bluuebunny/crossref_metadata_2025_split huggingface dataset:
Somatic mutation of Afadin leads to anchorage independent survival and metastatic growth of breast cancer through αE-catenin dependent destabilization of the adherens junction
Authors: Ratze Max A.K. , Enserink Lotte N.F.L. , Ishiyama Noboru , Veltman Christina H.J. , Nijman Isaac J. , Bernards Rene , van Diest Paul J. , Christgen Matthias , Derksen Patrick W.B. 
Published: July 2023

ABSTRACTLoss of E-cadherin (CDH1) and the adherens junction (AJ) drive development and progression of invasive lobular breast cancer (ILC). However, approximately 40% retain wild typeCDH1alleles, indicating that modulation of other genes attenuates the AJ during ILC etiology. To identify alternative drivers, we performed targeted sequencing inCDH1wild type samples, based on a defined set of 100 AJ, tight junction, and desmosome genes we designated as the ‘Adhesome’. In 146 ILC samples, we identified 62 cases (43%) with wild typeCDH1alleles in which we detected a total of 284 mutations in 36 Adhesome genes. After selection based on occurrence and potential loss of function, we identified an inactivating frameshift mutation in Afadin (AFDN; p.Lys630fs).Functional studies in E-cadherin-expressing breast cancer cells showed that Afadin knockout leads to immature AJs, and a non-cohesive phenotype accompanied by actomyosin dependent anoikis resistance, which are classical ILC hallmarks. Afadin reconstitutions show that F-actin organization critically depends on the ⍰E-catenin binding CC domain. Afadin loss in intraductal xenograft mouse breast cancer models leads to ILC-type morphologies and overt lung metastases.AFDNtruncate reconstitutions revealed that deletion of the C-terminal ⍰E-catenin binding CC domain is sufficient to drive metastatic ILC. In conclusion, we identified and functionally coupled a somatic frameshiftAFDNmutation in breast cancer to destabilization the epithelial AJ and the development of ILC hallmarks such as actomyosin-dependent anoikis resistance and single cell invasion. As such, Afadin represents a candidate tumor suppressor for E-cadherin-positive ILC development and progression.
Basal MET Phosphorylation is an Indicator of Hepatocyte Dysregulation in Liver Disease
Authors: Burbano de Lara Sebastian , Kemmer Svenja , Biermayer Ina , Feiler Svenja , Vlasov Artyom , D’Alessandro Lorenza A. , Helm Barbara , Dieter Yannik , Ghallab Ahmed , Hengstler Jan G. , Hoffmann Katrin , Schilling Marcel , Timmer Jens , Klingmüller Ursula 
Published: July 2023

AbstractChronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, Non-alcoholic fatty liver disease (NAFLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in NAFLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) a strong downregulation of the PI3K-AKT pathway and an upregulation of the MAPK pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.
Ubiquitin-derived artificial binding proteins targeting oncofetal fibronectin reveal scaffold plasticity by β-strand slippage
Authors: Katzschmann Anja , Haupts Ulrich , Reimann Anja , Settele Florian , Gloser-Bräunig Manja , Fiedler Erik , Parthier Christoph 
Published: July 2023

AbstractAffilin proteins (artificial binding proteins based on the ubiquitin scaffold) were generated using directed protein evolution to yieldde-novovariants that bind the extra-domain B (EDB) of oncofetal fibronectin, an abundant tumor marker in fetal and neoplastic tissues. Structures of two EDB-specific Affilin molecules reveal striking structural plasticity of the ubiquitin scaffold, characterized by β-strand slippage, leading to diverse register shifts of the β5 strands. This recruits residues from β5 to a loop region, enhancing the target-binding interface. The observed β-strand rearrangements, manifested by pressure of selection for target binding, challenge the accepted paradigm that directed evolution of binding proteins should base on rigid frameworks. Fold plasticity allowing β-strand slippages enhances the evolutionary potential of proteins beyond “simple” mutations significantly and provides a general mechanism to generate residue insertions/deletions in proteins. They are however difficult to predict, underlining the need for caution in interpretation of structure-activity relationships of evolved proteins.
Robust prediction of patient outcomes with immune checkpoint blockade therapy for cancer using common clinical, pathologic, and genomic features
Authors: Chang Tia-Gen , Cao Yingying , Sfreddo Hannah J. , Dhruba Saugato Rahman , Lee Se-Hoon , Valero Cristina , Yoo Seong-Keun , Chowell Diego , Morris Luc G. T. , Ruppin Eytan 
Published: July 2023

AbstractDespite the revolutionary impact of immune checkpoint blockade (ICB) in cancer treatment, accurately predicting patients’ responses remains elusive. We analyzed eight cohorts of 2881 ICB-treated patients across 18 solid tumor types, the largest dataset to date, examining diverse clinical, pathologic, and genomic features. We developed the LOgistic Regression-based Immunotherapy-response Score (LORIS) using a transparent, compact 6-feature logistic regression model. LORIS outperforms previous signatures in ICB response prediction and can identify responsive patients, even those with low tumor mutational burden or tumor PD-L1 expression. Importantly, LORIS consistently predicts both objective responses and short-term and long-term survival across most cancer types. Moreover, LORIS showcases a near-monotonic relationship with ICB response probability and patient survival, enabling more precise patient stratification across the board. As our method is accurate, interpretable, and only utilizes a few readily measurable features, we anticipate it will help improve clinical decision-making practices in precision medicine to maximize patient benefit.
Disregarding multimappers leads to biases in the functional assessment of NGS data
Authors: Almeida da Paz Michelle , Warger Sarah , Taher Leila 
Published: July 2023

ABSTRACTStandard ChIP-seq and RNA-seq processing pipelines typically disregard sequencing reads whose origin is ambiguous (“multimappers”). This usual practice has potentially important consequences for the functional interpretation of the data: genomic elements belonging to clusters composed of highly similar members are left unexplored. In particular, disregarding multimappers leads to the systematic underrepresentation in epigenetic studies of recently active transposons, such as AluYa5 and L1HS. Furthermore, this common strategy also has implications for transcriptomic analysis: members of repetitive gene families, such the ones including major histocompatibility complex (MHC) class I and II genes, are systematically underquantified. Based on these findings, we strongly advocate for the implementation of multimapper-aware bioinformatic genomic analyses.
Witnessed trauma exposure induces fear in mice through a reduction in endogenous neurosteroid synthesis
Authors: Evans-Strong Aidan , Walton Najah , Roper Abby , Donaldson S. Tiffany , Lewis Mike , Maguire Jamie 
Published: July 2023

AbstractNeurosteroids have been implicated in the pathophysiology of post-traumatic stress disorder (PTSD). Allopregnanolone is reduced in subsets of individuals with PTSD and has been explored as a novel treatment strategy. Both direct trauma exposure and witnessed trauma are risk factors for PTSD; however, the role of neurosteroids in the behavioral outcomes of these unique experiences has not been explored. Here we investigate whether observational fear is associated with a reduced capacity for endogenous neurosteroidogenesis and the relationship with behavioral outcomes. We demonstrate that both mice directly subjected to the threat (foot shocks) and those witnessing the threat have decreased plasma levels of allopregnanolone. The expression of a key enzyme involved in endogenous neurosteroid synthesis, 5α-reductase type 2, is decreased in the basolateral amygdala (BLA), which is a major emotional processing hub implicated in PTSD. We demonstrate that knockdown of 5α-reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas treatment with an exogenous, synthetic neuroactive steroid GABAAreceptor PAM with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound]) decreases the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5α-reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma.
Divergence in theSaccharomycesspecies’ heat shock response is indicative of their thermal tolerance
Authors: Fay Justin C. , Alonso-del-Real Javier , Miller James H. , Querol Amparo 
Published: July 2023

AbstractTheSaccharomycesspecies have diverged in their thermal growth profile. BothS. cerevisiaeandS. paradoxusgrow at temperatures well above the maximum growth temperature ofS. kudriavzeviiandS. uvarum, but grow more poorly at lower temperatures. In response to thermal shifts, organisms activate a stress response that includes heat shock proteins involved in protein homeostasis and acquisition of thermal tolerance. To determine whetherSaccharomycesspecies have diverged in their response to temperature we measured changes in gene expression in response to a 12°C increase or decrease in temperature for fourSaccharomycesspecies and their six pairwise hybrids. To ensure coverage of subtelomeric gene families we sequenced, assembled and annotated a completeS. uvarumgenome. All the strains exhibited a stronger response to heat than cold treatment. In response to heat, the cryophilic species showed a stronger response than the thermophilic species. The hybrids showed a mixture of parental stress responses depending on the time point. After the initial response, hybrids with a thermophilic parent were more similar toS. cerevisiaeandS. paradoxus, and theS. cerevisiaexS. paradoxushybrid showed the weakest heat shock response. Within the hybrids a small subset of temperature responsive genes showed species specific responses but most were also hybrid specific. Our results show that divergence in the heat shock response is indicative of a strain’s thermal tolerance, suggesting that cellular factors that signal heat stress or resolve heat induced changes are relevant to thermal divergence in theSaccharomycesspecies.
A cerebellar population coding model for sensorimotor learning
Authors: Wang Tianhe , Ivry Richard B. 
Published: July 2023

AbstractThe cerebellum is crucial for sensorimotor adaptation, using error information to keep the sensorimotor system well-calibrated. Here we introduce a population-coding model to explain how cerebellar-dependent learning is modulated by contextual variation. The model consists of a two-layer network, designed to capture activity in both the cerebellar cortex and deep cerebellar nuclei. A core feature of the model is that within each layer, the processing units are tuned to both movement direction and the direction of movement error. The model captures a large range of contextual effects including interference from prior learning and the influence of error uncertainty and volatility. While these effects have traditionally been taken to indicate meta learning or context-dependent memory within the adaptation system, our results show that they are emergent properties that arise from the population dynamics within the cerebellum. Our results provide a novel framework to understand how the nervous system responds to variable environments.
An Engineered Human-Antibody Fragment with Fentanyl Pan-Specificity that Reverses Carfentanil-Induced Respiratory Depression
Authors: Eubanks Lisa M. , Pholcharee Tossapol , Oyen David , Natori Yoshihiro , Zhou Bin , Wilson Ian A. , Janda Kim D. 
Published: July 2023

ABSTRACTThe opioid overdose crisis primarily driven by potent synthetic opioids resulted in more than 500,000 deaths in the US over the last 20 years. Though naloxone, a short acting medication, remains the primary treatment option for temporarily reversing opioid overdose effects, alternative countermeasures are needed. Monoclonal antibodies present a versatile therapeutic opportunity that can be tailored for synthetic opioids and that can help prevent post-treatment renarcotization. The ultrapotent analog carfentanil, is especially concerning due to its unique pharmacological properties. With this in mind, we generated a fully human antibody through a drug-specific B cell sorting strategy with a combination of carfentanil and fentanyl probes. The resulting pan-specific antibody was further optimized through scFv phage display. This antibody, C10-S66K, displays high affinity to carfentanil, fentanyl, and other analogs, and reversed carfentanil-induced respiratory depression. Additionally, x-ray crystal structures with carfentanil and fentanyl bound provided structural insight into key drug:antibody interactions.
CaaX-motif adjacent residues control G protein prenylation under suboptimal conditions
Authors: Tennakoon Mithila , Thotamune Waruna , Payton John L. , Karunarathne Ajith 
Published: July 2023

AbstractPrenylation is a universal and irreversible post-translational modification that supports membrane interactions of proteins involved in various cellular processes, including migration, proliferation, and survival. Thus, dysregulation of prenylation contributes to multiple disorders, including cancers, vascular diseases, and neurodegenerative diseases. During prenylation, prenyltransferase enzymes tether metabolically produced isoprenoid lipids to proteins via a thioether linkage. Pharmacological inhibition of the lipid synthesis pathway by statins has long been a therapeutic approach to control hyperlipidemia. Building on our previous finding that statins inhibit membrane association of G protein γ (Gγ) in a subtype-dependent manner, we investigated the molecular reasoning for this differential. We examined the prenylation efficacy of carboxy terminus (Ct) mutated Gγ in cells exposed to Fluvastatin and prenyl transferase inhibitors and monitored the subcellular localization of fluorescently tagged Gγ subunits and their mutants using live-cell confocal imaging. Reversible optogenetic unmasking-masking of Ct residues was used to probe their contribution to the prenylation process and membrane interactions of the prenylated proteins. Our findings suggest that specific Ct residues regulate membrane interactions of the Gγ polypeptide statin sensitivity, and prenylation efficacy. Our results also show that a few hydrophobic and charged residues at the Ct are crucial determinants of a protein’s prenylation ability, especially under suboptimal conditions. Given the cell and tissue-specific expression of different Gγ subtypes, our findings explain how and why statins differentially perturb heterotrimeric G protein signaling in specific cells and tissues. Our results may provide molecular reasoning for repurposing statins as Ras oncogene inhibitors and the failure of using prenyltransferase inhibitors in cancer treatment.
Exogenous corticosterone administration during pregnancy alters placental and fetal thyroid hormone availability in females
Authors: Paul Emmanuel N. , Shubitidze Salome , Rahim Rodaba , Rucker Imani , Valin Liana , Apostle Stefanos , Andrew Pospisilik J. , Racicot Karen E. , Smithb Arianna L. 
Published: July 2023

AbstractIntroductionMaternal prenatal stress is associated with adverse pregnancy outcomes and predisposition to long-term adverse health outcomes in children. While the molecular mechanisms that govern these associations has not been fully teased apart, stress-induced changes in placental function can drive sex-specific phenotypes in offspring. We sought to identify and examine molecular pathways in the placenta that are altered in response to maternal prenatal stress.MethodsUsing a mouse model of maternal prenatal stress, we conducted RNA-seq analysis of whole placenta at E18.5. We used qRT-PCR to validate gene expression changes in the placenta and in a trophoblast cell line. ELISAs were used to measure the abundance of thyroid hormones in maternal and fetal serum and in the placenta.ResultsDio2was amongst the top differentially expressed genes in response to elevated maternal stress hormone.Dio2expression was more downregulated in female placenta from stressed dams than both female control and male placenta. Consistent with Dio2’s role in production of bioactive thyroid hormone (T3), we found that there was a reduction of T3 in placenta and serum of female embryos from stressed dams at E18.5. Both T3 and T4 were reduced in the fetal compartment of the female placenta from stressed dams at E16.5. Stress hormone induced reduction in thyroid hormone in females was independent of circulating levels of TH in the dams.DiscussionThe placental thyroid hormone synthesis pathway may be a target of maternal stress and modulate fetal programming of health and disease of offspring in a sex-specific fashion.
A call to action: a stakeholder analysis of green logistics practices
Authors: Prataviera Lorenzo Bruno , Creazza Alessandro , Perotti Sara 
Published: July 2023

PurposeThere is a growing body of literature discussing the green logistics practices (GLPs) that companies could introduce to reduce the logistics environmental impact. Current approaches also identify several influencing factors within firms that could serve as barriers to, or enablers of, GLPs. However, less is known about the role of extra-firm stakeholders, even though these are crucial to operationalizing green logistics effectively. This study merges current theoretical understanding with empirical evidence to provide a detailed stakeholder analysis of GLPs.Design/methodology/approachUsing stakeholder theory as a theoretical lens, the authors aimed at offering a mid-range contribution by conducting multiple embedded case studies examining Italian logistics service providers and shippers. GLPs and the related influencing factors were examined as sub-units of analysis within broader companies' environmental sustainability strategies.FindingsThe authors identified cascading effects among factors influencing the adoption of GLPs (e.g. key economic factors are affected by external factors which also influence organizational and collaboration factors). These effects are moderated by interdependencies between primary and secondary stakeholders, and the study highlights the prominent involvement of secondary stakeholders, such as final consumers.Originality/valueThis paper contributes to better understanding how and why companies adopt GLPs, emphasizing the wide set of stakeholders involved and illustrating how different stakeholders impact on GLPs adoption by affecting a set of influencing factors. By combining insights from the available literature with contemporary empirical data, the authors emphasize how Logistics Service Providers (LSPs) and shippers can no longer address the adoption of GLPs as “focal companies”, but only as part of a “focal network of interconnected stakeholders”, all of them influencing GLPs adoption.
Just asking questions: can a far-right president turn agentic knowledge construction into political manipulation?
Authors: Russo Renato , Blikstein Paulo 
Published: July 2023

PurposeThere are several connections between education and disinformation, including the association between years of schooling and vulnerability to unfounded hypothesizing. The purpose of this paper is to inquire into a competing explanation: political leaders might be exploring powerful teaching and learning strategies to disseminate agendas based on baseless assumptions, exploiting human’s tendency to generate robust theories even with incomplete or incorrect information.Design/methodology/approachThe authors analyzed ten videos published online by a highly partisan YouTube channel. The footage contained informal encounters between former Brazilian President Jair Bolsonaro and supporters in front of his official residence. The team sought to answer two research questions: Do Mr Bolsonaro’s discursive moves include activators that lead the audience to understand that they are theorizing and reaching conclusions “on their own?” Does Mr Bolsonaro’s audience follow those clues and mention politically motivated hoaxes and conspiracy theories in their comments? This paper draws on perspectives from the field of educational research to investigate the mechanisms used by the president to shape public opinion.FindingsThe authors found evidence of the employment of elements akin to classroom discourse in the dialogues led by Mr Bolsonaro. Specifically, different types of rhetorical questions are present to a substantial extent in the data subset analyzed for this paper.Originality/valueThis work offers an alternative perspective to analyzing disinformation. By drawing from established literature from education research, this paper departs from facile explanations that take for granted the lack of intelligence of the audience. Conversely, it argues that popular, if not powerful, teaching and learning strategies might play an undesired role by shaping individuals’ cognitive processes to create robust, internally consistent theories about the world using flawed assumptions and incorrect “building blocks.”
Leading for employees' enterprise system ambidextrous use through contextual ambidexterity: the mediating role of user empowerment and moderating role of leader–member exchange
Authors: Tang Xiaofan , Wei Shaobo 
Published: July 2023

PurposeThis study aims to develop a cross-level research model to explore the relationship between team-level contextual ambidexterity and employees' enterprise system (ES) ambidextrous use, and the mediating role of user empowerment in and moderating effect of leader–member exchange (LMX) on the relationship.Design/methodology/approachThis study conducted a sequential mixed-methods approach, which included a quantitative survey and a qualitative case study. The survey, administered to 244 employees in 59 groups from a financial institution, analyzed the relationships between contextual ambidexterity and ES ambidextrous use. Furthermore, the cross-level mediation and moderation effects were explored. The case study, involving nine members in three groups from a manufacturing firm, served to reinforce the validity of the survey results.FindingsTeam-level contextual ambidexterity can affect ES ambidextrous use directly or through the partial mediator of user empowerment. Furthermore, this study highlights the moderating role of LMX in the relationship between contextual ambidexterity and user empowerment, thereby improving ES ambidextrous use.Originality/valueThis study contributes to the literature by uncovering the cross-level effect of contextual ambidexterity on ES ambidextrous use through user empowerment, thereby extending the ambidexterity perspective and self-determination theory to the ES context. Additionally, this study provides nuanced insights into how to enhance ES ambidextrous use by revealing the moderating role and moderated mediation effect of LMX anchoring on social exchange theory.