Search

The incredible complexity of biological processes across temporal and spatial scales hampers defining common underlying mechanisms driving the patterns of life. However, recent advances in sequencing, big data analysis, machine learning, and molecular dynamics simulation have renewed the hope and urgency of finding potential hidden rules of life. There currently exists no framework to develop such synoptic investigations. Some efforts aim to identify unifying rules of life across hierarchical levels of time, space, and biological organization, but not all phenomena occur across all the levels of these hierarchies. Instead of identifying the same parameters and rules across levels, we posit that each level of a temporal and spatial scale and each level of biological organization has unique parameters and rules that may or may not predict outcomes in neighboring levels. We define this neighborhood, or the set of levels, across which a rule functions as the zone of influence. Here, we introduce the zone of influence framework and explain using three examples: (a) randomness in biology, where we use a Poisson process to describe processes from protein dynamics to DNA mutations to gene expressions, (b) island biogeography, and (c) animal coloration. The zone of influence framework may enable researchers to identify which levels are worth investigating for a particular phenomenon and reframe the narrative of searching for a unifying rule of life to the investigation of how, when, and where various rules of life operate. [ABSTRACT FROM AUTHOR]

Background Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. Methods We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. Results Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1 , Hcrtr2 , Crhr2 , and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. Conclusion Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder. [ABSTRACT FROM AUTHOR]

Organisms often respond to environmental change via phenotypic plasticity, in which an individual modulates its phenotype according to the environment. Highly variable or changing environments can exceed physiological limits and generate maladapted plastic phenotypes, which is termed nonadaptive plasticity. In some cases, selection may reduce the negative or disruptive impacts of environmental stress and produce locally adapted populations. Salt is an increasingly prevalent contaminant of freshwater systems and can induce nonadaptive plastic phenotypes for freshwater organisms like amphibians. Hyla cinerea is a frog species with populations inhabiting brackish, coastal habitats, so we use this species to test whether coastal populations are locally adapted to tolerate saltwater by determining how salt exposure during the embryonic and larval stages alters mortality and plastic developmental and metamorphic phenotypes of coastal and inland populations. Coastal frogs have higher survival, faster growth rates, and metamorphose sooner than inland frogs across salinities. Coastal frogs also metamorphose smaller (likely a consequence of earlier metamorphosis) yet maintain constant size, while higher salinities reduce metamorphic size for inland frogs. Coastal frogs evolved to minimize nonadaptive and disruptive impacts of saltwater during larval development and accelerate the larval period to reduce time spent in a stressful environment. [ABSTRACT FROM AUTHOR]

Background: The continuing epidemic of methamphetamine addiction has prompted research aimed at understanding striatal dysfunctions potentially associated with long-term methamphetamine use. Methods: Here, we investigated transcriptional and translational alterations in the expression of neurotrophic factors in the rat striatum at 30 days following methamphetamine self-administration and footshock punishment. Male Sprague-- Dawley rats were trained to self-administer methamphetamine (0.1 mg/kg/injection, i.v.) or saline during twenty-two 9-hour sessions. Subsequently, rats were subjected to incremental footshocks for 13 additional methamphetamine selfadministration sessions. This paradigm led to the identification of rats with shock-resistant and shock-sensitive phenotypes. Thirty days following the last footshock session, the dorsal striatum was dissected and processed for gene expression and protein analyses. Results: PCR arrays revealed significant differences in neurotrophins and their receptors between the 2 phenotypes. Brainderived neurotrophic factor and nerve growth factor protein levels were increased in the dorsal striatum of both shockresistant and shock-sensitive rats. However, neurotrophic receptor tyrosine kinase 1 phosphorylation and nerve growth factor receptor protein expression were increased only in the shock-sensitive phenotype. Moreover, shock-sensitive rats showed increased abundance of several phosphorylated proteins known to participate in Ras/Raf/MEK/ERK signaling cascade including cRaf, ERK1/2, MSK1, and CREB. Conclusions: These findings support the notion that animals with distinct phenotypes for methamphetamine intake in the presence of adverse consequences also display differential changes in an intracellular signaling cascade activated by nerve growth factor-TrkA/p75NTR interactions. Thus, the development of pharmacological agents that can activate nerve growth factor-dependent pathways may be a promising therapeutic approach to combat methamphetamine addiction. [ABSTRACT FROM AUTHOR]

Recent research indicates that many convex optimization problems with random constraints exhibit a phase transition as the number of constraints increases. For example, this phenomenon emerges in the ℓ1 minimization method for identifying a sparse vector from random linear measurements. Indeed, the ℓ1 approach succeeds with high probability when the number of measurements exceeds a threshold that depends on the sparsity level; otherwise, it fails with high probability. This paper provides the first rigorous analysis that explains why phase transitions are ubiquitous in random convex optimization problems. It also describes tools for making reliable predictions about the quantitative aspects of the transition, including the location and the width of the transition region. These techniques apply to regularized linear inverse problems with random measurements, to demixing problems under a random incoherence model, and also to cone programs with random affine constraints. The applied results depend on foundational research in conic geometry. This paper introduces a summary parameter, called the statistical dimension, that canonically extends the dimension of a linear subspace to the class of convex cones. The main technical result demonstrates that the sequence of intrinsic volumes of a convex cone concentrates sharply around the statistical dimension. This fact leads to accurate bounds on the probability that a randomly rotated cone shares a ray with a fixed cone. [ABSTRACT FROM AUTHOR]

Emerging concepts in developmental biology, such as facilitated variation and dynamical patterning modules, address a major shortcoming of the Modern Synthesis in Biology: how genotypic variation is transduced into functional yet diverse phenotypic variation. Still, we lack a theory to explain how variation at the cellular and tissue level is coordinated into variation at the whole-organism level, especially as priority of cellular and tissue functions change over an individual’s lifetime and are influenced by environmental variation. Here, we propose that interactions among a limited subset of physiological factors that we call, integrators, regulate most phenotypic variation at the organismal level. Integrators are unique among physiological factors in that they have the propensity to coordinate the expression of conserved gene modules of most types of tissues because they participate as nodes in a hierarchical network. In other words, integrator networks impose physiological epistasis, meaning that whole-organism phenotypic responses will be influenced by previous experiences, current environmental conditions, and fitness priorities as encoded by individual integrators. Below, we provide examples of how integrator networks are responsible for both profound and irreversible phenotypic changes (i.e., metamorphosis, sexual differentiation) as well as subtler, transient (e.g., pelage color, seasonal fluctuations in lymphoid and reproductive tissues) variation. The goal of this article is not to describe completely how integrator networks function, but to stimulate discussion about the role of physiology in linking genetic to phenotypic variation. To generate useful data sets for understanding integrator networks and to inform whole-organism physiology generally, we describe several useful tools including vector-field editing, response-surface regression, and experiments of life-table responses. We then close by highlighting some implications of integrator networks for conservation and biomedicine. [ABSTRACT FROM AUTHOR]

The article examines the roles of policy-relevant beliefs and social capital as drivers of network structure with reference to regional planning in California. The theories of social capital focus on how cooperation is supported by norms of reciprocity and civic engagement. Testing the importance of network configurations needs statistical techniques, which take into account the interdependent nature of network relationships. Belief stability and policy relevance have an interactive effect on policy network structure.

Being overweight or obese is a major risk factor for developing type 2 diabetes but weight loss through lifestyle interventions can markedly reduce its incidence. The Internet provides an opportunity for the development and implementation of lifestyle intervention programs that promote self-managed behavioural change. We developed an online weight loss program emphasizing physical activity and dietary modifications and conducted a short- term qualitative evaluation of it, examining participant recruitment from the general public, website usage and satisfaction and use of self-reported health risk appraisal records. From a total of 808 registered participants who accessed the online services, 683 (84.5%) completed at least one online health risk appraisal and of those, 464 (68%) people (364 female, aged 19-70 years; 100 male, aged 20-71 years) enrolled in the weight loss program. The program was met with a high level of satisfaction by participants, with 56% of feedback respondents agreeing that the program helped them achieve their goals. The program home page, the principal arrival destination of participants, was viewed an average of 29 times per participant, suggesting that the website's services were used with a high frequency. These preliminary findings indicate that the general public will use an Internet-based weight loss program that involves physical activity and dietary behavioural interventions. Whether Internet delivery of these interventions can significantly reduce the risk for developing type 2 diabetes is worthy of further investigation. The findings have relevance for development of health promotion policies and practices. [ABSTRACT FROM AUTHOR]