bluuebunny/crossref_metadata_2025 huggingface dataset:
Questioning the Appropriateness of Examining Guanxi in a Wasta Environment: Why Context Should Be Front and Center in Informal Network Research – A Commentary on ‘De-Linking From Western Epistemologies: Using Guanxi-Type Relationships to Attract and Retain Hotel Guests in the Middle East’
Authors: Horak Sven , Abosag Ibrahim , Hutchings Kate , Alsarhan Fadi , Ali Sa'ad , Al-Twal Arwa , Weir David , ALHussan Fawaz Baddar , AL-Husan Faten Baddar
Published: November 2023

In this commentary we reflect on Shaalan, Eid, and Tourky's (2022) article in which they investigated the Chinese concept and practice of guanxi in the Middle East,1 a region in which wasta represents the common way of informal networking.2 While we encourage and welcome research into informal networks, we have serious concerns about the conceptual and methodological approaches taken by Shaalan et al. (2022) in investigating informal networks in the Middle East and explain herein why we do not believe guanxi should have been used in place of wasta.
The bureaucratic politics of authoritarian repression: intra-agency reform and surveillance capacity in communist Poland
Authors: Thomson Henry
Published: November 2023

Coercive institutions' internal structures remain poorly understood. Bureaucratic reorganizations within security institutions cause significant variation in their behavior, however. Intra-agency reforms interact with officers' careerist incentives to cause changes in coercive capacity or repression. In this paper, I test the effects of intra-agency reforms on surveillance capacity. I exploit a rare source of exogenous variation in the structure of the secret police in communist Poland. Difference-in-differences models find that when security headquarters were duplicated through an administrative reform, the proliferation of higher-level posts within the service caused a large and statistically significant increase in the number of informants it employed. Intra-agency reform substantially altered the agency's coercive capacity. Previously overlooked dynamics within coercive institutions have important effects on authoritarian repression.
RADIOCARBON DATING OF ASIAN LACQUERS: MOLECULAR CHARACTERIZATION AND ASSESSMENT OF A PRETREATMENT METHOD PRIOR TO ACCELERATOR MASS SPECTROMETRY
Authors: Wojcieszak M , Veenhoven J , Van den Brande T , Saverwyns S , Lynen F , Boudin M
Published: November 2023

Lacquerwork technologies comprise multiple techniques depending on countries, time, and traditions. Carved Asian lacquers applied on wooden objects consist of multiple thin uncolored or pigmented layers spread over the surface. To radiocarbon (14C) date these types of objects, often only the wooden structure is used. Here we report on a set of carved lacquered objects that were dated based on stylistic form,14C dating of the wooden structure and of the Asian lacquers. THM-Py-GC-MS and micro-Raman spectroscopy were used to confirm the molecular composition of the lacquers and helped assessing the pretreatment protocol. The lacquers analyzed contained between 20 and 50% wt carbon, thus 2–5 mg of sample were necessary for14C dating. The dates obtained on wood and lacquers showed a reliable correlation. The results suggest that, in most cases, it is sufficient to sample a part of the lacquer layers to date an object. We advise to perform an acid pretreatment followed by a successive solvent immersion with an increasing polarity. Dating different components of a lacquered object can also help to understand previous restoration interventions that frequently occur for ancient lacquered objects. Ceramic, metallic, and other objects covered with Asian lacquers can also be dated using this approach.
Bureaucratic Quality and the Gap between Implementation Burden and Administrative Capacities
Authors: FERNÁNDEZ-I-MARÍN XAVIER , KNILL CHRISTOPH , STEINBACHER CHRISTINA , STEINEBACH YVES
Published: November 2023

Democratic governments produce more policies than they can effectively implement. Yet, this gap between the number of policies requiring implementation and the administrative capacities available to do so is not the same in all democracies but varies across countries and sectors. We argue that this variation depends on the coupling of the sectoral bureaucracies in charge of policy formulation and those in charge of policy implementation. We consider these patterns of vertical policy-process integration an important feature of bureaucratic quality. The more the policymaking level is involved in policy implementation (top-down integration) and the easier the policy-implementing level finds it to feed its concerns into policymaking (bottom-up integration), the smaller the so-called “burden-capacity gap.” We demonstrate this effect through an empirical analysis in 21 OECD countries over a period of more than 40 years in the areas of social and environmental policies.
Alcaeus, Pittakos ‘son of “Hyrras”’, and the Lesbian aristocracy, or ‘How to do things with words’
Authors: Dale Alexander
Published: November 2023

This paper offers a reassessment of the representation of Pittakos, tyrant of Lesbos, in Alcaeus’ verse. I begin by examining the textual evidence for Pittakos’ father, Hyrras, before progressing to re-evaluate the evidence for the aristocratic clans of Lesbos as attested in the Lesbian poets. Building on this, and with reference to the patronymic/gentilicArkheanaktidāsseemingly used of Pittakos in Alcaeus, I relate the preponderance of patronymic forms found in Alcaeus’ verse to the iambic and comedic use of ‘characterizing’ patronymics in -(ι)δᾱς. I then argue that both ῎Υρρας and Ἀρχϵανακτίδας are to be interpreted via a cross-cultural and bilingual rhetoric of kingship, with the latter being in essence a calque of a Lydian intermediary of the Luwian designationura- handawati-, ‘great king’, with ὔρρας and its derivatives in Alcaeus a nominalization of the Luwian adjectival stemura-, ‘great’. This argument is then related to the increasing evidence for Lesbos as a central locus for Graeco-Anatolian cultural exchange. The end result is a comprehensive reassessment of historical reconstructions emanating from the texts of Sappho and Alcaeus, as well as a reassessment of Alcaeus’ poetic objectives in his attacks on Pittakos, ‘son of Hyrras’.
Fair equality of chances for prediction-based decisions
Authors: Loi Michele , Herlitz Anders , Heidari Hoda
Published: November 2023

This article presents a fairness principle for evaluating decision-making based on predictions: a decision rule is unfair when the individuals directly impacted by the decisions who are equal with respect to the features that justify inequalities in outcomes do not have the same statistical prospects of being benefited or harmed by them, irrespective of their socially salient morally arbitrary traits. The principle can be used to evaluate prediction-based decision-making from the point of view of a wide range of antecedently specified substantive views about justice in outcome distributions.
Abhilash Pillai's Midnight's Children: Performing Politics through Optics
Authors: SENGUPTA ASHIS
Published: November 2023

Abhilash Pillai's stage adaptation of Salman Rushdie's Midnight's Children (2005–6) introduced a new visual language to Indian theatre, conceiving performance between theatre and cinema. Pillai's work presents history as memory, amnesia and re-remembering within the framework of a multisensorial scenography that largely uses the vocabularies of the Bollywood film industry. The politics of the performance lies less in the thematic than in its optical dynamics, different as they are from both scene painting and the aestheticization of the public sphere. The production shows how theatre experience in a media society may primarily build on the perceptual, but without dismissing text or suspending the cognitive altogether. The visual media are used more as an intervention in politico-aesthetic discourse than as mere technology. As I explain the reasons for the long absence of any scholarly study of the production, I also consider its relevance to the current political scene in India.
Teaching Bioethics Today: Waking from Dogmatic Curricular Slumbers
Authors: Fleck Leonard M.
Published: November 2023

The Dobbs decision has precipitated renewed medical, political, and professional interest in the issue of abortion. Because this decision handed responsibility for regulation of abortion back to the states, and because the states are enacting or have enacted policies that tend to be very permissive or very restrictive, the result has been legal and professional confusion for physicians and their patients. Medical education cannot resolve either the legal or ethical issues regarding abortion. However, medical education must prepare future physicians for caring for patients seeking abortion-related services. Physicians must be prepared to interact appropriately (sensitively and with integrity) with patients or colleagues whose views on abortion differ significantly from their own. This essay describes our educational effort to achieve that objective. The motto that governed this exercise was “No Easy Answers.”
Logging in to Learn: The Effects of Online Civic Education Pedagogy on a Latinx and AAPI Civic Engagement Youth Conference
Authors: Lamb Matt
Published: November 2023

Civic education is essential to the health of any democracy. When COVID-19 emerged in the spring of 2020, almost all civic education efforts went online. This increased interest in the effectiveness of online civic education. Does it lead to similar outcomes as in-person education? I used student evaluations from a youth civic engagement conference co-run by Latinx and Asian American and Pacific Islander (AAPI) non-profit organizations to compare learning outcomes on multiple dimensions of civic education, from an in-person conference in 2019 and an online conference in 2020. I find that although students improved over the course of both conferences, the 2019 in-person conference yielded slightly greater improvement in civic knowledge confidence than the online conference. Other dimensions—verifiable knowledge, self-efficacy, and community consciousness—increased after participation in the conference in both years; however, the increases were similar between the online and in-person formats.
The United Nations of IR: power, knowledge, and empire in Global IR debates
Authors: Barkawi Tarak , Murray Christopher , Zarakol Ayşe
Published: November 2023

This paper critiques a core premise of Global IR: the association of knowledge with geography, which we term geo-epistemology. It argues that ‘American’ and Global IR share a Eurocentric spatial imaginary, one that was a product of Western expansion and empire. Through its geo-epistemology, Global IR enables a conservative appropriation of the critique of Eurocentrism in IR. Globality becomes a matter of assembling sufficient geographic representation rather than an analysis of the discipline's political, historical, and spatial assumptions. Anglo-American policymakers and intellectuals invented the national/international world to replace the world of empires and races that came apart in the era of the world wars. This UN world of sovereign nation-states and their regional groupings was the foundational move of both what Stanley Hoffman called ‘the American social science’ – IR – and the American-centred world order. The paper uses the reception and legacy of Hoffman's classic essay to show how culture replaced power and history in the study of the discipline, obfuscating the Eurocentrism of Global IR.
Antibody-mediated delivery of viral epitopes to redirect EBV-specific CD8+ T-cell immunity towards cancer cells
Authors: van der Wulp Willemijn , Remst Dennis F. G. , Kester Michel G. D. , Hagedoorn Renate S. , Parren Paul W. H. I. , van Kasteren Sander I. , Schuurman Janine , Hoeben Rob C. , Ressing Maaike E. , Bleijlevens Boris , Heemskerk Mirjam H. M.
Published: November 2023

Antibody-mediated delivery of immunogenic epitopes to redirect virus-specific CD8+ T-cells towards cancer cells is an emerging and promising new therapeutic strategy. These so-called antibody-epitope conjugates (AECs) rely on the proteolytic release of the epitopes close to the tumor surface for presentation by HLA class I molecules to eventually redirect and activate virus-specific CD8+ T-cells towards tumor cells. We fused the immunogenic EBV-BRLF1 epitope preceded by a protease cleavage site to the C-terminus of the heavy and/or light chains of cetuximab and trastuzumab. We evaluated these AECs and found that, even though all AECs were able to redirect the EBV-specific T-cells, AECs with an epitope fused to the C-terminus of the heavy chain resulted in higher levels of T-cell activation compared to AECs with the same epitope fused to the light chain of an antibody. We observed that all AECs were depending on the presence of the antibody target, that the level of T-cell activation correlated with expression levels of the antibody target, and that our AECs could efficiently deliver the BRLF1 epitope to cancer cell lines from different origins (breast, ovarian, lung, and cervical cancer and a multiple myeloma). Moreover, in vivo, the AECs efficiently reduced tumor burden and increased the overall survival, which was prolonged even further in combination with immune checkpoint blockade. We demonstrate the potential of these genetically fused AECs to redirect the potent EBV-specific T-cells towards cancer in vitro and in vivo.
A novel c-Met/TRK inhibitor 1D228 efficiently inhibits tumor growth by targeting angiogenesis and tumor cell proliferation
Authors: An Baijiao , Nie Wenyan , Hu Jinhui , Fan Yangyang , Nie Haoran , Wang Mengxuan , Zhao Yaxuan , Yao Han , Ren Yuanyuan , Zhang Chuanchuan , Wei Mengna , Li Wei , Liu Jiadai , Yang Chunhua , Zhang Yin , Li Xingshu , Tian Geng
Published: November 2023

Multiple tumors are synergistically promoted by c-Met and TRK, and blocking their cross-signalling pathway may give better effects. In this study, we developed a tyrosine kinase inhibitor 1D228, which exhibited excellent anti-tumor activity by targeting c-Met and TRK. Models in vitro, 1D228 showed a significant better inhibition on cancer cell proliferation and migration than the positive drug Tepotinib. Models in vivo, 1D228 showed robust anti-tumor effect on gastric and liver tumor growth with 94.8% and 93.4% of the TGI, respectively, comparing 67.61% and 63.9% of Tepotinib. Importantly, compared with the combination of Larotrectinib and Tepotinib, 1D228 monotherapy in MKN45 xenograft tumor models showed stronger antitumor activity and lower toxicity. Mechanistic studies showed that 1D228 can largely inhibit the phosphorylation of TRKB and c-Met. Interestingly, both kinases, TRKs and c-Met, have been found to be co-expressed at high levels in patients with gastric cancer through IHC. Furthermore, bioinformatics analysis has revealed that both genes are abnormally co-expressed in multiple types of cancer. Cell cycle analysis found that 1D228 induced G0/G1 arrest by inhibiting cyclin D1. Additionally, vascular endothelial cells also showed a pronounced response to 1D228 due to its expression of TRKB and c-Met. 1D228 suppressed the migration and tube formation of endothelial cells, which are the key functions of tumor angiogenesis. Taken together, compound 1D228 may be a promising candidate for the next generation of c-Met and TRK inhibitors for cancer treatment, and offers a novel potential treatment strategy for cancer patients with abnormal expressions of c-Met or NTRK, or simultaneous of them.
Gasdermin D promotes hyperinflammation and immunopathology during severe influenza A virus infection
Authors: Rosli Sarah , Harpur Christopher M. , Lam Maggie , West Alison C. , Hodges Christopher , Mansell Ashley , Lawlor Kate E. , Tate Michelle D.
Published: November 2023

Excessive inflammation and tissue damage during severe influenza A virus (IAV) infection can lead to the development of fatal pulmonary disease. Pyroptosis is a lytic and pro-inflammatory form of cell death executed by the pore-forming protein gasdermin D (GSDMD). In this study, we investigated a potential role for GSDMD in promoting the development of severe IAV disease. IAV infection resulted in cleavage of GSDMD in vivo and in vitro in lung epithelial cells. Mice genetically deficient in GSDMD (Gsdmd−/−) developed less severe IAV disease than wildtype mice and displayed improved survival outcomes. GSDMD deficiency significantly reduced neutrophil infiltration into the airways as well as the levels of pro-inflammatory cytokines TNF, IL-6, MCP-1, and IL-1α and neutrophil-attracting chemokines CXCL1 and CXCL2. In contrast, IL-1β and IL-18 responses were not largely impacted by GSDMD deficiency. In addition,Gsdmd−/−mice displayed significantly improved influenza disease resistance with reduced viral burden and less severe pulmonary pathology, including decreased epithelial damage and cell death. These findings indicate a major role for GSDMD in promoting damaging inflammation and the development of severe IAV disease.
Electrocatalytic on-site oxygenation for transplanted cell-based-therapies
Authors: Lee Inkyu , Surendran Abhijith , Fleury Samantha , Gimino Ian , Curtiss Alexander , Fell Cody , Shiwarski Daniel J. , Refy Omar , Rothrock Blaine , Jo Seonghan , Schwartzkopff Tim , Mehta Abijeet Singh , Wang Yingqiao , Sipe Adam , John Sharon , Ji Xudong , Nikiforidis Georgios , Feinberg Adam W. , Hester Josiah , Weber Douglas J. , Veiseh Omid , Rivnay Jonathan , Cohen-Karni Tzahi
Published: November 2023

Implantable cell therapies and tissue transplants require sufficient oxygen supply to function and are limited by a delay or lack of vascularization from the transplant host. Previous exogenous oxygenation strategies have been bulky and had limited oxygen production or regulation. Here, we show an electrocatalytic approach that enables bioelectronic control of oxygen generation in complex cellular environments to sustain engineered cell viability and therapy under hypoxic stress and at high cell densities. We find that nanostructured sputtered iridium oxide serves as an ideal catalyst for oxygen evolution reaction at neutral pH. We demonstrate that this approach exhibits a lower oxygenation onset and selective oxygen production without evolution of toxic byproducts. We show that this electrocatalytic on site oxygenator can sustain high cell loadings (>60k cells/mm3) in hypoxic conditions in vitro and in vivo. Our results showcase that exogenous oxygen production devices can be readily integrated into bioelectronic platforms, enabling high cell loadings in smaller devices with broad applicability.
Structures of the DarR transcription regulator reveal unique modes of second messenger and DNA binding
Authors: Schumacher Maria A. , Lent Nicholas , Chen Vincent B. , Salinas Raul
Published: November 2023

The mycobacterial repressor, DarR, a TetR family regulator (TFR), was the first transcription regulator shown to bind c-di-AMP. However, the molecular basis for this interaction and the mechanism involved in DNA binding by DarR remain unknown. Here we describe DarR-c-di-AMP and DarR-DNA structures and complementary biochemical assays. The DarR-c-di-AMP structure reveals a unique effector binding site for a TFR, located between DarR dimer subunits. Strikingly, we show this motif also binds cAMP. The location of the adenine nucleotide binding site between subunits suggests this interaction may facilitate dimerization and hence DNA binding. Indeed, biochemical assays show cAMP enhances DarR DNA binding. Finally, DarR-DNA structures reveal a distinct TFR DNA-binding mechanism involving two interacting dimers on the DNA. Thus, the combined data unveil a newly described second messenger binding motif and DNA binding mode for this important family of regulators.
The transcriptional legacy of developmental stochasticity
Authors: Ballouz Sara , Kawaguchi Risa Karakida , Pena Maria T. , Fischer Stephan , Crow Megan , French Leon , Knight Frank M. , Adams Linda B. , Gillis Jesse
Published: November 2023

Genetic and environmental variation are key contributors during organism development, but the influence of minor perturbations or noise is difficult to assess. This study focuses on the stochastic variation in allele-specific expression that persists through cell divisions in the nine-banded armadillo (Dasypus novemcinctus). We investigated the blood transcriptome of five wild monozygotic quadruplets over time to explore the influence of developmental stochasticity on gene expression. We identify an enduring signal of autosomal allelic variability that distinguishes individuals within a quadruplet despite their genetic similarity. This stochastic allelic variation, akin to X-inactivation but broader, provides insight into non-genetic influences on phenotype. The presence of stochastically canalized allelic signatures represents a novel axis for characterizing organismal variability, complementing traditional approaches based on genetic and environmental factors. We also developed a model to explain the inconsistent penetrance associated with these stochastically canalized allelic expressions. By elucidating mechanisms underlying the persistence of allele-specific expression, we enhance understanding of development’s role in shaping organismal diversity.
Tailoring chemical composition of solid electrolyte interphase by selective dissolution for long-life micron-sized silicon anode
Authors: Tian Yi-Fan , Tan Shuang-Jie , Yang Chunpeng , Zhao Yu-Ming , Xu Di-Xin , Lu Zhuo-Ya , Li Ge , Li Jin-Yi , Zhang Xu-Sheng , Zhang Chao-Hui , Tang Jilin , Zhao Yao , Wang Fuyi , Wen Rui , Xu Quan , Guo Yu-Guo
Published: November 2023

Micron-sized Si anode promises a much higher theoretical capacity than the traditional graphite anode and more attractive application prospect compared to its nanoscale counterpart. However, its severe volume expansion during lithiation requires solid electrolyte interphase (SEI) with reinforced mechanical stability. Here, we propose a solvent-induced selective dissolution strategy to in situ regulate the mechanical properties of SEI. By introducing a high-donor-number solvent, gamma-butyrolactone, into conventional electrolytes, low-modulus components of the SEI, such as Li alkyl carbonates, can be selectively dissolved upon cycling, leaving a robust SEI mainly consisting of lithium fluoride and polycarbonates. With this strategy, raw micron-sized Si anode retains 87.5% capacity after 100 cycles at 0.5 C (1500 mA g−1, 25°C), which can be improved to >300 cycles with carbon-coated micron-sized Si anode. Furthermore, the Si||LiNi0.8Co0.1Mn0.1O2 battery using the raw micron-sized Si anode with the selectively dissolved SEI retains 83.7% capacity after 150 cycles at 0.5 C (90 mA g−1). The selective dissolution effect for tailoring the SEI, as well as the corresponding cycling life of the Si anodes, is positively related to the donor number of the solvents, which highlights designing high-donor-number electrolytes as a guideline to tailor the SEI for stabilizing volume-changing alloying-type anodes in high-energy rechargeable batteries.
Essential gene complement of Planctopirus limnophila from the bacterial phylum Planctomycetes
Authors: Rivas-Marin Elena , Moyano-Palazuelo David , Henriques Valentina , Merino Enrique , Devos Damien P.
Published: November 2023

Planctopirus limnophilabelongs to the bacterial phylumPlanctomycetes, a relatively understudied lineage with remarkable cell biology features. Here, we report a genome-wide analysis of essential gene content inP. limnophila. We show that certain genes involved in peptidoglycan synthesis or cell division, which are essential in most other studied bacteria, are not essential for growth under laboratory conditions in this species. We identify essential genes likely involved in lipopolysaccharide biosynthesis, consistent with the view of Planctomycetes as diderm bacteria, and highlight other essential genes of unknown functions. Furthermore, we explore potential stages of evolution of the essential gene repertoire inPlanctomycetesand the related phylaVerrucomicrobiaandChlamydiae. Our results provide insights into the divergent molecular and cellular biology ofPlanctomycetes.
Low circulating adropin levels in late-middle aged African Americans with poor cognitive performance
Authors: Aggarwal Geetika , Malmstrom Theodore K. , Morley John E. , Miller Douglas K. , Nguyen Andrew D. , Butler Andrew A.
Published: November 2023

We recently reported accelerated cognitive decline in Europeans aged > 70 years with low circulating adropin levels. Adropin is a small, secreted peptide that is highly expressed in the human nervous system. Expression profiling indicate relationships between adropin expression in the human brain and pathways that affect dementia risk. Moreover, increased adropin expression or treatment using synthetic adropin improves cognition in mouse models of aging. Here we report that low circulating adropin concentrations associate with poor cognition (worst quintile for a composite score derived from the MMSE and semantic fluency test) in late-middle aged community-dwelling African Americans (OR = 0.775, P < 0.05; age range 45–65 y, n = 352). The binomial logistic regression controlled for sex, age, education, cardiometabolic disease risk indicators, and obesity. Previous studies using cultured cells from the brains of human donors suggest high expression in astrocytes. In snRNA-seq data from the middle temporal gyrus (MTG) of human donors, adropin expression is higher in astrocytes relative to other cell types. Adropin expression in all cell-types declines with advance age, but is not affected by dementia status. In cultured human astrocytes, adropin expression also declines with donor age. Additional analysis indicated positive correlations between adropin and transcriptomic signatures of energy metabolism and protein synthesis that are adversely affected by donor age. Adropin expression is also suppressed by pro-inflammatory factors. Collectively, these data indicate low circulating adropin levels are a potential early risk indicator of cognitive impairment. Declining adropin expression in the brain is a plausible link between aging, neuroinflammation, and risk of cognitive decline.
Recent co-evolution of two pandemic plant diseases in a multi-hybrid swarm
Authors: Rahnama Mostafa , Condon Bradford , Ascari João P. , Dupuis Julian R. , Del Ponte Emerson M. , Pedley Kerry F. , Martinez Sebastián , Valent Barbara , Farman Mark L.
Published: November 2023

Most plant pathogens exhibit host specificity but when former barriers to infection break down, new diseases can rapidly emerge. For a number of fungal diseases, there is increasing evidence that hybridization plays a major role in driving host jumps. However, the relative contributions of existing variation versus new mutations in adapting to new host(s) is unclear. Here we reconstruct the evolutionary history of two recently emerged populations of the fungus Pyricularia oryzae that are responsible for two new plant diseases: wheat blast and grey leaf spot of ryegrasses. We provide evidence that wheat blast/grey leaf spot evolved through two distinct mating episodes: the first occurred ~60 years ago, when a fungal individual adapted to Eleusine mated with another individual from Urochloa. Then, about 10 years later, a single progeny from this cross underwent a series of matings with a small number of individuals from three additional host-specialized populations. These matings introduced non-functional alleles of two key host-specificity factors, whose recombination in a multi-hybrid swarm probably facilitated the host jump. We show that very few mutations have arisen since the founding event and a majority are private to individual isolates. Thus, adaptation to the wheat or Lolium hosts appears to have been instantaneous, and driven entirely by selection on repartitioned standing variation, with no obvious role for newly formed mutations.
Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens
Authors: McCutcheon Sean R. , Swartz Adam M. , Brown Michael C. , Barrera Alejandro , McRoberts Amador Christian , Siklenka Keith , Humayun Lucas , ter Weele Maria A. , Isaacs James M. , Reddy Timothy E. , Allen Andrew S. , Nair Smita K. , Antonia Scott J. , Gersbach Charles A.
Published: November 2023

Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapies. Here we developed pooled, epigenetic CRISPR screening approaches to systematically profile the effects of activating or repressing 120 transcriptional and epigenetic regulators on human CD8+ T cell state. We found that BATF3 overexpression promoted specific features of memory T cells and attenuated gene programs associated with cytotoxicity, regulatory T cell function, and exhaustion. Upon chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. Moreover, BATF3 enhanced the potency of CAR T cells in both in vitro and in vivo tumor models and programmed a transcriptional profile that correlates with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens that defined cofactors and downstream mediators of the BATF3 gene network.
Three-dimensional dental microwear in type-Maastrichtian mosasaur teeth (Reptilia, Squamata)
Authors: Holwerda Femke M. , Bestwick Jordan , Purnell Mark A. , Jagt John W. M. , Schulp Anne S.
Published: November 2023

Mosasaurs (Squamata, Mosasauridae) were large aquatic reptiles from the Late Cretaceous that filled a range of ecological niches within marine ecosystems. The type-Maastrichtian strata (68–66 Ma) of the Netherlands and Belgium preserve remains of five species that seemed to have performed different ecological roles (carnivores, piscivores, durophages). However, many interpretations of mosasaur diet and niche partitioning are based on qualitative types of evidence that are difficult to test explicitly. Here, we apply three-dimensional dental microwear texture analysis (DMTA) to provide quantitative dietary constraints for type-Maastrichtian mosasaurs, and to assess levels of niche partitioning between taxa. DMTA indicates that these mosasaurs did not exhibit neatly defined diets or strict dietary partitioning. Instead, we identify three broad groups: (i) mosasaurs Carinodens belgicus and Plioplatecarpus marshi plotting in the space of modern reptiles that are predominantly piscivorous and/or consume harder invertebrate prey, (ii) Prognathodon saturator and Prognathodon sectorius overlapping with extant reptiles that consume larger amounts of softer invertebrate prey items, and (iii) Mosasaurus hoffmanni spanning a larger plot area in terms of dietary constraints. The clear divide between the aforementioned first two groups in texture-dietary space indicates that, despite our small sample sizes, this method shows the potential of DMTA to test hypotheses and provide quantitative constraints on mosasaur diets and ecological roles.
A cost-effective smart metering approach towards affordable deployment strategy
Authors: Ezhilarasi P. , Ramesh L. , Sanjeevikumar P. , Khan Baseem
Published: November 2023

Revamping the power grid into a smart grid and modernizing it with advanced metering infrastructure are essential steps in addressing ongoing energy challenges. Smart meters play a pivotal role in power grid modernization by providing real-time energy-related data which fuels the control activities of modern grid. While the advantages of smart meters are evident, their deployment necessitates a comprehensive redesign of the grid architecture, involving smart end devices for monitoring and communication networks for efficient data exchange. Yet, achieving cost-effective and widespread adoption of these technologies poses a challenge, particularly in developing and underdeveloped nations due to high capital costs, technological constraints and uneconomical deployment strategies. Moreover, the prevailing research often advocates a complete transition to new smart meters to achieve 'smartness,' neglecting the potential of existing metering infrastructure upgrades. To address these concerns, this study proposes and simulates the design of a low-cost Smart Network Meter. Notably, this meter upgrades the existing meter infrastructure while validating a cost-effective deployment strategy. Furthermore, a consumer opinion survey was also conducted to compelling evidence supporting the adoption of the proposed low-cost smart metering solution.
The genetics of falling susceptibility and identification of causal risk factors
Authors: Smith Matt C. , O’Loughlin Jessica , Karageorgiou Vasileios , Casanova Francesco , Williams Genevieve K. R. , Hilton Malcolm , Tyrrell Jessica
Published: November 2023

Falls represent a huge health and economic burden. Whilst many factors are associated with fall risk (e.g. obesity and physical inactivity) there is limited evidence for the causal role of these risk factors. Here, we used hospital and general practitioner records in UK Biobank, deriving a balance specific fall phenotype in 20,789 cases and 180,658 controls, performed a Genome Wide Association Study (GWAS) and used Mendelian Randomisation (MR) to test causal pathways. GWAS indicated a small but significant SNP-based heritability (4.4%), identifying one variant (rs429358) inAPOEat genome-wide significance (P < 5e-8). MR provided evidence for a causal role of higher BMI on higher fall risk even in the absence of adverse metabolic consequences. Depression and neuroticism predicted higher risk of falling, whilst higher hand grip strength and physical activity were protective. Our findings suggest promoting lower BMI, higher physical activity as well as psychological health is likely to reduce falls.
Localization of early infarction on non-contrast CT images in acute ischemic stroke with deep learning approach
Authors: Mohapatra Sulagna , Lee Tsong-Hai , Sahoo Prasan Kumar , Wu Ching-Yi
Published: November 2023

Localization of early infarction on first-line Non-contrast computed tomogram (NCCT) guides prompt treatment to improve stroke outcome. Our previous study has shown a good performance in the identification of ischemic injury on NCCT. In the present study, we developed a deep learning (DL) localization model to help localize the early infarction sign on NCCT. This retrospective study included consecutive 517 ischemic stroke (IS) patients who received NCCT within 12 h after stroke onset. A total of 21,436 infarction patches and 20,391 non-infarction patches were extracted from the slice pool of 1,634 NCCT according to brain symmetricity property. The generated patches were fed into different pretrained convolutional neural network (CNN) models such as Visual Geometry Group 16 (VGG16), GoogleNet, Residual Networks 50 (ResNet50), Inception-ResNet-v2 (IR-v2), Inception-v3 and Inception-v4. The selected VGG16 model could detect the early infarction in both supratentorial and infratentorial regions to achieve an average area under curve (AUC) 0.73 after extensive customization. The properly tuned-VGG16 model could identify the early infarction in the cortical, subcortical and cortical plus subcortical areas of supratentorial region with the mean AUC > 0.70. Further, the model could attain 95.6% of accuracy on recognizing infarction lesion in 494 out of 517 IS patients.
Wide-field endoscope accessory for multiplexed fluorescence imaging
Authors: Li Gaoming , Lee Miki , Chang Tse-Shao , Yu Joonyoung , Li Haijun , Duan Xiyu , Wu Xiaoli , Jaiswal Sangeeta , Feng Shuo , Oldham Kenn R. , Wang Thomas D.
Published: November 2023

A wide-field endoscope that is sensitive to fluorescence can be used as an adjunct to conventional white light endoscopy by detecting multiple molecular targets concurrently. We aim to demonstrate a flexible fiber-coupled accessory that can pass forward through the instrument channel of standard medical endoscopes for clinical use to collect fluorescence images. A miniature scan mirror with reflector dimensions of 1.30 × 0.45  mm2was designed, fabricated, and placed distal to collimated excitation beams at λex = 488, 660, and 785 nm. The mirror was driven at resonance for wide angular deflections in the X and Y-axes. A large image field-of-view (FOV) was generated in real time. The optomechanical components were packaged in a rigid distal tip with dimensions of 2.6 mm diameter and 12 mm length. The scan mirror was driven at 27.6 and 9.04 kHz in the fast (X) and slow (Y) axes, respectively, using a square wave with 50% duty cycle at 60 Vppto collect fluorescence images at 10 frames per sec. Maximum total divergence angles of ± 27.4° and ± 22.8° were generated to achieve a FOV of 10.4 and 8.4 mm, respectively, at a working distance of 10 mm. Multiplexed fluorescence images were collected in vivo from the rectum of live mice using 3 fluorescently-labeled peptides that bind to unique cell surface targets. The fluorescence images collected were separated into 3 channels. Target-to-background ratios of 2.6, 3.1, and 3.9 were measured. This instrument demonstrates potential for broad clinical use to detect heterogeneous diseases in hollow organs.
An expandable voice user interface as lab assistant based on an improved version of Google’s speech recognition
Authors: Avila Vazquez Maria Fernanda , Rupp Nicole , Ballardt Larissa , Opara Jeannine , Zuchner Thole
Published: November 2023

Voice assistants are potentially helpful when working in a scientific laboratory. A big challenge is the extremely specific use of language in every laboratory. As with any voice assistant, another concern is data security. Here, we present Rainbow—an open source voice user interface (VUI) for scientific laboratories, that is adaptable to any Windows PC with Internet access. We used Google Translate Site (GTS) as a voice input and output system to ensure communication to the user. The scripting language AutoIt controls GTS, executes all actions and builds the VUI. Rainbow performs tasks from three different areas—general Microsoft Windows tasks, lab-specific tasks, and device-specific tasks. We achieved significantly higher speech recognition accuracy with our VUI than with GTS alone (91.3% versus 85.1%). Because of Rainbow's architecture, it is possible to improve the voice assistant in terms of functionality and accuracy, allowing each laboratory to optimize its own Rainbow system in a user-friendly way. In a test setup, this led to a speech recognition accuracy of 98.6%. Taken together, Rainbow provides an opportunity for every scientist to implement highly specific scientific terms and tasks to this open source voice assistant system in a very user-friendly way.
Research on image recognition of three Fritillaria cirrhosa species based on deep learning
Authors: Chen Yuxiu , Li Yuyan , Zhang Sheng
Published: November 2023

Based on the deep learning method, a network model that can quickly and accurately identify the species ofFritillaria cirrhosaspecies was constructed. The learning method based on deep residual convolutional neural network was used to input the unprocessed original image directly as input, and the features of the image were extracted through convolution and pooling operations. On this basis, the ResNet34 model was improved, and the additional fully connected layer was added in front of the Softmax classifier to improve the learning ability of the network model. Total of 3915 images of three kinds ofFritillaria cirrhosawere used as data sources for the experiments, among which 160 images of each type were randomly selected to form the validation set. The final training set recognition accuracy rate was 95.8%, the validation set accuracy rate reached 92.3%, and the test set accuracy rate was 88.7%. The image recognition method ofFritillaria cirrhosabased on deep learning proposed in this paper is effective and feasible, which can quickly and accurately identify the species ofFritillaria cirrhosaspecies, and provides a new idea for the intelligent recognition of Chinese medicinal materials.
Dysfunctional TLR1 reduces the therapeutic efficacy of chemotherapy by attenuating HMGB1-mediated antitumor immunity in locally advanced colorectal cancer
Authors: Huang Kevin Chih-Yang , Ke Tao-Wei , Chen Jia-Yi , Hong Wei-Ze , Chiang Shu-Fen , Lai Chia-Ying , Chen Tsung-Wei , Yang Pei-Chen , Chen Liang-Chi , Liang Ji-An , Chen William Tzu-Liang , Chao K. S. Clifford
Published: November 2023

Regional lymph node metastasis is an important predictor for survival outcome and an indicator for postoperative adjuvant chemotherapy in patients with colorectal cancer. Even with advances in adjuvant chemotherapeutic regimens, 5-year distant metastasis and survival rates are still unsatisfactory. Here, we evaluate the clinical significance of polymorphisms in receptors for HMGB1, which is the hallmark of chemotherapy-induced immunogenic cell death, in patients with stage II–III colon carcinoma (COAD). We found that high cytosolic HMGB1 is elicited in stage III COAD patients who received adjuvant chemotherapy. Patients with the TLR1-N248S polymorphism (rs4833095), which causes loss-of-function in HMGB1-mediated TLR1–TLR2 signaling, may influence the therapeutic efficacy of adjuvant chemotherapy, leading to a high risk of distant metastasis within 5 years [HR = 1.694, 95% CI = 1.063–2.698, p = 0.027], suggesting that TLR1-N248S is an independent prognostic factor for locally advanced colon carcinoma patients. We found that defective TLR1 impaired TLR1/2 signaling during dendritic cell (DC) maturation for the antitumor immune response under immunogenic chemotherapy oxaliplatin (OXP) treatment. Defective TLR1 on DCs impaired their maturation ability by HMGB1 and reduced the secretion of IFNγ from T cells to eradicate tumor cells in vitro. Moreover, systemic inhibition of TLR1/2 dramatically reduced the tumor-infiltrating immune cells by OXP treatment, leading to poor therapeutic response to OXP. In contrast, administration of a TLR1/2 agonist synergistically increased the benefit of OXP treatment and triggered a high density of tumor-infiltrating immune cells. We also observed that fewer tumor-infiltrating cytotoxic T lymphocytes were located within the tumor microenvironment in patients bearing the TLR1-N248S polymorphism. Overall, our results suggest that dysfunctional TLR1 may reduce the therapeutic response to adjuvant chemotherapy by impairing HMGB1-mediated DC maturation and attenuating the antitumor immune response in locally advanced colon carcinoma patients.
Changes in peripapillary microvasculature in patients with type 2 diabetes patients: effect of systemic hypertension
Authors: Sung Jae-Yun , Lee Kook-Hyung , Jun Ji-Ho , Lee Min-Woo
Published: November 2023

To determine the effect of hypertension (HTN) on the peripapillary microvasculature in type 2 diabetes mellitus (T2DM) patients without diabetic retinopathy (DR). The patients were classified into three groups: the control group (group 1), T2DM group (group 2), and both T2DM and HTN group (group 3). Peripapillary vessel density (VD) was compared using analysis of covariance and linear regression analysis was performed to identify the factors affecting the peripapillary VD. A total of 286 eyes were enrolled: 124 in group 1, 111 in group 2, and 51 in group 3. The peripapillary VDs for the full area were 18.3 ± 0.6, 17.8 ± 1.0, and 17.3 ± 1.2 mm−1 in group 1, group 2, and group 3, respectively, which were significantly different after adjustment for age and best-corrected visual acuity (P < 0.001). In post hoc analyses, group 1 versus group 2 (P < 0.001), group 1 versus group 3 (P < 0.001), and group 2 versus group 3 (P = 0.001) showed significant differences. In linear regression analysis, HTN (B =  − 0.352, P = 0.043) and peripapillary retinal nerve fiber layer (pRNFL) thickness (B = 0.045, P < 0.001) were significantly associated with peripapillary VD in T2DM patients. Peripapillary VD in T2DM patients without clinical DR were lower compared to normal controls, and they were more decreased when HTN was comorbid. The combination of ischemic damage by high blood pressure and impairment of the neurovascular unit by hyperglycemia would result in more severe deterioration of peripapillary microvasculature, and this impairment could be also reflected by pRNFL thinning.
The metabolic effects of intermittent versus continuous feeding in critically ill patients
Authors: Wilkinson D. , Gallagher I. J. , McNelly A. , Bear D. E. , Hart N. , Montgomery H. E. , Le Guennec A. , Conte M. R. , Francis T. , Harridge S. D. R. , Atherton P. J. , Puthucheary Z. A.
Published: November 2023

Intermittent (or bolus) feeding regimens in critically ill patients have been of increasing interest to clinicians and scientists. Changes in amino acid, fat and carbohydrate metabolites over time might yet deliver other benefits (e.g. modulation of the circadian rhythm and sleep, and impacts on ghrelin secretion, insulin resistance and autophagy). We set out to characterise these changes in metabolite concentration. The Intermittent versus Continuous Feeding in Critically Ill paitents study (NCT02358512) was an eight-centre single-blinded randomised controlled trial. Patients were randomised to received a continuous (control arm) or intermittent (6x/day, intervention arm) enteral feeding regimen. Blood samples were taken on trial days 1, 7 and 10 immediately before and 30 min after intermittent feeds, and at equivalent timepoints in the control arm. A pre-planned targeted metabolomic analysis was performend using Nuclear Resonance Spectroscopy. Five hundred and ninety four samples were analysed from 75 patients. A total of 24 amino acid-, 19 lipid based-, and 44 small molecule metabolite features. Across the main two axes of variation (40–60% and 6–8% of variance), no broad patterns distinguished between intermittent or continuous feeding arms, across intra-day sampling times or over the 10 days from initial ICU admission. Logfold decreases in abundance were seen in metabolites related to amino acids (Glutamine − 0.682; Alanine − 0.594), ketone body metabolism (Acetone − 0.64; 3-Hydroxybutyric Acid − 0.632; Acetonacetic Acid − 0.586), fatty acid (carnitine − 0.509) and carbohydrate metabolism ( Maltose − 0.510; Citric Acid − 0.485). 2–3 Butanediol, a by-product of sugar-fermenting microbial metabolism also decreased (− 0.489). No correlation was seen with change in quadriceps muscle mass for any of the 20 metabolites varying with time (all p > 0.05). Increasing severity of organ failure was related to increasing ketone body metabolism (3 Hydroxybutyric Acid-1 and − 3; p = 0.056 and p = 0.014), carnitine deficiency (p = 0.002) and alanine abundancy (p − 0.005). A 6-times a day intermittent feeding regimen did not alter metabolite patterns across time compared to continuous feeding in critically ill patients, either within a 24 h period or across 10 days of intervention. Future research on intermittent feeding regimens should focus on clinical process benefits, or extended gut rest and fasting.