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The Role of Olfaction in MCH-regulated Spontaneous Maternal Responses.
Brain Res. 2019 May 20;
Melanin concentrating hormone (MCH) is involved in the initiation of maternal behavior during the postpartum period. Virgin females also display some aspects of maternal care independent of the hormonal and neurochemical changes associated with pregnancy and parturition. Maternal behavior in virgin females is triggered by pups-generated chemosensory signals. We therefore examined the role of MCH in maternal-related behaviors in virgin mice and whether it involves chemosensory mechanisms. We used mice with germline knock-out of MCH receptor (MCHR1 KO) and mice with conditional ablation of MCH neurons (MCH cKO) using Cre-inducible diphtheria toxin (iDTR) system. We report that germline deletion of MCHR1 and ablation of MCH neurons impair spontaneous maternal behavior that is induced upon pups' exposure. The latency and duration to retrieve pups by MCHR1 KO and MCH cKO mice are longer than their control littermate mice. In support of this finding, we found that in the three-chamber social test, both MCHR1 KO and MCH cKO mice display a lack of interest in interacting with pups. Strikingly, however, we found that while MCHR1 KO mice were unable to detect pups' chemosensory signals and displayed impairment in general olfactory discrimination, MCH cKO mice exhibited normal olfactory function. Our findings indicate that the lack of MCHR1 or of normal MCH levels causes defects in maternal behavior in non-sensitized virgin mice, and that disruption of the olfactory signaling might not count for these defects.
Getter T,Gulati S,Zimmerman R,Chen Y,Vinberg F,Palczewski K
Stereospecific modulation of dimeric rhodopsin.
FASEB J. 2019 May 23;:fj201900443RR
The classic concept that GPCRs function as monomers has been challenged by the emerging evidence of GPCR dimerization and oligomerization. Rhodopsin (Rh) is the only GPCR whose native oligomeric arrangement was revealed by atomic force microscopy demonstrating that Rh exists as a dimer. However, the role of Rh dimerization in retinal physiology is currently unknown. In this study, we identified econazole and sulconazole, two small molecules that disrupt Rh dimer contacts, by implementing a cell-based high-throughput screening assay. Racemic mixtures of identified lead compounds were separated and tested for their stereospecific binding to Rh using UV-visible spectroscopy and intrinsic fluorescence of tryptophan (Trp) 265 after illumination. By following the changes in UV-visible spectra and Trp265 fluorescence , we found that binding of -econazole modulates the formation of Meta III and quenches the intrinsic fluorescence of Trp265. In addition, electrophysiological recording revealed that -econazole slows photoresponse kinetics, whereas -econazole decreased the sensitivity of rods without effecting the kinetics. Thus, this study contributes new methodology to identify compounds that disrupt the dimerization of GPCRs in general and validates the first active compounds that disrupt the Rh dimer specifically.-Getter, T., Gulati, S., Zimmerman, R., Chen, Y., Vinberg, F., Palczewski, K. Stereospecific modulation of dimeric rhodopsin.
Mendez Luque LF,Blackmon AL,Ramanathan G,Fleischman AG
Key Role of Inflammation in Myeloproliferative Neoplasms: Instigator of Disease Initiation, Progression. and Symptoms.
Curr Hematol Malig Rep. 2019 May 22;
Chronic inflammation is a characteristic feature of myeloproliferative neoplasm (MPN) and impacts many aspects of the disease including initiation, progression, and symptomatology.
Lallai V,Grimes N,Fowler JP,Sequeira PA,Cartagena P,Limon A,Coutts M,Monuki ES,Bunney W,Demuro A,Fowler CD
Nicotine Acts on Cholinergic Signaling Mechanisms to Directly Modulate Choroid Plexus Function.
Neuronal cholinergic circuits have been implicated in cognitive function and neurological disease, but the role of cholinergic signaling in other cellular populations within the brain has not been as fully defined. Here, we show that cholinergic signaling mechanisms are involved in mediating the function of the choroid plexus, the brain structure responsible for generating CSF and releasing various factors into the brain. The choroid plexus was found to express markers of endogenous cholinergic signaling, including multiple nicotinic acetylcholine receptor (nAChR) subtypes in a region-specific manner, and application of nicotine was found to induce cellular activation, as evidenced by calcium influx in primary tissue. During intravenous nicotine self-administration in male rats, nicotine increased expression of transthyretin, a protein selectively produced and released by the choroid plexus, and microRNA-204 (mir-204), a transcript found in high levels in the choroid plexus and CSF. Finally, human choroid plexus tissue from both sexes was found to exhibit similar nAChR, transthyretin and mir-204 expression profiles, supporting the translational relevance of the findings. Together, these studies demonstrate functionally active cholinergic signaling mechanisms in the choroid plexus, the resulting effects on transthyretin and mir-204 expression, and reveal the direct mechanism by which nicotine modulates function of this tissue.
Mathew V,Wang AK
Inotersen: new promise for the treatment of hereditary transthyretin amyloidosis.
Drug Des Devel Ther. 2019;13:1515-1525
Hereditary transthyretin amyloidosis is a fatal autosomal dominant disorder characterized by deposition of transthyretin amyloid into the peripheral nervous system, heart, kidney, and gastrointestinal tract. Previous treatments using liver transplantation and small molecule stabilizers were not effective in stopping disease progression. Inotersen, a 2'-O-methyoxyethyl-modified antisense oligonucleotide, which acts by reducing the production of transthyretin, was recently demonstrated to improve disease course and quality of life in early hereditary transthyretin amyloidosis polyneuropathy in a 15-month Phase III study.
Filipp FV,Li C,Boiko AD
CD271 is a molecular switch with divergent roles in melanoma and melanocyte development.
Sci Rep. 2019 May 22;9(1):7696
Dysregulation of signaling networks controlling self-renewal and migration of developmental cell lineages is closely linked to the proliferative and invasive properties of tumors. Identification of such signaling pathways and their critical regulators is vital for successful design of effective targeted therapies against neoplastic tissue growth. The neurotrophin receptor (CD271/NGFR/p75NTR) is a key regulator of the melanocytic cell lineage through its ability to mediate cell growth, survival, and differentiation. Using clinical melanoma samples, normal melanocytes and global gene expression profiling we have investigated the role of CD271 in rewiring signal transduction networks of melanoma cells during neoplastic transformation. Our analysis demonstrates that depending on the cell fate of tumor initiation vs normal development, elevated levels of CD271 can serve as a switch between proliferation/survival and differentiation/cell death. Two divergent arms of neurotrophin signaling hold the balance between positive regulators of tumor growth controlled by E2F, MYC, SREBP1 and AKT3 pathways on the one hand, and differentiation, senescence, and apoptosis controlled by TRAF6/IRAK-dependent activation of AP1 and TP53 mediated processes on the other hand. A molecular network map revealed in this study uncovers CD271 as a context-specific molecular switch between normal development and malignant transformation.
Hervera A,Zhou L,Palmisano I,McLachlan E,Kong G,Hutson TH,Danzi MC,Lemmon VP,Bixby JL,Matamoros-Angles A,Forsberg K,De Virgiliis F,Matheos DP,Kwapis J,Wood MA,Puttagunta R,Del RŪo JA,Di Giovanni S
PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.
EMBO J. 2019 May 22;
The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regeneration-competent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia (DRG) sensory neurons, a regeneration-incompetent central spinal cord injury does not. This dichotomic response offers a unique opportunity to investigate the fundamental biological mechanisms underpinning regenerative ability. Following a pharmacological screen with small-molecule inhibitors targeting key epigenetic enzymes in DRG neurons, we identified HDAC3 signalling as a novel candidate brake to axonal regenerative growth. , we determined that only a regenerative peripheral but not a central spinal injury induces an increase in calcium, which activates protein phosphatase 4 that in turn dephosphorylates HDAC3, thus impairing its activity and enhancing histone acetylation. Bioinformatics analysis of H3K9ac ChIPseq and RNAseq from DRG followed by promoter acetylation and protein expression studies implicated HDAC3 in the regulation of multiple regenerative pathways. Finally, genetic or pharmacological HDAC3 inhibition overcame regenerative failure of sensory axons following spinal cord injury. Together, these data indicate that PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.
Howard JF,Bril V,Burns TM,Mantegazza R,Bilinska M,Szczudlik A,Beydoun S,Garrido FJRR,Piehl F,Rottoli M,Van Damme P,Vu T,Evoli A,Freimer M,Mozaffar T,Ward ES,Dreier T,Ulrichts P,Verschueren K,Guglietta A,de Haard H,Leupin N,Verschuuren JJGM,
Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis.
Neurology. 2019 May 22;
To investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment.
Aras E,Ramadori G,Kinouchi K,Liu Y,Ioris RM,Brenachot X,Ljubicic S,Veyrat-Durebex C,Mannucci S,Galiť M,Baldi P,Sassone-Corsi P,Coppari R
Light Entrains Diurnal Changes in Insulin Sensitivity of Skeletal Muscle via Ventromedial Hypothalamic Neurons.
Cell Rep. 2019 May 21;27(8):2385-2398.e3
Loss of synchrony between geophysical time and insulin action predisposes to metabolic diseases. Yet the brain and peripheral pathways linking proper insulin effect to diurnal changes in light-dark and feeding-fasting inputs are poorly understood. Here, we show that the insulin sensitivity of several metabolically relevant tissues fluctuates during the 24†h period. For example, in mice, the insulin sensitivity of skeletal muscle, liver, and adipose tissue is lowest during the light period. Mechanistically, by performing loss- and gain-of-light-action and food-restriction experiments, we demonstrate that SIRT1 in steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH) convey photic inputs to entrain the biochemical and metabolic action of insulin in skeletal muscle. These findings uncover a critical light-SF1-neuron-skeletal-muscle axis that acts to finely tune diurnal changes in insulin sensitivity and reveal a light regulatory mechanism of skeletal muscle function.
Abbondante S,Pearlman E
Breaching bacterial biofilm with neutrophil a-mannosidase.
J Leukoc Biol. 2019 May 22;
Thompson LM,Tuck NL,Pressman SD,Consedine NS
Real Men Don't Cry: Skill Expressing Discrete Emotions Differentially Predicts Cardiovascular Disease Risk in Men and Women.
Ann Behav Med. 2019 May 22;
Expressing emotions effectively is central to social functioning and has links to health and cardiovascular disease (CVD) risk. Previous work has linked the ability to smile to lower CVD risk in men but has not studied other expressions or considered the context of these skills.
Young SD,Wang W,Chakravarthy B
Crowdsourced Traffic Data as an Emerging Tool to Monitor Car Crashes.
JAMA Surg. 2019 May 22;
Grigorian A,Lekawa M,Dolich M,Schubl SD,Doben AR,Kuza CM,Barrios C,Nahmias J
Smoking is associated with an improved short-term outcome in patients with rib fractures.
Eur J Trauma Emerg Surg. 2019 May 18;
Smokers with cardiovascular disease have been reported to have decreased mortality compared to non-smokers. Rib fractures are associated with significant underlying injuries such as lung contusions, lacerations, and/or pneumothoraces. We hypothesized that blunt trauma patients with rib fractures who are smokers have decreased ventilator days and risk of in-hospital mortality compared to non-smokers.
Azadi P,Lashay A,Esfahani MR
Bilateral Multiple Serous Retinal Detachments Following Bone Marrow Transplantation.
J Ophthalmic Vis Res. 14(2):219-222
To describe a case of bilateral multiple serous retinal detachments (SRD) following bone marrow transplantation (BMT), which showed bilateral response to a single unilateral intravitreal bevacizumab injection.
Maoz U,Sita KR,van Boxtel JJA,Mudrik L
Does It Matter Whether You or Your Brain Did It? An Empirical Investigation of the Influence of the Double Subject Fallacy on Moral Responsibility Judgments.
Front Psychol. 2019;10:950
Despite progress in cognitive neuroscience, we are still far from understanding the relations between the brain and the conscious self. We previously suggested that some neuroscientific texts that attempt to clarify these relations may in fact make them more difficult to understand. Such texts-ranging from popular science to high-impact scientific publications-position the brain and the conscious self as two independent, interacting subjects, capable of possessing opposite psychological states. We termed such writing 'Double Subject Fallacy' (DSF). We further suggested that such DSF language, besides being conceptually confusing and reflecting dualistic intuitions, might affect people's conceptions of moral responsibility, lessening the perception of guilt over actions. Here, we empirically investigated this proposition with a series of three experiments (pilot and two preregistered replications). Subjects were presented with moral scenarios where the defendant was either (1) clearly guilty, (2) ambiguous, or (3) clearly innocent while the accompanying neuroscientific evidence about the defendant was presented using DSF or non-DSF language. Subjects were instructed to rate the defendant's guilt in all experiments. Subjects rated the defendant in the clearly guilty scenario as guiltier than in the two other scenarios and the defendant in the ambiguously described scenario as guiltier than in the innocent scenario, as expected. In Experiment 1 ( = 609), an effect was further found for DSF language in the expected direction: subjects rated the defendant less guilty when the neuroscientific evidence was described using DSF language, across all levels of culpability. However, this effect did not replicate in Experiment 2 ( = 1794), which focused on different moral scenario, nor in Experiment 3 ( = 1810), which was an exact replication of Experiment 1. Bayesian analyses yielded strong evidence against the existence of an effect of DSF language on the perception of guilt. Our results thus challenge the claim that DSF language affects subjects' moral judgments. They further demonstrate the importance of good scientific practice, including preregistration and-most critically-replication, to avoid reaching erroneous conclusions based on false-positive results.
Butler EE,Mueller ND,Huybers P
Reply to Kovaleski and Baseggio: Increased corn yields from historical climate trends are a double-edged sword.
Proc Natl Acad Sci U S A. 2019 May 21;116(21):10209-10210
Serra L,Macchietto M,Macias-MuŮoz A,McGill CJ,Rodriguez IM,Rodriguez B,Murad R,Mortazavi A
Hybrid Assembly of the Genome of the Entomopathogenic Nematode Identifies the X-chromosome.
G3 (Bethesda). 2019 May 21;
Entomopathogenic nematodes from the genus are lethal insect parasites that quickly kill their insect hosts with the help of their symbiotic bacteria. is one of the most studied entomopathogens due to its broad lethality to diverse insect species and its effective commercial use as a biological control agent for insect pests, as well as a genetic model for studying parasitism, pathogenesis, and symbiosis. In this study, we used long-reads from the Pacific Biosciences platform and BioNano Genomics Irys system to assemble the most complete genome of the ALL strain to date, comprising 84.5 Mb in 16 scaffolds, with an N50 of 7.36 Mb. The largest scaffold, with 20.9 Mb, was identified as chromosome X based on sex-specific genome sequencing. The high level of contiguity allowed us to characterize gene density, repeat content, and GC content. RNA-seq data from 17 developmental stages, spanning from embryo to adult, were used to predict 30,957 gene models. Using this improved genome, we performed a macrosyntenic analysis to and and found chromosome X to be primarily orthologous to and chromosome II and IV. We also investigated the expansion of protein families and gene expression differences between adult male and female stage nematodes. This new genome and more accurate set of annotations provide a foundation for additional comparative genomic and gene expression studies within the clade and across the Nematoda phylum.
Nelson AS,Carvajal Acosta N,Mooney KA
Plant chemical mediation of ant behavior.
Curr Opin Insect Sci. 2019 Apr;32:98-103
Ants are ecologically dominant members of terrestrial communities. Ant foraging is often strongly associated with plants and depends upon associative learning of chemicals in the environment. As a result, plant chemicals can affect ant behaviors and, in so doing, have strong multi-trophic indirect effects. Plant chemicals mediate ant behaviors in the contexts of floral visitation, seed dispersal and predation, leaf cutting, interactions with ant-mutualist host plants, interactions with mutualist and prey insects in plant canopies, and plant predation of ants by carnivorous plants. Here, we review what is known about these differing contexts in which plant chemicals influence ant behavior, the mechanisms by which ants are affected by plant chemicals, and future directions within these topics.
Daar DA,Abdou SA,Rosario L,Rifkin WJ,Santos PJ,Wirth GA,Lane KT
Is There a Preferred Incision Location for Nipple-Sparing Mastectomy? A Systematic Review and Meta-Analysis.
Plast Reconstr Surg. 2019 05;143(5):906e-919e
The incidence of nipple-sparing mastectomy is rising, but no single incision type has been proven to be superior. This study systematically evaluated the rate and efficacy of various nipple-sparing mastectomy incision locations, focusing on nipple-areola complex necrosis and reconstructive method.
Laurent O,Benmarhnia T,Milesi C,Hu J,Kleeman MJ,Cockburn M,Wu J
Relationships between greenness and low birth weight: Investigating the interaction and mediation effects of air pollution.
Environ Res. 2019 May 02;175:124-132
Associations between residential greenness and improved birth weight have been increasingly reported, but underlying mechanisms and interactions with other environmental exposures are still unclear.
Paraiso KD,Blitz IL,Zhou JJ,Cho KWY
Morpholinos Do Not Elicit an Innate Immune Response during Early Xenopus Embryogenesis.
Dev Cell. 2019 May 20;49(4):643-650.e3
It has recently been reported that a common side effect of translation-blocking morpholino antisense oligonucleotides is the induction of a set of innate immune response genes in Xenopus embryos and that splicing-blocking morpholinos lead to unexpected off-target mis-splicing events. Here, we present an†analysis of all publicly available Xenopus RNA sequencing (RNA-seq) data in a reexamination of the effects of translation-blocking morpholinos on the innate immune response. Our analysis does not†support the authors' general conclusion, which was†based on a limited number of RNA-seq datasets. Moreover, the strong induction of an immune response appears to be specific to the tbxt/tbxt2 morpholinos. The more comprehensive study presented here indicates that using morpholinos for targeted gene knockdowns remains of considerable value for the rapid identification of gene function.
Kern MJ,Berry C,deBruyne B,Fearon W,Jeremias A,Johnson N,Kandzari D,Kirtane A,Moses J,Krucoff M,Stone G
Conversation in cardiology: Is there a need for clinical trials for the nonhyperemic pressure ratios?
Catheter Cardiovasc Interv. 2019 May 20;
Martynova A,Nael A,O Neill C,Ramsingh G,Merchant A,Yaghmour B,Yaghmour G
Aggressive systemic mastocytosis: midostaurin is safe, feasible and associated with durable response post-haploidentical allogeneic stem cell transplant.
Br J Haematol. 2019 May 21;
Farhat A,Grigorian A,Nguyen NT,Smith B,Williams BJ,Schubl SD,Joe V,Elfenbein D,Nahmias J
Obese trauma patients have increased need for dialysis.
Eur J Trauma Emerg Surg. 2019 May 20;
Obesity is a risk factor for the development of acute kidney injury but its effect on the need for dialysis in trauma has not been elucidated. Additionally, the contribution that obesity has towards risk of mortality in trauma is unclear. We hypothesized that patients with a higher body mass index (BMI) will have a higher risk for need of dialysis and mortality after trauma.
Karimova NV,McCaslin LM,Gerber RB
Ion reactions in atmospherically-relevant clusters: mechanisms, dynamics and spectroscopic signatures.
Faraday Discuss. 2019 May 21;
Reactions of nitrogen oxides with seawater are of major atmospheric importance, but microscopic understanding of these processes is still largely unavailable. In this paper we explore models of reactions of N2O4 with ions in water in order to provide molecular-level understanding of the processes. Presented here are studies of N2O4 interacting with two ions, SO42- and Cl-, in small water clusters. Reactions of the asymmetric conformer of N2O4 with SO42- ions in water clusters are studied via ab initio molecular dynamics (AIMD) simulations in order to unravel the microscopic mechanism of the processes and predict the timescales of different steps. Spectroscopic signatures of the reaction are proposed. The mechanisms of chloride substitution and hydrolysis of symmetric and asymmetric N2O4 are explored via intrinsic reaction coordinate (IRC) calculations. Spectroscopic calculations for relevant species suggest possible experimental signatures for the processes. The results of these model ion-N2O4 reactions in water throw light on the molecular-level mechanisms of the reactions of nitrogen oxides with seawater.