The rockefeller university

Severe mental illnesses like schizophrenia and bipolar disorder are disabling, chronic conditions that are often accompanied by medical comorbidities. In this theoretical article, we review the allostatic load model representing the "wear and tear" that chronic stress exacts on the brain and body. We propose an innovative way of monitoring physical and psychiatric comorbidities by integrating the allostatic load model into clinical practice. By interpreting peripheral biomarkers differently, medical professionals can calculate a simple, count-based, allostatic load index known to predict diverse stress-related pathologies. In addition to screening for comorbidities, allostatic load indices can be used to monitor the effects of pharmacological and psychosocial interventions. This framework can also be used to generate a dialogue between patient and practitioner to promote preventive and proactive approaches to health care.

Neuronal responses to sensory inputs can vary based on genotype, development, experience, or stochastic factors. Existing neuronal recording techniques examine a single animal at a time, limiting understanding of the variability and range of potential responses. To scale up neuronal recordings, we here describe a system for simultaneous wide-field imaging of neuronal calcium activity from at least 20 Caenorhabditis elegans animals under precise microfluidic chemical stimulation. This increased experimental throughput was used to perform a systematic characterization of chemosensory neuron responses to multiple odors, odor concentrations, and temporal patterns, as well as responses to pharmacological manipulation. The system allowed recordings from sensory neurons and interneurons in freely moving animals, whose neuronal responses could be correlated with behavior. Wide-field imaging provides a tool for comprehensive circuit analysis with elevated throughput in C. elegans.

In a phosphorylation-dependent positive feedback loop, the cytidine deaminase AID amplifies the generation of double-strand DNA breaks, which shows it can also function downstream of deamination.

A long-standing literature linking endocannabinoids (ECBs) to stress, fear, and anxiety has led to growing interest in developing novel anxiolytics targeting the ECB system. Following rapid on-demand biosynthesis and degradation upon neuronal activation, the ECB N-arachidonoylethanolamide (anandamide, AEA) is actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH). Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key anxiety-mediating region the basolateral amygdala (BLA). Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior. Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA CBI (cannabinoid type 1) receptor signaling and synaptic plasticity in the BLA. These preclinical findings propose restoring deficient BLA AEA levels by pharmacologically inhibiting FAAH as a mechanism to therapeutically mitigate the effects of traumatic stress.

A full-length cDNA encoding a putative aspartic acid protease (AcAP1) was isolated for the first time from the flesh of pineapple (Ananas comosus) fruit. The deduced sequence of AcAP1 showed all the common features of a typical plant aspartic protease phytepsin precursor. Analysis of AcAP1 gene expression under postharvest chilling treatment in two pineapple varieties differing in their resistance to blackheart development revealed opposite trends. The resistant variety showed an up-regulation of AcAP1 precursor gene expression whereas the susceptible showed a down-regulation in response to postharvest chilling treatment. The same trend was observed regarding specific AP enzyme activity in both varieties. Taken together our results support the involvement of AcAP1 in postharvest chilling stress resistance in pineapple fruits. (C) 2013 Elsevier GmbH. All rights reserved.

Purpose: To investigate the reliability of simulations lot planning pancreatic irreversible electroporation (IRE) ablations compared with computed tomography (CT) and pathology outcomes in an animal Model. Materials and Methods: Simulations were performed varying treatment parameters, including field strength (1.5-2.5 kV/cm), pulse number (70-90 pulses), and pulse length (70-100 us). Pancreatic IRE was performed in six pigs under CT guidance. Two animals each were sacrificed for histology after 1 day, 14 days, and 28 days. Follow-up CT scans were performed on day 0, day 1, day 14, and day 28. Biochemical markets were collected before the procedure, 1 day after the procedure, and 14 days after the procedure. Results: All ablation zones could be visualized on CT scan immediately after the procedure and on day 1 follow-up CT scan, and all animals survived until the designated endpoints.,Histopathology revealed necrosis and edema on day 1 and fibrosis and glandular atrophy after 28 days. Blood vessels close to the ablation zone appeared normal. Laboratory analysis indicated mild to moderate amylasemia and lipasemia with normalization after 14 days: The ablation size on CT scan measured a mean (+/- SD) 146% +/- 18 (day 0, P < .126) and 168% +/- 18 (day 1, P < .026) of the simulation and on pathology measured 119% +/- 10 (day 1, not significant) of the simulation. Conclusions: Results from simulations for planning IRE ablations, CT, and pathology may differ from each other. Ablation zones on CT and pathology appear larger than,Simulated, suggesting that clinically used treatment-planning may underestimate the ablation size in the pancreas.

Asymmetric cell divisions (ACDs) result in two unequal daughter cells and are a hallmark of stemcells. ACDs can be achieved either by asymmetric partitioning of proteins and organelles or by asymmetric cell fate acquisition due to the microenvironment in which the daughters are placed. Increasing evidence suggests that in the mammalian epidermis, both of these processes occur. During embryonic epidermal development, changes occur in the orientation of the mitotic spindle in relation to the underlying basement membrane. These changes are guided by conserved molecular machinery that is operative in lower eukaryotes and dictates asymmetric partitioning of proteins during cell divisions. That said, the shift in spindle alignment also determines whether a division will be parallel or perpendicular to the basement membrane, and this in turn provides a differential microenvironment for the resulting daughter cells. Here, we review how oriented divisions of progenitors contribute to the development and stratification of the epidermis.

We have applied a super-resolution fluorescence imaging method, stochastic optical reconstruction microscopy (STORM), to visualize the structure of functional telomeres and telomeres rendered dysfunctional through removal of shelterin proteins. The STORM images showed that functional telomeres frequently exhibit a t-loop configuration. Conditional deletion of individual components of shelterin showed that TRF2 was required for the formation and/or maintenance of t-loops, whereas deletion of TRF1, Rap1, or the POT1 proteins (POT1a and POT1b) had no effect on the frequency of t-loop occurrence. Within the shelterin complex, TRF2 uniquely serves to protect telomeres from two pathways that are initiated on free DNA ends: classical nonhomologous end-joining (NHEJ) and ATM-dependent DNA damage signaling. The TRF2-dependent remodeling of telomeres into t-loop structures, which sequester the ends of chromosomes, can explain why NHEJ and the ATM signaling pathway are repressed when TRF2 is present.