Aggregation of an Amyloidogenic Peptide on Gold Surfaces.

Solid surfaces have been shown to affect the aggregation and assembly of many biomolecular systems. One important example is the formation of protein fibrils, which can occur on a range of biological and synthetic surfaces. The rate of fibrillation depends on both the protein structure and the surface chemistry, with the different molecular and oligomer structures adopted by proteins on surfaces likely to be crucial. In this paper, the aggregation of the model amyloidogenic peptide, Aß(16-22), corresponding to a hydrophobic segment of the amyloid beta protein on a gold surface is studied using molecular dynamics simulation. Previous simulations of this peptide on gold surfaces have shown that it adopts conformations on surfaces that are quite different from those in bulk solution. These simulations show that this then leads to significant differences in the oligomer structures formed in solution and on gold surfaces. In particular, oligomers formed on the surface are low in beta-strands so are unlike the structures formed in bulk solution. When oligomers formed in solution adsorb onto gold surfaces they can then restructure themselves. This can then help explain the inhibition of Aß(16-22) fibrillation by gold surfaces and nanoparticles seen experimentally.

Serum microRNA Levels as a Biomarker for Diagnosing Non-Alcoholic Fatty Liver Disease in Chinese Colorectal Polyp Patients.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and its prevalence is increasing worldwide. It is reported that NAFLD is associated with colorectal polyps. Since identifying NAFLD in its early stages could prevent possible disease progression to cirrhosis and decrease the risk of HCC by early intervention, patients with colorectal polyp may thus be considered a target group for screening NAFLD. This study aimed to investigate the potential of serum microRNAs (miRNAs) in identifying NAFLD for colorectal polyp patients. Serum samples were collected from 141 colorectal polyp patients, of which 38 had NAFLD. The serum level of eight miRNAs was determined by quantitative PCR and delta Ct values of different miRNA pairs which were compared between NAFLD and control groups. A miRNA panel was formulated from candidate miRNA pairs by multiple linear regression model and ROC analysis was performed to evaluate its diagnostic potential for NAFLD. Compared to the control group, the NAFLD group showed significantly lower delta Ct values of miR-18a/miR-16 (6.141 vs. 7.374, p = 0.009), miR-25-3p/miR-16 (2.311 vs. 2.978, p = 0.003), miR-18a/miR-21-5p (4.367 vs. 5.081, p = 0.021) and miR-18a/miR-92a-3p (8.807 vs. 9.582, p = 0.020). A serum miRNA panel composed of these four miRNA pairs significantly identified NAFLD in colorectal polyp patients with an AUC value of 0.6584 (p = 0.004). The performance of the miRNA panel was further improved to an AUC value of 0.8337 (p < 0.0001) when polyp patients with other concurrent metabolic disorders were removed from the analysis. The serum miRNA panel is a potential diagnostic biomarker for screening NAFLD in colorectal polyp patients. This serum miRNA test could be performed for colorectal polyp patients for early diagnosis and for prevention of the disease from progressing into more advanced stages.

Prediction of cooperative homeodomain DNA binding sites from high-throughput-SELEX data.

Homeodomain proteins constitute one of the largest families of metazoan transcription factors. Genetic studies have demonstrated that homeodomain proteins regulate many developmental processes. Yet, biochemical data reveal that most bind highly similar DNA sequences. Defining how homeodomain proteins achieve DNA binding specificity has therefore been a long-standing goal. Here, we developed a novel computational approach to predict cooperative dimeric binding of homeodomain proteins using High-Throughput (HT) SELEX data. Importantly, we found that 15 of 88 homeodomain factors form cooperative homodimer complexes on DNA sites with precise spacing requirements. Approximately one third of the paired-like homeodomain proteins cooperatively bind palindromic sequences spaced 3 bp apart, whereas other homeodomain proteins cooperatively bind sites with distinct orientation and spacing requirements. Combining structural models of a paired-like factor with our cooperativity predictions identified key amino acid differences that help differentiate between cooperative and non-cooperative factors. Finally, we confirmed predicted cooperative dimer sites in vivo using available genomic data for a subset of factors. These findings demonstrate how HT-SELEX data can be computationally mined to predict cooperativity. In addition, the binding site spacing requirements of select homeodomain proteins provide a mechanism by which seemingly similar AT-rich DNA sequences can preferentially recruit specific homeodomain factors.

BAG3: Nature's Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue.

BAG3 is a 575 amino acid protein that is found throughout the animal kingdom and homologs have been identified in plants. The protein is expressed ubiquitously but is most prominent in cardiac muscle, skeletal muscle, the brain and in many cancers. We describe BAG3 as a quintessential multi-functional protein. It supports autophagy of both misfolded proteins and damaged organelles, inhibits apoptosis, maintains the homeostasis of the mitochondria, and facilitates excitation contraction coupling through the L-type calcium channel and the beta-adrenergic receptor. High levels of BAG3 are associated with insensitivity to chemotherapy in malignant cells whereas both loss of function and gain of function variants are associated with cardiomyopathy.

Elucidation of microbial lignin degradation pathways using synthetic isotope-labelled lignin.

Pathways by which the biopolymer lignin is broken down by soil microbes could be used to engineer new biocatalytic routes from lignin to renewable chemicals, but are currently not fully understood. In order to probe these pathways, we have prepared synthetic lignins containing 13C at the sidechain ß-carbon. Feeding of [ß-13C]-labelled DHP lignin to Rhodococcus jostii RHA1 has led to the incorporation of 13C label into metabolites oxalic acid, 4-hydroxyphenylacetic acid, and 4-hydroxy-3-methoxyphenylacetic acid, confirming that they are derived from lignin breakdown. We have identified a glycolate oxidase enzyme in Rhodococcus jostii RHA1 which is able to oxidise glycolaldehyde via glycolic acid to oxalic acid, thereby identifying a pathway for the formation of oxalic acid. R. jostii glycolate oxidase also catalyses the conversion of 4-hydroxyphenylacetic acid to 4-hydroxybenzoylformic acid, identifying another possible pathway to 4-hydroxybenzoylformic acid. Formation of labelled oxalic acid was also observed from [ß-13C]-polyferulic acid, which provides experimental evidence in favour of a radical mechanism for α,ß-bond cleavage of ß-aryl ether units.

Scleraxis and fibrosis in the pressure-overloaded heart.

AIMS: In response to pro-fibrotic signals, scleraxis regulates cardiac fibroblast activation in vitro via transcriptional control of key fibrosis genes such as collagen and fibronectin; however, its role in vivo is unknown. The present study assessed the impact of scleraxis loss on fibroblast activation, cardiac fibrosis, and dysfunction in pressure overload-induced heart failure. METHODS AND RESULTS: Scleraxis expression was upregulated in the hearts of non-ischemic dilated cardiomyopathy patients, and in mice subjected to pressure overload by transverse aortic constriction (TAC). Tamoxifen-inducible fibroblast-specific scleraxis knockout (Scx-fKO) completely attenuated cardiac fibrosis, and significantly improved cardiac systolic function and ventricular remodelling, following TAC compared to Scx+/+ TAC mice, concomitant with attenuation of fibroblast activation. Scleraxis deletion, after the establishment of cardiac fibrosis, attenuated the further functional decline observed in Scx+/+ mice, with a reduction in cardiac myofibroblasts. Notably, scleraxis knockout reduced pressure overload-induced mortality from 33% to zero, without affecting the degree of cardiac hypertrophy. Scleraxis directly regulated transcription of the myofibroblast marker periostin, and cardiac fibroblasts lacking scleraxis failed to upregulate periostin synthesis and secretion in response to pro-fibrotic transforming growth factor ß. CONCLUSION: Scleraxis governs fibroblast activation in pressure overload-induced heart failure, and scleraxis knockout attenuated fibrosis and improved cardiac function and survival. These findings identify scleraxis as a viable target for the development of novel anti-fibrotic treatments.

Effect of Surface Hydrophobicity on the Adsorption of a Pilus-Derived Adhesin-like Peptide.

Bacterial colonization of abiotic surfaces such as those of medical implants, membrane filters, and everyday household items is a process of tremendous importance for public health. Bacteria use adhesive cell surface structures called adhesins to establish contact with abiotic surfaces. Among them, protein filaments called type IV pili are particularly important and found in many Gram-negative pathogens such as Pseudomonas aeruginosa. Understanding the interaction of such adhesin proteins with different abiotic surfaces at the molecular level thus represents a fundamental prerequisite for impeding bacterial colonization and preventing the spread of infectious diseases. In this work, we investigate the interaction of a synthetic adhesin-like peptide, PAK128-144ox, derived from the type IV pilus of P. aeruginosa with hydrophilic and hydrophobic self-assembled monolayers (SAMs). Using a combination of molecular dynamics (MD) simulations, quartz crystal microbalance with dissipation monitoring (QCM-D), and spectroscopic investigations, we find that PAK128-144ox has a higher affinity for hydrophobic than for hydrophilic surfaces. Additionally, PAK128-144ox adsorption on the hydrophobic SAM is furthermore accompanied by a strong increase in α-helix content. Our results show a clear influence of surface hydrophobicity and further indicate that PAK128-144ox adsorption on the hydrophobic surface is enthalpically favored, while on the hydrophilic surface, entropic contributions are more significant. However, our spectroscopic investigations also suggest aggregation of the peptide under the employed experimental conditions, which is not considered in the MD simulations and should be addressed in more detail in future studies.

Comparing Flaxseed and Perindopril in the Prevention of Doxorubicin and Trastuzumab-Induced Cardiotoxicity in C57Bl/6 Mice.

BACKGROUND: Two anti-cancer agents, doxorubicin (DOX) and trastuzumab (TRZ), are commonly used in the management of breast cancer in women. Despite their efficacy in reducing the morbidity and mortality of individuals with breast cancer, the use of these agents is limited by adverse cardiotoxic side effects. Both the nutraceutical agent flaxseed (FLX) and the pharmaceutical drug perindopril (PER) have been studied individually in the prevention of chemotherapy-mediated cardiac dysfunction. The objective of this study was to determine whether the prophylactic administration of FLX is comparable and/or synergistic with PER in preventing DOX + TRZ-induced cardiotoxicity. METHODS: Over a six-week period, 81 wild-type C57Bl/6 female mice (8-12 weeks old) were randomized to receive regular chow (RC) or 10% FLX-supplemented diets with or without PER (3 mg/kg/week; oral gavage). Starting at week 4, mice were randomized to receive a weekly injection of saline or DOX (8 mg/kg) + TRZ (3 mg/kg). Serial echocardiography was conducted weekly and histological and biochemical analyses were performed at the end of the study. RESULTS: In mice treated with RC + DOX + TRZ, left ventricular ejection (LVEF) decreased from 75 ± 2% at baseline to 37 ± 3% at week 6. However, prophylactic treatment with either FLX, PER, or FLX + PER partially preserved left ventricular systolic function with LVEF values of 61 ± 2%, 62 ± 2%, and 64 ± 2%, respectively. The administration of FLX, PER, or FLX + PER was also partially cardioprotective in preserving cardiomyocyte integrity and attenuating the expression of the inflammatory biomarker NF-κB due to DOX + TRZ administration. CONCLUSION: FLX was equivalent to PER at preventing DOX + TRZ-induced cardiotoxicity in a chronic in vivo murine model.

Hypericin and Pheophorbide a Mediated Photodynamic Therapy Fighting MRSA Wound Infections: A Translational Study from In Vitro to In Vivo.

High prevalence rates of methicillin-resistant Staphylococcus aureus (MRSA) and lack of effective antibacterial treatments urge discovery of alternative therapeutic modalities. The advent of antibacterial photodynamic therapy (aPDT) is a promising alternative, composing rapid, nonselective cell destruction without generating resistance. We used a panel of clinically relevant MRSA to evaluate hypericin (Hy) and pheophobide a (Pa)-mediated PDT with clinically approved methylene blue (MB). We translated the promising in vitro anti-MRSA activity of selected compounds to a full-thick MRSA wound infection model in mice (in vivo) and the interaction of aPDT innate immune system (cytotoxicity towards neutrophils). Hy-PDT consistently displayed lower minimum bactericidal concentration (MBC) values (0.625-10 µM) against ATCC RN4220/pUL5054 and a whole panel of community-associated (CA)-MRSA compared to Pa or MB. Interestingly, Pa-PDT and Hy-PDT topical application demonstrated encouraging in vivo anti-MRSA activity (>1 log10 CFU reduction). Furthermore, histological analysis showed wound healing via re-epithelization was best in the Hy-PDT group. Importantly, the dark toxicity of Hy was significantly lower (p < 0.05) on neutrophils compared to Pa or MB. Overall, Hy-mediated PDT is a promising alternative to treat MRSA wound infections, and further rigorous mechanistic studies are warranted.

Prevalence and Functional Implication of Silent Coronary Artery Disease in Marathon Runners Over 40 Years of Age: The MATCH-40 Study.

BACKGROUND: Marathon participation is becoming increasingly popular among individuals ≥40 years of age. Little is known about the prevalence of subclinical coronary artery disease (CAD) and corresponding ischemia in this patient population. The study objectives are: (1) to characterize the prevalence of silent CAD in marathoners ≥ 40 years old using cardiac computed tomography angiography (CCT); and (2) if subclinical CAD was detected, to determine the functional significance of occult lesions by stress echocardiography (SE). METHODS: Marathoners aged ≥ 40 years who completed a full marathon between 2018 and 2019 were recruited to undergo a prospective CCT. Coronary artery stenosis was graded as zero, mild (1%-49%), moderate (50%-69%), or severe (> 70%). All study participants diagnosed with mild-to-severe atherosclerotic CAD on CCT further underwent functional imaging with exercise treadmill SE. RESULTS: A total of 65 individuals (53 ± 7 years, 65% males, 24 ± 3 kg/m2) underwent a prospective CCT within 12 months of marathon completion. Of the total study population, 13 participants (20%) were diagnosed with CAD, of whom 10 (77%) had mild disease, 1 (8%) had moderate disease, and 2 (15%) had severe disease by CCT. Despite the identification of subclinical CAD on CCT, none of the 13 patients had any evidence of inducible ischemia on SE. CONCLUSIONS: This is the first study to incorporate both CCT and SE in the evaluation of subclinical CAD in marathoners ≥40 years old. Although the overall prevalence of anatomic CAD was 20%, there was no evidence of functional ischemia in this highly competitive cohort.

CONTEXTE: Les marathons ont gagné en popularité auprès des individus âgés de 40 ans ou plus. On en sait toutefois peu sur la prévalence de la coronaropathie subclinique et de l'ischémie qui lui est associée dans cette population de patients. L'étude visait à 1) caractériser la prévalence de la coronaropathie silencieuse chez les marathoniens âgés de 40 ans ou plus à l'aide d'une angiographie cardiaque par tomodensitométrie (ACTDM) si une coronaropathie subclinique était détectée, à déterminer l'importance fonctionnelle des lésions occultes par une échocardiographie d'effort (EE). MÉTHODOLOGIE: Des marathoniens âgés de 40 ans ou plus ayant réalisé un marathon entre 2018 et 2019 ont été recrutés et soumis à une ACTDM prospective. Les sténoses des artères coronaires étaient classées selon une échelle allant de zéro, légère (1 à 49 %), modérée (50 à 69 %) à sévère (> 70 %). Tous les participants à l'étude ayant reçu un diagnostic de coronaropathie athéroscléreuse légère à sévère à la suite de l'ACTDM ont été soumis à une imagerie fonctionnelle avec EE sur tapis roulant. RÉSULTATS: Au total, 65 sujets (53 ± 7 ans, 65 % d'hommes, 24 ± 3 kg/m2) ont été soumis à une ACTDM prospective dans un délai de 12 mois à la suite de leur dernier marathon. Dans l'ensemble de la population à l'étude, 13 participants (20 %) ont reçu un diagnostic de coronaropathie; 10 (77 %) présentaient une maladie bénigne, 1 (8 %) présentait une maladie modérée et 2 (15 %) présentaient une maladie sévère selon l'ACTDM. Même si une coronaropathie subclinique a été diagnostiquée lors de l'ACTDM, aucun des 13 patients ne présentait de signe d'ischémie inductible à l'EE. CONCLUSIONS: Il s'agit de la première étude à utiliser l'ACTDM et l'EE pour évaluer la présence d'une coronaropathie chez des marathoniens âgés de 40 ou plus. Même si la prévalence globale de la coronaropathie anatomique était de 20 %, il n'y avait aucun signe d'ischémie fonctionnelle au sein de cette cohorte hautement compétitive.

Primary Eccrine Adenocarcinoma: A Rare but Dangerous Lesion of the Eyelid.

Sweat gland carcinomas can be of eccrine or apocrine origin, with the former being more common in the eyelid. They can also be of three different types, the most common of which is mucin-producing sweat gland carcinoma, which is most often a low-grade malignancy. Here, we report a case of a primary estrogen receptor-positive eccrine adenocarcinoma of the eyelid that clinically presented like a cyst of Moll. Importantly, in our experience with this lesion, this rare malignancy was repeatedly misdiagnosed as less sinister lesions, surgical resection margins of the lesion could be easily underestimated, and close liaison with our general surgical colleagues was vital to exclude more common breast carcinoma. This case highlights the dangers of referral recommendation policies (e.g., procedures of limited clinical value as used by primary care) and the importance of incisional biopsy in the management of periocular lesions.

Elimination of endogenous high molecular weight FGF2 prevents pressure-overload-induced systolic dysfunction, linked to increased FGFR1 activity and NR1D1 expression.

Fibroblast growth factor 2 (FGF2), produced as high (Hi-) and low (Lo-) molecular weight isoforms, is implicated in cardiac response to injury. The role of endogenous FGF2 isoforms during chronic stress is not well defined. We investigated the effects of endogenous Hi-FGF2 in a mouse model of simulated pressure-overload stress achieved by transverse aortic constriction (TAC) surgery. Hi-FGF2 knockout mice, expressing only Lo-FGF2, FGF2(Lo), and wild-type mice, FGF2(WT), expressing both Hi-FGF2 and Lo-FGF2, were used. By echocardiography, a decline in systolic function was observed in FGF2(WT) but not FGF2(Lo) mice compared to corresponding sham-operated animals at 4-8 weeks post-TAC surgery. TAC surgery increased markers of myocardial stress/damage including B-type natriuretic peptide (BNP) and the pro-cell death protein BCL2/adenovirus E1B 19 kDa protein-interacting protein-3 (Bnip3) in FGF2(WT) but not FGF2(Lo) mice. In FGF2(Lo) mice, cardiac levels of activated FGF receptor 1 (FGFR1), and downstream signals, including phosphorylated mTOR and p70S6 kinase, were elevated post-TAC. Finally, NR1D1 (nuclear receptor subfamily 1 group D member 1), implicated in cardioprotection from pressure-overload stress, was downregulated or upregulated in the presence or absence, respectively, of Hi-FGF2 expression, post-TAC surgery. In wild-type cardiomyocyte cultures, endothelin-1 (added to simulate pressure-overload signals) caused NR1D1 downregulation and BNP upregulation, similar to the effect of TAC surgery on the FGF2(WT) mice. The NR1D1 agonist SR9009 prevented BNP upregulation, simulating post-TAC findings in FGF2(Lo) mice. We propose that elimination of Hi-FGF2 is cardioprotective during pressure-overload by increasing FGFR1-associated signaling and NR1D1 expression.

The Effects of Low Pressure Domiciliary Non-Invasive Ventilation on Clinical Outcomes in Patients with Severe COPD Regardless Having Hypercapnia.

BACKGROUND: The effectiveness of non-invasive home ventilation in patients with severe chronic obstructive pulmonary disease (COPD) is lacking. Non-invasive home ventilation might be more effective when high ventilator settings are used. However, high ventilator settings might reduce patient adherence. We have developed a multidisciplinary approach (ventilation practitioners, 24 hours support of respiratory nurses, physicians) to non-invasive ventilation aimed at optimizing patient adherence using low ventilator settings in severe COPD patients with high disease burden irrespectively having hypercapnia. METHODS: We included in a proof of concept, prospective interventional study, 48 GOLD stage III-IV COPD patients with a high disease burden (≥2 exacerbations in a year, and Medical Research Council dyspnea scores ≥3). Outcome measures included hospital admissions, capillary pCO2, Medical Research Council dyspnea scores (MRC), Clinical COPD Questionnaire scores (CCQ) and Hospital Anxiety and Depression Scale (HADS). RESULTS: After 1 year 32 patients could be evaluated. Hospital admissions decreased by 1.0 admission (mean difference ± SD: 1.0 ± 1.48; p = 0.001). In-hospital days decreased by 10.0 days (10.0 ± 15.48; p = 0.001). Capillary pCO2 decreased by 0.33 kPa (0.33 ± 0.81: p = 0.03). The MRC dyspnea score decreased by 0.66 (0.66 ± 1.35; p = 0.02). The CCQ score decreased by 0.59 (0.59 ± 1.39; p = 0.03). The HADS anxiety score decreased by 1.64 (1.64 ± 3.12; p = 0.01). The HADS depression score decreased by 1.64 (1.64 ± 3.91; p = 0.04). CONCLUSION: A proof of concept multidisciplinary approach, using low pressure domiciliary non-invasive ventilation, aimed at optimizing patient adherence in severe COPD patients regardless having hypercapnia, reduced hospital admissions and improved symptoms and quality of life measures. This may imply that severe COPD patients with high disease burden, irrespective being hypercapnic, are candidates to be treated with low pressure domiciliary non-invasive ventilation.

Salviae miltiorrhizae radix and puerariae lobatae radix herbal formula improves circulation, vascularization and gait function in a peripheral arterial disease rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: DG is a herbal formula, containing the root of Salvia miltiorrhiza Bunge (Danshen) and the root of Pueraria lobate (Willd.) Ohwi (Gegen), has a history of usage in China for cardiovascular protection and anti-atherosclerosis. AIM OF THE STUDY: The present study aims to determine the beneficial effect of DG on the hind-limb ischemia rat model which mimics peripheral arterial disease (PAD) and its vasodilative effect on isolated femoral artery. MATERIALS AND METHODS: The vasodilatory effects were assessed by contractile responses to DG in the isolated femoral artery and its underlying mechanisms were evaluated by the involvement of endothelium, potassium channel and calcium channel. For hind-limb ischemia study, treatment outcomes were assessed by evaluating hind-limb blood flow, functional limb recovery, muscle histology and angiogenesis. RESULTS: Our results demonstrated positive dose-dependent vasodilatory response to DG via an endothelium-independent mechanism that involved inwardly rectifying K+ channels and Ca2+ channels. We also demonstrated significant improvement in blood perfusion and micro-vessel density in the ischemic limb and positive effects in functional limb recovery. CONCLUSION: In conclusion, our study supported the potential use of DG as a novel treatment for symptomatic PAD.

Effect of the air-water interface on the conformation of amyloid beta.

It has long been recognized that liquid interfaces, such as the air-water interface (AWI), can enhance the formation of protein fibrils. This makes liquid interfaces attractive templates for fibril formation but fully realizing this requires knowledge of protein behavior at interfaces, which is currently lacking. To address this, molecular dynamics simulation is used to investigate fragments of amyloid beta, a model fibril forming protein, at the air-water interface. At the air-water interface, the enrichment of aggregation-prone helical conformations provides a mechanism for the enhancement of fibrillation at interfaces. The conformational ensemble at the air-water interface was also considerably reduced compared to bulk solution due to the tendency of hydrophobic side chains partitioning into the air restricting the range of conformations. Little overlap between the conformational ensembles at the AWI and in the bulk solution was found, suggesting that AWI induces the formation of a different set of structures compared to bulk solution. The smaller Aß(16-22) and Aß(25-35) fragments show an increase in the propensity for an ordered secondary structure at the air-water interface but with a increased propensity for turn over other motifs, illustrating the importance of intra-protein interactions for stabilizing helical and extended conformations.

Effect of surface chemistry on islet amyloid polypeptide conformation.

The formation of dense, linear arrays (fibrils) by biomolecules is the hallmark of a number of degenerative diseases, such as Alzheimer's and type-2 diabetes. Protein fibrils have also attracted interest as building blocks for new materials. It has long been recognized that surfaces can affect the fibrillation process. Recent work on the model fibril forming protein human islet amyloid polypeptide (hIAPP) has shown that while the protein concentration is highest at hydrophobic surfaces, the rate of fibril formation is lower than on other surfaces. To understand this, replica exchange molecular dynamics simulations were used to investigate the conformations that hIAPP adopts on surfaces of different hydrophobicities. The hydrophobic surface stabilizes α-helical structures which are significantly different to those found on the hydrophilic surface and in bulk solution. There is also a greatly reduced conformational ensemble on the hydrophobic surface due to long-lived contacts between hydrophobic residues on the protein and the surface. This new microscopic information will help us determine the mechanism of the enhancement of fibril formation on surfaces and provides new insight into the effect of nanointerfaces and protein conformation.

No-show rates to a sleep clinic: drivers and determinants.

STUDY OBJECTIVES: Attendance to sleep clinic appointments is imperative to diagnose sleep-related disorders and to offer appropriate treatment. As part of our quality assurance program, we assessed predictors of no-show rates at our sleep clinic. We hypothesize that no-show rates can be predicted by demographics, appointment type (new vs established) and timing, and insurance status. METHODS: We performed a 10-month, retrospective chart review of patients scheduled at Saint Louis University's SLUCare Sleep Disorders Center. Multivariable logistic regression was used to determine which factors were independently associated with no-show. RESULTS: A total of 2,532 clinical visits were reviewed, and the overall no-show rate was 21.2%. Factors associated with a higher incidence of no-show rates included younger age (17-40 years: 21.5%; 41-64 years: 23.5%; ≥65 years: 14.0%; P < .0001), appointment type (new: 30.5% vs established: 18.3%; P < .0001), and insurance status (no insurance: 24.6% vs public: 22.6% vs private: 15.9%; P < .0001). Multivariable logistic regression confirmed the independent association between no-show and age ≤ 40 years (adjusted odds ratio = 1.72; 95% confidence interval: 1.44, 2.20), new patient status (adjusted odds ratio = 1.78; 95% confidence interval: 1.44, 2.20), and absence of health insurance (adjusted odds ratio = 1.62; 95% confidence interval: 1.24, 2.11). Sex, appointment time, day of the week, and season did not significantly influence no-show rates. CONCLUSIONS: Independent predictors of no-show appointments included younger age, new patient status, and lack of health insurance. Our findings will aid future efforts to identify patients with high predictors of nonadherence. Further studies are needed to develop methods to decrease no-show rates once high-risk appointments have been identified.

The Cardioprotective Role of Flaxseed in the Prevention of Doxorubicin- and Trastuzumab-Mediated Cardiotoxicity in C57BL/6 Mice.

BACKGROUND: Although the combination of doxorubicin (DOX) and trastuzumab (TRZ) reduces the progression and recurrence of breast cancer, these anticancer drugs are associated with significant cardiotoxic side effects. OBJECTIVE: We investigated whether prophylactic administration of flaxseed (FLX) and its bioactive components, α-linolenic acid (ALA) and secoisolariciresinol diglucoside (SDG), would be cardioprotective against DOX + TRZ-mediated cardiotoxicity in a chronic in vivo female murine model. METHODS: Wild-type C57BL/6 female mice (10-12 wk old) received daily prophylactic treatment with one of the following diets: 1) regular control (RC) semi-purified diet; 2) 10% FLX diet; 3) 4.4% ALA diet; or 4) 0.44% SDG diet for a total of 6 wks. Within each arm, mice received 3 weekly injections of 0.9% saline or a combination of DOX [8 mg/(kg.wk)] and TRZ [3 mg/(kg.wk)] starting at the end of week 3. The main outcome was to evaluate the effects of FLX, ALA, and SDG on cardiovascular remodeling and markers of apoptosis, inflammation, and mitochondrial dysfunction. Significance between measurements was determined using a 4 (diet) × 2 (chemotherapy) × 2 (time) mixed factorial design with repeated measures. RESULTS: In the RC + DOX + TRZ-treated mice at week 6 of the study, the left ventricular ejection fraction (LVEF) decreased by 50% compared with the baseline LVEF (P < 0.05). However, the prophylactic administration of the FLX, ALA, or SDG diet was partially cardioprotective, with mice in these treatment groups showing an ∼68% increase in LVEF compared with the RC + DOX + TRZ-treated group at week 6 (P < 0.05). Although markers of inflammation (nuclear transcription factor κB), apoptosis [poly (ADP-ribose) polymerase-1 and the ratio of BCL2-associated X protein to B-cell lymphoma-extra large], and mitochondrial dysfunction (BCL2-interacting protein 3) were significantly elevated by approximately 2-fold following treatment with RC + DOX + TRZ compared with treatment with RC + saline at week 6, prophylactic administration of FLX, ALA, or SDG partially downregulated these signaling pathways. CONCLUSION: In a chronic in vivo female C57BL/6 mouse model of DOX + TRZ-mediated cardiotoxicity, FLX, ALA, and SDG were partially cardioprotective.

Scleraxis as a prognostic marker of myocardial fibrosis in hypertrophic cardiomyopathy (SPARC) study.

Interstitial fibrosis is a histopathological hallmark of hypertrophic cardiomyopathy (HCM). Although extracellular matrix (ECM) biomarkers, including matrix metalloproteinases, are overexpressed in HCM patients, they do not correlate with sudden cardiac death (SCD) risk. The objective of this study was to determine whether scleraxis, a transcription factor that regulates collagen gene expression, is detectable in HCM patients and correlates with disease burden. Between 2017 and 2018, a total of 46 HCM patients were enrolled (58 ± 14 years (31 males, 15 females)) with a mean 5 year SCD risk of 2.3% ± 1.3%. Cardiac MRI confirmed HCM in all patients with a mean interventricular septal thickness of 20 ± 2 mm. Late gadolinium enhancement (LGE) was present in 32 (70%) study participants occupying 18% ± 7% of the left ventricular (LV) myocardium. Serum scleraxis levels were significantly higher in the HCM patients by approximately twofold as compared to controls (0.76 ± 0.06 versus 0.32 ± 0.02 ng/mL, p < 0.05). No correlation was demonstrated between serum scleraxis levels and markers of disease severity in HCM patients, including maximum LV wall thickness, %LGE, and SCD risk factors. Serum scleraxis is elevated in the HCM population. Future studies are warranted to evaluate the prognostic value of scleraxis in identifying high-risk HCM patients who require aggressive management for prevention of SCD.

Understanding and Controlling Food Protein Structure and Function in Foods: Perspectives from Experiments and Computer Simulations.

The structure and interactions of proteins play a critical role in determining the quality attributes of many foods, beverages, and pharmaceutical products. Incorporating a multiscale understanding of the structure-function relationships of proteins can provide greater insight into, and control of, the relevant processes at play. Combining data from experimental measurements, human sensory panels, and computer simulations through machine learning allows the construction of statistical models relating nanoscale properties of proteins to the physicochemical properties, physiological outcomes, and tastes of foods. This review highlights several examples of advanced computer simulations at molecular, mesoscale, and multiscale levels that shed light on the mechanisms at play in foods, thereby facilitating their control. It includes a practical simulation toolbox for those new to in silico modeling.