Miracle-dz/UniFAR-FTUs huggingface dataset:
An overview of rational design of mRNA-based therapeutics and vaccines

ABSTRACT Introduction Messenger RNA (mRNA)-based therapeutics and vaccines have emerged as a disruptive new drug class for various applications, including regenerative medicine, cancer treatment, and prophylactic and therapeutic vaccinations. Areas covered This review provides an update about the rational structure-based design of various formats of mRNA-based therapeutics. The authors discuss the recent advances in the mRNA modifications that have been used to enhance stability, promote translation efficiency and regulate immunogenicity for specific applications. Expert opinion Extensive research efforts have been made to optimize mRNA constructs and preparation procedures to unleash the full potential of mRNA-based therapeutics and vaccines. Sequence optimization (untranslated region and codon usage), chemical engineering of nucleotides and modified 5ʹcap, and optimization of in vitro transcription and mRNA purification protocols have overcome the major obstacles (instability, delivery, immunogenicity and safety) hindering the clinical applications of mRNA therapeutics and vaccines. The optimized design parameters should not be applied as default to different biological systems, but rather individually optimized for each mRNA sequence and intended application. Further advancement in the mRNA design and delivery technologies for achieving cell type- and organ site-specificity will broaden the scope and usefulness of this new class of drugs.
Gene co-expression network analysis identifies BEH3 as a stabilizer of secondary vascular development in Arabidopsis.

In plants, vascular stem cells located in the cambium continuously undergo self-renewal and differentiation during secondary growth. Recent advancements in cell sorting techniques have enabled access to the transcriptional regulatory framework of cambial cells. However, mechanisms underlying the robust control of vascular stem cells remain unclear. Here, we identified a new cambium-related regulatory module through co-expression network analysis using multiple transcriptome datasets obtained from an ectopic vascular cell transdifferentiation system using Arabidopsis cotyledons, VISUAL. The cambium gene list included a gene encoding the transcription factor BES1/BZR1 Homolog 3 (BEH3), whose homolog BES1 negatively affects vascular stem cell maintenance. Interestingly, null beh3 mutant alleles showed a large variation in their vascular size, indicating that BEH3 functions as a stabilizer of vascular stem cells. Genetic analysis revealed that BEH3 and BES1 perform opposite functions in the regulation of vascular stem cells and the differentiation of vascular cells in the context of the VISUAL system. At the biochemical level, BEH3 showed weak transcriptional repressor activity and functioned antagonistically to other BES/BZR members by competing for binding to the brassinosteroid (BR) response element. Furthermore, mathematical modeling suggested that the competitive relationship between BES/BZR homologs leads to the robust regulation of vascular stem cells.
Establishing minimally invasive cardiac surgery in a low-volume mitral surgery centre.

INTRODUCTION Despite early enthusiasm, minimally invasive cardiac surgery has had a low uptake compared with novel techniques in interventional cardiology. Steep learning curves from high-volume centres have deterred smaller units from engaging, even though low-volume centres undertake a large proportion of surgical interventions worldwide. We sought to identify the safety and experience of learning minimally invasive cardiac surgery after undertaking a structured fellowship at Blackpool Victoria Hospital, a low-volume centre. MATERIALS AND METHODS A retrospective analysis of outcomes for all consecutive minimally invasive cardiac surgery procedures performed via a right mini-thoracotomy at our institution between 2007 and 2017 was undertaken. Clinical outcomes included death, conversion to sternotomy, stroke, renal failure and other organ support. Cardiopulmonary bypass, aortic cross-clamp times and learning cumulative sum sequential probability method curves were also assessed to determine how safely the procedure was adopted. RESULTS A total of 316 patients were operated on for mitral, tricuspid, atrial fibrillation, septal defects or other conditions. The mean logistic European System for Cardiac Operative Risk Evaluation score was 7.0 (± 8.5). Conversion to sternotomy occurred in 12 patients (3.8%) and in-hospital mortality was 7 (2.2%). None of the converted patients died. The learning curves showed an accelerated process of adoption, similar to reference figures from a high-volume German centre. DISCUSSION It is possible for low-volume cardiac surgical centres to undertake minimally invasive surgical programmes with good outcomes and short learning curves. Despite technical complexities, with a team approach, the learning curve can be navigated safely.
Unraveling the antitrypanosomal mechanism of benznidazole and related 2‐nitroimidazoles: From prodrug activation to DNA damage

Nitroheterocycles represent an important class of compound used to treat trypanosomiasis. They often function as prodrugs and can undergo type I nitroreductase (NTR1)‐mediated activation before promoting their antiparasitic activities although the nature of these downstream effects has yet to be determined. Here, we show that in an NTR1‐dependent process, benznidazole promotes DNA damage in the nuclear genome of Trypanosoma brucei, providing the first direct link between activation of this prodrug and a downstream trypanocidal mechanism. Phenotypic and protein expression studies revealed that components of the trypanosome’s homologous recombination (HR) repair pathway (TbMRE11, γH2A, TbRAD51) cooperate to resolve the benznidazole‐induced damage, indicating that the prodrug‐induced lesions are most likely double stand DNA breaks, while the sequence/recruitment kinetics of these factors parallels that in other eukaryotes HR systems. When extended to other NTR1‐activated 2‐nitroimidazoles, some were shown to promote DNA damage. Intriguingly, the lesions induced by these required TbMRE11 and TbCSB activities to fix leading us to postulate that TbCSB may operate in systems other than the transcription‐coupled nucleotide excision repair pathway. Understanding how existing trypanosomal drugs work will aid future drug design and help unlock novel reactions/pathways that could be exploited as targets for therapeutic intervention.
Age-based stereotype threat: a scoping review of stereotype priming techniques and their effects on the aging process

Abstract Objectives: In the current study, we reviewed and classified the different experimental methods reported in the literature to induce age-base stereotype threat in older adults, providing a comprehensive view of the methodologies present in the literature to date. Method: The current study has been developed as a literature scoping review. The PubMed, PsycINFO, Scopus, ISI Web of Science, and CINAHL database were searched. With this approach, we assessed developments in experimental age-based stereotype manipulations in the last decades. Results: 26 articles were considered for this scoping review. Through a thematic analysis, we classified the papers into three broad categories based on the priming technique addressed: manipulation by instructions, manipulation by tests and, manipulation by mental imagery. Conclusion: Our results seem to suggest how manipulations by instructions appeared to be more largely used and capable of producing more clear performance variations on cognitive, memory, and physical tasks. Age-related stereotypes showed potentially stronger effects when they are negative, implicit, and temporally closer to the test of performance.
Electrical neuromodulation in bladder dysfunction: Mapping the state‐of‐the‐art with bibliometric analysis of field and top 100 cited articles

Electrical neuromodulation of bladder function has been extensively investigated in the literature. To date, there has been no characterization of the field, and there is a lack of bibliometric literature to guide future studies. We directed this scientometric analysis to characterize the distribution, characteristics and relationships of the field, with subanalysis of top 100 articles.
Recognition and Repair of Oxidatively Generated DNA Lesions in Plasmid DNA by a Facilitated Diffusion Mechanism.

The oxidatively generated genotoxic spiroiminodihydantoin (Sp) lesions are well-known substrates of base excision repair (BER) pathway initiated by the bifunctional DNA glycosylase NEIL1. In this work we reported that the excision kinetics of the single Sp lesions site-specifically embedded in the covalently closed circular DNA plasmids (contour length 2686 base pairs) by NEIL1 are biphasic under single-turnover conditions ([NEIL1]>>[SpDNApl]) in contrast to monophasic excision kinetics of the same lesions embedded in147-mer Sp-modified DNA duplexes. Under conditions of a large excess of plasmid DNA base pairs over NEIL1 molecules, the kinetics of excision of Sp lesions are biphasic in nature, exhibiting an initial burst phase, followed by a slower rate of formation of excision products The burst phase is associated with NEIL1-DNA plasmid complexes, while the slow kinetic phase is attributed to the dissociation of non-specific NEIL1-DNA complexes. The amplitude of the burst phase is limited in amplitude because of the competing non-specific binding of NEIL1 to unmodified DNA sequences flanking the lesion. A numerical analysis of the incision kinetics yielded a value of φ » 0.03 for the fraction of NEIL1 encounters with plasmid molecules that result in the excision of the Sp lesion, and a characteristic dissociation time of non-specific NEIL1-DNA complexes (τ-ns » 8 s). The estimated average DNA translocation distance of NEIL1 is ~80 base pairs. This estimate suggests that facilitated diffusion enhances the probability that NEIL1 can locate its substrate embedded in an excess of unmodified plasmid DNA nucleotides by a factor of ~ 10.
Relationship between fine particulate air pollution and hospital admissions for depression: a case-crossover study in Taipei

ABSTRACT There are few apparent studies regarding the association between fine particulate matter (PM2.5) air pollution and development of depression. Data obtained from epidemiological studies are inconsistent and controversial. The aim of this case-crossover study was to examine the association between short-term exposure to PM2.5 alone and in combination with other pollutants and frequency of hospitalizations for depression from 2009 to 2013 in Taipei, Taiwan. In the single pollutant model without adjustment for other pollutants, 17% and 4% increase in admissions attributed to depression correlated with interquartile range (IQR) rise in PM2.5 levels was noted on warm and cool days, respectively. Data were also analyzed using two-pollutant models and it was found that on warm days, the association continued to be significant after including one of the following pollutants: sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3) or carbon monoxide (CO). On cool days, the significance was lost. In conclusion, the relationship between ambient outdoor PM2.5 exposure and rates of hospitalization for depression appeared to be temperature dependent in Taipei. Further research is needed to verify these observations as well as to distinguish the relative contributions of PM2.5 and temperature to development for hospital admissions for depression.
A pilot study of transdermal gabapentin in cats

Abstract Background Clinical use of gabapentin has increased; transdermal delivery in cats is incompletely studied. Objective To evaluate if gabapentin permeates feline skin in vitro and in vivo and to determine if pain scores improve after administration. Animals In vitro: cadaver skin from 6 cats; phase 1: 8 young, healthy client‐owned cats; phase 2: 15 client‐owned geriatric cats. Methods In vitro, gabapentin applied every q12h to ear or cervical skin in diffusion cells. Samples collected at 0, 2, 4, 12, and 24 hours after application. Phase 1: Cats assigned to 1 of 4 groups: 5 mg/kg or 10 mg/kg applied q8h for 5 days to either ear or cervical skin. Serum samples collected predose, and after 1 and 5 days. Phase 2: 10 mg/kg applied q8h for 5 days. Two validated pain scores recorded predose, and after days 1, 5, and 8. Serum samples collected predose, and after days 1 and 5. Samples were frozen at −80°C for concentration analysis utilizing a validated high‐performance liquid chromatography mass‐spectrometry method. Results Gabapentin was identified in all samples. Significant differences in gabapentin concentrations were observed from day 1 to day 5 (P < .02) and in pain scores from predose to day 5 (P < .05) and day 1 to day 5 (P < .05). No differences in pain scores were observed from predose to day 8 (P = .3). Conclusions and Clinical Relevance Gabapentin in a transdermal base penetrates feline skin in vitro, is absorbed systemically in cats, and may help decrease pain scores.
A novel injury paradigm in the central nervous system of adult Drosophila: molecular, cellular and functional aspects

ABSTRACT The mammalian central nervous system (CNS) exhibits limited regenerative capacity and the mechanisms that mediate its regeneration are not fully understood. Here, we present a novel experimental design to damage the CNS by using a contusion injury paradigm. The design of this protocol allows the study of long-term and short-term cellular responses, including those of the CNS and the immune system, and of any implications regarding functional recovery. We demonstrate for the first time that adult Drosophila melanogaster glial cells undergo spontaneous functional recovery following crush injury. This crush injury leads to an intermediate level of functional recovery after damage, which is ideal to screen for genes that facilitate or prevent the regeneration process. Here, we validate this model and analyse the immune responses of glial cells as a central regulator of functional regeneration. Additionally, we demonstrate that glial cells and macrophages contribute to functional regeneration through mechanisms involving the Jun N-terminal kinase (JNK) pathway and the Drosophila protein Draper (Drpr), characteristic of other neural injury paradigms. We show that macrophages are recruited to the injury site and are required for functional recovery. Further, we show that the proteins Grindelwald and Drpr in Drosophila glial cells mediate activation of JNK, and that expression of drpr is dependent on JNK activation. Finally, we link neuron-glial communication and the requirement of neuronal vesicular transport to regulation of the JNK pathway and functional recovery. This article has an associated First Person interview with the first author of the paper.
Multimodal guided wave inversion for arterial stiffness: methodology and validation in phantoms

Arterial stiffness is an important biomarker for many cardiovascular diseases. Shear wave elastography is a recent technique aimed at estimating local arterial stiffness using guided wave inversion (GWI), i.e. matching the computed and measured wave dispersion. This paper develops and validates a new GWI approach by synthesizing various recent observations and algorithms: (a) refinements to signal processing to obtain more accurate experimental dispersion curves; (b) an efficient forward model to compute theoretical dispersion curves for immersed, incompressible cylindrical waveguides; (c) an optimization framework based on the recent observation that the measured dispersion curve is multimodal, i.e. it matches for not one but two different wave modes in two different frequency ranges. The resulting inversion approach is validated using extensive experimental data from rubber tube phantoms, not only for modulus estimation but also to simultaneously estimate modulus and wall thickness. The observations indicate that the modulus estimates are best performed with the information on wall thickness. The approach, which takes less than half a minute to run, is shown to be accurate, with the modulus estimated with less than 4% error for 70% of the experiments.
A time-resolved experimental-mathematical model for predicting the response of glioma cells to single-dose radiation therapy.

PURPOSE To develop and validate a mechanism-based, mathematical model that characterizes 9L and C6 glioma cells' temporal response to single-dose radiation therapy in vitro by explicitly incorporating time-dependent biological interactions with radiation. METHODS We employed time-resolved microscopy to track the confluence of 9L and C6 glioma cells receiving radiation doses of 0, 2, 4, 6, 8, 10, 12, 14 or 16 Gy. DNA repair kinetics are measured by γH2AX expression via flow cytometry. The microscopy data (814 replicates for 9L, 540 replicates for C6 at various seeding densities receiving doses above) were divided into training (75%) and validation (25%) sets. A mechanistic model was developed, and model parameters were calibrated to the training data. The model was then used to predict the temporal dynamics of the validation set given the known initial confluences and doses. The predictions were compared to the corresponding dynamic microscopy data. RESULTS For 9L, we obtained an average (± standard deviation, SD) Pearson correlation coefficient between the predicted and measured confluence of 0.87 ± 0.16, and an average (±SD) concordance correlation coefficient of 0.72 ± 0.28. For C6, we obtained an average (±SD) Pearson correlation coefficient of 0.90 ± 0.17, and an average (±SD) concordance correlation coefficient of 0.71 ± 0.24. CONCLUSION The proposed model can effectively predict the temporal development of 9L and C6 glioma cells in response to a range of single-fraction radiation doses. By developing a mechanism-based, mathematical model that can be populated with time-resolved data, we provide an experimental-mathematical framework that allows for quantitative investigation of cells' temporal response to radiation. Our approach provides two key advances: (i) a time-resolved, dynamic death rate with a clear biological interpretation, and (ii) accurate predictions over a wide range of cell seeding densities and radiation doses.
Temperature effects on forest understory plants in hedgerows: a combined warming and transplant experiment.

BACKGROUND AND AIMS Hedgerows have been shown to improve forest connectivity, leading to an increased probability of species to track the shifting bioclimatic envelopes. However, it is still unknown how species in hedgerows respond to temperature changes, and whether effects differ compared to those in nearby forests. We aimed to elucidate how ongoing changes in the climate system will affect the efficiency of hedgerows to support forest plant persistence and migration in agricultural landscapes. METHODS Here we report results from the first warming experiment in hedgerows. We combined reciprocal transplantation of plants along an 860-km latitudinal transect with experimental warming to assess the effects of temperature on vegetative growth and reproduction of two common forest herbs (Anemone nemorosa and Geum urbanum) in hedgerows vs forests. KEY RESULTS Both species grew taller and produced more biomass in forests than in hedgerows, most likely due to a higher competition with ruderals and graminoids in hedgerows. Adult plant performance of both species generally benefitted from experimental warming, despite lower survival of A. nemorosa in heated plots. Transplantation affected the species differently: A. nemorosa plants grew taller, produced more biomass and showed higher survival when transplanted at their home site, indicating local adaptation, while individuals of G. urbanum showed larger height, biomass, reproductive output and survival when transplanted northwards, likely owing to the higher light availability associated with increasing photoperiod during the growing season. CONCLUSIONS These findings demonstrate that some forest herbs can show phenotypic plasticity to warming temperatures, potentially increasing their ability to benefit from hedgerows as ecological corridors. Our study thus provides novel insights into the impacts of climate change on understory plant community dynamics in hedgerows, and how rising temperature can influence the efficiency of these corridors to assist forest species' persistence and colonization within and beyond their current distribution range.
Case history on Epstein-Barr Virus-associated smooth muscle tumor (EBV-SMT) of cranio-cervical junction in an immunocompetent patient

Abstract Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) is a rare mesenchymal tumor that almost exclusively occurs in immunocompromised hosts. Here, we report a 75-year-old Taiwanese woman without definite immune-deficient history presenting with progressive occipital neuralgia, low cranial nerve deficits (CN9-12) and cervical (C1–C5) radiculopathy. Magnetic resonance imaging revealed a 4.5*4.0*6.7 cm infiltrating mass occupying posterior skull base and C1–C2 vertebra and C1–5 epidural extension with bone destruction and vertebral artery (VA) encasement. There was also a synchronous 2.7 cm tonsillar tumor. A two-stage operation for cranio-cervical tumor excision and stabilization was performed. Tumor was confirmed directly arising from VA intraoperatively. Pathology reported a spindle cell neoplasm and the diagnosis of EBV-SMT was confirmed by EBER (EBV-encoded small RNA) in situ hybridization. An immune survey and reconstruction should be conducted for patient with EBV-SMT. A near-total resection of tumor may be beneficial for local control, however, the role of surgical resection in treating CNS EBV-SMT remains to be determined.
Recent development in zebrafish model for bioactivity and safety evaluation of natural products

Abstract The zebrafish is a species of freshwater fish, popular in aquariums and laboratories. Several advantageous features have facilitated zebrafish to be extensively utilized as a valuable vertebrate model in the lab. It has been well-recognized that natural products possess multiple health benefits for humans. With the increasing demand for natural products in the development of functional foods, nutraceuticals, and natural cosmetics, the zebrafish has emerged as an unprecedented tool for rapidly and economically screening and identifying safe and effective substances from natural products. This review first summarized the key factors for the management of zebrafish in the laboratory, followed by highlighting the current progress on the establishment and applications of zebrafish models in the bioactivity evaluation of natural products. In addition, the zebrafish models used for assessing the potential toxicity or health risks of natural products were involved as well. Overall, this review indicates that zebrafish are promising animal models for the bioactivity and safety evaluation of natural products, and zebrafish models can accelerate the discovery of novel natural products with potential health functions.