bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving anxiety research: novel approach to reveal trait anxiety through summary measures of multiple states
Authors: Varga Zoltán K , Pejtsik Diána , Tóth Máté , Balogh Zoltán , Aliczki Manó , Szente László , Balla Gyula Y , Kontra Levente , Eckert Zsófia , Szebik Huba , Borhegyi Zsolt , Mikics Éva
Published: June 2023

The reliability and validity of preclinical anxiety testing is essential for translating animal research into clinical use. However, the commonly used anxiety tests lack inter-test correlations and face challenges with repeatability. While translational animal research should be able to capture stable individual anxiety traits, the current approach employs a single type of test at a single time that only measures transient states of animals, heavily influenced by experimental conditions. Here, we propose a validated, optimized test battery capable of reliably capturing trait anxiety in rats and mice of both sexes. Instead of developing novel tests, we combined widely used tests (elevated plus-maze, open field and light-dark test) to provide instantly applicable adjustments for better predictive validity. We repeated these tests three times to capture behaviour across multiple challenges, which we combined to generate summary measures (SuMs). Our approach resolved between-test correlation issues and provided better predictions for subsequent outcomes under anxiogenic conditions or fear conditioning. SuMs were also able to reveal differences in anxiety in an etiological stress model. Finally, we tested our method’s efficacy in discovering anxiety-related molecular pathways through RNA sequencing of the medial prefrontal cortex. Using SuMs, we identified four-times more molecular correlates of trait anxiety as compared to transient anxiety states, pointing out novel functional gene clusters. Furthermore, 16% of these molecular correlates of anxiety were replicated in amygdalar samples, as well. In summary, we provide a novel approach to capture trait anxiety in rodents, offering improved predictions for potential therapeutic targets for personalized medicine.
A novel monocarboxylate transporter involved in 3-hydroxykynurenine transport for ommochrome coloration
Authors: Uchiyama Hirosumi , Takasu Yoko , Moriyama Minoru , Yoshitake Kazutoshi , Uchiyama Hironobu , Iizuka Tetsuya , Uchino Keiro , Okude Genta , Banno Yutaka , Kuwazaki Seigo , Yamamoto Kimiko , Yajima Shunsuke , Sezutsu Hideki , Tamura Toshiki , Futahashi Ryo , Osanai-Futahashi Mizuko
Published: June 2023

Ommochromes are widespread pigments in invertebrates utilized for screening pigments in compound eyes and for reddish coloration in epidermis and wings. Ommochromes are derived from 3-hydroxykynurenine (3OHK), which is incorporated into cells from hemolymph or synthesized from tryptophan within cells. While the synthetic pathway from tryptophan to 3OHK has been well characterized, the gene responsible for cellular uptake of 3OHK has been poorly understood. In the silkwormBombyx mori, adult compound eyes and eggs contain a mixture of ommochrome pigments. By using positional cloning method, we found that a novel monocarboxylate transporter, 3-hydroxykynurenine transporter (3OHKT), is responsible for the recessive mutantmaternal brown of Tsujita(b-t) ofB. mori. Inb-tmutant, the color of the eggs is light brown, whereas the color of the compound eyes is normal, and we identified a 2-kb deletion in3OHKTgene. TALEN-mediated knockout of3OHKTgene produced the same coloration phenotype asb-tmutant, and the complementation test betweenb-tmutant and3OHKTknockout strain proved that3OHKTis responsible forb-tphenotype. 3OHKT protein was localized in the cellular membrane, and LC-MS analysis indicated that the uptake of 3OHK from hemolymph into the ovary was suppressed in theb-tmutant. Moreover, we confirmed that3OHKTgene is specifically expressed at the reddish region and the time of pigmentation in the pupal wing of nymphalid butterflies. RNA interference of3OHKTprevented reddish pigmentation in wings, highlighting its general involvement in ommochrome-based pigmentation other than compound eyes.

Significance

Ommochromes are widely distributed pigments in invertebrates and are synthesized from intracellular tryptophan or 3-hydroxykynurenine (3OHK). Ommochrome-based red markings on butterfly wings are often used for sexual selection, warning colors and mimicry. Most genes involved in the ommochrome synthesis pathway have been elucidated from analyses of eye color mutants inDrosophila. However, this study reveals that the ommochrome synthesis pathway has a different genetic repertoire depending on the tissues, and that the novel monocarboxylate transporter identified in this study has a major role in ommochrome pigmentation other than in compound eyes. In particular, our results suggest that classical ommochrome-related genes are rarely involved in the wing pigmentation of the nymphalid butterflies.
Maintenance of cooperation in a yeast population in a public-good driven system
Authors: Raj Namratha , Saini Supreet
Published: June 2023

The phenomenon of cooperation is prevalent at all levels of life. In microbial communities, some groups of cells exhibit cooperative behaviour by producing costly extracellular resources that are freely available to others. These resources are referred to as public goods.Saccharomyces cerevisiae secretes invertase (public good) in the periplasm to hydrolyse sucrose into glucose and fructose, which are further imported by the cells. After hydrolysis of sucrose, the cells retain only 1% of the monosaccharides, while 99% diffuse into the environment and can be utilised by all neighbouring cells. The non-producers of invertase (cheaters) exploit the invertase-producing cells (cooperators) by utilising the monosaccharides and paying nothing for the latter. In this work, we investigate the evolutionary dynamics of this cheater-cooperator system. If cheaters are selected for their higher fitness, the population will collapse. For cooperators to survive cheating and thrive in nature, they should have evolved some survival strategies. To understand the adaptation of cooperators in sucrose, we performed a coevolution experiment in sucrose. Our results show that cooperators increase in fitness as the experiment progresses. This phenomenon was not observed in environments which involved a non-public good system. Genome sequencing reveals the molecular basis for the cooperator adaptating is because of increased privatization of the public-good released carbon resource.
Antigen perception in T cells by long-term Erk and NFAT signaling dynamics
Authors: Wither Matthew J , White William L , Pendyala Sriram , Leanza Paul J , Fowler Doug , Kueh Hao Yuan
Published: June 2023

Immune system threat detection hinges on T cells’ ability to perceive varying peptide major-histocompatibility complex (pMHC) antigens. As the Erk and NFAT pathways link T cell receptor engagement to gene regulation, their signaling dynamics may convey information about pMHC inputs. To test this idea, we developed a dual reporter mouse strain and a quantitative imaging assay that, together, enable simultaneous monitoring of Erk and NFAT dynamics in live T cells over day-long timescales as they respond to varying pMHC inputs. Both pathways initially activate uniformly across various pMHC inputs, but diverge only over longer (9+ hrs) timescales, enabling independent encoding of pMHC affinity and dose. These late signaling dynamics are decoded via multiple temporal and combinatorial mechanisms to generate pMHC-specific transcriptional responses. Our findings underscore the importance of long timescale signaling dynamics in antigen perception, and establish a framework for understanding T cell responses under diverse contexts.

SIGNIFICANCE STATEMENT

To counter diverse pathogens, T cells mount distinct responses to varying peptide-major histocompatibility complex ligands (pMHCs). They perceive the affinity of pMHCs for the T cell receptor (TCR), which reflects its foreignness, as well as pMHC abundance. By tracking signaling responses in single living cells to different pMHCs, we find that T cells can independently perceive pMHC affinity vs dose, and encode this information through the dynamics of Erk and NFAT signaling pathways downstream of the TCR. These dynamics are jointly decoded by gene regulatory mechanisms to produce pMHC-specific activation responses. Our work reveals how T cells can elicit tailored functional responses to diverse threats and how dysregulation of these responses may lead to immune pathologies.
Efficient Analysis of Proteome-wide FPOP Data by FragPipe
Authors: Ramírez Carolina Rojas , Espino Jessica Arlett , Jones Lisa M. , Polasky Daniel A. , Nesvizhskii Alexey I.
Published: June 2023

Monitoring protein structure before and after perturbations can give insights into the role and function of proteins. Fast photochemical oxidation of proteins (FPOP) coupled with mass spectrometry (MS) allows monitoring of structural rearrangements by exposing proteins to OH radicals that oxidize solvent accessible residues, indicating protein regions undergoing movement. Some of the benefits of FPOP include high throughput and lack of scrambling due to label irreversibility. However, the challenges of processing FPOP data have thus far limited its proteome-scale uses. Here, we present a computational workflow for fast and sensitive analysis of FPOP datasets. Our workflow combines the speed of MSFragger search with a unique hybrid search method to restrict the large search space of FPOP modifications. Together, these features enable more than 10-fold faster FPOP searches that identify 50% more modified peptide spectra than previous methods. We hope this new workflow will increase the accessibility of FPOP to enable more protein structure and function relationships to be explored.
Some like it hot: adaptation to the urban heat island in common dandelion
Authors: Woudstra Yannick , Kraaiveld Ron , Jorritsma Alger , Vijverberg Kitty , Ivanovic Slavica , Erkens Roy , Huber Heidrun , Gravendeel Barbara , Verhoeven Koen J.F.
Published: June 2023

The Urban Heat Island Effect (UHIE) is a globally consistent pressure on species living in cities. Rapid adaptation to the UHIE may be necessary for urban wild flora to persist in cities, but experimental evidence is lacking. Here, we report the first evidence of genetic differentiation in a plant species in response to the UHIE. We collected seeds from common dandelion (Taraxacum officinale) individuals along an urban-rural gradient in the city of Amsterdam (The Netherlands). In common-environment greenhouse experiments, we assessed the effect of elevated temperatures on plant growth and the effect of vernalisation treatments on flowering phenology. We found that urban plants accumulate more biomass at higher temperatures and require shorter vernalisation to induce flowering compared to rural plants. Differentiation was also observed between different intra-urban subhabitats, with park plants displaying a higher vernalisation requirement than street plants. Our results show strong differentiation between urban and rural dandelions in temperature-dependent growth and phenology, consistent with adaptive divergence in response to the UHIE. Rapid adaptation to the UHIE may be a potential explanation for the widespread success of dandelions in urban environments.

Summary statement

The urban heat island effect (UHIE) is the most prominent and globally consistent characteristic of environmental change due to urbanisation, severely impacting human populations in cities as well as the cohabiting wildlife. Despite the profoundly mitigating effect of vegetation on urban heat, evidence for plant adaptation to the UHIE has been lacking. Here we provide the first experimental evidence to date, demonstrating adaptation in urban dandelions in response to elevated temperatures, similar to the UHIE. We furthermore show an urban-rural differentiation in flowering response to shorter vernalisation times (cold winter period to activate the onset of flowering in early spring). Given the predominantly asexual apomictic mode of reproduction in dandelions, this evolution is likely the result of environmental filtering on a diverse population of clonal genotypes. We conclude that plant adaptation to the UHIE exists and recommend future studies to contrast our findings with those in outcrossing sexual plant systems. Studies of urban heat adaptation can bring impactful contributions to building climate change-resilient environments and plants should be an integral part of this research.
ADrosophilamodel of chemotherapy-related cognitive impairment
Authors: Torre Matthew , Bukhari Hassan , Nithianandam Vanitha , Zanella Camila A , Mata Douglas A , Feany Mel B
Published: June 2023

Chemotherapy-related cognitive impairment (CRCI) is a common adverse effect of treatment and is characterized by deficits involving multiple cognitive domains including memory. Despite the significant morbidity of CRCI and the expected increase in cancer survivors over the coming decades, the pathophysiology of CRCI remains incompletely understood, highlighting the need for new model systems to study CRCI. Given the powerful array of genetic approaches and facile high throughput screening ability in Drosophila, our goal was to validate aDrosophilamodel of CRCI. We administered the chemotherapeutic agents cisplatin, cyclophosphamide, and doxorubicin to adult Drosophila. Neurocognitive deficits were observed with all tested chemotherapies, especially cisplatin. We then performed histologic and immunohistochemical analysis of cisplatin-treatedDrosophilatissue, demonstrating neuropathologic evidence of increased neurodegeneration, DNA damage, and oxidative stress. Thus, ourDrosophilamodel of CRCI recapitulates clinical, radiologic, and histologic alterations reported in chemotherapy patients. Our newDrosophilamodel can be used for mechanistic dissection of pathways contributing to CRCI and pharmacologic screens to identify novel therapies to ameliorate CRCI.

Summary Statement

We present aDrosophilamodel of chemotherapy-related cognitive impairment, which recapitulates neurocognitive and neuropathologic changes observed in cancer patients treated with chemotherapy.
Comparative B cell and antibody responses induced by adenoviral vectored and mRNA vaccines against COVID-19
Authors: Liu Yi , Sánchez-Ovando Stephany , Carolan Louise , Dowson Leslie , Khvorov Arseniy , Hadiprodjo Jessica , Tseng Yeu Yang , Delahunty Catherine , Khatami Ameneh , Macnish Marion , Dougherty Sonia , Hagenauer Michelle , Riley Kathryn E. , Jadhav Ajay , Harvey Joanne , Kaiser Marti , Mathew Suja , Hodgson David , Leung Vivian , Subbarao Kanta , Cheng Allen C. , Macartney Kristine , Koirala Archana , Marshall Helen , Clark Julia , Blyth Christopher C. , Wark Peter , Kucharski Adam J. , Sullivan Sheena G. , Fox Annette
Published: June 2023

Both vector and mRNA vaccines were an important part of the response to the COVID-19 pandemic and may be required in future outbreaks and pandemics. However, adenoviral vectored (AdV) vaccines may be less immunogenic than mRNA vaccines against SARS-CoV-2. We assessed anti-spike and anti-vector immunity among infection-naïve Health Care Workers (HCW) following two doses of AdV (AZD1222) versus mRNA (BNT162b2) vaccine. 183 AdV and 274 mRNA vaccinees enrolled between April and October 2021. Median ages were 42 and 39 years, respectively. Blood was collected at least once, 10-48 days after vaccine dose 2. Surrogate virus neutralization test (sVNT) and spike binding antibody titres were a median of 4.2 and 2.2 times lower, respectively, for AdV compared to mRNA vaccinees (p<0.001). Median percentages of memory B cells that recognized fluorescent-tagged spike and RBD were 2.9 and 8.3 times lower, respectively for AdV compared to mRNA vaccinees. Titres of IgG reactive with human Adenovirus type 5 hexon protein rose a median of 2.2-fold after AdV vaccination but were not correlated with anti-spike antibody titres. Together the results show that mRNA induced substantially more sVNT antibody than AdV vaccine due to greater B cell expansion and targeting of the RBD. Pre-existing AdV vector cross-reactive antibodies were boosted following AdV vaccination but had no detectable effect on immunogenicity.

Key points

mRNA SARS-CoV-2 vaccine induced higher surrogate neutralizing antibody titres than adenoviral vaccine

mRNA vaccine induced a more potent, RBD-targeted B cell response than AdV vaccine

Adenoviral vaccine boosted antibodies against human Adenovirus, but titres don’t correlate with anti-spike titres
Progressive accumulation of hyperinflammatory NKG2DlowNK cells in early childhood severe atopic dermatitis
Authors: Ochayon David E. , DeVore Stanley B. , Chang Wan-Chi , Krishnamurthy Durga , Seelamneni Harsha , Grashel Brittany , Spagna Daniel , Andorf Sandra , Martin Lisa J. , Biagini Jocelyn M. , Waggoner Stephen N. , Hershey Gurjit K. Khurana
Published: June 2023

Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development of food allergy, asthma, and allergic rhinitis. The prevailing paradigm holds that a reduced frequency and function of natural killer (NK) cell contributes to AD pathogenesis, yet the underlying mechanisms and contributions of NK cells to allergic comorbidities remain ill-defined. Herein, analysis of circulating NK cells in a longitudinal early life cohort of children with AD revealed a progressive accumulation of NK cells with low expression of the activating receptor NKG2D, which was linked to more severe AD and sensitivity to allergens. This was most notable in children co-sensitized to food and aero allergens, a risk factor for development of asthma. Individual-level longitudinal analysis in a subset of children revealed co-incident reduction of NKG2D on NK cells with acquired or persistent sensitization, and this was associated with impaired skin barrier function assessed by transepidermal water loss. Low expression of NKG2D on NK cells was paradoxically associated with depressed cytolytic function but exaggerated release of the proinflammatory cytokine TNF−α. These observations provide important insights into a potential mechanism underlying the development of allergic co-morbidity in early life in children with AD which involves altered NK-cell functional responses, and define an endotype of severe AD.
Racial Differences in Associations Between Adverse Childhood Experiences and Physical, Mental, and Behavioral Health
Authors: Lam-Hine Tracy , Riddell Corinne A. , Bradshaw Patrick T. , Omi Michael , Allen Amani M.
Published: June 2023

Introduction

Adverse childhood experiences (ACEs) are associated with poor adulthood health, with individuals experiencing multiple ACEs at greatest risk. Multiracial people have high mean ACEs scores and elevated risk of several outcomes, but are infrequently the focus of health equity research. This study aimed to determine whether this group should be targeted for prevention efforts.

Methods

We analyzed Waves 1 (1994-95), 3 (2001-02), and 4 (2008-09) of the National Longitudinal Study of Adolescent to Adult Health (n = 12,372) in 2023, estimating associations between four or more ACEs and physical (metabolic syndrome, hypertension, asthma), mental (anxiety, depression), and behavioral (suicidal ideation, drug use) outcomes. We estimated risk ratios for each outcome in modified Poisson models with a race × ACEs interaction, adjusted for hypothesized confounders of the ACE-outcome relationships. We used the interaction contrast to estimate excess cases per 1,000 individuals for each group relative to Multiracial participants.

Results

Excess case estimates of asthma were significantly smaller for White (−123 cases, 95% CI: -251, -4), Black (−141, 95% CI: -285, -6), and Asian (−169, 95% CI: -334, -7) participants compared to Multiracial participants. Black (−100, 95% CI: -189, -10), Asian (−163, 95% CI: -247, -79) and Indigenous (−144, 95% CI: -252, -42) participants had significantly fewer excess cases of and weaker (p < 0.001) relative scale association with anxiety compared to Multiracial participants.

Conclusions

Adjusted associations between ACEs and asthma or anxiety appear stronger for Multiracial people than other groups. ACEs are universally harmful but may contribute disproportionately to morbidity in this population.
Social, environmental and economic risk factors and determinants of sleep disturbances in Latin America: A systematic review and a meta-analysis of public health literature
Authors: Etindele Sosso Faustin Armel , Torres Silva Filipa , Queiroz Rodrigues Rita , Carvalho Margarida , Zoukal Sofia , Cordova Zarate Gabriel
Published: June 2023

Background

Mental health recovery is associated with healthy sleep, and disturbances of both, areas represent an increasing public health issue worldwide, particularly in Latin America. Among multiple determinants affecting sleep health, individual’s socioeconomic status (SES) is the most ignored and underestimated through literature. No systematic review on the relation between SES and sleep health has been previously conducted in Latin America.

Methods

PRISMA guidelines were used.

Results

Twenty cross-sectional studies were selected. 80,0% (n=16) were performed in Brazil, 10,0% (n=2) in Peru, 5,0% (n=1) in Chile, and 5,0% (n=1) were multicentric (11 countries). The combined total number of participants were N=128455, being 3,7% (n= 4693) children, 16,0% (n= 20586) adolescents and 80,3% (n=103176) adults. Higher SES was associated with lower sleep duration. Lower SES was associated with a decrease in sleep quality. Excessive Daytime Sleepiness (EDS) was significantly more prevalent in individuals with lower family income and less education. Sleep bruxism was associated with higher education and lower SES was associated with more sleep bruxism. A meta-analysis of random effects model showed that pooled prevalence of sleep disturbances was 27.32 % (95 % CI 21.71–33.75) with high heterogeneity (I2= 100 %). Pooled prevalence decreased with high education (OR 0.83; 95%CI [0.75-0.91]; I2= 79%), while it increased by low income (OR 1.26; 95%CI [1.12-1.42]; I2= 59%), unemployment (OR 2.84; 95%CI [2.14-3.76]; I2= 0%) or being housewife (OR 1.72; 95%CI [1.19-2.48]; I2=55.4%).

Discussion

Gradient of health disparity existing for some diseases like cardiovascular illness, seems the same for sleep disturbances regardless of world region. Therefore, sleep disturbances management should be address in a multidimensional approach with a significant investment of government in targeted public health program, to reduce sleep disparities and support research before the situation become uncontrollable.
Stabilisation of soil organic matter with rock dust partially counteracted by plants
Authors: Buss Wolfram , Hasemer Heath , Ferguson Scott , Borevitz Justin
Published: June 2023

Soil application of Ca– and Mg-rich silicates can capture and store atmospheric carbon dioxide as inorganic carbon but could also have the potential to stabilise soil organic matter (SOM). Synergies between these two processes have not been investigated. Here, we apply finely ground silicate rock mining residues (basalt and granite blend) to a loamy sand in a pot trial at a rate of 4% (equivalent to 50 t ha-1) and investigate the effects of a wheat plant and two watering regimes on soil carbon sequestration. Rock dust addition increased soil pH, electric conductivity and soil-exchangeable Ca and Mg contents, as expected for weathering, but decreased exchangeable levels of micronutrients Mn and Zn, likely related to soil pH. Importantly, it increased mineral-associated organic matter by 22% due to the supply of secondary minerals and associated sites for SOM sorption. Additionally, in the non-planted treatments, rock supply of Ca and Mg increased soil microaggregation that subsequently stabilised labile particulate organic matter as organic matter occluded in aggregates by 46%. Plants, however, reduced soil exchangeable Mg and Ca contents and hence counteracted the silicate rock effect on microaggregates and carbon within. We attribute this cation loss to plant exudates released to solubilise micronutrients and hence neutralise plant deficiencies. The effect of enhanced silicate rock weathering on SOM stabilisation could substantially boost its carbon sequestration potential when pH and micronutrient effects are considered.
A metabolic crosstalk between liposarcoma and muscle sustains tumor growth
Authors: Gabrielle Manteaux , Jaime Prieto Romero , Laurie Gayte , Blanche Riquier-Morcant , Alix Amsel , Solenn Jacq , Madi Y Cisse , Gaelle Perrot , Frédéric Chibon , Pascal Pomies , Sebastien Carrere , Nelly Firmin , Romain Riscal , Laetitia K Linares
Published: June 2023

Dedifferentiated (DD-LPS) and Well-differentiated (WD-LPS) liposarcoma are characterized by a systematic amplification of theMDM2oncogene. We recently demonstrated that p53-independent metabolic functions of chromatin-bound MDM2 (C-MDM2) are exacerbated in LPS and mediate an addiction to serine metabolism in order to sustain tumor growth. Here, we show that metabolic cooperation between LPS and distant muscle, which raise serine and glycine blood levels, is essential for LPS tumor growth. By releasing IL-6, tumor influence distant muscle to upregulate their serine synthesis machinery. Blocking IL-6 secretion or treating LPS cells with FDA approved IL-6 inhibitor, decreased serine production and impaired tumor proliferation. These data reveal IL-6 as a central tumorkine in metabolic crosstalk between tissues and identifies IL-6 as a plausible treatment for LPS patients.
Engineering ligand stabilized aquaporin reporters for magnetic resonance imaging
Authors: Yun Jason , Baldini Logan , Huang Yimeng , Li Eugene , Li Honghao , Chacko Asish N. , Miller Austin D.C. , Wan Jinyang , Mukherjee Arnab
Published: June 2023

Imaging transgene expression in live tissues requires reporters that are detectable with deeply penetrant modalities, such as magnetic resonance imaging (MRI). Here, we show that LSAqp1, a water channel engineered from aquaporin-1, can be used to create background-free, drug-gated, and multiplex images of gene expression using MRI. LSAqp1 is a fusion protein composed of aquaporin-1 and a degradation tag that is sensitive to a cell-permeable ligand, which allows for dynamic small molecule modulation of MRI signals. LSAqp1 improves specificity for imaging gene expression by allowing reporter signals to be conditionally activated and distinguished from the tissue background by difference imaging. In addition, by engineering destabilized aquaporin-1 variants with different ligand requirements, it is possible to image distinct cell types simultaneously. Finally, we expressed LSAqp1 in a tumor model and showed successful in vivo imaging of gene expression without background activity. LSAqp1 provides a conceptually unique approach to accurately measure gene expression in living organisms by combining the physics of water diffusion and biotechnology tools to control protein stability.
Identification of non-conventional small molecule degraders and stabilizers of squalene synthase
Authors: Hoock Joseph , Rossetti Cecilia , Bilgin Mesut , Depta Laura , Enemark-Rasmussen Kasper , Christianson John C. , Laraia Luca
Published: June 2023

Graphical abstract

Squalene synthase (SQS) is an essential enzyme in the mevalonate pathway whose abundance and activity control cholesterol biosynthesis and homeostasis. Although catalytic inhibitors of SQS have been developed to attenuate cholesterol, none so far have been approved for therapeutic use. Herein we sought to develop SQS degraders using targeted protein degradation (TPD) as an approach to lower overall cellular cholesterol content. We found that KY02111, a small molecule ligand of SQS, could selectively cause SQS to degrade in a proteasome-dependent manner. In contrast, compounds based on the same scaffold linked to E3 ligase recruiting ligands led to SQS stabilization. Whole cell proteomic analysis found KY02111 to reduce only the levels of SQS, while lipidomic analysis determined that KY02111 treatment concomitantly reduced cellular cholesteryl ester content. SQS stabilizers were shown to shield SQS from its natural turnover without recruiting their matching E3 ligase. Our work shows that degradation of SQS is possible despite a challenging biological setting and lays the groundwork for future development of either SQS degrading or stabilizing probes.
A Cannabidiol/Terpene Formulation Increases Restorative Sleep in Insomniacs: A Double-Blind, Placebo-controlled, Randomized, Crossover Study
Authors: Wang Michael , Faust Marcus , Abbott Scott , Patel Vikrant , Chang Eric , Clark John I. , Stella Nephi , Muchowski Paul J.
Published: June 2023

Study Objectives

Cannabidiol (CBD) is increasingly used as a health supplement, though few human studies have demonstrated benefits. The primary objective of this study was to evaluate the effects of an oral CBD-terpene formulation on sleep physiology in insomniacs.

Methods

In this double-blind, placebo-controlled, randomized clinical trial, 125 insomniacs received an oral administration of CBD (300 mg) and terpenes (1 mg each of linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene) for ≥ four days/week over four weeks using a crossover design. The study medication was devoid of Δ9-Tetrahydrocannabinol (Δ9-THC). The primary outcome measure was the percentage of time participants spent in the combination of slow wave sleep (SWS) and rapid eye movement (REM) sleep stages, as measured by a wrist-worn sleep-tracking device.

Results

This CBD-terpene regimen significantly increased the mean nightly percentage of time participants spent in SWS + REM sleep compared to the placebo [mean (SEM), 1.28% (0.60%), 95% C.I. 0.09 to 2.46,P= 0.03]. More robust increases were observed in participants with low baseline SWS + REM sleep, as well as in day-sleepers. For select participants, the increase in SWS + REM sleep averaged as much as 48 min/night over a four-week treatment period. This treatment had no effect on total sleep time (TST), resting heart rate or heart rate variability, and no adverse events were reported.

Conclusions

Select CBD-terpene ratios may increase SWS + REM sleep, and have the potential to provide a safe and efficacious alternative to over-the-counter (OTC) sleep aids and commonly prescribed sleep medications.

BRIEF SUMMARY

Current Knowledge/Study Rationale

Physicians are increasingly asked by their patients regarding the merits of using CBD for insomnia and other ailments, but lack any rigorous clinical research to support recommending its use. The current study represents the first double-blind, placebo-controlled and randomized crossover clinical trial to investigate how an oral formulation of cannabidiol (CBD) and terpenes influences sleep physiology in insomniacs.

Study Impact

In contrast to many OTC sleep aids and commonly prescribed sleep medicines, the CBD-terpene formulation increased SWS and REM sleep, which are critical for the immune system, tissue regeneration, cognition and memory. These results, if confirmed in larger clinical trials, suggests that CBD might offer a promising alternative to other prescription sleep medications and OTC sleep aids.
Probabilistic Coverage of the Frontal Aslant Tract in Young Adults: Insights into Individual Variability, Lateralization, and Language Functions
Authors: Linn Wen-Jieh , Barrios-Martinez Jessica , Fernandes-Cabral David , Jacquesson Timothée , Nuñez Maximiliano , Gomez Ricardo , Anania Yury , Fernandez-Miranda Juan , Yeh Fang-Cheng
Published: June 2023

The frontal aslant tract (FAT) is a crucial neural pathway of language and speech, but little is known about its connectivity and segmentation differences across populations. In this study, we utilized diffusion MRI automatic tractography to investigate the probabilistic coverage of the FAT in a large sample of 1065 young adults. Our primary goal was to reveal individual variability and lateralization of FAT and its structure-function correlations in language processing. Our results showed that the left anterior FAT exhibited the most substantial individual differences, particularly in the superior and middle frontal gyrus, with greater variability in the superior than the inferior region. Furthermore, we found significant left lateralization in FAT, with a greater difference in innervation coverage in the inferior and posterior portions. Additionally, our analysis revealed a significant correlation between the size of left FAT inferior innervation areas and Picture Vocabulary function, highlighting the structural and functional importance of the left FAT in language processing. In comparison, the anisotropy of FAT did not show significant correlation. Overall, our study provides valuable insights into individual and population differences in FAT connectivity and segmentation and sheds light on its critical role in language functions.
Pan-tissue mitochondrial phenotyping reveals lower OXPHOS expression and function across tumor types
Authors: Boykov Ilya N , Montgomery McLane M , Hagen James T , Aruleba Raphael T , McLaughlin Kelsey L , Coalson Hannah S , Nelson Margaret A , Pereyra Andrea S , Ellis Jessica M. , Zeczycki Tonya N , Vohra Nasreen A , Tan Su-Fern , Cabot Myles C. , Fisher-Wellman Kelsey H.
Published: June 2023

Targeting mitochondrial oxidative phosphorylation (OXPHOS) to combat cancer is increasingly being investigated using a variety of small molecule inhibitors. Clinical success for these inhibitors has been hampered due to serious side-effects potentially arising from the inability to discriminate between non-cancerous and cancerous mitochondria. Although mitochondrial oxidative metabolism is essential for malignant growth, mitochondria OXPHOS is also essential to the physiology of all organs, including high-energy-demand organs like the heart. In comparing tumor OXPHOS reliance to these preeminent oxidative organs it is unclear if a therapeutic window for targeting mitochondrial OXPHOS in cancer exists. To address this gap in knowledge, mitochondrial OXPHOS was comprehensively evaluated across various murine tumors and compared to both matched normal tissues and other organs. When compared to both matched normal tissues, as well as high OXPHOS reliant organs like heart, intrinsic expression of the OXPHOS complexes, as well as OXPHOS flux were consistently lower across distinct tumor types. Operating on the assumption that intrinsic OXPHOS expression/function predicts OXPHOS reliance in vivo, these data suggest that pharmacologic blockade of mitochondrial OXPHOS likely compromises bioenergetic homeostasis in healthy oxidative organs prior to impacting tumor mitochondrial flux in a clinically meaningful way. Although these data caution against the use of indiscriminate mitochondrial inhibitors for cancer treatment, considerable heterogeneity was observed across tumor types with respect to both mitochondrial proteome composition and substrate-specific flux, highlighting the possibility for targeting discrete mitochondrial proteins or pathways unique to a given tumor type.
Temporal transcriptome analysis of the endothelial response to tumour necrosis factor
Authors: Struck EC , Belova T , Hsieh P , Odeberg J , Kuijjer ML , Dusart P , Butler LM
Published: June 2023

The vascular endothelium acts as a dynamic interface between blood and tissue and provides an anti-inflammatory and anti-thrombotic surface under normal conditions. Tumour necrosis factor-α (TNF), a cytokine that drives acute and chronic inflammation, induces numerous transcriptional changes in endothelial cells (EC). However, the overall temporal dynamics of this response have not been fully elucidated. Here, we conducted an extended time-course analysis of the EC response to TNF, from 30 minutes to 72 hours. We identified TNF-regulated genes and used weighted gene correlation network analysis (WGCNA) to decipher co-expression profiles, uncovering two distinct temporal phases - an acute response initiated between 1-4 hours, followed by a later phase initiated between 12-24 hours. Several previously uncharacterised genes were strongly regulated during the acute phase, while the majority in the later phase were interferon-stimulated genes (ISGs). A lack of interferon transcription indicated that this TNF-induced ISG expression was independent ofde novointerferon production and autocrine signalling. Furthermore, we observed two different groups of genes whose transcription was inhibited by TNF, those that resolved towards baseline levels over time, and those that did not. Our study provides insights into the global temporal dynamics of the EC transcriptional response to TNF, highlighting distinct gene expression patterns during the acute and later phases. These findings may be useful in understanding the role of EC in inflammation and developing TNF signalling-targeting therapies.
Multi-scale Modeling and Experimental Data Enable Structural Models of theEscherichia ColiPeptidoglycan to be Constructed on the Whole-Cell Scale
Authors: Wehrspan Zachary J. , Elcock Adrian H.
Published: June 2023

The peptidoglycan (PG) layer ofEscherichia coliis a single, interconnected gigaDalton molecule that is the largest in the cell. Experimental studies have established a number of the PG’s properties, and previous computational studies have simulated aspects of its behavior on sub-cellular scales, but none have fully modeled the PG’s compositional heterogeneity and no models have yet been constructed on the whole-cell scale. Here we use a combination of computational modeling approaches to construct whole-cell PG models at a resolution of one coarse-grained (CG) bead per glycan that are consistent with a wide variety of available experimental data. In particular, we derive plausible glycan strand length distributions for the polar and cylindrical regions of the cell that cover the full range of possible strand lengths and that are consistent with all available experimental data. In addition, we develop stochastic simulation code that explicitly models a cross-linking experiment from the literature that has a direct bearing on the extent to which Braun’s lipoprotein (Lpp) is partitioned between periplasmic and surface-exposed locations. We then use all of these data as inputs to a new computer code,PG_maker, which builds CG models of the PG on a whole-cell scale in under an hour. Finally, we use the resulting 3D models as a basis for: (a) estimating pore size distributions – which, despite the idealized nature of the models, are shown to be in surprisingly good agreement with experimental estimates – and (b) calculating the effects of the large numbers of periplasmic Lpps on the ability of freely diffusing proteins to access the compartment that lies between the PG and the outer membrane. The ability to combine a wide range of experimental data into structural models that are physically realizable in 3D helps to set the stage for performing simulations of the PG on the whole-cell scale in the near future.
Tau Protein Modulates an Epigenetic Mechanism of Cellular Senescence
Authors: Magrin Claudia , Sola Martina , Piovesana Ester , Bolis Marco , Rinaldi Andrea , Papin Stéphanie , Paganetti Paolo
Published: June 2023

Progressive Tau deposition in neurofibrillary tangles and neuropil threads is the hallmark of tauopathies, a disorder group that includes Alzheimer’s disease. Since Tau is a microtubule-associated protein, a prevalent concept to explain the pathogenesis of tauopathies is that abnormal Tau modification contributes to dissociation from microtubules, assembly into multimeric β-sheets, proteotoxicity, neuronal dysfunction and cell loss. Tau also localizes in the cell nucleus and evidence supports an emerging function of Tau in DNA stability and epigenetic modulation. To better characterize the possible role of Tau in regulation of chromatin compaction and subsequent gene expression, we performed a bioinformatics analysis of transcriptome data obtained from Tau-depleted human neuroblastoma cells. Among the transcripts deregulated in a Tau-dependent manner, we found an enrichment of target genes for the polycomb repressive complex 2. We further describe decreased cellular amounts of the core components of the polycomb repressive complex 2 complex and a lower histone 3 trimethylation activity in Tau deficient cells. Among the de-repressed polycomb repressive complex 2 target gene products, IGFBP3 protein was found to be linked to increased senescence induction in Tau-deficient cells. Our findings propose a mechanism for Tau-dependent epigenetic modulation of cell senescence, a key event in pathologic aging.
Are you satisfied when your job fits? The perspective of career management
Authors: Du Yana , Li Jiangyu , Xu Qi
Published: June 2023

Purpose

The purpose of this paper is to discuss the relationships between person–job fit and job satisfaction, the mediating role of career self-management and the moderating role of job demands.

Design/methodology/approach

In this paper, 947 employees were surveyed using questionnaires, and hypothesis testing was conducted using structural equation modeling in Mplus.

Findings

Person–job fit was found to be positively related to career self-management, and career self-management plays a mediating role in the positive relationship between person–job fit and job satisfaction. Statistical analysis also confirmed that job demands moderate both the relationship between person–job fit and career self-management, as well as the relationship between person–job fit and job satisfaction via career self-management.

Research limitations/implications

The results of a single study offer limited generalizability and should thus be applied with caution. More cross-industry and cross-company studies should be conducted to verify the applicability of the findings to other industries, cultures and geographical contexts.

Practical implications

Managers should try to enhance employees' person–job fit and help or encourage them to engage in career self-management to increase job satisfaction. Additionally, managers should be aware of the negative influence of job demands and try to keep them at low levels.

Originality/value

This study extends and enriches the understanding of the positive influence of person–job fit on work outcomes, explores the mechanism of person–job fit on job satisfaction from a new perspective, namely career self-management, and explores the boundary condition (i.e. job demands) of the relationship between person–job fit and career self-management in the Chinese context.
Barriers and strategies for implementing lean six sigma in small- and medium sized enterprises (SMEs) in construction industry: a fuzzy TOPSIS analysis
Authors: De Silva Shamika Hasaranga , Ranadewa K.A.T.O. , Rathnasinghe Akila Pramodh
Published: June 2023

Purpose

Quality management barriers have been discovered in construction small- and medium-sized enterprises (SMEs), determining their long-term survival. Despite the recognition of Lean Six Sigma (LSS) as a valuable quality management technique for addressing the barriers faced by SMEs, LSS implementation within the construction SME context is alarmingly low. Therefore, this study aims to investigate the barriers for implementing LSS within construction SMEs and to determine the most effective strategies for overcoming these barriers.

Design/methodology/approach

A quantitative research approach was used, and data was collected in two stages: a questionnaire survey with 44 construction professionals and an expert opinion survey with 12 LSS specialists. The collected data was then analysed using the fuzzy TOPSIS method, achieving a higher degree of sensitivity.

Findings

The findings revealed the 15 most significant LSS barriers that need to be addressed. In addition, the ten most important strategies to be implemented in overcoming the identified barriers before LSS implementation were discovered and thematised, most notably the hiring of LSS specialists for project monitoring and the formation of a committee for strategic planning through LSS.

Originality/value

Previous research on LSS examined barriers and strategies for SMEs in general, but to the best of the authors’ knowledge, this study is the first of its kind, focusing especially on the construction SME context and involving the unique fuzzy TOPSIS approach.
Visitors’ eco-innovation adoption and green consumption behavior: the case of green hotels
Authors: Sharma Tanmay , Chen Joseph S. , Ramos William D. , Sharma Amit
Published: June 2023

Purpose

Green hospitality studies have not adequately focused on the diffusion of eco-innovative hotels amongst visitors. This study aims to fill this gap by identifying green hotel attributes that influence visitors’ adoption of eco-friendly hotel and their intentions to partake in green initiatives.

Design/methodology/approach

The paper uses a mixed-method approach to explore the drivers of customers’ green hotel adoption and consumption. In the qualitative phase, data were collected via 20 open-ended interviews and analyzed to derive a measurement scale. The scale was then tested through a survey comprising 500 respondents using structural equation modelling.

Findings

The study results elucidate how guests’ visit intentions and green consumption behavior is built through their perception of newness and uniqueness of eco-innovative attributes. Findings shed light on how green hotel’s sustainable communication and corporate social responsibility outreach efforts positively influence guest visit intentions.

Research limitations/implications

Study results reveal perceived eco-innovativeness as an important antecedent of visit intentions. Based on guest’s preferences, green hotels striving to increase its visitors’ base could begin by expanding their eco-innovative attributes.

Originality/value

Contrasting previous studies that have exclusively used the theory of planned behavior constructs, this study argues that diffusion of innovation constructs also offer valuable insights into guests’ visit intentions. While existing studies have covered limited number of eco-innovative attributes, this study adds to the literature by presenting a comprehensive set of attributes including trustworthiness of communication and observability of its social impacts.
Leveraging ChatGPT and other generative artificial intelligence (AI)-based applications in the hospitality and tourism industry: practices, challenges and research agenda
Authors: Dwivedi Yogesh K. , Pandey Neeraj , Currie Wendy , Micu Adrian
Published: June 2023

Purpose

The hospitality and tourism sector has witnessed phenomenal growth in customer numbers during the postpandemic times. This growth has been accompanied by the use of technologies in customer interface and backend activities, including the adoption of self-serving technologies. This study aims to analyze the existing practices and challenges and establish a research agenda for the implementation of generative artificial intelligence (AI) (such as ChatGPT) and similar tools in the hospitality and tourism industry.

Design/methodology/approach

This study analyzes the existing literature and practices. This study draws upon these practices to outline a novel research agenda for scholars and practitioners working in this domain.

Findings

The integration of generative AI technologies, such as ChatGPT, will have a transformational impact on the hospitality and tourism industry. This study highlights the potential challenges of implementing such technologies from the perspectives of companies, customers and regulators.

Research limitations/implications

This study serves as a reference material for those who are planning to use generative AI tools like ChatGPT in their hospitality and tourism businesses. This study also highlights potential pitfalls that ChatGPT-enabled systems may encounter during service delivery processes.

Originality/value

This study is a pioneering work that assesses the applications of ChatGPT in the hospitality and tourism industry. This study highlights the potential and challenges in implementing ChatGPT within the hospitality and tourism industry.