Miracle-dz/UniFAR-FTUs huggingface dataset:
Unravelling the mechanisms of Type 1A topoisomerases using single-molecule approaches

Abstract Topoisomerases are essential enzymes that regulate DNA topology. Type 1A family topoisomerases are found in nearly all living organisms and are unique in that they require single-stranded (ss)DNA for activity. These enzymes are vital for maintaining supercoiling homeostasis and resolving DNA entanglements generated during DNA replication and repair. While the catalytic cycle of Type 1A topoisomerases has been long-known to involve an enzyme-bridged ssDNA gate that allows strand passage, a deeper mechanistic understanding of these enzymes has only recently begun to emerge. This knowledge has been greatly enhanced through the combination of biochemical studies and increasingly sophisticated single-molecule assays based on magnetic tweezers, optical tweezers, atomic force microscopy and Förster resonance energy transfer. In this review, we discuss how single-molecule assays have advanced our understanding of the gate opening dynamics and strand-passage mechanisms of Type 1A topoisomerases, as well as the interplay of Type 1A topoisomerases with partner proteins, such as RecQ-family helicases. We also highlight how these assays have shed new light on the likely functional roles of Type 1A topoisomerases in vivo and discuss recent developments in single-molecule technologies that could be applied to further enhance our understanding of these essential enzymes.
Mitochondrial bioenergetics and enzymatic antioxidant defense differ in Paraná pine cell lines with contrasting embryogenic potential

Abstract Araucaria angustifolia is classified as a critically endangered species by the International Union for Conservation of Nature. This threat is worsened by the inefficiency of methods for ex-situ conservation and propagation. In conifers, somatic embryogenesis (SE) associated with cryopreservation is an efficient method to achieve germplasm conservation and mass clonal propagation. However, the efficiency of SE is highly dependent on genotype responsivity to the artificial stimulus used in vitro during cell line proliferation and later during somatic embryo development. In this study, we evaluated the activity of antioxidant enzymes and characterized mitochondrial functions during the proliferation of embryogenic cells of A. angustifolia responsive (SE1) and non-responsive (SE6) to the development of somatic embryos. The activities of the antioxidant enzymes GR (EC 1.6.4.2), MDHAR (EC 1.6.5.4), and POX (EC 1.11.1.7) were increased in SE1 culture, while in SE6 culture, only the activity of DHAR (EC 1.8.5.1) was significantly higher. Additionally, SE6 culture presented a higher number of mitochondria, which agreed with the increased rate of oxygen consumption compared to responsive SE1 culture; however, the mitochondrial volume was lower. Although the ATP levels did not differ, the NAD(P)H levels were higher in SE1 cells. NDs, AOX, and UCP were less active in responsive SE1 than in non-responsive cells. Our results show significant differences between SE1 and SE6 embryogenic cells regarding mitochondrial functions and antioxidant enzyme activities, which may be intrinsic to the in vitro proliferation phase of both cell lines, possessing a crucial role for the induction of in vitro maturation process.
[Xinfeng capsule inhibits immune inflammation in osteoarthritis by inhibiting the miR- 23a-3p/PETN/PI3K/AKT/mTOR pathway].

OBJECTIVE To observe the inhibitory effect of Xinfeng capsule (XFC) on immune inflammatory response in the coculture system of chondrocytes and CD4+ T cells from patients with osteoarthritis (OA). OBJECTIVE Thirty OA patients and 30 healthy subjects were examined for the expression of miR-23a-3p/PTEN/PI3K/AKT/mTOR. The changes in the miR-23a-3p/ PTEN/PI3K/AKT/mTOR pathway and the clinical indicators of the OA patients after XFC treatment were observed. OA-CD4+ T cells and OA-Chondrocytes cells were cultured in Transwel chambers, and the expressions of miR-23a-3p, PTEN, PI3K, AKT and mTOR mRNA were detected by RT-PCR; the levels of IL-1β, IL-6, IL-10 and TNF-α were detected by ELISA. The protein expressions of PTEN, PI3K, AKT, p-AKT, mTOR and p-mTOR were detected by Western blotting. OBJECTIVE Compared with healthy individuals, OA patients showed significantly increased expressions of miR-23a-3p, PTEN, PI3K, AKT, IL-1β, IL-6 and TNF-α and lowered expressions of PTEN and IL-10 (P < 0.01). Positive correlations were found between miR-23a-3p and IL-6 and between PI3K and IL-10; mTOR was positively correlated with IL-6, IL-10, complement C3 and C4 (P < 0.01 or 0.05). Intervention with XFC obviously down-regulated the expressions of IL-1β, IL-6, and TNF-α and up-regulated the expression of IL-10 (P < 0.01). In the cell co-culture systems, the expressions of miR-23a-3p, PI3K, Akt, mTOR, IL-1β, IL-6 and TNF-α were up-regulated while the expressions of PTEN and IL-10 were down-regulated in the model group (P < 0.01). Overexpression of miR-23a-3p significantly up-regulated the expressions of IL-1β, IL-6, TNF-α, miR-23a-3p, PI3K, AKT and mTOR and lowered the expressions of PTEN and IL-10 (P < 0.01 or 0.05). The expressions of IL-1β, IL-6, TNF-α, miR-23a-3p, PI3K, AKT and mTOR were down-regulated and the expressions of IL-10 and PTEN were up-regulated in XFC-treated cells (P < 0.01 or 0.05). OBJECTIVE XFC can reduce the inflammatory response in patients with OA by down-regulating the expression of miR-23a-3p, inhibiting the activation of the PTEN/PI3K/AKT/ mTOR pathway, and regulating the expression of IL-1β, IL-6, IL-10 and TNF-α.
Computational Modeling of Gene-Specific Transcriptional Repression, Activation and Chromatin Interactions in Leukemogenesis by LASSO-Regularized Logistic Regression

Many physiological and pathological pathways are dependent on gene-specific on/off regulation of transcription. Some genes are repressed, while others are activated. Although many previous studies have analyzed the mechanisms of gene-specific repression and activation, these studies are mainly based on the use of candidate genes, which are either repressed or activated, without simultaneously comparing and contrasting both groups of genes. There is also insufficient consideration of gene locations. Here we describe an integrated machine learning approach, using LASSO-regularized logistic regression, to model gene-specific repression and activation and the underlying contribution of chromatin interactions. LASSO-regularized logistic regression accurately predicted gene-specific transcriptional events and robustly detected the rate-limiting factors that underlie the differences of gene activation and repression. An example was provided by the leukemogenic transcription factor AML1-ETO, which is responsible for 10-15 percent of all acute myeloid leukemia cases. The analysis of AML1-ETO has also revealed novel networks of chromatin interactions and uncovered an unexpected role for E-proteins in AML1-ETO-p300 interactions and a role for the pre-existing gene state in governing the transcriptional response. Our results show that logistic regression-based probabilistic modeling is a promising tool to decipher mechanisms that integrate gene regulation and chromatin interactions in regulated transcription.
"Accidents waiting to happen" - insights from a simple model on the emergence of infectious agents in new hosts.

This study evaluates through modeling the possible individual and combined effect of three populational parameters of pathogens (reproduction rate; rate of novelty emergence; and propagule size) on the colonization of new host species - putatively the most fundamental process leading to the emergence of new infectious diseases. The results are analyzed under the theoretical framework of the Stockholm Paradigm using IBM simulations to better understand the evolutionary dynamics of the pathogen population and the possible role of Ecological Fitting. The simulations suggest that all three parameters positively influence the success of colonization of new hosts by a novel parasite population but contrary to the prevailing belief, the rate of novelty emergence (e.g. mutations) is the least important factor. Maximization of all parameters result in a synergetic facilitation of the colonization and emulates the expected scenario for pathogenic microorganisms. The simulations also provide theoretical support for the retention of the capacity of fast-evolving lineages to retro-colonize their previous host species/lineage by ecological fitting. Capacity is, thus, much larger than we can anticipate. Hence, the results support the empirical observations that opportunity of encounter (i.e. the breakdown in mechanisms for ecological isolation) is a fundamental determinant to the emergence of new associations - especially Emergent Infectious Diseases - and the dynamics of host exploration, as observed in SARS-CoV-2. Insights on the dynamics of Emergent Infectious Diseases derived from the simulations and from the Stockholm Paradigm are discussed.
Agonistic autoantibodies against ß2-adrenergic receptor influence retinal microcirculation in glaucoma suspects and patients

Purpose Agonistic β2-adrenergic receptor autoantibodies (β2-agAAb) have been observed in sera of patients with ocular hypertension and open-angle glaucoma (OAG). They target the β2-receptors on trabecular meshwork, ciliary body and pericytes (Junemann et al. 2018; Hohberger et al. 2019). In addition to their influence on the intraocular pressure, an association to retinal microcirculation is discussed. This study aimed to investigate foveal avascular zone (FAZ) characteristics by en face OCT angiography (OCT-A) in glaucoma suspects and its relationship to β2-agAAb status in patients with OAG. Material and methods Thirty-four patients (28 OAG, 6 glaucoma suspects) underwent standardized, clinical examination including sensory testing as white-on-white perimetry (Octopus G1, mean defect, MD) and structural measures as retinal nerve fibre layer (RNFL) thickness, neuroretinal rim width (BMO-MRW), retinal ganglion cell layer (RGCL) thickness, and inner nuclear layer (INL) thickness with high-resolution OCT. FAZ characteristics were measured by OCT-A scans of superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). FAZ-R was calculated (area FAZ (SVP)/area FAZ (ICP)). Using cardiomyocyte bioassays we analysed serum samples for the presence of β2-agAAb. Results (I) Total mean FAZ area [mm2]: 0.34±0.16 (SVP), 0.24±0.12 (ICP), and 0.49±0.24 (DCP); mean FAZ-R 1.58±0.94. No correlation was seen for FAZ-R with MD, RNFL, BMO-MRW, RGCL thickness and INL thickness (p>0.05). (II) ß2-agAAb have been observed in 91% patients and showed no correlation with MD, RNFL, BMO-MRW, RGCL thickness and INL thickness (p>0.05). (III) FAZ-R correlated significantly with the β2-agAAb-induced increase of the beat rate of cardiomyocyte (p = 0.028). Conclusion FAZ characteristics did not correlate with any glaucoma associated functional and morphometric follow-up parameter in the present cohort. However, level of β2-agAAb showed a significantly correlation with FAZ-ratio. We conclude that β2-agAAb might be a novel biomarker in glaucoma pathogenesis showing association to FAZ-ratio with OCT-A.
Elastic stent recoil in coronary total occlusions: Comparison of durable‐polymer zotarolimus eluting stent and ultrathin strut bioabsorbable‐polymer sirolimus eluting stent

To compare stent recoil (SR) of the thin‐strut durable‐polymer Zotarolimus‐eluting stent (dp‐ZES) and the ultrathin‐strut bioabsorbable‐polymer Sirolimus‐eluting stent (bp‐SES) in chronic total occlusions (CTOs) and to investigate the predictors of high SR in CTOs.
Estimation of Apnea-Hypopnea Index Using Deep Learning On 3-D Craniofacial Scans

Obstructive sleep apnea (OSA) is characterized by decreased breathing events that occur through the night, with severity reported as the apnea-hypopnea index (AHI), which is associated with certain craniofacial features. In this study, we used data from 1366 patients collected as part of Stanford Technology Analytics and Genomics in Sleep (STAGES) across 11 US and Canadian sleep clinics and analyzed 3D craniofacial scans with the goal of predicting AHI, as measured using gold standard nocturnal polysomnography (PSG). First, the algorithm detects pre-specified landmarks on mesh objects and aligns scans in 3D space. Subsequently, 2D images and depth maps are generated by rendering and rotating scans by 45-degree increments. Resulting images were stacked as channels and used as input to multi-view convolutional neural networks, which were trained and validated in a supervised manner to predict AHI values derived from PSGs. The proposed model achieved a mean absolute error of 11.38 events/hour, a Pearson correlation coefficient of 0.4, and accuracy for predicting OSA of 67% using 10-fold cross-validation. The model improved further by adding patient demographics and variables from questionnaires. We also show that the model performed at the level of three sleep medicine specialists, who used clinical experience to predict AHI based on 3D scan displays. Finally, we created topographic displays of the most important facial features used by the model to predict AHI, showing importance of the neck and chin area. The proposed algorithm has potential to serve as an inexpensive and efficient screening tool for individuals with suspected OSA.
Dietary intake of sulfur amino acids and risk of kwashiorkor malnutrition in eastern Democratic Republic of the Congo

ABSTRACT Background Kwashiorkor is an often-fatal type of severe acute malnutrition affecting hundreds of thousands of children annually, but whose etiology is still unknown. Evidence suggests inadequate sulfur amino acid (SAA) status may explain many signs of the condition but studies evaluating dietary protein intake in relation to the genesis of kwashiorkor have been conflicting. We know of no studies of kwashiorkor that have measured dietary SAAs. Objectives We aimed to determine whether children in a population previously determined to have high prevalence of kwashiorkor [high-prevalence population (HPP)] have lower dietary intakes of SAAs than children in a low-prevalence population (LPP). Methods A cross-sectional census survey design of 358 children compared 2 previously identified adjacent populations of children 36–59 mo old in North Kivu Province of the Democratic Republic of the Congo. Data collected included urinary thiocyanate (SCN), cyanogens in cassava-based food products, recent history of illness, and a 24-h quantitative diet recall for the child. Results The HPP and LPP had kwashiorkor prevalence of 4.5% and 1.7%, respectively. A total of 170 children from 141 households in the LPP and 169 children from 138 households in the HPP completed the study. A higher proportion of HPP children had measurable urinary SCN (44.8% compared with 29.4%, P < 0.01). LPP children were less likely to have been ill recently (26.8% compared with 13.6%, P < 0.01). Median [IQR] intake of SAAs was 32.4 [22.9–49.3] mg/kg for the LPP and 29.6 [18.1–44.3] mg/kg for the HPP (P < 0.05). Methionine was the first limiting amino acid in both populations, with the highest risk of inadequate intake found among HPP children (35.1% compared with 23.6%, P < 0.05). Conclusions Children in a population with a higher prevalence of kwashiorkor have lower dietary intake of SAAs than children in a population with a lower prevalence. Trial interventions to reduce incidence of kwashiorkor should consider increasing SAA intake, paying particular attention to methionine.
Physical activity in patients with rheumatoid arthritis - an agile lifelong behaviour: a qualitative meta-synthesis

Background Physical activity (PA) in rheumatoid arthritis (RA) is considered a cornerstone in the treatment. To highlight aspects involved in supporting a positive PA behaviour, it is important to understand the patients’ perceptions of the phenomenon. Objective The aim of this qualitative meta-synthesis was to explore and synthesise patient perceptions of PA in RA. Methods A purposeful search was conducted across three online databases (PubMed, CINAHL and Web of Science). The methodological quality of the included studies was appraised, and data were extracted and analysed using an interpretive inductive thematic synthesis. Results Fifteen studies met the inclusion criteria and were included. PA was identified as an agile lifelong behaviour, with one main theme: The disease as a persistent catalyst for or against PA illustrating how the constant presence of the disease itself underlies the entire process of a life with or without regular PA. Seven subthemes: ‘considering aggravated symptoms’, ‘acknowledging the impact on health’, ‘becoming empowered and taking action’, ‘keeping informed to increase awareness’, ‘creating body awareness’, ‘dealing with social support’ and ‘feeling satisfied with circumstances and achievements’ were interpreted as facilitators and/or challenges. Conclusion This synthesis has identified PA as an agile lifelong behaviour in which the disease pervades all aspects of an individuals’ perception of PA. Placed in a theoretical context, our findings outline a model for tailoring PA support to the drivers and determinants of a certain individual, which will improve clinical practice for the benefit of both health professionals and patients with RA.
Zeitgebers of skeletal muscle and implications for metabolic health

Metabolic health is a crucial area of current research, and is an outcome of innate physiology, and interactions with the environment. Environmental cues, such as the Earth's day‐night rhythm, partly regulate diurnal hormones and metabolites. Circadian physiology consists of highly conserved biological processes over ∼24‐h cycles, which are influenced by external cues (Zeitgebers – ‘time‐keepers’). Skeletal muscle has diurnal variations of a large magnitude, owing in part to the strong nature of physical activity throughout the day and other external Zeitgebers. The orchestration of whole‐body and skeletal muscle metabolism is a complex, finely tuned process, and molecular diurnal variations are regulated by a transcription‐translation feedback loop controlled by the molecular clock, as well as non‐transcriptional metabolic processes. The mitochondrion may play an important role in regulating diurnal metabolites within skeletal muscle, given its central role in the regulation of NAD+/NADH, O2, reactive oxygen species and redox metabolism. These molecular pathways display diurnal variation and illustrate the complex orchestration of circadian metabolism in skeletal muscle. Probably the most robust Zeitgeber of skeletal muscle is exercise, which alters glucose metabolism and flux, in addition to a range of other diurnal metabolic pathways. Indeed, performing exercise at different times of the day may alter metabolism and health outcomes in some cohorts. The objective of this Symposium Review is to briefly cover the current literature, and to speculate regarding future areas of research. Thus, we postulate that metabolic health may be optimized by altering the timing of external cues such as diet and exercise.
Extraction for analytical scale sample preparation (IUPAC Technical Report)

Abstract Approaches for sample preparation are developing rapidly as new strategies are implemented to improve sample throughput and to minimize material and solvent use in laboratory methods and to develop on-site capabilities. In majority of cases the key step in sample preparation is extraction, typically used to separate and enrich compounds of interests from the matrix in the extraction phase. In this contribution, the topic of analytical scale extraction is put in perspective emphasising the fundamental aspects of the underlying processes discussing the similarities and differences between different approaches. Classification of extraction techniques according to the mass transfer principles is provided.
NSMF promotes the replication stress-induced DNA damage response for genome maintenance

Abstract Proper activation of DNA repair pathways in response to DNA replication stress is critical for maintaining genomic integrity. Due to the complex nature of the replication fork (RF), problems at the RF require multiple proteins, some of which remain unidentified, for resolution. In this study, we identified the N-methyl-D-aspartate receptor synaptonuclear signaling and neuronal migration factor (NSMF) as a key replication stress response factor that is important for ataxia telangiectasia and Rad3-related protein (ATR) activation. NSMF localizes rapidly to stalled RFs and acts as a scaffold to modulate replication protein A (RPA) complex formation with cell division cycle 5-like (CDC5L) and ATR/ATR-interacting protein (ATRIP). Depletion of NSMF compromised phosphorylation and ubiquitination of RPA2 and the ATR signaling cascade, resulting in genomic instability at RFs under DNA replication stress. Consistently, NSMF knockout mice exhibited increased genomic instability and hypersensitivity to genotoxic stress. NSMF deficiency in human and mouse cells also caused increased chromosomal instability. Collectively, these findings demonstrate that NSMF regulates the ATR pathway and the replication stress response network for genome maintenance and cell survival.
Supercritical CO2 Confined in Palygorskite and Sepiolite Minerals: A Classical Molecular Dynamics Investigation

We have investigated the ability of two modular phyllosilicates (palygorskite and sepiolite) to store CO2 molecules inside their structural channels by means of classical molecular dynamics. Several models containing an increasing supercritical-CO2/H2O ratio into the phyllosilicate channels have been built and the structural and dynamic properties of carbon dioxide and water molecules investigated in detail. We found that both clay minerals can achieve this goal, with sepiolite being able to store more carbon dioxide molecules (and more stably) than palygorskite, due to the larger channels of the former. Interestingly, with the increase of CO2 molecules inside the minerals, the diffusivity of both water and carbon dioxide drastically decreases and carbon dioxide molecules tend to arrange themselves in an ordered pattern.
Stamen dimorphism in bird‐pollinated flowers: Investigating alternative hypotheses on the evolution of heteranthery

Heteranthery, the presence of distinct stamen types within a flower, is commonly explained as functional adaptation to alleviate the “pollen dilemma,” defined as the dual and conflicting function of pollen as pollinator food resource and male reproductive agent. A single primary hypothesis, “division of labor,” has been central in studies on heteranthery. This hypothesis postulates that one stamen type functions in rewarding pollen‐collecting pollinators and the other in reproduction, thereby minimizing pollen loss. Only recently, alternative functions (i.e., staggered pollen release), were proposed, but comparative and experimental investigations are lagging behind. Here, we used 63 species of the tribe Merianieae (Melastomataceae) to demonstrate that, against theory, heteranthery occurs in flowers offering rewards other than pollen, such as staminal food bodies or nectar. Although shifts in reward type released species from the “pollen dilemma,” heteranthery has evolved repeatedly de novo in food‐body‐rewarding, passerine‐pollinated flowers. We used field investigations to show that foraging passerines discriminated between stamen types and removed large stamens more quickly than small stamens. Passerines removed small stamens on separate visits towards the end of flower anthesis. We propose that the staggered increase in nutritive content of small stamens functions to increase chances for outcross‐pollen transfer.