Angiographic Coronary Slow Flow Is Not a Valid Surrogate for Invasively Diagnosed Coronary Microvascular Dysfunction.

BACKGROUND: Ischemia with no obstructive coronary arteries is frequently caused by coronary microvascular dysfunction (CMD). Consensus diagnostic criteria for CMD include baseline angiographic slow flow by corrected TIMI (Thrombolysis In Myocardial Infarction) frame count (cTFC), but correlations between slow flow and CMD measured by invasive coronary function testing (CFT) are uncertain. OBJECTIVES: The aim of this study was to investigate relationships between cTFC and invasive CFT for CMD. METHODS: Adults with ischemia with no obstructive coronary arteries underwent invasive CFT with thermodilution-derived baseline coronary blood flow, coronary flow reserve (CFR), and index of microcirculatory resistance (IMR). CMD was defined as abnormal CFR (<2.5) and/or abnormal IMR (≥25). cTFC was measured from baseline angiography; slow flow was defined as cTFC >25. Correlations between cTFC and baseline coronary flow and between CFR and IMR and associations between slow flow and invasive measures of CMD were evaluated, adjusted for covariates. All patients provided consent. RESULTS: Among 508 adults, 49% had coronary slow flow. Patients with slow flow were more likely to have abnormal IMR (36% vs 26%; P = 0.019) but less likely to have abnormal CFR (28% vs 42%; P = 0.001), with no difference in CMD (46% vs 51%). cTFC was weakly correlated with baseline coronary blood flow (r = -0.35; 95% CI: -0.42 to -0.27), CFR (r = 0.20; 95% CI: 0.12 to 0.28), and IMR (r = 0.16; 95% CI: 0.07-0.24). In multivariable models, slow flow was associated with lower odds of abnormal CFR (adjusted OR: 0.53; 95% CI: 0.35 to 0.80). CONCLUSIONS: Coronary slow flow was weakly associated with results of invasive CFT and should not be used as a surrogate for the invasive diagnosis of CMD.

Mechanically triggered on-demand degradation of polymers synthesized by radical polymerizations.

Polymers that degrade on demand have the potential to facilitate chemical recycling, reduce environmental pollution and are useful in implant immolation, drug delivery or as adhesives that debond on demand. However, polymers made by radical polymerization, which feature all carbon-bond backbones and constitute the most important class of polymers, have proven difficult to render degradable. Here we report cyclobutene-based monomers that can be co-polymerized with conventional monomers and impart the resulting polymers with mechanically triggered degradability. The cyclobutene residues act as mechanophores and can undergo a mechanically triggered ring-opening reaction, which causes a rearrangement that renders the polymer chains cleavable by hydrolysis under basic conditions. These cyclobutene-based monomers are broadly applicable in free radical and controlled radical polymerizations, introduce functional groups into the backbone of polymers and allow the mechanically gated degradation of high-molecular-weight materials or cross-linked polymer networks into low-molecular-weight species.

Encampment Clearings And Transitional Housing: A Qualitative Analysis Of Resident Perspectives.

The number of people experiencing homelessness in tent encampments in the US has increased significantly. Citing concerns over health and safety, many cities have pursued highly visible encampment removals. In January 2022, a major tent encampment in Boston, Massachusetts, was cleared using a unique approach: Most encampment residents were placed in transitional harm reduction housing. We conducted interviews between July 2022 and February 2023 with thirty former encampment residents to explore how the encampment clearing affected their health and sense of safety. We also explored participants' perspectives on harm reduction housing. Of those interviewed, fourteen people had been placed in such housing. Among those not placed, the encampment clearing tended to exacerbate health and safety concerns, especially those related to mental health conditions and risk for violence. Among people successfully placed, harm reduction housing improved health and safety and allowed participants to make meaningful progress toward long-term goals such as addiction recovery, management of chronic health conditions, and permanent housing. Our findings suggest that encampments can have safety-promoting characteristics, but if encampment removal is pursued, offering harm reduction housing after removal can be beneficial.

Assessment of seasonal forecasting errors of the ECMWF system in the eastern Indian Ocean.

The interannual variability of the Equatorial Eastern Indian Ocean (EEIO) is highly relevant for the climate anomalies on adjacent continents and affects global teleconnection patterns. Yet, this is an area where seasonal forecasting systems exhibit large errors. Here we investigate the reasons for these errors in the ECMWF seasonal forecasting system SEAS5 using tailored diagnostics and a series of numerical experiments. Results indicate that there are two fundamental and independent sources of forecast errors in the EEIO. The first one is of atmospheric nature and is largely related with too strong and stable easterly atmospheric circulation present in the equatorial Indian Ocean. This induces an easterly bias which leaves the coupled model predominantly in a state with a shallow thermocline and cold SSTs in the EEIO. The second error is of oceanic origin, associated with a too shallow thermocline, which enhances the SST errors arising from errors in the wind. Ocean initial conditions, which depend on both the quality of the assimilation and the ocean model, play an important role in this context. Nevertheless, it is found that the version of the ocean model used for the forecast can also play a non-negligible role at the seasonal time scales, by amplifying or damping the subsurface errors in the initial conditions. Errors in the EEIO are regime-dependent, having different causes in the warm (deep thermocline) regime with strong atmospheric convection and in the cold (shallow thermocline) regime. Errors also exhibit decadal variations, which challenges the calibration methods used in seasonal forecasts. Supplementary Information: The online version contains supplementary material available at 10.1007/s00382-023-06985-3.

In Situ Observation of Chemically Induced Protein Denaturation at Solvated Interfaces.

Proteins unfold in chaotropic salt solutions, a process that is difficult to observe at the single protein level. The work presented here demonstrates that a liquid-based atomic force microscope and graphene liquid-cell-based scanning transmission electron microscope make it possible to observe chemically induced protein unfolding. To illustrate this capability, ferritin proteins were deposited on a graphene surface, and the concentration-dependent urea- or guanidinium-induced changes of morphology were monitored for holo-ferritin with its ferrihydrite core as well as apo-ferritin without this core. Depending on the chaotropic agent the liquid-based imaging setup captured an unexpected transformation of natively folded holo-ferritin proteins into rings after urea treatment but not after guanidinium treatment. Urea treatment of apo-ferritin did not result in nanorings, confirming that nanorings are a specific signature of denaturation of holo-ferritins after exposture to sufficiently high urea concentrations. Mapping the in situ images with molecular dynamics simulations of ferritin subunits in urea solutions suggests that electrostatic destabilization triggers denaturation of ferritin as urea makes direct contact with the protein and also disrupts the water H-bonding network in the ferritin solvation shell. Our findings deepen the understanding of protein denaturation studied using label-free techniques operating at the solid-liquid interface.

Screening for Emotional Distress in Patients with Cardiovascular Disease.

PURPOSE OF REVIEW: In this article, we discuss the relationship between emotional distress and common cardiovascular disease condition, including coronary artery disease, atrial fibrillation, congestive heart failure, mechanical circulatory support, and heart transplant. We review screening measures that have been studied and used in clinical practice for each condition, as well as priorities for future research. RECENT FINDINGS: Studies consistently demonstrate failing to identify and treat emotional distress in patients with cardiovascular disease is associated with adverse outcomes. However, routine emotional distress screening is not formally recommended for all cardiovascular disease conditions and is limited to depression screening in select patient populations. Future research should focus on evaluating the validity and reliability of standardized screening measures across the scope of emotional distress in patients with or at risk for cardiovascular disease. Other areas of future research include implementation of evidence-based pharmaceutical treatments and integrated behavioral health approaches and interventions.

Agentic and communal narcissism in predicting different types of lies in romantic relationships.

Several studies have investigated a potential positive association between agentic narcissism and general dishonesty, revealing both supportive and contradicting evidence. Few have focused on dishonesty within romantic relationships, a phenomenon that occurs in almost all partnerships. With the present research, we first aimed to extend existing literature on narcissism by including its two complementary facets (i.e., agentic and communal narcissism). Second, we aimed to improve the understanding of narcissists' lying behavior in the context of partnerships by distinguishing between two different types of lies (i.e., self-centered and other-oriented lies). We hypothesized that both, people higher in agentic and communal narcissism, will report increased dishonesty toward their romantic partners (Hypothesis 1). Given the self-benefit function of self-centered lies and given that agentic narcissists aim to fulfill their relationship-based motives by agentic means, we predict agentic narcissism (compared with communal narcissism) will be a stronger predictor for self-centered lies (Hypothesis 1a). Given the other-benefiting function of other-oriented lies and given that communal narcissists aim to fulfill their motive of self-enhancement by communal means, we predict that communal narcissism (compared with agentic narcissism) will be a stronger predictor for other-oriented lies (Hypothesis 1b). In two preregistered online studies (N = 298: N = 256) we showed that people higher in agentic narcissism believed to be good liars, but this does not lead to higher self-reported frequencies of other-oriented and self-centered lies within romantic relationships historically; communal narcissism was also not related to self-reported deception. Limitations and directions for future research are discussed.

Simultaneous Determination of the Size and Shape of Single α-Synuclein Oligomers in Solution.

Soluble oligomers of amyloid-forming proteins are implicated as toxic species in the context of several neurodegenerative diseases. Since the size and shape of these oligomers influence their toxicity, their biophysical characterization is essential for a better understanding of the structure-toxicity relationship. Amyloid oligomers are difficult to characterize by conventional approaches due to their heterogeneity in size and shape, their dynamic aggregation process, and their low abundance. This work demonstrates that resistive pulse measurements using polymer-coated solid-state nanopores enable single-particle-level characterization of the size and shape of individual αSyn oligomers in solution within minutes. A comparison of the resulting size distribution with single-particle analysis by transmission electron microscopy and mass photometry reveals good agreement with superior resolution by nanopore-based characterization. Moreover, nanopore-based analysis has the capability to combine rapid size analysis with an approximation of the oligomer shape. Applying this shape approximation to putatively toxic oligomeric species that range in size from 18 ± 7 aggregated monomers (10S) to 29 ± 10 aggregated monomers (15S) and in concentration from picomolar to nanomolar revealed oligomer shapes that agree well with previous estimates by cryo-EM with the added advantage that nanopore-based analysis occurs rapidly, in solution, and has the potential to become a widely accessible technique.

Optical Monitoring of In Situ Iron Loading into Single, Native Ferritin Proteins.

Ferritin is a protein that stores and releases iron to prevent diseases associated with iron dysregulation in plants, animals, and bacteria. The conversion between iron-loaded holo-ferritin and empty apo-ferritin is an important process for iron regulation. To date, studies of ferritin have used either ensemble measurements to quantify the characteristics of a large number of proteins or single-molecule approaches to interrogate labeled or modified proteins. Here we demonstrate the first real-time study of the dynamics of iron ion loading and biomineralization within a single, unlabeled ferritin protein. Using optical nanotweezers, we trapped single apo- and holo-ferritins indefinitely, distinguished one from the other, and monitored their structural dynamics in real time. The study presented here deepens the understanding of the iron uptake mechanism of ferritin proteins, which may lead to new therapeutics for iron-related diseases.

Computational design of anisotropic nanocomposite actuators.

This paper presents a theoretical investigation of the design of a new actuator type made of anisotropic colloidal particles grafted with stimuli-responsive polymer chains. These artificial muscles combine the osmotic actuation principle of stimuli-responsive hydrogels with the structural alignment of colloidal liquid crystals to achieve directional motion. The solubility of the stimuli-responsive polymer in the neutral state, its degree of polymerization, the salt concentration, and the grafting density of the polymer chains on the surface of the colloidal particles are investigated and identified as important for actuator performance and tunability. The computational results suggest that the proposed mechanically active material matches or exceeds the performances of natural muscles and provide the guidelines for the realization of artificial muscles with predetermined actuation properties.

Facet joint violation after open and percutaneous posterior instrumentation: a comparative study.

PURPOSE: Posterior instrumentation is the state-of-the-art surgical treatment for fractures of the thoracic and lumbar spine. Options for pedicle screw placement comprise open or minimally invasive techniques. Open instrumentation causes large approach related muscle detachment, which minimally invasive techniques aim to reduce. However, concerns of accurate pedicle screw placement are still a matter of debate. Beside neurological complications due to pedicle screw malplacement, also affection of the facet joints and thus motion dependent pain is known as a complication. The aim of this study was to assess accuracy of pedicle screw placement concerning facet joint violation (FJV) after open- and minimally invasive posterior instrumentation. METHODS: A retrospective data analysis of postoperative computer tomographic scans of 219 patients (1124 pedicle screws) was conducted. A total of 116 patients underwent open screw insertion (634 screws) and 103 patients underwent minimally invasive, percutaneous screw insertion (490 screws). RESULTS: In the lumbar spine (segments L3, L4, L5), there were significantly more and higher grade (open = 0.55 vs. percutaneous = 1.2; p = 0.001) FJV's after percutaneously compared to openly inserted screws. In the thoracic spine, no significant difference concerning rate and grade of FJV was found (p > 0.56). CONCLUSION: FJV is more likely to occur in percutaneously placed pedicle screws. Additionally, higher grade FJV's occur after percutaneous instrumentation. However, in the thoracic spine we didn't find a significant difference between open and percutaneous technique. Our results suggest a precise consideration concerning surgical technique according to the fractured vertebrae in the light of the individual anatomic structures in the preop CT.

Assessment of atlantoaxial rotation: how accurate is clinical measurement? a comparative study of cervical range of motion using MRI and standard orthopedic techniques.

PURPOSE: Measurement of neck rotation is currently reliant on radiologic imaging. Given the radiation exposure for CT imaging and the additional inconvenience for the patients, an alternative assessment is needed. Goniometers are comfortably to use and easy to access, also for private consulting. The aim of this study was the assessment of whether a handheld goniometer can be used for accurately measuring the rotation of C1-C2. METHODS: Clinical measurement of rotation was taken in flexed position of the neck. As comparison functional MRI was used. The measured rotation of C1-C2 was compared to identify the accuracy of the goniometer, in comparison to functional MRI scan. RESULTS: Analysis of accuracy using a goniometer and dynamic MRI to assess C1-2 axial rotation showed significant differences for absolute values, but not regarding the percentage of rotation compared to total neck rotation. CONCLUSION: The goniometer is exact to impartially determine the percentage contribution of C1-2 rotation to total neck rotation.

Site-Specific C-Terminal Fluorescent Labeling of Tau Protein.

Formation of Tau protein aggregates in neurons is a pathological hallmark of several neurodegenerative diseases, including Alzheimer's disease. Fluorescently labeled Tau protein is therefore useful to study the aggregation of these pathological proteins and to identify potential therapeutic targets. Conventionally, cysteine residues are used for labeling Tau proteins; however, the full-length Tau isoform contains two cysteine residues in the microtubule-binding region, which are implicated in Tau aggregation by forming intermolecular disulfide bonds. To prevent the fluorescent label from disturbing the microtubule binding region, we developed a strategy to fluorescently label Tau at its C-terminus while leaving cysteine residues unperturbed. We took advantage of a Sortase A-mediated transpeptidation approach to bind a short peptide (GGGH6-Alexa647) with a His-tag and a covalently attached Alexa 647 fluorophore to the C-terminus of Tau. This reaction relies on the presence of a Sortase recognition motif (LPXTG), which we attached to the C-terminus of recombinantly expressed Tau. We demonstrate that C-terminal modification of Tau protein results in no significant differences between the native and C-terminally labeled Tau monomer with regard to aggregation kinetics, secondary structure, and fibril morphology.

Direct glass-to-glass bonding obtained via simplified ammonia-based low-temperature procedure resists high shear stress and powerful CW fiber laser irradiation.

Direct glass-to-glass bonding is important for high-technology components in optics, microfluidics, and micro-electromechanical systems applications. We studied direct bonding of 1 mm thick soda-lime float glass substrates. The process is based on the classic RCA-1 cleaning procedure from the semiconductor industry modified with an ammonium hydroxide rinse, followed by a thermal treatment under unidirectional pressure without the need for a dedicated drying step. RCA-1 uses a solution of ammonium hydroxide and hydrogen peroxide to clean contaminants off the surface of silicon and enable subsequent bonding. Bond quality was evaluated using destructive shear testing. Strong bonds (≈7.81 MPa on average) were achieved using unidirectional pressure of approximately 0.88 MPa and bonding temperatures between 160 °C and 300 °C applied for 30 min. Surface roughness and chemistry was characterized before and after cleaning. The optical robustness of the bonds was tested and shown to be capable of surviving high powered continuous wave (CW) fiber laser irradiation of at least 375 W focused for 2 s without delamination. Melting of the substrate was observed at higher powers and longer exposure times.

Design, synthesis, molecular modeling, and bioactivity evaluation of 1,10-phenanthroline and prodigiosin (Ps) derivatives and their Copper(I) complexes against mTOR and HDAC enzymes as highly potent and effective new anticancer therapeutic drugs.

Breast cancer is the second type of cancer with a high probability of brain metastasis and has always been one of the main problems of breast cancer research due to the lack of effective treatment methods. Demand for developing an effective drug against breast cancer brain metastasis and finding molecular mechanisms that play a role in effective treatment are gradually increasing. However, there is no effective anticancer therapeutic drug or treatment method specific to breast cancer, in particular, for patients with a high risk of brain metastases. It is known that mTOR and HDAC enzymes play essential roles in the development of breast cancer brain metastasis. Therefore, it is vital to develop some new drugs and conduct studies toward the inhibition of these enzymes that might be a possible solution to treat breast cancer brain metastasis. In this study, a series of 1,10-phenanthroline and Prodigiosin derivatives consisting of their copper(I) complexes have been synthesized and characterized. Their biological activities were tested in vitro on six different cell lines (including the normal cell line). To obtain additional parallel validations of the experimental data, some in silico modeling studies were carried out with mTOR and HDAC1 enzymes, which are very crucial drug targets, to discover novel and potent drugs for breast cancer and related brain metastases disease.

Phase II testing of Xenon International on Mount Schauinsland, Germany.

Station RN33 on Mount Schauinsland near Freiburg, Germany, is part of the International Monitoring System monitoring radioxenon in air (131mXe, 133Xe, 133mXe, and 135Xe) for verification of the Comprehensive Nuclear Test Ban Treaty. Here, we present data from phase II testing of a new system, Xenon International at RN33, July 14th, 2021 to Jan 22nd, 2022, together with SPALAX data from the same time period. Radioxenon could be detected in 473 of 719 samples, among them many multiple isotope detections. Activity concentrations of spiked and selected environmental samples were verified by laboratory reanalysis. The sensitivity of Xenon International for radioxenons is up to one order of magnitude better for the metastable isotopes than that of the SPALAX, with a shorter sampling duration of 6 h.

Natural and Modified Oligonucleotide Sequences Show Distinct Strand Displacement Kinetics and These Are Affected Further by Molecular Crowders.

DNA and RNA strand exchange is a process of fundamental importance in biology. Herein, we used a FRET-based assay to investigate, for the first time, the stand exchange kinetics of natural DNA, natural RNA, and locked nucleic acid (LNA)-modified DNA sequences in vitro in PBS in the absence or presence of molecular additives and macromolecular crowders such as diethylene glycol dimethyl ether (deg), polyethylene glycol (peg), and polyvinylpyrrolidone (pvp). The results show that the kinetics of strand exchange mediated by DNA, RNA, and LNA-DNA oligonucleotide sequences are different. Different molecular crowders further affect the strand displacement kinetics, highlighting the complexity of the process of nucleic acid strand exchange as it occurs in vivo. In a peg-containing buffer, the rate constant of displacement was slightly increased for the DNA displacement strand, while it was slightly decreased for the RNA and the LNA-DNA strands compared with displacement in pure PBS. When we used a deg-containing buffer, the rate constants of displacement for all three sequences were drastically increased compared with displacement in PBS. Overall, we show that interactions of the additives with the duplex strands have a significant effect on the strand displacement kinetics and this effect can exceed the one exerted by the chemical nature of the displacement strand itself.

Multi-Functionalized Heteroduplex Antisense Oligonucleotides for Targeted Intracellular Delivery and Gene Silencing in HeLa Cells.

Oligonucleotide therapeutics, antisense oligonucleotides (ASOs) and short interfering RNA (siRNA) are short synthetic nucleic acid molecules with a promising potential to treat a wide range of diseases. Despite considerable progress in the field, the development of safe and effective delivery systems that target organs and tissues other than the liver is challenging. While keeping possible off-target oligonucleotide interactions and toxicity related to chemical modifications in mind, innovative solutions for targeted intracellular delivery are highly needed. Herein, we report on the design, synthesis and testing of a novel multi-modified and multi-functionalized heteroduplex oligonucleotide (HDO) with respect to its intracellular delivery and its ability to silence genes in HeLa cells. Simultaneously, folic acid- and peptide- labeled HDO show proficient silencing of the green fluorescent protein (GFP) gene with an 84% reduction in the GFP fluorescence. In addition, the Bcl2 HDO achieved effective Bcl2 gene knockdown in the cells. The data show the proficiency of the multi-functionalization strategy and provide an example for advancing the design of safe and efficient forthcoming oligonucleotide therapeutics, such as HDO.

Harvesting Electrical Power during Carbon Capture using Various Amine Solvents.

There exists an urgent demand for the advancement of technologies that reduce and capture carbon dioxide (CO2) emissions to mitigate anthropogenic contributions to climate change. This paper compares the maximum power densities achieved from the combination of reverse electrodialysis (RED) with carbon capture (CC) using various CC solvents. Carbon capture reverse electrodialysis (CCRED) harvests energy from the salinity gradients generated from the reaction of CO2 with specific solvents, generally amines. To eliminate the requirement of freshwater as an external resource, we took advantage of a semiclosed system that would allow the inputs to be industrial emissions and heat and the outputs to be electrical power, clean emissions, and captured CO2. We assessed the power density that can be attained using CCRED with five commonly studied CC solvents: monoethanolamine (MEA), diethanolamine (DEA), N-methyldiethanolamine (MDEA), 2-amino-2-methyl-2-propanol (AMP), and ammonia. We achieved the highest power density, 0.94 W m-2 cell-1, using ammonia. This work provides a foundation for future iterations of CCRED that may help to incentivize adoption of CC technology.

Variability of ENSO Forecast Skill in 2-Year Global Reforecasts Over the 20th Century.

In order to explore temporal changes of predictability of El Niño Southern Oscillation (ENSO), a novel set of global biennial climate reforecasts for the historical period 1901-2010 has been generated using a modern initialized coupled forecasting system. We find distinct periods of enhanced long-range skill at the beginning and at the end of the twentieth century, and an extended multi-decadal epoch of reduced skill during the 1930s-1950s. Once the forecast skill extends beyond the first spring barrier, the predictability limit is much enhanced and our results provide support for the feasibility of skillful ENSO forecasts up to 18 months. Changes in the mean state, variability (amplitude), persistence, seasonal cycle and predictability suggest that multi-decadal variations in the dynamical characteristics of ENSO rather than the data coverage and quality of the observations have primarily driven the reported non-monotonic skill modulations.