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Allogeneic cellular immunotherapies hold promise for broad clinical implementation but face limitations due to potential rejection of donor cells by the host immune system. Silencing of beta-2 microglobulin (B2M) expression is commonly employed to evade T cell-mediated rejection by the host, although the absence of B2Mis expected to trigger missing-self responses by host natural killer (NK) cells. Here, we demonstrate that genetic deletion of the adhesion ligands CD54and CD58in B2M-deficient chimeric antigen receptor (CAR) T cells and multi-edited induced pluripotent stem cell (iPSC)-derived CAR NK cells reduces their susceptibility to rejection by host NK cells in vitroand in vivo. The absence of adhesion ligands limits rejection in a unidirectional manner in B2M-deficient and B2M-sufficient settings without affecting the antitumor functionality of the engineered donor cells. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection by host immune cells, facilitating the implementation of universal immunotherapy.

After 3 weeks of daily headache, a 28-year-old, otherwise healthy woman was admitted to the emergency department with a first-time generalized seizure. CT showed a left frontal mass with perifocal edema. Brain MRI raised the suspicion of cerebral lymphoma. Cerebrospinal fluid analysis revealed mononuclear pleocytosis of 14 cells/μL without malignant cells, normal protein levels, and absence of oligoclonal bands. FET PET/MRI of the lesion showed FET characteristics of inflammatory disease, and acute disseminated encephalomyelitis was suggested as diagnosis. Final histopathological results from brain biopsy confirmed acute disseminated encephalomyelitis.

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Rapid wound detection by distant leukocytes is essential for antimicrobial defence and post-infection survival1. The reactive oxygen species hydrogen peroxide and the polyunsaturated fatty acid arachidonic acid are among the earliest known mediators of this process2–4. It is unknown whether or how these highly conserved cues collaborate to achieve wound detection over distances of several hundreds of micrometres within a few minutes. To investigate this, we locally applied arachidonic acid and skin-permeable peroxide by micropipette perfusion to unwounded zebrafish tail fins. As in wounds, arachidonic acid rapidly attracted leukocytes through dual oxidase (Duox) and 5-lipoxygenase (Alox5a). Peroxide promoted chemotaxis to arachidonic acid without being chemotactic on its own. Intravital biosensor imaging showed that wound peroxide and arachidonic acid converged on half-millimetre-long lipid peroxidation gradients that promoted leukocyte attraction. Our data suggest that lipid peroxidation functions as a spatial redox relay that enables long-range detection of early wound cues by immune cells, outlining a beneficial role for this otherwise toxic process.

A 57-year-old male patient developed within 2 weeks rapid progressive gait instability, memory deficits, hypomania, and recurrent complex tic-like involuntary outbursts of vocalization 15 and 18 months after double autologous hematopoietic stem-cell transplantation for multiple myeloma. CSF showed 19 mononuclear cells/μL, and MRI revealed progressive multifocal cortico-subcortical T2/FLAIR-hyperintensities with high metabolic activity in FDG-PET/CT (Figures 1 and 2). Histopathology of a biopsied lesion revealed sparse inflammatory changes of cortico-subcortical areas. Within the next 2 weeks, he developed continuous rhythmic myoclonic jerks in the left hand (“myoclonia continua”), initially with and later without epileptic activity in EEG.1After excluding differential diagnoses, that is, intracerebral viral, malignant, demyelinating or other autoimmune disease, we diagnosed anti-GABAAreceptor antibody-positive autoimmune encephalitis,2presumably triggered by aberrant posttransplant immune reconstitution. After corticosteroids, plasma exchange, and rituximab, he showed near-complete recovery within several months. Encephalitis with severe seizures and multifocal brain lesions should prompt consideration of anti-GABAAreceptor encephalitis.

Epithelial injury induces rapid recruitment of antimicrobial leukocytes to the wound site. In zebrafish larvae, activation of the epithelial NADPH oxidase Duox at the wound margin is required early during this response. Before injury, leukocytes are near the vascular region, that is, ∼100–300 μm away from the injury site. How Duox establishes long-range signaling to leukocytes is unclear. We conceived that extracellular hydrogen peroxide (H2O2) generated by Duox diffuses through the tissue to directly regulate chemotactic signaling in these cells. But before it can oxidize cellular proteins, H2O2must get past the antioxidant barriers that protect the cellular proteome. To test whether, or on which length scales this occurs during physiological wound signaling, we developed a computational method based on reaction-diffusion principles that infers H2O2degradation rates from intravital H2O2-biosensor imaging data. Our results indicate that at high tissue H2O2levels the peroxiredoxin-thioredoxin antioxidant chain becomes overwhelmed, and H2O2degradation stalls or ceases. Although the wound H2O2gradient reaches deep into the tissue, it likely overcomes antioxidant barriers only within ∼30 μm of the wound margin. Thus, Duox-mediated long-range signaling may require other spatial relay mechanisms besides extracellular H2O2diffusion.

Polymer-modified bitumen (PmBs) has been characterised by fluorescence microscopy, conventional performance tests and by the rheological measurements, before and after the Rolling Thin Film Oven Test (RTFOT), and by multi-fractal analysis. The addition of 2–7 wt-% of linear styrene-butadiene-styrene block copolymer (SBS-L) or radial block copolymer (SBS-R) increased viscosity, softening point and complex modulus of PmBs. Hardening of PmBs occurred and the elastic response decreased after RTFOT aging. SBS-L PmBs are more susceptible to RTFOT aging. Digital fluorescence micrographs of sections of PmBs qualitatively exhibit different morphological structures which can be quantitatively probed by multi-fractal analysis: differences are reflected in the f (a) spectrum. The PmBs which appear less multi-fractal have the best rheological properties. In another approach, the focal fractal dimensions’ distributions for the SBS-modified bitumen have peak around 2.35 (which corresponds to the bitumen-rich phase) and around 2.7 (which corresponds to the noncontinuous SBS-rich phase).

The purpose of this article is to outline the evolution of science and technology within the sport of tennis, while simultaneously providing players and coaches with some specific practical applications that can be utilized by players of all ages and abilities. [ABSTRACT FROM AUTHOR]

Autologous hematopoietic stem cell transplantation (aHSCT) is a highly effective treatment of multiple sclerosis (MS). It depletes autoreactive cells and subsequently renews adaptive immune cells. The possible proinflammatory potential of surviving T cells early after aHSCT has not been studied. Here, we examined the dynamics of new and surviving T cells in 27 patients after aHSCT by multidimensional flow cytometry, T cell receptor (TCR) sequencing, specificity testing, telomere length profiling, and HLA genotyping. Early after aHSCT, naïve T cells are barely detectable, whereas effector memory (EM) T cells quickly reconstitute to pre-aHSCT values. EM CD4+T cells early after aHSCT have shorter telomeres, have higher expression of senescence and exhaustion markers, and proliferate less than those before aHSCT. We find a median TCR repertoire overlap of 26% between the early post-aHSCT EM CD4+T cells and pre-aHSCT, indicating persistence of EM CD4+T cells early after transplantation. The EM CD4+TCR repertoire overlap declines to 15% at 12 months after aHSCT, whereas the naïve TCR repertoire entirely renews. HLA-DR–associated EM CD4+T cell reactivity toward MS-related antigens decreased after aHSCT, whereas reactivity toward EBV increased. Our data show substantial survival of pre-aHSCT EM CD4+T cells early after transplantation but complete renewal of the T cell repertoire by nascent T cells later.

The article focuses on assessing ballasted activated sludge for wet weather flow management by wastewater utilities under existing infrastructure. Topics discussed include implementing ballasted activated sludge treatment into a plant's existing tankage without the need for physical expansion; use of magnetite as ballast material for wastewater treatment clarification; and handling high wet weather flows with the BioMag activated sludge treatment system.

Therapy for relapsing-remitting multiple sclerosis with natalizumab (Tysabri; Biogen Idec) has been shown to be effective in the reduction of the clinical relapse rate and disability progression. However, real-life longitudinal data, including years before baseline, are rare.

The aim of this study was to review the outcome of acromegaly treatment, as well as co-morbidity and mortality in a series of patients with acromegaly attending a single center in the last 10 yr. In that period, 53 patients were treated for acromegaly. Transsphenoidal operation was applied as the first-line therapy in 94.3% of patients and it led to disease remission in 59.2% of them. The remission criteria included a nadir GH<1 µg/l after glucose load, and normal age-related IGF-I levels. The remission rate after transsphenoidal surgery was significantly higher in the group of patients with microadenoma (76.9%), than in the group of patients with macroadenoma (52.8%). Patients with invasive tumors had remission rate of 16.7% after transsphenoidal surgery. There were no perioperative deaths. As the second-line treatment somatostatin analogues, radiotherapy, and dopaminergic agonists were used. Hypertension and diabetes were the most frequent co-morbidities in the group of patients. After successful treatment, 30% of patients with diabetes or impaired glucose tolerance had significant improvement of glycemic control. Transsphenoidal surgery is the appropriate first-line therapy in patients with somatotropinoma. Medical and radio-therapy should be reserved as the second-line therapy after surgery failure.

Abstract: Objective Hypercoagulability is a commonly described complication in patients with Cushing’s syndrome. Recent clinical studies have indicated various abnormalities of coagulation and fibrinolysis parameters which may be related to that phenomenon. The aim of this study was to investigate the mechanisms underlying the hypercoagulable state in patients with Cushing’s syndrome. Research methods and procedures A wide range of serum markers involved in the processes of blood coagulation and fibrinolysis was measured in a group of 33 patients with Cushing’s syndrome and 31 healthy controls. No participant was taking medication which could influence the result or had known diseases, except hypertension and diabetes, which could affect blood coagulation or fibrinolysis parameters. Results Patients with Cushing’s syndrome had higher levels of clotting factors II (P = 0.003), V (P < 0.001), VIII (P < 0.001), IX (P < 0.001), XI (P < 0.001) and XII (P = 0.019), protein C (P < 0.001), protein S (P < 0.001), C1-inhibitor (P < 0.001) and plasminogen activator inhibitor-1 (PAI-1) (P = 0.004). The activity of fibrinolytic markers, plasminogen (P < 0.001), antithrombin (P < 0.001) and antithrombin antigen (P = 0.001) was also increased in the patient group. Conclusion The study has demonstrated hypercoagulability in patients with Cushing’s syndrome manifest as increased prothrombotic activity and compensatory activation of the fibrinolytic system. We propose the introduction of thromboprophylaxis in the preoperative and early postoperative periods, combined with a close follow-up in order to prevent possible thromboembolic events in patients with Cushing’s syndrome.

The blending of styrene-acrylonitrile copolymer (SAN) and three different types of ethylene-propylene-diene terpolymer (EPDM) by reactive extrusion was studied and the free radical initiators: 2,5-dimethyl-2,5-di-(t-butylperoxy)hexane (Luperco 101 XL), 2,5-dimethyl-2,5-di-(t-butylperoxy)hexyne-3 (Luperco 130 XL), a,a'-di(t-butylperoxy)diisopropyl-benzene (Peroximon F40) and 2,2-azo-di-(2-acetoxy)propane (Luazo AP) were used. Besides, structural characteristics of the obtained blends, some rheological and mechanical properties were also established. The rheological behavior was determined using rheometer and corotating extruder. Measurements of mechanical properties included: tensile strength, impact strength and elongation at break have been made. Blends were separated on its structural components SAN, EPDM, graft (EPDM-g-SAN) and gel content, which were further characterized by solution viscosimetry and IR spectrophotometry. The obtained results elucidate the reactions that occur during extrusion process. The dominant grafting reaction was observed in blends prepared by using a Peroximon F40 as an initiator also showing outstanding mechanical and processing characteristics.

For the selection of the polymer materials and polymer blends for various fields of applications, dynamic-mechanical properties, the primary viscoelastic functions as well as the stability of materials on different loads are very important. Since polymer materials are viscoelastic, their mechanical properties are dependent on temperature and time. The dynamic-mechanical properties of high-impact polystyrene, (PS-HI) and blends of PS-HI and styrene-butadiene-styrene block copolymer, (SBS) were investigated. Under the conditions of dynamic-mechanical load, the investigated systems will have different behavior due to the various content of the hard phase, polystyrene and soft phase, polybutadiene. The investigations were done by DMA analysis. The primary viscoelastic functions were determined. The influence of the constant stress on the strain and moduls at various temperatures was examined. The effects of the time on moduls changes was obtained by generating the master curves. The viscoelastic functions and the stability on the constant load, the changes of the moduls with time and temperature depend on the amount of polystyrene in the examined copolymers and blends. This investigation presents the possibility of predicting a useful lifetime of materials.

The stability of polyolefins and their blends is very important for their practical use under high temperatures. The effect of styrene-butadiene-styrene block copolymers on the intensity of the thermo-oxidative degradation of HIPS can be followed through kinetic parameters. In styrene-butadiene copolymers soft, polybutadiene phase (PB), and hard, polystyrene phase (PS) have a different sensibility on thermal degradation. The thermooxidative stability of high impact polystyrene (PS-HI) and blends of PS-HI and styrene-butadiene-styrene copolymer, (SBS) were investigated. The investigation were done by isothermal DSC analysis. The kinetic parameters of the thermooxidative degradative process: the reaction rate constants, the reaction orders, and the activation energies have been determined. The total area under the exothermic curve was used to calculate the isothermal heat of degradation. On the basis of the heat of the thermooxidative degradation the conversion (α) and the rate of the thermooxidative degradation (dα/dt) have been obtained. The experimental data have been tested with kinetic model for auto-catalytic reactions: dα/dt (kαm (1-(α)n. The activation energy has been determined by Arrhenius equation. On the basis of the calculated kinetic parameters the order of thermooxidative stability of the investigated system has been obtained. The experimental data have a good agreement with the autocatalytic model.

A Correction to this paper has been published: https://doi.org/10.1038/s41556-021-00683-0.

•Largest study of rituximab in MOG-IgG-associated disorder, includes both adults and children.•Rituximab reduced relapse rates in MOG-IgG-associated disorder by 37%.•Compared to similar studies in AQP4-IgG-associated NMOSD, the efficacy seems lower.•Some patients relapsed despite apparent circulating B-cell depletion.

Mechanical data obtained on the blends described in a previous paper together with some new data have been correlated with the theory derived for the mechanical properties of polymer composites, to gain insight into the nature of domain interfaces. Thermoplastic polyurethanes are blended in the entire composition range, with styrene-acrylonitrile copolymers. Blending with thermoplastic polyurethanes improves the toughness. Improved toughness is indicated by the increase of elongation at break and by decrease of hardness.

Human monoclonal antibodies broadly neutralize multiple PML-causing JC polyomavirus variants.