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Abstract Long noncoding RNAs (lncRNAs) are versatile RNA molecules recently identified as key regulators of gene expression in response to environmental stress. Our primary focus in this study was to develop a robust computational pipeline for identifying structurally identical lncRNAs across replicates from publicly available bulk RNA-seq datasets. In order to demonstrate the effectiveness of the pipeline, we utilized the transcriptome of the thermophilic fungus Thermothelomyces thermophilus and assessed the expression pattern of lncRNAs in conjunction with Heat Shock Proteins (HSP), a well-known protein family critical for the cell’s response to high temperatures. Our findings demonstrate that the identification of structurally identical transcripts among replicates in this thermophilic fungus ensures the reliability and accuracy of RNA studies, contributing to the validity of biological interpretations. Furthermore, the majority of lncRNAs exhibited a distinct expression pattern compared to HSPs. Our study contributes to advancing the understanding of the biological mechanisms comprising lncRNAs in thermophilic fungi.

Abstract Cylindromas are rare, benign adnexal neoplasms primarily found on the scalp and face, with a higher incidence in women and typically manifesting in the second or third decade of life. These tumours can present as single or multiple nodules, with the latter form often linked to CYLD gene mutations, particularly in the context of CYLD cutaneous syndrome. Here, we report a case of a 61‐year‐old male presenting with multiple cylindromas of the scalp, prompting genetic testing that revealed a novel pathogenic variant in the CYLD gene.

Multi-dimensional parameter spaces are commonly encountered in physics theories that go beyond the standard model. However, they often possess complicated posterior geometries that are expensive to traverse using techniques traditional to astroparticle physics. Several recent innovations, which are only beginning to make their way into this field, have made navigating such complex posteriors possible. These include GPU acceleration, automatic differentiation, and neural-network-guided reparameterization. We apply these advancements to dark matter direct detection experiments in the context of non-standard neutrino interactions and benchmark their performances against traditional nested sampling techniques when conducting Bayesian inference. Compared to nested sampling alone, we find that these techniques increase performance for both nested sampling and Hamiltonian Monte Carlo, accelerating inference by factors of $\mathord{\sim} 100$ and $\mathord{\sim} 60$ , respectively. As nested sampling also evaluates the Bayesian evidence, these advancements can be exploited to improve model comparison performance while retaining compatibility with existing implementations that are widely used in the natural sciences. Using these techniques, we perform the first scan in the neutrino non-standard interactions parameter space for direct detection experiments whereby all parameters are allowed to vary simultaneously. We expect that these advancements are broadly applicable to other areas of astroparticle physics featuring multi-dimensional parameter spaces.

Abstract Type-1 and type-3 interferons (IFNs) are important for control of viral replication; however, less is known about the role of Type-2 IFN (IFNγ) in anti-viral immunity. We previously observed that lung infection with Mycobacterium bovis BCG achieved though intravenous (iv) administration provides strong protection against SARS-CoV-2 in mice yet drives low levels of type-1 IFNs but robust IFNγ. Here we examine the role of ongoing IFNγ responses to pre-established bacterial infection on SARS-CoV-2 disease outcomes in two murine models. We report that IFNγ is required for iv BCG induced reduction in pulmonary viral loads, an outcome dependent on IFNγ receptor expression by non-hematopoietic cells. Importantly, we show that BCG infection prompts pulmonary epithelial cells to upregulate IFN-stimulated genes with reported anti-viral activity in an IFNγ-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirm the anti-viral properties of IFNγ by demonstrating that the recombinant cytokine itself provides strong protection against SARS-CoV-2 challenge when administered intranasally. Together, our data show that a pre-established IFNγ response within the lung is protective against SARS-CoV-2 infection, suggesting that concurrent or recent infections that drive IFNγ may limit the pathogenesis of SARS-CoV-2 and supporting possible prophylactic uses of IFNγ in COVID-19 management.

Abstract We explore the complementarity of direct detection (DD) and spallation source (SS) experiments for the study of sterile neutrino physics. We focus on the sterile baryonic neutrino model: an extension of the Standard Model that introduces a massive sterile neutrino with couplings to the quark sector via a new gauge boson. In this scenario, the inelastic scattering of an active neutrino with the target material in both DD and SS experiments gives rise to a characteristic nuclear recoil energy spectrum that can allow for the reconstruction of the neutrino mass in the event of a positive detection. We first derive new bounds on this model based on the data from the COHERENT collaboration on CsI and LAr targets, which we find do not yet probe new areas of the parameter space. We then assess how well future SS experiments will be able to measure the sterile neutrino mass and mixings, showing that masses in the range ~15 − 50 MeV can be reconstructed. We show that there is a degeneracy in the measurement of the sterile neutrino mixing that substantially affects the reconstruction of parameters for masses of the order of 40 MeV. Thanks to their lower energy threshold and sensitivity to the solar tau neutrino flux, DD experiments allow us to partially lift the degeneracy in the sterile neutrino mixings and considerably improve its mass reconstruction down to 9 MeV. Our results demonstrate the excellent complementarity between DD and SS experiments in measuring the sterile neutrino mass and highlight the power of DD experiments in searching for new physics in the neutrino sector.

Despite major global efforts to eliminate tuberculosis, which is caused by Mycobacterium tuberculosis (Mtb), this disease remains as a major plague of humanity. Several factors associated with the host and Mtb interaction favor the infection establishment and/or determine disease progression. The Early Secreted Antigenic Target 6 kDa (ESAT-6) is one of the most important and well-studied mycobacterial virulence factors. This molecule has been described to play an important role in the development of tuberculosis-associated pathology by subverting crucial components of the host immune responses. This review highlights the main effector mechanisms by which ESAT-6 modulates the immune system, directly impacting cell fate and disease progression.

We presents an unique and significant case of Acute Generalized Exanthematous Pustulosis (AGEP) associated with the use of tadalafil, a phosphodiesterase type 5 inhibitor for erectile dysfunction. AGEP, typically linked to antibiotics and antiepileptics, had not been previously reported with tadaladil in the MEDLINE database. The case involved a 40-year-old male who developed an erythematous rash, fever and sterile pustules after starting tadalafil. A skin biopsy confirmed AGEP. Discontinuation of the drug and treatment with prednsiolone cleared the dermatosis. This case emphasizes the need for awareness among healthcare providers regarding this potential adverse reaction, considering the growing use of tadalafil.

Resin is a plastic-like product of trees. Older occurrences of such resin are referred to as amber and are considered fossil resin. Younger resins are termed copals. Even younger ones have been dubbed defaunation resins. Non-fossil resins remain in a terminological limbo, often referred to as “sub-fossils”. We report two lepidopteran caterpillars preserved in non-fossil resin: one from Madagascar, one from Brazil. Prominent hairs (=setae) and spines (=spine-like setae) of the specimens make it likely that they represent larvae of Erebidae (e.g., tussock moths and others). So far, most known caterpillars preserved in resins are either “naked” or bear protective cases; only few are armoured with spines or hairs. In particular, long-haired caterpillars such as the ones reported here are so far almost absent. Only one specimen with comparable setae has been reported from 15-million-year-old Dominican amber, but no significant details of this specimen are accessible. We briefly also review the record of caterpillars known from the Holocene, recognising that it is very sparse. The new specimens demonstrate that very hairy caterpillars can readily be preserved in resins in fine detail. Furthermore, the specimens increase the known size range of caterpillars preserved in resins, with one measuring more than 12 mm.

Diptera are one of the four megadiverse groups of holometabolan insects. Flies perform numerous ecological functions, especially in their larval stages. We can assume that this was already the case in the past; however, fly larvae remain rare in most deposits. Here we report new dipteran larvae preserved in Cretaceous (about 99 Ma) Kachin amber from Myanmar and, even older, Jurassic (about 165 Ma) compression fossils from China. Through light microscopy and micro-CT scanning we explore their peculiar morphology and discuss their possible phylogenetic affinities. Several larvae seem to represent the lineage of Stratiomyomorpha. A few others present characters unique to Xylophagidae (awl-flies), as well as to Athericidae (water sniper-flies), resulting in a chimeric morphology. Understanding the exact relationships of most of these specimens with a particular lineage remains challenging, since they differ considerably from any other known dipteran larvae and present some unique traits. Additionally, we report new specimens of Qiyia jurassica Chen et al., 2014, supposedly parasitic larvae, most likely representatives of Athericidae. These new findings offer valuable insights into the evolution of the early diversification of the brachyceran flies and underscore the importance of immature stages in understanding the evolutionary history and ecology of flies.

Viral co-infections have been implicated in worsening tuberculosis (TB) and during the COVID-19 pandemic, the global rate of TB-related deaths has increased for the first time in over a decade. We and others have previously shown that a resolved prior or concurrent influenza A virus infection in Mycobacterium tuberculosis (Mtb)-infected mice resulted in increased pulmonary bacterial burden, partly through type I interferon (IFN-I)-dependent mechanisms. Here we investigated whether SARS-CoV-2 (SCV2) co-infection could also negatively affect bacterial control of Mtb. Importantly, we found that K18-hACE2 transgenic mice infected with SCV2 one month before, or months after aerosol Mtb exposure did not display exacerbated Mtb infection-associated pathology, weight loss, nor did they have increased pulmonary bacterial loads. However, pre-existing Mtb infection at the time of exposure to the ancestral SCV2 strain in infected K18-hACE2 transgenic mice or the beta variant (B.1.351) in WT C57Bl/6 mice significantly limited early SCV2 replication in the lung. Mtb-driven protection against SCV2 increased with higher bacterial doses and did not require IFN-I, TLR2 or TLR9 signaling. These data suggest that SCV2 co-infection does not exacerbate Mtb infection in mice, but rather the inflammatory response generated by Mtb infection in the lungs at the time of SCV2 exposure restricts viral replication.

Family Corethrellidae has a worldwide distribution with most known extant species occurring in the Neotropics, many with only the adult stages described. Despite previous efforts, one remaining problem in the taxonomy of Corethrellidae is the challenge of delimiting species due to the current range of morphological characters included in descriptions to date. This paper discusses additional morphological evidence to distinguish species and their phylogenetic relationships. Together with fresh samples collected in Bahia, the only state in the Northeast Region with records of corethrellids, and slide-mounted specimens from other regions, five new species are described: Corethrella pindorama sp. nov., C. patasho sp. nov., C. fuscifimbria sp. nov. and C. unifasciata sp. nov. based on female adults; and C. bifida sp. nov. based on male and female adults, and larval and pupal exuviae. We also provide complementary descriptions comprising the novel characters for 33 previously described species, including the immature stages of nine. Fifteen species are newly recorded for Bahia and the Northeast Region, of which two are new records for Brazil. Additionally, we provide remarks about the biology of species, an updated list of species recorded in Brazil and an updated taxonomic key of New World species, modified from Borkent (2008).

Introduction Teaching is considered by the International Labor Organization as one of the most stressful professions, with consequences on the mental and physical health and on their professional performance. Intervention programs focused on physical activity usually present a significant decrease in the level of stress and an improvement in the quality of life of teachers. Physical activity is considered one of the main non-pharmacological strategies to reduce stress, generating a positive influence on mental health. Objectives To evaluate the impact of an intervention program based on the practice of physical activity on the level of stress and motivation for the regular practice of physical activity in teachers. Methods This study employed a pretest-posttest design. Measures: Portuguese versions of Stress Perception Scale and Motivation Inventory for Regular Physical Activity Practice. Sample: 33 teachers from Portugal and Brazil, 57,6% females, 54,5% from Portugal, 63,6% with age between 26 and 35 years. The intervention ran for 8 weeks, with a total of 40 sessions with cardiorespiratory conditioning exercises, muscle strengthening and stretching, relaxation and meditation techniques. Results On baseline we found significant relationship between “years of teaching experience” and the level of stress (p=.027). After the intervention, the level of stress significantly decreased in Portuguese teachers (p=.031). In 83% of the sample, there is a decrease in the levels of perceived stress. Concerning Brazilian teachers (p=.006), in 73% of the sample, there is a decrease in the levels of perceived stress. Regarding motivation, there is a significant increase in Portuguese teachers related to “stress control” (p

Introduction The Portuguese version of the Big Three Perfectionism Scale (BTPS), a 45-item self-report measure of rigid, self-critical, and narcissistic perfectionism, presented good reliability, construct and concurrent validity both in a sample of university students (Lino, Pereira et al. 2018) and of adults from the general population (Oliveira, Pereira et al. 2021). Objectives To develop and validate a Portuguese brief version of the BTPS, the Big Three Perfectionism Scale–Short Form (BTPS-SF) in a sample of university students. Methods The procedure followed to select items for the short version was based on the 45-items BTPS confirmatory factorial analysis (Lino, Pereira et al. 2018). Following Feher et al. (2020) strategy, with Canadian university students, we retained between one and two from each of the 10 perfectionism facets in the BTPS, 16 items in total. The 16 items selected had loadings ranging from .63 to .88 (Lino, Pereira et al. 2018), thus meeting the suggested requirement of high loadings being above .60 in magnitude (Afifi et al. 2011). Participants were 633 Portuguese students (medicine, dentistry and health technologies; 82.1% girls; mean age=21.25±3.115); they answered an online survey including the BTPS and the Depression Anxiety and Stress Scale (DASS; Xavier et al. 2017). Results Confirmatory Factor Analysis showed that both the first (χ2/df=3.074; RMSEA=.0573, p

Nanopore direct RNA Sequencing data contain information about the presence of RNA modifications, but their detection poses substantial challenges. Here the authors introduce Nanocompore, a new methodology for modification detection from Nanopore data.

Abstract The recent measurement of the muon anomalous magnetic moment by the Fermilab E989 experiment, when combined with the previous result at BNL, has confirmed the tension with the SM prediction at $$4.2\,\sigma $$ 4.2 σ CL, strengthening the motivation for new physics in the leptonic sector. Among the different particle physics models that could account for such an excess, a gauged $$U(1)_{L_\mu -L_{\tau }}$$ U ( 1 ) L μ - L τ stands out for its simplicity. In this article, we explore how the combination of data from different future probes can help identify the nature of the new physics behind the muon anomalous magnetic moment. In particular, we contrast $$U(1)_{L_\mu -L_{\tau }}$$ U ( 1 ) L μ - L τ with an effective $$U(1)_{L_\mu }$$ U ( 1 ) L μ -type model. We first show that muon fixed target experiments (such as NA64 $$\mu $$ μ ) will be able to measure the coupling of the hidden photon to the muon sector in the region compatible with $$(g-2)_\mu $$ ( g - 2 ) μ , and will have some sensitivity to the hidden photon’s mass. We then study how experiments looking for coherent elastic neutrino-nucleus scattering (CE $$\nu $$ ν NS) at spallation sources will provide crucial additional information on the kinetic mixing of the hidden photon. When combined with NA64 $$\mu $$ μ results, the exclusion limits (or reconstructed regions) of future CE $$\nu $$ ν NS detectors will also allow for a better measurement of the mediator mass. Finally, the observation of nuclear recoils from solar neutrinos in dark matter direct detection experiments will provide unique information about the coupling of the hidden photon to the tau sector. The signal expected for $$U(1)_{L_\mu -L_{\tau }}$$ U ( 1 ) L μ - L τ is larger than for $$U(1)_{L_\mu }$$ U ( 1 ) L μ with the same kinetic mixing, and future multi-ton liquid xenon proposals (such as DARWIN) have the potential to confirm the former over the latter. We determine the necessary exposure and energy threshold for a potential $$5\,\sigma $$ 5 σ discovery of a $$U(1)_{L_\mu -L_{\tau }}$$ U ( 1 ) L μ - L τ boson, and we conclude that the future DARWIN observatory will be able to carry out this measurement if the experimental threshold is lowered to $$1\,{\mathrm {keV}}_{\mathrm {nr}} $$ 1 keV nr .

The genus Corethrella Coquillet, 1902 are known as a group of nocturnal frog-biting-midges (Diptera: Corethrellidae) which locate their frog-hosts through the sound emitted by their conspicuous calls. The classical method to capture these midges consists in using modified Center Disease Control (CDC) traps in which speakers emitting frog calls replace the light bulb. However, the high cost, volume and weight of CDC traps hampers several studies in remote areas and in countries with low research investments. Therefore, the main objective of this study was to compare the capture rate of the classic modified CDC trap with a new trap recently developed, here referred as PTM. We conducted an experiment at flooded areas in the vicinity of a lake in Florianópolis, Santa Catarina State, southern Brazil in which we arranged PTM and modified CDC traps emitting frog calls of two species commonly found in the area, Physalaemus nanus (Boulenger, 1888) and P. cuvieri Fitzinger, 1826. In a total of 34,5h sampling hours per trap (one trial per night for five days), the PTM traps captured over 20 times more individuals than modified CDC traps (n= 1594; n=72, respectively) and the same number of species (3). Those results demonstrate that the PTM method had a higher capture rate, are more practical and has a lower cost than modified CDC traps. We suggest further studies to investigate which aspects could explain the differences between capture rates among PTM, BG sentinel, bottle and CDC modified methods.

Tuberculosis (TB) is a lethal disease and remains one of the top ten causes of mortality by an infectious disease worldwide. It can also result in significant morbidity related to persistent inflammation and tissue damage. Pulmonary TB treatment depends on the prolonged use of multiple drugs ranging from 6 months for drug-susceptible TB to 6–20 months in cases of multi-drug resistant disease, with limited patient tolerance resulting from side effects. Treatment success rates remain low and thus represent a barrier to TB control. Adjunct host-directed therapy (HDT) is an emerging strategy in TB treatment that aims to target the host immune response to Mycobacterium tuberculosis in addition to antimycobacterial drugs. Combined multi-drug treatment with HDT could potentially result in more effective therapies by shortening treatment duration, improving cure success rates and reducing residual tissue damage. This review explores the rationale and challenges to the development and implementation of HDTs through a succinct report of the medications that have completed or are currently being evaluated in ongoing clinical trials.

Abstract Plasminogen activator inhibitor 1 (PAI-1) is a functional biomarker of the metabolic syndrome. Previous studies have demonstrated that PAI-1 is a mechanistic contributor to several elements of the syndrome, including obesity, hypertension and insulin resistance. Here we show that PAI-1 is also a critical regulator of hepatic lipid metabolism. RNA sequencing revealed that PAI-1 directly regulates the transcriptional expression of numerous genes involved in mammalian lipid homeostasis, including PCSK9 and FGF21. Pharmacologic or genetic reductions in plasma PAI-1 activity ameliorates hyperlipidemia in vivo. These experimental findings are complemented with the observation that genetic deficiency of PAI-1 is associated with reduced plasma PCSK9 levels in humans. Taken together, our findings identify PAI-1 as a novel contributor to mammalian lipid metabolism and provides a fundamental mechanistic insight into the pathogenesis of one of the most pervasive medical problems worldwide.

Abstract Models of gauged U 1 L μ − L τ $$ \mathrm{U}{(1)}_{L_{\mu }-{L}_{\tau }} $$ can provide a solution to the long-standing discrepancy between the theoretical prediction for the muon anomalous magnetic moment and its measured value. The extra contribution is due to a new light vector mediator, which also helps to alleviate an existing tension in the determination of the Hubble parameter. In this article, we explore ways to probe this solution via the scattering of solar neutrinos with electrons and nuclei in a range of experiments and considering high and low solar metallicity scenarios. In particular, we reevaluate Borexino constraints on neutrino-electron scattering, finding them to be more stringent than previously reported, and already excluding a part of the (g − 2) μ explanation with mediator masses smaller than 2 × 10 −2 GeV. We then show that future direct dark matter detectors will be able to probe most of the remaining solution. Due to its large exposure, LUX-ZEPLIN will explore regions with mediator masses up to 5 × 10 −2 GeV and DARWIN will be able to extend the search beyond 10 −1 GeV, thereby covering most of the area compatible with (g − 2) μ . For completeness, we have also computed the constraints derived from the recent XENON1T electron recoil search and from the CENNS-10 LAr detector, showing that none of them excludes new areas of the parameter space. Should the excess in the muon anomalous magnetic moment be confirmed, our work suggests that direct detection experiments could provide crucial information with which to test the U 1 L μ − L τ $$ \mathrm{U}{(1)}_{L_{\mu }-{L}_{\tau }} $$ solution, complementary to efforts in neutrino experiments and accelerators.

ABSTRACT: Bovine alphaherpesvirus 2 (BoHV-2) is the agent of herpetic mammilitis (BHM), a cutaneous and self-limiting disease affecting the udder and teats of cows. The pathogenesis of BoHV-2 is pourly understood, hampering the development of therapeutic drugs, vaccines and other control measures. This study investigated the pathogenesis of BoHV-2 in calves after inoculation through different routes. Three- to four-months seronegative calves were inoculated with BoHV-2 (107TCID50.mL-1) intramuscular (IM, n=4), intravenous (IV, n=4) or transdermal (TD) after mild scarification (n=4) and submitted to virological, clinical and serological monitoring. Calves inoculated by the IV route presented as light increase in body temperature between days 6 to 9 post-inoculation (pi). Virus inoculation by the TD route resulted in mild inflammatory lesions at the sites of inoculation, characterized by hyperemia, small vesicles, mild exudation and scab formation, between days 2 and 8pi. Virus or viral DNA was detected by PCR in the crusts/swabs collected from lesions of 3 out of 4 animals inoculated TD from day 2 to 8pi. Viremia was detected in 3/4 animals of the IM group (from day 4 to 8pi); in 2/4 animals of the IV group (days 6 and 8pi) but not in the TD group. Calves from all inoculated groups seroconverted to BoHV-2 in titers from 4 to 64, as indicated by virus-neutralizing (VN) assays performed in sera collected at day 15pi. Administration of dexamethasone (Dex) to the inoculated calves at day 48pi, did not result in virus reactivation as indicated by lack of virus detection in the blood and/or in inoculation sites and no increase in VN antibody titers. These results demonstrated that BoHV-2 was able to replicate efficiently in calves following different routes of exposure, produced viremia after IM and IV inoculation and was not reactivated by Dex treatment.

Irg1 is an enzyme that generates itaconate, a metabolite that plays a key role in the regulation of inflammatory responses. Previous studies have implicated Irg1 as an important mediator in preventing excessive inflammation and tissue damage in Mycobacterium tuberculosis (Mtb) infection. Here, we investigated the pattern recognition receptors and signaling pathways by which Mtb triggers Irg1 gene expression by comparing the responses of control and genetically deficient BMDMs. Using this approach, we demonstrated partial roles for TLR-2 (but not TLR-4 or -9), MyD88 and NFκB signaling in Irg1 induction by Mtb bacilli. In addition, drug inhibition studies revealed major requirements for phagocytosis and endosomal acidification in Irg1 expression triggered by Mtb but not LPS or PAM3CSK4. Importantly, the Mtb-induced Irg1 response was highly dependent on the presence of the bacterial ESX-1 secretion system, as well as host STING and Type I IFN receptor (IFNAR) signaling with Type II IFN (IFN-γ) signaling playing only a minimal role. Based on these findings we hypothesize that Mtb induces Irg1 expression in macrophages via the combination of two independent triggers both dependent on bacterial phagocytosis: 1) a major signal stimulated by phagocytized Mtb products released by an ESX-1-dependent mechanism into the cytosol where they activate the STING pathway leading to Type I-IFN production, and 2) a secondary TLR-2, MyD88 and NFκB dependent signal that enhances Irg1 production independently of Type I IFN induction.

Dogs with thoracolumbar intervertebral disc extrusion (TL-IVDE) can exhibit variable neurologic deficits after decompressive surgery. The objectives of this study were to quantify changes in static weight distribution (SWD) and limb and body circumference over time in dogs recovering from surgery for TL-IVDE. Dogs with acute TL-IVDE were prospectively evaluated at baseline (48–72 h post-operatively), 2, 4, 8, and 12 weeks post-operatively. Commercially-available digital scales were used to measure weight distributed to the pelvic limbs (PL%) and asymmetry between left and right pelvic limbs (LRA), each expressed as a percentage of total body weight. Trunk and thigh circumference measurements were performed using a spring-loaded tape measurement device. Measurements were performed in triplicate, compared to neurologically normal small breed control dogs and analyzed for changes over time. P

Larvae of soldier flies and their closest relatives (Diptera: Stratiomyomorpha) are important decomposers of organic material, including wood, that take part in carbon cycling. They also play a certain role in the modern-day animal and human food industry, representing economic value. Larvae of Stratiomyomorpha are considered to be rather rare in the fossil record. Indeed, only very few larvae have been reported so far. Here, we demonstrate that larvae of Stratiomyomorpha are in fact abundant in the Cretaceous, at least in Myanmar amber (about 100 million years old), based on more than 100 amber pieces containing larvae. The specimens could be differentiated into three morphotypes, two already described in a previous work, and a new one. For one morphotype, three larval stages could be distinguished by analysing the dimensions of the head capsules. A quantitative analysis of body shapes indicates a lower morphological diversity of the fossil sample in comparison to the extant fauna, but suggests that they might have had a different ecology in the past. It appears that the data set is not yet saturated, i.e., that more fossil larvae of this group, including different morphologies, are expected to be found.

O surgimento do laser foi um marco para o avanço tecnológico e científico. Por isso há vários artigos descrevendo o processo histórico e suas aplicações, porém, sabendo que os feixes lasers têm perfil espacial gaussiano no plano transverso à propagação, nota-se que a literatura sobre luz estrutura com outras distribuições espaciais ainda é pouco divulgada. Com o intuito de contribuir para sanar esta carência, o presente trabalho pretende mostrar a natureza dos feixes ópticos respeitando o marco histórico de cada feixe e descrevendo matematicamente suas características, iniciando com feixes gaussianos passando por modos Hermite-Gauss, Laguerre-Gauss em seguida terminamos com feixes Bessel.

Oral squamous cell carcinoma (OSCC) is a worldwide public health problem, accounting for approximately 90% of all oral cancers, and is the eighth most common cancer in men. Cisplatin and carboplatin are the main chemotherapy drugs used in the clinic. However, in addition to their serious side effects, such as damage to the nervous system and kidneys, there is also drug resistance. Thus, the development of new drugs becomes of great importance. Naphthoquinones have been described with antitumor activity. Some of them are found in nature, but semi synthesis has been used as strategy to find new chemical entities for the treatment of cancer. In the present study, we promote a multiple component reaction (MCR) among lawsone, arylaldehydes, and benzylamine to produce sixteen chemoselectively derivated Mannich adducts of 1,4-naphthoquinones in good yield (up to 97%). The antitumor activities and molecular mechanisms of action of these compounds were investigated in OSCC models and the compound 6a induced cytotoxicity in three different tumor cell lines (OSCC4, OSCC9, and OSCC25) and was more selective (IS > 2) for tumor cells than the chemotropic drug carboplatin and the controls lapachol and shikonin, which are chemically similar compounds with cytotoxic effects. The 6a selectively and significantly reduced the amount of cell colony growth, was not hemolytic, and tolerable in mice with no serious side effects at a concentration of 100 mg/kg with a LD50 of 150 mg/kg. The new compound is biologically stable with a profile similar to carboplatin. Morphologically, 6a does not induce cell retraction or membrane blebs, but it does induce intense vesicle formation and late emergence of membrane bubbles. Exploring the mechanism of cell death induction, compound 6a does not induce ROS formation, and cell viability was not affected by inhibitors of apoptosis (ZVAD) and necroptosis (necrostatin 1). Autophagy followed by a late apoptosis process appears to be the death-inducing pathway of 6a, as observed by increased viability by the autophagy inhibitor (3-MA) and by the appearance of autophagosomes, later triggering a process of late apoptosis with the presence of caspase 3/7 and DNA fragmentation. Molecular modeling suggests the ability of the compound to bind to topoisomerase I and II and with greater affinity to hPKM2 enzyme than controls, which could explain the mechanism of cell death by autophagy. Finally, the in-silico prediction of drug-relevant properties showed that compound 6a has a good pharmacokinetic profile when compared to carboplatin and doxorubicin. Among the sixteen naphthoquinones tested, compound 6a was the most effective and is highly selective and well tolerated in animals. The induction of cell death in OSCC through autophagy followed by late apoptosis possibly via inhibition of the PKM2 enzyme points to a promising potential of 6a as a new preclinical anticancer candidate.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) remains a major public health problem worldwide due in part to the lack of an effective vaccine and to the lengthy course of antibiotic treatment required for successful cure. Combined immuno/chemotherapeutic intervention represents a major strategy for developing more effective therapies against this important pathogen. Because of the major role of CD4+ T cells in containing Mtb infection, augmentation of bacterial specific CD4+ T cell responses has been considered as an approach in achieving this aim. Here we present new data from our own research aimed at determining whether boosting CD4+ T cell responses can promote antibiotic clearance. In these studies, we first characterized the impact of antibiotic treatment of infected mice on Th1 responses to major Mtb antigens and then performed experiments aimed at sustaining CD4+ T cell responsiveness during antibiotic treatment. These included IL-12 infusion, immunization with ESAT-6 and Ag85B immunodominant peptides and adoptive transfer of Th1-polarized CD4+ T cells specific for ESAT-6 or Ag85B during the initial month of chemotherapy. These approaches failed to enhance antibiotic clearance of Mtb, indicating that boosting Th1 responses to immunogenic Mtb antigens highly expressed by actively dividing bacteria is not an effective strategy to be used in the initial phase of antibiotic treatment, perhaps because replicating organisms are the first to be eliminated by the drugs. These results are discussed in the context of previously published findings addressing this concept along with possible alternate approaches for harnessing Th1 immunity as an adjunct to chemotherapy.

Tuberculosis (TB) still causes significant morbidity and mortality worldwide, especially in persons living with human immunodeficiency virus (HIV). This disease is hallmarked by persistent oxidative stress and systemic inflammation. N-acetylcysteine (NAC), a glutathione (GSH) precursor, has been shown in experimental models to limit Mycobacterium tuberculosis infection and disease both by suppression of the host oxidative response and through direct antimicrobial activity. In a recent phase II randomized clinical trial (RIPENACTB study), use of NAC as adjunct therapy during the first two months of anti-TB treatment was safe. Whether adjunct NAC therapy of patients with TB-HIV coinfection in the context of anti-TB treatment could directly affect pro-oxidation and systemic inflammation has not been yet formally demonstrated. To test this hypothesis, we leveraged existing data and biospecimens from the RIPENACTB trial to measure a number of surrogate markers of oxidative stress and of immune activation in peripheral blood of the participants at pre-treatment and at the day 60 of anti-TB treatment. Upon initiation of therapy, we found that the group of patients undertaking NAC exhibited significant increase in GSH levels and in total antioxidant status while displaying substantial reduction in lipid peroxidation compared to the control group. Only small changes in plasma concentrations of cytokines were noted. Pharmacological improvement of the host antioxidant status appears to be a reasonable strategy to reduce TB-associated immunopathology.

The interplay between M. tuberculosis (Mtb) and humans is multifactorial. The susceptibility/resistance profile and the establishment of clinical tuberculosis (TB) still remains elusive. The gain-of-function variant rs10754558 in the NLRP3 gene (found in 30% of the world population) confers protection against the development of TB, indicating a prominent role played by NLRP3 inflammasome against Mtb. Through genotype-guided assays and various Mtb strains (BCG, H37Rv, Beijing-1471, MP287/03), we demonstrate that Mtb strains activate inflammasome according to the NLRP3/IL-1ß or NLRC4/IL18 preferential axis. NLRP3 and NLRC4 genetic variants contribute to the presentation of TB. For the first time, we have shown that loss-of-function variants in NLRC4 significantly contribute to the development of extra-pulmonary TB. The analysis of inflammasome activation in a cohort of TB patients and their “household contacts” (CNT) revealed that plasma IL-1ß/IFN-α ratio lets us distinguish patients from Mtb-exposed-but-healthy individuals from an endemic region. Moreover, NLRP3 inflammasome seemed “exhausted” in TB patients compared to CNT, indicating a more efficient activation of inflammasome in resistant individuals. These findings suggest that inflammasome genetics as well as virulence-dependent level of inflammasome activation contribute to the onset of a susceptible/resistant profile among Mtb-exposed individuals.

RNA, the transcriptional output of genomes, not only templates protein synthesis or directly engages in catalytic functions, but can feed back to the genome and serve as regulatory input for gene expression. Transcripts affecting the RNA abundance of other genes act by mechanisms similar to and in concert with protein factors that control transcription. Through recruitment or blocking of activating and silencing complexes to specific genomic loci, RNA and protein factors can favor transcription or lower the local gene expression potential. Most regulatory proteins enter nuclei from all directions to start the search for increased affinity to specific DNA sequences or to other proteins nearby genuine gene targets. In contrast, RNAs emerge from spatial point sources within nuclei, their encoding genes. A transcriptional burst can result in the local appearance of multiple nascent RNA copies at once, in turn increasing local nucleic acid density and RNA motif abundance before diffusion into the nuclear neighborhood. The confined initial localization of regulatory RNAs causing accumulation of protein co-factors raises the intriguing possibility that target specificity of non-coding, and probably coding, RNAs is achieved through gene/RNA positioning and spatial proximity to regulated genomic regions. Here we review examples of positional cis conservation of regulatory RNAs with respect to target genes, spatial proximity of enhancer RNAs to promoters through DNA looping and RNA-mediated formation of membrane-less structures to control chromatin structure and expression. We speculate that linear and spatial proximity between regulatory RNA-encoding genes and gene targets could possibly ease the evolutionary pressure on maintaining regulatory RNA sequence conservation.

Locating the position of a remote node on a wireless network is becoming more relevant, as we move forward in the Internet of things and in autonomous vehicles. This paper proposes a new system to implement the location of remote nodes. A new prototype Android application has been developed to collect real measurements and to study the performance of several smartphone's sensors and location algorithms, including an innovative one, based on the second order cone programming (SOCP) relaxation. The application collects the WiFi access points information and the terminal location. An internal odometry module developed for the prototype is used when Android's service is unavailable. This paper compares the performance of existing location estimators given in closed form, an existing SOCP one, and the new SOCP location estimator proposed, which has reduced complexity. An algorithm to merge measurements from non-identical terminals is also proposed. Cooperative and terminal stand-alone operations are compared, showing a higher performance for SOCP-based ones, that are capable of estimating the path loss exponent and the transmission power. The heterogeneous terminals were also used in the tests. Our results show that the accurate positioning of static remote entities can be achieved using a single smartphone. On the other hand, the accurate real-time positioning of the mobile terminal is provided when three or more scattered terminal nodes cooperate sharing the samples taken synchronously.

Abstract Background The mammalian genome is transcribed into large numbers of long noncoding RNAs (lncRNAs), but the definition of functional lncRNA groups has proven difficult, partly due to their low sequence conservation and lack of identified shared properties. Here we consider promoter conservation and positional conservation as indicators of functional commonality. Results We identify 665 conserved lncRNA promoters in mouse and human that are preserved in genomic position relative to orthologous coding genes. These positionally conserved lncRNA genes are primarily associated with developmental transcription factor loci with which they are coexpressed in a tissue-specific manner. Over half of positionally conserved RNAs in this set are linked to chromatin organization structures, overlapping binding sites for the CTCF chromatin organiser and located at chromatin loop anchor points and borders of topologically associating domains (TADs). We define these RNAs as topological anchor point RNAs (tapRNAs). Characterization of these noncoding RNAs and their associated coding genes shows that they are functionally connected: they regulate each other’s expression and influence the metastatic phenotype of cancer cells in vitro in a similar fashion. Furthermore, we find that tapRNAs contain conserved sequence domains that are enriched in motifs for zinc finger domain-containing RNA-binding proteins and transcription factors, whose binding sites are found mutated in cancers. Conclusions This work leverages positional conservation to identify lncRNAs with potential importance in genome organization, development and disease. The evidence that many developmental transcription factors are physically and functionally connected to lncRNAs represents an exciting stepping-stone to further our understanding of genome regulation.

Conservation agriculture has been promoted as the main strategy to regenerate soil life but its effect on soil enzyme activity remains little documented. This study investigated the β-glucosidase and arylsulfatase enzymes as tools to evaluate soil health at the field level. Croplands in four main grain-producing states in Brazil were selected for this study. In each cropland, three environments (high yield (HYE), medium yield (MYE), and low yield (LYE)) were delineated for soil sampling to determine soil chemical attributes and enzyme activity. In one of these fields with a large temporal database, soil DNA characterization was also undertaken. The two soil enzymes investigated were affected by a range of soil attributes and the most important of these were identified. Around 40% of the data points sampled had low soil organic matter content; these were associated with low enzyme activity. Furthermore, in HYE there was more biodiversity and a higher presence of plant-growth promoters, while in LYE there were more plant pathogenic organisms.

Aim: To present a a therapeutic approach in a case series of teeth that suffered some root fracture at different thirds with a follow-up period of 24 months. Summary: Dental trauma occurs with great frequency to the maxillary incisors, and, sometimes, horizontal root fractures are caused. The classification and severity of horizontal root fractures are based on the location of the fracture line and on the degree of dislocation of the coronal fragment. Diagnosis of horizontal root fractures is based on clinical findings, sensibility tests, and principally in radiographic and cone-beam computed tomography (CBCT) examination. The following cases report describes the diagnosis and treatment of four maxillary central incisors with horizontal root fractures. In three of the cases described, the healing occurred through the interposition of connective tissue where radiographically was possible to observe a radiolucent at the level of the fracture line and the rounding of the fragment angles. In one case, the healing occurred by calcified tissue, which can be seen radiographically in the fracture line, but the fragments are in close contact. In addition to a proper treatment plan, the International Association of Dental Traumatology (IADT) stresses the importance of patient compliance with follow-up, and daily care visits for better healing after dental trauma. Knowledge of existing protocols for this type of injury and periodic monitoring of cases has shown the success of the treatment so far. Key-learning points: (1) The diagnosis of root fractures requires a detailed examination, both clinical and radiographic. (2) The IADT developed a guideline in order to propose an effective treatment plan. (3) The CBCT facilitates the visualization of lines fracture. (4) An immediate approach after horizontal root fractures comprises reduction, splints and occlusal adjustment.

Abstract In order to develop an improved BCG vaccine against tuberculosis we have taken advantage of the adjuvant properties of a non-toxic derivative of Escherichia coli heat labile enterotoxin (LT), LTAK63. We have constructed rBCG strains expressing LTAK63 at different expression levels. Mice immunized with BCG expressing low levels of LTAK63 (rBCG-LTAK63lo) showed higher Th1 cytokines and IL-17 in the lungs, and when challenged intratracheally with Mycobacterium tuberculosis displayed a 2.0–3.0 log reduction in CFU as compared to wild type BCG. Histopathological analysis of lung tissues from protected mice revealed a reduced inflammatory response. Immunization with rBCG-LTAK63lo also protected against a 100-fold higher challenge dose. Mice immunized with rBCG-LTAK63lo produced an increase in TGF-β as compared with BCG after challenge, with a corresponding reduction in Th1 and Th17 cytokines, as determined by Real Time RT-PCR. Furthermore, rBCG-LTAK63lo also displays protection against challenge with a highly virulent Beijing isolate. Our findings suggest that BCG with low-level expression of the LTAK63 adjuvant induces a stronger immune response in the lungs conferring higher levels of protection, and a novel mechanism subsequently triggers a regulatory immune response, which then limits the pathology. The rBCG-LTAK63lo strain can be the basis of an improved vaccine against tuberculosis.

Despite the availability of effective antimicrobials, tuberculosis (TB) is still a serious health threat. Mortality is even higher in people living with HIV who are diagnosed with TB. New therapies are needed to shorten the time required to cure TB and decrease fatality rates in this population. N-acetylcysteine (NAC) is a glutathione precursor and has shown recently in experimental setting to present in vitro and in vivo anti-mycobacterial activity. We test the hypothesis that NAC is safe, well tolerated and secondarily efficacious as adjunctive anti-TB therapy in hospitalized individuals with HIV-associated TB. Patients were enrolled sequentially in a tertiary care center, in the Brazilian Amazon. We performed a randomized, parallel group, single-center, open study trial of two arms, in hospitalized patients over 18 years of age, with microbiologically confirmed pulmonary TB in HIV: one with rifampicin, isoniazid, pyrazinamide and ethambutol at standard doses (Control Group), and a second in which NAC 600 mg bid for eight weeks was added (NAC Group). A total of 21 and 18 patients were enrolled to the Control Group and NAC Group, respectively. Adverse event rates were similar in the two arms. Our findings suggest that in the more critical population of hospitalized patients with HIV-associated TB, the use of NAC was not unsafe, despite the low sample size, and a potential impact on faster negative cultures needs to be further explored in larger studies.

Heme oxygenase-1 (HO-1) catalyzes the degradation of heme molecules releasing equimolar amounts of biliverdin, iron and carbon monoxide. Its expression is induced in response to stress signals such as reactive oxygen species and inflammatory mediators with antioxidant, anti-inflammatory and immunosuppressive consequences for the host. Interestingly, several intracellular pathogens responsible for major human diseases have been shown to be powerful inducers of HO-1 expression in both host cells and in vivo. Studies have shown that this HO-1 response can be either host detrimental by impairing pathogen control or host beneficial by limiting infection induced inflammation and tissue pathology. These properties make HO-1 an attractive target for host-directed therapy (HDT) of the diseases in question, many of which have been difficult to control using conventional antibiotic approaches. Here we review the mechanisms by which HO-1 expression is induced and how the enzyme regulates inflammatory and immune responses during infection with a number of different intracellular bacterial and protozoan pathogens highlighting mechanistic commonalities and differences with the goal of identifying targets for disease intervention.

Cattle dung distribution in pastoral ecosystems is uneven and affects nutrient availability to plants. Thus, identifying its spatiotemporal patterns is crucial to understanding the mechanisms underlying the system functioning. We aimed to characterize the spatiotemporal distribution of dung patches in mixed black oat (Avena strigosa Schreb.) and Italian ryegrass (Lolium multiflorum Lam.) pastures grazed at different intensities (sward heights of 0.1, 0.2, 0.3 and 0.4 m) in the winter stocking period of an integrated soybean-beef system in southern Brazil. All dung patches were located and georeferenced every 20 days. Dung distribution was analyzed using Thiessen polygons and semivariogram analysis. The spatial pattern of dung deposition was virtually similar over time but created distinct patterns in paddocks managed at different grazing intensities. Dung patch density was greater close to attraction points, resting and socialization areas regardless of grazing intensity. Lighter grazing intensities presented stronger spatial patterns with increased dung density in those areas, but those patterns weakened with increasing grazing intensity. Dung patches covered 0.4%, 0.9%, 1.1% and 1.5% of the area in paddocks managed at 0.4, 0.3, 0.2 and 0.1 m sward heights, respectively. Geostatistics proved useful for identifying spatial patterns in integrated crop-livestock systems and will potentially support further investigations.

Lysosomal cathepsin B (CTSB) has been proposed to play a role in the induction of acute inflammation. We hypothesised that the presence of active CTSB in the cytosol is crucial for NLRP3-inflammasome assembly and, consequently, for mature IL-1β generation after mycobacterial infection in vitro. Elevated levels of CTSB was observed in the lungs of mice and rabbits following infection with Mycobacterium tuberculosis (Mtb) H37Rv as well as in plasma from acute tuberculosis patients. H37Rv-infected murine bone marrow-derived macrophages (BMDMs) displayed both lysosomal leakage, with release of CTSB into the cytosol, as well as increased levels of mature IL-1β. These responses were diminished in BMDM infected with a mutant H37Rv deficient in ESAT-6 expression. Pharmacological inhibition of cathepsin activity with CA074-Me resulted in a substantial reduction of both mature IL-1β production and caspase-1 activation in infected macrophages. Moreover, cathepsin inhibition abolished the interaction between NLRP3 and ASC, measured by immunofluorescence imaging in H37Rv-infected macrophages, demonstrating a critical role of the enzyme in NLRP3-inflammasome activation. These observations suggest that during Mtb infection, lysosomal release of activated CTSB and possibly other cathepsins inhibitable by CA07-Me is critical for the induction of inflammasome-mediated IL-1β processing by regulating NLRP3-inflammasome assembly in the cytosol.

The use of agroindustrial wastes for biosurfactant production is advantageous since the raw material represents a great part of the costs to obtain this bio-product. Low cost raw materials (Tiger nut fibre – TNF and corn steep liquor – CSL) were evaluated as potential carbon and nitrogen sources for biosurfactant production by Yarrowia lipolytica IMUFRJ 50682. It was demonstrated that it is possible to produce biosurfactant using corn steep liquor or tiger nut fiber in medium containing ammonium sulfate, with emulsification indexes (EI) around 40% for each residue. The culture medium containing ammonium sulfate, corn steep liquor and tiger nut fiber presented the same EI (60%) as the medium containing glucose, yeast extract, glycerol and ammonium sulfate (Control medium). This is the first report of the use of tiger nut by-product for biosurfactant production. It was estimated that the cost for ammonium sulfate, corn steep liquor and tiger nut fiber medium is one third the cost of control medium.

Execution of pluripotency requires progression from the naïve status represented by mouse embryonic stem cells (ESCs) to a state capacitated for lineage specification. This transition is coordinated at multiple levels. Non-coding RNAs may contribute to this regulatory orchestra. We identified a rodent-specific long non-coding RNA (lncRNA) linc1281, hereafter Ephemeron (Eprn), that modulates the dynamics of exit from naïve pluripotency. Eprn deletion delays the extinction of ESC identity, an effect associated with perduring Nanog expression. In the absence of Eprn, Lin28a expression is reduced which results in persistence of let-7 microRNAs, and the up-regulation of de novo methyltransferases Dnmt3a/b is delayed. Dnmt3a/b deletion retards ES cell transition, correlating with delayed Nanog promoter methylation and phenocopying loss of Eprn or Lin28a. The connection from lncRNA to miRNA and DNA methylation facilitates the acute extinction of naïve pluripotency, a pre-requisite for rapid progression from preimplantation epiblast to gastrulation in rodents. Eprn illustrates how lncRNAs may introduce species-specific network modulations.

The antioxidant enzyme heme oxygenase-1 (HO-1) is implicated in the pathogenesis of tuberculosis (TB) and has been proposed as a biomarker of active disease. Nevertheless, the mechanisms by which Mycobacterium tuberculosis (Mtb) induces HO-1 as well as how its expression is affected by HIV-1 coinfection and successful antitubercular therapy (ATT) are poorly understood. We found that HO-1 expression is markedly increased in rabbits, mice, and non-human primates during experimental Mtb infection and gradually decreased during ATT. In addition, we examined circulating concentrations of HO-1 in a cohort of 130 HIV-1 coinfected and uninfected pulmonary TB patients undergoing ATT to investigate changes in expression of this biomarker in relation to HIV-1 status, radiological disease severity, and treatment outcome. We found that plasma levels of HO-1 were elevated in untreated HIV-1 coinfected TB patients and correlated positively with HIV-1 viral load and negatively with CD4+ T cell count. In both HIV-1 coinfected and Mtb monoinfected patients, HO-1 levels were substantially reduced during successful TB treatment but not in those who experienced treatment failure or subsequently relapsed. To further delineate the molecular mechanisms involved in induction of HO-1 by Mtb, we performed a series of in vitro experiments using mouse and human macrophages. We found that Mtb-induced HO-1 expression requires NADPH oxidase-dependent reactive oxygen species production induced by the early-secreted antigen ESAT-6, which in turn triggers nuclear translocation of the transcription factor NRF-2. These observations provide further insight into the utility of HO-1 as a biomarker of both disease and successful therapy in TB monoinfected and HIV-TB coinfected patients and reveal a previously undocumented pathway linking expression of the enzyme with oxidative stress.

Apocynin was used as an inducer of nitric oxide (NO) synthesis in leaves of two maize (Zea mays L.) cultivars (SHS 3031 and DKB 240). The transcription of γ-glutamylcysteine synthetase (γ-ecs), glutathione synthetase (gshs), chalcone synthase (chs), flavanone 3-β-hydroxylase (fht1), glutathione S-transferase (gst23), ascorbate peroxidase (apx1, apx2), catalase (cat1, cat3), and superoxide dismutase (sod2) genes were quantified in leaves of maize and NO presence was detected by fluorescence microscopy. An increase in the fluorescence after apocynin treatment was not observed in leaves of DKB 240 but leaves of SHS 3031 showed higher fluorescence after 6 and 12 h of apocynin treatment. We observed that γ-ecs, apx1, cat1, and sod2 transcription increased after 24 h of apocynin treatment in SHS 3031.

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) that in most cases induces irreversible necrosis of lung tissue as a result of excessive inflammatory reactions. The murine model of TB in resistant C57BL/6 mice infected with reference Mtb strains is widely used in TB studies; however, these mice do not show a necrotic pathology, which restricts their use in studies of irreversible tissue damage. Recently, we demonstrated that necrotic lung lesions could be induced in the C57BL/6 mice by highly virulent Mtb strains belonging to the modern Beijing sublineage. However, the pathogenic mechanisms leading to necrosis in this model were not elucidated. In this study, we investigated the dynamics of lung lesions in mice infected with highly virulent Beijing Mtb strain M299, compared with those infected with laboratory Mtb strain H37Rv. The data demonstrate that necrotic lung lesions in mice infected by the strain M299 were associated with enhanced recruitment of myeloid cells, especially neutrophils, and increased levels of proinflammatory cytokines, consistent with exacerbated inflammation. High levels of IFN-γ production contributed to the control of bacterial growth. Further progression to chronic disease was associated with a reduction in the levels of inflammatory mediators in the lungs, the accumulation of foamy macrophages and partial healing of the necrotic tissue by fibrosis. At a late stage of disease, degradation of foamy cells resulted in the liberation of accumulated lipids and persisting bacilli and further activation of inflammation, which promoted lung consolidation. Overall, our studies show that C57BL/6 mice infected with highly virulent Mtb strain may serve as a TB model reproducing an exacerbated inflammatory response in a resistant host to hypervirulent mycobacteria, leading to irreversible necrotic lung lesions.

[This corrects the article DOI: 10.1371/journal.pone.0173715.].

ABSTRACT Heme oxygenase-1 (HO-1) is a stress response antioxidant enzyme which catalyzes the degradation of heme released during inflammation. HO-1 expression is upregulated in both experimental and human Mycobacterium tuberculosis infection, and in patients it is a biomarker of active disease. Whether the enzyme plays a protective versus pathogenic role in tuberculosis has been the subject of debate. To address this controversy, we administered tin protoporphyrin IX (SnPPIX), a well-characterized HO-1 enzymatic inhibitor, to mice during acute M. tuberculosis infection. These SnPPIX-treated animals displayed a substantial reduction in pulmonary bacterial loads comparable to that achieved following conventional antibiotic therapy. Moreover, when administered adjunctively with antimycobacterial drugs, the HO-1 inhibitor markedly enhanced and accelerated pathogen clearance. Interestingly, both the pulmonary induction of HO-1 expression and the efficacy of SnPPIX treatment in reducing bacterial burden were dependent on the presence of host T lymphocytes. Although M. tuberculosis expresses its own heme-degrading enzyme, SnPPIX failed to inhibit its enzymatic activity or significantly restrict bacterial growth in liquid culture. Together, the above findings reveal mammalian HO-1 as a potential target for host-directed monotherapy and adjunctive therapy of tuberculosis and identify the immune response as a critical regulator of this function. IMPORTANCE There is no reliable vaccine against tuberculosis (TB), and conventional antibiotic therapy is administered over at least 6 months. This prolonged treatment period can lead to noncompliance resulting in relapsed infection as well as the emergence of multidrug resistance. Thus, there is an urgent need for improved therapeutic regimens that can more rapidly and efficiently control M. tuberculosis in infected patients. Here, we describe a potential strategy for treating TB based on pharmacological inhibition of the host heme-degrading enzyme HO-1. This approach results in significantly reduced bacterial burdens in mice, and when administered in conjunction with conventional antibiotic therapy, leads to faster, more effective pathogen clearance without detectable direct effects on the mycobacteria themselves. Interestingly, the effects of HO-1 inhibition on M. tuberculosis infection in vivo are dependent on the presence of an intact host immune system. These observations establish mammalian HO-1 as a potential target for host-directed therapy of TB.

In order to develop and optimize a syngas fermentation using a hollow fiber membrane bioreactor (HFMB), this study proposes to characterize the surface of Clostridium carboxidivorans, a strictly anaerobic and gram- positive bacterium capable of producing biofuels and other chemicals. The choice for using syngas as substrate arises from the necessity to give a better destination to urban and industrial residues, which are destined to landfills. In a HFMB, a Clostridium carboxidivorans biofilm can be used for the purpose of enhancing cell density in the system, which is normally a problem for anaerobe bacterium; and the membrane can increase the mass transfer coefficient, a bottleneck in this process due to the gas-liquid mass transfer. The knowledge of the interactions between cells and surfaces, cell hydrophobicity and/or hydrophilicity, and how to enhance the force balance between electrostatic and van der Waals interactions, could enhance celladhesion, biofilm formation and cell interaction with substrate. The Contact Angle Measurement (CAM) showed that C. carboxidivorans have a total surface tension (?TOT) of 56.0 mJ m-2, and its components: Lifshitz-van der Waals (?LW) of 24.3 mJ m-2 and Lewis acid-base (?AB) of 31.7 mJ m-2. Also, the free energy of interaction between cells and water (?Gmwm) was 9.6 mJ m-2 and the free energy of interaction between cells and hexadecane when immersed in water (?Gmwh) was -14.7 mJ m-2. With these values, it was possible to determine that Clostridium carboxidivorans presents a hydrophilic surface character but is also capable ofbeing attracted by hydrophobic molecules, liquids and surfaces and capable of interacting with them when immersed in water. Moreover, Clostridium carboxidivorans presented an electron-donor character, which already appeared in previous studies but was confirmed with this test. Therefore, this strain, when immersed in an aqueous culture medium, has an affinity to a hydrophobic membrane, which would favor its adhesion.