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Most isolates of human rhinovirus, the common cold virus, replicate more robustly at the cool temperatures found in the nasal cavity (33-35°C) than at core body temperature (37°C). To gain insight into the mechanism of temperature-dependent growth, we compared the transcriptional response of primary mouse airway epithelial cells infected with rhinovirus at 33°C vs. 37°C. Mouse airway cells infected with mouse-adapted rhinovirus 1B exhibited a striking enrichment in expression of antiviral defense response genes at 37°C relative to 33°C, which correlated with significantly higher expression levels of type I and type III IFN genes and IFNstimulated genes (ISGs) at 37°C. Temperature-dependent IFN induction in response to rhinovirus was dependent on the MAVS protein, a key signaling adaptor of the RIG-I-like receptors (RLRs). Stimulation of primary airway cells with the synthetic RLR ligand poly I:C led to greater IFN induction at 37°C relative to 33°C at early time points poststimulation and to a sustained increase in the induction of ISGs at 37°C relative to 33°C. Recombinant type I IFN also stimulated more robust induction of ISGs at 37°C than at 33°C. Genetic deficiency of MAVS or the type I IFN receptor in infected airway cells permitted higher levels of viral replication, particularly at 37°C, and partially rescued the temperature-dependent growth phenotype. These findings demonstrate that in mouse airway cells, rhinovirus replicates preferentially at nasal cavity temperature due, in part, to a less efficient antiviral defense response of infected cells at cool temperature.is the most frequent cause of the common cold and has recently been recognized as the most frequent cause of exacerbations of asthma, a disease affecting ∼10% of the US population (1, 2). RV is also increasingly recognized to be a major cause of lung symptoms in patients with other chronic respiratory diseases and in young children (3). Previously, RV was thought to cause disease primarily in the nasal cavity, consistent with the observation that most RV strains replicate more robustly at the cooler temperatures found in the nasal cavity (33-35°C) than at lung temperature (37°C) (4, 5). However, the recent recognition that RV is an important cause of disease in the lung (2, 3) compels further investigation of the mechanisms that control the optimal replication temperature of this virus, which are unknown.Previous studies of the replication machinery of RV have not identified a virus-intrinsic reason for temperature-dependent growth, including studies of cell entry, uncoating, and polymerase activity (6, 7). Therefore, we considered the possibility that other factors, such as temperature-dependent host antiviral responses, might contribute to this phenotype. To investigate this possibility, we examined the effect of incubation temperature on the response to RV infection by the infected host cell. Using a mouse primary airway cell infection model, we observed that incubating cells at the lower temperature of the nasal cavity (33°C) greatly dim...

CNNs are poised to become integral parts of many critical systems. Despite their robustness to natural variations, image pixel values can be manipulated, via small, carefully crafted, imperceptible perturbations, to cause a model to misclassify images. We present an algorithm to process an image so that classification accuracy is significantly preserved in the presence of such adversarial manipulations. Image classifiers tend to be robust to natural noise, and adversarial attacks tend to be agnostic to object location. These observations motivate our strategy, which leverages model robustness to defend against adversarial perturbations by forcing the image to match natural image statistics. Our algorithm locally corrupts the image by redistributing pixel values via a process we term pixel deflection. A subsequent wavelet-based denoising operation softens this corruption, as well as some of the adversarial changes. We demonstrate experimentally that the combination of these techniques enables the effective recovery of the true class, against a variety of robust attacks. Our results compare favorably with current state-of-the-art defenses, without requiring retraining or modifying the CNN.

Most strains of rhinovirus (RV), the common cold virus, replicate better at cool temperatures found in the nasal cavity (33-35°C) than at lung temperature (37°C). Recent studies found that although 37°C temperature suppressed RV growth largely by engaging the type 1 IFN response in infected epithelial cells, a significant temperature dependence to viral replication remained in cells devoid of IFN induction or signaling. To gain insight into IFN-independent mechanisms limiting RV replication at 37°C, we studied RV infection in human bronchial epithelial cells and H1-HeLa cells. During the single replication cycle, RV exhibited temperature-dependent replication in both cell types in the absence of IFN induction. At 37°C, earlier signs of apoptosis in RV-infected cells were accompanied by reduced virus production. Furthermore, apoptosis of epithelial cells was enhanced at 37°C in response to diverse stimuli. Dynamic mathematical modeling and B cell lymphoma 2 (BCL2) overexpression revealed that temperature-dependent host cell death could partially account for the temperature-dependent growth observed during RV amplification, but also suggested additional mechanisms of virus control. In search of a redundant antiviral pathway, we identified a role for the RNA-degrading enzyme RNAseL. Simultaneous antagonism of apoptosis and RNAseL increased viral replication and dramatically reduced temperature dependence. These findings reveal two IFN-independent mechanisms active in innate defense against RV, and demonstrate that even in the absence of IFNs, temperature-dependent RV amplification is largely a result of host cell antiviral restriction mechanisms operating more effectively at 37°C than at 33°C. apoptosis | RNaseL | innate immunity | rhinovirus | respiratory immunity I n the 1960s, rhinoviruses (RVs) were first cultured from patient samples and shown to cause acute upper respiratory infections (a.k.a. common colds). Early work showed that RV isolates replicated best in culture when incubated at temperatures slightly cooler than core body temperature (33-35°C) (1, 2). This observation fit with the role of RV as a cause of disease in the nasal cavity, but not the lungs, as the nasal cavity is cooled by inhalation of environmental air, but the lungs are generally considered to be at core body temperature (37°C). The primary target cells of RV infection are the airway epithelial cells that line the respiratory tract. Similar to all cells of the body, airway epithelial cells are equipped with a cell-intrinsic innate immune system that can sense the presence of a viral infection, using pattern recognition receptors such as toll-like receptors (TLRs) and RIG-I like receptors (RLRs), and can respond to the infection by inducing antiviral effector mechanisms (3). Recently, we used mouse primary airway cells and a mouse-adapted RV to show that replicating RV is recognized by the RLRs within airway epithelial cells, leading to two innate immune signaling events that occur more robustly at warm temperature than at cool temperatu...

Abstract. The traditional edit-distance problem is to find the minimum number of insert-character and delete-character (and sometimes change character) operations required to transform one string into another. Here we consider the more general problem of strings being represented by a singly linked list (one character per node) and being able to apply these operations to the pointer associated with a vertex as well as the character associated with the vertex. That is, in O(1) time, not only can characters be inserted or deleted, but also substrings can be moved or deleted. We limit our attention to the ability to move substrings and leave substring deletions for future research. Note that O(1) time substring move operations imply O(1) substring exchange operations as well, a form of transformation that has been of interest in molecular biology. We show that this problem is NP-complete, show that a "recursive" sequence of moves can be simulated with at most a constant factor increase by a non-recursive sequence, and present a polynomial time greedy algorithm for non-recursive moves with a worst-case log factor approximation to optimal. The development of this greedy algorithm shows how to reduce moves of substrings to moves of characters, and how to convert moves with characters to only insert and deletes of characters.

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