bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circadian photoreceptor CRYPTOCHROME promotes wakefulness under short winter-like days via a GABAergic circuitry
Authors: Chen Lixia , Tian Danya , Su Chang , Zhang Luoying 
Published: October 2023

AbstractA cardinal symptom of seasonal affective disorder (SAD, also known as winter depression) is hypersomnolence, while the cause of this “winter sleepiness” is not known. Here we found that lack of the circadian photoreceptorcryptochrome(cry) leads to increased sleep under short winter-like days in fruit flies, reminiscent of the hypersomnolence in SAD. CRY functions in neurons that synthesize the major inhibitory neurotransmitter GABA, including the small ventral lateral neurons which are known to be circadian pacemakers, and down-regulates the GABAergic tone. This in turn leads to increased neural activity of the wake-promoting large ventral lateral neurons, a subset of circadian neurons that are inhibited by GABA-A receptor. CRY protein is known to be degraded by light, thus rendering CRY to be functional within this GABAergic circuitry to enhance wakefulness only under short day length. Taken together, we demonstrate a mechanism that specifically regulates wakefulness under short winter-like days, which may provide insights regarding the winter sleepiness in SAD.
EEG markers of drowsiness do not predict lapses in attention during sleep deprivation
Authors: Snipes Sophia , Meier Elias , Accascina Simone , Huber Reto 
Published: October 2023

ABSTRACTDuring drowsiness, maintaining consistent attention becomes difficult, leading to behavioral lapses. Oscillation bursts in the electroencephalogram (EEG) might predict such lapses, since alpha bursts increase with inattention and theta bursts increase with time spent awake. However, while lapses increase with time awake, paradoxically alpha bursts decrease, and the behavioral relevance of theta bursts is unknown. Therefore, we investigated whether theta or alpha bursts predicted lapses either when well rested (baseline, BL) or sleep deprived (SD). EEG was measured in 18 young adults performing the lateralized attention task, and the timing of bursts was related to trial outcomes (fast, slow, and lapse trials). Against expectations, neither theta nor alpha bursts were more likely during lapses, either at BL or SD. Both were more likely before fast trials, but only at BL. Fast and slow trials were followed by decreases in both theta and alpha bursts, but the effect was reduced during SD, partially due to local increases in bursts. Considering prior literature, these results indicate that bursts have a non-linear relationship with vigilance. The lack of a direct relationship to lapses may be because bursts originate from task-unrelated areas, and the differences during SD suggest these areas change with time awake.
Lipopolysaccharides derived fromPorphyromonas gingivalisandEscherichia coli:differential and interactive effects on novelty-induced hyperlocomotion, blood cytokine levels and TRL4-related processes
Authors: Saito Koji , Aono Yuri , Watanabe Arata , Kono Tetsuro , Hashizume-Takizawa Tomomi , Okada Hiroyuki , Kosuge Yasuhiro , Senpuku Hidenobu , Waddington John L. , Saigusa Tadashi 
Published: October 2023

AbstractLipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, activates Toll-like receptors (TLRs).Porphyromonas gingivalis(Pg) may be involved in the progression of periodontal disease. Mice exposed to a novel environment show hyperlocomotion that is inhibited by systemic administration of LPS derived fromEscherichia coli(Ec-LPS). However, whetherPg-LPS influences novelty-induced locomotion is unknown. Accordingly, we carried out an open field test to analyse the effects ofPg-LPS. For comparison, effects ofEc-LPS were also studied. We also investigated the influence of systemic administration ofPg-LPS orEc-LPS on IL-6, TNF-alpha, and IL-10 levels in blood, as they could be involved in the changes in locomotion. The TLR4 receptor antagonist TAK-242 was used to study the involvement of TLR4. SincePg-LPS may block TLR4in vitro, we analysed the effects ofPg-LPS onEc-LPS-induced changes in behavioural and biochemical parameters. Male ddY mice were used. Compounds were administered intraperitoneally.Ec-LPS (840 µg/kg), but notPg-LPS (100, 500 and 840 µg/kg), inhibited novelty-induced locomotion, which was reversed by TAK-242 (3.0 mg/kg).Ec-LPS (840 µg/kg) increased blood levels of IL-6 and IL-10, which was antagonized by TAK-242 (3.0 mg/kg). However, TAK-242 did not inhibitEc-LPS-induced increases in TNF-alpha levels in blood.Pg-LPS (100, 500, and 840 µg/kg) did not alter blood IL-6, TNF-alpha, or IL-10 levels. TheEc-LPS-induced increase in blood IL-10, but not IL-6 and TNF-alpha, levels was inhibited byPg-LPS (500 µg/kg). These results suggest that TLR4 stimulation mediates the inhibition of novel environment-induced locomotion in mice following systemic administration ofEc-LPS, while also increasing blood IL-6 and IL-10 levels. In contrast,Pg-LPS did not exhibit these effects. The present study also providesin vivoevidence thatPg-LPS can inhibit TLR4-mediated increases in blood IL-10 levels, which is thought to prevent the development of periodontal disease.
Diffusion of activated ATM explains γH2AX and MDC1 spread beyond the DNA damage site
Authors: Danovski Georgi , Panova Greta , Keister Bradley , Georgiev Georgi , Blagoev Krastan B. , Stoynov Stoyno S. 
Published: October 2023

SummaryDuring DNA repair, ATM-induced H2AX histone phosphorylation and MDC1 recruitment spread megabases beyond the damage site. The mechanism underlying this spread remains unclear. To elucidate this step of the DNA damage response, we measured ATM and MDC1 recruitment kinetics at micro-irradiation-induced complex DNA lesions. While MDC1 spreads beyond the damage-induced focus of ATM accumulation, cohesin loader NIPBL and cohesin subunit RAD21 accumulate later than MDC1. Such delayed recruitment suggests that, in complex DNA lesions, loop extrusion cannot alone explain γH2AX and MDC1 spread. To determine if diffusion of activated ATM could account for the observed behavior, we measured the exchange rate and diffusion constants of ATM and MDC1 within damaged and unperturbed chromatin. Based on these measurements, we introduced a quantitative model that describes the dynamic behavior of ATM and subsequent MDC1 spread at complex DNA lesions. Altogether, we propose activated ATM diffusion as an underlying mechanism of MDC1 spread.
Non-canonical activation of IRE1α duringCandida albicansinfection enhances macrophage fungicidal activity
Authors: McFadden Michael J. , Reynolds Mack B. , Michmerhuizen Britton C , Ólafsson Einar B. , Anderson Faith M. , Schultz Tracey L. , O’Riordan Mary X.D. , O’Meara Teresa R. 
Published: October 2023

AbstractWhile the canonical function of IRE1α is to detect misfolded proteins and activate the unfolded protein response (UPR) to maintain cellular homeostasis, microbial pathogens can also activate IRE1α, which modulates innate immunity and infection outcomes. However, how infection activates IRE1α and its associated inflammatory functions have not been fully elucidated. Recognition of microbe-associated molecular patterns can activate IRE1α, but it is unclear whether this depends on protein misfolding. Here, we report that a common and deadly fungal pathogen,Candida albicans, activates macrophage IRE1α through C-type lectin receptor signaling, reinforcing a role for IRE1α as a central regulator of host responses to infection by a broad range of pathogens. This activation did not depend on protein misfolding in response toC. albicansinfection. Moreover, lipopolysaccharide treatment was also able to activate IRE1α prior to protein misfolding, suggesting that pathogen-mediated activation of IRE1α occurs through non-canonical mechanisms. DuringC. albicansinfection, we observed that IRE1α activity promotes phagolysosomal fusion that supports the fungicidal activity of macrophages. Consequently, macrophages lacking IRE1α activity displayed inefficient phagosome maturation, enablingC. albicansto lyse the phagosome, evade fungal killing, and drive aberrant inflammatory cytokine production. Mechanistically, we show that IRE1α activity supports phagosomal calcium flux after phagocytosis ofC. albicans, which is crucial for phagosome maturation. Importantly, deletion of IRE1α activity decreased the fungicidal activity of phagocytesin vivoduring systemicC. albicansinfection. Together, these data provide mechanistic insight for the non-canonical activation of IRE1α during infection, and reveal central roles for IRE1α in macrophage antifungal responses.
Differential Chromatin Architecture and Risk Variants in Deep Layer Excitatory Neurons and Grey Matter Microglia Contribute to Major Depressive Disorder
Authors: Chawla Anjali , Cakmakci Doruk , Zhang Wenmin , Maitra Malosree , Rahimian Reza , Mitsuhashi Haruka , Davoli MA , Yang Jenny , Chen Gary Gang , Denniston Ryan , Mash Deborah , Mechawar Naguib , Suderman Matthew , Li Yue , Nagy Corina , Turecki Gustavo 
Published: October 2023

AbstractMajor depressive disorder (MDD) associated genetic variants reside primarily in the non-coding, regulatory genome. Here we investigate genome-wide regulatory differences and putative gene-regulatory effects of disease risk-variants by examining chromatin accessibility combined with single-cell gene-expression profiles in over 200,000 cells from the dorsolateral prefrontal cortex (DLPFC) of 84 individuals with MDD and neurotypical controls. MDD-associated accessibility alterations were prominent in deep-layer excitatory neurons characterized by transcription factor (TF) motif accessibility and binding of nuclear receptor (NR)4A2, an activity-dependent TF responsive to pathological stress. The same neurons were significantly enriched for MDD-associated genetic variation disrupting cis-regulatory sites and TF binding associated with genes involved in synaptic communication. Furthermore, a grey matter microglial cluster exhibited differentially closed chromatin in MDD affecting binding sites bound by TFs known to regulate immune homeostasis. In summary, our study points to specific cell types and regulatory mechanisms whereby genetic variation may increase predisposition to MDD.
Asymmetric cortical projections to striatal direct and indirect pathways distinctly control actions
Authors: Klug Jason R. , Yan Xunyi , Hoffman Hilary A. , Engelhardt Max D. , Osakada Fumitaka , Callaway Edward M. , Jin Xin 
Published: October 2023

AbstractThe striatal direct and indirect pathways constitute the core for basal ganglia function in action control. Although both striatal D1- and D2-spiny projection neurons (SPNs) receive excitatory inputs from the cerebral cortex, whether or not they share inputs from the same cortical neurons, and how pathway-specific corticostriatal projections control behavior remain largely unknown. Here using a new G-deleted rabies system in mice, we found that more than two-thirds of excitatory inputs to D2-SPNs also target D1-SPNs, while only one-third do sovice versa. Optogenetic stimulation of striatal D1- vs. D2-SPN-projecting cortical neurons differently regulate locomotion, reinforcement learning and sequence behavior, implying the functional dichotomy of pathway-specific corticostriatal subcircuits. These results reveal the partially segregated yet asymmetrically overlapping cortical projections on striatal D1- vs. D2-SPNs, and that the pathway-specific corticostriatal subcircuits distinctly control behavior. It has important implications in a wide range of neurological and psychiatric diseases affecting cortico-basal ganglia circuitry.In BriefKlug, Yan et al. employed a new modified rabies system in combination with slice physiology, optogenetics and behavioral tests to reveal that pathway-specific corticostriatal subcircuits distinctly control actions.HighlightsOne-third of the excitatory inputs to D1-SPNs project to D2-SPNs, while two-third of the excitatory inputs to D2-SPNs also target D1-SPNsActivation of D1-SPN projecting cortical neurons triggers behavioral effects in line with postsynaptic striatal direct pathway activationActivation of D2-SPN projecting cortical neurons causes behavioral effects similar with co-activation of both direct and indirect pathwaysCorticostriatal subcircuits control actions in a brain-region and pathway-specific manner
Predicting individualized treatment effects of corticosteroids in community-acquired-pneumonia: a data-driven analysis of randomized controlled trials
Authors: Smit J.M. , Van Der Zee P.A. , Stoof S.C.M. , Van Genderen M.E. , Snijders D. , Boersma W. G. , Confalonieri P. , Salton F. , Confalonieri M. , Shih M-C. , Meduri G.U. , Dequin P.-F. , Le Gouge A. , Lloyd M. , Karunajeewa H. , Bartminski G. , Fernández-Serrano S. , Suárez-Cuartín G. , van Klaveren D. , Briel M. , Schoenenberger C.M. , Steyerberg E.W. , Gommers D.A.M.P.J. , Bax H.I. , Bos W J. W. , Van De Garde E.M.W. , Wittermans E. , Grutters J.C. , Blum C.A. , Christ-Crain M. , Torres A. , Motos A. , Reinders M.J.T. , Van Bommel J. , Krijthe J.H. , Endeman H. 
Published: October 2023

AbstractBackgroundCorticosteroids could improve outcomes in patients with community-acquired pneumonia (CAP). However, we hypothesize that corticosteroid effectiveness varies among individual patients, resulting in inconsistent outcomes and unclear clinical indication. Therefore, we developed and validated a predictive, causal model based on baseline characteristics to predict individualized treatment effects (ITEs) of corticosteroids on mortality in patients with CAP.MethodsWe obtained individual patient data from six randomized controlled trials comparing corticosteroid therapy to placebo in 1,869 adult CAP patients. The study endpoint was 30-day mortality. We performed effect modelling through logistic regression and evaluated the predicted ITEs in terms of discrimination and calibration for benefit. Our modelling procedure involved variable selection, missing value imputation, data normalization, encoding treatment variables, creating interaction terms, optimizing penalization strength, and training logistic regression models. We evaluated discriminative performance using the newly proposed ‘AUC-benefit’.FindingsThe model identified high levels of CRP and glucose, at baseline, as main predictors for benefit of corticosteroid treatment. Using a decision threshold of ITE=0, the model predicted harm in 1,004 patient and benefit in 864 patients. We observed benefit in patients where the model predicted benefit, with an odds ratio of 0.5 (95% CI: 0.3 to 0.9) and a mortality reduction of 3.2% (95% CI: 0.7 to 5.6), and no statistically significant benefit in the patients where the model predicted harm, with an odds ratio of 1.1 (95% CI: 0.7 to 1.8) and a negative mortality reduction (hence, increase) of −0.3% (95% CI: −2.6 to 1.8). The model yielded an AUC-benefit of 184.9 (28.6 to 347.6, 95% CI), underestimated ITEs in the lower ITE region and slightly overestimated ITEs in the higher ITE region.InterpretationOur model has potential to identify patients with CAP who benefit from corticosteroid treatment, and aid in the design of personalized clinical trials. We will prospectively validate the model in two recent CAP trials.
Colchicine promotes atherosclerotic plaque stability independently of inflammation
Authors: Li Weizhen , Lin Alexander , Hutton Michael , Dhaliwal Harkirat , Nadel James , Rodor Julie , Tumanov Sergey , Örd Tiit , Hadden Matthew , Mokry Michal , Mol Barend M , Pasterkamp Gerard , Padula Matthew P , Geczy Carolyn L , Ramaswamy Yogambha , Sluimer Judith C , Kaikkonen Minna U , Stocker Roland , Baker Andrew H , Fisher Edward A , Patel Sanjay , Misra Ashish 
Published: October 2023

AbstractAtherosclerosis is a chronic inflammatory disease which is driven in part by the aberranttrans-differentiation of vascular smooth muscle cells (SMCs). No therapeutic drug has been shown to reverse detrimental SMC-derived cell phenotypes into protective phenotypes, a hypothesized enabler of plaque regression and improved patient outcome. Herein, we describe a novel function of colchicine in the beneficial modulation of SMC-derived cell phenotype, independent of its conventional anti-inflammatory effects. Using SMC fate mapping in an advanced atherosclerotic lesion model, colchicine induced plaque regression by converting pathogenic SMC-derived macrophage-like and osteoblast-like cells into protective myofibroblast-like cells which thickened, and thereby stabilized, the fibrous cap. This was dependent on Notch3 signaling in SMC-derived plaque cells. These findings may help explain the success of colchicine in clinical trials relative to other anti-inflammatory drugs. Thus, we demonstrate the potential of regulating SMC phenotype in advanced plaque regression through Notch3 signaling, in addition to the canonical anti-inflammatory actions of drugs to treat atherosclerosis.
M1-derived extracellular vesicles polarize recipient macrophages into M2 and alter skeletal muscle homeostasis in a hyper-glucose environment
Authors: Tacconi Stefano , Vari Francesco , Sbarigia Carolina , Vardanyan Diana , Longo Serena , Mura Francesco , Angilè Federica , Jalabart Audrey , Vergara Daniele , Fanizzi Francesco Paolo , Rossi Marco , Errazuriz-Cerda Elizabeth , Cassin Christel , Nieuwland Rienk , Giudetti Anna Maria , Rome Sophie , Dini Luciana 
Published: October 2023

ABSTRACTBackgroundMacrophages release not only cytokines but also extracellular vesicles (EVs). EVs are small lipid-derived vesicles with virus-like properties transferring lipids, RNA and proteins between cells. Until now, the consequences of macrophage plasticity on the release and the composition of EVs have been poorly explored. In this study, we determined the impact of high-glucose (HG) concentrations on macrophage metabolism, and characterized their derived EV subpopulations. Finally, we determined whether HG-treated macrophage-derived EVs participate in immune responses and in metabolic alterations of skeletal muscle cells.MethodsTHP1-macrophages (M0) were treated with 15mM (MG15) or 30mM (MG30) glucose. M1 or M2 canonical markers, pro– and anti-inflammatory cytokines and lactate production were evaluated. Macrophage-derived EVs were characterized by TEM, flow cytometry, and 1H-Nuclear magnetic resonance spectroscopy for lipid composition. M0 macrophages or C2C12 muscle cells were used as recipients of MG15 and MG30-derived EVs. The lipid profiles of recipient cells were determined, as well as protein and mRNA levels of relevant genes for macrophage polarization or muscle metabolism.ResultsM0 released 2 populations of small and large EVs (sEVs, lEVs) with specific lipid profiles. Proportionally to the glucose concentration, glucose-treatment induced glycolysis in M0 macrophages which consequently shifted into a pro-inflammatory M1 phenotype, containing increased triacylglycerol and cholesterol content. Glucose also affected macrophage sphingolipid and phospholipid compositions. The lipid profile differences between sEVs and lEVs were abolished and represented the lipid profile alterations of MG15 and MG30 macrophages. Both sEVs and lEVs from M15 and M30 macrophages polarized M0 into anti-inflammatory M2, with increased contents of triacylglycerol and cholesterol. MG15 lEVs and sEVs induced insulin-induced AKT hyper-phosphorylation and accumulation of triacylglycerol in muscle cells, a state observed in pre-diabetes. Conversely, MG30 lEVs and sEVs induced insulin resistance in myotubes.ConclusionsAs inflammation involves first M1 macrophages, then the activation of M2 macrophages to attenuate inflammation, this study demonstrates that the dialog between macrophages through the EV route is an intrinsic part of the inflammatory response. In a hyperglycemic context, EV macrophages could participate in the development of muscle insulin-resistance and chronic inflammation.
Asian Paints: a valuation dilemma
Authors: Chaudhury Arit , Dawar Varun 
Published: October 2023

Learning outcomes
This case study will allow students to understand and analyse the process for conducting equity valuation by building a three-statement financial model, to understand and apply the workings of discounted cash flow (DCF) valuation methodology and its components, to apply the concepts related to the calculation of the weighted average cost of capital in the determination of discounting rate, to understand the terminal value calculation and assumptions thereof and to analyse the intrinsic valuation for the target company using the traditional multi-stage DCF model for investment decision-making.

Case overview/synopsis
In July 2019, Kapil Agarwal, an equity analyst operating out of Mumbai, India, was carefully looking over the financials of Asian Paints, a leading paints company in India. As an equity analyst, Kapil was constantly on the lookout for fundamentally strong but undervalued companies that could create long-term wealth for his equity fund. To decide upon the right valuation of Asian Paints, Kapil conducted fundamental analysis using the DCF method on the basis of available financial information. This case study puts students in an investment analyst role wherein they forecast financial statements and conduct DCF valuation for Asian Paints to discover potentially undervalued stocks for investment decision-making.

Complexity academic level
This case study is designed for use in an undergraduate or postgraduate programme in business management, particularly in a course on business valuation or investment management or security analysis.

Supplementary materials
Teaching notes are available for educators only.

Subject code
CSS 1: Accounting and Finance.
Accounting information quality and cash holdings—Moderating effects based on state ownerships and local appointments
Authors: Zhu Liangyu , Sun Yulong 
Published: October 2023

PurposeThe purpose of this study is to explore the continuity and stability of the impact of accounting information quality on cash holdings, and the moderating effect of this relationship on state ownerships and local appointments.Design/methodology/approachBased on China's companies from 2011 to 2019, the authors divided cross-section and panel samples, adopted a linear and classification model and performed grouping regression.FindingsThe authors find that: first, the quality of corporate accounting information can significantly improve the level of cash holding, giving play to the strategic value effect of cash holding. But that boost is based on economies being able to solve agency problems. Second, the reduction of earnings management and the improvement of accounting information quality of NSOEs improve the level of cash holdings, while SOEs are on the contrary. Third, local appointments can play to the emotional strengths of their hometowns and play a synergistic role in this relationship, but the supervision effect of remote appointments is not obvious.Originality/valueThrough endogeneity and other tests, the conclusion is robust. Based on the agency and information asymmetry theory, the authors considered China's institutional and cultural factors, optimized accounting information's measurement and expanded the research boundary of the accounting field. The authors believe that applicable scenarios should be fully considered in the concluding relationship between accounting information quality and cash holdings. Enterprises should give full play to the advantages of cash holdings in strategic decision-making and financial efficiency, improve the quality of accounting information and also consider state ownerships and the differences in directors' emotions to reduce internal agency costs.