bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of social isolation due to the COVID-19 pandemic on patients with dementia and caregivers
Authors: Manca Riccardo , De Marco Matteo , Colston Amanda , Raymont Vanessa , Amin Jay , Davies Rhys , Kumar Pramod , Russell Gregor , Blackburn Daniel J. , Venneri Annalena
Published: April 2022

Objective:

Social distancing to limit COVID-19 transmission has led to extensive lifestyle changes, including for people with dementia (PWD). The aim of this study, therefore, was to assess the impact of lockdown on the mental health of PWD and their carers.

Methods:

Forty-five carers of PWD completed a telephone interview during the baseline assessment of the SOLITUDE study to gather information on life conditions and changes in symptoms of PWD during lockdown. Associations between changes in symptoms of PWD and carers’ concerns and mental health were investigated.

Results:

About 44% of carers experienced anxiety and irritability and reported changes in behavioural and cognitive symptoms in PWD. These changes were associated with worse carers’ mental health and concerns about faster disease progression (χ2 = 13.542, p < 0.001).

Conclusion:

COVID-19-related social isolation has had a negative impact on patients’ and carers’ mental health. Potential long-term neurocognitive consequences require further investigation.
Multigenomic modifications in human circulating immune cells in response to consumption of polyphenol-rich extract of yerba mate (Ilex paraguariensis A. St.-Hil.) are suggestive of cardiometabolic protective effects
Authors: Ruskovska Tatjana , Morand Christine , Bonetti Carla Indianara , Gebara Karimi Sater , Cardozo Junior Euclides Lara , Milenkovic Dragan
Published: April 2022

Mate is a traditional drink obtained from the leaves of yerba mate and rich in a diversity of plant bioactive compounds including polyphenols, particularly chlorogenic acids. Studies, even though limited, suggest that consumption of mate is associated with health effects, including prevention of cardiometabolic disorders. Molecular mechanisms underlying the potential health properties are still largely unknown, especially in humans. The aim of this study was to investigate nutrigenomic effects of mate consumption and identify regulatory networks potentially mediating cardiometabolic health benefits. Healthy middle-aged men at risk for CVD consumed a standardised mate extract or placebo for 4 weeks. Global gene expression, including protein coding and non-coding RNA profiles, was determined using microarrays. Biological function analyses were performed using integrated bioinformatic tools. Comparison of global gene expression profiles showed significant change following mate consumption with 2635 significantly differentially expressed genes, among which six are miRNA and 244 are lncRNA. Functional analyses showed that these genes are involved in regulation of cell interactions and motility, inflammation or cell signalling. Transcription factors, such as MEF2A, MYB or HNF1A, could have their activity modulated by mate consumption either by direct interaction with polyphenol metabolites or by interactions of metabolites with cell signalling proteins, like p38 or ERK1/2, that could modulate transcription factor activity and regulate expression of genes observed. Correlation analysis suggests that expression profile is inversely associated with gene expression profiles of patients with cardiometabolic disorders. Therefore, mate consumption may exert cardiometabolic protective effects by modulating gene expression towards a protective profile.
Geochronological and geochemical constraints on the origin of highly 13Ccarb-depleted calcite in basal Ediacaran cap carbonate
Authors: Lan Zhongwu , Wu Shitou , Roberts Nick M. W. , Zhang Shujing , Cao Rong , Wang Hao , Yang Yueheng
Published: April 2022

Ediacaran cap dolostone atop Marinoan glacial deposits contains complex sedimentary structures with extremely negative δ13Ccarb values in close association with oscillations in palaeoclimatic and oceanographic proxy records. However, the precise geological, geochronological and geochemical context of the cap dolostone is not clarified, which hampers us from correctly interpreting the extremely negative δ13Ccarb values and their causal relationships with the Snowball Earth hypothesis. In this study, we conducted detailed in situ geochronological and geochemical analyses on the calcite within the cap dolostone from the Ediacaran Doushantuo Formation in South China in order to define its formation and relationship to the Snowball Earth hypothesis. Petrographic observations show that formation of dolomite pre-dates precipitation of calcite and pyrite, which pre-dates quartz cementation in the basal cap carbonate. Calcite cement within the cap dolostone yielded a U–Pb age of 636.5 ± 7.4/17.8 Ma (2σ, MSWD = 1.6, n = 36/40), which is within uncertainty of a published dolomite U–Pb age of 632 ± 17 Ma (recalculated as 629.3 ± 16.7/22.9 Ma). These age constraints negate the possibility that the calcite cement was formed by late Ediacaran or Cambrian hydrothermal activity. The rare earth element distribution patterns suggest a dominant seawater origin overprinted by subsequent early Ediacaran hydrothermal activity. The combined age, petrographic and geochemical data suggest oxidization of methane clathrates in response to complicated interplay between eustasy and isostatic rebound and hydrothermal fluids.
Honourable Businessmen: Respectability and ‘Gentlemanly Capitalism’ in Spain, 1840–1880
Authors: San Narciso David
Published: April 2022

Revolution can lead to the complete political and social reconfiguration of a society. Such readjustment is often especially significant amongst the society's elites, as when ancient aristocrats had to converge with a newly emerging bourgeoisie. This article argues that over the course of the nineteenth century there was a steady process of negotiation that saw the evolution of a new form of elite, one defined by a new characteristic: respectability. This change saw successful businessmen, particularly magnates or tycoons, climbing to the top of the social ladder, as the culmination of a process that began in the eighteenth century. To illustrate this thesis, I discuss the case of Spain. I draw upon the lives of a large and diverse range of great Spanish bankers, industrialists, and businessmen. Traditionally, historiography has studied such men individually and from an economic history perspective. Here, a global, cultural approach is adopted. The chronology of the events described is not straightforward. Although the men studied are not all from a single birth cohort or even the same generation, I consider that they lived through the same social processes. The years between 1840 and 1880 were a period of intense industrial and business development in Spain during which modern economic practices were introduced. For the purposes of this article, I first situate the concept of respectability within the Spanish historiographical context, before analysing the discursive strategies that Spanish business magnates used to turn themselves into legitimate members of the county's new social elite. Finally, I study the three main symbolic tools that they employed to demonstrate their respectability and prove their status.
Soft-bottom tidepools within mixed reefs of native mussels and introduced oysters – refuge for associated species and parasites?
Authors: Weniger Eric , Cornelius Annika , Rolff Jens , Buschbaum Christian
Published: April 2022

The introduction of Pacific oysters to the sedimentary south-eastern North Sea coast and their establishment on intertidal native blue mussel beds has caused the development of mixed reefs of mussels and oysters with extensive tidepools. Tidepools have been intensively studied at rocky shores where they show community structures, which usually differ from that of the surrounding emerging substrates. Tidepools at sedimentary coasts, however, have received less attention. We compared the community structure and species interactions inside and outside tidepools in oyster reefs by determining densities of snails, barnacles and amphipods. Snail densities were similar in and outside tidepools. Barnacle coverage on bivalve shells, however, was lower inside tidepools, which may be caused by higher predation pressure and increased snail grazing under permanently submerged conditions, as was revealed by field and laboratory experiments. Additionally, we studied the occurrence of copepod and trematode parasites in blue mussels inside and outside tidepools. Prevalence and intensity of parasitic copepods was higher in mussels inside tidepools. Trematode parasites, by contrast, showed a lower intensity in mussels inside tidepools. This can be explained by high amphipod densities found inside tidepools because trematode larvae represent a food source of amphipods. Our study suggests that the community structure of oyster reefs within tidepools is not a submerged equivalent to that of intertidal reefs. As their counterparts at rocky shores, they show their own species distribution patterns with particular species interactions and only provide refuge for specific species such as parasitic copepods.
Naturalism, classical theism, and first causes
Authors: Schmid Joseph C.
Published: April 2022

Enric F. Gel has recently argued that classical theism enjoys a significant advantage over Graham Oppy's naturalism. According to Gel, classical theism – unlike Oppy's naturalism – satisfactorily answers two questions: first,how manyfirst causes are there, and second,whyis itthatnumber rather than another? In this article, I reply to Gel's argument for classical theism's advantage over Oppy's naturalism. I also draw out wider implications of my investigation for the gap problem and Christian doctrine along the way.
MICHAEL BLAKE'S STRING QUARTETS AND THE IDEA OF AFRICAN ART MUSIC
Authors: Muller Stephanus
Published: April 2022

This article considers if and how the five string quartets of the South African composer Michael Blake, written between 2001 and 2014, could be considered as contributing to the compositional and discursive construct that is ‘African art music’. ‘African art music’ has often been evoked in connection with the compositional practices of West African composers especially but has received little consideration and scrutiny of its possible applications to South African composition. The political and artistic isolation of South Africa from the rest of Africa during much of the twentieth century is an obvious reason why this has been the case. But there is also the possibility that white South African composers during and after apartheid have engaged in composition from different intellectual and aesthetic starting points, compared to their African counterparts, due to the specific kind of coloniality they inhabit. The five string quartets afford a perspective on how Michael Blake negotiated the continuities of compositional authority and universalised commitment to a traditional Western sound ideal in the string quartet, with the self-awareness that white composition in post-apartheid South Africa arguably requires.
Estimation of the incidence of hospitalisation for non-invasive pneumococcal pneumonia in the Norwegian population aged 50 years and older
Authors: Lyngstad Trude Marie , Kristoffersen Anja Bråthen , Winje Brita Askeland , Steens Anneke
Published: April 2022

The purpose of this study was to estimate simple measures of the burden of non-invasive pneumococcal pneumonia (PnPn) hospitalisations in those aged 50 years and older (50+) in Norway. We conducted a retrospective register-based study and used discharge codes from the Norwegian Patient Register (NPR). We identified episodes of non-invasive PnPn in 2015 to 2016 and predicted its incidence from 2015 to 2019 based on the trend found in notified invasive pneumococcal disease cases. Overall, we identified 45–46 hospital episodes per 100 000 population of non-invasive PnPn in 2015 and 2016, each episode taking 6–8 days, and with increasing incidence with higher age. Among all identified PnPn episodes, 3 out of 4 were classified as non-invasive. We predicted that the monthly number of non-invasive PnPn episodes ranges from 39 [95% confidence interval (CI) 24–55] in August to 97 (95% CI 74–134) in December. No annual trend was identified. This study indicates that the burden of non-invasive PnPn hospitalisation has a substantial impact on the health and health care use of the 50+ population in Norway, despite the childhood immunisation programme. Many hospitalisations may be prevented through vaccination.
In Defense of A Mandatory Public Service Requirement
Authors: Satz Debra
Published: April 2022

This paper defends mandatory national service as a response to democratic decay. Because democracy cannot be maintained by laws and incentives alone, citizens must care about the quality and attitudes of their society's members. In an age of increasing segregation and conflict on the basis of class and race, national service can bring citizens from different walks of life together to interact cooperatively on social problems. It offers a form of ‘forced solidarity’. The final sections of the paper consider objections to this proposal.
No More Benefit Cheats
Authors: Duffy Simon , Wolff Jonathan
Published: April 2022

The concept of the ‘benefit cheat’ plays a critical role in political rhetoric and public policy and it has been deployed to justify changes to the benefit system that have had a very negative impact on well being and justice. The authors argue that the concept is dangerous, adding to the existing burdens of poverty and exclusion and that it must be eradicated by a reorganisation of the welfare system. Dignity and a spirit of equality must be the starting point for any system of welfare that aims to promote universal well being.
On the Merits and Limits of Nationalising the Fossil Fuel Industry
Authors: Green Fergus , Robeyns Ingrid
Published: April 2022

We explore the desirability of an idea that has not received the attention it deserves by political philosophers: that governments should bring privately-owned fossil fuel companies into public ownership with a view to managing their wind-down in the public interest – often simply referred to as ‘nationalising the fossil fuel industry’. We aim to make a conditional case for public ownership of fossil fuel companies. We will assume certain conditions about government motivations and capacities that are similar to assumptions made generally in the philosophical and economic analysis of climate policies: that the government is suitably motivated, has effective control over the companies it acquires, and is able to sustain this motivation and control for long-enough to wind-down acquired companies in the public interest. We argue that bringing fossil fuel companies into public ownership, under these conditions, allows the government to take ten actions that are in the public interest, which will enhance social justice, enable a fair division of burdens and benefits, and strengthen democracy. We consider four plausible objections. While some of these point to the need for further research, they do not undermine our claim that nationalising the fossil fuel industry is a policy option that merits serious consideration.
How Should Liberal Democratic Governments Treat Conscientious Disobedience as a Response to State Injustice?: A Proposal
Authors: Wong Brian , Chan Joseph
Published: April 2022

This paper suggests that liberal democratic governments adopt a reconciliatory approach to conscientious disobedience. Central to this approach is the view – independent of whether conscientious disobedience is always morally justified – that conscientious disobedience is normatively distinct from other criminal acts with similar effects, and such distinction is worthy of acknowledgment by public apparatus and actors. The prerogative applies to both civil and uncivil instances of disobedience, as defined and explored in the paper. Governments and courts ought to take the normative distinction seriously and treat the conscientious disobedients in a more lenient way than they treat ordinary criminals. A comprehensive legislative scheme for governments to deal with prosecution, sentencing, and imprisonment of the conscientious disobedients will be proposed, with the normative and practical benefits of such an approach discussed in detail.
Radical Democratic Inclusion: Why We Should Lower the Voting Age to 12
Authors: O'Neill Martin
Published: April 2022

Democratic societies such as the United Kingdom have come to fail their young citizens, often sacrificing their interests in a political process that gives much greater weight to the preferences and interests of older citizens. Against this background of intergenerational injustice, this article presents the case for a shift in the political system in the direction of radical democratic inclusion of younger citizens, through reducing the voting age to 12. This change in the voting age can be justified directly, with reference to the status, interests, and capacities of younger citizens, and it can also be justified as a remedy to existing forms of intergenerational injustice. This change in the voting age would require a parallel transformation in the role of secondary schools as part of the ‘critical infrastructure' of a democratic society, which would be part of a broader shift towards a more genuinely democratic political culture. The proposal is defended against less radical alternatives (such as votes at 16) and more radical alternatives (such as votes for younger children). The article concludes with some reflections on democracy and intergenerational justice in light of the Covid pandemic and the climate emergency.
Hyperglycemia in pregnancy and developmental outcomes in children at 18–60 months of age: the PANDORA Wave 1 study
Authors: Titmuss Angela , D’Aprano Anita , Barzi Federica , Brown Alex D.H. , Wood Anna , Connors Christine , Boyle Jacqueline A. , Moore Elizabeth , OʼDea Kerin , Oats Jeremy , McIntyre H. David , Zimmet Paul , Shaw Jonathan E. , Craig Maria E. , Maple-Brown Louise J.
Published: April 2022

This study aimed to explore the association between hyperglycemia in pregnancy (type 2 diabetes (T2D) and gestational diabetes mellitus (GDM)) and child developmental risk in Europid and Aboriginal women.

PANDORA is a longitudinal birth cohort recruited from a hyperglycemia in pregnancy register, and from normoglycemic women in antenatal clinics. The Wave 1 substudy included 308 children who completed developmental and behavioral screening between age 18 and 60 months. Developmental risk was assessed using the Ages and Stages Questionnaire (ASQ) or equivalent modified ASQ for use with Aboriginal children. Emotional and behavioral risk was assessed using the Strengths and Difficulties Questionnaire. Multivariable logistic regression was used to assess the association between developmental scores and explanatory variables, including maternal T2D in pregnancy or GDM.

After adjustment for ethnicity, maternal and child variables, and socioeconomic measures, maternal hyperglycemia was associated with increased developmental “concern” (defined as score ≥1 SD below mean) in the fine motor (T2D odds ratio (OR) 5.30, 95% CI 1.77–15.80; GDM OR 3.96, 95% CI 1.55–10.11) and problem-solving (T2D OR 2.71, 95% CI 1.05–6.98; GDM OR 2.54, 95% CI 1.17–5.54) domains, as well as increased “risk” (score ≥2 SD below mean) in at least one domain (T2D OR 5.33, 95% CI 1.85–15.39; GDM OR 4.86, 95% CI 1.95–12.10). Higher maternal education was associated with reduced concern in the problem-solving domain (OR 0.27, 95% CI 0.11–0.69) after adjustment for maternal hyperglycemia.

Maternal hyperglycemia is associated with increased developmental concern and may be a potential target for intervention so as to optimize developmental trajectories.
Twins in Guinea-Bissau have a ‘thin-fat’ body composition compared to singletons
Authors: Wagh Rucha , Bjerregaard-Andersen Morten , Bandyopadhyay Souvik , Yajnik Pranav , Prasad Rashmi B. , Otiv Suhas , Byberg Stine , Hennild Ditte Egegaard , Gomes Gabriel Marciano , Christensen Kaare , Sodemann Morten , Jensen Dorte Møller , Yajnik Chittaranjan S.
Published: April 2022

The ‘thrifty phenotype’ hypothesis proposed that fetal undernutrition increases risk of diabetes in later life. Undernourished low birthweight Indian babies are paradoxically more adipose compared to well-nourished European babies, and are at higher risk of diabetes in later life. Twin pregnancies are an example of in utero growth restrictive environment due to shared maternal nutrition. There are few studies of body composition in twins. We performed secondary analysis of anthropometric body composition of twins and singletons in Guinea-Bissau, an economically deprived African country.

Anthropometric data were available on 7–34 year-old twins (n = 209, 97 males) and singletons (n = 182, 86 males) in the Guinea-Bissau Twin Registry at the Bandim Health Project. Twins had lower birthweight (2420 vs 3100 g, p < 0.001); and at follow-up, lower height (HAZ mean Z-score difference, −0.21, p = 0.055), weight (WAZ −0.73, p = 0.024) and BMI (BAZ −0.22, p = 0.079) compared to singletons but higher adiposity (skinfolds: +0.33 SD, p = 0.001). Twins also had higher fasting (+0.38 SD, p < 0.001) and 2-hour OGTT glucose concentrations (+0.29 SD, p < 0.05). Linear mixed-effect model accounting for intrapair correlations and interactions confirmed that twins were thinner but fatter across the age range. Data on maternal morbidity and prematurity were not available in this cohort.

African populations are known to have a muscular (less adipose) body composition. Demonstration of a thin-fat phenotype in twins in a low socio-economic African country supports the thesis that it could be a manifestation of early life undernutrition and not exclusive to Indians. This phenotype could increase risk of diabetes and related conditions.
Normierung und testtheoretische Überprüfung der deutschen Adaptation der Kurzform der Self-Control Scale (SCS-K-D)
Authors: Singh Ranjit Konrad
Published: April 2022

Zusammenfassung. Gegenstand dieses Artikels ist die deutsche Adaptation der Kurzform der Self-Control Scale (SCS-K-D; übersetzt von Bertrams und Dickhäuser). Es werden 3 Ziele verfolgt: (1) Die Dimensionalität der Skala formal zu prüfen, (2) die Skala auf Messinvarianz bezüglich Geschlecht, Bildung und Alter zu prüfen und (3) basierend auf einer Zufallsstichprobe der erwachsenen deutschen Bevölkerung ( N = 4 038) Normwerte abzuleiten. Die theoretisch erwartete eindimensionale Struktur konnte empirisch nicht bestätigt werden. Wird der Einfluss invertierter Items mit einem Methodenfaktor kontrolliert, verbessert sich die Modellgüte. Für eine angemessene Modellgüte musste die 13-Item Skala jedoch zusätzlich durch Itemausschluss auf eine 8-Item Skala reduziert werden. Diese 8-Item Variante erreichte auch in einer zweiten, unabhängigen Stichprobe ( N = 1 818) eine akzeptable Güte. Die Überprüfung der durch Messinvarianz erfolgte 8-Item Variante mit Methodenfaktor ergab skalare Messinvarianz für Geschlecht, konfigurale Messinvarianz für Bildung und deutliche Messinvarianzprobleme über Altersgruppen hinweg. Normwerte für die erwachsene, deutsche Bevölkerung werden sowohl für die 13-Item und die 8-Item Variante zur Verfügung gestellt und zudem differenziert nach Bildungsniveau und Alter dargeboten.
Testing the Consistency of the Moral Growth Mindset Measure Across	People With Different Political Perspectives
Authors: Han Hyemin , Dawson Kelsie J. , Choi Youn-Jeng
Published: April 2022

Abstract: Although the Moral Growth Mindset (MGM) Measure was tested and validated in general, whether it measures MGM consistently across people with different political perspectives associated with moral foundations, has not been tested. We examined measurement invariance (MI) and differential item functioning (DIF) across different political affiliations to test whether the MGM Measure functioned consistently. We also examined the relationship between MGM, moral foundations, and political affiliation with t-tests and regression analyses. The findings reported that first, at the test level, the strictest MI was achieved, so the measurement structure was consistent between the different political groups. Second, no item showed significant DIF, so the MGM Measure was not biased at the item level. Third, t-tests and regression analyses reported that MGM and its relationship with moral foundations were not significantly associated with political affiliation.
Sensitivity of Global Ocean Deoxygenation to Vertical and Isopycnal Mixing in an Ocean Biogeochemistry Model
Authors: Ito T. , Takano Y. , Deutsch C. , Long M. C.
Published: April 2022

Large‐scale loss of oxygen under global warming is termed “ocean deoxygenation” and is caused by the imbalance between physical supply and biological consumption of oxygen in the ocean interior. Significant progress has been made in the theoretical understanding of ocean deoxygenation; however, many questions remain unresolved. The oxygen change in the tropical thermocline is poorly understood, with diverging projections among different models. Physical oxygen supply is controlled by a suite of processes that transport oxygen‐rich surface waters into the interior ocean, which is expected to weaken due to increasing stratification under global warming. Using a numerical model and a series of sensitivity experiments, the role of ocean mixing is examined in terms of effects on the mean state and the response to a transient warming. Both vertical and horizontal (isopycnal) mixing coefficients are systematically varied over a wide range, and the resulting oxygen distributions in equilibrated and transient simulations are examined. The spatial patterns of oxygen loss are sensitive to both vertical and isopycnal mixing, and the sign of tropical oxygen trend under climate warming can reverse depending on the choice of mixing parameters. An elevated level of isopycnal mixing disrupts the vertical advective‐diffusive balance of the tropical thermocline, increasing the mean state oxygen as well as the magnitude of the transient oxygen decline. These results provide first‐order explanations for the diverging behaviors of simulated tropical oxygen with respect to ocean mixing parameters.
Internet addiction and its association with quality of life in patients with major depressive disorder: a network perspective
Authors: Bai Wei , Cai Hong , Wu Siqi , Zhang Ling , Feng Ke-Xin , Li Yu-Chen , Liu Huan-Zhong , Du Xiangdong , Zeng Zhen-Tao , Lu Chang-Mou , Mi Wen-Fang , Zhang Lan , Ding Yan-Hong , Yang Juan-Juan , Jackson Todd , Cheung Teris , An Feng-Rong , Xiang Yu-Tao
Published: April 2022

Depressive disorders and internet addiction (IA) are often comorbid. The aims of this study were to examine the network structure of IA in patients with major depressive disorders (MDD) and explore the association between IA and quality of life (QoL) in this population. This was a multicenter, cross-sectional survey. IA and QoL were assessed with the Internet Addiction Test (IAT) and the World Health Organization Quality of Life-brief version, respectively. Node expected influence (EI) was used to identify central symptoms in the network model, while the flow network of QoL was generated to examine its association with IA. A total of 1,657 patients with MDD was included. “Preoccupation with the Internet,” “Job performance or productivity suffer because of the Internet,” and “Neglect chores to spend more time online” were central symptoms. The symptom “Form new relationships with online users” had the strongest direct positive relation with QoL, while “Spend more time online over going out with others” and “Job performance or productivity suffer because of the Internet” had the strongest direct negative relations with QoL. Neglecting work caused by IA correlated with QoL, while making friends online appropriately was related to better QoL among MDD patients. Appropriate interventions targeting the central symptoms may potentially prevent or reduce the risk of IA in MDD patients.
Sleep in Alzheimer’s disease: a systematic review and meta-analysis of polysomnographic findings
Authors: Zhang Ye , Ren Rong , Yang Linghui , Zhang Haipeng , Shi Yuan , Okhravi Hamid R. , Vitiello Michael V. , Sanford Larry D. , Tang Xiangdong
Published: April 2022

Polysomnography (PSG) studies of sleep changes in Alzheimer’s disease (AD) have reported but not fully established the relationship between sleep disturbances and AD. To better detail this relationship, we conducted a systematic review and meta-analysis of reported PSG differences between AD patients and healthy controls. An electronic literature search was conducted in EMBASE, MEDLINE, All EBM databases, CINAHL, and PsycINFO inception to Mar 2021. Twenty-eight studies were identified for systematic review, 24 of which were used for meta-analysis. Meta-analyses revealed significant reductions in total sleep time, sleep efficiency, and percentage of slow-wave sleep (SWS) and rapid eye movement (REM) sleep, and increases in sleep latency, wake time after sleep onset, number of awakenings, and REM latency in AD compared to controls. Importantly, both decreased SWS and REM were significantly associated with the severity of cognitive impairment in AD patients. Alterations in electroencephalogram (EEG) frequency components and sleep spindles were also observed in AD, although the supporting evidence for these changes was limited. Sleep in AD is compromised with increased measures of wake and decreased TST, SWS, and REM sleep relative to controls. AD-related reductions in SWS and REM sleep correlate with the degree of cognitive impairment. Alterations in sleep EEG frequency components such as sleep spindles may be possible biomarkers with relevance for diagnosing AD although their sensitivity and specificity remain to be clearly delineated. AD-related sleep changes are potential targets for early therapeutic intervention aimed at improving sleep and slowing cognitive decline.
Desmosterol and 7-dehydrocholesterol concentrations in post mortem brains of depressed people: The role of trazodone
Authors: Cenik Basar , Palka Jayme M. , Thompson Bonne M. , McDonald Jeffrey G. , Tamminga Carol A. , Cenik Can , Brown E. Sherwood
Published: April 2022

Major depressive disorder (MDD) is a common, disabling, and heterogeneous condition that responds unpredictably to current treatments. We previously showed an association between depressive symptoms and plasma concentrations of two cholesterol precursors, desmosterol and 7-dehydrocholesterol (7DHC). Here, we measured total cholesterol and sterol concentrations with mass spectrometry in postmortem brain samples from depressed and control subjects. Mean (±SEM) desmosterol concentration was 8.9 ± 0.97 ng/mg in the depressed versus 10.7 ± 0.72 ng/mg in the control group. The mean of the posterior probability distribution for the difference in desmosterol concentration between the two groups was 2.36 (95% highest density interval [HDI] 0.59–4.17). Mean 7DHC concentrations, 12.5 ± 4.1 ng/mg in the depressed versus 5.4 ± 0.74 ng/mg in the control group, were unlikely to be different (95% HDI, [−1.37–0.34]). We found that presence of trazodone in the peri-mortem toxicology screen accounted for the observed difference in desmosterol concentrations. We also observed extremely high 7DHC levels in all 4 subjects who had taken trazodone. Trazodone has been recently found to inhibit 7-dehydrocholesterol reductase and alter sterol concentrations in rodents, cell culture, human fibroblasts, and blood. In this study, we demonstrate for the first time that trazodone alters human brain sterol composition. Given congenital deficiency of 7-dehydrocholesterol reductase results in Smith-Lemli-Opitz syndrome, our findings support the hypothesis that this commonly used medication may have previously unappreciated risks.
Adipose tissue aging: mechanisms and therapeutic implications
Authors: Ou Min-Yi , Zhang Hao , Tan Poh-Ching , Zhou Shuang-Bai , Li Qing-Feng
Published: April 2022

Adipose tissue, which is the crucial energy reservoir and endocrine organ for the maintenance of systemic glucose, lipid, and energy homeostasis, undergoes significant changes during aging. These changes cause physiological declines and age-related disease in the elderly population. Here, we review the age-related changes in adipose tissue at multiple levels and highlight the underlying mechanisms regulating the aging process. We also discuss the pathogenic pathways of age-related fat dysfunctions and their systemic negative consequences, such as dyslipidemia, chronic general inflammation, insulin resistance, and type 2 diabetes (T2D). Age-related changes in adipose tissue involve redistribution of deposits and composition, in parallel with the functional decline of adipocyte progenitors and accumulation of senescent cells. Multiple pathogenic pathways induce defective adipogenesis, inflammation, aberrant adipocytokine production, and insulin resistance, leading to adipose tissue dysfunction. Changes in gene expression and extracellular signaling molecules regulate the aging process of adipose tissue through various pathways. In addition, adipose tissue aging impacts other organs that are infiltrated by lipids, which leads to systemic inflammation, metabolic system disruption, and aging process acceleration. Moreover, studies have indicated that adipose aging is an early onset event in aging and a potential target to extend lifespan. Together, we suggest that adipose tissue plays a key role in the aging process and is a therapeutic target for the treatment of age-related disease, which deserves further study to advance relevant knowledge.
Tumor suppressive role of microRNA-4731-5p in breast cancer through reduction of PAICS-induced FAK phosphorylation
Authors: Lang Lei , Tao Jing , Yang Chaomei , Li Wei
Published: April 2022

A wide array of microRNAs (miRNAs) is differentially expressed in breast tumors and also functions as tumor suppressors. Herein, the current study sought to unravel the function of miR-4731-5p in breast cancer progression. First, breast cancer-related miRNA and mRNA microarray data sets were retrieved for differential analyses. Subsequently, the expression patterns of miR-4731-5p, PAICS, and FAK in breast cancer tissues and cells were determined, in addition to analyses of their roles in glycometabolism, migration, invasion, epithelial–mesenchymal transition (EMT) analyzed through functional assays. Next, the targeting relation between miR-4731-5p and PAICS was validated. Xenograft tumors in nude mice were further established to reproduce and verify the in vitro findings. miR-4731-5p was poorly expressed and PAICS was highly expressed in breast cancer tissues and cells. PAICS was confirmed as a target of miR-4731-5p. Moreover, miR-4731-5p exerted an inhibitory effect on glycolysis, EMT, migration, and invasion in breast cancer cells via regulation of PAICS-dependent phosphorylation of FAK. In vivo assay further validated the significance of the miR-4731-5p/PAICS/FAK axis in vivo tumorigenesis and lung metastasis in breast cancer. Collectively, our findings indicated that miR-4731-5p inhibited breast cancer cell glycolysis and EMT through the reduction of PAICS-induced phosphorylation of FAK.
FMNL2 suppresses cell migration and invasion of breast cancer: a reduction of cytoplasmic p27 via RhoA/LIMK/Cofilin pathway
Authors: Jiao Xinyan , Wang Bo , Yang Lu , Zhao Qingbin , Zhang Miao , Liu Xiaoxu , Zhou Can , Wang Ruiqi , Chen He , Wang Jichang , Ren Yu , Liu Peijun
Published: April 2022

Formin-like protein 2 (FMNL2) belongs to a highly conserved family of cytoskeletal remodeling proteins that have been reported to be implicated in various actin-dependent physiological and cancer-associated processes. In this study, we mainly investigated the effects of FMNL2 on breast cancer cell migration and invasion, and the underlying mechanisms involved. We found that FMNL2 reduced cell migration and invasion of breast cancer in vitro and in vivo. Further, FMNL2 disrupted actin cytoskeleton rearrangement and hampered the RhoA/LIMK/Cofilin pathway in breast cancer cells. Critically, both Rho inhibitor ZOL and LIMK inhibitor BMS3 significantly abrogated these migration-promoting effects in FMNL2-silencing MDA-MB-231 and BT549 cells. RhoA/LIMK/Cofilin pathway was involved in FMNL2 silencing-induced actin cytoskeleton rearrangement in MDA-MB-231 and BT549 cells. More importantly, cytoplasmic p27 promoted FMNL2-mediated cell migration and invasion through RhoA/LIMK/Cofilin pathway in MCF7 and MDA-MB-231 cells. In addition, the expression and prognosis of FMNL2 were associated with ER in breast cancer. Furthermore, ERα overexpression reduced the protein levels of FMNL2 in breast cancer cells, which were reversed by MG132. In conclusion, FMNL2 suppressed cell migration and invasion of breast cancer by inhibiting RhoA/LIMK/Cofilin pathway through a reduction of cytoplasmic p27. This finding implies that the interference of FMNL2-mediated RhoA/LIMK/Cofilin pathway involving the cytoplasmic p27 may be a promising strategy for ameliorating breast cancer metastasis and prognosis.
GDF-15 in tumor-derived exosomes promotes muscle atrophy via Bcl-2/caspase-3 pathway
Authors: Zhang Wanli , Sun Weikuan , Gu Xiaofan , Miao Chunxiao , Feng Lixing , Shen Qiang , Liu Xuan , Zhang Xiongwen
Published: April 2022

Tumor-derived exosomes are emerging mediators of cancer cachexia, a kind of multifactorial syndrome characterized by serious loss of skeletal muscle mass and function. Our previous study had showed that microRNAs in exosomes of C26 colon tumor cells were involved in induction of muscle atrophy. Here, we focus on studying proteins in tumor-derived exosomes which might also contribute to the development of cancer cachexia. Results of comparing the protein profiles of cachexic C26 exosomes and non-cachexic MC38 exosomes suggested that growth differentiation factor 15 (GDF-15) was rich in C26 exosomes. Western blotting analysis confirmed the higher levels of GDF-15 in C26 cells and C26 exosomes, compared with that of MC38 cells. Results of animal study also showed that GDF-15 was rich in tumor tissues, serum exosomes, and gastrocnemius (GA) muscle tissues of C26 tumor-bearing mice. GDF-15 protein could directly induce muscle atrophy of cultured C2C12 myotubes via regulating Bcl-2/caspase-3 pathways. What’s more, overexpression of GDF-15 in MC38 cells could increase the potency of MC38 conditioned medium or exosomes in inducing muscle atrophy. Knockdown of GDF-15 in C26 cells decreased the potency of C26 conditioned medium or exosomes in inducing muscle atrophy. These results suggested that GDF-15 in tumor-derived exosomes could contribute to induction of muscle atrophy and also supported the possibility of targeting GDF-15 in treatment of cancer cachexia.
Targeting lncRNAs in programmed cell death as a therapeutic strategy for non-small cell lung cancer
Authors: Luo Yanqin , Li Jingyang , Yu Peng , Sun Jiayi , Hu Yingfan , Meng Xianli , Xiang Li
Published: April 2022

Lung cancer is a leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) being the most common histological type. Owing to the limited therapeutic efficacy and side effects of currently available therapies for NSCLC, it is necessary to identify novel therapeutic targets for NSCLC. Long non-coding RNAs (lncRNAs) are non-protein-coding RNAs with a transcript length of more than 200 nucleotides, which play a vital role in the tumorigenesis and progression of multiple cancers, including NSCLC. Induction of programmed cell death (PCD) is the main mechanism leading to tumour cell death in most cancer treatments. Recent studies have demonstrated that lncRNAs are closely correlated with PCD including apoptosis, pyroptosis, autophagy and ferroptosis, which can regulate PCD and relevant death pathways to affect NSCLC progression and the efficacy of clinical therapy. Therefore, in this review, we focused on the function of lncRNAs in PCD of NSCLC and summarized the therapeutic role of targeting lncRNAs in PCD for NSCLC treatment, aiming to provide new sights into the underlying pathogenic mechanisms and propose a potential new strategy for NSCLC therapy so as to improve therapeutic outcomes with the ultimate goal to benefit the patients.
Immunosuppressive niche engineering at the onset of human colorectal cancer
Authors: Gatenbee Chandler D. , Baker Ann-Marie , Schenck Ryan O. , Strobl Maximilian , West Jeffrey , Neves Margarida P. , Hasan Sara Yakub , Lakatos Eszter , Martinez Pierre , Cross William C. H. , Jansen Marnix , Rodriguez-Justo Manuel , Whelan Christopher J. , Sottoriva Andrea , Leedham Simon , Robertson-Tessi Mark , Graham Trevor A. , Anderson Alexander R. A.
Published: April 2022

The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and neoantigen prediction in 62 patient samples. Modeling predicted recruitment of immunosuppressive cells would be the most common driver of transformation. As predicted, ecological analysis reveals that progressed adenomas co-localized with immunosuppressive cells and cytokines, while benign adenomas co-localized with a mixed immune response. Carcinomas converge to a common immune “cold” ecology, relaxing selection against immunogenicity and high neoantigen burdens, with little evidence for PD-L1 overexpression driving tumor initiation. These findings suggest re-engineering the immunosuppressive niche may prove an effective immunotherapy in CRC.
Doubly linked chiral phenanthrene oligomers for homogeneously π-extended helicenes with large effective conjugation length
Authors: Nakakuki Yusuke , Hirose Takashi , Sotome Hikaru , Gao Min , Shimizu Daiki , Li Ruiji , Hasegawa Jun-ya , Miyasaka Hiroshi , Matsuda Kenji
Published: April 2022

Helically twisted conductive nanocarbon materials are applicable to optoelectronic and electromagnetic molecular devices working on the nanometer scale. Herein, we report the synthesis of per-peri-perbenzo[5]- and [9]helicenes in addition to previously reported π-extended [7]helicene. The homogeneously π-extended helicenes can be regarded as helically fused oligo-phenanthrenes. The HOMO−LUMO gap decreased significantly from 2.14 to 1.15 eV with increasing helical length, suggesting the large effective conjugation length (ECL) of the π-extended helical framework. The large ECL of π-extended helicenes is attributed to the large orbital interactions between the phenanthrene subunits at the 9- and 10-positions, which form a polyene-like electronic structure. Based on the experimental results and DFT calculations, the ultrafast decay dynamics on the sub-picosecond timescale were attributed to the low-lying conical intersection.
Nuclearity enlargement from [PW9O34@Ag51] to [(PW9O34)2@Ag72] and 2D and 3D network formation driven by bipyridines
Authors: Wang Zhi , Zhu Yan-Jie , Li Ying-Zhou , Zhuang Gui-Lin , Song Ke-Peng , Gao Zhi-Yong , Dou Jian-Min , Kurmoo Mohamedally , Tung Chen-Ho , Sun Di
Published: April 2022

The structural transformations of metal nanoclusters are typically quite complex processes involving the formation and breakage of several bonds, and thus are challenging to study. Herein, we report a case where two lacunary Keggin polyoxometallate templated silver single-pods [PW9O34@Ag51] (SD/Ag51b) fuse to a double-pod [(PW9O34)2@Ag72] by reacting with 4,4’-bipyridine (bipy) or 1,4-bis(4-pyridinylmethyl)piperazine (pi-bipy). Their crystal structures reveal the formation of a 2D 44-sqllayer (SD/Ag72a) with bipy and a 3Dpcuframework (SD/Ag72c) with pi-bipy. The PW9O349−retains its structure during the cluster fusion and cluster-based network formation. Although the two processes, stripping of an Ag-ligands interface followed by fusion, and polymerization, are difficult to envisage, electrospray ionization mass spectrometry provides enough evidences for such a proposal to be made. Through this example, we expect the structural transformation to become a powerful method for synthesizing silver nanoclusters and their infinite networks, and to evolve from trial-and-error to rational.
Brain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions
Authors: Roy Dheeraj S. , Park Young-Gyun , Kim Minyoung E. , Zhang Ying , Ogawa Sachie K. , DiNapoli Nicholas , Gu Xinyi , Cho Jae H. , Choi Heejin , Kamentsky Lee , Martin Jared , Mosto Olivia , Aida Tomomi , Chung Kwanghun , Tonegawa Susumu
Published: April 2022

Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos+ brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage.
Synthesis of fluorescent organic nano-dots and their application as efficient color conversion layers
Authors: Khan Yeasin , Hwang Soonjae , Braveenth Ramanaskanda , Jung Young Hun , Walker Bright , Kwon Jang Hyuk
Published: April 2022

Efficient conversion of light from short wavelengths to longer wavelengths using color conversion layers (CCLs) underpins the successful operation of numerous contemporary display and lighting technologies. Inorganic quantum dots, based on CdSe or InP, for example, have received much attention in this context, however, suffer from instability and toxic cadmium or phosphine chemistry. Organic nanoparticles (NPs), though less often studied, are capable of very competitive performance, including outstanding stability and water-processability. Surfactants, which are critical in stabilizing many types of nano-structures, have not yet been used extensively in organic NPs. Here we show the utility of surfactants in the synthesis and processing of organic NPs by thoroughly characterizing the effect of ionic and non-ionic surfactants on the properties of fluorescent organic NPs. Using this information, we identify surfactant processing conditions that result in nearly 100 % conversion of organic fluorophores into sub-micrometer particles, or nano-dots, with outstanding performance as CCLs. Such water dispersions are environmentally benign and efficiently convert light. They can be used for a range of fluorophores covering a full spectral gamut, with excellent color purity, including full-width at half-maximum (FWHM) values as low as 21 nm. Compared to inorganic (InP) reference CCLs, the organic nano-dot based CCLs show superior color conversion efficiency and substantially improved long-term stability.