On the Capacity Limits of Privileged ERM

We study the supervised learning paradigm called Learning Using Privileged Information, first suggested by Vapnik and Vashist (2009). In this paradigm, in addition to the examples and labels, additional (privileged) information is provided only for training examples. The goal is to use this information to improve the classification accuracy of the resulting classifier, where this classifier can only use the non-privileged information of new example instances to predict their label. We study the theory of privileged learning with the zero-one loss under the natural Privileged ERM algorithm proposed in Pechyony and Vapnik (2010a). We provide a counter example to a claim made in that work regarding the VC dimension of the loss class induced by this problem; We conclude that the claim is incorrect. We then provide a correct VC dimension analysis which gives both lower and upper bounds on the capacity of the Privileged ERM loss class. We further show, via a generalization analysis, that worst-case guarantees for Privileged ERM cannot improve over standard non-privileged ERM, unless the capacity of the privileged information is similar or smaller to that of the non-privileged information. This result points to an important limitation of the Privileged ERM approach. In our closing discussion, we suggest another way in which Privileged ERM might still be helpful, even when the capacity of the privileged information is large.Comment: AISTATS 202

Low-Cost Parameterizations of Deep Convolutional Neural Networks

Convolutional Neural Networks (CNNs) filter the input data using a series of spatial convolution operators with compactly supported stencils and point-wise nonlinearities. Commonly, the convolution operators couple features from all channels. For wide networks, this leads to immense computational cost in the training of and prediction with CNNs. In this paper, we present novel ways to parameterize the convolution more efficiently, aiming to decrease the number of parameters in CNNs and their computational complexity. We propose new architectures that use a sparser coupling between the channels and thereby reduce both the number of trainable weights and the computational cost of the CNN. Our architectures arise as new types of residual neural network (ResNet) that can be seen as discretizations of a Partial Differential Equations (PDEs) and thus have predictable theoretical properties. Our first architecture involves a convolution operator with a special sparsity structure, and is applicable to a large class of CNNs. Next, we present an architecture that can be seen as a discretization of a diffusion reaction PDE, and use it with three different convolution operators. We outline in our experiments that the proposed architectures, although considerably reducing the number of trainable weights, yield comparable accuracy to existing CNNs that are fully coupled in the channel dimension.Comment: 10 pages, 2 figure

Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology

Alzheimer's disease has long been known to involve cholinergic deficits, but the linkage between cholinergic gene expression and the Alzheimer's disease amyloid pathology has remained incompletely understood. One known link involves synaptic acetylcholinesterase (AChE-S), shown to accelerate amyloid fibrils formation. Here, we report that the ‘Readthrough' AChE-R splice variant, which differs from AChE-S in its 26 C-terminal residues, inversely exerts neuroprotective effects from amyloid β (Aβ) induced toxicity. In vitro, highly purified AChE-R dose-dependently suppressed the formation of insoluble Aβ oligomers and fibrils and abolished Aβ toxicity to cultured cells, competing with the prevalent AChE-S protein which facilitates these processes. In vivo, double transgenic APPsw/AChE-R mice showed lower plaque burden, fewer reactive astrocytes and less dendritic damage than single APPsw mice, inverse to reported acceleration of these features in double APPsw/AChE-S mice. In hippocampi from Alzheimer's disease patients (n = 10), dentate gyrus neurons showed significantly elevated AChE-R mRNA and reduced AChE-S mRNA. However, immunoblot analyses revealed drastic reductions in the levels of intact AChE-R protein, suggesting that its selective loss in the Alzheimer's disease brain exacerbates the Aβ-induced damages and revealing a previously unforeseen linkage between cholinergic and amyloidogenic event

The effect of COVID-19 vaccination on 30-day mortality after cardiac surgery – Insights from the Israel national registries

Summary: Background: We compared the effect of perioperative COVID-19, before and after vaccination, on 30-day mortality after cardiac surgery. Methods: Data was extracted from several national registries. The study period was March 1st, 2020–March 31st, 2022. Results: 2594 adult patients underwent cardiac surgery before the availability of a universal COVID-19 vaccine. 33 patients were diagnosed with COVID-19 prior to surgery (mean age 58.3±10.0, mean length of time 73.6±60.1 days) and 7 patients were diagnosed with COVID-19 0–14 days after surgery (age 66.4±7.6). These were compared to 4426 patients who underwent cardiac surgery after the availability of a universal vaccine: 469 patients were diagnosed with COVID-19 prior to surgery (age 62.1±10.1, length of time 175.8±158.2) and 32 patients diagnosed with COVID-19 0–14 days after surgery (age 60.8±14.5). In patients diagnosed with COVID-19 prior to surgery, there was no excess 30-day mortality either before or after vaccination (1 (3.0%) vs. 57 (2.2%), respectively, P<0.8, and 8 (1.7%) vs. 87 (2.2%), respectively, P<0.5). Patients diagnosed with COVID-19 after surgery, but before vaccination, had significantly higher 30-day mortality compared to COVID-19 negative patients (2 (28.6%) vs. 56 (2.2%) respectively, P<0.0001). This excess mortality disappeared after universal vaccination (1 (3.1%) vs. 94 (2.1%) respectively, P<0.7). Conclusions: COVID-19, when diagnosed in the early post-operative period, was a risk factor for mortality before available vaccinations, but not after vaccination was widely available. Pre-surgery screening and post-surgical isolation is essential until vaccines are available. This data may be useful for patient management in future respiratory pandemics

Magnetic Targeting of Growth Factors Using Iron Oxide Nanoparticles

Growth factors play an important role in nerve regeneration and repair. An attractive drug delivery strategy, termed &ldquo;magnetic targeting&rdquo;, aims to enhance therapeutic efficiency by directing magnetic drug carriers specifically to selected cell populations that are suitable for the nervous tissues. Here, we covalently conjugated nerve growth factor to iron oxide nanoparticles (NGF-MNPs) and used controlled magnetic fields to deliver the NGF&ndash;MNP complexes to target sites. In order to actuate the magnetic fields a modular magnetic device was designed and fabricated. PC12 cells that were plated homogenously in culture were differentiated selectively only in targeted sites out of the entire dish, restricted to areas above the magnetic &ldquo;hot spots&rdquo;. To examine the ability to guide the NGF-MNPs towards specific targets in vivo, we examined two model systems. First, we injected and directed magnetic carriers within the sciatic nerve. Second, we injected the MNPs intravenously and showed a significant accumulation of MNPs in mouse retina while using an external magnet that was placed next to one of the eyes. We propose a novel approach to deliver drugs selectively to injured sites, thus, to promote an effective repair with minimal systemic side effects, overcoming current challenges in regenerative therapeutics

Type I bHLH Proteins Daughterless and Tcf4 Restrict Neurite Branching and Synapse Formation by Repressing Neurexin in Postmitotic Neurons

Proneural proteins of the class I/II basic-helix-loop-helix (bHLH) family are highly conserved transcription factors. Class I bHLH proteins are expressed in a broad number of tissues during development, whereas class II bHLH protein expression is more tissue restricted. Our understanding of the function of class I/II bHLH transcription factors in both invertebrate and vertebrate neurobiology is largely focused on their function as regulators of neurogenesis. Here, we show that the class I bHLH proteins Daughterless and Tcf4 are expressed in postmitotic neurons in Drosophila melanogaster and mice, respectively, where they function to restrict neurite branching and synapse formation. Our data indicate that Daughterless performs this function in part by restricting the expression of the cell adhesion molecule Neurexin. This suggests a role for these proteins outside of their established roles in neurogenesis

Amyloid Precursor Protein Translation Is Regulated by a 3'UTR Guanine Quadruplex.

A central event in Alzheimer's disease is the accumulation of amyloid β (Aβ) peptides generated by the proteolytic cleavage of the amyloid precursor protein (APP). APP overexpression leads to increased Aβ generation and Alzheimer's disease in humans and altered neuronal migration and increased long term depression in mice. Conversely, reduction of APP expression results in decreased Aβ levels in mice as well as impaired learning and memory and decreased numbers of dendritic spines. Together these findings indicate that therapeutic interventions that aim to restore APP and Aβ levels must do so within an ideal range. To better understand the effects of modulating APP levels, we explored the mechanisms regulating APP expression focusing on post-transcriptional regulation. Such regulation can be mediated by RNA regulatory elements such as guanine quadruplexes (G-quadruplexes), non-canonical structured RNA motifs that affect RNA stability and translation. Via a bioinformatics approach, we identified a candidate G-quadruplex within the APP mRNA in its 3'UTR (untranslated region) at residues 3008-3027 (NM_201414.2). This sequence exhibited characteristics of a parallel G-quadruplex structure as revealed by circular dichroism spectrophotometry. Further, as with other G-quadruplexes, the formation of this structure was dependent on the presence of potassium ions. This G-quadruplex has no apparent role in regulating transcription or mRNA stability as wild type and mutant constructs exhibited equivalent mRNA levels as determined by real time PCR. Instead, we demonstrate that this G-quadruplex negatively regulates APP protein expression using dual luciferase reporter and Western blot analysis. Taken together, our studies reveal post-transcriptional regulation by a 3'UTR G-quadruplex as a novel mechanism regulating APP expression

Data from: Amyloid precursor protein translation is regulated by a 3'UTR guanine quadruplex

A central event in Alzheimer’s disease is the accumulation of amyloid β (Aβ) peptides generated by the proteolytic cleavage of the amyloid precursor protein (APP). APP overexpression leads to increased Aβ generation and Alzheimer’s disease in humans and altered neuronal migration and increased long term depression in mice. Conversely, reduction of APP expression results in decreased Aβ levels in mice as well as impaired learning and memory and decreased numbers of dendritic spines. Together these findings indicate that therapeutic interventions that aim to restore APP and Aβ levels must do so within an ideal range. To better understand the effects of modulating APP levels, we explored the mechanisms regulating APP expression focusing on post-transcriptional regulation. Such regulation can be mediated by RNA regulatory elements such as guanine quadruplexes (G-quadruplexes), non-canonical structured RNA motifs that affect RNA stability and translation. Via a bioinformatics approach, we identified a candidate G-quadruplex within the APP mRNA in its 3’UTR (untranslated region) at residues 3008–3027 (NM_201414.2). This sequence exhibited characteristics of a parallel G-quadruplex structure as revealed by circular dichroism spectrophotometry. Further, as with other G-quadruplexes, the formation of this structure was dependent on the presence of potassium ions. This G-quadruplex has no apparent role in regulating transcription or mRNA stability as wild type and mutant constructs exhibited equivalent mRNA levels as determined by real time PCR. Instead, we demonstrate that this G-quadruplex negatively regulates APP protein expression using dual luciferase reporter and Western blot analysis. Taken together, our studies reveal post-transcriptional regulation by a 3’UTR G-quadruplex as a novel mechanism regulating APP expression

Crenshaw et al data file

Crenshaw et al data fil