bluuebunny/crossref_metadata_2025 huggingface dataset:
WITHDRAWN: Tartrazine cannot make live tissues transparent
Authors: Inagaki Shigenori , Imai Takeshi
Published: September 2024

Withdrawal Statement

The authors have withdrawn their manuscript because one of the conclusions was wrong. The authors sincerely apologize to Ou et al. and the research community for the confusion. In this preprint, the authors performed an abdominal skin clearing experiment following the methods section in Ou et al. (ref. 1) and observed only a marginal clearing effect. In this condition (Figure 1), the authors detected tartrazine only in the stratum corneum (SC) of the skin, where only dead cells are present (Figure 1E, F). However, following a more detailed protocol with additional tips kindly provided by Ou et al. (ref. 1), the abdominal skin became more transparent. It seems that mechanical damage to the SC barrier is critical for successful clearing. In this condition, the authors detected strong tartrazine signals under the SC, including the dermis where live cells are located. We are still concerned about the issue of osmolality and toxicity to live cells; cleared cells must be under hypertonic conditions (Figure 3 and 4). However, since Figure 1 (especially Figure 1E, F) no longer stands, and the title can be misinterpreted as if the original results (ref. 1) were irreproducible, the authors believe it is best to withdraw this preprint. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Phagocytosis is differentially regulated by LPS in M1- and M2-like macrophages via PGE2formation and EP4 signaling
Authors: Kirchhoff Rebecca , Chromik Michel André , Schebb Nils Helge
Published: October 2024

Phagocytosis is a key process in human innate immune response. Human macrophages are important phagocytes engulfing and neutralizing pathogens and cell debris. In addition, they modulate the inflammatory process by releasing cytokines and lipid mediators. However, the link between oxylipins and phagocytosis in different macrophage phenotypes remains poorly understood.

In order to better understand the link between phagocytosis and the arachidonic acid (ARA) cascade, we established a phagocytosis assay in primary human ‘inflammatory’ M1- and ‘anti-inflammatory’ M2-like macrophages from PBMCs, representing extremes of macrophage phenotypes. The branches of the ARA cascade were investigated by quantitative targeted proteomics and metabolomics.

M1-like macrophages show a higher abundance of cyclooxygenase (COX)-2 and its products particularly after LPS stimulus compared to M2-like macrophages. LPS increased phagocytosis in M2-like, but not in M1-like macrophages. We demonstrate that the COX product PGE2modulates the differential effects of LPS on phagocytosis: Via the EP4 receptor PGE2signaling suppresses phagocytosis in primary human macrophages. Thus, blockage of COX, e.g. by NSAID, leads to an increase of phagocytosis also in ‘inflammatory’ M1-like macrophages and may shift the macrophages towards a more pro-resolving phenotype. This supports the well-described anti-inflammatory effects of these drugs.
Mitochondria-centered metabolomic map of inclusion body myositis: sex-specific alterations in central carbon metabolism
Authors: Naddaf Elie , Shammas Ibrahim , Dasari Surendra , Petterson Xuan-Mai T. , Trushina Eugenia , Lanza Ian R.
Published: October 2024

Background

Inclusion body myositis (IBM) is a disease of aging characterized by progressive muscle loss. Despite its positioning at the intersection of aging, mitochondrial dysfunction and chronic inflammation, limited studies have evaluated the underlying metabolic disturbances in IBM.

Objective

To investigate the mitochondria-centered metabolomic map of IBM in muscle tissue, highlighting sex-specific differences, and to determine the correlation of the changes in metabolites and gene expression with clinical parameters.

Methods

37 IBM patients and 22 controls without a myopathy were included. All participants had bulk RNA sequencing performed previously. Clinical parameters included age at biopsy, disease duration, manual motor test (MMT) score, and modified Rankin scale (MRS). A complementary battery of metabolomics platforms was used, including untargeted metabolomics, Agilent dMRM Database and Method platform, and targeted metabolomics. Metabolite levels and RNA-metabolomics integrated modules were correlated with clinical parameters.

Results

Muscle samples from IBM patients had elevated TCA cycle intermediates with concomitant increase in anaplerotic amino acids, suggesting increased anaplerosis into the cycle. There was a decrease in upper glycolysis intermediates and an increase in most of the pentose phosphate pathway (PPP) metabolites. The PPP is the main source of NAPDH, a main antioxidant, and ribose-5-P a precursor of nucleic acids. There were marked sex-specific differences in the acylcarnitine profile, with a decrease in short-chain acylcarnitines only in males. Lastly, there was an increase in nucleic acid bases and a decrease in nucleotides. Several metabolites from various pathways had significant correlations with various clinical parameters, with the most pronounced sex-specific differences observed in correlations with acylcarnitines. RNA-metabolomics integration identified 4 modules, with the strongest correlation observed between one module and sex. The MMT score, an indicator of disease severity, showed a strong correlation with 3 modules. There were major sex specific differences with males having relatively similar correlation to the grouped (both sexes) analysis, while females had no significant correlation with any of the modules.

Conclusion

Taken together, our findings identified clinically significant alterations in central carbon metabolism in IBM, with major differences between males and females. Future studies are needed to determine the role of the detected metabolic alterations in IBM pathogenesis and track the changes longitudinally over the disease course.
Imprecise counting of observations in averaging tasks predicts primacy and recency effects
Authors: Prat-Carrabin Arthur , Woodford Michael
Published: October 2024

Primacy and recency effects — wherein early and recent observations exert disproportionate influence on judgments — have long been noted in cognitive tasks involving the sequential presentation of information. In studies where human subjects make decisions based on the average of a sequence of numbers, recency effects are typically modeled phenomenologically through exponential discounting, while primacy effects are neglected altogether. Here, we exhibit the prevalence of both effects in such tasks, and propose that they result from the observer’s imprecision in their running tally of how many pieces of information they have received. If their approximate counting follows a central tendency — a typical Bayesian pattern — then past information is overweighted near the beginning of the sequence, while new numbers are overweighted towards the end of the sequence. Thus both primacy and recency effects are simultaneously predicted by this single mechanism. The model moreover nests exponential discounting as a special case in which the observer has no information about the count. The behavioral data suggests that subjects indeed misestimate the count of observations, with biases similar to those observed in numerosity-estimation tasks. Finally, we present evidence that the central tendency of subjects shifts towards lower counts in tasks with shorter sequence lengths, consistent with a Bayesian estimation of the counts. These findings provide new insights into the cognitive processes underlying serial-position effects in averaging tasks, with broader implications for other cognitive domains.
HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes
Authors: Li Hongchen , Zhang Xinchao , Liang Xiaoben , Li Shuyan , Cui Ziyi , Zhao Xinyu , Wang Kai , Zha Bingbing , Ma Haijie , Xu Ming , Lv Lei , Xu Yanping
Published: October 2024

The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and TET2 knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of FBP1 promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.
Leveraging CRISPR activation for rapid assessment of gene editing products in human pluripotent stem cells
Authors: Wu Youjun , Zhong Aaron , Evangelisti Alessandro , Sidharta Mega , Studer Lorenz , Zhou Ting
Published: October 2024

Verification of genome editing in human pluripotent stem cells (hPSCs), particularly in silent locus is desirable but challenging because it often requires complex and time-intensive lineage-specific or tissue-specific differentiation to induce their expression. Here, we establish a rapid and effective workflow for the verification of hPSC lines with genome editing in unexpressed genes using CRISPR-mediated transcriptional activation (CRISPRa). We systematically compared the efficiency of various CRISPRa systems in hPSCs, identifying the SAM system as the most potent for activating silent genes in hPSCs. Furthermore, we demonstrated enhanced gene activation by combining the SAM system with TET1, a demethylation module. By inducing targeted gene activation in undifferentiated hPSCs using CRISPRa, we successfully verified single and dual reporter hPSC lines and conducted functional tests of dTAG knock-ins and silent gene knockouts within 48 hours. This approach eliminates the need for cell differentiation to access genes only expressed by differentiated cells, offering a handy assay for verifying gene editing in hPSCs.
Impaired speaking-induced suppression predicts degraded agency and hallucination severity in schizophrenia
Authors: Tan Songyuan , Jia Yingxin , Mathew Miriam , Jariwala Namasvi , Pongos Alvincé , Brent Kurtis , Ford Judith , Mathalon Daniel , Houde John , Nagarajan Srikantan , Subramaniam Karuna
Published: October 2024

Background

Agency is the awareness of being the originator of one’s own thoughts and actions. Patients with schizophrenia (SZ) show deficits in agency that contribute to distortions in reality-monitoring (distinguishing self-generated from externally-produced information) and result in psychotic symptoms. Agency is also critical for speech-monitoring (monitoring what we hear ourselves say while speaking). For example, disruptions in agency that manifest as hallucinations are thought to result from the misattribution of the source of patients’ inner thoughts/speech as external voices.

Methods

We used magnetoencephalography (MEG) to assay assess agency during reality-monitoring (RM) and speech-monitoring (SM) tasks. In healthy controls (HC) during SM, the auditory cortical (A1) response is smaller while speaking (speak condition) compared to listening to the same speech (listen condition). This is known as speaking-induced suppression (SIS) M100 response which is measured using MEG 100ms after speech onset.

Results

During RM, SZ (N=30) showed impairments in both self-agency (identification of self-generated information) and external-agency (identification of externally-produced information), compared to HC (N=30). During SM, SZ failed to enhance M100 A1 responses during the listen condition and suppress M100 A1 responses while speaking, revealing impaired SIS. Weakened SIS predicted worsening hallucination severity.

Conclusions

SZ showed degraded neural M100 responses in A1 during the listen condition which drove impaired suppression of M100 SIS during highly-predictable self-generated speech. Impaired SIS induced noisier auditory sensory predictions, making it more likely for SZ to misattribute the source of inner thoughts/speech as externally-derived, giving rise to disruptions in agency during RM and more severe hallucinations.
Spatiotemporal properties of cortical excitatory and inhibitory neuron activation by sustained and bursting electrical microstimulation
Authors: Hughes Christopher L , Stieger Kevin A , Chen Keying , Vazquez Alberto L , Kozai Takashi DY
Published: October 2024

Intracortical microstimulation (ICMS) of sensory cortices produces artificial sensation yet the neural mechanisms underlying evoked responses, particularly among inhibitory subpopulations, remain unclear. We investigated how long durations (30 s) of ICMS shape spatiotemporal patterns in excitatory and inhibitory network activation using two-photon imaging of visual cortex in transgenic mice. Inhibitory neurons were more likely to facilitate (increase in activation) across 30 s of ICMS, whereas excitatory neurons were more likely to adapt (decrease in activation) and exhibit post-ICMS depression. Different temporal profiles led to preferential activation of excitatory or inhibitory neurons, with theta-burst stimulation driving the strongest inhibitory response and 10-Hz burst patterns driving the strongest peak excitatory response. Neurons located farther from the electrode exhibited more diverse responses to ICMS, highlighting synaptic recruitment dynamics such as inhibition and disinhibition. This study reveals how ICMS differentially influences excitatory and inhibitory neuron activity across long durations of ICMS and suggests temporal patterning can be used to potentially target neuronal subpopulations and drive desirable activity patterns.
Promiscuous and multivalent interactions between Eps15 and partner protein Dab2 generate a complex interaction network
Authors: Papagiannoula Andromachi , Vedel Ida Marie , Motzny Kathrin , Tengo Maud , Saiti Arbesa , Milles Sigrid
Published: October 2024

Clathrin-mediated endocytosis depends on complex protein interactions. Eps15 plays a key role through interactions of its three EH domains with Asn-Pro-Phe (NPF) motifs in intrinsically disordered regions (IDRs) of other endocytic proteins. Using nuclear magnetic resonance spectroscopy, we investigate the interaction between Eps15’s EH domains and a highly disordered Dab2 fragment (Dab2₃₂₀₋₄₉₅). We find that the EH domains exhibit binding promiscuity, recognizing not only the NPF motif of Dab2 but also other phenylalanine containing motifs. This promiscuity enables interactions with Eps15’s own IDR (Eps15IDR), which lacks NPF motifs, suggesting an self-inhibitory state that promotes liquid-liquid phase separation. Despite competing for the same EH domain binding sites, Eps15IDRand Dab2₃₂₀₋₄₉₅ can bind EH123 simultaneously, forming a highly dynamic interaction network that facilitates the recruitment of Dab2₃₂₀₋₄₉₅ into Eps15 condensates. Our findings provide molecular insights into the competitive interactions shaping the early stages of clathrin-mediated endocytosis.
Fast label-free live imaging reveals key roles of flow dynamics and CD44-HA interaction in cancer cell arrest on endothelial monolayers
Authors: Follain Gautier , Ghimire Sujan , Pylvänäinen Joanna W. , Vaitkevičiūtė Monika , Wurzinger Diana , Guzmán Camilo , Conway James RW , Dibus Michal , Oikari Sanna , Rilla Kirsi , Salmi Marko , Ivaska Johanna , Jacquemet Guillaume
Published: October 2024

Leukocyte extravasation is a key component of the innate immune response, while circulating tumor cell extravasation is a critical step in metastasis formation. Despite their importance, the mechanisms underlying leukocyte and tumor cell extravasation remain incompletely understood. Here, we developed an imaging pipeline that integrates fast, label-free live-cell imaging with deep learning-based image analysis to quantitatively track and compare the initial steps of extravasation—cell landing and arrest on an endothelial monolayer—under physiological flow conditions. We find that pancreatic ductal adenocarcinoma (PDAC) cells exhibit variable adhesion strength and flow sensitivity. Remarkably, some PDAC cells demonstrate comparable endothelial engagement as leukocytes, preferentially arresting at endothelial junctions, potentially due to increased stiffness at these sites, which leads to exposure to the underlying basal extracellular matrix. PDAC cells also tend to cluster in regions with high, heterogeneous expression of the endothelial CD44 receptor. Simulations suggest that clustering results from the combination of CD44-mediated attachment and localized flow disturbances that facilitate subsequent cell attachment. Targeting CD44 using siRNA or function-blocking antibodies, or degrading its ligand hyaluronic acid (HA), almost completely abolishes PDAC cell attachment. Overall, we demonstrate that cancer and immune cells share both common and unique features in endothelial adhesion under flow, and identify CD44 and HA as key mediators of PDAC cell arrest.
Hard-wired visual filters for environment-agnostic object recognition
Authors: Kang Minjun , Baek Seungdae , Paik Se-Bum
Published: October 2024

Conventional deep neural networks (DNNs) are highly susceptible to variations in input domains, unlike biological brains which effectively adapt to environmental changes. Here, we demonstrate that hard-wired Gabor filters, replicating the structure of receptive fields in the brain’s early visual pathway, facilitate environment-agnostic object recognition without overfitting. Our approach involved fixing the pre-designed Gabor filters in the early layers of DNNs, preventing any alterations during training. Despite the restricted learning flexibility of this model, our networks maintained robust performance even under significant domain shifts, in contrast to conventional DNNs that typically fail in similar conditions. We found that our model effectively clustered identical “classes” across diverse domains, while conventional DNNs tend to cluster images by “domain” in the latent space. We observed that the fixed Gabor filters enabled networks to encode global shape information rather than local texture features, thereby mitigating the risk of overfitting.

One sentence summary

Hard-wired Gabor filters enable environment-agnostic object recognition without overfitting.

Research Highlights

Conventional deep neural networks (DNNs) are vulnerable to input domain variations

Hard-wired Gabor filters facilitate environment-agnostic object recognition

Fixed Gabor filters prevent overfitting and facilitate shape-based classifications

Our model cluster identical “classes” while conventional DNNs cluster by “domain”
A host-directed adjuvant resuscitates and sensitizes intracellular bacterial persisters to antibiotics
Authors: Lu Kuan-Yi , Yang Xiangbo , Eldridge Matthew J.G. , Wagner Nikki J. , Hardy Brian , Axtman Matthew , Rowe Sarah E. , Wang Xiaodong , Fowler Vance G. , Helaine Sophie , Pearce Kenneth H. , Conlon Brian P.
Published: October 2024

There are two major problems in the field of antimicrobial chemotherapy–antibiotic resistance and antibiotic tolerance. In the case of antibiotic tolerance, antibiotics fail to kill the bacteria as their phenotypic state affords them protection from the bactericidal activity of the antibiotic. Antibiotic tolerance can affect an entire bacterial population, or a subset of cells known as persister cells. Interaction with the host induces the formation of persister cells in numerous pathogens, with reactive oxygen and nitrogen species production being heavily implicated in the collapse of bacterial energy levels and entrance into an antibiotic tolerant state. Here, we developed a high-throughput screen to identify energy modulators for intracellularStaphylococcus aureus. The identified compound,KL1, increases intracellular bacterial energy and sensitizes the persister population to antibiotics, without causing cytotoxicity or bacterial outgrowth. We demonstrate thatKL1exhibits adjuvant activity in a murine model ofS. aureusbacteremia and intracellular infection ofSalmonella Typhimurium. Transcriptomic analysis and further studies on its mechanism of action reveal thatKL1modulates host immune response genes and suppresses the production of reactive species in host macrophages, alleviating one of the major stressors that induce antibiotic tolerance. Our findings highlight the potential to target intracellular persister cells by stimulating their metabolism and encourage larger efforts to address antibiotic tolerance at the host–pathogen interface, particularly within the intracellular milieu.
Jerusalem artichoke extracts regulate the gene expression of key enzymes involved in fatty acid biosynthesis
Authors: Bunch Heeyoun , Yoon Young-Ran , Calderwood Stuart K.
Published: October 2024

Jerusalem artichoke (JA) is a traditional remedy for alleviating symptoms of diabetes. In fact, the suppressive effects of JA on blood sugar have been reported in multiple studies since 1934. Recent studies have indicated that type II diabetes is often caused by insulin resistance rather than insulin reduction and that increased blood and interstitial fatty acid levels contribute to insulin resistance and the development of diabetes. However, whether JA affects lipogenesis has not been studied. Here, we elucidated the effects of JA on the expression of two key enzymes involved in fatty acid biosynthesis, fatty acid synthase (FASN) and acetyl-coA carboxylase (ACACA), using three immortalized human bone marrow, colon, and liver cell lines. Caffeine and ICRF193, a catalytic inhibitor of topoisomerase II (TOP2), were included as positive controls, and JA was extracted into water- or dimethyl sulfoxide-soluble components, termed H-JA and D-JA. D-JA significantly reduced the expression ofFASNandACACAat the mRNA and protein levels. D-JA-treated cells exhibited altered TOP2 levels andFASN/ACACAexpression appeared to be controlled by TOP2 activity and levels. Taken together, our study revealed a novel effect of JA extracts on inhibiting the expression of the key enzymes involved in the fatty acid synthesis and suggested the potential of JA as a natural medicinal agent to control lipogenesis in humans.

Highlights

Jerusalem artichoke extracts reduce the expression ofFASNandACACAgenes at the mRNA and protein levels

Topoisomerase II regulatesFASNandACACAgene expression

Jerusalem artichoke extracts and plasma glucose concentrations regulate cellular topoisomerase II protein expression
Quorum sensing and DNA methylation play active roles in clinicalBurkholderiaphase variation
Authors: Coulon Pauline M.L. , Groleau Marie-Christine , Hachani Abderrahman , Padula Matthew P. , Stinear Timothy P. , Déziel Eric
Published: October 2024

Phenotypic diversity in bacteria often results from adaptation to changing environmental conditions and is exemplified by variable colony morphotypes. Discrete genomic changes and modulation in gene expression occur inBurkholderia pseudomalleiundergoing adaptation. Alternatively, adapted colony morphotype variants of species belonging to theBurkholderia cepaciacomplex (Bcc) lose a complete replicon (the pC3 virulence megaplasmid), which affects their production of virulence factors. We report that variants arising inBurkholderia ambifariaclinical isolates - with affected phenotypes - have retained their pC3, suggesting that another phase variation mechanism can take place in this Bcc species. Proteomic and phenotypic characterisation showed that morphotype variants ofB. ambifariastrains CEP0996 (pC3-null) and HSJ1 (pC3-positive) share similarities in phenotypes controlled by the Cep quorum sensing system. Thus, we determined the role of quorum sensing inB. ambifariaHSJ1 phase variation and confirmed that the main quorum sensing system Cep is important for the emergence of variants. As DNA methylation is one of the main epigenetic factors involved in bacterial phase variation that regulates some virulence factors of the Bcc speciesBurkholderia cenocepacia, we hypothesized thatB. ambifariaHSJ1 phase variation could also be regulated by adenosine DNA methylation. By deleting the three putative adenosine DNA methyltransferases, we found that an orphan type II DNA methyltransferase prevents the emergence of phase variants. This is the first study to report quorum sensing and adenosine DNA methylation as two antagonistic systems independently controlling phase variation.

Importance

SomeBurkholderiaspecies are pathogenic to plants, animals, or humans. In immunocompromised individuals, such as those with cystic fibrosis, infection withBurkholderia cepaciacomplex (Bcc) bacteria can lead to "cepaciasyndrome." In the Australian Aboriginal population, melioidosis caused byB. pseudomalleiis prevalent, particularly among those with diabetes or alcoholism.Burkholderia’s phenotypic plasticity, including colony morphotype variation (CMV), enables rapid adaptation to diverse environments, enhancing survival and pathogenicity. This study reveals phase variation as a new CMV mechanism within the Bcc group. We found that quorum sensing and DNA methylation are involved in phase variation. Understanding the underlying CMV mechanisms could lead to the development of targeted therapies against these highly antibiotic-resistant bacteria.
Comparison of morphological and physiological response to drought stress among temperate forest understory forbs and graminoids
Authors: Petek-Petrik Anja , Petrík Peter , Halmová Marika , Plichta Roman , Matoušková Marie , Houšková Kateřina , Chudomelová Markéta , Urban Josef , Hedl Radim
Published: October 2024

Drought stress can profoundly affect plant growth and physiological vitality, yet there is a notable scarcity of controlled drought experiments focused on herbaceous species of the forest understory.

In this study, we collected seeds from five forb and four graminoid species growing in the temperate forest understory of the Czech Republic. These seeds were germinated under controlled glasshouse conditions and subjected to moderate drought stress for five weeks. We assessed biomass partitioning, stomatal and leaf morphology, leaf gas exchange, minimum leaf conductance (gmin), and chlorophyll fluorescence parameters.

The comparison of two ecological guilds revealed that graminoids exhibited a higher root-to-shoot ratio, improved water-use efficiency, greater carboxylation efficiency, and enhanced non-photochemical quenching under drought conditions compared to forbs. In contrast, forbs had significantly lowergmin, along with higher total biomass and total leaf area. Despite these differences in morpho-physiological functional traits, both groups experienced a similar relative reduction in biomass during drought stress. Key predictors of biomass accumulation under drought included photochemical quenching, stomatal traits, total leaf area andgmin. A negative correlation between biomass andgminsuggests that plants with lower residual water losses after stomatal closure can accumulate more biomass under drought stress. Additionally,gminwas positively correlated with guard cell length, suggesting that larger stomata contribute to higher residual water loss.

Graminoids exhibited morpho-physiological modifications that enhanced drought resistance, indicating a greater emphasis on stress tolerance as a survival strategy. In contrast, forbs maintained higher biomass and total leaf area, reflecting a competitive strategy for maximizing resource acquisition.
Combined explanation of LHC multilepton, diphoton, and top-quark excesses
Authors: Coloretti Guglielmo , Crivellin Andreas , Mellado Bruce
Published: October 2024

In this article, we propose the Δ2HDMS as a combined explanation of several excesses and anomalies observed at the LHC. Especially, tt¯ differential distributions point towards the associated production of new electroweak scale Higgs bosons decaying into bottom quarks and W bosons (>5σ) with masses consistent with the diphoton excesses at ≈95  GeV and ≈151.5  GeV (3.8σ and 4.9σ, respectively). Furthermore, CMS found indications for resonant tt¯ production at ≈400  GeV (3.5σ) and both ATLAS and CMS reported elevated four-top and tt¯W cross sections. The Δ2HDMS is obtained by supplementing the SM Higgs (H2) with a second scalar doublet (H1), real scalar singlet (S), and a Higgs triplet with zero hypercharge (Δ). We fix the masses of the neutral tripletlike and the singletlike scalars by the diphoton excesses, i.e., mΔ0=151.5  GeV and mS=95  GeV, respectively. H, the CP-even component of H1, is produced via gluon fusion from a top-loop and decays dominantly to S+Δ0 whose subsequent decays to W+W− and bb¯ explain the differential tt¯ distributions for σ(pp→H→SΔ0)≈5  pb. Choosing the top-Yukawa of H1 accordingly, the CP-odd Higgs boson A turns out to have the right production cross section to account for the resonant tt¯ excess at 400 GeV, while the top-associated production of H and A results in new physics pollution of Standard Model tt¯W and tt¯tt¯ cross sections, as preferred by the data.

Published by the American Physical Society
2024
Linearized second law for higher curvature gravity and nonminimally coupled vector fields
Authors: Wall Aron C. , Yan Zihan
Published: October 2024

Expanding the work of Wall [], we show that black holes obey a second law for linear perturbations to bifurcate Killing horizons, in any covariant higher curvature gravity coupled to scalar and vector fields. The vector fields do not need to be gauged, and (like the scalars) can have arbitrary nonminimal couplings to the metric. The increasing entropy has a natural expression in covariant phase space language, which makes it manifestly invariant under Jacobson-Kang-Myers ambiguities. An explicit entropy formula is given for f(Riemann) gravity coupled to vectors, where at most one derivative acts on each vector. Besides the previously known curvature terms, there are three extra terms involving differentiating the Lagrangian by the symmetric vector derivative (which therefore vanish for gauge fields).

Published by the American Physical Society
2024
Perceived experiential value and continued use intention of e-retail chatbots
Authors: Mpinganjira Mercy , Dlodlo Nobukhosi , Idemudia Efosa C.
Published: September 2024

Purpose

In the quest to build a sense of human contact, e-retailers are increasingly depending on the scalability of chatbots to promote assistive dialogue during online shopping. Not much is known about the experiential value of customer interaction. This research proposes and evaluates a conceptual model for understanding the value perceptions emanating from the experiences of fashion shoppers utilising e-retail chatbots.

Design/methodology/approach

Data were collected using an online survey administered to 460 online panellists. Structural equation modelling was used to test the proposed research model.

Findings

Continued chatbot use intentions (CUIs) are influenced positively by perceived hedonic and utilitarian experiential value. Perceived social experiential value had a negative effect on shoppers’ continued intention to use the chatbot. Both perceived chatbot anthropomorphism and perceived chatbot intelligence positively and significantly affect shoppers’ experiential value while perceived chatbot risk yields a significantly negative effect.

Social implications

By using conversational artificial intelligence chatbots, engagement at e-retail stores can be driven based on the user data and made more interactive.

Originality/value

The study introduces an e-retail chatbot model which asserts the power of selected chatbot attributes as catalysts of shoppers’ experiential value. Cumulatively, the model is a first-step approach providing a novel and balanced (both positive attributes and negative risks) view of chatbot continued use intentions.
The role of ICT as LT in shaping inclusive and special education – a systematic review for 2012–2023
Authors: Bosse Ingo Karl , Nussbaumer Daniela , Hövel Dennis Christian
Published: October 2024

Purpose

Digital inequalities are pressing concerns, especially for students in need of special educational support. In recent years, numerous reviews have been published on the use of learning technologies (LT) in inclusive and special education. They mostly provide findings for specific groups, technologies, and countries. This systematic review aims to identify changes in the use of information and communication technologies (ICT) as LT that evolved globally in inclusive and special education over the last 12 years.

Design/methodology/approach

Web of Science, Scopus, and EBSCOhost were systematically searched for publications for 2012 to 2023. Only peer-reviewed English publications were included to ensure a comprehensive review. The findings of the 421 included papers were then analysed, reflecting diverse perspectives at the technology, learners, teachers, and institutional levels.

Findings

The most used devices were computers, iPads/tablets, and specifically designed apps. More studies were conducted in separate settings than in inclusive ones. The primary participant groups were students on the autism spectrum. More than half the research publications were related to technology use. Technology development was the most common research objective, with approximately 40% of test hypotheses based on standardised tests or observations.

Research limitations/implications

By shifting the focus from specific disabilities to a more usability-based approach, we can envision a future in which the quality of education for all students is substantially improved.

Practical implications

LT have the potential to significantly contribute to creating the least restrictive learning environment for students in need of special educational support. One step for practitioners is to consider the interdependencies between the different dimensions of heterogeneity relevant to digital inclusion. In order to solve these complex pedagogical tasks appropriately, multidisciplinary cooperation is necessary, involving experts in technical, pedagogical, didactic and inclusive education in digitalised societies.

Originality/value

All data were meticulously collected and analysed to ensure credibility and originality.
Building sales through connections: how network capabilities and tie strength foster entrepreneurial marketing
Authors: Torres Gersson , Rojas-Berrio Sandra Patricia , Duque-Uribe Veronica , Robledo Sebastian
Published: October 2024

Purpose

The purpose of this study is to delve into the intricate relationship between network capabilities (NCs), entrepreneurial marketing (EM) and sales performance (SP), with a specific focus on uncovering the nuanced role that ties strength (TS) plays as a mediator.

Design/methodology/approach

This research was conducted using a survey method with a population of software small and medium-sized enterprises (SMEs) in Colombia using a sample size of 164 questionnaires. The data analysis method used was the partial least squares.

Findings

The results show that EM has an impact on SP. TS mediates the influence of NC and EM. Findings highlighted the importance of networking in EM and the relationship with SP.

Practical implications

NCs emerge as a vital determinant for fostering EM within SMEs. Owners should prioritize the development and enhancement of their NCs; for example, building relationships, fostering collaborations and leveraging connections within the industry. Also, this could lead to more innovative marketing strategies, differentiating the firm in a competitive marketplace. The mediating role of TS underscores the importance of not just having network connections but building strong, meaningful relationships with customers. SMEs with high NCs should design more targeted and customized marketing strategies.

Originality/value

The value of this research lies in its intricate exploration of the complex relationships between NCs, TS and EM. This study paves the way for a deeper understanding of network dynamics and their implications within EM. It sets the stage for subsequent studies that may lead to the formulation of more sophisticated network marketing strategies tailored for EM contexts.
Three days together around the table: using the group analysis method to value the expertise and lived experiences of key voices to innovate solutions
Authors: Plourde Chantal , Alarie-Vézina Pascale , Laventure Myriam , Tremblay Joël
Published: September 2024

Purpose

This paper presents the use of the Group Analysis Method (GAM), an innovative method developed in a francophone context, to discuss issues related to the services offered in the field of addiction in Quebec’s Indigenous communities and to identify perspectives for innovative solutions.

Design/methodology/approach

This article begins with a detailed description of the method’s phases and steps based on the French-language writings of the developers of the GAM. The authors then illustrate a concrete example of how this method has been applied to addiction intervention stakeholders in Indigenous communities in Quebec (Canada), highlighting the type of results possible.

Findings

The strengths and weaknesses of the GAM for addressing sensitive issues in an Indigenous context are discussed. Recommendations for further integration of the Indigenous perspective into the approach are proposed.

Originality/value

This article presents a relevant qualitative method for co-constructing solutions with groups which, to our knowledge, has not been described in the English-language literature. In the light of their experience in an Indigenous context, the authors adopt a critical perspective, demonstrating the relevance of the method and suggesting adaptations to ensure an equitable distribution of power through the process.
Agomelatine‐loaded nanostructured lipid carriers alleviate neuropathic pain in rats by Nrf2/HO‐1 signalling pathway
Authors: Firdoos Sundas , Dai Rongji , Younas Zahid , Shah Fawad Ali , Gul Maleeha , Rasheed Madiha
Published: October 2024

Neuropathic pain arises from impairments or malfunctions within the nervous system, resulting in atypical transmission and interpretation of pain signals. In the present study, we examined the neuroprotective effects of agomelatine (AGM) and agomelatine‐loaded nanostructured lipid carriers (AGM‐NLCs) in neuropathic animal models induced by chronic constriction injury (CCI) of the sciatic nerve. Male Sprague Dawley rats were divided into seven experimental groups to compare the effects of AGM and AGM‐NLCs, which were administered at 20 mg/kg for 14 consecutive days after CCI. Our finding demonstrated that CCI triggered the onset of analgesia in these animals, corroborated by mechanical allodynia and thermal hyperalgesia. Furthermore, CCI induced an elevation in inflammatory mediators such as interleukin (IL)‐1β and inducible nitric oxide synthase (iNOS), and downregulated heme oxygenase‐1 (HO‐1) and nuclear factor E2‐related factor (Nrf2). Treatment with AGM and AGM‐NLCs reversed inflammatory cascades and elevated antioxidant enzyme levels, leading to a reduction in paw withdrawal latency and threshold in rats. To further investigate the effect of AGM and AGM‐NLCs, all‐trans retinoic acid (ATRA) was administered, which antagonizes Nrf2. ATRA substantially downregulated Nrf2 expression and exacerbated thermal hyperalgesia, whereas Nrf2 and HO‐1 expressions were significantly upregulated after AGM‐NLCs administration. Overall, the results demonstrated that AGM‐NLCs offer promising antinociceptive and anti‐inflammatory properties in alleviating neuropathic pain symptoms, which can be attributed to improved drug delivery and therapeutic outcomes compared with AGM alone.
Pre‐ to post‐dialysis potassium gradient and mortality in patients on hemodialysis: A propensity‐matched analysis
Authors: Zhang Huixian , Liu Jing , Liu Xu , Guo Wang , Huang Hongdong , Liu Wenhu , Diao Zongli
Published: September 2024

Introduction

Pre‐ to post‐dialysis potassium gradient (ΔK) has arrhythmogenic effects; however, its effect on mortality remains unclear. The relationship between ΔK and mortality was assessed.

Methods

All patients undergoing hemodialysis in Beijing in 2014 were eligible for inclusion. The low (≤1.2 mmol/L), median (1.2–1.8 mmol/L), and high (>1.8 mmol/L) ΔK groups were matched by sex, age, diabetes, and dialysis time for enrollmen. The primary and secondary outcomes were all‐cause and cardiovascular death within the follow‐up. Cox regression analysis was performed to evaluate the effect of ΔK on mortality. We also analyzed the associations of combinations of ΔK and pre‐dialysis potassium with mortality.

Results

We enrolled 2181 patients in three matched groups (n = 727 per group). The median follow‐up was 72.0 (interquartile range, 53.7–72.0) months. All‐cause mortality occurred in 215/727 (29.6%), 95/727 (13.1%), and 198/727 (27.2%) patients in the low‐, median‐, and high‐ΔK groups, respectively. After adjusting for multiple factors, the median ΔK group had better survival than the low‐ (hazard ratio (HR), 1.91; 95% confidence interval [95% CI], 1.45–2.52; p < 0.001) and high‐ΔK groups (HR, 2.17; 95% CI, 1.57–2.99; p < 0.001). Further analysis based on pre‐dialysis potassium revealed that when maintaining a level of 4.5–5.5 mmol/L and ΔK of 1.2–1.8 mmol/L, patients had the lowest risk of mortality, whereas the highest risk was observed when pre‐dialysis potassium was >5.5 mmol/L and ΔK was >1.8 mmol/L.

Conclusion

Maintaining serum potassium within a appropriate range and reducing potassium fluctuations during dialysis may help to reduce the mortality risk of maintenance hemodialysis patients. These findings provide important data support for the quality control of hemodialysis.
Granulomas without foreign body giant cells in perianal fistula tissue suggest Crohn's disease
Authors: Han Yi Na , Gu Qian Ru , Wu Yan Chuang , Topatana Win , Jiang Zhi Nong
Published: October 2024

Objectives

Histopathological characteristics of granulomas in perianal fistula of patients with Crohn's disease (CD) remain unexplored. We aimed to assess the histopathological features of granulomas in perianal fistula in CD.

Methods

A retrospective analysis was conducted by reviewing the medical and pathological records of 4430 cases who underwent perianal fistulectomy at our hospital between June 2015 and June 2023. The patients were divided into the CD group, tuberculosis (TB), and non‐CD group, respectively, based on their final diangosis. The detection rate of granulomas and differential histopathological features were investigated.

Results

Among the 4430 patients, granulomas were identified in 41 cases, including 25 had CD, 2 had pulmonary TB, and 14 only exhibiting perianal lesions with no other comorbidities. Additionally, there were altogether 93 CD cases, resulting in a detection rate of granuloma of 26.9%, which was considerably higher than that in the non‐CD group (26.9% vs 0.3%, p < 0.001). The majority (85.7%) of the perianal fistula tissues in the non‐CD group contained foreign body giant cells, while this was observed in only 1 (4.0%) out of the 25 cases with CD. We proposed that granulomas in the perianal fistula in the non‐CD group were mostly foreign body granulomas. Moreover, granulomas in the non‐CD group were larger than that of the CD group (1135 μm vs 519 μm, p < 0.001).

Conclusion

Most CD cases have less granulomas (≤3) and no foreign body giant cells. Ribbon‐like granulomas can be seen only in CD cases.
Efficacy and safety of oral versus intravenous cyclophosphamide in treatment of connective tissue disease‐related interstitial lung disease
Authors: Feng Yuan , Chen Jia , Yang Xichao , Liu Jie , Cao Xue , Zhang Yan , Wu Zhenbiao
Published: October 2024

Objective

Interstitial lung disease (ILD) resulting from connective tissue disease (CTD) greatly undermines people's health. Cyclophosphamide (CYC) is a widely used agent in treating CTD‐ILD. We compared the efficacy and safety of oral and intravenous CYC in CTD‐ILD treatment.

Methods

The retrospectively enrolled CTD‐ILD patients were divided into the oral and intravenous CYC groups. The chest high‐resolution computed tomography examination, forced vital capacity (FVC), lung carbon monoxide diffusion capacity (Dlco) determinations, and 6 min walk test (6MWT) were performed pre‐treatment and at the 3rd, 6th, and 12th months posttreatment. Radiographic ILD severity was assessed using the Warrick score. Krebs Von den Lungen‐6, surfactant protein A (SP‐A), SP‐D, and erythrocyte sedimentation rate (ESR) before and at the 12th month post‐treatment were determined. CYC cumulative dose and occurrence of adverse reactions during treatment were recorded.

Results

CYC cumulative dose in the intravenous CYC group was reduced. Compared with oral CYC treatment, intravenous CYC caused decreased Warrick score and increased FVC and 6MWT at the 6th month, and elevated DLco at the 3rd and 6th months posttreatment. SP‐A, SP‐D and ESR levels in both groups were reduced 12 months posttreatment, with a more evident decrease in the intravenous CYC group. Intravenous CYC had lower total adverse reaction incidence.

Conclusion

Compared with oral CYC, intravenous CYC decreases Warrick score and increases FVC and 6MWT at 6 months posttreatment, and reduces SP‐A, SP‐D, and ESR levels after 12 months of treatment, which shows low CYC cumulative dose and adverse reaction incidence in treating CTD‐ILD.
Frailty and health‐related life quality in long‐term follow up of intensive care patients above 65 years old: Protocol for a Norwegian prospective, observational multicenter study
Authors: Kroken B. A. , Bergum D. , Berg K. S. , Espinasse M. , Fossum O. K. , Garratt A. M. , Klepstad Pal , Kvåle Reidar , Strand B. , Flaatten Hans Kristian , Frisvold Shirin K.
Published: October 2024

Background

Frailty is strongly correlated with mortality in intensive care unit patients, yet routine screening among intensive care patients is rarely performed.

The aim of this study is to assess frailty and health‐related quality of life (HRQoL) in patients before intensive care admission and to compare this with outcomes after 3 and 12‐months. The Clinical Frailty Scale and EQ‐5D‐5L will be used to assess frailty and HRQoL, respectively.

Methods

This is an ongoing, prospective observational study including patients from five Norwegian ICU's. Inclusion criteria are patients aged ≥65 years requiring invasive mechanical ventilation for ≥24 h. The Clinical Frailty Scale and EQ‐5D‐5L are administered at baseline (before critical illness) and at 3‐ and 12‐months post‐inclusion. Additional data collected includes patient characteristics, ICU treatment details, illness severity and mortality. The EQ‐5D‐5L will be compared to Norwegian population norms and assessed for measurement properties.

Results

Inclusion started July 2022 and will be stopped at 350 patients. The study will be completed in 2025.

Conclusion

The study will assess the feasibility and measurement properties of the Clinical Frailty Scale and EQ‐5D‐5L in ICU survivors by telephone at long‐term follow‐up study and will give additional information on the frailty and HRQoL of intensive care survivors.

Clinical trial registration

The study is registered in ClinicalTrials.gov NCT06012942. Protocol version 2.7.1, 19.05.2023.