New York Institute of Technology

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.
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\nFor example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.
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\nHere, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

Abstract Knowledge is too problematic a concept to make the task of building a dynamic knowledge‐based theory of the firm easy. We must also distinguish the theory from the resource‐based and evolutionary views. The paper begins with a multitype epistemology which admits both the pre‐ and subconscious modes of human knowing and, reframing the concept of the cognizing individual, the collective knowledge of social groups. While both Nelson and Winter, and Nonaka and Takeuchi, successfully sketch theories of the dynamic interactions of these types of organizational knowledge, neither indicates how they are to be contained. Callon and Latour suggest knowledge itself is dynamic and contained within actor networks, so moving us from knowledge as a resource toward knowledge as a process. To simplify this approach, we revisit sociotechnical systems theory, adopt three heuristics from the social constructionist literature, and make a distinction between the systemic and component attributes of the actor network. The result is a very different mode of theorizing, less an objective statement about the nature of firms ‘out there’ than a tool to help managers discover their place in the firm as a dynamic knowledge‐based activity system.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Abstract The explosion of interest in knowledge and its management reflects the trend towards ‘knowledge work’ and the Information Age, and recognition of knowledge as the principal source of economic rent. The papers in this Special Issue represent an attempt by strategy scholars (and some outside our traditional field) to come to terms with the implications of knowledge for the theory of the firm and its management. They are the product of a convergence of several streams of research which have addressed management implications of knowledge, including the management of technology, the economics of innovation and information, resource‐based theory, and organizational learning. At the theoretical level, knowledge‐centered approaches of Penrose, Arrow, Hayek and others have been enriched by contributions from evolutionary economists (notably Nelson and Winter) and epistemologists (notably M. Polanyi). At the empirical level, research into innovation and its diffusion originated by Mansfield, Griliches and others has been extended through studies which investigate tacit as well as explicit knowledge, and explore knowledge transfer within as well as across firms.

The high resolution surface profile of a 3-D diffuse object is obtained by measurement of the phase distribution across the image of a projected sinusoidal grating deformed by the surface. A shearing polarization interferometer is used for projection. Deformed grating images are detected by an array camera and processed by a microcomputer. Surface height resolutions of better than 10 μm have been attained, limited essentially by electronic quantization noise. In contrast to direct deformed grating analysis, this method, based on phase-shifting interferometric techniques, is capable of accurate measurement even with coarse projected gratings and low density image sensing arrays. Areas of application include industrial quality control, biostereometrics, robotics, and solid modeling for computer graphics.

Digital control of color television monitors—in particular, via frame buffers—has added precise control of a large subset of human colorspace to the capabilities of computer graphics. This subset is the gamut of colors spanned by the red, green, and blue (RGB) electron guns exciting their respective phosphors. It is called the RGB monitor gamut . Full-blown color theory is a quite complex subject involving physics, psychology, and physiology, but restriction to the RGB monitor gamut simplifies matters substantially. It is linear, for example, and admits to familiar spatial representations. This paper presents a set of alternative models of the RGB monitor gamut based on the perceptual variables hue (H), saturation (S), and value (V) or brightness (L). Algorithms for transforming between these models are derived. Particular emphasis is placed on an RGB to HSV non-trigonometric pair of transforms which have been used successfully for about four years in frame buffer painting programs. These are fast, accurate, and adequate in many applications. Computationally more difficult transform pairs are sometimes necessary, however. Guidelines for choosing among the models are provided. Psychophysical corrections are described within the context of the definitions established by the NTSC (National Television Standards Committee).

Digital control of color television monitors—in particular, via frame buffers—has added precise control of a large subset of human colorspace to the capabilities of computer graphics. This subset is the gamut of colors spanned by the red, green, and blue (RGB) electron guns exciting their respective phosphors. It is called the RGB monitor gamut. Full-blown color theory is a quite complex subject involving physics, psychology, and physiology, but restriction to the RGB monitor gamut simplifies matters substantially. It is linear, for example, and admits to familiar spatial representations. This paper presents a set of alternative models of the RGB monitor gamut based on the perceptual variables hue (H), saturation (S), and value (V) or brightness (L). Algorithms for transforming between these models are derived. Particular emphasis is placed on an RGB to HSV non-trigonometric pair of transforms which have been used successfully for about four years in frame buffer painting programs. These are fast, accurate, and adequate in many applications. Computationally more difficult transform pairs are sometimes necessary, however. Guidelines for choosing among the models are provided. Psychophysical corrections are described within the context of the definitions established by the NTSC (National Television Standards Committee).

Shadowing has historically been used to increase the intelligibility of scenes in electron microscopy and aerial survey. Various methods have been published for the determination of shadows in computer synthesized scenes. The display of shadows may make the shape and relative position of objects in such scenes more comprehensible; it is a technique lending vividness and realism to computer animation.To date, algorithms for the determination of shadows have been restricted to scenes constructed of planar polygons. A simple algorithm is described which utilizes Z-buffer visible surface computation to display shadows cast by objects modelled of smooth surface patches. The method can be applied to all environments, in fact, for which visible surfaces can be computed. The cost of determining the shadows associated with each light source is roughly twice the cost of rendering the scene without shadows, plus a fixed transformation overhead which depends on the image resolution. No extra entities are added to the scene description in the shadowing process. This comprehensive algorithm, which permits curved shadows to be cast on curved surfaces, is contrasted with a less costly method for casting the shadows of the environment on a single ground plane.In order to attain good results, the discrete nature of the visible-surface computations must be treated with care. The effects of dither, interpolation, and geometric quantization at different stages of the shadowing algorithm are examined. The special problems posed by self-shadowing surfaces are described.

Ninety-seven percent of drug-indication pairs that are tested in clinical trials in oncology never advance to receive U.S. Food and Drug Administration approval. While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not well understood. Using CRISPR-Cas9 mutagenesis, we investigated a set of cancer drugs and drug targets in various stages of clinical testing. We show that-contrary to previous reports obtained predominantly with RNA interference and small-molecule inhibitors-the proteins ostensibly targeted by these drugs are nonessential for cancer cell proliferation. Moreover, the efficacy of each drug that we tested was unaffected by the loss of its putative target, indicating that these compounds kill cells via off-target effects. By applying a genetic target-deconvolution strategy, we found that the mischaracterized anticancer agent OTS964 is actually a potent inhibitor of the cyclin-dependent kinase CDK11 and that multiple cancer types are addicted to CDK11 expression. We suggest that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit.

From the perspective of protein biosynthesis, the endoplasmic reticulum (ER) can be viewed as a processing plant for folding and posttranslational modification of secreted and integral membrane proteins.At any given time, the load of client proteins that the ER must handle is set by developmental programs and modulated by physiological considerations.Specific signaling pathways and effector mechanisms have evolved to deal with the temporal and developmental variation in ER load experienced by different cells in mutlicellular organisms.The upstream signal that activates these pathways is referred to as ER stress and is defined functionally as an imbalance between the load of client proteins facing the ER and the organelle's ability to process that load.ER stress can be provoked by a variety of pathophysiological conditions, for example, ischemia, hyperhomocystinemia, viral infections, and mutations that impair client protein folding (1-4).However, the phenotypes of mutations affecting components of the ER stress-response machinery reveal that ER stress is also a normal physiological phenomenon (reviewed in ref. 5).

The mapping of images onto surfaces may substantially increase the realism and information content of computer-generated imagery. The projection of a flat source image onto a curved surface may involve sampling difficulties, however, which are compounded as the view of the surface changes. As the projected scale of the surface increases, interpolation between the original samples of the source image is necessary; as the scale is reduced, approximation of multiple samples in the source is required. Thus a constantly changing sampling window of view-dependent shape must traverse the source image.

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Algorithms for adaptive, tapered quantization of color images are described. The research is motivated by the desire to display high-quality reproductions of color images with small frame buffers. It is demonstrated that many color images which would normally require a frame buffer having 15 bits per pixel can be quantized to 8 or fewer bits per pixel with little subjective degradation. In most cases, the resulting images look significantly better than those made with uniform quantization.

The analysis of fossil ungulate cheek teeth has long been one of the main sources of information about the terrestrial environments of the Cenozoic, but the methods used to extract this information have been either imprecise or prohibitively laborious. Here we present a method based on relative facet development that is quantitative, robust, and rapid. This method, which we term mesowear analysis, is based on the physical properties of ungulate foods as reflected in the relative amounts of attritive and abrasive wear that they cause on the dental enamel of the occlusal surfaces. Mesowear was recorded by examining the buccal apices of molar tooth cusps. Apices were characterized as sharp, rounded, or blunt, and the valleys between them either high or low. The method has been developed only for selenodont and trilophodont molars, but the principle is readily extendable to other crown types. Mesowear analysis is insensitive to wear stage as long as the very early and very late stages are excluded.Cluster analysis of the mesowear variables produces clusters reflecting four main groups from abrasion-dominated to attrition-dominated: grazers, graze-dominated mixed feeders, browse-dominated mixed feeders, and browsers. Most of the relatively few apparent anomalies are explained by more detailed dietary information. Mesowear analysis provides resolution within the main dietary classes and the clustering is virtually identical with and without the index of hypsodonty. Discriminant analysis using all mesowear variables and hypsodonty showed an overall correct classification of 76% of 64 species of living ungulates into the conventional dietary categories of browser, grazer, and mixed feeder, while a smaller set of 27 “typical” species was correctly classified at 96%. Alternative “conservative” and “radical” dietary classifications that were employed to accommodate cases where dietary information was controversial or unclear produced only marginally different results. Mesowear analysis successfully resolved a test case using the Serengeti grazing succession and appears to be superior to microwear analysis in two cases where the diet of fossil ungulates has been previously studied by microwear and other conventional methods.

Algorithms for adaptive, tapered quantization of color images are described. The research is motivated by the desire to display high-quality reproductions of color images with small frame buffers. It is demonstrated that many color images which would normally require a frame buffer having 15 bits per pixel can be quantized to 8 or fewer bits per pixel with little subjective degradation. In most cases, the resulting images look significantly better than those made with uniform quantization. The color image quantization task is broken into four phases: 1) Sampling the original image for color statistics 2) Choosing a colormap based on the color statistics 3) Mapping original colors to their nearest neighbors in the colormap 4) Quantizing and redrawing the original image (with optional dither). Several algorithms for each of phases 2-4 are described, and images created by each given.

Abstract COVID-19 has spread to most countries in the world. Puzzlingly, the impact of the disease varies in different countries. This variation is attributed to differences in cultural norms, mitigation efforts, and health infrastructure. Here, we propose that national differences in COVID-19 impact could be partially explained by different national policies with respect to Bacillus Calmette-Guérin (BCG) vaccination. BCG vaccination has been reported to offer broad protection from other respiratory infections besides tuberculosis. We compared BCG vaccination policies with the morbidity and mortality for COVID-19 for middle-high and high-income countries. We found that countries without universal policies of BCG vaccination (Italy, the Netherlands, USA) have been more severely affected compared to countries with universal and long-standing BCG policies. The difference cannot be accounted for by differences in disease onset, adoption of early social distancing policies, state of health services, nor income level. Reduced mortality suggests BCG vaccination could be a potential new tool in the fight against COVID-19.

Nitric oxide (NO) is one of the 10 smallest molecules found in nature. It is a simple gaseous free radical whose predominant functions is that of a messenger through cGMP. In mammals, NO is synthesized by the enzyme nitric oxide synthase (NOS) of which there are three isoforms. Neuronal (nNOS, NOS1) and endothelial (eNOS, NOS3) are constitutive calcium-dependent forms of the enzyme that regulate neural and vascular function respectively. The third isoform (iNOS, NOS2), is calcium-independent and is inducible. In many tumors, iNOS expression is high, however, the role of iNOS during tumor development is very complex and quite perplexing, with both promoting and inhibiting actions having been described. This review will aim to summarize the dual actions of iNOS-derived NO showing that the microenvironment of the tumor is a contributing factor to these observations and ultimately to cellular outcomes.

Various techniques have been developed that employ projections of the world as seen from a particular viewpoint. Blinn and Newell introduced reflection mapping for simulating mirror reflections on curved surfaces. Miller and Hoffman have presented a general illumination model based on environment mapping. World projections have also been used to model distant objects and to produce pictures with the fish-eye distortion required for Omnimax frames. This article proposes a uniform framework for representing and using world projections and argues that the best general-purpose representation is the is projection onto a cube. Surface shading and texture filtering are discussed in the context of environment mapping, and methods are presented for obtaining diffuse and specular surface illumination from prefiltered environment maps. Comparisons are made with ray tracing, noting that two problems with ray tracing-obtaining diffuse reflection and antialiasing specular reflection-can be handled effectively by environment mapping.

A new and greatly simplified methodology for the assessment of the dietary adaptations of living and fossil taxa has been developed which allows for microwear scar topography to be accurately analyzed at low magnification (35×) using a standard stereomicroscope. In addition to the traditional scratch and pit numbers, we introduce four qualitative variables: scratch texture, cross scratches, large pits, and gouges, which provide finer subdivisions within the basic dietary categories. A large extant comparative ungulate microwear database (809 individuals; 50 species) is presented and interpreted to elucidate the diets of extant ungulates. We distinguish three major trophic phases in extant ungulates: traditional browsers and grazers, two phases represented by only a few species, and a browsing-grazing transitional phase where most species fall, including all mixed feeders. There are two types of mixed feeders: seasonal or regional mixed feeders and meal-by-meal mixed feeders. Some species have results that separate them from traditional members of their trophic group; i.e., browsers, grazers, and mixed feeders. Duikers are unique in spanning almost the entire dietary spectrum. Okapia, Tapirus, Tragulus, and Moschus species have wear similar to duikers. Proboscideans fall in the browsing-grazing transitional phase, as do the two suids studied. The latter differ from each other by their degree of rooting.Archaic fossil equids spanning the supposed browsing-grazing transition were compared to extant ungulates. Two major clusters are discerned: (1) Hyracotherium has microwear most similar to that of the duiker Cephalopus silvicultor and was a fruit/seed eating browser. (2) Mesohippus spp., M. bairdii, Mesohippus hypostylus, Meso-Miohippus (a transitional form larger than M. bairdii), Parahippus spp., and Merychippus insignis differ from Hyracotherium and are most similar to the extant Cervus canadensis. Group (2) is characterized by fine scratches which are the result of C3 grazing, an initial phase of grazing in equids which most likely did not occur in open habitats. Finer differentiation of group (2) diets shows a dietary change in the expected direction (toward the incorporation of more grass in the diet) and follows the expected evolutionary transition from the Eocene to the Oligocene and early Miocene. Consequently, these equid taxa are reconstructed here as mixed feeders grazing on forest C3 grasses. The finer dietary differentiation shows a progressive decrease in the number of scratches and pits. Mesohippus has the most pits and scratches, followed by Parahippus, and then Merychippus (which has the least). The taxon incorporating the most grass into its dietary regime in this array is Merychippus. In Mesohippus-Parahippus versus Merychippus, differences in tooth morphology are major but microwear differences are slight.

Vehicular ad hoc networks (VANETs) have the potential to transform the way people travel through the creation of a safe interoperable wireless communications network that includes cars, buses, traffic signals, cell phones, and other devices. However, VANETs are vulnerable to security threats due to increasing reliance on communication, computing, and control technologies. The unique security and privacy challenges posed by VANETs include integrity (data trust), confidentiality, nonrepudiation, access control, real-time operational constraints/demands, availability, and privacy protection. The trustworthiness of VANETs could be improved by addressing holistically both data trust, which is defined as the assessment of whether or not and to what extent the reported traffic data are trustworthy, and node trust, which is defined as how trustworthy the nodes in VANETs are. In this paper, an attack-resistant trust management scheme (ART) is proposed for VANETs that is able to detect and cope with malicious attacks and also evaluate the trustworthiness of both data and mobile nodes in VANETs. Specially, data trust is evaluated based on the data sensed and collected from multiple vehicles; node trust is assessed in two dimensions, i.e., functional trust and recommendation trust, which indicate how likely a node can fulfill its functionality and how trustworthy the recommendations from a node for other nodes will be, respectively. The effectiveness and efficiency of the proposed ART scheme is validated through extensive experiments. The proposed trust management theme is applicable to a wide range of VANET applications to improve traffic safety, mobility, and environmental protection with enhanced trustworthiness.