In a search for \(\omega\) mesic states, the production of \(\omega\)-mesons in coincidence with forward going protons has been studied in photon induced reactions on \(^{12}\)C for incident photon ...energies of 1250 - 3100 MeV. The \(\pi^0 \gamma\) pairs from decays of bound or quasi-free \(\omega\)-mesons have been measured with the CBELSA/TAPS detector system in coincidence with protons registered in the MiniTAPS forward array. Structures in the total energy distribution of the \(\pi^0 \gamma\) pairs, which would indicate the population and decay of bound \(\omega~^{11}\)B states, are not observed. The \(\pi^0 \gamma\) cross section of 0.3 nb/MeV/sr observed in the bound state energy regime between -100 and 0 MeV may be accounted for by yield leaking into the bound state regime because of the large in-medium width of the \(\omega\)-meson. A comparison of the measured total energy distribution with calculations suggests the real part \(V_0\) of the \(\omega~^{11}\)B potential to be small and only weakly attractive with \(V_0(\rho=\rho_0) = -15\pm\) 35(stat) \(\pm\)20(syst) MeV in contrast to some theoretical predictions of attractive potentials with a depth of 100 - 150 MeV.
Recent research resolves the challenging problem of building biophysically plausible spiking neural models that are also capable of complex information processing. This advance creates new ...opportunities in neuroscience and neuromorphic engineering, which we discussed at an online focus meeting.
Leiomyosarcoma (LMS) is an aggressive sarcoma for which standard chemotherapies achieve response rates under 30%. There are no effective targeted therapies against LMS. Most LMS are characterized by ...chromosomal instability (CIN), resulting in part from TP53 and RB1 co-inactivation and DNA damage repair defects. We sought to identify therapeutic targets that could exacerbate intrinsic CIN and DNA damage in LMS, inducing lethal genotoxicity.
We performed clinical targeted sequencing in 287 LMS and genome-wide loss-of-function screens in 3 patient-derived LMS cell lines, to identify LMS-specific dependencies. We validated candidate targets by biochemical and cell-response assays in vitro and in seven mouse models.
Clinical targeted sequencing revealed a high burden of somatic copy-number alterations (median fraction of the genome altered =0.62) and demonstrated homologous recombination deficiency signatures in 35% of LMS. Genome-wide short hairpin RNA screens demonstrated PRKDC (DNA-PKcs) and RPA2 essentiality, consistent with compensatory nonhomologous end joining (NHEJ) hyper-dependence. DNA-PK inhibitor combinations with unconventionally low-dose doxorubicin had synergistic activity in LMS in vitro models. Combination therapy with peposertib and low-dose doxorubicin (standard or liposomal formulations) inhibited growth of 5 of 7 LMS mouse models without toxicity.
Combinations of DNA-PK inhibitors with unconventionally low, sensitizing, doxorubicin dosing showed synergistic effects in LMS in vitro and in vivo models, without discernable toxicity. These findings underscore the relevance of DNA damage repair alterations in LMS pathogenesis and identify dependence on NHEJ as a clinically actionable vulnerability in LMS.
Spatio-temporal pattern recognition is a fundamental ability of the brain which is required for numerous real-world activities. Recent deep learning approaches have reached outstanding accuracies in ...such tasks, but their implementation on conventional embedded solutions is still very computationally and energy expensive. Tactile sensing in robotic applications is a representative example where real-time processing and energy efficiency are required. Following a brain-inspired computing approach, we propose a new benchmark for spatio-temporal tactile pattern recognition at the edge through Braille letter reading. We recorded a new Braille letters dataset based on the capacitive tactile sensors of the iCub robot's fingertip. We then investigated the importance of spatial and temporal information as well as the impact of event-based encoding on spike-based computation. Afterward, we trained and compared feedforward and recurrent Spiking Neural Networks (SNNs) offline using Backpropagation Through Time (BPTT) with surrogate gradients, then we deployed them on the Intel Loihi neuromorphic chip for fast and efficient inference. We compared our approach to standard classifiers, in particular to the Long Short-Term Memory (LSTM) deployed on the embedded NVIDIA Jetson GPU, in terms of classification accuracy, power, and energy consumption together with computational delay. Our results show that the LSTM reaches ~97% of accuracy, outperforming the recurrent SNN by ~17% when using continuous frame-based data instead of event-based inputs. However, the recurrent SNN on Loihi with event-based inputs is ~500 times more energy-efficient than the LSTM on Jetson, requiring a total power of only ~30 mW. This work proposes a new benchmark for tactile sensing and highlights the challenges and opportunities of event-based encoding, neuromorphic hardware, and spike-based computing for spatio-temporal pattern recognition at the edge.
The study of changes in protein-DNA interactions measured by ChIP-seq on dynamic systems, such as cell differentiation, response to treatments or the comparison of healthy and diseased individuals, ...is still an open challenge. There are few computational methods comparing changes in ChIP-seq signals with replicates. Moreover, none of these previous approaches addresses ChIP-seq specific experimental artefacts arising from studies with biological replicates. We propose THOR, a Hidden Markov Model based approach, to detect differential peaks between pairs of biological conditions with replicates. THOR provides all pre- and post-processing steps required in ChIP-seq analyses. Moreover, we propose a novel normalization approach based on housekeeping genes to deal with cases where replicates have distinct signal-to-noise ratios. To evaluate differential peak calling methods, we delineate a methodology using both biological and simulated data. This includes an evaluation procedure that associates differential peaks with changes in gene expression as well as histone modifications close to these peaks. We evaluate THOR and seven competing methods on data sets with distinct characteristics from in vitro studies with technical replicates to clinical studies of cancer patients. Our evaluation analysis comprises of 13 comparisons between pairs of biological conditions. We show that THOR performs best in all scenarios.
Intraductal papillary mucinous neoplasms (IPMNs) are the most frequent cystic pancreatic tumors. Little is known about their molecular alterations, but mutations in GNAS have been reported to promote ...IPMN formation. A tumor-derived fraction of circulating cell-free DNA (cfDNA), isolated from blood samples, contains many of the same mutations as the primary tumor, and could be a tool for noninvasive disease monitoring. We found that the total amount of cfDNA can discriminate between individuals without pancreatic lesions (controls) and patients with Fukuoka-negative branch-duct IPMN or pancreatic cancer. Furthermore, we detected GNAS mutations in cfDNA from patients with IPMN, but not patients with serous cystadenoma or controls. Analyses of cfDNA might therefore be used in the diagnosis of patients with IMPN or in monitoring disease progression.
Cellulose nanocrystals (CNCs) are unique and promising natural nanomaterials that can be extracted from native cellulose fibers by acid hydrolysis. In this study, we developed chemically modified CNC ...derivatives by covalent tethering of PEGylated biotin and perylenediimide (PDI)-based near-infrared organic dye and evaluated their suitability for labeling and imaging of different cell lines including J774A.1 macrophages, NIH-3T3 fibroblasts, HeLa adenocarcinoma cells, and primary murine dendritic cells. PDI-labeled CNCs showed a superior photostability compared to similar commercially available dyes under long periods of constant and high-intensity illumination. All CNC derivatives displayed excellent cytocompatibility toward all cell types and efficiently labeled cells in a dose-dependent manner. Moreover, CNCs were effectively internalized and localized in the cytoplasm around perinuclear areas. Thus, our findings demonstrate the suitability of these new CNC derivatives for labeling, imaging, and long-time tracking of a variety of cell lines and primary cells.
It has been shown that insoluble Gd chelates are suitable MRI contrast agents for conditional activation by intracellular lipases. The DTPA-based, insoluble, inactive contrast agent was internalized ...into dendritic cells by phagocytosis. Cleavage of long aliphatic side chains by intracellular lipase activity leads to the contrast agents solubility and hereby its activation depending on the enzyme expression. Uptake and activation of the contrast agent was much reduced in Flt3+ CD11b+ progenitor cells. Detectability limits in the
T
1-weighted MR images were estimated in phantoms and in vivo in the rat brain. Marginal toxic effects were only observed at very high concentrations of the contrast agent. The chelate can easily be modified to be targeted by enzymes expressed during specific change of cell status like activation or differentiation. Such a system is suitable for functional cellular in vivo MR imaging.
Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we ...investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation
in vitro
. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-α on dendritic cell maturation
in vivo
, we treated dTGRs with the soluble TNF-α receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-κB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas
in vivo
TNF-α is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response.
PDF
