The Antagonistic Gene Paralogs Upf3a and Upf3b Govern Nonsense-Mediated RNA Decay.

Gene duplication is a major evolutionary force driving adaptation and speciation, as it allows for the acquisition of new functions and can augment or diversify existing functions. Here, we report a gene duplication event that yielded another outcome--the generation of antagonistic functions. One product of this duplication event--UPF3B--is critical for the nonsense-mediated RNA decay (NMD) pathway, while its autosomal counterpart--UPF3A--encodes an enigmatic protein previously shown to have trace NMD activity. Using loss-of-function approaches in vitro and in vivo, we discovered that UPF3A acts primarily as a potent NMD inhibitor that stabilizes hundreds of transcripts. Evidence suggests that UPF3A acquired repressor activity through simple impairment of a critical domain, a rapid mechanism that may have been widely used in evolution. Mice conditionally lacking UPF3A exhibit "hyper" NMD and display defects in embryogenesis and gametogenesis. Our results support a model in which UPF3A serves as a molecular rheostat that directs developmental events.

Transcranial electrical stimulation: How can a simple conductor orchestrate complex brain activity?

Transcranial electrical stimulation (tES) is one of the oldest and yet least understood forms of brain stimulation. The idea that a weak electrical stimulus, applied outside the head, can meaningfully affect neural activity is often regarded as mysterious. Here, we argue that the direct effects of tES are not so mysterious: Extensive data from a wide range of model systems shows it has appreciable effects on the activity of individual neurons. Instead, the real mysteries are how tES interacts with the brain's own activity and how these dynamics can be controlled to produce desirable therapeutic effects. These are challenging problems, akin to repairing a complex machine while it is running, but they are not unique to tES or even neuroscience. We suggest that models of coupled oscillators, a common tool for studying interactions in other fields, may provide valuable insights. By combining these tools with our growing, interdisciplinary knowledge of brain dynamics, we are now in a good position to make progress in this area and meet the high demand for effective neuromodulation in neuroscience and psychiatry.

Brain stimulation competes with ongoing oscillations for control of spike timing in the primate brain.

Transcranial alternating current stimulation (tACS) is a popular method for modulating brain activity noninvasively. In particular, tACS is often used as a targeted intervention that enhances a neural oscillation at a specific frequency to affect a particular behavior. However, these interventions often yield highly variable results. Here, we provide a potential explanation for this variability: tACS competes with the brain's ongoing oscillations. Using neural recordings from alert nonhuman primates, we find that when neural firing is independent of ongoing brain oscillations, tACS readily entrains spiking activity, but when neurons are strongly entrained to ongoing oscillations, tACS often causes a decrease in entrainment instead. Consequently, tACS can yield categorically different results on neural activity, even when the stimulation protocol is fixed. Mathematical analysis suggests that this competition is likely to occur under many experimental conditions. Attempting to impose an external rhythm on the brain may therefore often yield precisely the opposite effect.

Spontaneous activity in cortical neurons is stereotyped and non-Poisson.

Neurons fire even in the absence of sensory stimulation or task demands. Numerous theoretical studies have modeled this spontaneous activity as a Poisson process with uncorrelated intervals between successive spikes and a variance in firing rate equal to the mean. Experimental tests of this hypothesis have yielded variable results, though most have concluded that firing is not Poisson. However, these tests say little about the ways firing might deviate from randomness. Nor are they definitive because many different distributions can have equal means and variances. Here, we characterized spontaneous spiking patterns in extracellular recordings from monkey, cat, and mouse cerebral cortex neurons using rate-normalized spike train autocorrelation functions (ACFs) and a logarithmic timescale. If activity was Poisson, this function should be flat. This was almost never the case. Instead, ACFs had diverse shapes, often with characteristic peaks in the 1-700 ms range. Shapes were stable over time, up to the longest recording periods used (51 min). They did not fall into obvious clusters. ACFs were often unaffected by visual stimulation, though some abruptly changed during brain state shifts. These behaviors may have their origin in the intrinsic biophysics and dendritic anatomy of the cells or in the inputs they receive.

tACS entrains neural activity while somatosensory input is blocked.

Transcranial alternating current stimulation (tACS) modulates brain activity by passing electrical current through electrodes that are attached to the scalp. Because it is safe and noninvasive, tACS holds great promise as a tool for basic research and clinical treatment. However, little is known about how tACS ultimately influences neural activity. One hypothesis is that tACS affects neural responses directly, by producing electrical fields that interact with the brain's endogenous electrical activity. By controlling the shape and location of these electric fields, one could target brain regions associated with particular behaviors or symptoms. However, an alternative hypothesis is that tACS affects neural activity indirectly, via peripheral sensory afferents. In particular, it has often been hypothesized that tACS acts on sensory fibers in the skin, which in turn provide rhythmic input to central neurons. In this case, there would be little possibility of targeted brain stimulation, as the regions modulated by tACS would depend entirely on the somatosensory pathways originating in the skin around the stimulating electrodes. Here, we directly test these competing hypotheses by recording single-unit activity in the hippocampus and visual cortex of alert monkeys receiving tACS. We find that tACS entrains neuronal activity in both regions, so that cells fire synchronously with the stimulation. Blocking somatosensory input with a topical anesthetic does not significantly alter these neural entrainment effects. These data are therefore consistent with the direct stimulation hypothesis and suggest that peripheral somatosensory stimulation is not required for tACS to entrain neurons.

Transcranial alternating current stimulation entrains single-neuron activity in the primate brain.

Spike timing is thought to play a critical role in neural computation and communication. Methods for adjusting spike timing are therefore of great interest to researchers and clinicians alike. Transcranial electrical stimulation (tES) is a noninvasive technique that uses weak electric fields to manipulate brain activity. Early results have suggested that this technique can improve subjects' behavioral performance on a wide range of tasks and ameliorate some clinical conditions. Nevertheless, considerable skepticism remains about its efficacy, especially because the electric fields reaching the brain during tES are small, whereas the likelihood of indirect effects is large. Our understanding of its effects in humans is largely based on extrapolations from simple model systems and indirect measures of neural activity. As a result, fundamental questions remain about whether and how tES can influence neuronal activity in the human brain. Here, we demonstrate that tES, as typically applied to humans, affects the firing patterns of individual neurons in alert nonhuman primates, which are the best available animal model for the human brain. Specifically, tES consistently influences the timing, but not the rate, of spiking activity within the targeted brain region. Such effects are frequency- and location-specific and can reach deep brain structures; control experiments show that they cannot be explained by sensory stimulation or other indirect influences. These data thus provide a strong mechanistic rationale for the use of tES in humans and will help guide the development of future tES applications.

Voltage distributions in extracellular brain recordings.

Extracellular recordings of brain voltage signals have many uses, including the identification of spikes and the characterization of brain states via analysis of local field potential (LFP) or EEG recordings. Though the factors underlying the generation of these signals are time varying and complex, their analysis may be facilitated by an understanding of their statistical properties. To this end, we analyzed the voltage distributions of high-pass extracellular recordings from a variety of structures, including cortex, thalamus, and hippocampus, in monkeys, cats, and rodents. We additionally investigated LFP signals in these recordings as well as human EEG signals obtained during different sleep stages. In all cases, the distributions were accurately described by a Gaussian within ±1.5 standard deviations from zero. Outside these limits, voltages tended to be distributed exponentially, that is, they fell off linearly on log-linear frequency plots, with variable heights and slopes. A possible explanation for this is that sporadically and independently occurring events with individual Gaussian size distributions can sum to produce approximately exponential distributions. For the high-pass recordings, a second explanation results from a model of the noisy behavior of ion channels that produce action potentials via Hodgkin-Huxley kinetics. The distributions produced by this model, relative to the averaged potential, were also Gaussian with approximately exponential flanks. The model also predicted time-varying noise distributions during action potentials, which were observed in the extracellular spike signals. These findings suggest a principled method for detecting spikes in high-pass recordings and transient events in LFP and EEG signals.NEW & NOTEWORTHY We show that the voltage distributions in brain recordings, including high-pass extracellular recordings, the LFP, and human EEG, are accurately described by a Gaussian within ±1.5 standard deviations from zero, with heavy, exponential tails outside these limits. This offers a principled way of setting event detection thresholds in high-pass recordings. It also offers a means for identifying event-like, transient signals in LFP and EEG recordings which may correlate with other neural phenomena.

Genetic variant at coronary artery disease and ischemic stroke locus 1p32.2 regulates endothelial responses to hemodynamics.

Biomechanical cues dynamically control major cellular processes, but whether genetic variants actively participate in mechanosensing mechanisms remains unexplored. Vascular homeostasis is tightly regulated by hemodynamics. Exposure to disturbed blood flow at arterial sites of branching and bifurcation causes constitutive activation of vascular endothelium contributing to atherosclerosis, the major cause of coronary artery disease (CAD) and ischemic stroke (IS). Conversely, unidirectional flow promotes quiescent endothelium. Genome-wide association studies (GWAS) have identified chromosome 1p32.2 as strongly associated with CAD/IS; however, the causal mechanism related to this locus remains unknown. Using statistical analyses, assay of transposase accessible chromatin with whole-genome sequencing (ATAC-seq), H3K27ac/H3K4me2 ChIP with whole-genome sequencing (ChIP-seq), and CRISPR interference in human aortic endothelial cells (HAECs), our results demonstrate that rs17114036, a common noncoding polymorphism at 1p32.2, is located in an endothelial enhancer dynamically regulated by hemodynamics. CRISPR-Cas9-based genome editing shows that rs17114036-containing region promotes endothelial quiescence under unidirectional shear stress by regulating phospholipid phosphatase 3 (PLPP3). Chromatin accessibility quantitative trait locus (caQTL) mapping using HAECs from 56 donors, allelic imbalance assay from 7 donors, and luciferase assays demonstrate that CAD/IS-protective allele at rs17114036 in PLPP3 intron 5 confers increased endothelial enhancer activity. ChIP-PCR and luciferase assays show that CAD/IS-protective allele at rs17114036 creates a binding site for transcription factor Krüppel-like factor 2 (KLF2), which increases the enhancer activity under unidirectional flow. These results demonstrate that a human SNP contributes to critical endothelial mechanotransduction mechanisms and suggest that human haplotypes and related cis-regulatory elements provide a previously unappreciated layer of regulatory control in cellular mechanosensing mechanisms.

Correction to: Altered mitochondrial bioenergetics and ultrastructure in the skeletal muscle of young adults with type 1 diabetes.

In Fig. 1e the rate of mitochondrial H2O2 emission was incorrectly shown as being per second rather than per minute.

MILK Symposium review: Identifying constraints, opportunities, and best practices for improving milk production in market-oriented dairy farms in Sri Lanka.

Dairy is the most important subsector in the Sri Lankan livestock industry, due to the need to address the growing demand for fresh milk and milk products, and because of its potential influence on the rural economy. The USDA Food for Progress program awarded a 4.5-year Market-Oriented Dairy project to International Executive Service Corps, a not-for-profit organization based in Washington, DC. The objective of the Market-Oriented Dairy project is to support Sri Lanka's dairy sector and catalyze sustainable growth by strengthening the dairy sector through better technological, financial, and management practices benefiting all stakeholders and consumers along the dairy value chain. The University of Florida is working with International Executive Service Corps as technical experts in conducting dairy value chain assessments, identifying gaps and challenges in dairy management practices, extension services, milk quality management standards, and artificial insemination services. Assessment of the dairy value chain in 2018 identified a lack of good quality and quantity of feed, along with poor dairy management practices and ineffective extension services as major constraints to improving dairy productivity in Sri Lanka. In addition, lack of national milk quality standards that are consistent with international benchmarks and inadequate cooling facilities are significant challenges to improving milk quality. The nutritional status of cows is not suitable for optimal reproductive performance, compromising the success of artificial insemination in Sri Lanka. Based on these findings, we developed a dairy assessment tool and provided comprehensive training sessions targeting extension agents, veterinarians, and farmers to promote best practices in dairy management. Beyond training, however, industry support for standardization and monitoring of milk and feed quality are needed, providing opportunities for private investment to support the dairy industry. Similar opportunities are available for forage production and delivery to producers. The broader aim of the Market-Oriented Dairy project intervention is to reduce Sri Lanka's dependency on imported milk and contribute toward the goal of a safe, self-sufficient fresh milk supply.

PAI-1, the Plasminogen System, and Skeletal Muscle.

The plasminogen system is a critical proteolytic system responsible for the remodeling of the extracellular matrix (ECM). The master regulator of the plasminogen system, plasminogen activator inhibitor-1 (PAI-1), has been implicated for its role in exacerbating various disease states not only through the accumulation of ECM (i.e., fibrosis) but also its role in altering cell fate/behaviour. Examination of PAI-1 has extended through various tissues and cell-types with recent investigations showing its presence in skeletal muscle. In skeletal muscle, the role of this protein has been implicated throughout the regeneration process, and in skeletal muscle pathologies (muscular dystrophy, diabetes, and aging-driven pathology). Needless to say, the complete function of this protein in skeletal muscle has yet to be fully elucidated. Given the importance of skeletal muscle in maintaining overall health and quality of life, it is critical to understand the alterations-particularly in PAI-1-that occur to negatively impact this organ. Thus, we provide a comprehensive review of the importance of PAI-1 in skeletal muscle health and function. We aim to shed light on the relevance of this protein in skeletal muscle and propose potential therapeutic approaches to aid in the maintenance of skeletal muscle health.

Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal Muscle.

Regenerative capacity of skeletal muscle declines with age, the cause of which remains largely unknown. We investigated extracellular matrix (ECM) proteins and their regulators during early regeneration timepoints to define a link between aberrant ECM remodeling, and impaired aged muscle regeneration. The regeneration process was compared in young (three month old) and aged (18 month old) C56BL/6J mice at 3, 5, and 7 days following cardiotoxin-induced damage to the tibialis anterior muscle. Immunohistochemical analyses were performed to assess regenerative capacity, ECM remodeling, and the macrophage response in relation to plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), and ECM protein expression. The regeneration process was impaired in aged muscle. Greater intracellular and extramyocellular PAI-1 expression was found in aged muscle. Collagen I was found to accumulate in necrotic regions, while macrophage infiltration was delayed in regenerating regions of aged muscle. Young muscle expressed higher levels of MMP-9 early in the regeneration process that primarily colocalized with macrophages, but this expression was reduced in aged muscle. Our results indicate that ECM remodeling is impaired at early time points following muscle damage, likely a result of elevated expression of the major inhibitor of ECM breakdown, PAI-1, and consequent suppression of the macrophage, MMP-9, and myogenic responses.

Single-cell profiling reveals that eRNA accumulation at enhancer-promoter loops is not required to sustain transcription.

Enhancers are intergenic DNA elements that regulate the transcription of target genes in response to signaling pathways by interacting with promoters over large genomic distances. Recent studies have revealed that enhancers are bi-directionally transcribed into enhancer RNAs (eRNAs). Using single-molecule fluorescence in situ hybridization (smFISH), we investigated the eRNA-mediated regulation of transcription during estrogen induction in MCF-7 cells. We demonstrate that eRNAs are localized exclusively in the nucleus and are induced with similar kinetics as target mRNAs. However, eRNAs are mostly nascent at enhancers and their steady-state levels remain lower than those of their cognate mRNAs. Surprisingly, at the single-allele level, eRNAs are rarely co-expressed with their target loci, demonstrating that active gene transcription does not require the continuous transcription of eRNAs or their accumulation at enhancers. When co-expressed, sub-diffraction distance measurements between nascent mRNA and eRNA signals reveal that co-transcription of eRNAs and mRNAs rarely occurs within closed enhancer-promoter loops. Lastly, basal eRNA transcription at enhancers, but not E2-induced transcription, is maintained upon depletion of MLL1 and ERα, suggesting some degree of chromatin accessibility prior to signal-dependent activation of transcription. Together, our findings suggest that eRNA accumulation at enhancer-promoter loops is not required to sustain target gene transcription.

Adiponectin-Consideration for its Role in Skeletal Muscle Health.

Adiponectin regulates metabolism through blood glucose control and fatty acid oxidation, partly mediated by downstream effects of adiponectin signaling in skeletal muscle. More recently, skeletal muscle has been identified as a source of adiponectin expression, fueling interest in the role of adiponectin as both a circulating adipokine and a locally expressed paracrine/autocrine factor. In addition to being metabolically responsive, skeletal muscle functional capacity, calcium handling, growth and maintenance, regenerative capacity, and susceptibility to chronic inflammation are all strongly influenced by adiponectin stimulation. Furthermore, physical exercise has clear links to adiponectin expression and circulating concentrations in healthy and diseased populations. Greater physical activity is generally related to higher adiponectin expression while lower adiponectin levels are found in inactive obese, pre-diabetic, and diabetic populations. Exercise training typically restores plasma adiponectin and is associated with improved insulin sensitivity. Thus, the role of adiponectin signaling in skeletal muscle has expanded beyond that of a metabolic regulator to include several aspects of skeletal muscle function and maintenance critical to muscle health, many of which are responsive to, and mediated by, physical exercise.

Altered mitochondrial bioenergetics and ultrastructure in the skeletal muscle of young adults with type 1 diabetes.

AIMS/HYPOTHESIS: A comprehensive assessment of skeletal muscle ultrastructure and mitochondrial bioenergetics has not been undertaken in individuals with type 1 diabetes. This study aimed to systematically assess skeletal muscle mitochondrial phenotype in young adults with type 1 diabetes. METHODS: Physically active, young adults (men and women) with type 1 diabetes (HbA1c 63.0 ± 16.0 mmol/mol [7.9% ± 1.5%]) and without type 1 diabetes (control), matched for sex, age, BMI and level of physical activity, were recruited (n = 12/group) to undergo vastus lateralis muscle microbiopsies. Mitochondrial respiration (high-resolution respirometry), site-specific mitochondrial H2O2 emission and Ca2+ retention capacity (CRC) (spectrofluorometry) were assessed using permeabilised myofibre bundles. Electron microscopy and tomography were used to quantify mitochondrial content and investigate muscle ultrastructure. Skeletal muscle microvasculature was assessed by immunofluorescence. RESULTS: Mitochondrial oxidative capacity was significantly lower in participants with type 1 diabetes vs the control group, specifically at Complex II of the electron transport chain, without differences in mitochondrial content between groups. Muscles of those with type 1 diabetes also exhibited increased mitochondrial H2O2 emission at Complex III and decreased CRC relative to control individuals. Electron tomography revealed an increase in the size and number of autophagic remnants in the muscles of participants with type 1 diabetes. Despite this, levels of the autophagic regulatory protein, phosphorylated AMP-activated protein kinase (p-AMPKαThr172), and its downstream targets, phosphorylated Unc-51 like autophagy activating kinase 1 (p-ULK1Ser555) and p62, was similar between groups. In addition, no differences in muscle capillary density or platelet aggregation were observed between the groups. CONCLUSIONS/INTERPRETATION: Alterations in mitochondrial ultrastructure and bioenergetics are evident within the skeletal muscle of active young adults with type 1 diabetes. It is yet to be elucidated whether more rigorous exercise may help to prevent skeletal muscle metabolic deficiencies in both active and inactive individuals with type 1 diabetes.

Experimental Lung Injury Reduces Krüppel-like Factor 2 to Increase Endothelial Permeability via Regulation of RAPGEF3-Rac1 Signaling.

RATIONALE: Acute respiratory distress syndrome (ARDS) is caused by widespread endothelial barrier disruption and uncontrolled cytokine storm. Genome-wide association studies (GWAS) have linked multiple genes to ARDS. Although mechanosensitive transcription factor Krüppel-like factor 2 (KLF2) is a major regulator of endothelial function, its role in regulating pulmonary vascular integrity in lung injury and ARDS-associated GWAS genes remains poorly understood. OBJECTIVES: To examine KLF2 expression in multiple animal models of acute lung injury and further elucidate the KLF2-mediated pathways involved in endothelial barrier disruption and cytokine storm in experimental lung injury. METHODS: Animal and in vitro models of acute lung injury were used to characterize KLF2 expression and its downstream effects responding to influenza A virus (A/WSN/33 [H1N1]), tumor necrosis factor-α, LPS, mechanical stretch/ventilation, or microvascular flow. KLF2 manipulation, permeability measurements, small GTPase activity, luciferase assays, chromatin immunoprecipitation assays, and network analyses were used to determine the mechanistic roles of KLF2 in regulating endothelial monolayer integrity, ARDS-associated GWAS genes, and lung pathophysiology. MEASUREMENTS AND MAIN RESULTS: KLF2 is significantly reduced in several animal models of acute lung injury. Microvascular endothelial KLF2 is significantly induced by capillary flow but reduced by pathologic cyclic stretch and inflammatory stimuli. KLF2 is a novel activator of small GTPase Ras-related C3 botulinum toxin substrate 1 by transcriptionally controlling Rap guanine nucleotide exchange factor 3/exchange factor directly activated by cyclic adenosine monophosphate, which maintains vascular integrity. KLF2 regulates multiple ARDS GWAS genes related to cytokine storm, oxidation, and coagulation in lung microvascular endothelium. KLF2 overexpression ameliorates LPS-induced lung injury in mice. CONCLUSIONS: Disruption of endothelial KLF2 results in dysregulation of lung microvascular homeostasis and contributes to lung pathology in ARDS.

Myosin VI regulates gene pairing and transcriptional pause release in T cells.

Naive CD4 T cells differentiate into several effector lineages, which generate a stronger and more rapid response to previously encountered immunological challenges. Although effector function is a key feature of adaptive immunity, the molecular basis of this process is poorly understood. Here, we investigated the spatiotemporal regulation of cytokine gene expression in resting and restimulated effector T helper 1 (Th1) cells. We found that the Lymphotoxin (LT)/TNF alleles, which encode TNF-α, were closely juxtaposed shortly after T-cell receptor (TCR) engagement, when transcription factors are limiting. Allelic pairing required a nuclear myosin, myosin VI, which is rapidly recruited to the LT/TNF locus upon restimulation. Furthermore, transcription was paused at the TNF locus and other related genes in resting Th1 cells and released in a myosin VI-dependent manner following activation. We propose that homologous pairing and myosin VI-mediated transcriptional pause release account for the rapid and efficient expression of genes induced by an external stimulus.

Orexin Neurons Respond Differentially to Auditory Cues Associated with Appetitive versus Aversive Outcomes.

Orexin (Orx) neurons are known to be involved in the promotion and maintenance of waking because they discharge in association with cortical activation and muscle tone during waking and because, in their absence, waking with muscle tone cannot be maintained and narcolepsy with cataplexy ensues. Whether Orx neurons discharge during waking in association with particular conditions, notably with appetitive versus aversive stimuli or positive versus negative emotions, is debated and considered important in understanding their role in supporting particular waking behaviors. Here, we used the technique of juxtacellular recording and labeling in head-fixed rats to characterize the discharge of Orx neurons during the performance of an associative discrimination task with auditory cues for appetitive versus aversive outcomes. Of 57 active, recorded, and neurobiotin-labeled neurons in the lateral hypothalamus, 11 were immunohistochemically identified as Orx-positive (Orx(+)), whereas none were identified as melanin-concentrating hormone-positive. Orx(+) neurons discharged at significantly higher rates during the tone associated with sucrose than during the tone associated with quinine delivered upon licking. They also discharged at high rates after the tone associated with sucrose. Across periods and outcomes, their discharge was positively correlated with EEG gamma activity and EMG activity, which is indicative of cortical activation and behavioral arousal. These results suggest that Orx neurons discharge in a manner characteristic of reward neurons yet also characteristic of arousal neurons. Accordingly, the Orx neurons may respond to and participate in reward processes while modulating cortical activity and muscle tone to promote and maintain arousal along with learned adaptive behavioral responses. SIGNIFICANCE STATEMENT: Orexin neurons play a critical role in promoting and maintaining a waking state because, in their absence, narcolepsy with cataplexy ensues. Known to discharge during waking and not during sleep, they have also been proposed to be selectively active during appetitive behaviors. Here, we recorded and labeled neurons in rats to determine the discharge of immunohistochemically identified orexin neurons during performance of an associative discrimination task. Orexin neurons responded differentially to auditory cues associated with appetitive sucrose versus aversive quinine, indicating that they behave like reward neurons. However, correlated discharge with cortical and muscle activity indicates that they also behave like arousal neurons and can thus promote cortical activation with behavioral arousal and muscle tone during adaptive waking behaviors.

Geographical Information System Evaluation and Trends of Nonaccidental Trauma at a Level I Trauma Center, Pilot Study.

PREMISE: Although trauma may be considered a random act, geographical patterns of trauma potentially emerge. Our institution is unique in that it rests at an intersection of two of the highest areas of poverty and assault in New York City and has adequate data to analyze these patterns. METHODS: We review the incident reports logged by emergency medical services (EMS) technicians arriving with intentionally injured trauma patients from January 1 to December 31, 2013 at a single institution. After acquisition of this data, it was placed into a computer file using an individual identifying numbers for each incident along with latitude and longitude coordinates determined by global positioning software for each event. The data were separated into blunt and penetrating categories. Penetrating trauma was further separated into the type of instrument used: edged weapon or firearm. Kernel density estimate using the Crimestat program was then performed to determine the epicenters with the highest incidents of nonaccidental trauma. RESULTS: Two hundred eighty-three patients were evaluated for assault-related trauma. Two hundred fifty-four patients were included in the mapping of the data with almost equal blunt and penetrating trauma. Seventy-four percent of trauma occurred from 6 PM to 6 AM, and 41% occurring between midnight and 6 AM. Of patients, 32.7% were found to be assaulted at their home address. Regression analysis demonstrated that each type of trauma had unique epicenters of likelihood for occurrence. CONCLUSIONS: We can only speculate the reasons for many of these results at this time and further research into the sociological, psychological, and environmental factors is required. A high proportion of patients are assaulted at their home addresses. Further study is necessary to improve patient care with additional data provided by emergency medical services, police departments and surrounding hospitals.