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Neural information processing is widely understood to depend on correlations in neuronal activity. However, whether correlation is favorable or not is contentious. Here, we sought to determine how correlated activity and information processing are related in cortical circuits. Using recordings of hundreds of spiking neurons in organotypic cultures of mouse neocortex, we asked whether mutual information between neurons that feed into a common third neuron increased synergistic information processing by the receiving neuron. We found that mutual information and synergistic processing were positively related at synaptic timescales (0.05–14 ms), where mutual information values were low. This effect was mediated by the increase in information transmission—of which synergistic processing is a component—that resulted as mutual information grew. However, at extrasynaptic windows (up to 3,000 ms), where mutual information values were high, the relationship between mutual information and synergistic processing became negative. In this regime, greater mutual information resulted in a disproportionate increase in redundancy relative to information transmission. These results indicate that the emergence of synergistic processing from correlated activity differs according to timescale and correlation regime. In a low-correlation regime, synergistic processing increases with greater correlation, and in a high-correlation regime, synergistic processing decreases with greater correlation., Author Summary In the present work, we address the question of whether correlated activity in functional networks of cortical circuits supports neural computation. To do so, we combined network analysis with information theoretic tools to analyze the spiking activity of hundreds of neurons recorded from organotypic cultures of mouse somatosensory cortex. We found that, at timescales most relevant to direct neuronal communication, neurons with more correlated activity predicted greater computation, suggesting that correlated activity does support computation in cortical circuits. Importantly, this result reversed at timescales less relevant to direct neuronal communication, where even greater correlated activity predicted decreased computation. Thus, the relationship between correlated activity and computation depends on the timescale and the degree of correlation in neuronal interactions.

Surgical excision remains the most commonly utilized treatment for superficial basal cell carcinoma (sBCC). In the era of cost containment of healthcare, the rising incidence of BCC and the high cost of excision require a continuous search for efficient and cost-effective management.Examine the feasibility of the diagnosis and treatment of low-risk sBCC in a single visit.Retrospective chart review of sBCCs diagnosed and treated in a single visit.The study identified 151 histologically confirmed sBCCs in 86 patients over a 5-year period, 93 (61.6%) cases of which were diagnosed as low-risk sBCC and treated in a single appointment. The majority of the cases (Diagnosis and treatment of sBCC in a single visit is an efficient and cost-effective management option for those who are proficient in identifying low-risk sBCC.

Prenatal cannabis exposure (PCE) influences human brain development, but it is challenging to model PCE using animals and current cell culture techniques. Here, we developed a one-stop microfluidic platform to assemble and culture human cerebral organoids from human embryonic stem cells (hESC) to investigate the effect of PCE on early human brain development. By incorporating perfusable culture chambers, air-liquid interface, and one-stop protocol, this microfluidic platform can simplify the fabrication procedure, and produce a large number of organoids (169 organoids per 3.5 cm x 3.5 cm device area) without fusion, as compared with conventional fabrication methods. These one-stop microfluidic assembled cerebral organoids not only recapitulate early human brain structure, biology, and electrophysiology but also have minimal size variation and hypoxia. Under on-chip exposure to the psychoactive cannabinoid, delta-9-tetrahydrocannabinol (THC), cerebral organoids exhibited reduced neuronal maturation, downregulation of cannabinoid receptor type 1 (CB1) receptors, and impaired neurite outgrowth. Moreover, transient on-chip THC treatment also decreased spontaneous firing in microfluidic assembled brain organoids. This one-stop microfluidic technique enables a simple, scalable, and repeatable organoid culture method that can be used not only for human brain organoids, but also for many other human organoids including liver, kidney, retina, and tumor organoids. This technology could be widely used in modeling brain and other organ development, developmental disorders, developmental pharmacology and toxicology, and drug screening.

To understand how neural circuits process information, it is essential to identify the relationship between computation and circuit organization. Rich clubs, highly interconnected sets of neurons, are known to propagate a disproportionate amount of information within cortical circuits. Here, we test the hypothesis that rich clubs also perform a disproportionate amount of computation. To do so, we recorded the spiking activity of on average ∼300 well-isolated individual neurons from organotypic cortical cultures. We then constructed weighted, directed networks reflecting the effective connectivity between the neurons. For each neuron, we quantified the amount of computation it performed based on its inputs. We found that rich-club neurons compute ∼160% more information than neurons outside of the rich club. The amount of computation performed in the rich club was proportional to the amount of information propagation by the same neurons. This suggests that in these circuits, information propagation drives computation. In total, our findings indicate that rich-club organization in effective cortical circuits supports not only information propagation but also neural computation., Author Summary Here we answer the question of whether rich-club organization in functional networks of cortical circuits supports neural computation. To do so, we combined network analysis with information theoretic tools to analyze the spiking activity of hundreds of neurons recorded from organotypic cultures of mouse somatosensory cortex. We found that neurons in rich clubs computed significantly more than neurons outside of rich clubs, suggesting that rich clubs do support computation in cortical circuits. Indeed, the amount of computation that we found in the rich clubs was proportional to the amount of information they propagate, suggesting that in these circuits, information propagation drives computation.

Whether the brain operates at a critical “tipping” point is a long standing scientific question, with evidence from both cellular and systems-scale studies suggesting that the brain does sit in, or near, a critical regime. Neuroimaging studies of humans in altered states of consciousness have prompted the suggestion that maintenance of critical dynamics is necessary for the emergence of consciousness and complex cognition, and that reduced or disorganized consciousness may be associated with deviations from criticality. Unfortunately, many of the cellular-level studies reporting signs of criticality were performed in non-conscious systems (in vitro neuronal cultures) or unconscious animals (e.g. anaesthetized rats). Here we attempted to address this knowledge gap by exploring critical brain dynamics in invasive ECoG recordings from multiple sessions with a single macaque as the animal transitioned from consciousness to unconsciousness under different anaesthetics (ketamine and propofol). We use a previously-validated test of criticality: avalanche dynamics to assess the differences in brain dynamics between normal consciousness and both drug-states. Propofol and ketamine were selected due to their differential effects on consciousness (ketamine, but not propofol, is known to induce an unusual state known as “dissociative anaesthesia”). Our analyses indicate that propofol dramatically restricted the size and duration of avalanches, while ketamine allowed for more awake-like dynamics to persist. In addition, propofol, but not ketamine, triggered a large reduction in the complexity of brain dynamics. All states, however, showed some signs of persistent criticality when testing for exponent relations and universal shape-collapse. Further, maintenance of critical brain dynamics may be important for regulation and control of conscious awareness., Author summary Here we explore how different anaesthetic drugs change the nature of brain dynamics, using neural activity recorded from sub-dural electrophysiological arrays implanted in a macaque brain. Previous research has suggested that loss of consciousness under anaesthesia is associated with a movement away from critical brain dynamics, towards a less flexible regime. When comparing ketamine and propofol, two anaesthetics with largely different effects on consciousness, we find that propofol, but not ketamine, produces a dramatic reduction in the complexity of brain activity and restricts the range of scales where critical dynamics are plausible. These results suggest that maintenance of critical dynamics may be important for regulation and control of conscious awareness.

Perfluorooctanesulfonic acid (PFOS) is a persistent organic pollutant with worldwide bioaccumulation due to a very long half-life. Perfluorooctanesulfonic acid exposure results in significant hepatic effects including steatosis, proliferation, hepatomegaly, and in rodents, carcinogenesis. The objective of this study was to determine whether PFOS exposure exacerbates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis pathogenesis. Eight-week-old male C57BL/6 J mice (n = 5 per group) were fed ad libitum normal chow diet (ND) alone, 60% high-fat diet (HFD) alone, ND + PFOS, and HFD + PFOS (0.0001% w/w (1 mg/kg) of PFOS) for 6 weeks. Both HFD alone and the ND + PFOS treatment induced significant adiposity and hepatomegaly, but the HFD + PFOS treatment showed a marked protection. Oil Red O staining and quantitative analysis of hepatic lipid content revealed increased hepatic steatosis in ND + PFOS and in HFD alone fed mice, which was prevented in HFD + PFOS treatment. Further studies revealed that ND + PFOS treatment significantly affected expression of lipid trafficking genes to favor steatosis, but these changes were absent in HFD + PFOS group. Specifically, expression of CD36, the major lipid importer in the cells, and peroxisome proliferator-activated receptor gamma (PPARγ), its major regulator, were induced in HFD + no treatment (NT) and ND + PFOS-fed mice but remained unchanged in HFD + PFOS mice. In conclusion, these data indicate that coadministration of PFOS with HFD mitigates steatosis and hepatomegaly induced by HFD and that by PFOS fed in ND diet via regulation of cellular lipid import machinery. These findings suggest dietary lipid content be considered when performing risk management of PFOS in humans and the elucidation of PFOS-induced hepatotoxicity.

CD8 T-cell lymphomas comprise a wide spectrum of lymphomas, many which have yet to be formally classified. We present a case of a 43-year-old woman with an enlarging tumor distal to the distal interphalangeal joint of the fourth finger, compressing the underlying nail matrix. Magnetic resonance imaging showed bony involvement of the underlying distal phalanx. Histology showed a dense epidermotropic and pandermal infiltrate composed of medium-sized, uniformly pleomorphic lymphocytes with cleaved nuclei, which raised the possibility of primary cutaneous CD8 aggressive epidermotropic cytotoxic T-cell lymphoma. However, the patient's clinical photograph was inconsistent with this diagnosis. Other diagnoses, such as primary cutaneous acral CD8 T-cell lymphoma-a provisional entity, were also considered but did not capture all the features of this patient's lymphoma. We propose to classify this case as a primary cutaneous CD8 T-cell lymphoma, an indolent and locally aggressive form.

Neural information processing is widely understood to depend on correlations in neuronal activity. However, whether correlation is favorable or not is contentious. Here, we sought to determine how correlated activity and information processing are related in cortical circuits. Using recordings of hundreds of spiking neurons in organotypic cultures of mouse neocortex, we asked whether mutual information between neurons that feed into a common third neuron increased synergistic information processing by the receiving neuron. We found that mutual information and synergistic processing were positively related at synaptic timescales (0.05-14 ms), where mutual information values were low. This effect was mediated by the increase in information transmission—of which synergistic processing is a component—that resulted as mutual information grew. However, at extrasynaptic windows (up to 3000 ms), where mutual information values were high, the relationship between mutual information and synergistic processing became negative. In this regime, greater mutual information resulted in a disproportionate increase in redundancy relative to information transmission. These results indicate that the emergence of synergistic processing from correlated activity differs according to timescale and correlation regime. In a low-correlation regime, synergistic processing increases with greater correlation, and in a high correlation regime, synergistic processing decreases with greater correlation.AUTHOR SUMMARYIn the present work, we address the question of whether correlated activity in functional networks of cortical circuits supports neural computation. To do so, we combined network analysis with information theoretic tools to analyze the spiking activity of hundreds of neurons recorded from organotypic cultures of mouse somatosensory cortex. We found that, at timescales most relevant to direct neuronal communication, neurons with more correlated activity predicted greater computation, suggesting that correlated activity does support computation in cortical circuits. Importantly, this result reversed at timescales less relevant to direct neuronal communication, where even greater correlated activity predicted decreased computation. Thus, the relationship between correlated activity and computation depends on the timescale and the degree of correlation in neuronal interactions.

Spontaneous emission from excitonic transitions in InAs/GaAs quantum dots embedded in photonic crystal waveguides at 5K into non-guided and guided modes is determined by direct hyperspectral imaging. This enables measurement of the absolute coupling efficiency into the guided modes, the beta-factor, directly, without assumptions on decay rates used previously. Notably, we found beta-factors above 90% over a wide spectral range of 40meV in the fast light regime, reaching a maximum of (99 $\pm$ 1)%. We measure the directional emission of the circularly polarized transitions in a magnetic field into counter-propagating guided modes, to deduce the mode circularity at the quantum dot sites. We find that points of high directionality, up to 97%, correlate with a reduced beta-factor, consistent with their positions away from the mode field antinode. By comparison with calibrated finite-difference time-domain simulations, we use the emission energy, mode circularity and beta-factor to estimate the quantum dot position inside the photonic crystal waveguide unit cell.

Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), chemicals present in a multitude of consumer products, are persistent organic pollutants. Both compounds induce hepatotoxic effects in rodents, including steatosis, hepatomegaly and liver cancer. The mechanisms of PFOA- and PFOS-induced hepatic dysfunction are not completely understood. We present evidence that PFOA and PFOS induce their hepatic effects via targeting hepatocyte nuclear factor 4-alpha (HNF4α). Human hepatocytes treated with PFOA and PFOS at a concentration relevant to occupational exposure caused a decrease in HNF4α protein without affecting HNF4α mRNA or causing cell death. RNA sequencing analysis combined with Ingenuity Pathway Analysis of global gene expression changes in human hepatocytes treated with PFOA or PFOS indicated alterations in the expression of genes involved in lipid metabolism and tumorigenesis, several of which are regulated by HNF4α. Further investigation of specific HNF4α target gene expression revealed that PFOA and PFOS could promote cellular dedifferentiation and increase cell proliferation by down regulating positive targets (differentiation genes such as CYP7A1) and inducing negative targets of HNF4α (pro-mitogenic genes such as CCND1). Furthermore, in silico docking simulations indicated that PFOA and PFOS could directly interact with HNF4α in a similar manner to endogenous fatty acids. Collectively, these results highlight HNF4α degradation as novel mechanism of PFOA and PFOS-mediated steatosis and tumorigenesis in human livers.

Hepatocellular carcinoma (HCC) is the most common hepatic malignancy and the third leading cause of cancer related deaths. Previous studies have implicated bile acids in pathogenesis of HCC, but the mechanisms are not known. We investigated the mechanisms of HCC tumor promotion by bile acids the diethylnitrosamine (DEN)-initiation-cholic acid (CA)-induced tumor promotion protocol in mice. The data show that 0.2% CA treatment resulted in threefold increase in number and size of DEN-induced liver tumors. All tumors observed in DEN-treated mice were well-differentiated HCCs. The HCCs observed in DEN-treated CA-fed mice exhibited extensive CD3-, CD20-, and CD45-positive inflammatory cell aggregates. Microarray-based global gene expression studies combined with Ingenuity Pathway Analysis revealed significant activation of NF-κB and Nanog in the DEN-treated 0.2% CA-fed livers. Further studies showed significantly higher TNF-α and IL-1β mRNA, a marked increase in total and phosphorylated-p65 and phosphorylated IκBα (degradation form) in livers of DEN-treated 0.2% CA-fed mice. Treatment of primary mouse hepatocytes with various bile acids showed significant induction of stemness genes including Nanog, KLF4, Sox2, and Oct4. Quantification of total and 20 specific bile acids in liver, and serum revealed a tumor-associated bile acid signature. Finally, quantification of total serum bile acids in normal, cirrhotic, and HCC human samples revealed increased bile acids in serum of cirrhotic and HCC patients. Taken together, these data indicate that bile acids are mechanistically involved pathogenesis of HCC and may promote HCC formation via activation of inflammatory signaling.

Koebnerization of pemphigus vulgaris (PV) is an infrequently reported reaction. We present a 65-year-old man with Koebnerized pemphigus vulgaris after Mohs microscopic surgery for a basal cell carcinoma. We present this case to heighten awareness of the phenomenon in the dermatological community.

Accurately predicting the risk of future sexual offending posed by individuals is a key task within the criminal justice system, providing vital information to inform treatment planning and sentence management. In particular, risk prediction plays an important role in ensuring that a balance is struck between minimizing risk to the public and supporting self-improvement and change amongst individuals who have committed sexual offences. Although risk prediction is therefore widely utilized in criminal justice and rehabilitation settings, there are a number of theoretical and practical issues that are yet to be addressed regarding its use. These issues include the validity and generalizability of prediction tools, the indistinct nature of measured risk factors, and how to appropriately incorporate treatment change into the prediction of future behaviour. We hope that the discussion of these issues will prompt further thinking regarding the current role of risk prediction in treatment and sentence management and encourage further research to address these challenges.

To understand how neural circuits process information, it is essential to identify the relationship between computation and circuit topology. Rich-clubs, highly interconnected sets of neurons, are known to propagate a disproportionate amount of information within cortical circuits. Here, we test the hypothesis that rich-clubs also perform a disproportionate amount of computation. To do so, we recorded the spiking activity of on average ∼300 well-isolated individual neurons from organotypic cortical cultures. We then constructed weighted, directed networks reflecting the effective connectivity between the neurons. For each neuron, we quantified the amount of computation it performed based on its inputs. We found that rich-club neurons compute ∼200% more information than neurons outside of the rich club. Indeed, the amount of computation performed in the rich-club was proportional to the amount information propagation by the same neurons. This suggests that, in these circuits, information propagation drives computation. Comparing the computation-to-propagation ratio inside versus outside of the rich club showed that rich clubs compute at a slightly, though significantly, reduced level (∼4% lower). In total, our findings indicate that rich club topology in effective cortical circuits supports not only information propagation but also neural computation.AUTHOR SUMMARYHere we answer the question of whether rich club topology in functional cortical circuits supports neural computation as it has been previously shown to do for information propagation. To do so, we combined network analysis with information theoretic tools to analyze the spiking activity of hundreds of neurons recorded from organotypic cultures of mouse somatosensory cortex. We found that neurons in rich clubs computed significantly more than neurons outside of rich clubs, suggesting that rich-clubs do support computation in cortical circuits. Indeed, the amount of computation that we found in the rich club was proportional to the amount of information they propagate suggesting that, in these circuits, information propagation drives computation.

We examined the use of the clinically significant change (CSC) method with the Violence Risk Scale-Sexual Offender version (VRS-SO), and its implications for risk communication, in a combined sample of 945 treated sexual offenders from three international settings, followed up for a minimum 5 years post-release. The reliable change (RC) index was used to identify thresholds of clinically meaningful change and to create four CSC groups (already okay, recovered, improved, unchanged) based on VRS-SO dynamic scores and amount of change made. Outcome analyses demonstrated important CSC-group differences in 5-year rates of sexual and violent recidivism. However, when baseline risk was controlled via Cox regression survival analysis, the pattern and magnitude of CSC-group differences in sexual and violent recidivism changed to suggest that observed variation in recidivism base rates could be at least partly explained by pre-existing group differences in risk level. Implications for communication of risk-change information and applications to clinical practice are discussed. Copyright © 2015 John Wiley & Sons, Ltd. Language: en

Although relationships between networks of different scales have been observed in macroscopic brain studies, relationships between structures of different scales in networks of neurons are unknown. To address this, we recorded from up to 500 neurons simultaneously from slice cultures of rodent somatosensory cortex. We then measured directed effective networks with transfer entropy, previously validated in simulated cortical networks. These effective networks enabled us to evaluate distinctive nonrandom structures of connectivity at 2 different scales. We have 4 main findings. First, at the scale of 3–6 neurons (clusters), we found that high numbers of connections occurred significantly more often than expected by chance. Second, the distribution of the number of connections per neuron (degree distribution) had a long tail, indicating that the network contained distinctively high-degree neurons, or hubs. Third, at the scale of tens to hundreds of neurons, we typically found 2–3 significantly large communities. Finally, we demonstrated that communities were relatively more robust than clusters against shuffling of connections. We conclude the microconnectome of the cortex has specific organization at different scales, as revealed by differences in robustness. We suggest that this information will help us to understand how the microconnectome is robust against damage.

Recent work has shown that functional connectivity among cortical neurons is highly varied, with a small percentage of neurons having many more connections than others. Also, recent theoretical developments now make it possible to quantify how neurons modify information from the connections they receive. Therefore, it is now possible to investigate how information modification, or computation, depends on the number of connections a neuron receives (in-degree) or sends out (out-degree). To do this, we recorded the simultaneous spiking activity of hundreds of neurons in cortico-hippocampal slice cultures using a high-density 512-electrode array. This preparation and recording method combination produced large numbers of neurons recorded at temporal and spatial resolutions that are not currently available in any in vivo recording system. We utilized transfer entropy (a well-established method for detecting linear and nonlinear interactions in time series) and the partial information decomposition (a powerful, recently developed tool for dissecting multivariate information processing into distinct parts) to quantify computation between neurons where information flows converged. We found that computations did not occur equally in all neurons throughout the networks. Surprisingly, neurons that computed large amounts of information tended to receive connections from high out-degree neurons. However, the in-degree of a neuron was not related to the amount of information it computed. To gain insight into these findings, we developed a simple feedforward network model. We found that a degree-modified Hebbian wiring rule best reproduced the pattern of computation and degree correlation results seen in the real data. Interestingly, this rule also maximized signal propagation in the presence of network-wide correlations, suggesting a mechanism by which cortex could deal with common random background input. These are the first results to show that the extent to which a neuron modifies incoming information streams depends on its topological location in the surrounding functional network., Author Summary We recorded the electrical activity of hundreds of neurons simultaneously in brain tissue from mice and we analyzed these signals using state-of-the-art tools from information theory. These tools allowed us to ascertain which neurons were transmitting information to other neurons and to characterize the computations performed by neurons using the inputs they received from two or more other neurons. We found that computations did not occur equally in all neurons throughout the networks. Surprisingly, neurons that computed large amounts of information tended to be recipients of information from neurons with a large number of outgoing connections. Interestingly, the number of incoming connections to a neuron was not related to the amount of information that neuron computed. To better understand these results, we built a network model to match the data. Unexpectedly, the model also maximized information transfer in the presence of network-wide correlations. This suggested a way that networks of cortical neurons could deal with common random background input. These results are the first to show that the amount of information computed by a neuron depends on where it is located in the surrounding network.

Objective: To determine whether pro-social treatment change in sexual offenders would predict reductions in recidivism beyond static and dynamic risk factors measured at pretreatment and whether different methods for assessing change based on self-reports and structured clinical rating systems would show convergent validity. Method: We compared 3 methods for assessing treatment change with a sample of adult male sexual offenders against children (n = 218) who completed a prison-based cognitive-behavioral treatment program between 1993 and 2000. The methods were measures of change derived from offender self-reports on a psychometric battery administered both pre- and posttreatment, change across treatment on the Violence Risk Scale: Sexual Offender Version (VRS:SO; Olver, Wong, Nicholaichuk, & Gordon, 2007), and posttreatment ratings on the Standard Goal Attainment Scaling for Sex Offenders (SGAS; Hogue, 1994). Offenders were followed up for an average of 12.24 years after release. Results: All measures of treatment gain were positively correlated, and all significantly predicted reductions in sexual recidivism, with values for the area under the receiver-operating characteristic curve ranging from .66 (SGAS) to .70 (VRS:SO). Survival analyses showed that measures of change based on the psychometric battery significantly predicted recidivism after controlling for both static and dynamic factors measured at pretreatment, while results for the VRS:SO were similar but failed to reach significance. Conclusions: Measures of treatment change based on offender self-reports and structured clinical rating systems show convergent and predictive validity, which suggests that effective treatment that targets dynamic risk factors leads to a reduction in sexual recidivism. (PsycINFO Database Record (c) 2011 APA, all rights reserved). Language: en

Some forms of epilepsy may arise as a result of pathologic interactions among neurons. Many forms of collective activity have been identified, including waves, spirals, oscillations, synchrony, and neuronal avalanches. All these emergent activity patterns have been hypothesized to show pathologic signatures associated with epilepsy. Here, the authors used 60-channel multielectrode arrays to record neuronal avalanches in cortical tissue removed from juvenile epilepsy patients. For comparison, they also recorded activity in rat cortical slices. The authors found that some human tissue removed from epilepsy patients exhibited prolonged periods of hyperactivity not seen in rat slices. In addition, they found a positive correlation between the branching parameter, a measure of network gain, and firing rate in human slices during periods of hyperactivity. This relationship was not present in rat slices. The authors suggest that this positive correlation between the branching parameter and the firing rate is part of a positive feedback loop and may contribute to some forms of epilepsy. These results also indicate that neuronal avalanches are abnormally regulated in slices removed from pediatric epilepsy patients.

Therapy employing the fluoroquinolone antibiotic, trovafloxacin (TVX) was curtailed due to idiosyncratic hepatotoxicity. Previous studies in mice showed that a nonhepatotoxic inflammatory stress induced by tumor necrosis factor alpha (TNF) synergized with a nonhepatotoxic dose of TVX to cause liver injury. The purpose of this study was to explore mechanisms by which TVX interacts with TNF to cause liver injury. TVX pretreatment prolonged the peak of plasma TNF after its administration. This prolongation of TNF by TVX was critical to the development of hepatotoxicity. The prolongation of TNF concentration in plasma was primarily due to reduced clearance when compared with secondary biosynthesis. TNF is cleared from plasma by binding to soluble TNF receptors (TNFRs) which are eliminated by the kidney; however, the plasma concentrations of soluble TNFRs were not reduced, and biomarkers of renal dysfunction were not elevated in TVX/TNF-treated mice. Two injections of TNF mimicked the prolongation of the TNF peak by TVX and caused liver injury, but injury was less severe than after TVX/TNF coexposure. TVX enhanced the induction of proinflammatory cytokines by TNF. Additionally, TVX sensitized Hepa1c1c7 cells to TNF-induced killing in a concentration-dependent manner and increased both potency and efficacy of TNF to activate effector caspases that were critically involved in cell death from TVX/TNF coexposure. In summary, TVX reduced the clearance of TNF independent of either receptor shedding or kidney dysfunction. Additionally, TVX interacted with TNF to enhance inflammation and sensitize hepatocytes to TNF-induced cell death.

Plasticity is central to the ability of a neural system to learn and also to its ability to develop spontaneous seizures. What is the connection between the two? Learning itself is known to be a destabilizing process at the algorithmic level. We have investigated necessary constraints on a spontaneously active Hebbian learning system and find that the ability to learn appears to confer an intrinsic vulnerability to epileptogenesis on that system. We hypothesize that epilepsy arises as an abnormal learned response of such a system to certain repeated provocations. This response is a network-level effect. If epilepsy really is a learned response, then it should be possible to reverse it, that is, to unlearn epilepsy. Unlearning epilepsy may then provide a new approach to its treatment.

The authors studied the relationships between psychopathy, intelligence, and offending in a sample of treated child molesters ( N = 216). Regression analyses showed that psychopathy (as measured by the Psychopathy Checklist—Revised) was strongly related to both offense history and recidivism during follow-up. Intelligence (assessed using four-subtest short forms of the Wechsler Adult Intelligence Scale—Revised and Third Versions) was not related to offending. However, there was a significant interaction between intelligence and psychopathy on recidivism: Offenders with relatively low intelligence and high psychopathy scores were more than 4 times as likely to have received a sexual reconviction as other offenders. Results are discussed in terms of implications for risk assessment.

The performance of complex networks, like the brain, depends on how effectively their elements communicate. Despite the importance of communication, it is virtually unknown how information is transferred in local cortical networks, consisting of hundreds of closely spaced neurons. To address this, it is important to record simultaneously from hundreds of neurons at a spacing that matches typical axonal connection distances, and at a temporal resolution that matches synaptic delays. We used a 512-electrode array (60 μm spacing) to record spontaneous activity at 20 kHz from up to 500 neurons simultaneously in slice cultures of mouse somatosensory cortex for 1 h at a time. We applied a previously validated version of transfer entropy to quantify information transfer. Similar toin vivoreports, we found an approximately lognormal distribution of firing rates. Pairwise information transfer strengths also were nearly lognormally distributed, similar to reports of synaptic strengths. Some neurons transferred and received much more information than others, which is consistent with previous predictions. Neurons with the highest outgoing and incoming information transfer were more strongly connected to each other than chance, thus forming a “rich club.” We found similar results in networks recordedin vivofrom rodent cortex, suggesting the generality of these findings. A rich-club structure has been found previously in large-scale human brain networks and is thought to facilitate communication between cortical regions. The discovery of a small, but information-rich, subset of neurons within cortical regions suggests that this population will play a vital role in communication, learning, and memory.SIGNIFICANCE STATEMENTMany studies have focused on communication networks between cortical brain regions. In contrast, very few studies have examined communication networks within a cortical region. This is the first study to combine such a large number of neurons (several hundred at a time) with such high temporal resolution (so we can know the direction of communication between neurons) for mapping networks within cortex. We found that information was not transferred equally through all neurons. Instead, ∼70% of the information passed through only 20% of the neurons. Network models suggest that this highly concentrated pattern of information transfer would be both efficient and robust to damage. Therefore, this work may help in understanding how the cortex processes information and responds to neurodegenerative diseases.

Metastasis is the primary cause of death in breast cancer. Earlier studies using a mammary tumorigenesis mouse model identified Necdin (Ndn) as a germline modifier of metastasis. Differential expression of Ndn induces a gene-expression signature that predicts prognosis in human breast cancer. Additionally, a non-synonymous germline single nucleotide polymorphism (T50C; V17A) in Ndn distinguishes mouse strains with differing metastatic capacities. To better understand how hereditary factors influence metastasis in breast cancer, we characterized NDN-mediated transcription. Haplotype analysis in a well-characterized breast cancer cohort revealed that NDN germline variation is associated with both NDN expression levels and patient outcome. To examine the role of NDN in mammary tumor metastasis and transcriptional regulation, mouse mammary tumor cell lines stably over-expressing either the wildtype 50T or variant 50C Ndn allele were generated. Cells over-expressing Ndn 50T, but not Ndn 50C, exhibited significant decrease in cell invasiveness and pulmonary metastases compared to control cells. Transcriptome analyses identified a 71-gene expression signature that distinguishes cells over-expressing the two Ndn allelic variants. Furthermore, ChIP assays revealed c-Myc, a target gene of NDN, to be differentially regulated by the allelic variants. These data demonstrate that NDN and the T50C allele regulate gene expression and metastasis efficiency.

Understanding the detailed circuitry of functioning neuronal networks is one of the major goals of neuroscience. Recent improvements in neuronal recording techniques have made it possible to record the spiking activity from hundreds of neurons simultaneously with sub-millisecond temporal resolution. Here we used a 512-channel multielectrode array system to record the activity from hundreds of neurons in organotypic cultures of cortico-hippocampal brain slices from mice. To probe the network structure, we employed a wavelet transform of the cross-correlogram to categorize the functional connectivity in different frequency ranges. With this method we directly compare, for the first time, in any preparation, the neuronal network structures of cortex and hippocampus, on the scale of hundreds of neurons, with sub-millisecond time resolution. Among the three frequency ranges that we investigated, the lower two frequency ranges (gamma (30-80 Hz) and beta (12-30 Hz) range) showed similar network structure between cortex and hippocampus, but there were many significant differences between these structures in the high frequency range (100-1000 Hz). The high frequency networks in cortex showed short tailed degree-distributions, shorter decay length of connectivity density, smaller clustering coefficients, and positive assortativity. Our results suggest that our method can characterize frequency dependent differences of network architecture from different brain regions. Crucially, because these differences between brain regions require millisecond temporal scales to be observed and characterized, these results underscore the importance of high temporal resolution recordings for the understanding of functional networks in neuronal systems.

Trovafloxacin (TVX) is a drug that has caused idiosyncratic, drug-induced liver injury (IDILI) in humans. In a murine model of IDILI, otherwise nontoxic doses of TVX and the inflammagen lipopolysaccharide (LPS) interacted to produce pronounced hepatocellular injury. The liver injury depended on a TVX-induced, small but significant prolongation of tumor necrosis factor-α (TNF) appearance in the plasma. The enhancement of TNF expression by TVX was reproduced in vitro in RAW 264.7 murine macrophages (RAW cells) stimulated with LPS. The current study was designed to identify the molecular target of TVX responsible for this response in RAW cells. An in silico analysis suggested a favorable binding profile of TVX to eukaryotic topoisomerase II-α (TopIIα), and a cell-free assay revealed that TVX inhibited eukaryotic TopIIα activity. Topoisomerase inhibition is known to lead to DNA damage, and TVX increased the DNA damage marker phosphorylated histone 2A.X in RAW cells. Moreover, TVX induced activation of the DNA damage sensor kinases, ataxia telangiectasia mutated (ATM) and Rad3-related (ATR). The ATR inhibitor NU6027 [6-(cyclohexylmethoxy)-5-nitrosopyrimidine-2,4-diamine] prevented the TVX-mediated increases in LPS-induced TNF mRNA and protein release, whereas a selective ATM inhibitor [2-(4-morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one (KU55933)] was without effect. TVX prolonged TNF mRNA stability, and this effect was largely attenuated by NU6027. These results suggest that TVX can inhibit eukaryotic topoisomerase, leading to activation of ATR and potentiation of TNF release by macrophages, at least in part through increased mRNA stability. This off-target effect might contribute to the ability of TVX to precipitate IDILI in humans.

Should HIV/AIDS testing be required for health care workers and patients? This study compared the perceptions of 64 health care professionals and 97 nursing students on mandatory HIV testing, the risk of accidental infection, the appropriate industry response to infection, and the placement of costs. Significant differences were found between the two groups. While health care professionals favored testing for patients, students favored mandatory testing for both health care workers and patients. Students also viewed the risk of HIV/AIDS infection by a patient as significantly higher than did health care workers. Overall younger respondents tended to favor mandatory testing and also thought that hospitals should bear the cost.

Layer II/III of rat perirhinal cortex (PR) contains numerous late-spiking (LS) pyramidal neurons. When injected with a depolarizing current step, these LS cells typically delay spiking for one or more seconds from the onset of the current step and then sustain firing for the duration of the step. This pattern of delayed and sustained firing suggested a specific computational role for LS cells in temporal learning. This hypothesis predicts and requires that some layer II/III neurons should also exhibit delayed and sustained spiking in response to a train of excitatory synaptic inputs. Here we tested this prediction using visually guided, whole cell recordings from rat PR brain slices. Most LS cells (19 of 26) exhibited delayed spiking to synaptic stimulation (>1 s latency from the train onset), and the majority of these cells (13 of 19) also showed sustained firing that persisted for the duration of the synaptic train (5–10 s duration). Delayed and sustained firing in response to long synaptic trains has not been previously reported in vertebrate neurons. The data are consistent with our model that a circuit containing late spiking neurons can be used for encoding long time intervals during associative learning.

It has been notoriously difficult to understand interactions in the basal ganglia because of multiple recurrent loops. Another complication is that activity there is strongly dependent on behavior, suggesting that directional interactions, or effective connections, can dynamically change. A simplifying approach would be to examine just the direct, monosynaptic projections from cortex to striatum and contrast this with the polysynaptic feedback connections from striatum to cortex. Previous work by others on effective connectivity in this pathway indicated that activity in cortex could be used to predict activity in striatum, but that striatal activity could not predict cortical activity. However, this work was conducted in anesthetized or seizing animals, making it impossible to know how free behavior might influence effective connectivity. To address this issue, we applied Granger causality to local field potential signals from cortex and striatum in freely behaving rats. Consistent with previous results, we found that effective connectivity was largely unidirectional, from cortex to striatum, during anesthetized and resting states. Interestingly, we found that effective connectivity became bidirectional during free behaviors. These results are the first to our knowledge to show that striatal influence on cortex can be as strong as cortical influence on striatum. In addition, these findings highlight how behavioral states can affect basal ganglia interactions. Finally, we suggest that this approach may be useful for studies of Parkinson's or Huntington's diseases, in which effective connectivity may change during movement.

Idiosyncratic drug-induced liver injury (IDILI) continues to be a significant human health problem. IDILI is characterized as occurring in a minority of individuals exposed to a drug, yet it accounts for as much as 17% of all cases of acute liver failure. Despite these concerns, the mechanisms underlying IDILI remain unknown. Trovafloxacin (TVX), which causes IDILI in humans, also causes hepatocellular death in vitro when combined with tumor necrosis factor-alpha (TNF) treatment. However, the molecular mechanisms involved in this toxicity are not fully characterized. The purpose of this study was to identify mechanisms by which TVX and TNF interact to cause hepatocellular death, with a focus on a human hepatocyte cell line. TVX and TNF interacted to cause cytotoxicity in HepG2 cells at drug concentrations similar to those in people undergoing TVX therapy. TVX/TNF treatment caused apoptosis and DNA damage in HepG2 cells that depended on caspase activation. Prolonged activation of JNK occurred in TVX/TNF-induced cytotoxicity, and treatment with the JNK selective inhibitor SP600125 attenuated cytotoxicity. TVX/TNF cotreatment also caused cytotoxicity in isolated primary murine hepatocytes that was dependent on caspase activation. These results increase understanding of molecular signaling pathways involved in hepatocellular death caused by a drug with idiosyncratic liability in the presence of TNF.

Through a phenomenological perspective, this study describes the experiences of home health aides caring for people with acquired immunodeficiency syndrome. Six home health aides were asked the question, "What is it like to be a home health aide caring for persons with acquired immunodeficiency syndrome?" The essential meanings uncovered from this study were empathy, being there, self-reflection, support and communication, and coping. This research study about home health aides caring for persons with acquired immunodeficiency syndrome will help nursing develop additional programs to educate and support the home health aide in this experience.

The intrinsic membrane properties of perirhinal cortical neurons were studied by intracellular recording in in vitro rat brain slices. Gross morphology was also examined through injection of the fluorescent dye carboxyfluorescein. The cells encountered displayed a diversity of electrophysiological properties, and were similar to cells reported in other neocortical areas with regard to spiking patterns, afterpotentials, and morphology. However, very few (4%) intrinsically bursting neurons were encountered. Two pyramidal cells with thick apical dendrites were filled, and both fired doublets of action potentials for their first suprathreshold events. Of the filled pyramidal cells with thin apical dendrites, most (9/11) fired single action potentials for their first suprathreshold events. A variety of classification schemes were used to group the data, and several schemes were found to be equally successful. According to one of the schemes, cells recorded with carboxyfluorescein filled electrodes had significantly greater action potential widths at half-amplitude and more depolarized resting potentials than cells recorded without this dye.

In 2008, a group of clinicians, scientists, engineers, and industry representatives met to discuss advances in the application of engineering technologies to the diagnosis and treatment of patients with epilepsy. The presentations also provided a guide for further technological development, specifically in the evaluation of patients for epilepsy surgery, seizure onset detection and seizure prediction, intracranial treatment systems, and extracranial treatment systems. This article summarizes the discussions and demonstrates that cross-disciplinary interactions can catalyze collaborations between physicians and engineers to address and solve many of the pressing unmet needs in epilepsy.

Sulindac (SLD) is a nonsteroidal anti-inflammatory drug (NSAID) that has been associated with a greater incidence of idiosyncratic hepatotoxicity in human patients than other NSAIDs. In previous studies, cotreatment of rats with SLD and a modestly inflammatory dose of lipopolysaccharide (LPS) led to liver injury, whereas neither SLD nor LPS alone caused liver damage. In studies presented here, further investigation of this animal model revealed that the concentration of tumor necrosis factor-alpha (TNF-alpha) in plasma was significantly increased by LPS at 1 h, and SLD enhanced this response. Etanercept, a soluble TNF-alpha receptor, reduced SLD/LPS-induced liver injury, suggesting a role for TNF-alpha. SLD metabolites in plasma and liver were determined by LC/MS/MS. Cotreatment with LPS did not increase the concentrations of SLD or its metabolites, excluding the possibility that LPS contributed to liver injury through enhanced exposure to SLD or its metabolites. The cytotoxicities of SLD and its sulfide and sulfone metabolites were compared in primary rat hepatocytes and HepG2 cells; SLD sulfide was more toxic in both types of cells than SLD or SLD sulfone. TNF-alpha augmented the cytotoxicity of SLD sulfide in primary hepatocytes and HepG2 cells. These results suggest that TNF-alpha can enhance SLD sulfide-induced hepatotoxicity, thereby contributing to liver injury in SLD/LPS-cotreated rats.

SUMMARY 1 Our goal was to investigate the body distribution of serotonin (5-hydroxytryptamine; 5-HT) in rats infused with 5-HT (25 µg/kg per min) for 7 days and the contribution of the 5-HT transporter (SERT) for 5-HT uptake into the tissues. 2 Mini-osmotic pumps containing 5-HT or vehicle were implanted in rats knocked out for SERT (SERT-KO) or in wild-type (WT) rats. On the 8th day, tissues were harvested for measurements of 5-HT by high-performance liquid chromatography (HPLC). The 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA) was also measured by HPLC, because an increase in 5-HIAA in tissues from rats receiving 5-HT reflects 5-HT uptake followed by metabolism. 3 In WT rats infused with 5-HT, an increase in 5-HT or 5-HIAA was observed in the heart, pancreas, thyroid, adrenal gland, kidney, seminal vesicle, bladder, prostate, liver, oesophagus, stomach, femur, trachea, lung and spleen compared with vehicle-infused rats. An increase in 5-HT and 5-HIAA was not observed in aorta, vena cava and jejunum. In tissues from SERT-KO rats infused with 5-HT, the content of 5-HT or 5-HIAA was decreased in most of the tissues studied compared with 5-HT-infused WT rats. Although 5-HT uptake in the kidney, seminal vesicle, prostate, jejunum and trachea is SERT dependent, it is SERT independent in the pancreas. The remaining tissues display SERT-dependent and -independent mechanisms for 5-HT uptake. 4 Altogether, tissues from different systems, such as the cardiovascular, endocrine, genitourinary and gastrointestinal, accumulate 5-HT mainly via SERT and, thus, these systems are potential targets for drugs that interfere with 5-HT homeostasis.

Plasmid pLUC10, carrying the firefly luciferase gene, was transformed by electroporation into Mycobacterium avium A5. Bioluminescence production by strain A5(pLUC10), as measured in a microdilution plate luminometer, was approximately 1 relative light unit per 2 x 10(6) viable bacilli, whereas it was 0.0005 relative light unit for an equal number of parental cells. The susceptibility of strain A5(pLUC10) to eight concentrations of each of eight antimicrobial agents was evaluated by the luciferase microplate assay in parallel with a conventional broth macrodilution method with antimicrobial agents. Decreases in bioluminescence to levels that were < or = 10% of those of drug-free controls were observed in microplate wells containing inhibitory concentrations of drugs in as few as 3 days. The close correlation of these inhibitory concentrations with the MICs determined by a conventional broth macrodilution method suggests that the luciferase microplate method may offer a convenient and reliable means of evaluating the in vitro activities of antimicrobial agents against the M. avium complex.

Multi-microelectrode array devices can be used to simultaneously record activity from multiple neurons distributed in a tissue slice. One of the brain functions being investigated with microelectrode arrays is the periodic behavior of spontaneously active neurons in the cortex and basal ganglia.. However, these recording methods generate several hundred megabytes of data per hour and, currently, there is no efficient and accurate approach for the identification of the repeated pattern. We present an approach that uses the discrete wavelet transform to accelerate identification of repeating patterns of neural activity. We perform match filtering on the coefficient data, not the time-domain data. Our wavelet approach operates on 1/4 the data but provides similar classification abilities as the time domain correlation.

Recent studies have emphasized the importance of multiplex networks – interdependent networks with shared nodes and different types of connections – in systems primarily outside of neuroscience. Though the multiplex properties of networks are frequently not considered, most networks are actually multiplex networks and the multiplex specific features of networks can greatly affect network behavior (e.g. fault tolerance). Thus, the study of networks of neurons could potentially be greatly enhanced using a multiplex perspective. Given the wide range of temporally dependent rhythms and phenomena present in neural systems, we chose to examine multiplex networks of individual neurons with time scale dependent connections. To study these networks, we used transfer entropy – an information theoretic quantity that can be used to measure linear and nonlinear interactions – to systematically measure the connectivity between individual neurons at different time scales in cortical and hippocampal slice cultures. We recorded the spiking activity of almost 12,000 neurons across 60 tissue samples using a 512-electrode array with 60 micrometer inter-electrode spacing and 50 microsecond temporal resolution. To the best of our knowledge, this preparation and recording method represents a superior combination of number of recorded neurons and temporal and spatial recording resolutions to any currently available in vivo system. We found that highly connected neurons (“hubs”) were localized to certain time scales, which, we hypothesize, increases the fault tolerance of the network. Conversely, a large proportion of non-hub neurons were not localized to certain time scales. In addition, we found that long and short time scale connectivity was uncorrelated. Finally, we found that long time scale networks were significantly less modular and more disassortative than short time scale networks in both tissue types. As far as we are aware, this analysis represents the first systematic study of temporally dependent multiplex networks among individual neurons.

Networks of cortical neurons are essentially non-random [1]. Although it is known that such networks show interesting structure at multiple temporal and spatial scales [2], almost no experimental work has been done to reveal how structures at these different scales relate to each other. This study aimed to clarify important relations between non-randomness in groups of 3-6 neurons (clusters) and non-randomness in groups of 50-100 neurons (communities) through five steps. First, we recorded spontaneous activity of up to 500 neurons from rodent somatosensory cortex using a 512ch. multi-electrode system over one hour [3]. Second, we reconstructed effective connectivity using transfer entropy [4]. Third, we compared topologies of effective networks at the 3-6 neuron scale (clusters including motifs [Figure1-B]) with topologies of synaptic connections measured from 12 neuron simultaneous patch clamp experiments [5,6]. Fourth, we constructed community or modular structures representing non-randomness from larger groups of neurons. Fifth, we evaluated the extent to which structure at each of these scales was robust. We did this by swapping connections from high degree nodes (hubs) with those from low degree nodes (non-hubs). Figure 1 (A) An example of spatial distribution of neurons and effective connections. Different markers indicate different communities. The biggest two communities are covered by blue and red regions. Upper-right yellow region is an example cluster of 6 neurons. ... We found three things. First, the degree-distribution followed a power-law This demonstrated that hubs could not have been the result of random sampling from a Gaussian distribution. Second, effective networks consisting of hundreds of cortical neurons have distinctive non-random structures of connectivity at two different scales. Third, structure at the cluster level was relatively more fragile than structure at the community level. The difference between non-randomness evaluated by cluster and community will become the important first step to understand multiple different scales of cortical neuronal networks.

Introduction Epileptogenicity of neuronal tissues requires both altered excitability and altered synchronization of neurons. However, the network-level mechanisms responsible for neuronal hyperexcitability and synchronization remain unknown, and there is much to learn regarding how even small networks of neurons interact. The present study examines local and network properties of cortical neurons from epileptogenic human and excited (“epileptic”) rat cortex. Methods Epileptogenic cortex was harvested from pediatric patients with medically refractory seizures undergoing resective surgery. Local field potential signals (LFPs) were recorded continuously for up to several hours with a 60-channel microelectrode array. We also recorded LFPs from slices and organotypic and dissociated cultures of rat cortex bathed in high K+ and low Mg++. We then compared the human and rat data, applied a second-order maximum entropy model (MEM) to the data, and explored how well the MEM predicted sequences of correlated states over time. Results Both human and rat cortex produced LFP signals in the form of interictal spikes on almost all electrodes. However, only human cortex demonstrated spontaneous activity in normal cerebrospinal fluid, and the LFPs from human cortex showed greater synchrony across electrodes than the rat LFPs. Moreover, when a second-order MEM was applied to human and rat data, the model accounted for roughly 88% of network correlations. However, in 8/13 preparations the observed sequences of correlated states were significantly longer than predicted by independently concatenating states from the model, suggesting that temporal dependencies are a common feature of cortical network activity. Conclusion Excited slices of rat cortex fail to capture some important features of network activity found in epileptogenic human cortex. Furthermore, a second-order MEM successfully predicts correlated states in cortical networks, but not their evolution over time. Thus, higher-order MEMs are necessary to account for temporal correlations observed between states.

Necdin (NDN) is a transcription factor that regulates gene expression by cooperating with chromatin modifying factors. Earlier studies using mouse models of mammary tumorigenesis identified Ndn as a metastasis efficiency modifier that exerts its influence at the germline level. Differential expression of Ndn induces a gene expression signature that accurately predicts prognosis in human breast cancer. Mouse Ndn contains a non-synonymous germline single nucleotide polymorphism (SNP) (T50C; V17A) that distinguishes mouse strains with differing susceptibilities to mammary tumor metastasis. The aim of this study is to characterize how germline variation in Ndn regulates metastasis-associated transcription to enhance our understanding of how hereditary factors influence metastasis in breast cancer. We hypothesize that NDN, a known transcription factor, induces metastasis-predictive gene expression by interacting with chromatin to regulate transcription, and that Ndn coding variants differ in their capacity in regulating the transcription of target genes. To confirm the role of NDN in human breast cancer, haplotype analysis was performed in a population cohort consisting of 956 breast cancer patients. These analyses revealed that a two marker SNP haplotype in linkage disequilibrium with NDN is significantly associated with survival (P=0.0002). We examined the role of NDN in mammary tumor metastasis and transcriptional regulation by using cells stably over-expressing either the wildtype 17V or the variant 17A Ndn alleles in the highly metastatic Mvt-1 and 4T1 mouse mammary tumor cell lines. Orthotopic implantation of these cells into the mammary fat pad of NU/J and BALB/cJ mice demonstrated that cells expressing the wildtype Ndn 17V allele exhibit a significant decrease in pulmonary metastases compared to cells transduced with an empty vector control. However, these metastasis suppressive properties of Ndn were consistently lost in cells ectopically expressing the variant Ndn 17A allele, demonstrating a prominent role for this SNP in regulation of metastasis efficiency. Soft agar assays confirmed these results in vitro as well as, where a two-fold decrease in cell invasiveness was observed with the wildtype Ndn 17V allele compared to the control and cells over-expressing the variant Ndn 17A allele. Furthermore, microarray analyses revealed that a 71-gene expression signature accurately distinguished cells expressing the two Ndn allelic variants demonstrating that this SNP plays a significant part in gene regulation as well. These data collectively demonstrate that Ndn functions as a germline metastasis modifier, most likely by regulating gene expression at the transcriptional level. Additionally, our work illustrates that the Ndn V17A SNP plays a significant role in both metastasis and transcriptional regulation. Our ongoing work is focused on defining the mechanism of action of Ndn V17A SNP using ChIP-seq to identify target genes and pathways responsible for the profound influence of Ndn allelic variants on metastatic efficiency. Citation Format: Minnkyong Lee, Sarah M. Beggs, Jens Lichtenberg, Sujata B. Bupp, Niraj S. Trivedi, Ying Hu, David M. Bodine, Nigel P.S. Crawford. A germline polymorphism in Necdin causes changes in gene expression and mammary tumor metastasis. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C21.

Transfer entropy (TE) is an information-theoretic measure which has received recent attention in neuroscience for its potential to identify effective connectivity between neurons. Calculating TE for large ensembles of spiking neurons is computationally intensive, and has caused most investigators to probe neural interactions at only a single time delay and at a message length of only a single time bin. This is problematic, as synaptic delays between cortical neurons, for example, range from one to tens of milliseconds. In addition, neurons produce bursts of spikes spanning multiple time bins. To address these issues, here we introduce a free software package that allows TE to be measured at multiple delays and message lengths. To assess performance, we applied these extensions of TE to a spiking cortical network model (Izhikevich, 2006) with known connectivity and a range of synaptic delays. For comparison, we also investigated single-delay TE, at a message length of one bin (D1TE), and cross-correlation (CC) methods. We found that D1TE could identify 36% of true connections when evaluated at a false positive rate of 1%. For extended versions of TE, this dramatically improved to 73% of true connections. In addition, the connections correctly identified by extended versions of TE accounted for 85% of the total synaptic weight in the network. Cross correlation methods generally performed more poorly than extended TE, but were useful when data length was short. A computational performance analysis demonstrated that the algorithm for extended TE, when used on currently available desktop computers, could extract effective connectivity from 1 hr recordings containing 200 neurons in ∼5 min. We conclude that extending TE to multiple delays and message lengths improves its ability to assess effective connectivity between spiking neurons. These extensions to TE soon could become practical tools for experimentalists who record hundreds of spiking neurons.

Four mitochondrial marker enzymes were used to show that: (1) high-protein (24%) diet increased the rat liver concentration and content of total branched-chain 2-oxo acid dehydrogenase complex (BCDC) by 31% by increasing mitochondrial specific activity of BCDC; (2) starvation increased the liver concentration of BCDC by 25% by decreasing liver weight; the liver content of mitochondria and the mitochondrial specific activity of BCDC were unchanged; (3) protein-free diet decreased rat liver BCDC concentration and content by 20%, by decreasing the liver concentration and content of mitochondria. Protein-free diet increased liver mitochondrial specific activities of L-glutamate, 2-oxoglutarate and NAD-isocitrate dehydrogenases. The validity of a mitochondrial method for the determination of the liver concentration of BCDC and the percentage in the active form in vivo is confirmed, and improvements are described. The experimental basis of criticisms of its use in this regard by Zhang, Paxton, Goodwin, Shimomura & Harris [(1987) Biochem. J. 246, 625-631] was not confirmed. The finding by Harris, Powell, Paxton, Gillim & Nagae [(1985) Arch. Biochem. Biophys. 243, 542-555], that starvation has no effect on the percentage of BCDC in the active form in rat liver, is confirmed.

The activity of branched-chain 2-oxo acid dehydrogenase kinase was 3-fold greater in extracts of heart mitochondria than in extracts of liver mitochondria from rats fed on normal diet. Feeding rats on a 0%-casein diet for 10 days increased the activity of branched-chain kinase 4-fold in extracts of liver mitochondria and in branched-chain dehydrogenase complex purified from such extracts; starvation (48 h) was without effect. In extract of heart mitochondria, kinase activity was increased 2-fold by feeding on 0%-casein diet and 1.5-fold by 48 h of starvation.

Feeding rats 0% casein diet decreased liver activities of branched-chain ketoacid dehydrogenase complex (active form) and of activator protein (complete within 4 days), and increased activity of branched-chain ketoacid dehydrogenase kinase (complete within 9–10 days). Refeeding normal diet to rats fed 0% casein diet for 10 days resulted in a rapid and partial (approx. 50%) reversal of the above effects within 24 h; complete reversal required 20–30 days of refeeding.