Abstract Brain networks that govern parental response to infant signals have been studied with imaging techniques over the last 15 years. The complex interaction of thoughts and behaviors required ...for sensitive parenting enables the formation of each individual׳s first social bonds and critically shapes development. This review concentrates on magnetic resonance imaging experiments which directly examine the brain systems involved in parental responses to infant cues. First, we introduce themes in the literature on parental brain circuits studied to date. Next, we present a thorough chronological review of state-of-the-art fMRI studies that probe the parental brain with a range of baby audio and visual stimuli. We also highlight the putative role of oxytocin and effects of psychopathology, as well as the most recent work on the paternal brain. Taken together, a new model emerges in which we propose that cortico-limbic networks interact to support parental brain responses to infants. These include circuitry for arousal/salience/motivation/reward, reflexive/instrumental caring, emotion response/regulation and integrative/complex cognitive processing. Maternal sensitivity and the quality of caregiving behavior are likely determined by the responsiveness of these circuits during early parent-infant experiences. The function of these circuits is modifiable by current and early-life experiences, hormonal and other factors. Severe deviation from the range of normal function in these systems is particularly associated with (maternal) mental illnesses – commonly, depression and anxiety, but also schizophrenia and bipolar disorder. Finally, we discuss the limits and extent to which brain imaging may broaden our understanding of the parental brain given our current model. Developments in the understanding of the parental brain may have profound implications for long-term outcomes in families across risk, resilience and possible interventions. This article is part of a Special Issue entitled Oxytocin and Social Behav.
Imaging data contains a substantial amount of information which can be difficult to evaluate by eye. With the expansion of high throughput microscopy methodologies producing increasingly large ...datasets, automated and objective analysis of the resulting images is essential to effectively extract biological information from this data. CellProfiler is a free, open source image analysis program which enables researchers to generate modular pipelines with which to process microscopy images into interpretable measurements. Herein we describe CellProfiler 4, a new version of this software with expanded functionality. Based on user feedback, we have made several user interface refinements to improve the usability of the software. We introduced new modules to expand the capabilities of the software. We also evaluated performance and made targeted optimizations to reduce the time and cost associated with running common large-scale analysis pipelines. CellProfiler 4 provides significantly improved performance in complex workflows compared to previous versions. This release will ensure that researchers will have continued access to CellProfiler's powerful computational tools in the coming years.
Obesity is increasingly common before and after liver transplantation (LT), yet optimal management remains unclear. Our aim was to analyze the effectiveness of a multidisciplinary protocol for obese ...patients requiring LT, including a noninvasive pretransplant weight loss program, and a combined LT plus sleeve gastrectomy (SG) for obese patients who failed to lose weight prior to LT. Since 2006, all patients referred LT with a BMI > 35 were enrolled. There were 37 patients who achieved weight loss and underwent LT alone, and 7 who underwent LT combined with SG. In those who received LT alone, weight gain to BMI > 35 was seen in 21/34, post‐LT diabetes (DM) in 12/34, steatosis in 7/34, with 3 deaths plus 3 grafts losses. In patients undergoing the combined procedure, there were no deaths or graft losses. One patient developed a leak from the gastric staple line, and one had excess weight loss. No patients developed post‐LT DM or steatosis, and all had substantial weight loss (mean BMI = 29). Noninvasive pretransplant weight loss was achieved by a majority, though weight gain post‐LT was common. Combined LT plus SG resulted in effective weight loss and was associated with fewer post‐LT metabolic complications. Long‐term follow‐up is needed.
With a mean follow‐up of 17 months, liver transplantation with simultaneous sleeve gastrectomy provided effective weight loss and reduced posttransplant metabolic complications.
Reducing environmental stress imposed upon gametes and embryos in the IVF laboratory is crucial in optimizing culture conditions and development. One environmental parameter of particular importance ...is external pH (pHe) of culture media. An optimal pHe has not been identified.
Electronic searches were performed using keywords focused on pH and the embryo using PUBMED through August 2011, with no limits placed on a beginning time. Examples of keywords include CO(2), bicarbonate and hydrogen ion. Relevant papers were then examined to obtain additional publications.
Determining optimal pHe is problematic due to difficulty in isolating pHe from other variables, such as CO(2) and bicarbonate. Various commercial media companies recommend differing pHe ranges, most within the range of 7.2-7.4, with some companies recommending altering pHe based on the gamete or stage of the embryo. However, changing pHe during culture has not been experimentally shown to improve outcomes. Further complicating attempts to define an optimal pHe is that media components can impact intracellular pH (pHi). As a result, media with different concentrations of substances, such as lactate or amino acids, may have different pHi, despite being in the same pHe.
Due to the plasticity of embryos, a range of pHe's can support development, and defining an optimal pHe is difficult. It is unclear whether there is any benefit in changing pHe at various steps during IVF. The ideal pHe will likely vary from media to media and, until comparative studies have been performed isolating pHe, adherence to manufacturer recommendations and maintenance of a small acceptable pHe range are advisable.
It is becoming increasingly clear that the fundamental capacity to undergo conformational change in response to ligand binding is intrinsic to proteins. This property confers on proteins the ability ...to be allosterically modulated in order to shift substrate binding affinities, alter enzymatic activity or regulate protein–protein interaction. How this allosteric modulation occurs — the pathways of communication, the shifting of conformational ensembles and the altered molecular dynamics — has received considerable attention during the past two years. Recent progress has helped outline the molecular origins of allostery in proteins as diverse as Hsp70 molecular chaperones and signal integrating proteins, such as WASP. In addition, allosteric properties have been successfully engineered into proteins for drug design or the development of novel biosensors. Methodological advances have provided exciting prospects for new insights and new biological roles of allosteric systems have been uncovered.
We use a novel technique that allows for closed recirculation of vector genomes in the cardiac circulation using cardiopulmonary bypass, referred to here as molecular cardiac surgery with ...recirculating delivery (MCARD). We demonstrate that this platform technology is highly efficient in isolating the heart from the systemic circulation in vivo. Using MCARD, we compare the relative efficacy of single-stranded (ss) adeno-associated virus (AAV)6, ssAAV9 and self-complimentary (sc)AAV6-encoding enhanced green fluorescent protein, driven by the constitutive cytomegalovirus promoter to transduce the ovine myocardium in situ. MCARD allows for the unprecedented delivery of up to 48 green fluorescent protein genome copies per cell globally in the sheep left ventricular (LV) myocardium. We demonstrate that scAAV6-mediated MCARD delivery results in global, cardiac-specific LV gene expression in the ovine heart and provides for considerably more robust and cardiac-specific gene delivery than other available delivery techniques such as intramuscular injection or intracoronary injection; thus, representing a potential, clinically translatable platform for heart failure gene therapy.
Rapid yet accurate pKa prediction for druglike molecules is a key challenge in computational chemistry. This study uses PM6-DH+/COSMO, PM6/COSMO, PM7/COSMO, PM3/COSMO, AM1/COSMO, PM3/SMD, AM1/SMD, ...and DFTB3/SMD to predict the pKa values of 53 amine groups in 48 druglike compounds. The approach uses an isodesmic reaction where the pKa value is computed relative to a chemically related reference compound for which the pKa value has been measured experimentally or estimated using a standard empirical approach. The AM1- and PM3-based methods perform best with RMSE values of 1.4-1.6 pH units that have uncertainties of ±0.2-0.3 pH units, which make them statistically equivalent. However, for all but PM3/SMD and AM1/SMD the RMSEs are dominated by a single outlier, cefadroxil, caused by proton transfer in the zwitterionic protonation state. If this outlier is removed, the RMSE values for PM3/COSMO and AM1/COSMO drop to 1.0 ± 0.2 and 1.1 ± 0.3, whereas PM3/SMD and AM1/SMD remain at 1.5 ± 0.3 and 1.6 ± 0.3/0.4 pH units, making the COSMO-based predictions statistically better than the SMD-based predictions. For pKa calculations where a zwitterionic state is not involved or proton transfer in a zwitterionic state is not observed, PM3/COSMO or AM1/COSMO is the best pKa prediction method; otherwise PM3/SMD or AM1/SMD should be used. Thus, fast and relatively accurate pKa prediction for 100-1000s of druglike amines is feasible with the current setup and relatively modest computational resources.
The majority of research aimed at improving embryo development in vitro has focused on manipulation of the chemical environment, examining details such as energy substrate composition and impact of ...various growth factors or other supplements. In comparison, relatively little work has been done examining the physical requirements of preimplantation embryos and the role culture platforms or devices can play in influencing embryo development.
Electronic searches were performed using keywords centered on embryo culture techniques using PUBMED through June 2010 and references were searched for additional research articles.
Various approaches to in vitro embryo culture that involve manipulations of the physical culture environment are emerging. Novel culture platforms being developed examine issues such as media volume and embryo spacing. Furthermore, methods to permit dynamic embryo culture with fluid flow and embryo movement are now available, and novel culture surfaces are being tested.
Although several factors remain to be studied to optimize efficiency, manipulations of the embryo culture microenvironment through novel culture devices may offer a means to improve embryo development in vitro. Reduced volume systems that reduce embryo spacing, such as the well-of-the-well approach, appear beneficial, although more work is needed to verify the source of their true benefit in human embryos. Emerging microfluidic technology appears to be a promising approach. However, along with the work on specialized culture surfaces, more information is required to determine the impact on human embryo development.
Given the projected increase in multidrug-resistant HIV-1, there is an urgent need for development of antiretrovirals that act on virus life cycle stages not targeted by drugs currently in use. ...Host-targeting compounds are of particular interest because they can offer a high barrier to resistance. Here, we report identification of two related small molecules that inhibit HIV-1 late events, a part of the HIV-1 life cycle for which potent and specific inhibitors are lacking. This chemotype was discovered using cell-free protein synthesis and assembly systems that recapitulate intracellular host-catalyzed viral capsid assembly pathways. These compounds inhibit replication of HIV-1 in human T cell lines and peripheral blood mononuclear cells, and are effective against a primary isolate. They reduce virus production, likely by inhibiting a posttranslational step in HIV-1 Gag assembly. Notably, the compound colocalizes with HIV-1 Gag
; however, unexpectedly, selection experiments failed to identify compound-specific resistance mutations in
or
, even though known resistance mutations developed upon parallel nelfinavir selection. Thus, we hypothesized that instead of binding to Gag directly, these compounds localize to assembly intermediates, the intracellular multiprotein complexes containing Gag and host factors that form during immature HIV-1 capsid assembly. Indeed, imaging of infected cells shows compound colocalized with two host enzymes found in assembly intermediates, ABCE1 and DDX6, but not two host proteins found in other complexes. While the exact target and mechanism of action of this chemotype remain to be determined, our findings suggest that these compounds represent first-in-class, host-targeting inhibitors of intracellular events in HIV-1 assembly.
The success of antiretroviral treatment for HIV-1 is at risk of being undermined by the growing problem of drug resistance. Thus, there is a need to identify antiretrovirals that act on viral life cycle stages not targeted by drugs in use, such as the events of HIV-1 Gag assembly. To address this gap, we developed a compound screen that recapitulates the intracellular events of HIV-1 assembly, including virus-host interactions that promote assembly. This effort led to the identification of a new chemotype that inhibits HIV-1 replication at nanomolar concentrations, likely by acting on assembly. This compound colocalized with Gag and two host enzymes that facilitate capsid assembly. However, resistance selection did not result in compound-specific mutations in
, suggesting that the chemotype does not directly target Gag. We hypothesize that this chemotype represents a first-in-class inhibitor of virus production that acts by targeting a virus-host complex important for HIV-1 Gag assembly.
Conventional spectral Te studies use the real part of the admittance between gravity anomalies and topography or, alternatively, the square of the magnitude of the coherency (i.e., coherence). Here ...we show the utility of treating both the admittance and coherency as complex quantities. Inverting the real parts to estimate Te, we use the imaginary parts to tell if the inversion is biased by noise. One method inverts the square of the real coherency, with the internal‐to‐total load ratio F derived (as a function of wave number) directly from the gravity and topography. The other method inverts the real part of the admittance assuming that F is wave number‐independent. We test the methods using synthetic elastic plate models loaded at the surface and Moho in such a way that the final relief is the actual North American topography. In some of the models we add gravity noise generated by a model having both surface and internal loads such that the final topography is zero and find that both methods are susceptible to noise. Application of the two methods to North America gives Te maps showing substantial agreement except in regions affected by noise, but these are not a dominant part of the total area. Given the suggested mechanisms by which noise might arise, it is not surprising that it is not a more widespread feature of the North American craton. Importantly, both methods show that large parts of the Canadian Shield are characterized by Te > 100 km.
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