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Background: Synthetic cathinones (SC) are β-keto analogues of amphetamine. They usually produce short-lived stimulant effects, which trigger higher desire of re-dosing with potential risk of overdosing. Its consumption occurs frequently in the form of multiple administration during a single exposure-event (binge), mostly by young party attendees. Adolescence is a critical time of brain development, and any disruption has a high risk of inducing brain dysfunction. 4-chloroethcathinone (4-CEC), a briefly studied SC, has been identified in seized samples and linked to overdose cases [1,2], but its repercussions on cognitive functions have not been assessed, yet. Currently, there is limited information, even contradictory, on the short- and the long-term cognitive implications associated to SC use during adolescence, and even fewer when binge exposure is thought. Hence, this study aimed to demonstrate the short- and long-term effects of a single binge exposure to 4-CEC on cognitive and emotional functioning of young compared to adults. Methods: Young (1-month) and adult (6-months) mice were exposed to a single-binge (two-times 16mg/kg or two-times 32mg/kg, ip, 2h interval) of 4-CEC or saline and the effects on learning/memory were assessed, by the Morris watermaze, at 24h, one and 6-months (long-term) post exposure. Effects on emotional behaviors were assessed at the same three time points, too. Results: The obtained results demonstrate that a single binge exposure to 4-CEC elicited, long lasting, learning and memory impairment, associated to anxiolytic behaviour and increased apathy. Most importantly, young mice seem to be more susceptible to 4-CEC than adult mice. Conclusions: These results alert the cognitive impact and on mental health that a 4-CEC single binge exposure may have, especially during adolescence, when brain plasticity is still occurring., Scientific Letters, Vol. 1 No. Sup 1 (2023)

A lack of stratification methods in patients with amyotrophic lateral sclerosis (ALS) is likely implicated in therapeutic failures. Regional diversities and pathophysiological abnormalities in astrocytes from mice with SOD1 mutations (mSOD1-ALS) can now be explored in human patients using somatic cell reprogramming. Here, fibroblasts from four sporadic (sALS) and three mSOD1-ALS patients were transdifferentiated into induced astrocytes (iAstrocytes). ALS iAstrocytes were neurotoxic toward HB9-GFP mouse motor neurons (MNs) and exhibited subtype stratification through GFAP, CX43, Ki-67, miR-155 and miR-146a expression levels. Up- (two cases) and down-regulated (three cases) miR-146a values in iAstrocytes were recapitulated in their secretome, either free or as cargo in small extracellular vesicles (sEVs). We previously showed that the neuroprotective phenotype of depleted miR-146 mSOD1 cortical astrocytes was reverted by its mimic. Thus, we tested such modulation in the most miR-146a-depleted patient-iAstrocytes (one sALS and one mSOD1-ALS). The miR-146a mimic in ALS iAstrocytes counteracted their reactive/inflammatory profile and restored miR-146a levels in sEVs. A reduction in lysosomal activity and enhanced synaptic/axonal transport-related genes in NSC-34 MNs occurred after co-culture with miR-146a-modulated iAstrocytes. In summary, the regulation of miR-146a in depleted ALS astrocytes may be key in reestablishing their normal function and in restoring MN lysosomal/synaptic dynamic plasticity in disease sub-groups.

OBJECTIVE: We investigated the cause of recurring tuberculosis (rcTB) among pulmonary TB participants recruited from a prospective population-based study conducted between July 2012 and December 2015. METHODS: Mycobacterium tuberculosis complex isolates obtained from rcTB cases were characterized by standard mycobacterial genotyping tools in addition to whole genome sequencing, followed by phylogenetic analysis to assess strain relatedness. RESULTS: A greater proportion (58.3%, 21/36) of individuals with rcTB episodes had TB recurrence within 12 months post treatment. Only 19.4% (7/36) of participants with rcTB harbored a strain with isoniazid (INH) resistance at baseline of which 29% (2/7) were additionally resistant to rifampicin. However, 27.8% (10/36) harbored an INH resistant strain upon recurring of which 40% (4/10) were MDR-TB strains. Recurrent TB was attributed to relapse (same strain) in 75.0% (27/36) of participants with 25.0% (9/36) attributed to re-infection. CONCLUSION: Our findings indicate that unresolved previous infection due to inadequate treatment may be the major cause of rcTB.

The Lineage 2–Beijing (L2–Beijing) sub-lineage of Mycobacterium tuberculosis has received much attention due to its high virulence, fast disease progression, and association with antibiotic resistance. Despite several reports of the recent emergence of L2–Beijing in Africa, no study has investigated the evolutionary history of this sub-lineage on the continent. In this study, we used whole genome sequences of 781 L2 clinical strains from 14 geographical regions globally distributed to investigate the origins and onward spread of this lineage in Africa. Our results reveal multiple introductions of L2–Beijing into Africa linked to independent bacterial populations from East- and Southeast Asia. Bayesian analyses further indicate that these introductions occurred during the past 300 years, with most of these events pre-dating the antibiotic era. Hence, the success of L2–Beijing in Africa is most likely due to its hypervirulence and high transmissibility rather than drug resistance.

13 páginas, 4 figuras. Contiene material suplementario., Whole genome sequencing (WGS) of Mycobacterium tuberculosis has rapidly progressed from a research tool to a clinical application for the diagnosis and management of tuberculosis and in public health surveillance. This development has been facilitated by drastic drops in cost, advances in technology and concerted efforts to translate sequencing data into actionable information. There is, however, a risk that, in the absence of a consensus and international standards, the widespread use of WGS technology may result in data and processes that lack harmonization, comparability and validation. In this Review, we outline the current landscape of WGS pipelines and applications, and set out best practices for M. tuberculosis WGS, including standards for bioinformatics pipelines, curated repositories of resistance-causing variants, phylogenetic analyses, quality control and standardized reporting., C.J.M., B.O.-A., L.R. and B.C.d.J. are supported by a European Research Council grant (INTERRUPTB; no. 311725). I.C. and G.A.G. are supported by a European Research Council grant (TB-ACCELERATE; no. 638553). T.C.R. receives salary support from the not-for-profit organization Foundation for Innovative New Diagnostics (the terms of this arrangement have been reviewed and approved by the University of California, San Diego). T.M.W. is an NIHR Academic Clinical Lecturer. J.L.G. and J.G. receive funding from the University of British Columbia, Vancouver, Canada. T.A.K., C.U., V.D. and S.N. receive funding from the German Center for Infection Research (DZIF) and are funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy (EXC 22167–390884018). L.V., T.H.H. and A.V.R. are funded by FWO Odysseus G0F8316N. M.R.F. is supported by the US National Institutes of Health BD2K K01 (MRF ES026835). P.S. is supported by the Agence Nationale de la Recherche (ANR-16-CE35-0009).

Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages suggesting a distinction between generalists and specialists. Population genomic analyses showed that whereas the majority of human T cell epitopes were conserved in all sublineages the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration.

Human life expectancy has increased dramatically in the last century and as a result also the prevalence of a variety of age-related diseases and syndromes. One such syndrome is frailty, which is defined as a combination of organ dysfunctions leading to increased vulnerability to adverse health outcomes. In humans, frailty is associated with various biomarkers of ageing and predicts relevant outcomes such as responses to therapies and progression of health status and mortality. Moreover, it is relatively easy to assess. To foster translation of mechanistic understanding of the ageing process and, importantly, of interventions that may extend healthy lifespan, frailty scales have been reverse translated into mice in recent years. We will review these approaches with a view to identify what is known and what is not known at present about their validity, reproducibility and reliability with a focus on the potential for further improvement. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license.

Nerve cell injury by unconjugated bilirubin (UCB) has been implicated in brain damage during neonatal hyperbilirubinemia, particularly in the preterm newborn. Recently, it was shown that UCB is a substrate for the multidrug resistance-associated protein 1 (Mrp1), an ATP-dependent efflux pump, which may decrease UCB intracellular levels. To obtain a further insight into the role of Mrp1 in the increased vulnerability of immature cells to UCB, we evaluated the mRNA and the protein levels of Mrp1 throughout differentiation in primary cultures of rat neurons and astrocytes. Furthermore, in order to provide supportive evidence for the role of Mrp1 in the protection of nerve cells from UCB-induced effects, we evaluated cell susceptibility to UCB when Mrp1 was inhibited with MK571 ((E)-3-[[[3-[2-(7-chloro-2-quinolinyl) ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid). The results are the first to demonstrate that Mrp1 is expressed in neurons and that both mRNA and protein levels of Mrp1 increase with cell differentiation. Additionally, inhibition of Mrp1 was associated with an increase in UCB toxic effects, namely cell death, cell dysfunction, and secretion of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, as well as of glutamate. These results point to a novel role of Mrp1 in the susceptibility of premature babies to UCB encephalopathy, and provide a startup point for the development of a new therapeutic strategy.

Background Neonatal hyperbilirubinaemia remains one of the most common clinical conditions requiring therapeutic intervention. Nevertheless, reliable indicators of bilirubin toxicity are still missing. This prompted us to investigate (a) the progression o

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Unconjugated bilirubin binds to erythrocytes, eliciting crenation, lipid elution and hemolysis. The present work attempts to establish the role of acidosis on bilirubin-induced toxicity to human erythrocytes. To this end, pH values ranging from 7.0-8.0 we

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High levels of unconjugated bilirubin (UCB) can be neurotoxic. Nevertheless, the mechanism of UCB interaction with neural cells is still unknown. This study investigates whether cultured rat neurons and astrocytes respond differently to UCB exposure. UCB

The pathogenesis of bilirubin encephalopathy appears to result from accumulation of unconjugated bilirubin (UCB), which, in turn. may cause mitochondrial perturbation, release of intermembrane proteins, and, ultimately, cell death. Aging imparts to cells

Unconjugated bilirubin increasingly binds to erythrocytes as the bilirubin-to-albumin molar ratio exceeds unity, leading to toxic manifestations that can culminate in cell lysis. Our previous studies showed that bilirubin induces the release of lipids fro

Increased levels of unconjugated bilirubin, the end-product of heme catabolism, are detrimental to the central nervous system. To examine the role of apoptosis in bilirubin-induced toxicity and to characterize the biochemical pathway of cell death, we exp

Mitochondria have been implicated in the cytotoxicity of amyloid beta -peptide (A beta), which accumulates as senile plaques in the brain of Alzheimer's disease patients. Tauroursodeoxycholate (TUDC) modulates cell death, in part, by preventing mitochondr

Excessive hyperbilirubinemia can cause irreversible neurological damage in the neonatal period. However, the complete understanding of the pathogenesis of unconjugated bilirubin (UCB) encephalopathy remains a matter of debate. This study investigates whet

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Unconjugated bilirubin (UCB), like trifluoperazine (TFP), dibucaine (DBC) and praziquantel (PZQ), induces erythrocyte morphological changes, lysis and lipid exfoliation. In the present study we determined whether TFP, DBC and PZQ toxicity to erythrocytes

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Trifluoperazine (TFP) is a potent antipsychotic agent, dibucaine (DBC) is a local anaesthetic and praziquantel (PZQ) is a highly effective agent against schistosomiasis. The present work was conducted to (i) investigate the cytotoxic effects of TFP, DEC a

Background: The pathogenesis of bilirubin encephalopathy and Alzheimer's disease appears to result from accumulation of unconjugated bilirubin (UCB) and amyloid-beta (A beta) peptide, respectively, which may cause apoptosis. Permeabilization of the mitoch

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