bluuebunny/crossref_metadata_2025 huggingface dataset:
The T-type voltage-gated Ca2+channel CaV3.1 as a candidate receptor forPasteurella multocidatoxin and contributes to the disruption of respiratory epithelial barrier induced by the toxin
Authors: Bi Haixin , Wang Fei , Lin Lin , Zhang Dajun , Chen Menghan , Shang Yuyao , Hua Lin , Chen Huanchun , Wu Bin , Peng Zhong
Published: September 2024

Pasteurella multocidatoxin (PMT) is an exotoxin produced by several members of the zoonotic respiratory pathogenP. multocida. The role of PMT in disrupting the mammalian respiratory barrier remains to be elucidated. In this study, we discovered that inoculation of recombinantly expressed PMT increased the permeability of the respiratory epithelial barrier in mouse and respiratory cell models. This was evidenced by a decreased expression of tight junctions (ZO-1, occludin) and adherens junctions (β-catenin, E-cadherin), as well as enhanced cytoskeletal rearrangement. In mechanism, we demonstrated that PMT inoculation induced cytoplasmic Ca2+inflow, leading to an imbalance of cellular Ca2+homeostasis and endoplasmic reticulum stress. This process further stimulated the RhoA/ROCK signaling, promoting cytoskeletal rearrangement and reducing the expression of tight junctions and adherens junctions. Notably, the T-type voltage-gated Ca2+channel CaV3.1 was found to participate in PMT-induced cytoplasmic Ca2+inflow. Knocking out CaV3.1 significantly reduced the cytotoxicity induced by PMT on swine respiratory epithelial cells and mitigated cytoplasmic Ca2+inflow stimulated by PMT. Further analysis identified Ser (aa92), Glu (aa155), Tyr (aa167), and Leu (aa448) as crucial sites utilized by PMT to interact with CaV3.1. These findings suggest CaV3.1 serves as an important host receptor of PMT and contributes to PMT-induced respiratory epithelial barrier disruption.

Importance

PMT is a significant toxin produced by the zoonotic respiratory pathogenP. multocida, yet little is known about its pathogenesis beyond causing progressive atrophic rhinitis in pigs. In our study, we have discovered that PMT has the capacity to disrupt the integrity of the mammalian respiratory epithelial barrier. This disruption involves an imbalance in cellular Ca2+homeostasis, endoplasmic reticulum stress, and activation of the RhoA/ROCK signaling pathway induced by PMT. Importantly, we have identified CaV3.1 as a pivotal receptor that plays a crucial role in the pathogenic effects of PMT. Our findings highlight the potential of CaV3.1 as a target for intervention strategies aimed at combating the detrimental effects of PMT.
Resting State Cortical Network and Subcortical Hyperconnectivity in Youth With Generalized Anxiety Disorder in the ABCD Study
Authors: Sievertsen Sam A. , Zhu Jinhan , Fang Angela , Forsyth Jennifer K.
Published: September 2024

Introduction

Generalized anxiety disorder (GAD) frequently emerges during childhood or adolescence, yet, few studies have examined functional connectivity differences in youth GAD. Functional MRI studies of adult GAD have implicated multiple brain regions; however, frequent examination of individual brain seed regions and/or networks has limited a holistic view of GAD-associated differences. The current study therefore used resting-state fMRI data from the Adolescent Brain Cognitive Development study to investigate connectivity in youth with GAD across multiple cortical networks and subcortical regions implicated in adult GAD, considering diagnosis changes across two assessment periods.

Methods

Within- and between-network connectivity in 164 GAD youth and 3158 healthy controls for 6 cortical networks and 6 subcortical regions was assessed using linear mixed effect models. Changes in GAD-associated connectivity between baseline and 2-year follow-up were then compared for subjects with: continuous GAD, GAD at baseline and not follow-up (GAD-remitters), GAD at follow-up and not baseline (GAD-converters), and controls. Associations between GAD-associated connectivity metrics and Child Behavior Checklist (CBCL) symptom severity were assessed using mixed effects models.

Results

GAD youth showed greater within-ventral attention network (VAN) connectivity, and hyperconnectivity between the amygdala and cingulo-opercular network, and between striatal regions and the cingulo-opercular, default mode, and salience networks (FDR p<0.05). Within-VAN connectivity decreased for GAD-remitters between baseline and follow-up. Connectivity was not associated with symptom severity.

Discussion

Results indicate that GAD in childhood and adolescence is associated with altered subcortical to cortical network connectivity affecting multiple networks, and that within-VAN hyperconnectivity, in particular, is associated with clinically-significant GAD symptoms.
Predicting survival time for critically ill patients with heart failure using conformalized survival analysis
Authors: Wang Xiaomeng , Ren Zhimei , Ye Jiancheng
Published: September 2024

Heart failure (HF) is a serious public health issue, particularly for critically ill patients in intensive care units (ICUs). Predicting survival outcomes of critically ill patients with calibrated uncertainty calibration is a difficult yet crucially important task for timely treatment. This study applies a novel approach, conformalized survival analysis (CSA), to predicting the survival time to critically ill HF patients. CSA quantifies the uncertainty of point prediction by accompanying each predicted value with a lower bound guaranteed to cover the true survival time. Utilizing the MIMIC-IV dataset, we demonstrate that CSA delivers calibrated uncertainty quantification for the predicted survival time, while the methods based on parametric models (e.g., Cox model or the Accelerated Failure Time model) fail to do so. By applying CSA to a large, real-world dataset, the study highlights its potential to improve decision-making in critical care, offering a more nuanced and accurate tool for prognostication in a setting where precise predictions and calibrated uncertainty quantification can significantly influence patient outcomes.
Antigen specificity of clonally-enriched CD8+ T cells in multiple sclerosis
Authors: Mittl Kristen , Hayashi Fumie , Dandekar Ravi , Schubert Ryan D. , Gerdts Josiah , Oshiro Lindsay , Loudermilk Rita , Greenfield Ariele , Augusto Danillo G. , Ramesh Akshaya , Tran Edwina , Koshal Kaniskha , Kizer Kerry , Dreux Joanna , Cagalingan Alaina , Schustek Florian , Flood Lena , Moore Tamson , Kirkemo Lisa L. , Cooper Tiffany , Harms Meagan , Gomez Refujia ,   University of California, San Francisco MS-EPIC Team, Sibener Leah , Cree Bruce A. C. , Hauser Stephen L. , Hollenbach Jill A. , Gee Marvin , Wilson Michael R. , Zamvil Scott S. , Sabatino Joseph J.
Published: September 2024

CD8+ T cells are the dominant lymphocyte population in multiple sclerosis (MS) lesions where they are highly clonally expanded. The clonal identity, function, and antigen specificity of CD8+ T cells in MS are not well understood. Here we report a comprehensive single-cell RNA-seq and T cell receptor (TCR)-seq analysis of the cerebrospinal fluid (CSF) and blood from a cohort of treatment-naïve MS patients and control participants. A small subset of highly expanded and activated CD8+ T cells were enriched in the CSF in MS that displayed high activation, cytotoxicity and tissue-homing transcriptional profiles. Using a combination of unbiased and targeted antigen discovery approaches, MS-derived CD8+ T cell clonotypes recognizing Epstein-Barr virus (EBV) antigens and multiple novel mimotopes were identified. These findings shed vital insight into the role of CD8+ T cells in MS and pave the way towards disease biomarkers and therapeutic targets.Graphical Summary

Created in BioRender. Sabatino, J. (2024)BioRender.com/e66l598
Mechano-osmotic signals control chromatin state and fate transitions in pluripotent stem cells
Authors: McCreery Kaitlin P. , Stubb Aki , Stephens Rebecca , Fursova Nadezda A. , Cook Andrew , Kruse Kai , Michelbach Anja , Biggs Leah C. , Keikhosravi Adib , Nykanen Sonja , Hyden-Granskog Christel , Zou Jizhong , Lackmann Jan-Wilm , Niessen Carien M. , Vuoristo Sanna , Miroshnikova Yekaterina A. , Wickstrom Sara A.
Published: September 2024

Acquisition of specific cell shapes and morphologies is a central component of cell fate transitions. Although signaling circuits and gene regulatory networks that regulate pluripotent stem cell differentiation have been intensely studied, how these networks are integrated in space and time with morphological transitions and mechanical deformations to control state transitions remains a fundamental open question. Here, we focus on two distinct models of pluripotency, primed pluripotent stem cells and pre-implantation inner cell mass cells of human embryos to discover that cell fate transitions associate with rapid changes in nuclear shape and volume which collectively alter the nuclear mechanophenotype. Mechanistic studies in human induced pluripotent stem cells further reveal that these phenotypical changes and the associated active fluctuations of the nuclear envelope arise from growth factor signaling-controlled changes in chromatin mechanics and cytoskeletal confinement. These collective mechano-osmotic changes trigger global transcriptional repression and a condensation-prone environment that primes chromatin for a cell fate transition by attenuating repression of differentiation genes. However, while this mechano-osmotic chromatin priming has the potential to accelerate fate transitions and differentiation, sustained biochemical signals are required for robust induction of specific lineages. Our findings uncover a critical mechanochemical feedback mechanism that integrates nuclear mechanics, shape and volume with biochemical signaling and chromatin state to control cell fate transition dynamics.
Engineering elephant models of cold-adaptation and cancer resistance
Authors: Karpinski Emil , Badey Nikil , Mintzer Esther , Ashkenazy-Titelman Asaf , Li Li , Church George M.
Published: September 2024

Throughout their evolution, proboscideans have gotten larger and spread to occupy novel environments throughout the world. These phenotypic changes have been accompanied by a suite of genetic changes including those responsible for tumor suppression and environmental adaptation. Here we examine a handful of woolly mammoth-specific deletions, and their potential contributions to arctic adaptation, as well as the expanded TP53 genetic repertoire in elephants. We use CRISPR-Cas9 to introduce mammoth-specific noncoding deletions as well as knockouts of TP53, all 29 TP53 retrogenes, or both in combination in Asian elephant cell lines, and examine the transcriptomic response. We find that many of the mammoth-specific deletions likely contribute to various arctic phenotypes including vascular development, metabolism and thermogenesis, and hair and skin adaptations. Additionally, we find that while there is considerable overlap in the DNA damage responses of the TP53 and retrogene knockouts, there are also many unique pathways enriched in both. In particular, the retrogene knockouts exhibit strong enrichment of many extracellular pathways suggesting they may play a role in the tumor microenvironment and mitigating metastatic growth. This highlights the usability of cell culture models to disentangle the effects of regulatory mutations or complex genetic systems, especially in non-model species where the generation of animal models is not possible.
Protein degradation by small tag artificial bacterial E3 ligase
Authors: Liu Zhenyi , Tsai Ming-Chi , Ghosh Soumitra , Lawrence Jessica , Chu Sarah , Bingol Baris , Warming Søren
Published: September 2024

Targeting of proteins for degradation in a reversible manner is a powerful approach to decipher gene function and mimic drug effects, with great potential for drug target discovery and validation. A generalized approach is to tag a protein of interest and then use this tag to recruit an endogenously or exogenously expressed E3 ligase for its polyubiquitination and subsequent degradation via 26S proteasome. However, the often bulky size of the tag and the great variability of substrate-dependent degradation efficiency of mammalian E3 ligases pose great challenges in practice. Here we show that small tags (10-15 amino acids) can be used to efficiently tag endogenous proteins for degradation when coupled with an exogenously expressedartificialbacterialE3 ligase (ABEL) consisting of a tag-interacting moiety and the catalytic domain of the bacterial E3 ligase IpaH9.8. We name this versatile and efficient platformdegradation bysmall tagABEL(DESTABEL). Furthermore, we show that an ABEL containing a nanobody against human α-synuclein mediates efficient degradation in primary neurons as well as in the adult mouse brain. Taken together, our data show that tag-dependent and independent ABELs are powerful yet flexible tools for studies of protein function and drug target validation.
Aquavert – Imaging and Microfluidics for Vertical Swimming of Microorganisms
Authors: Obenshain Haley B. , Zarate Isaias , Hedman-Manzano Olivia , Goderich Jared , Lee Sungho , Lopez Bryant A. , Varela Emma , Suh Ga-Young Kelly , Pace Douglas A. , Ahrar Siavash
Published: September 2024

Investigating aquatic microorganisms’ swimming and feeding behaviors under well-controlled conditions is of great interest across multiple disciplines. Thus, broader access to resources that enable these investigations is desirable. Given the organisms’ microscopic dimensions, an ideal system should combine microscopy to visualize and fluidics to control and modulate their environments. We report an integrated device (Aquavert) that combines DIY microscopy and microfluidics for biomechanical investigations of marine microorganisms, emphasizing vertical swimming. The DIY microscope was developed for modularity, and imaging chambers were secured in vertical orientations (either in portrait or landscape mode). Fluid channels were used to introduce flow and fluid segmentation while remaining upright. Fluid segmentation established two distinct environments (e.g., with and without algae) in neighboring regions inside a chamber. System application with multiple marine larvae (sand dollars, sea urchins, and starfish) and introduction of unicellular algae were demonstrated. Finally, the device’s capabilities were extended to fluorescence imaging to visualize tracer beads. The role of gravity is often ignored in conventional plate or microfluidic experiments. Beyond the current application, Aquavert enables investigations of the behavior and physiology of microorganisms where the role of gravity is critical.
Biophysical modeling of membrane curvature generation and curvature sensing by the glycocalyx
Authors: Xiao Ke , Park Sujeong , Stachowiak Jeanne , Rangamani Padmini
Published: September 2024

Generation of membrane curvature is fundamental to cellular function. Recent studies have established that the glycocalyx, a sugar-rich polymer layer at the cell surface, can generate membrane curvature. While there have been some theoretical efforts to understand the interplay between the glycocalyx and membrane bending, there remain open questions about how the properties of the glycocalyx affect membrane bending. For example, the relationship between membrane curvature and the density of glycosylated proteins on its surface remains unclear. In this work, we use polymer brush theory to develop a detailed biophysical model of the energetic interactions of the glycocalyx with the membrane. Using this model, we identify the conditions under which the glycocalyx can both generate and sense curvature. Our model predicts that the extent of membrane curvature generated depends on the grafting density of the glycocalyx and the length of the polymers constituting the glycocalyx. Furthermore, when coupled with the intrinsic membrane properties such as spontaneous curvature and a line tension along the membrane, the curvature generation properties of the glycocalyx are enhanced. These predictions were tested experimentally by examining the propensity of glycosylated transmembrane proteins to drive the assembly of highly-curved filopodial protrusions at the plasma membrane of adherent mammalian cells. Our model also predicts that the glycocalyx has curvature-sensing capabilities, in agreement with the results of our experiments. Thus, our study develops a quantitative framework for mapping the properties of the glycocalyx to the curvature generation capability of the membrane.
Multi-strain phage induced clearance of bacterial infections
Authors: Marchi Jacopo , Ngoc Minh Chau Nguyen , Debarbieux Laurent , Weitz Joshua S.
Published: September 2024

Bacteriophage (or ‘phage’ – viruses that infect and kill bacteria) are increasingly considered as a therapeutic alternative to treat antibiotic-resistant bacterial infections. However, bacteria can evolve resistance to phage, presenting a significant challenge to the near- and long-term success of phage therapeutics. Application of mixtures of multiple phage (i.e., ‘cocktails’) have been proposed to limit the emergence of phage-resistant bacterial mutants that could lead to therapeutic failure. Here, we combine theory and computational models ofin vivophage therapy to study the efficacy of a phage cocktail, composed of two complementary phages motivated by the example ofPseudomonas aeruginosafacing two phages that exploit different surface receptors, LUZ19v and PAK P1. As confirmed in a Luria-Delbrück fluctuation test, this motivating example serves as a model for instances where bacteria are extremely unlikely to develop simultaneous resistance mutations against both phages. We then quantify therapeutic outcomes given single- or double-phage treatment models, as a function of phage traits and host immune strength. Building upon prior work showing monophage therapy efficacy in immunocompetent hosts, here we show that phage cocktails comprised of phage targeting independent bacterial receptors can improve treatment outcome in immunocompromised hosts and reduce the chance that pathogens simultaneously evolve resistance against phage combinations. The finding of phage cocktail efficacy is qualitatively robust to differences in virus-bacteria interactions and host immune dynamics. Altogether, the combined use of theory and computational analysis highlights the influence of viral life history traits and receptor complementarity when designing and deploying phage cocktails in immunocompetent and immunocompromised hosts.
Pentose Phosphate Pathway ProtectsE. colifrom Antibiotic Lethality
Authors: Seregina Tatyana , Shakulov Rustem , Shatalin Konstantin , Sklyarova Svetlana , Petrushanko Irina , Mitkevich Vladimir , Makarov Alexander , Mironov Alexander S. , Nudler Evgeny
Published: September 2024

Disruption of both branches of the canonical pentose phosphate pathway (PPP) inE. coliby combined inactivation of thezwfandtalABgenes provokes the restoration of the ancient anabolic variant of PPP (aPPP). In the aPPP, pentose-5-phosphates are synthesized unidirectionally from fructose-6-phosphate and glyceraldehyde-3-phosphate by transketolase B, aldolase A, and phosphatase GlpX, converting sedoheptulose-1,7-bisphosphate to sedoheptulose-7-phosphate. Unexpectedly, the doublezwf talABmutant exhibits decreased survival after treatment by diverse classes of antibiotics with little effect on the minimal inhibitory concentration. Simultaneously, we found that killing effect of antimicrobials on thezwf talABmutant could be reversed by the inactivation of eitherpurRordeoBgenes, both responsible for ribose-5-phosphate content in the mutant strain. Enhanced biosynthesis of the cell wall component ADP-heptose from sedoheptulose-7-phosphate also suppressed killing effect of antibiotics on thezwf talABmutant. Furthermore, the inactivation of the Entner-Doudoroff pathway (Δedd) or shifting the metabolic equilibrium by the addition of exogenous phosphogluconate reverts aPPP to glycolysis, preventing the accumulation of excess pentose phosphates and the occurrence of the futile cycle inzwf talABcells, thus desensitizing them to antibiotics. Our findings show that ribose-5-phosphate metabolism plays a crucial role in bacterial tolerance to a wide range of bactericidal antibiotics. We propose that targeting PPP could be a promising strategy for developing new therapeutic agents aimed at potentiating clinically significant antimicrobials.

IMPORTANCE

Recent studies have revealed the crucial role of bacterial cell’s metabolic status in its susceptibility to the lethal action of antibacterial drugs. However, there is still no clear understanding of which key metabolic nodes are optimal targets to improve the effectiveness of bacterial infection treatment. Our study establishes that the disruption of the canonical pentose phosphate pathway induces one-way anabolic synthesis of pentose phosphates (aPPP) inE. colicells, significantly increasing the killing efficiency of various antibiotics. It is also demonstrated that the activation of ribose-5-phosphate utilization processes restores bacterial tolerance to antibiotics. We consider the synthesis of ribose-5-phosphate to be one of the determining factors of bacterial cell stress resistance. Understanding bacterial metabolic pathways, particularly the aPPP’s role in antibiotic sensitivity, offers insights for developing novel adjuvant therapeutic strategies to enhance antibiotic potency.
NiCo Identifies Extrinsic Drivers of Cell State Modulation by Niche Covariation Analysis
Authors: Agrawal Ankit , Thomann Stefan , Basu Sukanya , Grün Dominic
Published: September 2024

Cell states are modulated by intrinsic driving forces such as gene expression noise and extrinsic signals from the tissue microenvironment. The distinction between intrinsic and extrinsic cell state determinants is essential for understanding the regulation of cell fate in tissues during development, homeostasis and disease. The rapidly growing availability of single-cell resolution spatial transcriptomics makes it possible to meet this challenge. However, available computational methods to infer topological tissue domains, spatially variable gene expression, or ligand-receptor interactions are limited in capturing cell state changes driven by crosstalk between individual cell types within the same niche. We present NiCo, a computational framework for integrating single-cell resolution spatial transcriptomics with matched single-cell RNA-sequencing reference data to infer the influence of the spatial niche on the cell state. By applying NiCo to mouse embryogenesis, adult small intestine and liver data, we demonstrate the capacity to predict novel niche interactions that govern cell state variation underlying tissue development and homeostasis. In particular, NiCo predicts a feedback mechanism between Kupffer cells and neighboring stellate cells limiting stellate cell activation in the normal liver. NiCo provides a powerful tool to elucidate tissue architecture and to identify drivers of cellular states in local niches.
Structural basis for sequence context-independent single-stranded DNA cytosine deamination by the bacterial toxin SsdA
Authors: Yin Lulu , Shi Ke , Chen Yanjun , Harris Reuben S. , Aihara Hideki
Published: September 2024

DNA deaminase toxins are involved in interbacterial antagonism and the generation of genetic diversity in surviving bacterial populations. These enzymes have also been adopted as genome engineering tools. The single-stranded (ss)DNA deaminase SsdA represents the bacterial deaminase toxin family-2 (BaDTF2) and it deaminates ssDNA cytosines with little sequence context dependence, which contrasts with the AID/APOBEC family of sequence-selective ssDNA cytosine deaminases.

Here we report the crystal structure of SsdA in complex with a ssDNA substrate. The structure reveals a unique mode of substrate binding, in which a cluster of aromatic residues of SsdA engages ssDNA in a V-shaped conformation sharply bent across the target cytosine. The bases 5’ or 3’ to the target cytosine are stacked linearly and make few sequence-specific protein contacts, thus explaining the broad substrate selectivity of SsdA. Unexpectedly, SsdA contains a β-amino acid isoaspartate, which is important for enzymatic activity and may contribute to the stability of SsdA as a toxin. Structure- function studies helped to design SsdA mutants active in human cells, which could lead to future applications in genome engineering.
Templated trimerization of the phage L decoration protein on capsids
Authors: Woodbury Brianna M. , Newcomer Rebecca L. , Alexandrescu Andrei T. , Teschke Carolyn M.
Published: September 2024

The 134-residue phage L decoration protein (Dec) forms a capsid-stabilizing homotrimer that has an asymmetric tripod-like structure when bound to phage L capsids. The N-termini of the trimer subunits consist of spatially separated globular OB-fold domains that interact with the virions of phage L or the related phage P22. The C-termini of the trimer form a three-stranded intertwined spike structure that accounts for nearly all the interactions that stabilize the trimer. A Dec mutant with the spike residues 99-134 deleted (Dec1-98) was used to demonstrate that the stable globular OB-fold domain folds independently of the C-terminal residues. However, Dec1-98was unable to bind phage P22 virions, indicating the C-terminal spike is essential for stable capsid interaction. The full-length Dec trimer is disassembled into monomers by acidification to pH <2. These monomers retain the folded globular OB-fold domain structure, but the spike is unfolded. Increasing the pH of the Dec monomer solution to pH 6 allowed for slow trimer formationin vitroover the course of days. The infectious cycle of phage L is only around an hour, however, implying Dec trimer assemblyin vivois templated by the phage capsid. The Thermodynamic Hypothesis holds that protein folding is determined by the amino acid sequence. Dec serves as an unusual example of an oligomeric folding step that is kinetically accelerated by a viral capsid template. The capsid templating mechanism could satisfy the flexibility needed for Dec to adapt to the unusual quasi-symmetric binding site on the mature phage L capsid.
SME supply chain resilience in disruptive times: the effects of supply chain robustness, access to government assistance and disruption intensity
Authors: Nakandala Dilupa , Chen Jiahe , Chikweche Tendai
Published: September 2024

Purpose

This study investigates the antecedents of supply chain resilience of small and medium-sized enterprises (SMEs) and the effects of government assistance and disruption intensity in long-term disruptions.

Design/methodology/approach

This study collected data from 626 SMEs in Australia in 2022 and analysed data using partial least squares structural equation modelling.

Findings

The study empirically confirms that digital capabilities, prior experience in disruptions, supplier proximity and relationships are antecedents of supply chain resilience of SMEs, with supply chain robustness as a mediator. It further confirms that SMEs' access to government assistance positively moderates the relationship between digital capabilities and supply chain robustness. The disruption intensity moderates the relationships between supplier proximity and supply chain robustness with supply chain resilience. Severe disruptions weaken the effects of prior disruption experiences and supplier relationships on supply chain resilience.

Practical implications

The findings inform SME practitioners of the importance of building supply chain robustness, leveraging their prior experience, supplier proximity and relationships and capabilities and flexibility for dynamic supply chain structures when disruptions are intense.

Originality/value

The novelty of our study is the use of the Contingent Resource-Based View to understand the effects of firm and supply chain-level antecedents on supply chain robustness and resilience, considering the contextual contingencies of disruption intensity and government assistance. The focus on long-term disruptions extends the conventional supply chain resilience studies on supply and demand disruptions of small scale. We also explore the firm-level effects of government assistance, which extends the commonly tested economic-level effects. Furthermore, we investigate supply chain robustness and resilience as different but connected constructs, deviating from common approaches. The finding that the relationship between digital capabilities and supply chain robustness, not the relationship between digital capabilities and supply chain resilience, becomes stronger with higher access to government support shows the importance of this approach to investigating specific effects.
Digital technologies and food supply chain: a scoping view from 2010 to 2024
Authors: Panigrahi Rashmi Ranjan , Singh Neha , Muduli Kamalakanta
Published: September 2024

Purpose

This paper aims to deepen the understanding of robust food supply chains (FSC) in SMEs by exploring and analyzing the literature through the lenses of digital technologies.

Design/methodology/approach

The study collected data from Scopus spanning from 2010 to 2024, employing selected keywords, and processed it using VOS-viewer and Biblioshiny to derive valid inferences and theoretical arguments.

Findings

The review paper identified several key themes shaping the future of supply chain management – Sustainability in SCM, Industry 4.0, Digitalization with FSCM, Circular Economy, Food Waste with Supply Chain, Food Security and Climate Change. These themes collectively bring transformative opportunities for both the adoption of digital technologies and sustainable practices in food supply chains.

Research limitations/implications

The review found limitations are rooted in financial constraints, institutional barriers and expertise-related challenges encountered within the realm of Digitalization and FSC. Government and corporate houses should focus on these limitations as well as convert them to strengthen the SMEs of FSC.

Originality/value

The study stands out as a pioneering review that not only explores Digitalization in FSC but also explores the link and evidence of SMEs in the unorganized sector, providing unique insights into a previously underexplored area.
Influencing search
Authors: Janssen Maarten C. W. , Williams Cole
Published: September 2024

We show that in search markets an influencer who recommends a product to her followers improves consumer surplus and total welfare despite the firm paying for her recommendation. As consumers learn their value for the product upon search, they will not buy at the recommended firm if they learn their value is low. The threat of search incentivizes firms to offer the influencer a financial contract involving a commission and incentivizes the influencer to be honest in her recommendation. Provided the influencer's search cost is not too high, she also has an incentive to acquire information and give informative recommendations. These informative equilibria are more difficult to sustain if influencers compete with each other.
A phase I drug–drug interaction study to assess the effect of futibatinib on P‐gp and BCRP substrates and of P‐gp inhibition on the pharmacokinetics of futibatinib
Authors: Long Amanda , Yamamiya Ikuo , Valentine Michelle , Machnes Ziv , Hangai Nanae , Anderson Bailey , Wacheck Volker , Gao Ling
Published: September 2024

Futibatinib, an inhibitor of fibroblast growth factor receptor 1–4, is approved for the treatment of patients with advanced cholangiocarcinoma with FGFR2 fusions/rearrangements. In this phase I drug–drug interaction study, the effects of futibatinib on P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) substrates, and of P‐gp inhibition on futibatinib pharmacokinetics (PK) were investigated in healthy adults aged 18–55 years. In part 1, 20 participants received digoxin (P‐gp substrate) and rosuvastatin (BCRP substrate). Following a ≥10‐day washout, futibatinib was administered for 7 days, with digoxin and rosuvastatin coadministered on the third day. In part 2, 24 participants received futibatinib. Following a ≥3‐day washout, quinidine (P‐gp inhibitor) was administered for 4 days, with futibatinib coadministered on day 4. Blood samples were collected predose and for 24 (futibatinib), 72 (rosuvastatin), and 120 h (digoxin) postdose. Urine samples (digoxin) were collected predose and for 120 h postdose. PK parameters were compared between treatments using analysis of variance. Coadministration with futibatinib had no effect on the PK of digoxin and rosuvastatin, and coadministration with quinidine had minimal effects on the PK of futibatinib. Differences in Cmax and AUC with and without futibatinib and quinidine, respectively, were <20%. The most common treatment‐emergent adverse events were diarrhea (80%) and increased blood phosphorous (75%) in part 1 and prolonged electrocardiogram QT interval (38%) in part 2. The data show that futibatinib has no clinically meaningful effects on the PK of P‐gp or BCRP substrates and that the effect of P‐gp inhibition on futibatinib PK is not clinically relevant.
Vonoprazan Dual or Triple Therapy Versus Bismuth‐Quadruple Therapy as First‐Line Therapy for Helicobacter pylori Infection: A Three‐Arm, Randomized Clinical Trial
Authors: Cheung Ka Shing , Lyu Tao , Deng Zijie , Han Shaowei , Ni Li , Wu Juan , Tan Jing Tong , Qin Jian , Ng Ho Yu , Leung Wai K. , Seto Wai‐Kay
Published: September 2024

Background

We compared efficacy of vonoprazan‐dual or triple therapies and bismuth‐quadruple therapy for treatment‐naive Helicobacter pylori (HP) infection in Southern China, where primary resistance rates of clarithromycin and levofloxacin are >30%.

Methods

This was an investigator‐initiated, three‐arm, randomized clinical trial in Southern China. Between March 2022 and August 2023, treatment‐naïve HP‐infected adults were randomly assigned to receive one of three 14‐day regimens (1:1:1 ratio): vonoprazan‐dual (VA‐dual; vonoprazan 20 mg twice daily and amoxicillin 1 g thrice daily), vonoprazan‐triple (VAC‐triple; vonoprazan 20 mg/amoxicillin 1 g/clarithromycin 500 mg twice daily), or bismuth‐quadruple therapy containing bismuth, esomeprazole, tetracycline, and metronidazole. Primary outcome was noninferiority in HP eradication, evaluated by UBT 4–6 weeks post‐treatment by intention‐to‐treat (ITT) and per‐protocol (PP) analysis (based on subjects who completed 14‐day treatment and rechecked UBT). Bonferroni‐adjusted p‐value of <0.017 was used to determine statistical significance.

Results

A total of 298 subjects (mean age: 35.7 ± 8.4 years; male: 134 [45.0%]; VC‐dual: 100, VAC‐triple: 98, bismuth‐quadruple: 100) were enrolled, and 292 (98.0%) had UBT rechecked. ITT analysis showed that both VA‐dual (eradication rate of 96.0%) and VAC‐triple therapies (95.9%) were noninferior to bismuth‐quadruple therapy (92.0%) (difference: 4.0%, 95% CI: −2.9% to 11.5%, p < 0.001; and 3.9%, 95% CI: −3.1% to 11.5%, p < 0.001, respectively). PP analysis also revealed noninferiority (96.7% or 96.7% vs. 97.4%, with difference: −2.9% and −2.9%, p = 0.009 and 0.010, respectively). The frequency of adverse events was 39.0%, 56.1%, and 71.0% in VA‐dual, VAC‐triple, and bismuth‐quadruple therapies, respectively.

Conclusions

VA‐dual and VA‐triple therapies are highly effective and noninferior to bismuth‐quadruple therapy in Southern China. Given the lower adverse effects and fewer antibiotic use, VA‐dual therapy is the preferred first‐line treatment for HP infection.

Trial Registration

Chinese Clinical Trial Registry (No. ChiCTR2200056375). Registered on February 4, 2022, https://www.chictr.org.cn/showproj.aspx?proj=14131.
Circular and return migration of Egyptian migrant workers in Libya
Authors: Elsayeh Mohamed
Published: September 2024

The return of Egyptian migrants to Egypt following the onset of crisis in Libya in 2011 raises important questions about their classification as “returnees.” This article demonstrates the impact of the crisis on Egyptians' livelihoods. Field research conducted in Egypt in 2016 reveals that, at least in part, from 2011 onwards Egyptians were engaged in circular migration to and from Libya as a livelihood strategy because of failed reintegration in Egypt. The Egyptian government, intergovernmental and non‐governmental organisations provided varied levels of protection and assistance in evacuating migrants; however, they lacked awareness about returnees' socio‐economic needs. Egyptians were largely unsupported by state and non‐state institutions upon their return and therefore remained reliant on families and social networks. Initiatives aimed at providing aid to returnees, such as those introduced in Ghana and Niger, were generally absent in the Egyptian context. The absence of support had other unintended consequences, including increased levels of domestic violence and reduced educational opportunities for children in households hosting returnees.
Sedative and behavioral effects of atomized intranasal midazolam in comparison with nebulized midazolam for children undergoing dental treatment: A randomized clinical trial
Authors: Elkhatib Amira Abdelhafeez , Mowafy Yousr Nader , Ghoneim Tamer A. M.
Published: September 2024

Background

Fear and anxiet are significant barriers of dental care in children. Sedation emerged as a valuable behaviour guidance technique to manage uncooperative children.

Aim

To evaluate the sedative and behavioral effectiveness of midazolam administered via nebulizer in comparison with intranasal atomizer in the behavior management of anxious children during dental treatment.

Study Design

Two‐arm randomized clinical trial with 68 children (3–5 years) assigned to receive nebulized midazolam (NEB MDZ) and atomized intranasal midazolam (AIN MDZ) during dental treatment. The onset time, sedation levels, and behavior of children were documented. The data were analyzed using the Wilcoxon signed‐rank test and Mann–Whitney U tests.

Results

Significant differences between the two groups in terms of onset time, sedation level, and behavior of children during the dental treatment. AIN MDZ was associated with a significantly faster onset time compared with NEB MD, (p < .001). Children who received NEB MDZ exhibited deeper levels of sedation compared with AIN MDZ group (p = .02). During the administration of local anesthesia, notable statistical differences were observed between the behavior of the two groups (p = .02).

Conclusions

Midazolam administered via either nebulizer or intranasal atomizer was the effective route of administration and proved effective in the management of anxious children undergoing dental treatment. AIN MDZ, however, exhibited a faster onset time, whereas children receiving NEB MDZ demonstrated superior behavior compared with those receiving AIN MDZ.
Platform‐led or seller‐led? Optimal ex ante information delivery strategy for online retail channels with product match uncertainty
Authors: Wang Chen , Fu Yujia , Yin Zhe
Published: September 2024

A fundamental weakness for online retail channels is that it is impossible for consumers to perfectly ascertain the match between their preferences and the product value before purchasing. In this paper, based on the investment decision of the ex ante product information delivery measure, we study how to solve this problem for a platform‐based supply chain that consists of an online platform and an online seller. According to which firm is responsible for building the product information delivery measure, two possible cases are considered under a game‐theoretic model: the platform‐led case and the seller‐led case. The basic results reveal that compared with the seller‐led product information delivery, the platform‐led case may lead to a higher matching probability for consumers, a higher profit for the whole supply chain, and a win‐win outcome for the platform and the seller. The basic results can still hold when the platform and the seller cooperate under the format of the proportional commission fee, the two firms have different investment efficiencies in the improvement of product information delivery, or consumers have to incur hassle costs to learn the product match probability. When product return is allowed, it is shown that the return policy can play a positive role in making the seller‐led case become a win‐win choice. When the joint investment of product information delivery between the two firms can be formed, the results show that the joint investment may achieve a higher matching probability and higher profits for both the seller and the platform.
Genomic selection strategies for the German Merino sheep breeding programme – A simulation study
Authors: Martin Rebecca , Pook Torsten , Bennewitz Jörn , Schmid Markus
Published: September 2024

Genomic selection is widely implemented in livestock breeding programmes across species. Its potential is also evident for sheep breeding; however, it has several limitations, particularly because of the high genetic diversity across and within sheep breeds. In Germany, the predominant sheep breed is the Merino sheep. Until now, there has been no use of genomic selection in the German Merino sheep breeding programme. In this simulation study, different genomic selection strategies were compared with a reference scenario with a breeding value estimation based on pedigree BLUP. A simplified version of the German Merino sheep breeding programme, including a health and a production trait in the breeding goal, was simulated via the R package Modular Breeding Program Simulator (MoBPS). Real genotype data were used to create a population specific simulation. The reference scenario was compared with several alternative scenarios in which selection was based on single‐step GBLUP (ssGBLUP) breeding value estimation with varying genotyping strategies. In addition to scenarios in which all male and all male plus all female lambs were genotyped, scenarios with a preselection of lambs, that is only a certain proportion (top 25%, top 50%) genotyped, were simulated. The results revealed that genetic gain increased with increasing numbers of available genotypes. However, marginal gains decreased with increasing numbers of genotypes. Compared with the reference scenario, genotyping the top 25% of male lambs increased the genetic gain for the breeding ram population by 13% for both traits whereas genotyping the top 50% of male lambs or all male lambs led to increases of 18% (17%) or 26% (21%) for the health (production) trait, respectively. The potential of genotyping females in addition to male lambs was less evident on the male side with no significant differences between the scenarios with different proportions of genotyped females. The results have shown that genomic selection can be a valuable tool to increase genetic gain in the German Merino sheep population and that the genotyping of a certain proportion of animals might lead to substantial improvement over pedigree‐based breeding value estimation. Nevertheless, further studies, especially economic evaluations, are needed before practical implementation.
Using a Nested Sampling Design Across Spatial Scales to Gain Insights Into Distribution Patterns of Fishes, Mussels and Macroinvertebrates in a Riverine System
Authors: Perez Rocha Mariana , Cottenie Karl , Clein Katherine , Elkins Lindsey , Mangold Rebecca , Nowlin Weston , Perkin Joshuah S. , Wright Kirby , Schwalb Astrid
Published: September 2024

Aim

The goal of our study was to use a nested sampling design to compare the distribution of different groups of organisms with different dispersal modes and examine their responses in community composition to environmental heterogeneity at different spatial scales (local pool vs. riffle habitat, sections within a river and between rivers).

Location

Upper Colorado River basin, Texas, USA.

Taxon

Fishes, mussels and macroinvertebrates.

Methods

We sampled 100 sites using a nested sampling design across five rivers (four tributaries and the mainstem), with four river sections and five sampling sites per section, each consisting of a pool and riffle habitat. Collected data on species abundances, local and landscape environmental variables and spatial variables were analysed using a combination of dissimilarity, redundancy and variation partitioning analysis.

Results

At the river scale, environmental heterogeneity explained 28% and 34% of the variation in mussel and fish communities, respectively, and 15% for macroinvertebrates. Community changes between sections in the tributaries were highest for fishes, but similarly high for fishes and macroinvertebrates in the mainstem. Significant patterns for mussels were only detected in rivers with higher abundances. No significant differences in dissimilarity were found between mesohabitats, but a small significant effect of mesohabitat was detected for mussels with RDA after removing the river effect.

Main Conclusions

Although the depauperate mussel communities made it more difficult to draw any conclusions, there were some indications that their distribution was driven by environmental heterogeneity across scales. Section and river scales were relevant for fish, whereas macroinvertebrates showed a weaker response to environmental heterogeneity at these scales. The combination of approaches detected more ecologically meaningful patterns than one analysis alone would have. This study highlights the complexity of riverine community dynamics and underscores the need for a multiscale approach to identify their distribution patterns.
A Multi‐Modelling Approach for Informing the Conservation of a Cold‐Adapted Terrestrial Amphibian in the Face of Climate Change
Authors: Čengić Mirza , Šunje Emina , Bonato Lucio , Van Damme Raoul , Lenders Rob H. J. , Huijbregts Mark A. J. , Lukić Bilela Lada , Schipper Aafke M.
Published: September 2024

Aim

We aimed to assess potential climate change impacts on the distribution of a cold‐adapted terrestrial amphibian that shows strong intraspecific differentiation.

Location

Alps and Dinarides.

Taxon

Alpine salamander (Salamandra atra).

Methods

We built SDMs for each of two major intraspecific lineages (S. a. atra, which is found throughout the Northern Alps, and S. a. prenjensis, which appears sparsely along the Dinarides) and for the entire species, using occurrence points from a carefully curated database, climate data with 1 km2 spatial resolution and eight modelling techniques. We projected climatically suitable areas to 2070 under two climate scenarios (RCP2.6 and RCP8.5), using 24 general circulation models.

Results

For S. a. atra, under RCP2.6 scenario, we detected a 3% increase in the extent of climatically suitable areas in the Alps (although with low model agreement), yet a 6% decrease under the RCP8.5 scenario. For S. a. prenjensis, we detected a decrease in the extent of climatically suitable areas in the Dinarides between 7% and 45% (RCP2.6 and RCP8.5, respectively). The SDM predictions for the entire species were most in line with those of the S. a. atra model. Although climate variables were not equally strong in predicting the climatic suitability for both lineages, the minimum temperature of the coldest month revealed an important predictor for the entire species, with clear decreases in suitability towards higher temperature.

Main Conclusions

All models reveal a considerable decrease in climate suitability throughout most of the range of S. atra, which is particularly visible in the Dinarides. We highlight the importance of considering intraspecific variation when modelling climate change impacts on geographically differentiated species whose populations vary in their climatic niche. We provide our study results (occurrence data and maps) via a web application that can be useful for guiding conservation efforts.