Singular expression of olfactory receptor genes.

Understanding the mechanisms of monogenic and monoallelic transcription of the large repertoire of olfactory receptor genes represents a challenging task. A picture is now emerging in which odorant receptor choice and stabilization involve an escape from silencing followed by the activation of an unconventional feedback loop.

The chemical MUPpeteer.

Rodents exhibit an innate fear-like behavior when they sense the chemical traces of predators. In this issue, Papes et al. (2010) report that the major urinary proteins (Mups) released by predators are detected by sensory neurons in the mouse vomeronasal organ (which also detects pheromones involved in aggression), triggering a fear response.

MicroRNA networks in FLT3-ITD acute myeloid leukemia.

MiR-126 and miR-155 are key microRNAs (miRNAs) that regulate, respectively, hematopoietic cell quiescence and proliferation. Herein we showed that in acute myeloid leukemia (AML), the biogenesis of these two miRNAs is interconnected through a network of regulatory loops driven by the FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD). In fact, FLT3-ITD induces the expression of miR-155 through a noncanonical mechanism of miRNA biogenesis that implicates cytoplasmic Drosha ribonuclease III (DROSHA). In turn, miR-155 down-regulates SH2-containing inositol phosphatase 1 (SHIP1), thereby increasing phosphor-protein kinase B (AKT) that in turn serine-phosphorylates, stabilizes, and activates Sprouty related EVH1 domain containing 1 (SPRED1). Activated SPRED1 inhibits the RAN/XPO5 complex and blocks the nucleus-to-cytoplasm transport of pre-miR-126, which cannot then complete the last steps of biogenesis. The net result is aberrantly low levels of mature miR-126 that allow quiescent leukemia blasts to be recruited into the cell cycle and proliferate. Thus, miR-126 down-regulation in proliferating AML blasts is downstream of FLT3-ITD­dependent miR-155 expression that initiates a complex circuit of concatenated regulatory feedback (i.e., miR-126/SPRED1, miR-155/human dead-box protein 3 [DDX3X]) and feed-forward (i.e., miR-155/SHIP1/AKT/miR-126) regulatory loops that eventually converge into an output signal for leukemic growth.

ZnO-Salen NPs Employed as Chemosensor for Detection of Al3+ and K+ in Aqueous Medium, Developing Human Cell Images.

ZnO nanoparticles (NPs) were prepared and characterized by different analytical methods and then they were used to decorate with N, N´-bis(salicylidene)ethylenediamine (salen) in order to perform as receptor for the metal ions in an aqueous medium. The results show that ZnO-salen selectively detects Al3+ ions in aqueous medium since the intensity of fluorescence has been enhanced significantly. However, the presence of K+ in the medium further intensified the fluorescence emission for the [ZnO-salen-Al3+] system. The above system has been applied to recognize Al3+ and K+ in cells by developing the cell images, for which, the fluorescence image is brightened if a human glioblastoma U251 cell contains [ZnO-salen-Al3+] + K+ ions, consisting of the fluorescence titration. The binding global constant for Al3+ and the subsequent recognition of K+ by ZnO-salen resulted in ß2(Al3+) = 6.61 × 103 and ß2(K+) = 3.71 × 103 with a detection limit of 36.51 µM for Al3+ and 17.39 µM for K+. In the cell toxicity analysis, the cell viability was over 85% for the ZnO-salen even in the concentration as high as 100 mM.

A severe case of reactive infectious mucocutaneous eruption associated with two possible triggers: Coronavirus and group A streptococcus.

Reactive infectious mucocutaneous eruption (RIME) is a newly defined condition characterized by mucocutaneous blistering secondary to upper respiratory infections and encompasses Mycoplasma pneumoniae-induced rash and mucositis, broadening the disease spectrum to include various infectious etiologies. We present a severe RIME case involving a 5-year-old female with concurrent coronavirus NL63 and group A streptococcus infections. Diagnosis complexity stemmed from overlapping clinical features with other severe mucocutaneous eruptions such as Stevens-Johnson syndrome/toxic epidermal necrolysis/drug-induced necrolysis. This case underscores the need for comprehensive infectious workup and emphasizes the clinical diagnostic spectrum of drug-induced and infection-induced desquamative skin and mucosal disease.

Postoperative fibrinolytic resistance is associated with early allograft dysfunction in liver transplantation: A prospective observational study.

Perioperative dysfunction of the fibrinolytic system may play a role in adverse outcomes for liver transplant recipients. There is a paucity of data describing the potential impact of the postoperative fibrinolytic system on these outcomes. Our objective was to determine whether fibrinolysis resistance (FR), on postoperative day one (POD-1), was associated with early allograft dysfunction (EAD). We hypothesized that FR, quantified by tissue plasminogen activator thrombelastography, is associated with EAD. Tissue plasminogen activator thrombelastography was performed on POD-1 for 184 liver transplant recipients at a single institution. A tissue plasminogen activator thrombelastography clot lysis at 30 minutes of 0.0% was identified as the cutoff for FR on POD-1. EAD occurred in 32% of the total population. Fifty-nine percent (n=108) of patients were categorized with FR. The rate of EAD was 42% versus 17%, p <0.001 in patients with FR compared with those without, respectively. The association between FR and EAD risk was assessed using multivariable logistic regression after controlling for known risk factors. The odds of having EAD were 2.43 times (95% CI, 1.07-5.50, p =0.03) higher in recipients with FR [model C statistic: 0.76 (95% CI, 0.64-0.83, p <0.001]. An additive effect of receiving a donation after circulatory determination of death graft and having FR in the rate of EAD was observed. Finally, compared with those without FR, recipients with FR had significantly shorter graft survival time ( p =0.03). In conclusion, FR on POD-1 is associated with EAD and decreased graft survival time. Postoperative viscoelastic testing may provide clinical utility in identifying patients at risk for developing EAD, especially for recipients receiving donation after circulatory determination of death grafts.

Fluorescence Sensing of Monosaccharides by Bis-boronic Acids Derived from Quinolinium Dicarboxamides: Structural and Spectroscopic Studies.

Three new diboronic acid-substituted bisquinolinium salts were synthesized, structurally described by single-crystal X-ray diffraction, and studied in-depth as fluorescent receptors for six monosaccharides and two open-chain polyols in water at physiological pH. The dicationic pyridine-2,6-dicarboxamide-based receptors contain two N-quinolinium rings as the fluorescent units covalently linked to three different isomers of phenylboronic acid (ortho, 2; meta, 3; and para, 4) as chelating binding sites for polyols. Additions of glucose/fructose in the micromolar concentration range to receptors 2 and 3 induce significant fluorescence changes, but in the presence of arabinose, galactose, mannose, and xylose, only modest optical changes are observed. This optical change is attributed to a static photoinduced electron transfer mechanism. The meta-diboronic receptor 3 exhibited a high affinity/selectivity toward glucose (K = 3800 M-1) over other monosaccharides including common interfering species such as fructose and mannitol. Based on multiple spectroscopic tools, electrospray ionization high-resolution mass spectrometry, crystal structures, and density functional theory calculations, the binding mode between 3 and glucose is proposed as a 1:1 complex with the glucofuranose form involving a cooperative chelating diboronate binding. These results demonstrate the usefulness of a new set of cationic fluorescent diboronic acid receptors with a strong ability for optical recognition of glucose in the sub-millimolar concentration range.

Histamine Recognition by Carbon Dots from Plastic Waste and Development of Cellular Imaging: Experimental and Theoretical Studies.

The present work highlights the sustainable approach for the transformation of plastic waste into fluorescent carbon dots (CDs) through carbonization and then they were functionalized with L-cysteine and o-phenylenediamine. CDs which were characterized by different analytical techniques such as X-ray diffraction (XRD), thermogravimetric analysis (TGA), Scanning electron microscopy (SEM), and transmission electron microscopy (TEM) are employed to recognize Cu2+, Fe2+, and Hg2+ ions. The results show that the fluorescence emission was considerably quenched, and it is consistent with the interference and Jobs plots. The detection limit was found to be 0.35µM for Cu(II), 1.38 µM for Hg(II), and 0.51µM Fe(III). The interaction of CDs with metal ions enhances the fluorescence intensity detecting histamine successfully. It shows that plastic waste-based CDs can be applied clinically to detect toxic metals and biomolecules. Moreover, the system was employed to develop the cellular images using Saccharomyces cerevisiae cells with the support of a confocal microscope. Furthermore, theoretical studies were performed for the naphthalene layer (AR) as a model for C-dots, then optimized its structure and analyzed by using the molecular orbital. The obtained TD-DFT spectra coincided with experimental spectra for CDs/M2+/histamine systems.

Bisphenols as promoters of the dysregulation of cellular junction proteins of the blood-testis barrier in experimental animals: A systematic review of the literature.

Daily, people are exposed to chemicals and environmental compounds such as bisphenols (BPs). These substances are present in more than 80% of human fluids. Human exposure to BPs is associated with male reproductive health disorders. Some of the main targets of BPs are intercellular junction proteins of the blood-testis barrier (BTB) in Sertoli cells because BPs alter the expression or induce aberrant localization of these proteins. In this systematic review, we explore the effects of BP exposure on the expression of BTB junction proteins and the characteristics of in vivo studies to identify potential gaps and priorities for future research. To this end, we conducted a systematic review of articles. Thirteen studies met our inclusion criteria. In most studies, animals treated with bisphenol-A (BPA) showed decreased occludin expression at all tested doses. However, bisphenol-AF treatment did not alter occludin expression. Cx43, ZO-1, ß-catenin, nectin-3, cortactin, paladin, and claudin-11 expression also decreased in some tested doses of BP, while N-cadherin and FAK expression increased. BP treatment did not alter the expression of α and γ catenin, E-cadherin, JAM-A, and Arp 3. However, the expression of all these proteins was altered when BPA was administered to neonatal rodents in microgram doses. The results show significant heterogeneity between studies. Thus, it is necessary to perform more research to characterize the changes in BTB protein expression induced by BPs in animals to highlight future research directions that can inform the evaluation of risk of toxicity in humans.

Phosphorylation of S11 in PHR1 negatively controls its transcriptional activity.

Plant responses to phosphate starvation (-Pi) are very well characterized at the biochemical and molecular levels. The expression of thousands of genes is modified under this stress condition, depending on the action of Phosphate starvation response 1 (PHR1). Existing data indicate that neither the PHR1 transcript nor the quantity or localization of its protein increase during nutrient stress, raising the question of how its activity is regulated. Here, we present data showing that SnRK1 kinase is able to phosphorylate some phosphate starvation response proteins (PSRs), including PHR1. Based on a model of the three-dimensional structure of the catalytic subunit SnRK1α1, docking simulations predicted the binding modes of peptides from PHT1;8, PHO1 and PHR1 with SnRK1. PHR1 recombinant protein interacted in vitro with the catalytic subunits SnRK1α1 and SnRK1α2. A BiFC assay corroborated the in vivo interaction between PHR1 and SnRK1α1 in the cytoplasm and nucleus. Analysis of phosphorylated residues suggested the presence of one phosphorylated site containing the SnRK1 motif at S11, and mutation in this residue disrupted the incorporation of 32 P, suggesting that it is a major phosphorylation site. Electrophoretic mobility shift assay results indicated that the binding of PHR1 to P1BS motifs was not influenced by phosphorylation. Importantly, transient expression assays in Arabidopsis protoplasts showed a decrease in PHR1 activity in contrast with the S11A mutant, suggesting a role for Ser11 as a negative regulatory phosphorylation site. Taken together, these findings suggest that phosphorylation of PHR1 at Ser11 is a mechanism to control the PHR1-mediated adaptive response to -Pi.

Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies.

OBJECTIVES: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. METHODS: We conducted a multicentre, international, retrospective cohort study. RESULTS: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. CONCLUSIONS: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

Control of the Two-photon Visual Process in ex vivo Retinas and in Living Mice.

Palcewska et al. first demonstrated near infrared (NIR) visual response in human volunteers upon two-photon absorption (TPA), in a seminal work of 2014, and assessed the process in terms of wavelength- and power-dependence on murine ex-vivo retinas. In the present study, ex-vivo electroretinography (ERG) is further developed to perform a complete characterization of the effect of NIR pulse duration, energy, and focal spot size on the response. The same set of measurements is successively tested on living mice. We discuss how the nonlinear intensity dependence of the photon absorption process is transferred to the amplitude of the visual response acquired by ERG. Finally, we show that the manipulation of the spectral phase of NIR pulses can be translated to predictable change in the two-photon induced response under physiological excitation conditions.

Hepatitis C virus infection screening reduces mortality and is cost-effective independently of the intervention test.

INTRODUCTION: Chronic infection due to hepatitis C virus (HCV) is frequently asymptomatic even in advanced stages of liver disease. Implementation of a screening program based on different HCV tests may enable an earlier diagnosis of HCV liver disease and subsequent application of highly effective treatment. PATIENTS AND METHODS: A Markov model which compares three different screening strategies for hepatitis C versus no screening in low-risk prevalence (general population) and high-risk prevalence population (people who inject drugs or prison population) was designed, taking into account age at the start of screening and participation. The three strategies were: 1) serological detection of antibodies against the HCV, 2) dried blood spot test (DBS) to detect antibodies against HCV and 3) detection of RNA from HCV. Quality-adjusted life-years (QALY) were taken as a measurement of effectiveness. The incremental cost-effectiveness ratio (ICER) was calculated and a deterministic and probabilistic sensitivity analysis was performed. RESULTS: All three screening strategies were found to be cost-effective with an ICER of €13,633, €12,015 and €12,328/QALY for AntiHCV, DBS-AntiHCV and DBS-RNA HCV, respectively. There was a decrease in mortality due to liver disease in comparison to no screening for AntiHCV (40.7% and 52%), DBS-AntiHCV (45% and 80%) and DBS-RNA HCV (45.2% and 80%) for low-prevalence and high-prevalence populations, respectively. CONCLUSION: All test interventions for HCV screening are cost-effective for the early detection of HCV infection, also achieving a reduction in mortality. Thus, implementation of screening programs for HCV should not be halted by decisions on monetary policy.

From immune to olfactory expression: neofunctionalization of formyl peptide receptors.

Variations in gene expression patterns represent a powerful source of evolutionary innovation. In a rodent living about 70 million years ago, a genomic accident led an immune formyl peptide receptor (FPR) gene to hijack a vomeronasal receptor regulatory sequence. This gene shuffling event forced an immune pathogen sensor to transition into an olfactory chemoreceptor, which thus moved from sensing the internal world to probing the outside world. We here discuss the evolution of the FPR gene family, the events that led to their neofunctionalization in the vomeronasal organ and the functions of immune and vomeronasal FPRs.

Unfavorable hydroxychloroquine COVID-19 research associated with authors having a history of political party donations.

We explored the degree to which political bias in medicine and study authors could explain the stark variation in Hydroxychloroquine (HCQ)/Chloroquine (CQ) study favorability in the US compared to the rest of the world. COVID-19/SARS-CoV-2 preprint and published papers between January 1, 2020-July 26, 2020 with Hydroxychloroquine and/or Chloroquine; 267 met study criteria, 68 from the US. A control subset was selected. HCQ/CQ study result favorability (favorable, unfavorable, or neutral) was noted. First and last main authors of each US study were entered into FollowTheMoney.org Website, extracting any history of political party donation. Of all US studies (68 total), 39/68 (57.4%) were unfavorable, with only 7/68 (10.3%) of US studies yielding favorable results-compared to 199 non-US studies, 66/199 (33.2%) unfavorable, 69/199 (34.7%) favorable, and 64/199 (32.2%) neutral. Studies with at least one US main author were 20.4% (SE 0.053, P < 0.05) more likely to report unfavorable results than non-US studies. US Studies with at least one main author donating to any political party were 25.6% (SE 0.085, P < 0.01) more likely to have unfavorable results. US studies with at least one author donating to the Democratic party were 20.4% (SE 0.045, P < 0.05) more likely to have unfavorable results. US authors were more likely to publish studies with medically harmful conclusions than non-US authors. Cardiology-specific HCQ/CQ studies were 44.2% more likely to yield harmful conclusions (P < 0.01). Inaccurate propagation of HCQ/CQ cardiac adverse effects with individual scientific author political bias has contributed to unfavorable US HCQ/CQ publication patterns and political polarization of the medications.

Fructooligosaccharides production by immobilized Pichia pastoris cells expressing Schedonorus arundinaceus sucrose:sucrose 1-fructosyltransferase.

Fructooligosaccharides (FOSs)-fructose-based oligosaccharides-are typical prebiotics with health-promoting effects in humans and animals. The trisaccharide 1-kestotriose is the most attractive inulin-type FOS. We previously reported a recombinant sucrose:sucrose 1-fructosyltransferase (1-SST, EC 2.4.1.99) from Schedonorus arundinaceus (Sa) that efficiently converts sucrose into 1-kestotriose. In this study, Pichia pastoris PGFT6x-308 constitutively expressing nine copies of the Sa1-SST gene displayed fructosyltransferase activity in undisrupted biomass (49.8 U/ml) and culture supernatant (120.7 U/ml) in fed-batch fermentation (72 hr) with sugarcane molasses. Toluene permeabilization increased 2.3-fold the Sa1-SSTrec activity of whole cells entrapped in calcium-alginate beads. The reaction with refined or raw sugar (600 g/l) yielded 1-kestotriose and 1,1-kestotetraose in a ratio of 8:2 with their sum representing above 55% (wt/wt) of total carbohydrates. The FOSs yield decreased to 45% (wt/wt) when sugarcane syrup and molasses were used as cheaper sucrose sources. The beads retained 80% residual Sa1-SSTrec activity after a 30-day batchwise operation with refined cane sugar at 30°C and pH 5.5. The immobilized biocatalyst is attractive for the continuous production of short-chain FOSs, most particularly 1-kestotriose.

Abatacept in interstitial lung disease associated with rheumatoid arthritis: national multicenter study of 263 patients.

OBJECTIVE: To assess the efficacy of abatacept (ABA) in RA patients with interstitial lung disease (ILD) (RA-ILD). METHODS: This was an observational, multicentre study of RA-ILD patients treated with at least one dose of ABA. ILD was diagnosed by high-resolution CT (HRCT). We analysed the following variables at baseline (ABA initiation), 12 months and at the end of the follow-up: Modified Medical Research Council (MMRC) scale (1-point change), forced vital capacity (FVC) or diffusion lung capacity for carbon monoxide (DLCO) (improvement or worsening ≥10%), HRCT, DAS on 28 joints evaluated using the ESR (DAS28ESR) and CS-sparing effect. RESULTS: We studied 263 RA-ILD patients [150 women/113 men; mean (s.d.) age 64.6 (10) years]. At baseline, they had a median duration of ILD of 1 (interquartile range 0.25-3.44) years, moderate or severe degree of dyspnoea (MMRC grade 2, 3 or 4) (40.3%), FVC (% of the predicted) mean (s.d.) 85.9 (21.8)%, DLCO (% of the predicted) 65.7 (18.3) and DAS28ESR 4.5 (1.5). The ILD patterns were: usual interstitial pneumonia (UIP) (40.3%), non-specific interstitial pneumonia (NSIP) (31.9%) and others (27.8%). ABA was prescribed at standard dose, i.v. (25.5%) or s.c. (74.5%). After a median follow-up of 12 (6-36) months the following variables did not show worsening: dyspnoea (MMRC) (91.9%); FVC (87.7%); DLCO (90.6%); and chest HRCT (76.6%). A significant improvement of DAS28ESR from 4.5 (1.5) to 3.1 (1.3) at the end of follow-up (P < 0.001) and a CS-sparing effect from a median 7.5 (5-10) to 5 (2.5-7.5) mg/day at the end of follow-up (P < 0.001) was also observed. ABA was withdrawn in 62 (23.6%) patients due to adverse events (n = 30), articular inefficacy (n = 27), ILD worsening (n = 3) and other causes (n = 2). CONCLUSION: ABA may be an effective and safe treatment for patients with RA-ILD.

Chemosensing of Guanosine Triphosphate Based on a Fluorescent Dinuclear Zn(II)-Dipicolylamine Complex in Water.

Guanosine triphosphate (GTP) is a key biomarker of multiple cellular processes and human diseases. The new fluorescent dinuclear complex [Zn2(L)(S)][OTf]4, 1 (asymmetric ligand, L = 5,8-Bis{[bis(2-pyridylmethyl)amino] methyl}quinoline, S = solvent, and OTf = triflate anion) was synthesized and studied in-depth as a chemosensor for nucleoside polyphosphates and inorganic anions in pure water. Additions at neutral pH of nucleoside triphosphates, guanosine diphosphate, guanosine monophosphate, and pyrophosphate (PPi) to 1 quench its blue emission (λem = 410 nm) with a pronounced selectivity toward GTP over other anions, including adenosine triphosphate (ATP), uridine triphosphate (UTP), and cytidine triphosphate (CTP). The efficient quenching response by the addition of GTP was observed in the presence of coexisting species in blood plasma and urine with a detection limit of 9.2 µmol L-1. GTP also shows much tighter binding to the receptor 1 on a submicromolar level. On the basis of multiple spectroscopic tools (1H, 31P NMR, UV-vis, and fluorescence) and DFT calculations, the binding mode is proposed through three-point recognition involving the simultaneous coordination of the N7 atom of the guanosine motif and two phosphate groups to the two Zn(II) atoms. Spectroscopic studies, MS-ESI, and DFT suggested that GTP bound to 1 in 1:1 and 2:2 models with high overall binding constants of log ß1 (1:1) = 6.05 ± 0.01 and log ß2 = 10.91 ± 0.03, respectively. The optical change and selectivity are attributed to the efficient binding of GTP to 1 by the combination of a strong electrostatic contribution and synergic effects of coordination bonds. Such GTP selectivity of an asymmetric metal-based receptor in water is still rare.

Automated generation of decision-tree models for the economic assessment of interventions for rare diseases using the RaDiOS ontology.

OBJECTIVE: The development of decision models to assess interventions for rare diseases require huge efforts from research groups, especially regarding collecting and synthesizing the knowledge to parameterize the model. This article presents a method to reuse the knowledge collected in an ontology to automatically generate decision tree models for different contexts and interventions. MATERIAL AND METHODS: We updated the reference ontology (RaDiOS) to include more knowledge required to generate a model. We implemented a transformation tool (RaDiOS-MTT) that uses the knowledge stored in RaDiOS to automatically generate decision trees for the economic assessment of interventions on rare diseases. RESULTS: We used a case study to illustrate the potential of the tool, and automatically generate a decision tree that reproduces an actual study on newborn screening for profound biotinidase deficiency. CONCLUSIONS: RaDiOS-MTT allows research groups to reuse the evidence collected, and thus speeding up the development of health economics assessments for interventions on rare diseases.

Evolution of immune chemoreceptors into sensors of the outside world.

Changes in gene expression patterns represent an essential source of evolutionary innovation. A striking case of neofunctionalization is the acquisition of neuronal specificity by immune formyl peptide receptors (Fprs). In mammals, Fprs are expressed by immune cells, where they detect pathogenic and inflammatory chemical cues. In rodents, these receptors are also expressed by sensory neurons of the vomeronasal organ, an olfactory structure mediating innate avoidance behaviors. Here we show that two gene shuffling events led to two independent acquisitions of neuronal specificity by Fprs. The first event targeted the promoter of a V1R receptor gene. This was followed some 30 million years later by a second genomic accident targeting the promoter of a V2R gene. Finally, we show that expression of a vomeronasal Fpr can reverse back to the immune system under inflammatory conditions via the production of an intergenic transcript linking neuronal and immune Fpr genes. Thus, three hijackings of regulatory elements are sufficient to explain all aspects of the complex expression patterns acquired by a receptor family that switched from sensing pathogens inside the organism to sensing the outside world through the nose.