bluuebunny/crossref_metadata_2025 huggingface dataset:
CD73 generated extracellular adenosine promotes resolution of neutrophil-mediated tissue injury and restrains metaplasia in pancreatitis
Authors: O’Brien Baylee J. , Faraoni Erika Y. , Strickland Lincoln N. , Ma Zhibo , Mota Victoria , Mota Samantha , Chen Xuebo , Mills Tingting , Eltzschig Holger K. , DelGiorno Kathleen E. , Bailey-Lundberg Jennifer M.
Published: September 2022

Background and Aims

Pancreatitis is currently the leading cause of gastrointestinal hospitalizations in the US. This condition occurs in response to abdominal injury, gallstones, chronic alcohol consumption or, less frequently, the cause remains idiopathic. CD73 is a cell surface ecto-5’-nucleotidase that generates extracellular adenosine, which can contribute to resolution of inflammation by binding adenosine receptors on infiltrating immune cells. We hypothesized genetic deletion of CD73 would result in more severe pancreatitis due to decreased generation of extracellular adenosine.

Methods

CD73 knockout (CD73-/-) and C57BL/6 (wild type, WT) mice were used to evaluate the progression and response of caerulein-induced acute and chronic pancreatitis.

Results

In response to caerulein-mediated chronic or acute pancreatitis, WT mice display resolution of pancreatitis at earlier timepoints than CD73-/- mice. Using immunohistochemistry and analysis of single cell RNA-seq (scRNA-seq) data, we determined CD73 localization in chronic pancreatitis is primarily observed in mucin/ductal cell populations and immune cells. In murine pancreata challenged with caerulein to induce acute pancreatitis, we compared CD73-/- to WT mice and observed a significant infiltration of Ly6G+, MPO+, and Granzyme B+ cells in CD73-/- compared to WT pancreata and we quantified a significant increase in acinar-to-ductal metaplasia demonstrating sustained metaplasia and inflammation in CD73-/- mice. Using neutrophil depletion in CD73-/- mice, we show neutrophil depletion significantly reduces metaplasia defined by CK19+ cells per field and significantly reduces acute pancreatitis.

Conclusions

These data identify CD73 agonists as a potential therapeutic strategy for patients with acute and chronic pancreatitis as adenosine generation and activation of adenosine receptors is critical to resolve persistent inflammation in the pancreas.

Graphical Abstract
Heterotypic electrostatic interactions control complex phase separation of tau and prion into multiphasic condensates and co-aggregates
Authors: Rai Sandeep K. , Khanna Roopali , Avni Anamika , Mukhopadhyay Samrat
Published: September 2022

Biomolecular condensates formed via phase separation of proteins and nucleic acids are thought to perform a wide range of critical cellular functions by maintaining spatiotemporal regulation and organizing intracellular biochemistry. However, aberrant phase transitions are implicated in a multitude of human diseases. Here, we demonstrate that two neuronal proteins namely, tau and prion undergo complex coacervation driven by domain-specific electrostatic interactions to yield highly dynamic, mesoscopic liquid-like droplets. The acidic N-terminal segment of tau interacts electrostatically with the polybasic N-terminal intrinsically disordered segment of the prion protein (PrP). We employed a unique combination of time-resolved tools that encompass several orders of magnitude of timescales ranging from nanoseconds to seconds. These studies unveil an intriguing orchestra of molecular events associated with the formation of heterotypic condensates comprising ephemeral, domain-specific, short-range electrostatic nanoclusters. Our results reveal that these heterotypic condensates can be tuned by RNA in a stoichiometry-dependent manner resulting in reversible, multiphasic, immiscible, ternary condensates of different morphologies ranging from core-shell to nested droplets. This ternary system exhibits a typical three-regime phase behavior reminiscent of other membraneless organelles including nucleolar condensates. We also show that upon aging, tau-PrP droplets gradually convert into solid-like co-assemblies by sequestration of persistent intermolecular interactions. Our vibrational Raman spectroscopic data in conjunction with atomic force microscopy and multi-color fluorescence imaging results reveal the presence of amorphous and amyloid-like co-aggregates upon maturation. Our findings provide mechanistic underpinnings of overlapping neuropathology involving tau and PrP and highlight a broader role of complex phase transitions in physiology and disease.
Thalamocortical interactions shape hierarchical neural variability during stimulus perception
Authors: Tauste Campo Adrià , Zainos Antonio , Vázquez Yuriria , Adell Segarra Raul , Álvarez Manuel , Deco Gustavo , Parra Sergio , Romo Ranulfo , Rossi-Pool Román
Published: September 2022

The brain is hierarchically organized to process sensory signals. But, to what extent do functional connections within and across areas shape this hierarchical order? We addressed this problem in the thalamocortical network, while monkeys judged the presence or absence of a vibrotactile stimulus. We quantified the variability by means of intrinsic timescales and Fano factor, and functional connectivity by means of a directionality measure in simultaneously recorded neurons sharing the same cutaneous receptive field from the somatosensory thalamus (VPL) and areas 3b and 1 from the somatosensory cortex. During the pre-stimulus periods, VPL and area 3b exhibited similarly fast dynamics while area 1 showed much slower timescales. Furthermore, during the stimulus presence, the Fano factor increased along the network VPL-3b-1. In parallel, VPL established two separate main feedforward pathways with areas 3b and 1 to process stimulus information. While feedforward interactions from VPL and area 3b were favored by neurons within specific Fano factor ranges, neural variability in area 1 was invariant to the incoming pathways. In contrast to VPL and area 3b, during the stimulus arrival, area 1 showed significant intra-area interactions, which mainly pointed to neurons with slow intrinsic timescales. Overall, our results suggest that the lower variability of VPL and area 3b regulates feedforward thalamocortical communication, while the higher variability of area 1 supports intra-cortical interactions during sensory processing. These results provide evidence of a hierarchical order along the thalamocortical network.
Gradual relation between perceptual awareness, recognition and pupillary responses to social threat
Authors: Poyo Solanas Marta , Zhan Minye , de Gelder Beatrice
Published: September 2022

There is substantial evidence about affective stimulus processing outside awareness in healthy participants and brain-damaged patients. However, there are still methodological concerns mainly relating to the methods used to assess awareness. In two experiments, we investigated the processing of social threat in healthy participants by combining the continuous flash suppression paradigm and the perceptual awareness scale, a finer measure of perceptual awareness than dichotomous (seen/unseen) responses. Our behavioral results show a gradual relationship between emotional recognition and perceptual awareness. Recognition sensitivity was also higher for fearful than angry bodies for all visual awareness levels except for the perceptual unawareness condition where performance was at chance level. Interestingly, angry body expressions were suppressed for a shorter duration than neutral and fearful ones. Pupil dilation was a function of affective expression, the duration of suppression and the level of perceptual awareness. In conclusion, behavioral as well as pupillary responses showed a gradual relationship with perceptual awareness, and this relationship was influenced by the specific stimulus category.
Pre- and post-task resting-state differs in clinical populations
Authors: Lor Cindy Sumaly , Zhang Mengfan , Karner Alexander , Steyrl David , Sladky Ronald , Scharnowski Frank , Haugg Amelie
Published: September 2022

Resting-state functional connectivity has generated great hopes as a potential brain biomarker for improving prevention, diagnosis, and treatment in psychiatry. This neuroimaging protocol can routinely be performed by patients and does not depend on the specificities of a task. Thus, it seems ideal for big data approaches that require aggregating data across multiple studies and sites. However, technical variability, diverging data analysis approaches, and differences in data acquisition protocols might introduce heterogeneity to the aggregated data. Besides these technical aspects, the psychological state of participants might also contribute to heterogeneity. In healthy participants, studies have shown that behavioral tasks can influence resting-state measures, but such effects have not yet been reported in clinical populations. Here, we fill this knowledge gap by comparing resting-state functional connectivity before and after clinically relevant tasks in two clinical conditions, namely substance use disorders and phobias. The tasks consisted of viewing craving-inducing and spider anxiety provoking pictures that are frequently used in cue-reactivity studies and exposure therapy. We found distinct pre- vs. post-task resting-state connectivity differences in each group, as well as decreased thalamo-cortical and increased intra-thalamic connectivity which might be associated with decreased vigilance in both groups. Notably, the pre- vs. post-task thalamus-amygdala connectivity change within a patient cohort seems more pronounced than the difference of that connection between the smoker vs. phobia clinical trait. Our results confirm that resting-state measures can be strongly influenced by changes in psychological states that need to be taken into account when pooling resting-state scans for clinical biomarker detection. This demands that resting-state datasets should include a complete description of the experimental design, especially when a task preceded data collection.
Computer Study of Metric Perturbations Impinging on Coupled Axon Tracts
Authors: Chawla Aman , Morgera Salvatore Domenic
Published: September 2022

Metric perturbations are deviations from a homogeneous spacetime background. In this paper, the authors extend an earlier investigation by using high precision computer simulations and show that there is definite impact of metric perturbations, that is, gravitational radiation, on the time-coded information conducted by a tract of neural axons as found in the human central nervous system.
Controlled Human Malaria Infection reveals that the Dantu blood group variant provides high level protection against uncomplicated malaria
Authors: Kariuki Silvia N , Macharia Alexander W , Makale Johnstone , Nyamu Wilfred , Hoffman Stephen L , Kapulu Melissa C , Bejon Philip , Rayner Julian C , Williams Thomas N ,   the CHMI-SIKA Study Team
Published: September 2022

Introduction

The long co-evolution ofHomo sapiensandPlasmodium falciparumhas resulted in the selection of numerous human genetic variants that confer an advantage against severe malaria and death. One such variant is the Dantu blood group antigen, which is associated with 74% protection against severe and complicatedP. falciparummalaria infections in homozygous individuals, similar to that provided by the sickle haemoglobin allele (HbS). Recentin vitrostudies suggest that Dantu exerts this protection by increasing the surface tension of red blood cells, thereby impeding the ability ofP. falciparummerozoites to invade them and reducing parasite multiplication. However, no studies have yet explored this hypothesisin vivo.

Methods

We investigated the effect of Dantu on early phaseP. falciparum(Pf) infections in a controlled human malaria infection (CHMI) study. 141 sickle negative Kenyan adults were inoculated with 3.2×103aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge) then monitored for blood-stage parasitaemia for 21 days by quantitative polymerase chain reaction (qPCR) analysis of the 18S ribosomal RNAP. falciparumgene. The primary endpoint was blood-stageP. falciparumparasitaemia of ≥500/μl while the secondary endpoint was the receipt of antimalarial treatment in the presence of parasitaemia of any density. On study completion, all participants were genotyped both for Dantu and for four other polymorphisms that are associated with protection against severe falciparum malaria: α+-thalassaemia, blood group O, G6PD deficiency, and the rs4951074 allele in the red cell calcium transporterATP2B4.

Results

The primary endpoint was reached in 25/111 (22.5%) non-Dantu subjects, in comparison to 0/27 (0%) Dantu heterozygotes and 0/3 (0.0%) Dantu homozygotes (p=0.01). Similarly, 49/111 (44.1%) non-Dantu subjects reached the secondary endpoint in comparison to only 7/27 (25.9%) and none of the 3 (0.0%) Dantu heterozygotes and homozygotes respectively (P=0.021). No significant impacts on either outcome were seen for any of the other variants under study.

Conclusion

This study reveals, for the first time, that the Dantu blood group is associated with high level protection against early, non-clinical,P. falciparummalaria infectionsin vivo. Learning more about the mechanisms involved could potentially lead to new approaches to the prevention or treatment of the disease. Our study illustrates the power of CHMI with PfSPZ Challenge for directly testing the protective impact of genotypes previously identified using other methods.
To start or to discontinue the pill – changes in progestogens reflected by resting-state connectivity and positive mood
Authors: Kimmig A-C.S. , Friedrich P. , Drotleff B. , Lämmerhofer M. , Sundström-Poromaa I. , Weis S. , Derntl B.
Published: September 2022

Oral contraceptive (OC) intake has been associated with alterations in functional brain architecture and socio-affective processes. However, most previous studies have been limited by cross-sectional designs and/or did not account for synthetic sex hormone concentrations. The aim of this longitudinal study was to determine the effects of starting vs discontinuing OCs on socio-affective functions such as mood and emotion cognition, and to identify their possible neuroendocrinological substrates.

To this end, 88 young healthy women performed the behavioral and fMRI measures twice, three to eight months apart: 26 natural cycling women twice during menstruation, 26 OC users twice during OC intake, 25 OC discontinuers and 11 OC starters before and after discontinuation or start, respectively. In addition to mean-based analyses, we used intersubject representational similarity analyses to determine relationships between interindividual variability in within-subject changes of hormone profiles, including concentrations of endogenous and synthetic hormones, region-specific resting state functional connectivity (parcelwise RSFC) and socio-affective measures.

Across the whole sample, interindividual patterns of changes in RSFC of fronto-parietal regions, parts of the left hippocampus and the right cerebellum reflected change patterns of progestogen levels. For the right superior orbitofrontal gyrus (OFG), a trinity of idiosyncratic patterns was found in changes of progestogens, RSFC and positive mood. Active OC intake was associated with higher self-reported depressive symptoms in OC discontinuers (and starters). Emotion recognition performance was not associated with changes in hormone profiles or RSFC.

Overall, progestogens rather than estrogens appear to be associated with functional brain architecture of the frontal and subcortical/cerebellar regions and positive mood. The right superior OFG represents a possible neural substrate for progestogen-induced changes in positive mood. This study indicates the importance of a multidimensional, longitudinal approach when being interested in effects of hormonal contraception on women’s brain and behavior.
The Interaction of Context Constraints and Predictive Validity during Sentence Reading
Authors: Terporten René , Huizeling Eleanor , Heidlmayr Karin , Hagoort Peter , Kösem Anne
Published: September 2022

Words are not processed in isolation, instead they are commonly embedded in phrases and sentences. The sentential context influences the perception and processing of a word. However, how this is achieved by brain processes and whether predictive mechanisms underlie this process remains a debated topic. To this end we employed an experimental paradigm in which we orthogonalized sentence context constraints and predictive validity, which was defined as the ratio of congruent to incongruent sentence endings within the experiment. While recording electroencephalography, participants read sentences with three levels of sentential context constraints (high, medium and low). Participants were also separated into two groups, which differed in their ratio of valid congruent to incongruent target words that could be predicted from the sentential context. For both groups we investigated modulations of alpha power before, and N400 amplitude modulations after target word onset. The results reveal that the N400 amplitude gradually decreases with higher context constraints. Contrary, alpha power is non-monotonically influenced, displaying the strongest decrease for high context constraints over frontal electrode sites, while alpha power between medium and low context constraints does not differ. This indicates that both neural correlates are influenced by the degree of context constraint but are not affected by changes in predictive validity. The results therefore suggest that both N400 and alpha power are not unequivocally linked to the predictability of a target word based on larger contextual information.
Mechanistic insights into zearalenone-accelerated colorectal cancer in mice using integrative multi-omics approaches
Authors: Lo Emily Kwun Kwan , Wang Xiuwan , Lee Pui-Kei , Wong Ho-Ching , Lee Jetty Chung-Yung , Gómez-Gallego Carlos , Zhao Danyue , El-Nezami Hani , Li Jun
Published: September 2022

Zearalenone (ZEA), a secondary metabolite ofFusariumfungi found in cereal-based foods, promotes the growth of colon, breast, and prostate cancer cellsin vitro. However, the lack of animal studies hinders a deeper mechanistic understanding of the cancer-promoting effects of ZEA. This study aimed to determine the effect of ZEA on colon cancer progression and its underlying mechanisms. Through integrative analyses of transcriptomics, metabolomics, metagenomics, and host phenotypes, we investigated the impact of a 4-week ZEA intervention on colorectal cancer in xenograft mice. Our results showed a twofold increase in tumor weight with the 4-week ZEA intervention. ZEA exposure significantly increased the mRNA and protein levels of BEST4, DGKB, and Ki67 and the phosphorylation levels of ERK1/2 and AKT. Serum metabolomic analysis revealed that the levels of amino acids, including histidine, arginine, citrulline, and glycine, decreased significantly in the ZEA group. Furthermore, ZEA lowered the alpha diversity of the gut microbiota and reduced the abundance of nine genera, includingTuzzerellaandRikenella. Further association analysis indicated thatTuzzerellawas negatively associated with the expression of BEST4 and DGKB genes, serum uric acid levels, and tumor weight. Additionally, circulatory hippuric acid levels positively correlated with tumor weight and the expression of oncogenic genes, including ROBO3, JAK3, and BEST4. Altogether, our results indicated that ZEA promotes colon cancer progression by enhancing the BEST4/AKT/ERK1/2 pathway, lowering circulatory amino acid concentrations, altering gut microbiota composition, and suppressing short chain fatty acids production.
Predicting gene and protein expression levels from DNA and protein sequences with Perceiver
Authors: Stefanini Matteo , Lovino Marta , Cucchiara Rita , Ficarra Elisa
Published: September 2022

Background and Objective

The functions of an organism and its biological processes result from the expression of genes and proteins. Therefore quantifying and predicting mRNA and protein levels is a crucial aspect of scientific research. Concerning the prediction of mRNA levels, the available approaches use the sequence straddling the Transcription Start Site (TSS) as input to neural networks. The State-of-the-art models (e.g., Xpresso and Basenjii) predict mRNA levels exploiting Convolutional (CNN) or Long Short Term Memory (LSTM) Networks. However, CNN prediction depends on convolutional kernel size, and LSTM suffers from capturing long-range dependencies in the sequence. Concerning the prediction of protein levels, as far as we know, there is no model for predicting protein levels by exploiting the gene or protein sequences.

Methods

Here, we exploit a new model type (called Perceiver) for mRNA and protein level prediction, exploiting a Transformer-based architecture with an attention module to attend to long-range interactions in the sequences. In addition, the Perceiver model overcomes the quadratic complexity of the standard Transformer architectures. This work’s contributions are 1. DNAPerceiver model to predict mRNA levels from the sequence straddling the TSS; 2. ProteinPerceiver model to predict protein levels from the protein sequence; 3. Protein&DNAPerceiver model to predict protein levels from TSS-straddling and protein sequences.

Results

The models are evaluated on cell lines, mice, glioblastoma, and lung cancer tissues. The results show the effectiveness of the Perceiver-type models in predicting mRNA and protein levels.

Conclusions

This paper presents a Perceiver architecture for mRNA and protein level prediction. In the future, inserting regulatory and epigenetic information into the model could improve mRNA and protein level predictions. The source code is freely available athttps://github.com/MatteoStefanini/DNAPerceiver

Graphical Abstract

Highlights

Predicting mRNA and protein levels from DNA and protein sequences is crucial in clinical applications.

A transformer-based architecture with asymmetric attention (Perceiver) is exploited for mRNA and protein level prediction.

The Perceiver architecture attends to longer range interactions compared to Transformer, CNN, and LSTM.

The proposed model achieves state-of-the-art performance for mRNA level prediction.

To the best of our knowledge, the protein level prediction task is addressed.

The proposed model is tested on glioblastoma and lung cancer tissues.
Crystal structure and Hirshfeld surface analysis of N-{[diphenyl(vinyl)silyl]methyl}-2-methylpropan-2-ammonium chloride
Authors: Schwab Christoph , Voss Andreas , Strohmann Carsten
Published: September 2022

N-{[Diphenyl(vinyl)silyl]methyl}-2-methylpropan-2-amine, C19H25NSi, is a newly synthesized secondary aminomethylsilane that can be used, for example, to study carbolithiation reactions of vinylsilanes. Because the neutral compound did not crystallize well, the hydrochloride salt, C19H26NSi+·Cl−, was formed, in which the two chloride ions in the asymmetric unit have crystallographic \overline{1} site symmetry. An unusually long Si—C bond of 1.9117 (10) Å is observed in the cation, which may be ascribed to electronic effects due to the β N+ species. In the crystal, the cations and anions are linked by N—H...Cl hydrogen bonds to generate [001] chains. To further investigate the intermolecular interactions, a Hirshfeld surface analysis was performed, which showed that H...H, C...H/H...C and H...Cl/Cl...H contacts contribute 70.4, 20.0 and 8.3%, respectively.
Crystal structure of the second extracellular domain of human tetraspanin CD9: twinning and diffuse scattering
Authors: Neviani Viviana , Lutz Martin , Oosterheert Wout , Gros Piet , Kroon-Batenburg Loes
Published: September 2022

Remarkable features are reported in the diffraction pattern produced by a crystal of the second extracellular domain of tetraspanin CD9 (deemed CD9EC2), the structure of which has been described previously [Oosterheert et al. (2020), Life Sci. Alliance, 3, e202000883]. CD9EC2 crystallized in space group P1 and was twinned. Two types of diffuse streaks are observed. The stronger diffuse streaks are related to the twinning and occur in the direction perpendicular to the twinning interface. It is concluded that the twin domains scatter coherently as both Bragg reflections and diffuse streaks are seen. The weaker streaks along c* are unrelated to the twinning but are caused by intermittent layers of non-crystallographic symmetry related molecules. It is envisaged that the raw diffraction images could be very useful for methods developers trying to remove the diffuse scattering to extract accurate Bragg intensities or using it to model the effect of packing disorder on the molecular structure.
COVID-19 two years on: a review of COVID-19-related empirical research in major tourism and hospitality journals
Authors: Huang Songshan (Sam) , Wang Xuequn
Published: September 2022

Purpose

This study aims to provide a timely review of the COVID-19-related empirical research published in 19 quartile one (Q1) and quartile two (Q2) tourism and hospitality journals in social science citation index (SSCI).

Design/methodology/approach

A total of 407 COVID-19-related empirical papers were collected from the 19 SSCI Q1 and Q2 tourism and hospitality journals via Scopus database. Thematic content analysis was supplemented with Leximancer software to identify the research themes/subthemes, research methods and countries/regions of research.

Findings

The study found studies of COVID-19’s impact on consumer behaviour predominate in number, followed by studies on response actions and recovery strategies, impact on industry or sectors and impact on workers and employees. Based on the research themes identified, a knowledge mapping framework was produced. Over 70% of the studies used quantitative methods with quantitative survey as the dominant method of data collection. The USA and China were found to be the most studied countries.

Research limitations/implications

The study reviewed empirical research papers until January 2022 and covered most of the COVID-19-related empirical works in the field. An overview of the current state of COVID-19-related empirical research was provided with some critical discussions and suggestions for future research topics.

Originality/value

The findings give researchers a clear index for the current state of the art of COVID-19 research in hospitality and tourism. The paper provides practical implications for industry practitioners to retrieve relevant knowledge from the recent COVID-19-related literature in tourism and hospitality in coping with practical challenges brought by the COVID-19 pandemic.
Women in mining: from subtle barriers to open prejudice
Authors: Valadares Sabrina Silva , De Carvalho Neto Antonio Moreira , Mota-Santos Carolina Mota , Diniz Daniela Martins
Published: September 2022

Purpose

The core of this study is women in mining. The aim of this study was to analyze the perception of women, about their work environment, their career, the human resources policies and practices and the work–family balance in the context of a multinational organization in the sector.

Design/methodology/approach

The case study was carried through semi-structured interviews with 27 women who work in this organization.

Findings

Although women report that they are capable of exercising any position/function in the company, they perceive wage gap in the investigated organization; that maternity leave and the fact of having children impact their career and their rise to higher positions in the organizational hierarchy negatively; situations of prejudice and discrimination experienced at work. Sometimes subtly, sometimes not so subtly, but they still constitute barriers faced by women in mining.

Originality/value

Although the debate around the issue of gender inequality in organizations is not recent, little has been produced about the working condition of women in occupational fields where male domination is strong, such as mining.
“The old order Changeth!” Building sustainable knowledge management post COVID-19 pandemic
Authors: Dutta Debolina , Vedak Chaitali , Sawant Harshal
Published: September 2022

Purpose

The global pandemic and the resulting rapid and large-scale digitization changed the way firms recognized and understood knowledge curation and management. The changing nature of work and work systems necessitated changes in knowledge management (KM), some of which are likely to have a long-term impact. Using the lens of technology in practice, the purpose of this study is to examine the impact of technology agency on KM structures and practices that evolved across five knowledge-intensive global organizations. This study then argues that sustainable knowledge management (SKM) systems evolve in specific contexts.

Design/methodology/approach

This study adopts a qualitative case study design to examine five multinational knowledge-intensive global organizations’ KM systems and practices across diverse industry sectors.

Findings

Based on the findings, the authors develop SKM systems and practices model relevant to a post-pandemic organizational context. The authors argue that KM digitization and adoption support socialization in knowledge sharing. Further formalization through organizational enabling systems aids the externalization of knowledge sharing. Deliberate practices promoted with leadership support are likely to sustain in the post-COVID era. Further, organizations that evolvedad-hocor idiosyncratic approaches to managing hybrid working are more likely to revert to legacy KM systems. The authors eventually theorize about the socialization of human-to-human and technology-mediated human interactions and develop the three emerging SKM structures.

Originality/value

This study contributed to practitioners and researchers by developing the various tenets of SKM.
Punching shear capacity of flat slabs with recycled aggregate
Authors: Farahat Amal A. , Elansary Ahmed A. , Abdalla Hany A.
Published: September 2022

Purpose

Punching can trigger catastrophic failures in flat slabs because of its sudden nature resulting from exceeding the shear capacity of slabs. Effect of using recycled aggregate, as an environmental-friendly alternative to traditional RC structures, on punching behavior of these slabs was not sufficiently investigated in the literature. Hence, this paper aims to experimentally study the effect of using recycled coarse aggregate (RCA) on the punching shear capacity (PSC) of RC flat slabs. The RCA is produced by crushing of waste of concrete standard cubes obtained from compression tests.

Design/methodology/approach

A total of 12 slab-column connection specimens with different slab thicknesses (140, 160 and 200 mm) and different RCA percentages (0%, 30% and 70%) were prepared and tested under a central point load, to test its effect on the behavior of flat slabs. The punching failure loads of the tested specimens were compared with those obtained according to the provisions of different international building codes.

Findings

Compared with natural aggregate concrete, mixes with 30% and 70% RCA experienced reductions in the compressive that did not exceed 4% and 21%, while reductions of 4% and 13% were observed for the tensile strength, respectively. The increase in the amount of RCA reduced the PSC by 0%–7%, 0%–4% and 4%–10% for slabs with a thickness of 140, 160 and 200 mm, respectively. For slabs with punching shear reinforcement (PSR), ACI 318 provided the closest estimation for the PSC by 9%, whereas EURO 2 overestimated the PSC by 25% and ECP 203 underestimated the PSC by 41%.

Research limitations/implications

The provided conclusions are obtained from the conducted experimental work where a constant W/C ratio, aggregate type and a maximum aggregate size of 19 mm for the RCA were adopted.

Originality/value

Enhancement in the behavior of flat slabs with various thicknesses and amounts of RCA because of introducing PSR is experimentally evaluated. The failure loads of the tested slabs with recycled and normal coarse aggregates were compared against different code provisions.
Secularization and its ethical consequences: orthodox Israeli Jews sanctifying ‘mundane’ Buddhist meditation
Authors: Mautner Ori
Published: September 2022

‘Insight’ orvipassanāmeditation refers to meditative practices employed within Buddhist traditions. But following the secularization ofvipassanāin recent decades – that is, its differentiation from Buddhism – orthodox Jewish Israeli meditators frame it as a religiously neutral, therapeutic technique centred on the mundane human body. They thus consider it as involving no forbidden ‘Eastern’ religious contents. Nevertheless, these ‘Jewish Vipassanā’ meditators also utilize insight meditation for improving their Jewish practice, characters, and ability to experience closeness to God; and some situate it within a national‐religious historical narrative culminating in redemption. The secularization ofvipassanāenables orthodox Jewish practitioners to engage with it in ways that are significant for them as observant Jews, and without continually being concerned over ‘idolatry’. Secularization therefore has important implications for people's ethical projects, or attempts to foster what they consider good. Examining these implications can both stimulate secular studies and contribute to anthropological research on ethics.
Estimating persistent and transient technical efficiency and their determinants in the presence of heterogeneity and endogeneity
Authors: Bokusheva Raushan , Čechura Lukáš , Kumbhakar Subal C.
Published: September 2022

We develop an estimation procedure that generates consistent estimates of the technology parameters, long‐run (persistent) and short‐run (transient) technical inefficiencies and the marginal effects of their determinants for the stochastic frontier model developed by Colombi et al. (2014, Journal of Productivity Analysis 42, 123) and Kumbhakar et al. (2014, Journal of Productivity Analysis 41, 321). Our approach accounts for three sources of potential endogeneity: (i) unobserved heterogeneity; (ii) simultaneity of input use with both types of technical efficiency; (iii) potential correlation of the noise term with the regressors. Using this approach we examine the effect of direct payments and farm size on the persistent and transient technical efficiency of French crop farms before and after the European Union's Common Agricultural Policy decoupling reform of 2003. Our results show that subsidy payments per hectare of utilised agricultural land had a significant positive effect on persistent technical efficiency and a significant negative effect on transient technical efficiency during the period before decoupling. For the period after the reform, the effect of subsidies is found to be significantly negative for persistent technical efficiency and insignificant for transient technical efficiency. The overall effect of subsidies on technical efficiency is found to be negative in both periods, albeit substantially lower in the period after decoupling. The effect of farm size on technical efficiency is found to be significant only for the period prior to the reform: it reduced persistent technical inefficiency but increased transient technical inefficiency during that period.
Multiplex gene precise editing and large DNA fragment deletion by the CRISPR‐Cas9‐TRAMA system in edible mushroom Cordyceps militaris
Authors: Chen Bai‐Xiong , Xue Ling‐Na , Wei Tao , Wang Na , Zhong Jing‐Ru , Ye Zhi‐Wei , Guo Li‐Qiong , Lin Jun‐Fang
Published: September 2022

The medicinal mushroom Cordyceps militaris contains abundant valuable bioactive ingredients that have attracted a great deal of attention in the pharmaceutical and cosmetic industries. However, the development of this valuable mushroom faces the obstacle of lacking powerful genomic engineering tools. Here, by excavating the endogenous tRNA‐processed element, introducing the extrachromosomal plasmid and alongside with homologous template, we develop a marker‐free CRISPR‐Cas9‐TRAMA genomic editing system to achieve the multiplex gene precise editing and large synthetic cluster deletion in C. militaris. We further operated editing in the synthetases of cordycepin and ergothioneine to demonstrate the application of Cas9‐TRAMA system in protein modification, promoter strength evaluation and 10 kb metabolic synthetic cluster deletion. The Cas9‐TRAMA system provides a scalable method for excavating the valuable metabolic resource of medicinal mushrooms and constructing a mystical cellular pathway to elucidate the complex cell behaviours of the edible mushroom.
What's in a Name? Investors' Reactions to Non‐GAAP Labels*†
Authors: Garavaglia Shannon
Published: September 2022

Using a mixed‐methods approach, I investigate how the terms that firms use to label non‐GAAP earnings interact with investors' scrutiny of non‐GAAP reporting to affect investors' information search behavior and investment decisions. This study informs regulators, who have expressed concern over the mislabeling of non‐GAAP measures, and managers, who are often criticized for their misuse of discretion in non‐GAAP reporting. I first provide descriptive evidence on the non‐GAAP labels used in practice, followed by a survey to understand what investors believe these labels convey about earnings quality. Finally, drawing on theory from psychology, I predict and then find in an experiment that investors who are more likely to scrutinize non‐GAAP reporting are not affected by non‐GAAP labels when deciding to seek out the non‐GAAP reconciliation, and react positively to appropriately used labels. However, investors who are less likely to scrutinize non‐GAAP reporting rely on the cue provided by the label when deciding whether to seek out the non‐GAAP reconciliation, and are more likely to be misled by inappropriately used labels. For regulators, these findings validate concerns related to the mislabeling of non‐GAAP measures and suggest increased non‐GAAP scrutiny helps counteract mislabeling. For managers, these findings suggest investors react favorably to the appropriate use of discretion in non‐GAAP reporting.
Reduced endosomal microautophagy activity in aging associates with enhanced exocyst‐mediated protein secretion
Authors: Krause Gregory J. , Diaz Antonio , Jafari Maryam , Khawaja Rabia R. , Agullo‐Pascual Esperanza , Santiago‐Fernández Olaya , Richards Alicia L. , Chen Kuei‐Ho , Dmitriev Phillip , Sun Yan , See Stephanie K. , Abdelmohsen Kotb , Mazan‐Mamczarz Krystyna , Krogan Nevan J. , Gorospe Myriam , Swaney Danielle L. , Sidoli Simone , Bravo‐Cordero Jose Javier , Kampmann Martin , Cuervo Ana Maria
Published: September 2022

Autophagy is essential for protein quality control and regulation of the functional proteome. Failure of autophagy pathways with age contributes to loss of proteostasis in aged organisms and accelerates the progression of age‐related diseases. In this work, we show that activity of endosomal microautophagy (eMI), a selective type of autophagy occurring in late endosomes, declines with age and identify the sub‐proteome affected by this loss of function. Proteomics of late endosomes from old mice revealed an aberrant glycation signature for Hsc70, the chaperone responsible for substrate targeting to eMI. Age‐related Hsc70 glycation reduces its stability in late endosomes by favoring its organization into high molecular weight protein complexes and promoting its internalization/degradation inside late endosomes. Reduction of eMI with age associates with an increase in protein secretion, as late endosomes can release protein‐loaded exosomes upon plasma membrane fusion. Our search for molecular mediators of the eMI/secretion switch identified the exocyst‐RalA complex, known for its role in exocytosis, as a novel physiological eMI inhibitor that interacts with Hsc70 and acts directly at the late endosome membrane. This inhibitory function along with the higher exocyst‐RalA complex levels detected in late endosomes from old mice could explain, at least in part, reduced eMI activity with age. Interaction of Hsc70 with components of the exocyst‐RalA complex places this chaperone in the switch from eMI to secretion. Reduced intracellular degradation in favor of extracellular release of undegraded material with age may be relevant to the spreading of proteotoxicity associated with aging and progression of proteinopathies.
LncRNA8276 primes cell–cell adhesion for regulation of spermatogenesis
Authors: Xiong Bohui , Jiang Yue , Wang Yandi , Han Xiao , Zhang Cong , Zhong Ruqing , Ge Wei , Han Baoquan , Ge Zhaojia , Huang Gui'an , Yin Shen , Shen Wei , Sun Qingyuang , Sun Zhongyi , Zhao Yong , Zhang Hongfu
Published: September 2022

Background

Human sperm concentration and motility have dropped dramatically (50%) in the past few decades, and environmental factors are involved in this decline. Long non‐coding RNAs (lncRNA) have been discovered to be involved in many cellular processes including spermatogenesis.

Objective

This investigation aimed to explore the role of lncRNA8276 in murine spermatogenesis.

Materials and methods

The expression of lncRNA8276 was modified by knockdown or overexpression in mouse testes and spermatogonial stem cells (C18‐4 cell line). Sperm quality was determined in the F0 and F1 generations of mice. Furthermore, the underlying mechanisms were studied through gene expression and/or protein expression of spermatogenesis‐related genes and cell junction‐related genes by different methods.

Results

In the current investigation, we discovered that sperm lncRNA8276 was decreased by NH3/H2S in three generations (F0, F1, and F2) of mouse sperm. In vivo testicular knockdown of lncRNA8276 led to a decline in sperm concentration and motility in both F0 (muF0) and F1 (muF1) generations Moreover, knockdown lncRNA8276 decreased the gene and protein levels of important genes related to cell–cell junctions and spermatogenesis. The data were further confirmed in mouse spermatogonia stem cell line C18‐4 cells through knockdown of lncRNA8276.

Discussion and conclusion

Our study suggests that lncRNA8276 may be involved in cell–cell junction formation in the mouse testis to regulate spermatogenesis. It may be a target for the modification of spermatogenesis and male fertility, or male contraception. This investigation offers a potential therapeutic strategy for male infertility.
Effect of capmatinib on the pharmacokinetics of substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with MET‐dysregulated solid tumours
Authors: Chen Xinhui , Isambert Nicolas , López‐López Rafael , Giovannini Monica , Pognan Nathalie , Kapoor Shruti , Quinlan Michelle , You Benoit , Cui Xiaoming , Rahmanzadeh Gholamreza , Mau‐Sorensen Morten
Published: September 2022

Background

Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time‐dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal–epithelial transition (MET)‐dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety.

Methods

This open‐label, multicentre, single‐sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug‐drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two‐drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re‐exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21‐day cycles until disease progression at the discretion of the investigator.

Results

A 22% (90% confidence interval [CI] 7‐38%) increase in the midazolam maximum plasma concentration (Cmax) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co‐administration with capmatinib resulted in 134% (90% CI 108‐163%) and 122% (90% CI 95‐153%) increases in the caffeine area under the plasma concentration‐time curve from time zero to infinity (AUCinf) and area under the plasma concentration‐time curve from time zero to the last measurable point (AUClast), respectively, with no change in Cmax. Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study.

Conclusion

The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure.
Ethnic and socioeconomic disparities in initiation of second‐line antidiabetic treatment for people with type 2 diabetes in England: A cross‐sectional study
Authors: Bidulka Patrick , Mathur Rohini , Lugo‐Palacios David G. , O'Neill Stephen , Basu Anirban , Silverwood Richard J. , Charlton Paul , Briggs Andrew , Smeeth Liam , Adler Amanda I. , Douglas Ian J. , Khunti Kamlesh , Grieve Richard
Published: September 2022

Aims

To assess any disparities in the initiation of second‐line antidiabetic treatments prescribed among people with type 2 diabetes mellitus (T2DM) in England according to ethnicity and social deprivation level.

Materials and methods

This cross‐sectional study used linked primary (Clinical Practice Research Datalink) and secondary care data (Hospital Episode Statistics), and the Index of Multiple Deprivation (IMD). We included people aged 18 years or older with T2DM who intensified to second‐line oral antidiabetic medication between 2014 and 2020 to investigate disparities in second‐line antidiabetic treatment prescribing (one of sulphonylureas [SUs], dipeptidyl peptidase‐4 [DPP‐4] inhibitors, or sodium‐glucose cotransporter‐2 [SGLT2] inhibitors, in combination with metformin) by ethnicity (White, South Asian, Black, mixed/other) and deprivation level (IMD quintiles). We report prescriptions of the alternative treatments by ethnicity and deprivation level according to predicted percentages derived from multivariable, multinomial logistic regression.

Results

Among 36 023 people, 85% were White, 10% South Asian, 4% Black and 1% mixed/other. After adjustment, the predicted percentages for SGLT2 inhibitor prescribing by ethnicity were 21% (95% confidence interval [CI] 19–23%), 20% (95% CI 18–22%), 19% (95% CI 16–22%) and 17% (95% CI 14–21%) among people with White, South Asian, Black, and mixed/other ethnicity, respectively. After adjustment, the predicted percentages for SGLT2 inhibitor prescribing by deprivation were 22% (95% CI 20–25%) and 19% (95% CI 17–21%) for the least deprived and the most deprived quintile, respectively. When stratifying by prevalent cardiovascular disease (CVD) status, we found lower predicted percentages of people with prevalent CVD prescribed SGLT2 inhibitors compared with people without prevalent CVD across all ethnicity groups and all levels of social deprivation.

Conclusions

Among people with T2DM, there were no substantial differences by ethnicity or deprivation level in the percentage prescribed either SGLT2 inhibitors, DPP‐4 inhibitors or SUs as second‐line antidiabetic treatment.