bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating nephrotoxicity reduction in a novel polymyxin B formulation: insights from a 3D kidney-on-a-chip model
Authors: Payasi Anurag , Yadav Manoj Kumar , Chaudhary Saransh , Aggarwal Anmol 
Published: September 2024

ABSTRACT

This study aimed to assess the nephrotoxicity associated with VRP-034 (novel formulation of polymyxin B [PMB]) compared to marketed PMB in a three-dimensional (3D) kidney-on-a-chip model. To model the human kidney proximal tubule for analysis, tubular structures were established using 23 triple-channel chips seeded with RPTEC/hTERT1 cells. These cells were exposed to VRP-034 or PMB at seven concentrations (1–200 µM) over 12, 24, and 48 h. A suite of novel kidney injury biomarkers, cell health, and inflammatory markers were quantitatively assessed in the effluent. Additionally, caspase and cytochrome C levels were measured, and cell viability was evaluated using calcein AM and ethidium homodimer-1 (EthD-1). Exposure to marketed PMB resulted in significantly elevated levels (
P
< 0.05) of four key biomarkers (KIM-1, cystatin C, clusterin, and OPN) compared to VRP-034, particularly at clinically relevant concentrations of ≥10 µM. At 25 µM, all biomarkers demonstrated a significant increase (
P
< 0.05) with marketed PMB exposure compared to VRP-034. Inflammatory markers (interleukin-6 and interleukin-8) increased significantly (
P
< 0.05) with marketed PMB at concentrations of ≥5 µM, relative to VRP-034. VRP-034 displayed superior cell health outcomes, exhibiting lower lactate dehydrogenase release, while ATP levels remained comparable. Morphological analysis revealed that marketed PMB induced more severe damage, disrupting tubular integrity. Both treatments activated cytochrome C, caspase-3, caspase-8, caspase-9, and caspase-12 in a concentration-dependent manner; however, caspase activation was significantly reduced (
P
< 0.05) with VRP-034. This study demonstrates that VRP-034 significantly reduces nephrotoxicity compared to marketed PMB within a 3D microphysiological system, suggesting its potential to enable the use of full therapeutic doses of PMB with an improved safety profile, addressing the need for less nephrotoxic polymyxin antibiotics.
Design of novel and highly selective SARS-CoV-2 main protease inhibitors
Authors: Poli Adi N. R. , Tietjen Ian , Nandwana Nitesh K. , Cassel Joel , Messick Troy E. , Register Emery T. , Keeney Frederick , Rajaiah Rajesh , Verma Atul K. , Pandey Kabita , Acharya Arpan , Byrareddy Siddappa N. , Montaner Luis J. , Salvino Joseph M. 
Published: September 2024

ABSTRACT

We have synthesized a novel and highly selective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease peptide mimetic inhibitor mimicking the replicase 1ab recognition sequence -Val-Leu-Gln- and utilizing a cysteine selective acyloxymethyl ketone as the electrophilic warhead to target the active site Cys145. Utilizing a constrained cyclic peptide that locks the conformation between the P3 (Val) and P2 (Leu) residues, we identified a highly selective inhibitor that fills the P2 pocket occupied by the leucine residue sidechain of PF-00835231 and the dimethyl-3-azabicyclo-hexane motif in nirmatrelvir (PF-07321332). This strategy resulted in potent and highly selective Mpro inhibitors without inhibiting essential host cathepsin cysteine or serine proteases. The lead prototype compound 1 (MPro IC
50
= 230 ± 18 nM) also inhibits the replication of multiple SARS-CoV-2 variants
in vitro
, including SARS-CoV-2 variants of concern, and can synergize at lower concentrations with the viral RNA polymerase inhibitor, remdesivir, to inhibit replication. It also reduces SARS-CoV-2 replication in SARS-CoV-2 Omicron-infected Syrian golden hamsters without obvious toxicities, demonstrating
in vivo
efficacy. This novel lead structure provides the basis for optimization of improved agents targeting evolving SARS-CoV-2 drug resistance that can selectively act on Mpro versus host proteases and are less likely to have off-target effects due to non-specific targeting. Developing inhibitors against the active site of the main protease (Mpro), which is highly conserved across coronaviruses, is expected to impart a higher genetic barrier to evolving SARS-CoV-2 drug resistance. Drugs that selectively inhibit the viral Mpro are less likely to have off-target effects warranting efforts to improve this therapy.
Plasma Concentrations of Multiple Oxysterols and Risk of Colorectal Adenomas
Authors: Passarelli Michael N. , McDonald Jeffrey G. , Thompson Bonne M. , Pomares-Millan Hugo , Palys Thomas J. , Rees Judy R. , Barry Elizabeth L. 
Published: September 2024

Abstract
Oxysterols are metabolites of cholesterol that regulate the homeostasis of cholesterol, fatty acids, and glucose. These metabolites are generated throughout the body, either enzymatically or from oxidative stress, and are detectable in peripheral circulation. We previously reported that circulating 27-hydroxycholesterol (27-OHC), an endogenous selective estrogen receptor modulator, may be a risk factor for colorectal adenomas. Here, in addition to 27-OHC, we report on four other circulating oxysterols: 25-hydroxycholesterol, 24(S)-hydroxycholesterol, 7ɑ-hydroxycholesterol, and 4β-hydroxycholesterol. Oxysterol concentrations were measured using liquid chromatography/mass spectrometry from fasting plasma collected at baseline from 1,246 participants of the Vitamin D/Calcium Polyp Prevention Study, a multicenter adenoma chemoprevention trial. To evaluate multiple oxysterols simultaneously, we used both log-linear regression and Bayesian kernel machine regression models developed for analyses of complex mixtures adjusted for potential confounding factors. Higher circulating 7ɑ-hydroxycholesterol was associated with higher adenoma risk (Bayesian kernel machine regression–based multivariable-adjusted risk ratios (RR; for the 75th vs. 25th percentile, 1.22; 95% credible interval, CI, 1.04–1.42). In contrast, higher circulating 4β-hydroxycholesterol was associated with lower risk of these polyps (RR, 0.84; 95% CI, 0.71–0.99). The positive association with advanced adenoma risk that we previously reported for circulating 27-OHC persisted when controlling for other oxysterols (RR, 1.26; 95% CI, 0.98–1.62), including among those with advanced adenomas at baseline (RR, 1.75; 95% CI, 1.01–3.06).
Prevention Relevance: Circulating concentrations of multiple oxysterols measured at the time of an initial colorectal adenoma diagnosis may be risk factors for subsequent incidence of these lesions. Novel colorectal cancer prevention strategies may target oxysterol formation.
СТРУКТУРНІ ЗМІНИ ПЕЧІНКИ У ХВОРИХ РІЗНИХ ВІКОВИХ ГРУП ЗАЛЕЖНО ВІД ТРИВАЛОСТІ МЕХАНІЧНОЇ ЖОВТЯНИЦІ
Authors: КАНІКОВСЬКИЙ О. Є. , КАРИЙ Я. В. , ДОВГАНЬ І. П. 
Published: September 2024

Мета роботи: вивчити структурні зміни печінки у хворих різних вікових груп залежно від тривалості механічної жовтяниці (МЖ).
Матеріали і методи. 50 хворих на МЖ були поділені на дві дослідні групи. І група (n=25) включала пацієнтів молодого (18–44 р.) і середнього віку (45–59 р.), ІІ групу (n=25) склали хворі похилого віку (60–74 р.) та старечого віку (75–90 р.). У кожній групі виділяли 5 підгруп хворих з різною тривалістю МЖ – до 7 діб, 7–14 діб, 14–21 доба, 21–28 діб, понад 28 діб.
Результати. У пацієнтів І групи при термінах МЖ до 7 діб, від 7 до 14 діб та у хворих ІІ групи з тривалістю МЖ до 7 діб морфологічні зміни печінки мали переважно зворотний перебіг і полягали у внутрішньопротоковому холестазі, запальній інфільтрації строми, дистрофії гепатоцитів. При термінах МЖ від 14 до 21 доби, від 21 до 28 доби у пацієнтів І групи і у хворих ІІ групи з тривалістю МЖ від 7 до 14 доби, від 14 до 21 доби зміни печінки мали як зворотний, так і незворотний перебіг у зв’язку з розвитком і прогресуванням внутрішньопротокового і внутрішньоклітинного холестазу, стромального гепатиту, вираженої дистрофії, дрібно- та великовогнищевого некрозу гепатоцитів, вираженого фіброзу. У пацієнтів І групи з тривалістю МЖ понад 28 діб та при тривалості МЖ від 21 до 28 доби та понад 28 діб у хворих ІІ групи морфологічні зміни печінки мали незворотний характер та полягали у множинних дифузних відкладаннях білірубіну поза- і внутрішньоклітинно, великовогнищевому некрозі гепатоцитів, вираженому фіброзі, розвитку цирозу печінки.
ОСОБЛИВОСТІ РОЗВИТКУ ОКСИДАТИВНОГО СТРЕСУ У ПЕЧІНЦІ ЩУРІВ РІЗНОЇ СТАТІ ІЗ МЕТАБОЛІЧНО АСОЦІЙОВАНОЮ СТЕАТОТИЧНОЮ ХВОРОБОЮ ПЕЧІНКИ І КОРЕКЦІЄЮ ЙОГО ІНОЗИТОЛОМ
Authors: СОПЕЛЬ О. В. , ДЕНЕФІЛЬ О. В. 
Published: September 2024

Мета роботи: дослідити зміни продуктів порексидного оиснення ліпідів і активність антиоксидантів та морфологічні зміни у печінці щурів різної статі з метаболічно асоційованою стеатотичною хворобою печінки і корекцією їх інозитолом.
Матеріали і методи. Досліди виконано на 96 щурах різної статі. Тварин розділено на 4 групи – контроль, МАСХП 4 місяці, МАСХП 4 місяці + міо-інозитол, МАСХП 4 місяці + D-chiro-інозито. У групах МАСХП 4 тварини вживали замість води 20 % розчин фруктози протягом 4 місяців. Через 2 місяці від початку експерименту протягом 2 місяців щурам групи МАСХП 4 місяці + Міо- інозитол інтрагастрально вводили міо-інозитол (400 мг/кг), групи МАСХП 4 місяці + D-chiro-інозитол – D-chiro-інозитол (30 мг/кг). Проводили забір печінки для морфологічного дослідження, у її гомогенатах визначали вміст дієнових і трієнових кон’югатів (ДК, ТК), основ Шиффа (ОШ), ТБК-активних продуктів (ТБК-ап), супероксиддисмутазну і каталазну активності (СОД, КАТ).
Результати. У самців контрольної групи, порівняно з самицями, вищі ДК, ТК, ТБК-ап, менша СОД. У тварин з МАСХП різко зросли ДК, ТК, ОШ, ТБК-ап, СОД і КАТ, причому ДК, ТК залишалися більшими у самців, а ОШ – у самиць. Міо-інозитол спричинив менше накопичення ДК, ТК, ОШ, ТБК-ап, СОД і КАТ у самців і самиць, причому тільки КАТ була менша у самиць. D-chiro- інозитол теж привів до меншого накопичення ДК, ТК, ОШ, ТБКап, СОД і КАТ у самців і самиць, але у самиць були вищими ДК, у самців – ТБК-ап, КАТ. Порівняно з міо-інозитолом, D-chiro-інозитол у самиць показав більший ефект відносно СОД. Аналогічно, досліджувані препарати покращували морфологічний стан печінки, зменшуючи стеатогепатоз.
Fetal origin of bronchopulmonary dysplasia: contribution of intrauterine inflammation
Authors: Yu Haoting , Li Danni , Zhao Xinyi , Fu Jianhua 
Published: September 2024

AbstractBronchopulmonary dysplasia (BPD) is a common chronic lung disease in infants and the most frequent adverse outcome of premature birth, despite major efforts to minimize injury. It is thought to result from aberrant repair response triggered by either prenatal or recurrent postnatal injury to the lungs during development. Intrauterine inflammation is an important risk factor for prenatal lung injury, which is also increasingly linked to BPD. However, the specific mechanisms remain unclear. This review summarizes clinical and animal research linking intrauterine inflammation to BPD. We assess how intrauterine inflammation affects lung alveolarization and vascular development. In addition, we discuss prenatal therapeutic strategies targeting intrauterine inflammation to prevent or treat BPD.
Distal femoral fractures: periprosthetic fractures have four times more complications than non-periprosthetic fractures and cerclage should be avoided: retrospective analysis of 206 patients
Authors: Direder Martin , Naß Cornelia , Andresen Julian Ramin , Dannenmann Theresa , Bur Florian , Hajdu Stefan , Haider Thomas 
Published: September 2024

Abstract
Background
Distal femoral fractures account for less than 1% of all fractures. The therapy of choice is usually surgical stabilization. Despite advances in implant development over the past few years, complication rate remains comparatively high. The aim of this study is to analyze our results with plate fixation of distal femoral fractures with a focus on complication and fracture healing rates.

Methods
In this retrospective cohort study, patients (> 18 years) with distal femoral fractures treated at an urban level I trauma center between 2015 and 2022 were analyzed.

Results
In total, 206 patients (167 female, 39 male) with an average age of 75 (SD 16) years were diagnosed with a fracture of the distal femur. One hundred fourteen of these patients were treated surgically by means of plate osteosynthesis. In 13 cases (11.41%), a revision procedure had to be performed. The indication for surgical revision was mechanical failure in eight cases (7.02%) and septic complication in five cases (4.39%). Periprosthetic fractures were more likely to cause complications overall (19.6% versus 4.76%) and further included all documented septic complications. The analysis of modifiable surgical factors in the context of plate osteosynthesis showed higher complication rates for cerclage in the fracture area compared with plate-only stabilizations (44.44% versus 22.22%).

Conclusions
The data show an increased amount of revisions and a significantly higher number of septic complications in the treatment of periprosthetic fractures of the distal femur compared with non-periprosthetic fractures. The detected combination of plates together with cerclage was associated with higher complication rates.
Level of evidence Level III retrospective comparative study.
Emergency care via video consultation: interviews on patient experiences from rural community hospitals in northern Sweden
Authors: Ärlebrant Lina , Dubois Hanna , Creutzfeldt Johan , Edin-Liljegren Anette 
Published: September 2024

Abstract
Background
Delivering emergency care in rural areas can be challenging, but video consultation (VC) offers opportunities to make healthcare more accessible. The communication and relationship between professionals and patients have a significant impact on the patient’s experience of safety and inclusion. Understanding the patient perspective is crucial to developing good quality healthcare, but little is known about patient experiences of emergency care via VC in a rural context. The aim of this study was to explore patient experiences of emergency care via VC in northern rural Sweden.

Methods
Using a qualitative approach, semi- structured interviews (n = 12) were conducted with individuals aged 18—89 who had received emergency care with a registered nurse (RN) on site and VC with a general practitioner (GP). The interviews were conducted between October 2021 and March 2023 at community hospitals (n = 7) in Västerbotten County, Sweden. Interviews were analysed with content analysis.

Results
The analysis resulted in main categories (n = 2), categories (n = 5) and subcategories (n = 20). In the main category, “We were a team of three”, patients described a sense of inclusion and ability to contribute. The patients perceived the interaction between the GP and RN to function well despite being geographically dispersed. Patients highly valued the opportunity to speak directly to the GP. In the main category, “VC was a two-sided coin”, some experienced the emergency care through VC to be effective and smooth, while some felt that they received a lower quality of care and preferred face-to-face consultation with the GP. The quality of the VC was highly dependent on the RN’s ability to function as the hub in the emergency room.

Conclusion
Patients in rural areas perceived being included in 'the team' during VC, however they experienced disadvantages with the system on individual basis. The nursing profession plays an important role, and a proper educational background is crucial to support RNs in their role as the hub of the visit. The GP’s presence via VC was seen as important, but to fully enable them to fulfil their commitments as medical professionals, VC needs to be further improved with education and support from technical devices.
Population structure and breed identification of Chinese indigenous sheep breeds using whole genome SNPs and InDels
Authors: Zhao Chang-heng , Wang Dan , Yang Cheng , Chen Yan , Teng Jun , Zhang Xin-yi , Cao Zhi , Wei Xian-ming , Ning Chao , Yang Qi-en , Lv Wen-fa , Zhang Qin 
Published: September 2024

Abstract
Background
Accurate breed identification is essential for the conservation and sustainable use of indigenous farm animal genetic resources. In this study, we evaluated the phylogenetic relationships and genomic breed compositions of 13 sheep breeds using SNP and InDel data from whole genome sequencing. The breeds included 11 Chinese indigenous and 2 foreign commercial breeds. We compared different strategies for breed identification with respect to different marker types, i.e. SNPs, InDels, and a combination of SNPs and InDels (named SIs), different breed-informative marker detection methods, and different machine learning classification methods.

Results
Using WGS-based SNPs and InDels, we revealed the phylogenetic relationships between 11 Chinese indigenous and two foreign sheep breeds and quantified their purities through estimated genomic breed compositions. We found that the optimal strategy for identifying these breeds was the combination of DFI_union for breed-informative marker detection, which integrated the methods of Delta, Pairwise Wright's FST, and Informativeness for Assignment (namely DFI) by merging the breed-informative markers derived from the three methods, and KSR for breed assignment, which integrated the methods of K-Nearest Neighbor, Support Vector Machine, and Random Forest (namely KSR) by intersecting their results. Using SI markers improved the identification accuracy compared to using SNPs or InDels alone. We achieved accuracies over 97.5% when using at least the 1000 most breed-informative (MBI) SI markers and even 100% when using 5000 SI markers.

Conclusions
Our results provide not only an important foundation for conservation of these Chinese local sheep breeds, but also general approaches for breed identification of indigenous farm animal breeds.
Signals of positive selection in genomes of palearctic Myotis-bats coexisting with a fungal pathogen
Authors: Twort V. G. , Laine V. N. , Field K. A. , Whiting-Fawcett F. , Ito F. , Reiman M. , Bartonicka T. , Fritze M. , Ilyukha V. A. , Belkin V. V. , Khizhkin E. A. , Reeder D. M. , Fukui D. , Jiang T. L. , Lilley T. M. 
Published: September 2024

AbstractDisease can act as a driving force in shaping genetic makeup across populations, even species, if the impacts influence a particularly sensitive part of their life cycles. White-nose disease is caused by a fungal pathogen infecting bats during hibernation. The mycosis has caused massive population declines of susceptible species in North America, particularly in the genus Myotis. However, Myotis bats appear to tolerate infection in Eurasia, where the fungal pathogen has co-evolved with its bat hosts for an extended period of time. Therefore, with susceptible and tolerant populations, the fungal disease provides a unique opportunity to tease apart factors contributing to tolerance at a genomic level to and gain an understanding of the evolution of non-harmful in host-parasite interactions. To investigate if the fungal disease has caused adaptation on a genomic level in Eurasian bat species, we adopted both whole-genome sequencing approaches and a literature search to compile a set of 300 genes from which to investigate signals of positive selection in genomes of 11 Eurasian bats at the codon-level. Our results indicate significant positive selection in 38 genes, many of which have a marked role in responses to infection. Our findings suggest that white-nose syndrome may have applied a significant selective pressure on Eurasian Myotis-bats in the past, which can contribute their survival in co-existence with the pathogen. Our findings provide an insight on the selective pressure pathogens afflict on their hosts using methodology that can be adapted to other host-pathogen study systems.
Gender-related stigma toward individuals with a history of sexual or physical violence in childhood
Authors: Rechenberg Theresia , Fleischer Toni , Sander Christian , Schomerus Georg 
Published: September 2024

Abstract
Background
Stigma is a key barrier to disclosing traumatic experiences of violence in childhood with adverse consequences for help-seeking behaviour. Disclosing behavior differs by gender and the form of violence experienced. However, there is a lack of comprehensive studies that address societal perceptions of males and females with a history of sexual or physical violence in childhood. Therefore, our aim is to focus on the impact of gender on the perception of individuals who experienced sexual or physical violence in childhood.

Methods
We conducted a study on a representative sample of the German general population in terms of age and gender. Participants were randomly assigned to brief case vignettes addressing sexual or physical violence in childhood. Analyses base on a sample of n = 659 individuals (50.1% female). Stigma was assessed through examining respondents’ readiness to address specific traumas in conversation and respondents’ attitudes toward the individuals in the vignettes. Mann–Whitney U tests were applied to check for differences between female and male victims and survivors as well as female and male respondents.

Results
Our results reveal that male victims and survivors face higher negative stereotypes (harm, unpredictability) and evoke communication barriers more often when compared to female victims and survivors, especially in male respondents. Sexual violence is associated with more distinct gender differences than physical violence.

Conclusions
Findings reflect greater stigma toward male victims and survivors of sexual violence than female ones. Men had a greater tendency to stigmatize – especially toward their same-gender peers. Socially ingrained gender roles may act as a basis for different communication cultures and the notion of victim-perpetrator constellations in which males are not envisaged as victims.