bluuebunny/crossref_metadata_2025 huggingface dataset:
Hospital Transfers for Digit Replants as Cost Saving and Safe While Access to Replantation Procedures Remains Limited
Authors: Hauc Sacha C. , Ihnat Jacqueline M. , Hu Kevin , Parikh Neil , Rivera Jean Carlo , Alperovich Michael
Published: September 2024

Background

Finger replantation outcomes are influenced both by injury characteristics and by hospital and patient factors, such as hospital type/location and patient gender or insurance. Finger replantation success rates have been shown to be higher at hospitals with higher volumes of finger replants. This study examines the hospital and patient factors that influence hospital transfer and successful replantation in patients experiencing traumatic finger amputation.

Methods

A total of 5219 patients were identified in the 2008–2015 National Inpatient Sample (NIS) as having experienced traumatic finger amputation with attempted replantation. Hospital transfer and replant outcomes were compared with variables such as patient demographics and hospital characteristics using χ2 tests, t tests, ANOVA, and logistic regression.

Results

Traumatic digit amputation patients were most likely to be transferred to medium or large hospitals in urban areas. Hospital transfer was 1.5 times more likely in White patients than Black or Hispanic patients and 1.6 times more likely in middle income quartile patients than the top income quartile. Postreplant amputation was more likely in patients in the lower three income quartiles, on Medicare, of older age, or with more chronic conditions. Hospital transfer was not associated with changes in the probability of requiring amputation after replantation but was associated with a decreased cost of $5000.

Conclusions

Hospital transfers for finger replants are safe with respect to replant failure rates and cost-effective, saving $5000 per procedure. Gaps in equitable access to care remain, warranting further study to improve health equity.
The Association Between the Origin of the Donation After Circulatory Death Liver Recovery Team and Graft Survival: A National Study
Authors: Ibeabuchi Tobenna , Li Eric , Cywes Claire , Bittermann Therese , Mahmud Nadim , Abt Peter L.
Published: September 2024

Background.

Transplant centers have traditionally relied upon procurement teams from their own programs (transplant program procurement team [TPT]) to recover donation after circulatory death (DCD) livers and rarely use surgical procurement teams not affiliated with the recipient center (nontransplant program procurement team [NTPT]). However, in the era of wider geographic organ sharing, greater reliance on NTPTs is often necessary.

Methods.

We used national data to study the association between the origin of the donor procurement team (NTPT versus TPT) and the risk of DCD liver allograft failure.

Results.

Five hundred NTPT and 2257 TPT DCD transplants were identified: 1-y graft survival was 88.9 and 88.6%, respectively (P = 0.962). In a multivariable model, the origin of the procurement team was not associated with graft failure NTPT versus TPT (hazard ratio, 0.92; 95% confidence interval, 0.71-1.22; P = 0.57) but rather with known risks for DCD graft loss including donor age, degree of recipient illness, cold ischemic time, and retransplantation. The overall incidence of retransplantation and ischemic cholangiopathy as an indication for retransplantation were similar between NTPT and TPT.

Conclusions.

This data suggests that transplant centers may be able to safely use DCD livers recovered by local surgical teams.
Fostering an aged care organizational culture that supports innovation
Authors: Davy Carol Patricia , Windle Alice , Harvey Gillian
Published: September 2024

Aim:

This study aimed to identify how aged care organizations can foster a culture that supports the implementation of innovation.

Introduction:

The aged care sector must innovate to meet clients’ evolving needs and increased regulatory requirements. Given the need to account for the values, beliefs, expectations, and assumptions held by a diverse range of stakeholders, implementing innovations within aged care can be exceptionally complex. Fostering a supportive organizational culture can facilitate the implementation of these critical innovations.

Methods:

Papers from a large scoping review that identified organizational culture as a barrier and/or enabler to implementing innovations in aged care were imported into NVivo. Data relating to how organizations fostered (or could foster) a culture that supported the implementation of innovations were then extracted, inductively coded, interpreted, and grouped into approaches.

Results:

Of the 193 papers from the original scoping review, 109 were included in this secondary analysis. From these 109 papers, we identified six key approaches: cultivating collaboration; valuing contributions; ensuring alignment between the organizational vision, culture, and innovation; demonstrating organizational commitment; developing and communicating the implementation plan; and accounting for stability.

Conclusions:

Our study outlines effective approaches that can be used by aged care organizations to cultivate a culture that supports the implementation of innovations. However, these approaches should not be viewed in isolation; rather, they are interconnected and mutually reinforcing. Together, these insights offer practical guidance for aged care entities seeking to adapt and evolve through innovation implementation.

Spanish abstract:

http://links.lww.com/IJEBH/A264
Leading the way: implementing aged care innovations
Authors: Davy Carol , Windle Alice , Marshall Amy , Harvey Gillian
Published: September 2024

Objectives:

The objective of this study was to identify the key characteristics of leaders that support the implementation of innovations in aged care settings.

Methods:

We conducted a secondary analysis of papers from a large scoping review that identified how leaders supported the implementation of innovations in aged care. Once imported into NVivo12, the findings were deductively coded using the domains of Bloom's taxonomy of learning. Each parent code was then inductively analyzed to identify key characteristics within each domain.

Results:

Our review identified four types of knowledge, five skills, and six attitudes that leaders should exhibit to better support the implementation of innovations within aged care settings. In addition to our findings regarding Bloom's learning domains, we identified nine leadership behaviors that participants in the included papers perceived as valuable for enhancing the implementation process. Furthermore, we identified four key organizational elements that support leaders in navigating and facilitating the implementation of innovations within aged care settings.

Conclusion:

Our review identified the characteristics that leaders should demonstrate when supporting the implementation of innovations in aged care. Importantly, our findings also emphasized the changing role of leadership from a hierarchical approach to a more collaborative, supportive, and empowering style. The insights identified in this review will help to guide aged care leaders, stressing the significance of adaptable and relational leadership styles that will guide the implementation of innovations within the aged care sector.

Spanish abstract:

http://links.lww.com/IJEBH/A271
Davy’s Notemaking
Authors: Lacey Andrew
Published: September 2024

In three sections, this article, building on David Knight’s early and important (but brief) assessment of the character of Humphry Davy’s (1778–1829) notemaking, presents and examines three of the main uses of Davy’s notebooks: as spaces or sites for experimentation; for projection; and for preservation. After providing an introductory overview of Davy’s notebook collection, it presents key readings, tied closely to Davy’s biography, of Davy notebooks from his early (notebooks 13C, 13E, 21B, 22A and 22C), middle (06 and 07), and later (14E) years. It also suggests ways in which we might apply organizing or guiding principles to what, on the surface, may appear to be a heterogeneous mass of almost overwhelmingly disparate information, and, taking a primarily comparative approach throughout, of interpreting Davy’s notebook collection as a whole.
Edmund T. Whittaker, physics and Catholicism. Thoughts of a convert
Authors: Navarro Jaume
Published: September 2024

In 1951, Pope Pius XII gave a long speech with the unequivocal title ‘The proofs for the existence of God in the light of modern natural science’, dealing with the relationship between modern science, Thomism and theology. The event was widely reported in the British press partly because the only living scientist quoted in that discourse was the Edinburgh emeritus professor of mathematics and convert to Catholicism, Edmund T. Whittaker (1873–1956), who was, in the 1930s and 1940s, producing his own corpus on the then-popular subject of science and religion. In this article, using the vast and unexplored correspondence between Whittaker and his son, the mathematician John M. Whittaker (1905–1984), I shall explore his thoughts and popular works, in which he mixed modern physics and mathematics, philosophy, apologetics, and theology. Whittaker is well known among historians of science for his
A history of the theories of aether and electricity
, the work of a hard-working, self-trained history aficionado. Similarly, after his conversion (in 1930, at the age of 57), Whittaker started reading and forming his own views around the official philosophy of the Catholic Church, Thomism. The core idea with which he justified his conversion and which would be the backbone of his speculations on natural theology was ‘sacramentality’. With it, he thought he could bridge the gap between mathematics, modern physics, and religion, and all with a
sui generis
embrace of Thomism.
The impact of cooking and burial on proteins: a characterisation of experimental foodcrusts and ceramics
Authors: Evans Miranda , Hagan Richard , Boyd Oliver J. , Bondetti Manon , Craig Oliver E. , Collins Matthew J. , Hendy Jessica
Published: September 2024

Foodcrusts have received relatively little attention in the burgeoning field of proteomic analysis of ancient cuisine. We remain ignorant of how cooking and burial impact protein survival, and crucially, the extent to which the extractome reflects the composition of input ingredients. Therefore, through experimental analogues, we explore the extent of protein survival in unburied and buried foodcrusts and ceramics using ‘typical’ Mesolithic ingredients (red deer, Atlantic salmon and sweet chestnut). We then explore a number of physicochemical properties theorised to aid protein preservation. The results reveal that proteins were much more likely to be detected in foodcrusts than ceramics using the methodology employed, that input ingredient strongly influences protein preservation, and that degradation is not universal nor linear between proteins, indicating that multiple protein physicochemical properties are at play. While certain properties such as hydrophobicity apparently aid protein preservation, none single-handedly explain why particular proteins/peptides survive in buried foodcrusts: this complex interplay requires further investigation. The findings demonstrate that proteins indicative of the input ingredient can be identifiable in foodcrust, but that the full proteome is unlikely to preserve. While this shows promise for the survival of proteins in archaeological foodcrust, further research is needed to accurately interpret foodcrust extractomes.
MAPK/ERK signaling in gliomas modulates interferon responses, T cell recruitment, microglia phenotype, and immune checkpoint blockade efficacy
Authors: Kim Kwang-Soo , Zhang Junyi , Arrieta Víctor A. , Dmello Crismita , Grabis Elena , Habashy Karl , Duffy Joseph , Zhao Junfei , Gould Andrew , Chen Li , Hu Jian , Balyasnikova Irina , Chand Dhan , Levey Dan , Canoll Peter , Zhao Wenting , Sims Peter A. , Rabadan Raul , Pandey Surya , Zhang Bin , Lee-Chang Catalina , Heiland Dieter Henrik , Sonabend Adam M.
Published: September 2024

Background

Glioblastoma (GB) remains a formidable challenge in neuro-oncology, with immune checkpoint blockade (ICB) showing limited efficacy in unselected patients. We previously recently established that MAPK/ERK signaling is associated with overall survival following anti-PD-1 and anti-CTLA-4 treatment in recurrent GB. However, the causal relationship between MAPK/ERK signaling and susceptibility to ICB, as well as the mechanisms underlying this association, remain poorly understood.

Method

We conductedin vivokinome-wide CRISPR/Cas9 screenings in murine gliomas to identify key regulators of susceptibility to anti-PD-1 and CD8+T cell responses and performed survival studies to validate the most relevant genes. Additionally, paired single cell RNA- sequencing (scRNA-seq) with p-ERK staining, spatial transcriptomics on GB samples, andex-vivoslice culture of a BRAFV600Emutant GB tumor treated with BRAFi/MEKi were used to determine the causal relationship between MAPK signaling, tumor cell immunogenicity, and modulation of microglia phenotype.

Results

CRISPR/Cas9 screens identified the MAPK pathway, particularly the RAF-MEK-ERK pathway, as the most critical modulator of glioma susceptibility to CD8+T cells, and anti-PD-1 across all kinases. Experimentally-induced ERK phosphorylation in gliomas enhanced survival with ICB treatment, led to durable anti-tumoral immunity upon re-challenge and memory T cell infiltration in long-term survivors. Elevated p-ERK in glioma cells correlated with increased interferon responses, antigen presentation and T cell infiltration in GB. Moreover, spatial transcriptomics and scRNA-seq analysis revealed the modulation of interferon responses by the MAPK/ERK pathway in BRAFV600Ehuman GB cells with ERK1/2 knockout and in slice cultures of human BRAFV600EGB tissue. Notably, BRAFi/MEKi treatment disrupted the interaction between tumor cells and tumor-associated macrophages/microglia in slice cultures from BRAFV600Emutant GB.

Conclusion

Our data indicate that the MAPK/ERK pathway is a critical regulator of GB cell susceptibility to anti-tumoral immunity, modulating interferon responses, and antigen-presentation in glioma cells, as well as tumor cell interaction with microglia. These findings not only elucidate the mechanistic underpinnings of immunotherapy resistance in GB but also highlight the MAPK/ERK pathway as a promising target for enhancing immunotherapeutic efficacy in this challenging malignancy.
Luminal Flow in the Connecting Tubule induces Afferent Arteriole Vasodilation
Authors: Wang Hong , Ortiz Pablo A. , Romero Cesar A.
Published: September 2024

Background

Renal autoregulatory mechanisms modulate renal blood flow. Connecting tubule glomerular feedback (CNTGF) is a vasodilator mechanism in the connecting tubule (CNT), triggered paracrinally when high sodium levels are detected via the epithelial sodium channel (ENaC). The primary activation factor of CNTGF—whether NaCl concentration, independent luminal flow, or the combined total sodium delivery—is still unclear. We hypothesized that increasing luminal flow in the CNT induces CNTGF via O2-generation and ENaC activation.

Methods

Rabbit afferent arterioles (Af-Arts) with adjacent CNTs were microperfusedex-vivowith variable flow rates and sodium concentrations ranging from <1 mM to 80 mM and from 5 to 40 nL/min flow rates.

Results

Perfusion of the CNT with 5 mM NaCl and increasing flow rates from 5 to 10, 20, and 40 nL/min caused a flow rate-dependent dilation of the Af-Art (p<0.001). Adding the ENaC blocker benzamil inhibited flow-induced Af-Art dilation, indicating a CNTGF response. In contrast, perfusion of the CNT with <1 mM NaCl did not result in flow-induced CNTGF vasodilation (p>0.05). Multiple linear regression modeling (R2=0.51;p<0.001) demonstrated that tubular flow (β=0.163 ± 0.04;p<0.001) and sodium concentration (β=0.14 ± 0.03;p<0.001) are independent variables that induce afferent arteriole vasodilation. Tempol reduced flow-induced CNTGF, and L-NAME did not influence this effect.

Conclusion

Increased luminal flow in the CNT induces CNTGF activation via ENaC, partially due to flow-stimulated O2-production and independent of nitric oxide synthase (NOS) activity.
Identification of potent biparatopic antibodies targeting FGFR2 fusion driven cholangiocarcinoma
Authors: Chaturantabut Saireudee , Oliver Sydney , Frederick Dennie T. , Kim Jiwan , Robinson Foxy P. , Sinopoli Alessandro , Song Tian-Yu , Rodriguez Diego J. , Chang Liang , Kesar Devishi , He Yao , Ching Meilani , Dzvurumi Ruvimbo , Atari Adel , Tseng Yuen-Yi , Bardeesy Nabeel , Sellers William R.
Published: September 2024

Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and predict response to FGFR kinase inhibitors. However, the rate and durability of response are limited due to the emergence of resistance, typically involving acquired FGFR2 kinase domain mutations, and to sub-optimal dosing, relating to drug adverse effects. Here, we report the development of biparatopic antibodies targeting the FGFR2 extracellular domain (ECD), as candidate therapeutics. Biparatopic antibodies can overcome drawbacks of standard bivalent monoparatopic antibodies, which often show poor inhibitory or even agonist activity against oncogenic receptors. We show that oncogenic transformation by FGFR2 fusions requires an intact ECD. Moreover, by systematically generating biparatopic antibodies that target distinct epitope pairs along the FGFR2 ECD, we identified antibodies that effectively block signaling and malignant growth driven by FGFR2-fusions. Importantly, these antibodies demonstrate efficacy in vivo, synergy with FGFR inhibitors, and activity against FGFR2 fusions harboring kinase domain mutations. Thus, biparatopic antibodies may serve as new treatment options for patients with FGFR2-altered cholangiocarcinoma.

We identify biparatopic FGFR2 antibodies that are effective against FGFR2 fusion driven cholangiocarcinoma.
Feasibility of laminar functional quantitative susceptibility mapping
Authors: Straub Sina , Zhou Xiangzhi , Tao Shengzhen , Westerhold Erin M. , Jin Jin , Middlebrooks Erik H.
Published: September 2024

Layer fMRI is an increasingly utilized technique that provides insights into the laminar organization of brain activity. However, both blood-oxygen-level-dependent (BOLD) fMRI and vascular space occupancy data (VASO) have certain limitations, such as bias towards larger cortical veins in BOLD fMRI and high specific absorption rate in VASO. This study aims to explore the feasibility of whole-brain laminar functional quantitative susceptibility mapping (fQSM) compared to laminar BOLD fMRI and VASO at ultra-high field. Data were acquired using 3D EPI techniques. Complex data were denoised with NORDIC and susceptibility maps were computed using 3D path-based unwrapping, the variable-kernel sophisticated harmonic artifact reduction as well as the streaking artifact reduction for QSM algorithms. To assess layer-specific activation, twenty layers were segmented in the somatosensory and motor cortices, obtained from a finger tapping paradigm, and further averaged into six anatomical cortical layers. The magnitude of signal change and z-scores were compared across layers for each technique. fQSM showed the largest activation-dependent mean susceptibility decrease in Layers II/III in M1 and Layers I/ II in S1 with up to -1.3 ppb while BOLD fMRI showed the strongest mean signal increase in Layer I. Our data suggest that fQSM demonstrates less bias towards activation in superficial layers compared to BOLD fMRI. Moreover, activation-based susceptibility change was comparable to VASO data. Studying whole-brain, layer-dependent activation with submillimeter fQSM is feasible, and reduces bias towards venous drainage effects on the cortical surface compared to BOLD fMRI, thereby enabling better localization of laminar activation.
Monitoring of Cell-free Human Papillomavirus DNA in Metastatic or Recurrent Cervical Cancer: Clinical Significance and Treatment Implications
Authors: Yin Zhuomin , Feng Tao , Xu Qing , Dai Wumin , Ni Maowei , Ni Juan , Lou Hanmei
Published: September 2024

Purpose

Monitoring of circulating human papillomavirus (HPV) cell-free DNA (cfDNA) is a minimally invasive approach for surveillance in HPV-associated cancers, particularly cervical cancer. The aim of this study was to monitor circulating HPV cfDNA levels in patients with recurrent or metastatic cervical cancer during treatment and follow-up to assess the utility of HPV cfDNA as a tumor marker for disease surveillance and in guiding clinical treatment decisions.

Experimental Design

In this prospective pilot observational study, levels of HPV cfDNA in serum samples from 28 patients with recurrent or metastatic HPV+ cervical cancer were measured via digital droplet polymerase chain reaction. Results for HPV cfDNA levels were matched to clinical outcomes and to serum levels of squamous cell carcinoma antigen (SCC-Ag) to assess the clinical potential of HPV cfDNA as a tumor marker.

Results

HPV cfDNA was detected in all 28 patients (100%). Notably, median baseline HPV cfDNA levels varied according to the metastatic pattern in individual patients (P=0.019). Specifically, patients with a combined multiple-metastasis pattern had higher median baseline HPV cfDNA levels than patients with a single metastasis (P=0.003). All participants exhibited changes in HPV cfDNA levels over a median monitoring period of 2 months (range 0.3–16.9) before evaluations for treatment response or disease progression. Among 26 patients initially diagnosed with squamous cell cervical cancer, the positivity rate was 100% for HPV cfDNA and 69.2% for SCC-Ag (P=0.004, 95% confidence interval, 0–0.391). Among 20 patients longitudinally monitored for squamous cell cervical cancer, the concordance with changes in disease status was 90% for HPV cfDNA and 50% for SCC-Ag (P=0.014, 95% confidence interval, 0.022–0.621).

Conclusions

HPV cfDNA is a promising tumor marker for HPV+ cervical cancer that offers advantages over SCC-Ag. In the context of precision medicine, HPV cfDNA is poised to play an increasingly pivotal role in monitoring treatment efficacy, providing valuable insights into disease progression, and guiding clinical decisions.
MEK1/2 kinases cooperate with c-Myc:MAX to prevent polycomb repression ofTERTin human pluripotent stem cells
Authors: Kotian Spandana , Rizzardi Lindsay F. , Stern Josh L.
Published: September 2024

Telomerase counteracts telomere shortening, enabling human embryonic stem cells (hESC) to undergo long-term proliferation. MAPK signaling plays a major role in regulating the self-renewal of hESC, and previous studies in induced pluripotent stem cells (iPSC) suggested that expression ofTERT, the gene encoding the catalytic subunit of telomerase, relies on MAPK signaling. We examined whether MEK-ERK signaling regulatedTERTtranscription in a model of normal hESC. Kinase inhibitors of MEK1 and MEK2 (MEKi) or ERK1 and ERK2 (ERKi) significantly repressedTERTmRNA levels. Using chromatin immunoprecipitation (ChIP) we observed that MEKi induced the accumulation of the repressive histone mark histone 3 lysine 27 trimethylation (H3K27me3) at theTERTproximal promoter. This increase corresponded with a loss of histone 3 lysine 27 acetylation (H3K27ac) which is associated with transcriptionally active loci. Inhibition of the polycomb repressive complex 2 (PRC2), which deposits H3K27me3, partially rescued the loss ofTERTexpression, indicating that MEK1/2 activity can limit PRC2 activity atTERT. Inhibition of MEK/ERK kinases also repressed expression of c-Myc, a transcription factor reported to regulateTERTin other immortalized cells. Consistent with a key role for c-Myc in regulatingTERT, low doses of a c-Myc:MAX dimerization inhibitor induced a striking and rapid gain of H3K27me3 atTERTand repressedTERTtranscription in hESC. Inhibiting c-Myc:MAX dimerization also resulted in lower MAX recruitment toTERT, suggesting that this complex acts in cis atTERT. Our study using a model of normal human pluripotent stem cells identifies new regulators and mechanisms controlling transcription of an important, developmentally regulated gene involved in telomere protection.
Unlocking precision: How corneal cell area analysis revolutionizes post-transplant stem cell monitoring
Authors: Parkinson Patrick , Makarenko Irina , Baylis Oliver J , Figueiredo Gustavo S , Lako Majlinda , Shukurov Anvar , Figueiredo Francisco C , Wadkin Laura E
Published: September 2024

The corneal epithelium is maintained by limbal stem cells (LSCs). Dysfunction of the LSCs, resulting from chemical and thermal burns, contact lens-related disease, congenial disorders, among other conditions, leads to limbal stem cell deficiency (LSCD), a sight-threatening condition. An effective treatment of LSCD, with 76% of patients reporting regained sight up to 24 months after the operation, consists of transplantingex-vivocultured LSCs from the patient’s other healthy eye (i.e. autologous) or donor (i.e. allogeneic) to the affected eye. The post-operative assessment of corneal recovery is crucial but relies on ponderous and generally subjective visual inspection of a large number of microscopic images of the corneal epithelial cells, relying on the personal experience of the practitioner to interpret imprecise, qualitative diagnostic criteria. From a unique library of 100,000 cornea cell images from 34 patients, we have randomly selected 10 individuals (3,668 images) to demonstrate that the frequency distribution of the epithelial cell areas is a sensitive diagnostic tool of the corneal epithelium status. After a successful operation the distribution of cell areas is rather flat, reflecting an anomalously wide range of cell areas. As the cornea recovers, the frequency distribution becomes narrower with high statistical confidence and eventually approaches that of the healthy cornea. The corneal epithelial cell shape is independent of the cornea status despite a widespread expectation that healthy cells have a hexagonal shape. We also show that the corneal epithelial cell area distribution and its variation with the depth within the cornea are specific to each patient.

Significance Statement

Chemical and thermal cornea burns, contact-lens damage and hereditary factors, among other conditions, cause limbal stem cell deficiency (LSCD), a widespread sight-threatening condition. An efficient LSCD treatment involves a stem cell transplant from the patient’s other healthy eye, in unilateral cases, or a donor, in bilateral cases. Traditional post-operative cornea monitoring is laborious and often subjective as it relies on visual inspection of microscopy corneal epithelial images. We show that the distribution of epithelial cell areas is a sensitive LSCD diagnostic, evolving systematically to a healthy form after a successful treatment. We have developed computer algorithms to implement this quantitative, sensitive and precise approach which can radically improve the quality of both cornea monitoring in disease and response to treatment.
Mutual dependence between membrane phase separation and bacterial division protein dynamics in synthetic cell models
Authors: Kanwa Nishu , Kohyama Shunshi , Fröhlich Leonard , Desai Amogh , Schwille Petra
Published: September 2024

Cell membranes in bacteria are laterally polarized to produce specific environments for membrane proteins, e.g., proteins involved in cell division which accumulate at mid-cell or the cell poles. An interesting result of such membrane-lipid interplay is the reorganization of lipid domains together with membrane-bound proteins at the onset of cell division, suggesting a functional significance of membrane compartments in the cell cycle. Here, by adopting the key bacterial division proteins MinCDE and FtsZ as an archetypal spatial patterning system, we present a simple vesicle-basedin vitromodel to explore the mutual dependence of protein pattern formation and membrane heterogeneity. Like many other peripheral membrane proteins, MinDE exhibit preferential binding and macro-scale pattern formation at Lddomains, which leads to altered oscillation mode selection in phase-separated membrane compartments (GUVs). Moreover, incorporating bacterial division proteins within phase-separated GUVs leads to blebbing-like membrane deformations followed by the reorganization of Lodomains aligning at the neck region of the bleb, which agrees well with the domain rearrangement in bacterial membranes immediately preceding the radial constriction process. Overall, the presentedin vitromodel system showcases a basic framework to better comprehend the cellular division mechanism in consideration of complex cellular lipid environments.
An extensive archaeological dental calculus dataset spanning 5000 years for ancient human oral microbiome research
Authors: Standeven Francesca J. , Dahlquist-Axe Gwyn , Hendy Jessica , Fiddyment Sarah , Holst Malin , McGrath Krista , Collins Matthew , Mundorff Amy , Radini Anita , Wagner Josef , Meehan Conor J. , Tedder Andrew , Speller Camilla F.
Published: September 2024

Archaeological dental calculus can provide detailed insights into the ancient human oral microbiome. We offer a multi-period, multi-site, ancient shotgun metagenomic dataset consisting of 174 samples obtained primarily from archaeological dental calculus derived from various skeletal collections in the United Kingdom. This article describes all the materials used including the skeletons’ historical period and burial location, biological sex, and age determination, data accessibility, and additional details associated with environmental and laboratory controls. In addition, this article describes the laboratory and bioinformatic methods associated with the dataset development and discusses the technical validity of the data following quality assessments, damage evaluations, and decontamination procedures. Our approach to collecting, making accessible, and evaluating bioarchaeological metadata in advance of metagenomic analysis aims to further enable the exploration of archaeological science topics such as diet, disease, and antimicrobial resistance (AMR).
Influence of formaldehyde on signaling pathways when used in mammalian cell culture
Authors: Ostmann Katharina , Kraegeloh Annette , Weber Wilfried
Published: September 2024

Formaldehyde is the smallest existing aldehyde, a highly reactive color less gas at room temperature and ubiquitously present in our atmosphere. Because of its reactivity leading to the crosslinking of macromolecules like proteins, it is widely used in industrial applications, but also in cell biology in order to preserve cells and tissues for further analysis. In this work, we show that formaldehyde releasing solutions commonly used for fixation of cells, can diffuse via the gas phase to the neighboring well and influence signaling processes in the therein cultured cells. To analyze this effect, we utilized a stable reporter cell line for YAP signaling or a gene expression-based reporter for activation of the NF-κB pathway. Especially the stable reporter cell line can also be used as sensor for bioavailable formaldehyde. The observed impact of formaldehyde on cellular signaling underscores the need for careful planning of experimental protocols and emphasizes the importance of implementing proper controls when utilizing this reagent in cellular signaling analyses.
A modular system for programming multistep activation of endogenous genes in stem cells
Authors: Puppala Anupama K. , Nielsen Andrew C. , Regan Maureen R. , Mancinelli Georgina E. , De Pooter Renee F. , Arnovitz Stephen , Harding Caspian , McGregor Michaele , Balanis Nikolas G. , Clarke Ryan , Merrill Bradley J.
Published: September 2024

Although genomes encode instructions for mammalian cell differentiation with rich syntactic relationships, existing methods for genetically programming cells have modest capabilities for stepwise regulation of genes. Here, we developed a sequential genetic system that enables transcriptional activation of endogenous genes in a preprogrammed, stepwise manner. The system relies on the removal of an RNA polymerase III termination signal to induce both the transcriptional activation and the DNA endonuclease activities of a Cas9-VPR protein to effect stepwise progression through cascades of gene activation events. The efficiency of the cascading system enables a new dimension for cellular programming by allowing the manipulation of the sequential order of gene activation for directing the differentiation of human stem cells.

One-Sentence Summary

Development of a synthetic biology system for preprogrammed, stepwise activation of endogenous genes.
Assessing Ebola Virus Circulation in the Tshuapa Province (Democratic Republic of the Congo): A One Health Investigation of Wildlife and Human Interactions
Authors: van Vredendaal Rianne , Joffrin Léa , Paviotti Antea , Mande Claude , Milolo Solange , Laurent Nicolas , Fourchault Léa , Adroabadrio Douglas , Baelo Pascal , Ngoy Steve , Ansobi Papy , Nebesse Casimir , Peeters Martine , Ayouba Ahidjo , Champagne Maeliss , Bouillin Julie , Těšíková Jana , Van Houtte Natalie , Gryseels Sophie , Salloum Maha , Bikioli Freddy , Thys Séverine , Mpato Jimmy , Ilonga Ruben , Kimina Henri , Larivière Ynke , Lemey Gwen , Van Damme Pierre , Van Geertruyden Jean-Pierre , Muhindo-Mavoko Hypolite , Mitashi Patrick , Leirs Herwig , Verheyen Erik , Gembu Guy-Crispin , Mariën Joachim
Published: September 2024

The wildlife reservoir and spillover mechanisms of the Ebola virus remain elusive despite extensive research efforts in endemic areas. This study employed a One Health approach to examine the virus’ circulation in wildlife and the associated human exposure risks in the Tshuapa province of the Democratic Republic of the Congo. In 2021, we collected 1015 samples from 888 animals, predominantly small mammals, and 380 inhabitants of Inkanamongo village, the site of an Ebola virus disease outbreak in 2014. These samples were screened for evidence of current (RNA) or past (IgG antibodies) Ebola virus infections. We also conducted interviews with 167 individuals in the surrounding districts to assess their interactions with wildlife. While no Ebola virus RNA was detected in the wildlife samples, anti-orthoebolavirus IgG antibodies were found in 13 bats and 38 rodents. Among the human participants, 120 individuals had IgG antibodies against at least one orthoebolavirus antigen, with 12 showing seropositivity for two antigens of the same orthoebolavirus, despite not having a prior Ebola disease diagnosis. Furthermore, over 50% of respondents reported frequent visits to the forest to hunt a variety of wild animals, particularly ungulates and rodents, which could account for occasional viral spillovers. The absence of active Ebola virus circulation in wildlife may reflect seasonal patterns in reservoir ecology, like those observed in bats. Similarly, seasonal human activities, like hunting and foraging, may result in periodic exposure risks. These findings highlight the importance of continuous, multidisciplinary surveillance to monitor changes in seasonal spillover risks.
Comparative Characterization of Bronchial and Nasal Mucus Reveals Key Determinants of Influenza A Virus Inhibition
Authors: Pohl Marie O , Violaki Kalliopi , Liu Lu , Gaggioli Elisabeth , Glas Irina , von Kempis Josephine , Lin Chia-wei , Terrettaz Céline , David Shannon C. , Charlton Frank , Motos Ghislain , Bluvshtein Nir , Schaub Aline , Klein Liviana K , Luo Beiping , Hugentobler Walter , Krieger Ulrich K , Peter Thomas , Kohn Tamar , Nenes Athanasios , Stertz Silke
Published: September 2024

Differentiated primary human respiratory epithelial cells grown at air-liquid interface have become a widely used cell culture model of the human conducting airways. These cultures contain secretory cells such as goblet and club cells, which produce and secrete mucus. Here, we characterize the composition of mucus harvested from airway cultures of nasal and bronchial origin. We find that despite inter-donor variability, the salt, sugar, lipid, and protein content and composition are very similar between nasal and bronchial mucus. However, subtle differences in the abundance of individual components in nasal versus bronchial mucus can influence its antimicrobial properties: The ability of mucus to neutralize influenza A virus varies with the anatomical origin of the airway cultures and correlates with the abundance of triglycerides and sialylated glycoproteins and glycolipids.
TheDrosophilamaternal-effect geneabnormal oocyte(ao) does not repress histone gene expression
Authors: Takenaka Risa , Simmerman Sierra M. , Schmidt Casey A. , Albanese Eric H. , Rieder Leila E. , Malik Harmit S.
Published: September 2024

Theabnormal oocyte(ao) gene ofDrosophila melanogasteris a maternal-effect lethal gene previously identified as encoding a transcriptional regulator of core histones. However, background genetic mutations in existingaomutant strains could compromise their utility in manipulating histone levels. To distinguish the trueaophenotype from background effects, we created two newaoreagents: a CRISPR/Cas9-mediated knockout of theaoallele for genetic and molecular analyses and an epitope-taggedaoallele for cytological experiments. Using these reagents, we confirm previous findings thataoexhibits maternal-effect lethality, which can be rescued by either a decrease in the histone gene copy number or by Y chromosome heterochromatin. We also confirm that the Ao protein localizes to the histone locus bodies in ovaries. Our data also suggest thataogenetically interacts with the histone genes and heterochromatin, as previously suggested. However, contrary to prior findings, we find thataodoes not repress core histone transcript levels. Thus, the molecular basis forao-associated maternal-effect lethality remains unknown.
Variant classification guidelines for animals to objectively evaluate genetic variant pathogenicity
Authors: Boeykens Fréderique , Abitbol Marie , Anderson Heidi , Casselman Iris , Dufaure de Citres Caroline , Hayward Jessica J. , Häggström Jens , Kittleson Mark D. , Lepri Elvio , Ljungvall Ingrid , Longeri Maria , Lyons Leslie A. , Ohlsson Åsa , Peelman Luc , Smets Pascale , Vezzosi Tommaso , van Steenbeek Frank G. , Broeckx Bart J.G.
Published: September 2024

Assessing the pathogenicity of a disease-associated variant in animals accurately is vital, both on a population and individual scale. At the population level, breeding decisions based on invalid DNA tests can lead to the incorrect exclusion of animals and compromise the long- term health of a population, and at the level of the individual animal, lead to incorrect treatment and even life-ending decisions. Criteria to determine pathogenicity are not standardized, hence no guidelines for animal variants are available. Here, we developed and optimized the animal variant classification guidelines, based on those developed for humans by The American College of Medical Genetics and Genomics, and demonstrated a superior classification in animals. We described methods to develop datasets for benchmarking the criteria and identified the most optimal in silico variant effect predictor tools. As the reproducibility was high, we classified 72 known disease-associated variants in cats and 40 other disease-associated variants in eight additional species.
Cholesterol binding to VCAM-1 promotes vascular inflammation
Authors: Kennelly John P. , Xiao Xu , Gao Yajing , Kim Sumin , Hong Soon-Gook , Villanueva Miranda , Ferrari Alessandra , Vanharanta Lauri , Nguyen Alexander , Nagari Rohith T. , Burton Nikolas R. , Tol Marcus J. , Becker Andrew P. , Lee Min Jae , Ikonen Elina , Backus Keriann M. , Mack Julia J. , Tontonoz Peter
Published: September 2024

Hypercholesterolemia has long been implicated in endothelial cell (EC) dysfunction, but the mechanisms by which excess cholesterol causes vascular pathology are incompletely understood. Here we used a cholesterol-mimetic probe to map cholesterol-protein interactions in primary human ECs and discovered that cholesterol binds to and stabilizes the adhesion molecule VCAM-1. We show that accessible plasma membrane (PM) cholesterol in ECs is acutely responsive to inflammatory stimuli and that the nonvesicular cholesterol transporter Aster-A regulates VCAM-1 stability in activated ECs by controlling the size of this pool. Deletion of Aster-A in ECs increases VCAM-1 protein, promotes immune cell recruitment to vessels, and impairs pulmonary immune homeostasis. Conversely, depleting cholesterol from the endotheliumin vivodampens VCAM-1 induction in response to inflammatory stimuli. These findings identify cholesterol binding to VCAM-1 as a key step during EC activation and provide a biochemical explanation for the ability of excess membrane cholesterol to promote immune cell recruitment to the endothelium.
RNA Polymerase II coordinates histone deacetylation at active promoters
Authors: Hoffman Jackson A. , Trotter Kevin W. , Archer Trevor K.
Published: September 2024

Nucleosomes at actively transcribed promoters have specific histone post-transcriptional modifications and histone variants. These features are thought to contribute to the formation and maintenance of a permissive chromatin environment. Recent reports have drawn conflicting conclusions about whether these histone modifications depend on transcription. We used triptolide to inhibit transcription initiation and degrade RNA Polymerase II and interrogated the effect on histone modifications. Transcription initiation was dispensable forde novoand steady-state histone acetylation at transcription start sites (TSSs) and enhancers. However, at steady state, blocking transcription initiation increased the levels of histone acetylation and H2AZ incorporation at active TSSs. These results demonstrate that deposition of specific histone modifications at TSSs is not dependent on transcription and that transcription limits the maintenance of these marks.
Comparison of Explainable AI Models for MRI-based Alzheimer’s Disease Classification
Authors: Chattopadhyay Tamoghna , Joshy Neha Ann , Jagad Chirag , Gleave Emma J. , Thomopoulos Sophia I. , Feng Yixue , Villalón-Reina Julio E. , Laltoo Emily , Joshi Himanshu , Venkatasubramanian Ganesan , John John P. , Steeg Greg Ver , Ambite Jose Luis , Thompson Paul M.
Published: September 2024

Deep learning models based on convolutional neural networks (CNNs) have been used to classify Alzheimer’s disease or infer dementia severity from 3D T1-weighted brain MRI scans. Here, we examine the value of adding occlusion sensitivity analysis (OSA) and gradient-weighted class activation mapping (Grad-CAM) to these models to make the results more interpretable. Much research in this area focuses on specific datasets such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI) or National Alzheimer’s Coordinating Center (NACC), which assess people of North American, predominantly European ancestry, so we examine how well models trained on these data generalize to a new population dataset from India (NIMHANS cohort). We also evaluate the benefit of using a combined dataset to train the CNN models. Our experiments show feature localization consistent with knowledge of AD from other methods. OSA and Grad-CAM resolve features at different scales to help interpret diagnostic inferences made by CNNs.
Pion gravitational form factors in the QCD instanton vacuum. I
Authors: Liu Wei-Yang , Shuryak Edward , Weiss Christian , Zahed Ismail
Published: September 2024

The pion form factors of the QCD energy-momentum tensor (EMT) are studied in the instanton liquid model (ILM) of the QCD vacuum. In this approach, the breaking of conformal symmetry is encoded in the form of stronger-than-Poisson fluctuations in the number of instantons. For the trace of the EMT, it is shown that the gluonic trace anomaly term contributes half the pion mass, with the other half coming from the quark-mass-dependent σ term. The Q2 dependence of the form factors is governed by glueball and scalar meson exchanges. For the EMT, the spin-0 (trace) and spin-2 (traceless rank-2 tensor) form factors are computed at next-to-leading order in the instanton density using effective quark operators. Relations between the gluon and quark contributions to the EMT form factors are derived. The form factors are also expressed in terms of the pion light-front wave functions in the ILM. The results at the low resolution scale of the inverse instanton size are evolved to higher scales using the renormalization group equation. The ILM results compare well with those of recent lattice QCD calculations.

Published by the American Physical Society
2024
Studying the
Ξ(2030)
as a predominantly
K¯*Σ
molecular state
Authors: Feng Jing-wen , Cheng Cai , Huang Yin
Published: September 2024

Since its discovery in 1977, the spin parity of Ξ(2030) has not been fully determined experimentally. The latest Particle Data Group listing suggests it may be a baryon with J=5/2. Therefore, studying the mass spectrum and decay properties of Ξ(2030) has become a current hot topic to definitively establish its spin parity. As the three-quark model fails to explain Ξ(2030), we previously proposed it may be a molecule primarily composed of K¯*Σ with JP=5/2+, based on its mass spectrum study. To verify its molecular state interpretation, this work proposes studying the strong decays of Ξ(2030) assuming it is a P-wave JP=5/2+ meson-baryon molecule predominantly composed of K¯*Σ. We calculated all experimentally measured two-body and three-body final state decay widths of Ξ(2030), including Ξ(2030)→K¯Λ,K¯Σ,πΞ,πΞ*, and Ξ(2030)→ππΞ,πK¯Σ,πK¯Λ. The results indicate that both the total decay width and partial decay widths agree well with experimental values within the error margins. This supports that Ξ(2030) is a molecule with spin-parity JP=5/2+, predominantly composed of K¯*Σ. Compared to the experimental central values, our results are slightly smaller, which suggests that Ξ(2030) may contain additional components besides meson-baryon molecular components, such as three-quark structures.

Published by the American Physical Society
2024
Pseudoscalar heavy quarkonium production in heavy ion ultraperipheral collision
Authors: Jiang Jun , Li Shi-Yuan , Liang Xiao , Liu Yan-Rui , Qiao Cong-Feng , Si Zong-Guo , Yang Hao
Published: September 2024

The inclusive production of pseudoscalar heavy quarkonia (ηc, ηb, and Bc) via photon-photon fusion in heavy ion ultraperipheral collision (UPC) are calculated to QCD next-to-leading order in the framework of nonrelativistic QCD (NRQCD). The total cross section of ηc produced in Pb-Pb UPC is 194  nb and 1275  nb at nucleon-nucleon c.m. energies SNN=5.52  TeV and 39.4 TeV, respectively. The cross sections for ηb and Bc mesons are more than two to three orders of magnitude smaller. We make a detailed phenomenological analysis on the ηc production; the uncertainties caused by the renormalization scale and the charm quark mass, the cross sections in other ultraperipheral nucleon-nucleon colliding systems, and the transverse momentum distribution are discussed. At the coming HL-LHC and future FCC, the heavy ion UPC opens another door of the study on the production of heavy quarkonium.

Published by the American Physical Society
2024