T-RECX: Tiny-Resource Efficient Convolutional neural networks with early-eXit

Deploying Machine learning (ML) on milliwatt-scale edge devices (tinyML) is gaining popularity due to recent breakthroughs in ML and Internet of Things (IoT). Most tinyML research focuses on model compression techniques that trade accuracy (and model capacity) for compact models to fit into the KB-sized tiny-edge devices. In this paper, we show how such models can be enhanced by the addition of an early exit intermediate classifier. If the intermediate classifier exhibits sufficient confidence in its prediction, the network exits early thereby, resulting in considerable savings in time. Although early exit classifiers have been proposed in previous work, these previous proposals focus on large networks, making their techniques suboptimal/impractical for tinyML applications. Our technique is optimized specifically for tiny-CNN sized models. In addition, we present a method to alleviate the effect of network overthinking by leveraging the representations learned by the early exit. We evaluate T-RecX on three CNNs from the MLPerf tiny benchmark suite for image classification, keyword spotting and visual wake word detection tasks. Our results show that T-RecX 1) improves the accuracy of baseline network, 2) achieves 31.58% average reduction in FLOPS in exchange for one percent accuracy across all evaluated models. Furthermore, we show that our methods consistently outperform popular prior works on the tiny-CNNs we evaluate.Comment: Accepted at 20th ACM International Conference on Computing Frontier

Correcting the NLRP3 inflammasome deficiency in macrophages from autoimmune NZB mice with exon skipping antisense oligonucleotides

Inflammasomes are molecular complexes activated by infection and cellular stress, leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) processing and cell death. The autoimmune NZB mouse strain does not express NLRP3, a key inflammasome initiator mediating responses to a wide variety of stimuli including endogenous danger signals, environmental irritants and a range of bacterial, fungal and viral pathogens. We have previously identified an intronic point mutation in the Nlrp3 gene from NZB mice that generates a splice acceptor site. This leads to inclusion of a pseudoexon that introduces an early termination codon and is proposed to be the cause of NLRP3 inflammasome deficiency in NZB cells. Here we have used exon skipping antisense oligonucleotides (AONs) to prevent aberrant splicing of Nlrp3 in NZB macrophages, and this restored both NLRP3 protein expression and NLRP3 inflammasome activity. Thus, the single point mutation leading to aberrant splicing is the sole cause of NLRP3 inflammasome deficiency in NZB macrophages. The NZB mouse provides a model for addressing a splicing defect in macrophages and could be used to further investigate AON design and delivery of AONs to macrophages in vivo

Antisense oligonucleotide induced exon skipping and the dystrophin gene transcript: cocktails and chemistries

<p>Abstract</p> <p>Background</p> <p>Antisense oligonucleotides (AOs) can interfere with exon recognition and intron removal during pre-mRNA processing, and induce excision of a targeted exon from the mature gene transcript. AOs have been used <it>in vitro </it>and <it>in vivo </it>to redirect dystrophin pre-mRNA processing in human and animal cells. Targeted exon skipping of selected exons in the dystrophin gene transcript can remove nonsense or frame-shifting mutations that would otherwise have lead to Duchenne Muscular Dystrophy, the most common childhood form of muscle wasting.</p> <p>Results</p> <p>Although many dystrophin exons can be excised using a single AO, several exons require two motifs to be masked for efficient or specific exon skipping. Some AOs were inactive when applied individually, yet pronounced exon excision was induced in transfected cells when the AOs were used in select combinations, clearly indicating synergistic rather than cumulative effects on splicing. The necessity for AO cocktails to induce efficient exon removal was observed with 2 different chemistries, 2'-O-methyl modified bases on a phosphorothioate backbone and phosphorodiamidate morpholino oligomers. Similarly, other trends in exon skipping, as a consequence of 2'-O-methyl AO action, such as removal of additional flanking exons or variations in exon skipping efficiency with overlapping AOs, were also seen when the corresponding sequences were prepared as phosphorodiamidate morpholino oligomers.</p> <p>Conclusion</p> <p>The combination of 2 AOs, directed at appropriate motifs in target exons was found to induce very efficient targeted exon skipping during processing of the dystrophin pre-mRNA. This combinatorial effect is clearly synergistic and is not influenced by the chemistry of the AOs used to induce exon excision. A hierarchy in exon skipping efficiency, observed with overlapping AOs composed of 2'-O-methyl modified bases, was also observed when these same sequences were evaluated as phosphorodiamidate morpholino oligomers, indicating design parameters established with one chemistry may be applied to the other.</p

Antisense-mediated splice intervention to treat human disease: the odyssey continues [version 1; peer review: 3 approved]

Recent approvals of oligonucleotide analogue drugs to alter gene expression have been welcomed by patient communities but not universally supported. These compounds represent a class of drugs that are designed to target a specific gene transcript, and they include a number of chemical entities to evoke different antisense mechanisms, depending upon the disease aetiology. To date, oligonucleotide therapeutics that are in the clinic or at advanced stages of translation target rare diseases, posing challenges to clinical trial design, recruitment and evaluation and requiring new evaluation paradigms. This review discusses the currently available and emerging therapeutics that alter exon selection through an effect on pre-mRNA splicing and explores emerging concerns over safety and efficacy. Although modification of synthetic nucleic acids destined for therapeutic application is common practice to protect against nuclease degradation and to influence drug function, such modifications may also confer unexpected physicochemical and biological properties. Negatively charged oligonucleotides have a strong propensity to bind extra- and intra-cellular proteins, whereas those analogues with a neutral backbone show inefficient cellular uptake but excellent safety profiles. In addition, the potential for incorporation of chemically modified nucleic acid monomers, yielded by nuclease degradation of exogenous oligonucleotides, into biomolecules has been raised and the possibility not entirely discounted. We conclude with a commentary on the ongoing efforts to develop novel antisense compounds and enhance oligonucleotide delivery in order to further improve efficacy and accelerate implementation of antisense therapeutics for human disease

Part 2: Making the "unproven" "proven"

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Mismatched single stranded antisense oligonucleotides can induce efficient dystrophin splice switching

<p>Abstract</p> <p>Background</p> <p>Antisense oligomer induced exon skipping aims to reduce the severity of Duchenne muscular dystrophy by redirecting splicing during pre-RNA processing such that the causative mutation is by-passed and a shorter but partially functional Becker muscular dystrophy-like dystrophin isoform is produced. Normal exons are generally targeted to restore the dystrophin reading frame however, an appreciable subset of dystrophin mutations are intra-exonic and therefore have the potential to compromise oligomer efficiency, necessitating personalised oligomer design for some patients. Although antisense oligomers are easily personalised, it remains unclear whether all patient polymorphisms within antisense oligomer target sequences will require the costly process of producing and validating patient specific compounds.</p> <p>Methods</p> <p>Here we report preclinical testing of a panel of splice switching antisense oligomers, designed to excise exon 25 from the dystrophin transcript, in normal and dystrophic patient cells. These patient cells harbour a single base insertion in exon 25 that lies within the target sequence of an oligomer shown to be effective at removing exon 25.</p> <p>Results</p> <p>It was anticipated that such a mutation would compromise oligomer binding and efficiency. However, we show that, despite the mismatch an oligomer, designed and optimised to excise exon 25 from the normal dystrophin mRNA, removes the mutated exon 25 more efficiently than the mutation-specific oligomer.</p> <p>Conclusion</p> <p>This raises the possibility that mismatched AOs could still be therapeutically applicable in some cases, negating the necessity to produce patient-specific compounds.</p

Incidence and correlates of STIs among black men who have sex with men participating in a US PrEP study

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Inferring the variation of climatic and glaciological contributions to West Greenland iceberg discharge in the twentieth century

Iceberg discharge is a major component of the mass balance of the Greenland Ice Sheet (GrIS). While bulk estimates of discharge variation over time exist, inferred remotely from measurements of grounding line ice velocities or surface mass balance calculations, few detailed measurements of discharge itself from individual marine-terminating glaciers existed until recent years. Recently, it has been shown, through a combination of ocean–iceberg modelling and non-linear system identification, that the century-long record of iceberg numbers crossing 48oN in the West Atlantic is a good first-order proxy for discharge from at least south and west Greenland. Here, we explore the varying relative importance of ice sheet, oceanic and climatic forcing of iceberg discharge from these areas over the twentieth century, by carrying out sensitivity studies of a non-linear auto-regressive mathematical model of the 48oN time series. We find that the relationships are mainly non-linear, with the contribution of the GrIS surface mass balance to iceberg discharge likely to be dominant in the first half of the century. This period is followed by several decades where oceanic temperature effects are most important in determining the model variation in iceberg discharge. In recent decades, all physical processes play a non-negligible part in explaining the iceberg discharge and the model suggests that the glacial response time to environmental changes may have decreased