Miracle-dz/UniFAR-FTUs huggingface dataset:
Stimulation of gp91 Phagocytic Oxidase and Reactive Oxygen Species in Neutrophils by an Avirulent Salmonella enterica Serovar Infantis Strain Protects Gnotobiotic Piglets from Lethal Challenge with Serovar Typhimurium Strain F98 without Inducing Intestinal Pathology

ABSTRACT Preinoculation of susceptible 5-day-old gnotobiotic piglets with Salmonella enterica serovar Infantis strain 1326/28Φr stimulates neutrophil migration into the intestine, which rapidly protects the pigs against a subsequent (normally lethal) challenge with S. enterica serovar Typhimurium strain F98. Here we show that inoculation with either 1326/28Φr or F98 activated reactive oxygen species (ROS) in neutrophils via NADPH pathways in vivo and in vitro and that the survival of both Salmonella strains was increased if neutrophils were cocultured with the ROS inhibitor N-acetylcysteine (captopril). Neither F98 nor 1326/28Φr significantly increased reactive nitrogen species (RNS) levels in neutrophils isolated from uninfected pigs. Our results indicate the following: (i) rapid protection of highly susceptible gnotobiotic piglets against F98-induced gastroenteritis by preinoculation with 1326/28Φr is likely to be due to stimulation of ROS-producing neutrophils in the intestinal epithelium prior to challenge with the lethal strain; (ii) pathological lesions of the intestine during severe gastroenteritis are not necessarily induced by neutrophil migration per se; and (iii) if neutrophil migration into the intestine is responsible for pathology, then neither increased production of ROS or RNS (in pigs inoculated with the lethal strain) nor reduced production (in protected pigs in which pathological lesions are ameliorated by preinoculation with 1326/28Φr) can account for this phenomenon.
Stress modeling of Cu/low-k BEoL - application to stress migration

Stress migration (SM) or stress-induced voiding (SIV) experiments were conducted for two BEoL (Back End of Line) technologies: Cu/FTEOS and Cu/Low-k. Experiments have shown the mean time to failure (MTF) depends on ILD (interlayer dielectric) materials properties, ILD stack and metal line width. Stress migration is worse in Cu/low-k, manifesting as significantly reduced MTF under accelerated testing. Line width also has a more profound effect on stress migration reliability in Cu/low-k than in Cu/FTEOS. Wider lines produce higher failure rates, due to larger stress magnitudes in Cu and larger active diffusion volumes. Stress modeling using Finite Element Analysis (FEA) was performed to quantify the stress fields in the via-chain test structure used for SM reliability testing. In order to account for the effect of process steps on stress evolution, a process-oriented modeling approach was developed. Stress in the metal line is a function of ILD (inter-layer dielectric) properties, ILD stack and metal line width. The concept of a SM Risk Index is proposed to assess BEoL stress migration reliability from the stress perspective. Comparison of the SM Risk Index for Cu/FTEOS and Cu/low-k shows that the latter is more prone to stress induced voiding. Stress migration tests verify that MTF values decrease with increasing line width. Modeling results are consistent with experimental findings, while providing more insightful understanding of stress-driven mechanisms in stress migration.
Impact of psychiatric comorbidity and cognitive deficit on function in 22q11.2 deletion syndrome.

OBJECTIVE Presence of psychiatric comorbidity is associated with poor functioning and is an important consideration in treatment. Many individuals with 22q11.2 deletion syndrome (22q11DS) develop comorbid psychiatric disorders, yet its pattern and impact on functioning have not been formally investigated. In this cross-sectional study, we examined the relationship between comorbid psychopathology and neurocognitive deficits and their association with global functioning. We hypothesized that higher psychiatric burden and psychosis-spectrum features would be associated with reduced functioning and increased neurocognitive deficits. METHOD The cohort included 171 individuals with 22q11DS and mean (SD) age of 17.4 (8.1) years, recruited from a tertiary children's hospital and nationally through social media between September 2010 and December 2013. Psychiatric diagnoses and functioning were assessed using semistructured interviews and the Global Assessment of Functioning (GAF) scale, respectively. On the basis of psychopathology and number of comorbid diagnoses, participants were assigned to unaffected (n = 32), nonpsychosis spectrum (n = 24), nonpsychosis spectrum-plus (n = 15), psychosis spectrum (n = 29), and psychosis spectrum-plus (n = 71) groups. Executive function, episodic memory, complex cognition, social cognition, and praxis speed were assessed using a computerized neurocognitive battery (CNB). Cognitive profile and GAF scores were compared among the groups, and the association of GAF with cognitive performance and psychopathology was examined. RESULTS We observed high rates of comorbid psychiatric disorders. Approximately 50% of the participants had ≥ 2 diagnoses. Psychosis spectrum disorders were most frequently comorbid with other disorders. GAF score was progressively worse with increased psychiatric burden. Mean (SD) GAF score for the unaffected group (81.1 [8.9]) was significantly different from those of nonpsychosis spectrum (68.6 [12.1]), nonpsychosis spectrum-plus (63.4 [8.8]), psychosis spectrum (58.7 [13.1]), or psychosis spectrum-plus (55.5 [13.3]) (P < .05) groups. All groups performed poorly and were comparable to each other on the CNB (P = .273). Notably, verbal memory (P = .003), spatial processing (P = .001), and parent education level (P < .001) were significantly associated with GAF. CONCLUSIONS Individuals with 22q11DS have high rates of comorbid psychiatric disorders and diffuse cognitive deficits regardless of psychiatric burden. Those with psychotic spectrum disorders and comorbid psychiatric disorders are at an increased risk for poor overall functioning.
The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors

Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/Vegf-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients. Mol Cancer Ther; 16(11); 2486–501. ©2017 AACR.
The Effect of a Preoperative Spiritual/Religious Intervention on Anxiety in Shia Muslim Patients Undergoing Coronary Artery Bypass Graft Surgery

Background: Coronary artery bypass grafting (CABG) is associated with anxiety. Preoperative anxiety is considered a predictor for a range of suboptimal postsurgical outcomes. Objective: To evaluate the effect of a spiritual/religious training intervention on anxiety in Shia Muslim individuals scheduled for CABG. Methods: A randomized controlled trial of a preoperative spiritual/religious training intervention, congruent with Islamic supplication (Zikr), was administered in five sessions of 45 minutes duration to test the impact on anxiety in comparison with standard care. Seventy participants were selected based on inclusion criteria and randomly allocated to treatment and control groups. Baseline levels of anxiety and the impact of the intervention were assessed using the Persian version of the Hamilton Anxiety Scale. Results: Baseline characteristics were comparable between the intervention and control groups. Following the intervention, there was a statistically significant difference in anxiety mean scores between intervention (19.48 ± 2.03) and control groups (43.27 ± 5.49), p < . 001. Conclusions: This study demonstrates that preoperative spiritual/religious training can reduce anxiety in Muslim patients undergoing CABG. Further evaluation of this intervention in other population groups is warranted and the study underscores the importance of culturally appropriate and interventions.
A New Rubisco-like Protein Coexists with a Photosynthetic Rubisco in the Planktonic Cyanobacteria Microcystis*

Two genes encoding proteins related to large subunits of Rubisco were identified in the genome of the planktonic cyanobacterium Microcystis aeruginosa PCC 7806 that forms water blooms worldwide. The rbcLI gene belongs to the form I subfamily typically encountered in cyanobacteria, green algae, and land plants. The second and newly discovered gene is of the form IV subfamily and widespread in the Microcystis genus. In M. aeruginosa PCC 7806 cells, the expression of both rbcLI and rbcLIV is sulfur-dependent. The purified recombinant RbcLIV overexpressed in Escherichia coli cells did not display CO2 fixation activity but catalyzed enolization of 2,3-diketo-5-methylthiopentyl-1-phosphate, and the rbcLIV gene rescued a Bacillus subtilis MtnW-deficient mutant. Therefore, the Microcystis RbcLIV protein functions both in vitro and in vivo and might be involved in a methionine salvage pathway. Despite variations in the amino acid sequences, RbcLIV shares structural similarities with all members of the Rubisco superfamily. Invariant amino acids within the catalytic site may thus represent the minimal set for enolization, whereas variations, especially located in loop 6, may account for the limitation of the catalytic reaction to enolization. Even at low protein concentrations in vitro, the recombinant RbcLIV assembles spontaneously into dimers, the minimal unit required for Rubisco forms I–III activity. The discovery of the coexistence of RbcLI and RbcLIV in cyanobacteria, the ancestors of chloroplasts, enlightens episodes of the chaotic evolutionary history of the Rubiscos, a protein family of major importance for life on Earth.
Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors.

BACKGROUND The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. METHODS We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. RESULTS Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib. CONCLUSIONS Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.
Factor XII Does not Initiate Prekallikrein Activation on Endothelial Cells

Summary It is well known that on artificial surfaces, binding and autoactivation of factor XII (FXII) is the initiating event of plasma prekallikrein (PK) activation. We performed investigations to examine whether this mechanism was true for FXII activation on endothelial cells (HUVEC). Activation of PK on HUVEC required an optimal substrate and Zn2+ concentration, the latter of which varied with the buffer’s carrier protein. Maximal PK activation required the addition of 250 μM or 10 μM Zn2+ to buffers containing bovine serum albumin (BSA) or gelatin, respectively. However, the actual free Zn2+ concentration in these buffers was the same at 8 μM. In both BSA- and gelatin-containing buffers and using two different chromogenic substrates for FXII, no autoactivation of FXII on HUVEC was seen when incubated for up to 60 min. Rather, initiation of FXII enzymatic activity required the presence of PK. FXII activation after PK activation contributed to the extent of measured enzymatic activity, but its role was secondary because treatment with corn trypsin inhibitor or a neutralizing antibody to FXIIa did not abolish the measured enzymatic activity. They also reduced the activity to the level seen with PK activation alone. Alternatively, soybean trypsin inhibitor abolished the proteolytic activity associated with PK and FXII activation on HUVEC. Further, only normal human and FXII-deficient plasmas, not PK-deficient plasma, had the ability to generate proteolytic activity when incubated over endothelial cells. In a purified system, maximal PK activation was measured after a 10-15 min incubation depending upon the concentration of reactants. When FXII was added with the PK, maximal activation occurred within 7.5-10 min. In normal human or FXII-deficient plasmas, but not in PK-deficient plasma, maximal activation was seen in 4 min. These data indicate that on HUVEC, unlike artificial surfaces, PK activation when bound to HK is the initiating activation event in this system. FXII activation is secondary to PK activation and contributes to the extent of measured enzymatic activity. These data challenge the accepted dogmas of “contact activation” and suggest that on biologic membranes a new notion as to how this system is activated needs to be considered.
Marketing of rural and remote pharmacy practice via the digital medium

Aim: The shortage of community and hospital pharmacists is particularly acute in rural and remote areas of Australia. Pharmacy students, in particular, as those who may be able to alleviate this shortage, need to be made more aware of the challenges and rewards of rural pharmacy practice. A marketing tool was developed to promote rural and remote pharmacy practice as a career option. A DVD was produced from interviews with health professionals working in rural and remote areas of Australia. This DVD will complement current rural practical placements, which have been incorporated into the curriculum of Australian schools of pharmacy.
Decreased serum level of tumor necrosis factor in animals treated with lipopolysaccharide and liposomes containing phosphatidylserine.

The rise in serum level of tumor necrosis factor (TNF), produced by lipopolysaccharide, has been measured in mice and rabbits treated with phospholipid liposomes. After 3 daily ip injection (mice) or 5 daily i.v. injections (rabbits) of 30 mg/kg of a phospholipid mixture enriched in phosphatidylserine, the action of lipopolysaccharide was 80-90% reduced. The phospholipid effect is dose dependent, requires a minimum of two daily injections before the administration of lipopolysaccharide, and is still manifest 2 days after the last phospholipid dose. Among individual purified phospholipids, phosphatidylserine and phosphatidylethanolamine were effective whereas phosphatidylinositol, phosphatidylglycerol, and phosphatidylcholine did not show significant activity. The data indicate that the parenteral administration of liposomes containing the aminophospholipids phosphatidylserine, and phosphatidylethanolamine is an efficient mode to reduce the endotoxin-induced production of TNF. As suggested by liposome pharmacokinetics, this effect may be related to phospholipid accumulation in the mononuclear phagocyte system of liver and spleen.
Transplanted bone marrow mesenchymal stem cells protects myocardium by regulating 14-3-3 protein in a rat model of diabetic cardiomyopathy.

OBJECTIVE This study examined the mechanism of bone marrow mesenchymal stem cells (BMSCs) up-regulating the expression of 14-3-3 protein, blocking the myocardial apoptosis in diabetic cardiomyopathy and thereby improving cardiac function. METHODS AND RESULTS (1) Rat model of diabetic cardiomyopathy was made by feeding rats with high fat/high sugar diet and intraperitoneal injection of small dose of streptozocin (STZ). The model was successfully established as confirmed by the detection of blood sugar, lipid profile, ultrasonographic and hemodynamic examinations. (2) Bone marrow (BM) liquid was taken from the rat femur and tibia bones. The BMSCs were obtained by culture and were confirmed by phase-contrast microscopy and flow cytometry. The BMSCs were transplanted into the rats and fluorescent microscopy showed that transplantation was successful. (3) TUNNEL, Western blotting revealed that in rats of DCM group, myocardial apoptosis was more severe and expression of capase-3 was significantly up-regulated while in rats receiving transplantation of BMSCs showed opposite changes, with the differences being statistically significant (P < 0.05). (4) Western blotting exhibited that, compared with DCM group, 14-3-3 and p-Ask1 protein was significantly increased while Ask1 was obviously decreased. CONCLUSION Our findings suggested that transplantation of bone marrow mesenchymal stem cells could inhibit the myocardial apoptosis in diabetic cardiomyopathy, possibly by up-regulating the expression of 14-3-3 protein and inhibiting the phosphorylation of Ask1.
Biomechanical Analysis of a Double-Bundle Posterior Cruciate Ligament Reconstruction*

The objective of this study was to experimentally evaluate a single-bundle versus a double-bundle posterior cruciate ligament reconstruction by comparing the resulting knee biomechanics with those of the intact knee. Ten human cadaveric knees were tested using a robotic/universal force-moment sensor testing system. The knees were subjected to a 134-N posterior tibial load at five flexion angles. Three knee conditions were tested: 1) intact knee, 2) single-bundle reconstruction, and 3) double-bundle reconstruction. Posterior tibial translation of the intact knee ranged from 4.9 2.7 mm at 90° to 7.2 1.5 mm at full extension. After the single-bundle reconstruction, posterior tibial translation increased to 7.3 3.9 mm and 9.2 2.8 mm at 90° and full extension, respectively, while the corresponding in situ forces in the graft were up to 44 19 N lower than those in the intact ligament. Conversely, with double-bundle reconstruction, the posterior tibial translation did not differ significantly from the intact knee at any flexion angle tested. This reconstruction also restored in situ forces more closely than did the single-bundle reconstruction. These data suggest that a double-bundle posterior cruciate ligament reconstruction can more closely restore the biomechanics of the intact knee than can the single-bundle reconstruction throughout the range of knee flexion.
Radiologic features poorly predict clinical outcomes in knee osteoarthritis

Objectives: To assess the impact of radiographic severity and progression on pain and disability. Methods: Measurements of mean joint space width (JSW), narrowest join space (NJS) point and assessment of symptoms by the WOMAC questionnaire were performed at baseline and after three years in 212 subjects over 50 years with primary knee OA. Results: At baseline, JSW and NJS were not significantly correlated with the scores recorded for the WOMAC global index or its pain, stiffness or function subscales. A statistically significant correlation was observed between the joint space narrowing over three years and the changes observed in the pain subscale of the WOMAC during the same period. The three-year changes in the global WOMAC index in patients within the lowest and the highest quartiles of mean joint space width at baseline showed, in both cases, a statistically (p < 0.05) significant favorable difference between patients treated with glucosamine sulphate and those having received placebo. Conclusion: Radiographic and clinical progressions of the disease are significantly associated but the clinical relevance of the association is questionable.
Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial.

PURPOSE To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) with anastrozole in the treatment of advanced breast cancer in patients whose disease progresses on prior endocrine treatment. PATIENTS AND METHODS In this double-blind, double-dummy, parallel-group study, postmenopausal patients were randomized to receive either an intramuscular injection of fulvestrant 250 mg once monthly or a daily oral dose of anastrozole 1 mg. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rate, duration of response (DOR), and tolerability. RESULTS Patients (n = 400) were followed for a median period of 16.8 months. Fulvestrant was as effective as anastrozole in terms of TTP (hazard ratio, 0.92; 95.14% confidence interval [CI], 0.74 to 1.14; P =.43); median TTP was 5.4 months with fulvestrant and 3.4 months with anastrozole. OR rates were 17.5% with both treatments. Clinical benefit rates (complete response + partial response + stable disease > or = 24 weeks) were 42.2% for fulvestrant and 36.1% for anastrozole (95% CI, -4.00% to 16.41%; P =.26). In responding patients, median DOR (from randomization to progression) was 19.0 months for fulvestrant and 10.8 months for anastrozole. Using all patients, DOR was significantly greater for fulvestrant compared with anastrozole; the ratio of average response durations was 1.35 (95% CI, 1.10 to 1.67; P < 0.01). Both treatments were well tolerated. CONCLUSION Fulvestrant was at least as effective as anastrozole, with efficacy end points slightly favoring fulvestrant. Fulvestrant represents an additional treatment option for postmenopausal women with advanced breast cancer whose disease progresses on tamoxifen therapy.
Etilefrine for the prevention of priapism in adult sickle cell disease

Summary. Priapism is a common complication of sickle cell disease (SCD) that could lead to erectile dysfunction and psychosocial problems. Treatment of established fulminant priapism is usually not satisfactory. It is therefore important to prevent this complication of SCD. The alpha‐adrenergic agonist etilefrine (50–100 mg/d) produced a good clinical response in 13 of 18 (72%) adults who have recurrent priapism; 17 had SCD and one sickle cell trait. After a follow‐up of 1–48 months, none of the 18 people on etilefrine developed hypertension or sexual dysfunction. Similar efficacy and safety profiles of the drug have been reported previously.