Miracle-dz/UniFAR-FTUs huggingface dataset:
Platelet gene therapy improves hemostatic function for integrin αIIbβ3-deficient dogs

Activated blood platelets mediate the primary response to vascular injury. Although molecular abnormalities of platelet proteins occur infrequently, taken collectively, an inherited platelet defect accounts for a bleeding diathesis in ≈1:20,000 individuals. One rare example of a platelet disorder, Glanzmann thrombasthenia (GT), is characterized by life-long morbidity and mortality due to molecular abnormalities in a major platelet adhesion receptor, integrin αIIbβ3. Transfusion therapy is frequently inadequate because patients often generate antibodies to αIIbβ3, leading to immune-mediated destruction of healthy platelets. In the most severe cases allogeneic bone marrow transplantation has been used, yet because of the risk of the procedure it has been limited to few patients. Thus, hematopoietic stem cell gene transfer was explored as a strategy to improve platelet function within a canine model for GT. Bleeding complications necessitated the use of a mild pretransplant conditioning regimen; therefore, in vivo drug selection was used to improve engraftment of autologously transplanted cells. Approximately 5,000 αIIbβ3 receptors formed on 10% of platelets. These modest levels allowed platelets to adhere to αIIbβ3’s major ligand (fibrinogen), form aggregates, and mediate retraction of a fibrin clot. Remarkably, improved hemostatic function was evident, with ≤135-fold reduced blood loss, and improved buccal bleeding times decreased to 4 min for up to 5 y after transplant. One of four transplanted dogs developed a significant antibody response to αIIbβ3 that was attenuated effectively with transient immune suppression. These results indicate that gene therapy could become a practical approach for treating inherited platelet defects.
Redirected T cells that target pancreatic adenocarcinoma antigens eliminate tumors and metastases in mice.

BACKGROUND & AIMS Pancreatic adenocarcinoma (PAC) is often diagnosed at an advanced and inoperable stage, and standard systemic treatments are generally ineffective. We investigated the effects of adoptive transfer of tumor-specific T cells that express chimeric antibody-based receptors (CAR) to mice with primary and metastatic PAC xenografts. METHODS Human effector T cells were genetically modified to express CAR against Her2/neu or CD24, a putative PAC stem cell antigen. The antitumor reactivity of the engineered T cells (T-bodies) was evaluated in SCID mice with different PAC xenografts. A total of 1 × 10(7) T-bodies were injected via the tail vein or directly administered to the subcutaneous tumor on 3 or 4 alternating days. Mice were then given twice-daily intraperitoneal injections of interleukin-2 for 10 days. RESULTS Intratumor injection of human CD24 and Her2/neu-specific T-bodies completely eliminated the tumors from most animals. Intravenous injection of T-bodies reduced tumor size and prolonged survival of mice with orthotopically transplanted tumors; more than 50% of animals appeared to be disease-free more than 2 months later. Additional systemic administration of T-bodies 8 weeks after the initial injection eliminated primary tumors, along with liver and draining lymph node metastases. A single administration of the Her2/neu-specific T-bodies prolonged the survival of mice with tumors in which most of the cells expressed the target antigen. In contrast, the CD24-specific T-bodies prolonged survival of mice in which only a subpopulation of the tumor cells expressed the antigen. CONCLUSIONS CAR-redirected T cells stop growth and metastasis of PAC xenografts in mice. T-bodies specific to CD24, a putative cancer stem cell antigen, were effective against PAC xenografts that had only a subset of antigen-expressing cells.
Introducing TOPMAST, the first double-blind randomized clinical trial specifically dedicated to perioperative maintenance fluid therapy in adults.

BACKGROUND Although prescribed to every patient undergoing surgery, maintenance fluid therapy is a poorly researched part of perioperative fluid therapy. The tonicity of the chosen solutions, could be an important cause of morbidity, with hyponatremia being a potential side effect of hypotonic solutions, where isotonic solution could lead to fluid overload. METHODS The TOPMAST-trial is an ongoing prospective single-center double-blind randomized trial comparing an isotonic and a hypotonic maintenance fluid strategy during and after surgery in patients undergoing different types of major thoracic surgery. Patients receive NaCl 0.9% in glucose 5% with an added 40 mmol L-1 of potassium chloride or a premixed solution containing 54 mmol L-1 sodium, 55 mmol L-1 chloride and 26 mmol of potassium at a rate of 27 mL per kg of body weight per day. The primary hypothesis is that isotonic maintenance solutions cause a more positive perioperative fluid balance than hypotonic fluids. Different secondary safety endpoints will be explored, especially the effect of the study treatments on the occurrence electrolyte disturbances (e.g. hyponatremia, hyperchloremia) and a set of clinical endpoints. Efficacy endpoints include the need for resuscitation fluids and assessment of renal and hormonal adaptive mechanisms. An anticipated 68 patients will be included between March 2017 and January 2018. DISCUSSION The study will provide the most comprehensive evaluation of clinically important outcomes associated with the choice of perioperative maintenance fluid therapy.
H+-ATPase activity on unilateral ureteral obstruction: interaction of endogenous nitric oxide and angiotensin II.

BACKGROUND A number of cytokines, vasoactive compounds, chemoattractant molecules, and growth factors are up-regulated in obstruction. Following the onset of ureteral obstruction, angiotensin II production is rapidly stimulated. Cytokine-induced expression of inducible nitric oxide synthase (iNOS) has been reported in primary cultures of inner medullary collecting duct (IMCD) cells. We found that the defective urinary acidification in unilateral ureteral obstruction (UUO) includes an intensive decrease in bafilomycin-sensitive H+-ATPase activity in microdissected IMCD segments. METHODS To investigate the interaction between endogenous nitric oxide and angiotensin II on H+-ATPase activity, we used microdissected IMCD segments of unilaterally obstructed, contralateral, and control kidneys to measure the bafilomycin-sensitive ATPase activity and nitric oxide synthase (NOS) activity. The generated NO was also evaluated. RESULTS Preincubation of obstructed IMCD segments in the presence of a competitive inhibitor of NOS, NG-nitro-L-arginine methyl ester (L-NAME) 1 mmol/L, and in the presence of a specific inhibitor of calcium/calmodulin-independent NOS (iNOS), aminoguanidine 1 mmol/L, each for 60 minutes, significantly increased bafilomycin-sensitive H+-ATPase. A greater increase on iNOS activity (fmol [3H] citrulline/min/microg protein) and a lesser increase in calcium/calmodulin-dependent NOS activity (cNOS) were observed in the obstructed renal medulla. This inhibitory effect of obstruction was abolished when IMCDs were incubated with 10-5 to 10-8 mol/L losartan. Decreasing doses of the angiotensin II type 1 (AT1) receptor inhibitor caused an increase in bafilomycin-sensitive H+-ATPase, with a maximum increase at 10-8 mol/L losartan. A decrease on iNOS activity was demonstrated in the obstructed renal medulla incubated with losartan in concentrations of 10-5 to 10-8 mol/L, the same losartan concentrations that showed recovery of vacuolar H+-ATPase activity. Similarly, a decrease on the generation of NO after incubation with losartan 10-5 to 10-8 mol/L was shown. CONCLUSION From these results, we suggest that endogenous NO increased by iNOS is involved in the inhibition of H+-ATPase activity in obstructed IMCD segments. The recovery of H+-ATPase activity in IMCD of obstructed kidneys induced by losartan may be related to a decrease of inducible NOS activity.
Concurrent validity of Indian Disability Evaluation and Assessment Scale with sociooccupational functioning scale in patients with schizophrenia

Background: The Government of India (GOI) has recommended the use of Indian Disability Evaluation and Assessment Scale (IDEAS) for the assessment and certification of disability in patients with mental illness. Although data are available in terms of internal consistency and construct validity of IDEAS, concurrent validity of IDEAS has rarely been evaluated. Aim: The aim was to study the concurrent validity of IDEAS with Global Assessment of Functioning (GAF) and Social and Occupational Functioning Scale (SOFS) in patients with schizophrenia. Materials and Methods: One hundred and seventy-eight consenting patients with schizophrenia in remission were assessed for disability, functioning, and psychopathology using the IDEAS, SOFS, GAF, and Positive and Negative symptom scale (PANSS) respectively. Results: Mean total PANSS score was 51.3 (standard deviation SD −11.19). Disability (>40%) was present in 84.8% of the sample. All the component scores of IDEAS (self-care, interpersonal activities, communication, and work), total IDEAS score, and Global IDEAS score correlated significantly (P < 0.001) with the three domains of SOFS (adaptive life skills, social appropriateness and communication, and interpersonal relationships) along with the total SOFS score. GAF total score had significant negative correlation (P < 0.001) with all the components of IDEAS, total IDEAS score and global IDEAS score. Higher residual psychopathology was also associated with overall higher disability as assessed by total IDEAS score and Global IDEAS score. Conclusions: This study shows that the GOI-modified IDEAS had good concurrent validity with global and sociooccupational functioning as assessed by GAF and SOFS respectively.
Activation of int-1 and int-2 mammary oncogenes in hormone-dependent and -independent mammary tumors of GR mice

Mammary tumors in the GR mouse strain are caused by the expression of an endogenous provirus of the mouse mammary tumor virus (MMTV). The tumors progress from a hormone-dependent growth phase to autonomous, hormone-independent growth. We studied proviral insertion of MMTV at the int-1 and int-2 mammary oncogenes and the transcription of these genes during progression of a series of transplanted mammary tumors. During the hormone-dependent phase, 6 of 15 transplanted tumors were positive for proviral insertion at int-1 or int-2 or both. These tumors were oligoclonal with respect to the fraction of tumor cells with novel int-1 and int-2 restriction fragments and, apparently, consisted of different tumor cells with proviruses integrated at different oncogenes, including genes that are not yet known. In 10 tumors we detected expression of the int genes, indicating that most tumors contain minor populations of cells with int-1 or int-2 activations. On transplantation the tumors remained oligoclonal during the hormone-dependent phase. The hormone-independent variants of the tumors emerged as clonal outgrowths of cells with MMTV proviruses that could be traced back in the hormone-dependent tumors, but not always those of cells that were positive for insertions near int-1 or int-2. The maintenance of oligoclonality during the hormone-dependent phase suggests a growth-controlling effect of different populations of cells on each other. The clonal, hormone-independent tumors that arise later seem to be the result of mutations that are unrelated to int activation.
Optofluidic single‐cell absorption flow analyzer for point‐of‐care diagnosis of malaria

In this work, an optofluidic flow analyzer, which can be used to perform malaria diagnosis at the point‐of‐care is demonstrated. The presented technique is based on quantitative optical absorption measurements carried out on a single cell level for a given population of Human Red Blood Cells (RBCs). By measuring the optical absorption of each RBC, the decrease in the Hemoglobin (Hb) concentration in the cytoplasm of the cell due to the invasion of malarial parasite is detected. Cells are assessed on a single cell basis, as they pass through a microfluidic channel. The proposed technique has been implemented with inexpensive off‐the‐shelf components like laser diode, photo‐detector and a micro‐controller. The ability of the optofluidic flow analyzer to asses about 308,049 cells within 3 minutes has been demonstrated. The presented technique is capable of detecting very low parasitemia levels with high sensitivity.
Contribution of the Kv3.1 potassium channel to high‐frequency firing in mouse auditory neurones

1 Using a combination of patch‐clamp, in situ hybridization and computer simulation techniques, we have analysed the contribution of potassium channels to the ability of a subset of mouse auditory neurones to fire at high frequencies. 2 Voltage‐clamp recordings from the principal neurones of the medial nucleus of the trapezoid body (MNTB) revealed a low‐threshold dendrotoxin (DTX)‐sensitive current (ILT) and a high‐threshold DTX‐insensitive current (IHT). 3 I HT displayed rapid activation and deactivation kinetics, and was selectively blocked by a low concentration of tetraethylammonium (TEA; 1 mm). 4 The physiological and pharmacological properties of IHT very closely matched those of the Shaw family potassium channel Kv3.1 stably expressed in a CHO cell line. 5 An mRNA probe corresponding to the C‐terminus of the Kv3.1 channel strongly labelled MNTB neurones, suggesting that this channel is expressed in these neurones. 6 TEA did not alter the ability of MNTB neurones to follow stimulation up to 200 Hz, but specifically reduced their ability to follow higher frequency impulses. 7 A computer simulation, using a model cell in which an outward current with the kinetics and voltage dependence of the Kv3.1 channel was incorporated, also confirmed that the Kv3.1‐ like current is essential for cells to respond to a sustained train of high‐frequency stimuli. 8 We conclude that in mouse MNTB neurones the Kv3.1 channel contributes to the ability of these cells to lock their firing to high‐frequency inputs.
Landscape barriers reduce gene flow in an invasive carnivore: geographical and local genetic structure of American mink in Scotland

To be effective, management programmes geared towards halting or reversing the spread of invasive species must focus on defined and defensible areas. This requires knowledge of the dispersal of non‐native species targeted for control to better understand invasion and recolonisation scenarios. We investigated the genetic structure of invasive American mink (Neovison vison) in Scotland, and incorporated landscape genetic approaches to examine resultant patterns in relation to geographical features that may influence dispersal. Populations of mink sampled from 10 sites in two regions (Argyll and Northeast Scotland) show a distinct genetic structure. First, the majority of pairwise population comparisons yielded FST values that were significantly greater than zero. Second, amova revealed that most of the genetic variance was attributable to differences among regions. Assignment tests placed 89 or more of individuals into their sampled region. Bayesian clustering methods grouped samples into two clusters according to their region of origin. Wombling approach identified the Cairngorms Mountains as a major impediment to gene flow between the regions. Mantel pairwise correlations between genetic and geographical distances estimated as least‐cost distance assuming a linear increase in the cost of movement with increasing elevation were higher than Euclidean distances or distance along waterways. Spatial autocorrelation analyses revealed stronger spatial structuring for females than for males. These results suggest that gene flow by American mink is restricted by landscape features (mountain ranges) and that eradication attempt should in the first instance break down the connectivity between management units separated by mountains.
SBML-PET: a Systems Biology Markup Language-based parameter estimation tool

UNLABELLED The estimation of model parameters from experimental data remains a bottleneck for a major breakthrough in systems biology. We present a Systems Biology Markup Language (SBML) based Parameter Estimation Tool (SBML-PET). The tool is designed to enable parameter estimation for biological models including signaling pathways, gene regulation networks and metabolic pathways. SBML-PET supports import and export of the models in the SBML format. It can estimate the parameters by fitting a variety of experimental data from different experimental conditions. SBML-PET has a unique feature of supporting event definition in the SMBL model. SBML models can also be simulated in SBML-PET. Stochastic Ranking Evolution Strategy (SRES) is incorporated in SBML-PET for parameter estimation jobs. A classic ODE Solver called ODEPACK is used to solve the Ordinary Differential Equation (ODE) system. AVAILABILITY http://sysbio.molgen. mpg.de/SBML-PET/. The website also contains detailed documentation for SBML-PET.
Individual differences in circadian locomotor parameters correlate with anxiety- and depression-like behavior

Disrupted circadian rhythms are a core feature of mood and anxiety disorders. Circadian rhythms are coordinated by a light-entrainable master clock located in the suprachiasmatic nucleus. Animal models of mood and anxiety disorders often exhibit blunted rhythms in locomotor activity and clock gene expression. Interestingly, the changes in circadian rhythms correlate with mood-related behaviours. Although animal models of depression and anxiety exhibit aberrant circadian rhythms in physiology and behavior, it is possible that the methodology being used to induce the behavioral phenotype (e.g., brain lesions, chronic stress, global gene deletion) affect behavior independently of circadian system. This study investigates the relationship between individual differences in circadian locomotor parameters and mood-related behaviors in healthy rats. The circadian phenotype of male Lewis rats was characterized by analyzing wheel running behavior under standard 12h:12h LD conditions, constant dark, constant light, and rate of re-entrainment to a phase advance. Rats were then tested on a battery of behavioral tests: activity box, restricted feeding, elevated plus maze, forced swim test, and fear conditioning. Under 12h:12h LD conditions, percent of daily activity in the light phase and variability in activity onset were associated with longer latency to immobility in the forced swim test. Variability in onset also correlated positively with anxiety-like behavior in the elevated plus maze. Rate of re-entrainment correlated positively with measures of anxiety in the activity box and elevated plus maze. Lastly, we found that free running period under constant dark was associated with anxiety-like behaviors in the activity box and elevated plus maze. Our results provide a previously uncharacterized relationship between circadian locomotor parameters and mood-related behaviors in healthy rats and provide a basis for future examination into circadian clock functioning and mood.
Expression and regulation of mRNA coding for acidic and basic fibroblast growth factor and transforming growth factor alpha in cells derived from human skin.

We investigated the regulation of mRNAs coding for acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), and transforming growth factor-alpha (TGF alpha) in cultures of human neonatal foreskin fibroblasts, keratinocytes, and melanocytes. Each cell type was propagated in an optimized serum-free medium. In rapidly growing fibroblasts, the addition of fetal bovine serum caused a modest induction of aFGF message within 2 h in conjunction with a concomitant elevation of bFGF transcripts. In these same cells, TGF alpha mRNA could not be detected in any experimental condition. In contrast, keratinocytes rapidly growing in the presence of epidermal growth factor (EGF) contained transcripts for TGF alpha that increased substantially when these cells were treated with serum. This observation suggests that factors present in serum can elevate the levels of TGF alpha mRNA beyond the levels already present in keratinocyte cultures growing in the presence of EGF. These same keratinocyte cultures had low to undetectable levels of bFGF or aFGF message, and the levels of these mRNAs were not affected by serum treatment. Treatment of keratinocytes proliferating in the presence of EGF with TGF beta for 48 h caused expression of bFGF mRNA in four of six independent cell strains. TGF beta-enhanced expression of bFGF mRNA occurred as early as 12-24 h after TGF beta exposure. TGF beta did not enhance the expression of mRNA for aFGF or TGF alpha in keratinocytes. Melanocytes failed to express detectable levels of mRNA coding for any of these growth factors in the presence of absence of TGF beta or serum. (ABSTRACT TRUNCATED AT 250 WORDS)
Effects of Hypoxia on Regulation of Prostanoid Production in Decidual Endothelial Cells in Normal and Preeclamptic Pregnancy

Objectives: To examine the effect on prostacyclin and thromboxane prodution of incubating decidual endothelial cells under hypoxic conditions, comparing cells from normal and preeclamptic pregnancies. Furthermore, to determine whether hypoxia is deleterious to cell growth, and test the effect of stimulation and inhibition on prostanoid production. Methods: Decidual endothelial cells were exposed for a total of 40 hours to normoxic (20% O2) or hypoxic (2% O2) conditions. Prostacyclin and thromboxane secretion over the final 24 hours of incubation was measured and cell numbers after incubation determined. Lipopolysaccharide (LPS) (1.0 μg/mL) was used as a stimulator and pirmagrel (1.0 μmol/L) and tranylcypromine (10.0 μmol/L)_ as prostanoid synthase inhibitors. Results: Incubations in hypoxia resuulted in increased thromboxane (P < .05) but no change in prostacyclin production. This thromboxane increase was abrogated by pirmagrel. LPS caused significant stimulation of prostacyclin and thromboxane secretion and both LPS and hypoxia resulted in lower cell numbers. Decidual endothelial cells from normal and preeclamptic pregnancies were generally not different. Conclusions: This study indicates that in preeclampsia, where decidual endothelial cells are in a relatively more hypoxic environment, thromboxane production by these cells is likely to be increased and the prostacyclin/thromboxane ratio decreased. The thromboxane synthase inhibitor, pirmagrel, was able to reverse this abnormal increased secretion of thromboxane in vitro.
Degrees of Freedom of the Broadcast Channel with Hybrid CSI at Transmitter and Receivers

In general, the different links of a broadcast channel may experience different fading dynamics and, potentially, unequal or hybrid channel state information (CSI) conditions. The faster the fading and the shorter the fading block length, the more often the link needs to be trained and estimated at the receiver, and the more likely that CSI is stale or unavailable at the transmitter. Disparity of link fading dynamics in the presence of CSI limitations can be modeled by a multi-user broadcast channel with both non-identical link fading block lengths as well as dissimilar link CSIR/CSIT conditions. This paper investigates a MISO broadcast channel where some receivers experience longer coherence intervals (static receivers) and have CSIR, while some other receivers experience shorter coherence intervals (dynamic receivers) and do not enjoy free CSIR. We consider a variety of CSIT conditions for the above mentioned model, including no CSIT, delayed CSIT, or hybrid CSIT. To investigate the degrees of freedom region, we employ interference alignment and beamforming along with a product superposition that allows simultaneous but non-contaminating transmission of pilots and data to different receivers. Outer bounds employ the extremal entropy inequality as well as a bounding of the performance of a discrete memoryless multiuser multilevel broadcast channel. For several cases, inner and outer bounds are established that either partially meet, or the gap diminishes with increasing coherence times.