Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular Determinants and Specificity of mRNA with Alternatively-Spliced UPF1 Isoforms, Influenced by an Insertion in the ‘Regulatory Loop’

The nonsense-mediated mRNA decay (NMD) pathway rapidly detects and degrades mRNA containing premature termination codons (PTCs). UP-frameshift 1 (UPF1), the master regulator of the NMD process, has two alternatively-spliced isoforms; one carries 353-GNEDLVIIWLR-363 insertion in the ‘regulatory loop (involved in mRNA binding)’. Such insertion can induce catalytic and/or ATPase activity, as determined experimentally; however, the kinetics and molecular level information are not fully understood. Herein, applying all-atom molecular dynamics, we probe the binding specificity of UPF1 with different GC- and AU-rich mRNA motifs and the influence of insertion to the viable control over UPF1 catalytic activity. Our results indicate two distinct conformations between 1B and RecA2 domains of UPF1: ‘open (isoform_2; without insertion)’ and ‘closed (isoform_1; with insertion)’. These structural movements correspond to an important stacking pattern in mRNA motifs, i.e., absence of stack formation in mRNA, with UPF1 isoform_2 results in the ‘open conformation’. Particularly, for UPF1 isoform_1, the increased distance between 1B and RecA2 domains has resulted in reducing the mRNA–UPF1 interactions. Lower fluctuating GC-rich mRNA motifs have better binding with UPF1, compared with AU-rich sequences. Except CCUGGGG, all other GC-rich motifs formed a 4-stack pattern with UPF1. High occupancy R363, D364, T627, and G862 residues were common binding GC-rich motifs, as were R363, N535, and T627 for the AU-rich motifs. The GC-rich motifs behave distinctly when bound to either of the isoforms; lower stability was observed with UPF1 isoform_2. The cancer-associated UPF1 variants (P533L/T and A839T) resulted in decreased protein–mRNA binding efficiency. Lack of mRNA stacking poses in the UPF1P533T system significantly decreased UPF1-mRNA binding efficiency and increased distance between 1B-RecA2. These novel findings can serve to further inform NMD-associated mechanistic and kinetic studies.
Age-Differentiated Leadership and Healthy Aging at Work: Evidence from the Early Stages of the COVID-19 Pandemic

Little is known about the relative influence of age-differentiated leadership on healthy aging at work. Likewise, the age-conditional influence of age-differentiated leadership is understudied, and especially so in the context of the COVID-19 pandemic. Using a three-wave longitudinal study, we examined the role that age-differentiated leadership plays in the prediction of work ability, as measured three times over six months (n = 1130) during the early stages of the COVID-19 pandemic in Germany (i.e., December 2019, March 2020, and June 2020). The results suggest that although there were no systematic changes in work ability on average, there was notable within-person variability in work ability over time. Additionally, we find that a balanced approach to age-differentiated leadership that considers the needs of both older and younger employees matters most and complements the positive influence of leader–member exchange for predicting within-person variability in work ability. We also find that older employees’ work ability benefits from an approach to age-differentiated leadership that considers older employee’s needs, whereas younger employees’ work ability especially benefits from leader–member exchange and a balanced approach to age-differentiated leadership. Overall, these results provide initial support for the idea that an age-differentiated approach to leadership is important when considering healthy aging at work.
Soybean miR159-GmMYB33 Regulatory Network Involved in Gibberellin-Modulated Resistance to Heterodera glycines

Soybean cyst nematode (SCN, Heterodera glycines) is an obligate sedentary biotroph that poses major threats to soybean production globally. Recently, multiple miRNAome studies revealed that miRNAs participate in complicated soybean-SCN interactions by regulating their target genes. However, the functional roles of miRNA and target genes regulatory network are still poorly understood. In present study, we firstly investigated the expression patterns of miR159 and targeted GmMYB33 genes. The results showed miR159-3p downregulation during SCN infection; conversely, GmMYB33 genes upregulated. Furthermore, miR159 overexpressing and silencing soybean hairy roots exhibited strong resistance and susceptibility to H. glycines, respectively. In particular, miR159-GAMYB genes are reported to be involve in GA signaling and metabolism. Therefore, we then investigated the effects of GA application on the expression of miR159-GAMYB module and the development of H. glycines. We found that GA directly controls the miR159-GAMYB module, and exogenous GA application enhanced endogenous biologically active GA1 and GA3, the abundance of miR159, lowered the expression of GmMYB33 genes and delayed the development of H. glycines. Moreover, SCN infection also results in endogenous GA content decreased in soybean roots. In summary, the soybean miR159-GmMYB33 module was directly involved in the GA-modulated soybean resistance to H. glycines.
Accessibility of Online Resources for Associations Providing Services to People with Brain Injuries in Covid-19 Pandemic

Background. Since the Covid-19 pandemic, many community-based services for people with traumatic brain injury (TBI) have been moved online, which may have hindered their accessibility. The study aims to assess the accessibility of online information and resources dedicated to people with TBI. Methods. The websites of 14 organizations offering information and resources to people with TBI in Quebec were evaluated. Two co-authors independently evaluated one page of each website and compared their results. Descriptive statistical analyses were performed. Results. The average accessibility score of the 14 websites evaluated was 54% with a standard deviation of 16%. Website design and writing were the most accessible aspects (72.3%). Only two out of the 14 websites (14%) presented multimedia content. This category presented the most barriers to accessibility with a score of 42%. Regarding images, they reached an accessibility score of 46%. Their main shortcoming was the absence of a caption. Conclusion. This study highlights accessibility issues specific to people with TBI to access online resources and identifies specific areas of improvement. The results of this study provide community organizations with avenues of improvement to make their online resources more accessible to people with TBI and may therefore lead to improved community practices.
Good news reduces trust in government and its efficacy: The case of the Pfizer/BioNTech vaccine announcement

The announcement of Pfizer/BioNTech’s COVID-19 vaccine success on November 9, 2020 led to a global stock market surge. But how did the general public respond to such good news? We leverage the unexpected vaccine announcement to assess the effect of good news on citizens’ government evaluations, anxiety, beliefs and elicited behaviors in the US and the UK. While most outcomes were unaffected by the news, trust in government and elected politicians (and their competency) saw a significant decline in both countries. As the news did not concern the governments, and the governments did not have time to act on the news, our results suggest that the decline of trust is more likely explained by the psychological impact of good news on reasoning style. In particular, we suggest two possible styles of reasoning that might explain our results: a form of motivated reasoning and a reasoning heuristic of relative comparison.
Identification of Risk Factors for Suicidal Ideation and Attempt Based on Machine Learning Algorithms: A Longitudinal Survey in Korea (2007–2019)

Investigating suicide risk factors is critical for socioeconomic and public health, and many researchers have tried to identify factors associated with suicide. In this study, the risk factors for suicidal ideation were compared, and the contributions of different factors to suicidal ideation and attempt were investigated. To reflect the diverse characteristics of the population, the large-scale and longitudinal dataset used in this study included both socioeconomic and clinical variables collected from the Korean public. Three machine learning algorithms (XGBoost classifier, support vector classifier, and logistic regression) were used to detect the risk factors for both suicidal ideation and attempt. The importance of the variables was determined using the model with the best classification performance. In addition, a novel risk-factor score, calculated from the rank and importance scores of each variable, was proposed. Socioeconomic and sociodemographic factors showed a high correlation with risks for both ideation and attempt. Mental health variables ranked higher than other factors in suicidal attempts, posing a relatively higher suicide risk than ideation. These trends were further validated using the conditions from the integrated and yearly dataset. This study provides novel insights into suicidal risk factors for suicidal ideations and attempts.
Finite element analysis of the instep fatigue trauma in the high-heeled gait ∗

Two-dimensional numerical model of the foot, incorporating, for the first time in the literature,realistic geometric and material properties of both skeletal and soft tissue components of the foot, was developed for biomechanical analysis of its structural behavior during gait. Using a Finite Element solver, the stress distribution within the first metatarsal vertical arch of the foot(FMVA) structure was obtained and regions of elevated stresses for three subphases of the stance (heel-strike, push-off, and toe-off) were located. Validation of the pressure state was achieved by comparing model predictions of contact pressure distribution with Novel pedar. The presently developed measurement and numerical analysis tools open new approaches for clinical applications, from simulation of the development mechanisms of common foot disorders to pre- and post-interventional evaluation of their treatment.
Regulation of the Cell-Intrinsic DNA Damage Response by the Innate Immune Machinery

Maintenance of genomic integrity is crucial for cell survival. As such, elegant DNA damage response (DDR) systems have evolved to ensure proper repair of DNA double-strand breaks (DSBs) and other lesions that threaten genomic integrity. Towards this end, most therapeutic studies have focused on understanding of the canonical DNA DSB repair pathways to enhance the efficacy of DNA-damaging therapies. While these approaches have been fruitful, there has been relatively limited success to date and potential for significant normal tissue toxicity. With the advent of novel immunotherapies, there has been interest in understanding the interactions of radiation therapy with the innate and adaptive immune responses, with the ultimate goal of enhancing treatment efficacy. While a substantial body of work has demonstrated control of the immune-mediated (extrinsic) responses to DNA-damaging therapies by several innate immune pathways (e.g., cGAS–STING and RIG-I), emerging work demonstrates an underappreciated role of the innate immune machinery in directly regulating tumor cell-intrinsic/cell-autonomous responses to DNA damage.
Combined/Composite Adaptive Control of a Quadrotor UAV in the Presence of Actuator Uncertainty

Many potential applications of adaptive control, such as adaptive flight control systems, require that the controller have high performance, stability guarantees, and robustness to time delays. These requirements typically lead to engineering trade-os, such as a trade-o between performance and robustness. In this paper, we examine a combined/composite model reference adaptive control (CMRAC) approach that can be used to achieve higher performance as well as higher levels of robustness. The CMRAC design is validated with flight tests of a light-weight, low-cost quadrotor UAV platform inside an indoor test facility. The combined/composite adaptive controller was found to oer increased robustness to parametric uncertainties. The design of the combined/composite adaptive controller is presented, followed by a comparison with the existing linear controller and a direct adaptive controller.
Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant

Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the TRPV6 gene. One mutation results in an in frame stop codon (R510stop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (G660R) that, surprisingly, does not affect the Ca2+ permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 G660R and R510stop mutants and combinations with wild type TRPV6. We show that both the G660R and R510stop mutant subunits are expressed and result in decreased calcium uptake, which is the result of the reduced abundancy of functional TRPV6 channels within the plasma membrane. We compared the proteomic profiles of a healthy placenta with that of the diseased infant and detected, exclusively in the latter two proteases, HTRA1 and cathepsin G. Our results implicate that the combination of the two mutant TRPV6 subunits, which are expressed in the placenta of the diseased child, is responsible for the decreased calcium uptake, which could explain the skeletal dysplasia. In addition, placental calcium deficiency also appears to be associated with an increase in the expression of proteases.
Instantaneous phase-angle estimation algorithm under unbalanced voltage-sag conditions

If a negative sequence is generated by voltage sag and/or unbalance, it appears as an oscillating error in a synchronous reference frame (SRF). In power conditioning equipment, the exact value of a positive sequence is needed to achieve the unity power factor and constant output voltage, whereas the exact value of a negative sequence is needed for unbalance compensation. To measure the positive sequence separately from the negative sequence, a low pass or notch filter having a narrow bandwidth is normally used. However, such a filter causes a lot of phase delay, thus the response time of the system tends to be lengthened. A method of estimating the positive- and the negative-sequence voltages separately is presented, without a significant delay, by utilising the weighted least-squares estimation (WLSE) method with the covariance resetting technique. A frequency update law is also proposed to accommodate the frequency varying environments. The authors demonstrate through simulation and experiment the superior performance of the proposed scheme in measuring the positive- and the negative-sequence voltages at the time of abrupt transition. This method can be applied to uninterruptable power supplies (UPS), pulsewidth modulation (PWM) AC/DC converters, active filters, AC voltage compensators etc.
NS-11021 Modulates Cancer-Associated Processes Independently of BK Channels in Melanoma and Pancreatic Duct Adenocarcinoma Cell Lines

Simple Summary Potassium channels permit the selective passage of K+ ions across the cell me brane and are important for setting the membrane potential and for the transmission of electrical signals in all cells. Ca2+ activated K+ channels provide a means to couple intracellular calcium signaling to changes of the membrane potential. Among these, the large-conductance Ca2+-activated K+ channel, known as BK, has been proposed to be involved in several cancer-associated processes. In the present work, we tested various BK channel activators for anti-cancer effects in melanoma and pancreatic duct carcinoma cell lines. Only one of the activators (NS-11021) had effects on cancer-associated processes. However, the compound, as a side-effect, also increased the intracellular Ca2+ concentration independently of BK channel activation. Overall, we conclude that the activation of the BK channel by itself is not sufficient to produce beneficial anti-cancer effects. Abstract Potassium channels have emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large-conductance Ca2+-activated K+ channel, often referred to as BK channel, is involved in several cancer-associated processes. Here, we investigated the effects of different BK activators, NS-11021, NS-19504, and BMS-191011, in IGR39 (primary melanoma cell line) and Panc-1 (primary pancreatic duct carcinoma cell line), highly expressing the channel, and in IGR37 (metastatic melanoma cell line) that barely express BK. Our data showed that NS-11021 and NS-19504 potently activated BK channels in IGR39 and Panc-1 cells, while no effect on channel activation was detected in IGR37 cells. On the contrary, BK channel activator BMS-191011 was less effective. However, only NS-11021 showed significant effects in cancer-associated processes, such as cell survival, migration, and proliferation in these cancer cell lines. Moreover, NS-11021 led to an increase of intracellular Ca2+ concentration, independent of BK channel activation, thus complicating any interpretation of its role in the regulation of cancer-associated mechanisms. Overall, we conclude that the activation of the BK channel by itself is not sufficient to produce beneficial anti-cancer effects in the melanoma and PDAC cell lines examined. Importantly, our results raise an alarm flag regarding the use of presumably specific BK channel openers as anti-cancer agents.
Blood–Brain Barrier in Brain Tumors: Biology and Clinical Relevance

The presence of barriers, such as the blood–brain barrier (BBB) and brain–tumor barrier (BTB), limits the penetration of antineoplastic drugs into the brain, resulting in poor response to treatments. Many techniques have been developed to overcome the presence of these barriers, including direct injections of substances by intranasal or intrathecal routes, chemical modification of drugs or constituents of BBB, inhibition of efflux pumps, physical disruption of BBB by radiofrequency electromagnetic radiation (EMP), laser-induced thermal therapy (LITT), focused ultrasounds (FUS) combined with microbubbles and convection enhanced delivery (CED). However, most of these strategies have been tested only in preclinical models or in phase 1–2 trials, and none of them have been approved for treatment of brain tumors yet. Concerning the treatment of brain metastases, many molecules have been developed in the last years with a better penetration across BBB (new generation tyrosine kinase inhibitors like osimertinib for non-small-cell lung carcinoma and neratinib/tucatinib for breast cancer), resulting in better progression-free survival and overall survival compared to older molecules. Promising studies concerning neural stem cells, CAR-T (chimeric antigen receptors) strategies and immunotherapy with checkpoint inhibitors are ongoing.
A novel strategy for driving car brain–computer interfaces: Discrimination of EEG-based visual-motor imagery

Abstract A brain–computer interface (BCI) based on kinesthetic motor imagery has a potential of becoming a groundbreaking technology in a clinical setting. However, few studies focus on a visual-motor imagery (VMI) paradigm driving BCI. The VMI-BCI feature extraction methods are yet to be explored in depth. In this study, a novel VMI-BCI paradigm is proposed to execute four VMI tasks: imagining a car moving forward, reversing, turning left, and turning right. These mental strategies can naturally control a car or robot to move forward, backward, left, and right. Electroencephalogram (EEG) data from 25 subjects were collected. After the raw EEG signal baseline was corrected, the alpha band was extracted using bandpass filtering. The artifacts were removed by independent component analysis. Then, the EEG average instantaneous energy induced by VMI (VMI-EEG) was calculated using the Hilbert–Huang transform (HHT). The autoregressive model was extracted to construct a 12-dimensional feature vector to a support vector machine suitable for small sample classification. This was classified into two-class tasks: visual imagination of driving the car forward versus reversing, driving forward versus turning left, driving forward versus turning right, reversing versus turning left, reversing versus turning right, and turning left versus turning right. The results showed that the average classification accuracy of these two-class tasks was 62.68 ± 5.08%, and the highest classification accuracy was 73.66 ± 6.80%. The study showed that EEG features of O1 and O2 electrodes in the occipital region extracted by HHT were separable for these VMI tasks.
‘The Drugs Did For Me What I Couldn’t Do For Myself’: A Qualitative Exploration of the Relationship Between Mental Health and Amphetamine-Type Stimulant (ATS) Use

Substance use and mental ill health constitute a major public health burden, and a key global policy priority is to reduce illicit and other harmful substance use. Amphetamine-type stimulants (ATS) are the second most used class of illicit drugs and a range of mental health issues have been documented amongst users. This paper explores the relationship between mental health and ATS use, through a thematic analysis of qualitative interviews with n = 18 current and former ATS users in England. The findings are presented by trajectory point of; (1) Initiation of ATS use; (2) continued and increased ATS use and (3) decreased and remitted ATS use. This work helps to develop understanding around the complex and bi-directional relationship between ATS use and mental health. Many ATS users lead chaotic lives and engage in multiple risk behaviours, however there is a need to better understand and conceptualise the dynamic interaction between different individual, social, environment and cultural factors that determine individuals’ mental health and substance use. There is no ‘one size fits all’ approach to prevention and treatment, and these findings highlight the need for more joined-up, tailored and holistic approaches to intervention development.
Splice-Variant Knock-Out of TGFβ Receptors Perturbates the Proteome of Ovarian Carcinoma Cells

The aim of this study was to analyze the biological role of different transforming growth factor-β (TGFβ) receptor splice variants in ovarian carcinoma (OC). Specific receptor variant knockouts (KO) were prepared using the CRISPR/Cas9 genome editing system in two OC cell lines, TβRI variant 1 (TβRIv1) KO in ES-2 cells and TβRII variant 1 (TβRIIv1) KO in OVCAR-8 cells. Control and KO cells were compared by proteomic analysis, functional tests, analysis of epithelial–mesenchymal transition (EMT) drivers, and Western blot of signaling proteins. Proteomic analysis revealed significant changes in protein pathways in the KO cells. TβRIv1 KO resulted in a significant reduction in both cellular motility and invasion, while TβRIIv1 KO significantly reduced cellular motility and increased Reactive Oxygen Species (ROS) production. Both receptor variant KOs reduced MET protein levels. Of the EMT drivers, a significant decrease in TWIST protein expression, and increase in SNAIL protein and MALAT1 mRNA levels were observed in the TβRIIv1 KO compared to control. A significant decrease in JNK1 and JNK2 activation was found in the TβRIv1 KO compared to control cells. These findings provide new insight regarding the biological role of the TGFβ receptor variants in the biology and potentially the progression of OC.