Trends in basic immunology research - 2001 and beyond

The immune system is primarily involved in protection against pathogens and opportunistic organisms. Similar to a nation's defence organization, the immune system involves different components. This diversity allows the immune system to defend against different types of attacks by microbes. The past century has witnessed tremendous progress in understanding the components and mechanisms involved in the immune response. This article attempts to highlight areas of active research in basic immunology in the coming years

Non-conventional deep brain stimulation in a network model of movement disorders

© 2024 The Author(s). This is an open access article distributed under the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Conventional deep brain stimulation (DBS) for movement disorders is a well-established clinical treatment. Over the last few decades, over 200,000 people have been treated by DBS worldwide for several neurological conditions, including Parkinson’s disease and Essential Tremor. DBS involves implanting electrodes into disorder-specific targets in the brain and applying an electric current. Although the hardware has developed in recent years, the clinically used stimulation pattern has remained as a regular frequency square pulse. Recent studies have suggested that phase-locking, coordinated reset or irregular patterns may be as or more effective at desynchronising the pathological neural activity. Such studies have shown efficacy using detailed neuron models or highly simplified networks and considered one frequency band. We previously described a population level model which generates oscillatory activity in both the beta band (20 Hz) and the tremor band (4 Hz). Here we use this model to look at the impact of applying regular, irregular and phase dependent bursts of stimulation, and show how this influences both tremor- and beta-band activity. We found that bursts are as or more effective at suppressing the pathological oscillations compared to continuous DBS. Importantly however, at higher amplitudes we found that the stimulus drove the network activity, as seen previously. Strikingly, this suppression was most apparent for the tremor band oscillations, with beta band pathological activity being more resistant to the burst stimulation compared to continuous, conventional DBS. Furthermore, our simulations showed that phase-locked bursts of stimulation did not convey much improvement on regular bursts of oscillation. Using a genetic algorithm optimisation approach to find the best stimulation parameters for regular, irregular and phase-locked bursts, we confirmed that tremor band oscillations could be more readily suppressed. Our results allow exploration of stimulation mechanisms at the network level to formulate testable predictions regarding parameter settings in DBS.Peer reviewe

Agent-based model of heterogeneous T cell activation in vitro (supplementary material)

We combine modelling and in vitro measurement of T-cell properties at the level of individual cells. Two types of heterogeneity are explicitly simulated: cell-surface marker expression that is time-dependent and varies from cell to cell, and spatial heterogeneity that arises from local influences such as the proximity of IL-2-producing cells. In vitro, the kinetics of the activation of cohorts of CD4+ T cells from 4-6 week-old BALB/c mice was studied, under stimulus with soluble or plate-bound anti-CD3, or a combination of PMA and ionomycin

A population model of deep brain stimulation in movement disorders from circuits to cells

For more than 30 years, deep brain stimulation (DBS) has been used to target the symptoms of a number of neurological disorders and in particular movement disorders such as Parkinson's disease (PD) and essential tremor (ET). It is known that the loss of dopaminergic neurons in the substantia nigra leads to PD, while the exact impact of this on the brain dynamics is not fully understood, the presence of beta-band oscillatory activity is thought to be pathological. The cause of ET, however, remains uncertain, however pathological oscillations in the thalamocortical-cerebellar network have been linked to tremor. Both of these movement disorders are treated with DBS, which entails the surgical implantation of electrodes into a patient's brain. While DBS leads to an improvement in symptoms for many patients, the mechanisms underlying this improvement is not clearly understood, and computational modeling has been used extensively to improve this. Many of the models used to study DBS and its effect on the human brain have mainly utilized single neuron and single axon biophysical models. We have previously shown in separate models however, that the use of population models can shed much light on the mechanisms of the underlying pathological neural activity in PD and ET in turn, and on the mechanisms underlying DBS. Together, this work suggested that the dynamics of the cerebellar-basal ganglia thalamocortical network support oscillations at frequency range relevant to movement disorders. Here, we propose a new combined model of this network and present new results that demonstrate that both Parkinsonian oscillations in the beta band and oscillations in the tremor frequency range arise from the dynamics of such a network. We find regions in the parameter space demonstrating the different dynamics and go on to examine the transition from one oscillatory regime to another as well as the impact of DBS on these different types of pathological activity. This work will allow us to better understand the changes in brain activity induced by DBS, and allow us to optimize this clinical therapy, particularly in terms of target selection and parameter setting

Illusions of Self‐Motion during Magnetic Resonance ‐Guided Focused Ultrasound Thalamotomy for Tremor

© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Objective: Brain networks mediating vestibular perception of self‐motion overlap with those mediating balance. A systematic mapping of vestibular perceptual pathways in the thalamus may reveal new brain modulation targets for improving balance in neurological conditions. Methods: Here, we systematically report how magnetic resonance‐guided focused ultrasound surgery of the nucleus ventralis intermedius of the thalamus commonly evokes transient patient‐reported illusions of self‐motion. In 46 consecutive patients, we linked the descriptions of self‐motion to sonication power and 3‐dimensional (3D) coordinates of sonication targets. Target coordinates were normalized using a standard atlas, and a 3D model of the nucleus ventralis intermedius and adjacent structures was created to link sonication target to the illusion. Results: A total of 63% of patients reported illusions of self‐motion, which were more likely with increased sonication power and with targets located more inferiorly along the rostrocaudal axis. Higher power and more inferiorly targeted sonications increased the likelihood of experiencing illusions of self‐motion by 4 and 2 times, respectively (odds ratios = 4.03 for power, 2.098 for location). Interpretation: The phenomenon of magnetic vestibular stimulation is the most plausible explanation for these illusions of self‐motion. Temporary unilateral modulation of vestibular pathways (via magnetic resonance‐guided focused ultrasound) unveils the central adaptation to the magnetic field‐induced peripheral vestibular bias, leading to an explicable illusion of motion. Consequently, systematic mapping of vestibular perceptual pathways via magnetic resonance‐guided focused ultrasound may reveal new intracerebral targets for improving balance in neurological conditions. ANN NEUROL 2024Peer reviewe

Functional loss of rffG and rfbB, encoding dTDP-glucose 4,6-dehydratase, alters colony morphology, cell shape, motility and virulence in Salmonella Typhimurium

Lipopolysaccharide (LPS) O-antigen and enterobacterial common antigen (ECA) play crucial roles in maintaining the outer membrane in Gram-negative bacteria. Mutations in the biosynthetic pathways of LPS and ECA may lead to accumulation of intermediates, resulting in morphological changes and activation of stress responses. However, the functional consequences of abrogation of both O-antigen and ECA synthesis in Salmonella enterica serovar Typhimurium (S. Typhimurium) are not well investigated. In this study, we generated single and double-deletion mutants of rfbB and rffG, encoding dTDP-glucose 4,6-dehydratase paralogs that are important in the synthesis of both O-antigen and ECA. Importantly, mutations in the dTDP-D-glucose 4,6-dehydratase encoding gene in humans are known to cause Catel-Manzke syndrome, a rare genetic disease. All four strains, i.e., wild type (WT), ΔrfbB, ΔrffG and ΔrfbBΔrffG, grew well in rich Luria Bertani (LB) liquid media at 37°C; however, the functional loss of both rfbB and rffG, but not in single-deletion strains, resulted in round cell morphology and smaller colony size in LB agar plates. There was no significant differences in the growth of the four strains in minimal media at 37°C (nutritional deficiency), in LB at 42°C (high temperature), acidic pH or LB with 3–4% NaCl (high osmolarity; however the ΔrfbBΔrffG strain was hypersensitive to bile and cell wall-targeting antibiotics). These results demonstrated that the ΔrfbBΔrffG strain was sensitive to some stress conditions. Interestingly, the ΔrfbBΔrffG strain displayed an altered LPS profile, autoaggregated rapidly compared to the WT and the single mutant strains and showed high N-phenylnaphthylamine (NPN) fluorescence indicating greater surface hydrophobicity. Furthermore, transcriptomic analysis identified flagellar and SPI-1 pathways to be highly downregulated in ΔrfbBΔrffG which led to impaired swimming as well as swarming motility, lower adhesion and invasion of HeLa cells. Importantly, the ΔrfbBΔrffG strain was less proficient in colonizing Peyer’s patches, spleen and liver, was unable to induce pro-inflammatory cytokines and was attenuated in both the oral and intraperitoneal models of S. Typhimurium infection in mice. Overall, this study highlights the importance of rfbB and rffG in maintaining cell wall and cell membrane integrity, colony and cellular morphology, motility and virulence in S. Typhimurium

Dex-CSDH randomised, placebo-controlled trial of dexamethasone for chronic subdural haematoma: report of the internal pilot phase.

The Dex-CSDH trial is a randomised, double-blind, placebo-controlled trial of dexamethasone for patients with a symptomatic chronic subdural haematoma. The trial commenced with an internal pilot, whose primary objective was to assess the feasibility of multi-centre recruitment. Primary outcome data collection and safety were also assessed, whilst maintaining blinding. We aimed to recruit 100 patients from United Kingdom Neurosurgical Units within 12 months. Trial participants were randomised to a 2-week course of dexamethasone or placebo in addition to receiving standard care (which could include surgery). The primary outcome measure of the trial is the modified Rankin Scale at 6 months. This pilot recruited ahead of target; 100 patients were recruited within nine months of commencement. 47% of screened patients consented to recruitment. The primary outcome measure was collected in 98% of patients. No safety concerns were raised by the independent data monitoring and ethics committee and only five patients were withdrawn from drug treatment. Pilot trial data can inform on the design and resource provision for substantive trials. This internal pilot was successful in determining recruitment feasibility. Excellent follow-up rates were achieved and exploratory outcome measures were added to increase the scientific value of the trial.NIHR HT

UDP-glucose 4, 6-dehydratase Activity Plays an Important Role in Maintaining Cell Wall Integrity and Virulence of Candida albicans

Candida albicans, a human fungal pathogen, undergoes morphogenetic changes that are associated with virulence. We report here that GAL102 in C. albicans encodes a homolog of dTDP-glucose 4,6-dehydratase, an enzyme that affects cell wall properties as well as virulence of many pathogenic bacteria. We found that GAL102 deletion leads to greater sensitivity to antifungal drugs and cell wall destabilizing agents like Calcofluor white and Congo red. The mutant also formed biofilms consisting mainly of hyphal cells that show less turgor. The NMR analysis of cell wall mannans of gal102 deletion strain revealed that a major constituent of mannan is missing and the phosphomannan component known to affect virulence is greatly reduced. We also observed that there was a substantial reduction in the expression of genes involved in biofilm formation but increase in the expression of genes encoding glycosylphosphatidylinositol-anchored proteins in the mutant. These, along with altered mannosylation of cell wall proteins together might be responsible for multiple phenotypes displayed by the mutant. Finally, the mutant was unable to grow in the presence of resident peritoneal macrophages and elicited a weak pro-inflammatory cytokine response in vitro. Similarly, this mutant elicited a poor serum pro-inflammatory cytokine response as judged by IFNγ and TNFα levels and showed reduced virulence in a mouse model of systemic candidiasis. Importantly, an Ala substitution for a conserved Lys residue in the active site motif YXXXK, that abrogates the enzyme activity also showed reduced virulence and increased filamentation similar to the gal102 deletion strain. Since inactivating the enzyme encoded by GAL102 makes the cells sensitive to antifungal drugs and reduces its virulence, it can serve as a potential drug target in combination therapies for C. albicans and related pathogens