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Background Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known.Objectives To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors.Methods In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health.Results From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86).Conclusion Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need.Trail registration number ISRCTN10980107.

Bicycle riding can be a positive experience for children and young people that builds confidence, independence and promotes healthy recreation. However, these benefits are dependent upon safe bicycle-riding practices. Between 1 January 2004 and 31 December 2011, 12 children and young people under the age of 18 years died in bicycle incidents in Queensland. An additional 1736 bicycle-related injuries requiring emergency department attendance are estimated to have occurred between 2008 and 2009 in Queensland for children and young people under the age of 18 years. Of the twelve bicycle-related deaths between 2004 and 2011 in Queensland, two children were aged between 5 and 9 years, five young people were 10-14 years of age and five young people were between 15 and17 years. The two children aged 5-9 years were riding their bikes for recreation. Children aged 10-14 years were most likely to have been killed in an incident while riding to school in the morning, with teenagers aged 15-17 years most likely to be killed in incidents occurring after school and in the evening. Bicycle riders are vulnerable road users, particularly children and young people. This is due to several factors that can begrouped into (i) developmental characteristics such as body size and proportions, perceptional and attentional issues, road safety awareness and risk taking behaviours, and (ii) environmental factors such as supervision and shared road use with vehicles. This paper examines safety issues for children and young people who have died in bicycle-related incidents in Queensland, and outlines areas of focus for injury prevention practitioners.

Abstract Dual-comb interferometry harnesses the interference of two laser frequency combs to provide unprecedented capability in spectroscopy applications. In the past decade, the state-of-the-art systems have reached a point where the signal-to-noise ratio per unit acquisition time is fundamentally limited by shot noise from vacuum fluctuations. To address the issue, we propose an entanglement-enhanced dual-comb spectroscopy protocol that leverages quantum resources to significantly improve the signal-to-noise ratio performance. To analyze the performance of real systems, we develop a quantum model of dual-comb spectroscopy that takes practical noises into consideration. Based on this model, we propose quantum combs with side-band entanglement around each comb lines to suppress the shot noise in heterodyne detection. Our results show significant quantum advantages in the uW to mW power range, making this technique particularly attractive for biological and chemical sensing applications. Furthermore, the quantum comb can be engineered using nonlinear optics and promises near-term experimentation.

Abstract Sialic acids (Sias) are a class of sugar molecules with a parent nine-carbon neuraminic acid, generally present at the ends of carbohydrate chains, either attached to cellular surfaces or as secreted glycoconjugates. Given their position and structural diversity, Sias modulate a wide variety of biological processes. However, little is known about the role of Sias in human adipose tissue, or their implications for health and disease, particularly among individuals following different dietary patterns. The goal of this study was to measure N-Acetylneuraminic acid (Neu5Ac), N-Glycolylneuraminic acid (Neu5Gc), and 2-keto-3-deoxy-d-glycero-d-galacto-nononic acid (KDN) concentrations in adipose tissue samples from participants in the Adventist Health Study-2 (AHS-2) and to compare the abundance of these Sias in individuals following habitual, long-term vegetarian or non-vegetarian dietary patterns. A method was successfully developed for the extraction and detection of Sias in adipose tissue. Sias levels were quantified in 52 vegans, 56 lacto-vegetarians, and 48 non-vegetarians using LC–MS/MS with Neu5Ac-D-1,2,3-13C3 as an internal standard. Dietary groups were compared using linear regression. Vegans and lacto-ovo-vegetarians had significantly higher concentrations of Neu5Ac relative to non-vegetarians. While KDN levels tended to be higher in vegans and lacto-ovo-vegetarians, these differences were not statistically significant. However, KDN levels were significantly inversely associated with body mass index. In contrast, Neu5Gc was not detected in human adipose samples. It is plausible that different Neu5Ac concentrations in adipose tissues of vegetarians, compared to those of non-vegetarians, reflect a difference in the baseline inflammatory status between the two groups. Epidemiologic studies examining levels of Sias in human adipose tissue and other biospecimens will help to further explore their roles in development and progression of inflammatory conditions and chronic diseases.

ABSTRACTIntroduction Gestational diabetes mellitus (GDM) complicates ∼16% of pregnancies in Australia and has significant implications for health of both mother and baby. Antenatal anxiety and depression are also associated with adverse pregnancy outcomes. The interaction between GDM and mental health in pregnancy is poorly understood. With the aim of exploring the nuanced interaction between GDM and mental health further, we investigated whether GDM treatment modality (diet versus insulin) influenced psychological wellbeing in women with GDM.Methods Psychological wellbeing was assessed in women with GDM treated with diet (GDM-Diet, n = 20) or insulin (GDM-Insulin, n = 15) and pregnant women without GDM (non-GDM, n = 20) using questionnaires [Edinburgh Depression Scale (EDS), State-Trait Anxiety Inventory (STAI-6), and in women with GDM, Problem Areas in Diabetes (PAID)] at 24–34 weeks gestation and again at ∼36 weeks gestation.Results Women in the GDM-insulin group had significantly higher levels of anxiety than the non-GDM group at both time points. Women in the GDM-Diet group had higher levels of anxiety at 24–34 weeks gestation than the non-GDM group but did not differ at ∼36 weeks gestation. Although depression scores tended to be higher in GDM-Insulin and GDM-Diet groups than in the non-GDM group at both time points, this was not statistically significant. Diabetes-related distress was similar in the GDM-Diet and GDM-Insulin groups at both time points and did not change during pregnancy. A high proportion of the GDM-Insulin group had past/current mental illness (60%).Conclusions In this pilot study GDM was associated with differences in psychological wellbeing, specifically increased anxiety in women treated with insulin. Specialised interventions to support women with GDM should be considered, especially those requiring insulin.Trial registration: Not applicable as this was a purely observational study.

Abstract Background Introgression of the bacterial endosymbiont Wolbachia into Aedes aegypti populations is a biocontrol approach being used to reduce arbovirus transmission. This requires mass release of Wolbachia-infected mosquitoes. While releases have been conducted using a variety of techniques, egg releases, using water-soluble capsules containing mosquito eggs and larval food, offer an attractive method due to its potential to reduce onsite resource requirements. However, optimisation of this approach is required to ensure there is no detrimental impact on mosquito fitness and to promote successful Wolbachia introgression. Methods We determined the impact of storage time and temperature on wild-type (WT) and Wolbachia-infected (wMel or wAlbB strains) Ae. aegypti eggs. Eggs were stored inside capsules over 8 weeks at 18 °C or 22 °C and hatch rate, emergence rate and Wolbachia density were determined. We next examined egg quality and Wolbachia density after exposing eggs to 4–40 °C to determine how eggs may be impacted if exposed to extreme temperatures during shipment. Results Encapsulating eggs for 8 weeks did not negatively impact egg viability or resulting adult emergence and Wolbachia density compared to controls. When eggs were exposed to temperatures within 4–36 °C for 48 h, their viability and resulting adult Wolbachia density were maintained; however, both were significantly reduced when exposed to 40 °C. Conclusions We describe the time and temperature limits for maintaining viability of Wolbachia-infected Ae. aegypti eggs when encapsulated or exposed to extreme temperatures. These findings could improve the efficiency of mass releases by providing transport and storage constraints to ensure only high-quality material is utilised during field releases. Graphical Abstract

Abstract Finding effective disease‐modifying treatment for Alzheimer's disease remains challenging due to an array of factors contributing to the loss of neural function. The current study demonstrates a new strategy, using multitargeted bioactive nanoparticles to modify the brain microenvironment to achieve therapeutic benefits in a well‐characterized mouse model of Alzheimer's disease. The application of brain‐penetrating manganese dioxide nanoparticles significantly reduces hypoxia, neuroinflammation, and oxidative stress; ultimately reducing levels of amyloid β plaques within the neocortex. Analyses of molecular biomarkers and magnetic resonance imaging‐based functional studies indicate that these effects improve microvessel integrity, cerebral blood flow, and cerebral lymphatic clearance of amyloid β. These changes collectively shift the brain microenvironment toward conditions more favorable to continued neural function as demonstrated by improved cognitive function following treatment. Such multimodal disease‐modifying treatment may bridge critical gaps in the therapeutic treatment of neurodegenerative disease.

Summary: Background: The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. Methods: This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group—robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)—at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. Findings: Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. Interpretation: Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although two-thirds of the population remained pre-frail or frail. This suggests comprehensive assessment and interventions targeting pre-frailty and frailty beyond the initial illness are required. Funding: UK Research and Innovation and National Institute for Health Research.

Abstract Genetic mutations have long been recognized as drivers of cancer drug resistance, but recent work has defined additional non-genetic mechanisms of plasticity, wherein cancer cells assume a drug resistant phenotype marked by altered epigenetic and transcriptional states. Currently, little is known about the real-time, dynamic nature of this phenotypic shift. Using a bladder cancer model of nongenetic plasticity, we discovered that rapid transition to drug resistance entails upregulation of mitochondrial gene expression and a corresponding metabolic shift towards the tricarboxylic acid cycle and oxidative phosphorylation. Based on this distinction, we were able to track cancer cell metabolic profiles in real time using fluorescence lifetime microscopy (FLIM). We observed single cells transitioning spontaneously to an oxidative phosphorylation state over hours to days, a trend that intensified with exposure to cisplatin chemotherapy. Conversely, pharmacological inhibition of oxidative phosphorylation significantly reversed the FLIM metabolic signature and reduced cisplatin resistance. These rapid, spontaneous metabolic shifts offer a new means of tracking nongenetic cancer plasticity and forestalling the emergence of drug resistance.

Summary: BAZ1B is a ubiquitously expressed nuclear protein with roles in chromatin remodeling, DNA replication and repair, and transcription. Reduced BAZ1B expression disrupts neuronal and neural crest development. Variation in the activity of BAZ1B has been proposed to underly morphological and behavioral aspects of domestication through disruption of neural crest development. Knockdown of baz1b in Xenopus embryos and Baz1b loss-of-function (LoF) in mice leads to craniofacial defects consistent with this hypothesis. We generated baz1b LoF zebrafish using CRISPR/Cas9 gene editing to test the hypothesis that baz1b regulates behavioral phenotypes associated with domestication in addition to craniofacial features. Zebrafish with baz1b LoF show mild underdevelopment at larval stages and distinctive craniofacial features later in life. Mutant zebrafish show reduced anxiety-associated phenotypes and an altered ontogeny of social behaviors. Thus, in zebrafish, developmental deficits in baz1b recapitulate both morphological and behavioral phenotypes associated with the domestication syndrome in other species.

Pancreatic β-cells respond to increased extracellular glucose levels by initiating a metabolic shift. That change in metabolism is part of the process of glucose-stimulated insulin secretion and is of particular interest in the context of diabetes. However, we do not fully understand how the coordinated changes in metabolic pathways and metabolite products influence insulin secretion. In this work, we apply systems biology approaches to develop a detailed kinetic model of the intracellular central carbon metabolic pathways in pancreatic β-cells upon stimulation with high levels of glucose. The model is calibrated to published metabolomics datasets for the INS1 823/13 cell line, accurately capturing the measured metabolite fold-changes. We first employed the calibrated mechanistic model to estimate the stimulated cell's fluxome. We then used the predicted network fluxes in a data-driven approach to build a partial least squares regression model. By developing the combined kinetic and data-driven modeling framework, we gain insights into the link between β-cell metabolism and glucose-stimulated insulin secretion. The combined modeling framework was used to predict the effects of common anti-diabetic pharmacological interventions on metabolite levels, flux through the metabolic network, and insulin secretion. Our simulations reveal targets that can be modulated to enhance insulin secretion. The model is a promising tool to contextualize and extend the usefulness of metabolomics data and to predict dynamics and metabolite levels that are difficult to measure in vitro. In addition, the modeling framework can be applied to identify, explain, and assess novel and clinically-relevant interventions that may be particularly valuable in diabetes treatment.

An ability to estimate quantities, such as the number of conspecifics or the size of a predator, has been reported in vertebrates. Fish, in particular zebrafish, may be instrumental in advancing the understanding of magnitude cognition. We review here the behavioral studies that have described the ecological relevance of quantity estimation in fish and the current status of the research aimed at investigating the neurobiological bases of these abilities. By combining behavioral methods with molecular genetics and calcium imaging, the involvement of the retina and the optic tectum has been documented for the estimation of continuous quantities in the larval and adult zebrafish brain, and the contributions of the thalamus and the dorsal-central pallium for discrete magnitude estimation in the adult zebrafish brain. Evidence for basic circuitry can now be complemented and extended to research that make use of transgenic lines to deepen our understanding of quantity cognition at genetic and molecular levels.

Abstract When injected into genetically modified mice, aggregates of the amyloid-β (Aβ) peptide from the brains of Alzheimer’s disease (AD) patients or transgenic AD mouse models seed cerebral Aβ deposition in a prion-like fashion. Within the brain, Aβ exists as a pool of distinct C-terminal variants with lengths ranging from 37 to 43 amino acids, yet the relative contribution of individual C-terminal Aβ variants to the seeding behavior of Aβ aggregates remains unknown. Here, we have investigated the relative seeding activities of Aβ aggregates composed exclusively of recombinant Aβ38, Aβ40, Aβ42, or Aβ43. Cerebral Aβ42 levels were not increased in App NL−F knock-in mice injected with Aβ38 or Aβ40 aggregates and were only increased in a subset of mice injected with Aβ42 aggregates. In contrast, significant accumulation of Aβ42 was observed in the brains of all mice inoculated with Aβ43 aggregates, and the extent of Aβ42 induction was comparable to that in mice injected with brain-derived Aβ seeds. Mice inoculated with Aβ43 aggregates exhibited a distinct pattern of cerebral Aβ pathology compared to mice injected with brain-derived Aβ aggregates, suggesting that recombinant Aβ43 may polymerize into a unique strain. Our results indicate that aggregates containing longer Aβ C-terminal variants are more potent inducers of cerebral Aβ deposition and highlight the potential role of Aβ43 seeds as a crucial factor in the initial stages of Aβ pathology in AD.

Using phasor-FLIM (Fluorescence Lifetime Imaging Microscopy), Wang et al. reveal differential usages of oxidative phosphorylation and glycolysis in living islet cells following glucose stimulation. This study suggests the applicability of FLIM as a drug discovery tool as it reports perturbations in glucose metabolism in living islet cells.

Abstract Protein misfolding diseases refer to a variety of disorders that develop as a consequence of the misfolding of proteins in various organs. The etiologies of Parkinson’s and Alzheimer’s disease remain unclear, but it seems that type two diabetes and other prediabetic states could contribute to the appearance of the sporadic forms of these diseases. In addition to amylin deposition, other amyloidogenic proteins implicated in the pathophysiology of neurodegenerative diseases could have important roles in the pathogenesis of this disease. As we have previously demonstrated the presence of α-synuclein deposits in the pancreas of patients with synucleinopathies, as well as tau and Aβ deposits in the pancreatic tissue of Alzheimer’s disease patients, we studied the immunoreactivity of amylin, tau and α-synuclein in the pancreas of 138 subjects with neurodegenerative diseases or type two diabetes and assessed whether the pancreatic β-cells of these subjects present cooccurrence of misfolded proteins. Furthermore, we also assessed the pancreatic expression of prion protein (PrP) in these subjects and its interaction, both in the pancreas and brain, with α-synuclein, tau, Aβ and amylin. Our study shows, for the first time, that along with amylin, pancreatic α-synuclein, Aβ, PrP and tau may contribute together to the complex pathophysiology of type two diabetes and in the appearance of insulin resistance in Alzheimer’s and Parkinson’s disease. Furthermore, we show that the same mixed pathologies that are observed in the brains of patients with neurodegenerative diseases are also present outside the nervous system. Finally, we provide the first histological evidence of an interaction between PrP and Aβ, α-synuclein, amylin or tau in the pancreas and locus coeruleus. These findings will shed more light on the common pathological pathways shared by neurodegenerative diseases and type two diabetes, benefiting the exploration of common therapeutic strategies to prevent or treat these devastating amyloid diseases.

Abstract Alzheimer’s disease (AD) is associated with memory impairment and altered peripheral metabolism. Mounting evidence indicates that abnormal signaling in a brain-periphery metabolic axis plays a role in AD pathophysiology. The activation of pro-inflammatory pathways in the brain, including the interleukin-6 (IL-6) pathway, comprises a potential point of convergence between memory dysfunction and metabolic alterations in AD that remains to be better explored. Using T2-weighted magnetic resonance imaging (MRI), we observed signs of probable inflammation in the hypothalamus and in the hippocampus of AD patients when compared to cognitively healthy control subjects. Pathological examination of post-mortem AD hypothalamus revealed the presence of hyperphosphorylated tau and tangle-like structures, as well as parenchymal and vascular amyloid deposits surrounded by astrocytes. T2 hyperintensities on MRI positively correlated with plasma IL-6, and both correlated inversely with cognitive performance and hypothalamic/hippocampal volumes in AD patients. Increased IL-6 and suppressor of cytokine signaling 3 (SOCS3) were observed in post-mortem AD brains. Moreover, activation of the IL-6 pathway was observed in the hypothalamus and hippocampus of AD mice. Neutralization of IL-6 and inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling in the brains of AD mouse models alleviated memory impairment and peripheral glucose intolerance, and normalized plasma IL-6 levels. Collectively, these results point to IL-6 as a link between cognitive impairment and peripheral metabolic alterations in AD. Targeting pro-inflammatory IL-6 signaling may be a strategy to alleviate memory impairment and metabolic alterations in the disease.

Spectral phasor analysis allows unmixing fluorescence microscopy images, but it requires user involvement and has a limited number of labels that can be analyzed and displayed. Here the authors present a semi-automated solution to visualise multiple spectral components of hyperspectral fluorescence images, simultaneously.

Macrophages mediate the fibrotic response after a heart attack by extracellular matrix turnover and cardiac fibroblasts activation. Here the authors identify an evolutionarily-conserved function of macrophages that contributes directly to the forming post-injury scar through cell-autonomous deposition of collagen.

Background The Impella® devices have increasingly become a desired treatment option for cardiogenic shock (CS) as demonstrated by studies analyzing real-world use of hemodynamic support devices. However, data regarding outcomes after Impella® device implant and optimal timing of device placement remains scarce. This study investigates prognostic factors including serial lactate levels in CS patients treated with Impella®. Methods This retrospective study reviewed 76 consecutive patients diagnosed with CS supported with Impella® at a large, tertiary-care university medical center. Clinical variables and outcomes examined include co-morbidities, pre- and post-procedural lactate levels, and mortality. Results Of the 76 patients requiring an Impella®, 70% of patients survived to hospital discharge. Those who died post-device implant had a higher prevalence of hyperlipidemia (HLD), chronic kidney disease (CKD), and were more likely to require multiple (>1) vasopressors. The mean pre-procedural lactate levels were significantly higher (5.86 +/- 5.11 vs 2.16 +/- 1.50, p = 0.01) in the population who died, along with the change in lactate levels (1.90 +/- 2.56 vs -0.40 +/- 1.73, p=0.04). Those who died within 24 hours of implant showed a trend toward higher mean pre-procedural lactate levels (8.46 +/- 6.00 vs 3.86 +/- 3.31, p = 0.12). Conclusions Higher pre-procedural lactate levels, HLD, CKD, and increased vasopressor requirement were predictive of increased mortality in CS patients post-Impella® placement, especially within 24 hours of implant. Through serial lactate measurements, we demonstrated favorable outcomes in patients with early stabilization or greater lowering of post-procedural lactate levels suggestive of improved end organ perfusion.

Predictable somatosensory feedback leads to a reduction in tactile sensitivity. This phenomenon, called tactile suppression, relies on a mechanism that uses an efference copy of motor commands to help select relevant aspects of incoming sensory signals. We investigated whether tactile suppression is modulated by (a) the task-relevancy of the predicted consequences of movement and (b) the intensity of related somatosensory feedback signals. Participants reached to a target region in the air in front of a screen; visual or tactile feedback indicated the reach was successful. Furthermore, tactile feedback intensity (strong vs. weak) varied across two groups of participants. We measured tactile suppression by comparing detection thresholds for a probing vibration applied to the finger either early or late during reach and at rest. As expected, we found an overall decrease in late-reach suppression, as no touch was involved at the end of the reach. We observed an increase in the degree of tactile suppression when strong tactile feedback was given at the end of the reach, compared to when weak tactile feedback or visual feedback was given. Our results suggest that the extent of tactile suppression can be adapted to different demands of somatosensory processing. Downregulation of this mechanism is invoked only when the consequences of missing a weak movement sequence are severe for the task. The decisive factor for the presence of tactile suppression seems not to be the predicted action effect as such, but the need to detect and process anticipated feedback signals occurring during movement.

Abstract In aging populations, omega‐3 polyunsaturated fatty acids (PUFAs) have been associated with better cognitive function, slower rates of cognitive decline, and lower risk of developing dementia. Animal studies have shown that diets rich in omega‐3 PUFAs reduce blood–brain barrier (BBB) disruption associated with aging, but this has yet to be observed in humans. Forty‐five healthy subjects (mean age, 76 years) were recruited and underwent cognitive assessment (verbal learning and memory, language, processing speed, executive function, and motor control) and measurement of PUFAs. Forty of the same subjects also underwent magnetic resonance imaging (MRI) to measure BBB integrity (Ktrans using dynamic contrast‐enhanced MRI). The long chain omega‐3 score (DHA+EPA) was negatively correlated with Ktrans values in the internal capsule, indicating higher omega‐3 levels were associated with greater BBB integrity in this region (r = –0.525, p = .004). Trends were observed for a positive correlation between the long chain omega‐3 score and both memory and language scores, but not with executive function, speed, or motor control. The omega‐6 score was not significantly correlated with any cognitive scores or Ktrans values. The significant correlations between long chain omega‐3 levels and BBB integrity provide a possible mechanism by which omega‐3 PUFAs are associated with brain health.

AimPopulation based studies indicate a positive association between type 2 diabetes (T2D) and Parkinson’s disease (PD) where there is an increased risk of developing PD in patients with T2D. PD is characterized by the abnormal accumulation of intraneuronal aggregated α-synuclein (α-syn) in Lewy bodies, which negatively impact neuronal viability. α-syn is also expressed in both pancreatic islets and skeletal muscle, key players in glucose regulation. Therefore, we examined the functional role of α-syn in these tissues.MethodsUsing mice lacking, overexpressing or transiently injected with α-syn, effects on glucose and insulin tolerance and insulin secretion were determined, with further characterization of the effects on GLUT4 translocation using GLUT4myc myotubes.ResultsMice genetically ablated for α-syn became glucose intolerant and insulin resistant with hyperinsulinemia and reduced glucose-stimulated insulin secretion (GSIS). Mice overexpressing human α-syn are more insulin senstive and glucose tolerant compared to controls with increased GSIS. Injection of purified α-syn monomers also led to improved glucose tolerance and insulin sensitivity with hightened GSIS. α-syn monomer treatments increased surface GLUT4 levels in myotubes but without any significant change in Akt phosphorylation. The increase in cell surface GLUT4 was largely due to a large reduction in GLUT4 endocytosis, however, with a compensatory reduction in GLUT4 exocytosis.ConclusionCumulatively, this data suggests that α-syn modulates both pancreatic beta cell function and glucose transport in peripheral tissues, thereby playing a pivitol role in the maintenance of normal glucose homeostasis.

Fluorescence lifetime imaging microscopy (FLIM) evaluates the metabolic state of tissue based on reduced nicotinamide adenine dinucleotide (NAD(P)H) and flavin adenine dinucleotide (FAD). Fluorescence lifetime imaging ophthalmoscopy (FLIO) can image the fundus of the eyes, but cannot detect NAD(P)H. We used multiphoton FLIM to study the metabolic state of the retina in fixed eyes of wild-type mice C57BL6/J. We sectioned the eye using a polyacrylamide gel-embedding technique and estimated the percentage of bound NAD(P)H. We found that oxidative phosphorylation was the predominant metabolic state, particularly in the inner retina, when a fixed retina was used. We also demonstrated the feasibility of FAD imaging of the retina. In addition, we demonstrated that autofluorescence and various FLIM channels, such as hemoglobin, melanin and collagen, can be used to evaluate the structure of the retina and other parts of the eye without any special staining.

GWAS have shown that the common R325W variant of SLC30A8 (ZnT8) increases the risk of type 2 diabetes (T2D). However, ZnT8 haploinsufficiency is protective against T2D in humans, counterintuitive to earlier work in humans and mouse models. Therefore, whether decreasing ZnT8 activity is beneficial or detrimental to β cell function, especially under conditions of metabolic stress, remains unknown. In order to examine whether the existence of human islet amyloid polypeptide (hIAPP), a coresident of the insulin granule, affects the role of ZnT8 in regulating β cell function, hIAPP-expressing transgenics were generated with reduced ZnT8 (ZnT8B+/– hIAPP) or null ZnT8 (ZnT8B–/– hIAPP) expression specifically in β cells. We showed that ZnT8B–/– hIAPP mice on a high-fat diet had intensified amyloid deposition and further impaired glucose tolerance and insulin secretion compared with control, ZnT8B–/–, and hIAPP mice. This can in part be attributed to impaired glucose sensing and islet cell synchronicity. Importantly, ZnT8B+/– hIAPP mice were also glucose intolerant and had reduced insulin secretion and increased amyloid aggregation compared with controls. These data suggest that loss of or reduced ZnT8 activity in β cells heightened the toxicity induced by hIAPP, leading to impaired β cell function and glucose homeostasis associated with metabolic stress.

Wolbachia is an endosymbiotic bacterium that can restrict the transmission of human pathogenic viruses by Aedes aegypti mosquitoes. Recent field trials have shown that dengue incidence is significantly reduced when Wolbachia is introgressed into the local Ae. aegypti population. Female Ae. aegypti are anautogenous and feed on human blood to produce viable eggs. Herein, we tested whether people who reside on Tri Nguyen Island (TNI), Vietnam developed antibodies to Wolbachia Surface Protein (WSP) following release of Wolbachia-infected Ae. aegypti, as a measure of exposure to Wolbachia. Paired blood samples were collected from 105 participants before and after mosquito releases and anti-WSP titres were measured by ELISA. We determined no change in anti-WSP titres after ~30 weeks of high levels of Wolbachia-Ae. aegypti on TNI. These data suggest that humans are not exposed to the major Wolbachia surface antigen, WSP, following introgression of Wolbachia-infected Ae. aegypti mosquitoes.

The bacterial endosymbiont Wolbachia is a biocontrol tool that inhibits the ability of the Aedes aegypti mosquito to transmit positive-sense RNA viruses such as dengue and Zika. Growing evidence indicates that when Wolbachia strains wMel or wAlbB are introduced into local mosquito populations, human dengue incidence is reduced. Despite the success of this novel intervention, we still do not fully understand how Wolbachia protects mosquitoes from viral infection. Here, we demonstrate that the Wolbachia strain wPip does not inhibit virus infection in Ae. aegypti. We have leveraged this novel finding, and a panel of Ae. aegypti lines carrying virus-inhibitory (wMel and wAlbB) and non-inhibitory (wPip) strains in a common genetic background, to rigorously test a number of hypotheses about the mechanism of Wolbachia-mediated virus inhibition. We demonstrate that, contrary to previous suggestions, there is no association between a strain's ability to inhibit dengue infection in the mosquito and either its typical density in the midgut or salivary glands, or the degree to which it elevates innate immune response pathways in the mosquito. These findings, and the experimental platform provided by this panel of genetically comparable mosquito lines, clear the way for future investigations to define how Wolbachia prevents Ae. aegypti from transmitting viruses.

Microtubule-associated protein tau assists in stabilizing microtubules and has been particularly implicated in Alzheimer's disease (AD). Given the importance of tau to AD pathogenesis and therapies, it is important to understand non-classic physiological functions for this protein inside and outside the central nervous system (CNS). Our group has previously shown that tau ablation triggers glucose intolerance and pancreatic dysfunction in mice, suggesting that tau plays a role in peripheral metabolic regulation. Little is known about the role of tau in anxiety. Moreover, inconsistent results have been generated regarding the effects of tau deletion in memory. Here, we characterize systemic insulin resistance, anxiety-related behavior and memory in 15 to 20 weeks old Wild-Type (WT), Tau knockout (TauKO) and a distinct hTau mouse model consisting of tau knockout expressing the longest isoform (2N4R) of a non-mutant WT human Tau protein under the prion promoter (hTau). Our findings demonstrate that tau deletion leads to anxiety-related behavior, impaired contextual and cued fear memory. The presence of a human Tau transgene did not ameliorate the phenotypes observed in animals lacking the mouse tau protein and it elicited impairments in learning, memory, and peripheral insulin sensitivity. Our results suggest that tau protein plays a role in memory and anxiety-related behavior. Our findings also indicate that previously unrecognized functions for tau protein may be a complicating factor in using animal models on the TauKO background. Understanding the link between tau pathophysiology and cognitive and metabolic alterations is of great importance to establish the complete contribution of tau protein to AD pathogenesis.

Bird-window collisions are the second leading cause of human-related avian mortality for songbirds in Canada. Our ability to accurately estimate the number of fatalities caused by window collisions is affected by several biases, including the removal of carcasses by scavengers prior to those carcasses being detected during surveys. We investigated the role of scavenger behavior in modifying perceived carcass removal rate while describing habitat-specific differences for the scavengers present in a relatively scavenger-depauperate island ecosystem. We used motion activated cameras to monitor the fate of hatchling chicken carcasses placed at building (under both windows and windowless walls) and forest (open and closed canopy) sites in western Newfoundland, Canada. We recorded the identity of scavengers, timing of events, and frequency of repeat scavenging at sites. Using 2 treatments, we also assessed how scavenging varied with 2 levels of carcass availability (daily versus every third day). Scavenger activities differed substantially between forest and building sites. Only common ravens (Corvus corax) removed carcasses at building sites, with 25 of 26 removals occurring under windows. Burying beetles (Nicrophorus spp.) dominated scavenging at forest sites (14 of 18 removals), completely removing carcasses from sight in under 24 hours. Availability had no effect on removal rate. These findings suggest that ravens look for carcasses near building windows, where bird-window collision fatalities create predictable food sources, but that this learning preceded the study. Such behavior resulted in highly heterogeneous scavenging rates at fine spatial scales indicating the need for careful consideration of carcass and camera placement when monitoring scavenger activity. Our observations of burying beetle activity indicate that future studies investigating bird collision mortality near forested habitats and with infrequent surveys, should consider local invertebrate community composition during survey design. The high incidence of invertebrate scavenging may compensate for the reduced vertebrate scavenger community of insular Newfoundland.

It is unclear how vegetarian dietary patterns influence plasma metabolites involved in biological processes regulating chronic diseases. We sought to identify plasma metabolic profiles distinguishing vegans (avoiding meat, eggs, dairy) from non-vegetarians (consuming ≥28 g/day red meat) of the Adventist Health Study-2 cohort using global metabolomics profiling with ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS). Differences in abundance of metabolites or biochemical subclasses were analyzed using linear regression models, adjusting for surrogate and confounding variables, with cross-validation to simulate results from an independent sample. Random forest was used as a learning tool for classification, and principal component analysis was used to identify clusters of related metabolites. Differences in covariate-adjusted metabolite abundance were identified in over 60% of metabolites (586/930), after adjustment for false discovery. The vast majority of differentially abundant metabolites or metabolite subclasses showed lower abundance in vegans, including xanthine, histidine, branched fatty acids, acetylated peptides, ceramides, and long-chain acylcarnitines, among others. Many of these metabolite subclasses have roles in insulin dysregulation, cardiometabolic phenotypes, and inflammation. Analysis of metabolic profiles in vegans and non-vegetarians revealed vast differences in these two dietary groups, reflecting differences in consumption of animal and plant products. These metabolites serve as biomarkers of food intake, many with potential pathophysiological consequences for cardiometabolic diseases.

Dengue virus (DENV) threatens almost 70% of the world’s population, with no effective therapeutic currently available and controversy surrounding the one approved vaccine. A key factor in dengue viral replication is the interaction between DENV nonstructural proteins (NS) 5 and 3 (NS3) in the infected cell. Here, we perform a proof-of-principle high-throughput screen to identify compounds targeting the NS5-NS3 binding interface. We use a range of approaches to show for the first time that two small molecules–repurposed drugs I-OMe tyrphostin AG538 (I-OMe-AG238) and suramin hexasodium (SHS)–inhibit NS5-NS3 binding at low μM concentration through direct binding to NS5 that impacts thermostability. Importantly, both have strong antiviral activity at low μM concentrations against not only DENV-2, but also Zika virus (ZIKV) and West Nile virus (WNV). This work highlights the NS5-NS3 binding interface as a viable target for the development of anti-flaviviral therapeutics.

Small ubiquitin-related modifiers (SUMOs) conjugated or bound to target proteins can affect protein trafficking, processing and solubility. SUMOylation has been suggested to play a role in the amyloid plaque and neurofibrillary tangle pathology of Alzheimer disease (AD) and related neurodegenerative diseases. The current study examines the impact of SUMO1 on processing of the amyloid precursor protein (APP) leading to the production and deposition of the amyloid-β (Aβ) peptide. An in vivo model of these pathways was developed by the generation of double transgenic mice over-expressing human SUMO1 and a mutant APP. The SUMO1-APP transgenics displayed normal APP processing but, at later ages, exhibited increased insoluble Aβ and plaque density accompanied by increased dendritic spine loss, more pronounced synaptic and cognitive deficits. These findings suggest a potential impairment in Aβ clearance as opposed to increased amyloid production. Examination of microglia indicated a reduction in the SUMO1-APP transgenics which is a possible mechanism for the SUMO1-mediated increase in amyloid load. These findings suggest an indirect activity of SUMO1 possibly in the removal of Aβ plaques rather than a direct impact on amyloid generation.

Mortality of migratory bat species at wind energy facilities is a well-documented phenomenon, and mitigation and management are partially constrained by the current limited knowledge of bat migratory movements. Analyses of biochemical signatures in bat tissues (“intrinsic markers”) can provide information about the migratory origins of individual bats. Many tissue samples for intrinsic marker analysis may be collected from living and dead bats, including carcasses collected at wind energy facilities. In this paper, we review the full suite of available intrinsic marker analysis techniques that may be used to study bat migration, with the goal of summarizing the current literature and highlighting knowledge gaps and opportunities. We discuss applications of the stable isotopes of hydrogen, oxygen, nitrogen, carbon, sulfur; radiogenic strontium isotopes; trace elements and contaminants; and the combination of these markers with each other and with other extrinsic markers. We further discuss the tissue types that may be analyzed for each and provide a synthesis of the generalized workflow required to link bats to origins using intrinsic markers. While stable hydrogen isotope techniques have clearly been the leading approach to infer migratory bat movement patterns across the landscape, here we emphasize a variety of lesser used intrinsic markers (i.e., strontium, trace elements, contaminants) that may address new study areas or answer novel research questions.

Sugar intake is a potentially important aspect of diet which has not previously been validated in the Adventist Health Study-2 (AHS-2). We sought to validate the food frequency questionnaire (FFQ) measurement of total sugars, added sugars, sucrose, and fructose against multiple 24-h dietary recalls (recalls) in AHS-2 participants. Food consumption data from a self-administered FFQ and six recalls from 904 participants were combined with nutrient profile data to estimate daily sugar intake. Validity was evaluated among all participants and by race. FFQ and recall means were compared and correlation coefficients (Spearman’s, energy-adjusted log-transformed Pearson’s, deattenuated Pearson’s) were calculated. Mean total energy, total sugars, and fructose intake were higher in the FFQ, whereas added sugars and sucrose were higher in recalls. The energy-adjusted (log-transformed) deattenuated correlations among all participants were: total sugars (r = 0.42, 95% CI 0.32–0.52), added sugars (r = 0.50, 95% CI 0.36–0.59), sucrose (r = 0.32, 95% CI 0.23–0.42), and fructose (r = 0.50, 95% CI 0.40–0.59). We observed moderate validity for added sugars and fructose and low-moderate validity for total sugars and sucrose measured by the AHS-2 FFQ in this population. Dietary sugar estimates from this FFQ may be useful in assessing possible associations of sugars intake with health outcomes.

Background: Few research studies have focused on the effects of dietary protein on metabolic syndrome and its components. Our objective was to determine the relationship between the type of dietary protein intake and animal to plant (AP) protein ratio with metabolic syndrome and its components. Methods: This population-based study had a cross sectional design and conducted on 518 participants of the Adventist Health Study 2 (AHS-2) Calibration Study. Two sets of three dietary 24-h recalls were obtained six months apart. Anthropometric measures and biochemical tests were performed in clinics. Regression calibration models were used to determine the association of type of dietary protein with metabolic syndrome and its components (raised triglyceride, raised blood pressure, reduced high-density lipoprotein cholesterol (HDL), raised fasting blood glucose and increased waist circumference). Results: The likelihood of metabolic syndrome was lower in those with higher total dietary protein and animal protein intake (p = 0.02).Total protein (β = 0.004, [95%CI: 0.002, 0.007]), animal protein intake (β = 0.004, [95%CI: 0.001, 0.007]) and AP protein intake ratio (β = 0.034, [95%CI: 0.021, 0.047]) were positively associated with waist circumference. Higher AP protein ratio was related to higher fasting blood glucose (β = 0.023, [95%CI: 0.005, 0.041]). Conclusion: Our study suggests that considering a significant amount of plant protein as a part of total dietary protein has beneficial effects on cardiometabolic risk factors.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12868-021-00644-1

Branching morphogenesis underlies organogenesis in vertebrates and invertebrates, yet is incompletely understood. Here, we show that the sarco-endoplasmic reticulum Ca2+ reuptake pump (SERCA) directs budding across germ layers and species. Clonal knockdown demonstrated a cell-autonomous role for SERCA in Drosophila air sac budding. Live imaging of Drosophila tracheogenesis revealed elevated Ca2+ levels in migratory tip cells as they form branches. SERCA blockade abolished this Ca2+ differential, aborting both cell migration and new branching. Activating protein kinase C (PKC) rescued Ca2+ in tip cells and restored cell migration and branching. Likewise, inhibiting SERCA abolished mammalian epithelial budding, PKC activation rescued budding, while morphogens did not. Mesoderm (zebrafish angiogenesis) and ectoderm (Drosophila nervous system) behaved similarly, suggesting a conserved requirement for cell-autonomous Ca2+ signaling, established by SERCA, in iterative budding.

Summary: Interrogation of gene regulatory circuits in complex organisms requires precise tools for the selection of individual cell types and robust methods for biochemical profiling of target proteins. We have developed a versatile, tissue-specific binary in vivo biotinylation system in zebrafish termed biotagging that uses genetically encoded components to biotinylate target proteins, enabling in-depth genome-wide analyses of their molecular interactions. Using tissue-specific drivers and cell-compartment-specific effector lines, we demonstrate the specificity of the biotagging toolkit at the biochemical, cellular, and transcriptional levels. We use biotagging to characterize the in vivo transcriptional landscape of migratory neural crest and myocardial cells in different cellular compartments (ribosomes and nucleus). These analyses reveal a comprehensive network of coding and non-coding RNAs and cis-regulatory modules, demonstrating that tissue-specific identity is embedded in the nuclear transcriptomes. By eliminating background inherent to complex embryonic environments, biotagging allows analyses of molecular interactions at high resolution. : A genetically encoded in vivo biotinylation system in zebrafish developed by Trinh et al. reveals cell-type- and subcellular-compartment-specific coding and non-coding RNAs in developing cardiomyocytes and neural crest cells. Characterization of non-coding RNAs in neural crest reveals bidirectionally transcribed cis-regulatory elements that define a specific gene regulatory signature. Keywords: in vivo biotinylation, nuclear transcriptome, neural crest, myocardium, enhancers, cis-regulation, bi-directional transcription