Shoulder injuries are a common problem in handball. One likely cause of such injuries is excessive throwing. However, it is difficult to measure the number of player throws in large cohort studies ...using existing methods accurately. Therefore, the purpose of this study is to develop and validate a method for identifying overhead throws using a low-cost inertial measurement unit (IMU) worn on the wrist. In a two-stage approach, we developed a threshold-based automatic identification method for overhead throws in a laboratory study using the IMU. Subsequently, we validated the suggested thresholds in a field setting by comparing throws identified by the threshold-method to throws identified by video recordings of handball practices. The best set of threshold values resulted in a per-player median sensitivity of 100% (range: 84-100%) and a median positive predictive value (PPV) of 96% (range: 86-100%) in the development study. In the validation study, the per-player median sensitivity dropped to 78% sensitivity (range: 52-91%), while the per-player median PPV dropped to 79% (range: 47-90%). The proposed method is a promising method for automatically identifying handball throws in a cheap and feasible way.
Over the last three decades, the appeal for monoclonal antibodies (mAbs) as therapeutics has been steadily increasing as evident with FDA's recent landmark approval of the 100th mAb. Unlike mAbs that ...bind to single targets, multispecific biologics (msAbs) have garnered particular interest owing to the advantage of engaging distinct targets. One important modular component of msAbs is the single-chain variable fragment (scFv). Despite the exquisite specificity and affinity of these scFv modules, their relatively poor thermostability often hampers their development as a potential therapeutic drug. In recent years, engineering antibody sequences to enhance their stability by mutations has gained considerable momentum. As experimental methods for antibody engineering are time-intensive, laborious and expensive, computational methods serve as a fast and inexpensive alternative to conventional routes. In this work, we show two machine learning approaches - one with pre-trained language models (PTLM) capturing functional effects of sequence variation, and second, a supervised convolutional neural network (CNN) trained with Rosetta energetic features - to better classify thermostable scFv variants from sequence. Both of these models are trained over temperature-specific data (TS50 measurements) derived from multiple libraries of scFv sequences. On out-of-distribution (refers to the fact that the out-of-distribution sequnes are blind to the algorithm) sequences, we show that a sufficiently simple CNN model performs better than general pre-trained language models trained on diverse protein sequences (average Spearman correlation coefficient,
, of 0.4 as opposed to 0.15). On the other hand, an antibody-specific language model performs comparatively better than the CNN model on the same task (
0.52). Further, we demonstrate that for an independent mAb with available thermal melting temperatures for 20 experimentally characterized thermostable mutations, these models trained on TS50 data could identify 18 residue positions and 5 identical amino-acid mutations showing remarkable generalizability. Our results suggest that such models can be broadly applicable for improving the biological characteristics of antibodies. Further, transferring such models for alternative physicochemical properties of scFvs can have potential applications in optimizing large-scale production and delivery of mAbs or bsAbs.
BACKGROUND
Fetal human platelet antigen (HPA) genotyping is required to determine whether the fetus is at risk and whether prenatal interventions to prevent fetal bleeding are required in pregnant ...women with a history of fetal and neonatal alloimmune thrombocytopenia (FNAIT). Methods for noninvasive genotyping of HPA alleles with the use of maternal plasma cell‐free DNA were published recently but do lack internal controls to exclude false‐negative results.
STUDY DESIGN AND METHODS
Cell‐free DNA was isolated from plasma of four pregnant women with a history of FNAIT caused by anti‐HPA‐1a and controls. A primer panel was designed to target sequences flanking single‐nucleotide polymorphisms (SNPs)/exonic regions of ITGB3 (HPA‐1), ITGA2B (HPA‐3), ITGA2 (HPA‐5), CD109 (HPA‐15), RHD, RHCE, KEL, DARC, SLC14A1, GYPA, GYPB, and SRY. These regions and eight anonymous SNPs were massively parallel sequenced by semiconductor technology.
RESULTS
The mean (±SD) number of reads for targeted SNPs was 5255 (±2838). Fetal DNA was detected at a median of 4.5 (range, 2‐8) polymorphic loci. The mean fractional fetal DNA concentration in cell‐free maternal plasma was 8.36% (range, 4.79%‐15.9%). For HPA‐1, nonmaternal ITGB3 sequences (c.176T, HPA‐1a) were detected in all HPA‐1ab fetuses. One HPA‐1bb fetus was unequivocally identified, showing the pregnancy was not at risk of FNAIT.
CONCLUSION
We have successfully established massively parallel sequencing as a novel reliable method for noninvasive genotyping of fetal HPA‐1a alleles. This technique may also allow the safe detection of other fetal blood group polymorphisms frequently involved in FNAIT and hemolytic disease of the newborn.
Inflation has attained the highest level in decades, with the Russian/Ukrainian war adding upward pressure on prices of energy and food. The recent war has exacerbated the already growth of consumer ...prices resulting from the COVID-19 and disrupted supply-chains. In a high-inflation environment where investors face inflationary pressures during their investment decision-making, it becomes increasingly important to diversify portfolios towards assets with potential inflation hedging abilities. This paper applies the dependence-switching copula and different dynamic downside risk measures to assess the role of Islamic stocks as a hedge for inflation, in comparison to their conventional counterparts. We use data for the period January 2000–October 2022, covering the periods prior to and post-COVID-19 and the war in Ukraine. We consider an investor simply wishing to hedge inflation (or a “safety first” investor) and an investor having a more ambitious target real return. For each of the investor targets, we identify the optimal portfolio composition depending on various scenarios. Prior to the pandemic and the Ukraine conflict, Islamic stock indices exhibit the best hedging properties under their bull states, extreme inflation episodes and for an investor willing just to protect against inflation. In considering the post-2020 concerns, Islamic stocks’ diversification potentials are going to be more relevant, reinforcing their strategic benefits as risk mitigation assets. But by increasing the target of real return, it is shown that the weight assigned to the Islamic equities in the portfolio is smaller relative to the conventional stocks. The fund managers and financial analysts can rely on these findings in order to help investors reach a well-diversified portfolio and achieve an optimal risk reduction in an inflationary environment.
•We compare the Islamic and conventional stock indices in different inflation scenarios.•We consider an investor who wants to hedge against inflation.•We assess the inflation-protecting asset allocation for an investor who desires an additional premium.•The inflation hedging properties of Islamic and conventional stocks are conditional on target real returns.•We obtain diversification benefits from allocating in Islamic stocks with small additions of its conventional counterpart.
Bispecific T cell engager (BiTE®) are single-chain bispecific antibody constructs with dual specificity for CD3 on T cells and a surface antigen on target cells. They can elicit a polyclonal ...cytotoxic T cell response that is not restricted by T cell receptor (TCR) specificity, and surface expression of MHC class I/peptide antigen complexes. Using human EpCAM/CD3-bispecific BiTE® antibody construct AMG 110, we here assessed to what extent surface expression of PD-L1, cytoplasmic expression of indoleamine-2,3-deoxygenase type 1, Bcl-2 and serpin PI-9, and the presence of transforming growth factor beta (TGF-β), interleukin-10 (IL-10) and adenosine in culture medium can impact redirected lysis by AMG 110-engaged T cells.
The seven factors, which are all involved in inhibiting T cell functions by cancer cells, were tested with human EpCAM-expressing Chinese hamster ovary (CHO) target cells at levels that in most cases exceeded those observed in a number of human cancer cell lines. Co-culture experiments were used to determine the impact of the evasion mechanisms on EC50 values and amplitude of redirected lysis by AMG 110, and on BiTE®-induced proliferation of previously resting human peripheral T cells.
An inhibitory effect on redirected lysis by AMG 110-engaged T cells was seen upon overexpression of serpin PI-9, Bcl-2, TGF-β and PD-L1. An inhibitory effect on induction of T cell proliferation was only seen with CHO cells overexpressing IDO. In no case, a single evasion mechanism rendered target cells completely resistant to BiTE®-induced lysis, and even various combinations could not.
Our data suggest that diverse mechanisms employed by cancer cells to fend off T cells cannot inactivate AMG 110-engaged T cells, and that inhibitory effects observed in vitro may be overcome by increased concentrations of the BiTE® antibody construct.
Purpose
– The purpose of this paper is to examine the price discovery and volatility spillovers in spot and futures prices of four currencies (namely, USD/INR, EURO/INR, GBP/INR and JPY/INR) and ...between futures prices of both stock exchanges namely, Multi-Commodity Stock Exchange (MCX-SX) and National Stock Exchange (NSE) in India.
Design/methodology/approach
– The study applies cointegration test of Johansen’s along with VECM to investigate the price discovery. GARCH-BEKK model is used to examine the volatility spillover between spot and futures and between futures prices. The other two models namely, constant conditional correlation and dynamic conditional correlation are used to demonstrate the constant and time-varying correlations. In order to confirm the volatility spillover results, the study also applies test of directional spillovers suggested by Diebold and Yilmaz (2009, 2012).
Findings
– The results of the study show that there is long-term equilibrium relationship between spot and futures and between futures markets. Between futures and spot prices, futures price appears to lead the spot price in the short-run. Volatility spillover results indicate that the movement of volatility spillover takes place from futures to spot in the short-run while spot to futures found in the long-run. However, the results of between futures markets exhibit the dominance of MCX-SX over NSE in terms of volatility spillovers. By and large, the findings of the study indicate the important role of futures market in price discovery as well as volatility spillovers in India’s currency market.
Practical implications
– The results highlight the role of futures market in the information transmission process as it appears to assimilate new information quicker than spot market. Hence, policymakers in emerging markets such as India should focus on the development of necessary institutional and fiscal architecture, as well as regulatory reforms, so that the currency market trading platforms can achieve greater liquidity and efficiency.
Originality/value
– Due to recent development of currency futures market, there is dearth of literature on this subject. With the apparent importance of currency market in recent time, this study attempts to study the efficient behavior of currency market by way of examining the price discovery and volatility spillovers between spot and futures and between futures prices of four currencies traded on two platforms. The study has strong implications for India’s stock market especially at the time when its currency is under great strain owing to the adverse impact of global financial crisis.
Wine prices rose rapidly between 2001 and 2011 but have now stagnated. The growth phase could be explained by the increased demand from emerging markets, while the subsequent stagnation may result ...from the crowding effect caused by the entry of numerous new varieties onto the wine market. The generalised model of ideal variety proposed by Hummels and Lugovskyy combines these two elements, and focusing on French exporters, we find partial support for this explanation at the world level. A 1 per cent increase in GDP per capita (income effect) generated an increase in price of 1.13 per cent between 2001 and 2011. In contrast, a 1 per cent increase in market size (competition effect) reduced prices by 1.10 per cent over the same period. This paper goes further into the analysis of these effects by considering wine exports according to the mode of transport used and indirectly evaluates economies of scale when wine is exported by land, sea or air (via a gravity equation). Economies of scale are observed for transport by plane and ship but not for road. A 10 per cent increase in the value of wine exported by road (plane) leads to a rise (reduction) in transport costs of 0.5 per cent (19 per cent).
This paper explores the prospect of CMOS devices to assay lead in drinking water, using calorimetry. Lead occurs together with traces of radioisotopes, e.g., 210Pb, producing γ-emissions with ...energies ranging from 10 keV to several 100 keV when they decay; this range is detectable in silicon sensors. In this paper we test a CMOS camera (Oxford Instruments Neo 5.5) for its general performance as a detector of X-rays and low energy γ-rays and assess its sensitivity relative to the World Health Organization upper limit on lead in drinking water. Energies from 6 keV to 60 keV are examined. The CMOS camera has a linear energy response over this range and its energy resolution is for the most part slightly better than 2%. The Neo sCMOS is not sensitive to X-rays with energies below ∼10 keV. The smallest detectable rate is 40±3mHz, corresponding to an incident activity on the chip of 7±4Bq. The estimation of the incident activity sensitivity from the detected activity relies on geometric acceptance and the measured efficiency vs. energy. We report the efficiency measurement, which is 0.08(2)% (0.0011(2)%) at 26.3keV (59.5keV). Taking calorimetric information into account we measure a minimal detectable rate of 4±1mHz (1.5±1mHz) for 26.3keV (59.5keV) γ-rays, which corresponds to an incident activity of 1.0±6Bq (57±33Bq). Toy Monte Carlo and Geant4 simulations agree with these results. These results show this CMOS sensor is well-suited as a γ- and X-ray detector with sensitivity at the few to 100 ppb level for 210Pb in a sample.
Abstract
Bispecific T-cell engager (BiTE) molecules have great potential to treat cancer. Nevertheless, dependent on the targeted tumor antigen, the mechanism of action that drives efficacy may also ...contribute to on-target/off-tumor toxicities. In this study, we characterize an anti-CD70 half-life extended BiTE molecule (termed N6P) which targets CD70, a TNF family protein detected in several cancers. First, the therapeutic potential of N6P was demonstrated using in vitro cytotoxicity assays and an orthotopic xenograft mouse study resulting in potent killing of CD70+ cancer cells. Next, in vitro characterization demonstrated specificity for CD70 and equipotent activity against human and cynomolgus monkey CD70+ cells. To understand the potential for on-target toxicity, a tissue expression analysis was performed and indicated CD70 is primarily restricted to lymphocytes in normal healthy tissues and cells. Therefore, no on-target toxicity was expected to be associated with N6P. However, in a repeat-dose toxicology study using cynomolgus monkeys, adverse N6P-mediated inflammation was identified in multiple tissues frequently involving the mesothelium and epithelium. Follow-up immunohistochemistry analysis revealed CD70 expression in mesothelial and epithelial cells in some tissues with N6P-mediated injury, but not in control tissues or those without injury. Collectively, the data indicate that for some target antigens such as CD70, BiTE molecules may exhibit activity in tissues with very low antigen expression or the antigen may be upregulated under stress enabling molecule activity. This work illustrates how a thorough understanding of expression and upregulation is needed to fully address putative liabilities associated with on-target/off-tumor activity of CD3 bispecific molecules.
In this paper, we examine the dynamic nature of equity market integration for the South Asian countries. The daily data for local equity indices are used from 6 January 2004 to 31 March 2015. Copula ...GARCH models and Diebold and Yilmaz methodology have been employed to study the inter-temporal process of equity market integration. Empirical results show that the sample countries of the region exhibit very little or no levels of integration between them. Equity portfolio flows within the South Asian region reconfirms this trend for low integration in the region. Further, trend analysis of the fundamental determinants of financial integration for the SAARC countries was performed and the same was compared with its neighbouring regional economic bloc in Asia i.e. ASEAN + 6. It indicated that SAARC countries have to show sincere political commitment and require collaboration in efforts of policy realignment to work on their governance parameters, improve on their trade linkages and trade tariffs and develop their equity market infrastructure to achieve higher levels of financial integration. The paper contributes to the International Finance literature, especially dealing with regional economic blocs and has important implications for policy-makers, portfolio managers and academia.
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