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HLA-E expression plays a central role for modulation of NK cell function by interaction with inhibitory NKG2A and stimulatory NKG2C receptors on canonical and adaptive NK cells, respectively. Here, we demonstrate that infection of human primary lung tissue with SARS-CoV-2 leads to increased HLA-E expression and show that processing of the peptide YLQPRTFLL from the spike protein is primarily responsible for the strong, dose-dependent increase of HLA-E. Targeting the peptide site within the spike protein revealed that a single point mutation was sufficient to abrogate the increase in HLA-E expression. Spike-mediated induction of HLA-E differentially affected NK cell function: whereas degranulation, IFN-γ production, and target cell cytotoxicity were enhanced in NKG2C+ adaptive NK cells, effector functions were inhibited in NKG2A+ canonical NK cells. Analysis of a cohort of COVID-19 patients in the acute phase of infection revealed that adaptive NK cells were induced irrespective of the HCMV status, challenging the paradigm that adaptive NK cells are only generated during HCMV infection. During the first week of hospitalization, patients exhibited a selective increase of early NKG2C+CD57− adaptive NK cells whereas mature NKG2C+CD57+ cells remained unchanged. Further analysis of recovered patients suggested that the adaptive NK cell response is primarily driven by a wave of early adaptive NK cells during acute infection that wanes once the infection is cleared. Together, this study suggests that NK cell responses to SARS-CoV-2 infection are majorly influenced by the balance between canonical and adaptive NK cells via the HLA-E/NKG2A/C axis.

Non-communicable diseases (NCDs) represent a high burden for the society and affected individuals. Conservative non-pharmacological interventions play a first-line role in the treatment and management of most NCDs. Systematic reviews (SRs) provide the highest level of evidence and significantly influence clinical decision-making. The primary aim of this study is to provide an overview of the evidence on the effectiveness of recommended conservative non-pharmacological interventions for highly burdensome NCDs. The secondary aim is to provide an overview of the evidence for guideline implementation. A literature search was performed in Medline (PubMed), EMBASE and Cochrane CENTRAL. Six reviewers will, in duplicate, independently screen and select studies following eligibility criteria. The population will include individuals with NCDs from disease categories chosen based on WHO burden of disease data and the importance of conservative rehabilitation for their management. Eligible interventions will encompass conservative non-pharmacological approaches recommended by clinical practice guidelines (ie, physical, psychological and education/advice). Eligible comparator will include no or minimal intervention and other competitive interventions. Outcomes will comprise proposed core outcomes for the respective diseases, including patient-reported (eg, pain) and performance-based (eg, physical functioning) outcomes. SRs published in the last 5 years as peer-reviewed journal article in the English language will be eligible. The overview will be reported in accordance with the Preferred Reporting Items for Overviews of reviews.

IntroductionNovel preventive strategies in periodontal disease target the bacterial-induced inflammatory host response to reduce associated tissue destruction. Strategies focus on the modulation of tissue-destroying inflammatory host response, particularly the reduction of inflammation and promotion of resolution. Thereby, nutrition is a potent immunometabolic non-pharmacological intervention. Human studies have demonstrated the benefit of olive oil-containing Mediterranean-style diets (MDs), the main component of which being mono-unsaturated fatty acid (FA) oleic acid (OA (C18:1)). Hence, nutritional OA strengthened the microarchitecture of alveolar trabecular bone and increased circulating pro-resolving lipid mediators following bacterial inoculation with periodontal pathogen Porphyromonas gingivalis, contrary to saturated FA palmitic acid (PA (C16:0)), which is abundant in Western-style diets. Additionally, the generalized distribution of inflammatory pathway mediators can occur in response to bacterial infection and compromise systemic tissue metabolism and bone homeostasis distant from the side of infection. Whether specific FA-enriched nutrition and periodontal inoculation are factors in systemic pathology that can be immune-modulatory targeted through dietary substitution is unknown and of clinical relevance.MethodsNormal-weight C57BL/6-mice received OA-or PA-enriched diets (PA-ED, OA-ED, PA/OA-ED) or a normal-standard diet (n=12/group) for 16 weeks and were orally infected with P. gingivalis/placebo to induce periodontal disease. Using histomorphometry and LC-MS/MS, systemic bone morphology, incorporated immunometabolic FA-species, serological markers of bone metabolism, and stress response were determined in addition to bone cell inflammation and interaction in vitro.ResultsIn contrast to OA-ED, PA-ED reduced systemic bone microarchitecture paralleled by increased lipotoxic PA-containing metabolite accumulation in bone. Substitution with OA reversed the bone-destructive impact of PA, which was accompanied by reduced diacylglycerols (DAG) and saturated ceramide levels. Further, PA-associated reduction in mineralization activity and concomitant pro-inflammatory activation of primary osteoblasts were diminished in cultures where PA was replaced with OA, which impacted cellular interaction with osteoclasts. Additionally, PA-ED increased osteoclast numbers in femurs in response to oral P. gingivalis infection, whereas OA-ED reduced osteoclast occurrence, which was paralleled by serologically increased levels of the stress-reducing lipokine PI(18:1/18:1).ConclusionOA substitution reverses the bone-destructive and pro-inflammatory effects of PA and eliminates incorporated lipotoxic PA metabolites. This supports Mediterranean-style OA-based diets as a preventive intervention to target the accumulation of PA-associated lipotoxic metabolites and thereby supports systemic bone tissue resilience after oral bacterial P. gingivalis infection.

This paper considers minimizers of the Ginzburg--Landau energy functional in specific multiscale spaces that are based on finite elements. The spaces are constructed by localized orthogonal decomposition techniques and their usage for solving the Ginzburg--Landau equation was first suggested in [B. D\"orich and P. Henning, SIAM J. Numer. Anal., 62 (2024), pp. 1313--1343]. In this work we further explore their approximation properties and give an analytical explanation for why vortex structures of energy minimizers can be captured more accurately in these spaces. We quantify the necessary mesh resolution in terms of the Ginzburg--Landau parameter\kappa and a stabilization parameter geq 0 that is used in the construction of the multiscale spaces. Furthermore, we analyze how\kappa affects the necessary locality of the multiscale basis functions and we prove that the choice = 0 yields typically the highest accuracy. Our findings are supported by numerical experiments. [ABSTRACT FROM AUTHOR]

Orthodontic tooth movement (OTM) is thought to be impeded by bisphosphonate (BP) therapy, mainly due to increased osteoclast apoptosis and changes in the periodontal ligament (PdL), a connecting tissue between the alveolar bone and teeth. PdL cells, mainly fibroblasts (PdLFs), are crucial regulators in OTM by modulating force-induced local inflammatory processes. Recently, we identified the TGF-β/BMP superfamily member GDF15 as an important modulator in OTM, promoting the pro-inflammatory mechanoresponses of PdLFs. The precise impact of the highly potent BP zoledronate (ZOL) on the mechanofunctionality of PdLFs is still under-investigated. Therefore, the aim of this study was to further characterize the ZOL-induced changes in the initial inflammatory mechanoresponse of human PdLFs (hPdLFs) and to further clarify a potential interrelationship with GDF15 signaling. Thus, two-day in vitro treatment with 0.5 µM, 5 µM and 50 µM of ZOL altered the cellular properties of hPdLFs partially in a concentration-dependent manner. In particular, exposure to ZOL decreased their metabolic activity, the proliferation rate, detected using Ki-67 immunofluorescent staining, and survival, analyzed using trypan blue. An increasing occurrence of DNA strand breaks was observed using TUNEL and an activated DNA damage response was demonstrated using H2A.X (phosphoS139) staining. While the osteogenic differentiation of hPdLFs was unaffected by ZOL, increased cellular senescence was observed using enhanced p21Waf1/Cip1/Sdi1 and β-galactosidase staining. In addition, cytokine-encoding genes such as IL6, IL8, COX2 and GDF15, which are associated with a senescence-associated secretory phenotype, were up-regulated by ZOL. Subsequently, this change in the hPdLF phenotype promoted a hyperinflammatory response to applied compressive forces with an increased expression of the pro-inflammatory markers IL1β, IL6 and GDF15, as well as the activation of monocytic THP1 cells. GDF15 appeared to be particularly relevant to these changes, as siRNA-mediated down-regulation balanced these hyperinflammatory responses by reducing IL-1β and IL-6 expression (IL1B p-value < 0.0001; IL6 p-value < 0.001) and secretion (IL-1β p-value < 0.05; IL-6 p-value < 0.001), as well as immune cell activation (p-value < 0.0001). In addition, ZOL-related reduced RANKL/OPG values and inhibited osteoclast activation were enhanced in GDF15-deficient hPdLFs (both p-values < 0.0001; all statistical tests: one-way ANOVA, Tukey’s post hoc test). Thus, GDF15 may become a promising new target in the personalized orthodontic treatment of bisphosphonatepatients.

Fatty acid unsaturation by stearoyl-CoA desaturase 1 (SCD1) protects against cellular stress through unclear mechanisms. Here the authors show 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) is an SCD1-derived signaling lipid that regulates stress-adaption, protects against cell death and promotes proliferation.

In patients presenting with low back pain (LBP), once specific causes are excluded (fracture, infection, inflammatory arthritis, cancer, cauda equina and radiculopathy) many clinicians pose a diagnosis of non-specific LBP. Accordingly, current management of non-specific LBP is generic. There is a need for a classification of non-specific LBP that is both data- and evidence-based assessing multi-dimensional pain-related factors in a large sample size. The “PRedictive Evidence Driven Intelligent Classification Tool for Low Back Pain” (PREDICT-LBP) project is a prospective cross-sectional study which will compare 300 women and men with non-specific LBP (aged 18–55 years) with 100 matched referents without a history of LBP. Participants will be recruited from the general public and local medical facilities. Data will be collected on spinal tissue (intervertebral disc composition and morphology, vertebral fat fraction and paraspinal muscle size and composition via magnetic resonance imaging [MRI]), central nervous system adaptation (pain thresholds, temporal summation of pain, brain resting state functional connectivity, structural connectivity and regional volumes via MRI), psychosocial factors (e.g. depression, anxiety) and other musculoskeletal pain symptoms. Dimensionality reduction, cluster validation and fuzzy c-means clustering methods, classification models, and relevant sensitivity analyses, will classify non-specific LBP patients into sub-groups. This project represents a first personalised diagnostic approach to non-specific LBP, with potential for widespread uptake in clinical practice. This project will provide evidence to support clinical trials assessing specific treatments approaches for potential subgroups of patients with non-specific LBP. The classification tool may lead to better patient outcomes and reduction in economic costs.

In this work, we consider the numerical computation of ground states and dynamics of single-component Bose–Einstein condensates (BECs). The corresponding models are spatially discretized with a multiscale finite element approach known as Localized Orthogonal Decomposition (LOD). Despite the outstanding approximation properties of such a discretization in the context of BECs, taking full advantage of it without creating severe computational bottlenecks can be tricky. In this paper, we therefore present two fully-discrete numerical approaches that are formulated in such a way that they take special account of the structure of the LOD spaces. One approach is devoted to the computation of ground states and another one for the computation of dynamics. A central focus of this paper is also the discussion of implementation aspects that are very important for the practical realization of the methods. In particular, we discuss the use of suitable data structures that keep the memory costs economical. The paper concludes with various numerical experiments in 1d, 2d and 3d that investigate convergence rates and approximation properties of the methods and which demonstrate their performance and computational efficiency, also in comparison to spectral and standard finite element approaches. [ABSTRACT FROM AUTHOR]

Measure of drug-mediated immune reactions that are dependent on the patient’s genotype determine individual medication protocols. Despite extensive clinical trials prior to the license of a specific drug, certain patient-specific immune reactions cannot be reliably predicted. The need for acknowledgement of the actual proteomic state for selected individuals under drug administration becomes obvious. The well-established association between certain HLA molecules and drugs or their metabolites has been analyzed in recent years, yet the polymorphic nature of HLA makes a broad prediction unfeasible. Dependent on the patient’s genotype, carbamazepine (CBZ) hypersensitivities can cause diverse disease symptoms as maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms or the more severe diseases Stevens-Johnson-Syndrome or toxic epidermal necrolysis. Not only the association between HLA-B*15:02 or HLA-A*31:01 but also between HLA-B*57:01 and CBZ administration could be demonstrated. This study aimed to illuminate the mechanism of HLA-B*57:01-mediated CBZ hypersensitivity by full proteome analysis. The main CBZ metabolite EPX introduced drastic proteomic alterations as the induction of inflammatory processes through the upstream kinase ERBB2 and the upregulation of NFκB and JAK/STAT pathway implying a pro-apoptotic, pro-necrotic shift in the cellular response. Anti-inflammatory pathways and associated effector proteins were downregulated. This disequilibrium of pro- and anti-inflammatory processes clearly explain fatal immune reactions following CBZ administration.

In this paper, we consider an energy-conserving continuous Galerkin discretization of the Gross–Pitaevskii equation with a magnetic trapping potential and a stirring potential for angular momentum rotation. The discretization is based on finite elements in space and time and allows for arbitrary polynomial orders. It was first analyzed by O. Karakashian and C. Makridakis (SIAM J. Numer. Anal. , 36(6) ,1779–1807, 1999) in the absence of potential terms and corresponding a priori error estimates were derived in |$2D$|⁠. In this work we revisit the approach in the generalized setting of the Gross–Pitaevskii equation with rotation and we prove uniform |$L^{\infty }$| -bounds for the corresponding numerical approximations in |$2D$| and |$3D$| without coupling conditions between the spatial mesh size and the time step size. With this result at hand, we are particularly able to extend the previous error estimates to the |$3D$| setting while avoiding artificial CFL conditions. [ABSTRACT FROM AUTHOR]

Tumor immune escape is associated with both, the expression of immune checkpoint molecules on peripheral immune cells and soluble forms of the human leukocyte antigen-G (HLA-G) in the blood, which are consequently discussed as clinical biomarker for disease status and outcome of cancer patients. HLA-G preferentially interacts with the inhibitory receptor immunoglobulin-like transcript (ILT) receptor-2 in the blood and can be secreted as free soluble molecules (sHLA-G) or via extracellular vesicles (EV). To investigate the contribution of these two forms to the expression of checkpoint molecules in peripheral blood, we primed peripheral blood mononuclear cells with purified soluble sHLA-G1 protein, or EV preparations derived from SUM149 cells transfected with membrane-bound HLA-G1 or control vector prior to anti-CD3/CD28 T cell activation. Our study demonstrated that priming of PBMC with sHLA-G1 protein prior to 48 h activation resulted in enhanced frequencies of ILT-2 expressing CD8+ T cells, and in an upregulation of immune checkpoint molecules CTLA-4, PD-1, TIM-3, and CD95 exclusively on ILT-2 positive CD8+ T cells. In contrast, when PBMC were primed with EV (containing HLA-G1 or not) upregulation of CTLA-4, PD-1, TIM-3, and CD95 occurred exclusively on ILT-2 negative CD8+ T cells. Taken together, our data suggest that priming with sHLA-G forms induces a pronounced immunosuppressive/exhausted phenotype and that priming with sHLA-G1 protein or EV derived from HLA-G1 positive or negative SUM149 cells affects CD8+ T cells complementary by targeting either the ILT-2 positive or negative subpopulation, respectively, after T cell activation.

Type B adverse drug reactions (ADRs) represent a significant threat as their occurrence arises unpredictable and despite proper application of the drug. The severe immune reaction Abacavir Hypersensitivity Syndrome (AHS) that arises in HIV+ patients treated with the antiretroviral drug Abacavir (ABC) strongly correlates to the presence of the human leukocyte antigen (HLA) genotype HLA-B*57:01 and discriminates HLA-B*57:01+ HIV+ patients from ABC treatment. However, not all HLA-B*57:01+ HIV+ patients are affected by AHS, implying the involvement of further patient-specific factors in the development of AHS. The establishment of a reliable assay to classify HLA-B*57:01 carriers as ABC sensitive or ABC tolerant allowed to investigate the T cell receptor (TCR) Vβ chain repertoire of effector cells and revealed Vβ6 and Vβ24 as potential public TCRs in ABC sensitive HLA-B*57:01 carriers. Furthermore, distinct effects of ABC on the cellular proteome of ABC sensitive and tolerant volunteers were observed and suggest enhanced activation and maturation of dentritic cells (DC) in ABC sensitive volunteers. Analysis of ABC-naïve cellular proteomes identified the T cell immune regulator 1 (TCIRG1) as a potential prognostic biomarker for ABC susceptibility and the involvement of significantly upregulated proteins, particularly in peptide processing, antigen presentation, interferon (IFN), and cytokine regulation.

The interrelationships between periodontal disease, obesity-related hyperlipidemia and mechanical forces and their modulating effects on the epigenetic profile of periodontal ligament (PdL) cells are assumed to be remarkably complex. The PdL serves as a connective tissue between teeth and alveolar bone and is involved in pathogen defense and the inflammatory responses to mechanical stimuli occurring during tooth movement. Altered inflammatory signaling could promote root resorption and tooth loss. Hyperinflammatory COX2/PGE2 signaling was reported for human PdL fibroblasts (HPdLFs) concomitantly stressed with Porphyromonas gingivalis lipopolysaccharides and compressive force after exposure to palmitic acid (PA). The aim of this study was to investigate the extent to which this was modulated by global and gene-specific changes in histone modifications. The expression of key epigenetic players and global H3Kac and H3K27me3 levels were quantitatively evaluated in dual-stressed HPdLFs exposed to PA, revealing a minor force-related reduction in repressive H3K27me3. UNC1999-induced H3K27me3 inhibition reversed the hyperinflammatory responses of dual-stressed PA cultures characterized by increased COX2 expression, PGE2 secretion and THP1 adhesion. The reduced expression of the gene encoding the anti-inflammatory cytokine IL-10 and the increased presence of H3K27me3 at its promoter-associated sites were reversed by inhibitor treatment. Thus, the data highlight an important epigenetic interplay between the different stimuli to which the PdL is exposed.

Background:Musculoskeletal (MSK) pain is the leading cause of disability worldwide. Telemedicine is of growing importance, yet impacts on treatment efficacy remain unclear. Objective:This umbrella review (CRD42022298047) examined the effectiveness of telemedicine interventions on pain intensity, disability, psychological function, quality of life, self-efficacy, and adverse events in MSK pain. Methods:PubMed, SPORTDiscus, Cochrane Library, EMBASE, and CINAHL were searched from inception to August 9, 2022, for systematic reviews with meta-analysis, including telemedicine-delivered exercise, education, and psychological interventions, in randomized controlled trials (RCTs). AMSTAR-2 was implemented. Standardized mean differences (SMDs; negative favors telemedicine) were extracted as effect estimates. Results:Of 1,135 records, 20 reviews (RCTs: n = 97, participants: n = 15,872) were included. Pain intensity SMDs were −0.66 to 0.10 for mixed pain (estimates: n = 16), −0.64 to −0.01 for low-back pain (n = 9), −0.31 to −0.15 for osteoarthritis (n = 7), −0.29 for knee pain (n = 1), −0.66 to −0.58 for fibromyalgia (n = 2), −0.16 for back pain (n = 1), and −0.09 for rheumatic disorders (n = 1). Disability SMDs were −0.50 to 0.10 for mixed pain (n = 14), −0.39 to 0.00 for low-back pain (n = 8), −0.41 to −0.04 for osteoarthritis (n = 7), −0.22 for knee pain (n = 1), and −0.56 for fibromyalgia (n = 1). Methodological quality was "critically low" for 17 reviews. Effectiveness tended to favor telemedicine for all secondary outcomes. Conclusions:Primary RCTs are required that compare telemedicine interventions with in-person delivery of the intervention (noninferiority trials), consider safety, assess videoconferencing, and combine different treatment approaches. [ABSTRACT FROM AUTHOR]