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This paper enters the ongoing volatility forecasting debate by examining the ability of a wide range of Machine Learning methods (ML), and specifically Artificial Neural Network (ANN) models. The ANN models are compared against traditional econometric models for ten Asian markets using daily data for the time period from 12 September 1994 to 05 March 2018. The empirical results indicate that ML algorithms, across the range of countries, can better approximate dependencies compared to traditional benchmark models. Notably, the predictive performance of such deep learning models is superior perhaps due to its ability in capturing long-range dependencies. For example, the Neuro Fuzzy models of ANFIS and CANFIS, which outperform the EGARCH model, are more flexible in modelling both asymmetry and long memory properties. This offers new insights for Asian markets. In addition to standard statistics forecast metrics, we also consider risk management measures including the value-at-risk (VaR) average failure rate, the Kupiec LR test, the Christoffersen independence test, the expected shortfall (ES) and the dynamic quantile test. The study concludes that ML algorithms provide improving volatility forecasts in the stock markets of Asia and suggest that this may be a fruitful approach for risk management. [ABSTRACT FROM AUTHOR]

This paper analyses the dynamic transmission mechanism of volatility spillovers between key global financial indicators and G20 stock markets. To examine volatility spillover relations, we combine a bivariate GARCH-BEKK model with complex network theory. Specifically, we construct a volatility network of international financial markets utilising the spatial connectedness of spillovers (consisting of nodes and edges). The findings show that spillover relations between global variables and G20 markets vary significantly across five identified sub-periods. Notably, networks are much denser in crisis periods compared to non-crisis periods. In comparing two crisis periods, Global Financial Crisis (2008) and COVID-19 Crisis (2020) periods, the network statistics suggest that volatility spillovers in the latter period are more transitive and intense than the former. This suggests that financial volatility spreads more rapidly and directly through key financial indicators to the G20 stock markets. For example, oil and bonds are the largest volatility senders, while the markets of Saudi Arabia, Russia, South Africa, and Brazil are the main volatility receivers. In the former crisis, the source of financial volatility concentrates primarily in the USA, Australia, Canada, and Saudi Arabia, which are the largest volatility senders and receivers. China emerges as generally the least sensitive market to external volatility. [ABSTRACT FROM AUTHOR]

Summary : Among 1299 older adults with 24-h Holter monitoring data at baseline, followed for approximately 15 years, 190 incident hip fractures occurred. Increased heart rate variability was independently associated with reduced risk of hip fracture among female participants. Purpose: Autonomic nervous system function modulates bone remodeling in rodent osteoporosis models. We tested whether cardiovascular autonomic function is associated with hip fracture risk in humans. Methods: Participants were 1299 subjects from the Cardiovascular Health Study (mean age 72.8 years). Eight heart rate variability (HRV) measures (time and frequency domains, detrended fluctuation analysis variables, and heart rate turbulence) were derived from 24-h Holter monitor scans in sinus rhythm. Median follow-up for incident hip fracture was 14.7 years [IQR 9.1, 20.2]. Cox proportional hazards models were used to calculate hazard ratios (95% confidence intervals, CI). Results: There were 144 hip fractures among 714 women (1.31 [1.06, 1.61] per 100-person years) and 46 among 585 men (0.62 [0.43, 0.90] per 100 person-years). From among HRV variables examined, a one standard deviation (SD) higher variation between normal heart beats over 24 h (the SD of NN intervals [SDNN]) was associated with a multivariable-adjusted lower hip fracture risk (HR = 0.80; 95% CI 0.65–0.99; p = 0.04) in women. The adjusted association between very low frequency power, and hip fracture was borderline statistically significant in women (HR = 0.82; 95% CI, 0.66–1.00; p = 0.06). When the 8 HRV variables were considered conjointly and adjusted for each other's association with hip fracture risk, a 1 SD higher SDNN value was significantly associated with reduced hip fracture risk in women (HR 0.74; 95% CI, 0.50–0.99; p = 0.05). No HRV variables were associated with hip fracture in men. Conclusions: In older women, increased heart rate variation is associated with hip fracture risk. [ABSTRACT FROM AUTHOR]

Introduction: Whole body energy expenditure and lipid oxidation (Lox) are upregulated during and after exercise. Persons with spinal cord injury (SCI) generally have a blunted ability to utilize fat during exercise, but it is unknown if their substrate partitioning is affected during recovery from exercise. Purpose: To determine the effect of a single session of upper body circuit resistance exercise (CRE) on energy expenditure and Lox during exercise recovery in persons with and without SCI. Methods: Twenty four persons (3 groups; 7 male and 1 female per group) without paralysis (neurologically intact; N) or with chronic (≥ 1 yr) paraplegia (P) or tetraplegia (T) participated. Energy expenditure and substrate partitioning were assessed via indirect calorimetry before, during, and three times after (up to 120 min after) a single session of CRE, or time-matched seated control (CON). Results: During CRE, all groups experienced a similar relative increase in oxygen consumption (49 ± 13, 55 ± 11, and 48 ± 15% VO2peak for N, P, and T, respectively). The Post0-120 energy expenditure was greater following CRE vs. CON (P < 0.01) and independent of injury characteristics (10.6, 22.6, and 14.3% higher than CON for N, P, and T; P = 0.21). The absolute increase in Lox above CON during recovery was similar for N, P, and T (5.74 ± 2.81, 6.62 ± 3.10, and 4.50 ± 3.91 g, respectively; P = 0.45). Conclusions: Energy expenditure and lipid utilization was increased similarly following circuit exercise in persons without and with spinal cord injury in a manner independent of level of injury. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising a distorted trimer and reduce the number of receptors bound to TNF from three to two. Here we present a biochemical and structural characterisation of the small molecule-stabilised TNF-TNFR1 complex, providing insights into how a distorted TNF trimer can alter signalling function. We demonstrate that the inhibitors reduce the binding affinity of TNF to the third TNFR1 molecule. In support of this, we show by X-ray crystallography that the inhibitor-bound, distorted, TNF trimer forms a complex with a dimer of TNFR1 molecules. This observation, along with data from a solution-based network assembly assay, leads us to suggest a model for TNF signalling based on TNF-TNFR1 clusters, which are disrupted by small molecule inhibitors. Small molecules stabilising a distorted TNF trimer can inhibit TNF signaling, but the underlying mechanism is unclear. Here, the authors characterize the inhibitor-bound TNF-receptor complex structurally and biochemically, showing that the inhibitors alter TNF-receptor binding stoichiometry and cluster formation. [ABSTRACT FROM AUTHOR]

We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer–small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF–TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples. We believe this work defines a role for monoclonal antibodies as tools to facilitate the discovery and development of small-molecule inhibitors of protein–protein interactions. TNF can be inhibited by small molecules that stabilize the TNF trimer in an asymmetric conformation. Here, the authors develop a monoclonal antibody that selectively binds this inactive form of TNF, enabling both target engagement assessment and structural characterization of TNF binding to TNF receptor 1. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions. While biologics have been successfully applied in TNF antagonist treatments, there are no clinically approved small molecules that target TNF. Here, the authors discover potent small molecule inhibitors of TNF, elucidate their molecular mechanism, and demonstrate TNF inhibition in vitro and in vivo. [ABSTRACT FROM AUTHOR]

In Alzheimer’s disease (AD) and other tauopathies, the cytosolic protein Tau misfolds and forms intracellular aggregates which accumulate within the brain leading to neurodegeneration. Clinical progression is tightly linked to the progressive spread of Tau pathology throughout the brain, and several lines of evidence suggest that Tau aggregates or “seeds” may propagate pathology by spreading from cell to cell in a “prion like” manner. Accordingly, blocking the spread of extracellular seeds with an antibody could be a viable therapeutic approach. However, as the structure of Tau seeds is unknown, it is only possible to rationally design therapeutic Tau antibodies by making a priori assumptions. To avoid this, we developed a robust and quantitative cell based assay and employed an unbiased screening approach to identify the antibody with the highest activity against human Tau seeds. The selected antibody (D), directed to the mid-region of Tau (amino acids 235-250), potently blocked the seeding of human AD Tau and was also fully efficacious against seeds from progressive supranuclear palsy. When we compared this antibody with previously described reference antibodies, we were surprised to find that none of these antibodies showed comparable efficacy against human pathological seeds. Our data highlight the difficulty of predicting antibody accessible epitopes on pathological Tau seeds and question the potential efficacy of some of the Tau antibodies that are currently in clinical development. [ABSTRACT FROM AUTHOR]

We study how the recent changes in the structure of the US banking market affect the banks' behavior in relation to competition, risk, and profit. Using the Herfindhal-Hirschman (HHI) and Lerner indices, we find a general increase in the concentration and market power of banks since the recent crisis period. Thus, we also consider whether bank-specific or general economic conditions have a greater impact on the competition, risk, and profit. The results support the view that changes in the market's structure while positively impacting profit and competition do not lead to increased risk. However, the banks' market share does lead to increased risk, albeit not for the largest banks. The results also support the view that banks can increase some elements of risk as well as profit during an economic expansion. However, an overriding feature of the results is the difference in the conditioning factors across the size strata and time. This difference leads to the conclusion that there is no simple relation between the market's structure and competition and risk. [ABSTRACT FROM AUTHOR]

Botulinum neurotoxin A (BoNT/A) belongs to the most dangerous class of bioweapons. Despite this, BoNT/A is used to treat a wide range of common medical conditions such as migraines and a variety of ocular motility and movement disorders. BoNT/A is probably best known for its use as an antiwrinkle agent in cosmetic applications (including Botox and Dysport). BoNT/A application causes long-lasting flaccid paralysis of muscles through inhibiting the release of the neurotransmitter acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) within presynaptic nerve terminals. Two types of BoNT/A receptor have been identified, both of which are required for BoNT/A toxicity and are therefore likely to cooperate with each other: gangliosides and members of the synaptic vesicle glycoprotein 2 (SV2) family, which are putative transporter proteins that are predicted to have 12 transmembrane domains, associate with the receptor-binding domain of the toxin. Recently, fibroblast growth factor receptor 3 (FGFR3) has also been reported to be a potential BoNT/A receptor. In SV2 proteins, the BoNT/A-binding site has been mapped to the luminal domain, but the molecular details of the interaction between BoNT/A and SV2 are unknown. Here we determined the high-resolution crystal structure of the BoNT/A receptor-binding domain (BoNT/A-RBD) in complex with the SV2C luminal domain (SV2C-LD). SV2C-LD consists of a right-handed, quadrilateral β-helix that associates with BoNT/A-RBD mainly through backbone-to-backbone interactions at open β-strand edges, in a manner that resembles the inter-strand interactions in amyloid structures. Competition experiments identified a peptide that inhibits the formation of the complex. Our findings provide a strong platform for the development of novel antitoxin agents and for the rational design of BoNT/A variants with improved therapeutic properties. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to compare changes in maximal oxygen uptake ( VO) in response to two regimens of chronic interval training. Methods: Twenty healthy sedentary women (mean ± SD age and VO = 23.0 ± 5.7 years and 30.1 ± 4.4 mL kg min, respectively) were randomized to complete 12 weeks of one of two interval training regimes, while an additional seven women served as controls. Training was performed 3 days week on a cycle ergometer and consisted of 6-10 bouts of 1 min duration at lower (60-80 % W = LO, n = 10) or more intense (80-90 % W = HI, n = 10) workloads separated by a brief recovery. Every 3 weeks, measures of VO and W were repeated to assign new training intensities. Changes in blood pressure and body composition were also examined. Results: Data revealed significant ( p < 0.001) improvements in VO in LO (22.3 ± 6.9 %) and HI (21.9 ± 11.6 %) that were similar ( p > 0.05) between groups. Approximately 60 % of the increase in VO in HI was observed in the initial 3 weeks, compared to only 20 % in LO. No change ( p > 0.05) in body weight or body composition was revealed in response to training. Results demonstrate that a relatively prolonged regimen of moderate or more intense interval training induces similar improvements in cardiorespiratory fitness, although HI induced greater increases in VO early on in training than LO. Completion of more intense interval training may be an effective means to expedite increases in VOmax soon after initiation of exercise training. [ABSTRACT FROM AUTHOR]

Humans demonstrate an innate desire to synchronize stepping when walking side by side. This behavior requires modification of each person's gait, which may increase for pairings with very different walking patterns. The purpose of this study was to compare locomotor behavior for conditions in which partners exhibited similar and substantially different walking patterns. Twenty-six unimpaired subjects walked on a motorized treadmill at their preferred walking speed for three trials: by themselves (SOLO), next to someone on an adjacent treadmill (PAIRED), and next to someone who purposely avoided synchronization by altering stride times and/or lengths (DeSYNC). Means, coefficients of variance, approximate entropy (ApEn), rate of autocorrelation decay (α), and estimates of maximal Lyapunov exponents (λ*) were calculated for several dependent variables taken from sagittal plane kinematic data. Few differences in behavior were noted when the PAIRED condition was compared to the SOLO condition. However, the DeSYNC condition resulted in several alterations in ApEn, α, and λ*. These results suggest that greater differences in walking pattern between partners will facilitate greater modification to an individual's gait. Additional study of side by side walking may hold implications for understanding the control of gait in humans and may have application in a clinical setting. [ABSTRACT FROM AUTHOR]

Web-based instruction of biomedical sciences courses has increased dramatically during the last decade, and this increase has been driven by the need to increase student access to educational programs and by the increasing demand for courses that are compatible with distance learning. Here, a blended learning curriculum in neuroimmune pharmacology is described that combines web-based learning modules with traditional face-to-face lectures. The course content is appropriate for graduate-level students and can be adapted to an entirely web-based course that can be deployed for distance learning. In addition to providing a course syllabus, this article describes the process of creating the web-based modules for course construction. [ABSTRACT FROM AUTHOR]

This paper seeks to extend the extant empirical evidence regarding asymmetric adjustment to equilibrium of short and long interest rates. Using an adaptation of the exponential smooth transition model to allow for sign asymmetry in the transition function, we show that equilibrium reversion exhibits two broad characteristics. First, small deviations are random, while large deviations are reverting. Second, deviations that arise when the long rate exceeds the short rate are characterised by quicker reversion than the opposite case. These results are consistent with the effects of arbitrage and central bank intervention. Finally, forecasting exercises support this model over alternate linear and non-linear specifications. [ABSTRACT FROM AUTHOR]

Whilst the existence of long-horizon returns predictability has been a recurrent theme in empirical finance research, extant work has focused almost exclusively on the US, and more recent work has cast doubt over the validity of such potential predictability due to non-stationarity and serial correlation in the data. The present paper examines long-horizon returns predictability in six South-East Asian markets in the context of unit root tests conducted under corrections for serial correlation and heteroscedasticity. The analysis conducted also extends the investigation of long-horizon predictability to the non-linear setting, and examines whether any detected non-linear predictability is consistent with behavioural approaches to asset pricing which emphasise the role of noise traders. The results obtained suggest the following conclusions. First, long-horizon predictability is present in each of the six South-East Asian markets considered. Second, whilst forecast power increases with horizon, for the majority of series it is maximised for forecast horizons of between 12 and 48 months. Third, non-linear predictability is reported for all series, suggesting that positive and negative values of the (demeaned) dividend yield impart different levels of predictability for returns at different forecast horizons. However, there is no consistency in the pattern of non-linearity reported, and whilst the observed patterns are consistent with noise traders models for some of the markets considered, this is not true of all the markets considered. Nevertheless, the non-linear dynamics detected are suggestive of potential market inefficiencies in all six cases. [ABSTRACT FROM AUTHOR]

Recent research examining high-frequency financial data has suggested that volatility dynamics may be confounded by the existence of an intra-day periodic pattern and multiple sources of volatility. This paper examines whether these dynamics are present in the US Dollar exchange rates of five Pacific Basin economies. Using 30-min sampled returns, evidence of a ‘U’-shape intra-day pattern in volatility for regional markets is reported and controlled for using a Flexible Fourier transform. Supportive evidence for the existence of multiple volatility components is offered by semi-parametric fractional difference estimates of the long-memory properties of absolute exchange rate returns at various intra-day data sampling frequencies. Further parametric evidence of an explicit component structure in such high frequency exchange rate volatility is offered by the estimates of a component-GARCH model which comprises both a long-run volatility component exhibiting slow shock decay and a short-run volatility component exhibiting far more rapid decay, and provides a generally superior fit to the data. Further application of these C-GARCH models in the analysis of high frequency volatility spillovers between the currencies considered also reveals that such spillovers are predominantly transitory rather than highly persistent in nature, but that where volatility spillovers do impact on the long-run component of exchange rate volatility the Australian Dollar plays a pivotal role in the localised causality transmission mechanism. [ABSTRACT FROM AUTHOR]

Investigates the introduction of a non-linear function in place of the linear error-correction term in an error-correction model. Improvement of the in-sample fit and out-of-sample forecasting performance for spot and forward exchange rate; Interaction between informed and noise traders; Specification tests to examine the best model in-sample fit.

Layered cellular mobile networks have been widely proposed as a way of accommodating traffic growth in mobile communications. There is a need, however, to give some form of priority to handover attempts over fresh call attempts to ensure that handovers are fast and reliable. A class of call control policies with state-dependent control of fresh call arrivals is considered for this purpose. A modified version of the Value Iteration Algorithm is used to solve a Markov decision model for the optimal call control policy. The network blocking performance under optimal state-dependent control is compared with the performance under a much simpler channel reservation policy for a model of a cellular sub-network. The channel reservation policy is shown to perform nearly as well as the optimal policy at lower loads, where fresh call blocking is less than 5%, indicating that it is both an effective and an efficient method for ensuring good handover performance. [ABSTRACT FROM AUTHOR]

Parathyroid hormone receptor 1 (PTH1R) belongs to the secretin class of G protein coupled receptors (GPCRs) and natively binds parathyroid hormone (PTH) and parathyroid hormone related peptide (PTHrP). Ligand binding to PTH1R involves binding to the large extracellular domain (ECD) and the orthosteric pocket, inducing conformational changes in the transmembrane domain and receptor activation. PTH1R regulates bone metabolism, signaling mainly through Gs and Gq/11 G-proteins. Here, we used phage display to generate PTH1R ECD-specific antibodies with the aim of modulating receptor functionality. We identified ECD-scFvhFc, which exhibited high affinity binding to both the isolated ECD and to the full-length receptor in styrene-maleic acid (SMA) lipid particles. Epitope mapping using hydrogen-deuterium exchange mass spectrometry (HDX-MS) indicates that the α1 helix of the ECD is ECD-scFvhFc's epitope which may partially overlap with the known PTH (1–34) binding site. However, PTH (1–34)-mediated Gs activation is Undisturbed by ECD-scFvhFc binding. In contrast, ECD-scFvhFc potently inhibits β-arrestin-2 recruitment after PTH (1–34)-driven receptor activation and thus represents the first monoclonal antibody to selectively inhibit distinct PTH1R signaling pathways. Given the complexity of PTH1R signaling and the emerging importance of biased GPCR activation in drug development, ECD-scFvhFc could be a valuable tool to study PTH1R signaling bias. [ABSTRACT FROM AUTHOR]

Background: Extracorporeal membrane oxygenation (ECMO) delivers cardiac and/or respiratory support to critically ill patients who have failed conventional medical therapies. If the large-bore cannulas used to deliver ECMO become infected or dislodged, the patient consequences can be catastrophic. ECMO cannula-related infection has been reported to be double the rate of other vascular devices (7.1 vs 3.4 episodes/1000 ECMO days respectively). The aim of this study was to assess the ability of cyanoacrylate tissue adhesive (TA) to inhibit bacterial growth at the ECMO cannulation site, and the effectiveness of TA and securement devices in securing ECMO cannulas and tubing.Methods: This in vitro study tested the (1) antimicrobial qualities of TA against standard transparent dressing with ECMO cannula; (2) chemical compatibility between cannula, TA and removal agent; (3) pull-out strength of transparent dressing and TA at the cannula insertion site; and (4) pull-out strength of adhesive bandage and commercial sutureless securement devices (SSDs) on circuit tubing. Fisher’s exact test was used to evaluate differences in bacterial growth observed between the transparent dressing and TA groups. Data from mechanical testing were analysed using one-way ANOVA, followed by Tukey’s multiple comparison test or t test as appropriate. Statistical significance was defined as p < 0.05.Results: No bacterial growth occurred under TA-covered cannulas compared with transparent dressing-covered cannulas (p = 0.002). Compared to plates lacking TA or transparent dressing, growth was observed at the insertion point and under the dressing in the transparent dressing group; however, no growth was observed in the TA group (p = 0.019). TA did not weaken the cannulas; however, the TA removal agent did after 60 min of exposure, compared with control (p < 0.01). Compared with transparent dressing, TA increased the pull-out force required for cannula dislodgement from the insertion point (p < 0.0001). SSDs significantly increased the force required to remove the tubing from the fixation points compared with adhesive bandage (p < 0.01).Conclusions: Our findings suggest that the combined use of TA at the cannula insertion site with a commercial device for tubing securement could provide an effective bedside strategy to prevent or minimise infection and line dislodgement. [ABSTRACT FROM AUTHOR]

Protein:protein interactions are fundamental in living organism homeostasis. Here we introduce VHH6, a junctional epitope antibody capable of specifically recognizing a neo-epitope when two proteins interact, albeit transiently, to form a complex. Orthogonal biophysical techniques have been used to prove the 'junctional epitope' nature of VHH6, a camelid single domain antibody recognizing the IL-6-gp80 complex but not the individual components alone. X-ray crystallography, HDX-MS and SPR analysis confirmed that the CDR regions of VHH6 interact simultaneously with IL-6 and gp80, locking the two proteins together. At the cellular level, VHH6 was able to alter the response of endothelial cells to exogenous IL-6, promoting a sustained STAT3 phosphorylation signal, an accumulation of IL-6 in vesicles and an overall pro-inflammatory phenotype supported further by transcriptomic analysis. Junctional epitope antibodies, like VHH6, not only offer new opportunities in screening and structure-aided drug discovery, but could also be exploited as therapeutics to modulate complex protein:protein interactions. [ABSTRACT FROM AUTHOR]

Webspinners (Insecta: Embioptera) have a distinctly unique behaviour with related morphological characteristics. Producing silk with the basitarsomeres of their forelegs plays a crucial role in the lives of these insects - providing shelter and protection. The correlation between body size, morphology and morphometrics of the spinning apparatus and the spinning behaviour of Embioptera was investigated for seven species using state-of-the-art methodology for behavioural as well as for morphological approaches. Independent contrast analysis revealed correlations between morphometric characters and body size. Larger webspinners in this study have glands with greater reservoir volume, but in proportionally smaller tarsi relative to body size than in the smaller species. Furthermore, we present a detailed description and review of the spinning apparatus in Embioptera in comparison to other arthropods and substantiate the possible homology of the embiopteran silk glands to class III dermal silk glands of insects. [ABSTRACT FROM AUTHOR]