Miracle-dz/UniFAR-FTUs huggingface dataset:
Occurrence and Fate of Natural Estrogens in Swiss Cattle and Pig Slurry.

Natural estrogens act as endocrine disruptors. However, the fate of livestock farming derived natural estrogens (17α-estradiol, 17β-estradiol, estrone, estriol) in slurry is not well understood. In this study, we assessed the effects of on farm-storage on natural estrogen concentrations in slurry. Furthermore, we monitored pig and cattle slurry pits from major agricultural areas in Switzerland and determined natural estrogen concentrations therein. They were relatively stable over time and mean concentrations ranged from 138 to 861 ng/L and 54 to 244 ng/L for cattle and pig slurry, respectively. 17α-estradiol and estriol were the most prevalent estrogens in cattle and pig slurry, respectively. Based on livestock numbers, agricultural area and estrogen concentrations in slurry, the estimated annual load of total natural estrogens applied on agricultural area amounted to 36 mg/ha. Our results indicate that slurry application is a relevant source of natural estrogens in the environment.
Polymyxin Delivery Systems: Recent Advances and Challenges

Polymyxins are vital antibiotics for the treatment of multiresistant Gram-negative ESKAPE pathogen infections. However, their clinical value is limited by their high nephrotoxicity and neurotoxicity, as well as their poor permeability and absorption in the gastrointestinal tract. This review focuses on various polymyxin delivery systems that improve polymyxin bioavailability and reduce drug toxicity through targeted and controlled release. Currently, the most suitable systems for improving oral, inhalation, and parenteral polymyxin delivery are polymer particles, liposomes, and conjugates, while gels, polymer fibers, and membranes are attractive materials for topical administration of polymyxin for the treatment of infected wounds and burns. In general, the application of these systems protects polymyxin molecules from the negative effects of both physiological and pathological factors while achieving higher concentrations at the target site and reducing dosage and toxicity. Improving the properties of polymyxin will be of great interest to researchers who are focused on developing antimicrobial drugs that show increased efficacy and safety.
Oxidative Stress and Genotoxicity in Melanoma Induction: Impact on Repair Rather Than Formation of DNA Damage?

Keratinocytes and melanocytes, two cutaneous cell types located within the epidermis, are the origin of most skin cancers, namely carcinomas and melanomas. These two types of tumors differ in many ways. First, carcinomas are almost 10 times more frequent than melanomas. In addition, the affected cellular pathways, the mutated genes and the metastatic properties of the tumors are not the same. This review addresses another specificity of melanomas: the role of photo‐oxidative stress. UVA efficiently produces reactive oxygen species in melanocytes, which results in more frequent oxidatively generated DNA lesions than in other cell types. The question of the respective contribution of UVB‐induced pyrimidine dimers and UVA‐mediated oxidatively generated lesions to mutagenesis in melanoma remains open. Recent results based on next‐generation sequencing techniques strongly suggest that the mutational signature associated with pyrimidine dimers is overwhelming in melanomas like in skin carcinomas. UVA‐induced oxidative stress may yet be indirectly linked to the genotoxic pathways involved in melanoma through its ability to hamper DNA repair activities.
Protective Effects of Vitamins C and E Against γ-ray-induced Chromosomal Damage in Mouse

The effects of vitamins C and E on bone marrow chromosomes of the mouse exposed to 1 Gy of whole-body γ-irradiation were studied. These vitamins, dissolved in water/peanut oil, were administered orally as acute doses, either 2 h before, immediately after, or 2 h after irradiation. Both vitamins significantly reduced the frequencies of micronuclei and chromosomal aberrations in bone marrow cells; radioprotection by vitamin E was, however, appreciably greater than that afforded by vitamin C. Administration of the vitamins to mice immediately after irradiation was as effective as that 2 h before irradiation. A sequential treatment consisting of both these vitamins did not result in additional radioprotection over that afforded by vitamin E alone. The probable mechanisms of radioprotection are discussed.
CM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on epidermal growth factor receptor mutant non‐small cell lung cancer in vitro and in vivo

CM082 is a novel angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR) and platelet‐derived growth factor receptor (PDGFR). The purpose of this research was to evaluate the antitumor activity of CM082 combined with gefitinib on epidermal growth factor receptor (EGFR) mutant non‐small cell lung cancer (NSCLC) in vitro and in vivo.
Beetroot juice lowers blood pressure and improves endothelial function in pregnant eNOS−/− mice: importance of nitrate‐independent effects

Maternal hypertension is associated with increased rates of pregnancy pathologies, including fetal growth restriction, due at least in part to reductions in nitric oxide (NO) bioavailability and associated vascular dysfunction. Dietary nitrate supplementation, from beetroot juice (BRJ), has been shown to increase NO bioavailability and improve cardiovascular function in both preclinical and clinical studies. This study is the first to investigate effects of dietary nitrate supplementation in a pregnant animal model. Importantly, the effects of nitrate‐containing BRJ were compared with both ‘placebo’ (nitrate‐depleted) BRJ as well as water to control for potential nitrate‐independent effects. Our data show novel, nitrate‐independent effects of BRJ to lower blood pressure and improve vascular function in endothelial nitric oxide synthase knockout (eNOS−/−) mice. These findings suggest potential beneficial effects of BRJ supplementation in pregnancy, and emphasize the importance of accounting for nitrate‐independent effects of BRJ in study design and interpretation.
Differential Sensitivity of Interleukin-1α and -β Precursor Proteins to Cleavage by Calpain, a Calcium-dependent Protease (*)

In view of the observations that the calcium ionophores, A23187 and ionomycin, enhance the processing and secretion of interleukin-1 (IL-1α) and IL-1β from macrophages, and IL-1α processing is mediated by calpain, a calcium-dependent protease, we evaluated the possibility that calpain might also play a role in the processing of IL-1β. Whereas calpain-containing P388D1 macrophage lysates and purified calpain processed precursor IL-1α to its mature 17-kDa form, precursor IL-1β was degraded by both sources of calpain. However, the activation of calpain in P388D1 cells that were transiently transfected with a cDNA expression vector encoding the precursor form of IL-1β did not result in the degradation of precursor IL-1β, but did result in the processing and secretion of IL-1α, implying that precursor IL-1β is protected from calpain degradation in vivo. Furthermore, calpain did not enhance the processing of the IL-1β precursor by the IL-1β-converting enzyme. These results indicate that calpain is not involved in the processing of precursor IL-1β in vitro or in vivo. The IL-1β precursor may be protected from calpain degradation by a sequestering mechanism that involves a cytoplasmic factor(s) that reduces the sensitivity of IL-1β to attack by calpain or localizes IL-1β to a site that precludes any interaction with the protease. Although MDL 28,170, a calpain inhibitor, prevented the ionomycin-induced processing of precursor IL-1α to the mature protein in P388D1 cells, it did not inhibit the ionomycin-induced secretion of the mature IL-1α and -β proteins expressed in these cells. These results indicate that a calcium-dependent factor other than calpain is involved in the secretion of the mature IL-1 proteins.
Changes in cognitive functions and quality of life in patients after transcatheter aortic valve implantation

Introduction Transcatheter aortic valve implantation (TAVI) has emerged as a therapeutic option for patients with severe aortic stenosis (AS). However, an association between cognitive functions (CF) and health-related quality of life (HRQoL) in TAVI patients is still unclear. Aim To assess the long-term changes in CF and HRQoL in elderly patients with AS after TAVI. Material and methods A total of 259 patients who underwent cardiological and psychological TAVI qualification were enrolled and divided into the normal (n = 174) and impaired cognition group (n = 85). CF and HRQoL characteristics assessed at baseline and 13 months were compared between groups. The analysis of multiple linear regression was performed to identify the association between HRQoL and CF and to assess the influence of TAVI on HRQoL. Results There was no difference in CF between baseline and follow-up. However, an improvement in attention functions and memory skills in the cognitively impaired group was noted at follow-up. In addition, HRQoL scores increased in both groups. An independent predictor associated with HRQoL was global CF (β = –213, p = 0.01), which explained 7% of CF variation. Improvements in all five dimensions of HRQoL, from 4.8% in self-care and up to 33.6% in pain/discomfort, were found. At follow-up, 60% of TAVI patients had improved health, 12% had worse health, 4% showed no change and 24% had a “mixed” change. Conclusions TAVI is associated with positive changes in the functioning of elderly patients at long-term follow-up.
Mind Wandering in a Multimodal Reading Setting: Behavior Analysis & Automatic Detection Using Eye-Tracking and an EDA Sensor

Mind wandering is a drift of attention away from the physical world and towards our thoughts and concerns. Mind wandering affects our cognitive state in ways that can foster creativity but hinder productivity. In the context of learning, mind wandering is primarily associated with lower performance. This study has two goals. First, we investigate the effects of text semantics and music on the frequency and type of mind wandering. Second, using eye-tracking and electrodermal features, we propose a novel technique for automatic, user-independent detection of mind wandering. We find that mind wandering was most frequent in texts for which readers had high expertise and that were combined with sad music. Furthermore, a significant increase in task-related thoughts was observed for texts for which readers had little prior knowledge. A Random Forest classification model yielded an F1-Score of 0.78 when using only electrodermal features to detect mind wandering, of 0.80 when using only eye-movement features, and of 0.83 when using both. Our findings pave the way for building applications which automatically detect events of mind wandering during reading.
Design and Characterization of Phosphatidylcholine-Based Solid Dispersions of Aprepitant for Enhanced Solubility and Dissolution

This study aimed to improve the solubility and dissolution of aprepitant, a drug with poor aqueous solubility, using a phosphatidylcholine (PC)-based solid dispersion system. When fabricating the PC-based solid dispersion, we employed mesoporous microparticles, as an adsorbent, and disintegrants to improve the sticky nature of PC and dissolution of aprepitant, respectively. The solid dispersions were prepared by a solvent evaporation technique and characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry, and X-ray powder diffraction. The FTIR results showed that aprepitant interacted with the PC carrier by both hydrogen bonds and van der Waals forces that can also be observed in the interaction between aprepitant and polymer carriers. The solid dispersions fabricated with only PC were not sufficient to convert the crystallinity of aprepitant to an amorphous state, whereas the formulations that included adsorbent and disintegrant successfully changed that of aprepitant to an amorphous state. Both the solubility and dissolution of aprepitant were considerably enhanced in the PC-based solid dispersions containing adsorbent and disintegrant compared with those of pure aprepitant and polymer-based solid dispersions. Therefore, these results suggest that our PC-based solid dispersion system is a promising alternative to conventional formulations for poorly water-soluble drugs, such as aprepitant.
Using Algorithms to Address Trade-Offs Inherent in Predicting Recidivism

Although risk assessment has increasingly been used as a tool to help reform the criminal justice system, some stakeholders are adamantly opposed to using algorithms. The principal concern is that any benefits achieved by safely reducing rates of incarceration will be offset by costs to racial justice claimed to be inherent in the algorithms themselves. But fairness trade-offs are inherent to the task of predicting recidivism, whether the prediction is made by an algorithm or human. Based on a matched sample of 67,784 Black and White federal supervisees assessed with the Post Conviction Risk Assessment, we compared how three alternative strategies for "debiasing" algorithms affect these trade-offs, using arrest for a violent crime as the criterion . These candidate algorithms all strongly predict violent reoffending (areas under the curve = 0.71-72), but vary in their association with race (r = 0.00-0.21) and shift trade-offs between balance in positive predictive value and false-positive rates. Providing algorithms with access to race (rather than omitting race or "blinding" its effects) can maximize calibration and minimize imbalanced error rates. Implications for policymakers with value preferences for efficiency versus equity are discussed.
The Common Bacterial Infections of the Digestive Tract and the Intoxications Arising from Them

ABSTRACT After presenting some general considerations relative to the bacterial flora of the human digestive tract in health, and showing that none of the experimental studies made by investigators is really conclusive as to the necessity of bacterial action in the digestive tract for the maintenance of health in adult mammals of the highest type, Dr. Herter proceeded:Clearly, then, the intestinal bacteria are not required to carry on the ordinary digestive processes of normal nutrition. It has been supposed that the intestinal bacteria aid in the digestion of cellulose which they are undoubtedly able to decompose fermentatively. This argument loses much of its force if it be true, as lately maintained by Bergmann, that most of the cellulose eaten by herbivora is provided with intracellular enzymes capable of decomposing cellulose.The real significance of the normal intestinal flora probably lies, not in any immediate relation to processes of digestion but
Method for economic evaluation of bacterial whole genome sequencing surveillance compared to standard of care in detecting hospital outbreaks.

BACKGROUND Whole genome sequencing (WGS) surveillance and electronic health record data mining have the potential to greatly enhance the identification and control of hospital outbreaks. The objective was to develop methods for examining economic value of a WGS surveillance-based infection prevention (IP) program compared to Standard of Care (SoC). METHODS The economic value of a WGS surveillance-based IP program was assessed from a hospital's perspective using historical outbreaks from 2011-2016. We used transmission network of outbreaks to estimate incremental cost per transmission averted. The number of transmissions averted depended on the effectiveness of intervening against transmission routes, time from transmission to positive culture results and time taken to obtain WGS results and intervene on the transmission route identified. The total cost of an IP program included cost of staffing, WGS, and treating infections. RESULTS Approximately 41 out of 89 (46%) transmissions could have been averted under the WGS surveillance-based IP program and it was found to be a less costly and more effective strategy than SoC. The results were most sensitive to the cost of performing WGS and the number of isolates sequenced per year under WGS surveillance. The probability of the WGS surveillance-based IP program being cost-effective was 80% if willingness to pay exceeded $2,400 per transmission averted. CONCLUSIONS The proposed economic analysis is a useful tool to examine economic value of a WGS surveillance-based IP program. These methods will be applied to a prospective evaluation of WGS surveillance compared to SoC.
Targeted inhibition of thrombin attenuates murine neonatal necrotizing enterocolitis

Significance Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants and is a leading cause of death in these patients. It is an orphan disease with no specific treatment. In this study, we investigated the mechanisms of NEC-related thrombocytopenia, a characteristic feature of this disease. We tested the hypothesis that platelet activation and depletion occur during NEC once mucosal disruption is well established and is secondary to bacterial translocation across the damaged mucosa. Surprisingly, platelet activation turned out to be an early thrombin-mediated pathogenetic event during NEC-like injury. We show that a targeted nanomedicine approach to inhibit thrombin can attenuate NEC-like injury. If confirmed in clinical studies, this would be a specific treatment for NEC. Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants and an orphan disease with no specific treatment. Most patients with confirmed NEC develop moderate-severe thrombocytopenia requiring one or more platelet transfusions. Here we used our neonatal murine model of NEC-related thrombocytopenia to investigate mechanisms of platelet depletion associated with this disease [K. Namachivayam, K. MohanKumar, L. Garg, B. A. Torres, A. Maheshwari, Pediatr. Res. 81, 817–824 (2017)]. In this model, enteral administration of immunogen trinitrobenzene sulfonate (TNBS) in 10-d-old mouse pups produces an acute necrotizing ileocolitis resembling human NEC within 24 h, and these mice developed thrombocytopenia at 12 to 15 h. We hypothesized that platelet activation and depletion occur during intestinal injury following exposure to bacterial products translocated across the damaged mucosa. Surprisingly, platelet activation began in our model 3 h after TNBS administration, antedating mucosal injury or endotoxinemia. Platelet activation was triggered by thrombin, which, in turn, was activated by tissue factor released from intestinal macrophages. Compared to adults, neonatal platelets showed enhanced sensitivity to thrombin due to higher expression of several downstream signaling mediators and the deficiency of endogenous thrombin antagonists. The expression of tissue factor in intestinal macrophages was also unique to the neonate. Targeted inhibition of thrombin by a nanomedicine-based approach was protective without increasing interstitial hemorrhages in the inflamed bowel or other organs. In support of these data, we detected increased circulating tissue factor and thrombin-antithrombin complexes in patients with NEC. Our findings show that platelet activation is an important pathophysiological event and a potential therapeutic target in NEC.
Statcking and separatio of photosystem I and photosystem II in plant thylak oid membranes: A physico‐chemical view

The main objective of this article is to highlight important experimental findings and discuss current theories on photosystem segregation and stacking in thylakoid membranes. The facts are put in a framework of recent theoretical developments in the field of membrane biochemistry and biophysics. Some important experiments not considered by the currently accepted theories are discussed. Modifications of these theories in order to incorporate new results are proposed. The currently accepted theories on formation of membrane domains (probably responsible for segregation of photosystem 1 and II) and on interlamellar interactions (stacking) are discussed. Finally, a scheme is put forward summarising the forces which are responsible for organisation of functional structure of thylakoid membranes.
Closing the reporting gap for childhood tuberculosis in South Africa: improving hospital referrals and linkages.

Setting A referral hospital in Cape Town, Western Cape Province, Republic of South Africa. Objective To measure the impact of a hospital-based referral service (intervention) to reduce initial loss to follow-up among children with tuberculosis (TB) and ensure the completeness of routine TB surveillance data. Design A dedicated TB referral service was established in the paediatric wards at Tygerberg Hospital, Cape Town, in 2012. Allocated personnel provided TB education and counselling, TB referral support and weekly telephonic follow-up after hospital discharge. All children identified with TB were matched to electronic TB treatment registers (ETR.Net/EDRWeb). Multivariable logistic regression was used to compare reporting of culture-confirmed and drug-susceptible TB cases before (2007-2009) and during (2012) the intervention. Results Successful referral with linkage to care was confirmed in 267/272 (98%) and successful reporting in 227/272 (84%) children. Children with drug-susceptible, culture-confirmed TB were significantly more likely to be reported during the intervention period than in the pre-intervention period (OR 2.52, 95%CI 1.33-4.77). The intervention effect remained consistent in multivariable analysis (adjusted OR 2.62; 95%CI 1.31-5.25) after adjusting for age, sex, human immunodeficiency virus status and the presence of TB meningitis. Conclusions A simple hospital-based TB referral service can reduce initial loss to follow-up and improve recording and reporting of childhood TB in settings with decentralised TB services.
The Role of Gut Dysbiosis in the Bone–Vascular Axis in Chronic Kidney Disease

Patients with chronic kidney disease (CKD) are at increased risk of bone mineral density loss and vascular calcification. Bone demineralization and vascular mineralization often concur in CKD, similar to what observed in the general population. This contradictory association is commonly referred to as the ‘calcification paradox’ or the bone–vascular axis. Mounting evidence indicates that CKD-associated gut dysbiosis may be involved in the pathogenesis of the bone–vascular axis. A disrupted intestinal barrier function, a metabolic shift from a predominant saccharolytic to a proteolytic fermentation pattern, and a decreased generation of vitamin K may, alone or in concert, drive a vascular and skeletal pathobiology in CKD patients. A better understanding of the role of gut dysbiosis in the bone–vascular axis may open avenues for novel therapeutics, including nutriceuticals.