Non-coding RNAs to treat vascular smooth muscle cell dysfunction.

Vascular smooth muscle cell (vSMC) dysfunction is a critical contributor to cardiovascular diseases, including atherosclerosis, restenosis and vein graft failure. Recent advances have unveiled a fascinating range of non-coding RNAs (ncRNAs) that play a pivotal role in regulating vSMC function. This review aims to provide an in-depth analysis of the mechanisms underlying vSMC dysfunction and the therapeutic potential of various ncRNAs in mitigating this dysfunction, either preventing or reversing it. We explore the intricate interplay of microRNAs, long-non-coding RNAs and circular RNAs, shedding light on their roles in regulating key signalling pathways associated with vSMC dysfunction. We also discuss the prospects and challenges associated with developing ncRNA-based therapies for this prevalent type of cardiovascular pathology.

Experimental Demonstration of Reservoir Computing with Self-Assembled Percolating Networks of Nanoparticles.

The complex self-assembled network of neurons and synapses that comprises the biological brain enables natural information processing with remarkable efficiency. Percolating networks of nanoparticles (PNNs) are complex self-assembled nanoscale systems that have been shown to possess many promising brain-like attributes and which are therefore appealing systems for neuromorphic computation. Here experiments are performed that show that PNNs can be utilized as physical reservoirs within a nanoelectronic reservoir computing framework and demonstrate successful computation for several benchmark tasks (chaotic time series prediction, nonlinear transformation, and memory capacity). For each task, relevant literature results are compiled and it is shown that the performance of the PNNs compares favorably to that previously reported from nanoelectronic reservoirs. It is then demonstrated experimentally that PNNs can be used for spoken digit recognition with state-of-the-art accuracy. Finally, a parallel reservoir architecture is emulated, which increases the dimensionality and richness of the reservoir outputs and results in further improvements in performance across all tasks.

Prostate Virtual High-dose-rate Brachytherapy Boost: 5-Year Results from the PROMETHEUS Prospective Multicentre Trial.

BACKGROUND AND OBJECTIVE: Despite the high efficacy of high-dose-rate brachytherapy boost (HDRB) in the management of prostate cancer (PC), use of this approach is declining. Similar dosimetry can be achieved using stereotactic body radiotherapy or "virtual HDRB" (vHDRB). The aim of the multicentre, single-arm, phase 2 PROMETHEUS trial (ACTRN12615000223538) was to evaluate the safety and efficacy of vHDRB in patients with PC. METHODS: Patients with intermediate-risk PC or selected patients with high-risk PC were eligible for inclusion. vHDRB was given as 19-20 Gy in two fractions, delivered 1 wk apart, followed by conventionally fractionated external beam radiotherapy (EBRT) at 46 Gy in 23 fractions or 36 Gy in 12 fractions. The primary endpoint was the biochemical/clinical relapse-free rate (bcRFR). Toxicity was graded using Common Terminology Criteria for Adverse Events version 4 and quality of life (QoL) data were collected used the Expanded Prostate Cancer Index Composite-26 questionnaire. KEY FINDINGS AND LIMITATIONS: From March 2014 to December 2018, 151 patients (74% intermediate risk, 26% high risk) with a median age of 69 yr were treated across five centres. Median follow-up was 60 mo. The 5-yr bcRFR was 94.1% (95% confidence interval [CI] 90-98%) and the local control rate was 98.7%. Acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity occurred in 6.6% and 23.2% of patients, respectively, with no acute grade 3 toxicity. At 60 mo after treatment, the prevalence of late grade ≥2 GI toxicity was 1.7% (95% CI 0.3-6.5%) and the prevalence of late grade ≥2 GU toxicity was 3.3% (95% CI 1.1-8.8%). Between baseline and 60 mo, QoL improved for urinary obstructive and hormonal domains, was stable for the bowel domain, and deteriorated slightly for the sexual and urinary incontinence domains. CONCLUSIONS: Delivery of gantry-based vHDRB followed by conventionally fractionated EBRT is feasible in a multicentre setting, with high 5-yr bcRFR and low toxicity. This approach is being compared with prostate ultrahypofractionated radiotherapy in the TROG 18.01 NINJA randomised trial (ACTRN12618001806257). PATIENT SUMMARY: The PROMETHEUS trial investigated noninvasive high-dose precision radiotherapy combined with conventional radiotherapy in patients with prostate cancer. We found that this new technique was well tolerated and resulted in better cancer control outcomes than historically reported.

Utility of 68Ga-DOTATATE PET-MRI for Gamma Knife® stereotactic radiosurgery treatment planning for meningioma.

OBJECTIVES: To investigate the impact of adding 68Ga-DOTATATE PET/MRI to standard MRI for target volume delineation in Gamma Knife® stereotactic radiosurgery (GKSRS) for meningioma. METHODS: Seventeen patients with 18 lesions undergoing GKSRS for WHO grade 1 meningioma were enrolled in a prospective study. All patients underwent pre-treatment 68Ga-DOTATATE PET/MRI examination in addition to standard procedures. Five clinicians independently contoured the gross tumour volume (GTV) based on standard MRI (GTVMRI) and PET/MRI (GTVPET/MRI) on separate occasions. Interobserver agreement was evaluated using Cohen's Kappa statistic (CKS), Dice similarity coefficient (DC), and Hausdorff distance (HD). Statistical analysis was performed with paired t-test and Wilcoxon signed rank test. RESULTS: The addition of PET/MRI significantly increased GTV contour volume (mean GTVPET/MRI 3.59 cm3 versus mean GTVMRI 3.18 cm3, P = .008). Using the treating clinician's pre-treatment GTVMRI as the reference, median CKS (87.2 vs 77.5, P = .006) and DC (87.2 vs 77.4, P = .006) were significantly lower, and median HD (25.2 vs 31.0, P = .001) was significantly higher with the addition of PET/MRI. No significant difference was observed in interobserver contouring reproducibility between GTVMRI and GTVPET/MRI. CONCLUSION: The addition of 68Ga-DOTATATE PET/MRI for target volume delineation in GKSRS for meningioma is associated with an increase in GTV volume and greater interobserver variation. PET/MRI did not affect interobserver contouring reproducibility. ADVANCES IN KNOWLEDGE: This study provides novel insights into the impact of 68Ga-DOTATATE PET/MRI on GTV delineation and interobserver agreement in meningioma GKSRS, highlighting its potential for improving GKSRS treatment accuracy.

The series of conformational states adopted by rotorless F1-ATPase during its hydrolysis cycle.

F1Fo ATP synthase interchanges phosphate transfer energy and proton motive force via a rotary catalytic mechanism and isolated F1-ATPase subcomplexes can also hydrolyze ATP to generate rotation of their central γ rotor subunit. As ATP is hydrolyzed, the F1-ATPase cycles through a series of conformational states that mediates unidirectional rotation of the rotor. However, even in the absence of a rotor, the α and ß subunits are still able to pass through a series of conformations, akin to those that generate rotation. Here, we use cryoelectron microscopy to establish the structures of these rotorless states. These structures indicate that cooperativity in this system is likely mediated by contacts between the ß subunit lever domains, irrespective of the presence of the γ rotor subunit. These findings provide insight into how long-range information may be transferred in large biological systems.

How to get rich from inflation.

We seem to have rich experience across our visual field. Yet we are surprisingly poor at tasks involving the periphery and low spatial attention. Recently, Lau and collaborators have argued that a phenomenon known as "subjective inflation" allows us to reconcile these phenomena. I show inflation is consistent with multiple interpretations, with starkly different consequences for richness and for theories of consciousness more broadly. What's more, we have only weak reasons favouring any of these interpretations over the others. I provisionally argue for an interpretation on which subjective experience is genuinely rich, but (in peripheral/unattended areas) unreliable as a guide to the external world. The main challenge for this view is that it appears to imply that experience in the periphery is not just unreliable but unstable. However, I argue that this consequence, while initially appearing unintuitive, is in fact plausible.

Risk Factors for Radiotherapy Failure in the Treatment of Spinal Metastases.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To build a predictive model for risk factors for failure of radiation therapy, hypothesizing a higher SINS would correlate with failure. METHODS: Patients with spinal metastasis being treated with radiation at a tertiary care academic center between September 2014 and October 2018 were identified. The primary outcome measure was radiation therapy failure as defined by persistent pain, need for re-irradiation, or surgical intervention. Risk factors were primary tumor type, Karnofsky and ECOG scores, time to treatment, biologically effective dose (BED) calculations using α/ß ratio = 10, and radiation modality. A logistic regression was used to construct a prediction model for radiation therapy failure. RESULTS: One hundred and seventy patients were included. Median follow up was 91.5 days. Forty-three patients failed radiation therapy. Of those patients, 10 required repeat radiation and 7 underwent surgery. Thirty-six patients reported no pain relief, including some that required re-irradiation and surgery. Total SINS score for those who failed reduction therapy was <7 for 27 patients (62.8%), between 7-12 for 14 patients (32.6%), and >12 for 2 patients (4.6%). In the final prediction model, BED (OR .451 for BED > 43 compared to BED ≤ 43; P = .174), Karnofksy score (OR .736 for every 10 unit increase in Karnofksy score; P = .008), and gender (OR 2.147 for male compared to female; P = .053) are associated with risk of radiation failure (AUC .695). A statistically significant association between SINS score and radiation therapy failure was not found. CONCLUSIONS: In the multivariable model, BED ≤ 43, lower Karnofksy score, and male gender are predictive for radiotherapy failure. SINS score was among the candidate risk factors included in multivariable model building procedure, but it was not selected in the final model. LEVEL OF EVIDENCE: Prognostic level III.

Computation via Neuron-like Spiking in Percolating Networks of Nanoparticles.

The biological brain is a highly efficient computational system in which information processing is performed via electrical spikes. Neuromorphic computing systems that work on similar principles could support the development of the next generation of artificial intelligence and, in particular, enable low-power edge computing. Percolating networks of nanoparticles (PNNs) have previously been shown to exhibit critical spiking behavior, with promise for highly efficient natural computation. Here we employ a rate coding scheme to show that PNNs can perform Boolean operations and image classification. Near perfect accuracy is achieved in both tasks by manipulating the spiking activity using certain control voltages. We demonstrate that the key to successful computation is that nanoscale tunnel gaps within the percolating networks transform input data through a powerful modulus-like nonlinearity. These results provide a basis for implementation of further computational schemes that exploit the brain-like criticality of these networks.

Structural basis of promiscuous substrate transport by Organic Cation Transporter 1.

Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1.

Prophylaxis with a recombinant factor VIII Fc in hemophilia A: long-term follow-up on joint health, efficacy, and safety from phase 3 studies in children and adults.

Background: Recurrent joint bleeds are a major cause of morbidity in severe hemophilia. Prophylaxis with efmoroctocog alfa (a recombinant factor VIII Fc fusion protein, [rFVIIIFc]) has demonstrated benefits beyond bleed control, including joint health maintenance. Objectives: To assess long-term efficacy and safety of rFVIIIFc prophylaxis in severe hemophilia A in phase 3 pivotal (A-LONG/Kids A-LONG) and extension (ASPIRE) studies. Methods: Longitudinal analysis included pooled data from A-LONG/Kids A-LONG and ASPIRE. Subgroup analyses investigated outcomes in modified Hemophilia Joint Health Score or Hemophilia Joint Health Score and target joints in subjects with 4 to 5 years follow-up on individualized prophylaxis (IP), and those with the highest annualized bleeding rate (ABR) quartile during Year 1 of IP. Results: Overall, rFVIIIFc consumption remained stable and low ABRs were maintained, with a median treatment duration of 4.2/3.4 years in subjects from A-LONG/Kids A-LONG, respectively. Median overall ABR also remained low (1.0-2.0) in subjects on IP for 4 to 5 years. Sustained improvements in modified Hemophilia Joint Health Score or Hemophilia Joint Health Score were demonstrated over a median follow-up of 3.7 years. In subjects from A-LONG/Kids A-LONG, 99.6% (n = 234)/100% (n = 9) of evaluable baseline target joints were resolved, with no recurrence in 95%/100% of target joints. In IP subjects within the highest ABR quartile in Year 1, continued improvements were observed over a median follow-up of 4.3 years in ABR and joint health, without increased factor consumption. No inhibitors or treatment-related serious adverse events were reported. Conclusion: Previously treated subjects of all ages receiving long-term prophylaxis with rFVIIIFc had sustained clinical benefits, including improved joint health and low ABR.

The development of Jack Jumper ant venom immunotherapy: our 25 years' experience.

Jack Jumper ant venom allergy is a uniquely Australian medical issue. The stinging ant is a leading cause of insect venom allergy in south-eastern Australia. An effective venom immunotherapy-based treatment was successfully developed by the Tasmanian Jack Jumper Allergy Research group. This paper provides a synopsis of our 25 years' research journey in developing this evidence-based treatment modality.

Broadly neutralizing SARS-CoV-2 antibodies through epitope-based selection from convalescent patients.

Emerging variants of concern (VOCs) are threatening to limit the effectiveness of SARS-CoV-2 monoclonal antibodies and vaccines currently used in clinical practice; broadly neutralizing antibodies and strategies for their identification are therefore urgently required. Here we demonstrate that broadly neutralizing antibodies can be isolated from peripheral blood mononuclear cells of convalescent patients using SARS-CoV-2 receptor binding domains carrying epitope-specific mutations. This is exemplified by two human antibodies, GAR05, binding to epitope class 1, and GAR12, binding to a new epitope class 6 (located between class 3 and 5). Both antibodies broadly neutralize VOCs, exceeding the potency of the clinical monoclonal sotrovimab (S309) by orders of magnitude. They also provide prophylactic and therapeutic in vivo protection of female hACE2 mice against viral challenge. Our results indicate that exposure to SARS-CoV-2 induces antibodies that maintain broad neutralization against emerging VOCs using two unique strategies: either by targeting the divergent class 1 epitope in a manner resistant to VOCs (ACE2 mimicry, as illustrated by GAR05 and mAbs P2C-1F11/S2K14); or alternatively, by targeting rare and highly conserved epitopes, such as the new class 6 epitope identified here (as illustrated by GAR12). Our results provide guidance for next generation monoclonal antibody development and vaccine design.

Association of Brachytherapy Boost with Overall Survival for Gleason 9-10 Prostate Cancer: The Impact of Primary versus Secondary Pattern 5.

PURPOSE: The addition of a brachytherapy (BT) boost to external beam radiotherapy (EBRT) reduces recurrence risk in men with high-risk prostate cancer (PCa) and may reduce PCa-mortality for Gleason grade group 5 (GG5). Whether the extent of pattern five, a risk factor for distant metastases, impacts the benefit of a BT boost is unclear. METHODS: Men with localized GG5 PCa treated with (1) EBRT or (2) EBRT+BT between 2010 and 2016 were identified in the National Cancer Database. EBRT monotherapy group received conventionally fractionated (1.8-2.0 Gy per fraction) ≥74 Gy or moderately hypofractionated (2.5-3.0 Gy per fraction) ≥60 Gy. EBRT + BT group received conventionally fractionated ≥45 Gy or moderately hypofractionated ≥37.5 Gy, and either LDR or HDR BT. All patients received concomitant ADT; none received chemotherapy, immunotherapy, or surgery. OS was compared using Kaplan-Meier, log-rank test, and multivariable Cox proportional hazards in the overall cohort, followed by subgroups based on primary versus secondary pattern 5. Propensity score- and exact-matching was used to corroborate results. RESULTS: A total of 8260 men were eligible: EBRT alone (89%) versus EBRT + BT (11%). 5-year OS for EBRT versus EBRT + BT was 76.3% and 85.0%, respectively (p = 0.002; multivariable adjusted HR 0.84, 95% CI 0.65-0.98; p = 0.04). These results remained consistent after propensity score and exact matching. The OS advantage of a BT boost was more prominent in men with Gleason 4 + 5 PCa (p = 0.001) and not observed in men with Gleason 5 + 5 or 5 + 4 PCa. CONCLUSIONS: Extent of pattern five may be useful in appropriately selecting men for EBRT+BT and should be considered as a pre-randomization stratification variable for future clinical trial design.

Changes within the central stalk of E. coli F1Fo ATP synthase observed after addition of ATP.

F1Fo ATP synthase functions as a biological generator and makes a major contribution to cellular energy production. Proton flow generates rotation in the Fo motor that is transferred to the F1 motor to catalyze ATP production, with flexible F1/Fo coupling required for efficient catalysis. F1Fo ATP synthase can also operate in reverse, hydrolyzing ATP and pumping protons, and in bacteria this function can be regulated by an inhibitory ε subunit. Here we present cryo-EM data showing E. coli F1Fo ATP synthase in different rotational and inhibited sub-states, observed following incubation with 10 mM MgATP. Our structures demonstrate how structural transitions within the inhibitory ε subunit induce torsional movement in the central stalk, thereby enabling its rotation within the Fο motor. This highlights the importance of the central rotor for flexible coupling of the F1 and Fo motors and provides further insight into the regulatory mechanism mediated by subunit ε.

Strength and Balance in Recreational Golfers and Non-Golfers Aged 65-79 Years in Community Settings.

Inactive older adults tend to have decreased strength and balance compared with their more active peers. Playing golf has the potential to improve strength and balance in older adults. The aim of the study was to compare the strength and balance of recreational golfers with non-golfers, aged 65-79 years. Grip strength, single leg balance, and Y Balance Test (YBT) were assessed. Golfers (n = 57) had significantly (right, p = .042; left, p = .047) higher maximal grip strength, than non-golfers (n = 17). Single leg stance times were significantly longer in golfers (right, p = .021; left, p = .001). Normalized YBT reach distances were significantly greater for golfers than non-golfers for composite, posteromedial, and posterolateral directions on both right and left legs. Playing golf appears to be associated with better grip and both static and dynamic balance in 65-79 year olds, indicating that a study of the effects of playing golf is warranted through a larger, fully powered, longitudinal study.

The Scientific Study of Consciousness Cannot and Should Not Be Morally Neutral.

A target question for the scientific study of consciousness is how dimensions of consciousness, such as the ability to feel pain and pleasure or reflect on one's own experience, vary in different states and animal species. Considering the tight link between consciousness and moral status, answers to these questions have implications for law and ethics. Here we point out that given this link, the scientific community studying consciousness may face implicit pressure to carry out certain research programs or interpret results in ways that justify current norms rather than challenge them. We show that because consciousness largely determines moral status, the use of nonhuman animals in the scientific study of consciousness introduces a direct conflict between scientific relevance and ethics-the more scientifically valuable an animal model is for studying consciousness, the more difficult it becomes to ethically justify compromises to its well-being for consciousness research. Finally, in light of these considerations, we call for a discussion of the immediate ethical corollaries of the body of knowledge that has accumulated and for a more explicit consideration of the role of ideology and ethics in the scientific study of consciousness.

Brain-like critical dynamics and long-range temporal correlations in percolating networks of silver nanoparticles and functionality preservation after integration of insulating matrix.

Random networks of nanoparticle-based memristive switches enable pathways for emulating highly complex and self-organized synaptic connectivity together with their emergent functional behavior known from biological neuronal networks. They therefore embody a distinct class of neuromorphic hardware architectures and provide an alternative to highly regular arrays of memristors. Especially, networks of memristive nanoparticles (NPs) poised at the percolation threshold are promising due to their capabilities of showing brain-like activity such as critical dynamics or long-range temporal correlation (LRTC), which are closely connected to the computational capabilities in biological neuronal networks. Here, we adapt this concept to networks of Ag-NPs poised at the electrical percolation threshold, where the memristive properties are governed by electro-chemical metallization. We show that critical dynamics and LRTC are preserved although the nature of individual memristive gaps throughout the network is fundamentally changed by filling the gaps with an insulating matrix. The results in this work generate important contributions towards the practical applicability of critical dynamics and LRTC in percolating NP networks by elucidating the consequences of NP network encapsulation, which is considered as an important step towards device integration.

Realization of unpinned two-dimensional dirac states in antimony atomic layers.

Two-dimensional (2D) Dirac states with linear dispersion have been observed in graphene and on the surface of topological insulators. 2D Dirac states discovered so far are exclusively pinned at high-symmetry points of the Brillouin zone, for example, surface Dirac states at [Formula: see text] in topological insulators Bi2Se(Te)3 and Dirac cones at K and [Formula: see text] points in graphene. The low-energy dispersion of those Dirac states are isotropic due to the constraints of crystal symmetries. In this work, we report the observation of novel 2D Dirac states in antimony atomic layers with phosphorene structure. The Dirac states in the antimony films are located at generic momentum points. This unpinned nature enables versatile ways such as lattice strains to control the locations of the Dirac points in momentum space. In addition, dispersions around the unpinned Dirac points are highly anisotropic due to the reduced symmetry of generic momentum points. The exotic properties of unpinned Dirac states make antimony atomic layers a new type of 2D Dirac semimetals that are distinct from graphene.