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The role of CD95/Fas ligand (CD95L/FasL) in the induction of CD95-mediated extrinsic apoptosis is well characterized. Trimerized, membrane-bound CD95L ligates the CD95 receptor activating downstream signaling resulting in the execution of cells by caspase proteins. However, the expression of CD95L has been reported to induce cell death in contexts in which this pathway is unlikely to be activated, such as in cell autonomous activation induced cell death (AICD) and in CD95-resistant cancer cell lines. Recent data suggests that the CD95L mRNA exerts toxicity through death induced by survival gene elimination (DISE). DISE results from the targeting of networks of survival genes by toxic short RNA (sRNA)s in the RNA-induced silencing complex (RISC). CD95L mRNA contributes to this death directly, through the processing of its mRNA into toxic sRNAs that are loaded into the RISC, and indirectly, by promoting the loading of other toxic sRNAs. Interestingly, CD95L is not the only mRNA that is processed and loaded into the RISC. Protein-coding mRNAs involved in protein translation are also selectively loaded. We propose a model in which networks of mRNA-derived sRNAs modulate DISE, with networks of genes providing non-toxic RISC substrate sRNAs that protect against DISE, and opposing networks of stress-activated genes that produce toxic RISC substrate sRNAs that promote DISE. [ABSTRACT FROM AUTHOR]

micro(mi)RNAs are short noncoding RNAs that through their seed sequence (pos. 2–7/8 of the guide strand) regulate cell function by targeting complementary sequences (seed matches) located mostly in the 3′ untranslated region (3′ UTR) of mRNAs. Any short RNA that enters the RNA induced silencing complex (RISC) can kill cells through miRNA-like RNA interference when its 6mer seed sequence (pos. 2–7 of the guide strand) has a G-rich nucleotide composition. G-rich seeds mediate 6mer Seed Toxicity by targeting C-rich seed matches in the 3′ UTR of genes critical for cell survival. The resulting Death Induced by Survival gene Elimination (DISE) predominantly affects cancer cells but may contribute to cell death in other disease contexts. This review summarizes recent findings on the role of DISE/6mer Seed Tox in cancer; its therapeutic potential; its contribution to therapy resistance; its selectivity, and why normal cells are protected. In addition, we explore the connection between 6mer Seed Toxicity and aging in relation to cancer and certain neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Sex is a significant social category, and adults derive information about it from both faces and bodies. Research indicates that young infants process sex category information in faces. However, no prior study has examined whether infants derive sex categories from bodies and match faces and bodies in terms of sex. In the current study, 5-month-olds exhibited a preference between sex congruent (face and body of the same sex) versus sex-incongruent (face and body belonging to different genders) images. In contrast, 3.5-month-olds failed to exhibit a preference. Thus, 5-month-olds process sex information from bodies and match it to facial information. However, younger infants’ failure to match suggests that there is a developmental change between 3.5 and 5 months of age in the processing of sex categories. These results indicate that rapid developmental changes lead to fairly sophisticated social information processing quite early in life. [ABSTRACT FROM AUTHOR]

Structural cues, such as the relative size and arrangement of parts, are key aspects of adults' representation of human bodies, and they are used to derive significant social information such as age, sex, and attractiveness. Prior studies have not clearly addressed young infants' sensitivity to these body characteristics. In the current experiments, 3.5-month-olds exhibited a preference between images of intact bodies versus those with parts in wrong locations. Infants also discriminated between intact bodies and those with distorted part proportions. In both cases, infants discriminated when images were presented upright but not when they were inverted. These results indicate that infants are sensitive to the arrangement and size of human body parts at least by 3.5 months of age. Thus, contrary to some prior reports, body representation early in life is developed enough to include structural information. [ABSTRACT FROM AUTHOR]

Even in the absence of facial information, adults are able to efficiently extract emotions from bodies and voices. Although prior research indicates that 6.5-month-old infants match emotional body movements to vocalizations, the developmental origins of this function are unknown. Moreover, it is not clear whether infants perceive emotion conveyed in static body postures and match them to vocalizations. In the current experiments, 6.5-month-olds matched happy and angry static body postures to corresponding vocalizations in upright images but not in inverted images. However, 3.5-month-olds failed to match. The younger infants also failed to match when tested with videos of emotional body movements that older infants had previously matched. Thus, whereas 6.5-month-olds process emotional cues from body images and match them to emotional vocalizations, 3.5-month-olds do not exhibit such emotion knowledge. These results indicate developmental changes that lead to sophisticated emotion processing from bodies and voices early in life. [ABSTRACT FROM AUTHOR]

Adults recognize emotions conveyed by bodies with comparable accuracy to facial emotions. However, no prior study has explored infants' perception of body emotions. In Experiment 1, 6.5-month-olds ( n = 32) preferred happy over neutral actions of actors with covered faces in upright but not inverted silent videos. In Experiment 2, infants ( n = 32) matched happy and angry videos to corresponding vocalizations when the videos were upright but not when they were inverted. Experiment 3 ( n = 16) demonstrated that infants' performance in Experiment 2 was not driven by information from the covered face and head. Thus, young infants are sensitive to emotions conveyed by bodies and match them to affective vocalizations, indicating sophisticated emotion processing capabilities early in life. [ABSTRACT FROM AUTHOR]

Highlights: [•] Configural spacing information contributes to face processing expertise in adults. [•] 5- and 9-month-olds discriminated spacing changes in human male and monkey faces. [•] However, infants failed to discriminate matched changes in house stimuli. [•] Thus, infants exhibited specialization on primate face stimuli. [•] Perceptual narrowing in face processing was not evident in this study. [Copyright &y& Elsevier]

Both objects and parts function as organizational entities in adult perception. Prior research has indicated that objects affect organization early in life: Infants grouped elements located within object boundaries and segregated them from those located on different objects. Here, we examined whether parts also induce grouping in infancy. Five- and 6.5-month-olds were habituated to two-part objects containing element pairs. In a subsequent test, infants treated groupings of elements that crossed part boundaries as novel, in comparison with groupings that had shared a common part during habituation. In contrast, the same arrangement of elements failed to elicit evidence of grouping in control conditions in which the elements were not surrounded by closed part boundaries. Thus, infants grouped and segregated elements on the basis of part structure. Part-based processing is a key aspect of many theories of perception. The present research adds to this literature by indicating that parts function as organizational entities early in life. [ABSTRACT FROM AUTHOR]

Learning can be highly adaptive if associations learned in one context are generalized to novel contexts. We examined the development of such generalization in infancy in the context of grouping. In Experiment 1, 3- to 4-month-olds and 6- to 7-month-olds were habituated to shapes grouped via the organizational principle of common region and were tested with familiar and novel pairs as determined by the principle of proximity. Older infants generalized from common region to proximity, but younger infants did not. Younger infants failed to generalize when the task was easier (Experiment 2), and their failure was not due to inability to group via proximity (Experiment 3). However, in Experiment 4, even younger infants generalized grouping on the basis of connectedness to proximity. Thus, the ability to transfer learned associations of shapes to novel contexts is evident early in life, although it continues to undergo quantitative change during infancy. Moreover, the operation of this generalization mechanism may be induced by means of bootstrapping onto functional organizational principles, which is consistent with a developmental framework in which core processes scaffold learning. [ABSTRACT FROM AUTHOR]

microRNAs (miRNAs) are (18-22nt long) noncoding short (s)RNAs that suppress gene expression by targeting the 3' untranslated region of target mRNAs. This occurs through the seed sequence located in position 2-7/8 of the miRNA guide strand, once it is loaded into the RNA induced silencing complex (RISC). G-rich 6mer seed sequences can kill cells by targeting C-rich 6mer seed matches located in genes that are critical for cell survival. This results in induction of Death Induced by Survival gene Elimination (DISE), through a mechanism we have called 6mer seed toxicity. miRNAs are often quantified in cells by aligning the reads from small (sm)RNA sequencing to the genome. However, the analysis of any smRNA Seq data set for predicted 6mer seed toxicity requires an alternative workflow, solely based on the exact position 2–7 of any short (s)RNA that can enter the RISC. Therefore, we developed SPOROS, a semi-automated pipeline that produces multiple useful outputs to predict and compare 6mer seed toxicity of cellular sRNAs, regardless of their nature, between different samples. We provide two examples to illustrate the capabilities of SPOROS: Example one involves the analysis of RISC-bound sRNAs in a cancer cell line (either wild-type or two mutant lines unable to produce most miRNAs). Example two is based on a publicly available smRNA Seq data set from postmortem brains (either from normal or Alzheimer's patients). Our methods (found at https://github.com/ebartom/SPOROS and at Code Ocean: https://doi.org/10.24433/CO.1732496.v1) are designed to be used to analyze a variety of smRNA Seq data in various normal and disease settings. Author summary: We recently discovered a kill code embedded in the genome with powerful anti-cancer activity. It is based on only 6 nucleotides (comprised of A, G, C, or U) that when present in the sequence of a small double stranded RNA allows it to act like a microRNA (miRNA). miRNAs are important regulators of many cell functions. The ~2,300 known miRNAs in the human genome function through their business end, the seed sequence. When this seed sequence is 6 nucleotides long (6mer seed) and is comprised of mostly Gs, then these small RNAs can kill all cancer cells. Hence, this code is found in a number of miRNAs that have anti-cancer activities. However, the code is not limited to miRNAs and may also affect normal tissue under certain conditions. We have now developed SPOROS, a semi-automated bioinformatics pipeline that allows one to analyze any data set of sequenced small RNAs with a focus on their 6mer seed content and their potential to kill cells. We present two examples of such an analysis: the first example is a data set we generated on the expression of all small RNAs in a human colon cancer cell line compared to a matching mutant cell line that cannot produce most miRNAs; the second example is a publicly available data set of small RNAs isolated from normal brains and from brains of patients with Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Adults' processing of own-race faces differs from that of other-race faces. The presence of an 'other-race' feature (ORF) has been proposed as a mechanism underlying this specialization. We examined whether this mechanism, which was previously identified in adults and in 9-month-olds, is evident at 3.5 months. Caucasian 3.5-month-olds looked longer at a pattern containing a single Asian face among seven Caucasian faces than at a pattern containing a single Caucasian face among seven Asian faces. Homogenous and inverted face control conditions indicated that infants' preference was not driven by the majority of faces in arrays or by low-level features. Thus, 3.5-month-olds found the presence of an other-race face among own-race faces to be more salient than the reverse configuration. This asymmetry suggests sensitivity to an ORF at 3.5 months. Thus, a key mechanism of race-based processing in adults has an early onset, indicating rapid development of specialization early in life. [ABSTRACT FROM AUTHOR]

Part representation is not only critical to object perception but also plays a key role in a number of basic visual cognition functions, such as figure-ground segregation, allocation of attention, and memory for shapes. Yet, virtually nothing is known about the development of part representation. If parts are fundamental components of object shape representation early in life, then the infant visual system should give priority to parts over other aspects of objects. We tested this hypothesis by examining whether part shapes are more salient than cavity shapes to infants. Five-month-olds were habituated to a stimulus that contained a part and a cavity. In a subsequent novelty preference test, 5-month-olds exhibited a preference for the cavity shape, indicating that part shapes were more salient than cavity shapes during habituation. The differential processing of part versus cavity contours in infancy is consistent with theory and empirical findings in the literature on adult figure-ground perception and indicates that basic aspects of part-based object processing are evident early in life. [ABSTRACT FROM AUTHOR]

Research indicates that object perception involves the decomposition of images into parts. A critical principle that governs part decomposition by adults is the short-cut rule, which states that, all else being equal, the visual system parses objects using the shortest possible cuts. We examined whether 6.5-month-olds' parsing of images also follows the short-cut rule. Infants in the experimental conditions were habituated to cross shapes and then tested for their preference between segregated patterns produced using long cuts versus short cuts. Infants in the control conditions were directly tested with the segregated patterns. Infants in the experimental conditions exhibited a greater novelty preference for the long-cut over the short-cut patterns than did those in the control conditions, thereby indicating that they are more likely to segregate cross shapes using short cuts rather than long cuts. This sensitivity to the short-cut rule was evident when two alternative parameters, part area and protrusion, were controlled in Experiments 1 and 2, respectively. Thus, a critical principle that governs part segregation in adulthood is operational by 6.5 months of age. [ABSTRACT FROM AUTHOR]

Over 80% of multiple-tested siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death characterized by simultaneous activation of multiple cell death pathways preferentially killing transformed and cancer stem cells. We now show these si/shRNAs kill cancer cells through canonical RNAi by targeting the 3'UTR of critical survival genes in a unique form of off-target effect we call DISE (death induced by survival gene elimination). Drosha and Dicer-deficient cells, devoid of most miRNAs, are hypersensitive to DISE, suggesting cellular miRNAs protect cells from this form of cell death. By testing 4666 shRNAs derived from the CD95 and CD95L mRNA sequences and an unrelated control gene, Venus, we have identified many toxic sequences - most of them located in the open reading frame of CD95L. We propose that specific toxic RNAi-active sequences present in the genome can kill cancer cells. [ABSTRACT FROM AUTHOR]

Like faces, bodies are significant sources of social information. However, research suggests that infants do not develop body representation (i.e., knowledge about typical human bodies) until the second year of life, although they are sensitive to facial information much earlier. Yet, previous research only examined whether infants are sensitive to the typical arrangement of body parts. We examined whether younger infants have body knowledge of a different kind, namely the relative size of body parts. Five- and 9-month-old infants were tested for their preference between a normal versus a proportionally distorted body. Nine-month-olds exhibited a preference for the normal body when images were presented upright but not when they were inverted. Five-month-olds failed to exhibit a preference in either condition. These results indicate that infants have knowledge about human bodies by the second half of the first year of life. Moreover, given that better performance on upright than on inverted stimuli has been tied to expertise, the fact that older infants exhibited an inversion effect with body images indicates that at least some level of expertise in body processing develops by 9 months of age. [ABSTRACT FROM AUTHOR]