Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to ...allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning.
Future changes in the stratospheric circulation could have an important impact on northern winter tropospheric climate change, given that sea level pressure (SLP) responds not only to tropospheric ...circulation variations but also to vertically coherent variations in troposphere‐stratosphere circulation. Here we assess northern winter stratospheric change and its potential to influence surface climate change in the Coupled Model Intercomparison Project‐Phase 5 (CMIP5) multimodel ensemble. In the stratosphere at high latitudes, an easterly change in zonally averaged zonal wind is found for the majority of the CMIP5 models, under the Representative Concentration Pathway 8.5 scenario. Comparable results are also found in the 1% CO2 increase per year projections, indicating that the stratospheric easterly change is common feature in future climate projections. This stratospheric wind change, however, shows a significant spread among the models. By using linear regression, we quantify the impact of tropical upper troposphere warming, polar amplification, and the stratospheric wind change on SLP. We find that the intermodel spread in stratospheric wind change contributes substantially to the intermodel spread in Arctic SLP change. The role of the stratosphere in determining part of the spread in SLP change is supported by the fact that the SLP change lags the stratospheric zonally averaged wind change. Taken together, these findings provide further support for the importance of simulating the coupling between the stratosphere and the troposphere, to narrow the uncertainty in the future projection of tropospheric circulation changes.
Key Points
Stratospheric easterly change is common feature in future climate projections
Significant intermodel spread in stratospheric northern winter climate change
Importance of stratospheric easterly change to narrow uncertainty in SLP change
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multielectrode array and patch-clamp recordings that hyperexcitability detected by ...clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1), C9orf72, and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected but otherwise isogenic SOD1(+/+) stem cell line do not display the hyperexcitability phenotype. SOD1(A4V/+) ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.
The mechanisms by which poikilothermic organisms ensure that biological processes are robust to temperature changes are largely unknown. Temperature compensation, the ability of circadian rhythms to ...maintain a relatively constant period over the broad range of temperatures resulting from seasonal fluctuations in environmental conditions, is a defining property of circadian networks. Temperature affects the alternative splicing (AS) of several clock genes in fungi, plants, and flies, but the splicing factors that modulate these effects to ensure clock accuracy throughout the year remain to be identified. Here we show that GEMIN2, a spliceosomal small nuclear ribonucleoprotein assembly factor conserved from yeast to humans, modulates low temperature effects on a large subset of pre-mRNA splicing events. In particular, GEMIN2 controls the AS of several clock genes and attenuates the effects of temperature on the circadian period in Arabidopsis thaliana . We conclude that GEMIN2 is a key component of a posttranscriptional regulatory mechanism that ensures the appropriate acclimation of plants to daily and seasonal changes in temperature conditions.
RNA processing, an important step in the regulation of gene expression, is mediated by proteins and RNA molecules that are highly sensitive to variations in temperature conditions. Most organisms do not control their own body temperature. Therefore, molecular mechanisms must have evolved that ensure that biological processes are robust to temperature changes. Here we identify a protein that buffers the effect of temperature on biological timing by enhancing the assembly of the spliceosome, a large ribonucleoprotein complex involved in RNA processing in organisms ranging from yeast to humans, and thereby controlling the alternative splicing of clock genes.
In this study, we evaluated the efficacy of various primers for the purpose of DNA barcoding old, pinned museum specimens of blackflies (Diptera: Simuliidae). We analysed 271 pinned specimens ...representing two genera and at least 36 species. Due to the age of our material, we targeted overlapping DNA fragments ranging in size from 94 to 407 bp. We were able to recover valid sequences from 215 specimens, of which 18% had 500‐ to 658‐bp barcodes, 36% had 201‐ to 499‐bp barcodes and 46% had 65‐ to 200‐bp barcodes. Our study demonstrates the importance of choosing suitable primers when dealing with older specimens and shows that even very short sequences can be diagnostically informative provided that an appropriate gene region is used. Our study also highlights the lack of knowledge surrounding blackfly taxonomy, and we briefly discuss the need for further phylogenetic studies in this socioeconomically important family of insects.
The purpose of this study was to perform a comparative analysis of powder-bed-based additive manufacturing (AM) technologies during the production of metallic components using Inconel 625 powder ...material. The AM technologies explored in this study include electron beam powder bed fusion (EPBF), laser powder bed fusion (LPBF), and binder jetting technology. Samples were fabricated in two build directions (X and Z build orientations) for this evaluation process, where all specimens underwent a hot isostatic pressing (HIP) post-process. The comparison was made in terms of microstructure and mechanical properties including ultimate tensile strength (UTS), yield strength (YS), percent elongation, and modulus of elasticity (E). Microstructural characterization showed evidence of equiaxed grain formation for binder jetting and LPBF parts, whereas EPBF parts displayed a more columnar grain formation parallel to the build direction. Six specimens were tested per technology, three built in the X orientation and three built in the Z orientation. All six specimens were built in a single run of each AM machine. Results indicated that all three technologies are capable of meeting the minimum requirements of the ASTM F3056-14 standard for parts produced in the X orientation, with properties that are similar to wrought Inconel 625. In the Z orientation, however, only LPBF was able to meet the minimum standard requirements. Through the comparative analysis of the mechanical properties, this work showed that LPBF outperformed the other technologies in a majority of the evaluated properties, followed by EPBF and binder jetting. An analysis of the fracture surfaces of tensile specimens was also performed, and it indicated ductile fracture (dimple rupture) for the specimens produced with all three of the AM technologies studied. Nevertheless, the characterization also showed certain differences in the fractured surfaces, such as the presence of un-sintered powder particles for the binder jetting processed Inconel 625, or the development of the so called woody structure for the EPBF processed material. This study can be used to determine distinct characteristics between the three powder-bed-based technologies for the fabrication of Inconel 625 that can further include other technologies and materials using similar approaches.
This study examines the basis of resistance and sensitivity of normal and transformed cells to histone deacetylase inhibitor (HDACi)-induced cell death, specifically the role of caspases and ...thioredoxin (Trx). An important attribute of HDACis is that they induce cancer cell death at concentrations to which normal cells are relatively resistant, making them well suited for cancer therapy. The mechanism underlying this selectivity has not been understood. In this study we found that the HDACi suberoylanilide hydroxamic acid (SAHA) and MS-275, a benzamide, cause an accumulation of reactive oxygen species (ROS) and caspase activation in transformed but not normal cells. Inhibition of caspases does not block HDACi-induced cell death. These studies provide a possible mechanism that can explain why normal but not certain transformed cells are resistant to HDACi-induced cell death. The HDACi causes an increase in the level of Trx, a major reducing protein for many targets, in normal cells but not in transformed cells. The SAHA-induced increase in Trx activity in normal cells is associated with no increase in ROS accumulation. Transfection of transformed cells with Trx small interfering RNA caused a marked decrease in the level of Trx protein with an increase in ROS, a decrease in cell proliferation, and an increase in sensitivity to SAHA-induced cell death. Thus, Trx, independent of the caspase apoptotic pathway, is an important determinant of resistance of cells to HDACi-induced cell death.
Delayed administration of active anti-infective therapy is associated with increased rates of adverse events, mortality, and costs among sepsis patients. Inherent limitations of conventional culture ...identification methods and the lengthy turnaround time of antimicrobial susceptibility testing are significant barriers to the timely delivery of life-saving therapy, particularly among antibiotic-resistant infections. Culture-independent diagnostic techniques that detect pathogens and antimicrobial resistance genes within clinical samples present a tremendous benefit to timely diagnosis and management of patients. Improved outcomes for rapid intervention with rapid diagnostics have been documented and include decreased mortality rates, decreased health care delivery costs, and faster delivery of appropriate therapeutics.
Abstract
Corporate environmental sustainability requires two complementary types of green practices—environmental protection hardware (EPH) and environmental protection software (EPS). Stakeholder ...greening pressures drive implementation; however, corporate responses vary, often lacking the balance and intensity of EPS and EPH needed. This paper explores the role of green human resource management (GHRM) in explaining variations in the implementation of EPH and EPS in response to stakeholders' pro‐environmental pressures. Drawing on stakeholder theory and the ability, motivation, and opportunity (AMO) framework, a mediating role is hypothesized. Empirical findings from Brazil using structural equation modeling reveal that increased green pressure from stakeholders drives the adoption of both types of green practices through a partial mediating role of GHRM that is stronger for EPH than for EPS. The value of this study lies in the consideration of EPH and EPS practices in the same model and expanding stakeholder theory on how stakeholders can improve environmental protection through GHRM. Implications are that organizations can level the field for the balanced application of EPS and EPH with a system of green human resource management practices—training, assessment, rewards, and teamwork—to channel the translation of stakeholder pressures into workplace green outcomes. Limitations, future research ideas, and policy and practice implications are detailed.
PDF
