The SpoVA membrane complex is required for dipicolinic acid import during sporulation and export during germination.

In response to starvation, endospore-forming bacteria differentiate into stress-resistant spores that can remain dormant for years yet rapidly germinate and resume growth in response to nutrients. The small molecule dipicolinic acid (DPA) plays a central role in both the stress resistance of the dormant spore and its exit from dormancy during germination. The spoVA locus is required for DPA import during sporulation and has been implicated in its export during germination, but the molecular bases are unclear. Here, we define the minimal set of proteins encoded in the Bacillus subtilis spoVA operon required for DPA import and demonstrate that these proteins form a membrane complex. Structural modeling of these components combined with mutagenesis and in vivo analysis reveal that the C and Eb subunits form a membrane channel, while the D subunit functions as a cytoplasmic plug. We show that point mutations that impair the interactions between D and the C-Eb membrane complex reduce the efficiency of DPA import during sporulation and reciprocally accelerate DPA release during germination. Our data support a model in which DPA transport into spores involves cycles of unplugging and then replugging the C-Eb membrane channel, while nutrient detection during germination triggers DPA release by unplugging it.

Dual regulations of cell cycle regulator DPa by auxin in Arabidopsis root distal stem cell maintenance.

The plant hormone auxin plays a key role to maintain root stem cell identity which is essential for root development. However, the molecular mechanism by which auxin regulates root distal stem cell (DSC) identity is not well understood. In this study, we revealed that the cell cycle factor DPa is a vital regulator in the maintenance of root DSC identity through multiple auxin signaling cascades. On the one hand, auxin positively regulates the transcription of DPa via AUXIN RESPONSE FACTOR 7 and ARF19. On the other hand, auxin enhances the protein stability of DPa through MITOGEN-ACTIVATED PROTEIN KINASE 3 (MPK3)/MPK6-mediated phosphorylation. Consistently, mutation of the identified three threonine residues (Thr10, Thr25, and Thr227) of DPa to nonphosphorylated form alanine (DPa3A) highly decreased the phosphorylation level of DPa, which decreased its protein stability and affected the maintenance of root DSC identity. Taken together, this study provides insight into the molecular mechanism of how auxin regulates root distal stem cell identity through the dual regulations of DPa at both transcriptional and posttranslational levels.

PET imaging of TSPO expression in immune cells can assess organ-level pathophysiology in high-consequence viral infections.

Ebola virus (EBOV) disease is characterized by lymphopenia, breach in vascular integrity, cytokine storm, and multiorgan failure. The pathophysiology of organ involvement, however, is incompletely understood. Using [18F]-DPA-714 positron emission tomography (PET) imaging targeting the translocator protein (TSPO), an immune cell marker, we sought to characterize the progression of EBOV-associated organ-level pathophysiology in the EBOV Rhesus macaque model. Dynamic [18F]-DPA-714 PET/computed tomography imaging was performed longitudinally at baseline and at multiple time points after EBOV inoculation, and distribution volumes (Vt) were calculated as a measure of peripheral TSPO binding. Using a mixed-effect linear regression model, spleen and lung Vt decreased, while the bone marrow Vt increased over time after infection. No clear trend was found for liver Vt. Multiple plasma cytokines correlated negatively with lung/spleen Vt and positively with bone marrow Vt. Multiplex immunofluorescence staining in spleen and lung sections confirmed organ-level lymphoid and monocytic loss/apoptosis, thus validating the imaging results. Our findings are consistent with EBOV-induced progressive monocytic and lymphocytic depletion in the spleen, rather than immune activation, as well as depletion of alveolar macrophages in the lungs, with inefficient reactive neutrophilic activation. Increased bone marrow Vt, on the other hand, suggests hematopoietic activation in response to systemic immune cell depletion and leukocytosis and could have prognostic relevance. In vivo PET imaging provided better understanding of organ-level pathophysiology during EBOV infection. A similar approach can be used to delineate the pathophysiology of other systemic infections and to evaluate the effectiveness of newly developed treatment and vaccine strategies.

Bioinformatics analysis identifies a key gene HLA_DPA1 in severe influenza-associated immune infiltration.

BACKGROUND: Severe influenza is a serious global health issue that leads to prolonged hospitalization and mortality on a significant scale. The pathogenesis of this infectious disease is poorly understood. Therefore, this study aimed to identify the key genes associated with severe influenza patients necessitating invasive mechanical ventilation. METHODS: The current study utilized two publicly accessible gene expression profiles (GSE111368 and GSE21802) from the Gene Expression Omnibus database. The research focused on identifying the genes exhibiting differential expression between severe and non-severe influenza patients. We employed three machine learning algorithms, namely the Least Absolute Shrinkage and Selection Operator regression model, Random Forest, and Support Vector Machine-Recursive Feature Elimination, to detect potential key genes. The key gene was further selected based on the diagnostic performance of the target genes substantiated in the dataset GSE101702. A single-sample gene set enrichment analysis algorithm was applied to evaluate the participation of immune cell infiltration and their associations with key genes. RESULTS: A total of 44 differentially expressed genes were recognized; among them, we focused on 10 common genes, namely PCOLCE2, HLA_DPA1, LOC653061, TDRD9, MPO, HLA_DQA1, MAOA, S100P, RAP1GAP, and CA1. To ensure the robustness of our findings, we employed overlapping LASSO regression, Random Forest, and SVM-RFE algorithms. By utilizing these algorithms, we were able to pinpoint the aforementioned 10 genes as potential biomarkers for distinguishing between both cases of influenza (severe and non-severe). However, the gene HLA_DPA1 has been recognized as a crucial factor in the pathological condition of severe influenza. Notably, the validation dataset revealed that this gene exhibited the highest area under the receiver operating characteristic curve, with a value of 0.891. The use of single-sample gene set enrichment analysis has provided valuable insights into the immune responses of patients afflicted with severe influenza that have further revealed a categorical correlation between the expression of HLA_DPA1 and lymphocytes. CONCLUSION: The findings indicated that the HLA_DPA1 gene may play a crucial role in the immune-pathological condition of severe influenza and could serve as a promising therapeutic target for patients infected with severe influenza.

Integrating TSPO PET imaging and transcriptomics to unveil the role of neuroinflammation and amyloid-ß deposition in Alzheimer's disease.

PURPOSE: Despite the revealed role of immunological dysfunctions in the development and progression of Alzheimer's disease (AD) through animal and postmortem investigations, direct evidence regarding the impact of genetic factors on microglia response and amyloid-ß (Aß) deposition in AD individuals is lacking. This study aims to elucidate this mechanism by integrating transcriptomics and TSPO, Aß PET imaging in clinical AD cohort. METHODS: We analyzed 85 patients with PET/MR imaging for microglial activation (TSPO, [18F]DPA-714) and Aß ([18F]AV-45) within the prospective Alzheimer's Disease Immunization and Microbiota Initiative Study Cohort (ADIMIC). Immune-related differentially expressed genes (IREDGs), identified based on AlzData, were screened and verified using blood samples from ADIMIC. Correlation and mediation analyses were applied to investigate the relationships between immune-related genes expression, TSPO and Aß PET imaging. RESULTS: TSPO uptake increased significantly both in aMCI (P < 0.05) and AD participants (P < 0.01) and showed a positive correlation with Aß deposition (r = 0.42, P < 0.001). Decreased expression of TGFBR3, FABP3, CXCR4 and CD200 was observed in AD group. CD200 expression was significantly negatively associated with TSPO PET uptake (r =-0.33, P = 0.013). Mediation analysis indicated that CD200 acted as a significant mediator between TSPO uptake and Aß deposition (total effect B = 1.92, P = 0.004) and MMSE score (total effect B =-54.01, P = 0.003). CONCLUSION: By integrating transcriptomics and TSPO PET imaging in the same clinical AD cohort, this study revealed CD200 played an important role in regulating neuroinflammation, Aß deposition and cognitive dysfunction.

PET imaging for the early evaluation of ocular inflammation in diabetic rats by using [18F]-DPA-714.

Ocular complications of diabetes mellitus (DM) are the leading cause of vision loss. Ocular inflammation often occurs in the early stage of DM; however, there are no proven quantitative methods to evaluate the inflammatory status of eyes in DM. The 18 kDa translocator protein (TSPO) is an evolutionarily conserved cholesterol binding protein localized in the outer mitochondrial membrane. It is a biomarker of activated microglia/macrophages; however, its role in ocular inflammation is unclear. In this study, fluorine-18-DPA-714 ([18F]-DPA-714) was evaluated as a specific TSPO probe by cell uptake, cell binding assays and micro positron emission tomography (microPET) imaging in both in vitro and in vivo models. Primary microglia/macrophages (PMs) extracted from the cornea, retina, choroid or sclera of neonatal rats with or without high glucose (50 mM) treatment were used as the in vitro model. Sprague-Dawley (SD) rats that received an intraperitoneal administration of streptozotocin (STZ, 60 mg/kg once) were used as the in vivo model. Increased cell uptake and high binding affinity of [18F]-DPA-714 were observed in primary PMs under hyperglycemic stress. These findings were consistent with cellular morphological changes, cell activation, and TSPO up-regulation. [18F]-DPA-714 PET imaging and biodistribution in the eyes of DM rats revealed that inflammation initiates in microglia/macrophages in the early stages (3 weeks and 6 weeks), corresponding with up-regulated TSPO levels. Thus, [18F]-DPA-714 microPET imaging may be an effective approach for the early evaluation of ocular inflammation in DM.

Biology and Total Synthesis of n-3 Docosapentaenoic Acid-Derived Specialized Pro-Resolving Mediators.

Research over the last 25 years related to structural elucidations and biological investigations of the specialized pro-resolving mediators has spurred great interest in targeting these endogenous products in total synthesis. These lipid mediators govern the resolution of inflammation as potent and stereoselective agonists toward individual G-protein-coupled receptors, resulting in potent anti-inflammatory activities demonstrated in many human disease models. Specialized pro-resolving mediators are oxygenated polyunsaturated products formed in stereoselective and distinct biosynthetic pathways initiated by various lipoxygenase and cyclooxygenase enzymes. In this review, the reported stereoselective total synthesis and biological activities of the specialized pro-resolving mediators biosynthesized from the polyunsaturated fatty acid n-3 docosapentaenoic acid are presented.

Neurological worsening in Wilson disease - clinical classification and outcome.

BACKGROUND & AIMS: Prevention of neurological worsening (NW) under therapy is an unmet need in the management of Wilson disease (WD). In this study, we aimed to characterize the occurrence, associated outcomes and potential reversibility of NW in WD. METHODS: From a total cohort of 457 patients with WD, 128 patients with WD and neurological features at any time point (all Caucasian, 63 females, median age at diagnosis 22 years) were identified by chart review at University Hospital Heidelberg and grouped according to initial presentation. The timing and occurrence of NW was assessed following a structured clinical examination during clinical visits. RESULTS: Early NW (within the first 3 months of therapy) was observed in 30 out of 115 (26.1%) patients with neurological or mixed presentation and never in patients with a purely hepatic or asymptomatic presentation (0%). Late NW (after >12 months) was seen in a further 23 (20%) with neurological or mixed presentation and in 13 out of 294 (4.4%) patients with a hepatic or asymptomatic presentation. The median time from start of treatment to late NW was 20 months. Only three patients experienced NW between 3 and 12 months. NW was observed with D-penicillamine, trientine and zinc therapy and was reversible in 15/30 (50%) with early NW and in 29/36 (81%) with late NW. CONCLUSIONS: In this study, we identified two peaks in NW: an early (≤3 months) treatment-associated peak and a late (>12 months of treatment) adherence-associated peak. Early paradoxical NW was attributed to treatment initiation and pre-existing neurological damage, and was not observed in those with a hepatic or asymptomatic presentation. Late NW is likely to be associated with non-adherence. IMPACT AND IMPLICATIONS: In patients with Wilson disease, defined as an excess accumulation of copper which can damage the liver, brain and other vital organs, neurological worsening can occur despite chelation therapy. The study identifies different patterns of 'early' (<3 months) vs. 'late' (>12 months) neurological worsening in relation to initiation of chelation therapy and establishes possible causes and the potential for reversibility. These data should be useful for counseling patients and for guiding the optimal management of chelation therapy.

Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge.

BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer's disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer's disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer's disease should aim to enhance protective microglial actions.

[18F]DPA-714: Effect of co-medications, age, sex, BMI and TSPO polymorphism on the human plasma input function.

PURPOSE: We aimed to assess the effect of concomitant medication, age, sex, body mass index and 18-kDa translocator protein (TSPO) binding affinity status on the metabolism and plasma pharmacokinetics of [18F]DPA-714 and their influence on the plasma input function in a large cohort of 201 subjects who underwent brain and whole-body PET imaging to investigate the role of neuroinflammation in neurological diseases. METHODS: The non-metabolized fraction of [18F]DPA-714 was estimated in venous plasma of 138 patients and 63 healthy controls (HCs; including additional arterial sampling in 16 subjects) during the 90 min brain PET acquisition using a direct solid-phase extraction method. The mean fraction between 70 and 90 min post-injection ([18F]DPA-71470-90) and corresponding normalized plasma concentration (SUV70-90) were correlated with all factors using a multiple linear regression model. Differences between groups (arterial vs venous measurements; HCs vs patients; high- (HAB), mixed- (MAB) and low-affinity binders (LAB); subjects with vs without co-medications, females vs males were also assessed using the non-parametric Mann-Whitney or Kruskal-Wallis ANOVA tests. Finally, the impact of co-medications on the brain uptake of [18F]DPA-714 at equilibrium was investigated. RESULTS: As no significant differences were observed between arterial and venous [18F]DPA-71470-90 and SUV70-90, venous plasma was used for correlations. [18F]DPA-71470-90 was not significantly different between patients and HCS (59.7 ± 12.3% vs 60.2 ± 12.9%) despite high interindividual variability. However, 47 subjects exhibiting a huge increase or decrease of [18F]DPA-71470-90 (up to 88% or down to 23%) and SUV70-90 values (2-threefold) were found to receive co-medications identified as inhibitors or inducers of CYP3A4, known to catalyse [18F]DPA-714 metabolism. Comparison between cortex-to-plasma ratios using individual input function (VTIND) or population-based input function derived from untreated HCs (VTPBIF) indicated that non-considering the individual metabolism rate led to a bias of about 30% in VT values. Multiple linear regression model analysis of subjects free of these co-medications suggested significant correlations between [18F]DPA-71470-90 and age, BMI and sex while TSPO polymorphism did not influence the metabolism of the radiotracer. [18F]DPA-714 metabolism fell with age and BMI and was significantly faster in females than in males. Whole-body PET/CT exhibited a high uptake of the tracer in TSPO-rich organs (heart wall, spleen, kidneys…) and those involved in metabolism and excretion pathways (liver, gallbladder) in HAB and MAB with a strong decrease in LAB (-89% and -85%) resulting in tracer accumulation in plasma (4.5 and 3.3-fold increase). CONCLUSION: Any co-medication that inhibits or induces CYP3A4 as well as TSPO genetic status, age, BMI and sex mostly contribute to interindividual variations of the radiotracer metabolism and/or concentration that may affect the input function of [18F]DPA-714 and consequently its human brain and peripheral uptake. TRIAL REGISTRATION: INFLAPARK, NCT02319382, registered December 18, 2014, retrospectively registered; IMABIO 3, NCT01775696, registered January 25, 2013, retrospectively registered; INFLASEP, NCT02305264, registered December 2, 2014, retrospectively registered; EPI-TEP, EudraCT 2017-003381-27, registered September 24, 2018.

Characterization of neuroinflammation pattern in anti-LGI1 encephalitis based on TSPO PET and symptom clustering analysis.

PURPOSE: TSPO PET with radioligand [18F]DPA-714 is an emerging molecular imaging technique that reflects cerebral inflammation and microglial activation, and it has been recently used in central nervous system diseases. In this study, we aimed to investigate the neuroinflammation pattern of anti-leucine-rich glioma-inactivated 1 (LGI1) protein autoimmune encephalitis (AIE) and to evaluate its possible correlation with clinical phenotypes. METHODS: Twenty patients with anti-LGI1 encephalitis from the autoimmune encephalitis cohort in Huashan Hospital and ten with other AIE and non-inflammatory diseases that underwent TSPO PET imaging were included in the current study. Increased regional [18F]DPA-714 retention in anti-LGI1 encephalitis was detected on a voxel basis using statistic parametric mapping analysis. Multiple correspondence analysis and hierarchical clustering were conducted for discriminate subgroups in anti-LGI1 encephalitis. Standardized uptake value ratios normalized to the cerebellum (SUVRc) were calculated for semiquantitative analysis of TSPO PET features between different LGI1-AIE subgroups. RESULTS: Increased regional retention of [18F]DPA-714 was identified in the bilateral hippocampus, caudate nucleus, and frontal cortex in LGI1-AIE patients. Two subgroups of LGI1-AIE patients were distinguished based on the top seven common symptoms. Patients in cluster 1 had a high frequency of facio-brachial dystonic seizures than those in cluster 2 (p = 0.004), whereas patients in cluster 2 had a higher frequency of general tonic-clonic (GTC) seizures than those in cluster 1 (p < 0.001). Supplementary motor area and superior frontal gyrus showed higher [18F]DPA-714 retention in cluster 2 patients compared with those in cluster 1 (p = 0.024; p = 0.04, respectively). CONCLUSIONS: Anti-LGI1 encephalitis had a distinctive molecular imaging pattern presented by TSPO PET scan. LGI1-AIE patients with higher retention of [18F]DPA-714 in the frontal cortex were more prone to present with GTC seizures. Further studies are required for verifying its value in clinical application.

Lipid mediator n-3 docosapentaenoic acid-derived protectin D1 enhances synaptic inhibition of hippocampal principal neurons by interaction with a G-protein-coupled receptor.

Epilepsy is a severe neurological disease manifested by spontaneous recurrent seizures due to abnormal hyper-synchronization of neuronal activity. Epilepsy affects about 1% of the population and up to 40% of patients experience seizures that are resistant to currently available drugs, thus highlighting an urgent need for novel treatments. In this regard, anti-inflammatory drugs emerged as potential therapeutic candidates. In particular, specific molecules apt to resolve the neuroinflammatory response occurring in acquired epilepsies have been proven to counteract seizures in experimental models, and humans. One candidate investigational molecule has been recently identified as the lipid mediator n-3 docosapentaenoic acid-derived protectin D1 (PD1n-3DPA ) which significantly reduced seizures, cell loss, and cognitive deficit in a mouse model of acquired epilepsy. However, the mechanisms that mediate the PD1n-3DPA effect remain elusive. We here addressed whether PD1n-3DPA has direct effects on neuronal activity independent of its anti-inflammatory action. We incubated, therefore, hippocampal slices with PD1n-3DPA and investigated its effect on excitatory and inhibitory synaptic inputs to the CA1 pyramidal neurons. We demonstrate that inhibitory drive onto the perisomatic region of the pyramidal neurons is increased by PD1n-3DPA , and this effect is mediated by pertussis toxin-sensitive G-protein coupled receptors. Our data indicate that PD1n-3DPA acts directly on inhibitory transmission, most likely at the presynaptic site of inhibitory synapses as also supported by Xenopus oocytes and immunohistochemical experiments. Thus, in addition to its anti-inflammatory effects, PD1n-3DPA anti-seizure and neuroprotective effects may be mediated by its direct action on neuronal excitability by modulating their synaptic inputs.

A Novel D-π-A Type Fluorescent Probe for Cu2+ Based on Styryl-Pyridinium Salts Conjugating Di-(2-picolyl)amine (DPA) Units.

A novel D-π-A type fluorescent probe L(NO3) for Cu (II) sensing was designed and fully characterized. The probe consists of a styryl-pyridine cation fluorescent group and a di-(2-picolyl)amine (DPA) receptor unit, which are linked by a phenyl group to form an electron donor-π-acceptor (D-π-A) conjugate system, especially the introduction of a nitrate counter anion for significantly enhanced water solubility of the probe. Fluorescence titration studies of the probe L(NO3) showed a higher selectivity for Cu2+ than other metal ions, and the emission spectrum was strongly quenched upon binding. The competitive binding assay and the low detection limit (0.932 µM) showed that the probe L(NO3) had strong anti-interference ability and excellent Cu2+ detection performance. The binding ratio of probe L(NO3) and Cu2+ was determined from Job's plot to be 1:1, which is consistent with the results obtained from X-ray crystal structures. Meanwhile, the probe showed instantaneous chemical reversibility when titrated with EDTA solution, indicating potential recycling properties of the probe. In addition, the design of inexpensive fluorescent test strips can perform the on-site and real-time detection Cu2+ with a color recognition application.

Ce3+-induced Fluorescence Amplification of Copper Nanoclusters Based on Aggregation-induced Emission for Specific Sensing 2,6-pyridine Dicarboxylic Acid.

A straightforward, cost-effective and biocompatible reduction approach was applied to fabricate soluble but non-luminous glutathione-stabilized copper nanocluster (GSH-CuNCs). Surprisingly, as high as 1 × 103 times fluorescence enhancement was acquired when Ce3+ was injected at an extremely low concentration of only 18 µM. Ce3+ outperformed other rare-earth metal ions in terms of inducing fluorescence amplification of the non-luminous GSH-CuNCs. Furthermore, Ce3+ was employed as inducer for aggregation-induce emission (AIE) effect as well as reactant to coordinate with target of 2,6-pyridine dicarboxylic acid (DPA) due to the stronger coordination ability between Ce3+ and DPA than that of Ce3+ and GSH. As a result, the Ce3+/GSH-CuNCs ensemble was developed as a novel sensor to detect DPA in the "on-off" mode. When DPA was introduced into the sensor, Ce3+ failed to interact with GSH and detached from the surface of GSH-CuNCs, leading to fluorescence quenching. In addition, static quenching process and internal filtration effect (IFE) between Ce3+/GSH-CuNCs and DPA were also responsible for fluorescence quenching effect. A good linear relationship was obtained from 0.3 µM to 18 µM, with a limit of detection (LOD) of 0.19 µM. The as-proposed probe displayed high specificity to DPA and provided a simple, fast rapid and cheap method for construction this type of ensemble sensors to detect other targets.

Identification of the novel HLA-DPA1*01:03:43 allele resulting from an intralocus recombination involving the DPA1*04:01:01:03 and DPA1*01:03:01:27 alleles sequenced by Next Generation Sequencing (NGS).

HLA-DPA1 intralocus recombination between DPA1*04:01:01:03 and DPA1*01:03:01:27, or closely related other alleles, results in a novel allele HLA-DPA1*01:03:43.

Partnering for change (P4C) in Sweden- a study protocol of a collaborative school-based service delivery model to create inclusive learning environments.

BACKGROUND: Inclusive learning environments are considered as crucial for children's engagement with learning and participation in school. Partnering for change (P4C) is a collaborative school-based service delivery model where services are provided at three levels of intensity based on children's needs (class, group-, individual interventions). Interventions in P4C are provided universally to support all children with learning, not only children with special education needs (SEN), and as such are expected to be health-promoting. AIM: The aim of the study is to evaluate the effectiveness and cost-effectiveness of P4C as well as school staff members' and children's experiences after P4C. METHODS: In a parallel, non-randomised controlled intervention design, 400 children, aged 6-12 years, and their teachers, will be recruited to either intervention classes, working according to the P4C, or to control classes (allocation ratio 1:1). Data will be collected at baseline, post-intervention (4 months), and 11 months follow-up post baseline. The primary outcome is children's engagement with learning in school. Secondary outcomes include for example children's health-related quality of life and wellbeing, occupational performance in school, attendance, and special educational needs. The difference-in-differences method using regression modelling will be applied to evaluate any potential changes following P4C. Focus group interviews focusing on children, and professionals' experiences will be performed after P4C. A health economic evaluation of P4C will be performed, both in the short term (post intervention) and the long term (11-month follow-up). This study will provide knowledge about the effectiveness of P4C on children's engagement with learning, mental health, and wellbeing, when creating inclusive learning environments using a combination of class-, group- and individual-level interventions. TRIAL REGISTRATION NUMBER: NCT05435937.

Determination of pioglitazone hydrochloride by flow injection chemiluminescence tris(2,2'-bipyridyl)ruthenium(II)-silver(III) complex system.

A novel flow injection-chemiluminescence (FI-CL) approach is proposed for the assay of pioglitazone hydrochloride (PG-HCl) based on its enhancing influence on the tris(2,2'-bipyridyl)ruthenium(II)-silver(III) complex (Ru(bipy)3 2+ -DPA) CL system in sulfuric acid medium. The possible CL reaction mechanism is discussed with CL and ultraviolet (UV) spectra. The optimum experimental conditions were found as: Ru(bipy)3 2+ , 5.0 × 10-5  M; sulfuric acid, 1.0 × 10-3  M; diperiodatoargentate(III) (DPA), 1.0 × 10-4  M; potassium hydroxide, 1.0 × 10-3  M; flow rate 4.0 ml min-1 for each flow stream and sample loop volume, 180 µl. The CL intensity of PG-HCl was linear in the range of 1.0 × 10-3 to 5.0 mg L-1 (R2 = 0.9998, n = 10) with limit of detection [LOD, signal-to-noise ratio (S/N) = 3] of 2.2 × 10-4  mg L-1 , limit of quantification (LOQ, S/N = 10) of 6.7 × 10-4  mg L-1 , relative standard deviation (RSD) of 1.0 to 3.3% and sampling rate of 106 h-1 . The methodology was satisfactorily used to quantify PG-HCl in pharmaceutical tablets with recoveries ranging from 93.17 to 102.77 and RSD from 1.9 to 2.8%.

Smartphone-integrated ratiometric fluorescence sensing platform based on bimetallic metal-organic framework nanowires for anthrax biomarker detection.

Developing an intelligent, sensitive, and visual strategy for quickly identifying anthrax biomarkers is crucial for ensuring food safety and preventing disease outbreaks. Herein, a smartphone-integrated ratiometric fluorescent sensing platform based on bimetallic metal-organic framework (Eux/Tb1-x-MOF) nanowires was designed for specific recognition of pyridine-2,6-dicarboxylic acid (DPA, anthrax biomarker). The Eux/Tb1-x-MOF was prepared by coordinating Eu3+ and Tb3+ with BBDC ligands, which exhibited a uniform fibrous morphology and dual-emission fluorescence at 543 and 614 nm. After the introduction of DPA, the red emission at 614 nm displayed obvious fluorescence quenching, while the green emission at 543 nm was gradually enhanced. The ratiometric sensing offered a wide linear equation in the range of 0.06-15 µg/mL and a low detection limit (LOD) of 20.69 ng/mL. Furthermore, a portable smartphone installing the color recognition application can achieve sensitive, real-time, and visual detection of DPA. As a simple and effective smartphone-assisted sensing platform, this work holds admirable promise to broaden the applications in biomarker real-time determinations and other fields.

Light-Induced Tunable Ferroelectric Polarization in Dipole-Embedded Metal-Organic Framework.

Reversible regulation of ferroelectric polarization possesses great potentials recently in bionic neural networks. Photoinduced cis-trans isomers have changeable dipole moments, but they cannot be directed to some specific orientation. Here, we construct a host-guest composite structure which consists of a porous ferroelectric metal (Ni)-organic framework [Ni(DPA)2] as host and photoisomer, azobenzene (AZB), as guest molecules. When AZB molecules are embedded in the nanopores of Ni(DPA)2 in the form of a single molecule, polarization strength tunable regulation is realized after ultraviolet irradiation of 365 and 405 nm via cis-trans isomerism transformation of AZB. An intrinsic built-in field originating from the distorted {NiN2O4} octahedra in Ni(DPA)2 directs the dipole moments of AZB to the applied electric field. As a result, the overlapped ferroelectric polarization strength changes with content of cis-AZB after ultraviolet and visible irradiation. Such a connection of ferroelectric Ni(DPA)2 structure with cis-trans isomers provides an important strategy for regulating the ferroelectric polarization strength.

Involvement of inflammation in the medial temporal region in the development of agitation in Alzheimer's disease: an in vivo positron emission tomography study.

BACKGROUND: The evaluation of 11 C-DPA-713 binding using positron emission tomography for quantifying the translocator protein can be a sensitive approach in determining the level of glial activation induced by neuroinflammation. Herein, we aimed to investigate the relationship between regional 11 C-DPA713-binding potential (BPND ) and neuropsychiatric symptoms (NPS) in amyloid-positive Alzheimer's disease (AD) patients. METHODS: Fifteen AD patients were enrolled in this study. Correlations were evaluated between the 11 C-DPA713-BPND and Neuropsychiatric Inventory Questionnaire (NPI-Q) scores, including scores in its four domains: agitation, psychosis, affective, and apathy. 11 C-DPA713-BPND values were compared between groups with and without the neuropsychiatric symptoms for which a relationship was observed in the abovementioned correlation analysis. RESULTS: A positive correlation was found between the severity of agitation and 11 C-DPA713-BPND in the Braak 1-3 area, including the amygdala, hippocampal and parahippocampal regions, and lingual and fusiform areas. An increase in the 11 C-DPA713-BPND was observed in AD patients with agitation. We did not find any significant effects of possible confounding factors, such as age, duration of illness, education, gender, Mini-Mental State Examination score, cerebrospinal fluid amyloid ß 42/40 ratio, and apolipoprotein E4 positivity, on either the 11 C-DPA713-BPND or agitation score. CONCLUSIONS: Neuroinflammation in the medial temporal region and its neighbouring area was shown to be associated with the development of agitation symptoms in AD patients. Our findings extend those of previous studies showing an association between some NPS and inflammation, suggesting that immunologically based interventions for agitation can serve as an alternative treatment for dementia.