid metabolism in IKE-induced ferroptosis. In addition, biodegradable polyethylene glycol-poly(lactic-co-glycolic acid) nanoparticles were employed to aid in IKE delivery and exhibited reduced toxicity compared with free IKE in a DLBCL xenograft model.
Next‐generation wearable electronics call for flexible nonvolatile devices for ubiquitous data storage. Thus far, only organic ferroelectric materials have shown intrinsic flexibility and ...processability on plastic substrates. Here, it is shown that by controlling the heating rate, ferroelectric hafnia films can be grown on plastic substrates. The resulting highly flexible capacitor with a film thickness of 30 nm yields a remnant polarization of 10 µC cm−2. Bending tests show that the film ferroelectricity can be retained under a bending radius below 8 mm with up to 1000 bending cycles. The excellent flexibility is due to the extremely thin hafnia film thickness. Using the ferroelectric film as a gate insulator, a low voltage nonvolatile vertical organic transistor is demonstrated on a plastic substrate with an extrapolated date retention time of up to 10 years.
Flexible nonvolatile memory is developed using inorganic ferroelectric thin films. By controlling the heating rate, ferroelectric hafnia films can be grown on flexible substrates. Excellent bending tolerance is observed due to the thin hafnia film thickness. Making use of the film as a gate insulator, a nonvolatile vertical field‐effect transistor is demonstrated with extrapolated data retention times to 10 years.
Artificial light at night (ALAN) is a recently acknowledged form of anthropogenic pollution of growing concern to the biology and ecology of exposed organisms. Though ALAN can have detrimental ...effects on physiology and behaviour, we have little understanding of how marine organisms in coastal areas may be impacted. Here, we investigated the effects of ALAN exposure on coral reef fish larvae during the critical recruitment stage, encompassing settlement, metamorphosis, and post-settlement survival. We found that larvae avoided illuminated settlement habitats, however those living under ALAN conditions for 10 days post-settlement experienced changes in swimming behaviour and higher susceptibility to nocturnal predation. Although ALAN-exposed fish grew faster and heavier than control fish, they also experienced significantly higher mortality rates by the end of the experimental period. This is the first study on the ecological impacts of ALAN during the early life history of marine fish.
Exposure of fish to artificial light at night during the recruitment stage. Results show various behavioural and physiological impacts of light pollution including habitat avoidance at settlement (A.), disruption to endocrine and metabolic systems during metamorphosis (B.) and increased susceptibility to predation as post-larvae (C.). Display omitted
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