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Background: The distance traveled by the positron before annihilation with an electron, the so‐called positron range, negatively effects the positron emission tomography (PET) image quality for radionuclides emitting high‐energy positrons such as Gallium‐68 (68Ga). Purpose: In this study, the effect of a tissue‐independent positron range correction for Gallium‐68 (68Ga‐PRC) was investigated based on phantom measurements. The effect of the 68Ga‐PRC was also explored in four patients. Methods: The positron range distribution profile of 68Ga in water was generated via Monte Carlo simulation. That profile was mapped to a spatially invariant 3D convolution kernel which was incorporated in the OSEM and Q.Clear reconstruction algorithms to perform the 68Ga‐PRC. In addition, each reconstruction method included point spread function (PSF) modeling and time‐of‐flight information. For both Fluorine‐18 (18F) and 68Ga, the NEMA IQ phantom was filled with a sphere‐to‐background ratio of 10:1 and scanned with the GE Discovery MI 5R PET/CT system. Standard non‐positron range correction (PRC) reconstructions were performed for both radionuclides, while also PRC reconstructions were performed for 68Ga. Reconstructions parameters (OSEM: number of updates, Q.Clear: beta value) were adapted to achieve similar noise levels between the corresponding reconstructions. The effect of 68Ga‐PRC was assessed for both OSEM and Q.Clear reconstructions and compared to non‐PRC reconstructions for 68Ga and 18F in terms of image contrast, noise, recovery coefficient (RC), and spatial resolution. For the clinical validation, 68Ga‐labeled prostate‐specific membrane antigen (68Ga‐PSMA) and 68Ga‐DOTATOC PET scans were included of two patients each. For each PET scan, patients were injected with 1.5 MBq/kg of 68Ga‐PSMA or 68Ga‐DOTATOC and the contrast‐to‐noise ratio (CNR) was calculated and compared to the non‐PRC reconstructions. Results: For OSEM reconstructions, including the 68Ga‐PRC improved the RC by 9.4% (3.7%–19.3%) and spatial resolution by 21.7% (4.6 mm vs. 3.6 mm) for similar noise levels. For Q.Clear reconstructions, 68Ga‐PRC modeling improved the RC by 6.7% (2.8%–10.5%) and spatial resolution by 15.3% (5.9 mm vs. 5.0 mm) while obtaining similar noise levels. In the patient data, the use of 68Ga‐PRC enhanced the CNR by 13.2%. Conclusions: Including 68Ga‐PRC in the PET reconstruction enhanced the image quality of 68Ga PET data compared to the standard non‐PRC reconstructions for similar noise levels. Limited patient results also supported this improvement. [ABSTRACT FROM AUTHOR]

Cyclobutanes are attracting a growing interest in medicinal chemistry because of their unique structure and potentially advantageous pharmacological properties. Specifically, 1,3‐disubstituted cyclobutanes have been explored as conformationally restricted propyl isosteres in drug development. In this study, a concise two‐diversification‐point library of 3‐amino‐3‐[(arenesulfonyl)methyl]cyclobutanols was synthesized through a hyperbaric [2+2] cycloaddition reaction between sulfonyl allenes and benzyl vinyl ether as the key step. Three different sulfonyl allenes were used for synthesizing the core structures that were further derivatized by the addition of up to seven amines. The amino groups were incorporated in a moderate to excellent diastereoselectivity through conjugate addition to the four‐membered‐ring scaffolds. Overall, this synthesis process demonstrates the potential for further chemical expansion and fragment growth in drug development. [ABSTRACT FROM AUTHOR]

Measuring glycosidase activity is important to monitor any aberrations in carbohydrate hydrolase activity, but also for the screening of potential glycosidase inhibitors. To this end, synthetic substrates are needed which provide an enzyme‐dependent read‐out upon hydrolysis by the glycosidase. Herein, we present two new routes for the synthesis of caged luminescent carbohydrates, which can be used for determining glycosidase activity with a luminescent reporter molecule. The substrates were validated with glycosidase and revealed a clear linear range and enzyme‐dependent signal upon the in situ generation of the luciferin moiety from the corresponding nitrile precursors. Besides, we showed that these compounds could directly be synthesized from unprotected glycosyl‐α‐fluorides in a two‐step procedure with yields up to 75 %. The intermediate methyl imidate appeared a key intermediate which also reacted with d‐cysteine to give the corresponding d‐luciferin substrate rendering this a highly attractive method for synthesizing glycosyl luciferins in good yields. [ABSTRACT FROM AUTHOR]

Aim: Subclinical bleeding and inflammation play a role in progression of haemophilic arthropathy. Synovial proliferation is predictive of joint bleeding and its early detection may guide treatment changes and prevent arthropathy progression. This study evaluated the prevalence of active and inactive subclinical synovial proliferation and investigated potential biochemical blood/urine markers to identify patients with active subclinical synovial proliferation. Methods: This cross‐sectional study included patients with severe haemophilia A born 1970–2006 who were evaluated during routine clinic visits. Patients with (a history of) inhibitors or recent joint bleeding were excluded. Elbows, knees and ankles were examined for subclinical synovial proliferation by ultrasound and physical examination. Active synovial proliferation was distinguished from inactive synovial proliferation using predefined criteria. Blood/urine biochemical markers (serum osteopontin, sVCAM‐1, Coll2‐1, COMP, CS846, TIMP, and urinary CTX‐II) were compared individually and as combined indexes between patients with and without active synovial proliferation. Results: This cohort consisted of 79 patients with a median age of 31 years (range 16.5–50.8 years) with 62/79 (78%) of the patients using continuous prophylaxis. The annualized joint bleeding rate over the last 5 years was.6 (.2–1.1). Active (17/79, 22%) and inactive subclinical synovial proliferation (17/79, 22%) were both prevalent in this cohort. Biochemical markers were not correlated with active subclinical synovial proliferation. Conclusion: Subclinical synovial proliferation, both active and inactive, was prevalent in patients with severe haemophilia A with access to prophylaxis and would be overlooked without routinely performed ultrasounds. Biochemical markers were unable to identify patients with active subclinical synovial proliferation. [ABSTRACT FROM AUTHOR]

The group of Costa Figueiredo reported Cu-based catalysts for the electrosynthesis of ammonia from nitrate, and X-ray photoelectron spectroscopy demonstrated that Cu(0) is the active phase during catalysis. The Hamlin and Bickelhaupt group performed high level quantum chemical analysis, showing that C(spn)-halogen bonds are easier to activate by a palladium catalyst when the halogen is larger, due to a difference in activation strain and a more favorable electrostatic attraction between the palladium catalyst and the substrate. The importance of catalysis has been recognized a long time ago and the first industrial application stems from the early nineteenth century. We develop new catalytic processes based on 1) rational ligand design in transition metal catalysis 2) Supramolecular catalysis 3) Bio-inspired catalysis. [Extracted from the article]

Non‐hydrogenative Para‐Hydrogen Induced Hyperpolarization (nhPHIP) is a Nuclear Magnetic Resonance (NMR) hyperpolarization technique which has experimentally been used to analyze complex biological samples containing amino acids using the Ir‐IMes hyperpolarization transfer catalyst. A computational study based on Density Function Theory (DFT) was performed on all relevant stereoisomers of [Ir(H)2(IMes)(AA)(Py)] (with AA=glycine, alanine, valine; Py=pyridine), for which R/S chirality and orientation of the amino acid chelation (C/A) were considered. A total of 30 structures were calculated comprising of 6 stereoisomers for achiral glycine, and 12 stereoisomers for each of the chiral amino acids. The abundances derived from the DFT energies confirmed the trends observed in thermal (non‐hyperpolarized) NMR experiments. Additionally, theoretical calculations of electronic (Wiberg bond indices, Natural Bond Orders, Frontier Orbital Analysis), bond dissociation energies, transition states, and activation energies related to interconversion between binding modes, and steric factors (Solid angle) were performed to provide detailed explanations for NMR experimental observations. [ABSTRACT FROM AUTHOR]

Background: This cross‐sectional study aimed to evaluate salivary concentrations of macrophage activation‐related chemokines and mitogen‐activated kinase kinase (MAPKK)‐degrading proteolytic activity in children and adolescents with and without type 1 diabetes mellitus (T1DM). Methods: A total of 122 children and adolescents (65 T1DM patients, 50.8% female, mean age:10.9 years; 57 systemically healthy controls, 36.8% female, mean age: 9.5 years) were included in the study. Salivary concentrations of interferon gamma inducible protein‐10 (IP‐10), monocyte chemoattractant protein (MCP)‐1, MCP‐2, MCP‐3, MCP‐4, macrophage‐derived chemokine (MDC), macrophage migration inhibitory factor (MIF), monokine induced by interferon gamma (MIG), and macrophage inflammatory protein‐1 alpha (MIP‐1α) were quantified using a bead‐based technique. MAPKK‐degrading proteolytic activity was detected using fluorescent peptide substrates. Results: The T1DM group had higher plaque index (PI%, p = 0.032) and bleeding on probing (BOP%, p = 0.045) scores, and lower decayed, missing, filled teeth (dmft/DMFT, p = 0.002) index scores compared to the healthy controls. Compared to the controls, salivary MCP‐1 (p = 0.007), MCP‐3 (p < 0.001), MIG (p = 0.007), and MIP‐1α (p = 0.033) concentrations were elevated whereas MCP‐4 concentrations decreased (p < 0.001) in the T1DM group. After adjusting for age, PI%, BOP%, and dmft/DMFT scores, significant differences in salivary concentrations of MIG (p = 0.033) and MIP‐1α (p = 0.017) were observed between the groups. Moreover, protease activities directed to the cleavage sites of MEK23‐18 (p = 0.001), MKK6b7‐22 (p = 0.007), MKK451‐66 (p = 0.005), MKK7b37‐52 (p = 0.034), and MKK7b69‐84 (p = 0.009) were elevated in the T1DM group. Conclusion: T1DM disrupts the salivary macrophage activation‐related chemokine profile and dysregulates proteolytic MAPKK cleavage. These findings can be an outcome of the impaired systemic immune response in T1DM. [ABSTRACT FROM AUTHOR]

Piperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six‐membered nitrogen‐containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool‐based (internal asymmetric induction), (2) chiral auxiliary‐based (relayed asymmetric induction) and (3) asymmetric catalysis‐based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products. [ABSTRACT FROM AUTHOR]

Introduction: Ankle joint distraction (AJD) is a promising treatment for patients with severe haemophilic ankle arthropathy (HAA). However, some patients showed no clinical improvement after AJD and these differences may be related to structural differences. Aim: Primarily to quantify the structural changes after AJD in patients with HAA by the use of 3D joint space width (JSW) measurements and biochemical markers and secondarily to correlate these findings with clinical pain/function. Methods: Patients with haemophilia A/B who underwent AJD were included for this study. Bone contours on MRI (performed before and 12 and 36 months after AJD) were drawn manually and percentage change in JSW was calculated. Blood/urine (before and 6, 12, 24 and 36 months after AJD) was collected for biomarker measurement (COMP, CS846, C10C, CALC2, PRO‐C2, CTX‐II) and combined indexes of markers were calculated. Mixed effects models were used for analyses on group level. Structural changes were compared with clinical parameters. Results: Eight patients were evaluated. On group level, percentage changes in JSW showed a slight decrease after 12 months followed by a non‐statistically significant increase in JSW after 36 months compared to baseline. Biochemical marker collagen/cartilage formation also showed an initial decrease, followed by a trend towards net formation 12, 24 and 36 months after AJD. On individual patient level, no clear correlations between structural changes and clinical parameters were observed. Conclusion: Cartilage restoration activity on group level in patients with HAA after AJD was in concordance with clinical improvements. Correlating structural modifications with clinical parameters in the individual patient remains difficult. [ABSTRACT FROM AUTHOR]

Aim: Minimally invasive colorectal surgery reduces surgical trauma with better preservation of abdominal wall integrity, but the extraction site is still at risk of incisional hernia (IH). The aim of this study was to determine pooled incidence of IH for each type of extraction site and to compare rates of IH after midline, nonmidline and Pfannenstiel extraction. Method: A systematic review and meta‐analysis was conducted using the PRISMA guidelines. Single‐armed and multiple‐armed cohort studies and randomized controlled trials regarding minimally invasive colorectal surgery were searched from five databases. Outcomes were pooled and compared with random‐effects, inverse‐variance models. Risk of bias within the studies was assessed using the Cochrane ROBINS‐I and RoB 2 tool. Results: Thirty six studies were included, with a total 11,788 patients. The pooled extraction site IH rate was 16.0% for midline (n = 4081), 9.3% for umbilical (n = 2425), 5.2% for transverse (n = 3213), 9.4% for paramedian (n = 134) and 2.1% for Pfannenstiel (n = 1449). Nonmidline extraction (transverse and paramedian) showed significantly lower odds ratios (ORs) for IH when compared with midline extraction (including umbilical). Pfannenstiel extraction resulted in a significantly lower OR for IH compared with midline [OR 0.12 (0.50–0.30)], transverse [OR 0.25 (0.13–0.50)] and umbilical (OR 0.072 [0.033–0.16]) extraction sites. The risks of surgical site infection, seroma/haematoma or wound dehiscence were not significantly different in any of the analyses. Conclusion: Pfannenstiel extraction is the preferred method in minimally invasive colorectal surgery. In cases where Pfannenstiel extraction is not possible, surgeons should avoid specimen extraction in the midline. [ABSTRACT FROM AUTHOR]

The blood coagulation cascade is a complex physiological process involving the action of multiple coupled enzymes, cofactors, and substrates, ultimately leading to clot formation. Serine proteases have a crucial role, and aberrations in their activity can lead to life‐threatening bleeding disorders and thrombosis. This review summarizes the essential proteases involved in blood coagulation and fibrinolysis, the endogenous peptide sequences they recognize and hydrolyze, and synthetic peptide probes based on these sequences to measure their activity. The information in this review can contribute to developing novel anticoagulant therapies and specific substrates for point‐of‐care diagnosis of coagulation pathologies. [ABSTRACT FROM AUTHOR]

Background: Biomonitoring may provide important insights into the impact of a whole blood donation for individual blood donors. Study Design and Methods: Here, we used unbiased mass spectrometry (MS)‐based proteomics to assess longitudinal changes in the global plasma proteome, after a single blood donation for new and regular donors. Subsequently, we compared plasma proteomes of 76 male and female whole blood donors, that were grouped based on their ferritin and hemoglobin (Hb) levels. Results: The longitudinal analysis showed limited changes in the plasma proteomes of new and regular donors after a whole blood donation during a 180‐day follow‐up period, apart from a significant short‐term decrease in fibronectin. No differences were observed in the plasma proteomes of donors with high versus low Hb and/or ferritin levels. Plasma proteins with the highest variation between and within donors included pregnancy zone protein, which was associated with sex, Alfa 1‐antitrypsin which was associated with the allelic variation, and Immunoglobulin D. Coexpression analysis revealed clustering of proteins that are associated with platelet, red cell, and neutrophil signatures as well as with the complement system and immune responses, including a prominent correlating cluster of immunoglobulin M (IgM), immunoglobulin J chain (JCHAIN), and CD5 antigen‐like (CD5L). Discussion: Overall, our proteomic approach shows that whole blood donation has a limited impact on the plasma proteins measured. Our findings suggest that plasma profiling can be successfully employed to consistently detect proteins and protein complexes that reflect the functionality and integrity of platelets, red blood cells, and immune cells in blood donors and thus highlights its potential use for donor health monitoring. [ABSTRACT FROM AUTHOR]

The click reaction between a functionalized trans‐cyclooctene (TCO) and a tetrazine (Tz) is a compelling method for bioorthogonal conjugation in combination with payload releasing capabilities. However, the synthesis of difunctionalized TCOs remains challenging. As a result, these compounds are poorly accessible, which impedes the development of novel applications. In this work, the scalable and accessible synthesis of a new bioorthogonal difunctionalized TCO is reported in only four single selective high yielding steps starting from commercially available compounds. The TCO‐Tz click reaction was assessed and revealed excellent kinetic rates and subsequently payload release was shown with various functionalized derivatives. Tetrazine triggered release of carbonate and carbamate payloads was demonstrated up to 100 % release efficiency and local drug release was shown in a cellular toxicity study which revealed a >20‐fold increase in cytotoxicity. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilic ankle arthropathy (HAA) causes major morbidity. When conservative treatment fails, major surgical interventions are indicated. An alternative treatment to maintain joint mobility and postpone these interventions is desired. Aim: To gather prospective data on clinical/structural changes after ankle joint distraction (AJD) in HAA. Methods: This study includes patients with severe HAA insufficiently responding to conservative treatment. AJD was performed during 8–10 weeks by use of an external frame. Questionnaires, physical examination and radiology were used to evaluate pain, function and structural changes before and 6, 12, 24 and 36 months after distraction. Mixed effect models were used for analysis. Results: This study includes eight cases (21–53 years). The fixed effects estimates of the visual analogue score (0–10) improved from 7.5 at baseline to 3.4 (p =.023) 3 years after distraction. The Haemophilia Activities List (HAL, 0–100) for basic/complex lower extremities functions improved from respectively 29.6 and 31.5 to 54.3 (p =.015) and 50.7 (p =.031). Joint mobility was maintained. Magnetic resonance imaging (MRI) showed thickened cartilage and reduced bone marrow oedema and subchondral cysts. Pin tract infections (n = 6) were effectively treated and no adverse bleeding events occurred. At 3‐year follow‐up, in none of the patients the originally indicated arthrodesis was performed. Conclusion: This first prospective study showed that AJD in HAA results in decreased pain, improved function and decreased arthropathy‐related MRI findings in the majority of patients for prolonged time. Although the study population is small and follow‐up is relatively short, AJD may be promising to postpone invalidating interventions and might be a breakthrough treatment. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) platelet‐derived growth factor receptor‐β (PDGFRβ) has been proposed as a biomarker of blood–brain barrier (BBB) breakdown. We studied PDGFRβ levels as a biomarker for cerebral amyloid angiopathy (CAA), amnestic mild cognitive impairment (aMCI), or Alzheimer's disease (AD). Methods: CSF PDGFRβ levels were quantified by enzyme‐linked immunosorbent assay in patients with CAA, patients with aMCI/AD, and in matched controls. In aMCI/AD we evaluated CSF PDGFRβ both by clinical phenotype and by using the AT(N) biomarker classification system defined by CSF amyloid (A), tau (T), and neurodegeneration (N) biomarkers. Results: PDGFRβ levels were similar in CAA patients and controls (P =.78) and in aMCI/AD clinical phenotype and controls (P =.91). aMCI/AD patients with an AD+ biomarker profile (A+T+[N+]) had increased PDGFRβ levels compared to (A–T–[N–]) controls (P =.006). Conclusion: Our findings indicate that PDGFRβ levels are associated with an AD+ biomarker profile but are not a suitable biomarker for CAA or aMCI/AD clinical syndrome. [ABSTRACT FROM AUTHOR]

Objective: To develop and validate a composite rheumatoid arthritis (RA) disease activity index using optical spectral transmission (OST) scores obtained with the HandScan, replacing tender and swollen joint counts. Methods: RA patients from a single center routinely undergoing HandScan measurements with at least 1 concurrent OST score and Disease Activity Score in 28 joints (DAS28) were included. Data were extracted from medical records. Linear regression analyses with the DAS28 as the outcome were performed to create a disease activity index (DAS‐OST). OST score, erythrocyte sedimentation rate (ESR), and patient global assessment (PtGA) visual analog scale (VAS), sex, age, disease duration, and rheumatoid factor status were evaluated as independent variables. Final models were derived based on the statistical significance of coefficients and model fit. Of the data, two‐thirds were used for development and one‐third for validation; external validation was performed in a cohort from another center. Agreement between DAS‐OST and DAS28 was assessed using the Bland‐Altman plot method and intraclass correlation coefficient (ICC). Diagnostic value of the DAS‐OST was determined for established definitions of remission, low disease activity (LDA), and high disease activity (HDA). Results: Data of 3,358 observations from 1,505 unique RA patients were extracted. DAS‐OST was defined as: –0.44 + OST × 0.03 + male × –0.11 + LN(ESR) × 0.77 + PtGA VAS × 0.03. The ICCs between DAS‐OST and DAS28 were 0.88 (95% confidence interval [95% CI] 0.87–0.90) and 0.82 (95% CI 0.75–0.86) and measurement errors were 0.58 and 0.87 in internal and external validation, respectively. Sensitivity for remission, LDA, and HDA was 79%, 91%, and 43%, respectively, and specificity was 92%, 80%, and 96% in external validation. Conclusion: Using the HandScan, RA disease activity can be accurately estimated if combined with ESR, PtGA VAS, and sex into a disease activity index (DAS‐OST). [ABSTRACT FROM AUTHOR]

Objective: To compare the effects of preventing radiographic progression (in its 3 components) of tocilizumab (TCZ) monotherapy with those of TCZ and methotrexate (MTX) in combination therapy (TCZ + MTX), and to evaluate possible effect modifiers in this model. Methods: Randomized trials that compared TCZ monotherapy to TCZ + MTX combination therapy for differences in radiographic progression were analyzed on an individual patient data level using mixed‐effects models, and data were collected from 820 subjects with either early rheumatoid arthritis (RA) or established RA. Outcomes were classified as the absence of radiographic progression after 2 years (i.e., preventing radiographic progression) as measured by total Sharp/van der Heijde score (SHS), erosion score, and joint space narrowing (JSN) score. Effect modification by baseline joint damage, disease duration, and Disease Activity Score in 28 joints (DAS28) was studied. Results: Overall, TCZ + MTX combination therapy was more effective in preventing radiographic progression compared to TCZ monotherapy, which was measured by total SHS score. However, in patients with early RA who had more joint damage compared to those with less joint damage at baseline (relative risk [RR] 1.02 versus RR 0.91, respectively) or in patients with a lower DAS28 score compared to those with a higher DAS28 score (RR 1.04 versus RR 0.92, respectively) at baseline, this advantage disappeared. In patients with established RA, the advantage of TCZ + MTX versus TCZ alone in the prevention of radiographic progression disappeared with a longer disease duration at baseline (RR 1.04 versus 0.83). Results of erosion scores as an outcome were in line with these findings, though findings for JSN scores were less clear. Conclusion: Combination therapy with TCZ + MTX is more effective in preventing radiographic progression compared to TCZ monotherapy, but the effectiveness of TCZ monotherapy may approximate the effectiveness of TCZ + MTX in patients with early RA who have more joint damage and/or a lower DAS28 at baseline and in patients with established RA who have longer disease duration. [ABSTRACT FROM AUTHOR]

Being able to anticipate events before they happen facilitates stimulus processing. The anticipation of the contents of events is thought to be implemented by the elicitation of prestimulus templates in sensory cortex. In contrast, the anticipation of the timing of events is typically associated with entrainment of neural oscillations. It is so far unknown whether and in which conditions temporal expectations interact with feature‐based expectations, and, consequently, whether entrainment modulates the generation of content‐specific sensory templates. In this study, we investigated the role of temporal expectations in a sensory discrimination task. We presented participants with rhythmically interleaved visual and auditory streams of relevant and irrelevant stimuli while measuring neural activity using magnetoencephalography. We found no evidence that rhythmic stimulation induced prestimulus feature templates. However, we did observe clear anticipatory rhythmic preactivation of the relevant sensory cortices. This oscillatory activity peaked at behaviourally relevant, in‐phase, intervals. Our results suggest that temporal expectations about stimulus features do not behave similarly to explicitly cued, nonrhythmic, expectations, yet elicit a distinct form of modality‐specific preactivation. [ABSTRACT FROM AUTHOR]

N‐Acyliminium ions are highly reactive intermediates that are important for creating CC‐bonds adjacent to nitrogen atoms. Here we report the characterization of cyclic N‐acyliminium ions in the gas phase, generated by collision induced dissociation tandem mass spectrometry followed by infrared ion spectroscopy using the FELIX infrared free electron laser. Comparison of DFT calculated spectra with the experimentally observed IR spectra provided valuable insights in the conformations of the N‐acyliminium ions. [ABSTRACT FROM AUTHOR]

This work investigates the addition of monosaccharides to marketed drugs to improve their pharmacokinetic properties for oral absorption. To this end, a set of chloromethyl glycoside synthons were developed to prepare a variety of glycosyloxymethyl‐prodrugs derived from 5‐fluorouracil, thioguanine, propofol and losartan. Drug release was studied in vitro using β‐glucosidase confirming rapid conversion of the monosaccharide prodrugs to release the parent drug, formaldehyde and the monosaccharide. To showcase this prodrug approach, a glucosyloxymethyl conjugate of the tetrazole‐containing drug losartan was used for in vivo experiments and showed complete release of the drug in a dog‐model. [ABSTRACT FROM AUTHOR]

Reported prevalence estimates of sporadic cerebral amyloid angiopathy (CAA) vary widely. CAA is associated with cognitive dysfunction and intracerebral hemorrhage, and linked to immunotherapy-related side-effects in Alzheimer’s disease (AD). Given ongoing efforts to develop AD immunotherapy, accurate estimates of CAA prevalence are important. CAA can be diagnosed neuropathologically or during life using MRI markers including strictly lobar microbleeds. In this meta-analysis of 170 studies including over 73,000 subjects, we show that in patients with AD, CAA prevalence based on pathology (48%) is twice that based on presence of strictly lobar cerebral microbleeds (22%); in the general population this difference is three-fold (23% vs 7%). Both methods yield similar estimated prevalences of CAA in cognitively normal elderly (5% to 7%), in patients with intracerebral hemorrhage (19% to 24%), and in patients with lobar intracerebral hemorrhage (50% to 57%). However, we observed large heterogeneity among neuropathology and MRI protocols, which calls for standardized assessment and reporting of CAA. [ABSTRACT FROM AUTHOR]

The scope of non‐hydrogenative parahydrogen hyperpolarization (nhPHIP) techniques has been expanding over the last years, with the continuous addition of important classes of substrates. For example, pyruvate can now be hyperpolarized using the Signal Amplification By Reversible Exchange (SABRE) technique, offering a fast, efficient and low‐cost PHIP alternative to Dynamic Nuclear Polarization for metabolic imaging studies. Still, important biomolecules such as amino acids have so far resisted PHIP, unless properly functionalized. Here, we report on an approach to nhPHIP for unmodified α‐amino acids that allows their detection and quantification in complex mixtures at sub‐micromolar concentrations. This method was tested on human urine, in which natural α‐amino acids could be measured after dilution with methanol without any additional sample treatment. [ABSTRACT FROM AUTHOR]

Background: Cerebral amyloid angiopathy (CAA) is characterized by progressive vascular deposition of amyloid‐β (Aβ), and can cause cognitive decline in the elderly. Currently, the diagnosis of CAA is based on neuroimaging and includes the identification of lobar (micro‐)bleeds and cortical superficial siderosis. There is, however, a need for alternative methods as these neuroimaging methods are not optimal for detection of CAA during life. Moreover, CAA is strongly associated with the risk to develop edematous or hemorrhagic amyloid‐related imaging abnormalities (ARIA) as a consequence of anti‐Aβ immunotherapy (e.g. aducanumab and lecanemab) for Alzheimer's disease (AD). There is a need for biomarkers that can provide an accurate and early diagnosis of CAA, and additionally help in the identification of AD patients with a high burden of CAA, who are at risk of developing ARIA due to immunotherapy. We aimed to identify novel biomarker candidates for CAA in cerebrospinal fluid (CSF) using a targeted proteomics approach. Method: We analyzed a panel of 367 proteins in CSF samples of 34 CAA patients and 51 age‐ and sex‐matched controls using the Olink Explore multiplex immunoassay platform (Neurology panel; Olink, Uppsala, Sweden). Proteins were considered measurable when their levels were above the limit of detection of the assay in at least 70% of the samples. Result: For 15 of the 263 proteins that could be measured in CSF, we identified significantly different (p<0.05) levels in CSF of CAA patients as compared to controls. The strongest difference was observed for neurofilament light chain (NFL). Among these 15 proteins, there were two proteins (milk fat globule‐epidermal growth factor 8 (MFG‐E8/lactadherin) and urokinase‐type plasminogen activator (uPA)) for which we previously observed a significant changed level in CSF of CAA patients compared to controls 1,2. Conclusion: Confirmation of previously identified CAA biomarker candidates shows the validity and strength of our biomarker identification study using a targeted proteomics approach. The 15 candidates identified in our study, therefore, hold promise for development into biomarkers that may improve the detection of CAA. References: 1 Marazuela et al, Acta Neuropathol Commun. 2021;9(1):154. 2 Vervuurt et al, Neuropathol Appl Neurobiol. 2022;48(5):e12804. [ABSTRACT FROM AUTHOR]

Background: We have previously shown that matrix metalloproteinase 9 (MMP9) and tissue inhibitor of proteinases 3 (TIMP3) are specifically expressed in the vasculature of patients with cerebral amyloid angiopathy (CAA). Moreover, we have demonstrated increased MMP9 and decreased TIMP3 levels, as well as an altered MMP9:TIMP3 ratio in the vasculature of CAA patients that suffered from intracerebral haemorrhages (CAA‐ICH) compared to CAA patients without ICH (CAA‐nonICH). We now extended our studies to investigate whether TIMP4 may have a similar role in CAA, as this has not been studied before. Method: Using immunohistochemistry, we studied occipital lobe tissue of 44 controls (mean age 78.4 years; 50% female) and 58 CAA patients (77.5 years; 55% female; 40 CAA‐nonICH and 18 CAA‐ICH). Vascular TIMP4 staining was scored in a semiquantitative manner. Using ELISA, we measured TIMP4 CSF levels of 33 CAA patients (mean age 72.2 years; 47% female) and 35 controls (mean age 71.2 years; 51% female). For a subset of CSF samples (11 CAA samples and 14 controls), the levels of MMP2, MMP9, and MMP14 have been determined previously, and now their ratios to TIMP4 were calculated. Differences between CAA patients and controls were assessed using (ordinal) linear regression analysis. Result: In brain tissue, CAA cases had increased vascular TIMP4 expression when compared to controls (p = 0.00002, figure 1). TIMP4 expression did not differ between CAA‐nonICH and CAA‐ICH cases. In the absence of vascular TIMP4 staining, we often observed perivascular staining. Decreased levels of perivascular TIMP4 staining were observed in CAA‐ICH cases when compared to CAA‐nonICH cases (p = 0.045) and to controls (p = 0.035). CSF levels of TIMP4 were decreased in CAA patients compared to controls (p = 0.03, figure 2). In addition, the ratios of MMP2 (p = 0.038), MMP9 (p = 0.005), and MMP14 (p = 0.025) to TIMP4 were increased in CAA patients compared to controls. Conclusion: We demonstrated increased TIMP4 expression in vessel walls of CAA patients compared to controls. In contrast, TIMP4 CSF levels were decreased in CAA patients compared to controls, whereas MMP:TIMP4 ratios were increased, indicating a disbalance of MMP/TIMP4 levels in CAA pathophysiology. Funding: BIONIC project (no. 733050822, ZonMW) and CAFÉ project (no. 5R01NS104147‐02, NIH). [ABSTRACT FROM AUTHOR]

In spite of the many resolution techniques available to separate enantiomers, diastereomeric resolution still remains the most widely used technique in industry. However, drawbacks of this technique are the limited yield of the desired enantiomer and the expensive enantiopure resolving agent that is required. We show here for the first time that a combination of diastereomeric resolution with Viedma ripening using a racemic resolving agent can also provide a single stereoisomer when using an excess of the racemic resolving agent, without the need for the resolving agent to racemize. The requirements of this process are, like for an enantiomeric system, that the compound crystallizes as a racemic conglomerate and that at least one chiral center in the target molecule is racemizable. In addition, owing to the presence of the racemization reaction, substantial improvement in the yield can be obtained. We here demonstrate this approach using a metastable conglomerate salt of rac‐2‐phenylglycinamide with rac‐N‐acetyl tryptophan. [ABSTRACT FROM AUTHOR]

Reaction monitoring by electrospray ionization mass spectrometry (ESI‐MS) is a popular method for investigation of reaction mechanisms. Here, we present a new approach based on a coupling between a modular capillary flow reactor and ESI‐MS. The flow reactor allows a sequential adding of the reactants. We demonstrate the approach for oxidation of Ph2S by ArIO catalyzed by [(TPA)Fe(TfO)2] (ArIO=2‐(tBuSO2)C6H4IO, TPA=tris(2‐pyridylmethyl)amine, TfO−=triflate). In steps, we could follow the formation of the reactive iron(IV)oxo complexes, then the oxygen transfer reaction from the iron(IV)oxo to the sulfide, and finally the reoxidation of the iron complexes. The flow reactor also allows kinetic experiments by changing relative concentrations of the reactants. We could analyze in detail the formation of various [(TPA)FeIVO(X)]2+/+ complexes (X=MeCN, ArI, ArIO, TfO−) and compare their relative reactivity with Ph2S. The [(TPA)FeIVO(MeCN)]2+ complex is the most reactive complex for the oxygen atom transfer reaction whilst [(TPA)FeIVO(ArIO)]2+ prevails in solution under catalytic conditions. [ABSTRACT FROM AUTHOR]

Introduction: Early intervention in the devastating process of haemophilic arthropathy (HA) is highly desirable, but no disease‐modifying therapy is currently available. Considering the pivotal role of iron in the development of HA, iron chelation is considered a promising therapeutic approach. A previous study in haemophilic mice demonstrated that treatment with the iron chelator deferasirox (DFX) 8 weeks before joint bleed induction, attenuated cartilage damage upon blood exposure. However, in haemophilia patients this approach is not opportune given the unpredictable occurrence of hemarthroses. Aim: To evaluate the effectiveness of on‐demand DFX treatment, initiated immediately after joint bleed induction. Methods: A joint bleed was induced in 66 factor VIII‐deficient mice by infra‐patellar needle puncture. Mice were randomly assigned to treatment with either placebo (drinking water) or DFX (dissolved in drinking water) throughout the study. Five weeks after joint bleed induction, inflammation and cartilage damage were assessed histologically. Joints of ten bleed naive haemophilic mice served as controls. Results: A joint bleed resulted in significant inflammation and cartilage damage in the blood‐exposed joint compared with those of control animals, in both the placebo and DFX group (all p = <.05). No differences in tibiofemoral or patellar inflammation (p =.305 and p =.787, respectively) nor cartilage damage (p =.265 and p =.802, respectively) were found between the blood‐exposed joints of both treatment groups. Conclusion: On‐demand treatment with DFX does not prevent joint damage following blood exposure in haemophilic mice. DFX seems unable to reach the joint in time to exert its effect before the irreversible harmful process is initiated. [ABSTRACT FROM AUTHOR]

Objective: To predict response to anti–tumor necrosis factor (anti‐TNF) prior to treatment in patients with rheumatoid arthritis (RA), and to comprehensively understand the mechanism of how different RA patients respond differently to anti‐TNF treatment. Methods: Gene expression and/or DNA methylation profiling on peripheral blood mononuclear cells (PBMCs), monocytes, and CD4+ T cells obtained from 80 RA patients before they began either adalimumab (ADA) or etanercept (ETN) therapy was studied. After 6 months, treatment response was evaluated according to the European League Against Rheumatism criteria for disease response. Differential expression and methylation analyses were performed to identify the response‐associated transcription and epigenetic signatures. Using these signatures, machine learning models were built by random forest algorithm to predict response prior to anti‐TNF treatment, and were further validated by a follow‐up study. Results: Transcription signatures in ADA and ETN responders were divergent in PBMCs, and this phenomenon was reproduced in monocytes and CD4+ T cells. The genes up‐regulated in CD4+ T cells from ADA responders were enriched in the TNF signaling pathway, while very few pathways were differential in monocytes. Differentially methylated positions (DMPs) were strongly hypermethylated in responders to ETN but not to ADA. The machine learning models for the prediction of response to ADA and ETN using differential genes reached an overall accuracy of 85.9% and 79%, respectively. The models using DMPs reached an overall accuracy of 84.7% and 88% for ADA and ETN, respectively. A follow‐up study validated the high performance of these models. Conclusion: Our findings indicate that machine learning models based on molecular signatures accurately predict response before ADA and ETN treatment, paving the path toward personalized anti‐TNF treatment. [ABSTRACT FROM AUTHOR]

Keywords: congenital neutropenia; neutrophils; granulocyte colony-stimulating factor; granulocyte colony-stimulating factor receptor; primary immunodeficiency EN congenital neutropenia neutrophils granulocyte colony-stimulating factor granulocyte colony-stimulating factor receptor primary immunodeficiency 930 934 5 12/07/20 20201201 NES 201201 To the Editor: The growth factor granulocyte colony-stimulating factor (G-CSF) has been described as a key regulator of neutrophil development by inducing proliferation, differentiation, and survival of myeloid progenitors. Both control and patient neutrophils showed STAT3 phosphorylation upon GM-CSF stimulation, whereas only control neutrophils demonstrated STAT3 phosphorylation after G-CSF stimulation (Fig 2D and Figure S6). In healthy controls, there is low expression of G-CSF-R on bone marrow neutrophils compared to circulating neutrophils as assessed by flow cytometry (Figure S7). The increase of G-CSF-R expression at the final stage of neutrophil development would also be compatible with the strong pro-survival effect of G-CSF on circulating and bone marrow neutrophils (data not shown). [Extracted from the article]

Background: Diagnosis of the highly prevalent disease cerebral amyloid angiopathy (CAA) is mainly based on radiological identification of cerebral micro‐ or macrobleeds (according to the diagnostically acclaimed Boston Criteria) in the end‐stage of disease. Body fluid biomarkers (e.g. in cerebrospinal fluid) could potentially act as alternatives and allow for earlier identification of disease in a minimally invasive manner. We have explored the involvement of potential CAA‐biomarker urokinase plasminogen activator (uPA) in CAA development and progression in human patients and rodent disease models (rTg‐DI). Additionally, we analyzed uPA cerebrospinal fluid (CSF) levels in rTg‐DI models and human CAA patients versus controls to assess diagnostic accuracy of uPA as a biomarker for CAA. Method: PLAU gene expression and uPA localization were studied in cerebrovascular tissue of a rTg‐DI models and wild‐type rats, alongside a human sporadic CAA patient and a control subject, using rt‐qPCR and immunohistochemistry respectively. Additionally, CSF Aβ40 and uPA levels were determined in rTg‐DI rats and in human patients with possible or probable CAA (according to the Boston Criteria; n=28), and control subjects (n=40), using ELISA. Result: Immunohistochemistry showed strong overexpression of uPA in brain tissue of rTg‐DI models and human CAA patients. Additionally, uPA showed a strong colocalization with Aβ peptides, restricted to the vasculature of rTg‐DI rats and human CAA patients. Expression and localization of both uPA and Aβ peptides were negligible in controls. Additionally, CAA rats displayed significant overexpression of the PLAU gene in brain vasculature as well as significant elevation of uPA in their CSF. In humans, CSF Aβ40 levels were reduced in CAA patients (7.66 ± 3.36 ng/mL) compared to controls (9.58 ± 3.88 ng/mL, p=0.04). CSF uPA levels were higher in CAA patients (median (IQR): 92.0 (76.1 ‐ 109.0) pg/mL compared to human controls (68.5 (56.6 ‐ 78.4) pg/mL; p<0.001). CSF Aβ40 and uPA combined yielded the highest AUC (0.87) to distinguish CAA from controls. Conclusion: uPA was overexpressed in rTg‐DI rats and its levels were significantly elevated in both rodent and human CAA. CSF Aβ40 and uPA serve as excellent biomarkers to discriminate CAA from controls, especially when combined. [ABSTRACT FROM AUTHOR]

Purpose: Knee joint distraction (KJD) is a joint-preserving treatment for younger osteoarthritis patients. KJD has shown positive results in regular care, but the external fixation frame often caused pin tract skin infections. Therefore, the use of cadexomer iodine was included in the wound care protocol. The goal of this cross-sectional study was to evaluate whether use of this ointment reduced the number of patients with infections during KJD treatment. Methods: Patients treated with KJD in regular care were included if they gave consent for use of their data and completed treatment with the newest distraction device before 2020. All patients followed a wound care protocol, which since March 2019 included using cadexomer iodine ointment. The number of patients experiencing pin tract infections was compared between patients who did (March 2019–December 2019) and did not (November 2017–March 2019) use the ointment. Results: Sixty-seven patients were included; 34 patients used cadexomer iodine and 33 patients did not. Patient who did not use cadexomer iodine experienced twice as many infections (64% vs 32%;p = 0.010). There was a significant difference in the number of patients with serious infections, requiring more antibiotics than the standard 7-day oral antibiotics (30% without vs 6% with cadexomer iodine; p = 0.009). Conclusions: The use of cadexomer iodine ointment during KJD results in a significant reduction of the number of patients experiencing pin tract infections during treatment. Use of this ointment should be considered standard protocol during KJD treatment and could be of value in general external fixator usage as well. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilic animal models are used to study blood‐induced cartilage damage, but quantitative and sensitive outcome measures are needed. Aim: To develop a novel quantitative method for detecting early cartilage degeneration in a haemophilic rat model of blood‐induced joint damage. Methods: The 35Sulphate incorporation (35SO42− assay) was applied to tibial and patellar cartilage of wild‐type rats to quantify baseline proteoglycan synthesis and to evaluate the effect of 4‐day blood exposure in vitro. Next, haemarthrosis was induced in 39 FVIII‐deficient rats and characterized by changes in knee joint diameter and development of bone pathology (using micro‐CT). Four‐ and 16‐day posthaemarthrosis proteoglycan synthesis rate (PSR) was assessed using the 35SO42− assay, with the contralateral knee as control. Results: In vitro, a decrease in PSR in tibial and patellar cartilage was demonstrated following blood exposure. In vivo, joint diameter and development of bone pathology confirmed successful induction of haemarthrosis. In the blood‐exposed knee, tibial and patellar PSR was inhibited 4 and 16 days after induced haemarthrosis. Interestingly, at day 16 the proteoglycan synthesis in the contralateral knee was also inhibited to an extent correlating with that of the blood‐exposed knee. Conclusion: For the first time, early changes in cartilage matrix synthesis upon blood exposure were quantified with the 35SO42− assay in a haemophilic rat model, establishing this assay as a novel method to study blood‐induced cartilage damage. [ABSTRACT FROM AUTHOR]

Cell‐based bone tissue engineering techniques utilize both osteogenic cells and biomedical materials, and have emerged as a promising approach for large‐volume bone repair. The success of such techniques is highly dependent on cell adhesion, spreading, and osteogenic activities. In this study, we investigated the effect of co‐administration of all‐trans retinoic acid (ATRA) and human salivary peptide histatin‐1 (Hst1) on the spreading and osteogenic activities of pre‐osteoblasts on bio‐inert glass surfaces. Pre‐osteoblasts (MC3T3‐E1 cell line) were seeded onto bio‐inert glass slides in the presence and absence of ATRA and Hst1. Cell spreading was scored by measuring surface areas of cellular filopodia and lamellipodia using a point‐counting method. The distribution of fluorogenic Hst1 within osteogenic cells was also analyzed. Furthermore, specific inhibitors of retinoic acid receptors α, β, and γ, such as ER‐50891, LE‐135, and MM‐11253, were added to identify the involvement of these receptors. Cell metabolic activity, DNA content, and alkaline phosphatase (ALP) activity were assessed to monitor their effects on osteogenic activities. Short‐term (2 h) co‐administration of 10 μm ATRA and Hst1 to pre‐osteoblasts resulted in significantly higher spreading of pre‐osteoblasts compared to ATRA or Hst1 alone. ER‐50891 and LE‐135 both nullified these effects of ATRA. Co‐administration of ATRA and Hst1 was associated with significantly higher metabolic activity, DNA content, and ALP activity than either ATRA or Hst1 alone. In conclusion, co‐administration of Hst1 with ATRA additively stimulated the spreading and osteogenicity of pre‐osteoblasts on bio‐inert glass surfaces in vitro. [ABSTRACT FROM AUTHOR]

Viedma ripening is a deracemization process that has been used to deracemize a range of chiral molecules. The method has two major requirements: the compound needs to crystallize as a conglomerate and it needs to be racemizable under the crystallization conditions. Although conglomerate formation can be induced in different ways, the number of racemization methods is still rather limited. To extend the scope of Viedma ripening, in the present research we applied UV‐light‐induced racemization in a Viedma ripening process, and report the successful deracemization of a BINOL derivative crystallizing as a conglomerate. Irradiation by UV light activates the target compound in combination with an organic base, required to promote the excited‐state proton transfer (ESPT), leading thereafter to racemization. This offers a new tool towards the development of Viedma ripening processes, by using a cheap and "green" catalytic source like UV light to racemize suitable chiral compounds. [ABSTRACT FROM AUTHOR]

Background: People with Down syndrome (DS) have a high genetic risk of developing Alzheimer's disease (AD) ‐related dementia and pathology. Triplication of a human chromosome 21 (Hsa21)‐located gene APP play an important role in AD pathology. Wiseman et al. demonstrated that triplication of a gene or genes on Hsa21, other than APP exacerbates amyloid‐β pathology in an APP transgenic mouse model. Multiple lines of evidence indicate that cysteine cathepsin activity influences APP cleavage and Aβ accumulation. Cystine cathepsins are predominantly expressed in microglia in the brain and are involved in key neuroinflammation pathways. Hsa21‐located gene CYSTATIN B (CSTB) is an endogenous inhibitor of cathepsin proteases. We hypothesise that three copies of CSTB inhibit cathepsin activity and that this could contribute to altered neuroinflammation in people with DS. Method: Human fibroblasts from individuals with DS and euploid controls, temporal cortex samples from individuals who had AD‐DS and Braak‐stage matched euploid cases of early‐onset AD (EOAD) or healthy aging and human iPSC‐derived microglia‐like cells (iMLCs: T21 and an isogenic control) were used. Western blot and immunocytochemistry were conducted to determine the abundance and subcellular localisation of CSTB. Cathepsin B (CatB) activity in human fibroblasts and temporal cortex samples was measured using an enzymatic assay (Abcam) and/or a pan‐cysteine cathepsin quenched activity‐based probe (BMV109). Result: Western blotting confirmed that trisomy of Hsa21 resulted in an increase in the protein level of CSTB, that endogenous CSTB is predominantly localised in the cytoplasm and that its subcellular localisation is not altered by trisomy of Hsa21. Significantly lower CatB activity occurs in the temporal cortex of people who had AD‐DS compared with individuals who had EOAD. However, CatB enzymatic activity was not significantly altered in Hsa21 trisomic fibroblasts. Conclusion: Next, we will determine in iMLCs, whether trisomy of chromosome 21 alters CatB activity and which genes have altered expression at baseline and after neuroinflammatory challenge. [ABSTRACT FROM AUTHOR]

The crystalline sponge method entails the elucidation of the (absolute) structure of molecules from a solution phase using single‐crystal X‐ray diffraction and eliminates the need for crystals of the target compound. An important limitation for the application of the crystalline sponge method is the instability of the available crystalline sponges that can act as host crystals. The host crystal that is most often used decomposes in protic or nucleophilic solvents, or when guest molecules with Lewis basic substituents are introduced. Here a new class of (water) stable host crystals based on f‐block metals is disclosed. It can be shown that these hosts not only increase the scope of the crystalline sponge method to a wider array of solvents and guests, but that they can even be applied to aqueous solutions containing hydrophilic guest molecules, thereby extending the crystalline sponge method to the important field of water‐based chemistry. [ABSTRACT FROM AUTHOR]

Poly(ADP‐ribose) polymerase (PARP) inhibitors are selectively cytotoxic in cancer cells with defects in homologous recombination (HR) (e.g., due to BRCA1/2 mutations). However, not all HR‐deficient tumors efficiently respond to PARP inhibition and often acquire resistance. It is therefore important to uncover how PARP inhibitors induce cytotoxicity and develop combination strategies to potentiate PARP inhibitor efficacy in HR‐deficient tumors. In this study, we found that forced mitotic entry upon ATR inhibition potentiates cytotoxic effects of PARP inhibition using olaparib in BRCA2‐depleted and Brca2 knockout cancer cell line models. Single DNA fiber analysis showed that ATR inhibition does not exacerbate replication fork degradation. Instead, we find ATR inhibitors accelerate mitotic entry, resulting in the formation of chromatin bridges and lagging chromosomes. Furthermore, using genome‐wide single‐cell sequencing, we show that ATR inhibition enhances genomic instability of olaparib‐treated BRCA2‐depleted cells. Inhibition of CDK1 to delay mitotic entry mitigated mitotic aberrancies and genomic instability upon ATR inhibition, underscoring the role of ATR in coordinating proper cell cycle timing in situations of DNA damage. Additionally, we show that olaparib treatment leads to increased numbers of micronuclei, which is accompanied by a cGAS/STING‐associated inflammatory response in BRCA2‐deficient cells. ATR inhibition further increased the numbers of cGAS‐positive micronuclei and the extent of cytokine production in olaparib‐treated BRCA2‐deficient cancer cells. Altogether, we show that ATR inhibition induces premature mitotic entry and mediates synergistic cytotoxicity with PARP inhibition in HR‐deficient cancer cells, which involves enhanced genomic instability and inflammatory signaling. [ABSTRACT FROM AUTHOR]

Chiral molecules exhibiting a quinone and/or hydroquinone moiety are ubiquitous in natural products and small molecule drugs. Herein, we describe a chiral quinone‐hydroquinone molecule that racemizes through a reversible redox reaction. Using a combined computational and experimental approach, we show that this racemization proceeds via an intermolecular reaction mechanism. Starting from two achiral reactants, this molecule could be obtained in enantiopure form using Viedma ripening. [ABSTRACT FROM AUTHOR]

The synthesis of N‐acetylneuraminic acid (Neu5Ac) derivatives is drawing more and more attention in glycobiology research because of the important role of sialic acids in e. g. cancer, bacterial, and healthy cells. Chemical preparation of these carbohydrates typically relies on multistep synthetic procedures leading to low overall yields. Herein we report a continuous flow process involving N‐acetylneuraminate lyase (NAL) immobilized on Immobead 150P (Immobead‐NAL) to prepare Neu5Ac derivatives. Batch experiments with Immobead‐NAL showed equal activity as the native enzyme. Moreover, by using a fivefold excess of either N‐acetyl‐D‐mannosamine (ManNAc) or pyruvate the conversion and isolated yield of Neu5Ac were significantly improved. To further increase the efficiency of the process, a flow setup was designed providing a chemoenzymatic entry into a series of N‐functionalized Neu5Ac derivatives in conversions of 48–82%, and showing excellent stability over 1 week of continuous use. [ABSTRACT FROM AUTHOR]

A revised modular approach to various synthetic (–)‐trans‐Δ8‐THC derivatives through late‐stage Suzuki–Miyaura cross‐coupling reactions is disclosed. Ten derivatives were synthesized allowing both sp2‐ and sp3‐hybridized cross‐coupling partners with minimal β‐hydride elimination. Importantly, we demonstrate that a para‐bromo‐substituted THC scaffold for Suzuki–Miyaura cross‐coupling reactions has been initially reported incorrectly in recent literature. A revised modular approach to various synthetic (–)‐trans‐Δ8‐THC derivatives is disclosed. Ten derivatives were sythesized using both sp2‐ and sp3‐hybridized fragment couplings. [ABSTRACT FROM AUTHOR]

Mefloquine is an important drug for prevention and treatment of malaria. It is commercially available as a racemic mixture, wherein only one enantiomer is active against malaria, while the other one causes severe psychotropic effects. By converting the drug into a compound that crystallizes as a racemizable racemic conglomerate, the deracemization of mefloquine into the desired enantiomer was achieved. Grinding out side‐effects: By grinding of a suspension of crystals in combination with a racemization reaction, the initial racemic mixture of the anti‐malaria drug mefloquine is deracemized to deliver the desired enantiomer. [ABSTRACT FROM AUTHOR]

Introduction: Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α‐synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α‐synuclein (α‐syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. Methods: The pathophysiological role of CSF α‐syn in asymptomatic subjects at risk of AD has not been explored. We performed a large‐scale cross‐sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT‐preAD). Results: We found a positive association between CSF α‐syn concentrations and brain β‐amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α‐syn and both CSF t‐tau and p‐tau181 concentrations. Discussion: Animal models presented evidence, indicating that α‐syn may synergistically and directly induce fibrillization of both tau and β‐amyloid. Our data indicate an association of CSF α‐syn with AD‐related pathophysiological mechanisms, during the preclinical phase of the disease. [ABSTRACT FROM AUTHOR]