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Jennifer Naftel,1,* Heena Mistry,1– 5,* Frances Ann Mitchell,4 Jane Belson,4 Mohammed Aref Kyyaly,2,4 Clair Barber,1,2 Hans Michael Haitchi,1– 3,6 Paddy Dennison,1– 3 Ratko Djukanovic,1– 3,6 Gregory Seumois,5 Pandurangan Vijayanand,2,5 Syed Hasan Arshad,1– 4,6 Ramesh J Kurukulaaratchy1– 4 1National Institute for Health Research (NIHR) Southampton Biomedical Research Centre at University Hospital Southampton NHS Foundation Trust, Southampton, UK; 2Clinical and Experimental Sciences Department, Faculty of Medicine, University of Southampton, Southampton, UK; 3Asthma, Allergy and Clinical Immunology Department, University Hospital Southampton NHS Foundation Trust, Southampton, UK; 4The David Hide Asthma & Allergy Research Centre, St Mary’s Hospital, Newport, Isle of Wight, UK; 5Vijayanand Laboratory, La Jolla Institute of Immunology, San Diego, CA, 92037, USA; 6Institute for Life Sciences, University of Southampton, Southampton, UK*These authors contributed equally to this workCorrespondence: Ramesh J Kurukulaaratchy, Respiratory Medicine & Allergy, Clinical Experimental Sciences, Mailpoint 810, F-Level, South Academic Block, Southampton General Hospital, Tremona Road, Southampton, Hampshire, SO16 6YD, United Kingdom, Tel +442381 208790, Email Rjk1s07@soton.ac.ukBackground: Despite most of the asthma population having mild disease, the mild asthma phenotype is poorly understood. Here, we aim to address this gap in knowledge by extensively characterising the mild asthma phenotype and comparing this with difficult-to-treat asthma.Methods: We assessed two real-world adult cohorts from the South of England using an identical methodology: the Wessex AsThma CoHort of difficult asthma (WATCH) (n=498) and a mild asthma cohort from the comparator arm of the Epigenetics Of Severe Asthma (EOSA) study (n=67). Data acquisition included detailed clinical, health and disease-related questionnaires, anthropometry, allergy and lung function testing, plus biological samples (blood and sputum) in a subset.Results: Mild asthma is predominantly early-onset and is associated with type-2 (T2) inflammation (atopy, raised fractional exhaled nitric oxide (FeNO), blood/sputum eosinophilia) plus preserved lung function. A high prevalence of comorbidities and multimorbidity was observed in mild asthma, particularly depression (58.2%) and anxiety (56.7%). In comparison to difficult asthma, mild disease showed similar female predominance (> 60%), T2-high inflammation and atopy prevalence, but lower peripheral blood/airway neutrophil counts and preserved lung function. Mild asthma was also associated with a greater prevalence of current smokers (20.9%). A multi-component T2-high inflammatory measure was comparable between the cohorts; T2-high status 88.1% in mild asthma and 93.5% in difficult asthma.Conclusion: Phenotypic characterisation of mild asthma identified early-onset disease with high prevalence of current smokers, T2-high inflammation and significant multimorbidity burden. Early comprehensive assessment of mild asthma patients could help prevent potential later progression to more complex severe disease.Keywords: mild asthma, difficult asthma, multimorbidity, type 2 inflammation

The sustainable biodiesel industry relies on converting biorefinery by-product glycerol into valuable chemicals. A wet-impregnated Pd/SBA-15 catalyst for the selective dehydration of glycerol to acrolein is presented in this study. Various analytical techniques were used to confirm the catalysts' physicochemical characteristics, including X-ray diffraction, pulse CO chemisorption, BET surface area, TEM, and H2-TPR. The results demonstrate that Pd nanoparticles were incorporated into SBA-15 in a homogeneous dispersion. Due to its high surface area and sufficient Bronsted acidic sites, the Pd/SBA-15 catalyst can enhance selectivity for acrolein and reduce poisoning susceptibility. A fixed-bed reactor operating in the vapour phase was used to verify the efficiency of the prepared acid catalysts for selectively converting glycerol to acrolein. It was discovered that 2 wt% Pd nanoparticles supported on the SBA-15 catalyst exhibit 89.6% glycerol conversion and 64.2% acrolein selectivity at 320 °C. It was found that the acidic sites (Lewis & Brønsted), homogenous Pd nanoparticle dispersion, and the support (i.e., SBA-15) conferred its superior catalytic activity. Various reaction parameters, including temperature, TOF, Pd loadings, and weight hour space velocity, also affect catalytic activity.

Combining conjugated polymers with transition-metal-based metal-organic frameworks offers an opportunity to produce efficient photocatalytic materials. Here, exposed active sites and efficient charge transfer lead to hydrogen evolution rates of up to 2438 µmol g−1 h−1 for composites of anisotropic phenanthroline-based ruthenium polymers grafted on titanium-based MOFs.

The need for eco-friendly materials has risen globally due to environmental consciousness. This work involved the extraction and utilization of silane treated and untreated Citrullus lanatus stem fiber for eco-friendly brake friction composites. The fibers were extracted from Citrullus lanatus plant stems using a conventional manual retting process followed by silane treatment. The silane-treated and untreated Citrullus lanatus stem fibers were analyzed for physical, chemical, and thermal characteristics. The application suitability was explored by developing brake friction composites in the form of brake pads using silane-treated and untreated Citrullus lanatus stem fiber in addition to parental ingredients by the conventional process and compared with the glass fiber-based one. The developed brake pads were analyzed for performance properties as per industrial standards. The tribological performance was measured using the Chase test following IS2742-Part-4. The test results showed that cellulose content was 60.3% for silane-treated Citrullus lanatus fibers while it was 53.7% for untreated Citrullus lanatus fibers. The normal friction properties showed that silane-treated Citrullus lanatus stem fibers-based brake pads had 0.413 while it was 0.41 for glass fiber-based brake pads and 0.392 for untreated fiber-based ones. Using a scanning electron microscope, the worn surface of Chase brake pads revealed features like plowing, plateau formations.

Transformation of levulinic acid (LA) to γ -valerolactone (GVL) via hydrogenation is a greener approach in synthesising the eco-friendly GVL fuel additive. In this work, highly active and stable pre-synthesized copper nanoparticles (CuNPs) are embedded and distributed into the ordered mesoporous carbon (OMC) support material by the chelate-assisted multicomponent assembly pathway method. The Cu/OMC nanocatalyst is characterized by different analytical instruments to determine the key properties. The ordered mesoporous carbon (OMC) structure was formed successfully by controlled synthesis steps via resol carbonization. The morphology and structure of OMC was confirmed by the XRD, TEM and HRTEM analysis. The OMC surface was functionalized with different oxygen-containing functional groups, which enhances the interactions with the Cu nanoparticles. The TEM micrographs reveal that Cu NPs with average size of ~5.5 nm was evenly distributed over the surface of the OMC matrix. The synthesized Cu/OMC catalyst showed remarkable activity and stability due to confinement effects of Cu in mesoporous carbon and the highly dispersed nanosized Cu particles, which are exposed sites over the support. More importantly, the stability of the Cu/OMC was excellent, and the activity did not decline even after 60 h time on stream test under optimized conditions (WHSV-2.28 h−1, 20 wt% aqueous LA, H2 flow- 30 mL/min, 260 °C at 0.1 MPa hydrogen pressure).

In this work, we designed versatile heterogeneous nanocatalysts based on palladium nanoparticles (PdNPs) decorated on metal oxides supports (i.e., PdNPs/γ-Al2O3, PdNPs/WO3 and PdNPs/Nb2O5) by step-wise controlled synthesis of novel monodispersed ∼2 nm PdNPs at room temperature and then impregnated over metal oxides. PdNPs supported catalysts were characterised by powder XRD, TEM, HRTEM, NH3-TPD, N2-BET, H2-TPR, and XPS techniques. PdNPs based catalysts studied in two different model reactions were presented i.e., biomass platform chemical intermediate γ-valerolactone (GVL) conversion into pentanoic acid (PA) studied in vapor phase hydrogenolysis and 4-Nitrophenol (4-NP) reduction to 4-Aminophenol (4-AP) in liquid phase using NaBH4 as reducing agent over 0.5 wt% Pd nanoparticles -based nanocatalysts. The relationship between the active sites and the catalytic performance was evaluated. The Under optimized reaction conditions, over 0.5 wt% PdNPs/γ-Al2O3 catalyst exhibited the highest PA yield of 100%, and over 0.5 wt% PdNPs/WO3, 0.5 wt% PdNPs/Nb2O5 exhibited PA yields of 98% and 96% respectively. Over PdNPs/γ-Al2O3, PdNPs/WO3, and PdNPs/Nb2O5, the reduction reaction rates in the 4-NP to 4-AP are 5.40 × 10−3 s−1, 2.55 × 10−3 s−1 and 2.30 × 10−3 s−1 respectively. The calculated thermodynamic parameters of the Ea values for 4-NP to 4-AP reaction were 25.30, 26.75, and 27.81 KJ/mol for the PdNPs/γ-Al2O3, PdNPs/WO3 and PdNPs/Nb2O5, respectively.

Chemoselective hydrogenation of biomass platform molecules into value-added chemicals and fuels is essential for the exploitation of biomass, and SBA-15 based metal catalysts with hydrogenation centers and acid sites seem promising in this regard. Valeric acid (VA) is the most important platform molecule for valeric biofuels and value-added chemicals production. The main issue with using such bifunctional catalysts for biomass conversion is maintaining the catalyst's stability in the liquid phase under harsh conditions. In-addition, direct one-pot selective hydrogenation of levulinic acid (LA) into VA synthesis is challenging due to its complex reaction conditions involved. Herein, we design a bifunctional mesoporous catalysts (SBA-15 mesoporous material doped with various metals Nb, Ti, and Zr) investigated for this reaction under the vapour phase. Different instrumental approaches were used to examine the structure, phase composition, morphology, and surface elemental analyses of catalysts as-prepared. Among those catalysts, Zr-doped mesoporous SBA-15 catalyst showed the 91% conversion of LA and the 68% selectivity toward VA and promising stability in a 52 h time on-stream run. Metal dispersion inside the SBA-15 and their surface acidity (sufficient number of acid sites and surface-active metal oxide species) and higher surface area are beneficial for the selectivity of VA. This work offers a highly-efficient bifunctional catalyst for selective hydrogenation of biomass feedstocks.

Wellen's sign occurs due to either critical stenosis in the proximal left anterior descending artery (LAD) or coronary steal phenomenon. Here we report a case of a 57-year-old gentleman with anomalous origin of the right coronary artery from mid LAD, where both these phenomena contributed together leading to Wellen's sign.

A direct alkaline hydrothermal method was used to synthesize mono- and bimetallic Ni and Cu on mesoporous silica (m-SiO2) as catalysts for the hydrogenation of furfural (FAL) to cyclopentanone (CPO). The catalysts were characterized by XRD, FTIR, H2-TPR, SEM, TEM, HR-TEM, XPS, ICP, BET, and CHN analysis. The results demonstrate that the addition of Cu metal improved the reducibility of Ni catalysts and revealed Ni-Cu alloy formation over m-SiO2. Furthermore, XPS and FTIR results reveal that the silanol groups on the catalyst surface play an important role in the ring rearrangement of furfuryl alcohol. Hence, the effect of silanol groups in the FOL rearrangement was studied in detail. Among the catalysts at fixed metal loading of 20 wt.%, Ni5Cu15/m-SiO2 catalyzed the formation of CPO as the main product due to the synergy of Ni-Cu alloy and surface silanol groups. Ni5Cu15 supported on a commercial mesoporous silica (Ni5Cu15/C-SiO2) showed inferior performance compared with the Ni5Cu15/m-SiO2 catalyst for the FAL hydrogenation. Reaction temperature and time were also optimized for the enhanced CPO yield over Ni5Cu15/m-SiO2. The Ni5Cu15/m-SiO2 catalyst is durable, as demonstrated by stability tests over multiple reuses. This effective and flexible NixCuy on m-SiO2 catalyst provides an effective candidate for efficient upgrading of furanics in selective hydrogenation reactions.

Conversion of biomass-derived furfural (FFA) platform molecule to value-added tetrahydrofurfuryl alcohol (THFA) molecule is a sustainable route using an efficient non-noble metallic catalyst in water solvent. In this work, Ni in various loadings on mesoporous titanium dioxide (m-TiO2) was synthesized in one pot by Evaporation-Induced Self-Assembly (EISA). The synthesised catalysts were evaluated for the hydrogenation of furfural to tetrahydrofurfuryl alcohol. The catalysts were characterised using a combination of spectroscopic techniques such as XRD, H2-TPR, H2-TPD, XPS, SEM-EDX, TEM, and HR-TEM. The characterization results show that the Ni/m-TiO2 materials exhibit enhanced electron-rich active sites, facilitated hydrogen spillover, uniform dispersion of small Ni particles (~5 nm), and strong metal support interaction between Ni and TiO2. Among the various Ni dopings, 7.5 wt.% Ni/m-TiO2 catalyst exhibited the best performance and achieved 99.9% FFA conversion and 93.2% THFA selectivity in water solvent at 100 °C and under 2 MPa H2. Additionally, detailed kinetic studies, process parameters, the stability and reusability of the catalyst were also studied. The results demonstrated that the 7.5 wt.% Ni/m-TiO2 catalyst is highly active and stable.

In recent years, functionalized metal oxides have been gaining popularity for biomass conversion to fuels and chemicals due to the global energy crisis. This study reports a novel catalyst based on noble metal immobilization on functionalized zirconia that has been successfully used in the production of biofuel alkyl levulinates (ALs) from lignocellulosic biomass-derived levulinic acid (LA) under vapor-phase. The wet impregnation method was used to immobilize Pt-metal nanoparticles on zirconia-based supports (silicotungstic acid zirconia, STA-ZrO2; sulfated zirconia, S-ZrO2; and tetragonal zirconia, t-ZrO2). A variety of physicochemical techniques were used to characterize the prepared catalysts, and these were tested under atmospheric pressure in continuous flow esterification of LA. The order of catalytic activity followed when ethyl levulinate was produced from levulinic acid via esterification: Pt/STA-ZrO2 ≫ Pt/S-ZrO2 ≫ Pt/t-ZrO2. Moreover, it was found that ALs synthesis from LA with different alcohols utilizing Pt/STA-ZrO2 catalyst followed the order ethyl levulinate ≫ methyl levulinate ≫ propyl levulinate≫ butyl levulinate. This work outlines an excellent approach to designing efficient catalysts for biofuels and value-added compounds made from biomass.

2-Methyltetrahydrofuran (MTHF) is a desirable biomass-based platform chemical with excellent potential as an ideal biofuel, green solvent, and raw material for synthesizing downstream chemicals. In this work, a series of copper nanoparticles encapsulated on SiO2 were prepared by the wet impregnation method and evaluated as efficient non-noble metal catalysts for the vapour-phase hydrogenation of γ-valerolactone (GVL) to MTHF in a fixed-bed reactor under mild reaction conditions. The obtained catalyst properties were determined by XRD, FE-SEM, TEM, UV-DRS, TPR, NH3-TPD, N2O decomposition and pore size distribution measurements. Meanwhile, the parameters/variables tuning their catalytic performance (activity, conversion, selectivity and stability) were examined. Various Cu loadings featured on the SiO2 support are essential for tuning the catalytic activity. Among the catalysts tested, a 5 wt% Cu/SiO2 catalyst showed a 97.2% MTHF selectivity with 71.9% GVL conversion, and showed a stability for 33 h time-on-stream, achieved at 260 °C and atmospheric pressure conditions. It was found that a huge dispersion of Cu metal in support, hydrogen activation ability, abundant acidic sites and surface area are all beneficial for improved MTHF selectivity.

The valuable products produced from glycerol transformation have become a research route that attracted considerable benefits owing to their huge volumes in recent decades (as a result of biodiesel production as a byproduct) as well as a myriad of chemical and biological techniques for transforming glycerol into high-value compounds, such as fuel additives, biofuels, precursors and other useful chemicals, etc. Biodiesel has presented another challenge in the considerable increase in its byproduct (glycerol). This review provides a recent update on the transformation of glycerol with an exclusive focus on the various catalysts’ performance in designing reaction operation conditions. The different products observed and cataloged in this review involved hydrogen, acetol, acrolein, ethylene glycol, and propylene glycol (1,3-propanediol and 1,2-propanediol) from reforming and dehydration and hydrogenolysis reactions of glycerol conversions. The future prospects and critical challenges are finally presented.

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.

Abstract In the VEST IV trial, the author concluded that external stenting of saphenous vein graft mitigates its remodeling and also significantly reduces the diffuse intimal hyperplasia and development of lumen irregularities at 4.5 years after coronary artery bypass grafting surgery. We also have valuable a suggestion in addition to external stenting that might nullify the pathology caused by the stent and might enhances graft patency.

While several lines of evidence suggest a protective role of T cells against disease associated with Dengue virus (DENV) infection, their potential contribution to immunopathology in the acute phase of DENV infection remains controversial, and it has been hypothesized that the more severe form of the disease (dengue hemorrhagic fever, DHF) is associated with altered T cell responses. To address this question, we determined the transcriptomic profiles of DENV-specific CD8+ T cells in a cohort of 40 hospitalized dengue patients with either a milder form of the disease (dengue fever, DF) or a more severe disease form (dengue hemorrhagic fever, DHF). We found multiple transcriptomic signatures, one associated with DENV-specific interferon-gamma responding cells and two other gene signatures, one specifically associated with the acute phase and the other with the early convalescent phase. Additionally, we found no differences in quantity and quality of DENV-specific CD8+ T cells based on disease severity. Taken together with previous findings that did not detect altered DENV-specific CD4 T cell responses, the current analysis argues against alteration in DENV-specific T cell responses as being a correlate of immunopathology.

Ramani Vijayan,1 Gauhar Afshan,2 Khalid Bashir,3 Mary Cardosa,4 Madhur Chadha,5 Pongparadee Chaudakshetrin,6 Khin Myo Hla,7 Muralidhar Joshi,8 Francis O Javier,9 Asif Gul Kayani,10 Andi Takdir Musba,11 Sasikaan Nimmaanrat,12 Dwi Pantjawibowo,13 Jocelyn C Que,14 Palanisamy Vijayanand15 1Department of Anaesthesiology, University Malaya Medical Centre, Kuala Lumpur, Malaysia; 2Department of Anaesthesiology, The Aga Khan University, Karachi, Pakistan; 3Department of Anaesthesia, Hameed Latif Hospital, Lahore, Pakistan; 4Department of Anaesthesiology, Hospital Selayang, Selangor, Malaysia; 5Department of Pain Medicine, Primus Hospital and Fortis Group of Hospitals, New Delhi, India; 6Pain Management Clinic, Department of Anesthesiology, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 7Department of Physical Medicine & Rehabilitation, Yangon General Hospital, University of Medicine-1, Yangon, Myanmar; 8Department of Anaesthesia & Pain Medicine, Virinchi Hospitals, Hyderabad, India; 9Pain Management Center, St Luke’s Medical Center, Metro Manila, Philippines; 10Department of Anesthesiology, Kulsum International Hospital, Islamabad, Pakistan; 11Department of Anesthesiology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia; 12Department of Anesthesiology, Faculty of Medicine, Prince of Songkla University, Hatyai, Songkhla, Thailand; 13Department of Anesthesiology, Intensive Therapy, and Hospital Pain Management, Premier Bintaro Hospital, South Tangerang, Indonesia; 14Center for Pain Medicine, Department of Anesthesiology, Faculty of Medicine and Surgery, University of Santo Tomas, Manila, Philippines; 15Pain Management Department, Sri Ramakrishna Hospital, Coimbatore, Tamil Nadu, India Background: The supply of controlled drugs is limited in the Far East, despite the prevalence of health disorders that warrant their prescription. Reasons for this include strict regulatory frameworks, limited financial resources, lack of appropriate training amongst the medical profession and fear of addiction in both general practitioners and the wider population. Consequently, the weak opioid tramadol has become the analgesic most frequently used in the region to treat moderate to severe pain.Methods: To obtain a clearer picture of the current role and clinical use of tramadol in Southeast Asia, pain specialists from 7 countries in the region were invited to participate in a survey, using a questionnaire to gather information about their individual use and experience of this analgesic.Results: Fifteen completed questionnaires were returned and the responses analyzed. Tramadol is used to manage acute and chronic pain caused by a wide range of conditions. Almost all the specialists treat moderate cancer pain with tramadol, and every one considers it to be significant or highly significant in the treatment of moderate to severe non-cancer pain. The reasons for choosing tramadol include efficacy, safety and tolerability, ready availability, reasonable cost, multiple formulations and patient compliance. Its safety profile makes tramadol particularly appropriate for use in elderly patients, outpatients, and for long-term treatment. The respondents strongly agreed that tighter regulation of tramadol would reduce its medical availability and adversely affect the quality of pain management. In some countries, there would no longer be any appropriate medication for cancer pain or the long-term treatment of chronic pain.Conclusions: In Southeast Asia, tramadol plays an important part in the pharmacological management of moderate to severe pain, and may be the only available treatment option. If it were to become a controlled substance, the standard of pain management in the region would decline. Keywords: tramadol, questionnaire, indications, efficacy, safety, controlled substance

We report the successful treatment of a rare case of chronic intrapericardial hematoma which presented with congestive cardiac failure 20 months after aortic valve replacement surgery for severe calcific aortic stenosis. Chest roentgenograph demonstrated paracardiac mass over lower left ventricle border, left pleural effusion and pulmonary venous hypertension. An echocardiographic study demonstrated intrapericardial mass posterolateral to left ventricle compressing left ventricular cavity both during systole and diastole causing septum to bulge into right ventricle. Computed tomography showed a loculated pericardial mass in left heart margin, left pleural effusion, bilateral axillary and mediastinal lymphadenopathy. Surgical resection was planned to relieve the symptoms and to confirm the diagnosis of the mass. The mass was completely resected through left anterolateral thoracotomy and histopathology findings confirmed the diagnosis of hematoma with cystic degeneration. Postoperative course was uneventful, and his symptoms improved markedly.

Cluster headache is a primary neurovascular unilateral headache associated with autonomic symptoms. The sphenopalatine ganglion plays an important role in the pathogenesis of this disorder. Although medications are the first line of treatment, percutaneous, and surgical interventions have been proposed to treat cluster headache. An attractive option is the radiofrequency ablation of the sphenopalatine ganglion for the treatment of cluster headache due to its relative safety and simplicity compared with other procedures.

A 42-year-old Asian Indian male with a history of conjunctival melanoma in the left eye presented with a recurrent tumor in the upper tarsal conjunctiva. The tumor was completely excised under margin control, followed by two-staged eyelid reconstruction. During the second stage of the eyelid reconstruction, a brown-colored discharge was noted at the punctum, which on cytology was confirmatory of melanoma. Left dacryocystectomy with en bloc nasolacrimal duct (NLD) excision was performed. Histopathology demonstrated infiltration of the NLD by the tumor with no presence of melanoma in the lacrimal sac. Lacrimal oncorrhea is a term used to describe tumor spread by free-floating cells in the tear film. All conjunctival tumors carry a risk of tumor spread by oncorrhea.

Although mucosal-associated invariant T (MAIT) cells provide rapid, innate-like responses, they are not pre-set, and memory-like responses have been described for MAIT cells following infections. The importance of metabolism for controlling these responses, however, is unknown. Here, following pulmonary immunization with a Salmonella vaccine strain, mouse MAIT cells expanded as separate CD127-Klrg1+ and CD127+Klrg1- antigen-adapted populations that differed in terms of their transcriptome, function and localization in lung tissue. These populations remained altered from steady state for months as stable, separate MAIT cell lineages with enhanced effector programmes and divergent metabolism. CD127+ MAIT cells engaged in an energetic, mitochondrial metabolic programme, which was critical for their maintenance and IL-17A synthesis. This programme was supported by high fatty acid uptake and mitochondrial oxidation and relied on highly polarized mitochondria and autophagy. After vaccination, CD127+ MAIT cells protected mice against Streptococcus pneumoniae infection. In contrast, Klrg1+ MAIT cells had dormant but ready-to-respond mitochondria and depended instead on Hif1a-driven glycolysis to survive and produce IFN-γ. They responded antigen independently and participated in protection from influenza virus. These metabolic dependencies may enable tuning of memory-like MAIT cell responses for vaccination and immunotherapies.

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

Systemic lupus erythematosus (SLE) is an incurable autoimmune disease disproportionately affecting women. A major obstacle in finding targeted therapies for SLE is its remarkable heterogeneity in clinical manifestations as well as in the involvement of distinct cell types. To identify cell-specific targets as well as cross-correlation relationships among expression programs of different cell types, we here analyze six major circulating immune cell types from SLE patient blood. Our results show that presence of an interferon response signature stratifies patients into two distinct groups (IFNneg vs. IFNpos). Comparing these two groups using differential gene expression and differential gene coexpression analysis, we prioritize a relatively small list of genes from classical monocytes including two known immune modulators: TNFSF13B/BAFF (target of belimumab, an approved therapeutic for SLE) and IL1RN (the basis of anakinra, a therapeutic for rheumatoid arthritis). We then develop a multi-cell type extension of the weighted gene coexpression network analysis (WGCNA) framework, termed mWGCNA. Applying mWGCNA to RNA-seq data from six sorted immune cell populations (15 SLE, 10 healthy donors), we identify a coexpression module with interferon-stimulated genes (ISGs) among all cell types and a cross-cell type correlation linking expression of specific T helper cell markers to B cell response as well as to TNFSF13B expression from myeloid cells, all of which in turn correlates with disease severity of IFNpos patients. Our results demonstrate the power of a hypothesis-free and data-driven approach to discover drug targets and to reveal novel cross-correlation across cell types in SLE with implications for other autoimmune diseases.

Invariant natural killer T cells (iNKT cells) differentiate into thymic and peripheral NKT1, NKT2 and NKT17 subsets. Here we use RNA-seq and ATAC-seq analyses and show iNKT subsets are similar, regardless of tissue location. Lung iNKT cell subsets possess the most distinct location-specific features, shared with other innate lymphocytes in the lung, possibly consistent with increased activation. Following antigenic stimulation, iNKT cells undergo chromatin and transcriptional changes delineating two populations: one similar to follicular helper T cells and the other NK or effector like. Phenotypic analysis indicates these changes are observed long-term, suggesting that iNKT cells gene programs are not fixed, but they are capable of chromatin remodeling after antigen to give rise to additional subsets.

Despite recent advances in asthma management with anti-IL-5 therapies, many patients have eosinophilic asthma that remains poorly controlled. IL-3 shares a common β subunit receptor with both IL-5 and GM-CSF but, through α-subunit-specific properties, uniquely influences eosinophil biology and may serve as a potential therapeutic target. We aimed to globally characterize the transcriptomic profiles of GM-CSF, IL-3, and IL-5 stimulation on human circulating eosinophils and identify differences in gene expression using advanced statistical modeling. Human eosinophils were isolated from the peripheral blood of healthy volunteers and stimulated with either GM-CSF, IL-3, or IL-5 for 48 h. RNA was then extracted and bulk sequencing performed. DESeq analysis identified differentially expressed genes and weighted gene coexpression network analysis independently defined modules of genes that are highly coexpressed. GM-CSF, IL-3, and IL-5 commonly upregulated 252 genes and downregulated 553 genes, producing a proinflammatory and survival phenotype that was predominantly mediated through TWEAK signaling. IL-3 stimulation yielded the most numbers of differentially expressed genes that were also highly coexpressed (n = 119). These genes were enriched in pathways involving JAK/STAT signaling. GM-CSF and IL-5 stimulation demonstrated redundancy in eosinophil gene expression. In conclusion, IL-3 produces a distinct eosinophil gene expression program among the β-chain receptor cytokines. IL-3-upregulated genes may provide a foundation for research into therapeutics for patients with eosinophilic asthma who do not respond to anti-IL-5 therapies.

Zika virus (ZIKV) constitutes an increasing public health problem. Previous studies have shown that CD8+ T cells play an important role in ZIKV-specific protective immunity. We have previously defined antigenic targets of the ZIKV-specific CD8+ T cell response in humans. In this study, we characterized the quality and phenotypes of these responses by a combined use of flow cytometry and transcriptomic methods, using PBMCs from donors deriving from different geographical locations collected in the convalescent phase of infection. We show that ZIKV-specific CD8+ T cells are characterized by a polyfunctional IFN-γ signature with upregulation of TNF-α, TNF receptors, and related activation markers, such as CD69, as well as a cytotoxic signature characterized by strong upregulation of GZMB and CRTAM. The signature is stable and not influenced by previous dengue virus exposure, geographical location, or time of sample collection postinfection. To our knowledge, this work elucidates the first in-depth characterization of human CD8+ T cells responding to ZIKV infection.

In the context of large-scale human system immunology studies, controlling for technical and biological variability is crucial to ensure that experimental data support research conclusions. In this study, we report on a universal workflow to evaluate both technical and biological variation in multiparameter flow cytometry, applied to the development of a 10-color panel to identify all major cell populations and T cell subsets in cryopreserved PBMC. Replicate runs from a control donation and comparison of different gating strategies assessed the technical variability associated with each cell population and permitted the calculation of a quality control score. Applying our panel to a large collection of PBMC samples, we found that most cell populations showed low intraindividual variability over time. In contrast, certain subpopulations such as CD56 T cells and Temra CD4 T cells were associated with high interindividual variability. Age but not gender had a significant effect on the frequency of several populations, with a drastic decrease in naive T cells observed in older donors. Ethnicity also influenced a significant proportion of immune cell population frequencies, emphasizing the need to account for these covariates in immune profiling studies. We also exemplify the usefulness of our workflow by identifying a novel cell-subset signature of latent tuberculosis infection. Thus, our study provides a universal workflow to establish and evaluate any flow cytometry panel in systems immunology studies.