Energy Efficient Memristor Based on Green-Synthesized 2D Carbonyl-Decorated Organic Polymer and Application in Image Denoising and Edge Detection: Toward Sustainable AI.

According to the United Nations, around 53 million metric tons of electronic waste is produced every year, worldwide, the big majority of which goes unprocessed. With the rapid advances in AI technologies and adoption of smart gadgets, the demand for powerful logic and memory chips is expected to boom. Therefore, the development of green electronics is crucial to minimizing the impact of the alarmingly increasing e-waste. Here, it is shown the application of a green synthesized, chemically stable, carbonyl-decorated 2D organic, and biocompatible polymer as an active layer in a memristor device, sandwiched between potentially fully recyclable electrodes. The 2D polymer's ultramicro channels, decorated with C═O and O─H groups, efficiently promote the formation of copper nanofilaments. As a result, the device shows excellent bipolar resistive switching behavior with the potential to mimic synaptic plasticity. A large resistive switching window (103), low SET/RESET voltage of ≈0.5/-1.5 V), excellent device-to-device stability and synaptic features are demonstrated. Leveraging the device's synaptic characteristics, its applications in image denoising and edge detection is examined. The results show a reduction in power consumption by a factor of 103 compared to a traditional Tesla P40 graphics processing unit, indicating great promise for future sustainable AI-based applications.

Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis.

Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.

A carbonyl-decorated two-dimensional polymer as a charge-trapping layer for non-volatile memory storage devices with a high endurance and wide memory window.

The charge-trapping mechanism in conjugated polymers is a performance obstacle in many optoelectronic devices harnessed for non-volatile memory applications. Herein, a carbonyl-decorated organic 2D-polymer (TpDb)-based charge-trapping memory device has been developed with a wide memory window (3.2 V) with low programming and erasing voltages of +3/-2 and -3/+2. The TpDb was synthesized by a potentially scalable solid-state aldol condensation reaction. The inherent structural defects and the semi-conjugated nature of the enone network in TpDb offer effective charge-trapping through the localization of charges in specific functional groups (CO). The interlayer hydrogen bonding enhances the packing density of the 2D-polymer layers thereby improving the memory storage properties of the material. Furthermore, the TpDb exhibits excellent features for non-volatile memory applications including over 10 000 cycles of write/read endurance and a prolonged retention performance of 104 seconds at high temperatures (100 °C).

Nano-scale charge trapping memory based on two-dimensional conjugated microporous polymer.

There is a growing interest in new semiconductor nanostructures for future high-density high-performance flexible electronic devices. Two-dimensional conjugated microporous polymers (2D-CMPs) are promising candidates because of their inherent optoelectronic properties. Here, we are reporting a novel donor-acceptor type 2D-CMP based on Pyrene and Isoindigo (PI) for a potential nano-scale charge-trapping memory application. We exfoliated the PI polymer into ~ 2.5 nm thick nanoparticles (NPs) and fabricated a Metal-Insulator-Semiconductor (MIS) device with PI-NPs embedded in the insulator. Conductive AFM (cAFM) is used to examine the confinement mechanism as well as the local charge injection process, where ultrathin high-κ alumina supplied the energy barrier for confining the charge carrier transport. We have achieved a reproducible on-and-off state and a wide memory window (ΔV) of 1.5 V at a relatively small reading current. The device displays a low operation voltage (V < 1 V), with good retention (104 s), and endurance (103 cycles). Furthermore, a theoretical analysis is developed to affirm the measured charge carriers' transport and entrapment mechanisms through and within the fabricated MIS structures. The PI-NPs act as a nanoscale floating gate in the MIS-based memory with deep trapping sites for the charged carriers. Moreover, our results demonstrate that the synthesized 2D-CMP can be promising for future low-power high-density memory applications.

A Rational Design of Isoindigo-Based Conjugated Microporous n-Type Semiconductors for High Electron Mobility and Conductivity.

The development of n-type organic semiconductors has evolved significantly slower in comparison to that of p-type organic semiconductors mainly due to the lack of electron-deficient building blocks with stability and processability. However, to realize a variety of organic optoelectronic devices, high-performance n-type polymer semiconductors are essential. Herein, conjugated microporous polymers (CMPs) comprising isoindigo acceptor units linked to benzene or pyrene donor units (BI and PI) showing n-type semiconducting behavior are reported. In addition, considering the challenges of deposition of a continuous and homogeneous thin film of CMPs for accurate Hall measurements, a plasma-assisted fabrication technique is developed to yield uniform thin films. The fully conjugated 2D networks in PI- and BI-CMP films display high electron mobility of 6.6 and 3.5 cm2 V-1 s-1 , respectively. The higher carrier concentration in PI results in high conductivity (5.3 mS cm-1 ). Both experimental and computational studies are adequately combined to investigate structure-property relations for this intriguing class of materials in the context of organic electronics.

Artificial visual perception neural system using a solution-processable MoS2-based in-memory light sensor.

Optoelectronic devices are advantageous in in-memory light sensing for visual information processing, recognition, and storage in an energy-efficient manner. Recently, in-memory light sensors have been proposed to improve the energy, area, and time efficiencies of neuromorphic computing systems. This study is primarily focused on the development of a single sensing-storage-processing node based on a two-terminal solution-processable MoS2 metal-oxide-semiconductor (MOS) charge-trapping memory structure-the basic structure for charge-coupled devices (CCD)-and showing its suitability for in-memory light sensing and artificial visual perception. The memory window of the device increased from 2.8 V to more than 6 V when the device was irradiated with optical lights of different wavelengths during the program operation. Furthermore, the charge retention capability of the device at a high temperature (100 °C) was enhanced from 36 to 64% when exposed to a light wavelength of 400 nm. The larger shift in the threshold voltage with an increasing operating voltage confirmed that more charges were trapped at the Al2O3/MoS2 interface and in the MoS2 layer. A small convolutional neural network was proposed to measure the optical sensing and electrical programming abilities of the device. The array simulation received optical images transmitted using a blue light wavelength and performed inference computation to process and recognize the images with 91% accuracy. This study is a significant step toward the development of optoelectronic MOS memory devices for neuromorphic visual perception, adaptive parallel processing networks for in-memory light sensing, and smart CCD cameras with artificial visual perception capabilities.

Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

Improvement of Refractory Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease with Single-Agent Blockade of IL-1ß and IL-18.

Systemic juvenile idiopathic arthritis associated with interstitial lung disease (SJIA-LD) represents a highly morbid subset of SJIA for which effective therapies are lacking. We report the case of a patient with refractory SJIA-LD who underwent treatment with MAS-825, an investigational bispecific monoclonal antibody targeting IL-1ß and IL-18. MAS-825 treatment was associated with a marked reduction in total IL-18 and free IL-18 in both serum and bronchoalveolar lavage fluid (BAL). Baseline oxygen saturation, exercise tolerance, and quality of life metrics improved after treatment with MAS-825, while pulmonary function testing remained stable. Following treatment, the BAL showed no evidence of pulmonary alveolar proteinosis and inflammatory infiltrates were markedly reduced, reflected by decreased numbers of CD4 T-cells, CD8 T-cells, and macrophages. The patient was able to wean entirely off systemic corticosteroids and other biologics after 10 months of treatment with MAS-825 and experienced no side effects of the drug. This case demonstrates improvement in pulmonary symptoms, lung inflammation, and burden of immunomodulatory therapy after treatment with MAS-825 and suggests that simultaneous targeting of both IL-1ß and IL-18 may be a safe and effective treatment strategy in SJIA-LD.

Immune aging in multiple sclerosis is characterized by abnormal CD4 T cell activation and increased frequencies of cytotoxic CD4 T cells with advancing age.

BACKGROUND: Immunosenescence (ISC) describes age-related changes in immune-system composition and function. Multiple sclerosis (MS) is a lifelong inflammatory condition involving effector and regulatory T-cell imbalance, yet little is known about T-cell ISC in MS. We examined age-associated changes in circulating T cells in MS compared to normal controls (NC). METHODS: Forty untreated MS (Mean Age 43·3, Range 18-72) and 49 NC (Mean Age 48·6, Range 20-84) without inflammatory conditions were included in cross-sectional design. T-cell subsets were phenotypically and functionally characterized using validated multiparametric flow cytometry. Their aging trajectories, and differences between MS and NC, were determined using linear mixed-effects models. FINDINGS: MS patients demonstrated early and persistent redistribution of naïve and memory CD4 T-cell compartments. While most CD4 and CD8 T-cell aging trajectories were similar between groups, MS patients exhibited abnormal age-associated increases of activated (HLA-DR+CD38+; (P = 0·013) and cytotoxic CD4 T cells, particularly in patients >60 (EOMES: P < 0·001). Aging MS patients also failed to upregulate CTLA-4 expression on both CD4 (P = 0·014) and CD8 (P = 0·009) T cells, coupled with abnormal age-associated increases in frequencies of B cells expressing costimulatory molecules. INTERPRETATION: While many aspects of T-cell aging in MS are conserved, the older MS patients harbour abnormally increased frequencies of CD4 T cells with activated and cytotoxic effector profiles. Age-related decreased expression of T-cell co-inhibitory receptor CTLA-4, and increased B-cell costimulatory molecule expression, may provide a mechanism that drives aberrant activation of effector CD4 T cells that have been implicated in progressive disease. FUNDING: Stated in Acknowledgements section of manuscript.

Utilizing trapped charge at bilayer 2D MoS2/SiO2interface for memory applications.

In this work we use conductive atomic force microscopy (cAFM) to study the charge injection process from a nanoscale tip to a single isolated bilayer 2D MoS2flake. The MoS2is exfoliated and bonded to ultra-thin SiO2/Si substrate. Local current-voltage (IV) measurements conducted by cAFM provides insight in charge trapping/de-trapping mechanisms at the MoS2/SiO2interface. The MoS2nano-flake provides an adjustable potential barrier for embedded trap sites where the charge is injected from AFM tip is confined at the interface. A window of (ΔV∼ 1.8 V) is obtain at a reading current of 2 nA between two consecutiveIVsweeps. This is a sufficient window to differentiate between the two states indicating memory behavior. Furthermore, the physics behind the charge entrapment and its contribution to the tunneling mechanisms is discussed.

Abnormal B-Cell and Tfh-Cell Profiles in Patients With Parkinson Disease: A Cross-sectional Study.

BACKGROUND AND OBJECTIVES: There has been growing interest in potential roles of the immune system in the pathogenesis of Parkinson disease (PD). The aim of the current study was to comprehensively characterize phenotypic and functional profiles of circulating immune cells in patients with PD vs controls. METHODS: Peripheral blood was collected from patients with PD and age- and sex-matched neurologically normal controls (NCs) in 2 independent cohorts (discovery and validation). Comprehensive multicolor flow cytometry was performed on whole blood leukocytes and peripheral blood mononuclear cells to characterize different immune subsets and their ex vivo responses. RESULTS: The discovery cohort included 17 NCs and 12 participants with PD, and the validation cohort included 18 NCs and 18 participants with PD. Among major immune cell types, B cells appeared to be preferentially affected in PD. Proliferating B cell counts were decreased in patients with PD compared with controls. Proportions of B-cell subsets with regulatory capacity such as transitional B cells were preferentially reduced in the patients with PD, whereas proportions of proinflammatory cytokine-producing B cells increased, resulting in a proinflammatory shift of their B-cell functional cytokine responses. Unsupervised principal component analysis revealed increased expression of TNFα and GM-CSF by both B cells and T cells of patients with PD. In addition, levels of follicular T cells, an important B-cell helper T-cell population, decreased in the patients with PD, correlating with their B-cell abnormality. DISCUSSION: Our findings define a novel signature of peripheral immune cells and implicate aberrant Tfh:B-cell interactions in patients with PD.

Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.

SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19. However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients. We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination. Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination. Treatment with aCD20 skewed responses, compromising circulating follicular helper T (TFH) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (TH1) cell priming. Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating TFH responses and more robust CD8 T cell responses. These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.

Author Correction: Photodetection Characteristics of Gold Coated AFM Tips and n-Silicon Substrate nano-Schottky Interfaces.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Multiplexed detection and isolation of viable low-frequency cytokine-secreting human B cells using cytokine secretion assay and flow cytometry (CSA-Flow).

The ability to functionally characterize cytokine-secreting immune cells has broad implications in both health and a range of immune-mediated and auto-immune diseases. Low-frequency cytokine-defined immune-cell subsets can play key immune-regulatory roles, yet their detailed study is often hampered by limited clinical sample availability. Commonly used techniques including intracellular cytokine staining require cell fixation, precluding subsequent functional interrogation. The cytokine-secretion assay (CSA) can overcome this limitation, though has mostly been used for detection of relatively high-frequency, single-cytokine secreting cells. We examined how adaptation of the CSA in combination with multiparametric flow-cytometry (CSA-Flow) may enable simultaneous isolation of multiple, low-frequency, cytokine-secreting cells. Focusing on human B cells (traditionally recognized as harder to assay than T cells), we show that single-capture CSA-Flow allows for isolation of highly-purified populations of both low-frequency (IL-10+; GM-CSF+) and high-frequency (TNF+) cytokine-defined B cells. Simultaneous detection and isolation of up to three viable and highly-purified cytokine-secreting B-cell subpopulations is feasible, albeit with some signal loss, with fractions subsequently amenable to gene expression analysis and in vitro cell culture. This multiplexing CSA-Flow approach will be of interest in many human cellular immunology contexts aiming to functionally characterize cytokine-secreting immune cells, especially when sample volumes and cell numbers are limited.

Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis.

Biomarkers predicting fingolimod (FTY) treatment response in relapsing-remitting multiple sclerosis (RRMS) are lacking. Here, we performed extensive functional immunophenotyping using multiparametric flow cytometry to examine peripheral immune changes under FTY treatment and explore biomarkers of FTY treatment response. From among 135 RRMS patients who initiated FTY in a 2-year multicentre observational study, 36 were classified as 'Active' or 'Stable' based on clinical and/or radiological activity on-treatment. Flow cytometric analysis of immune cell subsets was performed on pre- and on-treatment peripheral blood mononuclear cells (PBMC) samples. Decreased absolute counts of B cells and most T-cell subsets were seen on-treatment. Senescent CD8 + T cells, CD56 + T cells, CD56dim natural killer cells, monocytes and dendritic cells were not reduced in number and hence relatively increased in frequency on-treatment. An unbiased multiparametric and traditional manual analysis of T-cell subsets suggested a higher pre-treatment frequency of CD4 + central memory T cells (TCM) in patients who were subsequently Active versus Stable on-treatment. Lower pre-treatment terminally differentiated effector memory (TEMRA) cell frequencies were also seen in the subsequently Active cohort. Together, our data highlight differential effects of FTY on peripheral immune cell subsets and suggest that pre-treatment T-cell subset frequencies may have value in predicting FTY treatment response.

Time dependence of electrical characteristics during the charge decay from a single gold nanoparticle on silicon.

In this work, we investigate the time dependence of trapped charge in isolated gold nanoparticles (Au-NPS) dispersed on n-Si substrates, based on the electrical characteristics of nano metal-semiconductor junctions. The current-voltage (I-V) characteristics have been analysed on a single Au-NP at different time intervals, using conductive mode atomic force microscopy (AFM). The Au-NPs have been characterized for their morphology and optical properties using transmission electron microscopy (TEM), ultraviolet visible (UV-vis) spectroscopy and scanning electron microscopy (SEM). The tunneling current is found to be a direct function of the trapped charge in the NP, due to the charge screening effect of the electric field at the NP/n-Si interface. The evolution of the I-V curves is observed at different time intervals until all the trapped charge dissipates. Moreover, the time needed for nanoparticles to restore their initial state is verified and the dependence of the trapped charge on the applied voltage sweep is investigated.

Improved figures of merit of nano-Schottky diode by embedding and characterizing individual gold nanoparticles on n-Si substrates.

Improving Schottky diode characteristics in semiconducting devices is essential for better functionality in electronic and optoelectronic devices at nanoscale. In this paper, we investigate the electric transport characteristics of a gold (Au)-tip/n-Si-based nano-Schottky diode by using a conductive-mode atomic force microscope (CAFM). First, 10 nm average diameter Au nanoparticles (NPs) are monodispersed on the highly cleaned n-type Si substrate using an optimized spin-coating technique. The controlled and well dispersed NPs are confirmed by using the AC imaging mode of the AFM. The electrical characteristics are established by using an Au-coated AFM tip, by either soft engaging at the surface of the n-Si substrate or at the top of an individual Au NP. Landing of the AFM tip on the NP or n-Si substrate is validated by the force curves of the AFM. From the localized CAFM electrical characteristics, we observed the improvement in the figures of merit (FOM) that characterize the rectification performance including the (1-V) asymmetry (f ASYM), and the turn-on voltage due to placing the Au NP between the AFM tip and n-Si substrate. These improved FOM of the nanoscale diodes are explained based on the increase in the tunneling current at the nanoscale Au-NP/n-Si interface. Moreover, the nanoscale control of interface structure is extremely important to improve the characteristics of nano-Schottky diodes.

Photodetection Characteristics of Gold Coated AFM Tips and n-Silicon Substrate nano-Schottky Interfaces.

Silicon (Si)-based photodetectors are appealing candidates due to their low cost and compatibility with the complementary metal oxide semiconductor (CMOS) technology. The nanoscale devices based on Si can contribute efficiently in the field of photodetectors. In this report, we investigate the photodetection capability of nano-Schottky junctions using gold (Au) coated conductive atomic force microscope (C-AFM) tips, and highly cleaned n-Si substrate interface. The Au nanotip/n-Si interface forms the proposed structure of a nano Schottky diode based photodetector. The electrical characteristics measured at the nanoscale junction with different Au nanotip radii show that the tunneling current increases with decreasing the tip radius. Moreover, the tunneling process and photodetection effects are discussed in terms of barrier width/height decrease at the tip-semiconductor interface due to the applied electric field as well as the generation of plasmon-induced hot-electron at the nanoparticle (i.e. C-AFM tip)/n-Si interface. Furthermore, the photodetection sensitivity is investigated and it is found to be higher for C-AFM tips with smaller radii. Moreover, this research will open a new path for the miniaturization of photodetectors with high sensitivity based on nano-Schottky interfaces.

Abnormal effector and regulatory T cell subsets in paediatric-onset multiple sclerosis.

Elucidation of distinct T-cell subsets involved in multiple sclerosis immune-pathophysiology continues to be of considerable interest since an ultimate goal is to more selectively target the aberrant immune response operating in individual patients. While abnormalities of both effector (Teff) and regulatory (Treg) T cells have been reported in patients with multiple sclerosis, prior studies have mostly assessed average abnormalities in either limb of the immune response, rather than both at the same time, which limits the ability to evaluate the balance between effectors and regulators operating in the same patient. Assessing both phenotypic and functional responses of Teffs and Tregs has also proven important. In studies of adults with multiple sclerosis, in whom biological disease onset likely started many years prior to the immune assessments, an added challenge for any reported abnormality is whether the abnormality indeed contributes to the disease (and hence of interest to target therapeutically) or merely develops consequent to inflammatory injury (in which case efforts to develop targeted therapies are unlikely to be beneficial). Paediatric-onset multiple sclerosis, though rare, offers a unique window into early disease mechanisms. Here, we carried out a comprehensive integrated study, simultaneously assessing phenotype and functional responses of both effector and regulatory T cells in the same children with multiple sclerosis, monophasic inflammatory CNS disorders, and healthy controls, recruited as part of the multicentre prospective Canadian Pediatric Demyelinating Disease Study (CPDDS). Stringent standard operating procedures were developed and uniformly applied to procure, process and subsequently analyse peripheral blood cells using rigorously applied multi-parametric flow cytometry panels and miniaturized functional assays validated for use with cryopreserved cells. We found abnormally increased frequencies and exaggerated pro-inflammatory responses of CD8+CD161highTCR-Vα7.2+ MAIT T cells and CD4+CCR2+CCR5+ Teffs in paediatric-onset multiple sclerosis, compared to both control groups. CD4+CD25hiCD127lowFOXP3+ Tregs of children with multiple sclerosis exhibited deficient suppressive capacity, including diminished capacity to suppress disease-implicated Teffs. In turn, the implicated Teffs of multiple sclerosis patients were relatively resistant to suppression by normal Tregs. An abnormal Teff/Treg ratio at the individual child level best distinguished multiple sclerosis children from controls. We implicate abnormalities in both frequencies and functional responses of distinct pro-inflammatory CD4 and CD8 T cell subsets, as well as Treg function, in paediatric-onset multiple sclerosis, and suggest that mechanisms contributing to early multiple sclerosis development differ across individuals, reflecting an excess abnormality in either Teff or Treg limbs of the T cell response, or a combination of lesser abnormalities in both limbs.