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Introduction The Promoting Activity, Independence and Stability in Early Dementia (PrAISED) is delivering an exercise programme for people with dementia. The Lincolnshire partnership NHS foundation Trust successfully delivered PrAISED through a video-calling platform during the COVID-19 pandemic. Objectives This qualitative case-study identified participants that video delivery worked for, and highlighted its benefits and challenges. Methods Interviews were conducted with participants with dementia, caregivers and therapists, and analysed through thematic analysis. Results Video delivery worked best when participants had a supporting carer, when therapists showed enthusiasm and had an established rapport with the client. Benefits included time-efficiency of sessions, enhancing participants’ motivation, caregivers’ dementia awareness and therapists’ creativity. Limitations included users’ poor IT skills and resources. Conclusions The COVID-19 pandemic required innovative ways of delivering rehabilitation. This study supports that people with dementia can use tele rehab, but success is reliant on having a caregiver and an enthusiastic and known therapist.

Down syndrome (DS) is the most common cause of intellectual disability, yet little is known about the neurobiological pathways leading to cognitive impairments. Electroencephalographic (EEG) measures are commonly used to study neurodevelopmental disorders, but few studies have focused on young children with DS. Here we assess resting state EEG data collected from toddlers/preschoolers with DS (n = 29, age 13–48 months old) and compare their aperiodic and periodic EEG features with both age-matched (n = 29) and developmental-matched (n = 58) comparison groups. DS participants exhibited significantly reduced aperiodic slope, increased periodic theta power, and decreased alpha peak amplitude. A majority of DS participants displayed a prominent peak in the theta range, whereas a theta peak was not present in age-matched participants. Overall, similar findings were also observed when comparing DS and developmental-matched groups, suggesting that EEG differences are not explained by delayed cognitive ability.

Abstract Background We investigated the acceptability and feasibility of a new brief intervention for maternal prenatal anxiety within maternity services in London and Exeter, UK. Methods One hundred fourteen pregnant individuals attending their 12-week scan at a prenatal clinic with elevated symptoms of anxiety (GAD-7 score of ≥7) were randomly assigned to either the ACORN intervention + Treatment as usual (TAU) (n = 57) or to usual care only (n = 57). The ACORN intervention consisted of 3 2-h group sessions, led by a midwife and psychological therapist, for pregnant individuals and their partners. The intervention included psychoeducation about anxiety, strategies for problem-sovling and tolerating uncertainty during pregnancy, including communicating about these with others, and mindfulness exercises. Results Engagement rates with ACORN met or exceeded those in primary care services in England. In the intervention arm, 77% (n = 44) of participants attended at least one session, 51% (n = 29) were adherent, defined as attending two or more sessions. Feedback was positive, and participants in the ACORN treatment group demonstrated evidence of a larger drop in their levels of anxiety than the participants in the TAU-only group (Cohen’s d = 0.42). Conclusion The ACORN intervention was acceptable to pregnant individuals and their partners and resulted in reductions in anxiety. With further evaluation in a larger-scale trial with child outcomes, there is significant potential for large scale public health benefit.

Abstract Background Differences in face processing in individuals with ASD is hypothesized to impact the development of social communication skills. This study aimed to characterize the neural correlates of face processing in 12-month-old infants at familial risk of developing ASD by (1) comparing face-sensitive event-related potentials (ERP) (Nc, N290, P400) between high-familial-risk infants who develop ASD (HR-ASD), high-familial-risk infants without ASD (HR-NoASD), and low-familial-risk infants (LR), and (2) evaluating how face-sensitive ERP components are associated with development of social communication skills. Methods 12-month-old infants participated in a study in which they were presented with alternating images of their mother’s face and the face of a stranger (LR = 45, HR-NoASD = 41, HR-ASD = 24) as EEG data were collected. Parent-reported and laboratory-observed social communication measures were obtained at 12 and 18 months. Group differences in ERP responses were evaluated using ANOVA, and multiple linear regressions were conducted with maternal education and outcome groups as covariates to assess relationships between ERP and behavioral measures. Results For each of the ERP components (Nc [negative-central], N290, and P400), the amplitude difference between mother and stranger (Mother-Stranger) trials was not statistically different between the three outcome groups (Nc p = 0.72, N290 p = 0.88, P400 p = 0.91). Marginal effects analyses found that within the LR group, a greater Nc Mother-Stranger response was associated with better expressive language skills on the Mullen Scales of Early Learning, controlling for maternal education and outcome group effects (marginal effects dy/dx = 1.15; p

Abstract Background Early identification of autism spectrum disorder (ASD) provides an opportunity for early intervention and improved developmental outcomes. The use of electroencephalography (EEG) in infancy has shown promise in predicting later ASD diagnoses and in identifying neural mechanisms underlying the disorder. Given the high co-morbidity with language impairment, we and others have speculated that infants who are later diagnosed with ASD have altered language learning, including phoneme discrimination. Phoneme learning occurs rapidly in infancy, so altered neural substrates during the first year of life may serve as early, accurate indicators of later autism diagnosis. Methods Using EEG data collected at two different ages during a passive phoneme task in infants with high familial risk for ASD, we compared the predictive accuracy of a combination of feature selection and machine learning models at 6 months (during native phoneme learning) and 12 months (after native phoneme learning), and we identified a single model with strong predictive accuracy (100%) for both ages. Samples at both ages were matched in size and diagnoses (n = 14 with later ASD; n = 40 without ASD). Features included a combination of power and nonlinear measures across the 10‑20 montage electrodes and 6 frequency bands. Predictive features at each age were compared both by feature characteristics and EEG scalp location. Additional prediction analyses were performed on all EEGs collected at 12 months; this larger sample included 67 HR infants (27 HR-ASD, 40 HR-noASD). Results Using a combination of Pearson correlation feature selection and support vector machine classifier, 100% predictive diagnostic accuracy was observed at both 6 and 12 months. Predictive features differed between the models trained on 6- versus 12-month data. At 6 months, predictive features were biased to measures from central electrodes, power measures, and frequencies in the alpha range. At 12 months, predictive features were more distributed between power and nonlinear measures, and biased toward frequencies in the beta range. However, diagnosis prediction accuracy substantially decreased in the larger, more behaviorally heterogeneous 12-month sample. Conclusions These results demonstrate that speech processing EEG measures can facilitate earlier identification of ASD but emphasize the need for age-specific predictive models with large sample sizes to develop clinically relevant classification algorithms.

Abstract Background Portion size is known to be a key driver of food intake. As consumed portions are often pre-planned, ‘ideal portion size’—an individual’s preferred meal size selected prior to eating—has been identified as a strong predictor of actual consumption. However, assessments of ideal portion size have predominantly relied on laboratory-based computer tasks, limiting use online. Therefore, this cross-sectional study sought to pilot test the validity of a web-based tool to measure ideal portion size. Methods In an online study (N = 48), participants responded to images of a range of foods. Each food was photographed in a series of different portions and loaded into an ‘image carousel’ that would allow participants to change the size of the displayed portion by moving a slider left-to-right. Using this image carousel, participants selected their ideal portion size. They also completed measures of expected satiety and expected satiation and self-reported their age and body mass index (BMI). A non-parametric correlation matrix was used to explore associations between ideal portion size and identified predictors of food intake. Results Supporting convergent validity of this measure, ideal portion size was significantly correlated with expected satiety (r s = .480) and expected satiation (r s = −.310) after controlling for effects of baseline hunger and fullness, consistent with past research. Similarly, supporting divergent validity of this measure, ideal portion size was not significantly correlated with age (r s = −.032) or BMI (r s = −.111,). Conclusions Pilot results support the validity of this web-based portion size selection tool used to measure ideal portion size, though further research is needed to validate use with comparisons to actual food intake.

Ultrafiltration (UF) was evaluated as a process by which proteins can be selectively removed from white wine as an alternative approach to protein stabilization than traditional bentonite fining. Unfined Sauvignon Blanc wine (50 L) was fractionated by UF and the retentate stabilized either by heat and/or protease treatment or bentonite fining before being recombined with the permeate. The heat stability of recombined wine was significantly improved when retentate was heated following protease (Aspergillopepsin) addition and subsequently stabilized by bentonite treatment. The combined UF/heat/protease treatment removed 59% of protein and reduced the quantity of bentonite needed to achieve protein stability by 72%, relative to bentonite treatment alone. This innovative approach to protein stabilization had no significant impact on wine quality or sensory characteristics, affording industry greater confidence in adopting this technology as a novel approach to achieving protein stability.

The coronavirus pandemic has impacted dietary quality through increased emotional eating and extended time spent at home, as well as instances of panic buying due to uncertainty over food availability. We recruited an opportunistic sample of 40 adults living in the United Kingdom (Female = 25; Mean age = 41.9 years) (SD = 14.4) without any prior history of eating disorders. Semi-structured interviews were conducted in June 2020 and focused on the impacts of the COVID-19 lockdown on eating habits and experiences of panic buying. The data were transcribed and organized using the softwares Otter and Quirkos, respectively. Reflexive thematic analysis identified positive and negative changes to eating habits. Overall, themes highlighted that effective organization was vital to manage food purchases and consumption due to a reduced shopping frequency. However, overconsumption frequently occurred due to boredom and ease of accessing energy dense foods, which had negative implications for weight and body image. After indulging, participants attempted to revert to prior eating habits and adhere to a nutritious diet. Many also expressed the importance of having enough food to feed families, which was often reported as a reason for buying extra supplies. Understanding the long-term impacts of changes to eating habits that account for the novel coronavirus context is required to preserve health and prevent unintended changes to weight.

Abstract Background The lack of robust and reliable clinical biomarkers in Fragile X Syndrome (FXS), the most common inherited form of intellectual disability, has limited the successful translation of bench-to-bedside therapeutics. While numerous drugs have shown promise in reversing synaptic and behavioral phenotypes in mouse models of FXS, none have demonstrated clinical efficacy in humans. Electroencephalographic (EEG) measures have been identified as candidate biomarkers as EEG recordings of both adults with FXS and mouse models of FXS consistently exhibit alterations in resting state and task-related activity. However, the developmental timing of these EEG differences is not known as thus far EEG studies have not focused on young children with FXS. Further, understanding how EEG differences are associated with core symptoms of FXS is crucial to successful use of EEG as a biomarker, and may improve our understanding of the disorder. Methods Resting-state EEG was collected from FXS boys with full mutation of Fmr1 (2.5–7 years old, n = 11) and compared with both age-matched (n = 12) and cognitive-matched (n = 12) typically developing boys. Power spectra (including aperiodic and periodic components) were compared using non-parametric cluster-based permutation testing. Associations between 30 and 50 Hz gamma power and cognitive, language, and behavioral measures were evaluated using Pearson correlation and linear regression with age as a covariate. Results FXS participants showed increased power in the beta/gamma range (~ 25–50 Hz) across multiple brain regions. Both a reduction in the aperiodic (1/f) slope and increase in beta/gamma periodic activity contributed to the significant increase in high-frequency power. Increased gamma power, driven by the aperiodic component, was associated with better language ability in the FXS group. No association was observed between gamma power and parent report measures of behavioral challenges, sensory hypersensitivities, or adaptive behaviors. Limitations The study sample size was small, although comparable to other human studies in rare-genetic disorders. Findings are also limited to males in the age range studied. Conclusions Resting-state EEG measures from this study in young boys with FXS identified similar increases in gamma power previously reported in adults and mouse models. The observed positive association between resting state aperiodic gamma power and language development supports hypotheses that alterations in some EEG measures may reflect ongoing compensatory mechanisms.

Abstract Background ‘Food variety’ is a key term that is frequently used in dietary guidelines around the world. Consuming a variety of foods – be it within a meal, across meals, or as part of the whole diet – is one factor that has been shown to increase food intake. However, little is known about consumer understanding of variety, and this may be a potential barrier to the success of dietary guidelines in today’s ‘obesogenic’ environment. This research sought to explore 1) consumer recognition of different forms of variety, and 2) consumer definitions of variety. Methods In an online study (N = 240), participants were asked to discuss a range of photographs depicting different forms of variety, and to directly define the term ‘food variety’. They were unaware of the research aim. Results Using a mixed methods approach, directed content analysis of these data showed that individuals referenced multiple forms of variety in the presence of food photographs. However, when asked to define variety, participants tended to only discuss variety in the context of the whole diet. Conclusions These findings emphasise a need to educate consumers about variety to encourage adherence to dietary guidelines and help consumers better manage their own food intake.

Vascular endothelial cell (EC) dysfunction contributes to the occurrence of diabetic complications. Here the authors report that in diabetic conditions, upregulation of the RNA binding protein QKI-7 in ECs due to the imbalance of RNA splicing factors CUG-BP and hnRNPM contributes to EC dysfunction, and that in vivo QKI-7 silencing improves blood flow recovery in diabetic mice with limb ischemia.

AbstractLanguage development in children with autism spectrum disorder (ASD) varies greatly among affected individuals and is a strong predictor of later outcomes. Younger siblings of children with ASD have increased risk of ASD, but also language delay. Identifying neural markers of language outcomes in infant siblings could facilitate earlier intervention and improved outcomes. This study aimed to determine whether electroencephalography (EEG) measures from the first 2 years of life can explain heterogeneity in language development in children at low and high risk for ASD, and whether associations between EEG measures and language development are different depending on ASD risk status or later ASD diagnosis. In this prospective longitudinal study, EEG measures collected between 3 and 24 months were used in a multivariate linear regression model to estimate participants’ 24-month language development. Individual baseline longitudinal EEG measures included (1) the slope of EEG power across 3 to 12 months or 3 to 24 months of life for six canonical frequency bands, (2) the estimated EEG power at 6 months of age for the same frequency bands, and (3) terms representing the interaction between ASD risk status and EEG power measures. Modeled 24-month language scores using EEG data from either the first 2 years (Pearson p = 0.70, 95% CI [0.595, 0.783], p = 1 × 10−18) or the first year of life (Pearson p = 0.66, 95% CI [0.540, 0.761], p = 2.5 × 10−14) were highly correlated with observed scores. All models included significant interaction effects of risk on EEG measures, suggesting that EEG-language associations are different depending on risk status, and that different brain mechanisms affect language development in low- versus high-risk infants.

ABSTRACT The black-headed night monkey, Aotus nigriceps, has one of the largest distribution ranges of the 11 night monkey species found across Central and South America. Yet, only three studies have focused on their ecology, describing considerable variation in habitat, group composition, and population density. Therefore, we analyzed habitat use, group composition, population density, and diet of 14 groups at two field sites in southeastern Peru. All sampled groups were found in secondary tropical rainforest, often dominated by native bamboo species. Half of the observed sleeping sites were in bamboo stands, though groups also emerged from cane thickets and lianas. This contrasts with other Aotus studies which have found groups living in tree cavities and lianas. Population density estimates for both sites were 19 and 50 individuals per km2, outside the range previously reported for A. nigriceps (31−34 individuals per km2). We recovered seeds of 12 species from fecal samples over the course of two field seasons, belonging mainly to Cecropiaceae, Piperaceae and Moraceae. Our results suggest that the black-headed night monkey in Peru can survive and even thrive in secondary forest, feeding extensively on pioneer species, occupying a range of forest types, all while living near human settlements.

Abstract Objective: PRONTO!, a peer‐led rapid HIV‐testing service in Melbourne, Australia, opened to improve HIV testing among gay and bisexual men (GBM). We compared client characteristics and return testing among GBM testing at PRONTO! with GBM testing at Melbourne Sexual Health Centre (MSHC). Methods: All GBM attending PRONTO! and MSHC for HIV testing between August 2013 and April 2016 were included. We describe the number of tests, percentage of clients who returned during follow‐up, the mean number of tests and median time between tests at the two services. Results: At PRONTO!, 33% of 3,102 GBM and at MSHC 50% of 9,836 GBM returned for a further HIV test at least once. The mean number of tests per client was 1.7 and 2.5 at PRONTO! and MSHC (p

Abnormal uptake or metabolism of folate increases risk of human pregnancy complications, though the mechanism is unclear. Here, we explore how defective folate metabolism influences early development by analysing mice with the hypomorphic Mtrrgt mutation. MTRR is necessary for methyl group utilisation from folate metabolism, and the Mtrrgt allele disrupts this process. We show that the spectrum of phenotypes previously observed in Mtrrgt/gt conceptuses at embryonic day (E) 10.5 is apparent from E8.5 including developmental delay, congenital malformations, and placental phenotypes. Notably, we report misalignment of some Mtrrgt conceptuses within their implantation sites from E6.5. The degree of misorientation occurs across a continuum, with the most severe form visible upon gross dissection. Additionally, some Mtrrgt/gt conceptuses display twinning. Therefore, we implicate folate metabolism in blastocyst orientation and spacing at implantation. Skewed growth likely influences embryo development since developmental delay and heart malformations (but not defects in neural tube closure or trophoblast differentiation) associate with severe misalignment of Mtrrgt/gt conceptuses. Typically, the uterus is thought to guide conceptus orientation. To investigate a uterine effect of the Mtrrgt allele, we manipulate the maternal Mtrr genotype. Misaligned conceptuses were observed in litters of Mtrr+/+, Mtrr+/gt, and Mtrrgt/gt mothers. While progesterone and/or BMP2 signalling might be disrupted, normal decidual morphology, patterning, and blood perfusion are evident at E6.5 regardless of conceptus orientation. These observations argue against a post-implantation uterine defect as a cause of conceptus misalignment. Since litters of Mtrr+/+ mothers display conceptus misalignment, a grandparental effect is explored. Multigenerational phenotype inheritance is characteristic of the Mtrrgt model, though the mechanism remains unclear. Genetic pedigree analysis reveals that severe conceptus skewing associates with the Mtrr genotype of either maternal grandparent. Moreover, the presence of conceptus skewing after embryo transfer into a control uterus indicates that misalignment is independent of the peri- and/or post-implantation uterus and instead is likely attributed to an embryonic mechanism that is epigenetically inherited. Overall, our data indicates that abnormal folate metabolism influences conceptus orientation over multiple generations with implications for subsequent development. This study casts light on the complex role of folate metabolism during development beyond a direct maternal effect.

Smoke taint has become a prominent issue for the global wine industry as climate change continues to impact the length and extremity of fire seasons around the world. When grapevines are exposed to smoke, their leaves and fruit can adsorb volatile smoke compounds (for example, volatile phenols such as guaiacol, 4-methylguaiacol, o-, m- and p-cresol, and syringol), which can initially be detected in free (aglycone) forms but are rapidly converted to glycoconjugate forms due to glycosylation. During the fermentation process, these glycoconjugates can be broken down, releasing volatile phenols that contribute undesirable sensory characteristics to the resultant wine (i.e. smokey and ashy attributes). Several methods have been evaluated, both viticultural measures and winemaking techniques, for mitigating and/or remediating the negative effects of grapevine smoke exposure. While there is currently no single method that universally solves the problem of smoke taint, this paper outlines the tools available that can help to minimize the negative impacts of smoke taint (Figure 1).

Elevated serum concentrations of leucine-rich α-2-glycoprotein (LRG1) have been reported in patients with inflammatory, autoimmune, and cardiovascular diseases. This study aims to investigate the role of LRG1 in endothelial activation. LRG1 in endothelial cells (ECs) of arteries and serum of patients with critical limb ischemia (CLI) was assessed by immunohistochemistry and ELISA, respectively. LRG1 expression in sheared and tumor necrosis factor-α (TNF-α)-treated ECs was analyzed. The mechanistic role of LRG1 in endothelial activation was studied in vitro. Plasma of 37-week-old Lrg1–/– mice was used to investigate causality between LRG1 and tumor necrosis factor receptor 1 (TNFR1) shedding. LRG1 was highly expressed in ECs of stenotic but not normal arteries. LRG1 concentrations in serum of patients with CLI were elevated compared to healthy controls. LRG1 expression was shear dependent. It could be induced by TNF-α, and the induction of its expression was mediated by NF-κB activation. LRG1 inhibited TNF-α-induced activation of NF-κB signaling, expression of VCAM-1 and ICAM-1, and monocyte capture, firm adhesion, and transendothelial migration. Mechanistically, LRG1 exerted its function by causing the shedding of TNFR1 via the ALK5-SMAD2 pathway and the subsequent activation of ADAM10. Consistent with this mechanism, LRG1 and sTNFR1 concentrations were correlated in the serum of CLI patients. Causality between LRG1 and TNFR1 shedding was established by showing that Lrg1–/–mice had lower plasma sTNFR1 concentrations than wild type mice. Our results demonstrate a novel role for LRG1 in endothelial activation and its potential therapeutic role in inflammatory diseases should be investigated further.

Fatty acid nitroalkenes are reversibly-reactive electrophiles that are endogenously detectable at nM concentrations and display anti-inflammatory, pro-survival actions. These actions are elicited through the alteration of signal transduction proteins via a Michael addition on nucleophilic cysteine thiols. Nitrated fatty acids (NO 2 -FAs), like 9- or 10-nitro-octadec-9-enolic acid, will act on signal transduction proteins directly or on key regulatory proteins to cause an up-regulation or down-regulation of the protein’s expression, yielding an anti-inflammatory response. These responses have been characterized in many organ systems, such as the cardiovascular system, with the pulmonary system less well defined. Macrophages are one of the most abundant immune cells in the lung and are essential in maintaining lung homeostasis. Despite this, macrophages can play a role in both acute and chronic lung injury due to up-regulation of anti-inflammatory signal transduction pathways and down-regulation of pro-inflammatory pathways. Through their propensity to alter signal transduction pathways, NO 2 -FAs may be able to reduce macrophage activation during pulmonary injury. This review will focus on the implications of NO 2 -FAs on macrophage activation in the lung and the signal transduction pathways that may be altered, leading to reduced pulmonary injury.

Alzheimer’s disease (AD) is characterized by the progressive accumulation of amyloid-β and hyperphosphorylated tau (pTau), which can spread throughout the brain via extracellular vesicles (EVs). Membrane ceramide enrichment regulated by the enzyme neutral sphingomyelinase 2 (nSMase2) is a critical component of at least one EV biogenesis pathway. Our group recently identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), the most potent (30 nM) and selective inhibitor of nSMase2 reported to date. However, DPTIP exhibits poor oral pharmacokinetics (PK), modest brain penetration, and rapid clearance, limiting its clinical translation. To enhance its PK properties, we conjugated DPTIP to a hydroxyl-PAMAM dendrimer delivery system, creating dendrimer-DPTIP (D-DPTIP). In an acute brain injury model, orally administered D-DPTIP significantly reduced the intra-striatal IL-1β-induced increase in plasma EVs up to 72 h post-dose, while oral DPTIP had a limited effect. In a mouse tau propagation model, where a mutant hTau (P301L/S320F) containing adeno-associated virus was unilaterally seeded into the hippocampus, oral D-DPTIP (dosed 3× weekly) significantly inhibited brain nSMase2 activity and blocked the spread of pTau to the contralateral hippocampus. These data demonstrate that dendrimer conjugation of DPTIP improves its PK properties, resulting in significant inhibition of EV propagation of pTau in mice. Dendrimer-based delivery of DPTIP has the potential to be an exciting new therapeutic for AD.

Vineyard exposure to wildfire smoke can taint grapes and wine. To understand the impact of this taint, it is imperative that the analytical methods used are accurate and precise. This study compared the variance across nine commercial and research laboratories following quantitative analysis of the same set of smoke-tainted wines. In parallel, correlations between the interlaboratory consensus values for smoke-taint markers and sensory analyses of the same smoke-tainted wines were evaluated. For free guaiacol, the mean accuracy was 94 ± 11% in model wine, while the free cresols and 4-methylguaiacol showed a negative bias and/or decreased precision relative to guaiacol. Similar trends were observed in smoke-tainted wines, with the cresols and glycosidically bound markers demonstrating high variance. Collectively, the interlaboratory results show that data from a single laboratory can be used quantitatively to understand smoke-taint. Results from different laboratories, however, should not be directly compared due to the high variance between study participants. Correlations between consensus compositional data and sensory evaluations suggest the risk of perceivable smoke-taint can be predicted from free cresol concentrations, overcoming limitations associated with the occurrence of some volatile phenols, guaiacol in particular, as natural constituents of some grape cultivars and of the oak used for barrel maturation.

Abstract Melanins are a class of biopolymers that are widespread in nature and have diverse origins, chemical compositions, and functions. Their chemical, electrical, optical, and paramagnetic properties offer opportunities for applications in materials science, particularly for medical and technical uses. This review focuses on the application of analytical techniques to study melanins in multidisciplinary contexts with a view to their use as sustainable resources for advanced biotechnological applications, and how these may facilitate the achievement of the United Nations Sustainable Development Goals.

Scavenger receptor class F member 1 (SCARF1) is thought to play an important role in the selective recruitment of CD4+ T cells to liver sinusoidal endothelial cells during chronic liver disease. However, the contribution of SCARF1 to hepatocellular carcinoma (HCC) is currently unknown. We utilized publically-available RNA-sequencing data from The Cancer Genome Atlas (TGCA) to explore SCARF1 expression in HCC and correlated it with a number of clinicopathological features. Flow adhesion assays were used to determine the role of SCARF1 in CD4+ T cell subset recruitment. SCARF1 expression was downregulated in HCC tumor tissues, compared to non-tumoral tissues, and loss of SCARF1 expression was associated with poorly differentiated/aggressive tumors. Additionally, higher SCARF1 expression in HCC tumor tissues was highly prognostic of better overall, disease-free and progression-free survival. SCARF1 within HCC was largely associated with tumor endothelial cells and adhesion studies suggested that it played a role in the specific recruitment of proinflammatory CD4+ T cells (CD4+CD25−) to HCC tumor tissues. Endothelial SCARF1 expression in tumor biopsies may provide critical prognostic information. Additionally, SCARF1 may also be a novel endothelial target that could help re-programme the microenvironment of HCC by promoting effector T cell tumor infiltration.

Liver sinusoidal endothelial cells (LSEC) form a unique barrier between the liver sinusoids and the underlying parenchyma, and thus play a crucial role in maintaining metabolic and immune homeostasis, as well as actively contributing to disease pathophysiology. Whilst their endocytic and scavenging function is integral for nutrient exchange and clearance of waste products, their capillarisation and dysfunction precedes fibrogenesis. Furthermore, their ability to promote immune tolerance and recruit distinct immunosuppressive leukocyte subsets can allow persistence of chronic viral infections and facilitate tumour development. In this review, we present the immunological and barrier functions of LSEC, along with their role in orchestrating fibrotic processes which precede tumourigenesis. We also summarise the role of LSEC in modulating the tumour microenvironment, and promoting development of a pre-metastatic niche, which can drive formation of secondary liver tumours. Finally, we summarise closely inter-linked disease pathways which collectively perpetuate pathogenesis, highlighting LSEC as novel targets for therapeutic intervention.

The liver is our largest internal organ and it plays major roles in drug detoxification and immunity, where the ingestion of extracellular material through phagocytosis is a critical pathway. Phagocytosis is the deliberate endocytosis of large particles, microbes, dead cells or cell debris and can lead to cell-in-cell structures. Various types of cell endocytosis have been recently described for hepatic epithelia (hepatocytes), which are non-professional phagocytes. Given that up to 80% of the liver comprises hepatocytes, the biological impact of cell-in-cell structures in the liver can have profound effects in liver regeneration, inflammation and cancer. This review brings together the latest reports on four types of endocytosis in the liver -efferocytosis, entosis, emperipolesis and enclysis, with a focus on hepatocyte biology.

Abstract Mucopolysaccharidosis IIIA is a neuronopathic lysosomal storage disease, characterised by heparan sulphate and other substrates accumulating in the brain. Patients develop behavioural disturbances and cognitive decline, a possible consequence of neuroinflammation and abnormal substrate accumulation. Interleukin (IL)‐1β and interleukin‐1 receptor antagonist (IL‐1Ra) expression were significantly increased in both murine models and human MPSIII patients. We identified pathogenic mechanisms of inflammasome activation, including that disease‐specific 2‐O‐sulphated heparan sulphate was essential for priming an IL‐1β response via the Toll‐like receptor 4 complex. However, mucopolysaccharidosis IIIA primary and secondary storage substrates, such as amyloid beta, were both required to activate the NLRP3 inflammasome and initiate IL‐1β secretion. IL‐1 blockade in mucopolysaccharidosis IIIA mice using IL‐1 receptor type 1 knockout or haematopoietic stem cell gene therapy over‐expressing IL‐1Ra reduced gliosis and completely prevented behavioural phenotypes. In conclusion, we demonstrate that IL‐1 drives neuroinflammation, behavioural abnormality and cognitive decline in mucopolysaccharidosis IIIA, highlighting haematopoietic stem cell gene therapy treatment with IL‐1Ra as a potential neuronopathic lysosomal disease treatment.

ABSTRACT Kinetoplastid parasites, including Trypanosoma brucei, Trypanosoma cruzi, and Leishmania, harbor unique organelles known as glycosomes, which are evolutionarily related to peroxisomes. Glycosome/peroxisome biogenesis is mediated by proteins called peroxins that facilitate organelle formation, proliferation, and degradation and import of proteins housed therein. Import of matrix proteins occurs via one of two pathways that are dictated by their peroxisome targeting sequence (PTS). In PTS1 import, a C-terminal tripeptide sequence, most commonly SKL, is recognized by the soluble receptor Pex5. In PTS2 import, a less conserved N-terminal sequence is recognized by Pex7. The soluble receptors deliver their cargo to the import channel consisting minimally of Pex13 and Pex14. While much of the import process is conserved, kinetoplastids are the only organisms to have two Pex13s, Pex13.1 and Pex13.2. It is unclear why trypanosomes require two Pex13s when one is sufficient for most eukaryotes. To interrogate the role of Pex13.2, we have employed biochemical approaches to partially resolve the composition of the Pex13/Pex14 import complexes in T. brucei and characterized glycosome morphology and protein import in Pex13.2-deficient parasites. Here, we show that Pex13.2 is an integral glycosome membrane protein that interacts with Pex13.1 and Pex14. The N terminus of Pex13.2 faces the cytoplasmic side of the membrane, where it can facilitate interactions required for protein import. Two-dimensional gel electrophoresis revealed three glycosome membrane complexes containing combinations of Pex13.1, Pex13.2, and Pex14. The silencing of Pex13.2 resulted in parasites with fewer, larger glycosomes and disrupted glycosome protein import, suggesting the protein is involved in glycosome biogenesis as well as protein import. Furthermore, superresolution microscopy demonstrated that Pex13.2 localizes to discrete foci in the glycosome periphery, indicating that the glycosome periphery is not homogenous. IMPORTANCE Trypanosoma brucei causes human African trypanosomiasis and a wasting disease called Nagana in livestock. Current treatments are expensive, toxic, and difficult to administer. Because of this, the search for new drug targets is essential. T. brucei has glycosomes that are essential to parasite survival; however, our ability to target them in drug development is hindered by our lack of understanding about how these organelles are formed and maintained. This work forwards our understanding of how the parasite-specific protein Pex13.2 functions in glycosome protein import and lays the foundation for future studies focused on blocking Pex13.2 function, which would be lethal to bloodstream-form parasites that reside in the mammalian bloodstream.

Summary: Background: Building on substantial tobacco control action over the previous decade, Australia increased the taxes on tobacco by 25% without forewarning on April 30, 2010. Australia then became one of a few countries to pre-announce a series of increases in tobacco taxes, with annual 12·5% increases starting from December, 2013. We aimed to examine the effects of both tax increases on smoking prevalence. Methods: By use of survey data from Australians aged 14 years and older in five capital cities, we did an interrupted time-series analysis to model the monthly prevalence of smoking (overall, of factory-made cigarettes [FMC], and of roll-your-own tobacco [RYO]), in the total sample and stratified by socioeconomic status subgroups. We measured outcomes in May, 2001–April, 2010; May, 2010–November, 2013; and December, 2013–April, 2017. Findings: The 25% tax increase was associated with immediate (−0·745 percentage points; 95% CI −1·378 to −0·112) and sustained reductions in prevalence (monthly trend −0·023 percentage points; −0·044 to −0·003), which were driven by reductions in the prevalence of smoking of FMC. The prevalence of smoking of RYO increased between May, 2010, and November, 2013, after the 25% tax increase. At the start of the pre-announced annual 12·5% increases, we observed an immediate reduction in smoking (−0·997 percentage points; −1·632 to −0·362), followed by decreasing overall prevalence (monthly trend −0·044 percentage points; −0·063 to −0·026) due to ongoing decreases in the prevalence of FMC smoking and a cessation of increases in the prevalence of smoking of RYO. Immediate decreases in smoking and changing trends in the prevalence of smoking of RYO were most evident among groups with a lower socioeconomic status. Interpretation: Large tax increases are effective in reducing smoking prevalence, both as a single increase without forewarning and as a pre-announced series of increases. However, taxes on tobacco are best structured to apply equally to FMC and RYO products. Tobacco control policies should prohibit price marketing that otherwise erodes the full impact of such tax increases. Funding: Cancer Council Victoria.

Wildfire represents the largest areal disturbance of forested boreal peatlands and the spatial variability in the severity of these peat fires is both a leading source of uncertainty in boreal wildfire carbon emissions and a major challenge for regional wildfire management. Peat smoldering can emit large quantities of carbon and smoke to the atmosphere, and therefore can contribute to hazardous air quality. The wildland-industry interface and wildland-urban interface are both extensive across the sub-humid boreal plains (BP) ecozone where one-third of the area is covered by peatlands. As such, there is a growing research need to identify drivers of variability in smoldering combustion. This study uses hydrophysical peat properties to assess the drivers of cross-scale variability in peat smoldering combustion vulnerability in forested peatlands across the BP. Using a space-for-time chronosequence across the 120 year fire return interval and three main hydrogeological settings, and by incorporating hummock, hollow and margin locations, cross-scale variability is studied. We find that, based on peat properties such as specific yield (Sy) and gravimetric water content, forested peatland margins represent areas of high peat smoldering vulnerability, and that this is exacerbated with an increasing time-since-fire (stand-age). Although increasing Sy with time-since-fire in peatland middles may buffer water table drawdown, when accounting for increases in canopy fuel load, transpiration, and feather moss dominance forested peatland middles also become more vulnerable to smoldering combustion with time-since-fire. Moreover, the interaction of peatland margins with coarse- and heterogeneous-grained hydrogeological settings leads to lower Sy and higher density margin peat than in fine-grained settings, further increasing smoldering vulnerability. We estimate that forested peatland margins are vulnerable to combustion throughout their entire profile i.e., burn-out, under moderate-high water deficits in the BP. Furthermore, we identify peatland margin: total area ratio as a driver of smoldering vulnerability where small peatlands that are periodically disconnected from regional groundwater systems are the most vulnerable to high total peat carbon loss. We suggest that these drivers of cross-scale variability should be incorporated into peatland and wildfire management strategies, especially in areas near the wildland-industry and wildland-urban interface.

Summary: CD4+ T cells play critical roles in directing immunity, both as T helper and as regulatory T (Treg) cells. Here, we demonstrate that hepatocytes can modulate T cell populations through engulfment of live CD4+ lymphocytes. We term this phenomenon enclysis to reflect the specific enclosure of CD4+ T cells in hepatocytes. Enclysis is selective for CD4+ but not CD8+ cells, independent of antigen-specific activation, and occurs in human hepatocytes in vitro, ex vivo, and in vivo. Intercellular adhesion molecule 1 (ICAM-1) facilitates T cell early adhesion and internalization, whereas hepatocytes form membrane lamellipodia or blebs to mediate engulfment. T cell internalization is unaffected by wortmannin and Rho kinase inhibition. Hepatocytes engulf Treg cells more efficiently than non-Treg cells, but Treg cell-containing vesicles preferentially acidify overnight. Thus, enclysis is a biological process with potential effects on immunomodulation and opens a new field for research to fully understand CD4+ T cell dynamics in liver inflammation. : Enclysis describes the enclosure of live CD4+ T cells in intracellular vesicles. Davies et al. show that hepatocytes engulf regulatory T (Treg) cells and preferentially delete them. Enclysis is distinct from entosis, efferocytosis, and suicidal emperipolesis and may be targeted to control T cell populations in the liver during inflammation. Keywords: T cells, hepatocytes, enclysis, entosis, efferocytosis, endocytosis, emperipolesis, cell-in-cell structures, liver, β-catenin

Cell membrane thyroid hormone (TH) transport can be facilitated by the monocarboxylate transporter 8 (MCT8), encoded by the solute carrier family 16 member 2 (SLC16A2) gene. Human mutations of the gene, SLC16A2, result in the X-linked-inherited psychomotor retardation and hypomyelination disorder, Allan-Herndon-Dudley syndrome (AHDS). We posited that abrogating MCT8-dependent TH transport limits oligodendrogenesis and myelination. We show that human oligodendrocytes (OL), derived from the NKX2.1-GFP human embryonic stem cell (hESC) reporter line, express MCT8. Moreover, treatment of these cultures with DITPA (an MCT8-independent TH analog), up-regulates OL differentiation transcription factors and myelin gene expression. DITPA promotes hESC-derived OL myelination of retinal ganglion axons in co-culture. Pharmacological and genetic blockade of MCT8 induces significant OL apoptosis, impairing myelination. DITPA treatment limits OL apoptosis mediated by SLC16A2 down-regulation primarily signaling through AKT phosphorylation, driving myelination. Our results highlight the potential role of MCT8 in TH transport for human OL development and may implicate DITPA as a promising treatment for developmentally-regulated myelination in AHDS.

Abstract Background The 2012 regulatory approval of HIV rapid point of care (RPOC) tests in Australia and a national strategic focus on HIV testing provided a catalyst for implementation of non-clinical HIV testing service models. PRONTO! opened in 2013 as a two-year trial delivering peer-led community-based HIV RPOC tests targeting gay, bisexual and other men who have sex with men (GBM), with the aim of increasing HIV testing frequency. Initial data suggested this aim was not achieved and, as part of a broader service evaluation, we sought to explore client acceptability and barriers to testing at PRONTO! to refine the service model. Methods We present descriptive and thematic analyses of data from two in-depth evaluation surveys and four focus groups with PRONTO! clients focused on service acceptability, client testing history, intentions to test and barriers to testing for HIV and other sexually transmitted infections (STIs). Results The three novel aspects of the PRONTO! model, testing environment, rapid-testing, peer-staff, were reported to be highly acceptable among survey and focus group participants. Focus group discussions revealed that the PRONTO! model reduced anxiety associated with HIV testing and created a comfortable environment conducive to discussing sexual risk and health. However, an absence of STI testing at PRONTO!, driven by restrictions on medical subsidies for STI testing and limited funds available at the service level created a barrier to HIV testing. An overwhelming majority of PRONTO! clients reported usually testing for STIs alongside HIV and most reported plans to seek STI testing after testing for HIV at PRONTO!. When deciding where, when and what to test for, clients reported balancing convenience and relative risk and consequences for each infection as guiding their decision-making. Conclusions A community-based and peer-led HIV testing model reduced previously reported barriers to HIV testing, while introducing new barriers. The absence of STI testing at PRONTO! and the need to access multiple services for comprehensive sexual health screening, created a significant service engagement barrier for some clients. Understanding client motivations to access testing and ensuring novel service models meet client needs is crucial for developing acceptable sexual health services for high-risk populations.

Taint in grapes and wine following vineyard exposure to bushfire smoke continues to challenge the financial viability of grape and wine producers worldwide. In response, researchers are studying the chemical, sensory and physiological consequences of grapevine smoke exposure. However, studies involving winemaking trials are often limited by the availability of suitable quantities of smoke-affected grapes, either from vineyards exposed to smoke or from field trials involving the application of smoke to grapevines. This study compared the accumulation of volatile phenol glycosides (as compositional markers of smoke taint) in Viognier and Cabernet Sauvignon grapes exposed to smoke pre- vs. post-harvest, and found post-harvest smoke exposure of fruit gave similar levels of volatile phenol glycosides to fruit exposed to smoke pre-harvest. Furthermore, wines made from smoke-affected fruit contained similar levels of smoke-derived volatile phenols and their glycosides, irrespective of whether smoke exposure occurred pre- vs. post-harvest. Post-harvest smoke exposure therefore provides a valid approach to generating smoke-affected grapes in the quantities needed for winemaking trials and/or trials that employ both chemical and sensory analysis of wine.