EXPRESS: Contextual diversity and anchoring: Null effects on learning word forms and opposing effects on learning word meanings.

Words that appear in many contexts/topics are recognised faster than those occurring in fewer contexts (Nation, 2017). However, contextual diversity benefits are less clear in word learning studies. Mak et al. (2021) proposed that diversity benefits might be enhanced if new word meanings are anchored before introducing diversity. In our study, adults (N = 288) learned meanings for eight pseudowords, four experienced in six topics (high diversity) and four in one topic (low diversity). All items were first experienced five times in one topic (anchoring phase), and results were compared to Norman et al. (2022) which used a similar paradigm without an anchoring phase. An old-new decision post-test (did you learn this word?) showed null effects of contextual diversity on written form recognition accuracy and response time, mirroring Norman et al.. A cloze task involved choosing which pseudoword completed a sentence. For sentences situated in a previously experienced context, accuracy was significantly higher for pseudowords learned in the low diversity condition, whereas for sentences situated in a new context, accuracy was non-significantly higher for pseudowords learned in the high diversity condition. Anchoring modulated these effects. Low diversity item accuracy was unaffected by anchoring. However, for high diversity items, accuracy in familiar contexts was better in the current experiment (anchoring) than in Norman et al. (non-anchoring), but accuracy in new contexts did not differ between the two experiments. These results suggest that anchoring facilitates meaning use in familiar contexts, but not generalisation to new contexts, nor word recognition in isolation.

Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages.

A key event in atherogenesis is the formation of lipid-loaded macrophages, lipidotic cells, which exhibit irreversible accumulation of undigested modified low-density lipoproteins (LDL) in lysosomes. This event culminates in the loss of cell homeostasis, inflammation, and cell death. Nevertheless, the exact chemical etiology of atherogenesis and the molecular and cellular mechanisms responsible for the impairment of lysosome function in plaque macrophages are still unknown. Here, we demonstrate that macrophages exposed to cholesteryl hemiazelate (ChA), one of the most prevalent products of LDL-derived cholesteryl ester oxidation, exhibit enlarged peripheral dysfunctional lysosomes full of undigested ChA and neutral lipids. Both lysosome area and accumulation of neutral lipids are partially irreversible. Interestingly, the dysfunctional peripheral lysosomes are more prone to fuse with the plasma membrane, secreting their undigested luminal content into the extracellular milieu with potential consequences for the pathology. We further demonstrate that this phenotype is mechanistically linked to the nuclear translocation of the MiT/TFE family of transcription factors. The induction of lysosome biogenesis by ChA appears to partially protect macrophages from lipid-induced cytotoxicity. In sum, our data show that ChA is involved in the etiology of lysosome dysfunction and promotes the exocytosis of these organelles. This latter event is a new mechanism that may be important in the pathogenesis of atherosclerosis.

Older Migrants and Overcoming Employment Barriers: Does Community Activism Provide the Answer?

As populations age and pension ages rise, there is a growing interest in the ability of workers to extend working life. In response to a call for a more robust dialogue on the heterogeneity of the older workforce, this article explores the interplay between different employment barriers faced by one group facing significant employment barriers: older migrants. Older Chinese migrants in the United Kingdom face multiple barriers to work resulting from age, ethnicity and the intersectionality of such barriers which creates a unique set of barriers to continued work. Community activism can play an important role in supporting older constituents, particularly in matching the skills which they have to offer with the needs within and beyond the migrant community. In this study, we use Participatory Action Research to explore with older Chinese migrants the barriers they face in the job market and how community activism can empower them in maintaining employment. As government seeks to raise real retirement ages, more research is needed on its implications for vulnerable groups of older people including migrants.

Metabolic syndrome and breast cancer survivors: a follow-up analysis after completion of chemotherapy.

BACKGROUND: We previously reported that (neo)adjuvant chemotherapy adversely altered metabolic syndrome (MetS) components, body composition, and related biomarkers after a 12 to 18-week chemotherapy treatment course in women. Here, we sought to determine whether these measures worsened within 4-5 years post-chemotherapy among the same sample of early stage breast cancer survivors. METHODS: Twenty-eight breast cancer survivors were reassessed within 4-5 years post-chemotherapy. Participants were tested for MetS, lipid profile (total cholesterol; TC, low-density lipoprotein cholesterol; LDL-C), glucose metabolism (insulin, homeostatic model- insulin resistance; HOMA-IR, glycosylated hemoglobin; HbA1c), inflammation (C-reactive protein; CRP) and body composition (body weight; BW, percent body fat; BF, fat mass; FM) during follow-up physical exams. A comparison of measurements between post-chemotherapy and follow-up periods was performed using repeated measures analysis of covariance. RESULTS: Most study patients were Caucasian (44%) or Hispanic (30%) with a mean age of 48.2 years. Average time from completion of chemotherapy was 4.75 years. At follow-up, MetS components significantly increased (p < 0.01) compared with the post chemotherapy assessment. Additionally, BF, FM, lipids (TC, LDL), glucose metabolism (HOMA-IR, insulin, HbA1c), and inflammation (CRP) significantly increased (p < 0.01). Notably BW significantly increased; mean weight gain after chemotherapy was 6.1 kg and increased an additional 8.2% at follow-up (p < 0.01). CONCLUSION: MetS components, body composition, and biomarkers continued to worsen within 4-5 years post-chemotherapy in breast cancer survivors. Energy balance interventions should target breast cancer patients to reduce the exacerbation of MetS.

The experience of blood glucose monitoring in people with type 2 diabetes mellitus (T2DM).

BACKGROUND: Finger prick blood glucose (BG) monitoring remains a mainstay of management in people with type 2 diabetes (T2DM) who take sulphonylurea (SU) drugs or insulin. We recently examined patient experience of BG monitoring in people with type 1 diabetes (T1DM). There has not been any recent comprehensive assessment of the performance of BG monitoring strips or the patient experience of BG strips in people with T2DM in the UK. METHODS: An online self-reported questionnaire containing 44 questions, prepared following consultation with clinicians and patients, was circulated to people with T2DM. 186 responders provided completed responses (25.5% return rate). Fixed responses were coded numerically (eg not confident = 0 fairly confident = 1). RESULTS: Of responders, 84% were treated with insulin in addition to other agents. 75% reported having had an HbA1c check in the previous 6 months. For those with reported HbA1c ≥ 65 mmol/mol, a majority of people (70%) were concerned or really concerned about the shorter term consequences of running a high HbA1c This contrasted with those who did not know their recent HbA1c, of whom only 33% were concerned/really concerned and those with HbA1c <65 mmol/mol of whom 35% were concerned. Regarding BG monitoring/insulin adjustment, only 25% of responders reported having sufficient information with 13% believing that the accuracy and precision of their BG metre was being independently checked. Only 9% recalled discussing BG metre accuracy when their latest metre was provided and only 7% were aware of the International Standardisation Organisation (ISO) standards for BG metres. 77% did not recall discussing BG metre performance with a healthcare professional. CONCLUSION: The group surveyed comprised engaged people with T2DM but even within this group there was significant variation in (a) awareness of shorter term risks, (b) confidence in their ability to implement appropriate insulin dosage (c) awareness of the limitations of BG monitoring technology. There is clearly an area where changes in education/support would benefit many.

Thank ORP9 for FFAT: With endosomal ORP10, it's fission accomplished!

Heterogeneity in endosomal membrane phospholipid content is emerging as a regulator of endocytic trafficking pathways. Kawasaki et al. (2021. J. Cell. Biol.https://doi.org/10.1083/jcb.202103141) demonstrate exchange of endosomal PI4P for PS by ORP10 at ER-endosome contact sites, with the consequent recruitment of endosomal fission factors.

Exploiting Connections for Viral Replication.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the COVID-19 (coronavirus disease 2019) pandemic, is a positive strand RNA (+RNA) virus. Like other +RNA viruses, SARS-CoV-2 is dependent on host cell metabolic machinery to survive and replicate, remodeling cellular membranes to generate sites of viral replication. Viral RNA-containing double-membrane vesicles (DMVs) are a striking feature of +RNA viral replication and are abundant in SARS-CoV-2-infected cells. Their generation involves rewiring of host lipid metabolism, including lipid biosynthetic pathways. Viruses can also redirect lipids from host cell organelles; lipid exchange at membrane contact sites, where the membranes of adjacent organelles are in close apposition, has been implicated in the replication of several +RNA viruses. Here we review current understanding of DMV biogenesis. With a focus on the exploitation of contact site machinery by +RNA viruses to generate replication organelles, we discuss evidence that similar mechanisms support SARS-CoV-2 replication, protecting its RNA from the host cell immune response.

Serial Assessment of Urinary Incontinence in Breast Cancer Survivors Undergoing (Neo)Adjuvant Therapy.

BACKGROUND: Among breast cancer survivors, urinary incontinence (UI) is often attributed to cancer therapy. We prospectively assessed urinary symptoms before and after (neo)adjuvant treatment of early-stage breast cancer. METHODS: With consent, women with stage I-III breast cancer completed the Urogenital Distress Inventory and the Incontinence Impact Questionnaire before and 3 months after initiating (neo)adjuvant therapy. Patients with UI were at least slightly bothered by urinary symptoms. If UI was present pretreatment, it was considered prevalent; if UI was new or worse at 3 months posttreatment, it was considered incident; if prevalent UI was no worse at 3 months posttreatment, it was considered stable. Ordinal logistic regression models identified characteristics associated with the level of prevalent UI and with the degree of UI impact on quality of life (QoL). RESULTS: On pretreatment surveys, participants (N=203; age 54.5 ± 11.4 years) reported 79.8% prevalence of UI, including overactive bladder (29.1%), stress incontinence (10.8%), or both (39.9%). The level of prevalent UI increased with body mass index (BMI; P<.05). Of 163 participants assessed at both time points, incident UI developed in 12 of 32 patients without prevalent UI and 27 of 131 patients with prevalent UI. Regardless of whether UI was prevalent (n=162), incident (n=39), or stable (n=94) at QoL assessment, the impact of UI increased (P<.01) with the number and severity of UI symptoms, subjective urinary retention, and BMI. Adjusted for those characteristics, incident UI had less impact on QoL (P<.05) than did prevalent or stable UI. CONCLUSIONS: We found that UI is highly prevalent at breast cancer diagnosis and that new or worsened UI is common after (neo)adjuvant therapy. Because UI often impairs QoL, appropriate treatment strategies are needed.

Characterization of infections and hypogammaglobulinemia treated with the combination of pertuzumab and trastuzumab.

PURPOSE: We update a patient series that reported a high incidence of infection with Gram-positive cocci in women treated with the combination of pertuzumab and trastuzumab and further characterize this clinical problem. PATIENTS: Treating physicians and advanced practice partners identified women who developed infections while on treatment with pertuzumab and trastuzumab alone or in combination with chemotherapy and enrolled them onto this registry trial. RESULTS: Between March, 2014 and May, 2017, 48 patients with HER2-positive breast cancers were reported to have 59 individual infections. The median age was 48 years. Twenty-four patients received neoadjuvant therapy, 17 were treated for metastatic disease, and 7 were treated in the adjuvant setting. Pertuzumab and trastuzumab were combined with carboplatin and docetaxel in 24 (49%) patients, docetaxel in 10 (21%), nab-paclitaxel in 12 (24%), and without other agents in 2 (4%). Granulocyte growth factors were administered in 24 (49%) patients and no patients were documented to be neutropenic. Folliculitis developed in 25 (52%) patients and was counted as a single infection. Abscesses developed at a number of sites in 24 (49%) patients, including a septic knee requiring total knee replacement. Paronychia occurred in 7 (15%) patients, and 5 (10%) developed cellulitis. When cultures were obtained, Gram-positive cocci were consistently identified. Hypogammaglobulinemia was documented in 14 (36%) of the 33 patients tested. CONCLUSIONS: Our data continue to support an increased risk of infections with Gram-positive cocci as a potentially serious adverse event in women treated with pertuzumab and trastuzumab.

Smart tattoo: technology for monitoring blood glucose in the future.

New ways of measuring blood glucose bring hope of easing the burden of diabetes management for patients living with the conditions. The smart tattoo is an innovation that represents a nascent nanotechnology, which is designed to be implanted within the skin to provide continuous and reliable glucose detection for individuals diagnosed with diabetes. The potential benefits of the smart tattoo are compelling not only due to the potential of these nanodevices to prevent diabetic complications and decrease the related social costs, but also due to ease of use and relative user comfort. However, despite the advantages of the smart tattoo, it is important that health professionals, in embracing nanotechnology, understand the ethical implications of using these innovative devices.

Lipid transfer proteins: the lipid commute via shuttles, bridges and tubes.

Lipids are distributed in a highly heterogeneous fashion in different cellular membranes. Only a minority of lipids achieve their final intracellular distribution through transport by vesicles. Instead, the bulk of lipid traffic is mediated by a large group of lipid transfer proteins (LTPs), which move small numbers of lipids at a time using hydrophobic cavities that stabilize lipid molecules outside membranes. Although the first LTPs were discovered almost 50 years ago, most progress in understanding these proteins has been made in the past few years, leading to considerable temporal and spatial refinement of our understanding of the function of these lipid transporters. The number of known LTPs has increased, with exciting discoveries of their multimeric assembly. Structural studies of LTPs have progressed from static crystal structures to dynamic structural approaches that show how conformational changes contribute to lipid handling at a sub-millisecond timescale. A major development has been the finding that many intracellular LTPs localize to two organelles at the same time, forming a shuttle, bridge or tube that links donor and acceptor compartments. The understanding of how different lipids achieve their final destination at the molecular level allows a better explanation of the range of defects that occur in diseases associated with lipid transport and distribution, opening up the possibility of developing therapies that specifically target lipid transfer.

Roles for ER:endosome membrane contact sites in ligand-stimulated intraluminal vesicle formation.

Multivesicular endosomes/bodies (MVBs) sort membrane proteins between recycling and degradative pathways. Segregation of membrane proteins onto intraluminal vesicles (ILVs) of MVBs removes them from the recycling pathway and facilitates their degradation following fusion of MVBs with lysosomes. Sorting of many cargos onto ILVs depends on the ESCRT (Endosomal Sorting Complex Required for Transport) machinery, although ESCRT-independent mechanisms also exist. In mammalian cells, efficient sorting of ligand-stimulated epidermal growth factor receptors onto ILVs also depends on the tyrosine phosphatase, PTP1B, an ER-localised enzyme that interacts with endosomal targets at membrane contacts between MVBs and the ER. This review focuses on the potential roles played by ER:MVB membrane contact sites in regulating ESCRT-dependent ILV formation.

'Knowing where I am': self-monitoring of blood glucose in diabetes.

Although the prevalence of all types of chronic conditions is increasing, diabetes is one of the few long-term metabolic disorders that individuals can successfully manage, monitor and control on a day-to-day basis. Self-monitoring of blood glucose (SMBG) is considered an essential component of diabetes self-care management. When used appropriately, SMBG can help to identify factors associated with hyper- and hypoglycaemia, facilitate learning, and empower people with diabetes to make changes to improve their glycaemic control. SMBG can be a useful tool for healthcare providers, who can teach individuals to monitor glucose at specific times to assess the effectiveness of medications and guide medication management. However, there is an ongoing debate regarding whether, as is the case with type 1 diabetes, all people with type 2 diabetes should also be given the opportunity to learn about the value of, and skills required to, monitor blood glucose as appropriate to their specific needs.

Understanding the Lewis Acidity of Co(II) Sites on a Silica Surface.

Heterogeneous catalysts consisting of isolated transition-metal sites dispersed on the surface of metal oxide supports are commonly used in the chemical industry. Often their reactivity relies on the Lewis acidity of the active sites on the surface of the catalyst. A recent report from our group showed that silica-supported Co(II) sites, prepared via surface organometallic chemistry, are active in both alkene hydrogenation and alkane dehydrogenation, possibly linked to the Lewis acidity of the Co(II) sites. Here we use molecular probes and analogues to both qualitatively and quantitatively model the Lewis acidity of the surface sites. Some sites do not bind probe molecules like carbon monoxide, tetrahydrofuran, and olefins, while others exhibit a continuum of Lewis acidities. This is consistent with variations in the coordination environment of Co. These results suggest that only the most Lewis acidic sites are involved in dehydrogenation and hydrogenation, consistent with catalyst poisoning studies.

Advances on the Transfer of Lipids by Lipid Transfer Proteins.

Transfer of lipid across the cytoplasm is an essential process for intracellular lipid traffic. Lipid transfer proteins (LTPs) are defined by highly controlled in vitro experiments. The functional relevance of these is supported by evidence for the same reactions inside cells. Major advances in the LTP field have come from structural bioinformatics identifying new LTPs, and from the development of countercurrent models for LTPs. However, the ultimate aim is to unite in vitro and in vivo data, and this is where much progress remains to be made. Even where in vitro and in vivo experiments align, rates of transfer tend not to match. Here we set out some of the advances that might test how LTPs work.

Tubular lipid binding proteins (TULIPs) growing everywhere.

Tubular lipid binding proteins (TULIPs) have become a focus of interest in the cell biology of lipid signalling, lipid traffic and membrane contact sites. Each tubular domain has an internal pocket with a hydrophobic lining that can bind a hydrophobic molecule such as a lipid. This allows TULIP proteins to carry lipids through the aqueous phase. TULIP domains were first found in a large family of extracellular proteins related to the bacterial permeability-inducing protein (BPI) and cholesterol ester transfer protein (CETP). Since then, the same fold and lipid transfer capacity have been found in SMP domains (so-called for their occurrence in synaptotagmin, mitochondrial and lipid binding proteins), which localise to intracellular membrane contact sites. Here the methods for identifying known TULIPs are described, and used to find previously unreported TULIPs, one in the silk polymer and another in prokaryotes illustrated by the E. coli protein YceB. The bacterial TULIP alters views on the likely evolution of the domain, suggesting its presence in the last universal common ancestor. The major function of TULIPs is to handle lipids, but we still do not know how they work in detail, or how many more remain to be discovered. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.

Protecting Free-Living Dormice: Molecular Identification of Cestode Parasites in Captive Dormice (Muscardinus avellanarius) Destined for Reintroduction.

The success of any population translocation programme relies heavily on the measures implemented to control and monitor the spread of disease. Without these measures, programmes run the risk of releasing immunologically naïve species or, more dangerously, introducing novel infectious agents to native populations. As a precaution, a reintroduction programme for the common or hazel dormouse, Muscardinus avellanarius, in England screens dormice before release following captive breeding. Using PCR sequencing of a range of genes, we tested whether the same species of tapeworm(s) were present in captive and free-living dormice. Whilst only Rodentolepis straminea were identified in free-living dormice, cestode ova found in a captive individual produced a molecular match closely related to Hymenolepis microstoma and a previously unrecorded Rodentolepis species. To prevent putting at risk the free-living population, we recommended the continued treatment of dormice showing tapeworm infection before release. Our work demonstrates how molecular techniques can be used to inform reintroduction programmes, reduce risk from disease and increase chances of reintroduction success.

An observational study to examine changes in metabolic syndrome components in patients with breast cancer receiving neoadjuvant or adjuvant chemotherapy.

BACKGROUND: The authors sought to determine the effect of chemotherapy on the development of metabolic syndrome (MetS) in premenopausal and postmenopausal women undergoing (neo)adjuvant therapy for early-stage breast cancer. METHODS: A total of 86 women with early-stage (AJCC stage I-III) breast cancer who were free from clinically diagnosed MetS (defined as 3 of 5 components of MetS) were prospectively tested for the presence of the 5 components of MetS within 1 week before initiating and after completing (neo)adjuvant chemotherapy. The 5 components of MetS measured were waist circumference; blood pressure; and fasting levels of blood glucose, triglycerides, and high-density lipoprotein cholesterol. Anthropometrics (body weight, percentage body fat, fat mass), lipid profile (total cholesterol, low-density lipoprotein cholesterol), glucose metabolism (insulin, homeostatic model assessment of insulin resistance, glycated hemoglobin), and inflammation (C-reactive protein) also were examined before initiating and after completing treatment. RESULTS: The current study included 46 premenopausal and 40 postmenopausal women. All individual MetS components and the overall MetS score were found to be statistically significantly increased (P<.01) after chemotherapy. Body weight, percentage body fat, fat mass, lipids, glucose metabolism, and inflammation also were found to be statistically significantly increased (P<.01). CONCLUSIONS: A 12-week to 18-week course of chemotherapy appears to statistically significantly increase MetS and related anthropometrics, biomarkers of glucose metabolism, and inflammation in patients with early-stage breast cancer with no preexisting MetS. Lifestyle interventions such as diet and exercise may be preventive approaches for use during chemotherapy to reduce the onset of MetS in patients with breast cancer. Cancer 2016. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. Cancer 2016;122:2646-2653. © 2016 American Cancer Society.