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Reply to Semelidou and Skoulakis: "Short-term" habituation has multiple distinct mechanisms
No full textProcessing by RNase 1 forms tRNA halves and distinct Y RNA fragments in the extracellular environment
No full textExtracellular RNAs participate in intercellular communication, and are being studied as promising minimally invasive diagnostic markers. Several studies in recent years showed that tRNA halves and distinct Y RNA fragments are abundant in the extracellular space, including in biofluids. While their regulatory and diagnostic potential has gained a substantial amount of attention, the biogenesis of these extracellular RNA fragments remains largely unexplored. Here, we demonstrate that these fragments are produced by RNase 1, a highly active secreted nuclease. We use RNA sequencing to investigate the effect of a null mutation of RNase 1 on the levels of tRNA halves and Y RNA fragments in the extracellular environment of cultured human cells. We complement and extend our RNA sequencing results with northern blots, showing that tRNAs and Y RNAs in the non-vesicular extracellular compartment are released from cells as full-length precursors and are subsequently cleaved to distinct fragments. In support of these results, formation of tRNA halves is recapitulated by recombinant human RNase 1 in our in vitro assay. These findings assign a novel function for RNase 1, and position it as a strong candidate for generation of tRNA halves and Y RNA fragments in biofluids
Influence of On-Off dynamics and selective attention on the spatial pattern of correlated variability in neocortex
No full textCorrelated activity fluctuations in neocortex influence sensory responses and behavior. Neural correlations reflect anatomical connectivity and change dynamically with cognitive states, such as attention. Yet, how anatomical connectivity and cognitive states define the population structure of correlations is not known. We measured correlations in single cortical columns and found that the magnitude of correlations, their attentional modulation and dependence on lateral distance are predicted by On-Off dynamics, synchronous fluctuations in population activity across cortical layers. We developed a network model, in which spatial connectivity correlates the On-Off dynamics across nearby columns. We show that attentional inputs modulate the spatial extent of On-Off dynamics, resulting in spatially non-uniform changes in correlations. We confirm this prediction in our columnar recordings by showing that attentional modulation of correlations depends on lateral distance. Our results reveal how heterogeneous spatial patterns of correlations arise from the connectivity and network dynamics during attention
Metal-Free Synthesis of Functional 1-Substituted-1,2,3-Triazoles from Ethenesulfonyl Fluoride and Organic Azides
No full textThe boom in growth of 1,4-disubstituted triazole products, in particular, since the early 2000's, can be largely attributed to the birth of click chemistry and the discovery of the Cu(I) -catalyzed azide-alkyne cycloaddition (CuAAC). Yet the synthesis of relatively simple, albeit important, 1-substituted-1,2,3-triazoles has been surprisingly more challenging. Reported here is a straightforward and scalable click-inspired protocol for the synthesis of 1-substituted-1,2,3-triazoles from organic azides and the bench stable acetylene surrogate ethenesulfonyl fluoride (ESF). The new transformation tolerates a wide selection of substrates and proceeds smoothly under metal-free conditions to give the products in excellent yield. Under controlled acidic conditions, the 1-substituted-1,2,3-triazole products undergo a Michael addition reaction with a second equivalent of ESF to give the unprecedented 1-substituted triazolium sulfonyl fluoride salts
Early relapse on adjuvant gemcitabine associated with an exceptional response to 2nd line capecitabine chemotherapy in a patient with pancreatic adenosquamous carcinoma with strong intra-tumoural expression of cytidine deaminase: a case report.
Get PDFBACKGROUND: Pancreatic adenosquamous carcinoma has a poor prognosis, with limited prospective trial data to guide optimal treatment. The potential impact of drug metabolism on the treatment response of patients with pancreatic adenosquamous carcinoma is largely unknown. CASE PRESENTATION: We describe the case of a 51 year old woman with pancreatic adenosquamous carcinoma who, following surgical resection, experienced early disease relapse during adjuvant gemcitabine therapy. Paradoxically, this was followed by an exceptional response to capecitabine therapy lasting 34.6 months. Strong expression of cytidine deaminase was detected within the tumour. CONCLUSIONS: This case study demonstrates that early relapse during adjuvant chemotherapy for pancreatic adenosquamous carcinoma may be compatible with a subsequent exceptional response to second line chemotherapy, an important observation given the poor overall prognosis of patients with adenosquamous carcinoma. Cytidine deaminase is predicted to inactivate gemcitabine and, conversely, catalyze capecitabine activation. We discuss strong intra-tumoural expression of cytidine deaminase as a potential mechanism to explain this patient's disparate responses to gemcitabine and capecitabine therapy, and highlight the benefit that may be gained from considering similar determinants of response to chemotherapy in clinical practice
Nebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: a case series
No full textBACKGROUND: Mechanically ventilated patients with COVID-19 have a mortality of 24-53%, in part due to distal mucopurulent secretions interfering with ventilation. DNA from neutrophil extracellular traps (NETs) contribute to the viscosity of mucopurulent secretions and NETs are found in the serum of COVID-19 patients. Dornase alfa is recombinant human DNase 1 and is used to digest DNA in mucoid sputum. Here, we report a single-center case series where dornase alfa was co-administered with albuterol through an in-line nebulizer system. METHODS: Demographic and clinical data were collected from the electronic medical records of five mechanically ventilated patients with COVID-19-including three requiring veno-venous extracorporeal membrane oxygenation-treated with nebulized in-line endotracheal dornase alfa and albuterol, between March 31 and April 24, 2020. Data on tolerability and response were analyzed. RESULTS: The fraction of inspired oxygen requirements was reduced for all five patients after initiating dornase alfa administration. All patients were successfully extubated, discharged from hospital and remain alive. No drug-associated toxicities were identified. CONCLUSIONS: Results suggest that dornase alfa will be well-tolerated by patients with severe COVID-19. Clinical trials are required to formally test the dosing, safety, and efficacy of dornase alfa in COVID-19, and several have been recently registered
The Impact of Regulator of G-Protein Signaling 2 (RGS2) on Social Stress-Induced Behavioral Phenotypes
No full textA Statistical Growth Property of Plant Root Architectures.
Get PDFNumerous types of biological branching networks, with varying shapes and sizes, are used to acquire and distribute resources. Here, we show that plant root and shoot architectures share a fundamental design property. We studied the spatial density function of plant architectures, which specifies the probability of finding a branch at each location in the 3-dimensional volume occupied by the plant. We analyzed 1645 root architectures from four species and discovered that the spatial density functions of all architectures are population-similar. This means that despite their apparent visual diversity, all of the roots studied share the same basic shape, aside from stretching and compression along orthogonal directions. Moreover, the spatial density of all architectures can be described as variations on a single underlying function: a Gaussian density truncated at a boundary of roughly three standard deviations. Thus, the root density of any architecture requires only four parameters to specify: the total mass of the architecture and the standard deviations of the Gaussian in the three (x, y, z) growth directions. Plant shoot architectures also follow this design form, suggesting that two basic plant transport systems may use similar growth strategies
Semantic segmentation of microscopic neuroanatomical data by combining topological priors with encoder-decoder deep networks
No full textUnderstanding of neuronal circuitry at cellular resolution within the brain has relied on neuron tracing methods that involve careful observation and interpretation by experienced neuroscientists. With recent developments in imaging and digitization, this approach is no longer feasible with the large-scale (terabyte to petabyte range) images. Machine-learning-based techniques, using deep networks, provide an efficient alternative to the problem. However, these methods rely on very large volumes of annotated images for training and have error rates that are too high for scientific data analysis, and thus requires a substantial volume of human-in-the-loop proofreading. Here we introduce a hybrid architecture combining prior structure in the form of topological data analysis methods, based on discrete Morse theory, with the best-in-class deep-net architectures for the neuronal connectivity analysis. We show significant performance gains using our hybrid architecture on detection of topological structure (for example, connectivity of neuronal processes and local intensity maxima on axons corresponding to synaptic swellings) with precision and recall close to 90% compared with human observers. We have adapted our architecture to a high-performance pipeline capable of semantic segmentation of light-microscopic whole-brain image data into a hierarchy of neuronal compartments. We expect that the hybrid architecture incorporating discrete Morse techniques into deep nets will generalize to other data domains