Miracle-dz/UniFAR-FTUs huggingface dataset:
Survey of Clinical Translation of Cancer Nanomedicines-Lessons Learned from Successes and Failures.

In 1995, the year the first cancer nanomedicine, Doxil, was approved by the Food and Drug Administration (FDA), only 23 manuscripts appeared in a PubMed search for "nanoparticles for cancer" keywords. Now, over 25 000 manuscripts can be found using those same keywords, yet only 15 nanoparticle-based cancer nanomedicines are approved globally. Based on the clinicaltrials.gov database, a total of 75 cancer nanomedicines are under clinical investigation involving 190 clinical trials summarized here. In this Account, we focus on cancer nanomedicines that have been approved or reached clinical trials to understand this high attrition rate. We classify the various nanomedicines, summarize their clinical outcomes, and discuss possible reasons for product failures and discontinuation of product development efforts. Among ongoing and completed clinical trials, 91 (48 completed) are phase 1, 78 (59 completed) phase 2, and 21 (11 completed) phase 3. The success rate of phase 1 trials has been high-roughly 94%. Of those phase 1 trials with identified outcomes, 45 showed positive safety and efficacy results, with only one negative result (low efficacy) and two terminated due to adverse reactions. In some cases, findings from these trials have not only shown improved pharmacokinetics, but also avid drug accumulation within tumor tissues among active-targeting nanoparticles, including BIND-014, CALAA-01, and SGT-94. However, the success rate drops to ∼48% among completed phase 2 trials with identified outcomes (31 positive, 15 negative, and 4 terminated for toxicity or poor efficacy). A majority of failures in phase 2 trials were due to poor efficacy (15 of 19), rather than toxicity (4 of 19). Unfortunately, the success rate for phase 3 trials slumps to a mere ∼14%, with failures stemming from lack of efficacy. Although the chance of success for cancer nanomedicines starting from the proof-of-concept idea in the laboratory to valuable marketed product may seem daunting, we should not be discouraged. Despite low success rates, funding from the government, foundations, and research organizations are still strong-an estimated > $130 M spent by the National Institutes of Health (NIH) on R01s focused on nanomedicine in 2018 alone. In addition, the NIH created several special initiatives/programs, such as the National Cancer Institute (NCI) Alliance, to facilitate clinical translation of nanomedicines. Companies developing cancer nanomedicines raised diverse ranges of funds from venture capital, capital markets, and industry partnerships. In some cases, the development efforts resulted in regulatory approvals of cancer nanomedicines. In other cases, clinical failures and market pressure from improving standard of care products resulted in product terminations and business liquidation. Yet, recent approvals of nanomedicine products for orphan cancers and continuing development of nanoparticle based drugs for immune-oncology applications fuel continuing industrial and academic interest in cancer nanomedicines.
A Survey of Security Services, Attacks, and Applications for Vehicular Ad Hoc Networks (VANETs)

Vehicular ad hoc networks (VANETs) are an emerging type of mobile ad hoc networks (MANETs) with robust applications in intelligent traffic management systems. VANET has drawn significant attention from the wireless communication research community and has become one of the most prominent research fields in intelligent transportation system (ITS) because of the potential to provide road safety and precautionary measures for the drivers and passengers. In this survey, we discussed the basic overview of the VANET from the architecture, communication methods, standards, characteristics, and VANET security services. Second, we presented the threats and attacks and the recent state-of-the-art methods of the VANET security services. Then, we comprehensively reviewed the authentication schemes that can protect vehicular networks from malicious nodes and fake messages. Third, we discussed the latest simulation tools and the performance of the authentication schemes in terms of simulation tools, which was followed by the VANET applications. Lastly, we identified the open research challenges and gave future research directions. In sum, this survey fills the gap of existing surveys and summarizes the latest research development. All the security attacks in VANETs and their related countermeasures are discussed with respect to ensuring secure communication. The authentication schemes and comprehensive applications were introduced and analyzed in detail. In addition, open research challenges and future research directions were issued.
Molecular characterization and transcription analysis of DNA methyltransferase genes in tomato (Solanum lycopersicum)

Abstract DNA methylation plays an important role in plant growth and development, gene expression regulation, and maintenance of genome stability. However, only little information regarding stress-related DNA methyltransferases (MTases) genes is available in tomato. Here, we report the analysis of nine tomato MTases, which were categorized into four known subfamilies. Structural analysis suggested their DNA methylase domains are highly conserved, whereas the N-terminals are divergent. Tissue-specific analysis of these MTase genes revealed that SlCMT2, SlCMT3, and SlDRM5 were expressed higher in young leaves, while SlMET1, SlCMT4, SlDRM7, and SlDRM8 were highly expressed in immature green fruit, and their expression declined continuously with further fruit development. In contrast, SlMETL was highly expressed in ripening fruit and displayed an up-regulated tendency during fruit development. In addition, the expression of SlMET1 in the ripening of mutant rin and Nr tomatoes is significantly higher compared to wild-type tomato, suggesting that SlMET1 was negatively regulated by the ethylene signal and ripening regulator MADS-RIN. Furthermore, expression analysis under abiotic stresses revealed that these MTase genes were stress-responsive and may function diversely in different stress conditions. Overall, our results provide valuable information for exploring the regulation of tomato fruit ripening and response to abiotic stress through DNA methylation.
Brian 2, an intuitive and efficient neural simulator

Brian 2 allows scientists to simply and efficiently simulate spiking neural network models. These models can feature novel dynamical equations, their interactions with the environment, and experimental protocols. To preserve high performance when defining new models, most simulators offer two options: low-level programming or description languages. The first option requires expertise, is prone to errors, and is problematic for reproducibility. The second option cannot describe all aspects of a computational experiment, such as the potentially complex logic of a stimulation protocol. Brian addresses these issues using runtime code generation. Scientists write code with simple and concise high-level descriptions, and Brian transforms them into efficient low-level code that can run interleaved with their code. We illustrate this with several challenging examples: a plastic model of the pyloric network, a closed-loop sensorimotor model, a programmatic exploration of a neuron model, and an auditory model with real-time input.
Human papillomavirus vaccination in immigrants and descendants of immigrants in Denmark

Supplemental Digital Content is available in the text. Objective In Denmark, human papillomavirus (HPV) vaccination has been offered at age of 12 to girls born in 1996 and later. In this cohort study, we examined routine HPV vaccination uptake in immigrants and descendants from different countries and regions compared with native Danes, including the influence of socioeconomic characteristics and potential changes in uptake by birth cohort. Methods In nationwide registers, we identified all girls born in 1996–2003 (n = 260 251) and obtained information on country of origin, HPV vaccinations and parents’ income and employment. Vaccination was defined as receiving ≥1 dose within 2 years after eligibility for routine vaccination. Odds ratios (ORs) were estimated by logistic regression separately for birth cohorts 1996–2000 and 2001–2003. Results Uptake in immigrants and descendants varied by country and region of origin. Overall, immigrants had lower uptake than native Danes, in birth cohorts 1996–2000 [79% vs. 93%, OR = 0.31; 95% confidence interval (CI), 0.29–0.34] and 2001–2003 (63% vs. 73%, OR = 0.60; 95% CI, 0.54–0.66). Descendants had lower uptake than native Danes in cohorts 1996–2000 (89% vs. 93%, OR = 0.65; 95% CI, 0.60–0.68), but higher uptake in cohorts 2001–2003 (76% vs. 73%, OR = 1.15; 95% CI, 1.08–1.21). Most associations were attenuated, but not entirely explained, when adjusting for socioeconomic characteristics. Conclusion HPV vaccination uptake varied by country and region. Most immigrants had lower uptake than native Danes, and in most groups, this was not fully explained by socioeconomic differences. Patterns in descendants were mixed. Interventions to increase uptake should be tailored to specific groups of immigrants/descendants.
Attribute-Driven Granular Model for EMG-Based Pinch and Fingertip Force Grand Recognition

Fine multifunctional prosthetic hand manipulation requires precise control on the pinch-type and the corresponding force, and it is a challenge to decode both aspects from myoelectric signals. This paper proposes an attribute-driven granular model (AGrM) under a machine-learning scheme to solve this problem. The model utilizes the additionally captured attribute as the latent variable for a supervised granulation procedure. It was fulfilled for EMG-based pinch-type classification and the fingertip force grand prediction. In the experiments, 16 channels of surface electromyographic signals (i.e., main attribute) and continuous fingertip force (i.e., subattribute) were simultaneously collected while subjects performing eight types of hand pinches. The use of AGrM improved the pinch-type recognition accuracy to around 97.2% by 1.8% when constructing eight granules for each grasping type and received more than 90% force grand prediction accuracy at any granular level greater than six. Further, sensitivity analysis verified its robustness with respect to different channel combination and interferences. In comparison with other clustering-based granulation methods, AGrM achieved comparable pinch recognition accuracy but was of lowest computational cost and highest force grand prediction accuracy.
The Cisplatin-Derived Increase of Mitochondrial Reactive Oxygen Species Enhances the Effectiveness of Photodynamic Therapy via Transporter Regulation

Photodynamic therapy (PDT) is a cancer treatment involving the generation of reactive oxygen species (ROS) by laser irradiation of porphyrins that accumulate in cancer tissues. 5-aminolevulinic acid (ALA), a porphyrin precursor, is often used as a photosensitizer. ALA is imported into cells via peptide transporter 1 (PEPT1), and porphyrin is exported via ATP-binding cassette member 2 of subfamily G (ABCG2). Thus, cancer cell-specific porphyrin accumulation involves regulation of both transporters to enhance the ALA-PDT effect. We reported previously that mitochondrial ROS (mitROS) upregulated PEPT1 expression and downregulated ABCG2 expression. Therefore, we propose that increasing mitROS production will enhance ALA-PDT cytotoxicity. Cisplatin is a chemotherapeutic drug that induces intracellular ROS generation. In this study, we investigated whether cisplatin-increased mitROS production in gastric cancer cell lines (RGK36 and RGK45) enhanced the cytotoxicity of ALA-PDT by regulation the expression of both PEPT1 and ABCG2. The results showed that cisplatin increased intracellular mitROS production in cancer but not normal cells (RGM1). PEPT1 was upregulated and ABCG2 downregulated in cancer cells treated with cisplatin. Moreover, intracellular porphyrin accumulation and ALA-PDT cytotoxicity increased. We conclude that cisplatin treatment increases the intracellular mitROS concentration and upregulates PEPT1 and downregulates ABCG2 expression.
Rheumatoid Arthritis Treatment. A Back to the Drawing Board Project or High Expectations for Low Unmet Needs?

Despite the significant progress in Rheumatoid Arthritis (RA) therapeutics, there are several reports in the literature claiming that the size of unmet needs in RA is large. In the era before biologics, there was indeed a significant number of patients who did not achieve low disease activity (LDA) or disease remission due to limited therapeutic choices in the doctors’ armamentarium. Treatment wise, great progress has been achieved over the last decades with the discovery and introduction in therapeutics of new molecules, such as the biological (b) disease-modifying anti-rheumatic drugs (DMARDs), and the targeted synthetic (ts) DMARDs. Today, with such a plethora of conventional synthetic (cs) DMARDs, tsDMARDs, and bDMARDs, why are we unable to successfully treat RA patients? What is wrong? However, a new drug for RA does not mean it is necessary to switch to a new treatment. It is very easy to change and switch therapies when the patient complains about pain and stiffness. In this setting, it is obligatory to rule out other comorbidities and disorders that may be the cause of the pain first. Thus, clinicians must have a deep knowledge of the drug therapy and be able to adjust the treatment when needed. A minute clinical examination must be carried out on every visit with close monitoring of the patient. A treat-to-target (T2T) approach and the application of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) recommendations and strategies should minimize the unmet needs.
DPCSpell: A Transformer-based Detector-Purificator-Corrector Framework for Spelling Error Correction of Bangla and Resource Scarce Indic Languages

Spelling error correction is the task of identifying and rectifying misspelled words in texts. It is a potential and active research topic in Natural Language Processing because of numerous applications in human language understanding. The phonetically or visually similar yet semantically distinct characters make it an arduous task in any language. Earlier efforts on spelling error correction in Bangla and resource-scarce Indic languages focused on rule-based, statistical, and machine learning-based methods which we found rather ineﬀicient. In particular, machine learning-based approaches, which exhibit superior performance to rule-based and statistical methods, are ineffec-tive as they correct each character regardless of its appropriateness. In this work, we propose a novel detector-purificator-corrector framework based on denoising transformers by addressing previous issues. Moreover, we present a method for large-scale corpus creation from scratch which in turn resolves the resource limitation problem of any left-to-right scripted language. The empirical outcomes demonstrate the effectiveness of our approach that outperforms previous state-of-the-art methods by a significant margin for Bangla spelling error correction. The models and corpus are publicly available at https://tinyurl.com/DPCSpell .
Are Moderate and Vigorous Leisure-Time Physical Activity Associated With Musculoskeletal Pain? A Cross-Sectional Study Among 981 Physical Therapists

Purpose: Musculoskeletal pain (MP) is common among workers, especially for health-care professionals. Paradoxically, many of those rehabilitating patients for pain—that is, physical therapists (PTs)—also have pain. Adequate levels of physical activity are recommended for cardiovascular and musculoskeletal health. However, the association between physical activity and MP among PTs remains unknown. This study aims to determine the association between moderate and vigorous leisure-time physical activity levels and MP in PTs. Design: Cross-sectional study. Setting: Workplace. Participants: Nine hundred eighty-one PTs. Measures: Data on MP and leisure-time physical activity were collected using an online survey. Analysis: The odds for having lower level of MP as a function of physical activity were estimated using binary logistic regression controlled for various confounders. Results: Performing ≥75 min/week of vigorous leisure-time physical activity increased the odds of experiencing lower levels of neck–shoulder pain (odds ratio = 1.43, 95% confidence interval, 1.05-1.94). No association was found neither between vigorous nor between moderate leisure-time physical activity and MP in the arm-hand or back. Conclusion: Performing ≥75 min/week of vigorous leisure-time physical activity is associated with lower levels of MP in neck and shoulders among PTs. No associations were found between vigorous or moderate leisure-time physical activity and MP in arm-hand and back.
Dietary dilemmas over fats and cardiometabolic risk

CVD remains the greatest cause of death globally, and with the escalating prevalence of metabolic diseases, including type-2 diabetes, CVD mortality is predicted to rise. While the replacement of SFA has been the cornerstone of effective dietary recommendations to decrease CVD risk since the 1980s, the validity of these recommendations have been recently challenged. A review of evidence for the impact of SFA reduction revealed no effect on CVD mortality, but a significant reduction in risk of CVD events (7–17%). The greatest effect was found when SFA were substituted with PUFA, resulting in 27% risk reduction in CVD events, with no effect of substitution with carbohydrate or protein. There was insufficient evidence from randomised controlled trials to conclude upon the impact of SFA replacement with MUFA on CVD and metabolic outcomes. However, there was high-quality evidence that reducing SFA lowered serum total, and specifically LDL-cholesterol, a key risk factor for CVD, with greatest benefits achieved by replacing SFA with unsaturated fats. The exchange of SFA with either PUFA or MUFA, also produced favourable effects on markers of glycaemia, reducing HbA1c, a long-term marker of glycaemic control. In conclusion, the totality of evidence supports lowering SFA intake and replacement with unsaturated fats to reduce the risk of CVD events, and to a lesser extent, cardiometabolic risk factors, which is consistent with current dietary guidelines.
A large-scale analysis of task switching practice effects across the lifespan

Significance In modern life, we engage with many sources of information concurrently. To do this, we must continuously switch between different tasks, but this comes at a cost to performance, especially in older adults. Using a large dataset from an online cognitive-training platform, we develop a computational model of task switching that defines distinct latent measures of activating the relevant task, deactivating the irrelevant task, and making a decision. This model shows that, although task practice can improve task-switching performance, persistent costs remain even after extensive practice, and more so in older adults. We show that, with extensive task practice, older people can become functionally similar to less-practiced younger people. An important feature of human cognition is the ability to flexibly and efficiently adapt behavior in response to continuously changing contextual demands. We leverage a large-scale dataset from Lumosity, an online cognitive-training platform, to investigate how cognitive processes involved in cued switching between tasks are affected by level of task practice across the adult lifespan. We develop a computational account of task switching that specifies the temporal dynamics of activating task-relevant representations and inhibiting task-irrelevant representations and how they vary with extended task practice across a number of age groups. Practice modulates the level of activation of the task-relevant representation and improves the rate at which this information becomes available, but has little effect on the task-irrelevant representation. While long-term practice improves performance across all age groups, it has a greater effect on older adults. Indeed, extensive task practice can make older individuals functionally similar to less-practiced younger individuals, especially for cognitive measures that focus on the rate at which task-relevant information becomes available.
Effectiveness of daily rinsing of alfalfa sprouts with aqueous chlorine dioxide and ozonated water on the growth of Listeria monocytogenes during sprouting

Alfalfa sprouts have been implicated in multiple foodborne disease outbreaks. This study evaluated the growth of Listeria monocytogenes during sprouting of alfalfa seeds and the effectiveness of daily chlorine dioxide & ozone rinsing in controlling the growth. Alfalfa seeds inoculated with L. monocytogenes were sprouted for 5 days (25°C) with a daily aqueous ClO2 (3 ppm, 10 min) or ozone water (2 ppm, 5 min) rinse. Neither treatment significantly reduced the growth of L. monocytogenes on sprouting alfalfa seeds. The initial level of L. monocytogenes was 3·44 ± 0·27, which increased to c. 7·0 log CFU per g following 3 days of sprouting. There was no significant difference in the bacterial population between the treatment schemes. Bacterial distribution in roots (7·63 ± 0·511 log CFU per g), stems (7·51 ± 0·511 log CFU per g) and leaves (7·41 ± 0·511 log CFU per g) were similar after 5 days. Spent sanitizers had significantly lower levels of bacterial populations compared to the spent distilled water control. The results indicated that sprouting process provides a favourable condition for the growth of L. monocytogenes and the sanitizer treatment alone may not be able to reduce food safety risks.
Micronutrients, immunological parameters, and dengue virus infection in coastal Ecuador: A nested case-control study in an infectious disease surveillance program.

BACKGROUND Micronutrients are known to modulate host immunity and there is limited literature on this association in the context of dengue virus infection (DENV). METHODS Using a nested case-control design in a surveillance program, we measured anthropometry; nutritional biomarkers including serum ferritin, soluble transferrin receptor, retinol-binding protein (RBP), 25-hydroxy vitamin D, folate, and vitamin B12; and a panel of immune response markers and compared these measures across four illness categories: healthy control, non-febrile DENV, other febrile illness (OFI), and apparent DENV using multivariate polytomous logistic regression models. RESULTS Among 142 participants, serum ferritin (ng/mL) was associated with apparent DENV compared to healthy controls (OR 2.66; CI 1.53, 4.62; p=0.001), and RBP concentrations (µmol/L) were associated with apparent DENV (OR 0.03; CI 0.00, 0.30; p=0.003) and OFI (OR 0.02; CI 0.00, 0.24; p=0.003). In a subset of 71 participants, IL-15 levels (MFI) were positively associated with apparent DENV (OR 1.09; CI 1.03, 1.14; p=0.001) and negatively associated with non-febrile DENV (OR 0.89; CI 0.80, 0.99; p=0.03) compared to healthy controls. CONCLUSIONS After adjusting for the acute phase response, serum ferritin and RBP concentrations were associated with apparent DENV and may represent biomarkers of clinical importance in the context of dengue illness.