bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining the mechanism of galectin-3-mediated TGF-β1 activation and its role in lung fibrosis
Authors: Calver Jessica F. , Parmar Nimesh R. , Harris Gemma , Lithgo Ryan M. , Stylianou Panayiota , Zetterberg Fredrik R. , Gooptu Bibek , Mackinnon Alison C. , Slack Robert J. , Carr Stephen B. , Scott David J. , Jenkins R. Gisli , John Alison E. 
Published: October 2023

AbstractIntegrin-mediated activation of the pro-fibrotic mediator transforming growth factor-β1 (TGF-β1), plays a critical role in idiopathic pulmonary fibrosis (IPF) pathogenesis. Galectin-3 is believed to contribute to the pathological wound healing seen in IPF individuals, although its mechanism of action is not precisely defined. We hypothesised that galectin-3 potentiates TGF-β1 activation and/or signaling in the lung to promote fibrogenesis. We show that galectin-3 induces TGF-β1 activation in human lung fibroblasts (HLFs) and specifically that extracellular galectin-3 promotes oleoyl-L-α-lysophosphatidic acid sodium salt (LPA)-induced integrin-mediated TGF-β1 activation. Surface plasmon resonance (SPR) analysis confirmed that galectin-3 binds to the αv integrins, αvβ1, αvβS and αvβ6 and also to the TGFβRII subunit in a glycosylation-dependent manner. This galectin-3 binding is heterogeneous and not a 1:1 binding stoichiometry. These binding interactions were blocked by small molecule inhibitors of galectin-3 which target the carbohydrate recognition domain. Binding of galectin-3 to the β1 integrin was validatedin vitroby co-immunoprecipitation (Co-IP) in HLFs. In addition, proximity ligation assay (PLA) data indicates that galectin-3 and the β1 integrin colocalize closely (40 nm) on the cell surface of HLFs, that colocalization is increased by TGF-β1 treatment and galectin-3 inhibitors prevented this colocalization. In the absence of TGF-β1 stimulation, such colocalization was detectable only in HLFs isolated from IPF patients suggesting that the proteins are inherently more closely associated in the disease state. Taken together, this data suggests that galectin-3 promotes TGF-β1 signaling and may induce fibrogenesis by interacting directly with components of the TGF-β1 signaling cascade.Declaration of InterestsRGJ reports grants or contracts from AstraZeneca, Biogen, Galecto Biotech, GlaxoSmithKline, Nordic Biosciences, RedX, Plaint, consulting fees from Bristol Myers Squibb, Chiesi, Daewoong Veracyre, Resolution Therapeutics and Pliant, honoraria from Boehringer Ingelheim, Chiesi, Roche, PatientMPower, AstraZeneca, advisory roles with Boehringer Ingelheim, Galapagos and Vicore, non-financial support from NuMedii, and is a Trustee for Action for Pulmonary Fibrosis. AEJ reports grant funding from Galecto Biotech. BG reports CASE student project partnership with Galecto Biotech, honoraria from GlaxoSmithKline and Vertex and grants and fellowships from UKRI MRC and BBSRC, Alpha-1 Foundation, BLF/A+LUK, Wellcome Trust. RJS, ACM, FRZ, JFC are Galecto employees with shares/options in the company. NRP is a Roche employee. GH, RML, PS, SBC, DJS declare no competing interests.
Differential activation of mouse and human Panx1 channel variants
Authors: Cibelli Antonio , Dohare Preeti , Spray David C. , Scemes Eliana 
Published: October 2023

AbstractPannexins are ubiquitously expressed in human and mouse tissues. Pannexin 1 (Panx1), the most thoroughly characterized isoform of this family, forms plasmalemmal membrane channels permeable to relatively large molecules, such as ATP. Although human and mouse Panx1 amino acid sequences are conserved in the presently known regulatory sites involved in trafficking and modulation of the channel, differences are reported in the N- and C-termini of the protein, and the mechanisms of channel activation by different stimuli remain controversial. Here we used a neuroblastoma cell line to study the activation properties of endogenous mPanx1 and exogenously expressed hPanx1. Dye uptake and electrophysiological recordings revealed that in contrast to mouse Panx1, the human ortholog is insensitive to stimulation with high extracellular [K+] but responds similarly to activation of the purinergic P2X7 receptor. The two most frequent Panx1 polymorphisms found in the human population, Q5H (rs1138800) and E390D (rs74549886), exogenously expressed in Panx1-null N2a cells revealed that regarding P2X7 receptor mediated Panx1 activation, the Q5H mutant is a gain of function whereas the E390D mutant is a loss of function variant. Collectively, we demonstrate differences in the activation between human and mouse Panx1 orthologs and suggest that these differences may have translational implications for studies where Panx1 has been shown to have significant impact.
Bespoke single cell molecular and tissue-scale analysis reveals mechanisms underpinning development and disease in complex developing cell populations
Authors: Strauss Magdalena E , Ton Mai-Linh Nu , Mason Samantha , Bagri Jaana , Harland Luke TG , Imaz-Rosshandler Ivan , Wilson Nicola K , Nichols Jennifer , Tyser Richard CV , Göttgens Berthold , Marioni John C , Guibentif Carolina 
Published: October 2023

AbstractPerturbation studies using gene knockouts have become a key tool for understanding the roles of regulatory genes in development and disease. Here we systematically characterise the knockout effects of the key developmental regulatorsTandMixl1in chimeric mouse embryos during gastrulation and organogenesis. We present a comprehensive and effective suite of statistical tools for systematic characterisation of effects at the level of differential abundance of cell types, lineage development, and gene dysregulation. Applying our computational approach to a novel chimera data set withMixl1knockout reveals a disruption in Epicardium development in the absence ofMixl1, characterized by lack of upregulation of the key transcription factorTbx18and the Wnt regulatorSfrp5, and by dysregulation of the recently identified juxta-cardiac field. Finally, we demonstrate the wider utility of our framework by applying it to published acute myeloid leukemia (AML) patient data, and show how different responses to therapy are reflected in changes in gene expression along the myeloid trajectory between healthy and AML patients.
Disrupted endosomal trafficking of the Vangl-Celsr polarity complex underlies congenital anomalies in trachea-esophageal morphogenesis
Authors: Edwards Nicole A. , Rankin Scott A. , Kashyap Adhish , Warren Alissa , Agricola Zachary N. , Kenny Alan P. , Kofron Matthew J. , Shen Yufeng , Chung Wendy K. , Zorn Aaron M. 
Published: October 2023

SummaryDisruptions in foregut morphogenesis can result in life-threatening conditions where the trachea and esophagus fail to separate properly, such as esophageal atresia (EA) and tracheoesophageal fistulas (TEF). The developmental basis of these congenital anomalies is poorly understood, but recent genome sequencing reveals thatde novovariants in intracellular trafficking genes are enriched in EA/TEF patients. Here, we confirm that mutation of orthologous genes inXenopusdisrupts trachea-esophageal separation similar to EA/TEF patients. We show that the Rab11a recycling endosome pathway is required to localize Vangl-Celsr polarity complexes at the luminal cell surface where opposite sides of the foregut tube fuse. Partial loss of endosome trafficking or Vangl-Celsr complexes disrupts epithelial polarity and mutant cells accumulate at the fusion point, fail to downregulate Cadherin, and do not separate into distinct trachea and esophagus. These data provide insights into the mechanisms of congenital anomalies and general paradigms of tissue fusion during organogenesis.
Heterozygous expression of aKcnt1gain-of-function variant has differential effects on SST- and PV-expressing cortical GABAergic neurons
Authors: Shore Amy N. , Li Keyong , Safari Mona , Qunies Alshaima’a M. , Spitznagel Brittany D. , Weaver C. David , Emmitte Kyle A. , Frankel Wayne N. , Weston Matthew C. 
Published: October 2023

ABSTRACTMore than twenty recurrent missense gain-of-function (GOF) mutations have been identified in the sodium-activated potassium (KNa) channel geneKCNT1in patients with severe developmental and epileptic encephalopathies (DEEs), most of which are resistant to current therapies. Defining the neuron types most vulnerable to KCNT1 GOF will advance our understanding of disease mechanisms and provide refined targets for precision therapy efforts. Here, we assessed the effects of heterozygous expression of aKcnt1GOF variant (Y777H) on KNacurrents and neuronal physiology among cortical glutamatergic and GABAergic neurons in mice, including those expressing vasoactive intestinal polypeptide (VIP), somatostatin (SST), and parvalbumin (PV), to identify and model the pathogenic mechanisms of autosomal dominantKCNT1GOF variants in DEEs. Although theKcnt1-Y777H variant had no effects on glutamatergic or VIP neuron function, it increased subthreshold KNacurrents in both SST and PV neurons but with opposite effects on neuronal output; SST neurons became hypoexcitable with a higher rheobase current and lower action potential (AP) firing frequency, whereas PV neurons became hyperexcitable with a lower rheobase current and higher AP firing frequency. Further neurophysiological and computational modeling experiments showed that the differential effects of the Y777H variant on SST and PV neurons are not likely due to inherent differences in these neuron types, but to an increased persistent sodium current in PV, but not SST, neurons. The Y777H variant also increased excitatory input onto, and chemical and electrical synaptic connectivity between, SST neurons. Together, these data suggest differential pathogenic mechanisms, both direct and compensatory, contribute to disease phenotypes, and provide a salient example of how a pathogenic ion channel variant can cause opposite functional effects in closely related neuron subtypes due to interactions with other ionic conductances.
Pseudo-linear Summation explains Neural Geometry of Multi-finger Movements in Human Premotor Cortex
Authors: Shah Nishal P. , Avansino Donald , Kamdar Foram , Nicolas Claire , Kapitonava Anastasia , Vargas-Irwin Carlos , Hochberg Leigh , Pandarinath Chethan , Shenoy Krishna , Willett Francis R , Henderson Jaimie 
Published: October 2023

AbstractHow does the motor cortex combine simple movements (such as single finger flexion/extension) into complex movements (such hand gestures or playing piano)? Motor cortical activity was recorded using intracortical multi-electrode arrays in two people with tetraplegia as they attempted single, pairwise and higher order finger movements. Neural activity for simultaneous movements was largely aligned with linear summation of corresponding single finger movement activities, with two violations. First, the neural activity was normalized, preventing a large magnitude with an increasing number of moving fingers. Second, the neural tuning direction of weakly represented fingers (e.g. middle) changed significantly as a result of the movement of other fingers. These deviations from linearity resulted in non-linear methods outperforming linear methods for neural decoding. Overall, simultaneous finger movements are thus represented by the combination of individual finger movements by pseudo-linear summation.
Microbiome-based risk prediction in incident heart failure: a community challenge
Authors: Erawijantari Pande Putu , Kartal Ece , Liñares-Blanco José , Laajala Teemu D. , Feldman Lily Elizabeth ,   The FINRISK Microbiome DREAM Challenge and ML4Microbiome Communities, Carmona-Saez Pedro , Shigdel Rajesh , Claesson Marcus Joakim , Bertelsen Randi Jacobsen , Gomez-Cabrero David , Minot Samuel , Albrecht Jacob , Chung Verena , Inouye Michael , Jousilahti Pekka , Schultz Jobst-Hendrik , Friederich Hans-Christoph , Knight Rob , Salomaa Veikko , Niiranen Teemu , Havulinna Aki S. , Saez-Rodriguez Julio , Levinson Rebecca T. , Lahti Leo 
Published: October 2023

AbstractHeart failure (HF) is a major public health problem. Early identification of at-risk individuals could allow for interventions that reduce morbidity or mortality. The community-based FINRISK Microbiome DREAM challenge (synapse.org/finrisk) evaluated the use of machine learning approaches on shotgun metagenomics data obtained from fecal samples to predict incident HF risk over 15 years in a population cohort of 7231 Finnish adults (FINRISK 2002, n=559 incident HF cases). Challenge participants used synthetic data for model training and testing. Final models submitted by seven teams were evaluated in the real data. The two highest-scoring models were both based on Cox regression but used different feature selection approaches. We aggregated their predictions to create an ensemble model. Additionally, we refined the models after the DREAM challenge by eliminating phylum information. Models were also evaluated at intermediate timepoints and they predicted 10-year incident HF more accurately than models for 5- or 15-year incidence. We found that bacterial species, especially those linked to inflammation, are predictive of incident HF. This highlights the role of the gut microbiome as a potential driver of inflammation in HF pathophysiology. Our results provide insights into potential modeling strategies of microbiome data in prospective cohort studies. Overall, this study provides evidence that incorporating microbiome information into incident risk models can provide important biological insights into the pathogenesis of HF.
Effects of childhood and adult height on later life cardiovascular disease risk estimated through Mendelian randomization
Authors: Richardson Tom G , Urquijo Helena , Howe Laurence J , Hawkes Gareth , Frayling Timothy M , Davey Smith George 
Published: October 2023

AbstractBackgroundTaller individuals are at elevated and protected risk of various cardiovascular disease endpoints. Whether this is due to a direct consequence of their height during childhood, a long-term effect of remaining tall throughout the lifecourse, or confounding by other factors, is unknown.MethodsWe sought to address this by harnessing human genetic data to separate the independent effects of childhood and adulthood height using an approach known as lifecourse Mendelian randomization (MR). We analysed 5 cardiovascular disease endpoints (coronary artery disease (CAD), stroke, peripheral arterial disease (PAD), atrial fibrillation (AF) and thoracic aortic aneurysm (TAA)) using findings from large-scale genome-wide consortia (n=184,305 to 1,030,836).ResultsProtective effects of taller childhood height on risk of later life CAD (OR=0.78 per change in height category, 95% CI=0.70 to 0.86, P=4×10−10) and stroke (OR=0.93, 95% CI=0.86 to 1.00, P=0.03) were found using a univariable model, although evidence of these effects attenuated in a multivariable setting upon accounting for adulthood height. In contrast, direct effects of taller childhood height on increased risk of later life AF (OR=1.61, 95% CI=1.42 to 1.79, P=5×10−7) and TAA (OR=1.55, 95% CI=1.16 to 1.95, P=0.03) were found even after accounting for adulthood height in the multivariable model.ConclusionsThe protective effect of childhood height on risk of CAD and stroke is largely attributed to the causal pathway involving adulthood height, w hich may therefore be explained by taller children typically becoming taller individuals in later life. Conversely, the independent effect of childhood height on increased risk of AF and TAA may point towards developmental mechanisms in early life which confer a lifelong risk on these disease outcomes.
BASIS: BioAnalysis SEDFIT Integrated Software for cGMP Analysis of SV-AUC Data
Authors: Yarawsky Alexander E. , Gough Erik S. , Zai-Rose Valeria , Figueroa Natalya , Cunningham Hazel M. , Burgner John W. , DeLion Michael T. , Paul Lake N. 
Published: October 2023

AbstractSedimentation velocity analytical ultracentrifugation (SV-AUC) has long been an important method for characterization of antibody therapeutics. Recently, SV-AUC has experienced a wave of new interest and usage from the gene and cell therapy industry, where SV-AUC has proven itself to be the “gold-standard” analytical approach for determining capsid loading ratios for adeno-associate virus (AAV) and other viral vectors. While other more common approaches have existed in the realm of cGMP-compliant techniques for years, SV-AUC has long been used strictly for characterization, but not for release testing. This manuscript describes the challenges faced in bringing SV-AUC to a cGMP environment and describes a new program, “BASIS”, which allows for 21 CFR Part 11-compliant data handling and data analysis using the well-known and frequently cited SEDFIT analysis software.
Effects of voltage on microstructure and properties of micro-arc oxidation ceramic coatings on AZ31B magnesium alloy under constant current–constant voltage operation mode
Authors: Shu Y.F. , Jiang B. , Wang C. , Song R.G. 
Published: October 2023

Purpose
The purpose of this paper is to study the effects of voltage on microstructure and properties of micro-arc oxidation (MAO) ceramic coatings formed on AZ31B magnesium alloy under the constant current–constant voltage operation mode.

Design/methodology/approach
The wear and corrosion resistance of MAO coating on AZ31B magnesium alloy was studied by MAO in silicate electrolyte under constant current and constant voltage.

Findings
When the voltage is 360 V, the wear and corrosion resistance of AZ31B magnesium alloy is the best.

Originality/value
The wear and corrosion resistance of MAO coating on AZ31B magnesium alloy was studied by friction wear and electrochemical workstation.
An overview of legal and policy barriers to opioid analgesics access and opioid agonist therapy in Morocco
Authors: Tinasti Khalid , Outaleb Lahcen 
Published: October 2023

Purpose
Through its 1922 Act on poisonous substances and more recent national normative guidance, Morocco attempts to address high prevalence of HIV among people who inject illegal opioids, and to lift legal and policy barriers to the availability of opioid-based essential controlled medicines. This paper aims to map the Moroccan opioid regulation environment, with a focus on responses to the legal and illegal markets.

Design/methodology/approach
The policy paper focuses on legal provisions for the control of opioids for pain relief and methadone for substitution therapies. It reviews existing reported data from official national, regional and international sources, studies and grey literature. It allows, by presenting the current state of affairs, to measure the limited pace of policy changes.

Findings
The authors provide a clear mapping of the laws and regulations restricting access to opioids in Morocco; the health impacts on populations; and an overall overview of institutional barriers to policy change despite more efforts such as the introduction of opioid agonist therapies.

Research limitations/implications
Due to limited available data and sources, the policy paper exploits the maximum of existing evidence from national and international sources to provide an overall review of opioid control policies in Morocco.

Originality/value
To the best of the authors’ knowledge, this policy paper is among the first to explore the legal environment of opioid use and control in Morocco, to highlight policy reforms, and to analyse the barriers to access to opioids.
Landing on Tata runway for a rapid takeoff: Air India beyond 2021
Authors: P. Rameshan 
Published: October 2023

Learning outcomes
The case study highlights two strategic angles – that of the business unit (business strategy, profitability, market leadership. organizational culture, operational turnaround, industry structure and competitive dynamics) and the owner (returns, repositioning strategy and funding plan). By the end of this case study, students would be able to understand the changing competitive forces of a dynamic industry; analyse the circumstances leading to a change in the control of a firm from the state to the private sector; understand the logic of acquiring a perennially loss-making firm operating in a volatile environment without a unique strategy; identify a firm’s strategic and operational choices for financial turnaround, return to profitability and regaining market leadership; and learn about the actual strategic realities and choices confronting a troubled business organization in a difficult industry.

Case overview/synopsis
When the Tata Group took over Air India on 27 January 2022 from the state that had ownership for 68 years, Air India was under a long spell of poor performance, bleeding losses and unmanageable levels of debt. Unsatisfactory customer service, management issues and competition were the key reasons. Therefore, a crucial question facing the group’s Chairman N. Chandrasekaran was what workable strategy he could use to reposition Air India and make it profitable again so as to recover the $7.5bn of estimated investment involved in the acquisition and turnaround.

Complexity academic level
This case study is intended for undergraduate and graduate executive education levels in business administration and management and allied subjects, particularly for courses in strategic management, marketing, financial management, turnaround and transformation, mergers and acquisitions and organizational change.

Supplementary materials
Teaching notes are available for educators only.

Subject code
CSS 11: Strategy.
Can an arms race promote stability? The inter-Korean qualitative arms race and US extended deterrence
Authors: Rim Hyun Ji 
Published: October 2023

Purpose
This paper aims to provide a case study of complex conflict management within the arms race on the Korean Peninsula. Exploring the complex nexus of nuclear weapons, asymmetry and a qualitative arms race, the study explains how the arms race between Seoul and Pyongyang has promoted stability on the Korean Peninsula.

Design/methodology/approach
Presenting the limits of arguments that the US security guarantee is the factor that saved the two Koreas from going to war again, this paper explores the utility of the inter-Korean arms race as a stabilizer that promotes indirect negotiations. While presenting Korean anomalies, this paper analyzes the three stages of the inter-Korean arms race – especially its nuclear weapons, its asymmetry and the nature of arms races – and provides extant explanations on the causes and consequences of the qualitative arms race. These key elements drive the states’ strategic motives.

Findings
Using the case of the inter-Korean qualitative arms race and US extended nuclear deterrence on the Korean Peninsula, the study shows the complexities of conflict management today. This paper identifies three contributing factors – US nuclear weapons, asymmetry and the qualitative characteristic of the arms race – to explain the enduring stability on the peninsula despite the arms race’s intensification. The paper finds that although US nuclear-extended deterrence plays a critical role, it does not capture the full context of the ongoing, dynamic inter-Korean arms race; a prolonged arms race between the two Koreas has become a new regularity; the qualitative characteristic of the inter-Korean arms race, which is driven by technological advancement, contributes to stability in the arms race; and as the constant mismatch in priority technologies becomes more severe, the changes to the existing asymmetry could increase instability.

Originality/value
This paper offers a diverse perspective to the literature on conflict management and captures the complexities of 21st-century conflict management. Through a thorough examination of the inter-Korean arms race, it brings readers’ attention to the nested dynamics within the arms race and shows how an intensifying arms race can promote stability. Furthermore, the paper explains the implications for potential instability – fueled by the comprehensive mix of a dynamic qualitative arms race and the US extended nuclear deterrence – in the Indo-Pacific region.