Search

Abstract We review the physics opportunities of the Future Circular Collider, covering its e+e-, pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics.

Abstract We analyse new signals of Dark Matter (DM) at the Large Hadron Collider (LHC) in a 3-Higgs Doublet Model (3HDM) where only one doublet acquires a Vacuum Expectation Value (VEV), preserving a parity Z 2. The other two doublets are inert and do not develop a VEV, leading to a dark scalar sector controlled by Z 2, with the lightest CP-even dark scalar H 1 being the DM candidate. This leads to the loop induced decay of the next-to-lightest scalar, H2→H1ff¯f=u,d,c,s,b,e,μ,τ $$ {H}_2\to {H}_1f\overline{f}\left(f=u,d,c,s,b,e,\mu, \tau \right) $$, mediated by both dark CP-odd and charged scalars. This is a smoking-gun signal of the 3HDM since it is not allowed in the 2HDM with one inert doublet and is expected to be important when H 2 and H 1 are close in mass. In practice, this signature can be observed in the cascade decay of the SM-like Higgs boson, h→H1H2→H1H1ff¯ $$ h\to {H}_1{H}_2\to {H}_1{H}_1f\overline{f} $$ into two DM particles and di-leptons/di-jets, where h is produced from either gluon-gluon Fusion (ggF) or Vector Boson Fusion (VBF). However, this signal competes with the tree-level channel qq¯→H1H1Z∗→H1H1ff¯ $$ q\overline{q}\to {H}_1{H}_1{Z}^{\ast}\to {H}_1{H}_1f\overline{f} $$. We devise some benchmarks, compliant with collider, DM and cosmological data, for which the interplay between these modes is discussed. In particular, we show that the resulting detector signature, , with invariant mass of ff¯ $$ f\overline{f} $$ much smaller than m Z , can potentially be extracted already during Run 2 and 3. For example, the H 2 → H 1 γ * and γ * → e + e − case will give a spectacular QED mono-shower signal.

Abstract The goal of this report is to summarize the current situation and discuss possible search strategies for charged scalars, in non-supersymmetric extensions of the Standard Model at the LHC. Such scalars appear in Multi-Higgs-Doublet models, in particular in the popular Two-Higgs-Doublet model, allowing for charged and additional neutral Higgs bosons. These models have the attractive property that electroweak precision observables are automatically in agreement with the Standard Model at the tree level. For the most popular version of this framework, Model II, a discovery of a charged Higgs boson remains challenging, since the parameter space is becoming very constrained, and the QCD background is very high. We also briefly comment on models with dark matter which constrain the corresponding charged scalars that occur in these models. The stakes of a possible discovery of an extended scalar sector are very high, and these searches should be pursued in all conceivable channels, at the LHC and at future colliders.

Abstract We study a new physics scenario with two inert and one active scalar doublets, hence a 3-Higgs Doublet Model (3HDM). We impose a Z 2 × Z 2 ′ $$ {Z}_2\times {Z}_2^{\prime } $$ symmetry onto such a 3HDM with one inert doublet odd under the Z 2 transformation and the other odd under the Z 2 ′ $$ {Z}_2^{\prime } $$ one. Such a construction leads to a two-component Dark Matter (DM) model. It has been shown that, when there is a sufficient mass difference between the two DM candidates, it is possible to probe the light DM candidate in the nuclear recoil energy in direct detection experiments and the heavy DM component in the photon flux in indirect detection experiments. With the DM masses at the electroweak scale, we show that, independently of astrophysical probes, this model feature can be tested at the Large Hadron Collider via scalar cascade decays in final states. We study several observable distributions whose shapes hint at the presence of the two different DM candidates.

Abstract We study the production of a neutral Higgs boson at a Future Circular Collider in the electron-hadron mode (FCC-eh) through the leading process $$e^- p \rightarrow \nu _e h q $$ e - p → ν e h q assuming the decay channel $$h \rightarrow c \bar{c} $$ h → c c ¯ , where h is the Standard Model (SM)-like state discovered at the Large Hadron Collider (LHC). This process is studied in the context of a 2-Higgs Doublet Model Type III (2HDM-III) embedding a four-zero texture in the Yukawa matrices and a general Higgs potential, where both Higgs doublets are coupled with up- and down-type fermions. Flavour Changing Neutral Currents (FCNCs) are well controlled by this approach through the adoption of a suitable texture once flavour physics constraints are taken in account. Considering the parameter space where the signal is enhanced and in agreement with both experimental data and theoretical conditions, we analyse the aforementioned signal by taking into account the most important SM backgrounds, separating c-jets from light-flavour and gluon ones as well as b-jets by means of efficient flavour tagging. We find that the $$h c \bar{c} $$ h c c ¯ coupling strength can be accessed with good significance after a luminosity of 1 ab $$^{-1}$$ - 1 for a 50 TeV proton beam and a 60 GeV electron one, the latter with a 80% (longitudinal) polarisation.

A pellet-induced enhanced confinement (PiEC) phase, with general characteristics similar to those reported for the stellarator W7-X, is observed after single pellet injection (>10 ^19 H atoms) into the neutral beam injection heated phase of plasmas in the mid-sized heliac-type stellarator TJ-II. In addition to a step-like increase in density, plasma diamagnetic energy content rises significantly with respect to that of reference discharges, energy confinement time is similarly enhanced when compared to International Stellarator Scaling law predictions (Yamada et al 2005 Nucl. Fusion 45 1684) renormalized for TJ-II, and the triple product, n _e · T _i · τ _E , exhibits a clear bifurcation towards an improved confinement branch when compared to the branch product predicted by the same law. In this work, multiple pellets are injected in series into NBI-heated plasmas in the TJ-II and post-injection plasma performance is reported and discussed. For instance, a charge-exchange recombination spectroscopy diagnostic reveals significantly increased core ion temperatures after pellet injection compared to temperatures achieved in comparable reference plasmas, this pointing to increased ion energy content and improved ion energy confinement during a PiEC phase. It is also found that enhanced performance is independent of whether co- or counter-NBI heating beam is employed. Finally, record stored diamagnetic energy content and plasma beta values are achieved when the largest available pellets are employed. The results indicate that pellet injections extend the operational regime well beyond limits previously achieved in TJ-II without pellets.

We provide an overview of activities carried out at the TJ-II stellarator for improving our understanding of- and developing plasma physics models for particle density profiles in stellarators. Namely, we report on recent progress in turbulent particle transport simulation, validation of pellet deposition models, density profile shaping for performance control and new experimental techniques for edge turbulence and plasma-neutral interaction.

Abstract We study an extension of the Standard Model (SM) in which two copies of the SM Higgs doublet are added to the scalar sector. These extra doublets do not develop a vacuum expectation value, hence, they are inert. This essentially leads to a 3-Higgs Doublet Model (3HDM) with 2 inert and 1 active scalar doublets, which we denote as I(2+1)HDM. We allow for CP-violation in the inert sector, where the lightest inert state is protected from decaying to SM particles through the conservation of a $$Z_2$$ Z2 symmetry, so that it is a Dark Matter (DM) candidate. For this scenario, we identify a smoking gun signature of dark CP-violation in the form of production thresholds of pairs of inert neutral Higgs bosons at an $$e^+e^-$$ e+e- collider.

In this Letter we analyse, in the context of the general 2-Higgs Doublet Model, the structure of the Yukawa matrices, Y˜1,2q, by assuming a four-zero texture ansatz for their definition. In this framework, we obtain compact expressions for Y˜1,2q, which are reduced to the Cheng and Sher ansatz with the difference that they are obtained naturally as a direct consequence of the invariants of the fermion mass matrices. Furthermore, in order to avoid large flavour violating effects coming from charged Higgs exchange, we consider the main flavour constraints on the off-diagonal terms of Yukawa texture (χ˜jq)kl (k≠l). We perform a χ2-fit based on current experimental data on the quark masses and the Cabibbo–Kobayashi–Maskawa mixing matrix VCKM. Hence, we obtain the allowed ranges for the parameters Y˜1,2q at 1σ for several values of tan⁡β. The results are in complete agreement with the bounds obtained taking into account constraints on Flavour Changing Neutral Currents reported in the literature. Keywords: Higgs physics, Flavour physics

Objective: Nonproliferative diabetic retinopathy (NPDR) is a progressive disease that can lead to blindness. Current therapies for NPDR are invasive and not extensively used or accessible until the disease progresses, pointing to the need for an early noninvasive treatment. The objective of CANBERRA was to assess the safety, tolerability, and efficacy of oral administration of vicasinabin (RG7774) on the severity of diabetic retinopathy (DR) in participants with moderately severe to severe NPDR and good vision., Design: CANBERRA was a global, multicentric randomized, double-masked, parallel-group, placebo-controlled, phase II study. The study duration was 36 months., Participants: A total of 139 treatment-naïve patients with type 1 or type 2 diabetes mellitus and Diabetic Retinopathy Severity Scale (DRSS) levels of 47 or 53 in ≥1 eye were enrolled., Intervention: Eligible patients were randomized 1:1:1 to 36 weeks of daily oral placebo, vicasinabin 30 mg, or vicasinabin 200 mg. Participants were followed for an additional 12 weeks., Main Outcome Measures: The primary safety objective was to evaluate the safety and tolerability of vicasinabin by the frequency and severity of adverse events (AEs). The primary efficacy objective was to assess the effect of vicasinabin on the severity of DR, assessing the proportion of participants with ≥2-step improvement in DRSS from baseline at week 36 in the study eye., Results: Results are presented in the following order: placebo, vicasinabin 30 mg, vicasinabin 200 mg; 47, 48, and 44 participants were enrolled. Baseline characteristics were balanced. Adherence to treatment was approximately 90%, and pharmacokinetic analysis showed dose-dependent plasma exposure to vicasinabin. The primary efficacy endpoint was not met: the percentage of participants who improved their DRSS by ≥2 steps at week 36 from baseline were 7.9, 9.5, and 5.7, without statistically significant differences. The systemic and ocular safety profiles of vicasinabin were favorable, and AEs distributed evenly across arms. Vicasinabin did not induce changes in glycemic control or any kidney function or cardiovascular parameters. Three patients in the placebo arm discontinued the study due to serious AEs not related to the drug., Conclusions: At the doses tested, vicasinabin did not improve DRSS in participants with NPDR. The role of the cannabinoid system in DR remains elusive., Trial Registration: ClinicalTrials.gov identifier: NCT04265261. EUDRACT number: 2019-002067-10., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmologyé.)

Objective: To describe the spatial and temporal characteristics of hyperreflective material (HRM) on spectral-domain OCT (SD-OCT) in neovascular age-related macular degeneration (nAMD) during antiangiogenic treatment and explore associations with best-corrected visual acuity (BCVA) and macular atrophy (MA)., Design: Retrospective regrading of SD-OCT-images from the multicenter, randomized controlled AVENUE trial (NCT02484690, conducted from August 2015 to September 2017)., Participants: Treatment-naive nAMD patients enrolled from 50 sites in the US., Methods: Retrospective regrading and secondary analysis., Main Outcome Measures: Spectral-domain OCT images from 207 study eyes that fit criteria for the present analysis were graded for HRM features, its evolution, and associated hypertransmission into choroid (HTC), a proxy for MA. The appearance of a well-defined hyperreflective inner boundary that separated persistent HRM from the neurosensory retina continuous with the adjacent retinal pigment epithelium layer was defined as hyperreflective material boundary remodeling (HRM-BR). Patterns of HRM composition/evolution were defined as follows: (1) no subretinal HRM at baseline, (2) fully resolved, (3) persistent with complete HRM-BR, or (4) partial/absent HRM-BR. Associations of HRM patterns with BCVA and HTC were analyzed. Predictive factors for complete HRM-BR were explored., Results: Of 207 included eyes, subretinal HRM was present in 159 (76.8%) at baseline and persisted until month 9 in 118 (57.0%) eyes. Of these 118 eyes, 44.9% developed complete HRM-BR and had similar BCVA outcomes by month 9 compared with no/fully resolved subretinal HRM. Partial/absent HRM-BR had a strong negative association with BCVA outcome (-6.1 ETDRS letters; P = 0.016) and a higher frequency of intralesional HTC (69.2%) compared with eyes with complete HRM-BR (20.8%) at month 9. Older age (odds ratio [OR], 0.96; P = 0.054) and presence of intralesional HTC (OR, 0.06; P = 0.010) at baseline were associated with lower odds of complete HRM-BR at month 9., Conclusions: In nAMD eyes under antiangiogenic treatment, complete HRM-BR occurred frequently and was associated with better BCVA than when HRM-BR was only partial/absent., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling., Methods: We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg -1 ) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor ( IL6R ) variant (rs7529229), known to associate with circulating IL-6R levels., Results: We recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88)., Conclusion: Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect., Competing Interests: Conflict of interest: M. Toshner reports grants and personal fees from Bayer and Actelion, and personal fees from MSD and GSK, during the conduct of the study, and serves on the advisory board for MorphogenIX. Conflict of interest: C. Church has received travel grants and speaker fees from GSK, Actelion and Bayer. Conflict of interest: L. Harbaum has nothing to disclose. Conflict of interest: C. Rhodes reports personal fees for advisory board work from Actelion and United Therapeutics, outside the submitted work. Conflict of interest: S.S. Villar Moreschi has nothing to disclose. Conflict of interest: J. Liley has nothing to disclose. Conflict of interest: R. Jones has nothing to disclose. Conflict of interest: A. Arora has nothing to disclose. Conflict of interest: K. Batai has nothing to disclose. Conflict of interest: A.A. Desai has nothing to disclose. Conflict of interest: J.G. Coghlan reports research support, consultancy fees and speaker honoraria from Actelion. Conflict of interest: J.S.R. Gibbs reports personal fees from Acceleron, Arena, Bayer, Bellepheron, Complexa, Pfizer and United Therapeutics, grants and personal fees from Actelion, and personal fees and non-financial support from GSK, outside the submitted work. Conflict of interest: D. Gor was an employee of Roche, during the conduct of the study. Conflict of interest: S. Gräf has nothing to disclose. Conflict of interest: L. Harlow has nothing to disclose. Conflict of interest: J. Hernandez-Sanchez is an employee of Roche but was not at the time of trial conduct. Conflict of interest: L.S. Howard has received personal fees and institutional grants/research support from Bayer and personal fees from MSD, Daichii Sayo and Pfizer. Conflict of interest: M. Humbert has received personal fees from Actelion, Merck and United Therapeutics, and grants and personal fees from Bayer and GSK. Conflict of interest: J. Karnes has nothing to disclose. Conflict of interest: D.G. Kiely reports grants and personal fees from Bayer and Actelion, and personal fees from GSK and MSD, during the conduct of the study. Conflict of interest: R. Kittles has nothing to disclose. Conflict of interest: E. Knightbridge has nothing to disclose. Conflict of interest: B. Lam has nothing to disclose. Conflict of interest: K.A. Lutz has nothing to disclose. Conflict of interest: W.C. Nichols has nothing to disclose. Conflict of interest: M.W. Pauciulo has nothing to disclose. Conflict of interest: J. Pepke-Zaba has served on advisory boards of and received personal fees and institutional grant/research support from Actelion, Bayer, MSD and GSK. Conflict of interest: J. Suntharalingam has nothing to disclose. Conflict of interest: F. Soubrier has nothing to disclose. Conflict of interest: R.C. Trembath has nothing to disclose. Conflict of interest: T-H.L. Schwantes-An has nothing to disclose. Conflict of interest: S.J. Wort reports grants and personal fees from Actelion and Bayer, and personal fees from GSK and MSD, outside the submitted work. Conflict of interest: M.R. Wilkins has nothing to disclose. Conflict of interest: S. Gaine has received honoraria from Actelion and United Therapeutics; has received travel grants from Actelion, Novartis and Menerini; and has performed drug safety board monitoring for United Therapeutics, GSK and Novartis. Conflict of interest: N.W. Morrell reports personal fees from MorphogenIX, during the conduct of the study. Conflict of interest: P.A. Corris has served on speakers’ bureau and advisory boards of Actelion, Bayer and MSD, and received institutional grant/research support from Actelion and Bayer., (Copyright ©The authors 2022.)

Superinfection exclusion (Sie) of FhuA-dependent phages is carried out by Cor in the Escherichia coli mEp167 prophage lysogenic strain. In this work, we present evidence that Cor is an outer membrane (OM) lipoprotein that requires the participation of additional outer membrane proteins (OMPs) to exclude FhuA-dependent phages. Two Cor species of ~13 and ~8.5 kDa, corresponding to the preprolipoprotein/prolipoprotein and lipoprotein, were observed by Western blot. Cell mutants for CorC17F, CorA18D and CorA57E lost the Sie phenotype for FhuA-dependent phages. A copurification affinity binding assay combined with LC_ESI_MS/MS showed that Cor bound to OMPs: OmpA, OmpC, OmpF, OmpW, LamB, and Slp. Interestingly, Sie for FhuA-dependent phages was reduced on Cor overexpressing FhuA+ mutant strains, where ompA, ompC, ompF, ompW, lamB, fhuE, genes were knocked out. The exclusion was restored when these strains were supplemented with plasmids expressing these genes. Sie was not lost in other Cor overexpressing FhuA+ null mutant strains JW3938(btuB-), JW5100(tolB-), JW3474(slp-). These results indicate that Cor interacts and requires some OMPs to exclude FhuA-dependent phages.

The aims of this study were to investigate the medication adherence of patients on pulmonary hypertension (PH)-targeted therapies and uncover factors that might influence adherence values. Patients taking at least one specialist medicine (sildenafil, tadalafil, bosentan, ambrisentan, iloprost, epoprostenol, treprostinil) completed a Morisky Medication Adherence Scale-8 (MMAS-8) questionnaire. Participants' MMAS-8 scores were used to estimate overall medicine adherence. Potential adherence co-factor data were collected from patient databases and hospital discharge summaries. The MMAS-8 questionnaire was completed by 263 patients (mean age = 61.6 ± 14.8 years, 70.6% women). Data from MMAS-8 showed that 47.9% reported high adherence, 40.3% moderate adherence, and 11.8% low adherence. Factors associated with adherence as measured by the MMAS-8 included: older age; taking monotherapy; and having a higher number of co-morbidities or concurrent medicines. Higher administration frequency, greater length of time on targeted therapy, and use of a compliance aid had a negative association with adherence. Overall adherence to PH specialist medicines is relatively high but a proportion of patients report sub-optimal adherence behavior. A number of factors may help to recognize susceptible patients.

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH., Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured., Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival., Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation., (© 2017 The Authors.)

In this study, 796 male Duroc pigs were used to identify genomic regions controlling growth traits. Three production traits were studied: food conversion ratio, days to 100 KG, and average daily gain, using a panel of 39,436 single nucleotide polymorphisms. In total, we detected 11 genome-wide and 162 chromosome-wide single nucleotide polymorphism trait associations. The Gene ontology analysis identified 14 candidate genes close to significant single nucleotide polymorphisms, with growth-related functions: six for days to 100 KG (WT1, FBXO3, DOCK7, PPP3CA, AGPAT9, and NKX6-1), seven for food conversion ratio (MAP2, TBX15, IVL, ARL15, CPS1, VWC2L, and VAV3), and one for average daily gain (COL27A1). Gene ontology analysis indicated that most of the candidate genes are involved in muscle, fat, bone or nervous system development, nutrient absorption, and metabolism, which are all either directly or indirectly related to growth traits in pigs. Additionally, we found four haplotype blocks composed of suggestive single nucleotide polymorphisms located in the growth trait-related quantitative trait loci and further narrowed down the ranges, the largest of which decreased by ~60 Mb. Hence, our results could be used to improve pig production traits by increasing the frequency of favorable alleles via artificial selection.

A Han Chinese patient failed CYP2D6 genotype analysis with the AmpliChip CYP450 Test™. The CYP2D6 gene locus of the patient and her son were extensively genotyped including copy number variation and gene resequencing. Two SNPs were discovered on the patient's CYP2D6*1 allele, -498C>A and 1661G>C, while the son's CYP2D6*1 allele had -498C>A only. AmpliChip failure was attributed to the presence of a CYP2D6*1 allele carrying the 1661G>C SNP. Functional analyses of -498C>A did not reveal altered activity in vitro or in vivo suggesting that both novel CYP2D6*1 subvariants are functional. The implementation of pharmacogenetics-guided drug therapy relies on accurate clinical-grade genotype analysis. Although the AmpliChip is a reliable platform, numerous allelic (sub)variants and gene arrangements are not detected or may trigger no calls. While such cases may be rare, the clinical/genetic testing community must be aware of the challenges of CYP2D6 testing on the AmpliChip platform and implications regarding accuracy of test results.

Different studies have shown that retinoids and their receptors [retinoic acid receptors (RARs) and retinoid X receptors (RXRs)] have crucial effects on the differentiation and function of myeloid cells such as Dendritic cells (DCs) and the development of lymphoid tissue. However, the relationship between RARβ expression and DCs has not been previously studied in vivo. This work examined the effect of decreased RARβ expression on the number (and probably on differentiation) of splenic DCs and the structure of spleen using a conditional mouse that partially ablates floxed RARβ gene (RARβ(L-/L-) mice). Our results showed that RARβ is expressed mainly in cells of the splenic White Pulp (WP) zone of Wild type mice. As expected, low levels of RARβ expression were detected in the spleen of RARβ(L-/L-) conditional mice. These results were consistent with a decrease in the population of splenic CD11c(+)MHC-II(+) cells. Histopathological analyses of conditional mice spleen indicated defects in cell organization and structure. The expression of Toll-like receptor 2 was also down-regulated in the spleen of these mice. These results suggest that RARβ is involved in splenic cell organization as well as in the maintenance of splenic DCs population, indicating that RARβ expression is important in homeostasis of immune system components., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In this work, we analyzed the kinetics of anti-Trichinella spiralis newborn larva (NBL) antibodies (Ab) and the antigenic recognition pattern of NBL proteins and its dose effects. Wistar rats were infected with 0, 700, 2000, 4000 and 8000 muscle larvae (ML) and bled at different time intervals up to day 31 post infection (p.i.). Ab production was higher with 2000 ML dose and decreased with 8000, 4000 and 700 ML. Abs were not detected until day 10, peaked on day 14 for the 2000 ML dose and on day 19 for the other doses and thereafter declined slowly from 19 to 31 days p.i. In contrast, Abs to ML increased from day 10, peaked on day 19 and remained high until the end of the study. Abs bound strongly at least to three NBL components of 188, 205 and 49 kDa. NBL antigen of 188 and 205 kDa were recognized 10-26 days p.i. and that of 49 kDa from day 10 to day 31 p.i. A weak recognition towards antigens of 52, 54, 62 and 83 kDa was also observed during the infection. An early recognition of 31, 43, 45, 55, 68 and 85 kDa ML antigens was observed whereas the response to those of 43, 45, 48, 60, 64 and 97 kDa (described previously as TSL-1 antigens) occurred late in the infection. A follow-up of antigen recognition up to day 61 with the optimal immunization dose (2000 ML) evidenced a decline of Ab production to the 49 kDa NBL antigen 42 days p.i., which suggested antigenic differences with the previously reported 43 kDa ML antigen strongly recognized late in the infection. To analyze the stage-specificity of the 49 kDa NBL antigen, polyclonal antibodies (PoAb) were obtained in rats immunized with 49 kDa NBL antigen. PoAb reacted strongly with the 49 kDa NBL component in NBL total soluble extract but no reactivity was observed with soluble antigen of the other T. spiralis stages. Albeit with less intensity, the 49 kDa component was also recognized by PoAb together with other antigens of 53, 97 and 107 kDa, in NBL excretory-secretory products (NBL-ESP). Thus, our results reveal differences in the kinetics of anti-NBL and ML Ab responses. While anti-NBL Abs declined slowly from day 19 until the end of the experiment, Abs to ML antigen remained high in the same period. It is remarkable the optimal Ab response to NBL antigens with 2000 ML infective dose and the reduced number of NBL antigens identified throughout the experimental T. spiralis infection, standing out the immunodominant 49 kDa antigen. Interestingly, this antigen, which was prominently expressed in NBL somatic proteins, was also detected in NBL-ESP.

The expression of minigenes in bacteria inhibits protein synthesis and cell growth. Presumably, the translating ribosomes, harboring the peptides as peptidyl-tRNAs, pause at the last sense codon of the minigene directed mRNAs. Eventually, the peptidyl-tRNAs drop off and, under limiting activity of peptidyl-tRNA hydrolase, accumulate in the cells reducing the concentration of specific aminoacylable tRNA. Therefore, the extent of inhibition is associated with the rate of starvation for a specific tRNA. Here, we used minigenes harboring various last sense codons that sequester specific tRNAs with different efficiency, to inhibit the translation of reporter genes containing, or not, these codons. A prompt inhibition of the protein synthesis directed by genes containing the codons starved for their cognate tRNA (hungry codons) was observed. However, a non-specific in vitro inhibition of protein synthesis, irrespective of the codon composition of the gene, was also evident. The degree of inhibition correlated directly with the number of hungry codons in the gene. Furthermore, a tRNA(Arg4)-sequestering minigene promoted the production of an incomplete beta-galactosidase polypeptide interrupted, during bacterial polypeptide chain elongation at sites where AGA codons were inserted in the lacZ gene suggesting ribosome pausing at the hungry codons.

Lambda bacteriophage development is impaired in Escherichia coli cells defective for peptidyl (pep)-tRNA hydrolase (Pth). Single-base-pair mutations (bar(-)) that affect translatable two-codon open reading frames named bar minigenes (barI or barII) in the lambda phage genome promote the development of this phage in Pth-defective cells (rap cells). When the barI minigene is cloned and overexpressed from a plasmid, it inhibits protein synthesis and cell growth in rap cells by sequestering tRNA(2)(Ile) as pep-tRNA(2)(Ile). Either tRNA(2)(Ile) or Pth may reverse these effects. In this paper we present evidence that both barI and barII minigenes are translatable elements that sequester tRNA(2)(Ile) as pep-tRNA(2)(Ile). In addition, overexpression of the barI minigene impairs the development even of bar(-) phages in rap cells. Interestingly, tRNA or Pth may reestablish lambda phage development. These results suggest that lambda bar minigenes are expressed and tRNA(2)(Ile) is sequestered as pep-tRNA(2)(Ile) during lambda phage development.