Transmission analysis of a large tuberculosis outbreak in London: a mathematical modelling study using genomic data

Outbreaks of tuberculosis (TB) - such as the large isoniazid-resistant outbreak centred on London, UK, which originated in 1995 - provide excellent opportunities to model transmission of this devastating disease. Transmission chains for TB are notoriously difficult to ascertain, but mathematical modelling approaches, combined with whole-genome sequencing data, have strong potential to contribute to transmission analyses. Using such data, we aimed to reconstruct transmission histories for the outbreak using a Bayesian approach, and to use machine-learning techniques with patient-level data to identify the key covariates associated with transmission. By using our transmission reconstruction method that accounts for phylogenetic uncertainty, we are able to identify 21 transmission events with reasonable confidence, 9 of which have zero SNP distance, and a maximum distance of 3. Patient age, alcohol abuse and history of homelessness were found to be the most important predictors of being credible TB transmitters

Isoniazid-resistant tuberculosis: a cause for concern?

The drug isoniazid (INH) is a key component of global tuberculosis (TB) control programmes. It is estimated, however, that 16.1% of TB disease cases in former Soviet Union countries and 7.5% of cases outside of those settings have non-multidrug resistant (MDR) INH resistance. Resistance has been linked to poorer treatment outcomes, post-treatment relapse and death, at least for specific sites of disease. Multiple genetic loci are associated with phenotypic resistance, but the relationship between genotype and phenotype is complex. This restricts the use of rapid sequencing techniques as part of the diagnostic process to determine the most appropriate treatment regimens for patients. The burden of resistance also influences the usefulness of INH preventative therapy. Despite seven decades of the use of INH our knowledge in key areas - such as the epidemiology of resistant strains, their clinical consequences, whether tailored treatment regimens are required, and the role of INH resistance in fuelling the MDR -TB epidemic - is limited. The importance of non-MDR INH resistance needs to be re-evaluated both globally and by national TB control programmes

Increasing human motor skill acquisition by driving theta-gamma coupling

Skill learning is a fundamental adaptive process, but the mechanisms remain poorly understood. Some learning paradigms, particularly in the memory domain, are closely associated with gamma activity that is amplitude-modulated by the phase of underlying theta activity, but whether such nested activity patterns also underpin skill learning is unknown. Here we addressed this question by using transcranial alternating current stimulation (tACS) over sensorimotor cortex to modulate theta-gamma activity during motor skill acquisition, as an exemplar of a non-hippocampal-dependent task. We demonstrated, and then replicated, a significant improvement in skill acquisition with theta-gamma tACS, which outlasted the stimulation by an hour. Our results suggest that theta-gamma activity may be a common mechanism for learning across the brain and provides a putative novel intervention for optimising functional improvements in response to training or therapy

Relationship between physiological measures of excitability and levels of glutamate and GABA in the human motor cortex

Magnetic resonance spectroscopy (MRS) allows measurement of neurotransmitter concentrations within a region of interest in the brain. Inter-individual variation in MRS-measured GABA levels have been related to variation in task performance in a number of regions. However, it is not clear how MRS-assessed measures of GABA relate to cortical excitability or GABAergic synaptic activity. We therefore performed two studies investigating the relationship between neurotransmitter levels as assessed by MRS and transcranial magnetic stimulation (TMS) measures of cortical excitability and GABA synaptic activity in the primary motor cortex. We present uncorrected correlations, where the P value should therefore be considered with caution. We demonstrated a correlation between cortical excitability, as assessed by the slope of the TMS input-output curve and MRS-assessed glutamate levels (r = 0.803, P = 0.015) but no clear relationship between MRS-assessed GABA levels and TMS-assessed synaptic GABA(A) activity (2.5 ms inter-stimulus interval (ISI) short-interval intracortical inhibition (SICI); Experiment 1: r = 0.33, P = 0.31; Experiment 2: r = -0.23, P = 0.46) or GABA(B) activity (long-interval intracortical inhibition (LICI); Experiment 1: r = -0.47, P = 0.51; Experiment 2: r = 0.23, P = 0.47). We demonstrated a significant correlation between MRS-assessed GABA levels and an inhibitory TMS protocol (1 ms ISI SICI) with distinct physiological underpinnings from the 2.5 ms ISI SICI (r = -0.79, P = 0.018). Interpretation of this finding is challenging as the mechanisms of 1 ms ISI SICI are not well understood, but we speculate that our results support the possibility that 1 ms ISI SICI reflects a distinct GABAergic inhibitory process, possibly that of extrasynaptic GABA tone

Tuning the brakes – Modulatory role of transcranial random noise stimulation on inhibition

Electroencephalogram (EEG) and behavioural data (joystick) was collected from 15 healthy participants who completed a modified version of a Go/No-go task. This dataset consists of raw data, pre-processed EEG and behavioural data, along with impulsivity scores in a .csv file. The pre-processed data is in MATLAB .mat format. Raw Data The EEG and behavioural data (Joystick) along with trigger data was collected using a TMSi Porti amplifier with a sampling rate of 2,048Hz and is in .een format. The raw EEG files contain brain activity recorded in the first 16 channels and last 2 channels (channels 17 and 18) correspond to Joystick and Trigger information (used to identify the type of event – Go/Conflict/NoGo) respectively. The Raw data is segregated into 2 folders- Active and Sham which is further divided into baseline and after stimulation conditions. The main behavioural outcome is the change in NoGo errors (pre-processed folder- Figure 1C in from the article ‘Tuning the brakes – Modulatory role of transcranial random noise stimulation on inhibition,’ Brain Stimulation, 2024), comparing baseline and after-stimulation in sham and active conditions. Metadata corresponding to impulsivity scores and the change in NoGo behaviour are provided in ‘UPPS_nogo.csv’ (used for Figure 1D). The EEG data was recorded while the participants completed the task during baseline and after stimulation, and was used to calculate the spectral power (Figure 1E). The study also presents intermittent bursts from the EEG data, comparing the average burst durations at baseline and after-stimulation (Figure 1F) in sham and active stimulation conditions. Code All data were analysed in MATLAB (2018b) using a combination of EEGLAB, ERP LAB and FieldTrip packages. Installation guides can be found on https://sccn.ucsd.edu/eeglab/index.php https://matlab.mathworks.com/ https://erpinfo.org/erplab  https://www.fieldtriptoolbox.org/download/ The behavioural data plots use the software IOSR toolbox : https://github.com/IoSR-Surrey/MatlabToolbox Code_figure_IC.m: This script plots the NoGo error rates in baseline and after stimulation in sham and active conditions. This script uses the mat file ‘Nogo_behav_pre_post.mat’ Code_figure_1E.m: This script plots the spectral power and grand average of the after-stimulation EEG data with clusters obtained from a non-parametric analysis. This script uses the mat file ‘data_psd_trns_pre_post.mat’. Code_figure_1F.m: This script plots the intermittent burst durations during sham and active conditions and uses the file ‘Nogo_bursts_pre_post.mat

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

Influence of Nanoparticle Size and Shape on Oligomer Formation of an Amyloidogenic Peptide

Understanding the influence of macromolecular crowding and nanoparticles on the formation of in-register $\beta$-sheets, the primary structural component of amyloid fibrils, is a first step towards describing \emph{in vivo} protein aggregation and interactions between synthetic materials and proteins. Using all atom molecular simulations in implicit solvent we illustrate the effects of nanoparticle size, shape, and volume fraction on oligomer formation of an amyloidogenic peptide from the transthyretin protein. Surprisingly, we find that inert spherical crowding particles destabilize in-register $\beta$-sheets formed by dimers while stabilizing $\beta$-sheets comprised of trimers and tetramers. As the radius of the nanoparticle increases crowding effects decrease, implying smaller crowding particles have the largest influence on the earliest amyloid species. We explain these results using a theory based on the depletion effect. Finally, we show that spherocylindrical crowders destabilize the ordered $\beta$-sheet dimer to a greater extent than spherical crowders, which underscores the influence of nanoparticle shape on protein aggregation

Climate and plant controls on soil organic matter in coastal wetlands

Coastal wetlands are among the most productive and carbon‐rich ecosystems on Earth. Long‐term carbon storage in coastal wetlands occurs primarily belowground as soil organic matter (SOM). In addition to serving as a carbon sink, SOM influences wetland ecosystem structure, function, and stability. To anticipate and mitigate the effects of climate change, there is a need to advance understanding of environmental controls on wetland SOM. Here, we investigated the influence of four soil formation factors: climate, biota, parent materials, and topography. Along the northern Gulf of Mexico, we collected wetland plant and soil data across elevation and zonation gradients within 10 estuaries that span broad temperature and precipitation gradients. Our results highlight the importance of climate–plant controls and indicate that the influence of elevation is scale and location dependent. Coastal wetland plants are sensitive to climate change; small changes in temperature or precipitation can transform coastal wetland plant communities. Across the region, SOM was greatest in mangrove forests and in salt marshes dominated by graminoid plants. SOM was lower in salt flats that lacked vascular plants and in salt marshes dominated by succulent plants. We quantified strong relationships between precipitation, salinity, plant productivity, and SOM. Low precipitation leads to high salinity, which limits plant productivity and appears to constrain SOM accumulation. Our analyses use data from the Gulf of Mexico, but our results can be related to coastal wetlands across the globe and provide a foundation for predicting the ecological effects of future reductions in precipitation and freshwater availability. Coastal wetlands provide many ecosystem services that are SOM dependent and highly vulnerable to climate change. Collectively, our results indicate that future changes in SOM and plant productivity, regulated by cascading effects of precipitation on freshwater availability and salinity, could impact wetland stability and affect the supply of some wetland ecosystem services

Linear and nonlinear effects of temperature and precipitation on ecosystem properties in tidal saline wetlands

Climate greatly influences the structure and functioning of tidal saline wetland ecosystems. However, there is a need to better quantify the effects of climatic drivers on ecosystem properties, particularly near climate-sensitive ecological transition zones. Here, we used climate- and literature-derived ecological data from tidal saline wetlands to test hypotheses regarding the influence of climatic drivers (i.e., temperature and precipitation regimes) on the following six ecosystem properties: canopy height, biomass, productivity, decomposition, soil carbon density, and soil carbon accumulation. Our analyses quantify and elucidate linear and nonlinear effects of climatic drivers. We quantified positive linear relationships between temperature and above-ground productivity and strong positive nonlinear (sigmoidal) relationships between (1) temperature and above-ground biomass and canopy height and (2) precipitation and canopy height. Near temperature-controlled mangrove range limits, small changes in temperature are expected to trigger comparatively large changes in biomass and canopy height, as mangrove forests grow, expand, and, in some cases, replace salt marshes. However, within these same transition zones, temperature- induced changes in productivity are expected to be comparatively small. Interestingly, despite the significant above-ground height, biomass, and productivity relationships across the tropical–temperate mangrove–marsh transition zone, the relationships between temperature and soil carbon density or soil carbon accumulation were not significant. Our literature review identifies several ecosystem properties and many regions of the world for which there are insufficient data to fully evaluate the influence of climatic drivers, and the identified data gaps can be used by scientists to guide future research. Our analyses indicate that near precipitation-controlled transition zones, small changes in precipitation are expected to trigger comparatively large changes in canopy height. However, there are scant data to evaluate the influence of precipitation on other ecosystem properties. There is a need for more decomposition data across climatic gradients, and to advance understanding of the influence of changes in precipitation and freshwater availability, additional ecological data are needed from tidal saline wetlands in arid climates. Collectively, our results can help scientists and managers better anticipate the linear and nonlinear ecological consequences of climate change for coastal wetlands

Single cell sequencing data identify distinct B cell and fibroblast populations in stricturing Crohn's disease.

Single cell RNA sequencing of human full thickness Crohn's disease (CD) small bowel resection specimens was used to identify potential therapeutic targets for stricturing (S) CD. Using an unbiased approach, 16 cell lineages were assigned within 14,539 sequenced cells from patient-matched SCD and non-stricturing (NSCD) preparations. SCD and NSCD contained identical cell types. Amongst immune cells, B cells and plasma cells were selectively increased in SCD samples. B cell subsets suggested formation of tertiary lymphoid tissue in SCD and compared with NSCD there was an increase in IgG, and a decrease in IgA plasma cells, consistent with their potential role in CD fibrosis. Two Lumican-positive fibroblast subtypes were identified and subclassified based on expression of selectively enriched genes as fibroblast clusters (C) 12 and C9. Cells within these clusters expressed the profibrotic genes Decorin (C12) and JUN (C9). C9 cells expressed ACTA2; ECM genes COL4A1, COL4A2, COL15A1, COL6A3, COL18A1 and ADAMDEC1; LAMB1 and GREM1. GO and KEGG Biological terms showed extracellular matrix and stricture organization associated with C12 and C9, and regulation of WNT pathway genes with C9. Trajectory and differential gene analysis of C12 and C9 identified four sub-clusters. Intra sub-cluster gene analysis detected 13 co-regulated gene modules that aligned along predicted pseudotime trajectories. CXCL14 and ADAMDEC1 were key markers in module 1. Our findings support further investigation of fibroblast heterogeneity and interactions with local and circulating immune cells at earlier time points in fibrosis progression. Breaking these interactions by targeting one or other population may improve therapeutic management for SCD