Miracle-dz/UniFAR-FTUs huggingface dataset:
The role of gut microbiota in the modulation of drug action: a focus on some clinically significant issues

ABSTRACT Introduction: A healthy gut microbiota is necessary for the normal operation of several body functions, including gastrointestinal sensitivity and motility, lipid and glucid metabolism, immune surveillance, and host behavior. In addition, intestinal bacteria contribute to determining the pharmacological properties of several drugs by producing different drug metabolizing enzymes. Areas covered: Four enzymatic processes are discussed: prodrug activation; drug inactivation; drug deconjugation; and hydrolysis of natural glycosides with further metabolism of released aglycones. For each of these processes, a literature search has been undertaken on certain paradigmatic examples that have significant clinical implications: aminosalicylates and anthranoid laxatives; digoxin; irinotecan and non-steroidal anti-inflammatory drugs (NSAIDs); rutin, diosmin, and baicalin. Expert commentary: The modulation of certain reactions catalyzed by gut bacterial enzymes may offer new opportunities to improve the clinical efficacy of drugs such as aminosalicylates, and natural glycosides by increasing their metabolic transformation, and of digoxin by reducing its inactivation, or to decrease the lower intestinal toxicity of irinotecan, and NSAIDs by inhibiting the hydrolytic cleavage of their conjugates. Randomized clinical trials are awaited to clarify whether new intervention strategies may modulate these processes and provide clinical benefits such as improved therapeutic outcomes and drug safety profiles.
Flux analysis shows that hypoxia‐inducible‐factor‐1‐alpha minimally affects intracellular metabolism in tumor spheroids

Heterogeneous metabolic microenvironments in tumors affect local cell growth, survival, and overall therapeutic efficacy. Hypoxia‐inducible‐factor‐1α (HIF‐1α) is a transcription factor that responds to low‐oxygen environments by upregulating genes for cell survival and metabolism. To date, the metabolic effects of HIF‐1α in three‐dimensional tissue have not been investigated. Preliminary experiments have shown that the effects of HIF‐1α are dependent on glucose availability. Based on this observation, we hypothesized that HIF‐1α would not affect cell survival and metabolism in the center of spheroids, where the concentrations of oxygen and glucose are low, similar to hypoxic regions found in tumors. To test this hypothesis we used fluorescence microscopy and the tumor cylindroid model to quantify cellular viability in three‐dimensional tissue. Isotope labeling and metabolic flux analysis were also used to quantity the intracellular metabolism of wild‐type and HIF‐1α‐null spheroids. As hypothesized, cell survival and intracellular metabolism were not different between wild‐type and HIF‐1α‐null tissues. In addition, small spheroids, which contain less quiescent cells and are less nutritionally limited, were found to have increased carbon flux through the biosynthetic pentose phosphate and pyruvate carboxylase pathways. These results show how nutrient gradients affect cell growth and metabolism in spheroids and suggest that metabolic microenvironment should be taken into account when developing HIF‐1α‐based therapies. Biotechnol. Bioeng. 2007;96:1167–1182. © 2006 Wiley Periodicals, Inc.
Aberrant Mitochondria in a Bethlem Myopathy Patient with a Homozygous Amino Acid Substitution That Destabilizes the Collagen VI α2(VI) Chain*

Background: Collagen VI amino acid substitutions are common, and it is difficult to determine if they are pathogenic. Results: COL6A2 p.D871N chains are abnormal and cannot assemble. Alternatively spliced chains lacking the mutation cannot functionally substitute. Conclusion: COL6A2 p.D871N is a recessive mutation. Significance: Protein studies reveal the consequences of amino acid substitutions in the globular domains of collagen VI. Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD) sit at opposite ends of a clinical spectrum caused by mutations in the extracellular matrix protein collagen VI. Bethlem myopathy is relatively mild, and patients remain ambulant in adulthood while many UCMD patients lose ambulation by their teenage years and require respiratory interventions. Dominant and recessive mutations are found across the entire clinical spectrum; however, recessive Bethlem myopathy is rare, and our understanding of the molecular pathology is limited. We studied a patient with Bethlem myopathy. Electron microscopy of his muscle biopsy revealed abnormal mitochondria. We identified a homozygous COL6A2 p.D871N amino acid substitution in the C-terminal C2 A-domain. Mutant α2(VI) chains are unable to associate with α1(VI) and α3(VI) and are degraded by the proteasomal pathway. Some collagen VI is assembled, albeit more slowly than normal, and is secreted. These molecules contain the minor α2(VI) C2a splice form that has an alternative C terminus that does include the mutation. Collagen VI tetramers containing the α2(VI) C2a chain do not assemble efficiently into microfibrils and there is a severe collagen VI deficiency in the extracellular matrix. We expressed wild-type and mutant α2(VI) C2 domains in mammalian cells and showed that while wild-type C2 domains are efficiently secreted, the mutant p.D871N domain is retained in the cell. These studies shed new light on the protein domains important for intracellular and extracellular collagen VI assembly and emphasize the importance of molecular investigations for families with collagen VI disorders to ensure accurate diagnosis and genetic counseling.
Mercury in Yellow-cracking Boletes Xerocomus subtomentosus mushrooms and soils from spatially diverse sites: Assessment of bioconcentration potential by species and human intake

This study investigated the Hg concentrations in Yellow-cracking Boletes Xerocomus subtomentosus mushrooms and beneath soils collected from the wild at twelve sites across Poland. This mushroom species has some potential to bioconcentrate Hg in the fruiting bodies, and the amount of Hg sequestered, depending on geographical location, can pose health risk to consumers. The values of Hg bioconcentration factor (BCF) varied for the sites between 0.80 ± 0.20 and 17 ± 12 in caps and 0.50 ± 0.10 and 7.9 ± 6.6 in stipes of fruiting bodies but decreased as soil Hg content increased from 72 ± 32 to 570 ± 130 ng/g dry weight. The specimens collected from minerals rich area of Złotoryja contained the highest Hg concentration, which reached 630 ± 400 in caps and 420 ± 260 ng/g dw in stipes, while the lowest observed Hg concentrations at the other sites were 72 ± 32 and 57 ± 13 ng/g, for cap and stipes respectively. Available literature data on Hg in Yellow-cracking Boletes was also up-dated.
Linaclotide in irritable bowel syndrome with constipation: A Phase 3 randomized trial in China and other regions

Linaclotide is a guanylate cyclase‐C agonist approved in multiple countries to treat irritable bowel syndrome with constipation (IBS‐C). China has unmet need for well‐tolerated therapy that is effective in treating both bowel and abdominal symptoms of IBS‐C. This trial evaluated linaclotide's efficacy and safety in IBS‐C patients in China and other regions.
Rainbow Turán Problems for Paths and Forests of Stars

For a fixed graph $F$, we would like to determine the maximum number of edges in a properly edge-colored graph on $n$ vertices which does not contain a {\emph rainbow copy} of $F$, that is, a copy of $F$ all of whose edges receive a different color. This maximum, denoted by $ex^*(n,F)$, is the {\emph rainbow Tur\'an number} of $F$, and its systematic study was initiated by Keevash, Mubayi, Sudakov and Verstra\"ete in 2007. We determine $ex^*(n,F)$ exactly when $F$ is a forest of stars, and give bounds on $ex^*(n,F)$ when $F$ is a path with $k$ edges, disproving a conjecture in Keevash et al.
The effect of white matter hyperintensities on verbal memory

Objective To determine the relationship between white matter hyperintensities (WMH) presumed to indicate disease of the cerebral small vessels, temporal lobe atrophy, and verbal memory deficits in Alzheimer disease (AD) and other dementias. Methods We recruited groups of participants with and without AD, including strata with extensive WMH and minimal WMH, into a cross-sectional proof-of-principle study (n = 118). A consecutive case series from a memory clinic was used as an independent validation sample (n = 702; Sunnybrook Dementia Study; NCT01800214). We assessed WMH volume and left temporal lobe atrophy (measured as the brain parenchymal fraction) using structural MRI and verbal memory using the California Verbal Learning Test. Using path modeling with an inferential bootstrapping procedure, we tested an indirect effect of WMH on verbal recall that depends sequentially on temporal lobe atrophy and verbal learning. Results In both samples, WMH predicted poorer verbal recall, specifically due to temporal lobe atrophy and poorer verbal learning (proof-of-principle −1.53, 95% bootstrap confidence interval [CI] −2.45 to −0.88; and confirmation −0.66, 95% CI [−0.95 to −0.41] words). This pathway was significant in subgroups with (−0.20, 95% CI [−0.38 to −0.07] words, n = 363) and without (−0.71, 95% CI [−1.12 to −0.37] words, n = 339) AD. Via the identical pathway, WMH contributed to deficits in recognition memory (−1.82%, 95% CI [−2.64% to −1.11%]), a sensitive and specific sign of AD. Conclusions Across dementia syndromes, WMH contribute indirectly to verbal memory deficits considered pathognomonic of Alzheimer disease, specifically by contributing to temporal lobe atrophy.
Characteristics evaluation of the novel robotic catheter system

In this paper, a novel robotic catheter system was proposed, which can be used to assist surgeon to do the operation of vascular interventional surgery (VIS), the robotic catheter system can measure the contact force and friction between catheter and blood vessel, we used load cell to measure the friction between catheter and blood vessel, the friction can be transmitted to the operator's hand as feedback force, and this method was not paid attention in the past research, furthermore, we used an optical fiber force sensor to measure the contact force between catheter tip and blood vessel, the contact force information can be transmitted to the operator as visual information in real time. Meanwhile, the optical fiber force sensor is through inside the catheter as a guide wire, which is served to lead catheter forward. We did the simulation experiment (“In Vitro”) by using endovascular evaluator (EVE), the experimental results indicated that the developed robotic catheter system works well, and they can effectively assist surgeon to do the operation and improve safety during VIS.
A sophisticated convolutional neural network model for brain tumor classification

Magnetic Resonance Imaging(MRI) is one of the commonly used medical imaging modality that provides informative data for brain tumor diagnosis other than Computed Tomography(CT). A key challenge when a physician studies the MRI data is the time and effort he has to put in diagnosing the tumors. The objective of this research is to recognize the tumor type when a collection of MRI images of a patient is given. To achieve this goal, a deep learning algorithm is developed using Convolutional Neural Networks(CNNs). Nowadays, most of image classification problems use CNNs as they deliver higher precision and accuracy compared to other existing algorithms. Here, a sophisticated CNN model is developed, trained using cross validation and tested on brain MRI images obtained from open databases. The performance of the proposed model is promising.
Religiousness, Spirituality, and Salivary Cortisol in Breast Cancer Survivorship: A Pilot Study

Background: Psychoneuroimmunological theory suggests a physiological relationship exists between stress, psychosocial-behavioral factors, and neuroendocrine-immune outcomes; however, evidence has been limited. Objective: The primary aim of this pilot study was to determine feasibility and acceptability of a salivary cortisol self-collection protocol with a mail-back option for breast cancer survivors. A secondary aim was to examine relationships between religiousness/spirituality (R/S), perceptions of health, and diurnal salivary cortisol (DSC) as a proxy measure for neuroendocrine activity. Methods: This was an observational, cross-sectional study. Participants completed measures of R/S, perceptions of health, demographics, and DSC. Results: The sample was composed of female breast cancer survivors (n = 41). Self-collection of DSC using a mail-back option was feasible; validity of mailed salivary cortisol biospecimens was established. Positive spiritual beliefs were the only R/S variable associated with the peak cortisol awakening response (rs = 0.34, P = .03). Poorer physical health was inversely associated with positive spiritual experiences and private religious practices. Poorer mental health was inversely associated with spiritual coping and negative spiritual experiences. Conclusions: Feasibility, validity, and acceptability of self-collected SDC biospecimens with an optional mail-back protocol (at moderate temperatures) were demonstrated. Positive spiritual beliefs were associated with neuroendocrine-mediated peak cortisol awakening response activity; however, additional research is recommended. Implications for Practice: Objective measures of DSC sampling that include enough collection time points to assess DSC parameters would increase the rigor of future DSC measurement. Breast cancer survivors may benefit from nursing care that includes spiritual assessment and therapeutic conversations that support positive spiritual beliefs.
Genetic analysis of calf health in Charolais beef cattle1

Abstract The objective of this study was to investigate the factors that influence calf health and survival in Charolais cattle. Data from 2,740 calves, originating from 16 French farms and observed from birth until 30 d of age, were analyzed using models that took account of direct genetic, maternal genetic, and common environmental effects. Both direct and maternal genetic parameters were estimated for birth weight (BW), calving ease (CE), neonatal vitality (NV), survival at 30 d (Surv), and umbilical infection and diarrhea at different ages (0 to 5 d: Umb1 and Diar1; 6 to 20 d: Umb2 and Diar2; and 21 to 30 d: Umb3 and Diar3). The heritability values for direct and maternal genetic effects were, 0.026 (SE = 0.027) and 0.096 (SE = 0.042) for Surv, 0.280 (SE = 0.063) and 0.063 (SE = 0.038) for BW, 0.129 (SE = 0.041) and 0 for CE, 0.073 (SE = 0.035) and 0 for NV, 0.071 (SE = 0.038) and 0.017 (SE = 0.026) for Umb1, 0 and 0.082 (SE = 0.029) for Umb2, 0 and 0.044 (SE = 0.030) for Diar1, 0.016 (SE = 0.022) and 0.012 (SE = 0.026) for Diar2, and 0.016 (SE = 0.028) and 0 for Diar3, respectively. Significant genetic variability in beef cattle was thus revealed for five calf health traits: NV, Surv, Diar1, Umb1, and Umb2. In addition, for three traits (Surv, Diar1, and Umb2), maternal genetic effects clearly contributed more to health performance than direct genetic effects. Estimates of genetic correlation between traits varied markedly (from 0 to 1 in absolute values) depending on the traits in question, the age for a given trait, and the type (direct or maternal) of the genetic effects considered. These results suggest that not all health traits in Charolais cattle can be improved simultaneously, and breeders will therefore have to prioritize certain traits of interest in their breeding objectives. Overall, our results demonstrate the potential utility of collecting and integrating data on calf diseases, NV and survival in future beef cattle breeding programs. To ensure appropriate biological and genetic evaluations of calf health performance, it is important to accurately describe the phenotypes for diarrhea and umbilical infections (in terms of age ranges) and account for maternal genetic and common environmental effects that explain calf health performance traits. Further investigation and improved data collection are now necessary to maximize the efficiency of breeding schemes designed to simultaneously improve production and health traits.
Bags of phrases with codebooks alignment for near duplicate image detection

Image retrieval from large databases, such as popular social networks, collections of surveillance images and videos, or digital investigation archives, is a very important task for a number of applications. In digital investigation, hashing techniques are commonly used to index large quantities of images to detect copies from different archives. In the last few years, a number of image hashing techniques based on the Bags of Visual Words paradigm have been proposed. Recently, this paradigm has been augmented by using multiple descriptors (Bags of Visual Phrases) to exploit the coherence between different feature spaces. In this paper we propose to further improve the Bags of Visual Phrases approach exploiting the coherence between feature spaces not only in the image representation, but also in the codebooks generation. Experiments performed on real and synthetic near duplicate image datasets show the effectiveness of the proposed approach, which outperforms the original Bags of Visual Phrases approach.
Combining radiomic features with a miRNA classifier may improve prediction of malignant pathology for pancreatic intraductal papillary mucinous neoplasms

Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cancer precursors incidentally discovered by cross-sectional imaging. Consensus guidelines for IPMN management rely on standard radiologic features to predict pathology, but they lack accuracy. Using a retrospective cohort of 38 surgically-resected, pathologically-confirmed IPMNs (20 benign; 18 malignant) with preoperative computed tomography (CT) images and matched plasma-based ‘miRNA genomic classifier (MGC)’ data, we determined whether quantitative ‘radiomic’ CT features (+/- the MGC) can more accurately predict IPMN pathology than standard radiologic features ‘high-risk’ or ‘worrisome’ for malignancy. Logistic regression, principal component analyses, and cross-validation were used to examine associations. Sensitivity, specificity, positive and negative predictive value (PPV, NPV) were estimated. The MGC, ‘high-risk,’ and ‘worrisome’ radiologic features had area under the receiver operating characteristic curve (AUC) values of 0.83, 0.84, and 0.54, respectively. Fourteen radiomic features differentiated malignant from benign IPMNs (p<0.05) and collectively had an AUC=0.77. Combining radiomic features with the MGC revealed an AUC=0.92 and superior sensitivity (83%), specificity (89%), PPV (88%), and NPV (85%) than other models. Evaluation of uncertainty by 10-fold cross-validation retained an AUC>0.80 (0.87 (95% CI:0.84-0.89)). This proof-of-concept study suggests a noninvasive radiogenomic approach may more accurately predict IPMN pathology than ‘worrisome’ radiologic features considered in consensus guidelines.
Residual Lifetime Assessment of an Ancient Riveted Steel Road Bridge

Abstract: The present paper reports research work carried out to characterise the fatigue behaviour of the Portuguese Pinhão riveted road bridge, built in 1903 over the Douro river. The present traffic conditions are completely different from those foreseen by the bridge designer, rising new concerns, with respect to the bridge integrity, namely its fatigue behaviour. An experimental programme was performed using original material removed from the bridge. The chemical composition and microstructures of the removed materials were characterised. Also, the notch toughness, at room temperature, was evaluated using both notch impact and Crack Opening Displacement (COD) tests. Fatigue crack growth tests were also used to evaluate the fatigue crack growth behaviour. Finally, fatigue tests of riveted joints were conducted in order to define an appropriate S‐N curve. The experimental results were used to evaluate the residual fatigue strength of the bridge, adopting both S‐N and Fracture Mechanics approaches. The analysis revealed a good tolerance to fatigue cracking, even in the presence of small fatigue cracks, detected in the joints.
The use of functionally graded dental crowns to improve biocompatibility: a finite element analysis

Abstract In post-core crown restorations, the significant mismatch between stiffness of artificial crowns and dental tissues leads to stress concentration at the interfaces. The aim of the present study was to reduce the destructive stresses by using a class of inhomogeneous materials called functionally graded materials (FGMs). For the purpose of the study, a 3-dimentional computer model of a premolar tooth and its surrounding tissues were generated. A post-core crown restoration with various crown materials, homogenous and FGM materials, were simulated and analyzed by finite element method. Finite element and statistical analysis showed that, in case of oblique loading, a significant difference (p < 0.05) was found at the maximum von Mises stresses of the crown margin between FGM and homogeneous crowns. The maximum von Mises stresses of the crown margin generated by FGM crowns were lower than those generated by homogenous crowns (70.8 vs. 46.3 MPa) and alumina crown resulted in the highest von Mises stress at the crown margin (77.7 MPa). Crown materials of high modulus of elasticity produced high stresses at the cervical region. FGM crowns may reduce the stress concentration at the cervical margins and consequently reduce the possibility of fracture.
Electrophysiological and structural determinants of electrotonic modulation of repolarization by the activation sequence

Spatial dispersion of repolarization is known to play an important role in arrhythmogenesis. Electrotonic modulation of repolarization by the activation sequence has been observed in some species and tissue preparations, but to varying extents. Our study sought to determine the mechanisms underlying species- and tissue-dependent electrotonic modulation of repolarization in ventricles. Epi-fluorescence optical imaging of whole rat hearts and pig left ventricular wedges were used to assess epicardial spatial activation and repolarization characteristics. Experiments were supported by computer simulations using realistic geometries. Tight coupling between activation times (AT) and action potential duration (APD) were observed in rat experiments but not in pig. Linear correlation analysis found slopes of −1.03 ± 0.59 and −0.26 ± 0.13 for rat and pig, respectively (p < 0.0001). In rat, maximal dispersion of APD was 11.0 ± 3.1 ms but dispersion of repolarization time (RT) was relatively homogeneous (8.2 ± 2.7, p < 0.0001). However, in pig no such difference was observed between the dispersion of APD and RT (17.8 ± 6.1 vs. 17.7 ± 6.5, respectively). Localized elevations of APD (12.9 ± 8.3%) were identified at ventricular insertion sites of rat hearts both in experiments and simulations. Tissue geometry and action potential (AP) morphology contributed significantly to determining influence of electrotonic modulation. Simulations of a rat AP in a pig geometry decreased the slope of AT and APD relationships by 70.6% whereas slopes were increased by 75.0% when implementing a pig AP in a rat geometry. A modified pig AP, shortened to match the rat APD, showed little coupling between AT and APD with greatly reduced slope compared to the rat AP. Electrotonic modulation of repolarization by the activation sequence is especially pronounced in small hearts with murine-like APs. Tissue architecture and AP morphology play an important role in electrotonic modulation of repolarization.