Miracle-dz/UniFAR-FTUs huggingface dataset:
Endogenous macrophage migration inhibitory factor reduces the accumulation and toxicity of misfolded SOD1 in a mouse model of ALS

Significance Amyotrophic lateral sclerosis (ALS) can be caused by mutations in superoxide dismutase (SOD1), which lead to the accumulation of misfolded SOD1 proteins and to the death of motor neurons. Here we show that endogenous macrophage migration inhibitory factor (MIF) acts as a chaperone for misfolded SOD1 in vivo, because completely eliminating MIF in a mutant SOD1 mouse model of familial ALS enhanced the accumulation of misfolded SOD1, accelerated disease onset and late disease progression, and shortened the lifespan of mice expressing mutant SOD1. This study thus sheds light on the important implications of modulating MIF levels and provides insight into the potential therapeutic role of MIF in suppressing the selective accumulation of misfolded SOD1 in ALS. Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons in the brain and spinal cord. It has been suggested that the toxicity of mutant SOD1 results from its misfolding and accumulation on the cytoplasmic faces of intracellular organelles, including the mitochondria and endoplasmic reticulum (ER) of ALS-affected tissues. Recently, macrophage migration inhibitory factor (MIF) was shown to directly inhibit the accumulation of misfolded SOD1 and its binding to intracellular membranes, but the role of endogenous MIF in modulating SOD1 misfolding in vivo remains unknown. To elucidate this role, we bred MIF-deficient mice with SOD1G85R mice, which express a dismutase-inactive mutant of SOD1 and are considered a model of familial ALS. We found that the accumulation of misfolded SOD1, its association with mitochondrial and ER membranes, and the levels of sedimentable insoluble SOD1 aggregates were significantly higher in the spinal cords of SOD1G85R-MIF−/− mice than in their SOD1G85R-MIF+/+ littermates. Moreover, increasing MIF expression in neuronal cultures inhibited the accumulation of misfolded SOD1 and rescued from mutant SOD1-induced cell death. In contrast, the complete elimination of endogenous MIF accelerated disease onset and late disease progression and shortened the lifespan of the SOD1G85R mutant mice. These findings indicate that MIF plays a significant role in the folding and misfolding of SOD1 in vivo, and they have implications for the potential therapeutic role of up-regulating MIF within the nervous system to modulate the selective accumulation of misfolded SOD1.
Synthesis, DNA Binding, and Anticancer Properties of Bis-Naphthalimide Derivatives with Lysine-Modified Polyamine Linkers

A series of bis-naphthalimide derivatives with different diamine linkers were designed and synthesized. All of the synthesized bis-naphthalimide derivatives were characterized by NMR and HRMS spectra. The binding ability between the compounds and CT DNA was evaluated by using UV–Vis titration experiments. The bis-naphthalimide compound with an ethylenediamine linker showed the largest binding constant with CT DNA. Hence, it was used as the model compound to study the DNA binding selectivity by UV–Vis titration aiming at different DNA duplexes. As a result, this compound showed binding preference to AT-rich duplexes. The DNA binding modes of the compounds were also measured by viscosity titration. The cytotoxicity of the compounds was evaluated by MTT assay. Compounds with 1,6-diaminohexane or 1,4-phenylenedimethanamine linkers showed higher cytotoxicity compared with other bis-naphthalimide derivatives.
Ancient DNA evidence for the loss of a highly divergent brown bear clade during historical times

The genetic diversity of present‐day brown bears (Ursus arctos) has been extensively studied over the years and appears to be geographically structured into five main clades. The question of the past diversity of the species has been recently addressed by ancient DNA studies that concluded to a relative genetic stability over the last 35 000 years. However, the post‐last glacial maximum genetic diversity of the species still remains poorly documented, notably in the Old World. Here, we analyse Atlas brown bears, which became extinct during the Holocene period. A divergent brown bear mitochondrial DNA lineage not present in any of the previously studied modern or ancient bear samples was uncovered, suggesting that the diversity of U. arctos was larger in the past than it is now. Specifically, a significant portion (with respect to sequence divergence) of the intraspecific diversity of the brown bear was lost with the extinction of the Atlas brown bear after the Pleistocene/Holocene transition.
Interleukin-13 (IL-13)/IL-13 Receptor α1 (IL-13Rα1) Signaling Regulates Intestinal Epithelial Cystic Fibrosis Transmembrane Conductance Regulator Channel-dependent Cl− Secretion*

Interleukin-13 (IL-13) has been linked to the pathogenesis of inflammatory diseases of the gastrointestinal tract. It is postulated that IL-13 drives inflammatory lesions through the modulation of both hematopoietic and nonhematopoietic cell function in the intestine. To delineate the relevant contribution of elevated levels of intestinal IL-13 to intestinal structure and function, we generated an intestinal IL-13 transgenic mouse (iIL-13Tg). We show that constitutive overexpression of IL-13 in the small bowel induces modification of intestinal epithelial architecture (villus blunting, goblet cell hyperplasia, and increased epithelial proliferation) and epithelial function (altered basolateral → apical Cl− ion conductance). Pharmacological analyses in vitro and in vivo determined that elevated Cl− conductance is mediated by altered cystic fibrosis transmembrane conductance regulator expression and activity. Generation of iIL-13Tg/Il13rα1−/−, iIL-13Tg/Il13rα2−/−, and iIL-13Tg/Stat6−/− mice revealed that IL-13-mediated dysregulation of epithelial architecture and Cl− conductance is dependent on IL-13Rα1 and STAT-6. These observations demonstrate a central role for the IL-13/IL-13Rα1 pathway in the regulation of intestinal epithelial cell Cl− secretion via up-regulation of cystic fibrosis transmembrane conductance regulator, suggesting an important role for this pathway in secretory diarrhea.
Processing Time Ambiguity and Port Competitiveness

Container seaports play an important role in cross‐border logistics as firms increasingly expand their global footprint in sourcing, manufacturing and distribution. Besides convenience of access to hinterland regions, a key metric for a port's attractiveness is its processing time, that is, its ability to clear goods within a consistent, predictable time frame. Due to differences in infrastructure, government regulations, and operating procedures, ports may exhibit different degrees of predictability in processing times: some are more predictable while others are more ambiguous. We study how ambiguity in processing times affects a port's attractiveness under various circumstances. We find that even if a port maintains a consistent expected processing time, increased ambiguity can still affect its attractiveness to firms, although not always negatively. The effect of ambiguity depends on its nature, whether the shipments are time‐sensitive, attitudes toward ambiguity, and trade terms surrounding shipments.
2- to 9-year outcome of stemmed total knee arthroplasty

Background and purpose — There is an increase in demand for primary and revision total knee joint procedures. We studied implant survival and functional outcome of patients operated with a constrained condylar knee (CCK) or a rotating hinge implant (RH) as a primary or a revision total knee arthoplasty (TKA). Patients and methods — We evaluated clinically and radiographically 65 surgical procedures with a mean follow-up time of 5 (2–9) years (40 CCK and 25 RH). There were 24 primary TKAs—due to instability—and 41 revision TKAs, mostly due to aseptic loosening. Mean age at the index operation was 68 (31–88) years. Results — Overall, there were 12 failures, including 8 reoperations due to deep infection. The overall 5-year survival rate with reoperation as the endpoint was 82% (95% CI: 72–99). Radiolucent lines on either the femoral or the tibial side were seen in 36 cases. When comparing the cases that were operated as a primary TKA or as a revision TKA, function, health-related quality of life, and survival were similar. However, after primary TKA the patients generally had less pain and a higher proportion of patients were very satisfied or satisfied. Interpretation — Although a high rate of severe complications was observed, most patients improved in function after surgery regardless of whether it was a primary or a revision TKA. We found narrow radiolucent lines—mainly on the tibial side—in nearly half of the cases, but none of the implants were loose radiographically. Overall patient satisfaction and health-related quality of life were high, and a minority had problems with persistent pain.
A model of the glycine receptor deduced from Brownian dynamics studies

We have developed a three-dimensional model of the α1 homomeric glycine receptor by using Brownian dynamics simulations to account for its observed physiological properties. The model channel contains a large external vestibule and a shallow internal vestibule, connected by a narrow, cylindrical selectivity filter. Three rings of charged residues from the pore-lining M2 domain are modeled as point charges in the protein. Our simulations reproduce many of the key features of the channel, such as the current–voltage profiles, permeability ratios, and ion selectivity. When we replace the ring of alanine residues lining the selectivity filter with glutamates, the mutant model channel becomes permeable to cations, as observed experimentally. In this mutation, anions act as chaperones for sodium ions in the extracellular vestibule, and together they penetrate deep inside the channel against a steep energy barrier encountered by unaccompanied ions. Two subsequent amino acid mutations increase the cation permeability, enabling monovalent cations to permeate through the channel unaided and divalent cations to permeate when chaperoned by anions. These results illustrate the key structural features and underlying mechanism for charge selectivity in the glycine receptor.
Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia.

PURPOSE Older patients with acute myeloid leukemia (AML) have limited treatment options because of the lack of effectiveness and the toxicity of available therapies. We investigated the efficacy and toxicity of the hypomethylating agent decitabine as initial therapy in older patients with AML. PATIENTS AND METHODS In this multicenter, phase II study, patients older than 60 years who had AML (ie, > 20% bone marrow blasts) and no prior therapy for AML were treated with decitabine 20 mg/m(2) intravenously for 5 consecutive days of a 4-week cycle. Response was assessed by weekly CBC and bone marrow biopsy after cycle 2 and after each subsequent cycle. Patients continued to receive decitabine until disease progression or an unacceptable adverse event occurred. RESULTS Fifty-five patients (mean age, 74 years) were enrolled and were treated with a median of three cycles (range, one to 25 cycles) of decitabine. The expert-reviewed overall response rate was 25% (complete response rate, 24%). The response rate was consistent across subgroups, including in patients with poor-risk cytogenetics and in those with a history of myelodysplastic syndrome. The overall median survival was 7.7 months, and the 30-day mortality rate was 7%. The most common toxicities were myelosuppression, febrile neutropenia, and fatigue. CONCLUSION Decitabine given in a low-dose, 5-day regimen has activity as upfront therapy in older patients with AML, and it has acceptable toxicity and 30-day mortality.
Morning cortisol as a risk factor for subsequent major depressive disorder in adult women.

BACKGROUND Whether individual differences in cortisol contribute to subsequent major depressive disorder (MDD) is unknown. AIMS To determine whether premorbid levels of salivary cortisol and dehydroepiandrosterone (DHEA) were associated with subsequent MDD and how these related to psychosocial factors known to increase the risk for MDD. METHOD Adult women (n=116) were recruited from general practices. None was currently depressed; 83 were 'psychosocially vulnerable' to MDD, 33 were not. Salivary steroids (cortisol and DHEA at 08.00 h and 20.00 h), recent life events, current mood and social support were assessed at entry. Onset of MDD was recorded during 13 months' follow-up. RESULTS There were no associations between salivary cortisol or DHEA and recent life events or vulnerability. Twenty-eight onsets of MDD occurred during the follow-up period. This was associated with: severe adverse life events and difficulties during the follow-up period; mean morning cortisol levels at entry; and the presence of any of three vulnerability factors. CONCLUSIONS Individual differences in morning salivary cortisol levels may represent an independent risk factor for subsequent MDD. The origin of these differences in cortisol is not yet understood.
The Impact of Free Cash Flow, Equity Concentration and Agency Costs on Firm's Profitability

This paper examines how free cash flow and equity concentration are associated with agency costs, and how they influence the profitability of insurance firms listed in the Saudi Stock Market. The results indicate that equity concentration has no significant impact on agency costs, free cash flow has no significant impact on agency costs and agency costs has no significant impact on firm’s profitability. The finding of this study do not show any evidence to support the agency theory among insurance firms listed in the Saudi Stock Market.
A prospective, randomized comparison of 10-Fr versus 7-Fr bipolar electrocoagulation catheter in combination with adrenaline injection in the endoscopic treatment of bleeding peptic ulcers

OBJECTIVES:Our study compared the efficacy of bipolar electrocoagulation (gold probe) with 10-Fr (group A) versus 7-Fr (group B) catheter after adrenaline injection in the treatment of bleeding peptic ulcers.METHODS:A total of 77 consecutive patients with endoscopic evidence of peptic ulcer with active bleeding or a nonbleeding visible vessel were randomly assigned to one of the above protocols. Thirty-nine patients (31 male, eight female, mean age 62 yr) were included in group A and 38 (28 male, 10 female, mean age 61 yr) in group B.RESULTS:The initial hemostasis rate, rebleeding rate, duration of hospital stay, volume of blood transfused, number of operations needed, and number of deaths were not significantly different between the two groups. The mean number of electrocoagulations and the subsequent mean duration of electrocoagulations were significantly higher in group B patients (7.0 ± 3.8 and 14.1 ± 7.6 s, respectively) compared with those of group A (4.6 ± 2.6 and 9.3 ± 5.3 s, respectively) (p < 0.01). Multivariate stepwise logistic regression analysis revealed that among sex, age, location of bleeding, ulcer size, endoscopic severity of bleeding, and the size of the gold probes, lesser endoscopic severity of bleeding (χ2= 31.1, p < 0.01), large size of the gold probe (χ2= 23.9, p < 0.01), and small ulcer size (χ2= 13.4, p < 0.01) were the only factors significantly associated with a smaller number of electrocoagulations.CONCLUSIONS:In this study, the use of large-size gold probes was significantly associated with a lower number of electrocoagulations, resulting in the reduction of electrocoagulation duration. However, the clinical relevance of these findings is questionable because the efficacy of both sizes of gold probe after adrenaline injection in the treatment of bleeding peptic ulcers was similar.
Macrophage cell death in microbial infections

Macrophages can respond to microbial infections with programmed cell death. The major cell death pathways of apoptosis, pyroptosis and necroptosis are tightly regulated to ensure adequate immune reactions to virulent and persistent invaders. Macrophage death eliminates the replicative niche of intracellular pathogens and induces immune attack. Not surprisingly, successful pathogens have evolved strategies to modulate macrophage cell death pathways to enable microbial survival and replication. Uncontrolled macrophage death can also lead to tissue damage, which may augment bacterial dissemination and pathology. In this review, we highlight how pathogens hijack macrophage cell death signals to promote microbial survival and immune evasion.
Quantitative characterization of specific genomic promoters using agarose gel electrophoresis.

Over the past decade a large number of studies have focused attention on the role of nucleosomes as negative and positive regulators of specific nuclear functions. Due to the lack of an analytical method to determine the higher order conformation of the nucleosomal arrays that encompass specific genetic loci (e.g., promoters, enhancers), research emphasis has mostly been centered on chromatin remodeling and histone posttranslational modifications. We have recently developed an agarose gel electrophoresis method that permits us to analyze the higher order structure of specific in vivo assembled chromatin fragments. After calibration using a well-defined in vitro system, we have been able to experimentally determine the size, shape, and conformational flexibility of the Mouse Mammary Tumor Virus long-terminal repeat promoter region in its repressed and activated states. These studies pave the way for widespread analyses of the higher order structure of specific, functionally important chromosomal loci, and in so doing enhance our understanding of the roles that the higher order structure of chromatin play in genome regulations.
Hearing in acromegaly

Abstract Fifty-six individuals with acromegaly referred for pituitary surgery were studied to determine any relationship between acromegaly and sensorineural or conductive hearing loss. Compared to a matched population control sample, no significant difference between the acromegalics and controls has been found, either for air conduction or for bone conduction. The differences between these findings and those published previously are discussed, and reasons proposed to explain the discrepancies.
Bortezomib Sensitizes Malignant Human Glioma Cells to TRAIL, Mediated by Inhibition of the NF-κB Signaling Pathway

Previous studies have shown that the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has significant apoptosis-inducing activity in some glioma cell lines, although many lines are either moderately or completely resistant, which has limited the therapeutic applicability of this agent. Because our recent studies showed that inhibition of proteasomal function may be independently active as an apoptosis-inducing stimulus in these tumors, we investigated the sensitivity of a panel of glioma cell lines (U87, T98G, U373, A172, LN18, LN229, LNZ308, and LNZ428) to TRAIL alone and in combination with the proteasome inhibitor bortezomib. Analysis of these cell lines revealed marked differences in their sensitivity to these treatments, with two (LNZ308 and U373) of the eight cell lines revealing no significant induction of cell death in response to TRAIL alone. No correlation was found between sensitivity of cells to TRAIL and expression of TRAIL receptors DR4, DR5, and decoy receptor DcR1, caspase 8, apoptosis inhibitory proteins XIAP, survivin, Mcl-1, Bcl-2, Bcl-Xl, and cFLIP. However, TRAIL-resistant cell lines exhibited a high level of basal NF-κB activity. Bortezomib was capable of potentiating TRAIL-induced apoptosis in TRAIL-resistant cells in a caspase-dependent fashion. Bortezomib abolished p65/NF-κB DNA-binding activity, supporting the hypothesis that inhibition of the NF-κB pathway is critical for the enhancement of TRAIL sensitization in glioma cells. Moreover, knockdown of p65/NF-κB by shRNA also enhanced TRAIL-induced apoptosis, indicating that p65/NF-κB may be important in mediating TRAIL sensitivity and the effect of bortezomib in promoting TRAIL sensitization and apoptosis induction. Mol Cancer Ther; 10(1); 198–208. ©2011 AACR.
Detection of specific immunoglobulin M antibody to rubella virus by use of an enzyme-labeled antigen

A direct antibody capture enzyme immunoassay (EIA) for the detection of rubella-specific immunoglobulin M (IgM) antibody was developed. Polystyrene microtiter strips coated with rabbit anti-human IgM were used as solid phase, and a semipurified rubella antigen labeled with horseradish peroxidase was used as indicator. By testing a panel of 238 serum specimens (not including sera from newborns with congenital rubella), the direct EIA was compared with the indirect EIA used routinely in our diagnostic unit and with a commercial IgM capture EIA (RubEnz M II) that employs a horseradish peroxidase-labeled anti-rubella monoclonal antibody as indicator. Overall agreement of direct EIA with indirect EIA and RubEnz M II was 95%, whereas agreement between direct and indirect EIA was 96.2%, and agreement between direct EIA and RubEnz M II was 97.8%. Sensitivity of the direct assay was higher than that of the indirect EIA and similar to that of the RubEnz M II assay. Specific IgM antibody could always be detected in serum specimens taken from patients with primary acute rubella infection between days 4 and 56 after the onset of rash. The assay was highly specific, and it was not affected either by rheumatoid factor or by high levels of specific IgG in sera. Another important advantage that the direct EIA has over the indirect EIA is that it requires 10 to 20 times less antigen per serum specimen tested.
Influenza B virus with modified hemagglutinin cleavage site as a novel attenuated live vaccine.

BACKGROUND Both pandemic and interpandemic influenza is associated with high morbidity and mortality worldwide. Seasonal epidemics are caused by both influenza A and B virus strains that cocirculate with varying predominance and may give rise to severe illness equally. According to World Health Organization recommendations, current annual vaccines are composed of 2 type A and 1 type B virus-specific component. METHODS As a novel attenuated live vaccine against influenza B virus, we generated a hemagglutinin cleavage site mutant of strain B/Lee/40 by replacing the common monobasic cleavage site recognized by trypsinlike proteases with an elastase-sensitive site, and we investigated the in vitro properties, attenuation, humoral responses, and efficacy in mice. RESULTS This mutant virus replicated in cell culture equally well as the wild type but in a strictly elastase-dependent manner. In contrast to the mouse-pathogenic parental virus, the cleavage site mutant was fully attenuated in mice and not detectable in their lungs. After 1 intranasal immunization, the animals survived lethal challenge with wild-type virus without weight loss or any other signs of disease. Furthermore, no challenge virus could be reisolated from the lungs of vaccinated mice. CONCLUSIONS These findings demonstrate that proteolytic activation mutants can serve as live vaccine against influenza B virus.