bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptomics effects of per- and polyfluorinated alkyl substances in differentiated neuronal cells
Authors: Running Logan , Cristobal Judith R. , Karageorgiou Charikleia , Camdzic Michelle , Aguilar John Michael , Gokcumen Omer , Aga Diana S. , Atilla-Gokcumen G. Ekin
Published: January 2024

Per- and polyfluorinated alkyl substances (PFAS) are pervasive environmental contaminants that bioaccumulate in tissues and pose risks to human health. Increasing evidence links PFAS to neurodegenerative and behavioral disorders, yet the underlying mechanisms of their effects on neuronal function remain largely unexplored. In this study, we utilized SH-SY5Y neuroblastoma cells, differentiated into neuronal-like cells, to investigate the impact of six PFAS compounds— perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorodecanoic acid (PFDA), perfluorodecanesulfonic acid (PFDS), 8:2 fluorotelomer sulfonate (8:2 FTS), and 8:2 fluorotelomer alcohol (8:2 FTOH)—on neuronal health. Following a 30 μM exposure for 24 hours, PFAS accumulation ranged from 100–7500 ng/mg of protein. Transcriptomic analysis revealed 721 differentially expressed genes (DEGs) across treatments (padj< 0.05), with 11 DEGs shared among all PFAS exposures, indicating potential biomarkers for neuronal PFAS toxicity. PFOA-treated cells showed downregulation of genes involved in synaptic growth and neural function, while PFOS, PFDS, 8:2 FTS, and 8:2 FTOH exposures resulted in upregulation of genes related to hypoxia response and amino acid metabolism. Lipidomic profiling further demonstrated significant fatty acid upregulation with PFDA, PFDS, and 8:2 FTS, alongside triacylglycerol downregulation with 8:2 FTOH. These findings suggest that the neurotoxic effects of PFAS are structurally dependent, offering insights into the molecular processes that may drive PFAS-induced neuronal dysfunction.

Synopsis

Per- and poly fluorinated alkyl substances (PFAS) have been shown to bioaccumulate in human tissues and affect health. This study aims to provide insights into the specific biological processes through which PFAS exposure affects neuronal cells.
Proteostatic remodeling of small heat shock chaperones - crystallins by Ran-binding protein 2 and the peptidyl-prolylcis-transisomerase and chaperone activities of its cyclophilin domain
Authors: Patil Hemangi , Cho Kyoung-in , Ferreira Paulo A.
Published: January 2024

Disturbances in phase transitions and intracellular partitions of nucleocytoplasmic shuttling substrates promote protein aggregation - a hallmark of neurodegenerative diseases. The modular Ran-binding protein 2 (Ranbp2) is a cytosolic molecular hub for rate-limiting steps of disassembly and phase transitions of Ran-GTP-bound protein ensembles exiting nuclear pores. Chaperones also play central roles in phase transitions and proteostasis by suppressing protein aggregation.Ranbp2haploinsufficiency promotes the age-dependent neuroprotection of the chorioretina against photo-oxidative stress by proteostatic regulations of Ranbp2 substrates and by countering the build-up of poly-ubiquitylated substrates. Further, the peptidyl-prolylcis-transisomerase (PPIase) and chaperone activities of the cyclophilin domain (CY) of Ranbp2 modulate the proteostasis of selective neuroprotective substrates, such as hnRNPA2B1, STAT3, HDAC4 or L/M-opsin, while promoting a decline of ubiquitylated substrates. However, links between CY PPIase activity on client substrates and its effect(s) on ubiquitylated substrates are unclear. Here, proteomics of genetically modified mice with deficits of Ranbp2 uncovered the regulation of the small heat shock chaperones – crystallins by Ranbp2 in the chorioretina. Loss of CY PPIase of Ranbp2 up-regulates αA-crystallin proteostasis, which is repressed in non-lenticular tissues. Conversely, the αA-crystallin’s substrates, γ-crystallins, are down-regulated by impairment of CY‘s C-terminal chaperone activity. These CY-dependent effects cause the age-dependent decline of ubiquitylated substrates without overt chorioretinal morphological changes. A model emerges whereby the Ranbp2 CY-dependent remodeling of crystallins’ proteostasis subdues molecular aging and preordains chorioretinal neuroprotection by augmenting the chaperone buffering capacity and the decline of ubiquitylated substrates against proteostatic impairments. Further, CY’s moonlighting activity holdspan-therapeutic potential against neurodegeneration.
A general platform for targeting MHC-II antigens via a single loop
Authors: Du Haotian , Liu Jingjia , Jude Kevin M. , Yang Xinbo , Li Ying , Bell Braxton , Yang Hongli , Kassardjian Audrey , Mobedi Ali , Parekh Udit , Sperberg R. Andres Parra , Julien Jean-Philippe , Mellins Elizabeth D. , Garcia K. Christopher , Huang Po-Ssu
Published: January 2024

Class-II major histocompatibility complexes (MHC-IIs) are central to the communications between CD4+ T cells and antigen presenting cells (APCs), but intrinsic structural features associated with MHC-II make it difficult to develop a general targeting system with high affinity and antigen specificity. Here, we introduce a protein platform, Targeted Recognition of Antigen-MHC Complex Reporter for MHC-II (TRACeR-II), to enable the rapid development of peptide-specific MHC-II binders.TRACeR-IIhas a small helical bundle scaffold and uses an unconventional mechanism to recognize antigens via a single loop. This unique antigen-recognition mechanism renders this platform highly versatile and amenable to direct structural modeling of the interactions with the antigen. We demonstrate thatTRACeR-IIbinders can be rapidly evolved across multiple alleles, while computational protein design can produce specific binding sequences for a SARS-CoV-2 peptide of unknown complex structure.TRACeR-IIsheds light on a simple and straightforward approach to address the MHC peptide targeting challenge, without relying on combinatorial selection on complementarity determining region (CDR) loops. It presents a promising basis for further exploration in immune response modulation as well as a broad range of theragnostic applications.
MicroRNA-145 enhances lung cancer cell progression after exposure to lyophilized fertile hydatid cyst fluid ofEchinococcus granulosussensu stricto
Authors: Mosajakhah Hosein , Shanehbandi Dariush , Ahmadpour Ehsan , Mahami-Oskouei Mahmoud , Janghoor Khadijeh Sadeghi , Spotin Adel
Published: January 2024

There is increasing evidence that the secretory/excretory antigens of the larval stage ofEchinococcus granulosus(hydatid cyst fluid; HCF) can induce both anticancer and oncogenesis effects between parasite-derived metabolites and various cancer lines. The dual role of miR-145 as a tumor suppressor or oncogene has been previously reported in cancers. Nevertheless, it remains unknown, how miR-145 induces apoptosis in HCF-treated lung cancer cells. The fertile HCF was obtained from sheep and subjected to purification and lyophilization. H1299 human lung cancer cells were cultured into two groups: HCF-treated H1299 lung cancer cells and control cells. To evaluate the effects of HCF on the H1299 cells, cell viability was performed by MTT assay. The caspase-3 activity was assessed using fluorometric assay. Furthermore, the mRNA expression of VGEF, Vimentin, caspase-3, miRNA-145, Bax and Bcl-2 genes were characterized by Real-time PCR. A scratch test was done to assess the effects of HCF on cell mobility. MTT assay revealed that there is an increasing slope in the growth of H1299 cells when treated with 60 μg/mL of fertile HCF for 24 h. The fold change of caspase-3, miRNA-145, Bax/Bcl-2 ratio and caspase-3 activity was lower in the HCF-treated H1299 cells than in the control cell. The fold change of VGEF and Vimentin genes in the HCF-treated H1299 cells was higher than that in the control cell. The scratch outcome demonstrated that the mobility of H1299 cells was increased at 24 and 48 hours of scratched time after exposure to HCF. Our results suggest that induction of low expression of miR-145 in patients with hydatid cysts could be a possible oncogenic regulator of lung cancer growth. We conclude that miR-145 may be a promising marker for the diagnosis of lung cancer patients co-infected with pulmonary hydatid cysts. To validate this assumption, further study is needed to assess microRNA profile and potent oncogenesin vivosetting.
Synthetic spider silk forming highly-aligned nanoarchitectures on 2D-material surfaces
Authors: Whittall Dominic R , Kato Ryo , Okimura Akari , Takizawa Rio , Motai Kazunori , Maeda Hiroki , Yamazaki Yui , Yano Taka-aki , Takano Eriko , Hayamizu Yuhei
Published: January 2024

The synergy between silk proteins and nanomaterials can lead to novel materials with improved mechanical and electrical properties. Designed peptides have been previously utilised in the functionalisation of two-dimensional material surfaces in a self-assembly manner, including graphite, to develop highly sensitive electrical biosensors. These studies have predominantly focused on functionalising the surfaces with peptides of less than several kDa in size. In this work, we assessed the capability of a ∼35 kDa synthetic spider silk protein to serve as a candidate biomolecular scaffold on a range of two-dimensional materials: graphite, molybdenum disulphide and boron nitride. The structural properties of the synthetic spider silk protein at the 2D material surface were characterised at the nanoscale for the first time using a multi-analysis approach incorporating atomic force microscopy and fluorescence microscopy, in addition to polarised Raman and tip-enhanced Raman spectroscopy. The synthetic spider silk protein was revealed to self-assemble into stable nanowire structures of monolayer thickness. Our findings have demonstrated the feasibility of functionalising 2D materials with spider silk-based proteins and will unlock new possibilities in the development of next-generation high-performance biosensing devices.
Pancreatic cancer mutationscape: revealing the link between modular restructuring and intervention efficacy amidst common mutations
Authors: Plaugher Daniel , Murrugarra David
Published: January 2024

There is increasing evidence that biological systems are modular in both structure and function. Complex biological signaling networks such as gene regulatory networks (GRNs) are proving to be composed of subcategories that are interconnected and hierarchically ranked. These networks contain highly dynamic processes that ultimately dictate cellular function over time, as well as influence phenotypic fate transitions. In this work, we use a stochastic multicellular signaling network of pancreatic cancer (PC) to show that the variance in topological rankings of the most phenotypically influential modules implies a strong relationship between structure and function. We further show that induction of mutations alters the modular structure, which analogously influences the aggression and controllability of the diseasein silico. We finally present evidence that the impact and location of mutations with respect to PC modular structure directly corresponds to the efficacy of single agent treatmentsin silico, because topologically deep mutations require deep targets for control.
Transcriptomic and epigenetic responses shed light on soybean resistance toPhytophthora sansomeana
Authors: Lee Gwonjin , DiBiase Charlotte N. , Liu Beibei , Li Tong , McCoy Austin G. , Chilvers Martin I. , Sun Lianjun , Wang Dechun , Lin Feng , Zhao Meixia
Published: January 2024

Phytophthora root rot caused by oomycete pathogens in the Phytophthora genus poses a significant threat to soybean productivity. While resistance mechanisms againstPhytophthora sojaehave been extensively studied in soybean, the molecular basis underlying immune responses toPhytophthora sansomeanaremains unclear. We investigated transcriptomic and epigenetic responses of two resistant (Colfax and NE2701) and two susceptible (Williams 82 and Senaki) soybean lines at four time points (2, 4, 8, and 16 hours post inoculation, hpi) afterP. sansomeanainoculation. Comparative transcriptomic analyses revealed a greater number of differentially expressed genes (DEGs) upon pathogen inoculation in resistant lines, particularly at 8 and 16 hpi, predominantly associated with ethylene and reactive oxygen species-mediated defense pathways. Moreover, DE transposons were predominantly up-regulated after inoculation and enriched near genes in Colfax. A long non-coding RNA (lncRNA) within the mapped region of the resistance gene exhibited exclusive up-regulation in the resistant lines after inoculation, potentially regulating two flankingLURP-one-relatedgenes. Furthermore, DNA methylation analysis revealed increased CHH methylation levels in lncRNAs after inoculation, with delayed responses in Colfax compared to Williams 82. Overall, our results provide comprehensive insights into soybean responses toP. sansomeana, highlighting potential roles of lncRNAs and epigenetic regulation in plant defense.
Proton pump inhibitors are detrimental to overall survival of patients with glioblastoma multiforme: results from a nationwide real-world evidence database
Authors: Castro Michael P. , Quinn Jameson , Wasserman Asher , Awawda Alaa , Cole Zachariah D. , Shapiro Mark A. , Stuhlmiller Timothy J. , Kesari Santosh
Published: January 2024

Background

Aldehyde dehydrogenase-1A1 (ALDH1A1) is a primary metabolic enzyme impacting outcome of chemotherapy, including temozolomide, the standard-of-care (SOC) for glioblastoma multiforme (GBM). High expression of ALDH1A1 is associated with poor prognosis in multiple cancers. Proton pump inhibitors (PPIs) are often prescribed to manage corticosteroid-induced gastrointestinal toxicity but were recently identified as strong inducers of ALDH1A1, suggesting a negative impact on survival.

Methods

Real-world data on GBM patients was annotated from electronic medical records (EMR) according to the prospective observational study, XCELSIOR (NCT03793088). Patients withIDH1/2mutations were excluded. Causal effects on survival were analyzed using a multivariate, time-varying Cox Proportional Hazard (CPH) model with stratifications includingMGMTmethylation status, age, sex, duration of corticosteroid use, extent of resection, starting SOC, and PPI use.

Results

EMR data from 554 GBM patients across 225 cancer centers was collected, with 72% of patients receiving care from academic medical centers. Patients treated with PPIs had numerically lower median overall survival (mOS) and 2-year OS rates in the total population and across most strata, with the greatest difference for MGMT-methylated patients (mOS 29.2 mo vs. 40.1 mo). In a time-varying multivariate CPH analysis of the above strata, PPIs caused an adverse effect on survival (HR 1.67 [95% CI 1.15-2.44], p=0.007).

Conclusions

Evidence from a nationwide cancer registry has suggested PPIs have a strong detrimental effect on OS for GBM patients, particularly those withMGMTpromoter methylation. This suggests PPIs should be avoided for prophylactic management of gastrointestinal toxicity in patients with GBM receiving SOC chemoradiotherapy.

Key Points

Nationwide glioblastoma study suggests hazardous effect of proton pump inhibitors

Discretion advised when prescribing proton pump inhibitors to glioblastoma patients

Prophylactic proton pump inhibitor use to limit chemo toxicity may increase risk

Importance of the Study

Recent molecular evidence suggests off-target activity of proton pump inhibitors (PPIs) may counteract the activity of alkylating chemotherapy in glioblastoma clinical care. Utilizing a time-varying cox proportional hazard model and abstracted clinical data from medical records according to a nationwide observational research protocol, we found PPIs were significantly associated with greater risk of death, independent of corticosteroid use. Importantly, the detrimental effect was most impactful for patients with methylated MGMT promoters who gain the most benefit from standard-of-care temozolomide treatment and experience the best outcomes.
Spectral variation and pigmentary basis of ornamental and mimetic wing colour patches of swallowtail butterflies
Authors: Dharmaraaj Bhavya , Venkatesan Radhika , Kunte Krushnamegh
Published: January 2024

Colours and colour patterns are extraordinarily diverse traits that are often used as visual signals. To test ecological and evolutionary drivers of these visual signals, a clear understanding of their nature and variation is necessary. Here we characterise variation in wing colouration of Asian mormon swallowtail butterflies (Papilio, subgenusMenelaides). These species exhibit two kinds of colour patches on largely black wings: creamy white/yellow/green patches that are presumably used as sexual ornaments, and pure white patches that are presumably used as mimetic signals. Using reflectance spectrophotometry we quantified spectral properties of black wing background and colour patches between sexes, wing surfaces and mimicry status. We discovered that brightness and saturation of the black background were less variable across sexes, wing surfaces and mimetic/non-mimetic status. However, colour contrast and saturation were higher on dorsal surfaces than on ventral surfaces, and colour contrast between the black background and colour patches was higher in males than in females. Colour patches in non-mimetic butterflies were brighter and more saturated across the whole colour spectrum compared to mimetic butterflies. These patterns of colour variations in relation to their putative functions suggest that: (a) colour patches on dorsal and ventral wing surfaces evolve independently to accommodate differential strengths of natural and sexual selection, (b) sexual ornaments are brighter in non-mimetic males but they also occur in all non-mimetic females, indicating mutual sexual selection on these ornaments, but which is stronger in males, and (c) mimetic male and female butterflies display less sexual contrast in colour patches, indicating relatively similar strength of mimetic selection. Thus, our study characterises colour variation in an extraordinary signal radiation on the wings of swallowtail butterflies, a model clade in ecology, evolution and genetics. Finally, using liquid chromatography-mass spectrometry (LCMS) we identified the pigment papiliochrome-II to be the chemical basis of the presumed sexual ornaments in mormon swallowtails.
Discovery of Oncogenic Mediator Genes in Rectal Cancer Chemotherapy Response using Gene Expression Data from Matched Tumor and Patient-Derived Organoid
Authors: Huang Hanchen , Wu Chao , Colaprico Antonio , Bleu Paulina , Zambare Wini , Alvarez Janet , Kim Min Jung , Bercz Aron , Wang Lily , Paty Philip B. , Romesser Paul B. , Smith J. Joshua , Chen X. Steven
Published: January 2024

Rectal cancer (RC) presents significant treatment challenges, particularly in the context of chemotherapy resistance. Addressing this, our study pioneers the use of matched RC tumor tissue and patient-derived organoid (PDO) models coupled with the innovative computational tool, Moonlight, to explore the gene expression landscape of RC tumors and their response to chemotherapy. We analyzed 18 tissue samples and 32 matched PDOs, ensuring a high-fidelity representation of the tumor bioloy. Our comprehensive integration strategy involved differential expression analyses (DEAs) and gene regulatory network (GRN) analyses, facilitating the identification of 5,199 genes governing at least one regulon. By using the biological processes (BPs) collected from Moonlight closely related to cancer, we pinpointed 2,118 regulator-regulon groups with potential roles in oncogenic processes. Further, through integration of Moonlight and DEA results identified 334 regulator-regulon groups significantly enriched in both tissue and PDO samples, classifying them as oncogenic mediators (OMs). Among these, four genes (NCKAP1L, LAX1, RAD51AP1, and NAT2) demonstrated an association with drug responsiveness and recurrence-free survival (RFS), offering new insights into the molecular mechanisms of chemotherapy response in RC. Our integrated approach not only underscores the translational fidelity of PDOs, but also harnesses the analytical prowess of Moonlight, setting a new benchmark for targeted therapy research in rectal cancer.
Brain Functional Connectivity and Anatomical Features as Predictors of Cognitive Behavioral Therapy Outcome for Anxiety in Youths
Authors: Zugman Andre , Ringlein Grace V. , Finn Emily S. , Lewis Krystal M. , Berman Erin , Silverman Wendy K. , Lebowitz Eli R. , Pine Daniel S. , Winkler Anderson M.
Published: January 2024

Background

Because pediatric anxiety disorders precede the onset of many other problems, successful prediction of response to the first-line treatment, cognitive-behavioral therapy (CBT), could have major impact. However, existing clinical models are weakly predictive. The current study evaluates whether structural and resting-state functional magnetic resonance imaging can predict post-CBT anxiety symptoms.

Methods

Two datasets were studied: (A) one consisted of n=54 subjects with an anxiety diagnosis, who received 12 weeks of CBT, and (B) one consisted of n=15 subjects treated for 8 weeks. Connectome Predictive Modeling (CPM) was used to predict treatment response, as assessed with the PARS; additionally we investigated models using anatomical features, instead of functional connectivity. The main analysis included network edges positively correlated with treatment outcome, and age, sex, and baseline anxiety severity as predictors. Results from alternative models and analyses also are presented. Model assessments utilized 1000 bootstraps, resulting in a 95% CI forR2,rand mean absolute error (MAE).

Outcomes

The main model showed a mean absolute error of approximately 3.5 (95%CI: [3.1-3.8]) points aR2of 0.08 [−0.14 - 0.26] androf 0.38 [0.24 – 0.511]. When testing this model in the left-out sample (B) the results were similar, with a MAE of 3.4 [2.8 – 4.7],R2−0.65 [−2.29 – 0.16] androf 0.4 [0.24 – 0.54]. The anatomical metrics showed a similar pattern, where models rendered overall lowR2.

Interpretation

The analysis showed that models based on earlier promising results failed to predict clinical outcomes. Despite the small sample size, the current study does not support extensive use of CPM to predict outcome in pediatric anxiety.
Proximity labeling proteomics reveals Kv1.3 potassium channel immune interactors in microglia
Authors: Bowen Christine A , Nguyen Hai M , Lin Young , Bagchi Pritha , Natu Aditya , Espinosa-Garcia Claudia , Werner Erica , Kumar Prateek , Tobin Brendan R , Wood Levi , Faundez Victor , Wulff Heike , Seyfried Nicholas T , Rangaraju Srikant
Published: January 2024

Microglia are the resident immune cells of the brain and regulate the brain’s inflammatory state. In neurodegenerative diseases, microglia transition from a homeostatic state to a state referred to as disease associated microglia (DAM). DAM express higher levels of proinflammatory signaling, like STAT1 and TLR2, and show transitions in mitochondrial activity toward a more glycolytic response. Inhibition of Kv1.3 decreases the proinflammatory signature of DAM, though how Kv1.3 influences the response is unknown. Our goal was to establish the potential proteins interacting with Kv1.3 during the TLR4-mendiated transition to DAM. We utilized TurboID, a biotin ligase, fused to Kv1.3 to evaluate the potential interacting proteins with Kv1.3 via mass spectrometry in BV-2 microglia during an immune response. Electrophysiology, western blots, and flow cytometry were used to evaluate Kv1.3 channel presence and TurboID biotinylation activity. We hypothesized that Kv1.3 contains domain-specific interactors that vary during an TLR4-induced inflammatory response, some of which are dependent on the PDZ-binding domain on the C-terminus. We determined that the N-terminus of Kv1.3 is responsible for trafficking Kv1.3 to the cell surface and mitochondria (e.g.NUNDC, TIMM50). The C-terminus interacts with immune signaling proteins in an LPS-induced inflammatory response (e.g.STAT1, TLR2, and C3). There are 70 proteins that rely on the c-terminal PDZ-binding domain to interact with Kv1.3 (i.e.ND3, Snx3, and Sun1). Overall, we highlight that the Kv1.3 potassium channel functions beyond outward flux of potassium in an inflammatory context and contributes to activity of key immune signaling proteins, such as STAT1 and C3.

MAIN POINTS

Kv1.3 channels are highly abundant in pro-inflammatory microglia in neurological diseases. Kv1.3 channels may regulate microglial functions by interacting with other proteins via its N and C terminal domains.

Using proximity-based proteomics, we identified several novel proteins that interact with the N and C terminus of Kv1.3 channels, some of which are domain-specific.

Kv1.3 channels in microglia interact with many immune signaling proteins, including Tlr2, Stat1 and integrins.

Under homeostatic conditions, the N-terminus of Kv1.3 interacts with proteins involved in protein trafficking, to the cell surface and mitochondria. The PDZ-binding region was an important determinant of the C terminal interactome.

During an LPS-induced inflammatory response, the C-terminus of Kv1.3 uniquely interacts with immune and signaling proteins of disease relevance, including STAT1
Physcomitrium patensflavodiiron proteins form a redox-dependent heterocomplex
Authors: Beraldo Claudia , Traverso Eleonora , Boschin Marco , Cendron Laura , Morosinotto Tomas , Alboresi Alessandro
Published: January 2024

Flavodiiron proteins (FLVs) catalyze the reduction of oxygen to water by exploiting electrons from Photosystem I (PSI). In several photosynthetic organisms such as cyanobacteria, green algae, mosses and gymnosperms, FLV-dependent electron flow protects PSI from over-reduction and consequent damage especially under fluctuating light conditions. In this work we investigated biochemical and structural properties of FLVA and FLVB from the model mossPhyscomitrium patens. The two proteins, expressed and purified fromEscherichia coli, bind both iron and flavin cofactors and show NAD(P)H oxidase activity as well as oxygen reductase capacities. Moreover, the co-expression of both FLVA and FLVB, coupled to a tandem affinity purification procedure with two different affinity tags, enabled the isolation of the stable and catalytically active FLVA/B hetero multimer protein complex, that has never been isolated and characterized so far. The multimeric organization was shown to be stabilized by inter-subunit disulfide bonds. This investigation provides valuable new information on the biochemical properties of FLVs, with new insights into theirin vivorole and regulation.
Large structural variants in KOLF2.1J are unlikely to compromise neurological disease modelling
Authors: Ryan Mallory , McDonough Justin A. , Ward Michael E. , Cookson Mark R. , Skarnes William C. , Merkle Florian T.
Published: January 2024

Gracia-Diaz and colleagues analysed high-density DNA microarray and whole genome sequencing (WGS) data from the KOLF2.1J ‘reference’ human induced pluripotent stem cell (hiPSC) line1, and report the presence of five high-confidence heterozygous copy number variants (CNVs) at least 100kbp in length2. Since three of these CNVs span coding genes, some of which have been associated with neurodevelopmental disease, the authors raise the concern that these CNVs may compromise the utility of KOLF2.1J for neurological disease modelling. We appreciate their thorough analysis and thoughtful interpretation, and agree that potential users of this line should be made aware of all cases where KOLF2.1J differs from the reference genome. However, we believe that the benefits from the widespread use of KOLF2.1J outweigh the potential risks that might arise from the identified CNVs.
Creating something out of nothing: Symbolic and non-symbolic representations of numerical zero in the human brain
Authors: Barnett Benjy , Fleming Stephen M.
Published: January 2024

Representing the quantity zero as a symbolic concept is considered a unique achievement of abstract human thought. Despite considerable progress in understanding the neural code supporting natural numbers, how numerical zero is encoded in the human brain remains unknown. We find that both non-symbolic empty sets (the absence of dots on a screen) and symbolic zero (‘0’) occupy ordinal positions along graded neural number lines within posterior association cortex. Neural representations of zero are partly independent of numerical format, exhibiting distance effects with countable numerosities in the opposing (symbolic or non-symbolic) format. Our results show that format-invariant neural magnitude codes extend to judgements of numerical zero and help motivate theoretical accounts in which representations of symbolic zero are grounded in more basic representations of sensory absences.
Does actors' engagement with capacity-building training programs enable delivery of SDG-aligned public services? The case of senior public officials
Authors: Azmat Fara , Ferdous Ahmed Shahriar , Wali Faisal , Muttakin Mohammad Badrul , Haque Mohammed Ziaul
Published: January 2024

Purpose

This study examines whether engagement with Sustainable Development Goal (SDG)-focused specialized training programs enable senior public officials (focal actor) to collectively deliver on public services that have a transformational societal impact over time. Further, the study explores the factors that impede and facilitate the delivery of such services. The authors do so by using service mechanics theorization and drawing on the lens of actor and collective engagement.

Design/methodology/approach

This study undertakes a longitudinal exploratory qualitative study design. SDG-focused training programs were delivered, as interventions, for two cohorts of senior public officials from Bangladesh in an Australian University in 2017 and 2019. In-depth interviews were conducted upon the training's completion and then after 8- and 12-month intervals to assess the short- and long-term impact respectively.

Findings

An empirical framework is proposed from the study findings. It shows that engagement – cognitive, emotional and behavioral – with SDG-focused specialized training programs enables focal actors (i.e. senior public officials) to engage other actors (other public officials, community members) in networks, facilitated the delivery of SDG-aligned public services. Such engagement results in a transformative impact that spans micro (individual), meso (organizational) and macro (societal) levels over time. Factors that impede and facilitate SDG-aligned delivery of public services are also identified.

Research limitations/implications

Theoretically, the authors contribute to the literature that relates to actor and collective engagement, SDG-focused capacity-building training programs and service mechanics. Practically, this study informs organizations about the ways that they can effectively engage their senior employees with capacity-building training programs that focus on sustainability.

Originality/value

This study is one of the few that connects the interface between public service delivery for enacting societal changes and SDG-focused capacity-building training programs through service mechanics theorization and using the lens of actor and collective engagement.
A phenomenological study of university lecturers’ EFL teaching challenges in an Asian setting
Authors: Sipe Marlon , Segumpan Reynaldo Gacho
Published: January 2024

Purpose

English, the lingua franca of the world, permeates a global teaching-learning space not only for communication per se but also as a medium of instruction and social interaction. The authors studied the lived experiences of five English-speaking university lecturers as regards English as a foreign language (EFL) teaching in a non-English-speaking Asian country.

Design/methodology/approach

Using a phenomenological inquiry and through Zoom interviews, the authors studied the lived experiences of five English-speaking university lecturers as regards EFL teaching in a non-English-speaking Asian country.

Findings

Thematic analyses guided the authors' understanding of the participants’ lived experiences in the classroom, such as the following: (1) Local students have a negative perception of EFL; (2) lecturers’ professional standards are hardly imposed and (3) local students have a mixed level of English proficiency. The authors also examined the participants’ lived experiences in the organization, where the following issues surfaced: (1) sending of communication messages beyond working hours, (2) bureaucratic working environment and (3) changing of policies.

Practical implications

The authors' research implies the need for programs and policies that will help EFL teachers deal with instructional and other socio-cultural challenges in an Asian context.

Originality/value

In the Asian setting, there is a dearth of literature that focuses on the experience of university lecturers of English as a Foreign Language (EFL), in particular, their teaching challenges. The authors confronted this gap by understanding the local beliefs about EFL teaching among English-speaking university lecturers.
Gen Z buying patterns: comparing the influence of professional advising and social media engagement
Authors: Stoica Michael , Hickman Thomas M.
Published: January 2024

Purpose

This paper aims to assess retail shopping avenues for young consumers based on the type of guidance and assistance they pursue (social media vs professional service provider) in purchasing situations judged to be important. Young consumers consider themselves pet parents and pets represent an extension of self. Thus, pet-related products, by their importance, represent an excellent area of analysis for this inquiry.

Design/methodology/approach

Data collection was completed in a way that is contextually relevant and gives the results ecological validity with the assistance of a major supplier of pet food. A total of 470 Gen Z owners of small companion animals were obtained. The partial least squares structural equation modeling testing method is considered appropriate for the model analysis due to the structure and homogeneity of the sample and due to the precision of the method.

Findings

Results indicate that, in accordance with social media engagement (SME) theory, high SME elevated social commerce purchase intentions while professional advice seekers reported increased brick-and-mortar shopping. Thus, context-dependent, young consumers may purchase from brick-and-mortar sites.

Originality/value

This paper draws on SME and Advice Response Theory and proposes an original model explaining channel selection preferences for young consumers based on the type of advice sought for important purchasing decisions. The model represents a steppingstone to investigate the mechanism that translates information search sources into buying through different channels.
Constraints of digestion on swimming performance and stress tolerance vary with habitat in freshwater fish species
Authors: ZHANG Yongfei , LUO Yulian , HUANG Keren , LIU Qianying , FU Cheng , PANG Xu , FU Shijian
Published: January 2024

Limited aerobic scope (AS) during digestion might be the main constraint on the performance of bodily functions in water‐breathing animals. Thus, investigating the postprandial changes in various physiological functions and determining the existence of a shared common pattern because of possible dependence on residual AS during digestion in freshwater fish species are very important in conservation physiology. All species from slow‐flow habitats showed impaired swimming speed while digesting, whereas all species from fast‐flow habitats showed strong swimming performance, which was unchanged while digesting. Only two species from slow‐flow habitats showed impaired heat tolerance during digestion, suggesting that whether oxygen limitation is involved in the heat tolerance process is species‐specific. Three species from slow‐ or intermediate‐flow habitats showed impaired hypoxia tolerance during digestion because feeding metabolism cannot cease completely under hypoxia. Overall, there was no common pattern in postprandial changes in different physiological functions because: (1) the digestion process was suppressed under oxygen‐limiting conditions, (2) the residual AS decreased during digestion, and (3) performance was related to residual AS, while digestion was context‐dependent and species‐specific. However, digestion generally showed a stronger effect on bodily functions in species from slow‐flow habitats, whereas it showed no impairment in fishes from fast‐flow habitats. Nevertheless, the postprandial change in physiological functions varies with habitat, possibly due to divergent selective pressure on such functions. More importantly, the present study suggests that a precise prediction of how freshwater fish populations will respond to global climate change needs to incorporate data from postprandial fishes.
Exercise‐inducible circulating extracellular vesicle irisin promotes browning and the thermogenic program in white adipose tissue
Authors: Shi Hongwei , Hao Xiaojing , Sun Yaqin , Zhao Yating , Wang Yue , Cao Xiaorui , Gong Zeen , Ji Shusen , Lu Jiayin , Yan Yi , Yu Xiuju , Luo Xiaomao , Wang Juan , Wang Haidong
Published: January 2024

Aim

Exercise can reduce body weight and promote white fat browning, but the underlying mechanisms remain largely unknown. This study investigated the role of fibronectin type III domain‐containing protein 5 (FNDC5)/Irisin, a hormone released from exercising muscle, in the browning of white fat in circulating extracellular vesicles (EVs).

Methods

Mice were subjected to a 4 weeks of running table exercise, and fat browning was analyzed via histology, protein blotting and qPCR. Circulating EVs were extracted by ultrahigh‐speed centrifugation, and ELISA was used to measure the irisin concentration in the circulating EVs. Circulating EVs that differentially expressed irisin were applied to adipocytes, and the effect of EV‐irisin on adipocyte energy metabolism was analyzed by immunofluorescence, protein blotting, and cellular oxygen consumption rate analysis.

Results

During sustained exercise, the mice lost weight and developed fat browning. FNDC5 was induced, cleaved, and secreted into irisin, and irisin levels subsequently increased in the plasma during exercise. Interestingly, irisin was highly expressed in circulating EVs that effectively promoted adipose browning. Mechanistically, the circulating EV‐irisin complex is transported intracellularly by the adipocyte membrane receptor integrin αV, which in turn activates the AMPK signaling pathway, which is dependent on mitochondrial uncoupling protein 1 to cause mitochondrial plasmonic leakage and promote heat production. After inhibition of the AMPK signaling pathway, the effects of the EV‐irisin on promoting fat browning were minimal.

Conclusion

Exercise leads to the accumulation of circulating EV‐irisin, which enhances adipose energy metabolism and thermogenesis and promotes white fat browning in mice, leading to weight loss.
Do office tyrants and centralized decision making drive workplace creative behaviours?
Authors: Li Ci‐Rong , Lin Chen‐Ju , Pauleen David
Published: January 2024

Based on affective events theory and the cognitive–affective processing system, this study explores indirect positive and negative effects of perceived abusive supervision on employee creativity through employees' affective reactions at work and how the centralization of decision making can moderate the associations between employee‐perceived abusive supervision and anxiety/anger. Using a cross‐lagged panel method to collect an effective sample of 200 employee participants which provided three‐week survey data, we tested causality between research variables with a structural equation modelling analysis using Mplus 8.0. The findings showed that a positive effect on employee creativity may occur when an employee experiences anxiety rather than anger when subject to abusive supervision. In addition, the influence of employee‐experienced abusive supervision on employee anger increases when the organization has highly centralized decision making, which hinders employees' creative performance. Theoretically and practically, this study contributes interesting and somewhat conflicting views to three areas of management literature—abusive supervision, employees' affective reactions and creativity management—including challenging the supposition that only uplifting styles of leadership can encourage employees to create new ideas.
Tumor‐derived Prevotella intermedia aggravates gastric cancer by enhancing Perilipin 3 expression
Authors: Liang Wei , Zhou Zhengyang , Gao Qizhao , Zhu Zhichen , Zhu Jie , Lin Jiayao , Wen Yicheng , Qian Feinan , Wang Liang , Zhai Yaxuan , Lv Jingnan , Zhang Haifang , Zhong Fengyun , Du Hong
Published: January 2024

The indigenous microbial milieu within tumorous tissues exerts a pivotal influence on the genesis and advancement of gastric cancer (GC). This investigation scrutinizes the functions and molecular mechanisms attributed to Prevotella intermedia in the malignant evolution of GC. Isolation of P. intermedia from paired GC tissues was undertaken. Quantification of P. intermedia abundance in 102 tissues was accomplished using quantitative real‐time PCR (qRT‐PCR). Assessment of the biological effects of P. intermedia on GC cells was observed using culture medium supernatant. Furthermore, the protein profile of GC cells treated with tumor‐derived P. intermedia was examined through label‐free protein analysis. The functionality of perilipin 3 (PLIN3) was subsequently confirmed using shRNA. Our investigation revealed that the relative abundance of P. intermedia in tumor tissues significantly surpassed that of corresponding healthy tissues. The abundance of P. intermedia exhibited correlations with tumor differentiation (p = 0.006), perineural invasion (p = 0.004), omentum majus invasion (p = 0.040), and the survival duration of GC patients (p = 0.042). The supernatant derived from tumor‐associated P. intermedia bolstered the proliferation, clone formation, migration, and invasion of GC cells. After indirect co‐cultivation with tumor‐derived P. intermedia, dysregulation of 34 proteins, including PLIN3, was discerned in GC cells. Knockdown of PLIN3 mitigated the malignancy instigated by P. intermedia in GC cells. Our findings posit that P. intermedia from the tumor microenvironment plays a substantial role in the malignant progression of GC via the modulation of PLIN3 expression. Moreover, the relative abundance of P. intermedia might serve as a potential biomarker for the diagnosis and prognosis of GC.
The (patho)physiological roles of the individual deacylase activities of a sirtuin
Authors: Zheng Weiping
Published: January 2024

Since the discovery of the sirtuin family founding member (i.e., the yeast silent information regulator 2 (sir2) protein) in 2000, more and more sirtuin proteins have been identified and are currently known to be present in organisms from all the three kingdoms of life (i.e., bacteria, archaea, and eukarya). Seven sirtuin proteins have been identified in mammals including humans, that is, SIRT1/2/3/4/5/6/7. Sirtuin proteins are a class of enzymes with primary catalytic activity being the β‐nicotinamide adenine dinucleotide (β‐NAD+ or NAD+)‐dependent deacylation from the Nε‐acyl‐lysine residues on cellular proteins. Many sirtuins (e.g., human SIRT1/2/3/4/5/6/7) have been found to each possess multiple individual deacylase activities acting on Nε‐acyl‐lysine substrates with different acyl groups ranging from the simple formyl and acetyl to the more complex groups like succinyl and myristoyl; however, our current knowledge on the (patho)physiological roles of these individual deacylase activities is still limited, which could be due to the currently still thin research toolbox for investigation (i.e., the deacylase‐selective sirtuin mutant and inhibitor/activator). In this article, an updated account on the subject matter will be presented with biochemical and medicinal chemistry perspectives.
Risk factors for cerebral palsy: Caution with data, and data interpretation
Authors: Himmelmann Kate
Published: January 2024

This commentary is on the original article by Chen et al. on pages 1062–1073 of this issue.
Fatal attractions that trigger inflammation and drive atherosclerotic disease
Authors: Sharma Hitesh , Mossman Karen , Austin Richard C.
Published: January 2024

Background

Atherosclerosis is the salient, underlying cause of cardiovascular diseases, such as arrhythmia, coronary artery disease, cardiomyopathy, pulmonary embolism and myocardial infarction. In recent years, atherosclerosis pathophysiology has evolved from a lipid‐based to an inflammation‐centric ideology.

Methods

This narrative review is comprised of review and original articles that were found through the PubMed search engine. The following search terms or amalgamation of terms were used: “cardiovascular disease,” “atherosclerosis,” “inflammation,” “GRP78,” “Hsp60,” “oxidative low‐density lipoproteins,” “aldehyde dehydrogenase,” “β2‐glycoprotein,” “lipoprotein lipase A,” “human cytomegalovirus.” “SARS‐CoV‐2,” “chlamydia pneumonia,” “autophagy,” “thrombosis” and “therapeutics.”

Results

Emerging evidence supports the concept that atherosclerosis is associated with the interaction between cell surface expression of stress response chaperones, including GRP78 and Hsp60, and their respective autoantibodies. Moreover, various other autoantigens and their autoantibodies have displayed a compelling connection with the development of atherosclerosis, including oxidative low‐density lipoproteins, aldehyde dehydrogenase, β2‐glycoprotein and lipoprotein lipase A. Atherosclerosis progression is also concurrent with viral and bacterial activators of various diseases. This narrative review will focus on the contributions of human cytomegalovirus as well as SARS‐CoV‐2 and chlamydia pneumonia in atherosclerosis development. Notably, the interaction of an autoantigen with their respective autoantibodies or the presence of a foreign antigen can enhance inflammation development, which leads to atherosclerotic lesion progression.

Conclusion

We will highlight and discuss the complex role of the interaction between autoantigens and autoantibodies, and the presence of foreign antigens in the development of atherosclerotic lesions in relationship to pro‐inflammatory responses.