Miracle-dz/UniFAR-FTUs huggingface dataset:
Adherence to metformin and the onset of rheumatoid arthritis: a population-based cohort study

Objective: The aim of this retrospective cohort study was to examine whether adherence to metformin treatment may be associated with lower onset of rheumatoid arthritis (RA). Method: Using the computerized databases of a 2.3-million state-mandated health services organization in Israel, we identified incident RA cases among a cohort of 113 749 adult patients who initiated metformin therapy between 1998 and 2014. Adherence was assessed by calculating the mean proportion of follow-up days covered (PDC) with metformin. Results: During the 18 year study period, there were 558 incident RA cases (61 per 100 000 person-years). Adherence to metformin treatment was associated with a lower risk of developing RA, with the lowest risk recorded among patients with a PDC of 40–59% [adjusted hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.45–0.84] compared with non-adherent patients (PDC < 20%). A mean daily metformin dose of 2550 mg or more was also associated with a lower risk of developing RA (adjusted HR 0.62, 95% CI 0.46–0.84) compared to a daily dose of 850 mg or less. In stratified analyses by gender, the negative association between adherence and the risk of RA was limited to women alone. Conclusions: Adherence to metformin treatment is associated with a reduced risk of developing RA in women. Further studies are needed to assess the effect of metformin on RA development in other patient populations.
Propagation of Conformational Coordinates Across Angular Space in Mapping the Continuum of States from Cryo-EM Data by Manifold Embedding

Recent approaches to the study of biological molecules employ manifold learning to single-particle cryo-EM datasets to map the continuum of states of a molecule into a low-dimensional space spanned by eigenvectors, or "conformational coordinates". This is done separately for each projection direction (PD) on an angular grid. One important step in deriving a consolidated map of occupancies, from which the free energy landscape of the molecule can be derived, is to propagate the conformational coordinates from a given choice of "anchor PD" across the entire angular space. Even when one eigenvector dominates, its sign might invert from one PD to the next. The propagation of the second eigenvector is particularly challenging when eigenvalues of the second and third eigenvector are closely matched, leading to occasional inversions in their ranking as we move across the angular grid. In the absence of a computational approach, this propagation across the angular space has been done thus far "by hand" using visual clues, thus greatly limiting the general use of the technique. In this work we have developed a method that is able to solve the propagation problem computationally, by using optical flow and a probabilistic graphical model. We demonstrate its utility by selected examples.
Acid-Base Interaction Enhancing Oxygen Tolerance in Electrocatalytic Carbon Dioxide Reduction.

Catalytic electrodes with the capability to directly convert atmospheric CO 2 into value-added products are of potential environmental and economic benefit, but entail an effective CO 2 selection strategy to impede the competing O 2 reduction reaction. In this work, we have developed a new generation of hybrid electrodes with improved O 2 tolerance and unprecedented capability of CO 2 conversion to liquid products in the presence of O 2 . We introduce aniline molecules into the pore structure of a polymer of intrinsic microporosity to expand its gas separation functionality beyond pure physical sieving. The chemical interaction between the acidic CO 2 molecule and the basic amino group of aniline renders enhanced CO 2 separation from O 2 . Loaded with a cobalt phthalocyanine-based cathode catalyst, our hybrid electrode achieves a CO Faradaic efficiency of 71% with 10% O 2 in the CO 2 feed gas. The electrode can still perform CO production at an O 2 /CO 2 ratio as high as 9:1. Switching to a Sn-based catalyst, we for the first time realize O 2 -tolerant CO 2 electroreduction to liquid products, generating formate with nearly 100% selectivity and a current density of 56.7 mA/cm 2 in the presence of 5% O 2 .
Renal replacement therapy and conservative management: NICE guideline (NG 107) October 2018

In 2017, 966 children in the UK received long-term renal replacement therapy (RRT) for established end-stage kidney disease (ESKD); 76% of whom had functioning renal transplants while 24% were on dialysis (13% on haemodialysis (HD) and 11% on peritoneal dialysis (PD)). 1 The National Institute for Health and Care Excellence (NICE) published its guidance ‘ Renal replacement therapy and conservative management’ in October 2018 (NG 107, 2018). ### Information about the clinical guideline The guideline caters to both adult and paediatric populations with stages 4 and 5 chronic kidney disease (CKD) (defined as an estimated glomerular filtration rate (eGFR) between 15–29 and <15 mL/min/1.73 m22) and provides recommendations on initiation, preparation, choice, switching or stopping modalities for RRT. It also provides information for patients and coordinating care when commencing RRT. The guideline mainly targets healthcare professionals looking after the patients and their families with CKD stages 4 and 5. ### Previous guidelines The British Association for Paediatric Nephrology3 4 and more recently the Renal Association (2017)5 have produced guidance for HD and PD, respectively, in children. This guidance replaces previous NICE guidance CG125 and TA48 (NICE, 2011) (box 1). Box 1 ### Resources Joint decision-making involving the child/young person, their parents and the multidisciplinary team (MDT) is recommended at all the stages. The key points highlighted in this guideline relating to paediatric population are: 1. Indications for starting dialysis 1. Consider starting dialysis when indicated …
Onset of brain injury in infants with prenatally diagnosed congenital heart disease

Background The exact onset of brain injury in infants with congenital heart disease (CHD) is unknown. Our aim was, therefore, to assess the association between prenatal Doppler flow patterns, postnatal cerebral oxygenation and short-term neurological outcome. Methods Prenatally, we measured pulsatility indices of the middle cerebral (MCA-PI) and umbilical artery (UA-PI) and calculated cerebroplacental ratio (CPR). After birth, cerebral oxygen saturation (rcSO2) and fractional tissue oxygen extraction (FTOE) were assessed during the first 3 days after birth, and during and for 24 hours after every surgical procedure within the first 3 months after birth. Neurological outcome was determined preoperatively and at 3 months of age by assessing general movements and calculating the Motor Optimality Score (MOS). Results Thirty-six infants were included. MOS at 3 months was associated with MCA-PI (rho 0.41, P = 0.04), UA-PI (rho -0.39, P = 0.047, and CPR (rho 0.50, P = 0.01). Infants with abnormal MOS had lower MCA-PI (P = 0.02) and CPR (P = 0.01) and higher UA-PI at the last measurement (P = 0.03) before birth. In infants with abnormal MOS, rcSO2 tended to be lower during the first 3 days after birth, and FTOE was significantly higher on the second day after birth (P = 0.04). Intraoperative and postoperative rcSO2 and FTOE were not associated with short-term neurological outcome. Conclusion In infants with prenatally diagnosed CHD, the prenatal period may play an important role in developmental outcome. Additional research is needed to clarify the relationship between preoperative, intra-operative and postoperative cerebral oxygenation and developmental outcome in infants with prenatally diagnosed CHD.
Nek2 kinase displaces distal appendages from the mother centriole prior to mitosis

Viol et al. show that the conserved Never-in-mitosis-A–related kinase-2 (Nek2) removes distal appendage components from the mother centriole prior to mitosis in every cell cycle. These findings suggest that Nek2 prevents cilia maintenance during mitosis via distal appendage regulation.
Rehospitalization burden and morbidity risk in patients with heart failure with mid‐range ejection fraction

Heart failure with mid‐range ejection fraction (HFmrEF) has been proposed as a distinct HF phenotype, but whether patients on this category fare worse, similarly, or better than those with HF with reduced EF (HFrEF) or preserved EF (HFpEF) in terms of rehospitalization risks over time remains unclear.
Prevention of Doxorubicin-Induced Autophagy Attenuates Oxidative Stress and Skeletal Muscle Dysfunction

Clinical use of the chemotherapeutic doxorubicin (DOX) promotes skeletal muscle atrophy and weakness, adversely affecting patient mobility and strength. Although the mechanisms responsible for DOX-induced skeletal muscle dysfunction remain unclear, studies implicate the significant production of reactive oxygen species (ROS) in this pathology. Supraphysiological ROS levels can enhance protein degradation via autophagy, and it is established that DOX upregulates autophagic signaling in skeletal muscle. To determine the precise contribution of accelerated autophagy to DOX-induced skeletal muscle dysfunction, we inhibited autophagy in the soleus via transduction of a dominant negative mutation of the autophagy related 5 (ATG5) protein. Targeted inhibition of autophagy prevented soleus muscle atrophy and contractile dysfunction acutely following DOX administration, which was associated with a reduction in mitochondrial ROS and maintenance of mitochondrial respiratory capacity. These beneficial modifications were potentially the result of enhanced transcription of antioxidant response element-related genes and increased antioxidant capacity. Specifically, our results showed significant upregulation of peroxisome proliferator-activated receptor gamma co-activator 1-alpha, nuclear respiratory factor-1, nuclear factor erythroid-2-related factor-2, nicotinamide-adenine dinucleotide phosphate quinone dehydrogenase-1, and catalase in the soleus with DOX treatment when autophagy was inhibited. These findings establish a significant role of autophagy in the development of oxidative stress and skeletal muscle weakness following DOX administration.
The Future of Computed Tomography

Abstract Modern medicine cannot be imagined without the diagnostic capabilities of computed tomography (CT). Although the past decade witnessed a tremendous increase in scan speed, volume coverage, and temporal resolution, along with a considerable reduction of radiation dose, current trends in CT aim toward more patient-centric, tailored imaging approaches that deliver diagnostic information being personalized to each individual patient. Functional CT with dual-and multienergy, as well as dynamic, perfusion imaging became clinical reality and will further prosper in the near future, and upcoming photon-counting detectors will deliver images at a heretofore unmatched spatial resolution. This article aims to provide an overview of current trends in CT imaging, taking into account the potential of photon-counting detector systems, and seeks to illustrate how the future of CT will be shaped.
Spectroscopic and Structural Analysis of Cu2+-Induced Fluorescence Quenching of ZsYellow

Fluorescent proteins exhibit fluorescence quenching by specific transition metals, suggesting their potential as fluorescent protein-based metal biosensors. Each fluorescent protein exhibits unique spectroscopic properties and mechanisms for fluorescence quenching by metals. Therefore, the metal-induced fluorescence quenching analysis of various new fluorescent proteins would be important step towards the development of such fluorescent protein-based metal biosensors. Here, we first report the spectroscopic and structural analysis of the yellow fluorescent protein ZsYellow, following its metal-induced quenching. Spectroscopic analysis showed that ZsYellow exhibited a high degree of fluorescence quenching by Cu2+. During Cu2+-induced ZsYellow quenching, fluorescence emission was recovered by adding EDTA. The crystal structure of ZsYellow soaked in Cu2+ solution was determined at a 2.6 Å resolution. The electron density map did not indicate the presence of Cu2+ around the chromophore or the β-barrel surface, which resulted in fluorescence quenching without Cu2+ binding to specific site in ZsYellow. Based on these results, we propose the fluorescence quenching to occur in a distance-dependent manner between the metal and the fluorescent protein, when these components get to a closer vicinity at higher metal concentrations. Our results provide useful insights for future development of fluorescent protein-based metal biosensors.
Carbohydrates stimulated Amaryllidaceae alkaloids biosynthesis in Leucojum aestivum L. plants cultured in RITA® bioreactor

Background Leucojum aestivum L. is an important medicinal plant which produces Amaryllidaceae alkaloids, especially galanthamine and lycorine. Research is currently exploring the possibility of producing these alkaloids using biotechnological methods, including in vitro cultures. The biosynthesis of alkaloids may be affected by the types and concentrations of carbohydrate sources used in the medium. In the present investigation we performed such studies on in vitro cultures of L. aestivum with a view to obtaining plant material of good quality, characterized, in particular, by a high content of valuable Amaryllidaceae alkaloids. Methods We examined the effects of various types of carbohydrate sources—sucrose, glucose, fructose and maltose—at different concentrations (30, 60 and 90 g/L)—on the quality of L. aestivum plants grown in the RITA® bioreactor. The plants’ quality was assessed by their biomass increments, as well by as analysing photosynthetic pigments, endogenous sugar, phenolics and Amaryllidaceae alkaloid content. We also investigated the effect of sugars on the activity of the antioxidant enzymes catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD). Results The highest biomass increments were observed in plants cultivated in the medium containing 90 g/L sucrose. The highest CAT activity was noted in cultures growing in the medium supplemented with 90 g/L maltose, while the highest POD activity was observed in the presence of 90 g/L fructose and 60 g/L maltose. No differences in SOD activity were observed. Moreover, the sugars did not affect the contents of chlorophyll a and carotenoids, whereas the highest amount of chlorophyll b was recorded in plants growing in the medium with 60 g/L maltose. No statistically significant differences were observed in the contents of endogenous sugars and phenolics in any in vitro conditions. However, the addition of sugar had a decisive effect on the biosynthesis of the Amaryllidaceae alkaloids. The highest distribution of alkaloids occurred in plants cultured in the medium containing 60 g/L sucrose. Six Amaryllidaceae alkaloids were detected in the plant tissue. The addition of 30 g/L fructose in the medium resulted in the accumulation of five alkaloids, including ismine, which was not identified in other analysed tissues. The highest concentration of galanthamine was observed in plants cultured in the presence of 30 g/L fructose and 60 g/L sucrose (39.2 and 37.5 µg/g of dry weight (DW), respectively). The plants grown in the medium containing 60 g/L sucrose exhibited the highest lycorine content (1048 µg/g of DW). Conclusions The type and concentration of sugar used in the medium have an essential influence on the biosynthesis of Amaryllidaceae alkaloids in L. aestivum plants cultured in a RITA® bioreactor. The results point to an interesting approach for commercial production of galanthamine and lycorine.
Education Disparity Only Partially Explains Cognitive Gender Differences in Older Rural South Africans.

OBJECTIVES Direction and magnitude of gender differences in late-life cognitive function are inextricably tied to sociocultural context. Our study evaluates education and literacy in rural South Africa as primary drivers of gender inequality in late-life cognitive function. METHOD Data were collected on 1,938 participants aged 40-79 from Agincourt, South Africa. Cognitive function was measured via the Oxford Cognitive Screen-Plus, a tablet-based assessment with low literacy demands. Four cognitive domains were derived through confirmatory factor analysis: episodic memory, executive function, visual spatial, and language. Structural equation models tested domain-specific gender effects, incrementally controlling for demographic, education, health, and socioeconomic variables. RESULTS In the model adjusting only for demographic factors, men outperformed women on executive function and visual spatial domains. Adding education and literacy to the model revealed a robust female advantage in episodic memory, and reduced the magnitude of male advantage in executive function and visual spatial by 47% and 42%, respectively. Health and socioeconomic factors did not alter patterns of gender associations in subsequent models. DISCUSSION In this older South African cohort, gender inequality in cognitive performance was partially attributable to educational differences. Understanding biopsychosocial mechanisms that promote cognitive resilience in older women is critically important given the predominantly female composition of aging populations worldwide.
High Sensitive Biosensors Based on the Coupling Between Surface Plasmon Polaritons on Titanium Nitride and a Planar Waveguide Mode

High sensitivity biosensors based on the coupling of surface plasmon polaritons on titanium nitride (TiN) and a planar waveguide mode were built; they were proved by sensing three different media: air, water and dried egg white; sensors described here could be useful for sensing materials with a refractive index between 1.0 and 1.6; in particular, materials of biological interest with a refractive index in the range 1.3–1.6, like those containing biotin and/or streptavidin. They were built by depositing Nb2O5/SiO2/TiN multilayer structures on the flat surface of D-shaped sapphire prisms by using the dc magnetron sputtering technique. Attenuated total reflection (ATR) experiments in the Kretschmann configuration were accomplished for the air/TiN/Prism and S/Nb2O5/SiO2/TiN/Prism structures, S being the sample or sensing medium. ATR spectra for plasmons at the TiN/air interface showed a broad absorption band for angles of incidence between 36 and 85°, with full width at half maximum (FWHM) of approximately 40°. For the S/Nb2O5/SiO2/TiN/Prism structures, ATR spectra showed a sharp reflectivity peak, within the broad plasmonic absorption band, which was associated with Fano resonances. The angular position and FWHM of the Fano resonances strongly depend on the refractive index of the sensing medium. ATR spectra were fitted by using the transfer-matrix method. Additionally, we found that angular sensitivity and figure of merit increase with increasing the refractive index of the sensing medium.
Activity of Cinnamaldehyde on Quorum Sensing and Biofilm Susceptibility to Antibiotics in Pseudomonas aeruginosa

Quorum sensing (QS) plays an important role during infection for the opportunistic human pathogen Pseudomonas aeruginosa. Quorum sensing inhibition (QSI) can disrupt this initial event of infection without killing bacterial cells, and thus QS inhibitors have been suggested as novel approaches for anti-infective therapy. Cinnamaldehyde (CAD) is a P. aeruginosa biofilm inhibitor and disperser of preformed biofilms. In this study, the combined use of CAD and colistin (COL) revealed a synergistic activity, but this was not the case for CAD combined with carbenicillin, tobramycin (TOB), or erythromycin in checkerboard assays for P. aeruginosa. CAD demonstrated QSI activity by repression of the expression of lasB, rhlA and pqsA in GFP reporter assays. Approximately 70% reduction in GFP production was observed with the highest CAD concentration tested in all the QS reporter strains. TOB also showed strong QSI when combined with CAD in reporter assays. Combination treatments revealed an additive activity of CAD with COL and TOB in biofilm inhibition (75.2% and 83.9%, respectively) and preformed biofilm dispersion (~90% for both) when compared to the individual treatments. Therefore, a proposed method to mitigate P. aeruginosa infection is a combination therapy of CAD with COL or CAD with TOB as alternatives to current individual drug therapies.
Acrolein exposure from electronic cigarettes

In a recent study, Kuntic et al. reported that inhaled acrolein may be the main culprit for their observations of acute adverse effects of ecigarette use on vascular function, caused by oxidative stress in blood vessels. According to Table S3 of their manuscript, the aerosol generated for the current study contained 0.0032 mg of acrolein per puff. Assuming an average of 600 puffs per day this corresponds to a daily intake of 0.96 mg of acrolein. For a human with 60 kg bodyweight, this amount is 450-fold lower than the daily dose accepted by the WHO (7.5 mg/kg) and below the estimated daily intake from other sources. The WHO threshold refers to oral intake of acrolein, which may result in reduced bioavailability due to liver metabolism but is unlikely to compensate for a 450-fold difference. Moreover, a study measuring biomarkers of toxin exposure found that e-cigarette users were having similar exposure to acrolein [measured as N-acetyl-S-(3hydroxypropyl)-L-cysteine, an established biomarker of acrolein exposure] as former smokers using nicotine replacement therapies. Thus, exposure to acrolein from e-cigarette use appears to be too low to cause any adverse health effects. Kuntic et al. report on vascular oxidative stress in response to acrolein, shown as increased dihydroethidium (DHE) staining (a marker for superoxide formation) of mouse aortic cryosections that had been incubated with 1–10 mM acrolein (Figure 5E in their manuscript). Assuming a plasma volume of 3 L, 100% bioavailability, and accumulation of acrolein in the bloodstream without elimination or metabolism for 24 h, daily intake of 0.96 mg of acrolein from e-cigarette use would result in a plasma concentration of 0.0057 mM. Acrolein had no effect on DHE staining at a concentration of 0.1 mM, which is more than 17-fold higher than the concentration mentioned above. The 1 mM concentration that did increase DHE staining is more than 170-fold higher than the upper limit of the plasma concentration calculated with the unrealistic assumption that the aldehyde accumulates in blood for 24 h without metabolism or elimination. In conclusion, the findings by Kuntic et al. about the effects of acrolein exposure on inducing vascular oxidative stress and dysfunction are of questionable clinical relevance for e-cigarette users.
Smoking and disability progression in multiple sclerosis.

ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: https://www.tandfonline. com/loi/iern20 Smoking and disability progression in multiple sclerosis Anna Karin Hedström To cite this article: Anna Karin Hedström (2020): Smoking and disability progression in multiple sclerosis, Expert Review of Neurotherapeutics, DOI: 10.1080/14737175.2020. 1743176 To link to this article: https://doi.org/10.1080/14737175.2020. 1743176