Search

Abstract The discovery potential of both singlet and doublet vector-like leptons (VLLs) at the Large Hadron Collider (LHC) as well as at the not-so-far future muon and electron machines is explored. The focus is on a single production channel for LHC direct searches while double production signatures are proposed for the leptonic colliders. A Deep Learning algorithm to determine the discovery (or exclusion) statistical significance at the LHC is employed. While doublet VLLs can be probed up to masses of 1 TeV, their singlet counterparts have very low cross sections and can hardly be tested beyond a few hundreds of GeV at the LHC. This motivates a physics-case analysis in the context of leptonic colliders where one obtains larger cross sections in VLL double production channels, allowing to probe higher mass regimes otherwise inaccessible even to the LHC high-luminosity upgrade.

Abstract In this work, we continue our exploration of TeV-scale vector-like fermion signatures inspired by a Grand Unification scenario based on the trinification gauge group. A particular focus is given to pair-production topologies of vector-like quarks (VLQs) at the LHC, in a multi-jet plus a charged lepton and a missing energy signature. We employ Deep Learning methods and techniques based in evolutive algorithms that optimize hyper-parameters in the neural network construction, whose objective is to maximise the Asimov estimate for distinct VLQ masses. In this article, we consider the implications of an innovative approach by simultaneously combining detector images (also known as jet images) and tabular data containing kinematic information from the final states. With this technique we are able to exclude VLQs, that are specific for the considered model, up to a mass of 800 GeV in both the high-luminosity the Run-III phases of the LHC programme.

Abstract We propose a model with two Higgs doublets and several SU(2) scalar singlets with a global non-Abelian flavor symmetry Q 6 × Z 2 $$ {\mathcal{Q}}_6\times {\mathcal{Z}}_2 $$ . This discrete group accounts for the observed pattern of fermion masses and mixing angles after spontaneous symmetry breaking. In this scenario only the third generation of fermions get their masses as in the Standard Model (SM). The masses of the remaining fermions are generated through a seesaw-like mechanism. To that end, the matter content of the model is enlarged by introducing electrically charged vector-like fermions (VLFs), right handed Majorana neutrinos and several SM scalar singlets. Here we study the processes involving VLFs that are within the reach of the Large Hadron Collider (LHC). We perform collider studies for vector-like leptons (VLLs) and vector-like quarks (VLQs), focusing on double production channels for both cases, while for VLLs single production topologies are also included. Utilizing genetic algorithms for neural network optimization, we determine the statistical significance for a hypothetical discovery at future LHC runs. In particular, we show that we can not safely exclude VLLs for masses greater than 200 GeV. For VLQ’s in our model, we show that we can probe their masses up to 3.8 TeV, if we take only into account the high-luminosity phase of the LHC. Considering Run-III luminosities, we can also exclude VLQs for masses up to 3.4 TeV. We also show how the model with predicted VLL masses accommodates the muon anomalous magnetic moment.

A chiral-symmetric technicolor model successfully reconciles the tension between electroweak precision tests and traditional technicolor models. Focusing on its simplest realization preserving the conventional Higgs mechanism, we study its primordial gravitational wave signatures originating from first order phase transitions in the early Universe. We found that abundant phase transition patterns arise from a physically viable parameter space. Besides, we have also found gravitational wave signals possibly visible by future experiments, such as LISA, BBO and u-DECIGO. Our results stress the importance of gravitational wave detectors in exploring new physics complementary to ground colliders in the multi-messenger astronomy era.

Abstract In this paper, a model inspired by Grand Unification principles featuring three generations of vector-like fermions, new Higgs doublets and a rich neutrino sector at the low scale is presented. Using the state-of-the-art Deep Learning techniques we perform the first phenomenological analysis of this model focusing on the study of new charged vector-like leptons (VLLs) and their possible signatures at CERN’s Large Hadron Collider (LHC). In our numerical analysis we consider signal events for vector-boson fusion and VLL pair production topologies, both involving a final state containing a pair of charged leptons of different flavor and two sterile neutrinos that provide a missing energy. We also consider the case of VLL single production where, in addition to a pair of sterile neutrinos, the final state contains only one charged lepton. We propose a novel method to identify missing transverse energy vectors by comparing the detector response with Monte-Carlo simulated data. All calculated observables are provided as data sets for Deep Learning analysis, where a neural network is constructed, based on results obtained via an evolutive algorithm, whose objective is to maximise either the accuracy metric or the Asimov significance for different masses of the VLL. Taking into account the effect of the three analysed topologies, we have found that the combined significance for the observation of new VLLs at the high-luminosity LHC can range from 5.7σ, for a mass of 1.25 TeV, all the way up to 28σ if the VLL mass is 200 GeV. We have also shown that by the end of the LHC Run-III a 200 GeV VLL can be excluded with a confidence of 8.8 standard deviations. The results obtained show that our model can be probed well before the end of the LHC operations and, in particular, providing important phenomenological information to constrain the energy scale at which new gauge symmetries emergent from the considered Grand Unification picture can be manifest.

Early in Alzheimer's disease (AD), pericytes constrict capillaries, increasing their hydraulic resistance and trapping of immune cells and, thus, decreasing cerebral blood flow (CBF). Therapeutic approaches to attenuate pericyte-mediated constriction in AD are lacking. Here, using in vivo two-photon imaging with laser Doppler and speckle flowmetry and magnetic resonance imaging, we show that Ca 2+ entry via L-type voltage-gated calcium channels (CaVs) controls the contractile tone of pericytes. In AD model mice, we identifed pericytes throughout the capillary bed as key drivers of an immune reactive oxygen species (ROS)-evoked and pericyte intracellular calcium concentration ([Ca 2+ ] i )-mediated decrease in microvascular flow. Blocking CaVs with nimodipine early in disease progression improved CBF, reduced leukocyte stalling at pericyte somata and attenuated brain hypoxia. Amyloid β (Aβ)-evoked pericyte contraction in human cortical tissue was also greatly reduced by CaV block. Lowering pericyte [Ca 2+ ] i early in AD may, thus, offer a therapeutic strategy to enhance brain energy supply and possibly cognitive function in AD., (© 2024. The Author(s).)

Background: Aldosterone excess chronically induces oxidative stress and cell proliferation. Previously, a single study investigated primary aldosteronism (PA) in patients with papillary thyroid cancer (PTC), albeit without a matched control group., Methods: We conducted a propensity score matched case-control study to investigate the association between PA and PTC in individuals with arterial hypertension (HT). PA was investigated in 137 patients with PTC and HT. The control group included 137 (1:1) age, sex-, and body mass index (BMI)-matched individuals with HT. We conducted a secondary analysis in which the controls were also matched according to HT stage., Results: The prevalence of PA was 29.20% (95% confidence interval [CI], 21.91%-37.68%) in the PTC group and 20.44% (95% CI, 14.22%-28.35%) in the controls not matched for HT stage (p = 0.093). Although the PA prevalence was similar in both groups, the frequency of severe HT (stage III or resistant) was significantly lower in the PTC group (23%) compared to the hypertensive controls (73%, p < 0.001). After matching the controls by HT stage, the prevalence of PA in the PTC group was significantly higher compared to the hypertensive controls (9.56%; 95% CI, 5.39%-16.1%, p < 0.0001). In the multivariable analysis, PTC was independently associated with PA in both unmatched hypertensive individuals (odds ratio [OR] 4.74; 95% CI, 2.26-10.55; p< 0.001) and in those matched for HT stage (OR 5.88, 95% CI, 2.79-13.37; p< 0.001)., Conclusion: PTC was an independent variable associated with a diagnosis of PA in hypertensive individuals. Therefore, we propose the association between PTC and HT as a new recommendation for PA screening regardless of HT severity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with clinical heterogeneity and a high association with hereditary disease, affecting approximately 30 % of the cases. Differences in the presentation and genetic etiologies of PPGLs have been demonstrated between Chinese and European patients. The frequency of germline genetic diagnosis was remarkably higher in Brazilian patients (∼50 %) compared with other cohorts (Chinese 21 %, European 31 %, and The Cancer Genome Atlas Program cohort 27 %). Interestingly, germline SDHB genetic defects were also more prevalent in Brazilian patients (17 %) with PPGLs when compared with other cohorts (3-9 %). The SDHB exon 1 deletion was responsible for approximately 50 % of the SDHB pathogenic/likely pathogenic variants in Brazilian patients with PPGLs due to a founder effect. The germline SDHB exon 1 deletion represents ∼10 % of the germline drivers in Brazilian patients (and possibly in Latin America). Therefore, a single diagnostic PCR for the SDHB exon 1 deletion might be very useful in clinical practice for genetic testing and counseling of patients with PPGLs in Latin America., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In the protozoan parasite Leishmania, most genes encoding for ribosomal proteins (RPs) are present as two or more copies in the genome. However, their untranslated regions (UTRs) are predominantly divergent and might be associated with a distinct regulation of the expression of paralogous genes. Herein, we investigated the expression profiles of two RPs (S16 and L13a) encoded by duplicated genes in Leishmania major. The genes encoding for the S16 protein possess identical coding sequences (CDSs) and divergent UTRs, whereas the CDSs of L13a diverge by two amino acids and by their UTRs. Using CRISPR/Cas9 genome editing, we generated knockout (Δ) and endogenously tagged transfectants for each paralog of L13a and S16 genes. Combining tagged and Δ cell lines we found evidence of differential expression of both RPS16 and RPL13a isoforms throughout parasite development, with one isoform consistently more abundant than its respective copy. In addition, compensatory expression was observed for each paralog upon deletion of the corresponding isoform, suggesting functional conservation between these proteins. This differential expression pattern relates to post-translational processes, given compensation occurs at the level of the protein, with no alterations detected at transcript level. Ribosomal profiles for RPL13a indicate a standard behavior for these paralogues suggestive of interaction with heavy RNA-protein complexes, as already reported for other RPs in trypanosomatids. We identified paralog-specific bound to their 3'UTRs which may be influential in regulating paralog expression. In support, we identified conserved cis-elements within the 3'UTRs of RPS16 and RPL13a; cis-elements exclusive to the UTR of the more abundant paralog or to the less abundant ones were identified., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Borges et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Context: Confirmatory tests represent a fundamental step in primary aldosteronism (PA) diagnosis, but they are laborious and often require a hospital environment due to the risks involved., Objective: To evaluate the efficacy of oral furosemide as a new confirmatory test for PA diagnosis., Methods: We prospectively evaluated the diagnostic performance of 80 mg of oral furosemide in 64 patients with PA and 22 with primary hypertension (controls). Direct renin concentration (DRC) was measured before, and 2 hours and 3 hours after the oral furosemide. In addition, the oral furosemide test was compared with 2 other confirmatory tests: the furosemide upright test (FUT) and saline infusion test (SIT) or captopril challenge test (CCT) in all patients with PA., Results: The cut-off of 7.6 µU/mL for DRC at 2 hours after oral furosemide had a sensitivity of 92%, specificity of 82%, and accuracy of 90% for PA diagnosis. In 5 out of 6 controls with low-renin hypertension, which might represent a PA spectrum, renin remained suppressed. Excluding these 6 controls with low-renin hypertension, the DRC cut-off of 10 µU/mL at 2 hours after oral furosemide had a sensitivity of 95.3%, specificity of 93.7% and accuracy of 95% for PA diagnosis. DRC after 3 hours of oral furosemide did not improve diagnostic performance. Using the cut-off of 10 µU/mL, the oral furosemide test and the FUT were concordant in 62 out of 64 (97%) patients with PA. Only 4 out of 64 cases with PA (6.4%) ended the oral furosemide test with potassium <3.5 mEq/L. Hypotension was not evidenced in any patient with PA during the test., Conclusion: The oral furosemide test was safe, well-tolerated and represents an effective strategy for PA investigation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Limited information is available concerning the genetic spectrum of pheochromocytoma and paraganglioma (PPGL) patients in South America. Germline SDHB large deletions are very rare worldwide, but most of the individuals harboring the SDHB exon 1 deletion originated from the Iberian Peninsula., Objective: Our aim was to investigate the spectrum of SDHB genetic defects in a large cohort of Brazilian patients with PPGLs., Methods: Genetic investigation of 155 index PPGL patients was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and/or target next-generation sequencing panel. Common ancestrality was investigated by microsatellite genotyping with haplotype reconstruction, and analysis of deletion breakpoint., Results: Among 155 index patients, heterozygous germline SDHB pathogenic or likely pathogenic variants were identified in 22 cases (14.2%). The heterozygous SDHB exon 1 complete deletion was the most frequent genetic defect in SDHB, identified in 8 out of 22 (36%) of patients. Haplotype analysis of 5 SDHB flanking microsatellite markers demonstrated a significant difference in haplotype frequencies in a case-control permutation test (P = 0.03). More precisely, 3 closer/informative microsatellites were shared by 6 out of 8 apparently unrelated cases (75%) (SDHB-GATA29A05-D1S2826-D1S2644 | SDHB-186-130-213), which was observed in only 1 chromosome (1/42) without SDHB exon 1 deletion (X2 = 29.43; P < 0.001). Moreover, all cases with SDHB exon 1 deletion had the same gene breakpoint pattern of a 15 678 bp deletion previously described in the Iberian Peninsula, indicating a common origin., Conclusion: The germline heterozygous SDHB exon 1 deletion was the most frequent genetic defect in the Brazilian PPGL cohort. Our findings demonstrated a founder effect for the SDHB exon 1 deletion in Brazilian patients with paragangliomas., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Intracellular parasites from the Leishmania genus cause Leishmaniasis, a disease affecting millions of people worldwide. NLRP3 inflammasome is key for disease outcome, but the molecular mechanisms upstream of the inflammasome activation are still unclear. Here, we demonstrate that despite the absence of pyroptosis, Gasdermin-D (GSDMD) is active at the early stages of Leishmania infection in macrophages, allowing transient cell permeabilization, potassium efflux, and NLRP3 inflammasome activation. Further, GSDMD is processed into a non-canonical 25 kDa fragment. Gsdmd -/- macrophages and mice exhibit less NLRP3 inflammasome activation and are highly susceptible to infection by several Leishmania species, confirming the role of GSDMD for inflammasome-mediated host resistance. Active NLRP3 inflammasome and GSDMD are present in skin biopsies of patients, demonstrating activation of this pathway in human leishmaniasis. Altogether, our findings reveal that Leishmania subverts the normal functions of GSDMD, an important molecule to promote inflammasome activation and immunity in Leishmaniasis., (© 2023. The Author(s).)

The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an ACE2 sequence similar to human ACE2, angiotensin II evoked a small pericyte-mediated capillary constriction via AT1 receptors, but evoked a large constriction when the SARS-CoV-2 receptor binding domain (RBD, original Wuhan variant) was present. A mutated non-binding RBD did not potentiate constriction. A similar RBD-potentiated capillary constriction occurred in human cortical slices, and was evoked in hamster brain slices by pseudotyped virions expressing SARS-CoV-2 spike protein. This constriction reflects an RBD-induced decrease in the conversion of angiotensin II to angiotensin-(1-7) mediated by removal of ACE2 from the cell surface membrane and was mimicked by blocking ACE2. The clinically used drug losartan inhibited the RBD-potentiated constriction. Thus, AT1 receptor blockers could be protective in COVID-19 by preventing pericyte-mediated blood flow reductions in the brain, and perhaps the heart and kidney., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Acute kidney injury is common, with ~13 million cases and 1.7 million deaths/year worldwide. A major cause is renal ischaemia, typically following cardiac surgery, renal transplant or severe haemorrhage. We examined the cause of the sustained reduction in renal blood flow ('no-reflow'), which exacerbates kidney injury even after an initial cause of compromised blood supply is removed. Adult male Sprague-Dawley rats, or NG2-dsRed male mice were used in this study. After 60 min kidney ischaemia and 30-60 min reperfusion, renal blood flow remained reduced, especially in the medulla, and kidney tubule damage was detected as Kim-1 expression. Constriction of the medullary descending vasa recta and cortical peritubular capillaries occurred near pericyte somata, and led to capillary blockages, yet glomerular arterioles and perfusion were unaffected, implying that the long-lasting decrease of renal blood flow contributing to kidney damage was generated by pericytes. Blocking Rho kinase to decrease pericyte contractility from the start of reperfusion increased the post-ischaemic diameter of the descending vasa recta capillaries at pericytes, reduced the percentage of capillaries that remained blocked, increased medullary blood flow and reduced kidney injury. Thus, post-ischaemic renal no-reflow, contributing to acute kidney injury, reflects pericytes constricting the descending vasa recta and peritubular capillaries. Pericytes are therefore an important therapeutic target for treating acute kidney injury., Competing Interests: FF, DA No competing interests declared, (© 2022, Freitas and Attwell.)

Host manipulation is a common strategy for invading pathogens. Trypanosoma cruzi , the causative agent of Chagas Disease, lives intracellularly within host cells. During infection, parasite-associated modifications occur to the host cell metabolism and morphology. However, little is known about the effect of T. cruzi infection on the host cell nucleus and nuclear functionality. Here, we show that T. cruzi can modulate host transcription and splicing machinery in non-professional phagocytic cells during infection. We found that T. cruzi regulates host RNA polymerase II (RNAPII) in a time-dependent manner, resulting in a drastic decrease in RNAPII activity. Furthermore, host cell ribonucleoproteins associated with mRNA transcription (hnRNPA1 and AB2) are downregulated concurrently. We reasoned that T. cruzi may hijack the host U2AF35 auxiliary factor, a key regulator for RNA processing, as a strategy to affect the splicing machinery activities directly. In support of our hypothesis, we carried out in vivo splicing assays using an adenovirus E1A pre-mRNA splicing reporter, showing that intracellular T. cruzi directly modulates the host cells by appropriating U2AF35. For the first time, our results provide evidence of a complex and intimate molecular relationship between T. cruzi and the host cell nucleus during infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gachet-Castro, Freitas-Castro, Gonzáles-Córdova, da Fonseca, Gomes, Ishikawa-Ankerhold and Baqui.)

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. During the chronic phase of disease, while most infected people do not present symptoms, characterizing the asymptomatic form, some patients develop the cardiac form or chronic chagasic cardiomyopathy, which is considered the most severe manifestation of this disease. Considering that the activation of the PI3Kγ signaling pathway is essential for an efficient immune response against T. cruzi infection, we evaluated the PIK3CG C > T (rs1129293) polymorphism in exon 3 of this gene, which encodes the catalytic subunit of PI3Kγ. The PIK3CG CT and TT genotypes were found to be associated with an increased risk of developing the cardiac form of the disease rather than the asymptomatic or digestive forms. In conclusion, the presence of the T allele at single or double doses may differentiate the cardiac from other clinical manifestations of Chagas disease. This finding should help in further studies to evaluate the mechanisms underlying the differential association of PIK3CG in Chagas disease., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Expression dysregulation of HOX homeobox genes has been observed in several cancers, including head and neck squamous cell carcinoma (HNSC). Although characterization of HOX gene roles in HNSC development has been reported, there is still a need to better understand their real contribution to tumorigenesis., Objective: The present study aimed to evaluate the contribution of the protein-coding HOX genes (HOXA10, HOXC9, HOXC10, and HOXC13) in cellular processes related to carcinogenesis and progression of the HNSC., Methods: Expression of HOX genes was analyzed in HNSC RNA-Seq data from The Cancer Genome Atlas (TCGA) and by RT-qPCR in different tumor cell lines. siRNA-mediated knockdown of HOXA10, HOXC9, HOXC10 or HOXC13 was performed in HNSC cell lines, and predicted transcriptional targets HOX genes was analyzed by bioinformatic., Results: Thirty-one out of the 39 mammalian HOX genes were found upregulated in HNSC tissues and cell lines. The HOXC9, HOXC10 or HOXC13 knockdown attenuated cell migration, and lead to downregulation of epithelial-mesenchymal transition (EMT) markers, which were predicted as transcriptional targets of these three HOX genes. Diminished colony formation and cell cycle arrest after HOXC10 or HOXC13 knockdown were also observed, corroborating the fact that there was an enrichment for genes in proliferation/cell cycle pathways., Conclusions: In summary, we revealed roles for HOXC9, HOXC10, and HOXC13 in cell migration and proliferation/cell cycle progression in HNSC cells and suggested that those HOX members contribute to HNSC development possibly by regulating tumor growth and metastasis.

Antioxidant effects of statins have been implicated in the reduction in microvascular permeability and edema formation in experimental and clinical studies. Bradykinin (Bk)-induced increases in microvascular permeability are potentiated by IL-1β; however, no studies have examined the protection afforded by statins against microvascular hyperpermeability. We investigated the effects of simvastatin pretreatment on albumin-fluorescein isothiocyanate conjugate (FITC-albumin) permeability in post-capillary venules in rat cremaster muscle. Inhibition of nitric oxide synthase with L-NAME (10µM) increased basal permeability to FITC-albumin, which was abrogated by superoxide dismutase and catalase. Histamine-induced (1 µM) permeability was blocked by L-NAME but unaffected by scavenging reactive oxygen species with superoxide dismutase (SOD) and catalase. In contrast, bradykinin-induced (1-100 nM) permeability increases were unaffected by L-NAME but abrogated by SOD and catalase. Acute superfusion of the cremaster muscle with IL-1β (30 pM, 10 min) resulted in a leftward shift of the bradykinin concentration-response curve. Potentiation by IL-1β of bradykinin-induced microvascular permeability was prevented by the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) inhibitor apocynin (1 µM). Pretreatment of rats with simvastatin (5 mg·kg -1 , i.p.) 24 h before permeability measurements prevented the potentiation of bradykinin permeability responses by IL-1β, which was not reversed by inhibition of heme oxygenase-1 with tin protoporphyrin IX (SnPP). This study highlights a novel mechanism by which simvastatin prevents the potentiation of bradykinin-induced permeability by IL-1β, possibly by targeting the assembly of NADPH oxidase subunits. Our findings highlight the therapeutic potential of statins in the prevention and treatment of patients predisposed to inflammatory diseases.

In the last 30 years, significant advances in genetic manipulation tools along with complete genome and transcriptome sequencing have advanced our understanding of the biology of Leishmania parasites and their interplay with the sand fly and mammalian hosts. High-throughput sequencing in association with CRISPR/Cas9 have prepared the ground for significant advances. Given the richness of the progress made over the last decade, in this article, we focused on the most recent contributions of genome-wide and transcriptome analyses of Leishmania spp., which permit the comparison of life cycle stages, the evaluation of different strains and species in their natural niches and in the field and the simultaneously comparison of the gene expression profiles of parasites and hosts., (Copyright © 2019. Published by Elsevier Ltd.)

It is becoming increasingly apparent that disorders of the brain microvasculature contribute to many neurological disorders. In recent years it has become clear that a major player in these events is the capillary pericyte which, in the brain, is now known to control the blood-brain barrier, regulate blood flow, influence immune cell entry and be crucial for angiogenesis. In this review we consider the under-explored possibility that peripheral diseases which affect the microvasculature, such as hypertension, kidney disease and diabetes, produce central nervous system (CNS) dysfunction by mechanisms affecting capillary pericytes within the CNS. We highlight how cellular messengers produced peripherally can act via signalling pathways within CNS pericytes to reshape blood vessels, restrict blood flow or compromise blood-brain barrier function, thus causing neuronal dysfunction. Increased understanding of how renin-angiotensin, Rho-kinase and PDGFRβ signalling affect CNS pericytes may suggest novel therapeutic approaches to reducing the CNS effects of peripheral disorders., (© 2019 International Society for Neurochemistry.)

Leishmaniasis is a worldwide public health problem caused by protozoan parasites of the genus Leishmania. Leishmania braziliensis is the most important species responsible for tegumentary leishmaniases in Brazil. An understanding of the molecular mechanisms underlying the success of this parasite is urgently needed. An in-depth study on the modulation of gene expression across the life cycle stages of L. braziliensis covering coding and noncoding RNAs (ncRNAs) was missing and is presented herein. Analyses of differentially expressed (DE) genes revealed that most prominent differences were observed between the transcriptomes of insect and mammalian proliferative forms (6,576 genes). Gene ontology (GO) analysis indicated stage-specific enriched biological processes. A computational pipeline and 5 ncRNA predictors allowed the identification of 11,372 putative ncRNAs. Most of the DE ncRNAs were found between the transcriptomes of insect and mammalian proliferative stages (38%). Of the DE ncRNAs, 295 were DE in all three stages and displayed a wide range of lengths, chromosomal distributions and locations; many of them had a distinct expression profile compared to that of their protein-coding neighbors. Thirty-five putative ncRNAs were submitted to northern blotting analysis, and one or more hybridization-positive signals were observed in 22 of these ncRNAs. This work presents an overview of the L. braziliensis transcriptome and its adjustments throughout development. In addition to determining the general features of the transcriptome at each life stage and the profile of protein-coding transcripts, we identified and characterized a variety of noncoding transcripts. The novel putative ncRNAs uncovered in L. braziliensis might be regulatory elements to be further investigated.

After cardiac ischaemia, a prolonged decrease of coronary microvascular perfusion often occurs even after flow is restored in an upstream artery. This 'no-reflow' phenomenon worsens patient prognosis. In the brain, after stroke, a similar post-ischaemic 'no-reflow' has been attributed to capillary constriction by contractile pericytes. We now show that occlusion of a rat coronary artery, followed by reperfusion, blocks 40% of cardiac capillaries and halves perfused blood volume within the affected region. Capillary blockages colocalised strongly with pericytes, where capillary diameter was reduced by 37%. The pericyte relaxant adenosine increased capillary diameter by 21% at pericyte somata, decreased capillary block by 25% and increased perfusion volume by 57%. Thus, cardiac pericytes constrict coronary capillaries and reduce microvascular blood flow after ischaemia, despite re-opening of the culprit artery. Cardiac pericytes are therefore a novel therapeutic target in ischaemic heart disease.

Objective: We investigated the acute effects of SIM on cerebral microvascular rarefaction and dysfunction in SHRs., Methods: Male WKY and SHRs were divided into 4 groups of 8 animals each: WKY-CTL and SHR-CTL, treated with 0.9% saline; and WKY+SIM and SHR+SIM, treated with SIM (30 mg/kg/d) for 3 days by gavage. Cerebral FCD was assessed by intravital fluorescence videomicroscopy. mCBF before and after administration within the cranial window of angiotensin II (1 μmol L -1 ) was investigated using laser speckle contrast imaging., Results: Cerebral FCD was reduced in SHR-CTL compared to WKY-CTL (P < .05). SIM increased cerebral FCD in SHRs compared to SHR-CTL (P < .05). The mCBF was reduced in SHR-CTL compared to WKY-CTL (P < .05), and SIM increased mCBF compared with SHR-CTL (P < .05). Angiotensin II elicited a reduction of mCBF in SHR-CTL and increased mCBF in WKY-CTL (SHR-CTL -13.53 ± 2% vs WKY-CTL +13.74 ± 4%; P < .001), which was attenuated in SHRs treated with SIM (SHR+SIM -6.7 ± 1% vs SHR-CTL -13.53 ± 2%; P < .01)., Conclusions: The antihypertensive effect of SIM is associated with an improvement in cerebral microvascular perfusion and capillary density that may help to prevent hypertension-induced cerebrovascular damage independent of cholesterol-lowering., (© 2017 John Wiley & Sons Ltd.)

Non-coding RNAs (ncRNAs) are regulatory elements present in a wide range of organisms, including trypanosomatids. ncRNAs transcribed from the untranslated regions (UTRs) of coding genes have been described in the transcriptomes of several eukaryotes, including Trypanosoma brucei. To uncover novel putative ncRNAs in two Leishmania species, we examined a L. major cDNA library and a L. donovani non-polysomal RNA library. Using a combination of computational analysis and experimental approaches, we classified 26 putative ncRNA in L. major, of these, 5 arising from intergenic regions and 21 from untranslated regions. In L. donovani, we classified 37 putative ncRNAs, of these, 7 arising from intergenic regions, and 30 from UTRs. Our results suggest, for the first time, that UTR-transcripts may be a common feature in the eukaryote Leishmania similarly to those previously shown in T. brucei and other eukaryotes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The therapeutic potential of early exercise training following cerebral hypoperfusion was investigated on brain perfusion and inflammation in rats with permanent bilateral occlusion of the common carotid arteries (2VO). Wistar rats were subjected to 2VO or sham surgery and each group was then subdivided randomly into sedentary or exercise groups. Early exercise training was initiated after three days of 2VO or sham surgery and consisted of seven days of treadmill training (30min/day at ∼60% of maximal exercise test), composing four groups: 1) Sham sedentary (Sham-Sed), 2) Sham exercised (Sham-Ex), 3) 2VO sedentary (2VO-Sed) and 4) 2VO exercised (2VO-Ex). Microvascular cerebral blood flow (MCBF) and NADPH oxidase and eNOS gene expression were evaluated by laser speckle contrast imaging and RT-PCR, respectively, and brain functional capillary density and endothelial-leukocyte interactions were evaluated by fluorescence intravital video-microscopy. The 2VO-Sed group presented a decrease in MCBF (Sham-Sed: 230.9±12.2 vs. 2VO-Sed: 183.6±10.6 arbitrary perfusion units, P<0.05) and in functional capillary density (Sham-Sed: 336.4±25.3 vs. 2VO-Sed: 225.5±28.1capillaries/mm 2 , P<0.05). Early intervention with physical exercise was able to prevent the cerebral microvascular inflammation by decreasing endothelial-leukocyte interactions (2VO-Ex: 0.9±0.3 vs. 2VO-Sed: 5±0.6cells/min/100μm, P<0.0001) and reducing brain NADPH oxidase gene expression (2VO-Ex: 1.7±0.1 arbitrary units, P<0.05). Cerebral microcirculatory and inflammatory alterations appear to be triggered during the first days after 2VO surgery, and early intervention with physical exercise may represent a means of preventing the microvascular alterations induced by chronic cerebral hypoperfusion., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Cardiac microvascular rarefaction appears to be involved in hyperthyroidism-induced left ventricular hypertrophy and dysfunction. We investigated the effects of losartan, an AT1 receptor antagonist; diltiazem, a calcium channel blocker; and propranolol, a β-adrenergic receptor antagonist, on cardiac function and structural microcirculatory cardiac alterations in an experimental model of l-thyroxin-induced hyperthyroidism in rats. Hyperthyroidism (HYPER) was induced by intraperitoneal injections of l-thyroxin for 35 days (600 μg/kg/day; n = 32). The euthyroid group was treated with distilled water (EUT + VEH; n = 8). On the 14th day, the HYPER group was divided into four groups that received an oral treatment for 21 days with saline (HYPER + VEH; n = 8), losartan (10 mg/kg/day; HYPER + LOS, n = 8), diltiazem (10 mg/kg/day; HYPER + DILT, n = 8), or propranolol (10 mg/kg/day; HYPER + PROP, n = 8). An echocardiographic study was performed at baseline, at the beginning and at the end of the pharmacological treatment protocol (35th day). The structural capillary density in the left ventricle (LV) was analyzed using histochemical analysis with fluorescein isothiocyanate-conjugated Griffonia simplicifolia lectin. HYPER + VEH (182 ± 5 mmHg; P < 0.001) presented higher systolic blood pressure (SBP) compared with EUT + VEH (132 ± 3 mmHg). HYPER + LOS (144 ± 2 mmHg), HYPER + DILT (147 ± 3 mmHg) and HYPER + PROP (153 ± 4 mmHg) presented lower SBP compared with HYPER + VEH (P < 0.001). Chronic treatment with losartan, diltiazem, and propranolol reversed cardiac structural microvascular rarefaction (HYPER + VEH 0.16 ± 0.01; EUT + VEH 0.35 ± 0.02; HYPER + LOS 0.46 ± 0.03; HYPER + DILT 0.49 ± 0.02; HYPER + PROP 0.58 ± 0.04 (Vv[cap]/Vv[fib]); P < 0.001) and enhanced the LV ejection fraction of hyperthyroid rats (HYPER + VEH 71 ± 3; EUT + VEH 85 ± 2; HYPER + LOS 90 ± 3; HYPER + DILT 85 ± 3; HYPER + PROP 86 ± 2%; P < 0.05). In conclusion, chronic treatment with losartan, diltiazem, and propranolol improved the cardiac microcirculation and function in an experimental model of hyperthyroidism in rats., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

Monokalliapseudes schubarti is an endemic tanaidacean microcrustacean from southeastern Brazil to Uruguay inhabiting low energy estuaries. Saco da Fazenda is located in the estuary of the Itajaí-Açú River, state of Santa Catarina, Brazil. It is exposed to strong anthropic impact and receives intensive flows of domestic wastewater, solid residues, and drainage activities. Specimens of M. schubarti were collected monthly, in the intertidal and subtidal regions of Saco da Fazenda, in four stations defined as a function of the physiography of the environment during the period of July 2003 to June 2004. Fecundity values were high, with continuous reproductive activity during the whole period of study. The greatest population densities were observed in the intertidal region, where they are nevertheless intensely consumed by birds, swimming crabs, and fish. This species represents a fundamental link in the food chain of Saco da Fazenda, transferring energy from the detritus level to higher trophic levels. Habitat disturbance and high organic matter may represent factors controlling the distribution of populations of M. schubarti. For this reason, the species may be used to monitor anthropic effects in estuarine areas.

Objective: The pathophysiology underlying hyperthyroidism-induced left ventricle (LV) dysfunction and hypertrophy directly involves the heart and indirectly involves the neuroendocrine systems. The effects of hyperthyroidism on the microcirculation are still controversial in experimental models. We investigated the effects of hyperthyroidism on the cardiac function and microcirculation of an experimental rat model., Methods: Male Wistar rats (170-250 g) were divided into two groups: the euthyroid group (n = 10), which was treated with 0.9% saline solution, and the hyperthyroid group (n = 10), which was treated with l-thyroxine (600 μg/kg/day, i.p.) during 14 days. An echocardiographic study was performed to evaluate the alterations in cardiac function, structure and geometry. The structural capillary density and the expression of angiotensin II AT1 receptor in the LV were analyzed using histochemistry and immunohistochemistry, respectively., Results: Hyperthyroidism was found to induce profound cardiovascular alterations, such as systolic hypertension, tachycardia, LV dysfunction, cardiac hypertrophy, and myocardial fibrosis. This study demonstrates the existence of structural capillary rarefaction and the down-regulation of the cardiac angiotensin II AT1 receptor in the myocardium of hyperthyroid rats in comparison with euthyroid rats., Conclusions: Microvascular rarefaction may be involved in the pathophysiology of hyperthyroidism-induced cardiovascular alterations., (© 2013 John Wiley & Sons Ltd.)