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Convolutional networks for fast, energy-efficient neuromorphic computing
Deep networks are now able to achieve human-level performance on a broad spectrum of recognition tasks. Independently, neuromorphic computing has now demonstrated unprecedented energy-efficiency through a new chip architecture based on spiking neurons, low precision synapses, and a scalable communication network. Here, we demonstrate that neuromorphic computing, despite its novel architectural primitives, can implement deep convolution networks that (i) approach state-of-the-art classification accuracy across eight standard datasets encompassing vision and speech, (ii) perform inference while preserving the hardware’s underlying energy-efficiency and high throughput, running on the aforementioned datasets at between 1,200 and 2,600 frames/s and using between 25 and 275 mW (effectively >6,000 frames/s per Watt), and (iii) can be specified and trained using backpropagation with the same ease-of-use as contemporary deep learning. This approach allows the algorithmic power of deep learning to be merged with the efficiency of neuromorphic processors, bringing the promise of embedded, intelligent, brain-inspired computing one step closer.
Journal Article
A million spiking-neuron integrated circuit with a scalable communication network and interface
Inspired by the brain's structure, we have developed an efficient, scalable, and flexible non–von Neumann architecture that leverages contemporary silicon technology. To demonstrate, we built a 5.4-billion-transistor chip with 4096 neurosynaptic cores interconnected via an intrachip network that integrates 1 million programmable spiking neurons and 256 million configurable synapses. Chips can be tiled in two dimensions via an interchip communication interface, seamlessly scaling the architecture to a cortexlike sheet of arbitrary size. The architecture is well suited to many applications that use complex neural networks in real time, for example, multiobject detection and classification. With 400-pixel-by-240-pixel video input at 30 frames per second, the chip consumes 63 milliwatts.
Journal Article
Genome-scale RNA interference profiling of Trypanosoma brucei cell cycle progression defects
Trypanosomatids, which include major pathogens of humans and livestock, are flagellated protozoa for which cell cycle controls and the underlying mechanisms are not completely understood. Here, we describe a genome-wide RNA-interference library screen for cell cycle defects in
Trypanosoma brucei
. We induced massive parallel knockdown, sorted the perturbed population using high-throughput flow cytometry, deep-sequenced RNAi-targets from each stage and digitally reconstructed cell cycle profiles at a genomic scale; also enabling data visualisation using an online tool (
https://tryp-cycle.pages.dev/
). Analysis of several hundred genes that impact cell cycle progression reveals >100 flagellar component knockdowns linked to genome endoreduplication, evidence for metabolic control of the G
1
-S transition, surface antigen regulatory mRNA-binding protein knockdowns linked to G
2
M accumulation, and a putative nucleoredoxin required for both mitochondrial genome segregation and for mitosis. The outputs provide comprehensive functional genomic evidence for the known and novel machineries, pathways and regulators that coordinate trypanosome cell cycle progression.
Progression of the canonical eukaryotic cell cycle is tightly regulated. While the cell cycle control of flagellated protozoa Trypanosoma brucei shares conserved features with other eukaryotes certain cell cycle checkpoints are absent. Here, Marques et al. provide a genome-scale RNAi screen followed by sorting of parasites according to their cell cycle stage to inform about cell cycle regulators of bloodstream T. brucei.
Journal Article
Cell-type specific RNA-Seq reveals novel roles and regulatory programs for terminally differentiated Dictyostelium cells
Background
A major hallmark of multicellular evolution is increasing complexity by the evolution of new specialized cell types. During Dictyostelid evolution novel specialization occurred within taxon group 4. We here aim to retrace the nature and ancestry of the novel “cup” cells by comparing their transcriptome to that of other cell types.
Results
RNA-Seq was performed on purified mature spore, stalk and cup cells and on vegetative amoebas. Clustering and phylogenetic analyses showed that cup cells were most similar to stalk cells, suggesting that they share a common ancestor. The affinity between cup and stalk cells was also evident from promoter-reporter studies of newly identified cell-type genes, which revealed late expression in cups of many stalk genes. However, GO enrichment analysis reveal the unexpected prominence of GTPase mediated signalling in cup cells, in contrast to enrichment of autophagy and cell wall synthesis related transcripts in stalk cells. Combining the cell type RNA-Seq data with developmental expression profiles revealed complex expression dynamics in each cell type as well as genes exclusively expressed during terminal differentiation. Most notable were nine related
hssA-
like genes that were highly and exclusively expressed in cup cells.
Conclusions
This study reveals the unique transcriptomes of the mature cup, stalk and spore cells of
D. discoideum
and provides insight into the ancestry of cup cells and roles in signalling that were not previously realized. The data presented in this study will serve as an important resource for future studies into the regulation and evolution of cell type specialization.
Journal Article
Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry
Fixed, paraffin-embedded (FPE) tissues are a potentially rich resource for studying the role of NOTCH1 in cancer and other pathologies, but tests that reliably detect activated NOTCH1 (NICD1) in FPE samples have been lacking. Here, we bridge this gap by developing an immunohistochemical (IHC) stain that detects a neoepitope created by the proteolytic cleavage event that activates NOTCH1. Following validation using xenografted cancers and normal tissues with known patterns of NOTCH1 activation, we applied this test to tumors linked to dysregulated Notch signaling by mutational studies. As expected, frequent NICD1 staining was observed in T lymphoblastic leukemia/lymphoma, a tumor in which activating NOTCH1 mutations are common. However, when IHC was used to gauge NOTCH1 activation in other human cancers, several unexpected findings emerged. Among B cell tumors, NICD1 staining was much more frequent in chronic lymphocytic leukemia than would be predicted based on the frequency of NOTCH1 mutations, while mantle cell lymphoma and diffuse large B cell lymphoma showed no evidence of NOTCH1 activation. NICD1 was also detected in 38% of peripheral T cell lymphomas. Of interest, NICD1 staining in chronic lymphocytic leukemia cells and in angioimmunoblastic lymphoma was consistently more pronounced in lymph nodes than in surrounding soft tissues, implicating factors in the nodal microenvironment in NOTCH1 activation in these diseases. Among carcinomas, diffuse strong NICD1 staining was observed in 3.8% of cases of triple negative breast cancer (3 of 78 tumors), but was absent from 151 non-small cell lung carcinomas and 147 ovarian carcinomas. Frequent staining of normal endothelium was also observed; in line with this observation, strong NICD1 staining was also seen in 77% of angiosarcomas. These findings complement insights from genomic sequencing studies and suggest that IHC staining is a valuable experimental tool that may be useful in selection of patients for clinical trials.
Journal Article
The transcription factor Spores Absent A is a PKA dependent inducer of Dictyostelium sporulation
Sporulation in
Dictyostelium
fruiting bodies evolved from amoebozoan encystation with both being induced by cAMP acting on PKA, but with downstream components still being unknown. Using tagged mutagenesis to find missing pathway components, we identified a sporeless mutant defective in a nuclear protein, SpaA. Expression of prespore genes was strongly reduced in
spaA-
cells, while expression of many spore stage genes was absent. Chromatin immunoprecipitation (ChIP) of a SpaA-YFP gene fusion showed that (pre)spore gene promoters bind directly to SpaA, identifying SpaA as a transcriptional regulator. SpaA dependent spore gene expression required PKA
in vivo
and was stimulated
in vitro
by the membrane-permeant PKA agonist 8Br-cAMP. The PKA agonist also promoted SpaA binding to (pre)spore promoters, placing SpaA downstream of PKA. Sequencing of SpaA-YFP ChIPed DNA fragments revealed that SpaA binds at least 117 (pre)spore promoters, including those of other transcription factors that activate some spore genes. These factors are not in turn required for
spaA
expression, identifying SpaA as the major trancriptional inducer of sporulation.
Journal Article
Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides
Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont,
Wolbachia
, for survival and fecundity, making
Wolbachia
a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca’s 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-
Wolbachia
drugs that cure onchocerciasis and lymphatic filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the result of a partnership between the Anti-
Wolbachia
consortium (A∙WOL) and AstraZeneca. The campaign was informed throughout by rational prioritisation and triage of compounds using cheminformatics to balance chemical diversity and drug like properties reducing the chance of attrition from the outset. Ongoing development of these multiple chemotypes, all with superior time-kill kinetics than registered antibiotics with anti-
Wolbachia
activity, has the potential to improve upon the current therapeutic options and deliver improved, safer and more selective macrofilaricidal drugs.
Parasitic nematodes causing onchocerciasis and lymphatic filariasis rely on a bacterial endosymbiont,
Wolbachia
, which is a validated therapeutic target. Here, Clare et al. perform a high-throughput screen of 1.3 million compounds and identify 5 chemotypes with faster kill rates than existing anti-
Wolbachia
drugs.
Journal Article
Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD
BackgroundIn cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggest MBL interferes with phagocytosis of Haemophilus influenzae, a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD.MethodsPatients with COPD (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested subcohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA PCR and sequencing, or airway inflammation during stable and exacerbated COPD.FindingsPatients with MBL deficiency with COPD were significantly less likely to have severe exacerbations (incidence rate ratio (IRR) 0.66, 95% CI 0.48 to 0.90, p=0.009), or to have moderate or severe exacerbations (IRR 0.77, 95% CI 0.60 to 0.99, p=0.047). MBL deficiency did not affect rate of FEV1 decline or mortality. In the subcohort, patients with MBL deficiency had a more diverse lung microbiota (p=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency.InterpretationPatients with MBL deficient genotype with COPD have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD.
Journal Article
Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis
Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF (
Brugia malayi, Wuchereria bancrofti
) or onchocerciasis (
Onchocerca volvulus
) is doxycycline. The target of doxycycline is the essential endosymbiont,
Wolbachia.
Four to six weeks doxycycline therapy achieves >90% depletion of
Wolbachia
in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18–24 months post-treatment. Long treatment length and contraindications in children and pregnancy are obstacles to implementing doxycycline as a public health strategy. Here we determine, via preclinical infection models of
Brugia malayi
or
Onchocerca ochengi
that elevated exposures of orally-administered rifampicin can lead to
Wolbachia
depletions from filariae more rapidly than those achieved by doxycycline. Dose escalation of rifampicin achieves >90%
Wolbachia
depletion in time periods of 7 days in
B. malayi
and 14 days in
O. ochengi
. Using pharmacokinetic-pharmacodynamic modelling and mouse-human bridging analysis, we conclude that clinically relevant dose elevations of rifampicin, which have recently been determined as safe in humans, could be administered as short courses to filariasis target populations with potential to reduce anti-
Wolbachia
curative therapy times to between one and two weeks.
Journal Article