The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated ...in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.
From 2007 to 2013, the southeastern Bering Sea was dominated by extensive sea ice and below-average ocean temperatures. In 2014 there was a shift to reduced sea ice on the southern shelf and ...above-average ocean temperatures. These conditions continued in 2015 and 2016. During these three years, the spring bloom at mooring site M4 (57.9°N, 168.9°W) occurred primarily in May, which is typical of years without sea ice. At mooring site M2 (56.9°N, 164.1°W) the spring bloom occurred earlier especially in 2016. Higher chlorophyll fluorescence was observed at M4 than at M2. In addition, these three warm years continued the pattern near St. Matthew Island of high concentrations (>1 μM) of nitrite occurring during summer in warm years. Historically, the dominant parameters controlling sea-ice extent are winds and air temperature, with the persistence of frigid, northerly winds in winter and spring resulting in extensive ice. After mid-March 2014 and 2016 there were no cold northerly or northeasterly winds. Cold northerly winds persisted into mid-April in 2015, but did not result in extensive sea ice south of 58°N. The apparent mechanism that helped limit ice on the southeastern shelf was the strong advection of warm water from the Gulf of Alaska through Unimak Pass. This pattern has been uncommon, occurring in only one other year (2003) in a 37-year record of estimated transport through Unimak Pass. During years with no sea ice on the southern shelf (e.g. 2001-2005, 2014-2016), the depth-averaged temperature there was correlated to the previous summers ocean temperature.
What are the faintest distant galaxies we can see with the Hubble Space Telescope (HST) now, before the launch of the James Webb Space Telescope? This is the challenge taken up by the Frontier ...Fields, a Director's discretionary time campaign with HST and the Spitzer Space Telescope to see deeper into the universe than ever before. The Frontier Fields combines the power of HST and Spitzer with the natural gravitational telescopes of massive high-magnification clusters of galaxies to produce the deepest observations of clusters and their lensed galaxies ever obtained. Six clusters-Abell 2744, MACSJ0416.1-2403, MACSJ0717.5+3745, MACSJ1149.5+2223, Abell S1063, and Abell 370-have been targeted by the HST ACS/WFC and WFC3/IR cameras with coordinated parallel fields for over 840 HST orbits. The parallel fields are the second-deepest observations thus far by HST with 5 point-source depths of ∼29th ABmag. Galaxies behind the clusters experience typical magnification factors of a few, with small regions magnified by factors of 10-100. Therefore, the Frontier Field cluster HST images achieve intrinsic depths of ∼30-33 mag over very small volumes. Spitzer has obtained over 1000 hr of Director's discretionary imaging of the Frontier Field cluster and parallels in IRAC 3.6 and 4.5 m bands to 5 point-source depths of ∼26.5, 26.0 ABmag. We demonstrate the exceptional sensitivity of the HST Frontier Field images to faint high-redshift galaxies, and review the initial results related to the primary science goals.
Neurotropic viruses that conditionally infect or replicate in molecularly defined neuronal subpopulations, and then spread transsynaptically, are powerful tools for mapping neural pathways. ...Genetically targetable retrograde transsynaptic tracer viruses are available to map the inputs to specific neuronal subpopulations, but an analogous tool for mapping synaptic outputs is not yet available. Here we describe a Cre recombinase-dependent, anterograde transneuronal tracer, based on the H129 strain of herpes simplex virus (HSV). Application of this virus to transgenic or knockin mice expressing Cre in peripheral neurons of the olfactory epithelium or the retina reveals widespread, polysynaptic labeling of higher-order neurons in the olfactory and visual systems, respectively. Polysynaptic pathways were also labeled from cerebellar Purkinje cells. In each system, the pattern of labeling was consistent with classical circuit-tracing studies, restricted to neurons, and anterograde specific. These data provide proof-of-principle for a conditional, nondiluting anterograde transsynaptic tracer for mapping synaptic outputs from genetically marked neuronal subpopulations.
► A Cre-dependent, anterograde viral transynaptic tracer has been developed ► The tracer has been tested in the olfactory, visual, and cerebellar systems ► The pattern of labeling is consistent with classical studies and anterograde specific ► The tracer maps polysynaptic output pathways from genetically defined neuron subsets
Activation heat capacity is emerging as a crucial factor in enzyme thermoadaptation, as shown by the non-Arrhenius behaviour of many natural enzymes. However, its physical origin and relationship to ...the evolution of catalytic activity remain uncertain. Here we show that directed evolution of a computationally designed Kemp eliminase reshapes protein dynamics, which gives rise to an activation heat capacity absent in the original design. These changes buttress transition-state stabilization. Extensive molecular dynamics simulations show that evolution results in the closure of solvent-exposed loops and a better packing of the active site. Remarkably, this gives rise to a correlated dynamical network that involves the transition state and large parts of the protein. This network tightens the transition-state ensemble, which induces a negative activation heat capacity and non-linearity in the activity-temperature dependence. Our results have implications for understanding enzyme evolution and suggest that selectively targeting the conformational dynamics of the transition-state ensemble by design and evolution will expedite the creation of novel enzymes.
The brain is worthy of study because it is in charge of behavior. A flurry of recent technical advances in measuring and quantifying naturalistic behaviors provide an important opportunity for ...advancing brain science. However, the problem of understanding unrestrained behavior in the context of neural recordings and manipulations remains unsolved, and developing approaches to addressing this challenge is critical. Here we discuss considerations in computational neuroethology—the science of quantifying naturalistic behaviors for understanding the brain—and propose strategies to evaluate progress. We point to open questions that require resolution and call upon the broader systems neuroscience community to further develop and leverage measures of naturalistic, unrestrained behavior, which will enable us to more effectively probe the richness and complexity of the brain.
The goal of computational neuroethology is to understand the relationship between the brain and purposive behavior that evolved under natural selection. Technology is transforming how we measure and model naturalistic behavior, affording new insight into brain function.
The traditional likelihood‐based test for differences in multivariate dispersions is known to be sensitive to nonnormality. It is also impossible to use when the number of variables exceeds the ...number of observations. Many biological and ecological data sets have many variables, are highly skewed, and are zero‐inflated. The traditional test and even some more robust alternatives are also unreasonable in many contexts where measures of dispersion based on a non‐Euclidean dissimilarity would be more appropriate. Distance‐based tests of homogeneity of multivariate dispersions, which can be based on any dissimilarity measure of choice, are proposed here. They rely on the rotational invariance of either the multivariate centroid or the spatial median to obtain measures of spread using principal coordinate axes. The tests are straightforward multivariate extensions of Levene's test, with P‐values obtained either using the traditional F‐distribution or using permutation of either least‐squares or LAD residuals. Examples illustrate the utility of the approach, including the analysis of stabilizing selection in sparrows, biodiversity of New Zealand fish assemblages, and the response of Indonesian reef corals to an El Niño. Monte Carlo simulations from the real data sets show that the distance‐based tests are robust and powerful for relevant alternative hypotheses of real differences in spread.
Cell-free gene expression of a fluorescent protein (mCherry) is demonstrated within the molecularly crowded matrix of a polysaccharide/polypeptide coacervate.
•Enzymes can be created by computational design and directed evolution.•Insights from directed evolution:•Active-site organization by H-bonding networks and evolved energy landscapes.•Electrostatic ...redesign accelerates directed evolution.•Dynamical networks integrate the protein scaffold into catalysis.
De novo enzymes can be created by computational design and directed evolution. Here, we review recent insights into the origins of catalytic power in evolved designer enzymes to pinpoint opportunities for next-generation designs: Evolution precisely organizes active sites, introduces catalytic H-bonding networks, invokes electrostatic catalysis, and creates dynamical networks embedding the active site in a reactive protein scaffold. Such insights foster our fundamental knowledge of enzyme catalysis and fuel the future design of tailor-made enzymes.
This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature ...is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype‐guided warfarin dosing to achieve a target international normalized ratio of 2–3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.
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