Fast-Evolving Alignment Sites Are Highly Informative for Reconstructions of Deep Tree of Life Phylogenies.

The trimming of fast-evolving sites, often known as "slow-fast" analysis, is broadly used in microbial phylogenetic reconstruction under the assumption that fast-evolving sites do not retain an accurate phylogenetic signal due to substitution saturation. Therefore, removing sites that have experienced multiple substitutions would improve the signal-to-noise ratio in phylogenetic analyses, with the remaining slower-evolving sites preserving a more reliable record of evolutionary relationships. Here, we show that, contrary to this assumption, even the fastest-evolving sites present in the conserved proteins often used in Tree of Life studies contain reliable and valuable phylogenetic information, and that the trimming of such sites can negatively impact the accuracy of phylogenetic reconstruction. Simulated alignments modeled after ribosomal protein datasets used in Tree of Life studies consistently show that slow-evolving sites are less likely to recover true bipartitions than even the fastest-evolving sites. Furthermore, site-specific substitution rates are positively correlated with the frequency of accurately recovered short-branched bipartitions, as slowly evolving sites are less likely to have experienced substitutions along these intervals. Using published Tree of Life sequence alignment datasets, we also show that both slow- and fast-evolving sites contain similarly inconsistent phylogenetic signals, and that, for fast-evolving sites, this inconsistency can be attributed to poor alignment quality. Furthermore, trimming fast sites, slow sites, or both is shown to have a substantial impact on phylogenetic reconstruction across multiple evolutionary models. This is perhaps most evident in the resulting placements of the Eukarya and Asgardarchaeota groups, which are especially sensitive to the implementation of different trimming schemes.

Bioactivity of substances isolated from natural products on mollusks Biomphalaria glabrata (Say, 1818) (Planorbidae): a review.

Schistosomiasis is a neglected tropical disease caused by parasitic worms of several species of the genus Schistosoma. Transmission occurs by parasitic larvae that stay in freshwater snails of the genus Biomphalaria. Thus, the search for new products that are biodegradable has increased the interest in products of plant origin. The aim of this article is to review the isolated substances from natural products that showed molluscicidal activity against the species Biomphalaria glabrata in order to reevaluate the most promising prototypes and update the progress of research to obtain a new molluscicide. We perform searches using scientific databases, such as Scientific Electronic Library Online (SciELO), Google schoolar, PUBMED, Web of Science and Latin American and Caribbean Literature on Health Sciences (LILACS). From 2000 to 2022, using the keywords "isolated substances", "molluscicidal activity" and "Biomphalaria glabrata". In the present study, it was possible to observe 19 promising molluscicidal molecules with a lethal concentration below 20 µg/mL. Of these promising isolates, only 5 isolates had the CL90 calculated and within the value recommended by WHO: Benzoic acid, 2',4',6'-Trihydroxydihydrochalcone, Divaricatic acid, Piplartine and 2-hydroxy-1,4-naphthoquinone (Lapachol). We conclude that beyond a few results in the area, the researches don't follow the methodological pattern (exposure time and measure units, toxicity test), in this way, as they don't follow a pattern on the result's exposure (LC), not following, in sum, the recommended by WHO.

A Proterozoic microbial origin of extant cyanide-hydrolyzing enzyme diversity.

In addition to its role as a toxic environmental contaminant, cyanide has been hypothesized to play a key role in prebiotic chemistry and early biogeochemical evolution. While cyanide-hydrolyzing enzymes have been studied and engineered for bioremediation, the extant diversity of these enzymes remains underexplored. Additionally, the age and evolution of microbial cyanide metabolisms is poorly constrained. Here we provide comprehensive phylogenetic and molecular clock analyses of the distribution and evolution of the Class I nitrilases, thiocyanate hydrolases, and nitrile hydratases. Molecular clock analyses indicate that bacterial cyanide-reducing nitrilases were present by the Paleo- to Mesoproterozoic, and were subsequently horizontally transferred into eukaryotes. These results present a broad diversity of microbial enzymes that could be optimized for cyanide bioremediation.

Management of late-onset fetal growth restriction: pragmatic approach.

OBJECTIVES: There is limited prospective evidence to guide the management of late-onset fetal growth restriction (FGR) and its differentiation from small-for-gestational age. The aim of this study was to assess prospectively a novel protocol in which ultrasound criteria were used to classify women with suspected late FGR into two groups: those at low risk, who were managed expectantly until the anticipated date of delivery, and those at high risk, who were delivered soon after 37 weeks of gestation. We also compared the outcome of this prospective cohort with that of a historical cohort of women presenting similarly with suspected late FGR, in order to evaluate the impact of the new protocol. METHODS: This was a prospective study of women with a non-anomalous singleton pregnancy at ≥ 32 weeks' gestation attending a tertiary hospital in London, UK, between February 2018 and September 2019, with estimated fetal weight (EFW) ≤ 10th centile, or EFW > 10th centile in addition to a decrease in fetal abdominal circumference of ≥ 50 centiles compared with a previous scan, umbilical artery Doppler pulsatility index > 95th centile or cerebroplacental ratio < 5th centile. Women were classified as low or high risk based on ultrasound and Doppler criteria. Women in the low-risk group were delivered by 41 weeks of gestation, unless they subsequently met high-risk criteria, whereas women in the high-risk group (EFW < 3rd centile, umbilical artery Doppler pulsatility index > 95th centile or EFW between 3rd and 10th centiles (inclusive) with abdominal circumference drop or abnormal Dopplers) were delivered at or soon after 37 weeks. The primary outcome was adverse neonatal outcome and included hypothermia, hypoglycemia, neonatal unit admission, jaundice requiring treatment, suspected infection, feeding difficulties, 1-min Apgar score < 7, hospital readmission and any severe adverse neonatal outcome (perinatal death, resuscitation using inotropes or mechanical ventilation, 5-min Apgar score < 7, metabolic acidosis, sepsis, and cerebral, cardiac or respiratory morbidity). Secondary outcomes were adverse maternal outcome (operative delivery for abnormal fetal heart rate) and severe adverse neonatal outcome. Women managed according to the new protocol were compared with a historical cohort of 323 women delivered prior to the implementation of the new protocol, for whom management was guided by individual clinician expertise. RESULTS: Over 18 months, 321 women were recruited to the prospective cohort, of whom 156 were classified as low risk and 165 were high risk. Adverse neonatal outcome was significantly less common in the low-risk compared with the high-risk group (45% vs 58%; adjusted odds ratio (aOR), 0.6 (95% CI, 0.4-0.9); P = 0.022). There was no significant difference in the rate of adverse maternal outcome (18% vs 24%; aOR, 0.7 (95% CI, 0.4-1.2); P = 0.142) or severe adverse neonatal outcome (3.8% vs 8.5%; aOR, 0.5 (95% CI, 0.2-1.3); P = 0.153) between the low- and high-risk groups. Compared with women in the historical cohort classified retrospectively as low risk, low-risk women managed under the new protocol had a lower rate of adverse neonatal outcome (45% vs 58%; aOR, 0.6 (95% CI, 0.4-0.9); P = 0.026). CONCLUSIONS: Appropriate risk stratification to guide management of late FGR was associated with a reduced rate of adverse neonatal outcome in low-risk pregnancies. In clinical practice, a policy of expectantly managing women with a low-risk late-onset FGR pregnancy at term could improve neonatal and long-term development. Randomized controlled trials are needed to assess the effect of an evidence-based conservative management protocol for late FGR on perinatal morbidity and mortality and long-term neurodevelopment. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

DaTeR: error-correcting phylogenetic chronograms using relative time constraints.

MOTIVATION: A chronogram is a dated phylogenetic tree whose branch lengths have been scaled to represent time. Such chronograms are computed based on available date estimates (e.g. from dated fossils), which provide absolute time constraints for one or more nodes of an input undated phylogeny, coupled with an appropriate underlying model for evolutionary rates variation along the branches of the phylogeny. However, traditional methods for phylogenetic dating cannot take into account relative time constraints, such as those provided by inferred horizontal transfer events. In many cases, chronograms computed using only absolute time constraints are inconsistent with known relative time constraints. RESULTS: In this work, we introduce a new approach, Dating Trees using Relative constraints (DaTeR), for phylogenetic dating that can take into account both absolute and relative time constraints. The key idea is to use existing Bayesian approaches for phylogenetic dating to sample posterior chronograms satisfying desired absolute time constraints, minimally adjust or 'error-correct' these sampled chronograms to satisfy all given relative time constraints, and aggregate across all error-corrected chronograms. DaTeR uses a constrained optimization framework for the error-correction step, finding minimal deviations from previously assigned dates or branch lengths. We applied DaTeR to a biological dataset of 170 Cyanobacterial taxa and a reliable set of 24 transfer-based relative constraints, under six different molecular dating models. Our extensive analysis of this dataset demonstrates that DaTeR is both highly effective and scalable and that its application can significantly improve estimated chronograms. AVAILABILITY AND IMPLEMENTATION: Freely available from https://compbio.engr.uconn.edu/software/dater/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice.

Neuropathic pain is one of the most important clinical consequences of injury to the somatosensory system. Nevertheless, the critical pathophysiological mechanisms involved in neuropathic pain development are poorly understood. In this study, we found that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO1-expressing dendritic cells (DCs) accumulated in the dorsal root leptomeninges and led to an increase in kynurenine levels in the spinal cord. In the spinal cord, kynurenine was metabolized by kynurenine-3-monooxygenase-expressing astrocytes into the pronociceptive metabolite 3-hydroxykynurenine. Ultimately, 3-hydroxyanthranilate 3,4-dioxygenase-derived quinolinic acid formed in the final step of the canonical KYNPATH was also involved in neuropathic pain development through the activation of the glutamatergic N-methyl-D-aspartate receptor. In conclusion, these data revealed a role for DCs driving neuropathic pain development through elevation of the KYNPATH. This paradigm offers potential new targets for drug development against this type of chronic pain.

Beneficios de un modelo asistencial integral en pacientes con insuficiencia cardíaca y fracción de eyección preservada: Programa UMIPIC / Benefits of a comprehensive care model in patients with heart failure and preserved ejection fraction: The UMIPIC program

Antecedentes Los pacientes con insuficiencia cardíaca (IC) y fracción de eyección preservada (ICFEp), a diferencia de aquellos con fracción de eyección reducida, son más ancianos, presentan más comorbilidades y no son candidatos a medidas terapéuticas eficaces. Por todo ello presentan un riesgo elevado de ingreso hospitalario y mortalidad. En este estudio se evaluó el beneficio de un modelo asistencial, caracterizado por una atención integral y continuada (programa UMIPIC) en pacientes con ICFEp. Métodos Se analizaron prospectivamente los datos de 2.401 pacientes con ICFEp atendidos en servicios de medicina interna, procedentes del registro RICA. Se dividieron en 2 grupos, uno en seguimiento en el programa UMIPIC (grupo UMIPIC, n: 1.011) y otro atendido de forma convencional (grupo RICA, n: 1.390). Se seleccionaron por emparejamiento (propensity score matching) 753 pacientes en cada grupo y se evaluaron los ingresos y la mortalidad durante 12 meses de seguimiento, tras un episodio de hospitalización por IC. Resultados El grupo UMIPIC, con respecto al RICA, en la cohorte emparejada, tuvo una menor tasa de ingresos por IC (19,2% frente a 36,5% respectivamente; hazard ratio [HR]=0,56; intervalo de confianza del 95% [IC 95%]: 0,45-0,68; p<0,001) y de mortalidad (12,6% frente a 28%, respectivamente; HR=0,40; IC 95%: 0,31-0,51; p<0,001). No se observaron diferencias en cuanto a ingresos por causas distintas a la IC. Conclusiones La implementación del programa asistencial UMIPIC a pacientes con ICFEp y elevada comorbilidad, basado en una atención integral y continuada, reduce tanto los ingresos como la mortalidad al año de seguimiento (AU)

Background Patients with heart failure (HF) and preserved ejection fraction (HFpEF), in contrast to those with reduced ejection fraction, are older, have more comorbidities, and are not candidates for effective therapeutic measures. Therefore, they are at high risk for hospital admission and mortality. This study evaluated the benefit of a comprehensive continuous care program (UMIPIC program) in patients with HFpEF. Methods We prospectively analyzed data on 2,401 patients with HFpEF attended to in internal medicine departments who form part of the RICA registry. They were divided into 2 groups: one was followed-up on in the UMIPIC program (UMIPIC group, n: 1,011) and another received conventional care (RICA group, n: 1,390). A total of 753 patients in each group were selected by propensity score matching and admissions and mortality were assessed during 12 months of follow-up after an episode of hospitalization due to HF. Results Compared to the RICA group, the UMIPIC group had a lower rate of HF admissions (19.2% versus 36.5%, respectively; hazard ratio [HR]=0.56; 95% confidence interval [CI]: 0.45-0.68; p<.001) and mortality (12.6% versus 28%, respectively; HR=0.40; 95% CI: 0.31-0.51; p<.001). There were no differences in hospitalizations for non-HF causes. Conclusions Implementation of the UMIPIC program, which is based on comprehensive continuous care, for patients with HFpEF and a high degree of comorbidity reduces both admissions and mortality in the first year of follow-up (AU)

Detección de la interacción ácido acetilsalicílico – metamizol en pacientes de farmacia comunitaria / Screening for acetylsalicylic acid - metamizole interaction in community pharmacy patients

JUSTIFICACIÓN Y OBJETIVOS: Metamizol puede reducir el efecto del ácido acetilsalicílico (AAS) sobre la agregación plaquetaria cuando se administran concomitantemente. Por lo tanto, esta combinación se debe utilizar con precaución en pacientes que toman dosis bajas de AAS aspirina para cardioprotección. La elevada utilización de metamizol puede suponer una situación que favorezca la aparición de interacción farmacológica con AAS, fármaco ampliamente prescrito por su acción antiagregante plaquetaria. El objetivo de este estudio es describir los pacientes de farmacia comunitaria que pueden estar expuestos a la interacción AAS-metamizol e identificar aquellas situaciones en las que sería necesario intervenir de forma prioritaria.MÉTODOS: estudio observacional realizado en dos farmacias comunitarias de Málaga con los pacientes que acuden a por metamizol y/o AAS durante 3 meses (septiembre-octubre 2021). Se han registrado las interacciones farmacológicas (IF) con la ayuda de un programa informático que utiliza la base de datos del Consejo General de Colegios Oficiales de Farmacéuticos (CGCOF) y que es capaz de emitir una señal de alerta al farmacéutico ante asociaciones de medicamentos capaces de producir IF en el momento de la dispensación.RESULTADOS: se ha detectado esta IF en 34 pacientes, de los que un 29,4 % corresponde a hombres y un 70,6 % a mujeres. La media de edad ha sido de 69,9 (DE: 13,2), con un consumo medio de medicamentos de 9,3 (DE: 3,04). Todos los pacientes o cuidadores fueron informados de la existencia de la interacción, pero no se consiguió informar a los médicos de atención primaria. (AU)

Seafood safety and food-borne zoonoses from fish: Examining the risk of Anisakis in the Portuguese Population and Consumer Risk Perceptions of Fish Consumption.

Parasitic nematodes of the genus Anisakis are the causative agent of anisakiosis, an important fish-borne zoonosis. Humans are infected through consumption of raw or undercooked fish, contaminated with the parasite. Infection can result in both gastrointestinal and allergic symptoms. There are few reports of anisakiosis in Portugal, but evidence of Anisakis allergy exists, indicating that exposure is occurring in the population. The European Food Risk Assessment Fellowship Programme (EU-FORA) work programme, entitled: 'Food safety of fish and zoonoses: fish consumption and microbiological risk assessment and perception, from fisherman to final consumers in Portugal' was hosted by the Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), in Porto, Portugal. It aimed to gather information on risk perception and attitudes in the Portuguese population to contamination of fish with Anisakis spp. and on their knowledge of methods to prevent infection. In addition, it aimed to examine the risk of anisakiosis in the Portuguese population.

Benefits of a comprehensive care model in patients with heart failure and preserved ejection fraction: The UMIPIC program.

BACKGROUND: Patients with heart failure (HF) and preserved ejection fraction (HFpEF), in contrast to those with reduced ejection fraction, are older, have more comorbidities, and are not candidates for effective therapeutic measures. Therefore, they are at high risk for hospital admission and mortality. This study evaluated the benefit of a comprehensive continuous care program (UMIPIC program) in patients with HFpEF. METHODS: We prospectively analyzed data on 2401 patients with HFpEF attended to in internal medicine departments who form part of the RICA registry. They were divided into 2 groups: one was followed-up on in the UMIPIC program (UMIPIC group, n: 1011) and another received conventional care (RICA group, n: 1390). A total of 753 patients in each group were selected by propensity score matching and admissions and mortality were assessed during 12 months of follow-up after an episode of hospitalization due to HF. RESULTS: Compared to the RICA group, the UMIPIC group had a lower rate of HF admissions (19.2% versus 36.5%, respectively; hazard ratio [HR] = 0.56; 95% confidence interval [CI]: 0.45-0.68; p < 0.001) and mortality (12.6% versus 28%, respectively; HR = 0.40; 95% CI: 0.31-0.51; p < 0.001). There were no differences in hospitalizations for non-HF causes. CONCLUSIONS: Implementation of the UMIPIC program, which is based on comprehensive continuous care, for patients with HFpEF and a high degree of comorbidity reduces both admissions and mortality in the first year of follow-up.

The Archean origin of oxygenic photosynthesis and extant cyanobacterial lineages.

The record of the coevolution of oxygenic phototrophs and the environment is preserved in three forms: genomes of modern organisms, diverse geochemical signals of surface oxidation and diagnostic Proterozoic microfossils. When calibrated by fossils, genomic data form the basis of molecular clock analyses. However, different interpretations of the geochemical record, fossil calibrations and evolutionary models produce a wide range of age estimates that are often conflicting. Here, we show that multiple interpretations of the cyanobacterial fossil record are consistent with an Archean origin of crown-group Cyanobacteria. We further show that incorporating relative dating information from horizontal gene transfers greatly improves the precision of these age estimates, by both providing a novel empirical criterion for selecting evolutionary models, and increasing the stringency of sampling of posterior age estimates. Independent of any geochemical evidence or hypotheses, these results support oxygenic photosynthesis evolving at least several hundred million years before the Great Oxygenation Event (GOE), a rapid diversification of major cyanobacterial lineages around the time of the GOE, and a post-Cryogenian origin of extant marine picocyanobacterial diversity.

Foreign body in esophagus: Case report.

INTRODUCTION AND IMPORTANCE: The ingestion of foreign bodies is a frequent cause of consultation in the emergency department, especially in pediatric and elderly patients. CASE PRESENTATION: We present the case of a 48-year-old male patient who arrived to the emergency department with dysphagia after food intake. The diagnosis is confirmed by simple neck tomography. After a failed endoscopy, he underwent surgery, with subsequent resolution of the condition. DISCUSSION: The diagnosis is based on the clinical history, physical examination and is supported by extension studies such as radiography, tomography and/or endoscopy, this last one being also therapeutic. CONCLUSION: Although in most cases there is a spontaneous passage through the gastrointestinal tract, there is the possibility of requiring endoscopy (reported success greater than 95% of cases) or surgical treatment.

Muscle Assessment by Ultrasonography: Agreement with Dual-Energy X-Ray Absorptiometry (DXA) and Relationship with Physical Performance.

BACKGROUND: Different methods have been proposed to study skeletal muscle mass in sarcopenia diagnosis, although all have inherent drawbacks. The aim of this study was to evaluate the utility of muscle ultrasound in muscle assessment by studying its correlation with dual-energy x-ray absorptiometry (DXA) and calf circumference (CC), cut-off values for ultrasound-based detection of low muscle mass, and the correlation with muscle performance. METHODS: Fifty-seven participants older than 70 years, underwent a muscle ultrasound study, DXA, calf circumference (CC) and functional assessment. Ultrasound measurements were taken in the femoral quadriceps (transverse plane) and in the medial gastrocnemius (transverse and longitudinal planes). Muscle function was assessed by gait speed, Short Physical Performance Battery (SPPB) and grip strength. RESULTS: Median age was 78.9 years (IQR 74.9 - 81.9), and 33 were women (57.9%). We found good correlation between muscle thickness of gastrocnemius muscle in transverse and longitudinal plane and appendicular lean mass measured by DXA (r=0.546 and r=0.689 respectively) and good correlations between muscle thickness of gastrocnemius in transverse and longitudinal plane with CC (r=0.651 and r=0.447 respectively). The thickness of gastrocnemius medialis optimal cut-off points for low muscle mass were 18,5mm in the transverse plane (Sensitivity: 77,8%, Specificity: 77,1%), and 17.3mm in the longitudinal plane (Sensitivity: 100%,Specificity: 68.8%). Muscle thickness was also significantly correlated with gait speed, SPPB and grip strength. CONCLUSIONS: Measures of gastrocnemius medialis thickness obtained by ultrasound are reliable and correlate well with DXA and CC values and muscle performance.

Blockade of bradykinin receptors or angiotensin II type 2 receptor prevents paclitaxel-associated acute pain syndrome in mice.

BACKGROUND: Paclitaxel (PCX) is the first-line choice for the treatment of several types of cancer, including breast, ovarian, and lung cancers. However, patients who receive even a single dose with PCX commonly develop mechanical and cold allodynia, a symptom known as PCX-associated acute pain syndrome (P-APS). Here, we assessed possible involvement of kinin-kallikrein and renin-angiotensin systems in P-APS in mice. METHODS: Male mice C57Bl/6 wild type (WT) and knockouts for bradykinin receptors, B1 (B1-/- ) and B2 (B2-/- ), were used. Mechanical and cold allodynia were evaluated by using von Frey filaments and acetone test, respectively. P-APS was induced by administration of PCX 4 mg/kg, i.v.. ACE inhibitors (captopril and enalapril), antagonists for angiotensin II type 1 (losartan) and type 2 ([AT2R]; PD123319 and EMA 401) receptors were administrated prior the treatment with PCX. RT-PCR was used to analyse the expression of mRNA for B1, B2 and AT2R receptors. RESULTS: Administration of PCX in B1-/- and B2-/- mice induced lower mechanical and cold allodynia compared to the WT. However, the pre-treatment with ACE inhibitors reduced the development of mechanical and cold allodynia in P-APS. Surprisingly, we found that mice pre-treatment with the PD123319 or EMA401, but not losartan, prevented the development of mechanical and cold allodynia induced by PCX. CONCLUSION: Our results demonstrated the involvement of bradykinin receptors B1 and B2 as well as AT2R in the induction of P-APS in mice, and suggest the use of AT2R antagonists as a potential therapy for the prevention of P-APS in humans. SIGNIFICANCE: Kinin-kallikrein and renin-angiotensin systems, through B1, B2 and AT2 receptors, potentiates paclitaxel-associated acute pain syndrome (P-APS) in mice. Antagonists for AT2R are potential alternatives to prevent P-APS.

Molecular basis of carrageenan-induced cytokines production in macrophages.

BACKGROUND: Low molecular weight carrageenan (Cg) is a seaweed-derived sulfated polysaccharide widely used as inflammatory stimulus in preclinical studies. However, the molecular mechanisms of Cg-induced inflammation are not fully elucidated. The present study aimed to investigate the molecular basis involved in Cg-induced macrophages activation and cytokines production. METHODS: Primary culture of mouse peritoneal macrophages were stimulated with Kappa Cg. The supernatant and cell lysate were used for ELISA, western blotting, immunofluorescence. Cg-induced mouse colitis was also developed. RESULTS: Here we show that Cg activates peritoneal macrophages to produce pro-inflammatory cytokines such as TNF and IL-1ß. While Cg-induced TNF production/secretion depends on TLR4/MyD88 signaling, the production of pro-IL-1ß relies on TLR4/TRIF/SYK/reactive oxygen species (ROS) signaling pathway. The maturation of pro-IL1ß into IL-1ß is dependent on canonical NLRP3 inflammasome activation via Pannexin-1/P2X7/K+ efflux signaling. In vivo, Cg-induced colitis was reduced in mice in the absence of NLRP3 inflammasome components. CONCLUSIONS: In conclusion, we unravel a critical role of the NLRP3 inflammasome in Cg-induced pro-inflammatory cytokines production and colitis, which is an important discovery on the pro-inflammatory properties of this sulfated polysaccharide for pre-clinical studies. Video abstract Carrageenan (Cg) is one the most used flogistic stimulus in preclinical studies. Nevertheless, the molecular basis of Cg-induced inflammation is not totally elucidated. Herein, Lopes et al. unraveled the molecular basis for Cg-induced macrophages production of biological active IL-1ß. The Cg-stimulated macrophages produces pro-IL-1ß depends on TLR4/TRIF/Syk/ROS, whereas its processing into mature IL-1ß is dependent on the canonical NLRP3 inflammasome.

Functional impact of sequelae in drug-susceptible and multidrug-resistant tuberculosis.

BACKGROUND: Evidence on the impact of tuberculosis (TB) treatment on lung function is scarce. The aim of this study was to evaluate post-treatment sequelae in drug-susceptible and drug-resistant-TB (DR-TB) cases in Mexico and Italy.METHODS: At the end of TB treatment the patients underwent complete clinical assessment, functional evaluation of respiratory mechanics, gas exchange and a 6-minute walking test. Treatment regimens (and definitions) recommended by the World Health Organization were used throughout.RESULTS: Of 61 patients, 65.6% had functional impairment, with obstruction in 24/61 patients (39.4%), and 78% with no bronchodilator response. These effects were more prevalent among DR-TB cases (forced expiratory volume in 1 s/forced vital capacity [FEV1/FVC] < lower limit of normality, 14/24 vs. 10/34; P = 0.075). DR-TB patients showed moderately severe (FEV1 < 60%) and severe obstruction (FEV1 < 50%) (P = 0.008). Pre- and post-bronchodilator FEV1 and FEV1/FVC (% of predicted) were significantly lower among DR-TB cases. Plethysmography abnormalities (restriction, hyperinflation and/or air trapping) were more frequent among DR-TB cases (P = 0.001), along with abnormal carbon monoxide diffusing capacity (DLCO) (P = 0.003).CONCLUSION: The majority of TB patients suffer the consequences of post-treatment sequelae (of differing levels), which compromise quality of life, exercise tolerance and long-term prognosis. It is therefore important that lung function is comprehensively evaluated post-treatment to identify patient needs for future medication and pulmonary rehabilitation.

Assessing the accuracy of phylogenetic rooting methods on prokaryotic gene families.

Almost all standard phylogenetic methods for reconstructing gene trees result in unrooted trees; yet, many of the most useful applications of gene trees require that the gene trees be correctly rooted. As a result, several computational methods have been developed for inferring the root of unrooted gene trees. However, the accuracy of such methods has never been systematically evaluated on prokaryotic gene families, where horizontal gene transfer is often one of the dominant evolutionary events driving gene family evolution. In this work, we address this gap by conducting a thorough comparative evaluation of five different rooting methods using large collections of both simulated and empirical prokaryotic gene trees. Our simulation study is based on 6000 true and reconstructed gene trees on 100 species and characterizes the rooting accuracy of the four methods under 36 different evolutionary conditions and 3 levels of gene tree reconstruction error. The empirical study is based on a large, carefully designed data set of 3098 gene trees from 504 bacterial species (406 Alphaproteobacteria and 98 Cyanobacteria) and reveals insights that supplement those gleaned from the simulation study. Overall, this work provides several valuable insights into the accuracy of the considered methods that will help inform the choice of rooting methods to use when studying microbial gene family evolution. Among other findings, this study identifies parsimonious Duplication-Transfer-Loss (DTL) rooting and Minimal Ancestor Deviation (MAD) rooting as two of the most accurate gene tree rooting methods for prokaryotes and specifies the evolutionary conditions under which these methods are most accurate, demonstrates that DTL rooting is highly sensitive to high evolutionary rates and gene tree error, and that rooting methods based on branch-lengths are generally robust to gene tree reconstruction error.

DMH-CBD, a cannabidiol analog with reduced cytotoxicity, inhibits TNF production by targeting NF-kB activity dependent on A2A receptor.

Cannabidiol (CBD) is a natural compound with psychoactive therapeutic properties well described. Conversely, the immunological effects of CBD are still poorly explored. In this study, the potential anti-inflammatory effects and underlying mechanisms of CBD and its analog Dimethyl-Heptyl-Cannabidiol (DMH-CBD) were investigated using RAW 264.7 macrophages. CBD and DMH-CBD suppressed LPS-induced TNF production and NF-kB activity in a concentration-dependent manner. Both compounds reduced the NF-kB activity in a µM concentration range: CBD (IC50 = 15 µM) and DMH-CBD (IC50 = 38 µM). However, the concentrations of CBD that mediated NF-kB inhibition were similar to those that cause cytotoxicity (LC50 = 58 µM). Differently, DMH-CBD inhibited the NF-kB activation without cytotoxic effects at the same concentrations, although it provokes cytotoxicity at long-term exposure. The inhibitory action of the DMH-CBD on NF-kB activity was not related to the reduction in IkBα degradation or either p65 (NF-kB) translocation to the nucleus, although it decreased p38 MAP kinase phosphorylation. Additionally, 8-(3-Chlorostyryl) caffeine (CSC), an A2A antagonist, reversed the effect of DMH-CBD on NF-kB activity in a concentration-dependent manner. Collectively, our results demonstrated that CBD reduces NF-kB activity at concentrations intimately associated with those that cause cell death, whereas DMH-CBD decreases NF-kB activity at non-toxic concentrations in an A2A receptor dependent-manner.

Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis.

PI3K activation plays a central role in the development of pulmonary inflammation and tissue remodeling. PI3K inhibitors may thus offer an improved therapeutic opportunity to treat non-resolving lung inflammation but their action is limited by unwanted on-target systemic toxicity. Here we present CL27c, a prodrug pan-PI3K inhibitor designed for local therapy, and investigate whether inhaled CL27c is effective in asthma and pulmonary fibrosis. Mice inhaling CL27c show reduced insulin-evoked Akt phosphorylation in lungs, but no change in other tissues and no increase in blood glycaemia, in line with a local action. In murine models of acute or glucocorticoid-resistant neutrophilic asthma, inhaled CL27c reduces inflammation and improves lung function. Finally, inhaled CL27c administered in a therapeutic setting protects from bleomycin-induced lung fibrosis, ultimately leading to significantly improved survival. Therefore, local delivery of a pan-PI3K inhibitor prodrug reduces systemic on-target side effects but effectively treats asthma and irreversible pulmonary fibrosis.