bluuebunny/crossref_metadata_2025 huggingface dataset:
DeepGEEP: Data-Driven Prediction of Bacterial Biofilm Gene Expression Profiles
Authors: Arjmandi Hamidreza , Corre Christophe , Jahangir Hamidreza , Noel Adam
Published: September 2023

Predicting the gene expression profile (GEEP) of bacterial biofilms in response to spatial, temporal, and concentration profiles of stimulus molecules holds significant potential across microbiology, biotechnology, and synthetic biology domains. However, the resource and time-intensive nature of experiments within Petri dishes presents significant challenges. Data-driven methods offer a promising avenue to replace or reduce such experiments given sufficient data. Through wellcrafted data generation techniques, the data scarcity issue can be effectively addressed. In this paper, an innovative methodology is presented for generating GEEP data over a Petri dish that results from a specific chemical stimulus release profile. A twodimensional convolutional neural network (2D-CNN) architecture is subsequently introduced to leverage the synthesized dataset to predict GEEP variations across bacterial biofilms within the Petri dish. The approach, coined DeepGEEP, is applied to data generated by a particle-based simulator (PBS) to enable a flexible evaluation of its efficacy. The proposed method attains a significant level of accuracy in comparison to established benchmark models such as Linear SVM, Radial Basis Function SVM, Decision Tree, and Random Forest.
Substrate geometry affects population dynamics in a bacterial biofilm
Authors: Postek Witold , Staskiewicz Klaudia , Lilja Elin , Wacław Bartłomiej
Published: September 2023

Biofilms inhabit a range of environments, such as dental plaques or soil micropores, often characterized by intricate, non-even surfaces. However, the impact of surface irregularities on the population dynamics of biofilms remains elusive as most biofilm experiments are conducted on flat surfaces. Here, we show that the shape of the surface on which a biofilm grows influences genetic drift and selection within the biofilm. We cultureE. colibiofilms in micro-wells with an undulating bottom surface and observe the emergence of clonal sectors whose size corresponds to that of the undulations, despite no physical barrier separating different areas of the biofilm. The sectors are remarkably stable over time and do not invade each other; we attribute this stability to the characteristics of the velocity field within the growing biofilm, which hinders mixing and clonal expansion. A microscopically-detailed computer model fully reproduces these findings and highlights the role of mechanical (physical) interactions such as adhesion and friction in microbial evolution. The model also predicts clonal expansion to be severely limited even for clones with a significant growth advantage – a finding which we subsequently confirm experimentally using a mixture of antibiotic-sensitive and antibiotic-resistant mutants in the presence of sub-lethal concentrations of the antibiotic rifampicin. The strong suppression of selection contrasts sharply with the behavior seen in bacterial colonies on agar commonly used to study range expansion and evolution in biofilms. Our results show that biofilm population dynamics can be controlled by patterning the surface, and demonstrate how a better understanding of the physics of bacterial growth can pave the way for new strategies in steering microbial evolution.
How do antimicrobial peptides interact with the outer membrane of Gram-negative bacteria? Role of lipopolysaccharides in the peptide binding, anchoring and penetration
Authors: Stephani Justus C. , Gerhards Luca , Khairalla Bishoy , Solov’yov Ilia A. , Brand Izabella
Published: September 2023

Gram-negative bacteria possess a complex structural cell envelope that constitutes a barrier for antimicrobial peptides which neutralize the microbes by disrupting their cell membranes. Computational and experimental approaches were used to study a model outer membrane interaction with an antimicrobial peptide, melittin. The investigated membrane included di[3-deoxy-D-manno-octulosonyl]-lipid A (KLA) in the outer leaflet and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) in the inner leaflet. Molecular dynamics simulations revealed, that the positively charged helical C-terminus of melittin anchors rapidly into the hydrophilic head-group region of KLA, while the flexible N-terminus makes contacts with the phosphate groups of KLA moving melittin into the boundary between the hydrophilic and hydrophobic regions of the lipids. Electrochemical techniques confirmed binding of melittin to the model membrane. To probe the peptide conformation and orientation during interaction with the membrane, polarization modulation infrared reflection absorption spectroscopy was used. The measurements revealed conformational changes in the peptide accompanied by reorientation and translocation of the peptide at the membrane surface. The study suggests that melittin insertion into the outer membrane affects its permeability and capacitance, but does not disturb the membrane’s integrity, indicating a distinct mechanism of the peptide action on the outer membrane of Gram-negative bacteria.
Loss of the polarity protein Par3 promotes dendritic spine neoteny and enhances learning and memory
Authors: Voglewede Mikayla M. , Ozsen Elif Naz , Ivak Noah , Bernabucci Matteo , Sun Miao , Pang Zhiping P. , Zhang Huaye
Published: September 2023

The Par3 polarity protein is critical for subcellular compartmentalization in different developmental processes. Variants ofPARD3, which encodes PAR3, are associated with intelligence and neurodevelopmental disorders. However, the role of Par3 in glutamatergic synapse formation and cognitive functionsin vivoremains unknown. Here, we show that forebrain conditional knockout of Par3 leads to an increase in long, thin dendritic spines without significantly impacting mushroom spinesin vivo. In addition, we observed a decrease in the amplitude of miniature excitatory postsynaptic currents. Surprisingly, loss of Par3in vivoenhances hippocampal- dependent spatial learning. Phosphoproteomic analysis revealed proteins regulating cytoskeletal dynamics are significantly dysregulated downstream of Par3. Mechanistically, we found Par3 deletion causes increased activation of the Rac1 pathway. Together, our data reveal an unexpected role for Par3 as a molecular gatekeeper in regulating the pool of immature dendritic spines, a rate-limiting step of learning and memory, through modulating Rac1 activationin vivo.
Interlinked Bi-stable Switches Govern the Cell Fate Commitment of Embryonic Stem Cells
Authors: Giri Amitava , Kar Sandip
Published: September 2023

Cell fate decision-making events of embryonic stem (ES) cells are often governed by bi-stable switch-like steady state dynamics of two key transcription factors Oct4 and Nanog due to mutual positive feedback regulation. Intriguingly, for the differentiation of ES cells to either extraembryonic trophectoderm (TE) and primitive endoderm (PrE) lineages, Oct4 maintains either low (TE) or high PrE) expression levels relative to a moderate level in ES cells, while Nanog exhibits high expression in ES state and low expression in both the differentiated states. The dynamical origin for such kind of disparate steady-state level maintenance of Oct4 and Nanog remains elusive. Herein, we demonstrate that such complex steady-state dynamics can be hypothesized and explained by two different bistable switches interconnected either in a stepwise (Oct4) or in a mushroom-like (Nanog) manner. Our hypothesis qualitatively reconciles various experimental observations and elucidates how different feedback and feed-forward motifs orchestrate the extraembryonic development and stemness maintenance of ES cells. Importantly, the model predicts strategies to optimize the dynamics of self-renewal and differentiation of embryonic stem cells that may have therapeutic relevance in the future.
Tunable biomimetic materials elaborated by ice templating and self-assembly of collagen for tubular tissue engineering
Authors: Martinier Isabelle , Fage Florian , Kakar Alshaba , Castagnino Alessia , Saindoy Emeline , Frederick Joni , Onorati Ilaria , Besnard Valérie , Barakat Abdul I. , Dard Nicolas , Martinod Emmanuel , Planes Carole , Trichet Léa , Fernandes Francisco M.
Published: September 2023

Synthetic tubular grafts currently used in clinical context fail frequently, and the expectations that biomimetic materials could tackle these limitations are high. However, developing tubular materials presenting structural, compositional and functional properties close to those of native tissues remains an unmet challenge. Here we describe a combination of ice templating and topotactic fibrillogenesis of type I collagen, the main component of tissues’ extracellular matrix, yielding highly concentrated yet porous tubular collagen materials with controlled hierarchical architecture at multiple length scales, the hallmark of native tissues’ organization. By modulating the thermal conductivity of the cylindrical molds, we tune the macroscopic porosity defined by ice. Coupling the aforementioned porosity patterns with two different fibrillogenesis routes results in a new family of materials whose textural features and the supramolecular arrangement of type I collagen are achieved. The resulting materials present hierarchical elastic properties and are successfully colonized by human endothelial cells and alveolar epithelial cells on the luminal side, and by human mesenchymal stem cells on the external side. The results reported here demonstrate the relevance of the proposed straightforward protocol, likely to be adapted for larger graft sizes, to address ever-growing clinical needs such as peripheral arterial disease or tracheal and bronchial reconstructions.
Arabidopsis CML13 and CML14 Have Essential And Overlapping Roles In Plant Development
Authors: Symonds Kyle , Teresinski Howard , Hau Bryan , Chiasson David , Snedden Wayne A.
Published: September 2023

Calmodulin-like proteins (CaM-like; CML) are the largest family of calcium-binding proteins in plants, yet the functions of most CMLs are unknown. Arabidopsis CML13 and CML14 are closely related paralogs that interact with the isoleucine-glutamine (IQ) domains of myosins, IQ-domain (IQD) proteins, and CaM-activated transcription factors (CAMTAs). Here, we explored the physiological roles of CML13 and CML14 during development by using dexamethasone-inducible RNA silencing to suppress eitherCML13orCML14transcript levels. In the absence of inducible suppression,CML13- andCML14-RNA-interference lines were indistinguishable from WT plants throughout development. In contrast, induction of silencing treatment led to rapid increases in RNA-hairpin production that correlated with a targeted reduction inCML13orCML14transcript levels and a range of developmental and morphological effects. RNA suppression treatment did not impair the germination ofCML13- or 14-RNA-interference lines, but these seedlings were chlorotic, displayed high mortality, and failed to achieve seedling establishment. Induced RNA suppression of mature plants led to reduced silique length, shorter roots, and rapid leaf senescence inCML13-and14-RNA-interference plants. Plants induced for RNA suppression at 2 weeks post-germination exhibited a much stronger phenotype than treatment of 3-, 4-, or 5-week-old plants. Collectively, our data indicate that both CML13 and CML14 are essential for normal development and function across a broad range of tissues and developmental stages.

Highlight

CML13 and CML14 are biochemically unique among the CML family and interact with proteins that possess IQ domains. Here, we show that both paralogs are essential for normal plant growth and development.
Colour-analyzer: A new dual colour model-based imaging tool to quantify plant disease
Authors: Loranger Mackenzie Eli William , Yim Winfield , Accomazzi Vittorio , Morales Lizcano Nadia , Moeder Wolfgang , Yoshioka Keiko
Published: September 2023

Despite major efforts over the last decades, the rising demands of the growing global population makes it of paramount importance to increase crop yields and reduce losses caused by plant pathogens. One way to tackle this is to screen novel resistant genotypes and immunity-inducing agents, which must be conducted in a high-throughput manner. Colour-analyzer is a free web-based tool that can be used to rapidly measure the formation of lesions on leaves. Pixel colour values are often used to distinguish infected from healthy tissues. Some programs employ colour models, such as RGB, HSV or L*a*b*. Colour-analyzer uses two colour models, utilizing both HSV (Hue, Saturation, Value) and L*a*b* values. We found that thea* b*values of the L*a*b* colour model provided the clearest distinction between infected and healthy tissue, while theHandSchannels were best to distinguish the leaf area from the background. By combining the a* andb*channels to determine the lesion area, while using theHandSchannels to determine the leaf area, Colour-analyzer provides highly accurate information on the size of the lesion as well as the percentage of infected tissue in a high throughput manner and can accelerate the plant immunity research field.
Defining the extracellular matrix in non-cartilage soft tissues in osteoarthritis – a systematic review
Authors: Mimpen Jolet Y. , Raza Iwan G. A. , Snelling Sarah J. B.
Published: September 2023

Objective

Osteoarthritis (OA) is increasingly seen as a disease of global joint dysfunction, affecting not only cartilage but also the other joint tissues. Extracellular matrix (ECM) is a critical determinant of tissue mechanobiology, but ECM is poorly understood in osteoarthritic joint tissues beyond cartilage in human OA and animal models of OA. Therefore, we aimed to define the structural composition and architecture of non-cartilage soft joint tissue ECM in human OA, and to compare the ECM changes observed in humans to those seen in animal models of OA.

Design

A systematic search strategy, devised using relevant matrix, tissue, and disease nomenclature, was run through the MEDLINE, EMBASE, and Scopus databases. Demographic, clinical, and biological data were extracted from eligible studies. Bias analysis was performed.

Results

142 studies were included, which covered capsule, ligaments, meniscus, skeletal muscle, synovium, and tendon in both humans and animals, and fat pad and intervertebral disc in humans only. Overall, included studies show that the expression of structural ECM components changes in disease within an ECM that becomes disorganised with increasing joint degeneration.

Conclusions

This systematic review consolidates existing knowledge of a poorly defined aspect of OA pathophysiology. Changes in ECM composition and architecture occur across soft joint tissues in OA, but most of these remain poorly defined due to the low number of studies and lack of healthy comparator groups. Further research to better understand the context within which cartilage is damaged in OA may enable a better understanding of OA and its potential treatments.

Key messages

What is already known on this topic

Extracellular matrix (ECM) is a critical determinant of tissue mechanobiology and cell behaviour, but it is poorly described in osteoarthritic joint tissues beyond cartilage.

What this study adds

Our study highlights the global nature of ECM dysregulation across the osteoarthritic joint. In addition, this study describes practical and methodological challenges that should be addressed to improve the contribution of future studies to define the role of ECM in non-cartilage soft tissues in osteoarthritis.

How this study might affect research, practice or policy

A better understanding of ECM changes and their underlying mechanisms throughout the osteoarthritic joint may assist with disease classification and patient stratification and also holds promise for the development of ECM-targeting treatments which could modify the pathogenic cell behaviour that may drive osteoarthritis progression.
Effect of lifetime exposure to depression on brain structure and function in the UK Biobank
Authors: Wang Xinyi , Hoffstaedter Felix , Kasper Jan , Eickhoff Simon , Patil Kaustubh R. , Dukart Juergen
Published: September 2023

Importance

Despite several decades of neuroimaging studies reporting brain structural and functional alterations in depression, discrepancies in findings across various studies and limited convergence across several recent meta-analyses have raised questions about the consistency and robustness of the observed brain phenotypes.

Objective

To investigate the effects of six different operational criteria of lifetime exposure to depression on functional and structural neuroimaging measures.

Design, Setting, Participants

A cross-sectional study analyzed data from the UK biobank in individuals aged 45 to 80 years enrolled from 2014 to 2018. Six operational depression criteria were defined: Help-seeking for depression, Self-reported Depression, Antidepressant usage, Depression defined by Smith, Hospital International Classification of Disease, 10th Edition (ICD-10), and short-form Composite International Diagnostic Interview. Six increasingly conservative groups of lifetime depression were defined based on the six available depression criteria from meeting only one to more restrictive meeting all six criteria. We tested the effect of these definitions on voxel-wise measures of local functional activity, global connectivity, and gray matter volume.

Main Outcomes and Measures

Voxel-wise fractional amplitude of low-frequency fluctuations, local connectivity, global connectivity, and gray matter volume.

Results

We included 20,484 individuals with lifetime depression (12,645 women [61.73%]; mean [SD] age, 63.92 [7.6] years) and 25,462 healthy individuals (11,384 women [44.7%]; mean [SD] age, 65.05 [7.8] years) from the UK biobank. Across all depression definitions, individuals with lifetime depression displayed regionally consistent decreases in local functional activity in sensorimotor regions but not in global connectivity and gray matter volume. Previous hospital ICD10 diagnosis and antidepressant usage resulted in the most pronounced alterations.

Conclusions and Relevance

Lifetime exposure to depression is associated with robust functional changes with more restrictive criteria revealing more pronounced alterations. Different inclusion criteria for depression may strongly contribute to the substantial variation of imaging findings reported in the literature.
Severe preeclampsia is not associated with significant DNA methylation changes but cell proportion changes in the cord blood - caution on the importance of confounding adjustment
Authors: Liu Wenting , Yang Xiaotong , Mao Zhixin , Du Yuheng , Lassiter Cameron , AlAkwaa Fadhl M. , Benny Paula A , Garmire Lana X
Published: September 2023

Epigenome-wide DNA methylation analysis (EWAS) is an important approach to identify biomarkers for early disease detection and prognosis prediction, yet its results could be confounded by other factors such as cell-type heterogeneity and patient characteristics. In this study, we address the importance of confounding adjustment by examining DNA methylation patterns in cord blood exposed to severe preeclampsia (PE), a prevalent and potentially fatal pregnancy complication. Without such adjustment, a misleading global hypomethylation pattern is obtained. However, after adjusting cell type proportions and patient clinical characteristics, most of the so-called significant CpG methylation changes associated with severe PE disappear. Rather, the major effect of PE on cord blood is through the proportion changes in different cell types. These results are validated using a previously published cord blood DNA methylation dataset, where global hypomethylation pattern was also wrongfully obtained without confounding adjustment. Additionally, several cell types significantly change as gestation progress (eg. granulocyte, nRBC, CD4T, and B cells), further confirming the importance of cell type adjustment in EWAS study of cord blood tissues. Our study urges the community to perform confounding adjustments in EWAS studies, based on cell type heterogeneity and other patient characteristics.
An Individualized Tractography Pipeline for the Nucleus Basalis of Meynert Lateral Tract
Authors: Crockett Rachel A. , Wilkins Kevin B. , Zeineh Michael M. , McNab Jennifer A. , Henderson Jaimie M. , Buch Vivek P. , Brontë-Stewart Helen M.
Published: September 2023

Background

At the center of the cortical cholinergic network, the nucleus basalis of Meynert (NBM) is crucial for the cognitive domains most vulnerable in PD. Preclinical evidence has demonstrated the positive impact of NBM deep brain stimulation (DBS) on cognition but early human trials have had mixed results. It is possible that DBS of the lateral NBM efferent white matter fiber bundle may be more effective at improving cognitive-motor function. However, precise tractography modelling is required to identify the optimal target for neurosurgical planning. Individualized tractography approaches have been shown to be highly effective for accurately identifying DBS targets but have yet to be developed for the NBM.

Methods

Using structural and diffusion weighted imaging, we developed a tractography pipeline for precise individualized identification of the lateral NBM target tract. Using dice similarity coefficients, the reliability of the tractography outputs was assessed across three cohorts to investigate: 1) whether this manual pipeline is more reliable than an existing automated pipeline currently used in the literature; 2) the inter- and intra-rater reliability of our pipeline in research scans of patients with PD; and 3) the reliability and practicality of this pipeline in clinical scans of DBS patients.

Results

The individualized manual pipeline was found to be significantly more reliable than the existing automated pipeline for both the segmentation of the NBM region itself (p<0.001) and the reconstruction of the target lateral tract (p=0.002). There was also no significant difference between the reliability of two different raters in the PD cohort (p=0.25), which showed high inter- (mean Dice coefficient >0.6) and intra-rater (mean Dice coefficient >0.7) reliability across runs. Finally, the pipeline was shown to be highly reliable within the clinical scans (mean Dice coefficient = 0.77). However, accurate reconstruction was only evident in 7/10 tracts.

Conclusion

We have developed a reliable tractography pipeline for the identification and analysis of the NBM lateral tract in research and clinical grade imaging of healthy young adult and PD patient scans.
A comparison of large language model versus manual chart review for extraction of data elements from the electronic health record
Authors: Ge Jin , Li Michael , Delk Molly B. , Lai Jennifer C.
Published: September 2023

Structured Abstract

Importance

Large language models (LLMs) have proven useful for extracting data from publicly available sources, but their uses in clinical settings and with clinical data are unknown.

Objective

To determine the accuracy of data extraction using “Versa Chat,” a chat implementation of the general-purpose OpenAI gpt-35-turbo LLM model, versus manual chart review for hepatocellular carcinoma (HCC) imaging reports.

Design

We engineered a prompt for the data extraction task of six distinct data elements and input 182 abdominal imaging reports that were also manually tagged. We evaluated performance by calculating accuracy, precision, recall, and F1 scores.

Setting/Participants

Cross-sectional abdominal imaging reports of patients diagnosed with hepatocellular carcinoma enrolled in the Functional Assessment in Liver Transplantation (FrAILT) study.
Tracer-based lipidomics identifies novel disease-specific biomarkers in mitochondrial β-oxidation disorders
Authors: Schwantje Marit , Mosegaard Signe , Knottnerus Suzan JG , van Klinken Jan Bert , Wanders Ronald J , van Lenthe Henk , Hermans Jill , IJlst Lodewijk , Denis Simone W , Jaspers Yorrick RJ , Fuchs Sabine A , Houtkooper Riekelt H , Ferdinandusse Sacha , Vaz Frédéric M
Published: September 2023

Carnitine derivatives of disease-specific acyl-CoAs are the diagnostic hallmark for long-chain fatty acid oxidation disorders (lcFAOD), including carnitine shuttle deficiencies, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MPTD). The exact consequence of accumulating lcFAO-intermediates and possible influence on cellular lipid homeostasis are, however, still unknown. To investigate the fate and cellular effects of the accumulating lcFAO-intermediates and to explore new disease markers, we used tracer-based lipidomics with deuterium-labeled oleic acid (D9-C18:1) in lcFAOD patient-derived fibroblasts. In line with previous studies, we observed a trend towards neutral lipid accumulation in lcFAOD. In addition, we detected a direct connection between the chain length and patterns of (un)saturation of accumulating acylcarnitines and the various enzyme deficiencies. Our results also identified two new candidate disease markers. Lysophosphatidylcholine(14:1) (LPC(14:1)) was specifically increased in severe VLCADD compared to mild VLCADD and control samples. This was confirmed in plasma samples showing an inverse correlation with enzyme activity, which was better than the classic diagnostic marker C14:1-carnitine. The second biomarker is an unknown lipid class, which we identified as S-(3-hydroxyacyl)cysteamines. These are hypothesized to be degradation products of the CoA moiety of accumulating 3-hydroxyacyl-CoAs. S-(3-hydroxyacyl)cysteamines were significantly increased in LCHADD compared to controls and other lcFAOD, including MTPD. Our findings suggest extensive alternative lipid metabolism in lcFAOD and confirm that lcFAOD accumulate neutral lipid species. In addition, we present two new disease markers for VLCADD and LCHADD, that may have significant relevance for disease diagnosis, prognosis, and monitoring.
Full-length direct RNA sequencing uncovers stress-granule dependent RNA decay upon cellular stress
Authors: Dar Showkat A. , Malla Sulochan , Martinek Vlastimil , Payea Matthew J. , Lee Christopher T. , Martin Jessica , Khandeshi Aditya J. , Martindale Jennifer L. , Belair Cedric , Maragkakis Manolis
Published: September 2023

Cells react to stress by triggering response pathways, leading to extensive alterations in the transcriptome to restore cellular homeostasis. The role of RNA metabolism in shaping the cellular response to stress is vital, yet the global changes in RNA stability under these conditions remain unclear. In this work, we employ direct RNA sequencing with nanopores, enhanced by 5’ end adaptor ligation, to comprehensively interrogate the human transcriptome at single-molecule and nucleotide resolution. By developing a statistical framework to identify robust RNA length variations in nanopore data, we find that cellular stress induces prevalent 5’ end RNA decay that is coupled to translation and ribosome occupancy. Unlike typical RNA decay models in normal conditions, we show that stress-induced RNA decay is dependent on XRN1 but does not depend on deadenylation or decapping. We observed that RNAs undergoing decay are predominantly enriched in the stress granule transcriptome while inhibition of stress granule formation via genetic ablation of G3BP1 and G3BP2 rescues RNA length. Our findings reveal RNA decay as a key determinant of RNA metabolism upon cellular stress and dependent on stress-granule formation.
Precision Proteoform Design for 4R Tau Isoform Selective Templated Aggregation
Authors: Longhini Andrew P. , DuBose Austin , Lobo Samuel , Vijayan Vishnu , Bai Yeran , Rivera Erica Keane , Sala-Jarque Julia , Nikitina Arina , Carrettiero Daniel C. , Unger Matthew , Sclafani Olivia , Fu Valerie , Vigers Michael , Buee Luc , Landrieu Isabelle , Shell Scott , Shea Joan E. , Han Songi , Kosik Kenneth S.
Published: September 2023

Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. A 19-residue probe peptide containing a P301L mutation and spanning the R2/R3 splice junction of tau, folds and stacks into seeding-competent fibrils and induces aggregation of 4R, but not 3R tau. These tau peptide fibrils propagate aggregated intracellular tau over multiple generations, have a high β- sheet content, a colocalized lipid signal, and adopt a well-defined U-shaped fold found in 4R tauopathy brain-derived fibrils. Fully atomistic replica exchange molecular dynamics (MD) simulations were used to compute the free energy landscapes of the conformational ensemble of the peptide monomers. These identified an aggregation-prohibiting β-hairpin structure and an aggregation-competent U-fold unique to 4R tauopathy fibrils. Guided by MD simulations, we identified that the N-terminal-flanking residues to PHF6, which slightly vary between 4R and 3R isoforms, modulate seeding. Strikingly, when a single amino acid switch at position 305 replaced the serine of 4R tau with a lysine from the corresponding position in the first repeat of 3R tau, the seeding induced by the 19-residue peptide was markedly reduced. Conversely, a 4R tau mimic with three repeats, prepared by replacing those amino acids in the first repeat with those amino acids uniquely present in the second repeat, recovered aggregation when exposed to the 19- residue peptide. These peptide fibrils function as partial prions to recruit naïve 4R tau—ten times the length of the peptide—and serve as a critical template for 4R tauopathy propagation. These results hint at opportunities for tau isoform-specific therapeutic interventions.

Significance Statement

A structural motif corresponding to a short junction sequence spanning R2 and R3 forms fibrils that adopt a fold characteristic of 4R tauopathy fibrils and induces misfolding of the larger tau protein with loss of microtubule binding and a prion-like specificity for 4R tau. Simulations, validated experimentally, pinpointed the specific amino acids in the peptide that can toggle its properties between aggregation competent and incompetent. The modifications suggest design principles for a therapeutic intervention potentially capable of disaggregating tau or preventing its aggregation in the 4R tauopathies.
EfpA is required for re-growth ofMycobacterium tuberculosisfollowing isoniazid exposure
Authors: Roberts Adam H. , Moon Christopher W. , Faulkner Valwynne , Kendall Sharon L. , Waddell Simon , Bacon Joanna
Published: September 2023

Efflux of antibiotics is a survival strategy in bacteria.Mycobacterium tuberculosishas approximately sixty efflux pumps, but little is known about the role of each pump, or which moieties that they efflux. The putative efflux pump, EfpA, is a member of the major facilitator superfamily that has been shown to be essential by saturation transposon mutagenesis studies. It has been implicated in the efflux of the frontline drug isoniazid (INH) inM. tuberculosis. This is supported by evidence from transcriptional profiling thatefpAis induced in response to INH exposure. However, its role in physiology and adaptation ofM. tuberculosisto antibiotics, have yet to be determined. Here, we describe the repression ofefpAusing CRISPR interference and the direct effect of this on the ability ofM. tuberculosisto survive exposure to INH over a 45-day time-course. We determined that wild-type levels ofefpAwere required for the recovery ofM. tuberculosiscultures following INH exposure and that, after 45-days of INH exposure, no viable colonies were recoverable fromefpA-repressedM. tuberculosiscultures. We postulate that EfpA is required for the recovery ofM. tuberculosisfollowing INH-exposure and that EfpA may have a role in the development of resistance, during treatment and contributes to relapse in patients.
Ultralow background membrane editors for spatiotemporal control of lipid metabolism and signaling
Authors: Li Xiang-Ling , Tei Reika , Uematsu Masaaki , Baskin Jeremy M.
Published: September 2023

Phosphatidic acid (PA) is a multifunctional lipid with important metabolic and signaling functions, and efforts to dissect its pleiotropy demand strategies for perturbing its levels with spatiotemporal precision. Previous membrane editing approaches for generating local PA pools used light-mediated induced proximity to recruit a PA-synthesizing enzyme, phospholipase D (PLD), from the cytosol to the target organelle membrane. Whereas these optogenetic PLDs exhibited high activity, their residual activity in the dark led to undesired chronic lipid production. Here, we report ultralow background membrane editors for PA wherein light directly controls PLD catalytic activity, as opposed to localization and access to substrates, exploiting a LOV domain-based conformational photoswitch inserted into the PLD sequence and enabling their stable and non-perturbative targeting to multiple organelle membranes. By coupling organelle-targeted LOVPLD activation to lipidomics analysis, we discovered different rates of metabolism for PA and its downstream products depending on the subcellular location of PA production. We also elucidated signaling roles for PA pools on different membranes in conferring local activation of AMP-activated protein kinase signaling. This work illustrates how membrane editors featuring acute, optogenetic conformational switches can provide new insights into organelle-selective lipid metabolic and signaling pathways.

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High prevalence of asymptomatic malaria in Forest Guinea: Results from a rapid community survey
Authors: Hammer Charlotte C , Diallo Mariama Dalanda , Kann Boubacar , Sanoh Fatoumata , Leno Tamba N’fantoma , Mansare Oumar , Diakité Ismail , Sow Abdoulaye Djibril , Konate Yacouba , Ryan-Castillo Emilie , Barry Alpha Mahmoud , Standley Claire J
Published: September 2023

Malaria is endemic in Guinea, however, the extent and role in transmission of asymptomatic malaria are not well understood. In May 2023, we conducted a rapid community survey to determinePlasmodium falciparumprevalence among asymptomatic individuals in Middle Guinea (Dalaba) and Forest Guinea (Guéckédou). We used a cluster sampling approach with purposive selection of two prefectures and four communities and full enrolment of all individuals in the selected communities. Prevalence was calculated with a 95% confidence interval (CI). In Dalaba, 6/239 (2.1%, CI 0.9-4.8%) individuals tested positive for P.falciparumby rapid diagnostic test, while in Guéckédou, 147/235 (60.9%, CI 54.5-66.9%) of participants tested positive. Asymptomatic malaria needs to be considered more strongly as a driver for transmission when designing control strategies, especially in Forest Guinea and potentially other hyper-endemic settings.

Key results and their importance

Prevalence of asymptomatic malaria was very high (60.9%, CI 54.5-66.9%) in the selected communities in Forest Guinea.

Prevalence was expectedly low (2.1%, CI 0.9-4.8%) in the selected communities in Middle Guinea.

Current control strategies in Forest Guinea seem insufficient to reduce malaria prevalence, and likely also transmission.

Both policies and control strategies need to more proactively consider asymptomatic malaria in hyper-endemic settings.
The impacts of social needs and game playing type on esports consumers' positive eWOM sharing: applying the FIRO theory
Authors: Ock Deokkyung , Hwang Yongjin
Published: September 2023

Purpose

The current study aims to examine esports consumers' social needs (inclusion, affection and control) as antecedents of positive eWOM intention. Additionally, the moderating effects of game playing type (individual-based competition vs. team-based competition) were tested to determine whether the inherent socializing opportunities provided by each game playing type have different effects on the relationship between social needs and eWOM communication of esports consumers.

Design/methodology/approach

A cross-sectional survey design was applied to 387 responses collected from an online survey platform. After checking several assumptions, a series of regression analyses were performed to test the suggested hypotheses.

Findings

The results revealed that the needs for inclusion, affection and control were positively associated with eWOM intention. Furthermore, the relationships between inclusion and eWOM intention and affection and eWOM intention were moderated by game playing type.

Originality/value

The current study extended the fundamental interpersonal relations orientation theory from conventional interpersonal relationships to interpersonal communication in online platforms. This research also suggested that eWOM communication in esports could be supplemental social opportunities, especially for individual-based competition games.
Why customers buy an online product? The effects of advertising attractiveness, influencer marketing and online customer reviews
Authors: Arief Mohammad , Mustikowati Rita Indah , Chrismardani Yustina
Published: September 2023

Purpose

Digitalization in marketing activities has made it easier for people to make purchase decision. This platform encourages every firm to optimize digitalization as part of its marketing strategy. Optimization of attractive digital marketing involves advertising attractiveness, influencer marketing and online customer reviews. This study aims to investigate advertising attractiveness, influencer marketing and online customer reviews on purchase decision.

Design/methodology/approach

The study was conducted with a quantitative approach. A total of 120 respondents were involved in this study by using convenience sampling techniques in data collection. Multiple linear regression was used to analyze the data.

Findings

The results of the study show that influencer marketing and online customer reviews have an impact on online purchase decision. Meanwhile, advertising attractiveness does not show any influence on purchase decision.

Practical implications

Despite the start-ups have modified the website by increasing the content to make it more informative, it seems that customers are not interested in making a purchase. Therefore, notwithstanding the role of website attractiveness, the use of physical attractiveness is still considered an effective way to encourage customers to make purchasing decisions. In this way, a firm needs to make adjustments between the customers' personality, lifestyle and attitudes and endorsers.

Originality/value

This study developed previous empirical studies which a positive relationship between advertising attractiveness, influencer marketing, online customer reviews and purchase decision. The development of the model was carried out by elaborating variable indicators. In addition, the source of increasing credibility was not based on physical attractiveness, but rather emphasizes the website quality.
Limbic brain subregions associated with mental health symptoms in youth with and without prenatal alcohol exposure
Authors: Nakhid Daphne , Patel Darpal , McMorris Carly A. , Gibbard W. Ben , Tortorelli Christina , Pei Jacqueline , Lebel Catherine
Published: September 2023

Background

Prenatal alcohol exposure (PAE) can result in reduced brain volume and an increased risk of mental health challenges. Limbic brain structures such as the hippocampus, thalamus, and amygdala often exhibit smaller volumes in youth with PAE, and similar volume reductions are observed in unexposed youth with symptoms of depression, bipolar disorder, anxiety, and schizophrenia. However, the role of volume reductions in these brain regions in mental health challenges remains unclear for individuals with PAE.

Methods

Thirty‐four youth with PAE and 72 unexposed youth aged 7–16 years completed a T1‐weighted magnetic resonance imaging scan. FreeSurfer was used to process and extract volumes for hippocampal subfields, thalamic subnuclei, and amygdalar subnuclei. Depression and anxiety symptoms were measured using the Behavioral Assessment System for Children (BASC‐2/3‐PRS), the Children's Depression Inventory, and the Multidimensional Anxiety Scale for Children. We tested whether limbic subregion volumes differed between youth with and those without PAE and whether volumes were associated with depression and/or anxiety symptoms, controlling for age and gender.

Results

Multiple hippocampal and thalamic subregions, but not amygdalar subnuclei, were smaller in individuals with PAE. Multiple group‐brain interactions were observed for depression symptoms and subregion volumes. Negative associations between anxiety and limbic subregions were observed across groups.

Conclusions

These findings show extensive volume reductions in the hippocampus and thalamus in youth with PAE. PAE also appears to disrupt the association between depression symptoms and limbic subregions in youth, which may have implications for interventions in these individuals. Anxiety symptoms in youth with and without PAE are similarly associated with limbic volumes.
Letter: future studies of high‐dose thiamine should consider whether its effects on fatigue are related to the inhibition of carbonic anhydrase isoenzymes
Authors: Lubell Jeffrey M.
Published: September 2023

LINKED CONTENT

This article is linked to Bager et al papers. To view these articles, visithttps://doi.org/10.1111/apt.16166andhttps://doi.org/10.1111/apt.16293
Predicting clinical decompensation in patients with cirrhosis using the Hepquant‐SHUNT test
Authors: Fallahzadeh Mohammad Amin , Hansen Daniel J. , Trotter James F. , Everson Gregory T. , Saracino Giovanna , Rahimi Robert S. , Helmke Steve , Boutte Jodi , Asrani Sumeet K.
Published: September 2023

Background

Early identification of risk for decompensation in clinically stable cirrhotic patients helps specialists target early interventions and supports effective referrals from primary care providers to specialty centres.

Aims

To examine whether the HepQuant‐SHUNT test (HepQuant LLC, Greenwood Village, Colorado, USA) predicts decompensation and the need for liver transplantation, hospitalisation or liver‐related death.

Methods

Thirty‐five compensated and 35 subjects with a previous episode of decompensation underwent the SHUNT Test and were followed for a median of 4.2 years. The disease severity index (DSI) (range 0‐50) was examined for association with decompensation in compensated patients; and liver transplantation, liver‐related death, and the number and days of liver related hospitalisations in all. DSI prediction of decompensation was also evaluated in 84 subjects with compensated cirrhosis from the Hepatitis C Antiviral Long‐Term Treatment against Cirrhosis Trial (HALT‐C) followed for a median of 5.8 years.

Results

At baseline, subjects with prior decompensation had significantly higher DSI than compensated subjects (32.6 vs 20.9, P < 0.001). DSI ≥24 distinguished the decompensated from the compensated patients and independently predicted adverse clinical outcomes (hazard ratio: 4.92, 95% confidence interval: 1.42‐17.06). In the HALT‐C cohort, 65% with baseline DSI ≥24 vs 19% with DSI <24 experienced adverse clinical outcomes (relative risk 3.45, P < 0.0001).

Conclusions

The SHUNT test is a novel, noninvasive test that predicts risk of decompensation in previously compensated patients. DSI ≥24 is independently associated with risk for clinical decompensation, liver transplantation, death and hospitalisation.
Editorial: stratifying risk of adverse outcomes in cirrhosis: the Hepquant SHUNT test
Authors: Maan Raoel , Sonneveld Milan J.
Published: September 2023

LINKED CONTENT

This article is linked to Fallahzadeh et al and Asrani & Everson papers. To view these articles, visit https://doi.org/10.1111/apt.16283 and https://doi.org/10.1111/apt.16311
Letter: is the radiation therapy causing an IBD flare, or the IBD predisposing to radiation toxicity? Authors' reply
Authors: Laharie David , Riviere Pauline
Published: September 2023

LINKED CONTENT

This article is linked to Broussard et al and Lim et al papers. To view these articles, visit https://doi.org/10.1111/apt.16176 and https://doi.org/10.1111/apt.16289
Editorial: an expert consensus to standardise the assessment of histological disease activity in Crohn’s disease clinical trials—a missing link. Authors' reply
Authors: Jairath Vipul , Almradi Ahmed , Pai Rish K. , Ma Christopher
Published: September 2023

LINKED CONTENT

This article is linked to Almradi et al paper. To view this article, visit https://doi.org/10.1111/apt.16248
Editorial: co‐morbid gastrointestinal conditions are an important consideration in IBS management
Authors: Simons Madison , Taft Tiffany H.
Published: September 2023

LINKED CONTENT

This article is linked to Black et al and Black & Ford papers. To view these articles, visit https://doi.org/10.1111/apt.16322 and https://doi.org/10.1111/apt.16351
The molecular spectrum of amyloid‐beta (Aβ) in neurodegenerative diseases beyond Alzheimer's disease
Authors: Ichimata Shojiro , Yoshida Koji , Li Jun , Rogaeva Ekaterina , Lang Anthony E. , Kovacs Gabor G.
Published: September 2023

This study investigated the molecular spectrum of amyloid‐beta (Aβ) in neurodegenerative diseases beyond Alzheimer's disease (AD). We analyzed Aβ deposition in the temporal cortex and striatum in 116 autopsies, including Lewy body disease (LBD; N = 51), multiple system atrophy (MSA; N = 10), frontotemporal lobar degeneration‐TDP‐43 (FTLD‐TDP; N = 16), and progressive supranuclear palsy (PSP; N = 39). The LBD group exhibited the most Aβ deposition in the temporal cortex and striatum (90/76%, respectively), followed by PSP (69/28%), FTLD‐TDP (50/25%), and the MSA group (50/10%). We conducted immunohistochemical analysis using antibodies targeting eight Aβ epitopes in the LBD and PSP groups. Immunohistochemical findings were evaluated semi‐quantitatively and quantitatively using digital pathology. Females with LBD exhibited significantly more severe Aβ deposition, particularly Aβ42 and Aβ43, along with significantly more severe tau pathology. Furthermore, a quantitative analysis of all Aβ peptides in the LBD group revealed an association with the APOE‐ε4 genotypes. No significant differences were observed between males and females in the PSP group. Finally, we compared striatal Aβ deposition in cases with LBD (N = 15), AD without α‐synuclein pathology (N = 6), and PSP (N = 5). There were no differences in the pan‐Aβ antibody (6F/3D)‐immunolabeled deposition burden among the three groups, but the deposition burden of peptides with high aggregation capacity, especially Aβ43, was significantly higher in the AD and LBD groups than in the PSP group. Furthermore, considerable heterogeneity was observed in the composition of Aβ peptides on a case‐by‐case basis in the AD and LBD groups, whereas it was relatively uniform in the PSP group. Cluster analysis further supported these findings. Our data suggest that the type of concomitant proteinopathies influences the spectrum of Aβ deposition, impacted also by sex and APOE genotypes.