bluuebunny/crossref_metadata_2025_split huggingface dataset:
Super-Resolution Imaging Uncovers Nanoscale Tau Aggregate Hyperphosphorylation Patterns in Human Alzheimer’s Disease Brain Tissue
Authors: Santiago-Ruiz Adriana N. , Hugelier Siewert , Bond Charles R. , Lee Edward B. , Lakadamyali Melike 
Published: April 2024

AbstractTau aggregation plays a critical role in Alzheimer’s Disease (AD), where tau neurofibrillary tangles (NFTs) are a key pathological hallmark. While much attention has been given to NFTs, emerging evidence underscores nano-sized pre-NFT tau aggregates as potentially toxic entities in AD. By leveraging DNA-PAINT super-resolution microscopy, we visualized and quantified nanoscale tau aggregates (nano-aggregates) in human postmortem brain tissues from intermediate and advanced AD, and Primary Age-Related Tauopathy (PART). Nano-aggregates were predominant across cases, with AD exhibiting a higher burden compared to PART. Hyperphosphorylated tau residues (p-T231, p-T181, and p-S202/T205) were present within nano-aggregates across all AD Braak stages and PART. Moreover, nano-aggregates displayed morphological differences between PART and AD, and exhibited distinct hyperphosphorylation patterns in advanced AD. These findings suggest that changes in nano-aggregate morphology and hyperphosphorylation patterns may exacerbate tau aggregation and AD progression. The ability to detect and profile nanoscale tau aggregates in human brain tissue opens new avenues for studying the molecular underpinnings of tauopathies.
LEDGF interacts with the NID of MeCP2 and modulates MeCP2 condensates
Authors: Lesire Saskia , Lata Rodrigo , Hoogvliets Yannick , Herrebosch Kune , Van De Velde Paulien , Speleers Anouk , Christ Frauke , Van Belle Siska , Debyser Zeger 
Published: April 2024

AbstractMethyl-CpG-binding protein 2 (MeCP2) is a ubiquitously expressed nuclear protein that is involved in transcriptional regulation and chromatin remodeling. MeCP2 exists in two isoforms, MeCP2 E1 and MeCP2 E2, which share the same functional domains. Loss-of-function mutations in the MeCP2 gene are the main cause of Rett syndrome (RTT). Previous studies identified a direct interaction between MeCP2 and Lens Epithelium-derived Growth Factor (LEDGF), a transcriptional regulator that also exists in two isoforms, LEDGF/p75 and LEDGF/p52. Here, we further characterized the molecular and functional interaction between MeCP2 and LEDGF. The NID domain in MeCP2 is crucial for the binding to the PWWP-CR1 region of LEDGF. Introduction of R306C, a known RTT mutation in the NID of MeCP2, reduced the interaction with LEDGF. Our data reveal mutual inhibition of MeCP2 and LEDGF multimerization due to overlapping binding sites. In line with this observation, LEDGF depletion resulted in enlarged MeCP2 and heterochromatin condensates in NIH3T3 cells. Unraveling the molecular interaction and functional impact of the MeCP2-LEDGF interaction will increase our understanding of RTT pathogenesis.
Measuring PETase enzyme kinetics by single-molecule microscopy
Authors: Zhang Yuwei , Hancock William O. 
Published: April 2024

AbstractPolyethylene terephthalate (PET) is one of the most widely produced man-made polymers and is a significant contributor to microplastics pollution. The environmental and human health impacts of microplastics pollution have motivated a concerted effort to develop microbe- and enzyme-based strategies to degrade PET and similar plastics. A PETase derived from the bacteriaIdeonella sakaiensiswas previously shown to enzymatically degrade PET, triggering multidisciplinary efforts to improve the robustness and activity of this and other PETases. However, because these enzymes only erode the surface of the insoluble PET substrate, it is difficult to measure standard kinetic parameters, such as kon, koffand kcat, complicating interpretation of the activity of mutants using traditional enzyme kinetics frameworks. To address this challenge, we developed a single-molecule microscopy assay that quantifies the landing rate and binding duration of quantum dot-labeled PETase enzymes interacting with a surface-immobilized PET film. Wild-type PETase binding durations were well fit by a biexponential with a fast population having a 2.7 s time constant, interpreted as active binding events, and a slow population interpreted as non-specific binding interactions that last tens of seconds. A previously described hyperactive mutant, S238F/W159H had both a faster on-rate and a slower off-rate than wild-type PETase, potentially explaining its enhanced activity. Because this single-molecule approach provides a more detailed mechanistic picture of PETase enzymatic activity than standard bulk assays, it should aid future efforts to engineer more robust and active PETases to combat global microplastics pollution.Statement of significancePlastic pollution is a global environmental and human health problem. PETases are recently discovered enzymes that degrade the ubiquitous plastic polyethylene terephthalate (PET). A push is underway to understand and optimize these enzymes to enable large-scale microplastics remediation. Here, we use single-molecule fluorescence microscopy to visualize the interactions of PETase enzyme molecules with a thin film of PET. We identify specific binding interactions of a few seconds that differ between wild-type and PETase mutants that have been previously shown to have altered activities. These single-molecule investigations provide a new window into the mechanism and activity of PETase enzymes, and provide a platform for characterizing and optimizing novel PETases with improved function and stability.
Molecular Dynamics Simulations Unveil the Aggregation Patterns and Salting out of Polyarginines at Zwitterionic POPC Bilayers in Solutions of Various Ionic Strengths
Authors: Hong Man Nguyen Thi , Vazdar Mario 
Published: April 2024

AbstractThis study employs molecular dynamics (MD) simulations to investigate the adsorption and aggregation behavior of simple polyarginine cell-penetrating peptides (CPPs), specifically modeled as R9peptides, at zwitterionic phosphocholine POPC membranes under varying ionic strengths of two peptide concentrations and two concentrations of NaCl and CaCl2. The results reveal an intriguing phenomenon of R9aggregation at the membrane, which is dependent on the ionic strength indicating a salting-out effect. As the peptide concentration and ionic strength increase, peptide aggregation also increases, with aggregate lifetimes and sizes showing a corresponding rise, accompanied by the total decrease of adsorbed peptides at the membrane surface. Notably, in high ionic strength environments, large R9aggregates, such as octamers, are also observed occasionally. The salting-out, typically uncommon for short positively charged peptides, is attributed to the unique properties of arginine amino acid, specifically by its side chain containing amphiphilic guanidinium (Gdm+) ion which makes both intermolecular hydrophobic like-charge Gdm+– Gdm+and salt-bridge Gdm+ – C-terminus interactions, where the former are increased with the ionic strength, and the latter decreased due to electrostatic screening. The aggregation behavior of R9peptides at membranes can also linked to their CPP translocation properties, suggesting that aggregation may aid in translocation across cellular membranes.
Reassortant strains of infectious bursal disease virus (IBDV) belonging to genogroup A3B1 predominate in British broiler chicken flocks
Authors: Reddy Vishwanatha R. A. P. , Bianco Carlo , Poulos Christopher , Brodrick Andrew J. , Nazki Salik , Schock Alex , Broadbent Andrew J. 
Published: April 2024

AbstractAs part of ongoing epidemiological surveillance for infectious bursal disease virus (IBDV), the hypervariable region (HVR) of the VP2 capsid gene encoded by segment A, and a region of the VP1 polymerase gene, encoded by segment B, were sequenced from 20 IBDV-positive bursal samples obtained in 2020 and 2021, from 16 commercial British broiler farms. Of the 16 farms, none contained very virulent (vv) strains belonging to genogroup A3B2, but 5/16 (31%) contained strains of genogroup A3B1, demonstrating birds were infected with reassortant strains containing a vv segment A and a non-vv segment B. In addition, 3/16 (19%) farms contained vaccine or classical strains belonging to genogroup A1B1, and 8/16 (50%) were co-infected with both genogroup A1B1 and A3B1 strains. Therefore, a total of 13/16 (81%) of the farms contained genogroup A3B1 reassortant viruses, the majority of which 8/13 (62%)) were found to be co-infected with genogroup A1B1 strains. Moreover, of the flocks containing reassortant strains, 5/13 (38%) had HVR mutations Q219L, G254D, D279N, and N280T, consistent with a recently described Western European clade, but 8/13 had other mutations or no mutations, demonstrating that multiple clades were present in the samples. Taken together, vv strains were not detected in the British broiler flocks we sampled, whereas reassortant strains predominated, which belonged to different clades, and were frequently found in samples that were also infected with genogroup A1B1 strains.
Identification of MYC synthetic lethal genes and networks
Authors: Martin Timothy D. , Choi Mei Yuk , Patel Rupesh , Liang Anthony , Li Mamie Z. , Elledge Stephen J. 
Published: April 2024

SUMMARYMYC is a potent oncogene that is frequently overexpressed in human tumors arising in different tissues. To date there are no approved therapies to directly antagonize oncogenic MYC and its role in driving tumorigenesis. As an alternative approach we employed genetic screens using CRISPR and shRNA to identify the genes that are required for the survival and growth of cells harboring high levels of MYC expression. We find that cells with elevated MYC require the expression of many pro-growth and metabolic pathways including genes involved in mitochondrial citrate production and transport. This citrate producing pathway is critical for cells with elevated MYC to generate the necessary acetyl-CoA to drive the lipid synthesis required for increased proliferation. Inhibition of this pathway results in reduced proliferation and in vivo tumor growth providing a potential therapeutic strategy to target MYC-driven cancers.HIGHLIGHTS–CRISPR and shRNA screens identify synthetic lethal interactions with overexpressed MYC–MYC overexpressing cells are more sensitive to disruption of citrate production and transport–Inhibition of SLC25A1 reduces growth of MYC driven tumors
Photometric redshifts and intrinsic alignments: Degeneracies and biases in the
3×2pt
analysis
Authors: Leonard C. Danielle , Rau Markus Michael , Mandelbaum Rachel 
Published: April 2024

We present a systematic study of cosmological parameter bias in weak lensing and large-scale structure analyses for upcoming imaging surveys induced by the interplay of intrinsic alignments (IA) and photometric redshift (photo-z) model misspecification error. We first examine the degeneracies between the parameters of the tidal alignment–tidal torquing (TATT) model for IA and of a photo-z model including a mean shift (Δz¯) and variance (σz) for each tomographic bin of lenses and sources, under a variety of underlying true IA behaviors. We identify strong degeneracies between: (1) the redshift scaling of the tidal alignment amplitude and the mean shift and variances of source bins, (2) the redshift scaling of the tidal torquing amplitude and the variance of the lowest-z source bin, and (3) the IA source density weighting and the mean shift and variance of several source bins. We then use this information to guide our exploration of the level of cosmological parameter bias which can be induced given incorrect modeling of IA, photo-z, or both. We find that marginalizing over all the parameters of TATT is generally sufficient to preclude cosmological parameter bias in the scenarios we consider. However, this does not necessarily mean that IA and photo-z parameters are themselves unbiased, nor does it mean that the best-fit model is a good fit to the data. We also find scenarios where the inferred parameters produce χd.o.f.2 values indicative of a good fit but cosmological parameter bias is significant, particularly when the IA source density weighting parameter is not marginalized over.

Published by the American Physical Society
2024
Advancing social practice understandings of digital innovation delivery in construction project management
Authors: Collinge William Henry 
Published: April 2024

PurposeThe paper aims to apply social practice theory to clarify the process of innovation design and delivery from one successful digital innovation: the building information modelling (BIM) risk library. The paper clarifies the practices surrounding construction innovation and provides a schema useful for practitioners and technology designers through a social practice analysis.Design/methodology/approachThe paper applies Schatzki's “organisation of practice” concepts to a construction project innovation to clarify how the practice of innovation revolves around understandings, rules and teleoaffectivities (emotive behaviours). Sources for the study include notes from meetings, workshops with experts and the shared artefacts of innovation.FindingsThe practice of innovation design and delivery are clarified through a social practice analysis: a distinct “field of practice” and a “schema” of generalisable prescriptions and preferences for innovation delivery being presented.Practical implicationsThe paper informs the practice and process of innovation design and delivery; the insights clarify how collective understandings and rules of use evolve over time, becoming formalised into contracts, agreements and workplans. Practically, processes whereby innovation “sayings” evolve into innovation “doings” are clarified: a schema detailing prescriptions and preferences of practitioners and developers being presented.Originality/valueThe social practice analysis of one successful construction innovation is an original contribution to the body of knowledge, adding a level of detail regarding innovation design and delivery often missing from reported research.
Beyond the land of the living death: early-stage transformational entrepreneurs in digital healthcare as liminality navigator
Authors: Trincanato Edoardo , Vagnoni Emidia 
Published: April 2024

PurposeThe lean startup approach (LSA) is extensively utilized by early-stage entrepreneurs, with “pivot” serving as a key pillar. However, there is a research gap concerning the boundary conditions impacting LSA and pivot decisions, especially when addressing societal challenges, as in the context of transformational entrepreneurship. In this regard, the healthcare sector, further compounded by a lack of research on startups and scale-ups, presents an embraced opportunity to provide multiple contributions for both theory and practice.Design/methodology/approachThe present investigation employs a grounded approach to explore the experiences of the co-founders of a fast-growing Italian e-health startup. A narrative strategy was employed to organize conditions and evolving strategic action/interactions into three different pivoting phases of the startup – before the pivot, its enactment and aftermath – with primary and secondary data collected over a period of one year.FindingsPivoting in digital healthcare unfolded as a liminal experience marked by factors such as high regulation, multiple stakeholders, technological and symbolic ambivalence, resource-intensive demands and institutional actors acting as pathway pioneers, leading to an information overload and unforeseeable uncertainty to manage. These factors challenge entrepreneurs' ability to attain optimal distinctiveness, presenting the paradoxical need for vertical flexibility for scaling up.Social implicationsBy uniquely illuminating the sector’s constraints on entrepreneurial phenomena, this study provides a valuable guide for entrepreneurs and institutional actors in addressing societal challenges.Originality/valueThis study introduces a process model of transformational information crafting when pivoting, highlighting the role of entrepreneurs' transformational stance and platform-mediated solutions as engines behind strategies involving information breaking and transition, preceding knowledge-driven integration strategies.
Is lean manufacturing maturity a prerequisite for industry 4.0? Survey of SMEs in Japan and Brazil
Authors: Tsukada Osamu , Ibusuki Ugo , Kuchii Shigeru , de Almeida Anderson Tadeu de Santi Barbosa 
Published: April 2024

Purpose
The purpose of this study is to explore the relationship between Lean manufacturing and Industry 4.0 for small and medium size of enterprise in Japan and Brazil.

Design/methodology/approach
The authors conducted a quantitative survey (20 companies in Japan and 30 companies in Brazil) combined with a qualitative interview (2 companies in Japan and 15 companies in Brazil).

Findings
According to the quantitative study, 90% of them practice Lean manufacturing and 40% of them practice Industry 4.0. In the qualitative study in Brazil, four managers responded that the Lean manufacturing is a prerequisite for Industry 4.0 since any production process with waste cannot be productive, even with sophisticated digitalization technology.

Originality/value
The authors explored further the relationship between “defensive Digital Transformation (DX),” which is based mainly on Lean manufacturing, and “offensive DX,” which relates to customer value creation through Industry 4.0. This study clarifies the relationship and plays as a roadmap to develop better the manufacturing from current status to the vision of Industry 4.0.
Covid-19 heterogeneous effects on Italian workers’ incomes: the role of jobs routinization and teleworkability
Authors: Gallo Giovanni , Granato Silvia , Raitano Michele 
Published: April 2024

PurposeThe Covid-19 pandemic appears to have engendered heterogeneous effects on individuals’ labour market prospects. This paper focuses on two possible sources of a heterogeneous exposition to labour market risks associated with the pandemic outbreak: the routine task content of the job and the teleworkability. To evaluate whether these dimensions played a crucial role in amplifying employment and wage gaps among workers, we focus on the case of Italy, the first EU country hit by Covid-19.Design/methodology/approachInvestigating the actual effect of the pandemic on workers employed in jobs with a different degree of teleworkability and routinization, using real microdata, is currently unfeasible. This is because longitudinal datasets collecting annual earnings and the detailed information about occupations needed to capture a job’s routine task content and teleworkability are not presently available. To simulate changes in the wage distribution for the year 2020, we have employed a static microsimulation model. This model is built on data from the Statistics on Income and Living Conditions (IT-SILC) survey, which has been enriched with administrative data and aligned with monthly observed labour market dynamics by industries and regions.FindingsWe measure the degree of job teleworkability and routinization with the teleworkability index (TWA) built by Sostero et al. (2020) and the routine-task-intensity index (RTI) developed by Cirillo et al. (2021), respectively. We find that RTI and TWA are negatively and positively associated with wages, respectively, and they are correlated with higher (respectively lower) risks of a large labour income drop due to the pandemic. Our evidence suggests that labour market risks related to the pandemic – and the associated new types of earnings inequality that may derive – are shaped by various factors (including TWA and RTI) instead of by a single dimension. However, differences in income drop risks for workers in jobs with varying degrees of teleworkability and routinization largely reduce when income support measures are considered, thus suggesting that the redistributive effect of the emergency measures implemented by the Italian government was rather effective.Originality/valueNo studies have so far investigated the effect of the pandemic on workers employed in jobs with a different degree of routinization and teleworkability in Italy. We thus investigate whether income drop risks in Italy in 2020 – before and after income support measures – differed among workers whose jobs are characterized by a different degree of RTI and TWA.
Climate lessons from the cold edge: rethinking the university as an ethical ecology
Authors: Boxley Simon 
Published: April 2024

Purpose
This largely conceptual study aims to draw from the author’s experience of conversations with Svalbard’s educators, lessons for international higher education institutions’ engagement with climate change education and thinking for non-specialists.

Design/methodology/approach
In situ discussions with Svalbard’s educators informed the theoretical work of the author towards the development of conceptual conclusions. The theoretical frame used – “Red Biocentrism” – draws on both radical left and green thought to posit an emplaced, materialist understanding of author’s, participants’ and place’s intra-related contributions.

Findings
That, insofar as universities represent nodes in an ethical ecology, they have a capacity to realise that which is obvious in Svalbard – their role as embassies for their learning places, generative of spokespeople or ambassadors.

Originality/value
There is sparse published research into the work of Svalbard’s climate educators, as a pedagogical project undertaken under such extreme and rapidly changing environmental conditions. This study represents the first to reflect on what can be learnt from the educators of Svalbard by Universities elsewhere.
How healthy is your workplace? Testing the effectiveness of occupational health programs: insights from Germany
Authors: Afrahi Jasmin 
Published: April 2024

PurposeCompanies are increasingly struggling with the costs of absenteeism due to their employees’ physical and increasing psychological illnesses. At the same time, employers should recognize the value of healthy employees in terms of greater productivity and the development of positive organizational attitudes. Many organizations have implemented workplace health promotion (WHP) programs; however, we still have limited knowledge about the effectiveness of various measures. The present study is an examination of 18 WHP activities and their effect on employees’ perceived health support and actual absence rates.Design/methodology/approachI organized 112 German companies into four groups based on their subjective (employee perception of health promotion) and objective (absence rate) performance. Applying multinomial regression analysis, I assessed a company’s likelihood of falling into one of the four clusters if a specific measure was not implemented in it.FindingsI identified five measures that significantly differ between company clusters: healthy food offerings, sports offerings, having fitness rooms, systematically evaluating WHP programs and smoking cessation courses. Investing in occupational health management can be a strategic asset for organizations. The study results give companies recommendations on how to address WHP and how to implement these concrete measures.Originality/valueThe study’s originality lies in the incorporation of 18 concrete WHP measures and the comparison of their effects in objective and subjective terms. It shows that employers can enhance employee well-being by using simple WHP activities.