Parsing eye-tracking data of variable quality to provide accurate fixation duration estimates in infants and adults

Researchers studying infants’ spontaneous allocation of attention have traditionally relied on hand-coding infants’ direction of gaze from videos; these techniques have low temporal and spatial resolution and are labor intensive. Eye-tracking technology potentially allows for much more precise measurement of how attention is allocated at the subsecond scale, but a number of technical and methodological issues have given rise to caution about the quality and reliability of high temporal resolution data obtained from infants. We present analyses suggesting that when standard dispersal-based fixation detection algorithms are used to parse eye-tracking data obtained from infants, the results appear to be heavily influenced by interindividual variations in data quality. We discuss the causes of these artifacts, including fragmentary fixations arising from flickery or unreliable contact with the eyetracker and variable degrees of imprecision in reported position of gaze. We also present new algorithms designed to cope with these problems by including a number of new post hoc verification checks to identify and eliminate fixations that may be artifactual. We assess the results of our algorithms by testing their reliability using a variety of methods and on several data sets. We contend that, with appropriate data analysis methods, fixation duration can be a reliable and stable measure in infants. We conclude by discussing ways in which studying fixation durations during unconstrained orienting may offer insights into the relationship between attention and learning in naturalistic settings

Metabolic syndrome in polycystic ovary syndrome

Zespół metaboliczny (MS, metabolic syndrome) i zespół policystycznych jajników (PCOS, polycystic ovary syndrome) są często rozpoznawanymi zaburzeniami u kobiet. Częstość występowania zespołu metabolicznego u kobiet z PCOS zależy od zastosowanych kryteriów diagnostycznych. W prezentowanej pracy autorzy rozważają tezę, że przyczyną obu zaburzeń może być insulinooporność, będąca następstwem otyłości brzusznej. Ponadto dokonują przeglądu literatury dotyczącej występowania MS u kobiet z PCOS oraz omawiają wpływ wyboru określonych kryteriów diagnostycznych MS i PCOS na oszacowanie czêstoœci ich występowania.Both metabolic syndrome (MS) and polycystic ovary syndrome (PCOS) are common among women. The exact prevalence of MS in women with PCOS is dependent upon the diagnostic criteria used for each. However, the frequent co-occurrence of both MS and PCOS in women is suggestive of a common aetiology. In this short review article we argue that insulin resistance, as a consequence of abdominal obesity, may represent such a common aetiology. We also review the literature on the prevalence of MS in women with PCOS and consider the impact that the particular criteria used to diagnose both MS and PCOS may have had on these estimates of prevalence

Risks Posed by Reston, the Forgotten Ebolavirus

Out of the five members of the Ebolavirus family, four cause lifethreatening disease, whereas the fifth, Reston virus (RESTV), is nonpathogenic in humans. The reasons for this discrepancy remain unclear. In this review, we analyze the currently available information to provide a state-of-the-art summary of the factors that determine the human pathogenicity of Ebolaviruses. RESTV causes sporadic infections in cynomolgus monkeys and is found in domestic pigs throughout the Philippines and China. Phylogenetic analyses revealed that RESTV is most closely related to the Sudan virus, which causes a high mortality rate in humans. Amino acid sequence differences between RESTV and the other Ebolaviruses are found in all nine Ebolavirus proteins, though no one residue appears sufficient to confer pathogenicity. Changes in the glycoprotein contribute to differences in Ebolavirus pathogenicity but are not sufficient to confer pathogenicity on their own. Similarly, differences in VP24 and VP35 affect viral immune evasion and are associated with changes in human pathogenicity. A recent in silico analysis systematically determined the functional consequences of sequence variations between RESTV and human-pathogenic Ebolaviruses. Multiple positions in VP24 were differently conserved between RESTV and the other Ebolaviruses and may alter human pathogenicity. In conclusion, the factors that determine the pathogenicity of Ebolaviruses in humans remain insufficiently understood. An improved understanding of these pathogenicity-determining factors is of crucial importance for disease prevention and for the early detection of emergent and potentially human-pathogenic RESTVs

Drug-Adapted Cancer Cell Lines as Preclinical Models of Acquired Resistance

Acquired resistance formation limits the efficacy of anti-cancer therapies. Acquired and intrinsic resistance differ conceptually. Acquired resistance is the consequence of directed evolution, whereas intrinsic resistance depends on the (stochastic) presence of pre-existing resistance mechanisms. Preclinical model systems are needed to study acquired drug resistance because they enable: (1) in depth functional studies; (2) the investigation of non-standard treatments for a certain disease condition (which is necessary to identify small groups of responders); and (3) the comparison of multiple therapies in the same system. Hence, they complement data derived from clinical trials and clinical specimens, including liquid biopsies. Many groups have successfully used drug-adapted cancer cell lines to identify and elucidate clinically relevant resistance mechanisms to targeted and cytotoxic anti-cancer drugs. Hence, we argue that drug-adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data

Comparison of Drop Jump and Tuck Jump Knee Joint Kinematics in Elite Male Youth Soccer Players: Implications for Injury Risk Screening

Context: Despite the popularity of jump-landing tasks being used to identify injury risk factors, minimal data currently exist examining differences in knee kinematics during commonly used bilateral jumping tasks. This is especially the case for rebounding-based protocols involving young athletes. Objective: The purpose of this study was to compare the frontal plane projection angle (FPPA) during the drop vertical jump (DVJ) and tuck jump assessment (TJA) in a cohort of elite male youth soccer players of varying maturity status. Methods: A total of 57 male youth soccer players from an English championship soccer club participated in the study. Participants performed three trials of the DVJ and TJA, during which movement was recorded with two-dimensional video cameras. FPPA for both right (FPPA-r) and left (FPPA-l) legs, with values <180º indicative of medial knee displacement. Results: On a whole-group level, FPPA-r (172.7 ± 7.4 º versus 177.2 ± 11.7 º; p < 0.05; ES = 0.46) and FPPA-l (173.4 ± 7.3 º versus 179.2 ± 11.0 º; p < 0.05; ES = 0.62) was significantly greater for both limbs in the TJA compared to the DVJ; however, these differences were less consistent when grouped by maturity status. FPPA-r during the TJA was significantly and moderately greater in the circa-PHV group compared to the post-PHV cohorts (169.4 ± 6.4 º versus 175.3 ± 7.8 º; p < 0.05; ES = 0.49). Whole group data showed moderate relationships for FPPA-r and FPPA-l between the TJA and DVJ; however, stronger relationships were shown in circa and post-PHV players compared to the pre-PHV cohort. Conclusions: Considering that the TJA exposed players to a larger FPPA and was sensitive to between-group differences in FPPA-r, the TJA could be viewed as a more suitable screen for identifying FPPA in young male soccer players

Understanding of researcher behaviour is required to improve data reliability

Background: A lack of data reproducibility (“reproducibility crisis”) has been extensively debated across many academic disciplines. Main body: Although a reproducibility crisis is widely perceived, conclusive data on the scale of the problem and the underlying reasons are largely lacking. The debate is primarily focused on methodological issues. However, examples such as the use of misidentified cell lines illustrate that the availability of reliable methods does not guarantee good practice. Moreover, research is often characterised by a lack of established methods. Despite the crucial importance of researcher conduct, research and conclusive data on the determinants of researcher behaviour are widely missing. Conclusion: Meta-research is urgently needed that establishes an understanding of the factors that determine researcher behaviour. This knowledge can then be used to implement and iteratively improve measures, which incentivise researchers to apply the highest standards resulting in high quality data

Incorporation of doxorubicin in different polymer nanoparticles and their anticancer activity

Background: Nanoparticles are under investigation as carrier systems for anticancer drugs. The expression of efflux transporters such as the ATP-binding cassette (ABC) transporter ABCB1 is an important resistance mechanism in therapy-refractory cancer cells. Drug encapsulation into nanoparticles has been shown to bypass efflux-mediated drug resistance, but there are also conflicting results. To investigate whether easy-to-prepare nanoparticles made of well-tolerated polymers may circumvent transporter-mediated drug efflux, we prepared poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), and PEGylated PLGA (PLGA-PEG) nanoparticles loaded with the ABCB1 substrate doxorubicin by solvent displacement and emulsion diffusion approaches and assessed their anticancer efficiency in neuroblastoma cells, including ABCB1-expressing cell lines, in comparison to doxorubicin solution. Results: The resulting nanoparticles covered a size range between 73 and 246 nm. PLGA-PEG nanoparticle preparation by solvent displacement led to the smallest nanoparticles. In PLGA nanoparticles, the drug load could be optimised using solvent displacement at pH 7 reaching 53 µg doxorubicin/mg nanoparticle. These PLGA nanoparticles displayed sustained doxorubicin release kinetics compared to the more burst-like kinetics of the other preparations. In neuroblastoma cells, doxorubicin-loaded PLGA-PEG nanoparticles (presumably due to their small size) and PLGA nanoparticles prepared by solvent displacement at pH 7 (presumably due to their high drug load and superior drug release kinetics) exerted the strongest anticancer effects. However, nanoparticle-encapsulated doxorubicin did not display increased efficacy in ABCB1-expressing cells relative to doxorubicin solution. Conclusion: Doxorubicin-loaded nanoparticles made by different methods from different materials displayed substantial discrepancies in their anticancer activity at the cellular level. Optimised preparation methods resulted in PLGA nanoparticles characterised by increased drug load, controlled drug release, and high anticancer efficacy. The design of drug-loaded nanoparticles with optimised anticancer activity at the cellular level is an important step in the development of improved nanoparticle preparations for anticancer therapy. Further research is required to understand under which circumstances nanoparticles can be used to overcome efflux-mediated resistance in cancer cells

COVID-19-Related Coagulopathy—Is Transferrin a Missing Link?

SARS-CoV-2 is the causative agent of COVID-19. Severe COVID-19 disease has been associated with disseminated intravascular coagulation and thrombosis, but the mechanisms underlying COVID-19-related coagulopathy remain unknown. The risk of severe COVID-19 disease is higher in males than in females and increases with age. To identify gene products that may contribute to COVID-19-related coagulopathy, we analyzed the expression of genes associated with the Gene Ontology (GO) term “blood coagulation” in the Genotype-Tissue Expression (GTEx) database and identified four procoagulants, whose expression is higher in males and increases with age (ADAMTS13, F11, HGFAC, KLKB1), and two anticoagulants, whose expression is higher in females and decreases with age (C1QTNF1, SERPINA5). However, the expression of none of these genes was regulated in a proteomics dataset of SARS-CoV-2-infected cells and none of the proteins have been identified as a binding partner of SARS-CoV-2 proteins. Hence, they may rather generally predispose individuals to thrombosis without directly contributing to COVID-19-related coagulopathy. In contrast, the expression of the procoagulant transferrin (not associated to the GO term “blood coagulation”) was higher in males, increased with age, and was upregulated upon SARS-CoV-2 infection. Hence, transferrin warrants further examination in ongoing clinic-pathological investigation

Large inherent variability in data derived from highly standardised cell culture experiments.

Cancer drug development is hindered by high clinical attrition rates, which are blamed on weak predictive power by preclinical models and limited replicability of preclinical findings. However, the technically feasible level of replicability remains unknown. To fill this gap, we conducted an analysis of data from the NCI60 cancer cell line screen (2.8 million compound/cell line experiments), which is to our knowledge the largest depository of experiments that have been repeatedly performed over decades. The findings revealed profound intra-laboratory data variability, although all experiments were executed following highly standardised protocols that avoid all known confounders of data quality. All compound/ cell line combinations with > 100 independent biological replicates displayed maximum GI50 (50% growth inhibition) fold changes (highest/ lowest GI50) > 5% and 70.5% displayed maximum fold changes > 1000. The highest maximum fold change was 3.16 × 10 (lowest GI50: 7.93 ×10 µM, highest GI50: 25.0 µM). FDA-approved drugs and experimental agents displayed similar variation. Variability remained high after outlier removal, when only considering experiments that tested drugs at the same concentration range, and when only considering NCI60-provided quality-controlled data. In conclusion, high variability is an intrinsic feature of anti-cancer drug testing, even among standardised experiments in a world-leading research environment. Awareness of this inherent variability will support realistic data interpretation and inspire research to improve data robustness. Further research will have to show whether the inclusion of a wider variety of model systems, such as animal and/ or patient-derived models, may improve data robustness. [Abstract copyright: Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.