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The fundamental challenge underlying superconducting quantum computing is to characterize heterogeneity and disorder in the underlying quantum circuits. These nonuniform distributions often lead to local electric field concentration, charge scattering, dissipation and ultimately decoherence. It is particularly challenging to probe deep sub-wavelength electric field distribution under electromagnetic wave coupling at individual nano-junctions and correlate them with structural imperfections from interface and boundary, ubiquitous in Josephson junctions (JJ) used in transmon qubits. A major obstacle lies in the fact that conventional microscopy tools are incapable of measuring simultaneous at nanometer and terahertz, "nano-THz" scales, which often associate with frequency-dependent charge scattering in nano-junctions. Here we directly visualize interface nano-dipole near-field distribution of individual Al/AlO$_{x}$/Al junctions used in transmon qubits. Our THz nanoscope images show a remarkable asymmetry across the junction in electromagnetic wave-junction coupling response that manifests as "hot" vs "cold" cusp spatial electrical field structures and correlates with defected boundaries from the multi-angle deposition processes in JJ fabrication inside qubit devices. The asymmetric nano-dipole electric field contrast also correlates with distinguishing, "overshoot" frequency dependence that characterizes the charge scattering and dissipation at nanoscale, hidden in responses from topographic, structural imaging and spatially-averaged techniques. The real space mapping of junction dipole fields and THz charge scattering can be extended to guide qubit nano-fabrication for ultimately optimizing qubit coherence times.

Breast cancer is one of leading causes of death worldwide in the female population. Deaths from breast cancer could be reduced significantly through earlier and more efficient detection of the disease. Saliva, an oral fluid that contains an abundance of protein biomarkers, has been recognized as a promising diagnostic biofluid that is easy to isolate through non-invasive techniques. Assays on saliva can be performed rapidly and are cost-effective. Therefore, our work aimed to identify salivary biomarkers present in the initial stages of breast cancer, where cell alterations are not yet detectable by histopathological analysis. Using state-of-the-art techniques, we employed a transgenic mouse model of mammary cancer to identify molecular changes in precancerous stage breast cancer through protein analysis in saliva. Through corroborative molecular approaches, we established that proteins related to metabolic changes, inflammatory process and cell matrix degradation are detected in saliva at the onset of tumor development. Our work demonstrated that salivary protein profiles can be used to identify cellular changes associated with precancerous stage breast cancer through non-invasive means even prior to biopsy-evident disease.

In nature, plants experience rapid changes in light intensity and quality throughout the day. To maximize growth, they have established molecular mechanisms to optimize photosynthetic output while protecting components of the light-dependent reaction and CO

With the ever-increasing sensitivity and timing baselines of modern radio telescopes, a growing number of pulsars are being shown to exhibit transitions in their rotational and radio emission properties. In many of these cases, the two are correlated with pulsars assuming a unique spin-down rate ($\dot{\nu}$) for each of their specific emission states. In this work we revisit 17 radio pulsars previously shown to exhibit spin-down rate variations. Using a Gaussian process regression (GPR) method to model the timing residuals and the evolution of the profile shape, we confirm the transitions already observed and reveal new transitions in 8 years of extended monitoring with greater time resolution and enhanced observing bandwidth. We confirm that 7 of these sources show emission-correlated $\dot{\nu}$ transitions ($\Delta \dot{\nu}$) and we characterise this correlation for one additional pulsar, PSR B1642$-$03. We demonstrate that GPR is able to reveal extremely subtle profile variations given sufficient data quality. We also corroborate the dependence of $\Delta \dot{\nu}$ amplitude on $\dot{\nu}$ and pulsar characteristic age. Linking $\Delta \dot{\nu}$ to changes in the global magnetospheric charge density $\Delta \rho$, we speculate that $\dot{\nu}$ transitions associated with large $\Delta \rho$ values may be exhibiting detectable profile changes with improved data quality, in cases where they have not previously been observed., Comment: 20 pages, 16 figures, 3 tables

Polymorphonuclear cells (PMNs) controlStreptococcus pneumoniae(pneumococcus) infection through various antimicrobial activities. We previously found that reactive oxygen species (ROS) were required for optimal antibacterial function, however, the NADPH oxidase is known to be dispensable for the ability of PMNs to kill pneumococci. In this study, we explored the role of ROS produced by the mitochondria in PMN antimicrobial defense against pneumococci. We found that the mitochondria are an important source of overall intracellular ROS produced by murine PMNs in response to infection. We investigated the host and bacterial factors involved and found that mitochondrial ROS (MitROS) are produced independent of bacterial capsule or pneumolysin but presence of live bacteria that are in direct contact with PMNs enhanced the response. We further found that MyD88-/-PMNs failed to produce MitROS in response to pneumococcal infection suggesting that released bacterial products acting as TLR ligands are sufficient for inducing MitROS production in PMNs. To test the role of MitROS in PMN function, we used an opsonophagocytic killing assay and found that MitROS were required for the ability of PMNs to kill pneumococci. We then investigated the role of MitROS in host resistance and found that MitROS are produced by PMNs in response to pneumococcal infection. Importantly, treatment of mice with a MitROS scavenger prior to systemic challenge resulted in reduced survival of infected hosts. In exploring host pathways that control MitROS, we focused on extracellular adenosine, which is known to control PMN anti-pneumococcal activity, and found that signaling through the A2B adenosine receptor inhibits MitROS production by PMNs. A2BR-/-mice produced more MitROS and were significantly more resistant to infection. Finally, we verified the clinical relevance of our findings using human PMNs. In summary, we identified a novel pathway that controls MitROS production by PMNs, shaping host resistance againstS. pneumoniae.Author summaryDespite the presence of antibiotics and vaccines,Streptococcus pneumoniaeinfections remain a serious cause of mortality and morbidity globally. Understanding protective host responses is key for designing improved therapies against infection. Neutrophils are innate immune cells that are crucial for control ofS. pneumoniaeinfection. In this study we explored the mechanisms by which neutrophils killS. pneumoniae. We found that the mitochondria, whose primary role is energy production, also produce reactive oxygen species (ROS) that are critical for the ability of neutrophils to killS. pneumoniae.We explored the bacterial and host factors involved in mitochondrial ROS (MitROS) production by neutrophils. We found that recognition of bacterial products by neutrophils triggers this response and that the host A2B adenosine receptor regulates it. Importantly, MitROS were required for host resistance againstS. pneumoniae. This study describes a novel pathway that controls anti-microbial responses and can be a future therapeutic target.

Polymorphonuclear cells (PMNs) controlStreptococcus pneumoniae(pneumococcus) infection through various antimicrobial activities. We previously found that reactive oxygen species (ROS) were required for optimal antibacterial function, however, the NADPH oxidase is known to be dispensable for the ability of PMNs to kill pneumococci. In this study, we explored the role of ROS produced by the mitochondria in PMN antimicrobial defense against pneumococci. We found that the mitochondria are an important source of overall intracellular ROS produced by murine PMNs in response to infection. We investigated the host and bacterial factors involved and found that mitochondrial ROS (MitROS) are produced independent of bacterial capsule or pneumolysin but presence of live bacteria that are in direct contact with PMNs enhanced the response. We further found that MyD88-/-PMNs produced less MitROS in response to pneumococcal infection suggesting that released bacterial products acting as TLR ligands are sufficient for inducing MitROS production in PMNs. To test the role of MitROS in PMN function, we used an opsonophagocytic killing assay and found that MitROS were required for the ability of PMNs to kill pneumococci. We then investigated the role of MitROS in host resistance and found that MitROS are produced by PMNs in response to pneumococcal infection. Importantly, treatment of mice with a MitROS scavenger prior to systemic challenge resulted in reduced survival of infected hosts. In exploring host pathways that control MitROS, we focused on extracellular adenosine, which is known to control PMN anti-pneumococcal activity, and found that signaling through the A2B adenosine receptor inhibits MitROS production by PMNs. A2BR-/-mice produced more MitROS and were significantly more resistant to infection. Finally, we verified the clinical relevance of our findings using human PMNs. In summary, we identified a novel pathway that controls MitROS production by PMNs, shaping host resistance againstS.pneumoniae.

Background: Vagus nerve stimulation (VNS) has gained great importance as a promising therapy for a myriad of diseases. Of particular interest is the therapy of cardiovascular diseases, such as heart failure or atrial fibrillation using selective cardiac VNS. However, there is still a lack of organ-specific anatomical knowledge about the fascicular anatomy and topography of the cardiac branch (CB), which diminishes the therapeutic possibilities for selective cardiac neuromodulation. Here, we established a topographical and anatomical map of the superior cardiac VN in two animal species to dissect cervical and cardiac VN morphology.Methods: Autonomic nerves including superior CBs were harvested from domestic pigs and New Zeeland rabbits followed by imaging with microcomputed tomography (µCT) and 3D rendering. The data were analyzed in terms of relevant topographical and anatomical parameters.Results: Our data showed that cardiac vagal fascicles remained separated from other VN fascicles up to 22.19 mm (IQR 14.02–41.30 mm) in pigs and 7.68 mm (IQR 4.06–12.77 mm) in rabbits from the CB point and then started merging with other fascicles. Exchanges of nerve fascicles between sympathetic trunk (ST) and VN were observed in 3 out of 11 nerves, which might cause additional unwanted effects in unselective VNS. Our 3D rendered digital model of the cardiac fascicles was generated showing that CB first remained on the medial side where it branched off the VN, as also shown in the µCT data of 11 pig nerves, and then migrated towards the ventromedial site the further it was traced cranially.Conclusion: Our data provided an anatomical map of the cardiac vagal branches including cervical VN and ST for future approaches of selective cardiac neurostimulation, indicating the best position of selective cardiac VNS just above the CB point.

Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients.This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM.Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout.From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and 0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms.Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020- EU H2020-EU.1.2.2. - FET Proactive "NeuHeart" Nr. 824071 Background & Introduction In recent years, Vagus Nerve Stimulation (VNS) has proved to be a potential therapeutic approach for the treatment of cardiovascular diseases, such as Heart Failure or atrial fibrillation [1]. However, the lack of specific anatomical knowledge of the cervical VN [2, 3] and thus, of the cardiac autonomic innervation aggravates the side effects of unselective cervical VNS. Purpose The goal of this study was to investigate the cardiac vagus nerve branches for selective cardiac VNS stimulation using micro-computed tomography (µCT) and 3D renderings. Methods Vagus nerve specimens (n= 11 pig nerves, n= 5 rabbit nerves) were harvested from the nodose ganglion down to the cardiac branches in domestic pigs and New Zealand White rabbits on both sides, and the cardiac autonomic innervation was mapped µCT and 3D renderings. Results Our results provide anatomical and topographical key features on the cervical and cardiac autonomic innervation including course of the cardiac branch, cardiac branching patterns, fascicle number, and size of the autonomic nerves. We also compared these aforementioned anatomical parameters between pigs and rabbits and highlighted key anatomical differences among individuals within pigs. In pigs, the cardiac branches were partly composed of both nerves even when they branched off the VN whereas in rabbits, the two nerves were completely separated and the cardiac branch was solely parasympathetic. Finally, we generated a 3D model of various parts of the VN specimen and compared them to images of the native nerves taken during VN dissection surgery. Conclusions Here we present an imaging approach to map the anatomy and topography of the cardiac Vagus Nerve for selective stimulation of cardiac VN branches. We also characterized the morphology of the VN, the sympathetic trunk (ST), and the cardiac branch (CB) at the level of the cardiac branching point to highlight the complex interplay between the nerves. Our data provide one possible reason for unwanted side effects of cervical VNS. However, future studies are required to broaden the knowledge in this specific research field of selective cardiac VNS.

Palliative care (PC) teams commonly encounter patients with disorders of consciousness (DOC) following anoxic or traumatic brain injury (TBI). Primary teams may consult PC to help surrogates in making treatment choices for these patients. PC clinicians must understand the complexity of predicting neurologic outcomes, address clinical nihilism, and appropriately guide surrogates in making decisions that are concordant with patients' goals. The purpose of this article was to provide PC providers with a better understanding of caring for patients with DOC, specifically following anoxic or TBI. Many of the tips acknowledge the uncertainty of DOC and provide strategies to help tackle this dilemma.

After cancer treatment, female survivors often develop ovarian insufficiency or failure. Oocyte and embryo freezing are well-established fertility preservation options, but cannot be applied in pre-pubescent girls, in women with hormone-sensitive malignancies, or when gonadotoxic treatment cannot be delayed. Although ovarian tissue cryopreservation (OTC) has been used to restore fertility and endocrine function, the relative efficacy of its two major protocols, slow freezing and vitrification, remains controversial. This literature review evaluates clinical and lab-based studies published between January 2012 and June 2020 to determine whether vitrification, the optimal technique for oocyte and embryo cryopreservation, preserves ovarian tissue more effectively than slow freezing. Due to limited clinical data involving ovarian tissue vitrification, most clinical studies focus on slow freezing. Only 9 biochemical studies that directly compare the effects of slow freezing and vitrification of human ovarian tissue were noted. Most studies report no significant difference in follicular morphology and distribution between cryopreservation methods, but these findings must be interpreted in the context of high methodological variability. Discrepant findings regarding the effects of cryopreservation method on follicle viability, gene expression, and hormone production require further evaluation. Early clinical outcomes appear favorable for vitrification, but additional studies and longer term follow-up are needed to establish its efficacy. Sharing data through national or international registries would expedite this analysis. However, even if research corroborates conclusions of no clinical or biochemical difference between cryopreservation methods, the decreased costs and increased efficiency associated with vitrification make this method more accessible and cost-effective.

Background Resistance and tolerance are two coexisting defense strategies for fighting infections. Resistance is mediated by signaling pathways that induce transcriptional activation of resistance factors that directly eliminate the pathogen. Tolerance refers to adaptations that limit the health impact of a given pathogen burden, without targeting the infectious agent. The key players governing immune tolerance are largely unknown. In Drosophila, the histone H3 lysine 9 (H3K9) methyltransferase G9a was shown to mediate tolerance to virus infection and oxidative stress (OS), suggesting that abiotic stresses like OS may also evoke tolerance mechanisms. In response to both virus and OS, stress resistance genes were overinduced in Drosophila G9a mutants, suggesting an intact but overactive stress response. We recently demonstrated that G9a promotes tolerance to OS by maintaining metabolic homeostasis and safeguarding energy availability, but it remained unclear if this mechanism also applies to viral infection, or is conserved in other species and stress responses. To address these questions, we analyzed publicly available datasets from Drosophila, mouse, and human in which global gene expression levels were measured in G9a-depleted conditions and controls at different time points upon stress exposure. Results In all investigated datasets, G9a attenuates the transcriptional stress responses that confer resistance against the encountered stressor. Comparative analysis of conserved G9a-dependent stress response genes suggests that G9a is an intimate part of the design principles of stress resistance, buffering the induction of promiscuous stress signaling pathways and stress-specific resistance factors. Importantly, we find stress-dependent downregulation of metabolic genes to also be dependent on G9a across all of the tested datasets. Conclusions These results suggest that G9a sets the balance between activation of resistance genes and maintaining metabolic homeostasis, thereby ensuring optimal organismal performance during exposure to diverse types of stress across different species. We therefore propose G9a as a potentially conserved master regulator underlying the widely important, yet poorly understood, concept of stress tolerance.

The institution of private property forms the basis for ecological disaster. The profit-seeking of the vested interests, in conjunction with their modes of valuing nature through the apparatuses of...

Die molekulare Optogenetik hat zum Ziel, molekulare Prozesse in Zellen durch Lichtsignale zu steuern, indem genetisch kodierte Photorezeptoren an zelluläre Proteine fusioniert werden. Dadurch kann die zelluläre Signalleitung mit einer bisher nicht möglich gewesenen zeitlichen und örtlichen Präzision gesteuert werden. Hierzu wurden in den letzten Jahren zahlreiche Methoden entwickelt und neue Einblicke gewonnen. Beispielsweise konnte durch lichtabhängige Aktivierung des T-Zell-Rezeptors das kinetic proofreading Modell bestätigt werden. Außerdem ermöglichen lichtinduzierbare Cre-Rekombinasen eine noch präzisere Kontrolle über Genmanipulationen. Dieser Übersichtsartikel soll als Inspiration dafür dienen, wie die molekulare Optogenetik in der präklinischen Forschung Anwendung finden kann.

PURPOSE To compare the double-Maddox rod test with other methods of measuring cyclodeviation DESIGN: Retrospective cohort study. METHODS We retrospectively identified 153 adults in a clinical practice with cyclodeviation assessed using double-Maddox rods, of whom 105 were also assessed using fusible synoptophore targets, 73 using nonfusible synoptophore targets, 118 using single-Maddox rod, and 43 using fundus photography. Relationships between double-Maddox rod and other tests were evaluated by calculating mean differences with 95% confidence intervals (CI), intraclass correlation coefficients (ICC), and Bland-Altman plots with linear regression. RESULTS Synoptophore cross-in-circle targets and the largest (of right or left) single-Maddox rod values were similar to double-Maddox values (mean differences: -1.2° and 0.1°, respectively; ICC: 0.79 and 0.82, respectively). Synoptophore house targets measured less excyclodeviation (mean difference: -2.7°; ICC: 0.71). Mean summed single-Maddox rod values were somewhat similar to double-Maddox values (mean difference: 1.5°; ICC: 0.85), but differences increased with greater cyclodeviation (r2 = 0.2678; P < .001). Fundus photographs showed large, uncorrelated differences compared with double-Maddox rod test, when summing right and left eyes and when using the largest of right or left (mean differences: 12.2° and 6.2°; ICC: -0.02 and 0.21, respectively), and differences increased with greater cyclodeviation (r2 = 0.4094; P < .001 and r2 = .1143; P= .03, respectively). CONCLUSIONS There was good agreement between double-Maddox and the largest single- Maddox test values and synoptophore cross-in-circle targets but poorer agreement with other tests. Further study is needed to understand which measurements best reflect true cyclodeviation and relationships with symptoms.

PURPOSE To develop and evaluate a high spatial resolution (1.25 × 1.25 mm2 ) spiral first-pass myocardial perfusion imaging technique with whole-heart coverage at 3T, to better assess transmural differences in perfusion between the endocardium and epicardium, to quantify the myocardial ischemic burden, and to improve the detection of obstructive coronary artery disease. METHODS Whole-heart high-resolution spiral perfusion pulse sequences and corresponding motion-compensated reconstruction techniques for both interleaved single-slice (SS) and simultaneous multi-slice (SMS) acquisition with or without outer-volume suppression (OVS) were developed. The proposed techniques were evaluated in 34 healthy volunteers and 8 patients (55 data sets). SS and SMS images were reconstructed using motion-compensated L1-SPIRiT and SMS-Slice-L1-SPIRiT, respectively. Images were blindly graded by 2 experienced cardiologists on a 5-point scale (5, excellent; 1, poor). RESULTS High-quality perfusion imaging was achieved for both SS and SMS acquisitions with or without OVS. The SS technique without OVS had the highest scores (4.5 [4, 5]), which were greater than scores for SS with OVS (3.5 [3.25, 3.75], P < .05), MB = 2 without OVS (3.75 [3.25, 4], P < .05), and MB = 2 with OVS (3.75 [2.75, 4], P < .05), but significantly higher than those for MB = 3 without OVS (4 [4, 4], P = .95). SMS image quality was improved using SMS-Slice-L1-SPIRiT as compared to SMS-L1-SPIRiT (P < .05 for both reviewers). CONCLUSION We demonstrated the successful implementation of whole-heart spiral perfusion imaging with high resolution at 3T. Good image quality was achieved, and the SS without OVS showed the best image quality. Evaluation in patients with expected ischemic heart disease is warranted.

Background: The distal superficial femoral artery (SFA) is most commonly affected in peripheral artery disease (PAD). The effects of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab added to statin therapy on SFA atherosclerosis, downstream flow, and walking performance are unknown. Methods: Thirty-five patients with PAD on maximally tolerated statin therapy were recruited. Patients were randomized to alirocumab 150 mg subcutaneously ( n = 18) or matching placebo ( n = 17) therapy every 2 weeks for 1 year. The primary outcome was change in SFA plaque volume by black blood magnetic resonance imaging (MRI). Secondary outcomes were changes in calf muscle perfusion by cuff/occlusion hyperemia arterial spin labeling MRI, 6-minute walk distance (6MWD), low-density lipoprotein (LDL) cholesterol, and other biomarkers. Results: Age (mean ± SD) was 64 ± 8 years, 20 (57%) patients were women, 17 (49%) were Black individuals, LDL was 107 ± 36 mg/dL, and the ankle–brachial index 0.71 ± 0.20. The LDL fell more with alirocumab than placebo (mean [95% CI]) (−49.8 [−66.1 to −33.6] vs −7.7 [−19.7 to 4.3] mg/dL; p < 0.0001). Changes in SFA plaque volume and calf perfusion showed no difference between groups when adjusted for baseline (+0.25 [−0.29 to 0.79] vs −0.04 [−0.47 to 0.38] cm3; p = 0.37 and 0.22 [−8.67 to 9.11] vs 3.81 [−1.45 to 9.08] mL/min/100 g; p = 0.46, respectively), nor did 6MWD. Conclusion: In this exploratory study, the addition of alirocumab therapy to statins did not alter SFA plaque volume, calf perfusion or 6MWD despite significant LDL lowering. Larger studies with longer follow up that include plaque characterization may improve understanding of the effects of intensive LDL-lowering therapy in PAD (ClinicalTrials.gov Identifier: NCT02959047).

Drosophila melanogaster males reduce courtship behaviour after mating failure. In the lab, such conditioned courtship suppression, aka 'courtship conditioning', serves as a complex learning and memory assay. Interestingly, variations in the courtship conditioning assay can establish different types of memory. Here, we review research investigating the underlying cellular and molecular mechanisms that allow male flies to form memories of previous mating failures.

Background Quantitative cardiovascular magnetic resonance T1-mapping is increasingly used for myocardial tissue characterization. However, the lack of standardization limits direct comparability between centers and wider roll-out for clinical use or trials. Purpose To develop a quality assurance (QA) program assuring standardized T1 measurements for clinical use. Methods MR phantoms manufactured in 2013 were distributed, including ShMOLLI T1-mapping and reference T1 and T2 protocols. We first studied the T1 and T2 dependency on temperature and phantom aging using phantom datasets from a single site over 4 years. Based on this, we developed a multiparametric QA model, which was then applied to 78 scans from 28 other multi-national sites. Results T1 temperature sensitivity followed a second-order polynomial to baseline T1 values (R2 > 0.996). Some phantoms showed aging effects, where T1 drifted up to 49% over 40 months. The correlation model based on reference T1 and T2, developed on 1004 dedicated phantom scans, predicted ShMOLLI-T1 with high consistency (coefficient of variation 1.54%), and was robust to temperature variations and phantom aging. Using the 95% confidence interval of the correlation model residuals as the tolerance range, we analyzed 390 ShMOLLI T1-maps and confirmed accurate sequence deployment in 90%(70/78) of QA scans across 28 multiple centers, and categorized the rest with specific remedial actions. Conclusions The proposed phantom QA for T1-mapping can assure correct method implementation and protocol adherence, and is robust to temperature variation and phantom aging. This QA program circumvents the need of frequent phantom replacements, and can be readily deployed in multicenter trials., Highlights • CMR T1 correlated with reference T1 and T2; this derives the QA model for T1-map. • The proposed QA model is robust to temperature variations and phantom aging. • This QA method requires no frequent phantom replacements. • The T1-map QA program can be readily deployed in multicenter trials.

Cocrystallization of racemic-compound-forming chiral molecules can result in conglomerate cocrystals or diastereomerically related cocrystals, which enable the application of chiral separation techniques such as preferential crystallization and classic resolution. Here, a systematic method to identify the types and phase diagrams of cocrystals formed by chiral target compounds and candidate coformers in a particular solvent system is presented, which allows the design of suitable chiral resolution processes. The method is based on saturation temperature measurements of specific solution compositions containing both enantiomers of chiral molecules and a coformer. This method is applied to analyze three different systems. For racemic phenylalanine (Phe) in water/ethanol mixtures one of the enantiomers selectively cocrystallizes with the opposite enantiomer of valine (Val), forming the more stable diastereomerically related cocrystal. The racemic compound ibuprofen crystallizes with the nonchiral coformer 1,2-bis(4-pyridyl)ethane (BPN) as racemic compound cocrystals. More interestingly, when it is combined with trans-1-(2-pyridyl)-2-(4-pyridyl)ethylene (BPE), the racemic compound ibuprofen cocrystallizes as a conglomerate, which in principle enables the application of preferential crystallization of this racemic compound. The systematic method shows the benefit of using pseudo-binary phase diagrams. Such pseudo-binary phase diagrams depict the saturation temperature on a very specific route through the quaternary phase diagram, allowing the identification of various cocrystal types as well as the corresponding cocrystallization conditions. The systematic method can be used to identify a suitable solid phase for chiral separation, and the obtained phase diagram information enables the performance of a crystallization-mediated chiral resolution process design. Such a guideline for a chiral resolution process design has never been reported for conglomerate cocrystal systems such as IBU:BPE, presented in this study.

We report on the discovery and localization of fast radio bursts (FRBs) from the MeerTRAP project, a commensal fast radio transient-detection programme at MeerKAT in South Africa. Our hybrid approach combines a coherent search with an average field-of-view of 0.4 $\rm deg^{2}$ with an incoherent search utilizing a field-of-view of $\sim$1.27 $\rm deg^{2}$ (both at 1284~MHz). Here, we present results on the first three FRBs: FRB 20200413A (DM=1990.05 pc cm$^{-3}$), FRB 20200915A (DM=740.65 pc cm$^{-3}$), and FRB 20201123A (DM=433.55 pc cm$^{-3}$). FRB 20200413A was discovered only in the incoherent beam. FRB 20200915A (also discovered only in the incoherent beam) shows speckled emission in the dynamic spectrum which cannot be explained by interstellar scintillation in our Galaxy or plasma lensing, and might be intrinsic to the source. FRB 20201123A shows a faint post-cursor burst about 200 ms after the main burst and warrants further follow-up to confirm whether it is a repeating FRB. FRB 20201123A also exhibits significant temporal broadening consistent with scattering by a turbulent medium. The broadening exceeds that predicted for medium along the sightline through our Galaxy. We associate this scattering with the turbulent medium in the environment of the FRB in the host galaxy. Within the approximately $1'$ localization region of FRB 20201123A, we identify one luminous galaxy ($r \approx 15.67$; J173438.35$-$504550.4) that dominates the posterior probability for a host association. The galaxy's measured properties are consistent with other FRB hosts with secure associations., 14 pages, 9 figures, 3 tables, accepted for publication in MNRAS

Cardiac magnetic resonance (CMR) is considered the gold standard for the assessment of right ventricular ejection fraction (RVEF). Previous studies have suggested that RVEF may be a predictor of adverse outcomes in heart failure (HF). In this study, we aimed to systematically review the prognostic value of RVEF, evaluated by CMR, across the spectrum of left ventricular systolic function in patients with HF.Electronic databases were searched for studies investigating the prognostic value of RVEF in HF, irrespective of left ventricular ejection fraction (LVEF). A random-effects meta-analysis was conducted for mortality and HF hospitalization. Subgroup analyses were also performed based on the presence of reduced (50%) or preserved LVEF (≥50%).In total, 46 studies enrolling 14,344 patients were included. In the pooled analyses, impaired RVEF was a powerful predictor of mortality (HR: 1.26, 95% CI: 1.18-1.33, IImpaired RVEF on CMR strongly predicts adverse outcomes in patients with HF regardless of LVEF. RV systolic function should be carefully evaluated in these patients. Prospero Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021256967.

Deforestation alters wildlife communities and modifies human–wildlife interactions, often increasing zoonotic spillover potential. When deforested land reverts to forest, species composition differences between primary and regenerating (secondary) forest could alter spillover risk trajectory. We develop a mathematical model of land-use change, where habitats differ in their relative spillover risk, to understand how land reversion influences spillover risk. We apply this framework to scenarios where spillover risk is higher in deforested land than mature forest, reflecting higher relative abundance of highly competent species and/or increased human–wildlife encounters, and where regenerating forest has either very low or high spillover risk. We find the forest regeneration rate, the spillover risk of regenerating forest relative to deforested land, and how rapidly regenerating forest regains attributes of mature forest determine landscape-level spillover risk. When regenerating forest has a much lower spillover risk than deforested land, reversion lowers cumulative spillover risk, but instaneous spillover risk peaks earlier. However, when spillover risk is high in regenerating and cleared habitats, landscape-level spillover risk remains high, especially when cleared land is rapidly abandoned then slowly regenerates to mature forest. These results suggest that proactive wildlife management and awareness of human exposure risk in regenerating forests could be important tools for spillover mitigation.

Highlights: • Since 1960, management for biological invasions totalled at least $95.3 billion. • Damage costs from invasions were substantially higher ($1130.6 billion). • Pre-invasion management spending is 25-times lower than post-invasion. • Management and damage costs are increasing rapidly over time. • Proactive management substantially reduces future costs at the trillion-$ scale. Abstract: The global increase in biological invasions is placing growing pressure on the management of ecological and economic systems. However, the effectiveness of current management expenditure is difficult to assess due to a lack of standardised measurement across spatial, taxonomic and temporal scales. Furthermore, there is no quantification of the spending difference between pre-invasion (e.g. prevention) and post-invasion (e.g. control) stages, although preventative measures are considered to be the most cost-effective. Here, we use a comprehensive database of invasive alien species economic costs (InvaCost) to synthesise and model the global management costs of biological invasions, in order to provide a better understanding of the stage at which these expenditures occur. Since 1960, reported management expenditures have totalled at least US$95.3 billion (in 2017 values), considering only highly reliable and actually observed costs — 12-times less than damage costs from invasions ($1130.6 billion). Pre-invasion management spending ($2.8 billion) was over 25-times lower than post-invasion expenditure ($72.7 billion). Management costs were heavily geographically skewed towards North America (54%) and Oceania (30%). The largest shares of expenditures were directed towards invasive alien invertebrates in terrestrial environments. Spending on invasive alien species management has grown by two orders of magnitude since 1960, reaching an estimated $4.2 billion per year globally (in 2017 values) in the 2010s, but remains 1–2 orders of magnitude lower than damages. National management spending increased with incurred damage costs, with management actions delayed on average by 11 years globally following damage reporting. These management delays on the global level have caused an additional invasion cost of approximately $1.2 trillion, compared to scenarios with immediate management. Our results indicate insufficient management — particularly pre-invasion — and urge better investment to prevent future invasions and to control established alien species. Recommendations to improve reported management cost comprehensiveness, resolution and terminology are also made.

Left ventricular outflow tract obstruction (LVOTO) is common in hypertrophic cardiomyopathy (HCM), but relationships between anatomical metrics and obstruction are poorly understood. We aimed to develop machine learning methods to evaluate LVOTO in HCM patients and quantify relationships between anatomical metrics and obstruction. This retrospective analysis of 1905 participants of the HCM Registry quantified 11 anatomical metrics derived from 14 landmarks automatically detected on the three-chamber long axis cine CMR images. Linear and logistic regression was used to quantify strengths of relationships with the presence of LVOTO (defined by resting Doppler pressure drop of 30 mmHg), using the area under the receiver operating characteristic (AUC). Intraclass correlation coefficients between the network predictions and three independent observers showed similar agreement to that between observers. The distance from anterior mitral valve leaflet tip to basal septum (AML-BS) was most highly correlated with Doppler pressure drop (R

Molecular optogenetics is a highly dynamic research field. In the past two years, the field was characterized by the development of new allosteric switches as well as the forward integration of optogenetics research towards application. Further, two areas of research have significantly gathered momentum, the use of optogenetics to control liquid-liquid phase separation as well as the application of optogenetic tools in the extracellular space. Here, we review these areas and discuss future directions.

Growing at either 15 or 25°C, roots of Arabidopsis thaliana, Columbia accession, produce cells at the same rate and have growth zones of the same length. To determine whether this constancy is related to energetics, we measured oxygen uptake by means of a vibrating oxygen-selective electrode. Concomitantly, the spatial distribution of elongation was measured kinematically, delineating meristem and elongation zone. All seedlings were germinated, grown, and measured at a given temperature (15 or 25°C). Columbia was compared to lines where cell production rate roughly doubles between 15 and 25°C: Landsberg and two Columbia mutants, er-105 and ahk3-3. For all genotypes and temperatures, oxygen uptake rate at any position was highest at the root cap, where mitochondrial density was maximal, based on the fluorescence of a reporter. Uptake rate declined through the meristem to plateau within the elongation zone. For oxygen uptake rate integrated over a zone, the meristem had steady-state Q

To acquire information about anesthesia and analgesia protocols used by United States (US) veterinarians in primary care practices when performing routine ovariohysterectomy in dogs.Cross-sectional survey.Primary care veterinarians in the US.An online anonymous survey, originally created in New Zealand, was modified with permission and made available to Veterinary Information Network (VIN) members. The survey asked questions about performing ovariohysterectomy in healthy adolescent dogs in the categories of preanesthetic evaluation, premedication and induction protocols, maintenance protocols and monitoring equipment, and postoperative analgesic and sedation protocols and pain assessments.A total of 1213 US veterinarians completed the survey. Respondents (n; %) reported performing preoperative laboratory tests [packed cell volume (135; 11%), complete blood cell count (889; 73%) and biochemistry panels (1057; 87%)] and preanesthetic examinations on the morning of surgery (1083; 90%). The most commonly administered drugs for premedication were acepromazine (512; 42%), hydromorphone (475; 39%) or butorphanol (463; 38%), with propofol (637; 67%) for induction of anesthesia and isoflurane (882; 73%) for maintenance of anesthesia. Most veterinarians reported placing intravenous catheters (945; 78%), administering electrolyte solutions (747; 67%) and providing heat support (1160; 96%). Perioperative and postoperative analgesia included local anesthetics (545; 45%), opioids (844; 70%) and non-steroidal anti-inflammatory drugs (NSAIDs) (953; 79%); NSAIDs were dispensed for home use (985; 81%). Dogs were most frequently discharged on the day of surgery (1068; 88%) and the owners were contacted (914; 75%) for follow-up within 1-2 days.Anesthetic management for routine ovariohysterectomy in dogs varies among US veterinary VIN members. Information from this study is useful for all veterinarians for comparison with their practice management and for teachers of veterinary anesthesia to continue to emphasize options for analgesia.

PSR J0955$-$6150 is a member of a class of eccentric MSP+He WD systems (eMSPs), whose binary evolution is poorly understood and believed to be different to that of traditional MSP+He WD systems. Measuring the masses of the stars in this system is important for testing hypotheses for the formation of eMSPs. We have carried out observations of this pulsar with the Parkes and MeerKAT radio telescopes. Our observations reveal a strong frequency evolution of this pulsar's intensity, with a spectral index ($\alpha$) of $-3.13(2)$. The sensitivity of MeerKAT has resulted in a $>10$-fold improvement in the timing precision compared to older Parkes observations. Combined with the 8-year timing baseline, it has allowed precise measurements of a proper motion and three orbital "post-Keplerian" parameters: the rate of advance of periastron, $\dot{\omega} = 0.00152(1) \, {\rm deg} \, yr^{-1}$ and the orthometric Shapiro delay parameters, $h_3 = 0.89(7) \, \mu$s and $\varsigma = 0.88(2)$. Assuming general relativity, we obtain $M_{p} = 1.71(2) \, M_{\odot}$ for the mass of the pulsar and $M_{c} = 0.254(2) \, M_{\odot}$ for the mass of the companion; the orbital inclination is 83.2(4) degrees. We find that the spin axis has a misalignment relative to the orbital angular momentum of $> 4.8$ degrees at 99% CI. While the value of $M_{\rm p}$ falls within the wide range observed in eMSPs, $M_{\rm c}$ is significantly smaller than expected, allowing several formation hypotheses being ruled out. $M_{\rm c}$ is also significantly different from the expected value for an ideal low mass X-ray binary evolution scenario. The putative misalignment between the spin axis of the pulsar and the orbital angular momentum suggests that the unknown process that created the orbital eccentricity of the binary was also capable of changing its orbital orientation, an important evidence for understanding the origin of eMSPs., Comment: 20 pages, 9 figures, 5 tables, accepted for publication by the A&A