Scavenging neurotoxic aldehydes using lysine carbon dots.

Reactive aldehydes generated in cells and tissues are associated with adverse physiological effects. Dihydroxyphenylacetaldehyde (DOPAL), the biogenic aldehyde enzymatically produced from dopamine, is cytotoxic, generates reactive oxygen species, and triggers aggregation of proteins such as α-synuclein implicated in Parkinson's disease. Here, we demonstrate that carbon dots (C-dots) prepared from lysine as the carbonaceous precursor bind DOPAL molecules through interactions between the aldehyde units and amine residues on the C-dot surface. A set of biophysical and in vitro experiments attests to attenuation of the adverse biological activity of DOPAL. In particular, we show that the lysine-C-dots inhibit DOPAL-induced α-synuclein oligomerization and cytotoxicity. This work underlines the potential of lysine-C-dots as an effective therapeutic vehicle for aldehyde scavenging.

Bcl-2-Homology-Only Proapoptotic Peptides Modulate ß-Amyloid Aggregation and Toxicity.

Aggregation of the ß-Amyloid (Aß) peptide in brain tissues is the hallmark of Alzheimer's disease (AD). While Aß is presumed to be insidiously involved in the disease's pathophysiology, concrete mechanisms accounting for the role of Aß in AD are yet to be deciphered. While Aß has been primarily identified in the extracellular space, the peptide also accumulates in cellular compartments such as mitochondria and lysosomes and impairs cellular functions. Here, we show that prominent proapoptotic peptides associated with the mitochondrial outer membrane, the Bcl-2-homology-only peptides BID, PUMA, and NOXA, exert significant and divergent effects upon aggregation, cytotoxicity, and membrane interactions of Aß42, the main Aß homolog. Interestingly, we show that BID and PUMA accelerated aggregation of Aß42, reduced Aß42-induced toxicity and mitochondrial disfunction, and inhibited Aß42-membrane interactions. In contrast, NOXA exhibited opposite effects, reducing Aß42 fibril formation, affecting more pronounced apoptotic effects and mitochondrial disfunction, and enhancing membrane interactions of Aß42. The effects of BID, PUMA, and NOXA upon the Aß42 structure and toxicity may be linked to its biological properties and affect pathophysiological features of AD.

The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-ß chameleon functional amyloid.

Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 comprised antiparallel and parallel helical sheets, respectively, recapitulating properties of ß-sheets. Uperin 3.5 demonstrated chameleon properties of a secondary structure switch, forming mostly cross-ß fibrils in the absence of lipids. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/ß amyloid fibrils.

Ultra Long-Haul: An emerging business model accelerated by COVID-19.

The COVID-19 outbreak has sent shockwaves throughout the aviation industry, sending a myriad of liquidity-strapped airlines into administration or part government ownership. In turn, this paper argues that the novel phenomenon of Ultra Long Haul (ULH) operations already maintains the necessary characteristics to generate a competitive advantage that will not only succeed, but outperform other business models, in a post COVID-19 era. Our modelling and scenario analysis results suggest that point-to-point ULH services, with access to a strong domestic feeder system, will not only require minimal adjustments to cope with COVID-19, but will simultaneously produce higher seat-load factors and yields, heightened network flexibility, and unique health benefits tied to its ability to bypass densely populated hub airports.

Tyrosine carbon dots inhibit fibrillation and toxicity of the human islet amyloid polypeptide.

Misfolding and aggregation of the human islet amyloid polypeptide (hIAPP) are believed to play key roles in the pathophysiology of type-II diabetes. Here, we demonstrate that carbon dots (C-dots) prepared from the amino acid tyrosine inhibit fibrillation of hIAPP, reduce hIAPP-induced cell toxicity and block membrane disruption by the peptide. The pronounced inhibitory effect is traced to the display of ubiquitous aromatic residues upon the C-dots' surface, mimicking the anti-fibril and anti-toxic activity of natural polyphenolic compounds. Notably, spectroscopy and thermodynamics analysis demonstrated different hIAPP interactions and fibril inhibition effects induced by tyrosine-C-dots displaying phenolic residues and C-dots prepared from phenylalanine which exhibited phenyl units on their surface, underscoring the significance of hydrogen bonding mediated by the phenolic hydroxide moieties for the fibril modulation activity. The presented experiments attest to the potential of tyrosine-C-dots as a therapeutic vehicle for protein misfolding diseases, interfering in both π-π interactions as well as hydrogen bonding involving aromatic residues of amyloidogenic peptides.

Fibrils of α-Synuclein Abolish the Affinity of Cu2+-Binding Site to His50 and Induce Hopping of Cu2+ Ions in the Termini.

The effect of Cu2+ on α-synuclein (AS) aggregation is important because clinical studies of patients with Parkinson's disease have shown elevated levels of Cu2+ in the cerebrospinal fluid. So far, the molecular architectures of Cu2+-AS fibril complexes at atomic resolution are unknown. The current work identifies for the first time that His50 cannot bind Cu2+ ions in mature fibrils. Moreover, it shows hopping of Cu2+ ions between residues in AS fibrils and changes in the Cu2+ coordination mode in Cu2+ ions that bind in the termini of AS. The current study combines extensive experimental techniques, density functional theory calculations, and computational modeling tools to provide a complete description of the Cu2+ binding site in AS fibrils. Our findings illustrate for the first time the specific interactions between Cu2+ ions and AS fibrils, suggesting a new mechanistic perspective on the effect of Cu2+ ions on AS aggregation.

Multicenter Trial of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer: Survival and Toxicity Endpoints.

PURPOSE: The radiobiology of prostate cancer may favor the extreme hypofractionation inherent in stereotactic body radiation therapy (SBRT); however, data from a large multicenter study are lacking. We therefore examined the hypothesis that dose-escalated SBRT can be safely administered across multiple institutions, with favorable 5-year disease-free survival (DFS) rates compared with historical controls. METHODS AND MATERIALS: Twenty-one centers enrolled 309 patients with prostate adenocarcinoma: 172 with low-risk (LR) and 137 with intermediate-risk (IR) disease. All were treated with a non-coplanar robotic SBRT platform using real-time tracking of implanted fiducials. The prostate was prescribed 40 Gy in 5 fractions of 8 Gy. We assessed toxicities using Common Terminology Criteria for Adverse Events (CTCAE) version 3 and biochemical failure using the "nadir + 2" definition. The study population yielded 90% power to identify excessive (>10%) rates of grade ≥3 genitourinary (GU) or gastrointestinal toxicities and, in the LR group, 80% power to show superiority in DFS over a 93% historical comparison rate. RESULTS: At a median follow-up of 61 months, 2 LR patients (1.2%) and 2 IR patients (1.5%) experienced grade 3 GU toxicities, far below the 10% toxicity rate deemed excessive (upper limits of 95% confidence interval, 3.5% and 4.3%, respectively). No grade 4 or 5 toxicities occurred. All grade 3 toxicities were GU, occurring 11 to 51 months after treatment. For the entire group, the actuarial 5-year overall survival rate was 95.6% and the DFS rate was 97.1%. The 5-year DFS rate was 97.3% for LR patients (superior to the 93% DFS rate for historical controls; P = .0008; lower limit of 95% confidence interval, 94.6%) and 97.1% for IR patients. CONCLUSIONS: Dose-escalated prostate SBRT was administered with minimal toxicity in this multi-institutional study. Relapse rates compared favorably with historical controls. SBRT is a suitable option for LR and IR prostate cancer.

Testing the limits of the Maxwell distribution of velocities for atoms flying nearly parallel to the walls of a thin cell.

For a gas at thermal equilibrium, it is usually assumed that the velocity distribution follows an isotropic 3-dimensional Maxwell-Boltzmann (M-B) law. This assumption classically implies the assumption of a "cos θ" law for the flux of atoms leaving the surface. Actually, such a law has no grounds in surface physics, and experimental tests of this assumption have remained very few. In a variety of recently developed sub-Doppler laser spectroscopy techniques for gases one-dimensionally confined in a thin cell, the specific contribution of atoms moving nearly parallel to the boundary of the vapor container becomes essential. We report here on the implementation of an experiment to probe effectively the distribution of atomic velocities parallel to the windows for a thin (60 µm) Cs vapor cell. The principle of the setup relies on a spatially separated pump-probe experiment, where the variations of the signal amplitude with the pump-probe separation provide the information on the velocity distribution. The experiment is performed in a sapphire cell on the Cs resonance line, which benefits from a long-lived hyperfine optical pumping. Presently, we can analyze specifically the density of atoms with slow normal velocities ∼5-20 m/s, already corresponding to unusual grazing flight-at ∼85°-88.5° from the normal to the surface-and no deviation from the M-B law is found within the limits of our elementary setup. Finally we suggest tracks to explore more parallel velocities, when surface details-roughness or structure-and the atom-surface interaction should play a key role to restrict the applicability of an M-B-type distribution.

Serious Adverse Events Associated with Readmission Through One Year After Vertebral Augmentation with Either a Polyetheretherketone Implant or Balloon Kyphoplasty.

BACKGROUND: The KAST (Kiva Safety and Efficacy) investigation device exempt (IDE) study indicated that the majority of patients responded equally well to vertebral augmentation using either an implant-based approach or balloon kyphoplasty (BK). Additional investigation has suggested that a subset of patients may benefit further by avoiding repeated readmissions due to serious adverse events (SAEs) if they receive one vertebral augmentation approach over another. OBJECTIVES: The primary aim was to assess the effect of 2 different augmentation procedures on readmission rates for SAEs. STUDY DESIGN: The KAST trial is a pivotal, multicenter, randomized, controlled trial conducted to evaluate an implant-based vertebral augmentation approach (implant) against BK. Post-hoc analysis was performed to evaluate SAEs and readmission rates. SETTING: Twenty-one sites in North America and Europe. METHODS: The treatment effect of vertebral implant versus BK on SAEs requiring unplanned readmission was evaluated by estimating the risk of SAEs associated with readmissions in KAST while controlling for key baseline covariates using multivariate Poisson regression modeling. RESULTS: Forty (27.8%) patients with implants had 69 SAEs associated with readmission compared to 44 (31.2%) patients with BK having 103 events. The risk for all SAEs leading to readmission was 34.4% lower with the implant than for BK (95% confidence interval = 11.1%, 51.7%; P < 0.01). Multivariate analysis showed that the risk of SAEs associated with readmission was decreased in subjects treated with the implant compared to BK, and increased in patients with prior histories of vertebral compression fractures (VCFs) or significant osteoporosis. LIMITATIONS: The power of the KIVA study was based on clinical efficacy criteria to meet FDA requirements and recommendations for equivalency or noninferiority. The primary endpoint in this post-hoc analysis is SAEs associated with readmissions; as a result, the sample size is underpowered, although the results remain significant. CONCLUSION: The augmentation approaches compared here have similar pain relief and quality of life effects; the implant showed a lower risk of readmissions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01123512. Key words: Vertebral compression fracture, kiva implant, balloon kyphoplasty, vertebroplasty, health economics, osteoporosis.

Excitation enhancement in electric multipole transitions near a nanoedge.

We investigate enhancement of electric multipole excitations of atoms in the vicinity of an object with a nanoscale edge resulted from a large electromagnetic field gradient. We calculate the excitation efficiencies of a Rb atom around a nanoedge and find the excitations are enhanced by several orders of magnitude. The efficiencies with the change in the magnetic quantum number resolved are also examined. Each resolved efficiency shows rotationally symmetric spatial distribution, with continuous modification in shape from the far field to the near field. Furthermore, we estimate photon emission rates accompanied with multipole excitations in alkali (Rb and Cs) atoms and discuss the possibility to observe the enhancement in the multi-pole excitation in cold atoms.

A minimal length rigid helical peptide motif allows rational design of modular surfactants.

Extensive work has been invested in the design of bio-inspired peptide emulsifiers. Yet, none of the formulated surfactants were based on the utilization of the robust conformation and self-assembly tendencies presented by the hydrophobins, which exhibited highest surface activity among all known proteins. Here we show that a minimalist design scheme could be employed to fabricate rigid helical peptides to mimic the rigid conformation and the helical amphipathic organization. These designer building blocks, containing natural non-coded α-aminoisobutyric acid (Aib), form superhelical assemblies as confirmed by crystallography and microscopy. The peptide sequence is amenable to structural modularity and provides the highest stable emulsions reported so far for peptide and protein emulsifiers. Moreover, we establish the ability of short peptides to perform the dual functions of emulsifiers and thickeners, a feature that typically requires synergistic effects of surfactants and polysaccharides. This work provides a different paradigm for the molecular engineering of bioemulsifiers.

Study of Molecular Mechanisms of α-Synuclein Assembly: Insight into a Cross-ß Structure in the N-Termini of New α-Synuclein Fibrils.

Parkinson's disease is characterized by the self-assembly of α-synuclein (AS), in which its aggregates accumulate in the substantia nigra. The molecular mechanisms of the self-assembly of AS are challenging because AS is a relatively large intrinsically disordered protein, consisting of 140 residues. It is known that the N-termini of AS contribute to the toxicity of the proteins; therefore, it is important to investigate the self-assembly structure of the N-termini on AS as well. There have been extensive efforts to investigate the structural fibrils of AS(1-140), which have shown that the N-termini are disordered and do not participate in the fibrillary structure. This study illustrates for the first time that the N-termini of AS play a crucial role in the self-assembly of AS. This study reveals a new structure of AS(1-140) fibrils, in which the N-termini are essential parts of the cross-ß structure of the fibrillary structure. This study suggests that there are polymorphic states of the self-assembled AS(1-140). While the polymorphic states of the N-termini do not participate in the fibrillary structure and fluctuate, our predicted new fibrillary structure of the N-termini not only participates in the fibrillary structure but also stabilizes the fibrillary structure.

Optically controlled magnetic-field etching on the nano-scale.

Electric and magnetic fields play an important role in both chemical and physical reactions. However, since the coupling efficiency between magnetic fields and electrons is low in comparison with that between electric fields and electrons in the visible wavelength region, the magnetic field is negligible in photo-induced reactions. Here, we performed photo-etching of ZrO2 nano-stripe structures, and identified an etching-property polarisation dependence. Specifically, the etching rate and etched profiles depend on the structure width. To evaluate this polarisation-dependent etching, we performed numerical calculations using a finite-difference time-domain method. Remarkably, the numerical results revealed that the polarisation-dependent etching properties were determined by the magnetic field distributions, rather than the electric field distributions. As nano-scale structures induce a localised magnetic field, the discovery of this etching dependence on the magnetic field is expected to introduce a new perspective on advanced nano-scale structure fabrication.

Resonant infiltration of an opal: Reflection line shape and contribution from in-depth regions.

We analyze the resonant variation of the optical reflection on an infiltrated artificial opal made of transparent nanospheres. The resonant infiltration is considered as a perturbation in the frame of a previously described one-dimensional model based upon a stratified effective index. We show that for a thin slice of resonant medium, the resonant response oscillates with the position of this slice. We derive that for adequate conditions of incidence angle, this spatially oscillating behavior matches the geometrical periodicity of the opal and hence the related density of resonant infiltration. Close to these matching conditions, the resonant response of the global infiltration varies sharply in amplitude and shape with the incidence angle and polarization. The corresponding resonant reflection originates from a rather deep infiltration, up to several wavelengths or layers of spheres. Finally, we discuss the relationship between the present predictions and our previous observations on an opal infiltrated with a resonant vapor.

Comment on "Optical response of gas-phase atoms at less than λ/80 from a dielectric surface".

A Comment on the Letter by K. A. Whittaker et al., Phys. Rev. Lett. 112, 253201 (2014).PRLTAO0031-900710.1103/PhysRevLett.112.253201.

Casimir-Polder interactions in the presence of thermally excited surface modes.

The temperature dependence of the Casimir-Polder interaction addresses fundamental issues for understanding vacuum and thermal fluctuations. It is highly sensitive to surface waves, which, in the near field, govern the thermal emission of a hot surface. Here we use optical reflection spectroscopy to monitor the atom-surface interaction potential between a Cs*(7D3/2) atom and a hot sapphire surface at distances of ~100 nm. In our experiments, that explore a large range of temperatures (500-1,000 K), the surface is at thermal equilibrium with the vacuum. The observed increase of the interaction with temperature, by up to 50%, relies on the coupling between atomic virtual transitions in the infrared range and thermally excited surface-polariton modes. We extrapolate our findings to a broad distance range, from the isolated atom to the short distances relevant to physical chemistry. Our work also opens the prospect of controlling atom-surface interactions by engineering thermal fields.

Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES).

STUDY OBJECTIVE: To determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA). DESIGN, SETTING, AND PARTICIPANTS: The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures. INTERVENTION: Active or sham CPAP MEASUREMENTS: THREE NEUROCOGNITIVE VARIABLES, EACH REPRESENTING A NEUROCOGNITIVE DOMAIN: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F]) RESULTS: The primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test. CONCLUSIONS: CPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship. CLINICAL TRIAL INFORMATION: Registered at clinicaltrials.gov. Identifier: NCT00051363. CITATION: Kushida CA; Nichols DA; Holmes TH; Quan SF; Walsh JK; Gottlieb DJ; Simon RD; Guilleminault C; White DP; Goodwin JL; Schweitzer PK; Leary EB; Hyde PR; Hirshkowitz M; Green S; McEvoy LK; Chan C; Gevins A; Kay GG; Bloch DA; Crabtree T; Demen WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). SLEEP 2012;35(12):1593-1602.

Positive surgical margin and perioperative complication rates of primary surgical treatments for prostate cancer: a systematic review and meta-analysis comparing retropubic, laparoscopic, and robotic prostatectomy.

CONTEXT: Radical prostatectomy (RP) approaches have rarely been compared adequately with regard to margin and perioperative complication rates. OBJECTIVE: Review the literature from 2002 to 2010 and compare margin and perioperative complication rates for open retropubic RP (ORP), laparoscopic RP (LRP), and robot-assisted LRP (RALP). EVIDENCE ACQUISITION: Summary data were abstracted from 400 original research articles representing 167,184 ORP, 57,303 LRP, and 62,389 RALP patients (total: 286,876). Articles were found through PubMed and Scopus searches and met a priori inclusion criteria (eg, surgery after 1990, reporting margin rates and/or perioperative complications, study size>25 cases). The primary outcomes were positive surgical margin (PSM) rates, as well as total intra- and perioperative complication rates. Secondary outcomes included blood loss, transfusions, conversions, length of hospital stay, and rates for specific individual complications. Weighted averages were compared for each outcome using propensity adjustment. EVIDENCE SYNTHESIS: After propensity adjustment, the LRP group had higher positive surgical margin rates than the RALP group but similar rates to the ORP group. LRP and RALP showed significantly lower blood loss and transfusions, and a shorter length of hospital stay than the ORP group. Total perioperative complication rates were higher for ORP and LRP than for RALP. Total intraoperative complication rates were low for all modalities but lowest for RALP. Rates for readmission, reoperation, nerve, ureteral, and rectal injury, deep vein thrombosis, pneumonia, hematoma, lymphocele, anastomotic leak, fistula, and wound infection showed significant differences between groups, generally favoring RALP. The lack of randomized controlled trials, use of margin status as an indicator of oncologic control, and inability to perform cost comparisons are limitations of this study. CONCLUSIONS: This meta-analysis demonstrates that RALP is at least equivalent to ORP or LRP in terms of margin rates and suggests that RALP provides certain advantages, especially regarding decreased adverse events.

Platelet reduction after stentless pericardial aortic valve replacement.

The aim of the study was to investigate the multi-factorial phenomenon of possible postoperative thrombocytopenia after aortic valve replacement (AVR) with the freedom SOLO (FS) bioprosthesis. A total of 254 patients underwent AVR with FS bioprosthesis in two cardiac surgery institutes. Platelet counts were measured preoperatively, immediately postoperatively and daily until the 11th day postoperatively. A multivariate generalized estimating equation model was applied to identify prognostic factors for whether or not patients postoperative platelet counts indicated no thrombocytopenia (platelet count >150 10(3)/mm(3)) versus at least mild thrombocytopenia (≤150 10(3)/mm(3)). Preoperatively, 11.2% of patients showed thrombocytopenia. The preoperative platelet count averaged 233.0 ± 83.2 10(3)/mm(3). The postoperative mean of platelet counts decreased daily reaching a minimum mean of 88.4 ± 58.8 10(3)/mm(3) 3 days after surgery and then started to increase, with the Day 11 postoperative mean of 173.3 ± 51.8 10(3)/mm(3). Compared with patients with no preoperative thrombocytopenia, patients with preoperative thrombocytopenia had an 8.69 increased odds of being in the group with postoperative platelet count <150 10(3)/mm(3). No major haemorrhagic or thromboembolic event was reported during hospitalization. This study shows that thrombocytopenia after the FS bioprosthesis replacement is a transient postoperative phenomenon, largely resolved within a few days after surgery, with no clinical consequences and haemodynamic dysfunction.