A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro.

OBJECTIVES: Mycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states. METHODS: The natural growth data of M. tuberculosis H37Rv used in this study consisted of viability defined as cfu versus time based on data from an in vitro hypoxia system. External validation of the natural growth model was conducted using data representing the rate of incorporation of radiolabelled methionine into proteins by the bacteria. Rifampicin time-kill curves from log-phase (0.25-16 mg/L) and stationary-phase (0.5-64 mg/L) cultures were used to assess the model's ability to describe drug effects by evaluating different linear and non-linear exposure-response relationships. RESULTS: The final pharmacometric model consisted of a three-compartment differential equation system representing fast-, slow- and non-multiplying bacteria. Model predictions correlated well with the external data (R(2) = 0.98). The rifampicin effects on log-phase and stationary-phase cultures were separately and simultaneously described by including the drug effect on the different bacterial states. The predicted reduction in log10 cfu after 14 days and at 0.5 mg/L was 2.2 and 0.8 in the log-phase and stationary-phase systems, respectively. CONCLUSIONS: The model provides predictions of the change in bacterial numbers for the different bacterial states with and without drug effect and could thus be used as a framework for studying anti-tubercular drug effects in vitro

Anticipatory governance for social-ecological resilience

Anticipation is increasingly central to urgent contemporary debates, from climate change to the global economic crisis. Anticipatory practices are coming to the forefront of political, organizational, and citizens’ society. Research into anticipation, however, has not kept pace with public demand for insights into anticipatory practices, their risks and uses. Where research exists, it is deeply fragmented. This paper seeks to identify how anticipation is defined and understood in the literature and to explore the role of anticipatory practice to address individual, social, and global challenges. We use a resilience lens to examine these questions. We illustrate how varying forms of anticipatory governance are enhanced by multi-scale regional networks and technologies and by the agency of individuals, drawing from an empirical case study on regional water governance of Malaren, Sweden. Finally, we discuss how an anticipatory approach can inform adaptive institutions, decision making, strategy formation, and societal resilience

Adolescent Psychedelic Use and Psychotic or Manic Symptoms

Importance While psychedelic-assisted therapy has shown promise in the treatment of certain psychiatric disorders, little is known about the potential risk of psychotic or manic symptoms following naturalistic psychedelic use, especially among adolescents.Objective To investigate associations between naturalistic psychedelic use and self-reported psychotic or manic symptoms in adolescents using a genetically informative design.Design, Setting, and Participants This study included a large sample of adolescent twins (assessed at age 15, 18, and 24 years) born between July 1992 and December 2005 from the Swedish Twin Registry and cross-sectionally evaluated the associations between past psychedelic use and psychotic or manic symptoms at age 15 years. Individuals were included if they answered questions related to past use of psychedelics. Data were analyzed from October 2022 to November 2023.Main Outcomes and Measures Primary outcome measures were self-reported psychotic and manic symptoms at age 15 years. Lifetime use of psychedelics and other drugs was also assessed at the same time point.Results Among the 16 255 participants included in the analyses, 8889 were female and 7366 were male. Among them, 541 participants reported past use of psychedelics, most of whom (535 of 541 [99%]) also reported past use of other drugs (ie, cannabis, stimulants, sedatives, opioids, inhalants, or performance enhancers). When adjusting for substance-specific and substance-aggregated drug use, psychedelic use was associated with reduced psychotic symptoms in both linear regression analyses (β, −0.79; 95% CI, −1.18 to −0.41 and β, −0.39; 95% CI, −0.50 to −0.27, respectively) and co-twin control analyses (β, −0.89; 95% CI, −1.61 to −0.16 and β, −0.24; 95% CI, −0.48 to −0.01, respectively). In relation to manic symptoms, likewise adjusting for substance-specific and substance-aggregated drug use, statistically significant interactions were found between psychedelic use and genetic vulnerability to schizophrenia (β, 0.17; 95% CI, 0.01 to 0.32 and β, 0.17; 95% CI, 0.02 to 0.32, respectively) or bipolar I disorder (β, 0.20; 95% CI, 0.04 to 0.36 and β, 0.17; 95% CI, 0.01 to 0.33, respectively).Conclusions and Relevance The findings in this study suggest that, after adjusting for other drug use, naturalistic use of psychedelic may be associated with lower rates of psychotic symptoms among adolescents. At the same time, the association between psychedelic use and manic symptoms seems to be associated with genetic vulnerability to schizophrenia or bipolar I disorder. These findings should be considered in light of the study’s limitations and should therefore be interpreted with caution

Intramolecularly folded G-quadruplex and i-motif structures in the proximal promoter of the vascular endothelial growth factor gene

A polyguanine/polycytosine (polyG/polyC) tract in the proximal promoter of the vascular endothelial growth factor (VEGF) gene is essential for transcriptional activation. The guanine-rich (G-rich) and cytosine-rich (C-rich) strands on this tract are shown to form specific secondary structures, characterized as G-quadruplexes and i-motifs, respectively. Mutational analysis of the G-rich strand combined with dimethyl sulfate (DMS) footprinting, a polymerase stop assay, and circular dichroism (CD) spectroscopy revealed that the G-quadruplex containing a 1:4:1 double-chain reversal loop is the most thermodynamically stable conformation that this strand readily adopts. These studies provide strong evidence that the size of loop regions plays a critical role in determining the most favored folding pattern of a G-quadruplex. The secondary structure formed on the complementary C-rich strand was also determined by mutational analysis combined with Br2 footprinting and CD spectroscopy. Our results reveal that at a pH of 5.9 this strand is able to form an intramolecular i-motif structure that involves six C–C+ base pairs and a 2:3:2 loop configuration. Taken together, our results demonstrate that the G-quadruplex and i-motif structures are able to form on the G- and C-rich strands, respectively, of the polyG/polyC tract in the VEGF proximal promoter under conditions that favor the transition from B-DNA to non-B-DNA conformations

GRSDB2 and GRS_UTRdb: databases of quadruplex forming G-rich sequences in pre-mRNAs and mRNAs

G-quadruplex motifs in the RNA play significant roles in key cellular processes and human disease. While sequences capable of forming G-quadruplexes in the pre-mRNA are involved in regulation of polyadenylation and splicing events in mammalian transcripts, the G-quadruplex motifs in the UTRs may help regulate mRNA expression. GRSDB2 is a second-generation database containing information on the composition and distribution of putative Quadruplex-forming G-Rich Sequences (QGRS) mapped in ∼29 000 eukaryotic pre-mRNA sequences, many of which are alternatively processed. The data stored in the GRSDB2 is based on computational analysis of NCBI Entrez Gene entries with the help of an improved version of the QGRS Mapper program. The database allows complex queries with a wide variety of parameters, including Gene Ontology terms. The data is displayed in a variety of formats with several additional computational capabilities. We have also developed a new database, GRS_UTRdb, containing information on the composition and distribution patterns of putative QGRS in the 5′- and 3′-UTRs of eukaryotic mRNA sequences. The goal of these experiments has been to build freely accessible resources for exploring the role of G-quadruplex structure in regulation of gene expression at post-transcriptional level. The databases can be accessed at the G-Quadruplex Resource Site at: http://bioinformatics.ramapo.edu/GQRS/

Switching Transport through Nanopores with pH-Responsive Polymer Brushes for Controlled Ion Permeability

Several nanoporous platforms were functionalized with pH-responsive poly(methacrylic acid) (PMAA) brushes using surface-initiated atom transfer radical polymerization (SI-ATRP). The growth of the PMAA brush and its pH-responsive behavior from the nanoporous platforms were confirmed by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and atomic force microscopy (AFM). The swelling behavior of the pH-responsive PMAA brushes grafted only from the nanopore walls was investigated by AFM in aqueous liquid environment with pH values of 4 and 8. AFM images displayed open nanopores at pH 4 and closed ones at pH 8, which rationalizes their use as gating platforms. Ion conductivity across the nanopores was investigated with current–voltage measurements at various pH values. Enhanced higher resistance across the nanopores was observed in a neutral polymer brush state (lower pH values) and lower resistance when the brush was charged (higher pH values). By adding a fluorescent dye in an environment of pH 4 or pH 8 at one side of the PMAA-brush functionalized nanopore array chips, diffusion across the nanopores was followed. These experiments displayed faster diffusion rates of the fluorescent molecules at pH 4 (PMAA neutral state, open pores) and slower diffusion at pH 8 (PMAA charged state, closed pores) showing the potential of this technology toward nanoscale valve applications