bluuebunny/crossref_metadata_2025 huggingface dataset:
Danshen injection mitigated the cerebral ischemia/reperfusion injury by suppressing neuroinflammation via the HIF-1α/CXCR4/NF-κB signaling pathway
Authors: Chen Gao , Jin Zhan , Wang Xi , Yu Qi-Hui , Hu Gao-Bo
Published: May 2024

Danshen injection (DI) is effective in treating cardiovascular and cerebrovascular diseases, including ischemic stroke (IS), including IS, but its mechanism is unclear. A middle cerebral artery occlusion model was used to simulate ischemia/reperfusion (I/R) injury in SD rats. Overexpression of hypoxia-inducible factor 1α (HIF-1α) was achieved by AAV-HIF-1α. Rats were treated with DI or saline. Neurological scores and infarction rates were assessed. I/R damage was examined by HE, 2,3,5-triphenyltetrazolium and Nissl stainings. Expression levels of relative proteins [TNF-α, IL-6, IL-1β, SOD, MDA, ROS, HIF-1α, CXC chemokine receptor 4 (CXCR4) and NF-κB] were measured. DI treatment improved neurological scores and reduced infarction rates, suggesting that it inhibits inflammation and oxidative stress. The expression levels of HIF-1α, CXCR4 and NF-κB were decreased. However, the effectiveness of DI on inflammation inhibition was lost after HIF-1α overexpression. DI may directly target HIF-1α to suppress neuroinflammation and reduce I/R injury by suppressing the HIF-1α/CXCR4/NF-κB signaling pathway.
Increased prevalence of vertebrobasilar dolichoectasia in Parkinson’s disease and its effect on white matter microstructure and network
Authors: Li Sichen , Zhu Yuxia , Lai Hongyu , Da Xiaohui , Liao Ting , Liu Xi , Deng Fen , Chen Lifen
Published: May 2024

This study aimed to investigate the prevalence of vertebrobasilar dolichoectasia (VBD) in Parkinson’s disease (PD) patients and analyze its role in gray matter changes, white matter (WM) microstructure and network alterations in PD. This is a cross-sectional study including 341 PD patients. Prevalence of VBD in these PD patients was compared with general population. Diffusion tensor imaging and T1-weighted imaging analysis were performed among 174 PD patients with or without VBD. Voxel-based morphometry analysis was used to estimate gray matter volume changes. Tract-based spatial statistics and region of interest-based analysis were used to evaluate WM microstructure changes. WM network analysis was also performed. Significantly higher prevalence of VBD in PD patients was identified compared with general population. Lower fractional anisotropy and higher diffusivity, without significant gray matter involvement, were found in PD patients with VBD in widespread areas. Decreased global and local efficiency, increased hierarchy, decreased degree centrality at left Rolandic operculum, increased betweenness centrality at left postcentral gyrus and decreased average connectivity strength between and within several modules were identified in PD patients with VBD. VBD is more prevalent in PD patients than general population. Widespread impairments in WM microstructure and WM network involving various motor and nonmotor PD symptom–related areas are more prominent in PD patients with VBD compared with PD patients without VBD.
Incidence and Risk Factors for Medical Device-Related Pressure Injury in Hemodynamically Unstable Intensive Care Unit Patients
Authors: Bueno Luana Furtado , Coelho Manuela de Mendonça Figueirêdo , Cortez Daniel Nogueira , Moraes Juliano Teixeira
Published: May 2024

PURPOSE:

The purpose of this study was to determine the incidence and identify potential risk factors for medical device-related pressure injury (MDRPI) in critically ill and hemodynamically unstable adults (patients classified class III or IV on the Therapeutic Intervention Scoring System-28; TISS-28).

DESIGN:

Prospective cohort study.

SUBJECTS AND SETTING:

The target population was critically ill adults who were using one or more medical devices and categorized as class III or IV on the TISS-28. The study sample comprised 77 participants followed daily until discharge, death, transfer, or lesion development. Data were collected from January to March 2020. The study setting was an intensive care unit with 40 beds in a large hospital in a municipality in the state of Minas Gerais, Brazil.

METHODS:

Sociodemographic and pertinent clinical data, pressure injury (PI) risk assessed using the Braden Scale for Pressure Sore Risk, and head-to-toe skin inspections were completed. The incidence rate of MDRPIs was calculated, and survival analyses were completed via the Kaplan-Meier method and Cox regression model.

RESULTS:

Forty-nine of 77 participants developed an MDRPI, reflecting an incidence rate of 63.6%. Collectively, 71 MDRPIs occurred in these 49 participants. Univariate analysis indicated significant associations between MDRPI occurrences and level of consciousness (P = < .001), use of tube holder for ventilation devices (P = .013), nasal cannula (P = .034), nasogastric cannula (P = .034), presence of edema (P = .001), infection (P = .007), higher TISS score (P = .047), and greater number of medical devices (P = .022). Survival analysis indicated that a high or very high-risk score on the Braden Scale for Pressure Sore Risk (P = .043) and edema (P = .030) are risk factors for MDRPI occurrences in this vulnerable population.

CONCLUSIONS:

The incidence rate of MDRPIs was 63.6%. The categories with the highest high or very high risk scores on the Braden Scale for Risk of Pressure Pain and Edema emerged as risk factors for MDRPI in this critically ill and vulnerable population.
Sepal shape variability is robust to cell size heterogeneity in
Arabidopsis
Authors: Trinh Duy-Chi , Lionnet Claire , Trehin Christophe , Hamant Olivier
Published: May 2024

How organisms produce organs with robust shapes and sizes is still an open question. In recent years, the
Arabidopsis
sepal has been used as a model system to study this question because of its highly reproducible shape and size. One interesting aspect of the sepal is that its epidermis contains cells of very different sizes. Previous reports have qualitatively shown that sepals with more or less giant cells exhibit comparable final size and shape. Here, we investigate this question using quantitative approaches. We find that a mixed population of cell size modestly contribute to the normal width of the sepal but is not essential for its shape robustness. Furthermore, in a mutant with increased cell and organ growth variability, the change in final sepal shape caused by giant cells is exaggerated but the shape robustness is not affected. This formally demonstrates that sepal shape variability is robust to cell size heterogeneity.
Deterministic theory of evolutionary games on temporal networks
Authors: Wang Xiaofeng , Fu Feng , Wang Long
Published: May 2024

Recent empirical studies have revealed that social interactions among agents in realistic networks merely exist intermittently and occur in a particular sequential order. However, it remains unexplored how to theoretically describe evolutionary dynamics of multiple strategies on temporal networks. Herein, we develop a deterministic theory for studying evolutionary dynamics of any

n
×
n

pairwise games in structured populations where individuals are connected and organized by temporally activated edges. In the limit of weak selection, we derive replicator-like equations with a transformed payoff matrix characterizing how the mean frequency of each strategy varies over time, and then obtain critical conditions for any strategy to be evolutionarily stable on temporal networks. Interestingly, the re-scaled payoff matrix is a linear combination of the original payoff matrix with an additional one describing local competitions between any pair of different strategies, whose weights are solely determined by network topology and selection intensity. As a particular example, we apply the deterministic theory to analysing the impacts of temporal networks in the mini-ultimatum game, and find that temporally networked population structures result in the emergence of fairness. Our work offers theoretical insights into the subtle effects of network temporality on evolutionary game dynamics.
Early arc crust formation preserved in the Grenadines archipelago, southern Lesser Antilles arc
Authors: Camejo-Harry Michal , Melekhova Elena , Aufrère Sarah , McCarthy Anders , Blundy Jon
Published: May 2024

Intra-arc diversity in volcanic activity and composition is ubiquitous, but its underlying causes remain largely unresolved in many settings. In this work, we examine such variability in the Grenadines archipelago, southern Lesser Antilles arc. Here, juxtaposed volcanic centres exhibit eruptive longevities and chemistries distinct from northern counterparts in the same arc. Our goal is to explain this deviation by investigating variations in magmatic processes using petrological data from erupted crustal xenoliths and lavas, and interpreting these findings within the context of the archipelago’s tectonic history and geophysical structure. Textural analyses of xenoliths reveal crystallization over a wide range of pressure–temperature–melt composition conditions in the crust. Mineral phases display discrete compositional trends pointing towards significant inter-island variability in underlying plumbing systems. The geochemical variety of erupted magmas is reminiscent of the entire arc. We speculate that the Grenadines represents the early onset of subduction forming the modern-day Lesser Antilles arc. Extrusive volcanism initiated as submarine activity. Subsequent uplift eroded the original topography of these volcanic centres following the eventual cessation of volcanism in the Neogene. The positioning of the Grenadines on an elevated platform provides rare modern insight into early arc crust formation not commonly preserved in established active arcs.
A mathematical model of the Bray–Liebhafsky reaction
Authors: Dimsey Heath , Forbes Lawrence K. , Bassom Andrew P. , Quinn Courtney
Published: May 2024

It is known that the widely studied Bray–Liebhafsky reaction typically exhibits complex chemical behaviour. Numerous mathematical systems have been proposed to describe the iodine oscillations that occur during this process. Recently, a four-variable model of the Bray–Liebhafsky reaction has been proposed and analytical and numerical investigations suggested that chaotic solutions may exist. We revisit this four-variable model here and perform what appears to be the first detailed work on this system. We suggest that this model is perhaps not chaotic after all. Informed by these fresh insights, we propose a reduced two-variable model based upon the four-variable system. This model is created with the twin goals of enabling simpler mathematical analysis while retaining the underlying chemical mechanisms. We are able to demonstrate that our reduced problem performs very well when compared with the full model for realistic parameter values. In particular, key regions of parameter space are identified within which temporal oscillations can occur. Moreover, these persistent oscillations are consistent with the available qualitative experimental observations.
Sleep in the wild: the importance of individual effects and environmental conditions on sleep behaviour in wild boar
Authors: Mortlock Euan , Silovský Václav , Güldenpfennig Justine , Faltusová Monika , Olejarz Astrid , Börger Luca , Ježek Miloš , Jennings Dómhnall J. , Capellini Isabella
Published: May 2024

Sleep serves vital physiological functions, yet how sleep in wild animals is influenced by environmental conditions is poorly understood. Here we use high-resolution biologgers to investigate sleep in wild animals over ecologically relevant time scales and quantify variability between individuals under changing conditions. We developed a robust classification for accelerometer data and measured multiple dimensions of sleep in the wild boar (
Sus scrofa
) over an annual cycle. In support of the hypothesis that environmental conditions determine thermoregulatory challenges, which regulate sleep, we show that sleep quantity, efficiency and quality are reduced on warmer days, sleep is less fragmented in longer and more humid days, while greater snow cover and rainfall promote sleep quality. Importantly, this longest and most detailed analysis of sleep in wild animals to date reveals large inter- and intra-individual variation. Specifically, short-sleepers sleep up to 46% less than long-sleepers but do not compensate for their short sleep through greater plasticity or quality, suggesting they may pay higher costs of sleep deprivation. Given the major role of sleep in health, our results suggest that global warming and the associated increase in extreme climatic events are likely to negatively impact sleep, and consequently health, in wildlife, particularly in nocturnal animals.
Resilience assessment in complex natural systems
Authors: Sguotti Camilla , Vasilakopoulos Paraskevas , Tzanatos Evangelos , Frelat Romain
Published: May 2024

Ecological resilience is the capability of an ecosystem to maintain the same structure and function and avoid crossing catastrophic tipping points (i.e. undergoing irreversible regime shifts). While fundamental for management, concrete ways to estimate and interpret resilience in real ecosystems are still lacking. Here, we develop an empirical approach to estimate resilience based on the stochastic
cusp
model derived from catastrophe theory. The
cusp
model models tipping points derived from a
cusp
bifurcation. We extend
cusp
in order to identify the presence of stable and unstable states in complex natural systems. Our
Cusp Resilience Assessment
(CUSPRA) has three characteristics: (i) it provides estimates on how likely a system is to cross a tipping point (in the form of a
cusp
bifurcation) characterized by hysteresis, (ii) it assesses resilience in relation to multiple external drivers and (iii) it produces straightforward results for ecosystem-based management. We validate our approach using simulated data and demonstrate its application using empirical time series of an Atlantic cod population and marine ecosystems in the North Sea and the Mediterranean Sea. We show that
Cusp Resilience Assessment
is a powerful method to empirically estimate resilience in support of a sustainable management of our constantly adapting ecosystems under global climate change.
Target for lipid-to-carbohydrate intake minimizes cost of growth
Authors: Talal Stav , Chahal Aunmolpreet , Osgood Geoffrey M. , Brosemann Jonah , Harrison Jon F. , Cease Arianne J.
Published: May 2024

Many theoretical treatments of foraging use energy as currency, with carbohydrates and lipids considered interchangeable as energy sources. However, herbivores must often synthesize lipids from carbohydrates since they are in short supply in plants, theoretically increasing the cost of growth. We tested whether a generalist insect herbivore (
Locusta migratoria
) can improve its growth efficiency by consuming lipids, and whether these locusts have a preferred caloric intake ratio of carbohydrate to lipid (C : L). Locusts fed pairs of isocaloric, isoprotein diets differing in C and L consistently selected a 2C : 1L target. Locusts reared on isocaloric, isoprotein 3C : 0L diets attained similar final body masses and lipid contents to locusts fed the 2C : 1L diet, but they ate more and had a ~12% higher metabolic rate, indicating an energetic cost for lipogenesis. These results demonstrate that some animals can selectively regulate carbohydrate-to-lipid intake and that consumption of dietary lipids can improve growth efficiency.
Whole Genome 3D Blood Biopsy Profiling of Canine Cancers: Development and Validation of EpiSwitch Multi-Choice Array-Based Diagnostic Test
Authors: Hunter Ewan , Salter Matthew , Powell Ryan , Dring Ann , Naithani Tarun , Vugrinec Dominik , Shliaiev Kyrylo , Issa Mutaz , Weston Cicely , Hatton Abigail , Gebregzabhar Abel , Green Jayne , Blum Anthony , Guiel Thomas , Fritz Sara , Seelig Davis , Modiano Jaime F. , Akoulitchev Alexandre
Published: May 2024

Veterinary oncology has a critical need for an accurate, specific, and sensitive non-invasive (blood) biomarker assay to assess multiple canine oncological indications early to better inform therapeutic interventions. Extended from clinical applications in human oncology, here we report on a novel 3D genomics approach to identify systemic blood biomarkers for canine diffuse large B-cell lymphoma (DLBCL), T-zone lymphoma (TZL), hemangiosarcoma (HSA), histiocytic sarcoma, osteosarcoma, and canine malignant melanoma, in a single assay format that encompasses multiple classes and phenotypes of cancer. In the validation of the independent test cohort the 3D whole-genome profiling in peripheral blood demonstrated high sensitivity and specificity for lymphomas and sarcomas as a class, with accuracy >80%; and high sensitivity and specificity for individual indications, with accuracy >89%. This study demonstrates a 3D genomic approach can be used to develop a non-invasive, blood-based test for multiple choice diagnosis of canine oncological indications. The modular EpiSwitch® Specific Canine Blood (EpiSwitch SCB) test promises to help veterinary specialists to diagnose the disease, make more informed treatment decisions, better utilize alternative effective treatments, minimize or avoid unnecessarily toxicity, and efficiently manage costs and resources.
Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy
Authors: Zhang Xiaopei , Taylor Hannah , Valdivia Alain , Dasari Rajaneekar , Buckley Andrew , Bonacquisti Emily , Nguyen Juliane , Kanchi Krishna , Corcoran David L. , Herring Laura E. , Steindler Dennis A. , Baldwin Albert , Hingtgen Shawn , Satterlee Andrew Benson
Published: May 2024

Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate as their parental fibroblasts, and the TRAIL produced by iNSCs were naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies inex vivoorganotypic brain slice cultures showed Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays showed that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts around 3000-fold greater than treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additionalin vivotesting against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a new easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.
Decellularized biohybrid nerve promotes motor axon projections
Authors: Mehta Abijeet Singh , Zhang Sophia L. , Xie Xinran , Khanna Shreyaa , Tropp Joshua , Ji Xudong , Daso Rachel , Franz Colin K. , Jordan Sumanas W. , Rivnay Jonathan
Published: May 2024

Developing nerve grafts with intact mesostructures, superior conductivity, minimal immunogenicity, and improved tissue integration is essential for the treatment and restoration of neurological dysfunctions. A key factor is promoting directed axon growth into the grafts. To achieve this, we developed biohybrid nerves using decellularized rat sciatic nerve modified by in situ polymerization of poly(3,4-ethylenedioxythiophene) (PEDOT). We compared nine biohybrid nerves with varying polymerization conditions and cycles, selecting the best candidate through material characterization. Our results showed that a 1:1 ratio of FeCl3 oxidant to ethylenedioxythiophene (EDOT) monomer, cycled twice, provided superior conductivity (>0.2 mS/cm), mechanical alignment, intact mesostructures, and high compatibility with cells and blood. To test the biohybrid nerve’s effectiveness in promoting motor axon growth, we used human Spinal Cord Spheroids (hSCSs) from HUES 3 Hb9:GFP cells, with motor axons labeled with green fluorescent protein (GFP). Seeding hSCS onto one end of the conduit allowed motor axon outgrowth into the biohybrid nerve. Our construct effectively promoted directed motor axon growth, which improved significantly after seeding the grafts with Schwann cells. This study presents a promising approach for reconstructing axonal tracts in humans.
North Pontic crossroads: Mobility in Ukraine from the Bronze Age to the early modern period
Authors: Saag Lehti , Utevska Olga , Zadnikov Stanislav , Shramko Iryna , Gorbenko Kyrylo , Bandrivskyi Mykola , Pavliv Dmytro , Bruyako Igor , Grechko Denys , Okatenko Vitalii , Toshev Gennadi , Andrukh Svitlana , Radziyevska Vira , Buynov Yurii , Kotenko Viktoriia , Smyrnov Oleksandr , Petrauskas Oleg , Magomedov Borys , Didenko Serhii , Heiko Anatolii , Reida Roman , Sapiehin Serhii , Aksonov Viktor , Laptiev Oleksii , Terskyi Svyatoslav , Skorokhod Viacheslav , Zhyhola Vitalii , Sytyi Yurii , Järve Mari , Scheib Christiana Lyn , Anastasiadou Kyriaki , Kelly Monica , Williams Mia , Silva Marina , Barrington Christopher , Gilardet Alexandre , Macleod Ruairidh , Skoglund Pontus , Thomas Mark G.
Published: May 2024

The North Pontic region, which encompasses present-day Ukraine, was a crossroads of migration as it connected the vast Eurasian Steppe with Central Europe. We generated shotgun-sequenced genomic data for 91 individuals dating from around 7,000 BCE to 1,800 CE to study migration and mobility history in the region, with a particular focus on historically attested migrating groups during the Iron Age and the medieval period, such as Scythian, Chernyakhiv, Saltiv and Nogai associated peoples. We infer a high degree of temporal heterogeneity in ancestry, with fluctuating genetic affinities to present-day Western European, Eastern European, Western Steppe and East Asian groups. We also infer high heterogeneity in ancestry within geographically, culturally and socially defined groups. Despite this, we find that ancestry components which are widespread in Eastern and Central Europe have been present in the Ukraine region since the Bronze Age.
A longitudinal atlas of post-viral lung regeneration reveals persistent injury-associated cell states
Authors: Niethamer Terren K. , Planer Joseph D. , Morley Michael P. , Babu Apoorva , Basil Maria C. , Cantu Edward , Frank David B. , Diamond Joshua M. , Nottingham Ana N. , Li Shanru , Levin Lillian I. , Zhou Su , Morrisey Edward E.
Published: May 2024

Functional regeneration of the lung’s gas exchange surface following injury requires the coordination of a complex series of cell behaviors within the alveolar niche. Using a multi-modal approach, we have mapped the temporal sequencing of mouse lung regeneration after acute viral injury, demonstrating that this response is asynchronously phased across different cellular compartments. This longitudinal atlas of regeneration has produced a catalogue of new cell states that reflect transient and persistent transcriptional alterations in daughter cells as they transit across axes of differentiation. These new cell states include an injury-induced capillary endothelial cell (iCAP) that arises after injury, persists indefinitely, and shares transcriptional hallmarks with both developing lung endothelium and the endothelial aberrations found in degenerative human lung diseases. This comprehensive atlas of lung regeneration provides a foundational resource to understand the complexity of the cellular and molecular responses to injury, reveals the critical importance of capillary endothelium in maintaining and rebuilding the alveolar niche after injury, and correlates these responses to those found in development and human lung diseases.
Microplastics Identified in Commercial Over-the-counter Lubricant Eyedrops
Authors: Jaeger Julia E , Burke Matthew , Wu Duoduo , Curren Emily Ern-Min , Yew Leong Sandric Chee , Symons Robert , Lim Blanche Xiao Hong , Su Xinyi , Mehta Jodhbir Singh , Riau Andri Kartasasmita , Lim Chris Hong Long
Published: May 2024

Purpose

There is increasing evidence that microplastics exert harmful effects on human health and on the ocular surface. Recent studies have highlighted the presence of ocular surface exposure to microplastics via shedding from contact lenses. This study aims to investigate if microplastic particles are present in commonly used eyedrops in single-use plastic vials.

Design

Experimental study.

Methods

Nine commonly used commercial tear-replacement solutions available without a doctor’s prescription were tested (Brands A-I). All brands of eyedrops were analysed visually using light microscopy and the number of microplastic particles were manually counted. Brands A-F were further analysed using the 8700 Agilent Laser Direct Infrared (LDIR) chemical imaging system to identify the microplastic compositions.

Results

All eyedrops analysed contained microplastics. The number of microplastic particles identified using light microscopy ranged between 15 (Brand E) to >18,000 (Brand F). In total, nine types of microplastics were identified with LDIR – an average of 14 polyethylene, 8 polypropylene, 1 polystyrene, 2 polyvinylchloride, 21 polyethylene terephthalate, 1 polycarbonate, 19 polymethylmethacrylate, 23 polyamide and 22 polyurethane per millilitre of eyedrop were identified.

Conclusions

This is the first study that identified microplastics in commercial tear-replacement solutions. These particles may have been derived from secondary degradation of the plastic vials (polyethylene) during production, transportation, or storage, and represent a major source of exposure to the ocular surface, especially among patients who require chronic instillation of eyedrops.
Assessment of Ultraviolet and Infrared Radiations Transmission in Automobile Windshields and Side Windows
Authors: AlQahtani Nouf Jubran , AlEssa Ghada Naje , AlDushaishi Hoor Fayez , Bukair Amnah Nabil , Ali Syed Mehmood
Published: May 2024

Background

Although exposure to solar radiation is beneficial for humans, too much of it can cause severe health conditions, including sunburn and skin cancer. The biological effects of solar radiation vary enormously with wavelength and exposure time. Ultraviolet and infrared radiations are the two main invisible components of solar radiation, causing skin damage. People are becoming more aware of the significance of sun protection, though little attention is directed to the exposure of the skin to UV and IR radiations through car windows. According to a survey of 1293 participants, mainly from Saudi Arabia, the fact that UV radiation can penetrate through car windows is known by the majority, i.e., 82%. However, the capability of IR radiation to penetrate vehicle windows is unknown to most people. Even though car windows reduce the transmission of ultraviolet and infrared rays, drivers are not isolated from them completely. To the best of our knowledge, this is the first study that measures solar exposure in cars in the middle east region, which is famous for its hot and arid (dry) climate with temperatures reaching over 52°C. Specifically, this study aimed to determine the driver exposure to UV and IR radiations in Dammam, Saudi Arabia, and emphasize the need to take the necessary measures to avoid exposure to these rays.

Method

An experiment using a PMA2100 datalogger radiometer was conducted inside and outside twenty vehicles. The radiometer measured the transmitted radiation through the front and the side windows. Then, the UV and IR measurements were analyzed and evaluated inside all vehicles.

Results

The average transmission percentage of ultraviolet through the car’s side window was 10.47%, while the front window only transmitted 4.06%. In comparison, the average transmission percentage of infrared through the side window was 30.02% and 39.30% through the front windows.

Conclusion

These results highlight the importance of protection against UV and IR radiations since the drivers are exposed to significant UV and IR radiations. Furthermore, the protection methods must be increased in areas with a hot climate, such as the middle east region.
Macrophage Therapy for Acute Liver Injury (MAIL): a Phase 1 Randomised, Open-Label, Dose-Escalation Study to Evaluate Safety, Tolerability, and Activity of Allogeneic Alternatively Activated Macrophages in Patients with Paracetamol-induced Acute Liver Injury
Authors: Humphries Christopher , Addison Melisande , Aithal Guruprasad , Boyd Julia , Briody Lesley , Campbell John DM , Candela Maria Elena , Clarke Ellise , Coulson James , Downing-James Nicholas , Fontana Robert John , Geddes Ailsa , Grahamslaw Julia , Grant Alison , Heye Anna , Hutchinson James A , Jones Ashley , Mitchell Fiona , Moore Joanna , Riddell Alice , Rodriguez Aryelly , Thomas Angela , Tucker Garry , Walker Kim , Weir Christopher J , Woods Rachel , Zahra Sharon , Forbes Stuart J , Dear James
Published: May 2024

Introduction

Acute Liver Failure (ALF) has no effective treatment other than liver transplantation, and is commonly caused by paracetamol overdose. New treatments are needed to treat and prevent ALF. Alternatively activated macrophages (AAMs) can promote resolution of liver necrosis and stimulate hepatocyte proliferation. Using AAMs in unscheduled care requires the use of an allogeneic product. A clinical trial is needed to determine the safety and tolerability of allogeneic AAMs.

Methods and analysis

A single centre, open-label, dose-escalation, phase 1 randomised trial to determine whether there is dose-limiting toxicity of AAMs in patients with paracetamol-induced acute liver injury. Randomisation will occur at higher doses.

Ethics and dissemination

The trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and has been approved by North East – York Research Ethics Committee (reference 23/NE/0019), NHS Lothian Research and Development department, and the UK Medicines and Healthcare products Regulatory Agency. When the trial concludes, results will be shared by presentation and publication.

Trial registration number:ISRCTN 12637839.
Machine learning for the prediction of urosepsis using electronic health record data
Authors: Sarwal Varuni , Rakocz Nadav , Dominique Georgina , Chiang Jeffrey N. , Ackerman A. Lenore
Published: May 2024

Urosepsis, a medical condition resulting from the progression of urinary tract infection (UTI), is a leading cause of death in hospitals in the United States. Urosepsis commonly occurs due to complicated UTI and constitutes approximately 25% of all sepsis cases. Early prediction of urosepsis is critical in providing personalized care, reducing diagnostic uncertainty, and ultimately lowering mortality rates. While machine learning techniques have the potential to aid healthcare professionals in identifying potential risk factors, and high-risk patients, and recommending treatment options, no existing study has been developed so far to predict the development of urosepsis in patients with a suspected UTI presenting to an outpatient setting. In this research study, we develop and evaluate the utility of multiple machine learning models to predict the likelihood of hospital admission and urosepsis diagnosis for patients with an outpatient UTI encounter, leveraging de-identified electronic health records sourced from a large health care system encompassing a wide range of encounters spanning primary to quaternary care. Inclusion criteria included a positive diagnosis of urinary tract infection indicated by ICD-10 code N30 or N93.0 and positive bacteria result via urinalysis in an ambulatory setting (primary or emergent care settings). For these patients, we extracted demographic information, urinalysis findings, and any antibiotics prescribed for each instance of UTI. Reencounters we defined as all encounters within seven days of the initial UTI encounter. The reencounters were considered urosepsis-related if matching positive blood and urine cultures were found with a sepsis ICD-10 code of A41, R78, or R65. A variety of machine learning models were trained on this rich feature set and were evaluated on two tasks: the prediction of a reencounter leading to hospitalization, and the prediction of Urosepsis. Model performances were stratified by the patient ethnicities. Our models demonstrated high predictive performance with an area under the ROC curve (AUC) of 79.5% AUC and an area under the precision-recall curve (APR) of 13% APR for reencounters, and 90% ROC and 31% APR for Urosepsis. We computed shapley values to interpret our model predictions and found the patient age, sex, and urinary WBC count were the top three predictive features. Our study has the potential to assist clinicians in the identification of high-risk patients, making more informed decisions about antibiotic prescription and providing improved patient care.
Specifications of the ACMG/AMP variant curation guidelines for the analysis of germlineATMsequence variants
Authors: Richardson Marcy E. , Holdren Megan , Brannan Terra , de la Hoya Miguel , Spurdle Amanda B. , Tavtigian Sean V. , Young Colin C. , Zec Lauren , Hiraki Susan , Anderson Michael J. , Walker Logan C. , McNulty Shannon , Turnbull Clare , Tischkowitz Marc , Schon Katherine , Slavin Thomas , Foulkes William D. , Cline Melissa , Monteiro Alvaro N. , Pesaran Tina , Couch Fergus J.
Published: May 2024

The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology and variant interpretation. This VCEP made specifications for ACMG/AMP guidelines for the ataxia telangiectasia mutated (ATM) gene according to the Food and Drug Administration (FDA)-approved ClinGen protocol. These gene-specific rules forATMwere modified from the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines and were tested against 33ATMvariants of various types and classifications in a pilot curation phase. The pilot revealed a majority agreement between the HBOP VCEP classifications and the ClinVar-deposited classifications. Six pilot variants had conflicting interpretations in ClinVar and reevaluation with the VCEP’sATM-specific rules resulted in four that were classified as benign, one as likely pathogenic and one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretations in the public domain. Overall, 28 the 33 pilot variants were not VUS leading to an 85% classification rate. The ClinGen-approved, modified rules demonstrated value for improved interpretation of variants inATM.
Epigenome-wide association study, meta-analysis and risk profiling of whole blood in Parkinson’s disease
Authors: Lie Ingeborg Haugesag , Tan Manuela , Andersen Maren Stolp , Toft Mathias , Pihlstrøm Lasse
Published: May 2024

An increasing body of evidence indicates altered DNA methylation in Parkinson’s disease (PD), yet the reproducibility and utility of such methylation changes are largely unexplored. We conducted an epigenome-wide association study (EWAS) in whole blood, including 280 PD and 279 control participants from Oslo, Norway. In meta-analysis with data from the Parkinson’s Progression Markers Initiative (PPMI) and a previously published whole blood PD EWAS (total N=3068) we confirmSLC7A11hypermethylation and nominate a novel suggestive differentially methylated CpG nearLPIN1. A joint multiscore risk profiling model incorporating polygenic risk and methylation-based estimates of epigenetic PD risk, smoking and leukocyte proportions differentiated patients from control participants with an area under the receiver-operator curve or 0.82 in the Oslo cohort and 0.65 in PPMI. Our results highlight the power of DNA methylation profiling to capture multiple aspects of disease risk, indicating a biomarker potential for precision medicine in neurodegenerative disorders.
Temporal rules of fear memory cooperation and competition
Authors: Madeira Natália , Campelo Inês , Fonseca Rosalina
Published: May 2024

Memory consolidation is highly influenced by ongoing experiences. We explore the temporal rules that determine whether events are cooperatively associated or competitively separated. We show that neutral events are associated with fearful events if they occur within less than 30 minutes. In some individuals, memory association can lead to a competitive suppression of the fearful response by the neutral event. Activation of the thalamic MGm inputs to the lateral amygdala, led to an increase in memory association, whereas manipulation of the cortical inputs had no effect. Introducing a third event leads to competition depending on the temporal relationship between the initial association and the competitive event. Our results show a critical temporal rule of memory association, modulated by thalamic activity that shapes fear memory consolidation.
mRNA Vaccine-Induced SARS-CoV-2 Spike-Specific IFN-γ and IL-2 T-cell Responses are Predictive of Serological Neutralization and are Transiently Enhanced by Pre-Existing Cross-Reactive Immunity
Authors: Samaan Philip , Korosec Chapin , Budylowski Patrick , Chau Serena L.L. , Pasculescu Adrian , Qi Freda , Delgado-Brand Melanie , Tursun Tulunay R. , Mailhot Genevieve , Dayam Roya Monica , Arnold Corey R. , Langlois Marc-Andre , Patel Anjali , de Launay Keelia Quinn , Boyd Jamie M. , Takaoka Alyson , Colwill Karen , McGeer Allison , Straus Sharon , Gingras Anne-Claude , Heffernen Jane M , Ostrowski Mario
Published: May 2024

The contributions of SARS-CoV-2-specific T-cells to vaccine efficacy and durability are unclear. We investigated the relationships between mRNA vaccine-induced spike-specific IFN-gamma and IL-2 T-cell responses, anti-spike/RBD IgG/IgA antibodies, and live virus neutralizing capacity in long-term-care-home staff doubly vaccinated with BNT162b2 or mRNA-1273. The impacts of pre-existing cross-reactive T-cell immunity to SARS-CoV-2 on cellular and humoral responses to vaccination were additionally assessed. Mathematical modelling of the kinetics of spike-specific IFN-gamma and IL-2 T-cell responses over 6-months post-second dose was bifurcated into recipients who exhibited gradual increases (54% and 42%, respectively) with doubling times of 173 days, or decreases (46% and 58%, respectively) with half-lives of 115 days. Differences in kinetics did not correlate with any clinical phenotypes, although increases were proposed to be due to subclinical viral exposures. Serological anti-spike/RBD IgG/IgA antibody levels had otherwise decayed in all participants with half-lives of 55, 53, 76, and 59 days, respectively. Spike-specific T-cell responses induced at 2-6 weeks correlated with live viral neutralization at 6-months post-second dose, especially in hybrid immune individuals. Participants with pre-existing cross-reactive T-cell immunity to SARS-CoV-2 exhibited greater spike-specific T-cell responses, reduced anti-RBD IgA antibody levels, and a trending increase in neutralization at 2-6 weeks post-second dose. Non-spike-specific T-cells predominantly targeted SARS-CoV-2 non-structural protein at 6-months post-second dose in cross-reactive participants. mRNA vaccination was lastly shown to induce off-target T-cell responses against unrelated antigens. In summary, vaccine-induced spike-specific T-cell immunity appeared to influence serological neutralizing capacity, with only a modest effect induced by pre-existing cross-reactivity.
Polyphosphate mobilization influences the ability ofCryptococcus neoformansto cause disease in a murine model of cryptococcosis
Authors: Bhalla Kabir , León-Hing Eddy Sánchez , Huang Yu-Hsuan , French Victoria , Hu Guanggan , Wang Jennifer , Kretschmer Matthias , Qu Xianya , Moreira Raphaell , Foster E. Johan , Johnson Pauline , Kronstad James W.
Published: May 2024

Cryptococcus neoformans, an invasive basidiomycete fungal pathogen, causes one of the most prevalent, life-threatening diseases in immunocompromised individuals and accounts for ∼15% of AIDS-associated deaths. A dire need for the development of novel antifungal drugs, vaccines, and improved diagnostics has emerged with the increased frequency of fungal infections. Therefore, understanding the pathogenesis ofC. neoformansand its interactions with the host immune system is critical for the development of therapeutics against cryptococcosis. Previous research demonstrated thatC. neoformanscells lacking polyphosphate (polyP), an immunomodulatory polyanionic storage molecule, display altered cell surface architecture. However, the relevance of surface changes and the role of polyP in the virulence ofC. neoformansremain unclear. Here we show that mutants lacking the polyphosphatases (Xpp1 and Epp1) are attenuated for virulence in a murine inhalational model of cryptococcosis, demonstrate reduced proliferation in host tissue, and provoke an altered immune response. An analysis of mutants lacking the polyphosphatases and the Vtc4 protein for polyP synthesis indicated that the Xpp1 and Epp1 contribute to the organization of the cell surface, virulence factor production, the response to stress, and mitochondrial function. Overall, we conclude that polyP mobilization plays a multifaceted role in the pathogenesis ofC. neoformans.

Author Summary

Cryptococcus neoformanscauses one of the most prevalent fungal diseases in people with compromised immune systems and accounts for 15-20% of AIDS-associated deaths worldwide. The continual increase in the incidence of fungal infections and limited treatment options necessitate the development of new antifungal drugs and improved diagnostics. Polyphosphate (polyP), an under-explored biopolymer, functions as a storage molecule, modulates the host immune response, and contributes to the ability of many fungal and bacterial pathogens to cause disease. However, the role of polyP in cryptococcal disease remains unclear. In this study, we report that the enzymes that regulate polyP synthesis and turnover contribute to the virulence ofC. neoformansin a mouse model of cryptococcosis. The polyphosphatases, Xpp1 and Epp1, influenced the survival ofC. neoformansin macrophages and altered the host immune response. The loss of Xpp1 and Epp1 led to changes in cell surface architecture, cell size, impaired growth, and defects in both mitochondrial function and the stress response ofC. neoformans.Thus, our work establishes polyP as a key factor in the disease caused byC. neoformans, and identifies polyP mobilization as a novel target to support new therapeutic approaches.
POLQ mediates replication-stress induced structural variant formation throughout common fragile sites during mitosis
Authors: Wilson Thomas E. , Ahmed Samreen , Winningham Amanda , Glover Thomas W.
Published: May 2024

Genomic structural variants (SVs) greatly impact human health and disease, but much is unknown about their generative mechanisms, especially for the large class of nonrecurrent alterations. Common fragile sites (CFSs) are unstable loci that provide a model for SV formation, especially large deletions, under replication stress. We studied SV junction formation as it occurred in cells by applying error-minimized capture sequencing to CFS DNA harvested during replication stress. SV junctions formed throughout CFS genes at a 5-fold higher rate after cells passed from G2 into M-phase. Neither SV formation nor CFS expression depended on mitotic DNA synthesis (MiDAS), an error-prone form of conservative replication active at CFSs. Instead, analysis of tens of thousands ofde novoSV junctions combined with DNA repair pathway inhibition revealed a primary role for DNA polymerase theta (POLQ)-mediated end-joining (TMEJ) in M-phase SV formation. We propose an important role for TMEJ in nonrecurrent SV formation genome wide.
In vivoandin vitroanalysis of the role of the Prc protease in inducing mucoidy inPseudomonas aeruginosa
Authors: Sommerfield Alexis G. , Wang Michelle , Mamana Julia , Darwin Andrew J.
Published: May 2024

InPseudomonas aeruginosa,alginate biosynthesis gene expression is inhibited by the transmembrane anti-sigma factor MucA, which sequesters the AlgU sigma factor. Cell envelope stress initiates cleavage of the MucA periplasmic domain by site-1 protease AlgW, followed by further MucA degradation to release AlgU. However, after colonizing the lungs of people with cystic fibrosis,P. aeruginosaconverts to a mucoid form that produces alginate constitutively. Mucoid isolates often havemucAmutations, with the most common beingmucA22, which truncates the periplasmic domain. MucA22 is degraded constitutively, and genetic studies suggested that the Prc protease is responsible. Some studies also suggested that Prc contributes to induction in strains with wild type MucA, whereas others suggested the opposite. However, missing from all previous studies is a demonstration that Prc cleaves any protein directly, which leaves open the possibility that the effect of aprcnull mutation is indirect. To address the ambiguities and shortfalls, we reevaluated the roles of AlgW and Prc as MucA and MucA22 site-1 proteases.In vivoanalyses using three different assays, and two different inducing conditions, all suggested that AlgW is the only site-1 protease for wild type MucA in any condition. In contrast, genetics suggested that AlgW or Prc act as MucA22 site-1 proteases in inducing conditions, whereas Prc is the only MucA22 site-1 protease in non-inducing conditions. For the first time, we also show that Prc is unable to degrade the periplasmic domain of wild type MucA, but does degrade the mutated periplasmic domain of MucA22 directly.

IMPORTANCE

After colonizing the lungs of individuals with cystic fibrosis,P. aeruginosaundergoes mutagenic conversion to a mucoid form, worsening the prognosis. Most mucoid isolates have a truncated negative regulatory protein MucA, which leads to constitutive production of the extracellular polysaccharide alginate. The protease Prc has been implicated, but not shown, to degrade the most common MucA variant, MucA22, to trigger alginate production. This work provides the first demonstration that the molecular mechanism of Prc involvement is direct degradation of the MucA22 periplasmic domain, and perhaps other truncated MucA variants as well. MucA truncation and degradation by Prc might be the predominant mechanism of mucoid conversion in cystic fibrosis infections, suggesting that Prc activity could be a useful therapeutic target.
Quantification and optimization of travel time for ethnic minority populations in cancer clinical trials
Authors: Lee H , Trevino JG , Terry MB , Winkfield K , Janowitz T
Published: May 2024

Of all minority racial and ethnic groups, Hispanic populations are most under-represented in trials compared to the general US population. Transportation and socioeconomic burdens are two important inter-related quantifiable and modifiable variables associated with decreased clinical trial participation for underrepresented populations. In this study, Hispanic population sizes and socioeconomic deprivation indices of catchment areas within simulated 30-minute driving distances from all major U.S. cancer trial sites (N=78) and all U.S. hospitals (N=7,623) were calculated using OpenStreetMap and U.S. census data. In the proximity of major trial sites Hispanic ethnicity representation varied across a wide range (64% to 2%) and Hispanic populations were underrepresented compared to the national average in almost 2/3 of the sites (n=50). The cities with the highest number of hospitals identified with catchment populations of >60%, >40% or >20% Hispanic representation were San Antonio TX, Houston TX, and New York NY respectively. Data-driven analyses can quantify and optimize measurable factors associated with decreased clinical trial participation for under-represented populations and may aid selection of trial sites to enable participation.