Miracle-dz/UniFAR-FTUs huggingface dataset:
In vitro metabolism of mirtazapine enantiomers by human cytochrome P450 enzymes

The metabolism of mirtazapine enantiomers was investigated in vitro using human lymphoblast microsomes transfected with human cDNA to overexpress either CYP1A2, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 and assayed for mirtazapine enantiomers using a validated chiral method of high‐performance liquid chromatography. (+)‐Mirtazapine was extensively metabolised by CYP2D6 (Km = 9.3 ± 3.3 μmol/l, Vmax = 40.9 ± 7.9 μmol/h/mg, intrinsic clearance = 4.41 l/h/mg). CYP1A2 and CYP3A4 showed low metabolic activity towards (+)‐mirtazapine and (−)‐mirtazapine respectively. Neither CYP2C9 nor CYP2C19 appeared to be involved in the metabolism of the enantiomers of mirtazapine. Copyright © 2001 John Wiley & Sons, Ltd.
Significance of non‐sinking particulate organic carbon and dark CO2 fixation to heterotrophic carbon demand in the mesopelagic northeast Atlantic

It is generally assumed that sinking particulate organic carbon (POC) constitutes the main source of organic carbon supply to the deep ocean's food webs. However, a major discrepancy between the rates of sinking POC supply (collected with sediment traps) and the prokaryotic organic carbon demand (the total amount of carbon required to sustain the heterotrophic metabolism of the prokaryotes; i.e., production plus respiration, PCD) of deep‐water communities has been consistently reported for the dark realm of the global ocean. While the amount of sinking POC flux declines exponentially with depth, the concentration of suspended, buoyant non‐sinking POC (nsPOC; obtained with oceanographic bottles) exhibits only small variations with depth in the (sub)tropical Northeast Atlantic. Based on available data for the North Atlantic we show here that the sinking POC flux would contribute only 4–12% of the PCD in the mesopelagic realm (depending on the primary production rate in surface waters). The amount of nsPOC potentially available to heterotrophic prokaryotes in the mesopelagic realm can be partly replenished by dark dissolved inorganic carbon fixation contributing between 12% to 72% to the PCD daily. Taken together, there is evidence that the mesopelagic microheterotrophic biota is more dependent on the nsPOC pool than on the sinking POC supply. Hence, the enigmatic major mismatch between the organic carbon demand of the deep‐water heterotrophic microbiota and the POC supply rates might be substantially smaller by including the potentially available nsPOC and its autochthonous production in oceanic carbon cycling models.
Allosteric Adenosine Receptor Modulation Reduces Hypersensitivity Following Peripheral Inflammation by a Central Mechanism

Activation of adenosine A1 receptors by endogenous adenosine or synthetic agonists produces antinociception in animal models of acute pain and also reduces hypersensitivity in models of inflammatory and nerve-injury pain. Allosteric adenosine modulators facilitate and potentate the action of adenosine agonists at the A1 receptors. The purpose of the current study was to examine the effect and site of action for an allosteric adenosine modulator, T62 [2-amino-3-(4-chlorobenzoyl)-5,6, 7,8-tetrahydrobenzothiophene], in rat models of acute pain and inflammation. Intrathecal (i.t.) T62 did not change the withdrawal latency or threshold of normal rats to acute heat or to acute paw pressure. In contrast, i.t. T62 reversed thermal hypersensitivity in carrageenin-inflamed rats. Subcutaneous (s.c.) injection of T62 into the inflamed paw had no such effect. To investigate a potential site of action on nociceptors, single-unit afferent activity to mechanical stimuli on Aδ- and C-fibers was examined in normal or carrageenin-inflamed rats before and after intravenous (i.v.) T62 administration. Intravenous T62, 3 mg/kg, had no significant effect in either normal or inflamed conditions. These results support previous studies to suggest that adenosine receptor modulators lack efficacy to acute nociceptive stimuli in the normal condition, but reduce hypersensitivity during inflammation through a central mechanism.
DPP-4 Inhibition on Top of Angiotensin Receptor Blockade Offers a New Therapeutic Approach for Diabetic Nephropathy

Background: The need for an improved treatment for diabetic nephropathy is greatest in patients who do not adequately respond to angiotensin II receptor blockers (ARBs). This study investigated the effect of the novel dipeptidyl peptidase-4 inhibitor linagliptin alone and in combination with the ARB telmisartan on the progression of diabetic nephropathy in diabetic endothelial nitric oxide synthase (eNOS) knockout mice. Methods: Sixty male eNOS knockout C57BL/6J mice were divided into four groups after receiving intraperitoneal highdose streptozotocin: telmisartan (1 mg/kg), linagliptin (3 mg/kg), linagliptin + telmisartan (3 mg/kg + 1 mg/kg) and vehicle. Fourteen mice were used as non-diabetic controls. Results: After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan alone reduced systolic blood pressure by 5.9 mmHg versus diabetic controls (111.2 ± 2.3 mmHg vs 117.1 ± 2.2 mmHg; mean ± SEM; P=0.071). Combined treatment significantly reduced albuminuria compared with diabetic controls (71.7 ± 15.3 µg/24 h vs 170.8 ± 34.2 µg/24 h; P=0.017), whereas the effects of single treatment with either telmisartan (97.8 ± 26.4 µg/24 h) or linagliptin (120.8 ± 37.7 µg/24 h) were not statistically significant. DPP-4 inhibition, alone and in combination, led to significantly lower plasma osteopontin levels compared with telmisartan alone. Histological analysis revealed reduced glomerulosclerosis after Linagliptin alone and in combination with telmisartan in comparison to non treated diabetic animals (p<0.01 and p<0.05). Kidney malonaldehyde immune-reactivity, a marker of oxidative stress, was significantly lower in animals treated with linagliptin. Conclusions: DPP-4 inhibition on top of ARB treatment significantly reduced urinary albumin excretion and oxidative stress in diabetic eNOS knockout mice. Linagliptin on top of an angiotensin II receptor blocker may offer a new therapeutic approach for patients with diabetic nephropathy.
A Stack Model for Symbolic Buffer Overflow Exploitability Analysis

Vulnerability analysis aims to detect programming flaws inside software code in order to prevent their exploitation by external attackers, for instance by control-flow hijacking. One of the most challenging issues in vulnerability analysis is being able to distinguish between exploitable and nonexploitable flaws. In this work we propose a symbolic approach to assess the exploitability level of a path leading to a flaw. This approach operates on (disassembled) binary code and starts with the identification of “dangerous paths”, i.e., paths containing some patterns that depend on inputs. Then, we produce the corresponding path conditions augmented by symbolic constraints dedicated to exploitability.
Positionally‐dependent chondrogenesis induced by BMP4 is co‐regulated by sox9 and msx2

Cranial neural crest cells emigrate from the posterior midbrain and anterior hindbrain to populate the first branchial arch and eventually differentiate into multiple cell lineages in the maxilla and mandible during craniofacial morphogenesis. In the developing mouse mandibular process, the expression profiles of BMP4, Msx2, Sox9, and type II collagen demonstrate temporally and spatially restrictive localization patterns suggestive of their functions in the patterning and differentiation of cartilage. Under serumless culture conditions, beads soaked in BMP4 and implanted into embryonic day 10 (E10) mouse mandibular explants induced ectopic cartilage formation in the proximal position of the explant. However, BMP4‐soaked beads implanted at the rostral position did not have an inductive effect. Ectopic chondrogenesis was associated with the up‐regulation of Sox9 and Msx2 expression in the immediate vicinity of the BMP4 beads 24 hours after implantation. Control beads had no effect on cartilage induction or Msx2 and Sox9 expression. Sox9 was induced at all sites of BMP4 bead implantation. In contrast, Msx2 expression was induced more intensely at the rostral position when compared with the proximal position, and suggested that Msx2 expression was inhibitory to chondrogenesis. To test the hypothesis that over‐expression of Msx2 inhibits chondrogenesis, we ectopically expressed Msx2 in the mandibular process organ culture system using adenovirus gene delivery strategy. Microinjection of the Msx2‐adenovirus to the proximal position inhibited BMP4‐induced chondrogenesis. Over‐expression of Msx2 also resulted in the abrogation of endogenous cartilage and the down‐regulation of type II collagen expression. Taken together, these results suggest that BMP4 induces chondrogenesis, the pattern of which is positively regulated by Sox9 and negatively by Msx2. Chondrogenesis only occurs at sites where Sox9 expression is high relative to that of Msx2. The combinatorial action of these transcription factors appear to establish a threshold for Sox9 function and thereby restricts the position of chondrogenesis. Dev Den;217:401–414. © 2000 Wiley‐Liss, Inc.
Occupational exposures to aluminum and iron and risk of lung epithelium atypia in sudan

This study investigated the risk of lung cytological atypical changes in regards to occupational exposure to aluminum and iron. Detailed job histories were elicited from 130 incident cases with confirmed exposure to aluminum (50) or iron (80) and 157 population controls (nonexposed). Cytological atypia in sputum (dysplasia) was identified in four cases and none of controls (RR =10.8550; 95% CI = 0.5898 to 199.7815, P = 0.1086), hence, metaplasia was observed among 15 (11.5%) of the cases and 10 (6%) of controls (RR = 1.8115; 95% CI = 0.8424–3.8956; P = 0.1283). Evidences of viral infection were observed in 18 (14%) of the cases and 8 (5%) of controls (RR = 2.7173; 95% CI = 1.2213–6.0460; P = 0.0143). Moniliasis was observed in 28 (22%) of the cases and 19 (12%) of controls (RR = 1.6632; 95% CI = 0.9728–2.8435; P = 0.06). Cross‐categorizations of aluminum exposure and iron use suggest greater risk associated with iron exposure than aluminum in these workers. Diagn. Cytopathol. 2013. © 2012 Wiley Periodicals, Inc.
Outcome of fractures of dorso lumbar spine treated by short segment posterior stabilization with intermediate pedicle screws

Background: Spine fractures are common in today’s world due to high frequency of motor vehicle accidents and work place injuries. These are major cause of disability in adult population. The mortality rate following spinal injuries is 7%. The aim of the study was to study the functional and radiological outcome of fractures of dorso lumbar spine treated by short segment posterior stabilization with intermediate pedicle screws.Methods: Dorso-lumbar fractures with intact pedicle on the fractured segment, Load sharing classification score of equal or less than 6, Neurologic involvement caused by the fracture, loss of vertebral body height by more than 50% and kyphosis angle more than 20° are included. Patients with multiple level fractures and pathological fractures were excluded from the study. Denis classification and AO classification were used. Load sharing score is used to decision making for intermediate screw fixation.Results: L1 is more frequently fractured followed by D12. Distraction type (AO) and burst (Denis) are most common types. 4 of our patients had complete neurological deficit. 15 had incomplete deficit and 11 patients doesn’t have any neurological involvement. Frankel A grade cases remained in the same grade. Mean Kyphotic correction is 6.7°. Mean AVBCP in the postoperative cases 26. None of the cases developed kyphosis or loss of correction in the follow up. Outcome using Roland Morris disability questionnaire is excellent in 64.3%, good in 21.6% and poor in 14.3% cases.Conclusions: To conclude that short segment posterior stabilisation with intermediate screws provides better biomechanical stability when compared with conventional short segment fixation.
Biased partitioning of the multidrug efflux pump AcrAB-TolC underlies long-lived phenotypic heterogeneity

Drug efflux machinery inherited asymmetrically In dividing bacterial cells, asymmetric distribution of cell wall constituents occurs between mother cells and their progeny. Asymmetric distribution of efflux machinery in a growing population of bacterial cells results in heterogeneity in antibiotic resistance. One consequence is that in the presence of low levels of antibiotic, older cells tend to live longer than younger cells. Using a microfluidic device to trap and measure dividing cells, Bergmiller et al. showed that AcrAB-TolC, the main multidrug efflux pump of Escherichia coli, clusters at the pole of older cells (see the Perspective by Barrett et al.). As cell division proceeds and daughter cells age, they too gradually accumulate polar efflux pumps. Science, this issue p. 311; see also p. 247 Skewed inheritance of drug-efflux machinery means older bacterial cells show greater antibiotic resistance than their daughters. The molecular mechanisms underlying phenotypic variation in isogenic bacterial populations remain poorly understood. We report that AcrAB-TolC, the main multidrug efflux pump of Escherichia coli, exhibits a strong partitioning bias for old cell poles by a segregation mechanism that is mediated by ternary AcrAB-TolC complex formation. Mother cells inheriting old poles are phenotypically distinct and display increased drug efflux activity relative to daughters. Consequently, we find systematic and long-lived growth differences between mother and daughter cells in the presence of subinhibitory drug concentrations. A simple model for biased partitioning predicts a population structure of long-lived and highly heterogeneous phenotypes. This straightforward mechanism of generating sustained growth rate differences at subinhibitory antibiotic concentrations has implications for understanding the emergence of multidrug resistance in bacteria.
Inclusive trauma systems: do they improve triage or outcomes of the severely injured?

BACKGROUND Trauma systems decrease injury-related mortality, but not all systems have the same configuration. In some systems, nearly all acute care hospitals participate to the extent that their resources allow (inclusive systems), whereas in others, relatively few high-level centers participate (exclusive systems). We postulate that inclusive systems assure that severely injured patients are more likely to be triaged to a level I or II regional trauma center, and this greater degree of participation would lead to lower mortality. METHODS We used administrative discharge data for 2001 in 24 states with formal systems, and we included all urgently hospitalized adults with an Injury Severity Score>or=16. We categorized states by trauma system configuration ("exclusive", "more inclusive", "most inclusive") based on the proportion of all hospitals designated as a Level I through V trauma center (0-13%, 14-37%, 38-100%, respectively). We compared the rates of triage to a regional trauma center and inpatient death in inclusive states relative to exclusive states, while adjusting for patient- and state-level factors. RESULTS Out of 61,496 patients, 40,706 (66.2%) were hospitalized at regional trauma centers. Inpatient mortality was 14.7%. After adjusting for patient age, primary payer status, and system maturity, the odds of triage to a regional trauma center were similar in inclusive and exclusive systems. After adjusting for primary payer status, mechanism of injury, and system maturity, the odds of death were similar in more inclusive and exclusive systems (odds ratio, 0.93; 95% confidence interval, 0.80-1.08) but were significantly lower in the most inclusive systems (odds ratio, 0.77; 95% confidence interval, 0.60-0.99). CONCLUSIONS Severely injured trauma patients have greater inpatient survival in inclusive trauma systems even though they are no more likely to be hospitalized at a regional trauma center. Consideration should be given to continuing implementation of systems with an inclusive configuration, especially in light of other theoretical benefits of these systems, such as better dispersing of trauma care resources in the event of natural disasters or terrorist events.
A model for the evolution of the genome : The effect of stochasticity on genetic loads

In this paper a general model is given for the evolution of the genome incorporating stochastic factors. The model is applied to the substitutional genetic load problem. All of the major hard selection load formulae in the literature are extended and, where necessary, corrected (for stochasticity). Turning to rank selection, formulae for stochastic factors are also corrected and harmful mutations included. A simple formula for the selection coefficient as a function of the nonneutral substitution rate and the mutation profile is obtained. Further, it is noted that the formulae derived also apply (for different parameter values) to the mutation load, thus unifying the two loads under a single theory. A general formula for the mutation load under hard selection is given, extending previous results. Finally, the author derives a formula showing how many harmful mutations can be effectively eliminated by rank selection and discusses its relevance to the question of the possible buildup of harmful mutations in the human gene pool due to long-term exposure to low-level radiation.
Acclimation of sperm motility apparatus in seawater-acclimated euryhaline tilapia Oreochromis mossambicus

SUMMARY Euryhaline tilapia Oreochromis mossambicus can reproduce in freshwater and in seawater. Regulation of sperm motility appears to be modulated during acclimation of the fish from freshwater to seawater, being independent of extracellular Ca2+ in freshwater and dependent on extracellular Ca2+ in seawater. In the presence of extracellular Ca2+, sperm of seawater-acclimated tilapia (SWT) showed motility even in a hypertonic environment, whereas sperm of freshwater-acclimated tilapia (FWT) were not motile. The Ca2+ indicator, fluo-3, revealed that intracellular Ca2+ concentration, [Ca2+]i, of SWT sperm increased only in the presence of extracellular Ca2+ in hypotonic or hypertonic conditions. Since the increased [Ca2+]i in FWT sperm occurred under hypotonic conditions via intracellular Ca2+ stores, it is likely that tilapia modulate their source of increasing [Ca2+]i from intracellular stores (in FWT sperm) to extracellular stores (in SWT sperm). Experiments using demembranated sperm revealed that Ca2+ is necessary for activation of motility, suggesting that Ca2+ plays a key role in motility regulation in SWT sperm. We detected three phosphoproteins associated with the activation of sperm motility. Serine and threonine residues of two proteins of 15 kDa and 18 kDa became dephosphorylated in hypotonic conditions but remained phosphorylated in hypertonic conditions, suggesting that these protein phosphorylations were not only related to motility activation under hypertonic conditions but also resistant to osmotic pressure. The threonine residue(s) of a 41 kDa protein was also phosphorylated in dry sperm, even in FWT sperm in motility-feasible hypotonic conditions. It is likely that acclimation of the motility apparatus is associated with modulation of the flow of Ca2+ to increase [Ca2+]i and protein phosphorylation.
Pan-Cancer Study Detects Novel Genetic Risk Variants and Shared Genetic Basis in Two Large Cohorts

Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. However, no studies have investigated pan-cancer pleiotropy within single, well-defined populations unselected for phenotype. We undertook novel genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (413,870 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detected 21 novel genome-wide significant risk variants. In addition, numerous cancer sites exhibited clear heritability. Investigations of pleiotropy identified 12 cancer pairs exhibiting either positive or negative genetic correlations and 43 pleiotropic loci. We identified 158 pleiotropic variants, many of which were enriched for regulatory elements and influenced cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.
An Innovative Quasi Newton Method for Enhancing Ultrasound Medical Image Quality

The aim of this paper is to introduce a novel variational method for enhancement of quality of ultrasound image. Medical imaging provides an effective and non-invasive mapping of the anatomy of human body. Pathological conditions of body tissues produce different image patterns and the patterns exhibited by the biological tissues through their images have been in routine clinical use for medical diagnosis purposes. Medical image understanding is a computing process of object recognition in medical image using computer vision, applied mathematics, signal analysis and artificial intelligence Image processing is the use of computer algorithms to perform image processing on digital images. Quasi-Newton (QN) based iteration of the proposed algorithm helps in converging towards a saddle point with locally isotropic convergence. This convergence is regardless of the spatial and spectral distributions of medical images. Hence, this proposed QN – UICA (Unbiased Independent Component Analysis) gives major contribution in the classification of medical images. The experimental results show that the proposed QN-UICA has better classification accuracy and convergence rate to resolve the problems of mixed classes in the medical image classification. Keywords-Median Filter, Fuzzy C-Means Segmentation, Quasi-Newton, Ultrasound Images.