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Parkinson's disease dementia (PDD) is commonly developed in patients at the late stage of Parkinson's disease (PD) with unknown progression mechanisms. From the post-mortem tissues and animal models, the ventral tegmental area (VTA) and the CA2 regions are closely associated with dementia development in PDD. However, the structural connection between the two regions has not been fully traced. In this study, we applied tissue clearing and adeno-associated virus (AAV) tracing to map the neural circuits in a 3D manner. Hence, we have confirmed the direct connection between the regions with two dual AAV tracing systems and traced the VTA-CA2 circuit in 3D reconstruction. With the immunostaining, we have shown that the GABAergic neurons are the potential subtype of the postsynaptic CA2 neurons in the VTA-CA2 circuit. Under the 6-hydroxydopamine (6-OHDA), we have demonstrated the degeneration of the VTA-CA2 circuit from the observation of fragmented axonal projections. Collectively, we have first traced the direct connection of the whole VTA-CA2 circuit in an intact 3D manner and monitored the fragmentation of this target circuit in the 6-OHDA model. This VTA-CA2 circuit can be a target for future studies of the pathological spreading and degeneration mechanism from PD to PDD., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer's disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies., (© 2024. The Author(s).)

Circular RNAs represent a class of endogenous RNAs that regulate gene expression and influence cell biological decisions with implications for the pathogenesis of several diseases. Here, we disclose a novel gene-regulatory role of circHIPK3 by combining analyses of large genomics datasets and mechanistic cell biological follow-up experiments. Using time-course depletion of circHIPK3 and specific candidate RNA-binding proteins, we identify several perturbed genes by RNA sequencing analyses. Expression-coupled motif analyses identify an 11-mer motif within circHIPK3, which also becomes enriched in genes that are downregulated upon circHIPK3 depletion. By mining eCLIP datasets and combined with RNA immunoprecipitation assays, we demonstrate that the 11-mer motif constitutes a strong binding site for IGF2BP2 in bladder cancer cell lines. Our results suggest that circHIPK3 can sequester IGF2BP2 as a competing endogenous RNA (ceRNA), leading to target mRNA stabilization. As an example of a circHIPK3-regulated gene, we focus on the STAT3 mRNA as a specific substrate of IGF2BP2 and validate that manipulation of circHIPK3 regulates IGF2BP2- STAT3 mRNA binding and, thereby, STAT3 mRNA levels. Surprisingly, absolute copy number quantifications demonstrate that IGF2BP2 outnumbers circHIPK3 by orders of magnitude, which is inconsistent with a simple 1:1 ceRNA hypothesis. Instead, we show that circHIPK3 can nucleate multiple copies of IGF2BP2, potentially via phase separation, to produce IGF2BP2 condensates. Our results support a model where a few cellular circHIPK3 molecules can induce IGF2BP2 condensation, thereby regulating key factors for cell proliferation., Competing Interests: TO, AK, MN, AH, MG, MS, LK, SV, SP, LD, JK, JP, CD No competing interests declared, EY Reviewing editor, eLife, (© 2024, Okholm et al.)

Circular RNAs (circRNAs) represent a class of widespread endogenous RNAs that regulate gene expression and thereby influence cell biological decisions with implications for the pathogenesis of several diseases. Here, we disclose a novel gene-regulatory role of circHIPK3 by combining analyses of large genomics datasets and mechanistic cell biological follow-up experiments. Specifically, we use temporal depletion of circHIPK3 or specific RNA binding proteins (RBPs) and identify several perturbed genes by RNA sequencing analyses. Using expression-coupled motif analyses of mRNA expression data from various knockdown experiments, we identify an 11-mer motif within circHIPK3, which is also enriched in genes that become downregulated upon circHIPK3 depletion. By mining eCLIP datasets, we find that the 11-mer motif constitutes a strong binding site for IGF2BP2 and validate this circHIPK3-IGF2BP2 interaction experimentally using RNA-immunoprecipitation and competition assays in bladder cancer cell lines. Our results suggest that circHIPK3 and IGF2BP2 mRNA targets compete for binding. Since the identified 11-mer motif found in circHIPK3 is enriched in upregulated genes following IGF2BP2 knockdown, and since IGF2BP2 depletion conversely globally antagonizes the effect of circHIPK3 knockdown on target genes, our results suggest that circHIPK3 can sequester IGF2BP2 as a competing endogenous RNA (ceRNA), leading to target mRNA stabilization. As an example of a circHIPK3-regulated gene, we focus on the STAT3 mRNA as a specific substrate of IGF2BP2 and validate that manipulation of circHIPK3 regulates IGF2BP2- STAT3 mRNA binding and thereby STAT3 mRNA levels. However, absolute copy number quantifications demonstrate that IGF2BP2 outnumbers circHIPK3 by orders of magnitude, which is inconsistent with a simple 1:1 ceRNA hypothesis. Instead, we show that circHIPK3 can nucleate multiple copies of IGF2BP2, potentially via phase separation, to produce IGF2BP2 condensates. Finally, we show that circHIPK3 expression correlates with overall survival of patients with bladder cancer. Our results are consistent with a model where relatively few cellular circHIPK3 molecules function as inducers of IGF2BP2 condensation thereby regulating STAT3 and other key factors for cell proliferation and potentially cancer progression.

Background: Immunotherapy targeting pathological α-synuclein (α-syn) species is a promising strategy for slowing disease progression in neurodegenerative synucleinopathies, including Parkinson's disease (PD)., Objective: The aim was to evaluate the safety, tolerability, pharmacokinetics, and target engagement of ascending doses of Lu AF82422., Methods: In this first-in-human study (NCT03611569), healthy participants (18-55 years, cohort A) and patients with PD (40-80 years, Hoehn and Yahr stage ≤3, cohort B) were enrolled in ascending-dose cohorts and randomly assigned to receive single intravenous infusions of Lu AF82422 (cohorts A1-A6: 75, 225, 750, 2250 4500, and 9000 mg, respectively; cohorts B1 and B2: 2250 and 9000 mg, respectively) or placebo. Participants were monitored during a 12-week observational period., Results: Overall, single intravenous infusions of Lu AF82422 were safe and well tolerated, and no serious adverse events (AE) were observed; the most common AEs were related to the study on lumbar punctures, headache, and common infections. Lu AF82422 concentrations (in plasma and cerebrospinal fluid [CSF]) increased in a dose-proportional manner with no observable differences between cohorts; mean plasma half-life was 700 h. Plasma concentrations of Lu AF82422 had an immediate, concentration-dependent lowering effect on the plasma concentration of free α-syn and on the ratio of free to total α-syn in all cohorts and lowered the free-to-total α-syn ratio in CSF in the high-dose PD cohort., Conclusions: The safety and pharmacokinetic profile of Lu AF82422 were appropriate for further clinical development, and results indicated peripheral target engagement. The central target engagement observed in participants with PD indicates that the doses of Lu AF82422 tested may provide CSF concentrations sufficient to target aggregated forms of α-syn. © 2024 H. Lundbeck A/S. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 H. Lundbeck A/S. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Determination of myocardial blood flow (MBF) with MRI is usually performed with dynamic contrast enhanced imaging (MBF DCE ). MBF can also be determined from coronary sinus blood flow (MBF CS ), which has the advantage of being a noncontrast technique. However, comparative studies of MBF DCE and MBF CS in large cohorts are lacking., Purpose: To compare MBF CS and MBF DCE in a large cohort., Study Type: Prospective, sequence-comparison study., Population: 147 patients with type 2 diabetes mellitus (age: 56+/-12 years; 106 male; diabetes duration: 12.9+/-8.1 years), and 25 age-matched controls., Field Strength/sequences: 1.5 Tesla scanner. Saturation recovery sequence for MBF DCE vs. phase-contrast gradient-echo pulse sequence (free-breathing) for MBF CS ., Assessment: MBF DCE and MBF CS were determined at rest and during coronary dilatation achieved by administration of adenosine at 140 μg/kg/min. Myocardial perfusion reserve (MPR) was calculated as the stress/rest ratio of MBF values. Coronary sinus flow was determined twice in the same imaging session for repeatability assessment., Statistical Tests: Agreement between MBF DCE and MBF CS was assessed with Bland and Altman's technique. Repeatability was determined from single-rater random intraclass and repeatability coefficients., Results: Rest and stress flows, including both MBF DCE and MBF CS values, ranged from 33 to 146 mL/min/100 g and 92 to 501 mL/min/100 g, respectively. Intraclass and repeatability coefficients for MBF CS were 0.95 (CI 0.90; 0.95) and 5 mL/min/100 g. In Bland-Altman analysis, mean bias at rest was -1.1 mL/min/100 g (CI -3.1; 0.9) with limits of agreement of -27 and 24.8 mL/min/100 g. Mean bias at stress was 6.3 mL/min/100 g (CI -1.1; 14.1) with limits of agreement of -86.9 and 99.9. Mean bias of MPR was 0.11 (CI: -0.02; 0.23) with limits of agreement of -1.43 and 1.64., Conclusion: MBF may be determined from coronary sinus blood flow, with acceptable bias, but relatively large limits of agreement, against the reference of MBF DCE ., Level of Evidence: 1 TECHNICAL EFFICACY STAGE: 2., (© 2023 International Society for Magnetic Resonance in Medicine.)

The significant morbidity and premature mortality of type 2 diabetes mellitus (T2DM) is largely associated with its cardiovascular consequences. Focus has long been on the arterial atheromatosis of DM giving rise to early stroke and myocardial infarctions, whereas less attention has been given to its non-ischemic cardiovascular consequences. Irrespective of ischemic changes, T2DM is associated with heart failure (HF) most commonly with preserved ejection fraction (HFpEF). Largely due to increasing population ages, hypertension, obesity and T2DM, HFpEF is becoming the most prevalent form of heart failure. Unfortunately, randomized controlled trials of HFpEF have largely been futile, and it now seems logical to address the important different phenotypes of HFpEF to understand their underlying pathophysiology. In the early phases, HFpEF is associated with a significantly impaired ability to increase cardiac output with exercise. The lowered cardiac output with exercise results from both cardiac and peripheral causes. T2DM is associated with left ventricular (LV) diastolic dysfunction based on LV hypertrophy with myocardial disperse fibrosis and significantly impaired ability for myocardial blood flow increments with exercise. T2DM is also associated with impaired ability for skeletal muscle vasodilation during exercise, and as is the case in the myocardium, such changes may be related to vascular rarefaction. The present review discusses the underlying phenotypical changes of the heart and peripheral vascular system and their importance for an adequate increase in cardiac output. Since many of the described cardiovascular changes with T2DM must be considered difficult to change if fully developed, it is suggested that patients with T2DM are early evaluated with respect to their cardiovascular compromise., Competing Interests: MN is employed at Novo Nordisk A/S. YH, PL, and AB have received funding from Novo Nordisk A/S for an entirely different study from the current. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lav Madsen, Sejersen, Nyberg, Sørensen, Hellsten, Gaede and Bojer.)

Background: Patients with diabetes demonstrate early left ventricular systolic dysfunction. Notably reduced global longitudinal strain (GLS) is related to poor outcomes, the underlying pathophysiology is however still not clearly understood. We hypothesized that pathophysiologic changes with microvascular dysfunction and interstitial fibrosis contribute to reduced strain., Methods: 211 patients with type 2 diabetes and 25 control subjects underwent comprehensive cardiovascular phenotyping by magnetic resonance imaging. Myocardial blood flow (MBF), perfusion reserve (MPR), extracellular volume (ECV), and 3D feature tracking GLS and global circumferential (GCS) and radial strain (GRS) were quantified., Results: Patients (median age 57 [IQR 50, 67] years, 70% males) had a median diabetes duration of 12 [IQR 6, 18] years. Compared to control subjects GLS, GCS, and GRS were reduced in the total diabetes cohort, and GLS was also reduced in the sub-group of patients without diabetic complications compared to control subjects (controls - 13.9 ± 2.0%, total cohort - 11.6 ± 3.0%; subgroup - 12.3 ± 2.6%, all p < 0.05). Reduced GLS, but not GCS or GRS, was associated with classic diabetes complications of albuminuria (UACR ≥ 30 mg/g) [β (95% CI) 1.09 (0.22-1.96)] and autonomic neuropathy [β (95% CI) 1.43 (0.54-2.31)] but GLS was not associated with retinopathy or peripheral neuropathy. Independently of ECV, a 10% increase in MBF at stress and MPR was associated with higher GLS [multivariable regression adjusted for age, sex, hypertension, smoking, and ECV: MBF stress (β (95% CI) - 0.2 (- 0.3 to - 0.08), MPR (β (95% CI) - 0.5 (- 0.8 to - 0.3), p < 0.001 for both]. A 10% increase in ECV was associated with a decrease in GLS in univariable [β (95% CI) 0.6 (0.2 to 1.1)] and multivariable regression, but this was abolished when adjusted for MPR [multivariable regression adjusted for age, sex, hypertension, smoking, and MPR (β (95% CI) 0.1 (- 0.3 to 0.6)]. On the receiver operating characteristics curve, GLS showed a moderate ability to discriminate a significantly lowered stress MBF (AUC 0.72) and MPR (AUC 0.73)., Conclusions: Myocardial microvascular dysfunction was independent of ECV, a biomarker of myocardial fibrosis, associated with GLS. Further, 3D GLS could be a potential screening tool for myocardial microvascular dysfunction. Future directions should focus on confirming these results in longitudinal and/or interventional studies., (© 2024. The Author(s).)

Irritant contact dermatitis (ICD) occurs frequently with the use of diabetes devices, but no guidelines for treatment exist. Since subsequent devices need intact skin for intended use, quick healing is crucial. Normal wound healing is expected to be 7-10 days. This was a single-center cross-over study that investigated the effectiveness of an occlusive hydrocolloid-based patch versus nonocclusive treatment of ICD. Participants were aged 6-20 years with active ICD caused by using diabetes device. First study period was patch treatment for 3 days. A control arm was initiated if a new ICD occurred within 30 days. ICD healed completely in 21% of the patch group but none in the controls. Itching was reported as an adverse event (AE) in both arms, but only one additional AE was noted in the patch arm: an infection at a different site from investigated. The hydrocolloid-based patch showed signs of faster healing of ICD with no additional AEs, but larger studies are needed.

Background: Diffuse myocardial fibrosis and microvascular dysfunction are suggested to underlie cardiac dysfunction in patients with type 2 diabetes, but studies investigating their relative impact are lacking. We aimed to study imaging biomarkers of these and hypothesized that fibrosis and microvascular dysfunction would affect different phases of left ventricular (LV) diastole., Methods: In this cross-sectional study myocardial blood flow (MBF) at rest and adenosine-stress and perfusion reserve (MPR), as well as extracellular volume fraction (ECV), were determined with cardiovascular magnetic resonance (CMR) imaging in 205 patients with type 2 diabetes and 25 controls. Diastolic parameters included echocardiography-determined lateral e' and average E/e', and CMR-determined (rest and chronotropic-stress) LV early peak filling rate (ePFR), LV peak diastolic strain rate (PDSR), and left atrial (LA) volume changes., Results: In multivariable analysis adjusted for possible confounders including each other (ECV for blood flow and vice versa), a 10% increase of ECV was independently associated with ePFR/EDV (rest: β = - 4.0%, stress: β = - 7.9%), LA max /BSA (rest: β = 4.8%, stress: β = 5.8%), and circumferential (β = - 4.1%) and radial PDSR (β = 0.07%/sec). A 10% stress MBF increase was associated with lateral e' (β = 1.4%) and average E/e' (β = - 1.4%) and a 10% MPR increase to lateral e' (β = 2.7%), and average E/e' (β = - 2.8%). For all the above, p < 0.05. No associations were found with longitudinal PDSR or left atrial total emptying fraction., Conclusion: In patients with type 2 diabetes, imaging biomarkers of microvascular dysfunction and diffuse fibrosis impacts diastolic dysfunction independently of each other. Microvascular dysfunction primarily affects early left ventricular relaxation. Diffuse fibrosis primarily affects diastasis. Trial registration https://www., Clinicaltrials: gov . Unique identifier: NCT02684331. Date of registration: February 18, 2016., (© 2023. The Author(s).)

Objective: Myocardial interstitial fibrosis expands the extracellular volume (ECV) and in patients with type 2 diabetes is implicated in development of heart failure. ECV can be determined with gadolinium contrast MRI. We investigated which known risk factors for cardiovascular disease were associated with increased ECV in patients with type 2 diabetes., Research Design and Methods: A total of 296 patients with type 2 diabetes and 25 sex and age-matched control subjects were included in a cross-sectional MRI study. The influence of risk factors on ECV was investigated with multiple regression analysis., Results: Control subjects and patients with type 2 diabetes without complications had similar ECV (mean ± SD 27.4 ± 2.1% vs. 27.9 ± 2.6%, P = 0.4). Compared with patients without, ECV was significantly increased in patients with one or more complications (29.0 ± 3.3%, P = 0.02). Both in univariable analysis and after multivariable adjustment, ischemic heart disease, autonomic neuropathy, and active smoking were associated with increased levels of ECV. Active smoking exhibited the largest effect size (β = 2.0 percentage points, 95% CI 0.7-3.3). Former smokers ECV similar to that of never smokers. Albuminuria and systolic blood pressure were inversely associated with ECV in multivariable analysis, but after adjustment for medication suspected to affect ECV, the association with albuminuria was no longer significant (P = 0.1). Sodium-glucose cotransporter 2 inhibitor treatment was not significantly associated with reduced ECV (-0.8%, 95% CI -1.7 to 0.06, P = 0.067)., Conclusions: Patients with complications of diabetes have increased ECV, not seen in patients without complications. Ischemic heart disease, autonomic neuropathy, and active but not former smoking were highly associated with increased ECV., (© 2022 by the American Diabetes Association.)

Aims: It has long been considered that accumulation of pathological alpha-synuclein (aSyn) leads to synaptic/neuronal loss which then results in behavioural and cognitive dysfunction. To investigate this claim, we investigated effects downstream of aSyn preformed fibrils (PFFs) and 6-hydroxydopamine (6-OHDA), because aSyn PFFs induce spreading/accumulation of aSyn, and 6-OHDA rapidly causes local neuronal loss., Methods: We injected mouse aSyn PFFs into the medial forebrain bundle (MFB) of Sprague-Dawley rats. We investigated spread of pathological aSyn, phosphorylation of aSyn and tau, oxidative stress, synaptic/neuronal loss and cognitive dysfunction 60, 90 and 120 days after injection. Similarly, we injected 6-OHDA into the MFB and examined the same parameters 1 and 3 weeks after injection., Results: Following aSyn PFF injection, phosphorylated aSyn was found distant from the injection site in the hippocampus and frontal cortex. However, despite neuron loss being evident close to the site of injection in the substantia nigra at 120 days post injection, there were no other neurodegeneration-associated features associated with aSyn including synaptic loss. In contrast, 6-OHDA caused severe neuronal loss in the substantia nigra at 3 weeks post injection that was accompanied by phosphorylation of aSyn and tau, oxidative stress, loss of synaptic proteins, cognitive and motor dysfunction., Conclusions: Our results demonstrate that spread/replication and slow accumulation of pathological aSyn may not be sufficient to induce neurodegenerative changes. In contrast, oxidative stress responses in addition to aSyn accumulation were associated with other Parkinson's disease (PD)-associated abnormalities and cognitive dysfunction. Our results may be important when considering why only some PD patients develop dementia., (© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Laboratory investigations on terrestrial model-species, typically of temperate origin, have demonstrated that terrestrial ectotherms can cope with daily temperature variations through rapid hardening responses. However, few studies have investigated this ability and its physiological basis in the field. Especially in polar regions, where the temporal and spatial temperature variations can be extreme, are hardening responses expected to be important. Here, we examined diurnal adjustments in heat and cold tolerance in the Greenlandic seed bug Nysius groenlandicus by collecting individuals for thermal assessment at different time points within and across days. We found a significant correlation between observed heat or cold tolerance and the ambient microhabitat temperatures at the time of capture, indicating that N. groenlandicus continuously and within short time-windows respond physiologically to thermal changes and/or other environmental variables in their microhabitats. Secondly, we assessed underlying metabolomic fingerprints using GC-MS metabolomics in a subset of individuals collected during days with either low or high temperature variation. Concentrations of metabolites, including sugars, polyols, and free amino acids varied significantly with time of collection. For instance, we detected elevated sugar levels in animals caught at the lowest daily field temperatures. Polyol concentrations were lower in individuals collected in the morning and evening and higher at midday and afternoon, possibly reflecting changes in temperature. Additionally, changes in concentrations of metabolites associated with energetic metabolism were observed across collection times. Our findings suggest that in these extreme polar environments hardening responses are marked and likely play a crucial role for coping with microhabitat temperature variation on a daily scale, and that metabolite levels are actively altered on a daily basis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Noer, Sørensen, Colinet, Renault, Bahrndorff and Kristensen.)

Aim: To investigate if short-term treatment with liraglutide, a glucagon-like peptide-1 receptor agonist, improves left ventricular diastolic function., Materials and Methods: An investigator-initiated, double-blind, randomized, placebo-controlled trial on the effect of 18 weeks of treatment with liraglutide on diastolic function was assessed in patients with type 2 diabetes with signs of diastolic dysfunction (echo-Doppler determined E/e' ≥ 9 and/or lateral e' ≤ 10 cm/s). Primary outcomes were improved left ventricle filling (the early peak filling rate [ePFR]) and left atrium ease of emptying (the passive emptying fraction [LA PEF ]), assessed by cardiac magnetic resonance imaging at rest and during chronotropic stress. Secondary outcomes included left ventricular and left atrial volumes and systolic function, measures of aortic stiffness and echocardiographic diastolic variables., Results: Forty patients were randomized to liraglutide subcutaneously 1.8 mg/day (n = 20) or placebo (n = 20). Liraglutide reduced HbA1c (-0.47%, 95% CI [-0.88% to -0.06%] [-5.1, 95% CI {-9.7 to -0.62} mmol/mol]) and weight (-2.9, 95% CI [-4.6 to -1.2] kg); both P < .03. Liraglutide did not change ePFR at rest (-24 ± 60 vs. -6 ± 46 mL/s), during stress (2 ± 58 vs. -2 ± 38 mL/s), or the changes from rest to stress (12.9 ± 72.5 vs. 4.7 ± 104.0; all P > .05). LA PEF decreased with liraglutide during stress (-3.1% [-9.0%, 1.1%] vs. 1.0% [-2.9%, 6.1%]; P = .049), but no changes were evident at rest (-4.3% [-7.9%, 1.9%] vs. -0.6% [-3.1%, 2.2%]; P = .19), or for the changes from rest to stress (-1.7 ± 8.4 vs. 0.8 ± 8.2; P = .4). Secondary outcomes were unchanged by liraglutide., Conclusions: Short-term treatment with liraglutide did not improve left ventricular diastolic function, suggesting the cardioprotective effect is not exerted through the improvement in diastolic dysfunction., (© 2021 John Wiley & Sons Ltd.)

Terrestrial arthropods in the Arctic and Antarctic are exposed to extreme and variable temperatures, and climate change is predicted to be especially pronounced in these regions. Available ecophysiological studies on terrestrial ectotherms from the Arctic and Antarctic typically focus on the ability of species to tolerate the extreme low temperatures that can occur in these regions, whereas studies investigating species plasticity and the importance of evolutionary adaptation to periodically high and increasing temperatures are limited. Here, we provide an overview of current knowledge on thermal adaptation to high temperatures of terrestrial arthropods in Arctic and Antarctic regions. Firstly, we summarize the literature on heat tolerance for terrestrial arthropods in these regions, and discuss variation in heat tolerance across species, habitats and polar regions. Secondly, we discuss the potential for species to cope with increasing and more variable temperatures through thermal plasticity and evolutionary adaptation. Thirdly, we summarize our current knowledge of the underlying physiological adjustments to heat stress in arthropods from polar regions. It is clear that very little data are available on the heat tolerance of arthropods in polar regions, but that large variation in arthropod thermal tolerance exists across polar regions, habitats and species. Further, the species investigated show unique physiological adjustments to heat stress, such as their ability to respond quickly to increasing or extreme temperatures. To understand the consequences of climate change on terrestrial arthropods in polar regions, we suggest that more studies on the ability of species to cope with stressful high and variable temperatures are needed., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Terrestrial arthropods in the Arctic and Antarctic are exposed to extreme and variable temperatures, and climate change is predicted to be especially pronounced in these regions. Available ecophysiological studies on terrestrial ectotherms from the Arctic and Antarctic typically focus on the ability of species to tolerate the extreme low temperatures that can occur in these regions, whereas studies investigating species plasticity and the importance of evolutionary adaptation to periodically high and increasing temperatures are limited. Here, we provide an overview of current knowledge on thermal adaptation to high temperatures of terrestrial arthropods in Arctic and Antarctic regions. Firstly, we summarize the literature on heat tolerance for terrestrial arthropods in these regions, and discuss variation in heat tolerance across species, habitats and polar regions. Secondly, we discuss the potential for species to cope with increasing and more variable temperatures through thermal plasticity and evolutionary adaptation. Thirdly, we summarize our current knowledge of the underlying physiological adjustments to heat stress in arthropods from polar regions. It is clear that very little data are available on the heat tolerance of arthropods in polar regions, but that large variation in arthropod thermal tolerance exists across polar regions, habitats and species. Further, the species investigated show unique physiological adjustments to heat stress, such as their ability to respond quickly to increasing or extreme temperatures. To understand the consequences of climate change on terrestrial arthropods in polar regions, we suggest that more studies on the ability of species to cope with stressful high and variable temperatures are needed., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Although it is known that stronger cell-extracellular matrix interactions will be developed as neurons mature, how such change influences their response against traumatic injury remains largely unknown. In this report, by transecting axons with a sharp atomic force microscope tip, we showed that the injury-induced retracting motion of axon can be temporarily arrested by tight NCAM (neural cell adhesion molecule) mediated adhesion patches, leading to a retraction curve decorated with sudden bursts. Interestingly, although the size of adhesion clusters (~0.5-1 μm) was found to be more or less the same in mature and immature neurons (after 7- and 3-days of culturing, respectively), the areal density of such clusters is three times higher in mature axons resulting in a much reduced retraction in response to injury. A physical model was also adopted to explain the observed retraction trajectories which suggested that apparent adhesion energy between axon and the substrate increases from ~0.12 to 0.39 mJ/m 2 as neural cell matures, in good agreement with our experiments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shao, Sørensen, Fang, Chang, Chu and Lin.)

Background: Cardiovascular magnetic resonance imaging (CMR) have described localised non-ischemic late gadolinium enhancement (LGE) lesions of prognostic importance in various non-ischemic cardiomyopathies. Ischemic LGE lesions are prevalent in diabetes (DM), but non-ischemic LGE lesions have not previously been described or systematically studied in DM., Methods: 296 patients with type 2 DM (T2DM) and 25 sex-matched control subjects underwent echocardiography and CMR including adenosine-stress perfusion, T 1 -mapping and LGE., Results: 264 patients and all control subjects completed the CMR protocol. 78.4% of patients with T2DM had no LGE lesions; 11.0% had ischemic LGE lesions only; 9.5% had non-ischemic LGE lesions only; and 1.1% had both one ischemic and one non-ischemic lesion. The non-ischemic LGE lesions were situated mid-myocardial in the basal lateral or the basal inferolateral part of the left ventricle and the affected segments showed normal to high wall thickness and normal contraction. Patients with non-ischemic LGE lesions in comparison with patients without LGE lesions had increased myocardial mass (150 ± 34 vs. 133 ± 33 g, P = 0.02), average E/e'(9.9 IQR8.7-12.6 vs. 8.8 IQR7.4-10.7, P = 0.04), left atrial maximal volume (102 IQR84.6-115.2 vs. 91 IQR75.2-100.0 mL, P = 0.049), NT-proBNP (8.9 IQR5.9-19.7 vs. 5.9 IQR5.9-10.1 µmol/L, P = 0.02) and high-sensitive troponin (15.6 IQR13.0-26.1 vs. 13.0 IQR13.0-14.6 ng/L, P = 0.007) and a higher prevalence of retinopathy (48 vs. 25%, P = 0.009) and autonomic neuropathy (52 vs. 30.5%, P = 0.005)., Conclusion: A specific LGE pattern with lesions in the basal lateral or the basal inferolateral part of the left ventricle was found in patients with type 2 diabetes. Trial registration https://www.clinicaltrials.gov . Unique identifier: NCT02684331.

Background: The biomarker fibroblast growth factor-23 (FGF-23) has been associated with increased cardiovascular morbidity and mortality in both patients with and without type 2 diabetes. The aim of this study was to evaluate the relationship between FGF-23 and cardiac structure, function and perfusion in patients with type 2 diabetes and normal or mildly impaired kidney function. Furthermore, to investigate the association between FGF-23, anti-diabetes therapy and the classic complications and risk factors associated with type 2 diabetes., Methods: In this cross-sectional study, 246 patients with type 2 diabetes underwent echocardiography and advanced cardiac magnetic resonance imaging to assess left ventricular (LV) structure and function. In addition, myocardial blood flow (MBF) during rest and pharmacological stress (adenosine 140 µg/kg/min) were evaluated in 183 of the patients. Patients with eGFR < 60 ml/min/1.73 m 2 were excluded., Results: Median (Q1-Q3) FGF-23 was 74 (58-91) ng/L. Patients with FGF-23 above the median had lower MBF during stress (2.3 ± 0.9 vs. 2.7 ± 0.9 ml/min/g, P = 0.001) and lower overall myocardial perfusion reserve (MPR) (2.7 ± 0.8 vs. 3.3 ± 1.1, P < 0.001). LV mass (143 ± 40 vs. 138 ± 36 g, P = 0.04) and E/e* (8.5 ± 3.2 vs. 7.6 ± 2.7, P = 0.04) were higher in patients with FGF-23 above the median. In a linear model adjusted for age, sex, eGFR and hypertension, increasing FGF-23 was associated with decreased MPR (P < 0.01, R 2  = 0.11) and increased E/e* (P < 0.01, R 2  = 0.07). FGF-23 was lower in patients receiving glucagon like peptide-1 (GLP-1) analogues (71 (57-86) vs. 80 (60-98) ng/L, P = 0.01) than in those who did not receive GLP-1 analogues., Conclusions: In patients with type 2 diabetes and normal or mildly impaired kidney function, increased levels of FGF-23 are associated with impaired cardiac diastolic function and decreased MPR, caused by a decrease in maximal MBF during stress. Use of GLP-1 analogues is associated with decreased levels of FGF-23. Clinical trial registration https://www.clinicaltrials.gov . Unique identifier: NCT02684331. Date of registration: February 18, 2016.

Aims: Coronary microvascular disease (CMD) is a known complication in type 2 diabetes mellitus (T2DM). We examined the relationship between diabetic complications, left ventricular (LV) function and structure and myocardial perfusion reserve (MPR) as indicators of CMD in patients with T2DM and control subjects., Methods and Results: This was a cross-sectional study of 193 patients with T2DM and 25 controls subjects. Patients were grouped as uncomplicated diabetes (n = 71) and diabetes with complications (albuminuria, retinopathy, and autonomic neuropathy). LV structure, function, adenosine stress, and rest myocardial perfusion were evaluated by cardiovascular magnetic resonance. Echocardiography was used to evaluate diastolic function. Patients with uncomplicated T2DM did not have significantly different LV mass and E/e* but decreased MPR (3.8 ± 1.0 vs. 5.1 ± 1.5, P < 0.05) compared with controls. T2DM patients with albuminuria and retinopathy had decreased MPR (albuminuria: 2.4 ± 0.9 and retinopathy 2.6 ± 0.7 vs. 3.8 ± 1.0, P < 0.05 for both) compared with uncomplicated T2DM patients, along with significantly higher LV mass (149 ± 39 and 147 ± 40 vs. 126 ± 33 g, P < 0.05) and E/e* (8.3 ± 2.8 and 8.1 ± 2.2 vs. 7.0 ± 2.5, P < 0.05). When entered in a multiple regression model, reduced MPR was associated with increasing E/e* and albuminuria and retinopathy were associated with reduced MPR., Conclusions: Patients with uncomplicated T2DM have reduced MPR compared with control subjects, despite equivalent LV mass and E/e*. T2DM patients with albuminuria or retinopathy have reduced MPR and increased LV mass and E/e* compared with patients with uncomplicated T2DM. E/e* and MPR are significantly associated after adjustment for age, hypertension, and LV mass, suggesting a link between CMD and cardiac diastolic function., Clinical Trial Registration: https://www.clinicaltrials.org. Unique identifier: NCT02684331., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objective: To examine differences in myocardial blood flow (MBF) at rest and during stress between patients with type 2 diabetes and control subjects, and to identify potential predictors of changes in MBF at rest and during stress., Research Design and Methods: A cross-sectional study was conducted of 193 patients with type 2 diabetes and 20 age- and sex-matched control subjects. Cardiovascular magnetic resonance was used to evaluate left ventricular structure and function and MBF at rest and during adenosine-induced stress. MBF was derived as the mean of the flow within all segments of a midventricular slice., Results: Patients with type 2 diabetes had higher global MBF at rest (0.81 ± 0.19 mL/min/g) and lower global MBF during stress (2.4 ± 0.9 mL/min/g) than control subjects (0.61 ± 0.11 at rest, 3.2 ± 0.8 mL/min/g under stress; both P < 0.01). Patients with macroalbuminuria had lower MBF during stress (1.6 ± 0.5 mL/min/g) than did patients with microalbuminuria (2.1 ± 0.7 mL/min/g; P = 0.04), who in turn had lower MBF during stress than did normoalbuminuric patients (2.7 ± 0.9 mL/min/g; P < 0.01). Patients with severe retinopathy had lower MBF during stress (1.8 ± 0.6 mL/min/g) than patients with simplex retinopathy (2.3 ± 0.7 mL/min/g; P < 0.05) and those who did not have retinopathy (2.6 ± 1.0 mL/min/g; P < 0.05). Albuminuria and retinopathy were associated with reduced MBF during stress in a multiple regression analysis. Stress-related MBF inversely correlated with myocardial extracellular volume ( P < 0.001; R 2 = 0.37), a measure of diffuse myocardial fibrosis. A trend toward lower basal MBF was observed in patients treated with sodium-glucose cotransporter 2 inhibitors ( P = 0.07)., Conclusions: Patients with type 2 diabetes have higher global MBF at rest and lower maximal MBF during vasodilator-induced stress than control subjects. Reduced MBF during stress is associated with diabetes complications (albuminuria and retinopathy) and is inversely correlated with diffuse myocardial fibrosis., (© 2020 by the American Diabetes Association.)

Objectives: Regaining muscle strength is essential for successful outcome after anterior cruciate ligament injury, why progression of exercise intensity in anterior cruciate ligament injury rehabilitation is important. Thus, this study evaluated hamstring and quadriceps muscle activity progression during bodyweight exercises used in a validated anterior cruciate ligament injury rehabilitation program., Design: The study design involved single-occasion repeated measures in a randomized manner. Twenty healthy athletes (nine females) performed nine bodyweight exercises (three exercises per rehabilitation phase). Surface electromyography signals were recorded for hamstring (semitendinosus, biceps femoris) and quadriceps (vastus medialis, vastus lateralis) muscles and normalized to isometric peak electromyography., Results: Hamstring muscle activity did not increase from one rehabilitation phase to the next, ranging between 8% and 45% normalized electromyography for semitendinosus and 11% and 54% normalized electromyography for biceps femoris. Only one exercise (Cook hip lift) exhibited hamstring muscle activities more than 60% normalized electromyography. By contrast, quadriceps muscle activity increased, and late-phase exercises displayed high normalized electromyography (vastus lateralis >60% and vastus medialis >90% normalized electromyography)., Conclusions: The examined bodyweight exercises did not progress for hamstring muscle activity but successfully progressed for quadriceps muscles activity. This study highlights the need for consensus on exercise selection when targeting the hamstring muscles in the rehabilitation after anterior cruciate ligament injury.

The ability to cope with increasing and more variable temperatures, due to predicted climate changes, through plastic and/or evolutionary responses will be crucial for the persistence of Arctic species. Here, we investigate plasticity of heat tolerance of the Greenlandic seed bug Nysius groenlandicus, which inhabits areas with widely fluctuating temperatures. We test the heat tolerance and hardening capacity (plasticity) of N. groenlandicus using both static (heat knock down time, HKDT) and dynamic (critical thermal maximum, CT max ) assays. We find that N. groenlandicus is able to tolerate short-term exposure to temperatures up to almost 50°C and that it can quickly increase heat resistance following heat hardening. Furthermore, we find that this hardening response is reversible within hours after hardening. These findings contrast with common observations from temperate and tropical insects and suggest high thermal plasticity in some Arctic insects which enables them to cope with extreme temperature variability in their habitats.

Springtails are important members of the soil fauna and play a key role in plant litter decomposition, for example through stimulation of the microbial activity. However, their interaction with soil microorganisms remains poorly understood and it is unclear which microorganisms are associated to the springtail (endo) microbiota. Therefore, we assessed the structure of the microbiota of the springtail Orchesella cincta (L.) using 16S rRNA gene amplicon sequencing. Individuals were sampled across sites in the field and the microbiota and in particular the endomicrobiota were investigated. The microbiota was dominated by the families of Rickettsiaceae, Enterobacteriaceae and Comamonadaceae and at the genus level the most abundant genera included Rickettsia, Chryseobacterium, Pseudomonas, and Stenotrophomonas. Microbial communities were distinct for the interior of the springtails for measures of community diversity and exhibited structure according to collection sites. Functional analysis of the springtail bacterial community suggests that abundant members of the microbiota may be associated with metabolism including decomposition processes. Together these results add to the understanding of the microbiota of springtails and interaction with soil microorganisms including their putative functional roles.

Introduction: Evaluation of assay performance with new modified coagulation factors, such as N9-GP, may require testing of different assays and assay conditions. Validation of assays used for clinical monitoring of haemophilia B patients is challenging due to limited availability of blood samples from patients exposed to these new agents., Aim: The aim of the study is to investigate correlations between assays measuring N9-GP concentration and factor IX (FIX) activity, and to evaluate whether in vitro FIX-deficient plasma samples spiked with N9-GP and in vivo post-administration samples from patients exposed to N9-GP perform similarly in these assays., Methods: In vitro samples, prepared by adding N9-GP to FIX-deficient plasma, were compared to samples from haemophilia B patients participating in the phase 3 paradigm 2(™) clinical trial (in vivo samples), in assays measuring N9-GP concentration (ELISA) and FIX activity (one-stage clotting assay and chromogenic assay). The results of the FIX activity assays and ELISAs were compared and analysed to determine the similarity between the in vitro and in vivo sample analyses., Results: Regression analysis demonstrated a linear relationship between N9-GP concentration and FIX activity. Furthermore, there was no significant difference between the regression lines for the in vitro and in vivo sample analyses., Conclusion: The one-stage clot assay using SynthAFax and the chromogenic assay show promise for use in measuring FIX activity in haemophilia B patients treated with N9-GP. Since in vitro and in vivo samples performed similarly in these assays, N9-GP-spiked FIX-deficient plasma could be used as controls in routine measurements of N9-GP activity in haemophilia B patients., (© 2015 John Wiley & Sons Ltd.)

Objective: The main objective of this study was to investigate the association between two markers of low-grade inflammation; soluble urokinase plasminogen activator receptor (suPAR) and high-sensitive C-reactive protein (hs-CRP); and coronary artery calcification (CAC) score detected by cardiac computed tomography (CT) scan., Design: A cross sectional study of 1126 randomly sampled middle-aged men and women., Methods: CAC score was measured by a non-contrast cardiac CT scan and total 10-year cardiovascular mortality risk was estimated using the Systematic Coronary Risk Evaluation (SCORE). Plasma samples were analysed for suPAR and hs-CRP. The association of suPAR and hs-CRP to CAC was evaluated by logistic regression analyses adjusting for categorised SCORE. The additive effect of suPAR to SCORE was evaluated by comparing area under curve (AUC) and net reclassification improvement (NRI)., Results: The odds of being in a higher CAC category, i.e. having more severe CAC, increased 16% (odds ratio (OR) 1.16, p = 0.02) when plasma suPAR concentration increased 1 ng/ml, and this was more pronounced in women (OR 1.30, p = 0.01) than in men (OR 1.15, p = 0.05). In comparison, hs-CRP was not associated with CAC category (OR 1.00, p = 0.90). When adding suPAR to categorised SCORE, AUC increased from 0.66 to 0.70 (p = 0.04) in women and from 0.65 to 0.68 (p = 0.03) in men. NRI was significant in men (NRI 19.3%, 95% CI 6.1-32.6, p = 0.004) as well as in women (NRI 20.8%, 95%CI 1.0-40.7, p = 0.04), without significant gender difference., Conclusions: suPAR, but not hs-CRP, appeared to be associated with CAC score independently of SCORE. The association was strongest in women., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Concizumab (mAb 2021) is a monoclonal IgG4 antibody (mAb) that binds to the Kunitz-type protease inhibitor (KPI) 2 domain of TFPI thereby blocking the interaction of this domain with the active site of FXa. The objective of the present study was to characterize the pharmacokinetics of concizumab in Cynomolgus monkeys after intravenous (iv) and subcutaneous (sc) administration., Methods: Data from two studies were included in the modelling, all in all data from 52 monkeys distributed into 9 groups. Three groups received three escalating sc doses of concizumab with a one week dosing interval, two groups were administered a single dose, and four groups received multiple doses over 13 weeks of concizumab. The plasma concentration was measured using a standard ELISA, and pharmacokinetic data were analysed using NONMEM., Results: The pharmacokinetics of concizumab were characterised by a high bioavailability (93%) after sc administration. The time course of the elimination of concizumab from the circulation was well described by the proposed target mediated drug disposition (TMDD) model. The clearance of concizumab was estimated to be 0.14 ml/h/kg, the target clearance was characterized by a 50% saturation level of 0.54 μg/ml (Km), and the clearance at target saturation was estimated to be 11 μg/h/kg., Conclusion: Concizumab displays a typical TMDD profile with important implications for a putative treatment regime in haemophilia patients. Compared to current standard haemophilia treatment, concizumab has a high bioavailability after sc administration and may provide a viable alternative to intravenous dosing for the treatment of haemophilia., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives: The aim was to examine and compare the impact of HeartScore and coronary artery calcification (CAC) score on subsequent changes in the use of medication., Methods: A total of 1156 healthy men and women, aged 50 or 60, had a baseline medical examination and a coronary artery CT-scan as a part of a screening programme. Using the European HeartScore, the total 10-year cardiovascular mortality risk was estimated (≥5% risk was considered as high). Risk factors and CAC scores were reported to both the patients and their general practitioner. Six months after the screening, follow-up questionnaires addressing current medication were mailed to the participants., Results: A completed questionnaire was returned by 1075 (93%) subjects. At follow up, the overall use of prophylactic medication was significantly increased. Of those with CAC (n = 462) or high HeartScore (n = 233), 21 and 19%, respectively, received lipid-lowering treatment, while 25 and 32%, respectively, received antihypertensive treatment. In multivariate logistic regression analyses, the presence of CAC was associated with an increased use of lipid-lowering treatment (OR 2.2; 95% CI 1.2-4.0), while the presence of a high HeartScore was associated with an increased use of lipid-lowering (OR 2.9; 95% CI 1.6-5.5) and antihypertensive medication (OR 3.4; 95% CI 1.9-6.0)., Conclusion: Knowledge of present cardiovascular risk factors like high HeartScore and/or CAC leads to beneficial changes in medication. However, at follow up only a minority of high-risk subjects did received prophylactic treatment. CAC score was not superior to HeartScore regarding these motivational outcomes.

An approach for preserving the mode field diameter (MFD) in fiber tapers is demonstrated. The approach utilizes concentric dual-core fibers, which couple light from an inner core to an outer core through a taper. Fibers with a 6 μm MFD feedthrough and a 15 μm polarization maintaining feedthrough are demonstrated experimentally. Simulations of the MFD in the tapered dual-core fibers are also presented., (© 2011 Optical Society of America)

A single charge screening model of surface charge sensors in liquids (De Vico et al., Nanoscale, 2011, 3, 706-717) is extended to multiple charges to model the effect of the charge distributions of analyte proteins on FET sensor response. With this model we show that counter-intuitive signal changes (e.g. a positive signal change due to a net positive protein binding to a p-type conductor) can occur for certain combinations of charge distributions and Debye lengths. The new method is applied to interpret published experimental data on Streptavidin (Ishikawa et al., ACS Nano, 2009, 3, 3969-3976) and Nucleocapsid protein (Ishikawa et al., ACS Nano, 2009, 3, 1219-1224).

In this work, we present a computational methodology for predicting the change in signal (conductance sensitivity) of a nano-BioFET sensor (a sensor based on a biomolecule binding another biomolecule attached to a nano-wire field effect transistor) upon binding its target molecule. The methodology is a combination of the screening model of surface charge sensors in liquids developed by Brandbyge and co-workers [Sørensen et al., Appl. Phys. Lett., 2007, 91, 102105], with the PROPKA method for predicting the pH-dependent charge of proteins and protein-ligand complexes, developed by Jensen and co-workers [Li et al., Proteins: Struct., Funct., Bioinf., 2005, 61, 704-721, Bas et al., Proteins: Struct., Funct., Bioinf., 2008, 73, 765-783]. The predicted change in conductance sensitivity based on this methodology is compared to previously published data on nano-BioFET sensors obtained by other groups. In addition, the conductance sensitivity dependence from various parameters is explored for a standard wire, representative of a typical experimental setup. In general, the experimental data can be reproduced with sufficient accuracy to help interpret them. The method has the potential for even more quantitative predictions when key experimental parameters (such as the charge carrier density of the nano-wire or receptor density on the device surface) can be determined (and reported) more accurately.

Treatment with stem cells with a regenerative potential is a new form of therapy that is being studied intensively. Mesenchymal stem cells or stromal cells (MSC) are a promising source of stem cells for regenerative therapy. MSC are easy to isolate and culture, expand in vitro and have a multipotent differentiation capacity. Clinical MSC studies on patients with ischaemic heart disease have shown improved left ventricular function and perfusion and also a reduction in infarct size and symptoms. In this short review we provide a status on MSC regenerative treatment in cardiovascular disease.

Dispersion limits performance in many optical systems. In surface plasmon resonance (SPR) biosensors, the sensing area is an optical element in which the dispersion depends on the effective refractive index of the biochemical compounds to be measured. We report a method of compensating for wavelength dispersion in SPR biosensors employing two integrated diffractive optical coupling elements in a polymer substrate. The dispersion compensation is achieved over the whole dynamic measurement range and provides a biosensor more robust to wavelength fluctuations than prism-coupler SPR systems. The concept can readily be employed in other types of sensor measuring refractive-index changes.

The [3.2.0]bicyclic beta-nucleoside analogue 5 has been designed as a conformationally restricted analogue of the anti-HIV drug AZT. The synthesis of 5 as well as its alpha-anomer 29 is hereby described. The synthesis was accomplished from D-arabinose via a modified Corey-Link procedure stereoselectively incorporating the azide moiety as well as a methyl ester function. When the tert-butyldiphenylsilyl group was used as a permanent protecting group, a selective formation of an oxetane ring failed. When using the p-methoxyphenyl group as a permanent protecting group, 5 and 29 were efficiently obtained via a selective reduction of the ester, a nucleobase coupling followed by separation of the anomers and ring-closing procedures. The nucleoside 5 is conformationally restricted in an unusual O4'-endo (East) conformation, which is an intermediate between the North- and South-type conformations. Nevertheless, neither 5 nor 29 displayed any anti-HIV activity.