Miracle-dz/UniFAR-FTUs huggingface dataset:
Activation of NRF2 by Nitrosative Agents and H2O2 Involves KEAP1 Disulfide Formation*

The NRF2 transcription factor regulates a major environmental and oxidative stress response. NRF2 is itself negatively regulated by KEAP1, the adaptor of a Cul3-ubiquitin ligase complex that marks NRF2 for proteasomal degradation by ubiquitination. Electrophilic compounds activate NRF2 primarily by inhibiting KEAP1-dependent NRF2 degradation, through alkylation of specific cysteines. We have examined the impact on KEAP1 of reactive oxygen and nitrogen species, which are also NRF2 inducers. We found that in untreated cells, a fraction of KEAP1 carried a long range disulfide linking Cys226 and Cys613. Exposing cells to hydrogen peroxide, to the nitric oxide donor spermine NONOate, to hypochlorous acid, or to S-nitrosocysteine further increased this disulfide and promoted formation of a disulfide linking two KEAP1 molecules via Cys151. None of these oxidants, except S-nitrocysteine, caused KEAP1 S-nitrosylation. A cysteine mutant preventing KEAP1 intermolecular disulfide formation also prevented NRF2 stabilization in response to oxidants, whereas those preventing intramolecular disulfide formation were functionally silent. Further, simultaneously inactivating the thioredoxin and glutathione pathways led both to major constitutive KEAP1 oxidation and NRF2 stabilization. We propose that KEAP1 intermolecular disulfide formation via Cys151 underlies the activation of NRF2 by reactive oxygen and nitrogen species.
Hepatic metastases from colorectal carcinoma: Impact of surgical resection on the natural history

From 1960 to 1987, 1209 patients with colorectal liver metastases were recorded, and followed until 1 January 1990. In 242 cases the diagnosis was based on external imaging, whereas 967 patients had operative confirmation and staging of their liver disease. Three groups of patients were analysed: group 1 involved 921 cases, of whom 902 were deemed non‐resectable whereas 19 could not be unequivocally classified. Only 21 patients lived for longer than 3 years, seven survived for 4 years, but there were no 5‐year survivors. Group 2 comprised 62 highly selected patients who at laparotomy demonstrated resectable metastasic spread confined to the liver, but this was not treated mainly because of a formerly different therapeutic approach. These patients had a significantly longer median survival time (14.2 versus 6.9 months), but also failed to achieve 5‐year survival. The 226 patients forming group 3 underwent hepatic resection with intent to cure. Nine of them had minimal macroscopic disease left, and 34 with all gross tumour removed had positive margins. Survival of patients with these 43 eventually non‐radical resections followed an identical course as in group 2 (median survival 13–3 months, maximum 42 months). Of the 183 patients with potentially curative resection ten died after surgery (5.5 per cent). Actuarial 5 and 10‐year survival rates in the remaining 173 patients were 40 and 27 per cent with 25 and seven patients alive at respective periods of time. Until 1 January 1990, 64 patients remained free from recurrent disease for up to 24 years. In three patients the tumour status at death was unclear. The other 106 patients developed definite cancer relapse. Nevertheless they demonstrated a prolongation of survival time by a median of 1 year when compared with the 43 non‐radically resected patients or the 62 untreated patients with resectable liver‐only metastases, and accomplished a maximum survival time of 8 years. Radical excision of colorectal secondaries to the liver therefore offers effective palliation, and in a small number the chance of a cure.
Hsp20-Mediated Activation of Exosome Biogenesis in Cardiomyocytes Improves Cardiac Function and Angiogenesis in Diabetic Mice

Decreased heat shock protein (Hsp) expression in type 1 and type 2 diabetes has been implicated as a primary factor contributing to diabetes-induced organ damage. We recently showed that diabetic cardiomyocytes could release detrimental exosomes, which contain lower levels of Hsp20 than normal ones. To investigate whether such detrimental exosomes could be modified in cardiomyocytes by raising Hsp20 levels to become protective, we used a transgenic (TG) mouse model with cardiac-specific overexpression of Hsp20. TG and control wild-type (WT) mice were injected with streptozotocin (STZ) to induce diabetes. We observed that overexpression of Hsp20 significantly attenuated STZ-caused cardiac dysfunction, hypertrophy, apoptosis, fibrosis, and microvascular rarefaction. Moreover, Hsp20-TG cardiomyocytes exhibited an increased generation/secretion of exosomes by direct interaction of Hsp20 with Tsg101. Of importance, exosomes derived from TG cardiomyocytes encased higher levels of Hsp20, p-Akt, survivin, and SOD1 than WT exosomes and protected against in vitro hyperglycemia-triggered cell death, as well as in vivo STZ-induced cardiac adverse remodeling. Last, blockade of exosome generation by GW4869 remarkably offset Hsp20-mediated cardioprotection in diabetic mice. Our results indicate that elevation of Hsp20 in cardiomyocytes can offer protection in diabetic hearts through the release of instrumental exosomes. Thus, Hsp20-engineered exosomes might be a novel therapeutic agent for diabetic cardiomyopathy.
Robust stability: A relaxation method for the generation of polyhedral Lyapunov functions

In this paper we consider the robustness analysis problem for linear continuous-time systems subject to parametric time-varying uncertainties, making use polyhedral Lyapunov functions. In the literature it has been shown that the class of polyhedral functions is universal for the robust stability problem, while, for instance, the class of quadratic functions is not. This fact justifies the effort of developing efficient algorithms for the construction of optimal polyhedral Lyapunov functions. In this context, we provide a novel convex condition for the construction of a polyhedral Lyapunov function. Finally, to show the effectiveness of the method, we consider a numerical problem that represents a sort of benchmark for the robust stability analysis.
Understanding and Addressing Stigma and Attachment Insecurity in HIV-Positive Women Who Experience Intimate Partner Violence: A Model of Medical and Psychosocial Care

Low-income women of color who are HIV positive and living in violent relationships are at significant risk for stigma and problems with attachment security. This article explores the ways in which these women may experience internalized stigma from incorporating society's negative views of HIV and domestic violence. It also addresses the ways in which insecure attachment may develop or intensify in this population through violence in their adult intimate relationships and/or living with a life threatening illness. A model of medical and psychosocial care utilized at the Women's HIV Program at the University of California San Francisco is offered as an intervention to reduce stigma and enhance healthy attachment. Clinical examples demonstrate how this system of medical and psychosocial care can help women in this situation establish stability and improve their lives despite the intense challenges they face.
Children born to mentally retarded women: a 1–21 year follow-up study of 41 cases

Synopsis Fifteen mentally retarded Swedish women, judged to be a representative sample, gave birth to 41 children. These children were followed up at the age of 1–21 years with regard to registrations in the Social Register, the Board for Provisions and Services to the Mentally Retarded and the files of the Child and Youth Psychiatric Departments. One child had died, and of the remaining 40 85% had or had exhibited severe psychosocial problems according to register data. The implications of the findings are discussed.
MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients.

BACKGROUND MET amplification has been detected in approximately 20% of non-small-cell lung cancer patients (NSCLC) with epidermal growth factor receptor (EGFR) mutations progressing after an initial response to tyrosine kinase inhibitor (TKI) therapy. PATIENTS AND METHODS We analyzed MET gene copy number using FISH in two related NSCLC cell lines, one sensitive (HCC827) and one resistant (HCC827 GR6) to gefitinib therapy and in two different NSCLC patient populations: 24 never smokers or EGFR FISH-positive patients treated with gefitinib (ONCOBELL cohort) and 182 surgically resected NSCLC not exposed to anti-EGFR agents. RESULTS HCC827 GR6-resistant cell line displayed MET amplification, with a mean MET copy number >12, while sensitive HCC827 cell line had a mean MET copy number of 4. In the ONCOBELL cohort, no patient had gene amplification and MET gene copy number was not associated with outcome to gefitinib therapy. Among the surgically resected patients, MET was amplified in 12 cases (7.3%) and only four (2.4%) had a higher MET copy number than the resistant HCC827 GR6 cell line. CONCLUSIONS MET gene amplification is a rare event in patients with advanced NSCLC. The development of anti-MET therapeutic strategies should be focused on patients with acquired EGFR-TKI resistance.
Rotavirus Virus-Like Particles as Surrogates in Environmental Persistence and Inactivation Studies

ABSTRACT Virus-like particles (VLPs) with the full-length VP2 and VP6 rotavirus capsid proteins, produced in the baculovirus expression system, have been evaluated as surrogates of human rotavirus in different environmental scenarios. Green fluorescent protein-labeled VLPs (GFP-VLPs) and particles enclosing a heterologous RNA (pseudoviruses), whose stability may be monitored by flow cytometry and antigen capture reverse transcription-PCR, respectively, were used. After 1 month in seawater at 20°C, no significant differences were observed between the behaviors of GFP-VLPs and of infectious rotavirus, whereas pseudovirus particles showed a higher decay rate. In the presence of 1 mg of free chlorine (FC)/liter both tracers persisted longer in freshwater at 20°C than infectious viruses, whereas in the presence of 0.2 mg of FC/liter no differences were observed between tracers and infectious rotavirus at short contact times. However, from 30 min of contact with FC onward, the decay of infectious rotavirus was higher than that of recombinant particles. The predicted Ct value for a 90% reduction of GFP-VLPs or pseudoviruses induces a 99.99% inactivation of infectious rotavirus. Both tracers were more resistant to UV light irradiation than infectious rotavirus in fresh and marine water. The effect of UV exposure was more pronounced on pseudovirus than in GFP-VLPs. In all types of water, the UV dose to induce a 90% reduction of pseudovirus ensures a 99.99% inactivation of infectious rotavirus. Recombinant virus surrogates open new possibilities for the systematic validation of virus removal practices in actual field situations where pathogenic agents cannot be introduced.
An accessible pharmacodynamic transcriptional biomarker for notch target engagement

γ‐Secretase mediates amyloid production in Alzheimer's disease (AD) and oncogenic activity of Notch. γ‐Secretase inhibitors (GSIs) are thus of interest for AD and oncology. A peripheral biomarker of Notch activity would aid determination of the therapeutic window and dosing regimen for GSIs, given toxicities associated with chronic Notch inhibition. This study examined the effects of GSI MK‐0752 on blood and hair follicle transcriptomes in healthy volunteers. The effects of a structurally diverse GSI on rhesus blood and hair follicles were also compared. Significant dose‐related effects of MK‐0752 on transcription were observed in hair follicles, but not blood. The GSI biomarker identified in follicles exhibited 100% accuracy in a clinical test cohort, and was regulated in rhesus by a structurally diverse GSI. This study identified a translatable, accessible pharmacodynamic biomarker of GSI target engagement and provides proof of concept of hair follicle RNA as a translatable biomarker source.
Wnt7a Deficiency Could Predict Worse Disease-Free and Overall Survival in Estrogen Receptor-Positive Breast Cancer

Purpose Wnt7a is a glycoprotein involved in embryonic development and the progression of different types of malignant tumors. This study aimed to detect the level of Wnt7a expression in breast cancer and explore its role in the disease progression and prognosis. Methods A total of 258 patients diagnosed with invasive ductal carcinoma of the breast were included in this study. Using tissue microarray and immunohistochemical staining, we evaluated the association between Wnt7a expression and clinicopathological parameters, and the prognostic value of Wnt7a. Results Wnt7a expression was significantly correlated with estrogen receptor (ER) expression (odds ratio, 3.95; 95% confidence interval [CI], 1.99–7.80; p<0.001). On univariate and multivariate analyses, loss of Wnt7a expression was associated with poor disease-free survival (DFS) (multivariate hazard ratio [HR], 9.12; 95% CI, 1.80–46.09; p=0.008), but not with poor overall survival (OS). In the ER-positive group (n=114), loss of Wnt7a expression was an independent prognostic factor for shorter DFS (multivariate HR, 13.54; 95% CI, 1.11–165.73; p=0.042) and OS (multivariate HR, 4.76; 95% CI, 1.29–17.61; p=0.019) on univariate and multivariate analyses. However, in the ER-negative group, there was no significant difference in DFS and OS according to Wnt7a expression. Conclusion The loss of Wnt7a expression might be a meaningful factor in assessing DFS and OS, especially in ER-positive breast cancer.
Inferring invasive species abundance using removal data from management actions.

Evaluation of the progress of management programs for invasive species is crucial for demonstrating impacts to stakeholders and strategic planning of resource allocation. Estimates of abundance before and after management activities can serve as a useful metric of population management programs. However, many methods of estimating population size are too labor intensive and costly to implement, posing restrictive levels of burden on operational programs. Removal models are a reliable method for estimating abundance before and after management using data from the removal activities exclusively, thus requiring no work in addition to management. We developed a Bayesian hierarchical model to estimate abundance from removal data accounting for varying levels of effort, and used simulations to assess the conditions under which reliable population estimates are obtained. We applied this model to estimate site-specific abundance of an invasive species, feral swine (Sus scrofa), using removal data from aerial gunning in 59 site/time-frame combinations (480-19,600 acres) throughout Oklahoma and Texas, USA. Simulations showed that abundance estimates were generally accurate when effective removal rates (removal rate accounting for total effort) were above 0.40. However, when abundances were small (<50) the effective removal rate needed to accurately estimates abundances was considerably higher (0.70). Based on our post-validation method, 78% of our site/time frame estimates were accurate. To use this modeling framework it is important to have multiple removals (more than three) within a time frame during which demographic changes are minimized (i.e., a closed population; ≤3 months for feral swine). Our results show that the probability of accurately estimating abundance from this model improves with increased sampling effort (8+ flight hours across the 3-month window is best) and increased removal rate. Based on the inverse relationship between inaccurate abundances and inaccurate removal rates, we suggest auxiliary information that could be collected and included in the model as covariates (e.g., habitat effects, differences between pilots) to improve accuracy of removal rates and hence abundance estimates.
Noradrenergic component in the vasoconstriction induced by 5‐hydroxytryptamine in goat cerebral arteries

5‐Hydroxytryptamine (5‐HT) elicited dose‐dependent increases in tension in the middle cerebral artery of the goat, which were significantly antagonized by lysergic acid diethylamide (LSD, 10−8 M) and methysergide (10−7 M). In the presence of phentolamine (10−6 M), the dose‐response curve to 5‐HT was shifted to the right, the pA2 value for this antagonism was 6·52. Pretreatment of goats with reserpine (0·02 mg kg−1 day−1 for three days) or removal of both superior cervical ganglia 15 days before the experiment brought about a significant decrease in the vasoconstriction induced by doses of 5‐HT higher than 10−7 M. The remaining contraction produced by 5‐HT in arterial segments from reserpinized or gangliectomized goats was further reduced in the presence of LSD. In addition, high concentrations of 5‐HT induced tritium release from goat pial arteries preloaded with (−)‐[3H]noradrenaline, 2 × 10−7 M) which was significantly decreased in vessels from gangliectomized or reserpinized goats. These results in goat cerebral arteries indicate that in the contraction evoked by 5‐HT there are two components. The first appears with low concentrations (up to 10−7 M) in which 5‐HT acts directly on 5‐HT receptors. The second occurs at high doses (>10−7 M) in which 5‐HT also acts indirectly on α‐adrenoceptors by release of noradrenaline from noradrenergic nerve endings.
An Exploratory Investigation of Organizational Factors and e-Business Motivations Among SMFOEs in the US

It is well recognized that e‐business supports all parts of an organization's value chain, and offers valuable competitive advantage to firms. SMFOEs (Small and Medium‐sized Family Owned Enterprises) represent the majority of firms worldwide and yet many have lagged in their adoption of e‐business. This paper investigates the influence of key organizational demographics, owner/manager characteristics, and organizational strategy on SMFOEs' motivations for e‐business. Eight hypotheses were formulated and tested. Characteristics found to have the greatest influence on e‐business motivation are the business strategy of the firm, new product strategy, and market scope. Owner/manager education, industry sector, and firm size were also influential, but to a lesser degree. The overall conclusion is that e‐business is in the early stages of evolution in small organizations and is favoured largely by entrepreneurial and innovative firms.
Plasmid-borne high-level resistance to gentamicin in Enterococcus hirae, Enterococcus avium, and Enterococcus raffinosus

Enterococcus hirae, E. avium, and E. raffinosus isolated in Romania, Tunisia, and Portugal harbored plasmids pICC8, pIP1700, and pIP1701, respectively, encoding resistance to high levels of gentamicin (Gmr). The Gmr marker was carried on pIP1700 by a Tn4001-like element and on pICC8 and pIP1701 by Tn4001-truncated structures. pICC8 carried, in addition to Gmr, chloramphenicol, erythromycin, and tetracycline-minocycline (TetM) resistance determinants. The gene tetM of pICC8 was carried on a Tn916-like element.
Early evidence of San material culture represented by organic artifacts from Border Cave, South Africa

Recent archaeological discoveries have revealed that pigment use, beads, engravings, and sophisticated stone and bone tools were already present in southern Africa 75,000 y ago. Many of these artifacts disappeared by 60,000 y ago, suggesting that modern behavior appeared in the past and was subsequently lost before becoming firmly established. Most archaeologists think that San hunter–gatherer cultural adaptation emerged 20,000 y ago. However, reanalysis of organic artifacts from Border Cave, South Africa, shows that the Early Later Stone Age inhabitants of this cave used notched bones for notational purposes, wooden digging sticks, bone awls, and bone points similar to those used by San as arrowheads. A point is decorated with a spiral groove filled with red ochre, which closely parallels similar marks that San make to identify their arrowheads when hunting. A mixture of beeswax, Euphorbia resin, and possibly egg, wrapped in vegetal fibers, dated to ∼40,000 BP, may have been used for hafting. Ornaments include marine shell beads and ostrich eggshell beads, directly dated to ∼42,000 BP. A digging stick, dated to ∼39,000 BP, is made of Flueggea virosa. A wooden poison applicator, dated to ∼24,000 BP, retains residues with ricinoleic acid, derived from poisonous castor beans. Reappraisal of radiocarbon age estimates through Bayesian modeling, and the identification of key elements of San material culture at Border Cave, places the emergence of modern hunter–gatherer adaptation, as we know it, to ∼44,000 y ago.
40Ar/39Ar Dates from the West Siberian Basin: Siberian Flood Basalt Province Doubled

Widespread basaltic volcanism occurred in the region of the West Siberian Basin in central Russia during Permo-Triassic times. New 40Ar/39Ar age determinations on plagioclase grains from deep boreholes in the basin reveal that the basalts were erupted 249.4 ± 0.5 million years ago. This is synchronous with the bulk of the Siberian Traps, erupted further east on the Siberian Platform. The age and geochemical data confirm that the West Siberian Basin basalts are part of the Siberian Traps and at least double the confirmed area of the volcanic province as a whole. The larger area of volcanism strengthens the link between the volcanism and the end-Permian mass extinction.
Advanced magnetic resonance imaging of neuromyelitis optica: a multiparametric approach

Background: Several authors have used advanced magnetic resonance imaging (MRI) techniques to investigate whether patients with neuromyelitis optica (NMO) have occult damage in normal-appearing brain tissue, similarly to multiple sclerosis (MS). To date, the literature contains no data derived from the combined use of several advanced MRI techniques in the same NMO subjects. Objective: We set out to determine whether occult damage could be detected in the normal-appearing brain tissue of a small group of patients with NMO using a multiparametric MRI approach. Methods: Eight female patients affected by NMO (age range 44–58 years) and seven sex- and age-matched healthy controls were included. The techniques used on a 1.5 T MRI imaging scanner were magnetization transfer imaging, diffusion tensor imaging, tract-based spatial statistics, spectroscopy and voxel-based morphometry in order to analyse normal-appearing white matter and normal-appearing grey matter. Results: Structural and metabolic parameters showed no abnormalities in normal-appearing white matter of patients with NMO. Conversely, tract-based spatial statistics demonstrated a selective alteration of the optic pathways and the lateral geniculate nuclei. Diffusion tensor imaging values in the normal-appearing grey matter were found to be significantly different in the patients with NMO versus the healthy controls. Moreover, voxel-based morphometry analysis demonstrated a significant density and volume reduction of the sensorimotor cortex and the visual cortex. Conclusions: Our data disclosed occult structural damage in the brain of patients with NMO, predominantly involving regions connected with motor and visual systems. This damage seems to be the direct consequence of transsynaptic degeneration triggered by lesions of the optic nerve and spine.