Long-range potential fluctuations and 1/f noise in hydrogenated amorphous silicon

We present a microscopic theory of the low-frequency voltage noise (known as "1/f" noise) in micrometer-thick films of hydrogenated amorphous silicon. This theory traces the noise back to the long-range fluctuations of the Coulomb potential produced by deep defects, thereby predicting the absolute noise intensity as a function of the distribution of defect activation energies. The predictions of this theory are in very good agreement with our own experiments in terms of both the absolute intensity and the temperature dependence of the noise spectra.Comment: 8 pages, 3 figures, several new parts and one new figure are added, but no conceptual revision

Haemogenic Gastruloids Recapitulate Developmental Haematopoiesis and Provide an Ontogeny-Relevant Context to Dissect the Origins of Infant Leukemia

Meeting abstract presented at the 64th ASH Annual Meeting and Exposition, New Orleans, LA, USA, 10-13 Dec 2022..Modelling of developmental hematopoiesis has historically been challenging due to the inability to produce hematopoietic stem cells (HSC) and recapitulate microenvironment interactions ex vivo. Gastruloids are 3D aggregates of embryonic stem (ES) cells which display developmentally-specific spatial and temporal organization that recapitulate gastrulation. We adapted the gastruloid protocol to introduce hematopoietic signalling cues, and generated an in vitro model of embryonic hematopoiesis that sequentially recapitulates the formation of hemogenic endothelium, hematopoietic progenitors, and pre-HSC, over a culture period of 216 hours. Flow cytometry analysis detected the presence of c-Kit+ endothelium at 120h, followed by emergence of CD41+ hematopoietic progenitors at 144h, and the appearance of CD45+ cells from 192h. CD45+ cells were observed in small clusters adjoining endothelium-lined structures, reminiscent of developmental hemogenic-to-endothelial transition and intra-aortic clusters. Single-cell RNA sequencing revealed specification of pre-definitive and definitive waves of embryonic hematopoiesis, aligning 144h-CD41+ cells with erythro-myeloid progenitors (EMP), and late CD45+ with lympho-myeloid progenitors and pre-HSC, altogether supporting the hemogenic gastruloid as a model that is temporally and topographically congruous with the embryo. The close recapitulation of developmental ontogeny led us to explore hemogenic gastruloids to understand cell and stage-specific susceptibility to forms of Acute Myeloid Leukaemia exclusively observed in infants. The chromosomal translocation t(7;12)(q36;p13), characterized by the ectopic overexpression of the MNX1 gene, is found in up to one third of infant AML cases, but has been challenging to model using conventional strategies, largely due to the inability of MNX1 to transform adult hematopoietic cells. The age-selectivity of t(7;12) has been proposed to reflect a transient developmental window for a target cell of origin absent in adult life, but its nature is yet to be defined. In order to identify the context of MNX1-driven leukemogenesis, we produced hemogenic gastruloids using lentiviral-transduced mouse ES cells in which we overexpressed MNX1 as a proxy of t(7;12). Although MNX1 did not interfere with ES cell pluripotent cultures, it primed incipient hemogenic programmes and promoted hemogenic gastruloid formation. Critically, expression of MNX1 resulted in transformation of gastruloid-derived hematopoietic cells, as assessed by serial colony-forming cell replating, with expansion of a phenotypic myeloid cell, a phenomenon not observed in adult tissues. Detailed analysis of the cellular composition of MNX1-overexpressing hemogenic gastruloids revealed a significant effect in the output of CD41+ and c-Kit+ populations at 144h, but no effect in CD45+ cells at 192-216h, suggesting that the target of MNX1 lies within the EMP stage, an observation supported by single-cell RNA-seq analysis of MNX1 vs control gastruloids. Systematic comparison of the temporal transcriptional profiles of hemogenic gastruloids, MNX1-overexpressing gastruloids, and t(7;12) patients, pinpoints the target cell of MNX1 at the HE-to-EMP transition. In summary, we propose a novel model of embryonic hematopoiesis capable of capturing developmentally-relevant cellularity and topography of the early hematopoietic microenvironment, with the ability to mechanistically elucidate developmental associations of infant leukemia

A New Mixed-Backbone Oligonucleotide against Glucosylceramide Synthase Sensitizes Multidrug-Resistant Tumors to Apoptosis

Enhanced ceramide glycosylation catalyzed by glucosylceramide synthase (GCS) limits therapeutic efficiencies of antineoplastic agents including doxorubicin in drug-resistant cancer cells. Aimed to determine the role of GCS in tumor response to chemotherapy, a new mixed-backbone oligonucleotide (MBO-asGCS) with higher stability and efficiency has been generated to silence human GCS gene. MBO-asGCS was taken up efficiently in both drug-sensitive and drug-resistant cells, but it selectively suppressed GCS overexpression, and sensitized drug-resistant cells. MBO-asGCS increased doxorubicin sensitivity by 83-fold in human NCI/ADR-RES, and 43-fold in murine EMT6/AR1 breast cancer cells, respectively. In tumor-bearing mice, MBO-asGCS treatment dramatically inhibited the growth of multidrug-resistant NCI/ADR-RE tumors, decreasing tumor volume to 37%, as compared with scrambled control. Furthermore, MBO-asGCS sensitized multidrug-resistant tumors to chemotherapy, increasing doxorubicin efficiency greater than 2-fold. The sensitization effects of MBO-asGCS relied on the decreases of gene expression and enzyme activity of GCS, and on the increases of C18-ceramide and of caspase-executed apoptosis. MBO-asGCS was accumulation in tumor xenografts was greater in other tissues, excepting liver and kidneys; but MBO-asGCS did not exert significant toxic effects on liver and kidneys. This study, for the first time in vivo, has demonstrated that GCS is a promising therapeutic target for cancer drug resistance, and MBO-asGCS has the potential to be developed as an antineoplastic agent

The influence of a consumer-wearable activity tracker on sedentary time and prolonged sedentary bouts: secondary analysis of a randomized controlled trial

Abstract Objective A recent meta-analysis surmised pedometers were a useful panacea to independently reduce sedentary time (ST). To further test and expand on this deduction, we analyzed the ability of a consumer-wearable activity tracker to reduce ST and prolonged sedentary bouts (PSB). We originally conducted a 12-month randomized control trial where 800 employees from 13 organizations were assigned to control, activity tracker, or one of two activity tracker plus incentive groups designed to increase step count. The primary outcome was accelerometer measured moderate-to-vigorous physical activity. Results We conducted a secondary analysis on accelerometer measured daily ST and PSB bouts. A general linear mixed model was used to examine changes in ST and prolonged sedentary bouts, followed by between-group pairwise comparisons. Regression analyses were conducted to examine the association of changes in step counts with ST and PSB. The changes in ST and PSB were not statistically significant and not different between the groups (P < 0.05). Increases in step counts were concomitantly associated with decreases in ST and PSB, regardless of intervention (P < 0.05). Caution should be taken when considering consumer-wearable activity trackers as a means to reduce sedentary behavior. Trial registration NCT01855776 Registered: August 8, 201

IMPROVED AGING PERFORMANCE OF VIRGIN EPDM ROOF-SHEETING COMPOUNDS WITH AMINE-DEVULCANIZED EPDM WEATHERSTRIP MATERIAL

Sulfur-cured EPDM building-profile material was reclaimed in a co-rotating twin-screw extruder using hexadecylamine as reclaiming aid. This reclaim was blended with increasing amounts of a virgin EPDM roof-sheeting masterbatch and cured at temperatures allowing for a reversion-free vulcanization. The trends in cure characteristics showed that increasing amounts of reclaim employed in the blends lowered the reversion-free cure temperature and the maximum torque values, while the vulcanization speed was increased. The insoluble fraction and crosslink density both decreased, while the ratio of mono- to di- and polysulfidic crosslinks increased with growing reclaim contents. A SEM-EDX morphology study of the blends, in order to evaluate the dispersion of the reclaim into the virgin rubber matrix showed, that even large amounts of reclaimed material resulted in homogeneous and smooth compounds. Tensile strength, modulus at 300% strain and hardness decreased, while elongation at break, tear strength and compression set at 70 degrees C increased with increasing reclaim ratios. Irrespective of the blend ratios, the mechanical properties all fulfilled the most stringent UEAtc specifications for EPDM roof-sheeting. Increasing reclaim contents improve the aging resistance and prolong the time before a practical limiting value for elongation at break of 250% for EPDM roof-sheeting purposes is reached