How do our senses help us to understand the world? This question, which preoccupied Enlightenment thinkers, also emerged as a key theme in depictions of animals in eighteenth-century art. This book ...examines the ways in which painters such as Chardin, as well as sculptors, porcelain modelers, and other decorative designers portrayed animals as sensing subjects who physically confirmed the value of material experience. The sensual style known today as the Rococo encouraged the proliferation of animals as exemplars of empirical inquiry, ranging from the popular subject of the monkey artist to the alchemical wonders of the life-sized porcelain animals created for the Saxon court. Examining writings on sensory knowledge by La Mettre, Condillac, Diderot and other philosophers side by side with depictions of the animal in art, Cohen argues that artists promoted the animal as a sensory subject while also validating the material basis of their own professional practice.
Elucidating the role of the rodent hippocampus in object recognition memory is critical for establishing the appropriateness of rodents as models of human memory and for their use in the development ...of memory disorder treatments. In mammals, spatial memory 1–6 and nonspatial memory 7, 8 depend upon the hippocampus and associated medial temporal lobe (MTL) structures. Although well established in humans 1, 9, the role of the rodent hippocampus in object memory remains highly debated due to conflicting findings across temporary and permanent hippocampal lesion studies 10–22 and evidence that the perirhinal cortex may support object memory 17, 23, 24. In the current studies, we used intrahippocampal muscimol microinfusions to transiently inactivate the male C57BL/6J mouse hippocampus at distinct stages during the novel object recognition (NOR) task: during object memory encoding and consolidation, just consolidation, and/or retrieval. We also assessed the effect of temporary hippocampal inactivation when objects were presented in different contexts, thus eliminating the spatial or contextual components of the task. Lastly, we assessed extracellular dorsal hippocampal glutamate efflux and firing properties of hippocampal neurons while mice performed the NOR task. Our results reveal a clear and compelling role of the rodent hippocampus in nonspatial object memory.
•In mice, the hippocampus is required for distinct stages of object memory processing•Retrieval of object memory independent of context also requires the hippocampus•Glutamate efflux measurements during NOR support hippocampal involvement in mice•NOR test session performance increased firing rates of hippocampal pyramidal neurons
•Recent papers on the role of hippocampus in NOR are reviewed.•Object recognition is a well accepted task for testing rodent nonspatial memory.•Temporary and permanent hippocampal lesions ...inconsistently affect NOR performance.•Differences in exploration criterion and delay confound interpretation of results.•Need for the standardization of NOR procedures is stressed.
The novel object recognition (NOR) task has emerged as a popular method for testing the neurobiology of nonspatial memory in rodents. This task exploits the natural tendency of rodents to explore novel items and depending on the amount of time that rodents spend exploring the presented objects, inferences about memory can be established. Despite its wide use, the underlying neural circuitry and mechanisms supporting NOR have not been clearly defined. In particular, considerable debate has focused on whether the hippocampus plays a significant role in the object memory that is encoded, consolidated and then retrieved during discrete stages of the NOR task. Here we analyzed the results of all published reports in which the role of the rodent hippocampus in object memory was inferred from performance in the task with restricted parameters. We note that the remarkable variability in NOR methods across studies complicates the ability to draw meaningful conclusions from the work. Focusing on 12 reports in which a minimum criterion of sample session object exploration was imposed, we find that temporary or permanent lesion of the hippocampus consistently disrupts object memory when a delay of 10min or greater is imposed between the sample and test sessions. We discuss the significance of a delay-dependent role of the hippocampus in NOR within the framework of the medial temporal lobe. We assert that standardization of the NOR protocol is essential for obtaining reliable data that can then be compared across studies to build consensus as to the specific contribution of the rodent hippocampus to object memory.
Fatty acids (FAs) provide cellular energy under starvation, yet how they mobilize and move into mitochondria in starved cells, driving oxidative respiration, is unclear. Here, we clarify this process ...by visualizing FA trafficking with a fluorescent FA probe. The labeled FA accumulated in lipid droplets (LDs) in well-fed cells but moved from LDs into mitochondria when cells were starved. Autophagy in starved cells replenished LDs with FAs, increasing LD number over time. Cytoplasmic lipases removed FAs from LDs, enabling their transfer into mitochondria. This required mitochondria to be highly fused and localized near LDs. When mitochondrial fusion was prevented in starved cells, FAs neither homogeneously distributed within mitochondria nor became efficiently metabolized. Instead, FAs reassociated with LDs and fluxed into neighboring cells. Thus, FAs engage in complex trafficking itineraries regulated by cytoplasmic lipases, autophagy, and mitochondrial fusion dynamics, ensuring maximum oxidative metabolism and avoidance of FA toxicity in starved cells.
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•Starvation-induced autophagy supplies lipid droplets (LDs) with fatty acids (FAs)•Cytoplasmic lipases release FAs from LDs for transfer into mitochondria•Mitochondrial fusion is required to distribute and oxidize transferred FAs•Mitochondrial fusion deficiency reroutes fatty acids to LDs and out of the cell
Mobilization of fatty acids (FAs) to mitochondria is crucial for cellular survival during nutrient stress. By visualizing FAs in live cells, Rambold et al. demonstrate that coordinated organelle dynamics—involving liberation of FAs from lipid droplets, autophagy, and mitochondrial fission/fusion—control FA flow to sustain mitochondrial respiration during nutrient stress.
For decades, it has been speculated that specific loci on eukaryotic chromosomes are inherently susceptible to breakage. The advent of high-throughput genomic technologies has now paved the way to ...their identification. A wealth of data suggests that transcriptionally active loci are particularly fragile and that a specific DNA damage response is activated and dedicated to their repair. Here, we review current understanding of the crosstalk between transcription and double-strand break repair, from the reasons underlying the intrinsic fragility of genes to the mechanisms that restore the integrity of damaged transcription units.
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•Novel sequencing-based methods revealed that active genes are particularly prone to breakage.•In G2, homologous recombination is favored at active genes.•Other less characterized pathways may ensure robust sequence recovery at active genes particularly in G1.•Transcription is subjected to a complex and dynamic regulation at damaged genes.
Maternal tolerance of the semiallogenic fetus necessitates conciliation of competing interests. Viviparity evolved with a placenta to mediate the needs of the fetus and maternal adaptation to the ...demands of pregnancy and to ensure optimal survival for both entities. The maternal-fetal interface is imagined as a 2-dimensional porous barrier between the mother and fetus, when in fact it is an intricate multidimensional array of tissues and resident and circulating factors at play, encompassing the developing fetus, the growing placenta, the changing decidua, and the dynamic maternal cardiovascular system. Pregnancy triggers dramatic changes to maternal hemodynamics to meet the growing demands of the developing fetus. Nearly a century of extensive research into the development and function of the placenta has revealed the role of placental dysfunction in the great obstetrical syndromes, among them preeclampsia. Recently, a debate has arisen questioning the primacy of the placenta in the etiology of preeclampsia, asserting that the maternal cardiovascular system is the instigator of the disorder.
It was the clinical observation of the high rate of preeclampsia in hydatidiform mole that initiated the focus on the placenta in the etiology of the disease. Over many years of research, shallow trophoblast invasion with deficient remodeling of the maternal spiral arteries into vessels of higher capacitance and lower resistance has been recognized as hallmarks of the preeclamptic milieu. The lack of the normal decrease in uterine artery resistance is likewise predictive of preeclampsia. In abdominal pregnancies, however, an extrauterine pregnancy develops without remodeling of the spiral arteries, yet there is reduced resistance in the uterine arteries and distant vessels, such as the maternal ophthalmic arteries.
Proponents of the maternal cardiovascular model of preeclampsia point to the observed maternal hemodynamic adaptations to pregnancy and maladaptation in gestational hypertension and preeclampsia and how the latter resembles the changes associated with cardiac disease states.
Recognition of the importance of the angiogenic-antiangiogenic balance between placental-derived growth factor and its receptor soluble fms-like tyrosine kinase-1 and disturbance in this balance by an excess of a circulating isoform, soluble fms-like tyrosine kinase-1, which competes for and disrupts the proangiogenic receptor binding of the vascular endothelial growth factor and placental-derived growth factor, opened new avenues of research into the pathways to normal adaptation of the maternal cardiovascular and other systems to pregnancy and maladaptation in preeclampsia.
The significance of the “placenta vs heart” debate goes beyond the academic: understanding the mutuality of placental and maternal cardiac etiologies of preeclampsia has far-reaching clinical implications for designing prevention strategies, such as aspirin therapy, prediction and surveillance through maternal hemodynamic studies or serum placental-derived growth factor and soluble fms-like tyrosine kinase-1 testing, and possible treatments to attenuate the effects of insipient preeclampsia on women and their fetuses, such as RNAi therapy to counteract excess soluble fms-like tyrosine kinase-1 produced by the placenta.
In this review, we will present an integrated model of the maternal-placental-fetal array that delineates the commensality among the constituent parts, showing how a disruption in any component or nexus may lead to the multifaceted syndrome of preeclampsia.
Inverse associations between dairy consumption and CVD have been reported in several epidemiological studies. Our objective was to conduct a meta-analysis of prospective cohort studies of dairy ...intake and CVD. A comprehensive literature search was conducted to identify studies that reported risk estimates for total dairy intake, individual dairy products, low/full-fat dairy intake, Ca from dairy sources and CVD, CHD and stroke. Random-effects meta-analyses were used to generate summary relative risk estimates (SRRE) for high v. low intake and stratified intake dose-response analyses. Additional dose-response analyses were performed. Heterogeneity was examined in sub-group and sensitivity analyses. In total, thirty-one unique cohort studies were identified and included in the meta-analysis. Several statistically significant SRRE below 1.0 were observed, namely for total dairy intake and stroke (SRRE=0·91; 95% CI 0·83, 0·99), cheese intake and CHD (SRRE=0·82; 95% CI 0·72, 0·93) and stroke (SRRE=0·87; 95% CI 0·77, 0·99), and Ca from dairy sources and stroke (SRRE=0·69; 95% CI 0·60, 0·81). However, there was little evidence for inverse dose-response relationships between the dairy variables and CHD and stroke after adjusting for within-study covariance. The results of this meta-analysis of prospective cohort studies have shown that dairy consumption may be associated with reduced risks of CVD, although additional data are needed to more comprehensively examine potential dose-response patterns.
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. We report the safety, ...tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mavorixafor from a phase 2 open-label dose-escalation and extension study in 8 adult patients with genetically confirmed WHIM syndrome. Mavorixafor is an oral small molecule selective antagonist of the CXCR4 receptor that increases mobilization and trafficking of white blood cells from the bone marrow. Patients received escalating doses of mavorixafor, up to 400 mg once daily. Five patients continued on the extension study for up to 28.6 months. Mavorixafor was well tolerated with no treatment-related serious adverse events. At a median follow-up of 16.5 months, we observed dose-dependent increases in absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). At doses ≥300 mg/d, ANC was maintained at >500 cells per microliter for a median of 12.6 hours, and ALC was maintained at >1000 cells per microliter for up to 16.9 hours. Continued follow-up on the extension study resulted in a yearly infection rate that decreased from 4.63 events (95% confidence interval, 3.3-6.3) in the 12 months prior to the trial to 2.27 events (95% confidence interval, 1.4-3.5) for patients on effective doses. We observed an average 75% reduction in the number of cutaneous warts. This study demonstrates that mavorixafor, 400 mg once daily, mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. The trial was registered at www.clinicaltrials.gov as #NCT03005327.
Sea star wasting disease (SSWD) describes a suite of disease signs believed to have led to catastrophic die-offs in many asteroid species, beginning in 2013. While most studies have focused on large, ...easily visible sea stars with widely-dispersing larvae, less information is available on the effect of this disease outbreak on smaller sea star species, such as the six-armed sea star Leptasterias spp. Unlike many larger sea stars, Leptasterias brood non-feeding young instead of broadcast-spawning planktonic larvae. Limited dispersal and thus limited gene flow may make these sea stars more vulnerable to local selective pressures, such as disease outbreaks. Here, we examined Leptasterias populations at sites along the California coast and documented abundance changes coincident with recent Pacific coast SSWD in 2014. Detection of Leptasterias in central California declined, and Leptasterias were not detected at multiple sites clustered around the San Francisco Bay outflow in the most recent surveys. Additionally, we categorized disease signs in Leptasterias in the field and laboratory, which mirrored those seen in larger sea stars in both settings. Finally, we found that magnesium chloride (MgCl2) slowed the progression of physical deterioration related to SSWD when applied to sea stars in the laboratory, suggesting that MgCl2 may prolong the survival of diseased individuals.
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