Miracle-dz/UniFAR-FTUs huggingface dataset:
Current Perspective: 3D Spheroid Models Utilizing Human-Based Cells for Investigating Metabolism-Dependent Drug-Induced Liver Injury

Drug-induced liver injury (DILI) remains a leading cause for the withdrawal of approved drugs. This has significant financial implications for pharmaceutical companies, places increasing strain on global health services, and causes harm to patients. For these reasons, it is essential that in-vitro liver models are capable of detecting DILI-positive compounds and their underlying mechanisms, prior to their approval and administration to patients or volunteers in clinical trials. Metabolism-dependent DILI is an important mechanism of drug-induced toxicity, which often involves the CYP450 family of enzymes, and is associated with the production of a chemically reactive metabolite and/or inefficient removal and accumulation of potentially toxic compounds. Unfortunately, many of the traditional in-vitro liver models fall short of their in-vivo counterparts, failing to recapitulate the mature hepatocyte phenotype, becoming metabolically incompetent, and lacking the longevity to investigate and detect metabolism-dependent DILI and those associated with chronic and repeat dosing regimens. Nevertheless, evidence is gathering to indicate that growing cells in 3D formats can increase the complexity of these models, promoting a more mature-hepatocyte phenotype and increasing their longevity, in vitro. This review will discuss the use of 3D in vitro models, namely spheroids, organoids, and perfusion-based systems to establish suitable liver models to investigate metabolism-dependent DILI.
Discovering Music Relations with Sequential Attention

The element-wise attention mechanism has been widely used in modern sequence models for text and music. The original attention mechanism focuses on token-level similarity to determine the attention weights. However, these models have difﬁculty capturing sequence-level relations in music, including repetition, retrograde, and sequences. In this paper, we introduce a new attention module called the sequential attention (SeqAttn), which calculates attention weights based on the similarity between pairs of sub-sequences rather than individual tokens. We show that the module is more powerful at capturing sequence-level music relations than the original design. The module shows potential in both music relation discovery and music generation. 1
PCSK9 positively correlates with plasma sdLDL in community-dwelling population but not in diabetic participants after confounder adjustment

Abstract This study aimed to investigate the relationship between plasma proprotein convertase subtilisin kexin 9 (PCSK9) and small dense low-density lipoprptein (sdLDL) in diabetic and non-diabetic participants in a community-dwelling cohort. The plasma levels of PCSK9 and sdLDL were detected in 1766 participants (median age: 61.40 years; 733 males vs 1033 females; 383 diabetic vs 1383 non-diabetic patients) from the Pingguoyuan community of Beijing, China. Results showed that Pearson correlation analysis revealed a positive correlation between PCSK9 and sdLDL (r = 0.263, P < .001). Multiple linear regression analysis showed a significant positive correlation between plasma PCSK9 and sdLDL in the whole population study. sdLDL was used as the dependent variable, and the potential cofounders were adjusted. However, any independent relationship was not observed between circulating PCSK9 and sdLDL in the diabetic subpopulation (r = 0.269, P < .05, β = 9.591, P > .05). Thus, there is a positive correlation between plasma PCSK9 and sdLDL in a community-dwelling cohort, but not in type 2 diabetic subpopulation, after confounder adjustment.
Effects in Cancer Cells of the Recombinant l-Methionine Gamma-Lyase from Brevibacterium aurantiacum. Encapsulation in Human Erythrocytes for Sustained l-Methionine Elimination

Methionine deprivation induces growth arrest and death of cancer cells. To eliminate l-methionine we produced, purified, and characterized the recombinant pyridoxal 5′-phosphate (PLP)-dependent l-methionine γ-lyase (MGL) BL929 from the cheese-ripening Brevibacterium aurantiacum. Transformation of an Escherichia coli strain with the gene BL929 from B. aurantiacum optimized for E. coli expression led to production of the MGL-BL929. Elimination of l-methionine and cytotoxicity in vitro were assessed, and methylation-sensitive epigenetics was explored for changes resulting from exposure of cancer cells to the enzyme. A bioreactor was built by encapsulation of the protein in human erythrocytes to achieve sustained elimination of l-methionine in extracellular fluids. Catalysis was limited to α,γ-elimination of l-methionine and l-homocysteine. The enzyme had no activity on other sulfur-containing amino acids. Enzyme activity decreased in presence of serum albumin or plasma resulting from reduction of PLP availability. Elimination of l-methionine induced cytotoxicity on a vast panel of human cancer cell lines and spared normal cells. Exposure of colorectal carcinoma cells to the MGL-BL929 reduced methyl-CpG levels of hypermethylated gene promoters including that of CDKN2A, whose mRNA expression was increased, together with a decrease in global histone H3 dimethyl lysine 9. The MGL-erythrocyte bioreactor durably preserves enzyme activity in vitro and strongly eliminates l-methionine from medium.
Alterations and Correlations in Microbial Community and Metabolome Characteristics in Generalized Aggressive Periodontitis

This study aimed to characterize the microbial community and metabolic profiles in generalized aggressive periodontitis (AgP) using 16S ribosomal RNA (rRNA) gene high-throughput sequencing and gas chromatography-mass spectrometry (GC-MS). A total of 146 subgingival plaque samples and 50 gingival crevicular fluid (GCF) samples were collected from 24 patients with AgP and 10 periodontally healthy subjects (PH). Striking differences were observed in subgingival microbiome and GCF metabolomics between patients with AgP and PH, but not between samples with different probing depths (PDs). Metabolomics analysis combined with enrichment analysis showed that periodontitis significantly altered the concentration of compounds associated with biosynthesis of amino acids (e.g., alanine, leucine, isoleucine, and valine), galactose metabolism (e.g., myo-inositol, galactose, glucose, and hexitol), and pyrimidine metabolism (e.g., uracil, uridine, beta alanine, and thymine). Correlation analysis showed that the genera with significant difference between AgP and PH were usually significantly correlated with more metabolites, such as Aggregatibacter, Rothia, Peptostreptococcaceae_[XI][G-5], and Bacteroidaceae_[G-1]. While glucose and oxoproline had the most significant correlations with microorganisms. Our results revealed distinct microbial communities and metabolic profiles between AgP and PH. The significant correlation between microbial taxa and metabolites suggested the possible mechanisms for periodontitis. Our results also provided effective approaches for detecting periodontal disease and managing periodontitis.
A Comparative Study of the Innate Humoral Immune Response to Avian Influenza Virus in Wild and Domestic Mallards

Domestic mallards (Anas platyrhynchos domesticus) are traditionally used as a model to investigate infection dynamics and immune responses to low pathogenic avian influenza viruses (LPAIVs) in free-living mallards. However, it is unclear whether the immune response of domestic birds reflects the response of their free-living counterparts naturally exposed to these viruses. We investigated the extent to which the innate humoral immune response was similar among (i) wild-type domestic mallards in primary and secondary infection with LPAIV H4N6 in a laboratory setting (laboratory mallards), (ii) wild-type domestic mallards naturally exposed to LPAIVs in a semi-natural setting (sentinel mallards), and (iii) free-living mallards naturally exposed to LPAIVs. We quantified innate humoral immune function by measuring non-specific natural antibodies (agglutination), complement activity (lysis), and the acute phase protein haptoglobin. We demonstrate that complement activity in the first 3 days after LPAIV exposure was higher in primary-exposed laboratory mallards than in sentinel and free-living mallards. LPAIV H4N6 likely activated the complement system and the acute phase response in primary-exposed laboratory mallards, as lysis was higher and haptoglobin lower at day 3 and 7 post-exposure compared to baseline immune function measured prior to exposure. There were no differences observed in natural antibody and haptoglobin concentrations among laboratory, sentinel, and free-living mallards in the first 3 days after LPAIV exposure. Our study demonstrates that, based on the three innate humoral immune parameters measured, domestic mallards seem an appropriate model to investigate innate immunology of their free-living counterparts, albeit the innate immune response of secondary-LPAIV exposed mallards is a better proxy for the innate immune response in pre-exposed free-living mallards than that of immunologically naïve mallards.
No associations between physical activity and clinical outcomes among hospitalized patients with severe COVID-19

Purpose: This small-scale, prospective cohort study nested within a randomized controlled trial aimed to investigate the possible associations between physical activity levels and clinical outcomes among hospitalized patients with severe COVID-19. Methods: Hospitalized patients with severe COVID-19 were recruited from Clinical Hospital of the School of Medicine of the University of Sao Paulo (a quaternary referral teaching hospital), and from Ibirapuera Field Hospital, both located in Sao Paulo, Brazil. Physical activity levels were assessed by Baecke Questionnaire of Habitual Physical Activity. The primary outcome was hospital length of stay. The secondary outcomes were: mortality, admission to the intensive care unit (ICU), and mechanical ventilation requirement. Results: Mean hospital length of stay was 8.5 (7.1) days; 3.3% of patients died, 13.8% were admitted to ICU, and 8.6% required mechanical ventilation. Linear regression models showed that physical activity indexes were not associated with hospital length of stay (work index: B=-0.57 [95%CI: -1.80 to 0.65], p=0.355; sport index: B=0.43 [95%CI: -0.94 to 1.80], p=0.536; leisure-time index: B=1.18 [95%CI: -0.22 to 2.59], p=0.099; total activity index: B=0.20 [95%CI: -0.48 to 0.87], p=0.563. Physical activity indexes were not associated with mortality, admission to ICU and mechanical ventilation requirement (all p>0.05). Conclusions: Among hospitalized patients with COVID-19, physical activity did not associate with hospital length of stay or any other clinically-relevant outcomes. These findings suggest that previous physical activity levels may not change the prognosis of severe COVID-19.
Bacterial mechanosensing: the force will be with you, always

ABSTRACT Whether bacteria are in the planktonic state, free-swimming or free-floating in liquid, or in the biofilm state, sessile on surfaces, they are always subject to mechanical forces. The long, successful evolutionary history of bacteria implies that they are capable of adapting to varied mechanical forces, and probably even actively respond to mechanical cues in their changing environments. However, the sensing of mechanical cues by bacteria, or bacterial mechanosensing, has been under-investigated. This leaves the mechanisms underlying how bacteria perceive and respond to mechanical cues largely unknown. In this Review, we first examine the surface-associated behavior of bacteria, outline the clear evidence for bacterial mechanosensing and summarize the role of flagella, type-IV pili, and envelope proteins as potential mechanosensors, before presenting indirect evidence for mechanosensing in bacteria. The general themes underlying bacterial mechanosensing that we highlight here may provide a framework for future research. Summary: Very little is known about whether, and how, prokaryotes sense and respond to mechanical inputs. We review the emerging field of bacterial mechanosensing and indicate promising directions for future investigation.
Semi-supervised estimation of covariance with application to phenome-wide association studies with electronic medical records data

Electronic medical records data are valuable resources for discovery research. They contain detailed phenotypic information on individual patients, opening opportunities for simultaneously studying multiple phenotypes. A useful tool for such simultaneous assessment is the phenome-wide association study, which relates a genomic or biological marker of interest to a wide spectrum of disease phenotypes, typically defined by the diagnostic billing codes. One challenge arises when the biomarker of interest is expensive to measure on the entire electronic medical record cohort. Performing phenome-wide association study based on supervised estimation using only subjects who have marker measurements may yield limited power. In this paper, we focus on the setting where the marker is measured on a small fraction of the patients while a few surrogate markers such as historical measurements of the biomarker are available on a large number of patients. We propose an efficient semi-supervised estimation procedure to estimate the covariance between the biomarker and the billing code, leveraging the surrogate marker information. We employ surrogate marker values to impute the missing outcome via a two-step semi-non-parametric approach and demonstrate that our proposed estimator is always more efficient than the supervised counterpart without requiring the imputation model to be correct. We illustrate the proposed procedure by assessing the association between the C-reactive protein and some inflammatory diseases with an electronic medical record study of inflammatory bowel disease performed with the Partners HealthCare electronic medical record database where C-reactive protein was only measured for a small fraction of the patients due to budget constraints.
Comparison of Extenders With the Addition of Egg Yolk for Cooling Alpaca Sperm Obtained From Deferent Ducts

The use of non-commercial and commercial extenders for cooling alpaca sperm has already been reported, the latter showing certain advantages over the first. The Andromed® (AM) extender was created for use in ruminants and has also been tested in ejaculated and epididymal alpaca sperm. According to the manufacturer, this extender does not need the addition of egg yolk (EY); however, it is known that the addition of EY to some extenders improves the preservation of cooled sperm. The objective of this study therefore was to compare a non-commercial extender (Tris) with the addition of EY vs. the commercial extender AM with and without the addition of EY, for cooling alpaca sperm obtained from diverted deferent ducts. Fifteen pools of deferent duct sperm were formed using samples from two or three different males for each. Each sperm pool was evaluated and then divided into three aliquots that were diluted to a final concentration of 30 × 106 sperm ml-1 (0 h) with either: (1) Tris with 20% EY (T-EY), (2) AM, or (3) AM with 20% EY (AM-EY). Samples were cooled to 5°C and the following sperm parameters were evaluated after 24 and 48 h of storage: motility, viability, membrane function, acrosome integrity, morphology, and chromatin condensation. Motility was also evaluated after 72 h of storage. The samples that best preserved progressive and total sperm motility at the 24 and 48 h evaluation periods were the ones diluted with AM-EY, observing that with this extender these motility patterns decreased significantly after 72 h of storage compared to time 0 h (p < 0.05). A significant decrease (p < 0.05) in total and progressive motility was observed at 48 h for the T-EY and AM extender compared to 0 h. AM was the only extender in which the percentages of viable sperm decreased significantly (p < 0.05) after 48 h of conservation. For the rest of sperm parameters evaluated, no significant differences were observed between any of the extenders at any evaluation time. The Andromed® extender with the addition of 20% EY could be an alternative option for cooling alpaca sperm obtained from deferent ducts.
A small intergenic region of lp17 is required for evasion of adaptive immunity and induction of pathology by the Lyme disease spirochete

The causative agent of Lyme disease, Borrelia burgdorferi, harbours a single linear chromosome and upwards of 23 linear and circular plasmids. Only a minority of these plasmids, including linear plasmid 17, are maintained with near‐absolute fidelity during extended in vitro passage, and characterisation of any putative virulence determinants they encode has only recently begun. In this work, a mutant lacking a ~4.7 kb fragment of lp17 was studied. Colonisation of murine tissues by this lp17 mutant was significantly impaired, as was the ability to induce carditis and arthritis. The deficiency in tissue colonisation was alleviated in severe combined immunodeficient (SCID) mice, implicating a role for this plasmid region in adaptive immune evasion. Through genetic complementation, the mutant phenotype could be fully attributed to a 317 bp intergenic region that corresponds to the discontinued bbd07 ORF and upstream sequence. The intergenic region was found to be transcriptionally active, and mutant spirochetes lacking this region exhibited an overall difference in the antigenic profile during infection of an immunocompetent murine host. Overall, this study is the first to provide evidence for the involvement of lp17 in colonisation of joint and heart tissues, along with the associated pathologies caused by the Lyme disease spirochete.
Chemoresistance in Breast Cancer Patients Associated With Changes in P2X7 and A2A Purinergic Receptors in CD8+ T Lymphocytes

Breast cancer (BRCA) is the most frequent cancer type that afflicts women. Unfortunately, despite all the current therapeutic strategies, many patients develop chemoresistance hampering the efficacy of treatment. Hence, an early indicator of therapy efficacy might aid in the search for better treatment and patient survival. Although emerging evidence indicates a key role of the purinergic receptors P2X7 and A2A in cancer, less is known about their involvement in BRCA chemoresistance. In this sense, as the chemotherapeutic treatment stimulates immune system response, we evaluated the expression and function of P2X7 and A2A receptors in CD8+ T cells before and four months after BRCA patients received neoadjuvant chemotherapy. The results showed an increase in the levels of expression of P2X7 and a decrease in the expression of A2A in CD8+ T cells in non-chemoresistant (N-CHR) patients, compared to chemoresistant (CHR) patients. Interestingly, in CHR patients, reduced expression of P2X7 occurs along with a decrease in the CD62L shedding and the production of IFN-γ. In the case of the A2A function, the inhibition of IFN-γ production was not observed after chemotherapy in CHR patients. A possible relationship between the modulation of the expression and function of the P2X7 and A2A receptors was found, according to the molecular subtypes, where the patients that were triple-negative and human epidermal growth factor receptor 2 (HER2)-enriched presented more alterations. Comorbidities such as overweight/obesity and type 2 diabetes mellitus (T2DM) participate in the abnormalities detected. Our results demonstrate the importance of purinergic signaling in CD8+ T cells during chemoresistance, and it could be considered to implement personalized therapeutic strategies.
Scots pine forest in Central Europe as a habitat for Harmonia axyridis: temporal and spatial patterns in the population of an alien ladybird

Abstract Understanding of habitat favourability has wide relevance to the invasion biology of alien species. We studied the seasonal dynamics of the alien ladybird Harmonia axyridis (Coleoptera: Coccinellidae) in monoculture Scots pine forest stands in south-west Slovakia, Central Europe, from April 2013 to March 2015. Adult H. axyridis were collected monthly across seven randomly selected pine stands of different ages and canopy closure, from the lower branches of pine trees, and larvae were recorded qualitatively. Adults were recorded all year round, most abundantly in November and least abundantly in February. The relationship between the abundance of H. axyridis and selected forest stand characteristics was modelled using the negative binomial Generalized Additive Model with penalized spline component in month (seasonality) effect, year, canopy closure and age effects and the random effect of forest stand (sample area effect). The abundance of H. axyridis was significantly influenced by the age of stand and seasonality (with month granularity) for both closed and open canopy stands, whereas the effects of canopy closure and sample area were not significant. The bimodal pattern of seasonal dynamics of H. axyridis on Scots pine was common for closed and open canopy stands, with two peaks reflecting the cyclic movement of the species from and to overwintering sites. Harmonia axyridis utilized certain pine stands preferably for foraging during the growing season and certain stands for refuge during winter. The ladybirds were found in highest numbers in the 15 year old closed canopy stand (overwintering site). The occurrence of both adults and larvae in most stands indicated a suitability of Scots pine forest for ladybird breeding. The model of year-round dynamics of H. axyridis has been presented for the first time within the invaded range of the ladybird in Europe.
Evaluation of Reinforcement Learning Traffic Signalling Strategies for Alternative Objectives: Implementation in the Network of Nicosia, Cyprus

Abstract Smart Cities promise to their residents, quick journeys in a clean and sustainable environment. Despite, the benefits accrued by the introduction of traffic management solutions (e.g. improved travel times, maximisation of throughput, etc.), these solutions usually fall short on assessing the environmental impact around the implementation areas. However, environmental performance corresponds to a primary goal of contemporary mobility planning and therefore, solutions guaranteeing environmental sustainability are significant. This study presents an advanced Artificial Intelligence-based (AI) signal control framework, able to incorporate environmental considerations into the core of signal optimisation processes. More specifically, a highly flexible Reinforcement Learning (RL) algorithm has been developed towards the identification of efficient but-more importantly-environmentally friendly signal control strategies. The methodology is deployed on a large-scale micro-simulation environment able to realistically represent urban traffic conditions. Alternative signal control strategies are designed, applied, and evaluated against their achieved traffic efficiency and environmental footprint. Based on the results obtained from the application of the methodology on a core part of the road urban network of Nicosia, Cyprus the best strategy achieved a 4.8% increase of the network throughput, 17.7% decrease of the average queue length and a remarkable 34.2% decrease of delay while considerably reduced the CO emissions by 8.1%. The encouraging results showcase ability of RL-based traffic signal controlling to ensure improved air-quality conditions for the residents of dense urban areas.