bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-Term Clinical Outcomes of Keratolimbal Allograft Alone or in Combination With Keratoplasty in Chronic and Delayed-Onset Mustard Gas Keratopathy
Authors: Karimian Farid , Jafarinasab Mohammad-Reza , Feizi Sepehr , Javadi Mohammadali , Ansari Mohammad-Hassan , Hassanpour Kiana 
Published: March 2023

Purpose:
The purpose of this study was to investigate the long-term clinical outcome of keratolimbal allograft (KLAL) alone or in combination with keratoplasty, in the management of patients with chronic and delayed-onset mustard gas keratopathy (MGK).

Methods:
Patients who had KLAL for MGK with or without corneal transplantation between 2002 and 2016 were recalled to be enrolled in this retrospective interventional case series. The primary outcome was the success rate of the KLAL demonstrated by Kaplan–Meier cumulative survival analysis. The secondary outcomes were postoperative BCVA and the need for further surgery.

Results:
A total of 108 eyes of 68 patients with MGK underwent KLAL. All patients were male with an average age of 54 ± 6 years with an average follow-up duration of 81.9 ± 38.4 months. Sectoral KLAL alone was performed in 62 eyes (57.4%), combined with lamellar keratoplasty (LKP) in 40 eyes (37%) and combined with penetrating keratoplasty in 6 eyes (5.6%). The cumulative probability of success was 75% within the follow-up duration. The mean duration of successful KLAL survival was 80.6 ± 38 months. 88.1% of these eyes needed only 1 operation to stabilize the ocular surface. Average BCVA did not improve significantly after KLAL alone, except in those accompanied by keratoplasty. KLAL combined with LKP achieved the superior clinical outcome compared with KLAL alone. Infectious keratitis occurred in 6 eyes (5.5%). No adverse event due to postoperative systemic immunosuppression was observed.

Conclusions:
KLAL alone or combined with LKP is effective, durable, and visually acceptable in the reconstruction of ocular surface in patients with limbal stem cell deficiency secondary to MGK.
IDENTIFICATION AND CLINICAL VALIDATION OF HYPOXIA-INDUCIBLE FACTOR 1α PROTEIN AS THE POTENTIAL BIOMARKER IN PATIENTS WITH SEPSIS
Authors: Ruan Hang , Li Yao-zhuo , Zhang Qin , Wang Bin-ran , Wu Rongxue , Li Shu-sheng , Ran Xiao 
Published: April 2023

ABSTRACT

Objective: Sepsis is a complex disease characterized by an inflammatory response and tissue hypoxia. Hypoxia-inducible factor 1α (HIF-1α) expression level is regulated by hypoxia and inflammation. This study aimed to explore the correlation between HIF-1α expression level and sepsis by bioinformatics analysis and clinical investigation. Methods: Bioinformatics tools were used to identify differentially expressed genes between sepsis and nonsepsis groups using the Gene Expression Omnibus data set. A clinical investigation was carried out to validate HIF-1α protein level in 54 nonseptic patients and 173 septic patients who were followed up for 28 days. Results: Bioinformatics analysis revealed that HIF-1α messenger RNA level was significantly different between septic and nonseptic patients (P < 0.05). Consistent with the study hypothesis, higher HIF-1α levels in plasma were found in septic patients compared with those in nonseptic patients. The diagnostic accuracy for sepsis, as quantified by the area under the curve, was 0.926 (0.885–0.968) for HIF-1α expression level combined with oxygen saturation to fraction of inspired oxygen (SpO2/FiO2), white blood cell, and blood urea nitrogen. The HIF-1α expression level was also significantly correlated with the severity of the disease. The results of the restricted cubic splines model indicated a U-shaped relationship between HIF-1α expression level and intensive care unit (ICU) mortality. Univariate and multivariate linear regression analyses indicated that septic patients with the elevated HIF-1α expression levels had shorter length of ICU stay versus those with the lower HIF-1α expression levels. Conclusion: Hypoxia-inducible factor 1α expression level can be used for diagnosing disease, assessing severity, and predicting length of ICU stay in septic patients.
Assessing Random Forest self-reproducibility for optimal short biomarker signature discovery
Authors: Poulet Christophe , Debit Ahmed , Josse Claire , Jerusalem Guy , Azencott Chloe-Agathe , Bours Vincent , Van Steen Kristel 
Published: April 2023

AbstractBiomarker signature discovery remains the main path to develop clinical diagnostic tools when the biological knowledge on a pathology is weak. Shortest signatures are often preferred to reduce the cost of the diagnostic. The ability to find the best and shortest signature relies on the robustness of the models that can be built on such set of molecules. The classification algorithm that will be used is selected based on the average performance of its models, often expressed via the average AUC. However, it is not garanteed that an algorithm with a large AUC distribution will keep a stable performance when facing data. Here, we propose two AUC-derived hyper-stability scores, the HRS and the HSS, as complementary metrics to the average AUC, that should bring confidence in the choice for the best classification algorithm. To emphasize the importance of these scores, we compared 15 different Random Forests implementation. Additionally, the modelization time of each implementation was computed to further help deciding the best strategy. Our findings show that the Random Forest implementation should be chosen according to the data at hand and the classification question being evaluated. No Random Forest implementation can be used universally for any classification and on any dataset. Each of them should be tested for both their average AUC performance and AUC-derived stability, prior to analysis.Author summaryTo better measure the performance of a Machine Learning (ML) implementation, we introduce a new metric, the AUC hyper-stability, to be used in parallel with the average AUC. This AUC hyper-stability is able to discriminate ML implementations that show the same AUC performance. This metric can therefore help researchers in choosing the best ML method to get stable short predictive biomarker signatures. More specifically, we advocate a tradeoff between the average AUC performance, the hyper-stability scores, and the modeling time.
Large-scale Annotation of Biochemically Relevant Pockets and Tunnels in Cognate Enzyme-Ligand Complexes
Authors: Vavra O. , Tyzack J. , Haddadi F. , Stourac J. , Damborsky J. , Mazurenko S. , Thornton J. , Bednar D. 
Published: March 2023

AbstractTunnels in enzymes with buried active sites are key structural features allowing the entry of substrates and the release of products, thus contributing to the catalytic efficiency. Targeting the bottlenecks of protein tunnels is also a powerful protein engineering strategy. However, the identification of functional tunnels in multiple protein structures is a non-trivial task that can only be addressed computationally. We present a pipeline integrating automated structural analysis with anin-housemachine-learning predictor for the annotation of protein pockets, followed by the calculation of the energetics of ligand transport via biochemically relevant tunnels. A thorough validation using eight distinct molecular systems revealed that CaverDock analysis of ligand un/binding is on par with time-consuming molecular dynamics simulations, but much faster. The optimized and validated pipeline was applied to annotate more than 17,000 cognate enzyme-ligand complexes. Analysis of ligand un/binding energetics indicates that the top priority tunnel has the most favourable energies in 75 % of cases. Moreover, energy profiles of cognate ligands revealed that a simple geometry analysis can correctly identify tunnel bottlenecks only in 50 % of cases. Our study provides essential information for the interpretation of results from tunnel calculation and energy profiling in mechanistic enzymology and protein engineering. We formulated several simple rules allowing identification of biochemically relevant tunnels based on the binding pockets, tunnel geometry, and ligand transport energy profiles.
In Rhesus monkeys, CSF-contacting neurons are the only neurons present in the medullo-spinal peri-ependymal zone
Authors: Kastner Anne , Wanaverbecq Nicolas 
Published: April 2023

ABSTRACTIn spinal cord and medulla, ependymal cells re organized in a monolayer forming the central canal (cc). In rodents, this region, also known as a stem cell niche, was shown to contain cerebrospinal fluid-contacting neurons (CSF-cNs). These neurons are GABAergic and because of their chemo- and mechanosensory properties they would represent a novel sensory system intrinsic to the central nervous system. In primates, little is known about these neurons and more generally about the region around the cc. Here, using immunohistochemical approaches, we investigated the organization of the cc region and CSF-cN properties inMacaca mulattaRhesus monkey. In contrast to rodent, we observe along the whole medullo-spinal axis a large zone around the cc delimited by long radial ependymal fibers that is enriched with astrocytes and microglia but largely devoid of neuronal elements except for CSF-cNs. These primate CSF-cNs share with rodent CSF-cNs similar morphological and phenotypical features with a largely immature profile. Our data suggest that they extend their axons in the longitudinal axis to form fiber bundles close to the cc and we further show that CSF-cNs receive GABAergic and serotoninergic synaptic contacts on their soma and dendrite. Taken together our results reveal inRh.monkey a specific organization of the region around the cc potentially forming a buffer zone between CSF and parenchyma where CSF-cNs would play a crucial role in the detection of CSF signals and their transmission to the central nervous system, a role that would need to be further investigated.
Coordinated stimulation of axon regenerative and neurodegenerative transcriptional programs by ATF4 following optic nerve injury
Authors: Somasundaram Preethi , Farley Madeline M. , Rudy Melissa A. , Sigal Katya , Asencor Andoni I. , Stefanoff David G. , Shah Malay , Goli Puneetha , Heo Jenny , Wang Shufang , Tran Nicholas M. , Watkins Trent A. 
Published: April 2023

AbstractStress signaling is important for determining the fates of neurons following axonal insults. Previously we showed that the stress-responsive kinase PERK contributes to injury-induced neurodegeneration (Larhammar et al., 2017). Here we show that PERK acts primarily through Activating Transcription Factor-4 (ATF4) to stimulate not only pro-apoptotic but also pro-regenerative responses following optic nerve damage. Using conditional knockout mice, we find an extensive PERK/ATF4-dependent transcriptional response that includes canonical ATF4 target genes and modest contributions by C/EBP Homologous Protein (CHOP). Overlap with c-Jun-dependent transcription suggests interplay with a parallel stress pathway that orchestrates regenerative and apoptotic responses. Accordingly, neuronal knockout of ATF4 recapitulates the neuroprotection afforded by PERK deficiency, and PERK or ATF4 knockout impairs optic axon regeneration enabled by disrupting the tumor suppressor PTEN. These findings reveal an integral role for PERK/ATF4 in coordinating neurodegenerative and regenerative responses to CNS axon injury.
A concurrently available negative reinforcer robustly decreases cocaine self-administration in male and female rats
Authors: Marcus Madison M. , Banks Matthew L. 
Published: April 2023

AbstractContinued drug-taking despite adverse consequences is hypothesized to be an insidious behavioral hallmark of drug addiction. Although most preclinical research has focused on drug self-administration in the presence of positive punishment, another source of potential adverse consequences is behavioral allocation away from negative reinforcers (i.e., escape/avoid electric shock) and towards drug reinforcers. The goals of the present study were to establish a discrete-trial cocaine-vs-negative reinforcer choice procedure in male and female rats and determine sensitivity of choice behavior to environmental and pharmacological manipulations. Rats could make up to nine discrete choices between an intravenous cocaine infusion (0.32 – 1.8 mg/kg/inf) under a fixed-ratio (FR) 3 schedule and a negative reinforcer (escape or avoidance of electric shock, 0.1 – 0.7 mA) under an FR1 schedule. The negative reinforcer was consistently chosen over all cocaine doses. Lowering shock magnitude decreased negative reinforcer trials, increased omitted trials, and failed to promote behavioral reallocation towards cocaine. Increasing the negative reinforcement response requirement between sessions only increased omitted trials. Introduction of 12-hr extended access cocaine self-administration sessions across two weeks resulted in high daily cocaine intakes but failed to significantly increase cocaine choice. Acute diazepam pretreatment also did not impact choice behavior up to doses that produced behavioral depression. Overall, the lack of behavioral allocation between cocaine infusions and a negative reinforcer suggests these two reinforcers may be economic independents. Additionally, the failure of extended cocaine access to increase cocaine choice highlights the importance of alternative reinforcers and environmental context in preclinical models of drug addiction.
Effects of six pyrimidine analogs on the growth ofTetrahymena thermophilaand their implications in pyrimidine metabolism
Authors: Harpel Zander , Chang Wei-Jen , Circelli Jacob , Chen Richard , Chang Ian , Rivera Jason , Wu Stephanie , Wei Zonhan 
Published: April 2023

AbstractTetrahymenaare ciliated protists that have been used to study the effects of toxic chemicals, including anticancer drugs. In this study, we tested the inhibitory effects of six pyrimidine analogs (5-fluorouracil, floxuridine, 5’-deoxy-5-fluorouridine, 5-fluorouridine, gemcitabine, cytarabine) on wild-type CU428 and conditional mutant NP1Tetrahymena thermophilaat room temperature and the restrictive temperature (37°C) where NP1 does not form the oral apparatus. We found that cytarabine was the only tested analog that did not inhibit growth, and phagocytosis was not required for pyrimidine analog entry. IC50 values did not significantly differ between strains for the same analog at either temperature. To investigate the mechanism of inhibition, we used two pyrimidine bases (uracil and thymine) and three nucleosides (uridine, thymidine, 5-methyluridine) to help determine whether the inhibitory effects from analogs were reversible. We found that the inhibitory effects from 5-fluorouracil could be reversed by uracil and thymine, from floxuridine could be reversed by thymidine, and from 5’-deoxy-5-fluorouridine could be reversed by uracil. None of the tested nucleobases or nucleosides could reverse the inhibitory effects of gemcitabine or 5-fluorouridine. Our results suggest that the five pyrimidine analogs act on different sites to inhibitT. thermophilagrowth and that nucleobases and nucleosides are metabolized differently.
PySilSub: An open-source Python toolbox for implementing the method of silent substitution in vision and non-visual photoreception research
Authors: Martin Joel T. , Boynton Geoffrey M. , Baker Daniel H. , Wade Alex R. , Spitschan Manuel 
Published: April 2023

AbstractThe normal human retina contains several classes of photosensitive cell—rods for low-light vision, three cone classes for daylight vision, and intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin for non-image-forming functions including pupil control, melatonin suppression and circadian photoentrainment. The spectral sensitivities of the photoreceptors overlap significantly, which means that most lights will stimulate all photoreceptors, to varying degrees. The method of silent substitution is a powerful tool for stimulating individual photoreceptor classes selectively and has found much use in research and clinical settings. The main hardware requirement for silent substitution is a spectrally calibrated light stimulation system with at least as many primaries as there are photoreceptors under consideration. Device settings that will produce lights to selectively stimulate the photoreceptor(s) of interest can be found using a variety of analytic and algorithmic approaches. Here we presentPySilSub(https://github.com/PySilentSubstitution/pysilsub), a novel Python package for silent substitution featuring flexible object-oriented support for individual colorimetric observer models (including human and mouse observers), multi-primary stimulation devices, and solving silent substitution problems with linear algebra and constrained numerical optimisation. The toolbox is registered with the Python Package Index and includes example data sets from various multi-primary systems. We hope thatPySilSubwill facilitate the application of silent substitution in research and clinical settings.
Patterned embryonic invagination evolved in response to mechanical instability
Authors: Vellutini Bruno C. , Cuenca Marina B. , Krishna Abhijeet , Szałapak Alicja , Modes Carl D. , Tomančák Pavel 
Published: April 2023

AbstractMechanical forces are crucial for driving and shaping the morphogenesis of tissues and organs during embryonic development. However, their relevance for the evolution of morphogenetic processes remains poorly understood. Here we show that a morphogenetic innovation present in fly embryos—a deep epithelial fold known as the cephalic furrow—plays a mechanical role duringDrosophilagastrulation. By integratingin vivoexperiments andin silicosimulations, we find that the formation of the cephalic furrow effectively prevents mechanical instabilities at the head–trunk epithelium by absorbing the compressive stresses generated by concurrent morphogenetic movements. Furthermore, by comparing the expression of known and novel genes involved in cephalic furrow formation between fly species, we find that the presence of the cephalic furrow is linked to the appearance of a novelbuttonheadexpression domain at the head–trunk boundary. These data suggest that the genetic control of cephalic furrow formation was established through the integration of a new player into the ancestral head–trunk patterning system, and that mechanical instability may have been the selective pressure associated with the evolution of the cephalic furrow. Our findings uncover empirical evidence for how mechanical forces can influence the evolution of morphogenetic innovations in early development.
Sin3a Associated Protein 130kDa, sap130, plays an evolutionary conserved role in zebrafish heart development
Authors: DeMoya Ricardo A. , Forman-Rubinsky Rachel E. , Fontaine Deon , Shin Joseph , Watkins Simon C. , Lo Cecilia , Tsang Michael 
Published: April 2023

AbstractHypoplastic left heart syndrome (HLHS) is a congenital heart disease where the left ventricle is reduced in size. A forward genetic screen in mice identified SIN3A associated protein 130kDa (Sap130), a protein in the chromatin modifying SIN3A/HDAC1 complex, as a gene contributing to the digenic etiology of HLHS. Here, we report the role of zebrafishsap130genes in heart development. Loss ofsap130a,one of twoSap130orthologs, resulted in smaller ventricle size, a phenotype reminiscent to the hypoplastic left ventricle in mice. While cardiac progenitors were normal during somitogenesis, diminution of the ventricle size suggest the Second Heart Field (SHF) was the source of the defect. To explore the role ofsap130ain gene regulation, transcriptome profiling was performed after the heart tube formation to identify candidate pathways and genes responsible for the small ventricle phenotype. Genes involved in cardiac differentiation and cell communication were dysregulated insap130a, but not insap130bmutants. Confocal light sheet analysis measured deficits in cardiac output inMZsap130asupporting the notion that cardiomyocyte maturation was disrupted. Lineage tracing experiments revealed a significant reduction of SHF cells in the ventricle that resulted in increased outflow tract size. These data suggest thatsap130ais involved in cardiogenesis via regulating the accretion of SHF cells to the growing ventricle and in their subsequent maturation for cardiac function. Further, genetic studies revealed an interaction betweenhdac1andsap130a, in the incidence of small ventricles. These studies highlight the conserved role of Sap130a and Hdac1 in zebrafish cardiogenesis.
Assessing bias and robustness of social network metrics using GPS based radio-telemetry data
Authors: Kaur Prabhleen , Ciuti Simone , Ossi Federico , Cagnacci Francesca , Morellet Nicolas , Loison Anne , Atmeh Kamal , McLoughlin Philip , Reinking Adele K. , Beck Jeffrey L. , Ortega Anna C. , Kauffman Matthew , Boyce Mark S. , Salter-Townshend Michael 
Published: April 2023

AbstractSocial network analysis of animal societies allows scientists to test hypotheses about social evolution, behaviour, dynamical processes, and transmission events such as the spread of disease. However, the accuracy of estimated social network metrics depends on the proportion of individuals sampled, actual sample size, and frequency of observations. Robustness of network metrics derived from a sample has thus far been examined through various simulation studies. However, simulated data do not necessarily reflect the nuances of real empirical data.We used some of the largest available GPS telemetry relocation datasets from five species of ungulates characterised by different behavioural and ecological traits and living in distinct environmental contexts to study the bias and robustness of social network metrics. We introduced novel statistical methods to quantify the uncertainty in network metrics obtained from a partial population suited to autocorrelated data such as telemetry relocations. We analysed how social network metrics respond to down-sampling from the observed data and applied pre-network data permutation techniques, a bootstrapping approach, correlation, and regression analyses to assess the stability of network metrics when based on samples of a population.We found that global network metrics like density remain robust when the sample size is lowered, whereas some local network metrics, such as eigenvector centrality, are entirely unreliable when a large proportion of the population is not monitored. We show how to construct confidence intervals around the point estimates of these metrics representing the uncertainty as a function of the number of nodes in the network.Our uncertainty estimates enable the statistical comparison of social network metrics under different conditions, such as analysing daily and seasonal changes in the density of a network. Despite the striking differences in the ecology and sociality among the five different ungulate species, the various social network metrics behave similarly under downsampling, suggesting that our approach can be applied to a wider range of species across vertebrates. Our methods can guide methodological decisions about animal social network research (e.g., sampling design and sample sizes) and allow more accurate ecological inferences from the available data.