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This paper uses a model of value maximization to derive a condition for the optimal amount of financial leverage to maximize the value of equity for a real estate investment entity. Both untaxed en...

For the constellation of neurologic disorders known as chemotherapy-induced peripheral neuropathy, mechanistic understanding and treatment remain deficient. Here, we present the first evidence that chronic sensory neuropathy depends on nonlinear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism, and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as one potential contributor to sensory neuron dysfunction. Validated measures of sensorimotor behavior in awake, behaving animals revealed dysfunction after chronic chemotherapy treatment was exacerbated by cancer. Notably, errors in precise forelimb placement emerged as a novel behavioral deficit unpredicted by our previous study of chemotherapy alone. These original findings identify novel contributors to peripheral neuropathy and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer. Significance: These findings highlight the need to account for pathobiological interactions between cancer and chemotherapy as a major contributor to neuropathy and will have significant and immediate impact on future investigations in this field.

Understanding of the molecular basis of host cell-miRNA interactions is prerequisite to the successful application of miRNAs as potential therapeutic agents. We studied the morphological and molecular consequences of over expression of three sequence divergent miRNAs previously implicated in the mesenchymal-to-epithelial transition process (MET) in three distinct mesenchymal-like cancer cell lines. The ability of miRNAs to induce morphological changes characteristic of MET positively correlated with induced changes in the expression of genes previously implicated in the process. Variability in the responses of different mesenchymal-like cells to over expression of the same miRNAs was attributable to inherent differences in trans-regulatory profiles pre-disposing these cells to miRNA-induced MET. Collectively our results indicate that miRNA-mediated regulation of MET is a highly integrated process that is significantly modulated by the molecular background of individual cells.

This article proposes an automatically placed and routed methodology for asynchronous single flux quantum (SFQ) circuits using passive transmission line lines and utilizing a commercial electronic design automation (EDA) tool, Cadence Innovus. At the cell level, dual rail SFQ asynchronous cells were developed to be implemented in the place and route methodology. Scripts were written that could convert any single rail netlist synthesized from behavioral Verilog using an EDA tool (such as Design Vision) containing single rail cells into dual rail asynchronous cells. Then, automatic placement and routing using Innovus was achieved through specific cell layout design choices that allowed the finished circuit design layout to pass checks by layout vs schematic and design rule check. Finally, back annotation was performed by reincorporating transmission line lengths from place and route stage in analog simulation to verify correct functionality of the design. As an example, a 4-b arithmetic logic unit design is used to illustrate the various stages of the methodology.

Summary Recent findings indicate that changes underlying cancer onset and progression are not only attributable to changes in DNA structure and expression of individual genes but to changes in interactions among these genes as well. We examined co-expression changes in gene-network structure occurring during the onset and progression of nine different cancer types. Network complexity is generally reduced in the transition from normal precursor tissues to corresponding primary tumors. Cross-tissue cancer network similarity generally increases in early-stage cancers followed by a subsequent loss in cross-tissue cancer similarity as tumors reacquire cancer-specific network complexity. Gene-gene connections remaining stable through cancer development are enriched for “housekeeping” gene functions, whereas newly acquired interactions are associated with established cancer-promoting functions. Surprisingly, >90% of changes in gene-gene network interactions in cancers are not associated with changes in the expression of network genes relative to normal precursor tissues., Graphical abstract, Highlights • Gene-gene network complexity is reduced in the transition from normal to cancer • Network similarity across cancer types is higher in early-stage versus late-stage cancers • Network interactions among housekeeping genes are stable through cancer development •, Classification Description: Systems biology; Cancer systems biology; Transcriptomics

Background Obtaining steroid-free remission in Ulcerative Colitis (UC) is a clinically important parameter that can mitigate the development of disease-related complications and lead to improved quality of life. Aims A systematic review to assess the effects and safety of methotrexate for induction in patients with UC. Methods MEDLINE, EMBASE, CENTRAL were searched from inception to August 20, 2020. Randomized controlled trials (RCTs) comparing methotrexate with placebo or an active comparator in patients with active ulcerative colitis were considered for inclusion. The primary outcome measure was the proportion of patients who achieved clinical remission and withdrawal from steroids as defined by the studies and expressed as a percentage of the total number of patients randomized (intention-to-treat analysis). The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria. Results Three studies (n=212) were included in the review. Two studies were randomized controlled trials comparing methotrexate to placebo for induction of remission of active ulcerative colitis. The first study (n = 67) compared oral methotrexate (12.5 mg/week) to placebo. Forty-seven percent (14/30) of methotrexate patients achieved clinical remission and complete withdrawal from steroids during the study period compared to 49% (18/37) of placebo patients (RR 0.96, 95% CI 0.58 to 1.59). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data. The second study (n=111) compared subcutaneous/intramuscular methotrexate 25 mg/week to placebo. The primary outcome, steroid-free remission at week 16, was present in 32% (19/60) of patients on methotrexate in comparison to 20%(10/51) of patients in the placebo arm (RR 1.62; 95% CI 0.83 to 3.15; P-value of 0.15). A GRADE analysis indicated downgrading of the evidence to low given very sparse data (29 events). An additional head-to-head randomised controlled study (n = 34) compared oral methotrexate (15 mg/week) to 6-mercaptopurine (1.5 mg/kg/day) and 5-aminosalicylic acid (3 g/day). This final study was judged to be at high risk of bias due to an open-label design. At 30 weeks, 58% (7/12) of methotrexate patients achieved clinical remission and withdrawal from steroids compared to 79% (11/14) of 6-mercaptopurine patients (RR 0.74, 95% CI 0.43 to 1.29) and 25% (2/8) of 5-aminosalicylic acid patients (RR 2.33, 95% CI 0.64 to 8.49). GRADE analyses indicated that the overall quality of the evidence was very low due to very sparse data and high risk of bias. Conclusions Methotrexate demonstrated no benefit over placebo or active comparators for the induction of steroid-free remission. Future research is ongoing to explore the utility of combination therapy with monoclonal antibody biologic therapy for the treatment of active ulcerative colitis. Funding Agencies None

The control processes that guide attention to a visual-search target can result in the selection of an irrelevant object with similar features (a distractor). Once attention is captured by such a distractor, search for a subsequent target is momentarily impaired if the two stimuli appear at different locations. The textbook explanation for this impairment is based on the notion of an indivisible focus of attention that moves to the distractor, illuminates a nontarget that subsequently appears at that location, and then moves to the target once the nontarget is rejected. Here, we show that such delayed orienting to the target does not underlie the behavioral cost of distraction. Observers identified a color-defined target appearing within the second of two stimulus arrays. The first array contained irrelevant items, including one that shared the target's color. ERPs were examined to test two predictions stemming from the textbook serial-orienting hypothesis. Namely, when the target and distractor appear at different locations, (1) the target should elicit delayed selection activity relative to same-location trials, and (2) the nontarget search item appearing at the distractor location should elicit selection activity that precedes selection activity tied to the target. Here, the posterior contralateral N2 component was used to track selection of each of these search-array items and the previous distractor. The results supported neither prediction above, thereby disconfirming the serial-orienting hypothesis. Overall, the results show that the behavioral costs of distraction are caused by perceptual and postperceptual competition between concurrently attended target and nontarget stimuli.

Increased attention to threat is considered a core feature of anxiety. However, there are multiple mechanisms of attention and multiple types of threat, and the relationships among attention, threat, and anxiety are poorly understood. In the present study, we used event-related potentials (ERPs) to separately isolate attentional selection (N2pc) and suppression (PD) of pictorial threats (photos of weapons, snakes, etc.) and conditioned threats (colored shapes paired with electric shock). In a sample of 48 young adults, both threat types were initially selected for increased attention (an N2pc), but only conditioned threats elicited subsequent suppression (a PD) and a reaction time (RT) bias. Levels of trait anxiety were unrelated to N2pc amplitude, but increased anxiety was associated with larger PDs (i.e., greater suppression) and reduced RT bias to conditioned threats. These results suggest that anxious individuals do not pay more attention to threats but rather engage more attentional suppression to overcome threats.