156 research outputs found
Effect of infra-red power level on the sintering behaviour in the high speed sintering process
Purpose: To investigate the effects of the infra-red power level on sintering
behaviour in the High Speed Sintering process.
Design/methodology/approach: Single-layer parts were produced using the
High Speed Sintering process, in order to determine the effect of the infra-red
power level on the maximum achievable layer thickness, and the degree of
sintering. The parts were examined using both optical microscopy and
contact methods.
Findings: Whilst it was expected that an increase in the infra-red lamp
powder might allow an increase in the depth of sintering that could be
achieved, as a result of increased thermal transfer through the powder, results
in fact indicated that there is a maximum layer thickness that can be achieved,
as a result of part shrinkage in the z direction.
Optical microscopy images have shown that a greater degree of sintering
occurs at higher power levels, which would be expected to correspond to an
improvement in the mechanical properties of the parts produced. These
images also indicate that the RAM forms in small ‘islands’ on the powder bed
surface. However, these islands begin to merge as sintering progresses, to a
greater degree as the infra-red lamp power is increased.
Research limitations/implications: These results are based only on single
layer parts. Further work will examine the sintering characteristics of multiple
layer parts.
Practical implications: Results have shown that, whilst it is not possible to
increase the achievable layer thickness of the parts produced by modifying
the infra-red lamp power, the degree of sintering can be improved greatly by
increasing the power.
Originality/value: High Speed Sintering is an entirely new process which is
currently still under development; the results presented here will directly
impact the direction of further development and research into this process
Paleoseismological data from a new trench across the El Camp Fault(Catalan Coastal Ranges, NE Iberian Peninsula)
The El Camp Fault (Catalan Coastal Ranges, NE Iberian Peninsula) is a slow slipping normal fault whose
seismic potential has only recently been recognised. New geomorphic and trench investigations were carried out
during a training course across the El Camp Fault at the La Porquerola alluvial fan site. A new trench (trench 8)
was dug close to a trench made previously at this site (trench 4). With the aid of two long topographic profiles
across the fault scarp we obtained a vertical slip rate ranging between 0.05 and 0.08 mm/yr. At the trench site,
two main faults, which can be correlated between trenches 8 and 4, make up the fault zone. Using trench analysis
three paleoseismic events were identified, two between 34.000 and 125.000 years BP (events 3 and 2) and another
event younger than 13 500 years BP (event 1), which can be correlated, respectively, with events X (50.000-
125.000 years BP), Y (35.000-50.000 years BP) and Z (3000-25.000 years BP). The last seismic event at the La
Porquerola alluvial fan site is described for the first time, but with some uncertainties
Cardiac-specific suppression of NF-kappa B signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system
Activation of NF-kappa B signaling in the heart may be protective or deleterious depending on the pathological context. in diabetes, the role of NF-kappa B in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-kappa B modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated I kappa B-alpha in the heart (3M mice), which prevented activation of canonical NF-kappa B signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. in contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. in diabetic WT mice, an increase in the phospholamban/sarco(endo) plasmic reticulum Ca2+-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca2+ handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. in conclusion, these results demonstrate that inhibition of NF-kappa B signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca2+ handling and inhibition of the cardiac renin-angiotensin system.National Heart, Lung, and Blood InstituteTexas A&M Hlth Sci Ctr, Div Mol Cardiol, Dept Med, Coll Med, Temple, TX USABaylor Scott & White Hlth, Temple, TX USACent Texas Vet Hlth Care Syst, Temple, TX USAUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilLoyola Univ Chicago, Maywood, IL USAUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilNational Heart, Lung, and Blood Institute: 5-R01-HL-090817Web of Scienc
Repression of cyclin D1 as a target for germ cell tumors
Metastatic germ cell tumors (GCT) are curable, however GCTs refractory to cisplatin-based chemotherapy have a poor prognosis. This study explores D-type cyclins as molecular targets in GCTs because all-trans-retinoic acid (RA)-mediated differentiation of the human embryonal carcinoma (EC) cell line NT2/D1 is associated with G1 cell cycle arrest and proteasomal degradation of cyclin D1. RA effects on D-type cyclins are compared in human EC cells that are RA sensitive or dually RA and cisplatin resistant (NT2/D1-R1) and in clinical GCTs that have both EC and mature teratoma components. Notably, GCT differentiation was associated with reduced cyclin D1 but increased cyclin D3 expression. RA was shown here to repress cyclin D1 through a transcriptional mechanism in addition to causing its degradation. The siRNA-mediated repression of individual cyclin D species resulted in growth inhibition in both RA sensitive and resistant EC cells. Only repression of cyclin D1 occurred in vitro and when clinical GCTs mature, implicating cyclin D1 as a molecular therapeutic target. To confirm this, the EGFR-tyrosine kinase inhibitor, Erlotinib, was used to repress cyclin D1. This inhibited proliferation in RA and cisplatin sensitive and resistant EC cells. Taken together, these findings implicate cyclin D1 targeting agents for the treatment of GCTs
Oligodendrocytes contribute to motor neuron death in ALS via SOD1 dependent mechanism
Oligodendrocytes have recently been implicated in the pathophysiology of ALS. Here we show that, in vitro, mutant SOD1 mouse oligodendrocytes induce wild-type motor neuron hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls, sporadic and familial ALS patients using two different reprogramming methods. All ALS oligodendrocyte lines induced motor neuron death through conditioned medium and in co-culture. Conditioned medium-mediated motor neuron death was associated with decreased lactate production and release, while toxicity in co-culture was lactate independent, demonstrating that motor neuron survival is not only mediated by soluble factors.
Remarkably, human SOD1 shRNA treatment resulted in motor neuron rescue in both mouse and human cultures when knockdown was achieved in progenitor cells, while it was ineffective in differentiated oligodendrocytes.
Early SOD1 knockdown, in fact, rescued lactate impairment and cell toxicity in all lines tested with exclusion of samples carrying C9orf72 repeat expansions. These did not respond to SOD1 knockdown nor showed lactate release impairment.
Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type some damage might be irreversible. In addition, we demonstrate that C9ORF72 patients represent an independent patient group that might not respond to the same treatment
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Longitudinal proteomic profiling of dialysis patients with COVID-19 reveals markers of severity and predictors of death
Funder: The Sidharth Burman endowmentEnd-stage kidney disease (ESKD) patients are at high risk of severe COVID-19. We measured 436 circulating proteins in serial blood samples from hospitalised and non-hospitalised ESKD patients with COVID-19 (n = 256 samples from 55 patients). Comparison to 51 non-infected patients revealed 221 differentially expressed proteins, with consistent results in a separate subcohort of 46 COVID-19 patients. Two hundred and three proteins were associated with clinical severity, including IL6, markers of monocyte recruitment (e.g. CCL2, CCL7), neutrophil activation (e.g. proteinase-3), and epithelial injury (e.g. KRT19). Machine-learning identified predictors of severity including IL18BP, CTSD, GDF15, and KRT19. Survival analysis with joint models revealed 69 predictors of death. Longitudinal modelling with linear mixed models uncovered 32 proteins displaying different temporal profiles in severe versus non-severe disease, including integrins and adhesion molecules. These data implicate epithelial damage, innate immune activation, and leucocyte–endothelial interactions in the pathology of severe COVID-19 and provide a resource for identifying drug targets
2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis:Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization
<i>Mycobacterium tuberculosis</i> (<i>MTb</i>) possesses
two nonproton pumping type II NADH dehydrogenase (NDH-2)
enzymes which are predicted to be jointly essential for respiratory
metabolism. Furthermore, the structure of a closely related bacterial
NDH-2 has been reported recently, allowing for the structure-based
design of small-molecule inhibitors. Herein, we disclose <i>MTb</i> whole-cell structure–activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the <i>ndh</i> encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in <i>MTb</i> was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by <i>ndhA</i> in <i>MTb</i>. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial <i>MTb</i> SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors
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